The roles and potential therapeutic implications of CXCL4 and its variant CXCL4L1 in the pathogenesis of chronic liver allograft dysfunction.

PubMed

Li, Jing; Liu, Bin; Yan, Lu-nan; Lau, Wan-yee

2015-02-01

Chronic liver allograft dysfunction is the leading cause of patient morbidity and late allograft loss after liver transplantation. The pathogenesis of chronic liver allograft dysfunction remains unknown. Recent studies have demonstrated that CXCL4 and its variant CXCL4L1 are involved in organ damage induced through inflammatory and immune responses throughout all stages of liver transplantation. CXCL4 and CXCL4L1 are low-molecular-weight proteins that have been implicated in hematopoiesis, angiostasis, organ fibrogenesis, mitogenesis, tumor growth and metastasis. The purpose of this review is to discuss the current status and future developments of research into the roles of CXCL4 and CXCL4L1 in the pathogenesis of chronic liver allograft dysfunction. The potential utilization of CXCL4 and CXCL4L1 as therapeutic targets for chronic liver allograft dysfunction will also be discussed. Copyright © 2014 Elsevier Ltd. All rights reserved.

Differential Simultaneous Liver and Kidney Transplant Benefit Based on Severity of Liver Damage at the Time of Transplantation

PubMed Central

Habib, Shahid; Khan, Khalid; Hsu, Chiu-Hsieh; Meister, Edward; Rana, Abbas; Boyer, Thomas

2017-01-01

Background We evaluated the concept of whether liver failure patients with a superimposed kidney injury receiving a simultaneous liver and kidney transplant (SLKT) have similar outcomes compared to patients with liver failure without a kidney injury receiving a liver transplantation (LT) alone. Methods Using data from the United Network of Organ Sharing (UNOS) database, patients were divided into five groups based on pre-transplant model for end-stage liver disease (MELD) scores and categorized as not having (serum creatinine (sCr) ≤ 1.5 mg/dL) or having (sCr > 1.5 mg/dL) renal dysfunction. Of 30,958 patients undergoing LT, 14,679 (47.5%) had renal dysfunction, and of those, 5,084 (16.4%) had dialysis. Results Survival in those (liver failure with renal dysfunction) receiving SLKT was significantly worse (P < 0.001) as compared to those with sCr < 1.5 mg/dL (liver failure only). The highest mortality rate observed was 21% in the 36+ MELD group with renal dysfunction with or without SLKT. In high MELD recipients (MELD > 30) with renal dysfunction, presence of renal dysfunction affects the outcome and SLKT does not improve survival. In low MELD recipients (16 - 20), presence of renal dysfunction at the time of transplantation does affect post-transplant survival, but survival is improved with SLKT. Conclusions SLKT improved 1-year survival only in low MELD (16 - 20) recipients but not in other groups. Performance of SLKT should be limited to patients where a benefit in survival and post-transplant outcomes can be demonstrated. PMID:28496531

Albumin in chronic liver disease: structure, functions and therapeutic implications.

PubMed

Spinella, Rosaria; Sawhney, Rohit; Jalan, Rajiv

2016-01-01

Human serum albumin is a critical plasma protein produced by the liver with a number of accepted clinical indications in chronic liver disease including management of circulatory and renal dysfunction in patients with ascites. Advanced cirrhosis is characterised by reduced albumin concentration as well as impaired albumin function as a result of specific structural changes and oxidative damage. Traditionally, the biologic and therapeutic role of albumin in liver disease was attributed to its oncotic effects but it is now understood that albumin has a wide range of other important physiologic functions such as immunomodulation, endothelial stabilisation, antioxidant effects and binding multiple drugs, toxins and other molecules. This review discusses the multifunctional properties of albumin and, in particular, the biologic and clinical implications of structural and functional changes of albumin that are associated with cirrhosis. Based on these insights, we explore the current and potential future therapeutic uses of albumin in liver disease.

Sexual dysfunction in chronic liver disease: is liver transplantation an effective cure?

PubMed

Burra, Patrizia; Germani, Giacomo; Masier, Annalisa; De Martin, Eleonora; Gambato, Martina; Salonia, Andrea; Bo, Patrizio; Vitale, Alessandro; Cillo, Umberto; Russo, Francesco Paolo; Senzolo, Marco

2010-06-27

The goal of liver transplantation is not only to ensure patient long-term survival but also to offer the opportunity to achieve psychologic and physical integrity. Quality of life after liver transplantation may be affected by unsatisfactory sexual function. Before liver transplantation, sexual dysfunction and sex hormone disturbances are reported in men and women mainly due to abnormality of physiology of the hypothalamic-pituitary-gonadal axis and, in some cases, origin of liver disease. Successful liver transplantation should theoretically restore hormonal balance and improve sexual function both in men and women, thus improving the reproductive performance. However, after transplantation, up to 25% of patients report persistent sexual dysfunction, and approximately one third of patients describe the appearance of de novo sexual dysfunction. Despite the described high prevalence of this condition, epidemiologic data are relatively scant. Further studies on pathophysiology and risk factors in the field of sexual function after liver transplantation along with new strategies to support and inform patients on the waiting list and after surgery are needed.

Inhibition of Experimental Liver Cirrhosis in Mice by Telomerase Gene Delivery

NASA Astrophysics Data System (ADS)

Rudolph, Karl Lenhard; Chang, Sandy; Millard, Melissa; Schreiber-Agus, Nicole; DePinho, Ronald A.

2000-02-01

Accelerated telomere loss has been proposed to be a factor leading to end-stage organ failure in chronic diseases of high cellular turnover such as liver cirrhosis. To test this hypothesis directly, telomerase-deficient mice, null for the essential telomerase RNA (mTR) gene, were subjected to genetic, surgical, and chemical ablation of the liver. Telomere dysfunction was associated with defects in liver regeneration and accelerated the development of liver cirrhosis in response to chronic liver injury. Adenoviral delivery of mTR into the livers of mTR-/- mice with short dysfunctional telomeres restored telomerase activity and telomere function, alleviated cirrhotic pathology, and improved liver function. These studies indicate that telomere dysfunction contributes to chronic diseases of continual cellular loss-replacement and encourage the evaluation of ``telomerase therapy'' for such diseases.

[An adult with chronic active Epstein-Barr virus infection associated with repeated liver dysfunction].

PubMed

Endo, Tetsu; Mori, Yuki; Fukushi, Tsugumi; Yamaguchi, Kohei; Sato, Ken; Sakamoto, Juichi; Fukuda, Shinsaku; Wada, Ryuichi

2010-08-01

A 30-year-old woman with hepatitis for 5 months was admitted to our hospital. She had been given a diagnosis of liver dysfunction 2 years previously, and the hepatitis in this case was believed to be drug-induced. On admission, the patient was asymptomatic. Serologic tests for hepatitis A, B, and C were negative, and the laboratory results showed a WBC count of 7600/mm3 (lymphocytes, 85%), an AST level of 559 U/L, ALT level of 427 U/L, and EBV-DNA of 2.9x10(6) copies/microg DNA. Histopathological examination of the liver biopsy specimens revealed moderate lymphocyte infiltration in the sinusoids and positive Epstein-Barr-encoded RNA (EBER) -lymphocytes. Therefore, chronic active Epstein-Barr virus infection (CAEBV) was diagnosed. However, 9 months after the diagnosis she died of mycotic sepsis. We presume that the patient may have developed CAEBV at the prior diagnosis of liver dysfunction 2 years previously. Therefore, CAEBV associated with liver dysfunction should be considered during the differential diagnosis of patients showing persistent liver dysfunction.

Direct peritoneal resuscitation improves obesity-induced hepatic dysfunction after trauma.

PubMed

Matheson, Paul J; Franklin, Glen A; Hurt, Ryan T; Downard, Cynthia D; Smith, Jason W; Garrison, Richard N

2012-04-01

The metabolic syndrome and associated fatty liver disease are thought to contribute to poor outcomes in trauma patients. Experimentally, obesity compromises liver blood flow. We sought to correlate the effect of obesity, injury severity, and liver dysfunction with trauma outcomes. We hypothesized that obesity-related liver dysfunction could be mitigated with the novel technique of adjunctive direct peritoneal resuscitation (DPR). This study has clinical and experimental arms. The clinical study was a case-controlled retrospective analysis of ICU trauma patients (n = 72 obese, n = 187 nonobese). The experimental study was a hemorrhagic shock model in obese rats to assess the effect of DPR on liver blood flow, liver function, and inflammatory mediators. In trauma patients, univariate and multivariate analyses demonstrated increasing mortality (p < 0.05), septic complications (p < 0.05), liver dysfunction (p < 0.001), and renal impairment (p < 0.05) with increasing body mass index and injury severity score. Obesity in rats impairs liver blood flow, liver function, renal function, and inflammation (interleukin [IL]-1β, IL-6, high mobility group protein B1[HMGB-1]). The addition of DPR to shock resuscitation restores liver blood flow, improves organ function, and reverses the systemic proinflammatory response. Our clinical review substantiates that obesity worsens trauma outcomes regardless of injury severity. Obesity-related liver and renal dysfunction is aggravated by injury severity. In an obese rat model of resuscitated hemorrhagic shock, the addition of DPR abrogates trauma-induced liver, renal, and inflammatory responses. We conclude that the addition of DPR to the clinical resuscitation regimen will benefit the obese trauma patient. Published by Elsevier Inc.

Effects of simvastatin administration on rodents with lipopolysaccharide-induced liver microvascular dysfunction.

PubMed

La Mura, Vincenzo; Pasarín, Marcos; Meireles, Cintia Z; Miquel, Rosa; Rodríguez-Vilarrupla, Aina; Hide, Diana; Gracia-Sancho, Jorge; García-Pagán, Juan Carlos; Bosch, Jaime; Abraldes, Juan G

2013-03-01

Endothelial dysfunction drives vascular derangement and organ failure associated with sepsis. However, the consequences of sepsis on liver sinusoidal endothelial function are largely unknown. Statins might improve microvascular dysfunction in sepsis. The present study explores liver vascular abnormalities and the effects of statins in a rat model of endotoxemia. For this purpose, lipopolysaccharide (LPS) or saline was given to: (1) rats treated with placebo; (2) rats treated with simvastatin (25 mg/kg, orally), given at 3 and 23 hours after LPS/saline challenge; (3) rats treated with simvastatin (25 mg/kg/24 h, orally) from 3 days before LPS/saline injection. Livers were isolated and perfused and sinusoidal endothelial function was explored by testing the vasodilation of the liver circulation to increasing concentrations of acetylcholine. The phosphorylated endothelial nitric oxide synthase (PeNOS)/endothelial nitric oxide synthase (eNOS) ratio was measured as a marker of eNOS activation. LPS administration induced an increase in baseline portal perfusion pressure and a decrease in vasodilation to acetylcholine (sinusoidal endothelial dysfunction). This was associated with reduced eNOS phosphorylation and liver inflammation. Simvastatin after LPS challenge did not prevent the increase in baseline portal perfusion pressure, but attenuated the development of sinusoidal endothelial dysfunction. Treatment with simvastatin from 3 days before LPS prevented the increase in baseline perfusion pressure and totally normalized the vasodilating response of the liver vasculature to acetylcholine and reduced liver inflammation. Both protocols of treatment restored a physiologic PeNOS/eNOS ratio. LPS administration induces intrahepatic endothelial dysfunction that might be prevented by simvastatin, suggesting that statins might have potential for liver protection during endotoxemia. Copyright © 2012 American Association for the Study of Liver Diseases.

Perioperative Non-Invasive Indocyanine Green-Clearance Testing to Predict Postoperative Outcome after Liver Resection

PubMed Central

Haegele, Stefanie; Reiter, Silvia; Wanek, David; Offensperger, Florian; Pereyra, David; Stremitzer, Stefan; Fleischmann, Edith; Brostjan, Christine; Gruenberger, Thomas; Starlinger, Patrick

2016-01-01

Background Postoperative liver dysfunction may lead to morbidity and mortality after liver resection. Preoperative liver function assessment is critical to identify preexisting liver dysfunction in patients prior to resection. The aim of this study was to evaluate the predictive potential of perioperative indocyanine green (ICG)-clearance testing to prevent postoperative liver dysfunction and morbidity using standardized outcome parameters in a routine Western-clinical-setting. Study Design 137 patients undergoing partial hepatectomy between 2011 and 2013, at the general hospital of Vienna, were included. ICG-clearance was recorded one day prior to surgery as well as on the first and fifth postoperative day. Postoperative liver dysfunction was defined according to the International Study Group of Liver Surgery and evaluation of morbidity was based on the Dindo-Clavien classification. Statistical analyses were based on non-parametric tests. Results Preoperative reduced ICG—plasma disappearance rate (PDR) as well as increased ICG—retention rate at 15 min (R15) were able to significantly predict postoperative liver dysfunction (Area under the curve = PDR: 0.716, P = 0.018; R15: 0.719, P = 0.016). Furthermore, PDR <17%/min. or R15 >8%, were able to accurately predict postoperative complications prior to surgery. In addition to this, ICG-clearance on postoperative day 1 comparably predicted postoperative liver dysfunction (Area under the curve = PDR: 0.895; R15: 0.893; both P <0.001), specifically, PDR <10%/min or R15 >20% on postoperative day 1 predicted poor postoperative outcome. Conclusion PDR and R15 may represent useful parameters to distinguish preoperative high and low risk patients in a Western collective as well as on postoperative day 1, to identify patients who require closer monitoring for potential complications. PMID:27812143

Hepatic dysfunction.

PubMed

McCord, Kelly W; Webb, Craig B

2011-07-01

This article reviews the common pathophysiology that constitutes hepatic dysfunction, regardless of the inciting cause. The systemic consequences of liver failure and the impact of this condition on other organ systems are highlighted. The diagnostic tests available for determining the cause and extent of liver dysfunction are outlined, treatment strategies aimed at supporting hepatic health and recovery are discussed, and prognosis is briefly covered. The article emphasizes the fact that because of the central role of the liver in maintaining normal systemic homeostasis, hepatic dysfunction cannot be effectively addressed as an isolated entity. Copyright © 2011 Elsevier Inc. All rights reserved.

Renal dysfunction in liver cirrhosis and its correlation with Child-Pugh score and MELD score

NASA Astrophysics Data System (ADS)

Siregar, G. A.; Gurning, M.

2018-03-01

Renal dysfunction (RD) is a serious and common complication in a patient with liver cirrhosis. It provides a poor prognosis. The aim of our study was to evaluate the renal function in liver cirrhosis, also to determine the correlation with the graduation of liver disease assessed by Child-Pugh Score (CPS) and MELD score. This was a cross-sectional study included patients with liver cirrhosis admitted to Adam Malik Hospital Medan in June - August 2016. We divided them into two groups as not having renal dysfunction (serum creatinine < 1.5 mg/dL) and having renal dysfunction (serum creatinine ≤ 1.5 mg/dL). For the processing of data, SPSS 22.0 was used. Statistical methods used: Chi-square, Fisher exact, one way ANOVA, Kruskal Wallis test and Pearson coefficient of correlation. The level of significance was p<0.05. 55 patients with presented with renal dysfunction were 16 (29.1 %). There was statistically significant inverse correlation between GFR and CPS (r = -0.308), GFR and MELD score (r = -0.278). There was a statistically significant correlation between creatinine and MELD score (r = 0.359), creatinine and CPS (r = 0.382). The increase of the degree of liver damage is related to the increase of renal dysfunction.

Clinical Advancements in the Targeted Therapies against Liver Fibrosis

PubMed Central

Nagórniewicz, Beata; Prakash, Jai

2016-01-01

Hepatic fibrosis, characterized by excessive accumulation of extracellular matrix (ECM) proteins leading to liver dysfunction, is a growing cause of mortality worldwide. Hepatocellular damage owing to liver injury leads to the release of profibrotic factors from infiltrating inflammatory cells that results in the activation of hepatic stellate cells (HSCs). Upon activation, HSCs undergo characteristic morphological and functional changes and are transformed into proliferative and contractile ECM-producing myofibroblasts. Over recent years, a number of therapeutic strategies have been developed to inhibit hepatocyte apoptosis, inflammatory responses, and HSCs proliferation and activation. Preclinical studies have yielded numerous targets for the development of antifibrotic therapies, some of which have entered clinical trials and showed improved therapeutic efficacy and desirable safety profiles. Furthermore, advancements have been made in the development of noninvasive markers and techniques for the accurate disease assessment and therapy responses. Here, we focus on the clinical developments attained in the field of targeted antifibrotics for the treatment of liver fibrosis, for example, small molecule drugs, antibodies, and targeted drug conjugate. We further briefly highlight different noninvasive diagnostic technologies and will provide an overview about different therapeutic targets, clinical trials, endpoints, and translational efforts that have been made to halt or reverse the progression of liver fibrosis. PMID:27999454

Dietary grape seed proanthocyanidin extract regulates metabolic disturbance in rat liver exposed to lead associated with PPARα signaling pathway.

PubMed

Yang, Daqian; Jiang, Huijie; Lu, Jingjing; Lv, Yueying; Baiyun, Ruiqi; Li, Siyu; Liu, Biying; Lv, Zhanjun; Zhang, Zhigang

2018-06-01

Lead, a pervasive environmental hazard worldwide, causes a wide range of physiological and biochemical destruction, including metabolic dysfunction. Grape seed proanthocyanidin extract (GSPE) is a natural production with potential metabolic regulation in liver. This study was performed to investigate the protective role of GSPE against lead-induced metabolic dysfunction in liver and elucidate the potential molecular mechanism of this event. Wistar rats received GSPE (200 mg/kg) daily with or without lead acetate (PbA, 0.5 g/L) exposure for 56 d. According to biochemical and histopathologic analysis, GSPE attenuated lead-induced metabolic dysfunction, oxidative stress, and liver dysfunction. Liver gene expression profiling was assessed by RNA sequencing and validated by qRT-PCR. Expression of some genes in peroxisome proliferator-activated receptor alpha (PPARα) signaling pathway was significantly suppressed in PbA group and revived in PbA + GSPE group, which was manifested by Gene Ontology analysis and Kyoto Encyclopedia of Genes and Genomes pathway analysis and validated by western blot analysis. This study supports that dietary GSPE ameliorates lead-induced fatty acids metabolic disturbance in rat liver associated with PPARα signaling pathway, and suggests that dietary GSPE may be a protector against lead-induced metabolic dysfunction and liver injury, providing a novel therapy to protect liver against lead exposure. Copyright © 2018 Elsevier Ltd. All rights reserved.

Usefulness of Magnetic Resonance Imaging for the Diagnosis of Hemochromatosis with Severe Hepatic Steatosis in Nonalcoholic Fatty Liver Disease.

PubMed

Nozaki, Yuichi; Sato, Noriko; Tajima, Tsuyoshi; Hasuo, Kanehiro; Kojima, Yasushi; Umemoto, Kumiko; Mishima, Saori; Mikami, Shintaro; Nakayama, Tomohiro; Igari, Toru; Akiyama, Junichi; Imamura, Masatoshi; Masaki, Naohiko; Yanase, Mikio

2016-01-01

The ratio of the number of patients with non-alcoholic steatohepatitis (NASH) to the total number of patients with liver dysfunction has increased in many countries around the world. Liver dysfunction is also caused by multiple blood transfusions in patients with leukemia and other hematological diseases, with liver dysfunction often accompanied by secondary hemochromatosis. This study describes a 25-year-old man with secondary hemochromatosis combined with NASH. Magnetic resonance imaging was useful for visualizing the distributions of both iron and fat in the liver of this patient in order to make a differential diagnosis and to evaluate the effect of treatment.

Rapid reversal of neuromuscular blockade by sugammadex after continuous infusion of rocuronium in patients with liver dysfunction undergoing hepatic surgery.

PubMed

Fujita, Ai; Ishibe, Natsuki; Yoshihara, Tatsuya; Ohashi, Jun; Makino, Hideichi; Ikeda, Mizuko; Setoguchi, Hidekazu

2014-06-01

Sugammadex rapidly reverses neuromuscular blockade (NMB) induced by rocuronium. NMB induced by rocuronium is prolonged in patients with liver dysfunction, because the drug is mainly excreted into the bile. However, the efficacy and safety of sugammadex in terms of reversing rocuronium-induced NMB in patients with liver dysfunction undergoing hepatic surgery have not been evaluated. This observational study investigated the efficacy and safety of sugammadex after continuous infusion of rocuronium in patients with liver dysfunction undergoing hepatic surgery. Remifentanil/propofol anesthesia was administered to 31 patients: 15 patients in the control group, and 16 patients from a group with liver dysfunction. Rocuronium (0.6 mg/kg) was administered, followed by continuous infusion. The enrolled patients were then subdivided into two groups according to the dose of sugammadex. In the first group a single dose of sugammadex (2.0 mg/kg) was given at the reappearance of the second twitch (T2). In the second group a single dose of sugammadex (4.0 mg/kg) was given at the first twitch response if T2 did not reappear in 15 minutes after stopping rocuronium. The primary outcome was time from administration of sugammadex to recovery of a train-of-four ratio to 0.9. The dose of rocuronium required in the liver dysfunction group was lower than that in the control group (6.2 vs. 8.2 μg/kg/min, p = 0.002). The mean time from the administration of sugammadex to recovery of the train-of-four ratio to 0.9 was not significantly different between the liver dysfunction group and the control group (2.2 minutes vs. 2.0 minutes in the 2 mg/kg administration group, p = 0.44 and 1.9 minutes vs. 1.7 minutes in the 4 mg/kg administration group, p = 0.70, respectively). No evidence of recurarization was observed in any of the patients. Most of the adverse events were found to be mild and such events were not related to the use of sugammadex. None of the patients was eliminated from the study because of an adverse event. One patient died due to cholestatic liver cirrhosis because of repeated hepatic surgery. Sugammadex can rapidly reverse NMB after continuous infusion of rocuronium in patients with liver dysfunction undergoing hepatic surgery. Sugammadex was found to be safe and well tolerated. However, further studies of sugammadex under similar conditions should be conducted involving a large number of patients with liver dysfunction undergoing hepatic surgery. Copyright © 2014. Published by Elsevier B.V.

Decreased Taurine and Creatine in the Thalamus May Relate to Behavioral Impairments in Ethanol-Fed Mice: A Pilot Study of Proton Magnetic Resonance Spectroscopy.

PubMed

Xu, Su; Zhu, Wenjun; Wan, Yamin; Wang, JiaBei; Chen, Xi; Pi, Liya; Lobo, Mary Kay; Ren, Bin; Ying, Zhekang; Morris, Michael; Cao, Qi

2018-01-01

Minimal hepatic encephalopathy (MHE) is highly prevalent, observed in up to 80% of patients with liver dysfunction. Minimal hepatic encephalopathy is defined as hepatic encephalopathy with cognitive deficits and no grossly evident neurologic abnormalities. Clinical management may be delayed due to the lack of in vivo quantitative methods needed to reveal changes in brain neurobiochemical biomarkers. To gain insight into the development of alcoholic liver disease-induced neurological dysfunction (NDF), a mouse model of late-stage alcoholic liver fibrosis (LALF) was used to investigate changes in neurochemical levels in the thalamus and hippocampus that relate to behavioral changes. Proton magnetic resonance spectroscopy of the brain and behavioral testing were performed to determine neurochemical alterations and their relationships to behavioral changes in LALF. Glutamine levels were higher in both the thalamus and hippocampus of alcohol-treated mice than in controls. Thalamic levels of taurine and creatine were significantly diminished and strongly correlated with alcohol-induced behavioral changes. Chronic long-term alcohol consumption gives rise to advanced liver fibrosis, neurochemical changes in the nuclei, and behavioral changes which may be linked to NDF. Magnetic resonance spectroscopy represents a sensitive and noninvasive measurement of pathological alterations in the brain, which may provide insight into the pathogenesis underlying the development of MHE.

[A complete response to one-shot hepatic arterial infusion of epirubicin in a patient with highly advanced hepatocellular carcinoma].

PubMed

Takamatsu, Manabu; Matsuda, Takeru; Kawaguchi, Katsunori; Ku, Yonson

2007-11-01

A 61-year-old male was admitted for advanced hepatocellular carcinoma (HCC) with multiple lung metastases and tumor thrombus in the portal vein and superior vena cava. At first, we planned to perform transcatheter arterial embolization (TAE) to avoid the rupture of the liver tumor. But, due to the severe liver dysfunction, ie Child-Pugh C and 36% ICG R15, hepatic arterial infusion (HAI) of epirubicin 40 mg was performed. After that, the patient was followed at the outpatient ward and his general condition has gradually improved without a special treatment. At the present, one year and ten month after HAI, the serum alpha-fetoprotein (AFP) is almost within normal limits and CT scans show that HCC with multiple lung metastases, and tumor thrombus in the portal vein and superior vena cava almost disappeared. Although, spontaneous regression of HCC was a rare phenomenon, it might have played a major role in the good anticancer efficacy of this patient as well as high anti-cancer agent sensitivity of his liver tumor.

Calcium homeostasis and organelle function in the pathogenesis of obesity and diabetes

PubMed Central

Arruda, Ana Paula; Hotamisligil, Gökhan S.

2015-01-01

Summary A number of chronic metabolic pathologies, including obesity, diabetes, cardiovascular disease, asthma, and cancer cluster together to present the greatest threat to human health. As research in this field has advanced, it has become clear that unresolved metabolic inflammation, organelle dysfunction, and other cellular and metabolic stresses underlie the development of these chronic metabolic diseases. However, the relationship between these systems and pathological mechanisms is poorly understood. Here, we will discuss the role of cellular Ca2+ homeostasis as a critical mechanism integrating the myriad of cellular and subcellular dysfunctional networks found in metabolic tissues such as liver and adipose tissue in the context of metabolic disease particularly in obesity and diabetes. PMID:26190652

Sinusoidal Endothelial Dysfunction Precedes Inflammation and Fibrosis in a Model of NAFLD

PubMed Central

Pasarín, Marcos; La Mura, Vincenzo; Gracia-Sancho, Jorge; García-Calderó, Héctor; Rodríguez-Vilarrupla, Aina; García-Pagán, Juan Carlos; Bosch, Jaime; Abraldes, Juan G.

2012-01-01

Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome. Most morbidity associated with the metabolic syndrome is related to vascular complications, in which endothelial dysfunction is a major pathogenic factor. However, whether NAFLD is associated with endothelial dysfunction within the hepatic vasculature is unknown. The aims of this study were to explore, in a model of diet-induced overweight that expresses most features of the metabolic syndrome, whether early NAFLD is associated with liver endothelial dysfunction. Wistar Kyoto rats were fed a cafeteria diet (CafD; 65% of fat, mostly saturated) or a control diet (CD) for 1 month. CafD rats developed features of the metabolic syndrome (overweight, arterial hypertension, hypertryglyceridemia, hyperglucemia and insulin resistance) and liver steatosis without inflammation or fibrosis. CafD rats had a significantly higher in vivo hepatic vascular resistance than CD. In liver perfusion livers from CafD rats had an increased portal perfusion pressure and decreased endothelium-dependent vasodilation. This was associated with a decreased Akt-dependent eNOS phosphorylation and NOS activity. In summary, we demonstrate in a rat model of the metabolic syndrome that shows features of NAFLD, that liver endothelial dysfunction occurs before the development of fibrosis or inflammation. PMID:22509248

[A Long-Term Disease-Free Survival Case of Synchronous Pulmonary and Liver Metastasis of Rectal Cancer with Systemic Chemotherapy and Radiofrequency Ablation Therapy for Liver Metastasis].

PubMed

Enomoto, Masaya; Katsumata, Kenji; Kasahara, Kenta; Kuwabara, Hiroshi; Matsudo, Takaaki; Shigoka, Masatoshi; Enomoto, Masanobu; Ishizaki, Tetsuo; Tsuchida, Akihiko

2017-11-01

A 55-year-old woman underwent laparoscopic anterior resection and D2 lymph node dissection for recto-sigmoid colon cancer in November 2014, which was diagnosed as T3N1M1(H3, PUL2), stage IV , for the purpose of preserving the ileus. FOLFOX therapy with panitumumab(Pmab)was started in January 2015.A t the end of 11 courses, pulmonary metastasis changed to CR, and liver metastasis was down-graded to H2 on the CT.Because of the risk of hepatic dysfunction with advanced fatty liver due to chemotherapy and extrahepatic lesions, we chose radiofrequency ablation(RFA)therapy for liver metastasis.Pmab combined FOLFIRI therapy was administered, and maintenance therapy was initiated.This patient is alive 2 years and 7 months after surgery and 10 months after RFA without relapse.It is suggested that RFA therapy for liver metastasis of colon cancer with pulmonary metastasis combined with chemotherapy could be an effective treatment strategy.

Spaceflight Activates Lipotoxic Pathways in Mouse Liver

PubMed Central

Jonscher, Karen R.; Alfonso-Garcia, Alba; Suhalim, Jeffrey L.; Orlicky, David J.; Potma, Eric O.; Ferguson, Virginia L.; Bouxsein, Mary L.; Bateman, Ted A.; Stodieck, Louis S.; Levi, Moshe; Friedman, Jacob E.; Gridley, Daila S.; Pecaut, Michael J.

2016-01-01

Spaceflight affects numerous organ systems in the body, leading to metabolic dysfunction that may have long-term consequences. Microgravity-induced alterations in liver metabolism, particularly with respect to lipids, remain largely unexplored. Here we utilize a novel systems biology approach, combining metabolomics and transcriptomics with advanced Raman microscopy, to investigate altered hepatic lipid metabolism in mice following short duration spaceflight. Mice flown aboard Space Transportation System -135, the last Shuttle mission, lose weight but redistribute lipids, particularly to the liver. Intriguingly, spaceflight mice lose retinol from lipid droplets. Both mRNA and metabolite changes suggest the retinol loss is linked to activation of PPARα-mediated pathways and potentially to hepatic stellate cell activation, both of which may be coincident with increased bile acids and early signs of liver injury. Although the 13-day flight duration is too short for frank fibrosis to develop, the retinol loss plus changes in markers of extracellular matrix remodeling raise the concern that longer duration exposure to the space environment may result in progressive liver damage, increasing the risk for nonalcoholic fatty liver disease. PMID:27097220

A phase I dose-finding study of silybin phosphatidylcholine (milk thistle) in patients with advanced hepatocellular carcinoma.

PubMed

Siegel, Abby B; Narayan, Rupa; Rodriguez, Rosa; Goyal, Abhishek; Jacobson, Judith S; Kelly, Kara; Ladas, Elena; Lunghofer, Paul J; Hansen, Ryan J; Gustafson, Daniel L; Flaig, Thomas W; Tsai, Wei Yann; Wu, David P H; Lee, Valerie; Greenlee, Heather

2014-01-01

To determine the maximum tolerated dose per day of silybin phosphatidylcholine (Siliphos) in patients with advanced hepatocellular carcinoma (HCC) and hepatic dysfunction. Patients with advanced HCC not eligible for other therapies based on poor hepatic function were enrolled in a phase I study of silybin phosphatidylcholine. A standard phase I design was used with 4 planned cohorts, dose escalating from 2, 4, 8, to 12 g per day in divided doses for 12 weeks. Three participants enrolled in this single institution trial. All enrolled subjects consumed 2 g per day of study agent in divided doses. Serum concentrations of silibinin and silibinin glucuronide increased within 1 to 3 weeks. In all 3 patients, liver function abnormalities and tumor marker α-fetoprotein progressed, but after day 56 the third patient showed some improvement in liver function abnormalities and inflammatory biomarkers. All 3 participants died within 23 to 69 days of enrolling into the trial, likely from hepatic failure, but it could not be ruled out that deaths were possibly due to the study drug. Short-term administration of silybin phosphatidylcholine in patients with advanced HCC resulted in detectable increases in silibinin and its metabolite, silibinin glucuronide. The maximum tolerated dose could not be established. Since patients died soon after enrollment, this patient population may have been too ill to benefit from an intervention designed to improve liver function tests.

Nonalcoholic steatohepatitis (NASH) after pancreaticoduodenectomy: association of pancreatic exocrine deficiency and infection.

PubMed

Murata, Yasuhiro; Mizuno, Shugo; Kato, Hiroyuki; Kishiwada, Masashi; Ohsawa, Ichiro; Hamada, Takashi; Usui, Masanobu; Sakurai, Hiroyuki; Tabata, Masami; Nishimura, Keisuke; Fukutome, Kazuo; Isaji, Shuji

2011-08-01

Previous clinical study has demonstrated that 30-40% of patients undergoing pancreaticoduodenectomy (PD) developed hepatic steatosis. However, nonalcoholic steatohepatitis (NASH) is a little-known complication after PD. Recently we encountered two patients with PD who later developed NASH diagnosed by liver biopsy. Case 1 was a 79-year-old woman who underwent PD for intraductal papillary mucinous neoplasm (IPMN). She had postoperative severe diarrhea due to pseudomembranous enterocolitis. Severe liver dysfunction was observed on the 31st postoperative day. Abdominal computed tomography (CT) on the 32nd day showed remarkably decreased hepatic CT value of 6 HU. Immediate liver biopsy revealed NASH (Brunt criteria: grade 2, stage 2). Case 2 was a 71-year-old woman who underwent PD for IPMN. Liver biopsy on 70th postoperative day, which was performed for assessment of moderate liver dysfunction and decreased hepatic CT value of 44 HU, demonstrated simple steatosis. In the 21st postoperative month, she developed severe urinary tract infection together with marked liver dysfunction. Immediate liver biopsy revealed NASH (Brunt criteria: grade 1, stage 1). For each patient, treatment of infection and high-dose pancreatic enzyme supplements improved liver dysfunction and liver steatosis. Clinical features of our cases seem to support the current leading hypothesis of the pathogenesis of NASH, i.e., the two-hit theory.

Effect of evacuation on liver function after the Fukushima Daiichi Nuclear Power Plant accident: The Fukushima Health Management Survey.

PubMed

Takahashi, Atsushi; Ohira, Tetsuya; Hosoya, Mitsuaki; Yasumura, Seiji; Nagai, Masato; Ohira, Hiromasa; Hashimoto, Shigeatsu; Satoh, Hiroaki; Sakai, Akira; Ohtsuru, Akira; Kawasaki, Yukihiko; Suzuki, Hitoshi; Kobashi, Gen; Ozasa, Kotaro; Yamashita, Shunichi; Kamiya, Kenji; Abe, Masafumi

2017-04-01

The Great East Japan Earthquake and subsequent Fukushima Daiichi Nuclear Power Plant accident caused residents to switch from their normal lives to lives focused on evacuation. We evaluated liver function before and after this disaster to elucidate the effects of evacuation on liver function. This study was a longitudinal survey of 26,006 Japanese men and women living near the Fukushima Daiichi Nuclear Power Plant. This study was undertaken using data from annual health checkups conducted for persons aged 40-90 years between 2008 and 2010. Follow-up examinations were conducted from June 2011 to the end of March 2013, with a mean follow up of 1.6 years. Changes in liver function before and after the disaster were compared among evacuees and non-evacuees. We also assessed groups according to alcohol drinking status. The prevalence of liver dysfunction significantly increased in all participants from 16.4% before to 19.2% after the disaster. The incidence of liver dysfunction was significantly higher in evacuees than in non-evacuees. Multivariate logistic regression analysis showed that evacuation was significantly associated with liver dysfunction among residents. This is the first study to show that evacuation due to the Fukushima Daiichi nuclear power plant disaster was associated with an increase in liver dysfunction. Copyright © 2016 The Authors. Production and hosting by Elsevier B.V. All rights reserved.

Recurrence of clinically significant hepatitis A following liver transplantation for fulminant hepatitis A.

PubMed

Eisenbach, Christoph; Longerich, Thomas; Fickenscher, Helmut; Schalasta, Gunnar; Stremmel, Wolfgang; Encke, Jens

2006-01-01

We report hepatitis A virus (HAV) infection of a liver allograft following transplantation for fulminant liver failure due to HAV infection. This rare condition has been described in only three patients to date. After liver transplantation allograft function was good, but starting 80 days after transplantation, episodes of acute graft dysfunction were observed. To elucidate the reason for acute hepatic dysfunction a large number of differential diagnoses were tested. HAV RNA was undetectable for more than 80 days after transplantation. Detection of genomic HAV RNA by RT-PCR in serum and stool at the time of graft dysfunction led to the diagnosis of recurrent HAV infection. We suggest that the risk of HAV reinfection after liver transplantation may be far higher than expected as results may be misinterpreted as rejection episodes.

Liver mitochondrial dysfunction and electron transport chain defect induced by high dietary copper in broilers.

PubMed

Yang, Fan; Cao, Huabin; Su, Rongsheng; Guo, Jianying; Li, Chengmei; Pan, Jiaqiang; Tang, Zhaoxin

2017-09-01

Copper is an important trace mineral in the diet of poultry due to its biological activity. However, limited information is available concerning the effects of high copper on mitochondrial dysfunction. In this study, 72 broilers were used to investigate the effects of high dietary copper on liver mitochondrial dysfunction and electron transport chain defect. Birds were fed with different concentrations [11, 110, 220, and 330 mg of copper/kg dry matter (DM)] of copper from tribasic copper chloride (TBCC). The experiment lasted for 60 d. Liver tissues on d 60 were subjected to histopathological observation. Additionally, liver mitochondrial function was recorded on d 12, 36, and 60. Moreover, a site-specific defect in the electron transport chain in liver mitochondria was also identified by using various chemical inhibitors of mitochondrial respiration. The results showed different degrees of degeneration, mitochondrial swelling, and high-density electrons in hepatocytes. In addition, the respiratory control ratio (RCR) and oxidative phosphorylation rate (OPR) in liver mitochondria increased at first and then decreased in high-dose groups. Moreover, hydrogen peroxide (H2O2) generation velocity in treated groups was higher than that in control group, which were magnified by inhibiting electron transport at Complex IV. The results indicated that high dietary copper could decline liver mitochondrial function in broilers. The presence of a site-specific defect at Complex IV in liver mitochondria may be responsible for liver mitochondrial dysfunction caused by high dietary copper. © 2017 Poultry Science Association Inc.

Naringin Improves Diet-Induced Cardiovascular Dysfunction and Obesity in High Carbohydrate, High Fat Diet-Fed Rats

PubMed Central

Alam, Md. Ashraful; Kauter, Kathleen; Brown, Lindsay

2013-01-01

Obesity, insulin resistance, hypertension and fatty liver, together termed metabolic syndrome, are key risk factors for cardiovascular disease. Chronic feeding of a diet high in saturated fats and simple sugars, such as fructose and glucose, induces these changes in rats. Naturally occurring compounds could be a cost-effective intervention to reverse these changes. Flavonoids are ubiquitous secondary plant metabolites; naringin gives the bitter taste to grapefruit. This study has evaluated the effect of naringin on diet-induced obesity and cardiovascular dysfunction in high carbohydrate, high fat-fed rats. These rats developed increased body weight, glucose intolerance, increased plasma lipid concentrations, hypertension, left ventricular hypertrophy and fibrosis, liver inflammation and steatosis with compromised mitochondrial respiratory chain activity. Dietary supplementation with naringin (approximately 100 mg/kg/day) improved glucose intolerance and liver mitochondrial dysfunction, lowered plasma lipid concentrations and improved the structure and function of the heart and liver without decreasing total body weight. Naringin normalised systolic blood pressure and improved vascular dysfunction and ventricular diastolic dysfunction in high carbohydrate, high fat-fed rats. These beneficial effects of naringin may be mediated by reduced inflammatory cell infiltration, reduced oxidative stress, lowered plasma lipid concentrations and improved liver mitochondrial function in rats. PMID:23446977

Non-Alcoholic Fatty Liver Disease: The Emerging Burden in Cardiometabolic and Renal Diseases.

PubMed

Han, Eugene; Lee, Yong Ho

2017-12-01

As the number of individuals with non-alcoholic fatty liver disease (NAFLD) has increased, the influence of NAFLD on other metabolic diseases has been highlighted. Accumulating epidemiologic evidence indicates that NAFLD not only affects the liver but also increases the risk of extra-hepatic diseases such as type 2 diabetes mellitus, metabolic syndrome, dyslipidemia, hypertension, cardiovascular or cerebrovascular diseases, and chronic kidney disease. Non-alcoholic steatohepatitis, an advanced type of NAFLD, can aggravate these inter-organ relationships and lead to poorer outcomes. NAFLD induces insulin resistance and exacerbates systemic chronic inflammation and oxidative stress, which leads to organ dysfunction in extra-hepatic tissues. Although more research is needed to identify the pathophysiological mechanisms and causal relationship between NAFLD and cardiometabolic and renal diseases, screening for heart, brain, and kidney diseases, risk assessment for diabetes, and a multidisciplinary approach for managing these patients should be highly encouraged. Copyright © 2017 Korean Diabetes Association.

Decreased C-reactive protein induces abnormal vascular structure in a rat model of liver dysfunction induced by bile duct ligation.

PubMed

Jun, Ji Hye; Choi, Jong Ho; Bae, Si Hyun; Oh, Seh Hoon; Kim, Gi Jin

2016-09-01

Chronic liver disease leads to liver fibrosis, and although the liver does have a certain regenerative capacity, this disease is associated with dysfunction of the liver vessels. C-reactive protein (CRP) is produced in the liver and circulated from there for metabolism. CRP was recently shown to inhibit angiogenesis by inducing endothelial cell dysfunction. The objective of this study was to determine the effect of CRP levels on angiogenesis in a rat model of liver dysfunction induced by bile duct ligation (BDL). The diameter of the hepatic vein was analyzed in rat liver tissues using hematoxylin and eosin (H&E) staining. The expression levels of angiogenic factors, albumin, and CRP were analyzed by real-time PCR and Western blotting. A tube formation assay was performed to confirm the effect of CRP on angiogenesis in human umbilical vein endothelial cells (HUVECs) treated with lithocholic acid (LCA) and siRNA-CRP. The diameter of the hepatic portal vein increased significantly with the progression of cirrhosis. The expression levels of angiogenic factors were increased in the cirrhotic liver. In contrast, the expression levels of albumin and CRP were significantly lower in the liver tissue obtained from the BDL rat model than in the normal liver. The CRP level was correlated with the expression of albumin in hepatocytes treated with LCA and siRNA-CRP. Tube formation was significantly decreased in HUVECs when they were treated with LCA or a combination of LCA and siRNA-CRP. CRP seems to be involved in the abnormal formation of vessels in hepatic disease, and so it could be a useful diagnostic marker for hepatic disease.

A Phase I Dose-Finding Study of Silybin Phosphatidylcholine (Milk Thistle) in Patients With Advanced Hepatocellular Carcinoma

PubMed Central

Siegel, Abby B.; Narayan, Rupa; Rodriguez, Rosa; Goyal, Abhishek; Jacobson, Judith S.; Kelly, Kara; Ladas, Elena; Lunghofer, Paul J.; Hansen, Ryan J.; Gustafson, Daniel L.; Flaig, Thomas W.; Tsai, Wei Yann; Wu, David P. H.; Lee, Valerie; Greenlee, Heather

2013-01-01

Purpose To determine the maximum tolerated dose per day of silybin phosphatidylcholine (Siliphos) in patients with advanced hepatocellular carcinoma (HCC) and hepatic dysfunction. Experimental Design Patients with advanced HCC not eligible for other therapies based on poor hepatic function were enrolled in a phase I study of silybin phosphatidylcholine. A standard phase I design was used with 4 planned cohorts, dose escalating from 2, 4, 8, to 12 g per day in divided doses for 12 weeks. Results Three participants enrolled in this single institution trial. All enrolled subjects consumed 2 g per day of study agent in divided doses. Serum concentrations of silibinin and silibinin glucuronide increased within 1 to 3 weeks. In all 3 patients, liver function abnormalities and tumor marker α-fetoprotein progressed, but after day 56 the third patient showed some improvement in liver function abnormalities and inflammatory biomarkers. All 3 participants died within 23 to 69 days of enrolling into the trial, likely from hepatic failure, but it could not be ruled out that deaths were possibly due to the study drug. Conclusion Short-term administration of silybin phosphatidylcholine in patients with advanced HCC resulted in detectable increases in silibinin and its metabolite, silibinin glucuronide. The maximum tolerated dose could not be established. Since patients died soon after enrollment, this patient population may have been too ill to benefit from an intervention designed to improve liver function tests. PMID:23757319

Primary graft dysfunction of the liver: definitions, diagnostic criteria and risk factors.

PubMed

Neves, Douglas Bastos; Rusi, Marcela Balbo; Diaz, Luiz Gustavo Guedes; Salvalaggio, Paolo

2016-01-01

Primary graft dysfunction is a multifactorial syndrome with great impact on liver transplantation outcomes. This review article was based on studies published between January 1980 and June 2015 and retrieved from PubMed database using the following search terms: "primary graft dysfunction", "early allograft dysfunction", "primary non-function" and "liver transplantation". Graft dysfunction describes different grades of graft ischemia-reperfusion injury and can manifest as early allograft dysfunction or primary graft non-function, its most severe form. Donor-, surgery- and recipient-related factors have been associated with this syndrome. Primary graft dysfunction definition, diagnostic criteria and risk factors differ between studies. RESUMO A disfunção primária do enxerto hepático é uma síndrome multifatorial com grande impacto no resultado do transplante de fígado. Foi realizada uma ampla revisão da literatura, consultando a base de dados PubMed, em busca de estudos publicados entre janeiro de 1980 e junho de 2015. Os termos descritivos utilizados foram: "primary graft dysfunction", "early allograft dysfunction", "primary non-function" e "liver transplantation". A disfunção traduz graus diferentes da lesão de isquemia e reperfusão do órgão, e pode se manifestar como disfunção precoce ou, na forma mais grave, pelo não funcionamento primário do enxerto. Fatores relacionados ao doador, ao transplante e ao receptor contribuem para essa síndrome. Existem definições diferentes na literatura quanto ao diagnóstico e aos fatores de risco associados à disfunção primária.

[Simultaneous Hepatorenal Transplantation from a Brain-Dead Donor for Graft Dysfunction and Renal Insufficiency in a Liver Transplant Recipient : A Case Report].

PubMed

Takada, Hideaki; Kobayashi, Takashi; Ogawa, Kohei; Miyata, Hitomi; Sawada, Atsuro; Akamatsu, Shusuke; Negoro, Hiromitsu; Saito, Ryoichi; Terada, Naoki; Yamasaki, Toshinari; Inoue, Takahiro; Teramoto, Yuki; Shibuya, Shinsuke; Haga, Hironori; Kaido, Toshimi; Uemoto, Shinji; Ogawa, Osamu

2017-08-01

We report a case of lethal hepatorenal insufficiency in a 52-year-old man who received successful simultaneous hepatorenal transplantation from a deceased donor. The patient had undergone live-donor liver transplantation for type-C hepatitis and liver cirrhosis 11 years before he developed graft liver dysfunction due to recurrent viral hepatitis and cirrhosis. At that instance, he also developed end-stage renal dysfunction due to calcineurin inhibitor nephropathy and hepatorenal syndrome. Although he needed three open hemostases and abundant blood transfusion, he was withdrawn from continuous hemodiafiltration on the 55th day and discharged from the hospital on the 272nd day postoperatively. Simultaneous hepatorenal transplantation was reported to be associated with more favorable outcomes of graft function, lower rejection rates, but higher perioperative complication rates compared with liver transplantation alone in patients on hemodialysis. Particularly, close attention should be paid for hemostasis since patients have a hemorrhagic tendency until the recovery of graft liver function.

 Rapid identification system of frontal dysfunction in subclinical hepatic encephalopathy.

PubMed

Moretti, Rita; Gazzin, Silvia; Crocè, Lory Saveria; Baso, Beatrice; Masutti, Flora; Bedogni, Giorgio; Tiribelli, Claudio

2016-01-01

 Introduction and aim. Liver disease is associated with cognitive dysfunction also at early stages, and minimal hepatic encephalopathy, affecting 20-70% of patients, is frequently under-recognized. The main purpose of this work was to demonstrate that a substantial number of patients, enrolled due to an acute confusional state in absence of a diagnosis of liver disease, suffers of hepatic encephalopathy. Before a diagnosis of a well-compensated liver diseases was performed, 410 patients with an acute confusional state were enrolled in this study. Even in the presence of minimal alterations of hepatic function, the psychometric tests applied demonstrated early signs of cerebral frontal alteration. The alteration was associated with the severity of liver disease, paralleling the progression of the patient to minimal hepatic failure or chronic liver disease. These psychometric tests are essential to detect early and subclinical frontal failure. Frontal dysfunction may be a useful tool in the follow-up of these patients.

Consensus Statement on Dose Modifications of Antidiabetic Agents in Patients with Hepatic Impairment

PubMed Central

Gangopadhyay, Kalyan Kumar; Singh, Parminder

2017-01-01

Liver disease is an important cause of mortality in type 2 diabetes mellitus (T2DM). It is estimated that diabetes is the most common cause of liver disease in the United States. Virtually, entire spectrum of liver disease is seen in T2DM including abnormal liver enzymes, nonalcoholic fatty liver disease, cirrhosis, hepatocellular carcinoma, and acute liver failure. The treatment of diabetes mellitus (DM) in cirrhotic patients has particular challenges as follows: (1) about half the patients have malnutrition; (2) patients already have advanced liver disease when clinical DM is diagnosed; (3) most of the oral antidiabetic agents (ADAs) are metabolized in the liver; (4) patients often have episodes of hypoglycemia. The aim of this consensus group convened during the National Insulin Summit 2015, Puducherry, was to focus on the challenges with glycemic management, with particular emphasis to safety of ADAs across stages of liver dysfunction. Published literature, product labels, and major clinical guidelines were reviewed and summarized. The drug classes included are biguanides (metformin), the second- or third-generation sulfonylureas, alpha-glucosidase inhibitors, thiazolidinediones, dipeptidyl peptidase-4 inhibitors, sodium-glucose co-transporter 2 inhibitors, glucagon-like peptide-1 receptor agonists, and currently available insulins. Consensus recommendations have been drafted for glycemic targets and dose modifications of all ADAs. These can aid clinicians in managing patients with diabetes and liver disease. PMID:28459036

Occurrence of thyroxine tablet (Thyradin S(®)) - induced liver dysfunction in a patient with subclinical hypothyroidism.

PubMed

Kang, Shino; Amino, Nobuyuki; Kudo, Takumi; Nishihara, Eijun; Ito, Mitsuru; Hirokawa, Mitsuyoshi; Miyauchi, Akira; Tamada, Daisuke; Yasuda, Takenori

2015-01-01

A 54-year-old woman with subclinical hypothyroidism developed liver dysfunction after increasing dose of levothyroxine (L-T4) in tablet form (Thyradin S(®)) from 25μg to 50μg. Viral hepatitis, autoimmune hepatitis and NASH were ruled out with examinations. After cessation of levothyroxine in 50μg tablet form, liver enzymes gradually returned to normal. She was diagnosed levothyroxine-induced liver injury, based on criteria proposed in DDW-J 2004 workshop. Thyradin S(®) powder 0.01% (here in after referred to as L-T4 in powder form) was tried as an alternative, and liver enzymes have remained within normal range. As for Thyradin S(®) tablet, additives are different for each type of levothyroxine sodium content. The difference of additive is whether Fe2O3 is contained or not: it is not included in Thyradin S(®) 50μg tablet and powder form. Although there are two case reports in the Japanese literature and three case reports in the English literature of liver dysfunction suspected due to L-T4, we cannot find past reports about cases of drug induced liver dysfunction due to Fe2O3 free levothyroxine tablet form. This is a rare case report of drug induced liver injury due to Fe2O3 free levothyroxine tablet form, and administration of L-T4 in powder form may be useful for treatment of cases similar to this one.

Redox imbalance due to the loss of mitochondrial NAD(P)-transhydrogenase markedly aggravates high fat diet-induced fatty liver disease in mice.

PubMed

Navarro, Claudia D C; Figueira, Tiago R; Francisco, Annelise; Dal'Bó, Genoefa A; Ronchi, Juliana A; Rovani, Juliana C; Escanhoela, Cecilia A F; Oliveira, Helena C F; Castilho, Roger F; Vercesi, Anibal E

2017-12-01

The mechanisms by which a high fat diet (HFD) promotes non-alcoholic fatty liver disease (NAFLD) appear to involve liver mitochondrial dysfunctions and redox imbalance. We hypothesized that a HFD would increase mitochondrial reliance on NAD(P)-transhydrogenase (NNT) as the source of NADPH for antioxidant systems that counteract NAFLD development. Therefore, we studied HFD-induced liver mitochondrial dysfunctions and NAFLD in C57Unib.B6 congenic mice with (Nnt +/+ ) or without (Nnt -/- ) NNT activity; the spontaneously mutated allele (Nnt -/- ) was inherited from the C57BL/6J mouse substrain. After 20 weeks on a HFD, Nnt -/- mice exhibited a higher prevalence of steatohepatitis and content of liver triglycerides compared to Nnt +/+ mice on an identical diet. Under a HFD, the aggravated NAFLD phenotype in the Nnt -/- mice was accompanied by an increased H 2 O 2 release rate from mitochondria, decreased aconitase activity (a redox-sensitive mitochondrial enzyme) and higher susceptibility to Ca 2+ -induced mitochondrial permeability transition. In addition, HFD led to the phosphorylation (inhibition) of pyruvate dehydrogenase (PDH) and markedly reduced the ability of liver mitochondria to remove peroxide in Nnt -/- mice. Bypass or pharmacological reactivation of PDH by dichloroacetate restored the peroxide removal capability of mitochondria from Nnt -/- mice on a HFD. Noteworthy, compared to mice that were chow-fed, the HFD did not impair peroxide removal nor elicit redox imbalance in mitochondria from Nnt +/+ mice. Therefore, HFD interacted with Nnt mutation to generate PDH inhibition and further suppression of peroxide removal. We conclude that NNT plays a critical role in counteracting mitochondrial redox imbalance, PDH inhibition and advancement of NAFLD in mice fed a HFD. The present study provide seminal experimental evidence that redox imbalance in liver mitochondria potentiates the progression from simple steatosis to steatohepatitis following a HFD. Copyright © 2017. Published by Elsevier Inc.

Radiation hepatology of the rat: The effects of the proliferation stimulus induced by subtotal hepatectomy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Geraci, J.P.; Mariano, M.S.

1994-11-01

The effect of an 80 to 90% hepatectomy in stimulating proliferation immediately after irradiation of the liver was studied. A dose of 15 Gy was not lethal for animals with intact livers, but all animals with subtotal hepatectomies exposed to this dose died from apparent liver failure 28 to 60 days after exposure. To elucidate the mechanism for this mortality, plasma aspartate aminotransferase, retention of intravenous injected rose bengal, liver weight and liver hydroxyproline content were measured 0 to 90 days after 15 Gy irradiation of the liver to determine temporal changes in necrosis, function, mass and fibrosis, respectively, inmore » animals with either intact livers or livers with subtotal resection. Irradiation of the liver had no significant effect on these parameters in animals with intact livers. In subtotally hepatectomized animals the same radiation dose that suppressed liver mass restoration significantly increased hepatocyte necrosis within 7 days, which was followed by increased liver hydroxyproline concentration and hepatic dysfunction. This radiation-induced temporal change in hepatic dysfunction correlated with increased concentration of hydroxyproline but not with liver mass, indicating that liver fibrosis was the cause of hepatic dysfunction. Since similar sequelae are produced in intact livers after higher doses and longer intervals after irradiation, the proliferation stimulus induced by partial hepatectomy must accelerate the expression of damage and lower the radiation tolerance of the liver. However, in subtotally hepatectomized animals radiation-induced hepatocyte necrosis precedes fibrosis, whereas the reverse is normally true for animals with intact livers. 35 refs., 5 figs.« less

Beneficial effects of apple peel polyphenols on vascular endothelial dysfunction and liver injury in high choline-fed mice.

PubMed

Jia, Mengfan; Ren, Daoyuan; Nie, Yan; Yang, Xingbin

2017-03-22

This study was designed to investigate the preventive effects of Red Fuji apple peel polyphenolic extract (APP) on vascular endothelial dysfunction and liver injury in mice fed a high choline diet. The mice were fed 3% dietary choline in drinking water for 8 weeks and displayed vascular dysfunction and liver damage (p < 0.01). The administration of APP at 600 and 900 mg per kg bw significantly elevated serum NO, HDL and 6-Keto-PGF1a levels and lowered serum TC, TG, LDL, ET-1 and TXB2 levels in the HC-fed mice. Besides, APP also caused the reduction of AST, ALT activities and MDA, CRP, TNF-α levels, and increased the hepatic GSH-Px and SOD activities of the HC-fed mice. Furthermore, the histopathology of the liver by conventional H&E and oil red O staining confirmed the liver steatosis induced by a choline diet and the hepatoprotective effect of APP. The experiment results indicated that the polyphenolic extract from apple peel might be regarded as a preventive and therapeutic product for the amelioration of HC diet-induced vascular dysfunction and hepatic injury.

Immune dysfunction in cirrhosis.

PubMed

Sipeki, Nora; Antal-Szalmas, Peter; Lakatos, Peter L; Papp, Maria

2014-03-14

Innate and adaptive immune dysfunction, also referred to as cirrhosis-associated immune dysfunction syndrome, is a major component of cirrhosis, and plays a pivotal role in the pathogenesis of both the acute and chronic worsening of liver function. During the evolution of the disease, acute decompensation events associated with organ failure(s), so-called acute-on chronic liver failure, and chronic decompensation with progression of liver fibrosis and also development of disease specific complications, comprise distinct clinical entities with different immunopathology mechanisms. Enhanced bacterial translocation associated with systemic endotoxemia and increased occurrence of systemic bacterial infections have substantial impacts on both clinical situations. Acute and chronic exposure to bacteria and/or their products, however, can result in variable clinical consequences. The immune status of patients is not constant during the illness; consequently, alterations of the balance between pro- and anti-inflammatory processes result in very different dynamic courses. In this review we give a detailed overview of acquired immune dysfunction and its consequences for cirrhosis. We demonstrate the substantial influence of inherited innate immune dysfunction on acute and chronic inflammatory processes in cirrhosis caused by the pre-existing acquired immune dysfunction with limited compensatory mechanisms. Moreover, we highlight the current facts and future perspectives of how the assessment of immune dysfunction can assist clinicians in everyday practical decision-making when establishing treatment and care strategies for the patients with end-stage liver disease. Early and efficient recognition of inappropriate performance of the immune system is essential for overcoming complications, delaying progression and reducing mortality.

Immune dysfunction in cirrhosis

PubMed Central

Sipeki, Nora; Antal-Szalmas, Peter; Lakatos, Peter L; Papp, Maria

2014-01-01

Innate and adaptive immune dysfunction, also referred to as cirrhosis-associated immune dysfunction syndrome, is a major component of cirrhosis, and plays a pivotal role in the pathogenesis of both the acute and chronic worsening of liver function. During the evolution of the disease, acute decompensation events associated with organ failure(s), so-called acute-on chronic liver failure, and chronic decompensation with progression of liver fibrosis and also development of disease specific complications, comprise distinct clinical entities with different immunopathology mechanisms. Enhanced bacterial translocation associated with systemic endotoxemia and increased occurrence of systemic bacterial infections have substantial impacts on both clinical situations. Acute and chronic exposure to bacteria and/or their products, however, can result in variable clinical consequences. The immune status of patients is not constant during the illness; consequently, alterations of the balance between pro- and anti-inflammatory processes result in very different dynamic courses. In this review we give a detailed overview of acquired immune dysfunction and its consequences for cirrhosis. We demonstrate the substantial influence of inherited innate immune dysfunction on acute and chronic inflammatory processes in cirrhosis caused by the pre-existing acquired immune dysfunction with limited compensatory mechanisms. Moreover, we highlight the current facts and future perspectives of how the assessment of immune dysfunction can assist clinicians in everyday practical decision-making when establishing treatment and care strategies for the patients with end-stage liver disease. Early and efficient recognition of inappropriate performance of the immune system is essential for overcoming complications, delaying progression and reducing mortality. PMID:24627592

Metabolomics discloses donor liver biomarkers associated with early allograft dysfunction.

PubMed

Cortes, Miriam; Pareja, Eugenia; García-Cañaveras, Juan C; Donato, M Teresa; Montero, Sandra; Mir, Jose; Castell, José V; Lahoz, Agustín

2014-09-01

Early allograft dysfunction (EAD) dramatically influences graft and patient outcome after orthotopic liver transplantation and its incidence is strongly determined by donor liver quality. Nevertheless, objective biomarkers, which can assess graft quality and anticipate organ function, are still lacking. This study aims to investigate whether there is a preoperative donor liver metabolomic biosignature associated with EAD. A comprehensive metabolomic profiling of 124 donor liver biopsies collected before transplantation was performed by mass spectrometry coupled to liquid chromatography. Donor liver grafts were classified into two groups: showing EAD and immediate graft function (IGF). Multivariate data analysis was used to search for the relationship between the metabolomic profiles present in donor livers before transplantation and their function in recipients. A set of liver graft dysfunction-associated biomarkers was identified. Key changes include significantly increased levels of bile acids, lysophospholipids, phospholipids, sphingomyelins and histidine metabolism products, all suggestive of disrupted lipid homeostasis and altered histidine pathway. Based on these biomarkers, a predictive EAD model was built and further evaluated by assessing 24 independent donor livers, yielding 91% sensitivity and 82% specificity. The model was also successfully challenged by evaluating donor livers showing primary non-function (n=4). A metabolomic biosignature that accurately differentiates donor livers, which later showed EAD or IGF, has been deciphered. The remarkable metabolomic differences between donor livers before transplant can relate to their different quality. The proposed metabolomic approach may become a clinical tool for donor liver quality assessment and for anticipating graft function before transplant. Copyright © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Fatal chronic active Epstein-Barr virus infection mimicking autoimmune hepatitis.

PubMed

Chiba, Tetsuhiro; Goto, Shigemasa; Yokosuka, Osamu; Imazeki, Fumio; Tanaka, Masamichi; Fukai, Kenichi; Takahashi, Yoko; Tsujimura, Hideki; Saisho, Hiromitsu

2004-02-01

We report a 22-year-old female who presented with pyrexia, pancytopenia and liver dysfunction. The patient showed mild liver dysfunction with low-grade fever and mild hepatosplenomegaly 6 years previously, and autoimmune hepatitis (AIH) was diagnosed based on the examination of the laboratory data and liver biopsy. On admission, both markers of Epstein-Barr virus (EBV) and in-situ hybridisation from a liver biopsy specimen indicated chronic active EBV infection (CAEBV). The patient was administered an immunosuppressive agent and antiviral drug added to steroid therapy, but ultimately died from liver failure and virus-associated haemophagocytosis 10 months after the definite diagnosis. Retrospective examination of the serum at the diagnosis of AIH revealed extremely high titres of antibody to EBV, and EBV-DNA was also detectable by polymerase chain reaction. These results suggest the possibility that the patient may already have suffered from CAEBV at the initial diagnosis. We presume that hepatic involvement of CAEBV should be considered as differential diagnosis in cases showing liver dysfunction with clinical and biochemical features observed in AIH.

Neutrophil Gelatinase Associated Lipocalin (NGAL) - a biomarker of renal dysfunction in patients with liver cirrhosis: Do we have enough proof?

PubMed

Firu, S G; Streba, C T; Firu, D; Tache, D E; Rogoveanu, I

2015-01-01

Renal dysfunction has a serious impact on the natural evolution of liver cirrhosis. Treatment and prognosis may be improved if an early diagnosis could be established, and specific therapeutic interventions would be applied. Although RIFLE and AKIN classifications have been successfully implemented in the clinical practice of Nephrology and Intensive Care Units, these did not provide major improvements in patients with liver cirrhosis. In the last decade, various biomarkers of kidney injury have been assessed, and Neutrophil Gelatinase-Associated Lipocalin (NGAL) is one of the most promising and most studied novel biomarker. To offer a brief evaluation on current data on the utility of this biomarker in patients with liver cirrhosis. We have searched through current literature and analyzed all significant full text articles on this topic. NGAL and other new kidney injury molecules may be useful in patients with liver cirrhosis, particularly in identifying structural kidney dysfunction, but larger validation studies to confirm this observation are needed.

Advances in ultrasound-targeted microbubble-mediated gene therapy for liver fibrosis.

PubMed

Huang, Cuiyuan; Zhang, Hong; Bai, Ruidan

2017-07-01

Hepatic fibrosis develops as a wound-healing scar in response to acute and chronic liver inflammation and can lead to cirrhosis in patients with chronic hepatitis B and C. The condition arises due to increased synthesis and reduced degradation of extracellular matrix (ECM) and is a common pathological sequela of chronic liver disease. Excessive deposition of ECM in the liver causes liver dysfunction, ascites, and eventually upper gastrointestinal bleeding as well as a series of complications. However, fibrosis can be reversed before developing into cirrhosis and has thus been the subject of extensive researches particularly at the gene level. Currently, therapeutic genes are imported into the damaged liver to delay or prevent the development of liver fibrosis by regulating the expression of exogenous genes. One technique of gene delivery uses ultrasound targeting of microbubbles combined with therapeutic genes where the time and intensity of the ultrasound can control the release process. Ultrasound irradiation of microbubbles in the vicinity of cells changes the permeability of the cell membrane by its cavitation effect and enhances gene transfection. In this paper, recent progress in the field is reviewed with emphasis on the following aspects: the types of ultrasound microbubbles, the construction of an ultrasound-mediated gene delivery system, the mechanism of ultrasound microbubble-mediated gene transfer and the application of ultrasound microbubbles in the treatment of liver fibrosis.

Pilot study to assess toxicity and pharmacokinetics of docetaxel in patients with metastatic breast cancer and impaired liver function secondary to hepatic metastases.

PubMed

Eckmann, Karen; Michaud, Laura B; Rivera, Edgardo; Madden, Timothy L; Esparza-Guerra, Laura; Kawedia, Jitesh; Booser, Daniel J; Green, Marjorie C; Hortobagyi, Gabriel N; Valero, Vicente

2014-04-01

Limited clinical data are available regarding the safety of docetaxel in metastatic breast cancer patients with liver dysfunction. Eligible patients had breast cancer with impaired liver function secondary to hepatic metastases and were candidates for docetaxel therapy. They were assigned to one of five groups on the basis of total bilirubin, alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase levels. All other causes of liver dysfunction were excluded, and bile duct obstruction was corrected, if possible, prior to study entry. Patients received docetaxel every three weeks. The chemotherapy dose was chosen on the basis of the patient's level of hepatic dysfunction and escalated as tolerated. The primary outcome of this study was safety. The secondary outcomes were pharmacokinetic data and efficacy in terms of time to disease progression. Twenty-three patients were enrolled. No unexpected toxicities occurred. Grade 3/4 fatigue (65%), neutropenia (30%), myalgias (26%), neutropenic fever (26%), vomiting (9%), and rash (9%) were the most common serious adverse events. The median time to progression was three months (range 1-18 months). Pharmacokinetic results indicated that patients with more severe hepatic dysfunction may have been underdosed based on our conservative dosing strategy. Docetaxel can be administered to patients with metastatic breast cancer and liver dysfunction after dose attenuation. However, because of a narrow therapeutic index in this clinical setting, therapy should be closely monitored with subsequent dose escalation when possible.

Predictors of renal recovery in patients with pre-orthotopic liver transplant (OLT) renal dysfunction.

PubMed

Iglesias, Jose; Frank, Elliot; Mehandru, Sushil; Davis, John M; Levine, Jerrold S

2013-07-13

Renal dysfunction occurs commonly in patients awaiting orthotopic liver transplantation (OLT) for end-stage liver disease. The use of simultaneous liver-kidney transplantation has increased in the MELD scoring era. As patients may recover renal function after OLT, identifying factors predictive of renal recovery is a critical issue, especially given the scarcity of available organs. Employing the UNOS database, we sought to identify donor- and patient-related predictors of renal recovery among 1720 patients with pre-OLT renal dysfunction and transplanted from 1989 to 2005. Recovery of renal function post-OLT was defined as a composite endpoint of serum creatinine (SCr) ≤1.5 mg/dL at discharge and survival ≥29 days. Pre-OLT renal dysfunction was defined as any of the following: SCr ≥2 mg/dL at any time while awaiting OLT or need for renal replacement therapy (RRT) at the time of registration and/or OLT. Independent predictors of recovery of renal function post-OLT were absence of hepatic allograft dysfunction, transplantation during MELD era, recipient female sex, decreased donor age, decreased recipient ALT at time of OLT, decreased recipient body mass index at registration, use of anti-thymocyte globulin as induction therapy, and longer wait time from registration. Contrary to popular belief, a requirement for RRT, even for prolonged periods in excess of 8 weeks, was not an independent predictor of failure to recover renal function post-OLT. These data indicate that the duration of renal dysfunction, even among those requiring RRT, is a poor way to discriminate reversible from irreversible renal dysfunction.

An alternative medicine, Agaricus blazei, may have induced severe hepatic dysfunction in cancer patients.

PubMed

Mukai, Hirofumi; Watanabe, Toru; Ando, Masashi; Katsumata, Noriyuki

2006-12-01

We report three cases of patients with advanced cancer who showed severe hepatic damage, and two of whom died of fulminant hepatitis. All the patients were taking Agaricus blazei (Himematsutake) extract, one of the most popular complementary and alternative medicines among Japanese cancer patients. In one patient, liver functions recovered gradually after she stopped taking the Agaricus blazei, but she restarted taking it, which resulted in deterioration of the liver function again. The other patients who were admitted for severe liver damage had started taking the Agaricus blazei several days before admission. Although several other factors cannot be completely ruled out as the causes of liver damage, a strong causal relationship between the Agaricus blazei extract and liver damage was suggested and, at least, taking the Agaricus blazei extract made the clinical decision-making process much more complicated. Doctors who are aware of their patients taking the extract may accept it probably because they believe there is no harm in a complementary and alternative medicine. When unexpected liver damage is documented, however, doctors should consider the use of the Agaricus blazei extract as one of its causal factors. It is necessary to evaluate many modes of complementary and alternative medicines, including the Agaricus blazei extract, in rigorous, scientifically designed and peer-reviewed clinical trials.

Hepatic dysfunction contributes to coagulation disturbances in patients undergoing whole body hyperthermia by use of extracorporeal circulation.

PubMed

Worel, Nina; Knöbl, Paul; Karanikas, Georgios; Fuchs, Eva-Maria; Bojic, Andja; Brodowicz, Thomas; Jilma, Petra; Zielinski, Christoph C; Köstler, Wolfgang J; Locker, Gottfried J

2014-09-01

This phase I study was performed to evaluate coagulation alterations during extracorporeal circulation (ECC) induced whole body hyperthermia (WBHT) in 12 patients with advanced soft tissue sarcomas. To distinguish between effects of normothermic ECC and ECC-WBHT, blood samples were drawn at different time points: at baseline, after 30 min on normothermic ECC, at the end of the heating period, and 24 h and 7 days thereafter. Standard coagulation tests, coagulation factors, thrombelastography,platelets and reticulated platelets, liver enzymes, and scintigraphic platelet imaging were performed. Normothermic ECC resulted in coagulation alterations most likely due to systemic anticoagulation. Induction of hyperthermia caused thrombocytopenia, increased fibrin degradation products,prolonged clotting times, alteration in coagulation factors, and increased liver enzymes. The majority of these effects was most pronounced 24 h after ECC-WBHT. In addition, late liver sequestration of platelets was demonstrated in scintigraphic imaging at that time point. Temporal correlation between hemostatic alterations and elevation in liver enzymes leads to the assumption that liver impairment might play a crucial role in coagulation disturbances observed during ECC-WBHT and thereafter, thus strongly supported by liver sequestration of platelets.Therefore a close monitoring of hepatic derived coagulation alterations in patients undergoing extracorporeal whole body hypothermia is warranted.

Hepatic sarcoidosis in patients presenting with liver dysfunction: imaging appearance, pathological correlation and disease evolution.

PubMed

Fetzer, David T; Rees, Mitchell A; Dasyam, Anil K; Tublin, Mitchell E

2016-09-01

We hypothesize that hepatic sarcoidosis is a dynamic process that can lead to cirrhosis and portal hypertension, independent of the course of thoracic disease. Therefore, we assess the imaging appearance and progression of hepatic sarcoidosis in subjects presenting with hepatic dysfunction. An IRB-approved, HIPAA-compliant, single-institution retrospective review identified 39 subjects with sarcoidosis-related liver dysfunction. Clinical information was collected. Two abdominal radiologists analyzed baseline and follow-up imaging studies, scoring features of cirrhosis. Chest CT was also analyzed. At presentation, 23 subjects (59.0 %) exhibited >3 cirrhotic features and 15 (38.5 %) >2 findings of portal hypertension. Of subjects with available follow-up, 57.9 % (19 subjects; mean interval 4.7 years) showed worsening of >3 cirrhotic features (Pearson rho = 0.58; p = 0.009). Parenchymal nodules were uncommon (25.6 %), and most regressed. Although 87.2 % of subjects were diagnosed with thoracic sarcoidosis, there was poor correlation between severity of hepatic and chest disease (Pearson rho = 0.30; p = 0.119). A mean of 7.2 years elapsed between diagnosis of pulmonary and liver involvement. Sarcoidosis may present as liver dysfunction, cirrhosis or portal hypertension. Sarcoid-related liver disease may progress and can manifest without, alongside or significantly after a diagnosis of pulmonary disease. • Patients often present with elevated liver function tests indicating cholestasis. • Patients may present with portal hypertension, and some progress to cirrhosis. • Though biopsy can be considered for focal liver lesions, most will regress. • Extent of intra-abdominal involvement may not correlate with severity of thoracic disease. • Liver disease may manifest alongside, prior to or significantly after initial diagnosis.

Advancement of 31P Magnetic Resonance Spectroscopy Using GRAPPA Reconstruction on a 3D Volume

NASA Astrophysics Data System (ADS)

Clevenger, Tony

The overall objective of this research is to improve currently available metabolic imaging techniques for clinical use in monitoring and predicting treatment response to radiation therapy in liver cancer. Liver metabolism correlates with inflammatory and neoplastic liver diseases, which alter the intracellular concentration of phosphorus- 31 (31P) metabolites [1]. It is assumed that such metabolic changes occur prior to physical changes of the tissue. Therefore, information on regional changes of 31P metabolites in the liver, obtained by Magnetic Resonance Spectroscopic Imaging (MRSI) [1,2], can help in diagnosis and follow-up of various liver diseases. Specifically, there appears to be an immediate need of this technology for both the assessment of tumor response in patients with Hepatocellular Carcinoma (HCC) treated with Stereotactic Body Radiation Therapy (SBRT) [3--5], as well as assessment of radiation toxicity, which can result in worsening liver dysfunction [6]. Pilot data from our lab has shown that 31P MRSI has the potential to identify treatment response five months sooner than conventional methods [7], and to assess the biological response of liver tissue to radiation 24 hours post radiation therapy [8]. While this data is very promising, commonly occurring drawbacks for 31P MRSI are patient discomfort due to long scan times and prone positioning within the scanner, as well as reduced data quality due to patient motion and respiration. To further advance the full potential of 31P MRSI as a clinical diagnostic tool in the management of liver cancer, this PhD research project had the following aims: I) Reduce the long acquisition time of 3D 31P MRS by formulating and imple- menting an appropriate GRAPPA undersampling scheme and reconstruction on a clinical MRI scanner II) Testing and quantitative validation of GRAPPA reconstruction on 3D 31P MRSI on developmental phantoms and healthy volunteers At completion, this work should considerably advance 31P MRSI as a clinical diagnos- tic tool for liver cancer, and potentially other cancer types, by reducing the amount of time needed to get relevant data for treatment efficacy of SBRT patients. Imple- mentation of this work into our ongoing clinical study will further provide insights into whether the 31P MSRI method can be an early predictor of normal tissue toxicity and/or treatment response.

Acute and chronic hepatobiliary manifestations of sickle cell disease: A review

PubMed Central

Shah, Rushikesh; Taborda, Cesar; Chawla, Saurabh

2017-01-01

Sickle cell disease (SCD) is a common hemoglobinopathy which can affect multiple organ systems in the body. Within the digestive tract, the hepatobiliary system is most commonly affected in SCD. The manifestations range from benign hyperbilirubinemia to overt liver failure, with the spectrum of acute clinical presentations often referred to as “sickle cell hepatopathy”. This is an umbrella term referring to liver dysfunction and hyperbilirubinemia due to intrahepatic sickling process during SCD crisis leading to ischemia, sequestration and cholestasis. In this review, we detail the pathophysiology, clinical presentation and biochemical features of various acute and chronic hepatobiliary manifestations of SCD and present and evaluate existing evidence with regards to management of this disease process. We also discuss recent advances and controversies such as the role of liver transplantation in sickle cell hepatopathy and highlight important questions in this field which would require further research. Our aim with this review is to help increase the understanding, aid in early diagnosis and improve management of this important disease process. PMID:28868180

Mitochondrial remodeling in the liver following chronic alcohol feeding to rats.

PubMed

Han, Derick; Johnson, Heather S; Rao, Madhuri P; Martin, Gary; Sancheti, Harsh; Silkwood, Kai H; Decker, Carl W; Nguyen, Kim Tho; Casian, Joseph G; Cadenas, Enrique; Kaplowitz, Neil

2017-01-01

The feeding of alcohol orally (Lieber-DeCarli diet) to rats has been shown to cause declines in mitochondrial respiration (state III), decreased expression of respiratory complexes, and decreased respiratory control ratios (RCR) in liver mitochondria. These declines and other mitochondrial alterations have led to the hypothesis that alcohol feeding causes "mitochondrial dysfunction" in the liver. If oral alcohol feeding leads to mitochondrial dysfunction, one would predict that increasing alcohol delivery by intragastric (IG) alcohol feeding to rats would cause greater declines in mitochondrial bioenergetics in the liver. In this study, we examined the mitochondrial alterations that occur in rats fed alcohol both orally and intragastrically. Oral alcohol feeding decreased glutamate/malate-, acetaldehyde- and succinate-driven state III respiration, RCR, and expression of respiratory complexes (I, III, IV, V) in liver mitochondria, in agreement with previous results. IG alcohol feeding, on the other hand, caused a slight increase in glutamate/malate-driven respiration, and significantly increased acetaldehyde-driven respiration in liver mitochondria. IG feeding also caused liver mitochondria to experience a decline in succinate-driven respiration, but these decreases were smaller than those observed with oral alcohol feeding. Surprisingly, oral and IG alcohol feeding to rats increased mitochondrial respiration using other substrates, including glycerol-3-phosphate (which delivers electrons from cytoplasmic NADH to mitochondria) and octanoate (a substrate for beta-oxidation). The enhancement of glycerol-3-phosphate- and octanoate-driven respiration suggests that liver mitochondria remodeled in response to alcohol feeding. In support of this notion, we observed that IG alcohol feeding also increased expression of mitochondrial glycerol phosphate dehydrogenase-2 (GPD2), transcription factor A (TFAM), and increased mitochondrial NAD + -NADH and NADP + -NADPH levels in the liver. Our findings suggest that mitochondrial dysfunction represents an incomplete picture of mitochondrial dynamics that occur in the liver following alcohol feeding. While alcohol feeding causes some mitochondrial dysfunction (i.e. succinate-driven respiration), our work suggests that the major consequence of alcohol feeding is mitochondrial remodeling in the liver as an adaptation. This mitochondrial remodeling may play an important role in the enhanced alcohol metabolism and other adaptations in the liver that develop with alcohol intake. Copyright © 2016 Elsevier Inc. All rights reserved.

Lychee (Litchi chinensis Sonn.) Pulp Phenolic Extract Provides Protection against Alcoholic Liver Injury in Mice by Alleviating Intestinal Microbiota Dysbiosis, Intestinal Barrier Dysfunction, and Liver Inflammation.

PubMed

Xiao, Juan; Zhang, Ruifen; Zhou, Qiuyun; Liu, Lei; Huang, Fei; Deng, Yuanyuan; Ma, Yongxuan; Wei, Zhencheng; Tang, Xiaojun; Zhang, Mingwei

2017-11-08

Liver injury is the most common consequence of alcohol abuse, which is promoted by the inflammatory response triggered by gut-derived endotoxins produced as a consequence of intestinal microbiota dysbiosis and barrier dysfunction. The aim of this study was to investigate whether modulation of intestinal microbiota and barrier function, and liver inflammation contributes to the hepatoprotective effect of lychee pulp phenolic extract (LPPE) in alcohol-fed mice. Mice were treated with an ethanol-containing liquid diet alone or in combination with LPPE for 8 weeks. LPPE supplementation alleviated ethanol-induced liver injury and downregulated key markers of inflammation. Moreover, LPPE supplementation reversed the ethanol-induced alteration of intestinal microbiota composition and increased the expression of intestinal tight junction proteins, mucus protecting proteins, and antimicrobial proteins. Furthermore, in addition to decreasing serum endotoxin level, LPPE supplementation suppressed CD14 and toll-like receptor 4 expression, and repressed the activation of nuclear factor-κB p65 in the liver. These data suggest that intestinal microbiota dysbiosis, intestinal barrier dysfunction, and liver inflammation are improved by LPPE, and therefore, the intake of LPPE or Litchi pulp may be an effective strategy to alleviate the susceptibility to alcohol-induced hepatic diseases.

IGF-1 decreases portal vein endotoxin via regulating intestinal tight junctions and plays a role in attenuating portal hypertension of cirrhotic rats.

PubMed

Zhao, Tian-Yu; Su, Li-Ping; Ma, Chun-Ye; Zhai, Xiao-Han; Duan, Zhi-Jun; Zhu, Ying; Zhao, Gang; Li, Chun-Yan; Wang, Li-Xia; Yang, Dong

2015-07-08

Intestinal barrier dysfunction is not only the consequence of liver cirrhosis, but also an active participant in the development of liver cirrhosis. Previous studies showed that external administration of insulin-like growth factor 1 (IGF-1) improved intestinal barrier function in liver cirrhosis. However, the mechanism of IGF-1 on intestinal barrier in liver cirrhosis is not fully elucidated. The present study aims to investigate the mechanisms of IGF-1 improving intestinal barrier function via regulating tight junctions in intestines. We used carbon tetrachloride induced liver cirrhotic rats to investigate the effect of IGF-1 on intestinal claudin-1 and occludin expressions, serum alanine transaminase (ALT) and aspartate transaminase (AST) levels, severity of liver fibrosis, portal pressures, enterocytic apoptosis and lipopolysaccharides (LPS) levels in portal vein. The changes of IGF-1 in serum during the development of rat liver cirrhosis were also evaluated. Additionally, we assessed the effect of IGF-1 on claudin-1 and occludin expressions, changes of transepithelial electrical resistance (TEER) and apoptosis in Caco-2 cells to confirm in vivo findings. Serum IGF-1 levels were decreased in the development of rat liver cirrhosis, and external administration of IGF-1 restored serum IGF-1 levels. External administration of IGF-1 reduced serum ALT and AST levels, severity of liver fibrosis, LPS levels in portal vein, enterocytic apoptosis and portal pressure in cirrhotic rats. External administration of IGF-1 increased the expressions of claudin-1 and occludin in enterocytes, and attenuated tight junction dysfunction in intestines of cirrhotic rats. LPS decreased TEER in Caco-2 cell monolayer. LPS also decreased claudin-1 and occludin expressions and increased apoptosis in Caco-2 cells. Furthermore, IGF-1 attenuated the effect of LPS on TEER, claudin-1 expression, occludin expression and apoptosis in Caco-2 cells. Tight junction dysfunction develops during the development of liver cirrhosis, and endotoxemia will develop subsequently. Correspondingly, increased endotoxin in portal system worsens tight junction dysfunction via decreasing intestinal occludin and claudin-1 expressions and increasing enterocytic apoptosis. Endotoxemia and intestinal barrier dysfunction form a vicious circle. External administration of IGF-1 breaks this vicious circle. Improvement of tight junctions might be one possible mechanism of the restoration of intestinal barrier function mediated by IGF-1.

Tyrosine kinase inhibitor BIBF1120 ameliorates inflammation, angiogenesis and fibrosis in CCl4-induced liver fibrogenesis mouse model

PubMed Central

Öztürk Akcora, Büsra; Storm, Gert; Prakash, Jai; Bansal, Ruchi

2017-01-01

Hepatic fibrosis, a progressive chronic disease mainly caused by hepatitis viral infections, alcohol abuse or metabolic syndrome leading to liver dysfunction and is the growing cause of mortality worldwide. Tyrosine kinase inhibitor BIBF1120 (Nintedanib) has been evaluated in clinical trials for idiopathic pulmonary fibrosis and advanced Hepatocellular carcinoma, but has not been explored for liver fibrosis yet. In this study, we aimed to investigate the therapeutic effects and mechanism of BIBF1120 in liver fibrogenesis. The effects of BIBF1120 were evaluated in TGFβ-activated mouse 3T3 fibroblasts, LX2 cells, primary human hepatic stellate cells (HSCs) and CCl4-induced liver fibrogenesis mouse model. Fibroblasts-conditioned medium studies were performed to assess the paracrine effects on macrophages and endothelial cells. In-vitro in TGFβ-activated fibroblasts, BIBF1120 significantly inhibited expression of major fibrotic parameters, wound-healing and contractility. In vivo in CCl4-induced acute liver injury model, post-disease BIBF1120 administration significantly attenuated collagen accumulation and HSC activation. Interestingly, BIBF1120 drastically inhibited intrahepatic inflammation and angiogenesis. To further elucidate the mechanism of action, 3T3-conditioned medium studies demonstrated increased 3T3-mediated macrophage chemotaxis and endothelial cells tube formation and activation, which was significantly decreased by BIBF1120. These results suggests that BIBF1120 can be a potential therapeutic approach for the treatment of liver fibrosis. PMID:28291245

Transient postpartum diabetes insipidus associated with HELLP syndrome.

PubMed

Ellidokuz, Ender; Uslan, Ihsan; Demir, Serap; Cevrioglu, Serhan; Tufan, Gulnihal

2006-12-01

Diabetes insipidus in pregnancy has different causes. The association of diabetes insipidus with disturbances of liver function has been reported, however, diabetes insipidus has rarely been reported in HELLP syndrome. We present a 23-year-old primigravida with a singleton gestation complicated by HELLP syndrome who developed postpartum diabetes insipidus. Labor was induced promptly to terminate pregnancy because of intrauterine fetal death and liver dysfunction. 1-deamino-8-D-arginine-vasopressin was administered. Diabetes insipidus and liver dysfunction resolved within 2 weeks. Development of diabetes insipidus may result from increased vasopressinase activity mainly caused by deterioration of liver functions caused by HELLP syndrome. In pregnant women with liver disease as a result of any cause, the development of diabetes insipidus should be assessed with particular attention.

Novel interactions of mitochondria and reactive oxygen/nitrogen species in alcohol mediated liver disease

PubMed Central

Mantena, Sudheer K; King, Adrienne L; Andringa, Kelly K; Landar, Aimee; Darley-Usmar, Victor; Bailey, Shannon M

2007-01-01

Mitochondrial dysfunction is known to be a contributing factor to a number of diseases including chronic alcohol induced liver injury. While there is a detailed understanding of the metabolic pathways and proteins of the liver mitochondrion, little is known regarding how changes in the mitochondrial proteome may contribute to the development of hepatic pathologies. Emerging evidence indicates that reactive oxygen and nitrogen species disrupt mitochondrial function through post-translational modifications to the mitochondrial proteome. Indeed, various new affinity labeling reagents are available to test the hypothesis that post-translational modification of proteins by reactive species contributes to mitochondrial dysfunction and alcoholic fatty liver disease. Specialized proteomic techniques are also now available, which allow for identification of defects in the assembly of multi-protein complexes in mitochondria and the resolution of the highly hydrophobic proteins of the inner membrane. In this review knowledge gained from the study of changes to the mitochondrial proteome in alcoholic hepatotoxicity will be described and placed into a mechanistic framework to increase understanding of the role of mitochondrial dysfunction in liver disease. PMID:17854139

Perioperative management of liver surgery-review on pathophysiology of liver disease and liver failure.

PubMed

Gasteiger, Lukas; Eschertzhuber, Stephan; Tiefenthaler, Werner

2018-01-01

An increasing number of patients present for liver surgery. Given the complex pathophysiological changes in chronic liver disease (CLD), it is pivotal to understand the fundamentals of chronic and acute liver failure. This review will give an overview on related organ dysfunction as well as recommendations for perioperative management and treatment of liver failure-related symptoms.

Predictors of renal recovery in patients with pre-orthotopic liver transplant (OLT) renal dysfunction

PubMed Central

2013-01-01

Background Renal dysfunction occurs commonly in patients awaiting orthotopic liver transplantation (OLT) for end-stage liver disease. The use of simultaneous liver-kidney transplantation has increased in the MELD scoring era. As patients may recover renal function after OLT, identifying factors predictive of renal recovery is a critical issue, especially given the scarcity of available organs. Methods Employing the UNOS database, we sought to identify donor- and patient-related predictors of renal recovery among 1720 patients with pre-OLT renal dysfunction and transplanted from 1989 to 2005. Recovery of renal function post-OLT was defined as a composite endpoint of serum creatinine (SCr) ≤1.5 mg/dL at discharge and survival ≥29 days. Pre-OLT renal dysfunction was defined as any of the following: SCr ≥2 mg/dL at any time while awaiting OLT or need for renal replacement therapy (RRT) at the time of registration and/or OLT. Results Independent predictors of recovery of renal function post-OLT were absence of hepatic allograft dysfunction, transplantation during MELD era, recipient female sex, decreased donor age, decreased recipient ALT at time of OLT, decreased recipient body mass index at registration, use of anti-thymocyte globulin as induction therapy, and longer wait time from registration. Contrary to popular belief, a requirement for RRT, even for prolonged periods in excess of 8 weeks, was not an independent predictor of failure to recover renal function post-OLT. Conclusion These data indicate that the duration of renal dysfunction, even among those requiring RRT, is a poor way to discriminate reversible from irreversible renal dysfunction. PMID:23849513

Correlation between plasma endothelin-1 levels and severity of septic liver failure quantified by maximal liver function capacity (LiMAx test). A prospective study.

PubMed

Kaffarnik, Magnus F; Ahmadi, Navid; Lock, Johan F; Wuensch, Tilo; Pratschke, Johann; Stockmann, Martin; Malinowski, Maciej

2017-01-01

To investigate the relationship between the degree of liver dysfunction, quantified by maximal liver function capacity (LiMAx test) and endothelin-1, TNF-α and IL-6 in septic surgical patients. 28 septic patients (8 female, 20 male, age range 35-80y) were prospectively investigated on a surgical intensive care unit. Liver function, defined by LiMAx test, and measurements of plasma levels of endothelin-1, TNF-α and IL-6 were carried out within the first 24 hours after onset of septic symptoms, followed by day 2, 5 and 10. Patients were divided into 2 groups (group A: LiMAx ≥100 μg/kg/h, moderate liver dysfunction; group B: LiMAx <100 μg/kg/h, severe liver dysfunction) for analysis and investigated regarding the correlation between endothelin-1 and the severity of liver failure, quantified by LiMAx test. Group B showed significant higher results for endothelin-1 than patients in group A (P = 0.01, d5; 0.02, d10). For TNF-α, group B revealed higher results than group A, with a significant difference on day 10 (P = 0.005). IL-6 showed a non-significant trend to higher results in group B. The Spearman's rank correlation coefficient revealed a significant correlation between LiMAx and endothelin-1 (-0.434; P <0.001), TNF-α (-0.515; P <0.001) and IL-6 (-0.590; P <0.001). Sepsis-related hepatic dysfunction is associated with elevated plasma levels of endothelin-1, TNF-α and IL-6. Low LiMAx results combined with increased endothelin-1 and TNF-α and a favourable correlation between LiMAx and cytokine values support the findings of a crucial role of Endothelin-1 and TNF-α in development of septic liver failure.

Correlation between plasma endothelin-1 levels and severity of septic liver failure quantified by maximal liver function capacity (LiMAx test). A prospective study

PubMed Central

Kaffarnik, Magnus F.; Ahmadi, Navid; Lock, Johan F.; Wuensch, Tilo; Pratschke, Johann; Stockmann, Martin; Malinowski, Maciej

2017-01-01

Aim To investigate the relationship between the degree of liver dysfunction, quantified by maximal liver function capacity (LiMAx test) and endothelin-1, TNF-α and IL-6 in septic surgical patients. Methods 28 septic patients (8 female, 20 male, age range 35–80y) were prospectively investigated on a surgical intensive care unit. Liver function, defined by LiMAx test, and measurements of plasma levels of endothelin-1, TNF-α and IL-6 were carried out within the first 24 hours after onset of septic symptoms, followed by day 2, 5 and 10. Patients were divided into 2 groups (group A: LiMAx ≥100 μg/kg/h, moderate liver dysfunction; group B: LiMAx <100 μg/kg/h, severe liver dysfunction) for analysis and investigated regarding the correlation between endothelin-1 and the severity of liver failure, quantified by LiMAx test. Results Group B showed significant higher results for endothelin-1 than patients in group A (P = 0.01, d5; 0.02, d10). For TNF-α, group B revealed higher results than group A, with a significant difference on day 10 (P = 0.005). IL-6 showed a non-significant trend to higher results in group B. The Spearman's rank correlation coefficient revealed a significant correlation between LiMAx and endothelin-1 (-0.434; P <0.001), TNF-α (-0.515; P <0.001) and IL-6 (-0.590; P <0.001). Conclusions Sepsis-related hepatic dysfunction is associated with elevated plasma levels of endothelin-1, TNF-α and IL-6. Low LiMAx results combined with increased endothelin-1 and TNF-α and a favourable correlation between LiMAx and cytokine values support the findings of a crucial role of Endothelin-1 and TNF-α in development of septic liver failure. PMID:28542386

Hepatotoxicity and endothelial dysfunction induced by high choline diet and the protective effects of phloretin in mice.

PubMed

Ren, Daoyuan; Liu, Yafei; Zhao, Yan; Yang, Xingbin

2016-08-01

The involvement of choline and its metabolite trimethylamine-N-oxide (TMAO) in endothelial dysfunction and atherosclerosis has been repeatedly confirmed. Phloretin, a dihydrochalcone flavonoid usually present in apples, possesses a variety of biological activities including vascular nutrition. This study was designed to investigate whether phloretin could alleviate or prevent high choline-induced vascular endothelial dysfunction and liver injury in mice. Mice were provided with 3% high choline water and given phloretin orally daily for 10 weeks. The high choline-treated mice showed the significant dyslipidemia and hyperglycemia with the impaired liver and vascular endothelium (p < 0.01). Administration of phloretin at 200 and 400 mg/kg bw significantly reduced the choline-induced elevation of serum TC, TG, LDL-C, AST, ALT, ET-1 and TXA2 (p < 0.01), and markedly antagonized the choline-induced decrease of serum PGI2, HDL-C and NO levels. Furthermore, phloretin elevated hepatic SOD and GSH-Px activities and decreased hepatic MDA levels of the mice exposed to high choline water. Moreover, histopathological test with the H&E and Oil Red O staining of liver sections confirmed the high choline diet-caused liver steatosis and the hepatoprotective effect of phloretin. These findings suggest that high choline causes oxidative damage, and phloretin alleviate vascular endothelial dysfunction and liver injury. Copyright © 2016 Elsevier Ltd. All rights reserved.

Increased expression of stathmin and elongation factor 1α in precancerous nodules with telomere dysfunction in hepatitis B viral cirrhotic patients

PubMed Central

2014-01-01

Background Telomere dysfunction is important in carcinogenesis, and recently, stathmin and elongation factor 1α (EF1α) were reported to be up-regulated in telomere dysfunctional mice. Methods In the present study, the expression levels of stathmin and EF1α in relation to telomere length, telomere dysfunction-induced foci (TIF), γ-H2AX, and p21WAF1/CIP1 expression were assessed in specimens of hepatitis B virus (HBV)-related multistep hepatocarcinogenesis, including 13 liver cirrhosis specimens, 14 low-grade dysplastic nodules (DN), 17 high-grade DNs, and 14 hepatocellular carcinomas (HCC). Five normal liver specimens were used as controls. TIF were analyzed by telomere fluorescent in situ hybridization (FISH) combined with immunostaining, while the protein expressions of stathmin, EF1α, γ-H2AX, and p21WAF1/CIP1 were detected by immunohistochemistry. Result The expressions of stathmin and EF1α gradually increased as multistep hepatocarcinogenesis progressed, showing the highest levels in HCC. Stathmin mRNA levels were higher in high-grade DNs than normal liver and liver cirrhosis, whereas EF1α mRNA expression did not show such a difference. The protein expressions of stathmin and EF1α were found in DNs of precancerous lesions, whereas they were absent or present at very low levels in normal liver and liver cirrhosis. Stathmin histoscores were higher in high-grade DNs and low-grade DNs than in normal liver (all, P < 0.05). EF1α histoscores were higher in high-grade DNs than in normal liver and liver cirrhosis (all, P < 0.05). Stathmin mRNA levels and histoscores, as well as EF1α histoscores (but not mRNA levels), were positively correlated with telomere shortening and γ-H2AX labeling index (all, P < 0.05). EF1α histoscores were also positively correlated with TIF (P < 0.001). Significantly greater inactivation of p21WAF1/CIP1 was observed in low-grade DNs, high-grade DNs, and HCC, compared to liver cirrhosis (all, P < 0.05). p21WAF1/CIP1 labeling index was inversely correlated with TIF, stathmin mRNA level, and EF1α histoscore (all, P < 0.05). Conclusion Stathmin and EF1α are suggested to be closely related to telomere dysfunction, DNA damage, and inactivation of p21WAF1/CIP1 in HBV-related multistep hepatocarcinogenesis. Accordingly, assessment of stathmin and EF1α levels as a reflection of telomere dysfunction may be helpful in evaluating the biological characteristics of precancerous hepatic nodules in hepatitis B viral cirrhotic patients. PMID:24885363

Increased expression of stathmin and elongation factor 1α in precancerous nodules with telomere dysfunction in hepatitis B viral cirrhotic patients.

PubMed

Ahn, Ei Yong; Yoo, Jeong Eun; Rhee, Hyungjin; Kim, Myung Soo; Choi, Junjeong; Ko, Jung Eun; Lee, Jee San; Park, Young Nyun

2014-05-31

Telomere dysfunction is important in carcinogenesis, and recently, stathmin and elongation factor 1α (EF1α) were reported to be up-regulated in telomere dysfunctional mice. In the present study, the expression levels of stathmin and EF1α in relation to telomere length, telomere dysfunction-induced foci (TIF), γ-H2AX, and p21WAF1/CIP1 expression were assessed in specimens of hepatitis B virus (HBV)-related multistep hepatocarcinogenesis, including 13 liver cirrhosis specimens, 14 low-grade dysplastic nodules (DN), 17 high-grade DNs, and 14 hepatocellular carcinomas (HCC). Five normal liver specimens were used as controls. TIF were analyzed by telomere fluorescent in situ hybridization (FISH) combined with immunostaining, while the protein expressions of stathmin, EF1α, γ-H2AX, and p21WAF1/CIP1 were detected by immunohistochemistry. The expressions of stathmin and EF1α gradually increased as multistep hepatocarcinogenesis progressed, showing the highest levels in HCC. Stathmin mRNA levels were higher in high-grade DNs than normal liver and liver cirrhosis, whereas EF1α mRNA expression did not show such a difference. The protein expressions of stathmin and EF1α were found in DNs of precancerous lesions, whereas they were absent or present at very low levels in normal liver and liver cirrhosis. Stathmin histoscores were higher in high-grade DNs and low-grade DNs than in normal liver (all, P<0.05). EF1α histoscores were higher in high-grade DNs than in normal liver and liver cirrhosis (all, P<0.05). Stathmin mRNA levels and histoscores, as well as EF1α histoscores (but not mRNA levels), were positively correlated with telomere shortening and γ-H2AX labeling index (all, P<0.05). EF1α histoscores were also positively correlated with TIF (P<0.001). Significantly greater inactivation of p21WAF1/CIP1 was observed in low-grade DNs, high-grade DNs, and HCC, compared to liver cirrhosis (all, P<0.05). p21WAF1/CIP1 labeling index was inversely correlated with TIF, stathmin mRNA level, and EF1α histoscore (all, P<0.05). Stathmin and EF1α are suggested to be closely related to telomere dysfunction, DNA damage, and inactivation of p21WAF1/CIP1 in HBV-related multistep hepatocarcinogenesis. Accordingly, assessment of stathmin and EF1α levels as a reflection of telomere dysfunction may be helpful in evaluating the biological characteristics of precancerous hepatic nodules in hepatitis B viral cirrhotic patients.

Advanced Hepatocellular Carcinoma: Which Staging Systems Best Predict Prognosis?

PubMed Central

Huitzil-Melendez, Fidel-David; Capanu, Marinela; O'Reilly, Eileen M.; Duffy, Austin; Gansukh, Bolorsukh; Saltz, Leonard L.; Abou-Alfa, Ghassan K.

2010-01-01

Purpose The purpose of cancer staging systems is to accurately predict patient prognosis. The outcome of advanced hepatocellular carcinoma (HCC) depends on both the cancer stage and the extent of liver dysfunction. Many staging systems that include both aspects have been developed. It remains unknown, however, which of these systems is optimal for predicting patient survival. Patients and Methods Patients with advanced HCC treated over a 5-year period at Memorial Sloan-Kettering Cancer Center were identified from an electronic medical record database. Patients with sufficient data for utilization in all staging systems were included. TNM sixth edition, Okuda, Barcelona Clinic Liver Cancer (BCLC), Cancer of the Liver Italian Program (CLIP), Chinese University Prognostic Index (CUPI), Japan Integrated Staging (JIS), and Groupe d'Etude et de Traitement du Carcinome Hepatocellulaire (GETCH) systems were ranked on the basis of their accuracy at predicting survival by using concordance index (c-index). Other independent prognostic variables were also identified. Results Overall, 187 eligible patients were identified and were staged by using the seven staging systems. CLIP, CUPI, and GETCH were the three top-ranking staging systems. BCLC and TNM sixth edition lacked any meaningful prognostic discrimination. Performance status, AST, abdominal pain, and esophageal varices improved the discriminatory ability of CLIP. Conclusion In our selected patient population, CLIP, CUPI, and GETCH were the most informative staging systems in predicting survival in patients with advanced HCC. Prospective validation is required to determine if they can be accurately used to stratify patients in clinical trials and to direct the appropriate need for systemic therapy versus best supportive care. BCLC and TNM sixth edition were not helpful in predicting survival outcome, and their use is not supported by our data. PMID:20458042

Risk factors of hepatic dysfunction in patients with Graves’ hyperthyroidism and the efficacy of 131iodine treatment

PubMed Central

Wang, Renfei; Tan, Jian; Zhang, Guizhi; Zheng, Wei; Li, Chengxia

2017-01-01

Abstract Hepatic dysfunction is often observed in patients with Graves’ hyperthyroidism. The aims of this study were to investigate the risk factors for hepatic dysfunction and to analyze the efficacy of 131I (radioactive iodine-131) treatment. In total, 2385 patients with Graves’ hyperthyroidism (478 males, 1907 females; age 42.8 ± 13.5 years) were involved in our study. Of these, 1552 cases with hepatic dysfunction received 131I treatment. All clinical data were retrospectively reviewed to explore the risk factors associated with hepatic dysfunction using logistic regression analysis. Furthermore, we observed thyroid and liver function indices for the 1552 subjects at 3, 6 and 12 months after 131I treatment, in order to evaluate efficacy. Overall, 65% patients were affected by hepatic dysfunction. The most common abnormality was elevated alkaline phosphatase (ALP), of which the prevalence was 52.3%. The percentages of hepatocellular injury type, bile stasis, and mixed type were 45.8%, 32.4%, and 21.8%, respectively. Both univariate and multivariate analyses demonstrated that age, duration of Graves hyperthyroidism, free triiodothyronine (FT3)level, and thyrotrophin receptor antibody (TRAb) concentration were the most significant risk factors predicting hepatic dysfunction. Additionally, the patients with mild hepatic dysfunction, or hepatocellular injury type were more likely to attain normal liver function after 131I treatment. Furthermore, after 131I treatment, liver function was more likely to return to normal in the cured group of patients compared with the uncured group. Older patients and cases with a longer history of Graves’ hyperthyroidism, higher FT3 or TRAb concentration were more likely to be associated with hepatic dysfunction, and the prognosis of hepatic dysfunction was closely associated with the outcomes of Graves’ hyperthyroidism after 131I treatment. PMID:28151911

Risk factors and outcomes of acute kidney injury in patients with acute liver failure.

PubMed

Tujios, Shannan R; Hynan, Linda S; Vazquez, Miguel A; Larson, Anne M; Seremba, Emmanuel; Sanders, Corron M; Lee, William M

2015-02-01

Patients with acute liver failure (ALF) frequently develop renal dysfunction, yet its overall incidence and outcomes have not been fully assessed. We investigated the incidence of acute kidney injury (AKI) among patients with ALF, using defined criteria to identify risk factors and to evaluate its effect on overall outcomes. We performed a retrospective review of data from 1604 patients enrolled in the Acute Liver Failure Study Group, from 1998 through 2010. Patients were classified by the Acute Kidney Injury Network criteria, as well as for etiology of liver failure (acetaminophen-based, ischemic, and all others). Seventy percent of patients with ALF developed AKI, and 30% received renal replacement therapy (RRT). Patients with severe AKI had higher international normalized ratio values than those without renal dysfunction (P < .001), and a higher proportion had advanced-grade coma (coma grades 3 or 4; P < .001) or presented with hypotension requiring vasopressor therapy (P < .001). A greater proportion of patients with acetaminophen-induced ALF had severe kidney injury than of patients with other etiologies of ALF; 34% required RRT, compared with 25% of patients with ALF not associated with acetaminophen or ischemia (P < .002). Of the patients with ALF who were alive at 3 weeks after study entry, significantly fewer with AKI survived for 1 year. Although AKI reduced the overall survival time, more than 50% of patients with acetaminophen-associated or ischemic ALF survived without liver transplantation (even with RRT), compared with 19% of patients with ALF attribute to other causes (P < .001). Only 4% of patients requiring RRT became dependent on dialysis. Based on a retrospective analysis of data from more than 1600 patients, AKI is common in patients with ALF and affects short- and long-term outcomes, but rarely results in chronic kidney disease. Acetaminophen-induced kidney injury is frequent, but patients have better outcomes than those with other forms of ALF. Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.

An mtDNA mutation accelerates liver aging by interfering with the ROS response and mitochondrial life cycle.

PubMed

Niemann, Jan; Johne, Cindy; Schröder, Susanne; Koch, Franziska; Ibrahim, Saleh M; Schultz, Julia; Tiedge, Markus; Baltrusch, Simone

2017-01-01

Mitochondrial dysfunction affects liver metabolism, but it remains unclear whether this interferes with normal liver aging. We investigated several mitochondrial pathways in hepatocytes and liver tissue from a conplastic mouse strain compared with the control C57BL/6NTac strain over 18 months of life. The C57BL/6NTac-mtNODLtJ mice differed from C57BL/6NTac mice by a point mutation in mitochondrial-encoded subunit 3 of cytochrome c oxidase. Young C57BL/6NTac-mtNODLtJ mice showed reduced mitochondrial metabolism but similar reactive oxygen species (ROS) production to C57BL/6NTac mice. Whereas ROS increased almost equally up to 9 months in both strains, different mitochondrial adaptation strategies resulted in decreasing ROS in advanced age in C57BL/6NTac mice, but persistent ROS production in C57BL/6NTac-mtNODLtJ mice. Only the conplastic strain developed elongated mitochondrial networks with artificial loop structures, depressed autophagy, high mitochondrial respiration and up-regulated antioxidative response. Our results indicate that mtDNA mutations accelerate liver ballooning degeneration and carry a serious risk of premature organ aging. Copyright © 2016 Elsevier Inc. All rights reserved.

CXCL4 Contributes to the Pathogenesis of Chronic Liver Allograft Dysfunction

PubMed Central

Li, Jing; Shi, Yuan; Xie, Ke-Liang; Yin, Hai-Fang; Yan, Lu-nan; Lau, Wan-yee; Wang, Guo-Lin

2016-01-01

Chronic liver allograft dysfunction (CLAD) remains the most common cause of patient morbidity and allograft loss in liver transplant patients. However, the pathogenesis of CLAD has not been completely elucidated. By establishing rat CLAD models, in this study, we identified the informative CLAD-associated genes using isobaric tags for relative and absolute quantification (iTRAQ) proteomics analysis and validated these results in recipient rat liver allografts. CXCL4, CXCR3, EGFR, JAK2, STAT3, and Collagen IV were associated with CLAD pathogenesis. We validated that CXCL4 is upstream of these informative genes in the isolated hepatic stellate cells (HSC). Blocking CXCL4 protects against CLAD by reducing liver fibrosis. Therefore, our results indicated that therapeutic approaches that neutralize CXCL4, a newly identified target of fibrosis, may represent a novel strategy for preventing and treating CLAD after liver transplantation. PMID:28053995

CXCL4 Contributes to the Pathogenesis of Chronic Liver Allograft Dysfunction.

PubMed

Li, Jing; Liu, Bin; Shi, Yuan; Xie, Ke-Liang; Yin, Hai-Fang; Yan, Lu-Nan; Lau, Wan-Yee; Wang, Guo-Lin

2016-01-01

Chronic liver allograft dysfunction (CLAD) remains the most common cause of patient morbidity and allograft loss in liver transplant patients. However, the pathogenesis of CLAD has not been completely elucidated. By establishing rat CLAD models, in this study, we identified the informative CLAD-associated genes using isobaric tags for relative and absolute quantification (iTRAQ) proteomics analysis and validated these results in recipient rat liver allografts. CXCL4, CXCR3, EGFR, JAK2, STAT3, and Collagen IV were associated with CLAD pathogenesis. We validated that CXCL4 is upstream of these informative genes in the isolated hepatic stellate cells (HSC). Blocking CXCL4 protects against CLAD by reducing liver fibrosis. Therefore, our results indicated that therapeutic approaches that neutralize CXCL4, a newly identified target of fibrosis, may represent a novel strategy for preventing and treating CLAD after liver transplantation.

Correlation of serum liver fibrosis markers with severity of liver dysfunction in liver cirrhosis: a retrospective cross-sectional study

PubMed Central

Zhu, Cuihong; Qi, Xingshun; Li, Hongyu; Peng, Ying; Dai, Junna; Chen, Jiang; Xia, Chunlian; Hou, Yue; Zhang, Wenwen; Guo, Xiaozhong

2015-01-01

Hyaluronic acid (HA), laminin (LN), amino-terminal pro-peptide of type III pro-collagen (PIIINP), and collagen IV (CIV) are four major serum markers of liver fibrosis. This retrospective cross-sectional study aimed to evaluate the correlations of the four serum markers with the severity of liver dysfunction in cirrhotic patients. Between January 2013 and June 2014, a total of 228 patients with a clinical diagnosis with liver cirrhosis and without malignancy underwent the tests of HA, LN, PIIINP, and CIV levels. Laboratory data were collected. Child-Pugh and model for the end-stage of liver diseases (MELD) scores were calculated. Of them, 32%, 40%, and 18% had Child-Pugh class A, B, and C, respectively. MELD score was 7.58±0.50. HA (coefficient r: 0.1612, P=0.0203), LN (coefficient r: 0.2445, P=0.0004), and CIV (coefficient r: 0.2361, P=0.0006) levels significantly correlated with Child-Pugh score, but not PIIINP level. Additionally, LN (coefficient r: 0.2588, P=0.0002) and CIV (coefficient r: 0.1795, P=0.0108) levels significantly correlated with MELD score, but not HA or PIIINP level. In conclusions, HA, LN, and CIV levels might be positively associated with the severity of liver dysfunction in cirrhotic patients. However, given a relatively weak correlation between them, our findings should be cautiously interpreted and further validated. PMID:26131195

Magnetic resonance imaging measurement of iron overload

PubMed Central

Wood, John C.

2010-01-01

Purpose of review To highlight recent advances in magnetic resonance imaging estimation of somatic iron overload. This review will discuss the need and principles of magnetic resonance imaging-based iron measurements, the validation of liver and cardiac iron measurements, and the key institutional requirements for implementation. Recent findings Magnetic resonance imaging assessment of liver and cardiac iron has achieved critical levels of availability, utility, and validity to serve as the primary endpoint of clinical trials. Calibration curves for the magnetic resonance imaging parameters R2 and R2* (or their reciprocals, T2 and T2*) have been developed for the liver and the heart. Interscanner variability for these techniques has proven to be on the order of 5–7%. Summary Magnetic resonance imaging assessment of tissue iron is becoming increasingly important in the management of transfusional iron load because it is noninvasive, relatively widely available and offers a window into presymptomatic organ dysfunction. The techniques are highly reproducible within and across machines and have been chemically validated in the liver and the heart. These techniques will become the standard of care as industry begins to support the acquisition and postprocessing software. PMID:17414205

"Non alcoholic fatty liver disease and eNOS dysfunction in humans".

PubMed

Persico, Marcello; Masarone, Mario; Damato, Antonio; Ambrosio, Mariateresa; Federico, Alessandro; Rosato, Valerio; Bucci, Tommaso; Carrizzo, Albino; Vecchione, Carmine

2017-03-07

NAFLD is associated to Insulin Resistance (IR). IR is responsible for Endothelial Dysfunction (ED) through the impairment of eNOS function. Although eNOS derangement has been demonstrated in experimental models, no studies have directly shown that eNOS dysfunction is associated with NAFLD in humans. The aim of this study is to investigate eNOS function in NAFLD patients. Fifty-four NAFLD patients were consecutively enrolled. All patients underwent clinical and laboratory evaluation and liver biopsy. Patients were divided into two groups by the presence of NAFL or NASH. We measured vascular reactivity induced by patients' platelets on isolated mice aorta rings. Immunoblot assays for platelet-derived phosphorylated-eNOS (p-eNOS) and immunohistochemistry for hepatic p-eNOS have been performed to evaluate eNOS function in platelets and liver specimens. Flow-mediated-dilation (FMD) was also performed. Data were compared with healthy controls. Twenty-one (38, 8%) patients had NAFL and 33 (61, 7%) NASH. No differences were found between groups and controls except for HOMA and insulin (p < 0.0001). Vascular reactivity demonstrated a reduced function induced from NAFLD platelets as compared with controls (p < 0.001), associated with an impaired p-eNOS in both platelets and liver (p < 0.001). NAFL showed a higher impairment of eNOS phosphorylation in comparison to NASH (p < 0.01). In contrast with what observed in vitro, the vascular response by FMD was worse in NASH as compared with NAFL. Our data showed, for the first time in humans, that NAFLD patients show a marked eNOS dysfunction, which may contribute to a higher CV risk. eNOS dysfunction observed in platelets and liver tissue didn't match with FMD.

Physiological Ranges of Matrix Rigidity Modulate Primary Mouse Hepatocyte Function In Part Through Hepatocyte Nuclear Factor 4 Alpha

PubMed Central

Desai, Seema S.; Tung, Jason C.; Zhou, Vivian X.; Grenert, James P.; Malato, Yann; Rezvani, Milad; Español-Suñer, Regina; Willenbring, Holger; Weaver, Valerie M.; Chang, Tammy T.

2016-01-01

Matrix rigidity has important effects on cell behavior and is increased during liver fibrosis; however, its effect on primary hepatocyte function is unknown. We hypothesized that increased matrix rigidity in fibrotic livers would activate mechanotransduction in hepatocytes and lead to inhibition of hepatic-specific functions. To determine the physiologically relevant ranges of matrix stiffness at the cellular level, we performed detailed atomic force microscopy analysis across liver lobules from normal and fibrotic livers. We determined that normal liver matrix stiffness was around 150Pa and increased to 1–6kPa in areas near fibrillar collagen deposition in fibrotic livers. In vitro culture of primary hepatocytes on collagen matrix of tunable rigidity demonstrated that fibrotic levels of matrix stiffness had profound effects on cytoskeletal tension and significantly inhibited hepatocyte-specific functions. Normal liver stiffness maintained functional gene regulation by hepatocyte nuclear factor 4 alpha (HNF4α) whereas fibrotic matrix stiffness inhibited the HNF4α transcriptional network. Fibrotic levels of matrix stiffness activated mechanotransduction in primary hepatocytes through focal adhesion kinase (FAK). In addition, blockade of the Rho/Rho-associated protein kinase (ROCK) pathway rescued HNF4α expression from hepatocytes cultured on stiff matrix. Conclusion Fibrotic levels of matrix stiffness significantly inhibit hepatocyte-specific functions in part by inhibiting the HNF4α transcriptional network mediated through the Rho/ROCK pathway. Increased appreciation of the role of matrix rigidity in modulating hepatocyte function will advance our understanding of the mechanisms of hepatocyte dysfunction in liver cirrhosis and spur development of novel treatments for chronic liver disease. PMID:26755329

Cabozantinib-induced thyroid dysfunction: a review of two ongoing trials for metastatic bladder cancer and sarcoma.

PubMed

Yavuz, Sahzene; Apolo, Andrea B; Kummar, Shivaani; del Rivero, Jaydira; Madan, Ravi A; Shawker, Thomas; Reynolds, James; Celi, Francesco S

2014-08-01

Thyroid dysfunction is a common adverse event associated with tyrosine kinase inhibitors (TKI), but its underlying pathophysiology is unclear. Cabozantinib is a novel TKI currently Food and Drug Administration approved for advanced medullary thyroid cancer and tested in clinical trials on solid tumors including prostate, liver, bladder, breast, and ovarian cancer. We analyzed the thyroid function of patients enrolled in two phase 2 clinical trials using cabozantinib at the National Institutes of Health Clinical Center. Two cases of thyroiditis associated with cabozantinib therapy are presented in detail, and a systematic review of the literature on TKI-associated thyroid dysfunction is also discussed. Between September 2012 and September 2013, 33 patients were treated with cabozantinib, and follow-up thyroid function tests were available for 31 (20 males, 11 females; age 59±1 years). Thyroid dysfunction was recorded in the majority of patients (93.1%), with a predominance of subclinical hypothyroidism. Two cases showed a biphasic pattern of thyroid dysfunction characterized by a transient thyrotoxicosis followed by hypothyroidism. Color Doppler demonstrated an increase in vascularization during the thyrotoxic phase, but no uptake was visualized on nuclear medicine imaging. A systematic review of the literature resulted in the identification of 40 original manuscripts, of which 13 were case series and 6 were case reports describing TKI-associated thyroid dysfunction. TKI therapy often results in clinically significant thyroid dysfunction. Cabozantinib treatment commonly results in thyroid dysfunction varying from subclinical hypothyroidism to symptomatic thyrotoxicosis. Early detection and characterization of cabozantinib-associated thyroid dysfunction and close follow-up are essential to provide adequate management of this common adverse event.

Cabozantinib-Induced Thyroid Dysfunction: A Review of Two Ongoing Trials for Metastatic Bladder Cancer and Sarcoma

PubMed Central

Yavuz, Sahzene; Apolo, Andrea B.; Kummar, Shivaani; del Rivero, Jaydira; Madan, Ravi A.; Shawker, Thomas; Reynolds, James

2014-01-01

Background: Thyroid dysfunction is a common adverse event associated with tyrosine kinase inhibitors (TKI), but its underlying pathophysiology is unclear. Cabozantinib is a novel TKI currently Food and Drug Administration approved for advanced medullary thyroid cancer and tested in clinical trials on solid tumors including prostate, liver, bladder, breast, and ovarian cancer. Methods: We analyzed the thyroid function of patients enrolled in two phase 2 clinical trials using cabozantinib at the National Institutes of Health Clinical Center. Two cases of thyroiditis associated with cabozantinib therapy are presented in detail, and a systematic review of the literature on TKI-associated thyroid dysfunction is also discussed. Results: Between September 2012 and September 2013, 33 patients were treated with cabozantinib, and follow-up thyroid function tests were available for 31 (20 males, 11 females; age 59±1 years). Thyroid dysfunction was recorded in the majority of patients (93.1%), with a predominance of subclinical hypothyroidism. Two cases showed a biphasic pattern of thyroid dysfunction characterized by a transient thyrotoxicosis followed by hypothyroidism. Color Doppler demonstrated an increase in vascularization during the thyrotoxic phase, but no uptake was visualized on nuclear medicine imaging. A systematic review of the literature resulted in the identification of 40 original manuscripts, of which 13 were case series and 6 were case reports describing TKI-associated thyroid dysfunction. Conclusion: TKI therapy often results in clinically significant thyroid dysfunction. Cabozantinib treatment commonly results in thyroid dysfunction varying from subclinical hypothyroidism to symptomatic thyrotoxicosis. Early detection and characterization of cabozantinib-associated thyroid dysfunction and close follow-up are essential to provide adequate management of this common adverse event. PMID:24724719

Physiological ranges of matrix rigidity modulate primary mouse hepatocyte function in part through hepatocyte nuclear factor 4 alpha.

PubMed

Desai, Seema S; Tung, Jason C; Zhou, Vivian X; Grenert, James P; Malato, Yann; Rezvani, Milad; Español-Suñer, Regina; Willenbring, Holger; Weaver, Valerie M; Chang, Tammy T

2016-07-01

Matrix rigidity has important effects on cell behavior and is increased during liver fibrosis; however, its effect on primary hepatocyte function is unknown. We hypothesized that increased matrix rigidity in fibrotic livers would activate mechanotransduction in hepatocytes and lead to inhibition of liver-specific functions. To determine the physiologically relevant ranges of matrix stiffness at the cellular level, we performed detailed atomic force microscopy analysis across liver lobules from normal and fibrotic livers. We determined that normal liver matrix stiffness was around 150 Pa and increased to 1-6 kPa in areas near fibrillar collagen deposition in fibrotic livers. In vitro culture of primary hepatocytes on collagen matrix of tunable rigidity demonstrated that fibrotic levels of matrix stiffness had profound effects on cytoskeletal tension and significantly inhibited hepatocyte-specific functions. Normal liver stiffness maintained functional gene regulation by hepatocyte nuclear factor 4 alpha (HNF4α), whereas fibrotic matrix stiffness inhibited the HNF4α transcriptional network. Fibrotic levels of matrix stiffness activated mechanotransduction in primary hepatocytes through focal adhesion kinase. In addition, blockade of the Rho/Rho-associated protein kinase pathway rescued HNF4α expression from hepatocytes cultured on stiff matrix. Fibrotic levels of matrix stiffness significantly inhibit hepatocyte-specific functions in part by inhibiting the HNF4α transcriptional network mediated through the Rho/Rho-associated protein kinase pathway. Increased appreciation of the role of matrix rigidity in modulating hepatocyte function will advance our understanding of the mechanisms of hepatocyte dysfunction in liver cirrhosis and spur development of novel treatments for chronic liver disease. (Hepatology 2016;64:261-275). © 2016 by the American Association for the Study of Liver Diseases.

Anesthesia for Patients With Liver Disease

PubMed Central

Rahimzadeh, Poupak; Safari, Saeid; Faiz, Seyed Hamid Reza; Alavian, Seyed Moayed

2014-01-01

Context: Liver plays an important role in metabolism and physiological homeostasis in the body. This organ is unique in its structure and physiology. So it is necessary for an anesthesiologist to be familiar with various hepatic pathophysiologic conditions and consequences of liver dysfunction. Evidence Acquisition: We searched MEDLINE (Pub Med, OVID, MD Consult), SCOPUS and the Cochrane database for the following keywords: liver disease, anesthesia and liver disease, regional anesthesia in liver disease, epidural anesthesia in liver disease and spinal anesthesia in liver disease, for the period of 1966 to 2013. Results: Although different anesthetic regimens are available in modern anesthesia world, but anesthetizing the patients with liver disease is still really tough. Spinal or epidural anesthetic effects on hepatic blood flow and function is not clearly investigated, considering both the anesthetic drug-induced changes and outcomes. Regional anesthesia might be used in patients with advanced liver disease. In these cases lower drug dosages are used, considering the fact that locally administered drugs have less systemic effects. In case of general anesthesia it seems that using inhalation agents (Isoflurane, Desflurane or Sevoflurane), alone or in combination with small doses of fentanyl can be considered as a reasonable regimen. When administering drugs, anesthetist must realize and consider the substantially changed pharmacokinetics of some other anesthetic drugs. Conclusions: Despite the fact that anesthesia in chronic liver disease is a scary and pretty challenging condition for every anesthesiologist, this hazard could be diminished by meticulous attention on optimizing the patient’s condition preoperatively and choosing appropriate anesthetic regimen and drugs in this setting. Although there are paucity of statistics and investigations in this specific group of patients but these little data show that with careful monitoring and considering the above mentioned rules a safe anesthesia could be achievable in these patients. PMID:25031586

Sexual dysfunction after liver transplantation.

PubMed

Burra, Patrizia

2009-11-01

1. The goal of liver transplantation is not only to ensure the survival of patients but also to offer patients the opportunity to achieve a good balance between the functional efficacy of the graft and their psychological and physical integrity. The quality of life after transplantation may be affected by unsatisfactory sexual activity and reproductive performance. 2. Sexual dysfunction and sex hormone disturbances are widely reported in men and women with chronic liver disease before liver transplantation. 3. Successful liver transplantation should lead to improvements in sexual function and sex hormone disturbances in both men and women, therefore improving reproductive performance, but immunosuppressive drugs may interfere with hormone metabolism. 4. Pregnancy is often successful after liver transplantation, despite the potentially toxic effects of immunosuppressive drug therapy, but fetal and maternal outcomes should be regularly assessed. 5. More detailed and comprehensive data are needed in the field of sexual function after transplantation, and new strategies are needed to support and inform patients on the waiting list and after liver transplantation. (c) 2009 AASLD.

Gastrointestinal dysfunction in liver cirrhosis

PubMed Central

Kalaitzakis, Evangelos

2014-01-01

Patients with liver cirrhosis exhibit several features of gut dysfunction which may contribute to the development of cirrhosis complications as well as have an impact on nutritional status and health-related quality of life. Gastrointestinal symptoms are common in cirrhosis and their pathophysiology probably involves factors related to liver disease severity, psychological distress, and gut dysfunction (e.g., increased gastric sensitivity to distension and delayed gut transit). They may lead to reduced food intake and, thus, may contribute to the nutritional status deterioration in cirrhotic patients. Although tense ascites appears to have a negative impact on meal-induced accommodation of the stomach, published data on gastric accommodation in cirrhotics without significant ascites are not unanimous. Gastric emptying and small bowel transit have generally been shown to be prolonged. This may be related to disturbances in postprandial glucose, insulin, and ghrelin levels, which, in turn, appear to be associated to insulin resistance, a common finding in cirrhosis. Furthermore, small bowel manometry disturbances and delayed gut transit may be associated with the development of small bowel bacterial overgrowth. Finally, several studies have reported intestinal barrier dysfunction in patients with cirrhosis (especially those with portal hypertension), which is related to bacterial translocation and permeation of intestinal bacterial products, e.g., endotoxin and bacterial DNA, thus potentially being involved in the pathogenesis of complications of liver cirrhosis. PMID:25356031

Ammonia-induced mitochondrial dysfunction and energy metabolism disturbances in isolated brain and liver mitochondria, and the effect of taurine administration: relevance to hepatic encephalopathy treatment

PubMed Central

Niknahad, Hossein; Jamshidzadeh, Akram; Zarei, Mahdi; Ommati, Mohammad Mehdi

2017-01-01

Introduction Ammonia-induced oxidative stress, mitochondrial dysfunction, and energy crisis are known as some the major mechanisms of brain injury in hepatic encephalopathy (HE). Hyperammonemia also affects the liver and hepatocytes. Therefore, targeting mitochondria seems to be a therapeutic point of intervention in the treatment of HE. Taurine is an abundant amino acid in the human body. Several biological functions including the mitochondrial protective properties are attributed to this amino acid. The aim of this study is to evaluate the effect of taurine administration on ammonia-induced mitochondrial dysfunction. Material and methods Isolated mice liver and brain mitochondria were exposed to different concentrations of ammonia (1, 5, 10, and 20 mM) and taurine (1, 5, and 10 mM), and several mitochondrial indices were assessed. Results It was found that ammonia inhibited mitochondrial dehydrogenases activity caused collapse of mitochondrial membrane potential (MMP), induced mitochondrial swelling (MPP), and increased reactive oxygen species (ROS) in isolated liver and brain mitochondria. Furthermore, a significant amount of lipid peroxidation (LPO), along with glutathione (GSH) and ATP depletion, was detected in ammonia exposed mitochondria. Taurine administration (5 and 10 mM) mitigated ammonia-induced mitochondrial dysfunction. Conclusions The current investigation demonstrates that taurine is instrumental in preserving brain and liver mitochondrial function in a hyperammonemic environment. The data suggest taurine as a potential protective agent with a therapeutic capability against hepatic encephalopathy and hyperammonemia. PMID:29062904

Quantification by magnetic resonance imaging and liver consequences of post-transfusional iron overload alone in long term survivors after allogeneic hematopoietic stem cell transplantation (HSCT).

PubMed

Rose, Christian; Ernst, Olivier; Hecquet, Bernard; Maboudou, Patrice; Renom, Pascale; Noel, Marie Pierre; Yakoub-Agha, Ibrahim; Bauters, Francis; Jouet, Jean Pierre

2007-06-01

We quantified and studied the impact of post transfusional iron overload alone in post allogeneic HSCT. Median number of RBCs was 18. Ferritin was 532 mg/L. Liver iron content (LIC) was 117 mmoles/gdw. Correlation RBCs and ferritin was (r=0.81); RBCs and LIC was (r=0.84). The high ferritin group differed from normal ferritin group in terms of RBCs transfused (p<10(-3)), ALT (p<0.009). But occurrence of liver dysfunction was not significant. Magnitude of iron overload correlates closely to the number of RBCs and is quantified by MRI. Impact on liver dysfunction is moderate in absence of co-morbidity.

Assessment of Mitochondrial Dysfunction Arising from Treatment with Hepatotoxicants

PubMed Central

King, Adrienne L.; Bailey, Shannon M.

2010-01-01

Studies demonstrate that mitochondrial dysfunction is a key causative factor in liver disease. Indeed, defects in mitochondrial energy metabolism, disrupted calcium handling, and increased reactive oxygen/nitrogen species production are observed in many metabolic disorders and diseases induced by toxicants. Mitochondria have emerged as a main research focus through work defining new functions of this key organelle in normal cellular physiology and pathophysiology. Specifically, studies show a critical role of mitochondrial reactive oxygen/nitrogen species production in regulating cellular signaling pathways involved in cell survival and death. Given this, along with advances made in proteomics technologies, mitochondria are recognized as top candidates for proteomics analysis. However, assessment of mitochondrial function and it’s proteome following toxicant exposure are not trivial undertakings. In this chapter a technique used to isolate mitochondria from liver tissue is presented along with methods needed to assess mitochondria functionality. The methods described include measurement of mitochondrial respiration, calcium accumulation, and reactive oxygen species production. A presentation of proteomics approaches is also included to allow researchers the basic tools needed to identify alterations in the mitochondrial proteome that contribute to toxicant-mediated diseases. Specifically, methods are presented that demonstrate how thiol labeling reagents in combination with electrophoresis and western blotting can be used to detect oxidant-mediated alterations in mitochondrial protein thiols. A few select pieces data are presented highlighting the power of proteomics to identify mitochondrial targets that contribute to mitochondrial dysfunction and hepatotoxicity in response to specific toxicant exposures and metabolic stressors such as alcohol and environmental tobacco smoke. PMID:23045017

Hypothermic temperature effects on organ survival and restoration

PubMed Central

Ishikawa, Jun; Oshima, Masamitsu; Iwasaki, Fumitaka; Suzuki, Ryoji; Park, Joonhong; Nakao, Kazuhisa; Matsuzawa-Adachi, Yuki; Mizutsuki, Taro; Kobayashi, Ayaka; Abe, Yuta; Kobayashi, Eiji; Tezuka, Katsunari; Tsuji, Takashi

2015-01-01

A three-dimensional multicellular organism maintains the biological functions of life support by using the blood circulation to transport oxygen and nutrients and to regulate body temperature for intracellular enzymatic reactions. Donor organ transplantation using low-temperature storage is used as the fundamental treatment for dysfunctional organs. However, this approach has a serious problem in that donor organs maintain healthy conditions only during short-term storage. In this study, we developed a novel liver perfusion culture system based on biological metabolism that can maintain physiological functions, including albumin synthesis, bile secretion and urea production. This system also allows for the resurrection of a severely ischaemic liver. This study represents a significant advance for the development of an ex vivo organ perfusion system based on biological metabolism. It can be used not only to address donor organ shortages but also as the basis of future regenerative organ replacement therapy. PMID:25900715

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lawrence, T.S.; Robertson, J.M.; Anscher, M.S.

Radiation-induced liver disease (RILD), often called radiation hepatitis, is a syndrome characterized by the development of anicteric ascites approximately 2 weeks to 4 months after hepatic irradiation. There has been a renewed interest in hepatic irradiation because of two significant advances in cancer treatment; three dimensional radiation therapy treatment planning and bone marrow transplantation using total body irradiation. RILD resulting from liver radiation can usually be distinguished clinically from the resulting from the preparative regime associated with bone marrow transplantation. However, both syndromes demonstrate the same pathological lesion; veno-occlusive disease. Recent evidence suggests that elevated transforming growth factor {beta} levelsmore » may play a role in the development of veno-occlusive disease. Three dimensional treatment planning offers the potential to determine the radiation dose and volume dependence of RILD, permitting the safe delivery of high doses of radiation to parts of the liver. The chief therapy for RILD is diuretics, although some advocate steroids of severe cases. The characteristics of RILD permit the development of a grading system modeled after the NCI Acute Common Toxicity Criteria, which incorporates standard criteria of hepatic dysfunction. 64 refs., 5 figs., 1 tab.« less

Cholemic nephropathy - Historical notes and novel perspectives.

PubMed

Krones, Elisabeth; Pollheimer, Marion J; Rosenkranz, Alexander R; Fickert, Peter

2018-04-01

Acute kidney injury is common in patients with liver disease and associated with significant morbidity and mortality. Besides bacterial infections, fluid loss, and use of nephrotoxic drugs AKI in liver disease may be triggered by tubular toxicity of cholephiles. Cholemic nephropathy, also known as bile cast nephropathy, supposedly represents a widely underestimated but important cause of renal dysfunction in cholestasic or advanced liver diseases with jaundice. Cholemic nephropathy describes impaired renal function along with characteristic histomorphological changes consisting of intratubular cast formation and tubular epithelial cell injury directed towards distal nephron segments. The underlying pathophysiologic mechanisms are not entirely understood and clear defined diagnostic criteria are still missing. This review aims to summarize (i) the present knowledge on clinical and morphological characteristics of cholemic nephropathy, (ii) available preclinical models, (iii) potential pathomechanisms especially the potential role of bile acids, and (iv) future diagnostic and therapeutic strategies for cholemic nephropathy. This article is part of a Special Issue entitled: Cholangiocytes in Health and Disease edited by Jesus Banales, Marco Marzioni, Nicholas LaRusso and Peter Jansen. Copyright © 2017 Elsevier B.V. All rights reserved.

Assessment of hepatoprotective and nephroprotective potential of withaferin A on bromobenzene-induced injury in Swiss albino mice: possible involvement of mitochondrial dysfunction and inflammation.

PubMed

Vedi, Mahima; Sabina, Evan Prince

2016-10-01

Bromobenzene is a well-known environmental toxin which causes liver and kidney damage through CYP450-mediated bio-activation to generate reactive metabolites and, consequently, oxidative stress. The present study aimed to evaluate the possible protective role of withaferin A against bromobenzene-induced liver and kidney damage in mice. Withaferin A (10 mg/kg) was administered orally to the mice for 8 days before intragastric intubation of bromobenzene (10 mmol/kg). As results of this experiment, the levels of liver and kidney functional markers, lipid peroxidation, and cytokines (TNF-α and IL-1β) presented an increase and there was a decrease in anti-oxidant activity in the bromobenzene-treated group of mice. Pre-treatment with withaferin A not only significantly decreased the levels of liver and kidney functional markers and cytokines but also reduced oxidative stress, as evidenced by improved anti-oxidant status. In addition, the mitochondrial dysfunction shown through the decrease in the activities of mitochondrial enzymes and imbalance in the Bax/Bcl-2 expression in the livers and kidneys of bromobenzene-treated mice was effectively prevented by pre-administration of withaferin A. These results validated our conviction that bromobenzene caused liver and kidney damage via mitochondrial pathway and withaferin A provided significant protection against it. Thus, withaferin A may have possible usage in clinical liver and kidney diseases in which oxidative stress and mitochondrial dysfunction may be existent.

Isolated heart and liver transplant recipients are at low risk for polyomavirus BKV nephropathy.

PubMed

Puliyanda, Dechu P; Amet, Nurmamet; Dhawan, Archana; Hilo, Lara; Radha, Raju K; Bunnapradist, Suphamai; Czer, Lawrence; Martin, Paul; Jordan, Stanley; Toyoda, Mieko

2006-01-01

BKV infection and nephropathy is a significant cause of allograft dysfunction in kidney transplantation. BKV viremia, rather than viruria, corresponds to BKV nephropathy. The prevalence of BKV viremia in non-renal solid organ transplants has not been systematically evaluated. We determined prevalence of BKV viremia in kidney, combined kidney-heart, kidney-liver, kidney-pancreas, kidney-heart-liver, and heart and liver transplant recipients using BKV-PCR. Seven out of 173 (4%) kidney transplant recipients had BKV viremia, with BKV>2 x 10(5) copies/mL in 6/7 and 1.9 x 10(3) in the remaining one patient. BKV viremia was not found in 24 heart transplant recipients, whereas 1/37 (2.7%) liver transplants showed low copy numbers (< or =10(3)). BKV-PCR< or =10(3) copies/mL were also found in one of each combined kidney-heart and kidney-liver transplant recipients. BKV nephropathy was proven by biopsy in 4/6 patients with high BKV viral loads. All six patients showed renal dysfunction, requiring reduction in immunosuppression and antiviral therapy. All four patients with low BKV viral loads (1.9 x 10(3) or < or =10(3)) showed stable renal function after reduction of immunosuppression or no treatment, respectively. Higher BKV levels in plasma are associated with renal dysfunction. Kidney transplant recipients are at high risk compared with recipients of isolated heart or liver allografts, for development of BKV nephropathy.

Exertional heat stroke and acute liver failure: a late dysfunction

PubMed Central

Carvalho, Ana Sofia; Rodeia, Simão C; Silvestre, Joana; Póvoa, Pedro

2016-01-01

Heat stroke (HS) is defined as a severe elevation of core body temperature along with central nervous system dysfunction. Exertional heat stroke (EHS) with acute liver failure (ALF) is a rare condition. The authors report the case of a 25-year-old man with a history of cognitive enhancers’ intake who developed hyperthermia and neurological impairment while running an outdoor marathon. The patient was cooled and returned to normal body temperature after 6 h. He subsequently developed ALF and was transferred to the intensive care unit. Over-the-counter drug intake may have been related to heat intolerance and contributed to the event. The patient was successfully treated with conservative measures. In the presence of EHS, it is crucial to act promptly with aggressive total body cooling, in order to prevent progression of the clinical syndrome. Liver function must also be monitored, since it can be a late organ dysfunction. PMID:26969359

Glycyrrhizin ameliorates metabolic syndrome-induced liver damage in experimental rat model.

PubMed

Sil, Rajarshi; Ray, Doel; Chakraborti, Abhay Sankar

2015-11-01

Glycyrrhizin, a major constituent of licorice (Glycyrrhiza glabra) root, has been reported to ameliorate insulin resistance, hyperglycemia, dyslipidemia, and obesity in rats with metabolic syndrome. Liver dysfunction is associated with this syndrome. The objective of this study is to investigate the effect of glycyrrhizin treatment on metabolic syndrome-induced liver damage. After induction of metabolic syndrome in rats by high fructose (60%) diet for 6 weeks, the rats were treated with glycyrrhizin (50 mg/kg body weight, single intra-peritoneal injection). After 2 weeks of treatment, rats were sacrificed to collect blood samples and liver tissues. Compared to normal, elevated activities of serum alanine transaminase, alkaline phosphatase and aspartate transaminase, increased levels of liver advanced glycation end products, reactive oxygen species, lipid peroxidation, protein carbonyl, protein kinase Cα, NADPH oxidase-2, and decreased glutathione cycle components established liver damage and oxidative stress in fructose-fed rats. Activation of nuclear factor κB, mitogen-activated protein kinase pathways as well as signals from mitochondria were found to be involved in liver cell apoptosis. Increased levels of cyclooxygenase-2, tumor necrosis factor, and interleukin-12 proteins suggested hepatic inflammation. Metabolic syndrome caused hepatic DNA damage and poly-ADP ribose polymerase cleavage. Fluorescence-activated cell sorting using annexin V/propidium iodide staining confirmed the apoptotic hepatic cell death. Histology of liver tissue also supported the experimental findings. Treatment with glycyrrhizin reduced oxidative stress, hepatic inflammation, and apoptotic cell death in fructose-fed rats. The results suggest that glycyrrhizin possesses therapeutic potential against hepatocellular damage in metabolic syndrome.

Organ dysfunction, injury and failure in acute heart failure: from pathophysiology to diagnosis and management. A review on behalf of the Acute Heart Failure Committee of the Heart Failure Association (HFA) of the European Society of Cardiology (ESC).

PubMed

Harjola, Veli-Pekka; Mullens, Wilfried; Banaszewski, Marek; Bauersachs, Johann; Brunner-La Rocca, Hans-Peter; Chioncel, Ovidiu; Collins, Sean P; Doehner, Wolfram; Filippatos, Gerasimos S; Flammer, Andreas J; Fuhrmann, Valentin; Lainscak, Mitja; Lassus, Johan; Legrand, Matthieu; Masip, Josep; Mueller, Christian; Papp, Zoltán; Parissis, John; Platz, Elke; Rudiger, Alain; Ruschitzka, Frank; Schäfer, Andreas; Seferovic, Petar M; Skouri, Hadi; Yilmaz, Mehmet Birhan; Mebazaa, Alexandre

2017-07-01

Organ injury and impairment are commonly observed in patients with acute heart failure (AHF), and congestion is an essential pathophysiological mechanism of impaired organ function. Congestion is the predominant clinical profile in most patients with AHF; a smaller proportion presents with peripheral hypoperfusion or cardiogenic shock. Hypoperfusion further deteriorates organ function. The injury and dysfunction of target organs (i.e. heart, lungs, kidneys, liver, intestine, brain) in the setting of AHF are associated with increased risk for mortality. Improvement in organ function after decongestive therapies has been associated with a lower risk for post-discharge mortality. Thus, the prevention and correction of organ dysfunction represent a therapeutic target of interest in AHF and should be evaluated in clinical trials. Treatment strategies that specifically prevent, reduce or reverse organ dysfunction remain to be identified and evaluated to determine if such interventions impact mortality, morbidity and patient-centred outcomes. This paper reflects current understanding among experts of the presentation and management of organ impairment in AHF and suggests priorities for future research to advance the field. © 2017 The Authors. European Journal of Heart Failure © 2017 European Society of Cardiology.

Liver dysfunction in patients with severe anorexia nervosa.

PubMed

Rosen, Elissa; Sabel, Allison L; Brinton, John T; Catanach, Brittany; Gaudiani, Jennifer L; Mehler, Philip S

2016-02-01

Evaluation of liver dysfunction in patients with severe anorexia nervosa (AN) has typically been limited to small case series. We report an investigation into the admission characteristics and clinical outcomes associated with liver dysfunction in a large cohort of adults hospitalized for medical stabilization of severe AN. We retrospectively evaluated electronic medical records to quantify the cumulative incidence of elevated aspartate aminotransferase (AST) and alanine aminotransferase (ALT). We compared mean (±SD), frequencies (%), and median (IQR) values of clinical covariates of interest by incidence of liver enzyme elevation. The study included 181 adults, admitted for medical stabilization of AN, from October 1, 2008 to December 31, 2013. AST and ALT were mildly elevated in 27.6% of patients and severely elevated (more than three times the upper limit of normal) in 35.4% of patients. On admission, patients with severely elevated liver enzymes had a lower body mass index (BMI) (11.9 ± 1.8 kg/m(2) vs.13.3 ± 1.7 kg/m(2)), lower percentage ideal body weight (56.5% ± 7.7% vs. 63.5% ± 8.3%), and lower prealbumin (64% vs. 37%) compared with the rest of the cohort (p < 0.001). While hospitalized, patients with severely elevated liver enzymes more often developed hypoglycemia, hypophosphatemia, and experienced longer lengths of stay (p < 0.001). Elevated liver enzymes are common in our patient population with severe AN. Liver enzymes reached near normal values by the time of discharge. Severely elevated liver enzymes were associated with a lower BMI and the development of hypoglycemia. © 2015 Wiley Periodicals, Inc.

Outcomes in Adults With Acute Liver Failure Between 1998 and 2013: An Observational Cohort Study.

PubMed

Reuben, Adrian; Tillman, Holly; Fontana, Robert J; Davern, Timothy; McGuire, Brendan; Stravitz, R Todd; Durkalski, Valerie; Larson, Anne M; Liou, Iris; Fix, Oren; Schilsky, Michael; McCashland, Timothy; Hay, J Eileen; Murray, Natalie; Shaikh, Obaid S; Ganger, Daniel; Zaman, Atif; Han, Steven B; Chung, Raymond T; Smith, Alastair; Brown, Robert; Crippin, Jeffrey; Harrison, M Edwyn; Koch, David; Munoz, Santiago; Reddy, K Rajender; Rossaro, Lorenzo; Satyanarayana, Raj; Hassanein, Tarek; Hanje, A James; Olson, Jody; Subramanian, Ram; Karvellas, Constantine; Hameed, Bilal; Sherker, Averell H; Robuck, Patricia; Lee, William M

2016-06-07

Acute liver failure (ALF) is a rare syndrome of severe, rapid-onset hepatic dysfunction-without prior advanced liver disease-that is associated with high morbidity and mortality. Intensive care and liver transplantation provide support and rescue, respectively. To determine whether changes in causes, disease severity, treatment, or 21-day outcomes have occurred in recent years among adult patients with ALF referred to U.S. tertiary care centers. Prospective observational cohort study. (ClinicalTrials .gov: NCT00518440). 31 liver disease and transplant centers in the United States. Consecutively enrolled patients-without prior advanced liver disease-with ALF (n = 2070). Clinical features, treatment, and 21-day outcomes were compared over time annually for trends and were also stratified into two 8-year periods (1998 to 2005 and 2006 to 2013). Overall clinical characteristics, disease severity, and distribution of causes remained similar throughout the study period. The 21-day survival rates increased between the two 8-year periods (overall, 67.1% vs. 75.3%; transplant-free survival [TFS], 45.1% vs. 56.2%; posttransplantation survival, 88.3% vs. 96.3% [P < 0.010 for each]). Reductions in red blood cell infusions (44.3% vs. 27.6%), plasma infusions (65.2% vs. 47.1%), mechanical ventilation (65.7% vs. 56.1%), and vasopressors (34.9% vs. 27.8%) were observed, as well as increased use of N-acetylcysteine (48.9% vs. 69.3% overall; 15.8% vs. 49.4% [P < 0.001] in patients with ALF not due to acetaminophen toxicity). When examined longitudinally, overall survival and TFS increased throughout the 16-year period. The duration of enrollment, the number of patients enrolled, and possibly the approaches to care varied among participating sites. The results may not be generalizable beyond such specialized centers. Although characteristics and severity of ALF changed little over 16 years, overall survival and TFS improved significantly. The effects of specific changes in intensive care practice on survival warrant further study. National Institutes of Health.

Hyperammoniemic coma in a patient with ureterosigmoidostomy and normal liver function.

PubMed

Van Laethem, J L; Gay, F; Franck, N; Van Gossum, A

1992-11-01

Hyperammoniemic encephalopathy has been reported after ureterosigmoidostomy. Its development is related to a problem of bacterial overgrowth and, most often, is favored by the presence of an underlying liver dysfunction. We report the case of a 43-year-old woman with a ureterosigmoidostomy done 28 years earlier who developed hyperammoniemic coma induced by an acute rectocolitis and in the absence of any detectable liver dysfunction. Neither administration of Lactilol and neomycin nor rectal tube drainage were effective; systemic antimicrobial therapy effective against the urease-producing gram-negative bacilli was required and led to a decrease in serum ammonia levels and a dramatic clinical improvement.

FC-99 ameliorates sepsis-induced liver dysfunction by modulating monocyte/macrophage differentiation via Let-7a related monocytes apoptosis.

PubMed

Zhao, Yarong; Zhu, Haiyan; Wang, Haining; Ding, Liang; Xu, Lizhi; Chen, Dai; Shen, Sunan; Hou, Yayi; Dou, Huan

2018-03-13

The liver is a vital target for sepsis-related injury, leading to inflammatory pathogenesis, multiple organ dysfunction and high mortality rates. Monocyte-derived macrophage transformations are key events in hepatic inflammation. N 1 -[(4-methoxy)methyl]-4-methyl-1,2-benzenediamine (FC-99) previously displayed therapeutic potential on experimental sepsis. However, the underlying mechanism of this protective effect is still not clear. FC-99 treatment attenuated the liver dysfunction in septic mice that was accompanied with reduced numbers of pro-inflammatory Ly6C hi monocytes in the peripheral blood and CD11b + F4/80 lo monocyte-derived macrophages in the liver. These effects were attributed to the FC-99-induced apoptosis of CD11b + cells. In PMA-differentiated THP-1 cells, FC-99 repressed the expression of CD11b, CD14 and caspase3 and resulted in a high proportion of Annexin V + cells. Moreover, let-7a-5p expression was abrogated upon CLP stimulation in vivo , whereas it was restored by FC-99 treatment. TargetScan analysis and luciferase assays indicated that the anti-apoptotic protein BCL-XL was targeted by let-7a-5p. BCL-XL was inhibited by FC-99 in order to induce monocyte apoptosis, leading to the impaired monocyte-to-macrophage differentiation. Murine acute liver failure was generated by caecal ligation puncture surgery after FC-99 administration; Blood samples and liver tissues were collected to determine the monocyte/macrophage subsets and the induction of apoptosis. Human acute monocytic leukemia cell line (THP-1) cells were pretreated with FC-99 followed by phorbol-12-myristate-13-acetate (PMA) stimulation, in order to induce monocyte-to-macrophage differentiation. The target of FC-99 and the mechanistic analyses were conducted by microarrays, qRT-PCR validation, TargetScan algorithms and a luciferase report assay. FC-99 exhibits potential therapeutic effects on CLP-induced liver dysfunction by restoring let-7a-5p levels.

High regenerative capacity of the liver and irreversible injury of male reproductive system in carbon tetrachloride-induced liver fibrosis rat model.

PubMed

Bubnov, Rostyslav V; Drahulian, Maria V; Buchek, Polina V; Gulko, Tamara P

2018-03-01

Liver fibrosis (LF) is a chronic disease, associated with many collateral diseases including reproductive dysfunction. Although the normal liver has a large regenerative capacity the complications of LF could be severe and irreversible. Hormone and sex-related issues of LF development and interactions with male reproductive have not been finally studied. The aim was to study the reproductive function of male rats in experimental CCl 4 -induced liver fibrosis rat model, and the capability for restoration of both the liver and male reproduction system. Studies were conducted on 20 3-month old Wistar male rats. The experimental animals were injected with freshly prepared 50% olive oil solution of carbohydrate tetrachloride (CCl 4 ). On the 8th week after injection we noted the manifestations of liver fibrosis. The rats were left to self-healing of the liver for 8 weeks. All male rats underwent ultrasound and biopsy of the liver and testes on the 8th and 16th weeks. The male rats were mated with healthy females before CCl 4 injection, after modeling LF on the 8th week, and after self-healing of the liver. Pregnancy was monitored on ultrasound. On the 8th week of experiment we observed ultrasound manifestation of advanced liver fibrosis, including hepatosplenomegaly, portal hypertension. Ultrasound exam of the rat testes showed testicular degeneration, hydrocele, fibrosis, scarring, petrifications, size reduction, and restriction of testicular descent; testes size decreased from 1.24 ± 0.62 ml to 0.61 ± 0.13, p  < 0.01. Liver histology showed granular dystrophy of hepatocytes, necrotic areas, lipid inclusions in parenchyma. Rats with liver fibrosis demonstrated severe injury of the reproductive system and altering of fertility: the offspring of male rats with advanced LF was 4.71 ± 0.53 born alive vs 9.55 ± 0.47 born from mating with healthy males, p  < 0.001. Eight weeks after last CCl 4 injection, we revealed signs of liver regeneration, significant recovery of its structure. The ALT and AST levels significantly decreased and reached background measurements. As a result of the second interbreeding after liver self-healing no significant difference was found vs previous mating. Carbohydrate tetrachloride induces injury of liver parenchyma evoking fast and severe liver fibrosis, and is associated with irreversible structural and functional changes in testes, reducing fertility, decreasing potential pregnancy rate, and affecting its development. Liver showed high potential to regenerate, however the self-restoring after liver fibrosis was not accompanied with recovery of the reproductive system.

Study of Abnormal Liver Function Test during Pregnancy in a Tertiary Care Hospital in Chhattisgarh.

PubMed

Mishra, Nalini; Mishra, V N; Thakur, Parineeta

2016-10-01

Abnormal liver function tests (LFTs) in pregnancy require proper interpretation in order to avoid pitfalls in the diagnosis. The underlying disorder can have a significant effect on the outcome of both mother and foetus. The present study was done with the objective to study the clinical profile, incidence and possible causes of derangements of liver function tests. Eighty pregnant women with abnormal liver dysfunction were studied prospectively. Women with chronic liver disease and drug-induced abnormal liver function test were excluded. All available LFTs including LDH were studied along with some more definitive tests to aid identification of underlying cause. Foetomaternal outcome was noted in all. The incidence of abnormal LFT was 0.9 %. 13/80 (16.75 %) women had liver disorder not specific to pregnancy, whereas 67/80 (83.25 %) women had pregnancy-specific liver dysfunction. Of these, 65(81.25 %) women with liver dysfunction had pre-eclampsia including 11 (13.75 %) with HELLP and six women with eclampsia. 48/65 (60 %) women had pre-eclampsia in the absence of HELLP syndrome or eclampsia. The mean value for bilirubin (mg %) in hypertensive disorders of pregnancy ranged from 1.64 to 3.8, between 5 and 10 for ICP and AFLP and >10 in infective hepatitis. Transaminases were highest in infective hepatitis, whereas alkaline phosphate was highest in ICP. Total 27 (33.75 %) women suffered from adverse outcome with four (5 %) maternal deaths and 23 (28.75 %) major maternal morbidities. 33/80 (41.25 %) women had intrauterine death. 26.25 % babies were small for date. Pregnancy-specific disorders are the leading cause of abnormal liver function test during pregnant state particularly in the third trimester. Pre-eclampsia-related disorder is the commonest. Gestational age of pregnancy and relative values of various liver function tests in different pregnancy-specific and pregnancy nonspecific disorders appear to be the best guide to clinch the diagnosis.

Capybara Oil Improves Hepatic Mitochondrial Dysfunction, Steatosis, and Inflammation in a Murine Model of Nonalcoholic Fatty Liver Disease.

PubMed

Marinho, Polyana C; Vieira, Aline B; Pereira, Priscila G; Rabelo, Kíssila; Ciambarella, Bianca T; Nascimento, Ana L R; Cortez, Erika; Moura, Aníbal S; Guimarães, Fernanda V; Martins, Marco A; Barquero, Gonzalo; Ferreira, Rodrigo N; de Carvalho, Jorge J

2018-01-01

Nonalcoholic fatty liver disease (NAFLD) is recognized as the most common cause of liver dysfunction worldwide and is commonly associated with obesity. Evidences suggest that NAFLD might be a mitochondrial disease, which contributes to the hepatic steatosis, oxidative stress, cytokine release, and cell death. Capybara oil (CO) is a rich source of polyunsaturated fatty acids (PUFA), which is known to improve inflammation and oxidative stress. In order to determine the effects of CO on NAFLD, C57Bl/6 mice were divided into 3 groups and fed a high-fat diet (HFD) (NAFLD group and NAFLD + CO group) or a control diet (CG group) during 16 weeks. The CO (1.5 g/kg/daily) was administered by gavage during the last 4 weeks of the diet protocol. We evaluated plasma liver enzymes, hepatic steatosis, and cytokine expression in liver as well as hepatocyte ultrastructural morphology and mitochondrial function. CO treatment suppressed hepatic steatosis, attenuated inflammatory response, and decreased plasma alanine aminotransferase (ALT) in mice with NAFLD. CO was also capable of restoring mitochondrial ultrastructure and function as well as balance superoxide dismutase and catalase levels. Our findings indicate that CO treatment has positive effects on NAFLD improving mitochondrial dysfunction, steatosis, acute inflammation, and oxidative stress.

Risk factors and outcome of bacterial infections in cirrhosis

PubMed Central

Bruns, Tony; Zimmermann, Henning W; Stallmach, Andreas

2014-01-01

Viable and non-viable pathological bacterial translocation promote a self-perpetuating circle of dysfunctional immune activation and systemic inflammation facilitating infections and organ failure in advanced cirrhosis. Bacterial infections and sepsis are now recognized as a distinct stage in the natural progression of chronic liver disease as they accelerate organ failure and contribute to the high mortality observed in decompensated cirrhosis. The increasing knowledge of structural, immunological and hemodynamic pathophysiology in advanced cirrhosis has not yet translated into significantly improved outcomes of bacterial infections over the last decades. Therefore, early identification of patients at the highest risk for developing infections and infection-related complications is required to tailor the currently available measures of surveillance, prophylaxis and therapy to the patients in need in order to improve the detrimental outcome of bacterial infections in cirrhosis. PMID:24627590

Practice-Based Recommendations from the American Society of Transplantation Liver and Intestine Community of Practice

PubMed Central

Levitsky, J.; O’Leary, J.G.; Asrani, S.; Sharma, P.; Fung, J.; Wiseman, A.; Niemann, C.U.

2016-01-01

Acute and chronic kidney disease after liver transplantation is common and results in significant morbidity and mortality. The introduction of MELD has directly correlated with an increased prevalence of perioperative renal dysfunction and the number of simultaneous liver-kidney transplants performed. Thus, kidney dysfunction in this population is typically multifactorial and related to pre-existing conditions, pre-transplant renal injury, peri-operative events, and post-transplant nephrotoxic immunosuppressive therapies. The management of kidney disease following liver transplantation is challenging, as by the time the serum creatinine is significantly elevated, few interventions impact the course of progression. Also, immunological factors such as antibody-mediated rejection have become of greater interest given the rising liver-kidney transplant population. Therefore this review, assembled by experts in the field and endorsed by the American Society of Transplantation Liver and Intestinal Community of Practice, provides a critical assessment of measures of renal function and interventions aimed at preserving renal function early and late after liver and simultaneous liver-kidney transplantation. Key points and practice-based recommendations for the prevention and management of kidney injury in this population are provided to offer guidance for clinicians and identify gaps in knowledge for future investigations. PMID:26932352

Inhibition of cyclooxygenase-2 alleviates liver cirrhosis via improvement of the dysfunctional gut-liver axis in rats.

PubMed

Gao, Jin-Hang; Wen, Shi-Lei; Tong, Huan; Wang, Chun-Hui; Yang, Wen-Juan; Tang, Shi-Hang; Yan, Zhao-Ping; Tai, Yang; Ye, Cheng; Liu, Rui; Huang, Zhi-Yin; Tang, Ying-Mei; Yang, Jin-Hui; Tang, Cheng-Wei

2016-06-01

Inflammatory transport through the gut-liver axis may facilitate liver cirrhosis. Cyclooxygenase-2 (COX-2) has been considered as one of the important molecules that regulates intestinal epithelial barrier function. This study was aimed to test the hypothesis that inhibition of COX-2 by celecoxib might alleviate liver cirrhosis via reduction of intestinal inflammatory transport in thiacetamide (TAA) rat model. COX-2/prostaglandin E2 (PGE2)/EP-2/p-ERK integrated signal pathways regulated the expressions of intestinal zonula occludens-1 (ZO-1) and E-cadherin, which maintain the function of intestinal epithelial barrier. Celecoxib not only decreased the intestinal permeability to a 4-kDa FITC-dextran but also significantly increased expressions of ZO-1 and E-cadherin. When celecoxib greatly decreased intestinal levels of LPS, TNF-α, and IL-6, it significantly enhanced T cell subsets reduced by TAA. As a result, liver fibrosis induced by TAA was significantly alleviated in the celecoxib group. These data indicated that celecoxib improved the integrity of intestinal epithelial barrier, blocked inflammatory transport through the dysfunctional gut-liver axis, and ameliorated the progress of liver cirrhosis. Copyright © 2016 the American Physiological Society.

Recombinant AAV-directed gene therapy for type I glycogen storage diseases

PubMed Central

Chou, JY; Mansfield, BC

2011-01-01

Introduction Glycogen storage disease (GSD) type Ia and Ib are disorders of impaired glucose homeostasis affecting the liver and kidney. GSD-Ib also affects neutrophils. Current dietary therapies cannot prevent long-term complications. In animal studies, recombinant adeno-associated virus (rAAV) vector-mediated gene therapy can correct or minimize multiple aspects of the disorders, offering hope for human gene therapy. Areas covered A summary of recent progress in rAAV-mediated gene therapy for GSD-I; strategies to improve rAAV-mediated gene delivery, transduction efficiency and immune avoidance; and vector refinements that improve expression. Expert opinion rAAV-mediated gene delivery to the liver can restore glucose homeostasis in preclinical models of GSD-I, but some long-term complications of the liver and kidney remain. Gene therapy for GSD-Ib is less advanced than for GSD-Ia and only transient correction of myeloid dysfunction has been achieved. A question remains whether a single rAAV vector can meet the expression efficiency and tropism required to treat all aspects of GSD-I, or if a multi-prong approach is needed. An understanding of the strengths and weaknesses of rAAV vectors in the context of strategies to achieve efficient transduction of the liver, kidney, and hematopoietic stem cells is required for treating GSD-I. PMID:21504389

Mechanistic Biomarkers in Acetaminophen-induced Hepatotoxicity and Acute Liver Failure: From Preclinical Models to Patients

PubMed Central

McGill, Mitchell R.; Jaeschke, Hartmut

2015-01-01

SUMMARY Introduction Drug hepatotoxicity is a major clinical issue. Acetaminophen (APAP) overdose is especially common. Serum biomarkers used to follow patient progress reflect either liver injury or function, but focus on biomarkers that can provide insight into the basic mechanisms of hepatotoxicity is increasing and enabling us to translate mechanisms of toxicity from animal models to humans. Areas covered We review recent advances in mechanistic serum biomarker research in drug hepatotoxicity. Specifically, biomarkers for reactive drug intermdiates, mitochondrial dysfunction, nuclear DNA damage, mode of cell death and inflammation are discussed, as well as microRNAs. Emphasis is placed on APAP-induced liver injury. Expert Opinion Several serum biomarkers of reactive drug intermediates, mitochondrial damage, nuclear DNA damage, apoptosis and necrosis, and inflammation have been described. These studies have provided evidence that mitochondrial damage is critical in APAP hepatotoxicity in humans, while apoptosis has only a minor role, and inflammation is important for recovery and regeneration after APAP overdose. Additionally, mechanistic serum biomarkers have been shown to predict outcome as well as, or better than, some clinical scores. In the future, such biomarkers will help determine the need for liver transplantation and, with improved understanding of the human pathophysiology, identify novel therapeutic targets. PMID:24836926

Protective Effects of the Third Generation Vasodilatory Βeta - Blocker Nebivolol against D-Galactosamine - Induced Hepatorenal Syndrome in Rats

PubMed Central

Atwa, Ahmed; Hegazy, Rehab; Mohsen, Rania; Yassin, Neamat; Kenawy, Sanaa

2017-01-01

BACKGROUND: Renal dysfunction is very common in patients with advanced liver cirrhosis and portal hypertension. The development of renal failure in the absence of clinical, anatomical or pathological causes renal of failure is termed hepatorenal syndrome (HRS). AIM: The present study was constructed to investigate the possible protective effects of nebivolol (Nebi) against D-galactosamine (Gal)-induced HRS in rats. MATERIAL AND METHODS: Rats were treated with Nebi for ten successive days. On the 8th day of the experiment, they received a single dose of Gal. Serum levels of Cr, BUN, Na+ and K+ as well as AST, ALT, total bilirubin (TB), NH3 and endothelin-1 (ET-1) were determined following Gal administration. Moreover, renal and liver contents of MDA, GSH, F2-isoprostanes (F2-IPs), tumor necrosis factor-alpha (TNF-α), nuclear factor kappa-B (NF-κB), total nitric oxide (NO), in addition to activities of caspase-3 (Cas-3), heme oxygenase-1 (HO-1), inducible and endothelial NO synthase (iNOS and eNOS) enzymes were also assessed. Finally, histopathological examination was performed. RESULTS: Nebi attenuated Gal-induced renal and hepatic dysfunction. It also decreased the Gal-induced oxidative stress and inflammatory recruitment. CONCLUSION: Results demonstrated both nephroprotective and hepatoprotective effects of Nebi against HRS and suggested a role of its antioxidant, anti-inflammatory, anti-apoptotic and NO-releasing properties. PMID:29362613

Impact of perioperative liver dysfunction on in-hospital mortality and long-term survival in infective endocarditis patients.

PubMed

Diab, M; Sponholz, C; von Loeffelholz, C; Scheffel, P; Bauer, M; Kortgen, A; Lehmann, T; Färber, G; Pletz, M W; Doenst, T

2017-12-01

Infective endocarditis (IE) is often associated with multiorgan dysfunction and mortality. The impact of perioperative liver dysfunction (LD) on outcome remains unclear and little is known about factors leading to postoperative LD. We performed a retrospective, single-center analysis on 285 patients with left-sided IE without pre-existing chronic liver disease referred to our center between 2007 and 2013 for valve surgery. Sequential organ failure assessment (SOFA) score was used to evaluate organ dysfunction. Chi-square, Cox regression, and multivariate analyses were used for evaluation. Preoperative LD (Bilirubin >20 μmol/L) was present in 68 of 285 patients. New, postoperative LD occurred in 54 patients. Hypoxic hepatitis presented the most common origin of LD, accompanied with high short-term mortality. In-hospital mortality was higher in patients with preoperative and postoperative LD compared to patients without LD (51.5, 24.1, and 10.4%, respectively, p < 0.001). 5-year survival was worse in patients with pre- or postoperative LD compared to patients without LD (20.1, 37.1, and 57.0% respectively). A landmark analysis revealed similar 5-year survival between groups after patient discharge. Quality of life was similar between groups when patients survived the perioperative period. Logistic regression analysis identified duration of cardiopulmonary bypass and S. aureus infection as independent predictors of postoperative LD. Perioperative liver dysfunction in patients with infective endocarditis is an independent predictor of short- and long-term mortalities. After surviving the hospital stay, 5-year prognosis is not different and quality of life is not affected by LD. S. aureus and duration of cardiopulmonary bypass represent risk factors for postoperative LD.

Liver Function Assessment by Magnetic Resonance Imaging.

PubMed

Ünal, Emre; Akata, Deniz; Karcaaltincaba, Musturay

2016-12-01

Liver function assessment by hepatocyte-specific contrast-enhanced magnetic resonance imaging is becoming a new biomarker. Liver function can be assessed by T1 mapping (reduction rate) and signal intensity measurement (relative enhancement ratio) before and after GD-EOB-DTPA (gadoxetic acid) administration, as alternative to Tc-99m galactosyl serum albumin scintigraphy, 99m Tc-labeled mebrofenin scintigraphy, and indocyanine green clearance test. Magnetic resonance imaging assessment of liver function can enable diagnosis of cirrhosis, nonalcoholic fatty liver disease associated fibrosis and steatohepatitis, primary sclerosing cholangitis, toxic hepatitis, and chemotherapy and radiotherapy-related changes, which may be only visible on hepatobiliary phase images. Simple visual assessment of signal intensity at hepatobiliary phase images is important for the diagnosis of different patterns of liver dysfunction including diffuse, lobar, segmental, and subsegmental forms. Furthermore, preoperative assessment of liver function is feasible before oncologic hepatic surgery, which may be important to prevent posthepatectomy liver failure and to estimate future remnant volume. Functional magnetic resonance cholangiography obtained by T1-weighted images at hepatobiliary phase can allow diagnosis of acalculous cholecystitis, biliary leakage, bile reflux to the stomach, sphincter of oddi dysfunction, and lesions with communication to biliary tree. Functional information can be easily obtained when Gd-EOB-DTPA is used for liver magnetic resonance imaging. Copyright © 2016 Elsevier Inc. All rights reserved.

Mitochondrial gene polymorphisms alter hepatic cellular energy metabolism and aggravate diet-induced non-alcoholic steatohepatitis.

PubMed

Schröder, Torsten; Kucharczyk, David; Bär, Florian; Pagel, René; Derer, Stefanie; Jendrek, Sebastian Torben; Sünderhauf, Annika; Brethack, Ann-Kathrin; Hirose, Misa; Möller, Steffen; Künstner, Axel; Bischof, Julia; Weyers, Imke; Heeren, Jörg; Koczan, Dirk; Schmid, Sebastian Michael; Divanovic, Senad; Giles, Daniel Aaron; Adamski, Jerzy; Fellermann, Klaus; Lehnert, Hendrik; Köhl, Jörg; Ibrahim, Saleh; Sina, Christian

2016-04-01

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease and is associated with an enhanced risk for liver and cardiovascular diseases and mortality. NAFLD can progress from simple hepatic steatosis to non-alcoholic steatohepatitis (NASH). However, the mechanisms predisposing to this progression remain undefined. Notably, hepatic mitochondrial dysfunction is a common finding in patients with NASH. Due to a lack of appropriate experimental animal models, it has not been evaluated whether this mitochondrial dysfunction plays a causative role for the development of NASH. To determine the effect of a well-defined mitochondrial dysfunction on liver physiology at baseline and during dietary challenge, C57BL/6J-mt(FVB/N) mice were employed. This conplastic inbred strain has been previously reported to exhibit decreased mitochondrial respiration likely linked to a non-synonymous gene variation (nt7778 G/T) of the mitochondrial ATP synthase protein 8 (mt-ATP8). At baseline conditions, C57BL/6J-mt(FVB/N) mice displayed hepatic mitochondrial dysfunction characterized by decreased ATP production and increased formation of reactive oxygen species (ROS). Moreover, genes affecting lipid metabolism were differentially expressed, hepatic triglyceride and cholesterol levels were changed in these animals, and various acyl-carnitines were altered, pointing towards an impaired mitochondrial carnitine shuttle. However, over a period of twelve months, no spontaneous hepatic steatosis or inflammation was observed. On the other hand, upon dietary challenge with either a methionine and choline deficient diet or a western-style diet, C57BL/6J-mt(FVB/N) mice developed aggravated steatohepatitis as characterized by lipid accumulation, ballooning of hepatocytes and infiltration of immune cells. We observed distinct metabolic alterations in mice with a mitochondrial polymorphism associated hepatic mitochondrial dysfunction. However, a second hit, such as dietary stress, was required to cause hepatic steatosis and inflammation. This study suggests a causative role of hepatic mitochondrial dysfunction in the development of experimental NASH.

Mitochondrial gene polymorphisms alter hepatic cellular energy metabolism and aggravate diet-induced non-alcoholic steatohepatitis

PubMed Central

Schröder, Torsten; Kucharczyk, David; Bär, Florian; Pagel, René; Derer, Stefanie; Jendrek, Sebastian Torben; Sünderhauf, Annika; Brethack, Ann-Kathrin; Hirose, Misa; Möller, Steffen; Künstner, Axel; Bischof, Julia; Weyers, Imke; Heeren, Jörg; Koczan, Dirk; Schmid, Sebastian Michael; Divanovic, Senad; Giles, Daniel Aaron; Adamski, Jerzy; Fellermann, Klaus; Lehnert, Hendrik; Köhl, Jörg; Ibrahim, Saleh; Sina, Christian

2016-01-01

Objective Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease and is associated with an enhanced risk for liver and cardiovascular diseases and mortality. NAFLD can progress from simple hepatic steatosis to non-alcoholic steatohepatitis (NASH). However, the mechanisms predisposing to this progression remain undefined. Notably, hepatic mitochondrial dysfunction is a common finding in patients with NASH. Due to a lack of appropriate experimental animal models, it has not been evaluated whether this mitochondrial dysfunction plays a causative role for the development of NASH. Methods To determine the effect of a well-defined mitochondrial dysfunction on liver physiology at baseline and during dietary challenge, C57BL/6J-mtFVB/N mice were employed. This conplastic inbred strain has been previously reported to exhibit decreased mitochondrial respiration likely linked to a non-synonymous gene variation (nt7778 G/T) of the mitochondrial ATP synthase protein 8 (mt-ATP8). Results At baseline conditions, C57BL/6J-mtFVB/N mice displayed hepatic mitochondrial dysfunction characterized by decreased ATP production and increased formation of reactive oxygen species (ROS). Moreover, genes affecting lipid metabolism were differentially expressed, hepatic triglyceride and cholesterol levels were changed in these animals, and various acyl-carnitines were altered, pointing towards an impaired mitochondrial carnitine shuttle. However, over a period of twelve months, no spontaneous hepatic steatosis or inflammation was observed. On the other hand, upon dietary challenge with either a methionine and choline deficient diet or a western-style diet, C57BL/6J-mtFVB/N mice developed aggravated steatohepatitis as characterized by lipid accumulation, ballooning of hepatocytes and infiltration of immune cells. Conclusions We observed distinct metabolic alterations in mice with a mitochondrial polymorphism associated hepatic mitochondrial dysfunction. However, a second hit, such as dietary stress, was required to cause hepatic steatosis and inflammation. This study suggests a causative role of hepatic mitochondrial dysfunction in the development of experimental NASH. PMID:27069868

Diastolic dysfunction characterizes cirrhotic cardiomyopathy

PubMed Central

Somani, Piyush O.; contractor, Qais; Chaurasia, Ajay S.; Rathi, Pravin M.

2014-01-01

Aim Present study aims to study the occurrence of cirrhotic cardiomyopathy and its correlation to hepatorenal syndrome by assessing the cardiac status in patients with cirrhosis of liver and healthy controls. Methods Thirty alcoholic cirrhotic, thirty non-alcoholic cirrhotic and thirty controls were enrolled for the study. Cardiac parameters were assessed by color doppler echocardiography. Patients were followed up for twelve months period for development of hepatorenal syndrome. Results Mild diastolic dysfunction was present in 18 cirrhotic patients (30%): grade I in fifteen patients and grade II in three. Diastolic dysfunction was unrelated to age; sex and etiology of cirrhosis. Among all the echocardiographic parameters, only deceleration time was found to be statistically significant. Echocardiographic parameters in systolic and diastolic function were not different in compensated vs decompensated patients in different Child-Pugh classes or cirrhosis aetiologies. At one year follow-up, no significant differences were found in survival between patients with or without diastolic dysfunction. Hepatorenal syndrome developed in only two patients and its correlation with diastolic dysfunction was not statistically significant. Conclusions Present study shows that although diastolic dysfunction is a frequent event in cirrhosis, it is usually of mild degree and does not correlate with severity of liver dysfunction. There are no significant differences in echocardiographic parameters between alcoholic and non-alcoholic cirrhosis. HRS is not correlated to diastolic dysfunction in cirrhotic patients. There is no difference in survival at one year between patients with or without diastolic dysfunction. Diastolic dysfunction in cirrhosis is unrelated to circulatory dysfunction, ascites and HRS. PMID:25634400

Preoperative liver dysfunction influences blood product administration and alterations in circulating haemostatic markers following ventricular assist device implantation.

PubMed

Woolley, Joshua R; Kormos, Robert L; Teuteberg, Jeffrey J; Bermudez, Christian A; Bhama, Jay K; Lockard, Kathleen L; Kunz, Nicole M; Wagner, William R

2015-03-01

Preoperative liver dysfunction may influence haemostasis following ventricular assist device (VAD) implantation. The Model for End-stage Liver Disease (MELD) score was assessed as a predictor of bleeding and levels of haemostatic markers in patients with currently utilized VADs. Sixty-three patients (31 HeartMate II, 15 HeartWare, 17 Thoratec paracorporeal ventricular assist device) implanted 2001-11 were analysed for preoperative liver dysfunction (MELD) and blood product administration. Of these patients, 21 had additional blood drawn to measure haemostatic marker levels. Cohorts were defined based on high (≥18.0, n = 7) and low (<18.0, n = 14) preoperative MELD scores. MELD score was positively correlated with postoperative administration of red blood cell (RBC), platelet, plasma and total blood product units (TBPU) , as well as chest tube drainage and cardiopulmonary bypass time. Age and MELD were preoperative predictors of TBPU by multivariate analysis. The high-MELD cohort had higher administration of TBPU, RBC and platelet units and chest tube drainage postimplant. Similarly, patients who experienced at least one bleeding adverse event were more likely to have had a high preoperative MELD. The high-MELD group exhibited different temporal trends in F1 + 2 levels and platelet counts to postoperative day (POD) 55. D-dimer levels in high-MELD patients became elevated versus those for low-MELD patients on POD 55. Preoperative MELD score predicts postoperative bleeding in contemporary VADs. Preoperative liver dysfunction may also alter postoperative subclinical haemostasis through different temporal trends of thrombin generation and platelet counts, as well as protracted fibrinolysis. © The Author 2014. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.

TIMP3 deficiency exacerbates iron overload-mediated cardiomyopathy and liver disease.

PubMed

Zhabyeyev, Pavel; Das, Subhash K; Basu, Ratnadeep; Shen, Mengcheng; Patel, Vaibhav B; Kassiri, Zamaneh; Oudit, Gavin Y

2018-05-01

Chronic iron overload results in heart and liver diseases and is a common cause of morbidity and mortality in patients with genetic hemochromatosis and secondary iron overload. We investigated the role of tissue inhibitor of metalloproteinase 3 (TIMP3) in iron overload-mediated tissue injury by subjecting male mice lacking Timp3 ( Timp3 -/- ) and wild-type (WT) mice to 12 wk of chronic iron overload. Whereas WT mice with iron overload developed diastolic dysfunction, iron-overloaded Timp3 -/- mice showed worsened cardiac dysfunction coupled with systolic dysfunction. In the heart, loss of Timp3 was associated with increased myocardial fibrosis, greater Timp1, matrix metalloproteinase ( Mmp) 2, and Mmp9 expression, increased active MMP-2 levels, and gelatinase activity. Iron overload in Timp3 -/- mice showed twofold higher iron accumulation in the liver compared with WT mice because of constituently lower levels of ferroportin. Loss of Timp3 enhanced the hepatic inflammatory response to iron overload, leading to greater neutrophil and macrophage infiltration and increased hepatic fibrosis. Expression of inflammation-related MMPs (MMP-12 and MMP-13) and inflammatory cytokines (IL-1β and monocyte chemoattractant protein-1) was elevated to a greater extent in iron-overloaded Timp3 -/- livers. Gelatin zymography demonstrated equivalent increases in MMP-2 and MMP-9 levels in WT and Timp3 -/- iron-overloaded livers. Loss of Timp3 enhanced the susceptibility to iron overload-mediated heart and liver injury, suggesting that Timp3 is a key protective molecule against iron-mediated pathology. NEW & NOTEWORTHY In mice, loss of tissue inhibitor of metalloproteinase 3 ( Timp3) was associated with systolic and diastolic dysfunctions, twofold higher hepatic iron accumulation (attributable to constituently lower levels of ferroportin), and increased hepatic inflammation. Loss of Timp3 enhanced the susceptibility to iron overload-mediated injury, suggesting that Timp3 plays a key protective role against iron-mediated pathology.

Prevalence and determinants of biochemical dysfunction of the liver in Atayal Aboriginal community of Taiwan: Is betel nut chewing a risk factor?

PubMed Central

Lin, Ching-Feng; Shiau, Tun-Jen; Ko, Ying-Chin; Chen, Ping-Ho; Wang, Jung-Der

2008-01-01

Background We address the independent and interactive roles of habitual betel quid chewing and other known risk factors for biochemical dysfunction and cirrhosis of the liver. Methods To determine the prevalence rates and risk factors associated with biochemical dysfunction of the liver, a total of 3,010 adult residents in an Atayal Aboriginal community were invited to participate in the study. Abdominal ultrasonography was used to diagnose liver cirrhosis. Results There were 2,063 Atayal Aboriginal and 947 non-Aboriginal in this study. The result showed overall prevalence rates for hepatitis B surface antigen (HBsAg) and hepatitis C virus (HCV) were 21.2 % and 2.9 %, respectively. There were 16.5 %, 15.1 % and 22.4 % subjects with abnormal alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma glutamyl transpeptidase (GGT), accordingly. Multiple logistic regression analysis showed that combined infections with HBV and HCV presented with the highest risks with OR (odds ratio) and 95% CI (confidence interval) of 4.2 (1.2–17.4) and 3.8 (1.0–14.1), respectively for elevation of ALT and AST; followed by alcohol (1.7 and 3.1), male gender (1.7 and 1.6), betel quid (1.5 and 1.3), smoking (1.4 and 1.8), and aboriginal (1.4 and 1.3). There is effect-measure modification between viral infection and betel quid chewing for increased severity of abnormal ALT elevation. Among 1,382 subjects consenting to abdominal ultrasonography, 41(3.0%) were found to have liver cirrhosis with the same factors associated with higher risks. Conclusion In addition to infections with viral hepatitis B and/or C, we found Atayal Aboriginal, males, current smokers, drinkers and betel quid chewers were independently associated with biochemical dysfunction and probably cirrhosis of the liver. Further study is needed to corroborate the above hypothesis. PMID:18439308

Inhibition of soluble epoxide hydrolase lowers portal hypertension in cirrhotic rats by ameliorating endothelial dysfunction and liver fibrosis.

PubMed

Deng, Wensheng; Zhu, Yiming; Lin, Jiayun; Zheng, Lei; Zhang, Chihao; Luo, Meng

2017-07-01

Epoxyeicostrienoic acids (EETs) are arachidonic acid derived meditators which are catalyzed by soluble epoxide hydrolase (sEH) to less active dihydroeicostrienoics acids (DHETS). The aim of our study is to investigate the effects of sEH inhibition on hepatic and systemic hemodynamics, hepatic endothelial dysfunction, and hepatic fibrosis in CCl4 cirrhotic rats. The sEH inhibitor,trans-4-{4-[3-(4-trifluoromethoxyphenyl)-ureido]cyclohexyloxy}benzoic acid (t-TUCB) was administered to stabilize hepatic EETs by gavage at a dose of 1mg/kg/d. Our results showed that hepatic sEH expression was markedly increased in portal hypertension, and led to a lower ratio of EETs/DHETs which was effectively reversed by t-TUCB administration. t-TUCB significantly decreased portal pressure without significant changes in systemic hemodynamics, which was associated with the attenuation of intrahepatic vascular resistance (IHVR) and liver fibrosis. t-TUCB ameliorated endothelial dysfunction, increased hepatic endothelial nitric oxide synthase (eNOS) phosphorylation and nitric oxide (NO) production. In addition, t-TUCB significantly reduced alpha-Smooth Muscle Actin (α-SMA) expression and liver fibrosis, which was associated with a decrease in NF-κB signaling. Taken together, inhibition of sEH reduces portal pressure, liver fibrosis and attenuates hepatic endothelial dysfunction in cirrhotic rats. Our results indicate that sEH inhbitors may be useful in the treatment of portal hypertension in patients with cirrhosis. Copyright © 2017 Elsevier Inc. All rights reserved.

Impact of Liver Indicators on Clinical Outcome in Patients Undergoing Transcatheter Aortic Valve Implantation.

PubMed

Wendt, Daniel; Kahlert, Philipp; Canbay, Ali; Knipp, Stephan; Thoenes, Martin; Cremer, Gordina; Al-Rashid, Fadi; Jánosi, Rolf-Alexander; El-Chilali, Karim; Kamler, Markus; El Gabry, Mohamed; Marx, Philipp; Dohle, Daniel Sebastian; Tsagakis, Konstantinos; Benedik, Jaroslav; Gerken, Guido; Rassaf, Tienush; Jakob, Heinz; Thielmann, Matthias

2017-10-01

Liver dysfunction increases death and morbidity after cardiac operations. There are currently no data evaluating liver function in patients undergoing transcatheter aortic valve replacement (TAVR). We aimed therefore to evaluate our TAVR results in regard to liver function. A total of 640 consecutive TAVR patients were evaluated. Of those, 11 patients presented with chronic liver disease before TAVR. The Model for End-Stage Liver Disease score was used to measure liver function in these patients. The primary study end point was 30-day mortality in patients presenting with liver dysfunction. Secondary study end point was liver enzymes after TAVR. The mean Model for End-Stage Liver Disease score in patients with chronic liver disease was 16.8 ± 6.2 (median, 18; range, 7 to 26). The 30-day mortality was 9.1% (57 of 629) in patients presenting without liver disease and 9.1% (1 of 11) in patients with liver disease (p = 1.00). Patients with chronic liver disease showed significantly higher preoperative levels of γ-glutamyl transpeptidase (p < 0.001). After TAVR, we observed a significant increase in alanine aminotransferase on postoperative day 3 compared with preoperative values (p < 0.001), accompanied by a decrease in albumin (p < 0.001). Liver cirrhosis per se is not considered as a contraindication for cardiac operations. In the present study, we did not observe a higher 30-day mortality rate in liver cirrhotic patients undergoing TAVR, suggesting TAVR as a feasible alternative with acceptable outcomes in patients with chronic liver disease. Moreover, the present study is the first to evaluate liver variables in patients undergoing TAVR. Copyright © 2017 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.

Fasting-induced liver GADD45β restrains hepatic fatty acid uptake and improves metabolic health.

PubMed

Fuhrmeister, Jessica; Zota, Annika; Sijmonsma, Tjeerd P; Seibert, Oksana; Cıngır, Şahika; Schmidt, Kathrin; Vallon, Nicola; de Guia, Roldan M; Niopek, Katharina; Berriel Diaz, Mauricio; Maida, Adriano; Blüher, Matthias; Okun, Jürgen G; Herzig, Stephan; Rose, Adam J

2016-06-01

Recent studies have demonstrated that repeated short-term nutrient withdrawal (i.e. fasting) has pleiotropic actions to promote organismal health and longevity. Despite this, the molecular physiological mechanisms by which fasting is protective against metabolic disease are largely unknown. Here, we show that, metabolic control, particularly systemic and liver lipid metabolism, is aberrantly regulated in the fasted state in mouse models of metabolic dysfunction. Liver transcript assays between lean/healthy and obese/diabetic mice in fasted and fed states uncovered "growth arrest and DNA damage-inducible" GADD45β as a dysregulated gene transcript during fasting in several models of metabolic dysfunction including ageing, obesity/pre-diabetes and type 2 diabetes, in both mice and humans. Using whole-body knockout mice as well as liver/hepatocyte-specific gain- and loss-of-function strategies, we revealed a role for liver GADD45β in the coordination of liver fatty acid uptake, through cytoplasmic retention of FABP1, ultimately impacting obesity-driven hyperglycaemia. In summary, fasting stress-induced GADD45β represents a liver-specific molecular event promoting adaptive metabolic function. © 2016 The Authors. Published under the terms of the CC BY 4.0 license.

Liver - guardian, modifier and target of sepsis.

PubMed

Strnad, Pavel; Tacke, Frank; Koch, Alexander; Trautwein, Christian

2017-01-01

Sepsis and septic shock are characterized by life-threatening organ dysfunction caused by a dysregulated host response to infection. The liver has a central role during sepsis, and is essential to the regulation of immune defence during systemic infections by mechanisms such as bacterial clearance, acute-phase protein or cytokine production and metabolic adaptation to inflammation. However, the liver is also a target for sepsis-related injury, including hypoxic hepatitis due to ischaemia and shock, cholestasis due to altered bile metabolism, hepatocellular injury due to drug toxicity or overwhelming inflammation, as well as distinct pathologies such as secondary sclerosing cholangitis in critically ill patients. Hence, hepatic dysfunction substantially impairs the prognosis of sepsis and serves as a powerful independent predictor of mortality in the intensive care unit. Sepsis is particularly problematic in patients with liver cirrhosis (who experience increased bacterial translocation from the gut and impaired microbial defence) as it can trigger acute-on-chronic liver failure - a syndrome with high short-term mortality. Here, we review the importance of the liver as a guardian, modifier and target of sepsis, the factors that contribute to sepsis in patients with liver cirrhosis and new therapeutic strategies.

Case Report: Ursodeoxycholic acid treatment in Niemann-Pick disease type C; clinical experience in four cases

PubMed Central

Movsesyan, Nina; Platt, Frances M.

2017-01-01

In this case series, we demonstrate that Ursodeoxycholic acid (UDCA) improves liver dysfunction in Niemann-Pick type C (NPC) and may restore a suppressed cytochrome p450 system. NPC disease is a progressive neurodegenerative lysosomal storage disease caused by mutations in either the NPC1 or NPC2 genes. Liver disease is a common feature presenting either acutely as cholestatic jaundice in the neonatal period, or in later life as elevated liver enzymes indicative of liver dysfunction. Recently, an imbalance in bile acid synthesis in a mouse model of NPC disease was linked to suppression of the P450 detoxification system and was corrected by UDCA treatment. UDCA (3α, 7β-dihydroxy-5β-cholanic acid), a hydrophilic bile acid, is used to treat various cholestatic disorders. In this report we summarise the findings from four independent cases of NPC, three with abnormal liver enzyme levels at baseline, that were subsequently treated with UDCA. The patients differed in age and clinical features, they all tolerated the drug well, and in those with abnormal liver function, there were significant improvements in their liver enzyme parameters. PMID:29119141

Early graft dysfunction and mortality rate in marginal donor liver transplantation.

PubMed

Sarkut, Pmar; Gülcü, Bariş; Işçimen, Remzi; Kiyici, Murat; Türker, Gürkan; Topal, Naile Bolca; Ozen, Yilmaz; Kaya, Ekrem

2014-01-01

To determine the effect of marginal donor livers on mortality and graft survival in liver transplantation (LT) recipients. Donors with any 1 of following were considered marginal donors: age ≥65 years, sodium level ≥ 165 mmol/L and cold ischemia time ≥ 12 h. Donors were classified according to the donor risk index (DRI) < 1.7 and ≥ 1.7. The transplant recipients' model for end-stage liver disease (MELD) scores were considered low if < 20 and high if ≥ 20. Early graft dysfunction (EGD) and mortality rate were evaluated. During the study period 47 patients underwent cadaveric LT. The mean age of the donors and recipients was 45 years (range: 5-72 years) and 46 years (range: 4-66 years), respectively. In all, there were 15 marginal donors and 18 donors with a DRI > 1.7. In total, 4 LT patients that received livers from marginal donors and 5 that received livers from donors with a DRI ≥ 1.7 had EGD. Among the recipients of marginal livers, 5 died, versus 4 of the recipients of standard livers. There was no significant difference in EGD or mortality rate between the patients that received livers from marginal donors or those with a DRI ≥ 1.7 and patients that received standard donor livers. Marginal and DRI ≥ 1.7 donors negatively affected LT outcomes, but not significantly.

Implantation of healthy matrix-embedded endothelial cells rescues dysfunctional endothelium and ischemic tissue in liver engraftment

PubMed Central

Melgar-Lesmes, Pedro; Balcells, Mercedes; Edelman, Elazer R.

2017-01-01

Objective Liver transplantation is limited by ischemic injury which promotes endothelial cell and hepatocyte dysfunction and eventually organ failure. We sought to understand how endothelial state determines liver recover after hepatectomy and engraftment. Design Matrix-embedded endothelial cells (MEECs) with retained healthy phenotype or control acellular matrices were implanted in direct contact with the remaining median lobe of donor mice undergoing partial hepatectomy (70%), or in the interface between the remaining median lobe and an autograft or isograft from the left lobe in hepatectomized recipient mice. Hepatic vascular architecture, DNA fragmentation and apoptosis in the median lobe and grafts, serum markers of liver damage and phenotype of macrophage and lymphocyte subsets in the liver after engraftment were analyzed 7 days post-op. Results Healthy MEECs create a functional vascular splice in donor and recipient liver after 70% hepatectomy in mouse protecting these livers from ischemic injury, hepatic congestion and inflammation. Macrophages recruited adjacent to the vascular nodes into the implants switched to an anti-inflammatory and regenerative profile M2. MEECs improved liver function and the rate of liver regeneration and prevented apoptosis in donor liver lobes, autologous grafts, and allogeneic engraftment. Conclusions Implants with healthy endothelial cells rescue liver donor and recipient endothelium and parenchyma from ischemic injury after major hepatectomy and engraftment. This study highlights endothelial-hepatocyte crosstalk in hepatic repair and provides a promising new approach to improve regenerative medicine outcomes and liver transplantation. PMID:26851165

Silybum marianum oil attenuates oxidative stress and ameliorates mitochondrial dysfunction in mice treated with D-galactose

PubMed Central

Zhu, Shu Yun; Dong, Ying; Tu, Jie; Zhou, Yue; Zhou, Xing Hua; Xu, Bin

2014-01-01

Background: Silybum marianum has been used as herbal medicine for the treatment of liver disease, liver cirrhosis, and to prevent liver cancer in Europe and Asia since ancient times. Silybum marianum oil (SMO), a by-product of silymarin production, is rich in essential fatty acids, phospholipids, sterols, and vitamin E. However, it has not been very good development and use. Objective: In the present study, we used olive oil as a control to investigate the antioxidant and anti-aging effect of SMO in D-galactose (D-gal)-induced aging mice. Materials and Methods: D-gal was injected intraperitoneally (500 mg/kg body weight daily) for 7 weeks while SMO was simultaneously administered orally. The triglycerides (TRIG) and cholesterol (CHOL) levels were estimated in the serum. Superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), total antioxidant capacity (T-AOC), monoamine oxidase (MAO), malondialdehyde (MDA), caspase-3, and Bcl-2 were determined in the liver and brain. The activities of Na+-K+-adenosine triphosphatase (ATPase), Ca2+-Mg2+-ATPase, membrane potential (ΔΨm), and membrane fluidity of the liver mitochondrial were estimated. Results: SMO decreased levels of TRIG and CHOL in aging mice. SMO administration elevated the activities of SOD, GSH-Px, and T-AOC, which are suppressed by aging. The levels of MAO and MDA in the liver and brain were reduced by SMO administration in aging mice. Enzyme linked immunosorbent assay showed that SMO significantly decreased the concentration of caspase-3 and improved the activity of Bcl-2 in the liver and brain of aging mice. Furthermore, SMO significantly attenuated the D-gal induced liver mitochondrial dysfunction by improving the activities of Na+-K+-ATPase, Ca2+-Mg2+-ATPase, membrane potential (ΔΨm), and membrane fluidity. Conclusion: These results indicate that SMO effectively attenuated oxidative damage and improved apoptosis related factors as well as liver mitochondrial dysfunction in aging mice. PMID:24914315

COMBINATION OF MOLECULAR ADSORBENT RECIRCULATING SYSTEM AND RADIOIODINE FOR THE TREATMENT OF CONCURRENT HYPERTHYROIDISM AND SEVERE LIVER DYSFUNCTION: A RETROSPECTIVE COHORT STUDY.

PubMed

Zhang, Qing; Guan, Yanxing; Xiang, Tianxin; Liu, Shaozheng; Chen, Qingjie; Zhang, Qing

2017-02-01

The treatment of hyperthyroidism associated with severe liver dysfunction (LD) is a clinical challenge, and there has been no unified examination of this problem. The objective of this study was to assess the efficacy and safety of radioiodine ( 131 I) in combination with a molecular adsorbent recirculating system (MARS) for the treatment of hyperthyroidism complicated by severe liver LD. A total of 116 hyperthyroidism patients with concomitant LD who received MARS treatment were studied retrospectively. The patients were grouped according to whether or not they also received 131 I treatment: Group 1 (59 patients) received 131 I following MARS treatment, while Group 2 (57 cases) received only MARS. Clinical outcomes, including thyroid hormone levels, liver function parameters, and therapeutic efficacy were calculated. The overall response rate was significantly greater in Group 1 than in Group 2 (P<.01). The clinical indicators improved significantly in both groups 3 months after treatment compared with before treatment (P<.05), but Group 1 showed a greater improvement. Compared with Group 1, patients in Group 2 had a longer stay in hospital (P<.05), and received more frequent MARS treatments (P<.05). The combination of MARS and 131 I for the treatment of hyperthyroidism complicated by severe LD was effective and safe. The use of this system could rapidly improve liver function and metabolism, allowing 131 I therapy to be applied as early as possible with a shortened recovery time of liver function. ALSS = artificial liver support system ALT = alanine transaminase AST = aspartate transaminase ATD = antithyroid drugs DBil = direct bilirubin FT3 = free tri-iodothyronine FT4 = free thyroxine 131 I = radioiodine INR = international normalized ratio LD = liver dysfunction MARS = molecular adsorbent recirculating system MELD = model for end-stage liver disease PT = prothrombin time TBil = total bilirubin TSH = thyroid-stimulating hormone.

FC-99 ameliorates sepsis-induced liver dysfunction by modulating monocyte/macrophage differentiation via Let-7a related monocytes apoptosis

PubMed Central

Zhao, Yarong; Zhu, Haiyan; Wang, Haining; Ding, Liang; Xu, Lizhi; Chen, Dai; Shen, Sunan; Hou, Yayi; Dou, Huan

2018-01-01

Background The liver is a vital target for sepsis-related injury, leading to inflammatory pathogenesis, multiple organ dysfunction and high mortality rates. Monocyte-derived macrophage transformations are key events in hepatic inflammation. N1-[(4-methoxy)methyl]-4-methyl-1,2-benzenediamine (FC-99) previously displayed therapeutic potential on experimental sepsis. However, the underlying mechanism of this protective effect is still not clear. Results FC-99 treatment attenuated the liver dysfunction in septic mice that was accompanied with reduced numbers of pro-inflammatory Ly6Chi monocytes in the peripheral blood and CD11b+F4/80lo monocyte-derived macrophages in the liver. These effects were attributed to the FC-99-induced apoptosis of CD11b+ cells. In PMA-differentiated THP-1 cells, FC-99 repressed the expression of CD11b, CD14 and caspase3 and resulted in a high proportion of Annexin V+ cells. Moreover, let-7a-5p expression was abrogated upon CLP stimulation in vivo, whereas it was restored by FC-99 treatment. TargetScan analysis and luciferase assays indicated that the anti-apoptotic protein BCL-XL was targeted by let-7a-5p. BCL-XL was inhibited by FC-99 in order to induce monocyte apoptosis, leading to the impaired monocyte-to-macrophage differentiation. Materials and Methods Murine acute liver failure was generated by caecal ligation puncture surgery after FC-99 administration; Blood samples and liver tissues were collected to determine the monocyte/macrophage subsets and the induction of apoptosis. Human acute monocytic leukemia cell line (THP-1) cells were pretreated with FC-99 followed by phorbol-12-myristate-13-acetate (PMA) stimulation, in order to induce monocyte-to-macrophage differentiation. The target of FC-99 and the mechanistic analyses were conducted by microarrays, qRT-PCR validation, TargetScan algorithms and a luciferase report assay. Conclusions FC-99 exhibits potential therapeutic effects on CLP-induced liver dysfunction by restoring let-7a-5p levels. PMID:29599918

Molecular evidence of offspring liver dysfunction after maternal exposure to zinc oxide nanoparticles.

PubMed

Hao, Yanan; Liu, Jing; Feng, Yanni; Yu, Shuai; Zhang, Weidong; Li, Lan; Min, Lingjiang; Zhang, Hongfu; Shen, Wei; Zhao, Yong

2017-08-15

Recently, reproductive, embryonic and developmental toxicity have been considered as one important sector of nanoparticle (NP) toxicology, with some studies already suggesting varying levels of toxicity and possible transgenerational toxic effects. Even though many studies have investigated the toxic effects of zinc oxide nanoparticles (ZnO NPs), little is known of their impact on overall reproductive outcome and transgenerational effects. Previously we found ZnO NPs caused liver dysfunction in lipid synthesis. This investigation, for the first time, explored the liver dysfunction at the molecular level of gene and protein expression in offspring after maternal exposure to ZnO NPs. Three pathways were investigated: lipid synthesis, growth related factors and cell toxic biomarkers/apoptosis at 5 different time points from embryonic day-18 to postnatal day-20. It was found that the expression of 15, 16, and 16 genes in lipid synthesis, growth related factors and cell toxic biomarkers/apoptosis signalling pathway respectively in F1 animal liver were altered by ZnO NPs compared to ZnSO 4 . The proteins in these signalling pathways (five in each pathways analyzed) in F1 animal liver were also changed by ZnO NPs compared to ZnSO 4 . The results suggest that ZnO NPs caused maternal liver defects can also be detected in offspring that might result in problems on offspring liver development, mainly on lipid synthesis, growth, and lesions or apoptosis. Along with others, this study suggests that ZnO NPs may pose reproductive, embryonic and developmental toxicity; therefore, precautions should be taken with regard to human exposure during daily life. Copyright © 2017 Elsevier Inc. All rights reserved.

Iron Chelation Therapy with Deferasirox Results in Improvement of Liver Enzyme Level in Patients with Iron Overload-Associated Liver Dysfunction

PubMed Central

Miura, Yasuo; Matsui, Yusuke; Kaneko, Hitomi; Watanabe, Mitsumasa; Tsudo, Mitsuru

2010-01-01

Iron chelation therapy (ICT) has been applied for the patients with iron overload-associated liver dysfunction since it is one of the causes of death in patients with intractable hematological diseases requiring multiple red blood cell transfusions. Recently, deferasirox (DSX), a novel, once-daily oral iron chelator, was demonstrated to have similar efficacy to the conventional continuous infusion of deferoxamine on a decrease in serum ferritin (SF) level in heavily transfused patients. We show three cases of transfusion-mediated iron-overloaded patients with an elevated serum alanine aminotransaminase (ALT). All three patients who received the ICT with DSX showed a decrease in ALT level in association with a decrease in SF level. It is suggested that DSX therapy could be considered to expect the improvement of liver damage for iron-overloaded patients with an abnormal ALT level. PMID:20592762

[Change in Perioperative Hemostatic Function in Patients Undergoing Hepatic Resection for Primary and Metastatic Liver Cancer].

PubMed

Komasawa, Nobuyasu; Ueki, Ryusuke; Atagi, Kazuaki; Nishi, Shinichi

2015-08-01

Patients undergoing primary hepatic resection often develop hemostatic dysfunction associated with cirrhosis. We retrospectively surveyed pre- and postoperative prothrombin time (PT) and the PT expressed as international normalized ratio (PT-INR) in 39 patients undergoing primary liver resection. We also compared PT changes between primary and metastatic cancer cases (8 cases). Postoperative PT-INR was 1.40 ± 0.38, which was significantly prolonged compared to preoperative PT-INR of 1.08 ± 0.07. Preoperative PT was over 70% in all 39 patients undergoing primary liver resection, whereas postoperative PT was less than 60% in 13 of 39 patients. No significant difference was found in preoperative PT-INR between primary and metastatic cancer cases, but postoperative PT-INR was significantly prolonged in primary cancer cases. Patients undergoing primary liver resection are susceptible to hemostatic dysfunction, even with preoperative PT levels within normal limits.

The role of external beam radiotherapy in the treatment of hepatocellular cancer.

PubMed

Chino, Fumiko; Stephens, Sarah Jo; Choi, Steve S; Marin, Daniele; Kim, Charles Y; Morse, Michael A; Godfrey, Devon J; Czito, Brian G; Willett, Christopher G; Palta, Manisha

2018-04-12

Hepatocellular carcinoma (HCC) is increasing in incidence and mortality. Although the prognosis remains poor, long-term survival has improved from 3% in 1970 to an 18% 5-year survival rate today. This is likely because of the introduction of well tolerated, oral antiviral therapies for hepatitis C. Curative options for patients with HCC are often limited by underlying liver dysfunction/cirrhosis and medical comorbidities. Less than one-third of patients are candidates for surgery, which is the current gold standard for cure. Nonsurgical treatments include embolotherapies, percutaneous ablation, and ablative radiation. Technological advances in radiation delivery in the past several decades now allow for safe and effective ablative doses to the liver. Conformal techniques allow for both dose escalation to target volumes and normal tissue sparing. Multiple retrospective and prospective studies have demonstrated that hypofractionated image-guided radiation therapy, used as monotherapy or in combination with other liver-directed therapies, can provide excellent local control that is cost effective. Therefore, as the HCC treatment paradigm continues to evolve, ablative radiation treatment has moved from a palliative treatment to both a "bridge to transplant" and a definitive treatment. Cancer 2018. © 2018 American Cancer Society. © 2018 American Cancer Society.

Score of liver ultrasonography predicts treatment-related severe neutropenia and neutropenic fever in induction chemotherapy with docetaxel for locally advanced head and neck cancer patients with normal serum transamines.

PubMed

Wang, Ting-Yao; Chen, Wei-Ming; Yang, Lan-Yan; Chen, Chao-Yu; Chou, Wen-Chi; Chen, Yi-Yang; Chen, Chih-Cheng; Lee, Kuan-Der; Lu, Chang-Hsien

2016-11-01

Induction chemotherapy with docetaxel improved outcome in advanced head and neck squamous cell carcinoma (HNSCC) patients, but docetaxel was not recommended in liver dysfunction patients for treatment toxicities. Severe neutropenic events (SNE) including severe neutropenia (SN) and febrile neutropenia (FN) still developed in these patients with normal serum transaminases. Ultrasonography (US) fibrotic score represented degree of hepatic parenchymal damage and showed good correlation to fibrotic changes histologically. This study aims to evaluate the association of US fibrotic score with docetaxel treatment-related SNE in advanced HNSCC patients with normal serum transaminases. Between 1 January 2011 and 31 December 2013, a total of 47 advanced HNSCC patients treated with induction docetaxel were enrolled. The clinical features were collected to assess predictive factors for SNE. The patients were divided into two groups by the US fibrotic score with a cutoff value of 7. The Mann-Whitney U test and logistic regression method were used for the risk factor analysis. The background, treatment, and response were similar in both groups except for lower lymphocyte and platelet count in patients with higher US score. Twenty-seven patients (51 %) developed grade 3/4 neutropenia, and more SNE developed in patients with US score ≧7. In multivariate analysis, only US score ≥7 was independent predictive factor for developing SN (hazard ratio 7.71, p = 0.043) and FN (hazard ratio 20.95, p = 0.008). US score ≥7 is an independent risk factor for SNE in advanced HNSCC patients treated with induction docetaxel. US score could be used for risk prediction of docetaxel-related SNE.

Pulmonary arterial hypertension associated with chronic active Epstein-Barr virus infection.

PubMed

Fukuda, Yutaka; Momoi, Nobuo; Akaihata, Mitsuko; Nagasawa, Katsutoshi; Mitomo, Masaki; Aoyagi, Yoshimichi; Endoh, Kisei; Hosoya, Mitsuaki

2015-08-01

Chronic active Epstein-Barr virus (EBV) infection (CAEBV), characterized by persistent infectious mononucleosis-like symptoms, can lead to cardiovascular complications including coronary artery aneurysm or myocarditis. Here, we present the case of an 11-year-old boy with pulmonary arterial hypertension (PAH) and junctional ectopic tachycardia associated with CAEBV. The patient did not have any major symptoms attributed to CAEBV, such as fever, lymphadenopathy or splenomegaly when the PAH developed. Mild liver dysfunction was found at the first examination, and it persisted. Two years after the PAH symptoms appeared, CAEBV was evident, based on deteriorated liver function, hepatosplenomegaly, and coronary artery aneurysms. CAEBV should be considered as a cause of secondary PAH, particularly when liver dysfunction coexists. © 2015 Japan Pediatric Society.

Mesenchymal stem cells correct haemodynamic dysfunction associated with liver injury after extended resection in a pig model.

PubMed

Tautenhahn, Hans-Michael; Brückner, Sandra; Uder, Christiane; Erler, Silvio; Hempel, Madlen; von Bergen, Martin; Brach, Janine; Winkler, Sandra; Pankow, Franziska; Gittel, Claudia; Baunack, Manja; Lange, Undine; Broschewitz, Johannes; Dollinger, Matthias; Bartels, Michael; Pietsch, Uta; Amann, Kerstin; Christ, Bruno

2017-06-01

In patients, acute kidney injury (AKI) is often due to haemodynamic impairment associated with hepatic decompensation following extended liver surgery. Mesenchymal stem cells (MSCs) supported tissue protection in a variety of acute and chronic diseases, and might hence ameliorate AKI induced by extended liver resection. Here, 70% liver resection was performed in male pigs. MSCs were infused through a central venous catheter and haemodynamic parameters as well as markers of acute kidney damage were monitored under intensive care conditions for 24 h post-surgery. Cytokine profiles were established to anticipate the MSCs' potential mode of action. After extended liver resection, hyperdynamic circulation, associated with hyponatraemia, hyperkalaemia, an increase in serum aldosterone and low urine production developed. These signs of hepatorenal dysfunction and haemodynamic impairment were corrected by MSC treatment. MSCs elevated PDGF levels in the serum, possibly contributing to circulatory homeostasis. Another 14 cytokines were increased in the kidney, most of which are known to support tissue regeneration. In conclusion, MSCs supported kidney and liver function after extended liver resection. They probably acted through paracrine mechanisms improving haemodynamics and tissue homeostasis. They might thus provide a promising strategy to prevent acute kidney injury in the context of post-surgery acute liver failure.

Two and a Half Hours of Cardiopulmonary Resuscitation in a Deceased Brain Dead Donor before Liver Transplantation - A Good Idea to Accept?

PubMed

Hoyer, Dieter P; Kaiser, Gernot M; Paul, Andreas; Machairas, Nikolaos; Molmenti, Ernesto P; Sotiropoulos, Georgios C

2017-01-01

The sequelae of cardiac arrest (CA) and cardiopulmonary resuscitation (CPR) in organ donors potentially results in ischemic organ injury and graft dysfunction after transplantation. Thresholds of resuscitation times in brain dead liver donors have not been established so far. We report the case of a brain dead liver donor who experienced 2.5 hours of CPR whose liver was successfully transplanted. A 75-year-old male experienced CA and was treated by CPR with streptokinase application for 2.5 hours until stabilization of cardiac function. Brain death was diagnosed at the day of admission and organ donation carried out within 24 hours. The DRI was 2.2 with a CIT of 8.8 hours. The liver was transplanted into a 64-year-old recipient suffering from alcoholic liver cirrhosis and a MELD-score of 10 non representative for severity of disease. During follow up of 4 years ERCP and stenting was performed regularly for biliary anastomosis stenosis. The patient remained in a very good overall state of health without any signs of liver dysfunction. This case demonstrates that an extensive period of CPR is not an obligatory exclusion criterion for liver donation. Thresholds of CPR times as well as predictive factors in donors with CA should be established. Celsius.

Plasma cholesterol-lowering and transient liver dysfunction in mice lacking squalene synthase in the liver[S

PubMed Central

Nagashima, Shuichi; Yagyu, Hiroaki; Tozawa, Ryuichi; Tazoe, Fumiko; Takahashi, Manabu; Kitamine, Tetsuya; Yamamuro, Daisuke; Sakai, Kent; Sekiya, Motohiro; Okazaki, Hiroaki; Osuga, Jun-ichi; Honda, Akira; Ishibashi, Shun

2015-01-01

Squalene synthase (SS) catalyzes the biosynthesis of squalene, the first specific intermediate in the cholesterol biosynthetic pathway. To test the feasibility of lowering plasma cholesterol by inhibiting hepatic SS, we generated mice in which SS is specifically knocked out in the liver (L-SSKO) using Cre-loxP technology. Hepatic SS activity of L-SSKO mice was reduced by >90%. In addition, cholesterol biosynthesis in the liver slices was almost eliminated. Although the hepatic squalene contents were markedly reduced in L-SSKO mice, the hepatic contents of cholesterol and its precursors distal to squalene were indistinguishable from those of control mice, indicating the presence of sufficient centripetal flow of cholesterol and/or its precursors from the extrahepatic tissues. L-SSKO mice showed a transient liver dysfunction with moderate hepatomegaly presumably secondary to increased farnesol production. In a fed state, the plasma total cholesterol and triglyceride were significantly reduced in L-SSKO mice, primarily owing to reduced hepatic VLDL secretion. In a fasted state, the hypolipidemic effect was lost. mRNA expression of liver X receptor α target genes was reduced, while that of sterol-regulatory element binding protein 2 target genes was increased. In conclusion, liver-specific ablation of SS inhibits hepatic cholesterol biosynthesis and induces hypolipidemia without increasing significant mortality. PMID:25755092

Current perspectives on the health risks associated with the consumption of advanced glycation end products: recommendations for dietary management

PubMed Central

Palimeri, Sotiria; Palioura, Eleni; Diamanti-Kandarakis, Evanthia

2015-01-01

Advanced glycation end products (AGEs) constitute a complex group of compounds produced endogenously during the aging process and under conditions of hyperglycemia and oxidative stress. AGEs also have an emerging exogenous origin. Cigarette smoke and diet are the two main exogenous sources of AGEs (glycotoxins). Modern Western diets are rich in AGEs which have been implicated in the pathogenesis of several metabolic and degenerative disorders. Accumulating evidence underlies the beneficial effect of the dietary restriction of AGEs not only in animal studies but also in patients with diabetic complications and metabolic diseases. This article reviews the evidence linking dietary glycotoxins to several disorders from diabetic complications and renal failure to liver dysfunction, female reproduction, eye and cognitive disorders as well as cancer. Furthermore, strategies for AGE reduction are discussed with a focus on dietary modification. PMID:26366100

Dietary fructose as a risk factor for non-alcoholic fatty liver disease (NAFLD).

PubMed

Alwahsh, Salamah Mohammad; Gebhardt, Rolf

2017-04-01

Glucose is a major energy source for the entire body, while fructose metabolism occurs mainly in the liver. Fructose consumption has increased over the last decade globally and is suspected to contribute to the increased incidence of non-alcoholic fatty liver disease (NAFLD). NAFLD is a manifestation of metabolic syndrome affecting about one-third of the population worldwide and has progressive pathological potential for liver cirrhosis and cancer through non-alcoholic steatohepatitis (NASH). Here we have reviewed the possible contribution of fructose to the pathophysiology of NAFLD. We critically summarize the current findings about several regulators, and their potential mechanisms, that have been studied in humans and animal models in response to fructose exposure. A novel hypothesis on fructose-dependent perturbation of liver regeneration and metabolism is advanced. Fructose intake could affect inflammatory and metabolic processes, liver function, gut microbiota, and portal endotoxin influx. The role of the brain in controlling fructose ingestion and the subsequent development of NAFLD is highlighted. Although the importance for fructose (over)consumption for NAFLD in humans is still debated and comprehensive intervention studies are invited, understanding of how fructose intake can favor these pathological processes is crucial for the development of appropriate noninvasive diagnostic and therapeutic approaches to detect and treat these metabolic effects. Still, lifestyle modification, to lessen the consumption of fructose-containing products, and physical exercise are major measures against NAFLD. Finally, promising drugs against fructose-induced insulin resistance and hepatic dysfunction that are emerging from studies in rodents are reviewed, but need further validation in human patients.

Glycogenic hepatopathy: A narrative review.

PubMed

Sherigar, Jagannath M; Castro, Joline De; Yin, Yong Mei; Guss, Debra; Mohanty, Smruti R

2018-02-27

Glycogenic hepatopathy (GH) is a rare complication of the poorly controlled diabetes mellitus characterized by the transient liver dysfunction with elevated liver enzymes and associated hepatomegaly caused by the reversible accumulation of excess glycogen in the hepatocytes. It is predominantly seen in patients with longstanding type 1 diabetes mellitus and rarely reported in association with type 2 diabetes mellitus. Although it was first observed in the pediatric population, since then, it has been reported in adolescents and adults with or without ketoacidosis. The association of GH with hyperglycemia in diabetes has not been well established. One of the essential elements in the pathophysiology of development of GH is the wide fluctuation in both glucose and insulin levels. GH and non-alcoholic fatty liver disease (NAFLD) are clinically indistinguishable, and latter is more prevalent in diabetic patients and can progress to advanced liver disease and cirrhosis. Gradient dual-echo MRI can distinguish GH from NAFLD; however, GH can reliably be diagnosed only by liver biopsy. Adequate glycemic control can result in complete remission of clinical, laboratory and histological abnormalities. There has been a recent report of varying degree of liver fibrosis identified in patients with GH. Future studies are required to understand the biochemical defects underlying GH, noninvasive, rapid diagnostic tests for GH, and to assess the consequence of the fibrosis identified as severe fibrosis may progress to cirrhosis. Awareness of this entity in the medical community including specialists is low. Here we briefly reviewed the English literature on pathogenesis involved, recent progress in the evaluation, differential diagnosis, and management.

Angiotensin-converting enzyme inhibitor prevents oxidative stress, inflammation, and fibrosis in carbon tetrachloride-treated rat liver.

PubMed

Reza, Hasan Mahmud; Tabassum, Nabila; Sagor, Md Abu Taher; Chowdhury, Mohammed Riaz Hasan; Rahman, Mahbubur; Jain, Preeti; Alam, Md Ashraful

2016-01-01

Hepatic fibrosis is a common feature of chronic liver injury, and the involvement of angiotensin II in such process has been studied earlier. We hypothesized that anti-angiotensin II agents may be effective in preventing hepatic fibrosis. In this study, Long Evans female rats were used and divided into four groups such as Group-I, Control; Group-II, Control + ramipril; Group-III, CCl4; and Group-IV, CCl4 + ramipril. Group II and IV are treated with ramipril for 14 d. At the end of treatment, the livers were removed, and the level of hepatic marker enzymes (aspartate aminotransferase, Alanine aminotransferase, and alkaline phosphatase), nitric oxide, advanced protein oxidation product , catalase activity, and lipid peroxidation were determined. The degree of fibrosis was evaluated through histopathological staining with Sirius red and trichrome milligan staining. Carbon-tetrachloride (CCl4) administration in rats developed hepatic dysfunction and raised the hepatic marker enzymes activities significantly. CCl4 administration in rats also produced oxidative stress, inflammation, and fibrosis in liver. Furthermore, angiotensinogen-inhibitor ramipril normalized the hepatic enzymes activities and improved the antioxidant enzyme catalase activity. Moreover, ramipril treatment ameliorated lipid peroxidation and hepatic inflammation in CCl4-treated rats. Ramipril treatment also significantly reduced hepatic fibrosis in CCl4-administered rats. In conclusion, our investigation suggests that the antifibrotic effect of ramipril may be attributed to inhibition of angiotensin-II mediated oxidative stress and inflammation in liver CCl4-administered rats.

Alcoholic liver disease.

PubMed

Penny, Steven M

2013-01-01

In the United States, approximately 100,000 deaths are attributed to alcohol abuse each year. In 2009, the World Health Organization listed alcohol use as one of the leading causes of the global burden of disease and injury. Alcoholic liver disease, a direct result of chronic alcohol abuse, insidiously destroys the normal functions of the liver. The end result of the disease, cirrhosis, culminates in a dysfunctional and diffusely scarred liver. This article discusses the clinical manifestations, imaging considerations, and treatment of alcoholic liver disease and cirrhosis. Normal liver function, liver hemodynamics, the disease of alcoholism, and the deleterious effects of alcohol also are reviewed.

Steroidal compounds in commercial parenteral lipid emulsions.

PubMed

Xu, Zhidong; Harvey, Kevin A; Pavlina, Thomas; Dutot, Guy; Hise, Mary; Zaloga, Gary P; Siddiqui, Rafat A

2012-08-01

Parenteral nutrition lipid emulsions made from various plant oils contain steroidal compounds, called phytosterols. During parenteral administration of lipid emulsions, phytosterols can reach levels in the blood that are many fold higher than during enteral administration. The elevated phytosterol levels have been associated with the development of liver dysfunction and the rare development of liver failure. There is limited information available in the literature related to phytosterol concentrations in lipid emulsions. The objective of the current study was to validate an assay for steroidal compounds found in lipid emulsions and to compare their concentrations in the most commonly used parenteral nutrition lipid emulsions: Liposyn(®) II, Liposyn(®) III, Lipofundin(®) MCT, Lipofundin(®) N, Structolipid(®), Intralipid(®), Ivelip(®) and ClinOleic(®). Our data demonstrates that concentrations of the various steroidal compounds varied greatly between the eight lipid emulsions, with the olive oil-based lipid emulsion containing the lowest levels of phytosterols and cholesterol, and the highest concentration of squalene. The clinical impression of greater incidences of liver dysfunction with soybean versus MCT/LCT and olive/soy lipid emulsions may be reflective of the levels of phytosterols in these emulsions. This information may help guide future studies and clinical care of patients with lipid emulsion-associated liver dysfunction.

Steroidal Compounds in Commercial Parenteral Lipid Emulsions

PubMed Central

Xu, Zhidong; Harvey, Kevin A.; Pavlina, Thomas; Dutot, Guy; Hise, Mary; Zaloga, Gary P.; Siddiqui, Rafat A.

2012-01-01

Parenteral nutrition lipid emulsions made from various plant oils contain steroidal compounds, called phytosterols. During parenteral administration of lipid emulsions, phytosterols can reach levels in the blood that are many fold higher than during enteral administration. The elevated phytosterol levels have been associated with the development of liver dysfunction and the rare development of liver failure. There is limited information available in the literature related to phytosterol concentrations in lipid emulsions. The objective of the current study was to validate an assay for steroidal compounds found in lipid emulsions and to compare their concentrations in the most commonly used parenteral nutrition lipid emulsions: Liposyn® II, Liposyn® III, Lipofundin® MCT, Lipofundin® N, Structolipid®, Intralipid®, Ivelip® and ClinOleic®. Our data demonstrates that concentrations of the various steroidal compounds varied greatly between the eight lipid emulsions, with the olive oil-based lipid emulsion containing the lowest levels of phytosterols and cholesterol, and the highest concentration of squalene. The clinical impression of greater incidences of liver dysfunction with soybean versus MCT/LCT and olive/soy lipid emulsions may be reflective of the levels of phytosterols in these emulsions. This information may help guide future studies and clinical care of patients with lipid emulsion-associated liver dysfunction. PMID:23016123

Safety and efficacy of sofosbuvir and ribavirin for genotype 2 hepatitis C Japanese patients with renal dysfunction.

PubMed

Sho, Takuya; Suda, Goki; Nagasaka, Atsushi; Yamamoto, Yoshiya; Furuya, Ken; Kumagai, Kenichi; Uebayashi, Minoru; Terashita, Katsumi; Kobayashi, Tomoe; Tsunematsu, Izumi; Onodera, Manabu; Meguro, Takashi; Kimura, Megumi; Ito, Jun; Umemura, Machiko; Izumi, Takaaki; Kawagishi, Naoki; Ohara, Masatsugu; Ono, Yuji; Nakai, Masato; Natsuizaka, Mitsuteru; Morikawa, Kenichi; Ogawa, Koji; Sakamoto, Naoya

2018-06-01

The safety and efficacy of sofosbuvir (SOF) and ribavirin (RBV) have not been well clarified in patients with renal dysfunction because clinical trials have not included such patients. We evaluated the safety and efficacy of SOF and RBV for genotype 2 hepatitis C virus (HCV)-infected patients with renal dysfunction. The study included genotype 2 HCV-infected patients who received SOF and RBV between July 2014 and May 2017. The sustained virologic response (SVR) after the treatment and safety during the therapy were evaluated according to renal function. A total of 231 patients were included in this study. The median age was 62 years old, and 45.9% (106/231) were men. Of the 231 patients, 191 (82.8%) and 40 (17.2%) were classified as having chronic kidney disease (CKD) stages G1/2 and G3, respectively. The overall SVR rate was 97% (224/231). The SVR rates in patients with CKD stages G1, 2, G3a, and G3b were 98.1%, 98.6%, 87.9%, and 100%, respectively, and this therapy was tolerated. Multivariate analysis indicated that renal dysfunction was significantly associated with a non-SVR (odds ratio, 6.963; 95% confidence interval, 1.494-32.41; P = 0.013). The patients with renal dysfunction were older, had advanced liver fibrosis, lower baseline platelet and hemoglobin levels, and a higher rate of RBV dose reduction. Sofosbuvir and RBV therapy is highly effective and safe for genotype 2 HCV-infected Japanese patients. However, attention should be paid to baseline renal function when SOF- and RBV-containing regimens are used for patients with renal dysfunction. © 2018 The Japan Society of Hepatology.

Talazoparib in Treating Patients With Advanced or Metastatic Solid Tumors That Cannot Be Removed by Surgery and Liver or Kidney Dysfunction

ClinicalTrials.gov

2017-04-20

Estrogen Receptor Negative; Head and Neck Squamous Cell Carcinoma; HER2/Neu Negative; Hormone-Resistant Prostate Cancer; Metastatic Pancreatic Adenocarcinoma; Progesterone Receptor Negative; Solid Neoplasm; Stage III Mesothelioma; Stage IIIA Gastric Cancer; Stage IIIA Non-Small Cell Lung Cancer; Stage IIIA Ovarian Cancer; Stage IIIA Small Cell Lung Carcinoma; Stage IIIB Gastric Cancer; Stage IIIB Non-Small Cell Lung Cancer; Stage IIIB Ovarian Cancer; Stage IIIB Small Cell Lung Carcinoma; Stage IIIC Gastric Cancer; Stage IIIC Ovarian Cancer; Stage IV Mesothelioma; Stage IV Non-Small Cell Lung Cancer; Stage IV Ovarian Cancer; Stage IV Small Cell Lung Carcinoma; Triple-Negative Breast Carcinoma

Outcomes in Adults With Acute Liver Failure Between 1998 and 2013

PubMed Central

Reuben, Adrian; Tillman, Holly; Fontana, Robert J.; Davern, Timothy; McGuire, Brendan; Stravitz, R. Todd; Durkalski, Valerie; Larson, Anne M.; Liou, Iris; Fix, Oren; Schilsky, Michael; McCashland, Timothy; Hay, J. Eileen; Murray, Natalie; Shaikh, Obaid S.; Ganger, Daniel; Zaman, Atif; Han, Steven B.; Chung, Raymond T.; Smith, Alastair; Brown, Robert; Crippin, Jeffrey; Harrison, M. Edwyn; Koch, David; Munoz, Santiago; Reddy, K. Rajender; Rossaro, Lorenzo; Satyanarayana, Raj; Hassanein, Tarek; Hanje, A. James; Olson, Jody; Subramanian, Ram; Karvellas, Constantine; Hameed, Bilal; Sherker, Averell H.; Robuck, Patricia; Lee, William M.

2017-01-01

Background Acute liver failure (ALF) is a rare syndrome of severe, rapid-onset hepatic dysfunction without prior advanced liver disease that is associated with high morbidity and mortality. Intensive care and liver transplantation provide support and rescue, respectively. Objective To determine whether changes in causes, disease severity, treatment, or 21-day outcomes have occurred in recent years among adult patients with ALF referred to U.S. tertiary care centers. Design Prospective observational cohort study. (ClinicalTrials.gov: NCT00518440) Setting 31 liver disease and transplant centers in the United States. Patients Consecutively enrolled patients–without prior advanced liver disease–with ALF (n = 2070). Measurements Clinical features, treatment, and 21-day outcomes were compared over time annually for trends and were also stratified into two 8-year periods (1998 to 2005 and 2006 to 2013). Results Overall clinical characteristics, disease severity, and distribution of causes remained similar throughout the study period. The 21-day survival rates increased between the two 8-year periods (overall, 67.1% vs. 75.3%; transplant-free survival [TFS], 45.1% vs. 56.2%; posttransplantation survival, 88.3% vs. 96.3% [P < 0.010 for each]). Reductions in red blood cell infusions (44.3% vs. 27.6%), plasma infusions (65.2% vs. 47.1%), mechanical ventilation (65.7% vs. 56.1%), and vasopressors (34.9% vs. 27.8%) were observed, as well as increased use of N-acetylcysteine (48.9% vs. 69.3% overall; 15.8% vs. 49.4% [P < 0.001] in patients with ALF not due to acetaminophen toxicity). When examined longitudinally, overall survival and TFS increased throughout the 16-year period. Limitations The duration of enrollment, the number of patients enrolled, and possibly the approaches to care varied among participating sites. The results may not be generalizable beyond such specialized centers. Conclusion Although characteristics and severity of ALF changed little over 16 years, overall survival and TFS improved significantly. The effects of specific changes in intensive care practice on survival warrant further study. Primary Funding Source National Institutes of Health. PMID:27043883

An Evaluation of the Usefulness of Extracorporeal Liver Support Techniques in Patients Hospitalized in the ICU for Severe Liver Dysfunction Secondary to Alcoholic Liver Disease

PubMed Central

Piechota, Mariusz; Piechota, Anna

2016-01-01

Background The mortality rate in patients with severe liver dysfunction secondary to alcoholic liver disease (ALD) who do not respond to the standard treatment is exceptionally high. Objectives The main aim of this study was to evaluate the usefulness of applying extracorporeal liver support techniques to treat this group of patients. Patients and Methods The data from 23 hospital admissions of 21 patients with ALD who were admitted to the department of anesthesiology and intensive therapy (A&IT) at the Dr Wł. Biegański Regional Specialist Hospital in Łódź between March 2013 and July 2015 were retrospectively analyzed. Results A total of 111 liver dialysis procedures were performed during the 23 hospitalizations, including 13 dialyses using fractionated plasma separation and adsorption (FPSA) with the Prometheus® system, and 98 procedures using the single pass albumin dialysis (SPAD) system. Upon admission to the intensive care unit (ICU), the median (interquartile range [IQR]) Glasgow coma scale (GCS), sequential organ failure assessment (SOFA), acute physiology and chronic health evaluation (APACHE) II, and simplified acute physiology score (SAPS) II scores were 15 (14 - 15), 9 (7 - 13), 17 (14 - 24), and 32 (22 - 50), respectively. The ICU, 30-day, and three-month mortality rates were 43.48%, 39.13%, and 73.91%, respectively. As determined by the receiver operative characteristic (ROC) analysis for single-factor models, the significant predictors of death in the ICU included the patients’ SOFA, APACHE II, SAPS II, and model of end-stage liver disease modified by the united network for organ sharing (MELD UNOS Modification) scores; the duration of stay (in days) in the A&IT Department; and bile acid, creatinine and albumin levels upon ICU admission. The ROC analysis indicated the significant discriminating power of the SOFA, APACHE II, SAPS II, and MELD UNOS modification scores on the three-month mortality rate. Conclusions The application of extracorporeal liver support techniques in patients with severe liver dysfunction secondary to ALD appears justified in the subset of patients with MELD UNOS Modification scores of 18 - 30. PMID:27642344

Ameliorative Effect of Caffeic Acid on Capecitabine-Induced Hepatic and Renal Dysfunction: Involvement of the Antioxidant Defence System

PubMed Central

Olayinka, Ebenezer Tunde; Ore, Ayokanmi; Adeyemo, Oluwatobi Adewumi

2017-01-01

Background: It has been postulated that during liver and kidney damage there is a decreased in the antioxidant status associated with a simultaneous increase in the reactive oxygen species and lipid peroxidation. In consonant with this, Capecitabine, an oral chemotherapy and inactive non-cytotoxic fluoropyrimidine considered for the treatment of advance colorectal cancer, has also been shown to induce oxidative stress in liver tissues. Caffeic acid, a typical hydroxycinnamic, has been claimed to be effective against oxidative stress. Therefore, this present work studied the protective effect of caffeic acid on oxidative stress-induced liver and kidney damage by the administration of capecitabine. Methods: Twenty-four male Wistar strain rats were randomly divided into four treatment groups: A. control, B. capecitabine (CPTB)-treated group (30 mg/kg b.w. CPTB), C. caffeic acid (CFA)-treated group (100 mg/kg b.w. CFA) and D. co-treated group with CFA (100 mg/kg b.w.) and CPTB (30 mg/kg b.w.). Results: Caffeic acid administration significantly ameliorated the elevated plasma biomarkers of hepatic and renal tissue damage induced by the capecitabine and improved enzymatic and non-enzymatic antioxidant levels in liver organ. Conclusions: The protective effect of caffeic acid could be attributed to its ability to boost the antioxidant defence system and reduce lipid peroxidation. PMID:29068374

Diabetic cognitive dysfunction is associated with increased bile acids in liver and activation of bile acid signaling in intestine.

PubMed

Wang, Xue; Wang, Fangyu; Zhang, Yidan; Xiong, Hui; Zhang, Yanjun; Zhuang, Pengwei; Zhang, Youcai

2018-05-01

Impaired regulation of bile acid (BA) homeostasis has been suggested to be associated with adverse metabolic consequences. However, whether BA homeostasis is altered in diabetes-induced cognitive dysfunction (DCD) remains unknown. In the present study, mice were divided into four groups, namely normal control (NC) group, high-fat diet (HFD) group, diabetes without cognitive dysfunction (unDCD) group, and DCD group. Compared to HFD mice, the concentration of total BAs in liver was higher in unDCD and DCD mice, due to increased intestinal BA absorption. DCD mice tended to have higher BA concentrations in both liver and ileum than unDCD mice. Consequently, DCD mice had increased basolateral BA efflux (Ostα, Ostβ, and Mrp4) and decreased BA synthesis (Cyp7a1, Cyp8b1, and Cyp7b1) in the liver as well as activated Fxr-Fgf15 signaling in the ileum. DCD mice also had increased BA hydroxylation (Cyp3a11) and BA sulfation (Sult2a1) in the liver compared to HFD mice. Furthermore, the bacterial community composition was altered in the cecum of DCD mice, characterized with a marked increase in Defferribacteres and Candidatus Saccharibacteria. In summary, the present study provides the first comprehensive analysis of BA homeostasis in DCD mice, and revealed a potential role of BAs in DCD development. Copyright © 2018 Elsevier B.V. All rights reserved.

Hepatoprotective Effect of Essential Oils from Hyptis crenata in Sepsis-Induced Liver Dysfunction.

PubMed

Lima, Glauber Cruz; Vasconcelos, Yuri de Abreu Gomes; de Santana Souza, Marilia Trindade; Oliveira, Alan Santos; Bomfim, Rangel Rodrigues; de Albuquerque Júnior, Ricardo Luiz Cavalcanti; Camargo, Enilton Aparecido; Portella, Viviane Gomes; Coelho-de-Souza, Andrelina Noronha; Diniz, Lúcio Ricardo Leite

2018-02-28

No specific therapeutics are available for the treatment of sepsis-induced liver dysfunction, a clinical complication strongly associated with the high mortality rate of septic patients. This study investigated the effect of the essential oil of Hyptis crenata (EOHc), a lamiaceae plant used to treat liver disturbances in Brazilian folk medicine, on liver function during early sepsis. Sepsis was induced by the cecal ligation and puncture (CLP) model. Rats were divided into four groups: Sham, Sham+EOHc, CLP, and CLP+EOHc. EOHc (300 mg/kg) was orally administered 12 and 24 h after surgery. The animals were sacrificed for blood collection and liver tissue samples 48 h after surgery. Hepatic function was evaluated by measuring serum bilirubin, alkaline phosphatase (ALP), aspartate aminotransferase, and alanine aminotransferase (ALT) levels. The levels of malondialdehyde and the activity of superoxide dismutase, catalase, and GSH peroxidase (GSH-Px) were measured for assessment of oxidative stress. Liver morphology was analyzed by hematoxylin and eosin staining. EOHc normalized serum ALP, ALT, and bilirubin levels and inhibited morphological changes. In addition, we observed that EOHc inhibited elevation in hepatic lipid peroxidation and reduction of the glutathione peroxidase activity induced by sepsis. Our data show that EOHc plays a protective effect against liver injury induced by sepsis.

Fatty acid methyl esters are detectable in the plasma and their presence correlates with liver dysfunction.

PubMed

Aleryani, Samir Lutf; Cluette-Brown, Joanne E; Khan, Zia A; Hasaba, Hasan; Lopez de Heredia, Luis; Laposata, Michael

2005-09-01

Methanol is a component of certain alcoholic beverages and is also an endogenously formed product. On this basis, we have proposed that methanol may promote synthesis of fatty acid methyl esters (FAMEs) in the same way that ethanol promotes fatty acid ethyl ester (FAEE) synthesis. We tested the hypothesis that FAMEs appear in the blood after ethanol intake. Patient plasma samples obtained from our laboratory (n=78) were grouped according to blood ethanol concentrations (intoxicated, blood ethanol >800 mg/l) and non-intoxicated. These samples were further subdivided into groups based on whether the patient had normal or abnormal liver function tests (abnormal, defined as > or =1 abnormality of plasma alanine and aspartate aminotransferase, albumin, total bilirubin, and alkaline phosphatase). A separate set of plasma samples were also divided into normal and abnormal groups based on pancreatic function tests (amylase and lipase). There were no patients with detectable ethanol in this group. Patients with abnormalities in pancreatic function tests were included upon recognition of endogenously produced FAMEs by patients with liver function test abnormalities. FAMEs were extracted from plasma and individual species of FAMEs quantified by gas chromatography-mass spectrometry (GC/MS). Increased concentrations of FAME were found in patient samples with evidence of liver dysfunction, regardless of whether or not they were intoxicated (n=21, p=0.01). No significant differences in plasma FAME concentrations were found between patients with normal (n=15) versus abnormal pancreatic function tests (n=22, p=0.72). The presence of FAMEs in human plasma may be related to the existence of liver disease, and not to blood ethanol concentrations or pancreatic dysfunction. The metabolic pathways associated with FAME production in patients with impaired liver function remain to be identified.

Glutamine Supplementation Attenuates Ethanol-Induced Disruption of Apical Junctional Complexes in Colonic Epithelium and Ameliorates Gut Barrier Dysfunction and Fatty Liver in Mice

PubMed Central

Chaudhry, Kamaljit K.; Shukla, Pradeep K.; Mir, Hina; Manda, Bhargavi; Gangwar, Ruchika; Yadav, Nikki; McMullen, Megan; Nagy, Laura E.; Rao, RadhaKrishna

2015-01-01

Previous in vitro studies showed that glutamine (Gln) prevents acetaldehyde-induced disruption of tight junctions and adherens junctions in Caco-2 cell monolayers and human colonic mucosa. In the present study, we evaluated the effect of Gln supplementation on ethanol-induced gut barrier dysfunction and liver injury in mice in vivo. Ethanol feeding caused a significant increase in inulin permeability in distal colon. Elevated permeability was associated with a redistribution of tight junction and adherens junction proteins and depletion of detergent-insoluble fractions of these proteins, suggesting that ethanol disrupts apical junctional complexes in colonic epithelium and increases paracellular permeability. Ethanol-induced increase in colonic mucosal permeability and disruption of junctional complexes were most severe in mice fed Gln-free diet. Gln supplementation attenuated ethanol-induced mucosal permeability and disruption of tight junctions and adherens junctions in a dose-dependent manner, indicating the potential role of glutamine in nutritional intervention to alcoholic tissue injury. Gln supplementation dose-dependently elevated reduced-protein thiols in colon without affecting the level of oxidized-protein thiols. Ethanol feeding depleted reduced protein thiols and elevated oxidized protein thiols. Ethanol-induced protein thiol oxidation was most severe in mice fed Gln-free diet and absent in mice fed Gln-supplemented diet, suggesting that antioxidant effect is one of the likely mechanisms involved in Gln-mediated amelioration of ethanol-induced gut barrier dysfunction. Ethanol feeding elevated plasma transaminase and liver triglyceride, which was accompanied by histopathologic lesions in the liver; ethanol-induced liver damage was attenuated by Gln supplementation. These results indicate that Gln supplementation ameliorates alcohol-induced gut and liver injury. PMID:26365579

Malnutrition-associated liver steatosis and ATP depletion is caused by peroxisomal and mitochondrial dysfunction.

PubMed

van Zutphen, Tim; Ciapaite, Jolita; Bloks, Vincent W; Ackereley, Cameron; Gerding, Albert; Jurdzinski, Angelika; de Moraes, Roberta Allgayer; Zhang, Ling; Wolters, Justina C; Bischoff, Rainer; Wanders, Ronald J; Houten, Sander M; Bronte-Tinkew, Dana; Shatseva, Tatiana; Lewis, Gary F; Groen, Albert K; Reijngoud, Dirk-Jan; Bakker, Barbara M; Jonker, Johan W; Kim, Peter K; Bandsma, Robert H J

2016-12-01

Severe malnutrition in young children is associated with signs of hepatic dysfunction such as steatosis and hypoalbuminemia, but its etiology is unknown. Peroxisomes and mitochondria play key roles in various hepatic metabolic functions including lipid metabolism and energy production. To investigate the involvement of these organelles in the mechanisms underlying malnutrition-induced hepatic dysfunction we developed a rat model of malnutrition. Weanling rats were placed on a low protein or control diet (5% or 20% of calories from protein, respectively) for four weeks. Peroxisomal and mitochondrial structural features were characterized using immunofluorescence and electron microscopy. Mitochondrial function was assessed using high-resolution respirometry. A novel targeted quantitative proteomics method was applied to analyze 47 mitochondrial proteins involved in oxidative phosphorylation, tricarboxylic acid cycle and fatty acid β-oxidation pathways. Low protein diet-fed rats developed hypoalbuminemia and hepatic steatosis, consistent with the human phenotype. Hepatic peroxisome content was decreased and metabolomic analysis indicated peroxisomal dysfunction. This was followed by changes in mitochondrial ultrastructure and increased mitochondrial content. Mitochondrial function was impaired due to multiple defects affecting respiratory chain complex I and IV, pyruvate uptake and several β-oxidation enzymes, leading to strongly reduced hepatic ATP levels. Fenofibrate supplementation restored hepatic peroxisome abundance and increased mitochondrial β-oxidation capacity, resulting in reduced steatosis and normalization of ATP and plasma albumin levels. Malnutrition leads to severe impairments in hepatic peroxisomal and mitochondrial function, and hepatic metabolic dysfunction. We discuss the potential future implications of our findings for the clinical management of malnourished children. Severe malnutrition in children is associated with metabolic disturbances that are poorly understood. In order to study this further, we developed a malnutrition animal model and found that severe malnutrition leads to an impaired function of liver mitochondria which are essential for energy production and a loss of peroxisomes, which are important for normal liver metabolic function. Copyright © 2016 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Propylthiouracil-Induced Acute Liver Failure: Role of Liver Transplantation

PubMed Central

Carrion, Andres F.; Czul, Frank; Arosemena, Leopoldo R.; Selvaggi, Gennaro; Garcia, Monica T.; Tekin, Akin; Tzakis, Andreas G.; Martin, Paul; Ghanta, Ravi K.

2010-01-01

Propylthiouracil- (PTU-) induced hepatotoxicity is rare but potentially lethal with a spectrum of liver injury ranging from asymptomatic elevation of transaminases to fulminant hepatic failure and death. We describe two cases of acute hepatic failure due to PTU that required liver transplantation. Differences in the clinical presentation, histological characteristics, and posttransplant management are described as well as alternative therapeutic options. Frequent monitoring for PTU-induced hepatic dysfunction is strongly advised because timely discontinuation of this drug and implementation of noninvasive therapeutic interventions may prevent progression to liver failure or even death. PMID:21234410

A specific amino acid formula prevents alcoholic liver disease in rodents.

PubMed

Tedesco, Laura; Corsetti, Giovanni; Ruocco, Chiara; Ragni, Maurizio; Rossi, Fabio; Carruba, Michele O; Valerio, Alessandra; Nisoli, Enzo

2018-05-01

Chronic alcohol consumption promotes mitochondrial dysfunction, oxidative stress, defective protein metabolism, and fat accumulation in hepatocytes (liver steatosis). Inadequate amino acid metabolism is worsened by protein malnutrition, frequently present in alcohol-consuming patients, with reduced circulating branched-chain amino acids (BCAAs). Here we asked whether dietary supplementation with a specific amino acid mixture, enriched in BCAAs (BCAAem) and able to promote mitochondrial function in muscle of middle-aged rodents, would prevent mitochondrial dysfunction and liver steatosis in Wistar rats fed on a Lieber-DeCarli ethanol (EtOH)-containing liquid diet. Supplementation of BCAAem, unlike a mixture based on the amino acid profile of casein, abrogated the EtOH-induced fat accumulation, mitochondrial impairment, and oxidative stress in liver. These effects of BCAAem were accompanied by normalization of leucine, arginine, and tryptophan levels, which were reduced in liver of EtOH-consuming rats. Moreover, although the EtOH exposure of HepG2 cells reduced mitochondrial DNA, mitochondrial transcription factors, and respiratory chain proteins, the BCAAem but not casein-derived amino acid supplementation halted this mitochondrial toxicity. Nicotinamide adenine dinucleotide levels and sirtuin 1 (Sirt1) expression, as well as endothelial nitric oxide (eNOS) and mammalian/mechanistic target of rapamycin (mTOR) signaling pathways, were downregulated in the EtOH-exposed HepG2 cells. BCAAem reverted these molecular defects and the mitochondrial dysfunction, suggesting that the mitochondrial integrity obtained with the amino acid supplementation could be mediated through a Sirt1-eNOS-mTOR pathway. Thus a dietary activation of the mitochondrial biogenesis and function by a specific amino acid supplement protects against the EtOH toxicity and preserves the liver integrity in mammals. NEW & NOTEWORTHY Dietary supplementation of a specific amino acid formula prevents both fat accumulation and mitochondrial dysfunction in hepatocytes of alcohol-consuming rats. These effects are accompanied also by increased expression of anti-reactive oxygen species genes. The amino acid-protective effects likely reflect activation of sirtuin 1-endothelial nitric oxide synthase-mammalian target of rapamycin pathway able to regulate the cellular energy balance of hepatocytes exposed to chronic, alcoholic damage.

Systems pharmacology modeling of drug‐induced hyperbilirubinemia: Differentiating hepatotoxicity and inhibition of enzymes/transporters

PubMed Central

Battista, C; Woodhead, JL; Stahl, SH; Mettetal, JT; Watkins, PB; Siler, SQ; Howell, BA

2017-01-01

Elevations in serum bilirubin during drug treatment may indicate global liver dysfunction and a high risk of liver failure. However, drugs also can increase serum bilirubin in the absence of hepatic injury by inhibiting specific enzymes/transporters. We constructed a mechanistic model of bilirubin disposition based on known functional polymorphisms in bilirubin metabolism/transport. Using physiologically based pharmacokinetic (PBPK) model‐predicted drug exposure and enzyme/transporter inhibition constants determined in vitro, our model correctly predicted indinavir‐mediated hyperbilirubinemia in humans and rats. Nelfinavir was predicted not to cause hyperbilirubinemia, consistent with clinical observations. We next examined a new drug candidate that caused both elevations in serum bilirubin and biochemical evidence of liver injury in rats. Simulations suggest that bilirubin elevation primarily resulted from inhibition of transporters rather than global liver dysfunction. We conclude that mechanistic modeling of bilirubin can help elucidate underlying mechanisms of drug‐induced hyperbilirubinemia, and thereby distinguish benign from clinically important elevations in serum bilirubin. PMID:28074467

Acute presentation of gestational diabetes insipidus with pre-eclampsia complicated by cerebral vasoconstriction: a case report and review of the published work.

PubMed

Mor, Amir; Fuchs, Yael; Zafra, Kathleen; Haberman, Shoshana; Tal, Reshef

2015-08-01

Gestational diabetes insipidus (GDI) is a rare, self-limited complication of pregnancy. As it is related to excess placental vasopressinase enzyme activity, which is metabolized in the liver, GDI is more common in pregnancies complicated by conditions associated with liver dysfunction. We present a case of a 41-year-old woman at 38 weeks' gestation who presented with pre-eclampsia with severe features, including impaired liver function and renal insufficiency. Following cesarean section she was diagnosed with GDI, which was further complicated by cerebral vasoconstriction as demonstrated by magnetic resonance angiography. This case raises the possibility that cerebral vasoconstriction may be related to the cause of GDI. A high index of suspicion of GDI should be maintained in patients who present with typical signs and symptoms, especially in the setting of pregnancy complications associated with liver dysfunction. © 2015 The Authors. Journal of Obstetrics and Gynaecology Research © 2015 Japan Society of Obstetrics and Gynecology.

The Effects of Gymnema sylvestre in High-Fat Diet-Induced Metabolic Disorders.

PubMed

Kim, Hyeon-Jeong; Kim, Sanghwa; Lee, Ah Young; Jang, Yoonjeong; Davaadamdin, Orkhonselenge; Hong, Seong-Ho; Kim, Jun Sung; Cho, Myung-Haing

2017-01-01

This study used an integrated approach to investigate the effects of Gymnema sylvestre (GS) extract as a functional dietary supplement with a high-fat diet. This approach examined insulin resistance, the dysfunction of adipose tissue, and liver steatosis. Male C57BL/6J mice were fed a normal chow or high-fat diet (HFD) for the acute and chronic study, in addition to GS in different doses (100, 250 and 500[Formula: see text]mg/kg body weight). Their body composition changes, serum lipid and glucose parameters, adipose and liver tissue histology, and gene expression were measured. It was found that GS significantly suppressed the increase of body weight, serum levels of lipid, insulin and leptin, and adipose tissue, and liver inflammation. GS also demonstrated hypoglycemic effects due to the amylase inhibition activity. Our results support the existence of a relationship between the HFD induced insulin resistance, adipose dysfunction and liver steatosis. In conclusion, GS works as a functional dietary supplement with preventative effects against metabolic disorder.

Early organ-specific mitochondrial dysfunction of jejunum and lung found in rats with experimental acute pancreatitis

PubMed Central

Mittal, Anubhav; Hickey, Anthony JR; Chai, Chau C; Loveday, Benjamin PT; Thompson, Nichola; Dare, Anna; Delahunt, Brett; Cooper, Garth JS; Windsor, John A; Phillips, Anthony RJ

2011-01-01

Introduction Multiple organ dysfunction is the main cause of death in severe acute pancreatitis. Primary mitochondrial dysfunction plays a central role in the development and progression of organ failure in critical illness. The present study investigated mitochondrial function in seven tissues during early experimental acute pancreatitis. Methods Twenty-eight male Wistar rats (463 ± 2 g; mean ± SEM) were studied. Group 1 (n = 8), saline control; Group 2 (n = 6), caerulein-induced mild acute pancreatitis; Group 3 (n = 7) sham surgical controls; and Group 4 (n = 7), taurocholate-induced severe acute pancreatitis. Animals were euthanased at 6 h from the induction of acute pancreatitis and mitochondrial function was assessed in the heart, lung, liver, kidney, pancreas, duodenum and jejunum by mitochondrial respirometry. Results Significant early mitochondrial dysfunction was present in the pancreas, lung and jejunum in both models of acute pancreatitis, however, the Heart, liver, kidney and duodenal mitochondria were unaffected. Conclusions The present study provides the first description of early organ-selective mitochondrial dysfunction in the lung and jejunum during acute pancreatitis. Research is now needed to identify the underlying pathophysiology behind the organ selective mitochondrial dysfunction, and the potential benefits of early mitochondrial-specific therapies in acute pancreatitis. PMID:21492333

Targeting the vascular and perivascular niches as a regenerative therapy for lung and liver fibrosis.

PubMed

Cao, Zhongwei; Ye, Tinghong; Sun, Yue; Ji, Gaili; Shido, Koji; Chen, Yutian; Luo, Lin; Na, Feifei; Li, Xiaoyan; Huang, Zhen; Ko, Jane L; Mittal, Vivek; Qiao, Lina; Chen, Chong; Martinez, Fernando J; Rafii, Shahin; Ding, Bi-Sen

2017-08-30

The regenerative capacity of lung and liver is sometimes impaired by chronic or overwhelming injury. Orthotopic transplantation of parenchymal stem cells to damaged organs might reinstate their self-repair ability. However, parenchymal cell engraftment is frequently hampered by the microenvironment in diseased recipient organs. We show that targeting both the vascular niche and perivascular fibroblasts establishes "hospitable soil" to foster the incorporation of "seed," in this case, the engraftment of parenchymal cells in injured organs. Specifically, ectopic induction of endothelial cell (EC)-expressed paracrine/angiocrine hepatocyte growth factor (HGF) and inhibition of perivascular NOX4 [NADPH (reduced form of nicotinamide adenine dinucleotide phosphate) oxidase 4] synergistically enabled reconstitution of mouse and human parenchymal cells in damaged organs. Reciprocally, genetic knockout of Hgf in mouse ECs ( Hgf iΔEC/iΔEC ) aberrantly up-regulated perivascular NOX4 during liver and lung regeneration. Dysregulated HGF and NOX4 pathways subverted the function of vascular and perivascular cells from an epithelially inductive niche to a microenvironment that inhibited parenchymal reconstitution. Perivascular NOX4 induction in Hgf iΔEC/iΔEC mice recapitulated the phenotype of human and mouse liver and lung fibrosis. Consequently, EC-directed HGF and NOX4 inhibitor GKT137831 stimulated regenerative integration of mouse and human parenchymal cells in chronically injured lung and liver. Our data suggest that targeting dysfunctional perivascular and vascular cells in diseased organs can bypass fibrosis and enable reparative cell engraftment to reinstate lung and liver regeneration. Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Fibrosing cholestatic hepatitis after successful interferon and ribavirin therapy for recurrent hepatitis C post living related liver transplantation: a case report.

PubMed

Yamamoto, Takatsugu; Tanaka, Shogo; Uenishi, Takahiro; Kanazawa, Akishige; Kubo, Shoji; Hirohashi, Kazuhiro

2014-12-01

A 33-year-old Japanese man who had suffered from liver cirrhosis due to hepatitis C virus (HCV) underwent living related liver transplantation (LRLT). The allograft was given by his brother, who was healthy with no history of hepatitis or hepatic virus infection. After LRLT, the patient's hepatitis C recurred. Liver biopsy revealed chronic viral hepatitis and no allograft rejection such as shown by portal lymphocytic infiltration or mild bridging fibrosis. Interferon and ribavirin were administered, and sustained viral response (SVR) was obtained. Although serum hepatitis B virus (HBV)-DNA/HCV-RNA polymerase chain reaction found no presence of hepatic virus, the serum examination demonstrated liver dysfunction seven months after SVR. Liver biopsies histopathologically showed portal fibrosis invading to the sinusoids, cholestasis, mild hyperplasia of the cholangioles, and no features of allograft rejection. Fibrosing cholestatic hepatitis (FCH) was diagnosed. The FCH was resistant to treatment and advanced, and the patient died 17 months post-LRLT. Several serum examinations failed to demonstrate the existence of HBV/HCV during the patient's course. FCH is a type of viral hepatitis that is characterized by recurrent viral hepatitis after allograft transplantation. Because SVR obtained by anti-viral therapy commonly resolves FCH, we believe that this patient represented a rare case of FCH. The present case suggests that not only direct viral cytotoxicity, but other factors as well, promote the development of fibrosis and cholestasis. FCH sometimes progresses irreversibly despite the absence of serum viral load. The present case informed us that immediate anti-viral therapy should be initiated when recurrent allograft viral hepatitis is diagnosed.

Panhypopituitarism due to Absence of the Pituitary Stalk: A Rare Aetiology of Liver Cirrhosis.

PubMed

Gonzalez Rozas, Marta; Hernanz Roman, Lidia; Gonzalez, Diego Gonzalez; Pérez-Castrillón, José Luis

2016-01-01

Studies have established a relationship between hypothalamic-pituitary dysfunction and the onset of liver damage, which may occasionally progress to cirrhosis. Patients with hypopituitarism can develop a metabolic syndrome-like phenotype. Insulin resistance is the main pathophysiological axis of metabolic syndrome and is the causal factor in the development of nonalcoholic fatty liver disease (NAFLD). We present the case of a young patient with liver cirrhosis of unknown aetiology that was finally attributed to panhypopituitarism.

Panhypopituitarism due to Absence of the Pituitary Stalk: A Rare Aetiology of Liver Cirrhosis

PubMed Central

Gonzalez Rozas, Marta; Hernanz Roman, Lidia; Gonzalez, Diego Gonzalez; Pérez-Castrillón, José Luis

2016-01-01

Studies have established a relationship between hypothalamic-pituitary dysfunction and the onset of liver damage, which may occasionally progress to cirrhosis. Patients with hypopituitarism can develop a metabolic syndrome-like phenotype. Insulin resistance is the main pathophysiological axis of metabolic syndrome and is the causal factor in the development of nonalcoholic fatty liver disease (NAFLD). We present the case of a young patient with liver cirrhosis of unknown aetiology that was finally attributed to panhypopituitarism. PMID:27213061

Donor information based prediction of early allograft dysfunction and outcome in liver transplantation.

PubMed

Hoyer, Dieter P; Paul, Andreas; Gallinat, Anja; Molmenti, Ernesto P; Reinhardt, Renate; Minor, Thomas; Saner, Fuat H; Canbay, Ali; Treckmann, Jürgen W; Sotiropoulos, Georgios C; Mathé, Zoltan

2015-01-01

Poor initial graft function was recently newly defined as early allograft dysfunction (EAD) [Olthoff KM, Kulik L, Samstein B, et al. Validation of a current definition of early allograft dysfunction in liver transplant recipients and analysis of risk factors. Liver Transpl 2010; 16: 943]. Aim of this analysis was to evaluate predictive donor information for development of EAD. Six hundred and seventy-eight consecutive adult patients (mean age 51.6 years; 60.3% men) who received a primary liver transplantation (LT) (09/2003-12/2011) were included. Standard donor data were correlated with EAD and outcome by univariable/multivariable logistic regression and Cox proportional hazards to identify prognostic donor factors after adjustment for recipient confounders. Estimates of relevant factors were utilized for construction of a new continuous risk index to develop EAD. 38.7% patients developed EAD. 30-day survival of grafts with and without EAD was 59.8% and 89.7% (P < 0.0001). 30-day survival of patients with and without EAD was 68.5% and 93.1% (P < 0.0001) respectively. Donor body mass index (P = 0.0112), gGT (P = 0.0471), macrosteatosis (P = 0.0006) and cold ischaemia time (CIT) (P = 0.0031) were predictors of EAD. Internal cross validation showed a high predictive value (c-index = 0.622). Early allograft dysfunction correlates with early results of LT and can be predicted by donor data only. The newly introduced risk index potentially optimizes individual decisions to accept/decline high risk organs. Outcome of these organs might be improved by shortening CIT. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Pretransplantation Cystatin C, but not Creatinine, Predicts 30-day Cardiovascular Events and Mortality in Liver Transplant Recipients With Normal Serum Creatinine Levels.

PubMed

Kwon, H-M; Moon, Y-J; Jung, K-W; Jun, I-G; Song, J-G; Hwang, G-S

2018-05-01

The connection between renal dysfunction and cardiovascular dysfunction has been consistently shown. In patients with liver cirrhosis, renal dysfunction shows a tight correlation with prognosis after liver transplantation (LT); therefore, precise renal assessment is mandatory. Cystatin C, a sensitive biomarker for assessing renal function, has shown superiority in detecting mild renal dysfunction compared to classical biomarker creatinine. In this study, we aimed to compare cystatin C and creatinine in predicting 30-day major cardiovascular events (MACE) and all-cause mortality in LT recipients with normal serum creatinine levels. Between May 2010 and October 2015, 1181 LT recipients (mean Model for End-stage Liver Disease score 12.1) with pretransplantation creatinine level ≤1.4 mg/dL were divided into tertiles according to each renal biomarker. The 30-day MACE was a composite of troponin I >0.2 ng/mL, arrhythmia, congestive heart failure, death, and cerebrovascular events. The highest tertile of cystatin C (≥0.95 mg/L) was associated with a higher risk for a 30-day MACE event (odds ratio: 1.62; 95% confidence interval: 1.07 to 2.48) and higher risk of death (hazard ratio: 1.96; 95% confidence interval: 1.04 to 3.67) than the lowest tertile (<0.74 mg/L) after multivariate adjustments. However, the highest tertile of creatinine level showed neither increasing MACE event rate nor worse survival rate compared with the lowest tertile (both insignificant after multivariate adjustment). Pretransplantation cystatin C is superior in risk prediction of MACE and all-cause mortality in LT recipients with normal creatinine, compared to creatinine. It would assist further risk stratification which may not be detected with creatinine. Copyright © 2018 Elsevier Inc. All rights reserved.

RABL2 Is Required for Hepatic Fatty Acid Homeostasis and Its Dysfunction Leads to Steatosis and a Diabetes-Like State.

PubMed

Yi Lo, Jennifer Chi; O'Connor, Anne E; Andrews, Zane B; Lo, Camden; Tiganis, Tony; Watt, Matthew J; O'Bryan, Moira K

2016-12-01

Fatty liver, or hepatic steatosis, is an alarmingly common pathology in western societies, in large part because if left unheeded, it can lead to life-threatening forms of nonalcoholic fatty liver disease, including nonalcoholic steatohepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma. As such, it is essential that we attain a greater understanding of the pathways that control energy partitioning in the liver and ultimately how they are impacted by environmental factors. Here, we define the essential requirement for a member of the Ras-related protein in the brain (RAB)-like (RABL) clade of small GTPases, RABL2, in fatty acid metabolism including in microtubule-associated mitochondrial movement within the liver. RABL2 dysfunction, even in mice fed a low-fat chow diet, leads to retarded hepatic mitochondria movement associated with and a cascading phenotype of interrelated metabolic defects reminiscent of a type 2 diabetic state: hepatic steatosis, insulin resistance, glucose intolerance, and adult onset obesity. RABL2 dysfunction does not, however, alter mitochondrial content, or the inherent respiratory capacity of individual mitochondria per se. Rather, it is associated with a decreased capacity for fatty oxidation in the context of the intact cell, suggesting a complex, and important, role for mitochondrial movement in metabolic health. Our data highlight the importance of RABL2 and mitochondrial dynamics in hepatic fatty acid oxidation and in the achievement of metabolic balance.

The effect of a low fructose and low glycemic index/load (FRAGILE) dietary intervention on indices of liver function, cardiometabolic risk factors, and body composition in children and adolescents with nonalcoholic fatty liver disease (NAFLD).

PubMed

Mager, Diana R; Iñiguez, Ingrid Rivera; Gilmour, Susan; Yap, Jason

2015-01-01

Nonalcoholic fatty liver disease (NAFLD) is a common liver disease in obese children. Diets high in added fructose (high fructose corn syrup; HFCS) and glycemic index (GI)/glycemic load (GL) are associated with increased risk of NAFLD. Lifestyle modification is the main treatment, but no guidelines regarding specific dietary interventions for childhood NAFLD exist. We hypothesized that reductions in dietary fructose (total, free, and HFCS)/GI/GL over 6 months would result in improvements in body composition and markers of liver dysfunction and cardiometabolic risk in childhood NAFLD. Children and adolescents with NAFLD (n = 12) and healthy controls (n = 14) 7-18 years were studied at baseline and 3 and 6 months post-dietary intervention. Plasma markers of liver dysfunction (ALT, AST, γGT), cardiometabolic risk (TG, total cholesterol, LDL-HDL cholesterol, Apo-B100, Apo-B48, Apo-CIII, insulin, homeostasis model of assessment of insulin resistance [HOMA-IR]), inflammation (TNF-α, IL-6, IL-10), anthropometric, and blood pressure (BP) were studied using validated methodologies. Significant reductions in systolic BP (SBP), percentage body fat (BF), and plasma concentrations of ALT (P = .04), Apo-B100 (P < .001), and HOMA-IR were observed in children with NAFLD at 3 and 6 months (P < .05). Dietary reductions in total/free fructose/HFCS and GL were related to reductions in SBP (P = .01), ALT (P = .004), HOMA-IR (P = .03), and percentage BF in children with NAFLD. Reductions in dietary GI were associated with reduced plasma Apo-B100 (P = .02) in both groups. With the exception of Apo-B100, no changes in laboratory variables were observed in the control group. Modest reductions in fructose (total/free, HFCS) and GI/GL intake result in improvements of plasma markers of liver dysfunction and cardiometabolic risk in childhood NAFLD. © 2013 American Society for Parenteral and Enteral Nutrition.

Plasma cystatin C is a predictor of renal dysfunction, acute-on-chronic liver failure, and mortality in patients with acutely decompensated liver cirrhosis.

PubMed

Markwardt, Daniel; Holdt, Lesca; Steib, Christian; Benesic, Andreas; Bendtsen, Flemming; Bernardi, Mauro; Moreau, Richard; Teupser, Daniel; Wendon, Julia; Nevens, Frederik; Trebicka, Jonel; Garcia, Elisabet; Pavesi, Marco; Arroyo, Vicente; Gerbes, Alexander L

2017-10-01

The development of acute-on-chronic liver failure (ACLF) in patients with liver cirrhosis is associated with high mortality rates. Renal failure is the most significant organ dysfunction that occurs in ACLF. So far there are no biomarkers predicting ACLF. We investigated whether cystatin C (CysC) and neutrophil gelatinase-associated lipocalin (NGAL) can predict development of renal dysfunction (RD), hepatorenal syndrome (HRS), ACLF, and mortality. We determined the plasma levels of CysC and NGAL in 429 patients hospitalized for acute decompensation of cirrhosis in the EASL-CLIF Acute-on-Chronic Liver Failure in Cirrhosis (CANONIC) study. The patients were followed for 90 days. Patients without RD or ACLF at inclusion but with development of either had significantly higher baseline concentrations of CysC and NGAL compared to patients without. CysC, but not NGAL, was found to be predictive of RD (odds ratio, 9.4; 95% confidence interval [CI], 1.8-49.7), HRS (odds ratio, 4.2; 95% CI, 1.2-14.8), and ACLF (odds ratio, 5.9; 95% CI, 1.3-25.9). CysC at day 3 was not found to be a better predictor than baseline CysC. CysC and NGAL were both predictive of 90-day mortality, with hazard ratios for CysC of 3.1 (95% CI, 2.1-4.7) and for NGAL of 1.9 (95% CI, 1.5-2.4). Baseline CysC is a biomarker of RD, HRS, and ACLF and an independent predictor of mortality in patients with acutely decompensated liver cirrhosis, though determining CysC at day 3 did not provide any benefit; while NGAL is also associated with short-term mortality, it fails to predict development of RD, HRS, and ACLF. Baseline CysC may help to identify patients at risk earlier and improve clinical management. (Hepatology 2017;66:1232-1241). © 2017 by the American Association for the Study of Liver Diseases.

Spinal Cord Injury Causes Chronic Liver Pathology in Rats

PubMed Central

Sauerbeck, Andrew D.; Laws, J. Lukas; Bandaru, Veera V.R.; Popovich, Phillip G.; Haughey, Norman J.

2015-01-01

Abstract Traumatic spinal cord injury (SCI) causes major disruption to peripheral organ innervation and regulation. Relatively little work has investigated these post-SCI systemic changes, however, despite considerable evidence that multiple organ system dysfunction contributes to chronic impairments in health. Because metabolic dysfunction is common after SCI and the liver is a pivotal site for metabolic homeostasis, we sought to determine if liver pathology occurs as a result of SCI in a rat spinal contusion model. Histologic evidence showed excess lipid accumulation in the liver for at least 21 days post-injury after cervical or midthoracic SCI. Lipidomic analysis revealed an acute increase in hepatic ceramides as well as chronically elevated lactosylceramide. Post-SCI hepatic changes also included increased proinflammatory gene expression, including interleukin (IL)-1α, IL-1β, chemokine ligand-2, and tumor necrosis factor-α mRNA. These were coincident with increased CD68+ macrophages in the liver through 21 days post-injury. Serum alanine transaminase, used clinically to detect liver damage, was significantly increased at 21 days post-injury, suggesting that early metabolic and inflammatory damage preceded overt liver pathology. Surprisingly, liver inflammation was even detected after lumbar SCI. Collectively, these results suggest that SCI produces chronic liver injury with symptoms strikingly similar to those of nonalcoholic steatohepatitis (fatty liver disease). These clinically significant hepatic changes after SCI are known to contribute to systemic inflammation, cardiovascular disease, and metabolic syndrome, all of which are more prevalent in persons with SCI. Targeting acute and prolonged hepatic pathology may improve recovery and reduce long-term complications after SCI. PMID:25036371

Nonalcoholic fatty liver disease in hispanic youth with dysglycemia: Risk for subclinical atherosclerosis?

USDA-ARS?s Scientific Manuscript database

Obese Hispanic adolescents (OHAs) with dysglycemia have increased cardiovascular disease risk burden. To investigate if nonalcoholic fatty liver disease (NAFLD) confers added risk for endothelial dysfunction in these youth. Cross-sectional study. Academic institution. Thirty-six OHAs (15.360.4 years...

Special coverage of 41st IDSA conference. Study: Syphilitic hepatitis connected to liver disease. Diagnosis is uncommon, but does occur.

PubMed

2003-12-01

Investigators in Washington, DC, have discovered cases of HIV patients who have significant liver dysfunction that is caused by secondary syphilis instead of the usual suspects--hepatitis C, medication side effects, and substance abuse.

Variables associated with the risk of early death after liver transplantation at a liver transplant unit in a university hospital.

PubMed

Azevedo, L D; Stucchi, R S; de Ataíde, E C; Boin, I F S F

2015-05-01

Graft dysfunction after liver transplantation is a serious complication that can lead to graft loss and patient death. This was a study to identify risk factors for early death (up to 30 days after transplantation). It was an observational and retrospective analysis at the Liver Transplantation Unit, Hospital de Clinicas, State University of Campinas, Brazil. From July 1994 to December 2012, 302 patients were included (>18 years old, piggyback technique). Of these cases, 26% died within 30 days. For analysis, Student t tests and chi-square were used to analyze receptor-related (age, body mass index, serum sodium, graft dysfunction, Model for End-Stage Liver Disease score, renal function, and early graft dysfunction [EGD type 1, 2, or 3]), surgery (hot and cold ischemia, surgical time, and units of packed erythrocytes [pRBC]), and donor (age, hypotension, and brain death cause) factors. Risk factors were identified by means of logistic regression model adjusted by the Hosmer-Lemeshow test with significance set at P < .05. We found that hyponatremic recipients had a 6.26-fold higher risk for early death. There was a 9% reduced chance of death when the recipient serum sodium increased 1 unit. The chance of EGD3 to have early death was 18-fold higher than for EGD1 and there was a 13% increased risk for death for each unit of pRBC transfused. Donor total bilirubin, hyponatremia, massive transfusion, and EGD3 in the allocation graft should be observed for better results in the postoperative period. Copyright © 2015 Elsevier Inc. All rights reserved.

Gilbert syndrome

MedlinePlus

Icterus intermittens juvenilis; Low-grade chronic hyperbilirubinemia; Familial non-hemolytic-non-obstructive jaundice; Constitutional liver dysfunction; Unconjugated benign bilirubinemia; Gilbert disease

Antioxidant dietary approach in treatment of fatty liver: New insights and updates

PubMed Central

Ferramosca, Alessandra; Di Giacomo, Mariangela; Zara, Vincenzo

2017-01-01

Non-alcoholic fatty liver disease (NAFLD) is a common clinicopathological condition, encompassing a range of conditions caused by lipid deposition within liver cells. To date, no approved drugs are available for the treatment of NAFLD, despite the fact that it represents a serious and growing clinical problem in the Western world. Identification of the molecular mechanisms leading to NAFLD-related fat accumulation, mitochondrial dysfunction and oxidative balance impairment facilitates the development of specific interventions aimed at preventing the progression of hepatic steatosis. In this review, we focus our attention on the role of dysfunctions in mitochondrial bioenergetics in the pathogenesis of fatty liver. Major data from the literature about the mitochondrial targeting of some antioxidant molecules as a potential treatment for hepatic steatosis are described and critically analysed. There is ample evidence of the positive effects of several classes of antioxidants, such as polyphenols (i.e., resveratrol, quercetin, coumestrol, anthocyanins, epigallocatechin gallate and curcumin), carotenoids (i.e., lycopene, astaxanthin and fucoxanthin) and glucosinolates (i.e., glucoraphanin, sulforaphane, sinigrin and allyl-isothiocyanate), on the reversion of fatty liver. Although the mechanism of action is not yet fully elucidated, in some cases an indirect interaction with mitochondrial metabolism is expected. We believe that such knowledge will eventually translate into the development of novel therapeutic approaches for fatty liver. PMID:28694655

Antioxidant dietary approach in treatment of fatty liver: New insights and updates.

PubMed

Ferramosca, Alessandra; Di Giacomo, Mariangela; Zara, Vincenzo

2017-06-21

Non-alcoholic fatty liver disease (NAFLD) is a common clinicopathological condition, encompassing a range of conditions caused by lipid deposition within liver cells. To date, no approved drugs are available for the treatment of NAFLD, despite the fact that it represents a serious and growing clinical problem in the Western world. Identification of the molecular mechanisms leading to NAFLD-related fat accumulation, mitochondrial dysfunction and oxidative balance impairment facilitates the development of specific interventions aimed at preventing the progression of hepatic steatosis. In this review, we focus our attention on the role of dysfunctions in mitochondrial bioenergetics in the pathogenesis of fatty liver. Major data from the literature about the mitochondrial targeting of some antioxidant molecules as a potential treatment for hepatic steatosis are described and critically analysed. There is ample evidence of the positive effects of several classes of antioxidants, such as polyphenols ( i.e ., resveratrol, quercetin, coumestrol, anthocyanins, epigallocatechin gallate and curcumin), carotenoids ( i.e ., lycopene, astaxanthin and fucoxanthin) and glucosinolates ( i.e ., glucoraphanin, sulforaphane, sinigrin and allyl-isothiocyanate), on the reversion of fatty liver. Although the mechanism of action is not yet fully elucidated, in some cases an indirect interaction with mitochondrial metabolism is expected. We believe that such knowledge will eventually translate into the development of novel therapeutic approaches for fatty liver.

DPP-4 inhibitors improve liver dysfunction in type 2 diabetes mellitus.

PubMed

Kanazawa, Ippei; Tanaka, Ken-ichiro; Sugimoto, Toshitsugu

2014-09-17

Dipeptidyl peptidase-4 (DPP-4) inhibitors might have pleiotropic effects because receptors for incretin exist in various tissues, including liver. We examined whether DPP-4 inhibitors affect liver function in patients with type 2 diabetes. A retrospective review of 459 patients with type 2 diabetes who were prescribed DPP-4 inhibitors was performed. After exclusion of patients with hepatitis B or C, steroid use, and other diseases that might affect liver function and diabetes status, 224 patients were included in the analysis. Forty-four patients (19.6%) with liver injury defined by aspartate transaminase (AST) or alanine transaminase (ALT) over the normal level of 40 U/L. In the patients with liver injury, AST and ALT were significantly decreased after 6 months from the first date of DPP-4 prescription, with mean changes of -6.2 U/L [95% confidence interval (CI) -10.9 to -1.4, p=0.012] and of -11.9 U/L (95%CI -19.5 to -4.2, p=0.003), respectively. Percent changes in AST were significantly and negatively correlated with baseline AST and ALT (r=-0.27, p<0.001 and r=-0.23, p=0.002, respectively), and percent changes in ALT were also negatively correlated with them (r=-0.23, p=0.001 and r=-0.27, p<0.001, respectively). DPP-4 inhibitors improved liver dysfunction in patients with type 2 diabetes.

Chemical and Hormonal Effects on STAT5b-Dependent Sexual Dimorphism of the Liver Transcriptome.

EPA Science Inventory

The growth hormone (GH)-activated transcription factor signal transducer and activator of transcription 5b (STAT5b) is a key regulator of sexually dimorphic gene expression in the liver. Suppression of hepatic STAT5b signaling is associated with lipid metabolic dysfunction leadi...

Altered Peripheral Blood Monocyte Phenotype and Function in Chronic Liver Disease: Implications for Hepatic Recruitment and Systemic Inflammation.

PubMed

Gadd, Victoria L; Patel, Preya J; Jose, Sara; Horsfall, Leigh; Powell, Elizabeth E; Irvine, Katharine M

2016-01-01

Liver and systemic inflammatory factors influence monocyte phenotype and function, which has implications for hepatic recruitment and subsequent inflammatory and fibrogenic responses, as well as host defence. Peripheral blood monocyte surface marker (CD14, CD16, CD163, CSF1R, CCR2, CCR4, CCR5, CXCR3, CXCR4, CX3CR1, HLA-DR, CD62L, SIGLEC-1) expression and capacity for phagocytosis, oxidative burst and LPS-stimulated TNF production were assessed in patients with hepatitis C (HCV) (n = 39) or non-alcoholic fatty liver disease (NAFLD) (n = 34) (classified as non-advanced disease, compensated cirrhosis and decompensated cirrhosis) and healthy controls (n = 11) by flow cytometry. The selected markers exhibited similar monocyte-subset-specific expression patterns between patients and controls. Monocyte phenotypic signatures differed between NAFLD and HCV patients, with an increased proportion of CD16+ non-classical monocytes in NAFLD, but increased expression of CXCR3 and CXCR4 in HCV. In both cohorts, monocyte CCR2 expression was reduced and CCR4 elevated over controls. CD62L expression was specifically elevated in patients with decompensated cirrhosis and positively correlated with the model-for-end-stage-liver-disease score. Functionally, monocytes from patients with decompensated cirrhosis had equal phagocytic capacity, but displayed features of dysfunction, characterised by lower HLA-DR expression and blunted oxidative responses. Lower monocyte TNF production in response to LPS stimulation correlated with time to death in 7 (46%) of the decompensated patients who died within 8 months of recruitment. Chronic HCV and NAFLD differentially affect circulating monocyte phenotype, suggesting specific injury-induced signals may contribute to hepatic monocyte recruitment and systemic activation state. Monocyte function, however, was similarly impaired in patients with both HCV and NAFLD, particularly in advanced disease, which likely contributes to the increased susceptibility to infection in these patients.

Portal vein thrombosis in paroxysmal nocturnal haemoglobinuria.

PubMed

Tomizuka, H; Hatake, K; Kitagawa, S; Yamashita, K; Arai, H; Miura, Y

1999-01-01

A 28-year-old man was hospitalized with nausea, vomiting, abdominal pain and low-grade fever. He had a 6-month history of paroxysmal nocturnal haemoglobinuria (PNH), and laboratory data showed anaemia and liver dysfunction. An abdominal ultrasonography showed ascites and portal vein thrombosis. After receiving antithrombotic treatment, the portal vein thrombosis did not extend. Portal vein thrombosis is very rare but should be considered when we encounter liver dysfunction associated with PNH as well as hepatic vein thrombosis. Ultrasonography is very useful in detecting portal vein thrombosis and facilitating early diagnosis. Warfarin is very effective in preventing exacerbation of portal vein thrombosis in PNH.

Imaging follow-up after liver transplantation

PubMed Central

Rossi, Massimo; Mennini, Gianluca; Melandro, Fabio; Anzidei, Michele; De Vizio, Silvia; Koryukova, Kameliya; Catalano, Carlo

2016-01-01

Liver transplantation (LT) represents the best treatment for end-stage chronic liver disease, acute liver failure and early stages of hepatocellular carcinoma. Radiologists should be aware of surgical techniques to distinguish a normal appearance from pathological findings. Imaging modalities, such as ultrasound, CT and MR, provide for rapid and reliable detection of vascular and biliary complications after LT. The role of imaging in the evaluation of rejection and primary graft dysfunction is less defined. This article illustrates the main surgical anastomoses during LT, the normal appearance and complications of the liver parenchyma and vascular and biliary structures. PMID:27188846

Nomogram and Validity of a Model for Predicting Malnutrition in Patients on Liver Transplant Lists.

PubMed

García-Rodríguez, María Teresa; Pértega-Díaz, Sonia; López-Calviño, Beatriz; Piñón-Villar, María Del Carmen; Otero-Ferreiro, Alejandra; Suárez-López, Francisco; Gómez-Gutiérrez, Manuel; Seoane-Pillado, María Teresa; Pita-Fernández, Salvador

2018-04-25

Malnutrition is associated with increased morbimortality in liver transplant patients, and it is important to identify factors related to nutritional status in these patients. Determine variables associated with malnutrition and create a nomogram in liver transplant candidates. Cross-sectional study (n = 110). demographic variables, imbalances due to the disease, transplant aetiology and analytical parameters. Physical examination was performed and degree of hepatic dysfunction calculated. Nutritional status was assessed: Controlling Nutritional Status, Spanish Society of Parenteral and Enteral Nutrition criteria, Nutritional Risk Index, Prognostic Nutritional Index or Onodera Index and The Subjective Global Assessment. Logistic regression analysis was performed. A predictive nomogram (discrimination and calibration analysis) was generated. Malnourishment was defined according to at least 4 or more of the methods studied. Patients with ascites, encephalopathy and portal hypertension presented malnourishment more frequently. Malnutrition was associated with greater liver dysfunction and lower grip strength. Variables independently associated with malnourishment were encephalopathy and lower albumin values. A nomogram was created to predict malnourishment, with good discriminatory power and calibration. A score was developed for evaluating malnutrition risk. This would provide a tool that makes it possible to quickly and easily identify the risk of malnutrition in liver transplant candidates.

METABOLISM AND DISPOSITION OF ACETAMINOPHEN: RECENT ADVANCES IN RELATION TO HEPATOTOXICITY AND DIAGNOSIS

PubMed Central

McGill, Mitchell R.; Jaeschke, Hartmut

2013-01-01

Acetaminophen (APAP) is one of the most widely used drugs. Though safe at therapeutic doses, overdose causes mitochondrial dysfunction and centrilobular necrosis in the liver. The first studies of APAP metabolism and activation were published more than forty years ago. Most of the drug is eliminated by glucuronidation and sulfation. These reactions are catalyzed by UDP-glucuronosyltransferases (UGT1A1 and 1A6) and sulfotransferases (SULT1A1, 1A3/4, and 1E1), respectively. However, some is converted by CYP2E1 and other cytochrome P450 enzymes to a reactive intermediate that can bind to sulfhydryl groups. The metabolite can deplete liver glutathione (GSH) and modify cellular proteins. GSH binding occurs spontaneously, but may also involve GSH-S-transferases. Protein binding leads to oxidative stress and mitochondrial damage. The glucuronide, sulfate, and GSH conjugates are excreted by transporters in the canalicular (Mrp2 and Bcrp) and basolateral (Mrp3 and Mrp4) hepatocyte membranes. Conditions that interfere with metabolism and metabolic activation can alter the hepatotoxicity of the drug. Recent data providing novel insights into these processes, particularly in humans, are reviewed in the context of earlier work, and the effects of altered metabolism and reactive metabolite formation are discussed. Recent advances in the diagnostic use of serum adducts are covered. PMID:23462933

Early outcomes of liver transplants in patients receiving organs from hypernatremic donors.

PubMed

Khosravi, Mohammad Bagher; Firoozifar, Mohammad; Ghaffaripour, Sina; Sahmeddini, Mohammad Ali; Eghbal, Mohammad Hossien

2013-12-01

Uncorrected hypernatremia in organ donors has been associated with poor graft or patient survival during liver transplants. However, recent studies have found no association between the donor serum sodium and transplant outcome. This study sought to show the negative effect donor hypernatremia has on initial liver allograft function. This is the first study to investigate international normalized ratio and renal factors of patients with normal and those with hypernatremic donor livers. This study was conducted at the Shiraz Transplant Research Center in Shiraz, Iran, between May 2009, and July 2011. Four hundred seven consecutive adult orthotopic liver transplants were performed at the University of Shiraz Medical Center. There were 93 donors in the group with hypernatremia with terminal serum sodium of 155 mEq/L or greater (group 1), and 314 with terminal serum sodium less than 155 mEq/L (group 2). Posttransplant data after 5 days showed that aspartate aminotransferase, alanine aminotransferase, international normalized ratio, and kidney function did not differ between the groups. Hypernatremia is the most important complication after brain death. Previous studies have suggested donor hypernatremia results in a greater incidence of early postoperative graft dysfunction in liver transplant and is considered one of the extended criteria donor. However, in recent years, this hypothesis has been questioned. Our study shows no difference between patients' initial results of liver and kidney functioning with normal and hypernatremic donor livers. This is the first study to investigate international normalized ratio as a fundamental factor in defining early allograft dysfunction and renal factors between patients with normal and hypernatremic donor's livers.

AISF-SIMTI position paper: the appropriate use of albumin in patients with liver cirrhosis.

PubMed

Caraceni, Paolo; Angeli, Paolo; Prati, Daniele; Bernardi, Mauro; Liumbruno, Giancarlo M; Bennardello, Francesco; Piccoli, Pierluigi; Velati, Claudio

2016-01-01

The use of human albumin is common in hepatology since international scientific societies support its administration to treat or prevent severe complications of cirrhosis, such as the prevention of post-paracentesis circulatory dysfunction after large-volume paracentesis and renal failure induced by spontaneous bacterial peritonitis, and the treatment of hepatorenal syndrome in association with vasoconstrictors. However, these indications are often disregarded, mainly because the high cost of human albumin leads health authorities and hospital administrations to restrict its use. On the other hand, physicians often prescribe human albumin in patients with advanced cirrhosis for indications that are not supported by solid scientific evidence and/or are still under investigation in clinical trials.In order to implement appropriate prescription of human albumin and to avoid its futile use, the Italian Association for the Study of the Liver (AISF) and the Italian Society of Transfusion Medicine and Immunohaematology (SIMTI) nominated a panel of experts, who reviewed the available clinical literature and produced practical clinical recommendations for the use of human albumin in patients with cirrhosis.

Prevalence and prognostic significance of hyperkalemia in hospitalized patients with cirrhosis.

PubMed

Maiwall, Rakhi; Kumar, Suman; Sharma, Manoj Kumar; Wani, Zeeshan; Ozukum, Mulu; Sarin, Shiv Kumar

2016-05-01

The prevalence and clinical significance of hyponatremia in cirrhotics have been well studied; however, there are limited data on hyperkalemia in cirrhotics. We evaluated the prevalence and prognostic significance of hyperkalemia in hospitalized patients with cirrhosis and developed a prognostic model incorporating potassium for prediction of liver-related death in these patients. The training derivative cohort of patients was used for development of prognostic scores (Group A, n = 1160), which were validated in a large prospective cohort of cirrhotic patients. (Group B, n = 2681) of cirrhosis. Hyperkalemia was seen in 189 (14.1%) and 336 (12%) in Group A and Group B, respectively. Potassium showed a significant association that was direct with creatinine (P < 0.001) and urea (P < 0.001) and inverse with sodium (P < 0.001). Mortality was also significantly higher in patients with hyperkalemia (P = 0.0015, Hazard Ratio (HR) 1.3, 95% confidence interval 1.11-1.57). Combination of all these parameters into a single value predictor, that is, renal dysfunction index predicted mortality better than the individual components. Combining renal dysfunction index with other known prognostic markers (i.e. serum bilirubin, INR, albumin, hepatic encephalopathy, and ascites) in the "K" model predicted both short-term and long-term mortality with an excellent accuracy (Concordance-index 0.78 and 0.80 in training and validation cohorts, respectively). This was also superior to Model for End-stage Liver Disease, Model for End-stage liver disease sodium (MELDNa), and Child-Turcott-Pugh scores. Cirrhotics frequently have impaired potassium homeostasis, which has a prognostic significance. Serum potassium correlates directly with serum creatinine and urea and inversely with serum sodium. The model incorporating serum potassium developed from this study ("K"model) can predict death in advanced cirrhotics with an excellent accuracy. © 2015 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.

Liver fibrosis in non-alcoholic fatty liver disease - diagnostic challenge with prognostic significance

PubMed Central

Stål, Per

2015-01-01

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in the Western world, with a prevalence of 20%. In a subgroup of patients, inflammation, ballooning degeneration of hepatocytes and a varying degree of fibrosis may develop, a condition named non-alcoholic steatohepatitis. Advanced liver fibrosis (stage F3) and cirrhosis (stage F4) are histologic features that most accurately predict increased mortality in both liver-related and cardiovascular diseases. Patients with advanced fibrosis or cirrhosis are at risk for complications such as hepatocellular carcinoma and esophageal varices and should therefore be included in surveillance programs. However, liver disease and fibrosis are often unrecognized in patients with NAFLD, possibly leading to a delayed diagnosis of complications. The early diagnosis of advanced fibrosis in NAFLD is therefore crucial, and it can be accomplished using serum biomarkers (e.g., the NAFLD Fibrosis Score, Fib-4 Index or BARD) or non-invasive imaging techniques (transient elastography or acoustic radiation force impulse imaging). The screening of risk groups, such as patients with obesity and/or type 2 diabetes mellitus, for NAFLD development with these non-invasive methods may detect advanced fibrosis at an early stage. Additionally, patients with a low risk for advanced fibrosis can be identified, and the need for liver biopsies can be minimized. This review focuses on the diagnostic challenge and prognostic impact of advanced liver fibrosis in NAFLD. PMID:26494963

Liver fibrosis in non-alcoholic fatty liver disease - diagnostic challenge with prognostic significance.

PubMed

Stål, Per

2015-10-21

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in the Western world, with a prevalence of 20%. In a subgroup of patients, inflammation, ballooning degeneration of hepatocytes and a varying degree of fibrosis may develop, a condition named non-alcoholic steatohepatitis. Advanced liver fibrosis (stage F3) and cirrhosis (stage F4) are histologic features that most accurately predict increased mortality in both liver-related and cardiovascular diseases. Patients with advanced fibrosis or cirrhosis are at risk for complications such as hepatocellular carcinoma and esophageal varices and should therefore be included in surveillance programs. However, liver disease and fibrosis are often unrecognized in patients with NAFLD, possibly leading to a delayed diagnosis of complications. The early diagnosis of advanced fibrosis in NAFLD is therefore crucial, and it can be accomplished using serum biomarkers (e.g., the NAFLD Fibrosis Score, Fib-4 Index or BARD) or non-invasive imaging techniques (transient elastography or acoustic radiation force impulse imaging). The screening of risk groups, such as patients with obesity and/or type 2 diabetes mellitus, for NAFLD development with these non-invasive methods may detect advanced fibrosis at an early stage. Additionally, patients with a low risk for advanced fibrosis can be identified, and the need for liver biopsies can be minimized. This review focuses on the diagnostic challenge and prognostic impact of advanced liver fibrosis in NAFLD.

Is there a standard for surgical therapy of hepatocellular carcinoma in healthy and cirrhotic liver? A comparison of eight guidelines

PubMed Central

Manzini, Giulia; Henne-Bruns, Doris; Porzsolt, Franz; Kremer, Michael

2017-01-01

Background and aims Liver resection (LR) and transplantation are the most reliable treatments for hepatocellular carcinoma (HCC). Aim was to compare different guidelines regarding indication for resection and transplantation because of HCC with and without underlying cirrhosis. Methods We compared the following guidelines published after 1 January 2010: American (American Association for the Study of Liver Diseases (AASLD)), Spanish (Sociedad Espanola de Oncologia Medica (SEOM)), European (European Association for the study of liver-European Organization for Research and Treatment of Cancer (EASL-EORTC) and European Society for Medical Oncology-European Society of Digestive Oncology (ESMO-ESDO)), Asian (Asian Pacific Association for the Study of Liver (APASL)), Japanese (Japan Society of Hepatology (JSH)), Italian (Associazione Italiana Oncologia Medica (AIOM)) and German (S3) guidelines. Results All guidelines recommend resection as therapy of choice in healthy liver. Guidelines based on the Barcelona Clinic Liver Cancer staging system recommend resection for single HCC<2 cm and Child-Pugh A cirrhosis and for HCC≤5 cm with normal bilirubin and portal pressure, whereas transplantation is recommended for multiple tumours between Milan criteria and for single tumours ≤5 cm and advanced liver dysfunction. Patients with HCC and Child-Pugh C cirrhosis are not candidates for transplantation. JSH guidelines recommend LR for patients with Child-Pugh A/B with HCC without tumour size restriction; APASL guidelines in general exclude patients with Child-Pugh A from transplantation. In patients with Child-Pugh B, transplantation is the second-line therapy, if resection is not possible for patients within Milan criteria. German and Italian guidelines recommend transplantation for all patients within Milan criteria. Conclusions Whereas resection is the standard therapy of HCC in healthy liver, a standard regarding the indication for LR and transplantation for HCC in cirrhotic liver does not exist, although nearly all guidelines claim to be evidence based. Surprisingly, despite European guidelines, Germany and Italy use their own national guidelines which partially differ from the European. Possible solutions of the problems are discussed. PMID:28405349

Is there a standard for surgical therapy of hepatocellular carcinoma in healthy and cirrhotic liver? A comparison of eight guidelines.

PubMed

Manzini, Giulia; Henne-Bruns, Doris; Porzsolt, Franz; Kremer, Michael

2017-01-01

Liver resection (LR) and transplantation are the most reliable treatments for hepatocellular carcinoma (HCC). Aim was to compare different guidelines regarding indication for resection and transplantation because of HCC with and without underlying cirrhosis. We compared the following guidelines published after 1 January 2010: American (American Association for the Study of Liver Diseases (AASLD)), Spanish (Sociedad Espanola de Oncologia Medica (SEOM)), European (European Association for the study of liver-European Organization for Research and Treatment of Cancer (EASL-EORTC) and European Society for Medical Oncology-European Society of Digestive Oncology (ESMO-ESDO)), Asian (Asian Pacific Association for the Study of Liver (APASL)), Japanese (Japan Society of Hepatology (JSH)), Italian (Associazione Italiana Oncologia Medica (AIOM)) and German (S3) guidelines. All guidelines recommend resection as therapy of choice in healthy liver. Guidelines based on the Barcelona Clinic Liver Cancer staging system recommend resection for single HCC<2 cm and Child-Pugh A cirrhosis and for HCC≤5 cm with normal bilirubin and portal pressure, whereas transplantation is recommended for multiple tumours between Milan criteria and for single tumours ≤5 cm and advanced liver dysfunction. Patients with HCC and Child-Pugh C cirrhosis are not candidates for transplantation. JSH guidelines recommend LR for patients with Child-Pugh A/B with HCC without tumour size restriction; APASL guidelines in general exclude patients with Child-Pugh A from transplantation. In patients with Child-Pugh B, transplantation is the second-line therapy, if resection is not possible for patients within Milan criteria. German and Italian guidelines recommend transplantation for all patients within Milan criteria. Whereas resection is the standard therapy of HCC in healthy liver, a standard regarding the indication for LR and transplantation for HCC in cirrhotic liver does not exist, although nearly all guidelines claim to be evidence based. Surprisingly, despite European guidelines, Germany and Italy use their own national guidelines which partially differ from the European. Possible solutions of the problems are discussed.

Synergistic Interaction of Light Alcohol Administration in the Presence of Mild Iron Overload in a Mouse Model of Liver Injury: Involvement of Triosephosphate Isomerase Nitration and Inactivation

PubMed Central

Gao, Wanxia; Zhao, Jie; Gao, Zhonghong

2017-01-01

It is well known that iron overload promotes alcoholic liver injury, but the doses of iron or alcohol used in studies are usually able to induce liver injury independently. Little attention has been paid to the coexistence of low alcohol consumption and mild iron overload when either of them is insufficient to cause obvious liver damage, although this situation is very common among some people. We studied the interactive effects and the underlining mechanism of mild doses of iron and alcohol on liver injury in a mouse model. Forty eight male Kunming mice were randomly divided into four groups: control, iron (300 mg/kg iron dextran, i.p.), alcohol (2 g/kg/day ethanol for four weeks i.g.), and iron plus alcohol group. After 4 weeks of treatment, mice were sacrificed and blood and livers were collected for biochemical analysis. Protein nitration level in liver tissue was determined by immunoprecipitation and Western blot analysis. Although neither iron overload nor alcohol consumption at our tested doses can cause severe liver injury, it was found that co-administration of the same doses of alcohol and iron resulted in liver injury and hepatic dysfunction, accompanied with elevated ratio of NADH/NAD+, reduced antioxidant ability, increased oxidative stress, and subsequent elevated protein nitration level. Further study revealed that triosephosphate isomerase, an important glycolytic enzyme, was one of the targets to be oxidized and nitrated, which was responsible for its inactivation. These data indicate that even under low alcohol intake, a certain amount of iron overload can cause significant liver oxidative damage, and the modification of triosephosphate isomerasemight be the important underlining mechanism of hepatic dysfunction. PMID:28103293

Death receptor and mitochondria-mediated hepatocyte apoptosis underlies liver dysfunction in rats exposed to organic pollutants from drinking water

PubMed Central

Yang, Guanghong; Zhou, Zhiwei; Cen, Yanli; Gui, Xiaolin; Zeng, Qibing; Ao, Yunxia; Li, Qian; Wang, Shiran; Li, Jun; Zhang, Aihua

2015-01-01

Persistent organic pollutants in drinking water impose a substantial risk to the health of human beings, but the evidence for liver toxic effect and the underlying mechanism is scarce. This study aimed to examine the liver toxicity and elucidate the molecular mechanism of organic pollutants in drinking water in normal human liver cell line L02 cells and rats. The data showed that organic extraction from drinking water remarkably impaired rat liver function, evident from the increase in the serum level of alanine aminotransferase, aspartate aminotransferase, and cholinesterase, and decrease in the serum level of total protein and albumin. Organic extraction dose-dependently induced apoptotic cell death in rat liver and L02 cells. Administration of rats with organic extraction promoted death receptor signaling pathway through the increase in gene and protein expression level of Fas and FasL. Treatment of rats with organic extraction also induced mitochondria-mediated apoptosis via increasing the expression level of proapoptotic protein, Bax, but decreasing the expression level of antiapoptotic protein, Bcl-2, resulting in an upregulation of cytochrome c and activation of caspase cascade at both transcriptional and post-transcriptional levels. Moreover, organic extraction enhanced rat liver glutathione S-transferases activity and reactive oxygen species generation, and upregulated aryl hydrocarbon receptor and glutathione S-transferase A1 at both transcriptional and translational levels. Collectively, the results indicate that organic extraction from drinking water impairs liver function, with the involvement of death receptor and mitochondria-mediated apoptosis in rats. The results provide evidence and molecular mechanisms for organic pollutants in drinking water-induced liver dysfunction, which may help prevent and treat organic extraction-induced liver injury. PMID:26316710

Death receptor and mitochondria-mediated hepatocyte apoptosis underlies liver dysfunction in rats exposed to organic pollutants from drinking water.

PubMed

Yang, Guanghong; Zhou, Zhiwei; Cen, Yanli; Gui, Xiaolin; Zeng, Qibing; Ao, Yunxia; Li, Qian; Wang, Shiran; Li, Jun; Zhang, Aihua

2015-01-01

Persistent organic pollutants in drinking water impose a substantial risk to the health of human beings, but the evidence for liver toxic effect and the underlying mechanism is scarce. This study aimed to examine the liver toxicity and elucidate the molecular mechanism of organic pollutants in drinking water in normal human liver cell line L02 cells and rats. The data showed that organic extraction from drinking water remarkably impaired rat liver function, evident from the increase in the serum level of alanine aminotransferase, aspartate aminotransferase, and cholinesterase, and decrease in the serum level of total protein and albumin. Organic extraction dose-dependently induced apoptotic cell death in rat liver and L02 cells. Administration of rats with organic extraction promoted death receptor signaling pathway through the increase in gene and protein expression level of Fas and FasL. Treatment of rats with organic extraction also induced mitochondria-mediated apoptosis via increasing the expression level of proapoptotic protein, Bax, but decreasing the expression level of antiapoptotic protein, Bcl-2, resulting in an upregulation of cytochrome c and activation of caspase cascade at both transcriptional and post-transcriptional levels. Moreover, organic extraction enhanced rat liver glutathione S-transferases activity and reactive oxygen species generation, and upregulated aryl hydrocarbon receptor and glutathione S-transferase A1 at both transcriptional and translational levels. Collectively, the results indicate that organic extraction from drinking water impairs liver function, with the involvement of death receptor and mitochondria-mediated apoptosis in rats. The results provide evidence and molecular mechanisms for organic pollutants in drinking water-induced liver dysfunction, which may help prevent and treat organic extraction-induced liver injury.

The Effect Of Hypotensive Resuscitation And Fluid Type On Mortality, Bleeding,Coagulation And Dysfunctional Inflammation In A Swine Grade V Liver Injury Model

DTIC Science & Technology

2012-01-01

Once the swine were anesthetized, left cervical cut downs were performed and a central venous polyethylene catheter was inserted into the external...open and the liver injury will be examined for evidence of re-bleeding. The venous and arterial pressures at which re-bleeding occur will be...Fig. 1) Figure 1. Clamp used for the pig liver injury model The clamp is placed centrally in the liver and it produces laceration of 1

A Mitochondrial-Targeted Coenzyme Q Analog Prevents Weight Gain and Ameliorates Hepatic Dysfunction in High-Fat–Fed Mice

PubMed Central

Fink, Brian D.; Herlein, Judith A.; Guo, Deng Fu; Kulkarni, Chaitanya; Weidemann, Benjamin J.; Yu, Liping; Grobe, Justin L.; Rahmouni, Kamal; Kerns, Robert J.

2014-01-01

We hypothesized that the mitochondrial-targeted antioxidant, mitoquinone (mitoQ), known to have mitochondrial uncoupling properties, might prevent the development of obesity and mitigate liver dysfunction by increasing energy expenditure, as opposed to reducing energy intake. We administered mitoQ or vehicle (ethanol) to obesity-prone C57BL/6 mice fed high-fat (HF) or normal-fat (NF) diets. MitoQ (500 µM) or vehicle (ethanol) was added to the drinking water for 28 weeks. MitoQ significantly reduced total body mass and fat mass in the HF-fed mice but had no effect on these parameters in NF mice. Food intake was reduced by mitoQ in the HF-fed but not in the NF-fed mice. Average daily water intake was reduced by mitoQ in both the NF- and HF-fed mice. Hypothalamic expression of neuropeptide Y, agouti-related peptide, and the long form of the leptin receptor were reduced in the HF but not in the NF mice. Hepatic total fat and triglyceride content did not differ between the mitoQ-treated and control HF-fed mice. However, mitoQ markedly reduced hepatic lipid hydroperoxides and reduced circulating alanine aminotransferase, a marker of liver function. MitoQ did not alter whole-body oxygen consumption or liver mitochondrial oxygen utilization, membrane potential, ATP production, or production of reactive oxygen species. In summary, mitoQ added to drinking water mitigated the development of obesity. Contrary to our hypothesis, the mechanism involved decreased energy intake likely mediated at the hypothalamic level. MitoQ also ameliorated HF-induced liver dysfunction by virtue of its antioxidant properties without altering liver fat or mitochondrial bioenergetics. PMID:25301169

A mitochondrial-targeted coenzyme q analog prevents weight gain and ameliorates hepatic dysfunction in high-fat-fed mice.

PubMed

Fink, Brian D; Herlein, Judith A; Guo, Deng Fu; Kulkarni, Chaitanya; Weidemann, Benjamin J; Yu, Liping; Grobe, Justin L; Rahmouni, Kamal; Kerns, Robert J; Sivitz, William I

2014-12-01

We hypothesized that the mitochondrial-targeted antioxidant, mitoquinone (mitoQ), known to have mitochondrial uncoupling properties, might prevent the development of obesity and mitigate liver dysfunction by increasing energy expenditure, as opposed to reducing energy intake. We administered mitoQ or vehicle (ethanol) to obesity-prone C57BL/6 mice fed high-fat (HF) or normal-fat (NF) diets. MitoQ (500 µM) or vehicle (ethanol) was added to the drinking water for 28 weeks. MitoQ significantly reduced total body mass and fat mass in the HF-fed mice but had no effect on these parameters in NF mice. Food intake was reduced by mitoQ in the HF-fed but not in the NF-fed mice. Average daily water intake was reduced by mitoQ in both the NF- and HF-fed mice. Hypothalamic expression of neuropeptide Y, agouti-related peptide, and the long form of the leptin receptor were reduced in the HF but not in the NF mice. Hepatic total fat and triglyceride content did not differ between the mitoQ-treated and control HF-fed mice. However, mitoQ markedly reduced hepatic lipid hydroperoxides and reduced circulating alanine aminotransferase, a marker of liver function. MitoQ did not alter whole-body oxygen consumption or liver mitochondrial oxygen utilization, membrane potential, ATP production, or production of reactive oxygen species. In summary, mitoQ added to drinking water mitigated the development of obesity. Contrary to our hypothesis, the mechanism involved decreased energy intake likely mediated at the hypothalamic level. MitoQ also ameliorated HF-induced liver dysfunction by virtue of its antioxidant properties without altering liver fat or mitochondrial bioenergetics. U.S. Government work not protected by U.S. copyright.

Mitochondrial reactive oxygen species generation triggers inflammatory response and tissue injury associated with hepatic ischemia-reperfusion: therapeutic potential of mitochondrially-targeted antioxidants

PubMed Central

Mukhopadhyay, Partha; Horváth, Bėla; Zsengellėr, Zsuzsanna; Bátkai, Sándor; Cao, Zongxian; Kechrid, Malek; Holovac, Eileen; Erdėlyi, Katalin; Tanchian, Galin; Liaudet, Lucas; Stillman, Isaac E.; Joseph, Joy; Kalyanaraman, Balaraman; Pacher, Pál

2012-01-01

Mitochondrial reactive oxygen species generation has been implicated in the pathophysiology of ischemia-reperfusion (I/R) injury, however its exact role and its spatial-temporal relationship with inflammation are elusive. Herein we explored the spatial-temporal relationship of oxidative/nitrative stress and inflammatory response during the course of hepatic I/R and the possible therapeutic potential of mitochondrial-targeted antioxidants, using a mouse model of segmental hepatic ischemia-reperfusion injury. Hepatic I/R was characterized by early (at 2 hours of reperfusion) mitochondrial injury, decreased complex I activity, increased oxidant generation in the liver or liver mitochondria, and profound hepatocellular injury/dysfunction with acute pro-inflammatory response (TNF-α, MIP-1αCCL3, MIP-2/CXCL2) without inflammatory cell infiltration, followed by marked neutrophil infiltration and more pronounced secondary wave of oxidative/nitrative stress in the liver (starting from 6 hours of reperfusion and peaking at 24 hours). Mitochondrially-targeted antioxidants, MitoQ or Mito-CP, dose-dependently attenuated I/R-induced liver dysfunction, the early and delayed oxidative and nitrative stress response (HNE/carbonyl adducts, malondialdehyde, 8-OHdG, and 3-nitrotyrosine formation), mitochondrial and histopathological injury/dysfunction, as well as delayed inflammatory cell infiltration and cell death. Mitochondrially generated oxidants play a central role in triggering the deleterious cascade of events associated with hepatic I/R, which may be targeted by novel antioxidants for therapeutic advantage. PMID:22683818

Epidemiological Distribution and Subtype Analysis of Premenstrual Dysphoric Disorder Syndromes and Symptoms Based on TCM Theories

PubMed Central

Wang, Haijun; Zhan, Xianghong; Liu, Hongqi; Wang, Xiaoyun; Li, Xia; Wang, Xiaoru; Wu, Jibiao

2017-01-01

We performed an epidemiological investigation of subjects with premenstrual dysphoric disorder (PMDD) to identify the clinical distribution of the major syndromes and symptoms. The pathogenesis of PMDD mainly involves the dysfunction of liver conveyance and dispersion. Excessive liver conveyance and dispersion are associated with liver-qi invasion syndrome, while insufficient liver conveyance and dispersion are expressed as liver-qi depression syndrome. Additionally, a nonconditional logistic regression was performed to analyze the symptomatic features of liver-qi invasion and liver-qi depression. As a result of this analysis, two subtypes of PMDD are proposed, namely, excessive liver conveyance and dispersion (liver-qi invasion syndrome) and insufficient liver conveyance and dispersion (liver-qi depression syndrome). Our findings provide an epidemiological foundation for the clinical diagnosis and treatment of PMDD based on the identification of different types. PMID:28698873

Recent Advancements in Diagnosis and Therapy of Liver Cirrhosis.

PubMed

Romanelli, Roberto Giulio; Stasi, Cristina

2016-01-01

Cirrhosis is a diffuse pathophysiological state of the liver considered to be the final stage of various liver injuries, characterized by chronic necroinflammatory and fibrogenetic processes, with subsequent conversion of normal liver architecture into structurally abnormal nodules, dense fibrotic septa, concomitant parenchymal exaustment and collapse of the liver tissue. Alcoholic liver disease and chronic infections due to HBV and/or HCV constitute the main causes of liver cirrhosis worldwide. During a lag time of 15 to 30 years, chronic liver diseases can lead to liver cirrhosis and its complications. Active hepatic inflammation plays a pivotal role in the inflammation- necrosis-regeneration process, which eventually leads to liver cirrhosis and hepatocellular carcinoma. Prognosis of liver cirrhosis is highly variable and influenced by several variables, such as etiology, severity of liver disease, presence of complications and comorbidities. In advanced cirrhosis, survival decreases to one or two years. Correct advanced diagnosis and selected treatment with different molecules may help in understanding mechanisms of fibrogenesis, the driving forces of cirrhosis's pathogenesis, and the scrupulous approach to more effective therapeutic procedures. Prevention of fibrosis with further deterioration of liver function through specific treatments is always required, through the removal of the underlying causes of liver disease. Advanced liver disease, with subsequent complications, requires targeted treatment. Therefore, the aim of this review is to assess the diagnosis and treatment of liver cirrhosis on the pathophysiological bases, searching for relevant studies published in English using the PubMed database from 2011 to the present.

Non-Exertional Heatstroke: A Case Report and Review of the Literature

PubMed Central

Mozzini, Chiara; Xotta, Giovanni; Garbin, Ulisse; Pasini, Anna Maria Fratta; Cominacini, Luciano

2017-01-01

Patient: Female, 41 Final Diagnosis: Heatstroke Symptoms: Coma Medication: — Clinical Procedure: Intensive Care Unit-Internal Medicine Specialty: Critical Care Medicine Objective: Rare co-existance of disease or pathology Background: Heatstroke (HS) is a life-threatening condition characterized by an elevation of the core body temperature above 40°C, central nervous system dysfunction, and possible multi-organ failure. HS can trigger systemic inflammation, disseminated intravascular coagulation (DIC), rhabdomyolysis, cerebral edema and seizures, pulmonary edema, heart dysfunctions, and renal and hepatic failure. Case Report: We report the case of a 41-year-old Romanian woman with a history of alcoholism who developed HS after arriving by bus in Verona, Italy in June 2016. The patient developed consecutive multi-organ dysfunction, including liver and renal failure, rhabdomyolysis, DIC, and arrhythmia. The patient was successfully treated with conservative measures. After 17 days, she recovered completely. Conclusions: The exact mechanism of HS-related multiple organ dysfunction is not completely understood and its pathogenesis is complex. It involves inflammation, oxidative stress, endoplasmic reticulum (ER) stress, and mitochondrial dysfunction. Development of a model in which chronic alcohol abuse alters oxidative, inflammatory, and ER stress response could also be a conceivable solution to the positive prognosis of severe HS patients, in which liver failure has a prominent role. PMID:28974669

The Role of Akt in Chronic Liver Disease and Liver Regeneration.

PubMed

Morales-Ruiz, Manuel; Santel, Ansgar; Ribera, Jordi; Jiménez, Wladimiro

2017-02-01

The liver is continuously exposed to diverse insults, which may culminate in pathological processes causing liver disease. An effective therapeutic strategy for chronic liver disease should control the causal factors of the disease and stimulate functional liver regeneration. Preclinical studies have shown that interventions aimed at maintaining Akt activity in a dysfunctional liver meet most of the criteria. Although the central function of Akt is cell survival, other cellular aspects such as glucose uptake, glycogen synthesis, cell-cycle progression, and lipid metabolism have been shown to be prominent functions of Akt in the context of hepatic physiology. In this review, the authors describe the benefits of the Akt signaling pathway, emphasizing its importance in coordinating proper cellular growth and differentiation during liver regeneration, hepatic function, and liver disease. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Lapatinib in Treating Patients With Locally Advanced or Metastatic Biliary Tract or Liver Cancer That Cannot Be Removed By Surgery

ClinicalTrials.gov

2018-03-22

Adult Primary Hepatocellular Carcinoma; Advanced Adult Primary Liver Cancer; Localized Unresectable Adult Primary Liver Cancer; Recurrent Adult Primary Liver Cancer; Recurrent Extrahepatic Bile Duct Cancer; Recurrent Gallbladder Cancer; Unresectable Extrahepatic Bile Duct Cancer; Unresectable Gallbladder Cancer

Living Donor Liver Transplantation for Unresectable Liver Adenomatosis Associated with Congenital Absence of Portal Vein: A Case Report and Literature Review.

PubMed

Brasoveanu, Vladislav; Ionescu, Mihnea Ioan; Grigorie, Razvan; Mihaila, Mariana; Bacalbasa, Nicolae; Dumitru, Radu; Herlea, Vlad; Iorgescu, Andreea; Tomescu, Dana; Popescu, Irinel

2015-09-19

Abernethy malformation (AM), or congenital absence of portal vein (CAPV), is a very rare disease which tends to be associated with the development of benign or malignant tumors, usually in children or young adults. We report the case of a 21-year-old woman diagnosed with type Ib AM (portal vein draining directly into the inferior vena cava) and unresectable liver adenomatosis. The patient presented mild liver dysfunction and was largely asymptomatic. Living donor liver transplantation was performed using a left hemiliver graft from her mother. Postoperatively, the patient attained optimal liver function and at 9-month follow-up has returned to normal life. We consider that living donor liver transplantation is the best therapeutic solution for AM associated with unresectable liver adenomatosis, especially because compared to receiving a whole liver graft, the waiting time on the liver transplantation list is much shorter.

MicroRNA-146b-5p Identified in Porcine Liver Donation Model is Associated with Early Allograft Dysfunction in Human Liver Transplantation

PubMed Central

Li, Cheukfai; Zhao, Qiang; Zhang, Wei; Chen, Maogen; Ju, Weiqiang; Wu, Linwei; Han, Ming; Ma, Yi; Zhu, Xiaofeng; Wang, Dongping; Guo, Zhiyong; He, Xiaoshun

2017-01-01

Background Poor transplant outcome was observed in donation after brain death followed by circulatory death (DBCD), since the donor organs suffered both cytokine storm of brain death and warm ischemia injury. MicroRNAs (miRNAs) have emerged as promising disease biomarkers, so we sought to establish a miRNA signature of porcine DBCD and verify the findings in human liver transplantation. Material/Methods MiRNA expression was determined with miRNA sequencing in 3 types of the porcine model of organ donation, including donation after brain death (DBD) group, donation after circulatory death (DCD) group, and DBCD group. Bioinformatics analysis was performed to reveal the potential regulatory behavior of target miRNA. Human liver graft biopsy samples after reperfusion detected by fluorescence in situ hybridization were used to verify the expression of target miRNA. Results We compared miRNA expression profiles of the 3 donation types. The porcine liver graft miR-146b was significantly increased and selected in the DBCD group versus in the DBD and DCD groups. The donor liver expression of human miR-146b-5p, which is homologous to porcine miR-146b, was further examined in 42 cases of human liver transplantations. High expression of miR-146b-5p successfully predicted the post-transplant early allograft dysfunction (EAD) with the area under the ROC curve (AUC) 0.759 (P=0.004). Conclusions Our results revealed the miRNA signature of DBCD liver grafts for the first time. The miR-146b-5p may have important clinical implications for monitoring liver graft function and predicating transplant outcomes. PMID:29227984

A compromised liver alters polychlorinated biphenyl-mediated toxicity.

PubMed

Wahlang, Banrida; Perkins, Jordan T; Petriello, Michael C; Hoffman, Jessie B; Stromberg, Arnold J; Hennig, Bernhard

2017-04-01

Exposure to environmental toxicants namely polychlorinated biphenyls (PCBs) is correlated with multiple health disorders including liver and cardiovascular diseases. The liver is important for both xenobiotic and endobiotic metabolism. However, the responses of an injured liver to subsequent environmental insults has not been investigated. The current study aims to evaluate the role of a compromised liver in PCB-induced toxicity and define the implications on overall body homeostasis. Male C57Bl/6 mice were fed either an amino acid control diet (CD) or a methionine-choline deficient diet (MCD) during the 12-week study. Mice were subsequently exposed to either PCB126 (4.9mg/kg) or the PCB mixture, Arcolor1260 (20mg/kg) and analyzed for inflammatory, calorimetry and metabolic parameters. Consistent with the literature, MCD diet-fed mice demonstrated steatosis, indicative of a compromised liver. Mice fed the MCD-diet and subsequently exposed to PCB126 showed observable wasting syndrome leading to mortality. PCB126 and Aroclor1260 exposure worsened hepatic fibrosis exhibited by the MCD groups. Interestingly, PCB126 but not Aroclor1260 induced steatosis and inflammation in CD-fed mice. Mice with liver injury and subsequently exposed to PCBs also manifested metabolic disturbances due to alterations in hepatic gene expression. Furthermore, PCB exposure in MCD-fed mice led to extra-hepatic toxicity such as upregulated circulating inflammatory biomarkers, implicating endothelial cell dysfunction. Taken together, these results indicate that environmental pollution can exacerbate toxicity caused by diet-induced liver injury which may be partially due to dysfunctional energy homeostasis. This is relevant to PCB-exposed human cohorts who suffer from alcohol or diet-induced fatty liver diseases. Copyright © 2017 Elsevier B.V. All rights reserved.

Puerarin protects against CCl4-induced liver fibrosis in mice: possible role of PARP-1 inhibition.

PubMed

Wang, Shuai; Shi, Xiao-Lei; Feng, Min; Wang, Xun; Zhang, Zhi-Heng; Zhao, Xin; Han, Bing; Ma, Hu-Cheng; Dai, Bo; Ding, Yi-Tao

2016-09-01

Liver fibrosis, which is the pathophysiologic process of the liver due to sustained wound healing in response to chronic liver injury, will eventually progress to cirrhosis. Puerarin, a bioactive isoflavone glucoside derived from the traditional Chinese medicine pueraria, has been reported to have many anti-inflammatory and anti-fibrosis properties. However, the detailed mechanisms are not well studied yet. This study aimed to investigate the effects of puerarin on liver function and fibrosis process in mice induced by CCl4. C57BL/6J mice were intraperitoneally injected with 10% CCl4 in olive oil(2mL/kg) with or without puerarin co-administration (100 and 200mg/kg intraperitoneally once daily) for four consecutive weeks. As indicated by the ameliorative serum hepatic enzymes and the reduced histopathologic abnormalities, the data collected showed that puerarin can protect against CCl4-induced chronic liver injury. Moreover, CCl4-induced development of fibrosis, as evidenced by increasing expression of alpha smooth muscle actin(α-SMA), collagen-1, transforming growth factor (TGF)-β and connective tissue growth factor(CTGF) in liver, were suppressed by puerarin. Possible mechanisms related to these suppressive effects were realized by inhibition on NF-κB signaling pathway, reactive oxygen species(ROS) production and mitochondrial dysfunction in vivo. In addition, these protective inhibition mentioned above were driven by down-regulation of PARP-1 due to puerarin because puerarin can attenuate the PARP-1 expression in CCl4-damaged liver and PJ34, a kind of PARP-1 inhibitor, mimicked puerarin's protection. In conclusion, puerarin played a protective role in CCl4-induced liver fibrosis probably through inhibition of PARP-1 and subsequent attenuation of NF-κB, ROS production and mitochondrial dysfunction. Copyright © 2016 Elsevier B.V. All rights reserved.

Hemorrhage-induced hepatic injury and hypoperfusion can be prevented by direct peritoneal resuscitation.

PubMed

Hurt, Ryan T; Zakaria, El Rasheid; Matheson, Paul J; Cobb, Mahoney E; Parker, John R; Garrison, R Neal

2009-04-01

Crystalloid fluid resuscitation after hemorrhagic shock (HS) that restores/maintains central hemodynamics often culminates in multi-system organ failure and death due to persistent/progressive splanchnic hypoperfusion and end-organ damage. Adjunctive direct peritoneal resuscitation (DPR) using peritoneal dialysis solution reverses HS-induced splanchnic hypoperfusion and improves survival. We examined HS-mediated hepatic perfusion (galactose clearance), tissue injury (histopathology), and dysfunction (liver enzymes). Anesthetized rats were randomly assigned (n = 8/group): (1) sham (no HS); (2) HS (40% mean arterial pressure for 60 min) plus conventional i.v. fluid resuscitation (CR; shed blood + 2 volumes saline); (3) HS + CR + 30 mL intraperitoneal (IP) DPR; or (4) HS + CR + 30 mL IP saline. Hemodynamics and hepatic blood flow were measured for 2 h after CR completion. In duplicate animals, liver and splanchnic tissues were harvested for histopathology (blinded, graded), hepatocellular function (liver enzymes), and tissue edema (wet-dry ratio). Group 2 decreased liver blood flow, caused liver injuries (focal to submassive necrosis, zones 2 and 3) and tissue edema, and elevated liver enzymes (alanine aminotransferase (ALT), 149 +/- 28 microg/mL and aspartate aminotransferase (AST), 234 +/- 24 microg/mL; p < 0.05) compared to group 1 (73 +/- 9 and 119 +/- 10 microg/mL, respectively). Minimal/no injuries were observed in group 3; enzymes were normalized (ALT 89 +/- 9 microg/mL and AST 150 +/- 17 microg/mL), and tissue edema was similar to sham. CR from HS restored and maintained central hemodynamics but did not restore or maintain liver perfusion and was associated with significant hepatocellular injury and dysfunction. DPR added to conventional resuscitation (blood and crystalloid) restored and maintained liver perfusion, prevented hepatocellular injury and edema, and preserved liver function.

Etiology, clinical profile, and outcome of liver disease in pregnancy with predictors of maternal mortality: A prospective study from Western India.

PubMed

Solanke, Dattatray; Rathi, Chetan; Pandey, Vikas; Patil, Mallanagoud; Phadke, Aniruddha; Sawant, Prabha

2016-11-01

The aim of this study is to study the etiology, clinical profile, and prognostic factors related to maternal and fetal health in pregnant patients with liver disease in Western India. This study included 103 consecutive pregnant patients with liver dysfunction from August 2013 to July 2015, who underwent regular biochemical tests, viral markers, ultrasound of abdomen, etc. and were followed up for 6 weeks postpartum or until death. Pregnancy-specific causes of liver dysfunction were found in 39 % (40/103) patients. Liver diseases were most frequent in third trimester 69.9 % (72/103). Etiologies in third trimester were viral hepatitis 36.1 % (26/72), pregnancy induced hypertension (PIH) 30.5 % (22/72), intrahepatic cholestasis of pregnancy 11.1 % (8/72), acute fatty liver of pregnancy (2/72), etc. Hepatitis E was the commonest agent among viral hepatitis 71.8 % (28/39). Causes of maternal mortality (n = 25) were hepatitis E 40 % (10/25), PIH 32 % (8/25), and tropical diseases 20 % (5/25). Fetal mortality (n = 31) was 38.7 % (12/31) in hepatitis E. Maternal mortality was significantly associated with presence of jaundice, fever, abdominal pain, oliguria, anemia, leukocytosis, and coagulopathy. Model for end-stage liver disease (MELD) score >21 predicted maternal mortality with 80 % sensitivity and 91 % specificity (area under the receiver operating characteristic curve = 0.878 and p < 0.001). Liver disease was most common in the third trimester of pregnancy. Hepatitis E was the most common cause of liver disease in pregnant women in western India with significant maternal mortality, predicted by high MELD score.

How can we utilize livers from advanced aged donors for liver transplantation for hepatitis C?

PubMed

Uemura, Tadahiro; Nikkel, Lucas E; Hollenbeak, Christopher S; Ramprasad, Varun; Schaefer, Eric; Kadry, Zakiyah

2012-06-01

Advanced age donors have inferior outcomes of liver transplantation for Hepatitis C (HCV). Aged donors grafts may be transplanted into young or low model for end stage liver disease (MELD) patients in order to offset the effect of donor age. However, it is not well understood how to utilize liver grafts from advanced aged donors for HCV patients. Using the UNOS database, we retrospectively studied 7508 HCV patients who underwent primary liver transplantation. Risk factors for graft failure and graft survival using advanced aged grafts (donor age ≥ 60 years) were analyzed by Cox hazards models, donor risk index (DRI) and organ patient index (OPI). Recipient's age did not affect on graft survival regardless of donor age. Advanced aged grafts had significant inferior survival compared to younger aged grafts regardless of MELD score (P < 0.0001). Risk factors of HCV patients receiving advanced aged grafts included donation after cardiac death (DCD, HR: 1.69) and recent hospitalization (HR: 1.43). Advanced aged grafts showed significant difference in graft survival of HCV patients with stratification of DRI and OPI. In conclusion, there was no offsetting effect by use of advanced aged grafts into younger or low MELD patients. Advanced aged grafts, especially DCD, should be judiciously used for HCV patients with low MELD score. © 2012 The Authors. Transplant International © 2012 European Society for Organ Transplantation.

[Two young adult cases of Epstein-Barr virus associated-hemophagocytic lymphohistiocytosis with monoclonal proliferation of virus-infected cells within a short period after primary infection].

PubMed

Idutsu, Kensaku; Abe, Yasunobu; Matsushima, Takamitsu; Sada, Eriko; Ohtsuka, Rie; Kiyasu, Junichi; Shiratsuchi, Motoaki; Kotoh, Kazuhiro; Nishimura, Junji; Ohga, Shouichi; Takayanagi, Ryoichi

2008-11-01

Hemophagocytic lymphohistiocytosis (HLH) is a rare but severe complication of Epstein-Barr virus (EBV) infection. Interactions between EBV-infected T cells and activated macrophages cause several conditions such as pancytopenia, liver dysfunction and coagulopathy. We describe here two young adults with EBV-associated HLH with monoclonal proliferation of EBV-infected T cells within a short period after infectious mononucleosis as a primary infection. One patient was a 16-year-old man who developed severe pancytopenia and liver dysfunction two months after infectious mononucleosis. Bone marrow examination showed hemophagocytosis, and laboratory data demonstrated monoclonal proliferation of EBV-infected T cells. Several treatments such as immunosuppressive therapy, chemotherapy and hematopoietic stem cell transplantation were not effective, and the patient died of progressive disease. The other patient was a 19-year-old woman who developed thrombocytopenia and liver dysfunction two months after infectious mononucleosis. Findings of hemophagocytosis and monoclonal proliferation of EBV-infected T cells were similar to those in the first case. Clinical signs and symptoms were resolved completely by immunosuppressive therapy containing methyl-prednisolone and cyclosporine. Since these two cases each demonstrated a distinct clinical course, an investigation of the prognostic factors and treatment strategies for EBV-HLH is warranted.

Gut epithelial barrier dysfunction in human immunodeficiency virus-hepatitis C virus coinfected patients: Influence on innate and acquired immunity.

PubMed

Márquez, Mercedes; Fernández Gutiérrez del Álamo, Clotilde; Girón-González, José Antonio

2016-01-28

Even in cases where viral replication has been controlled by antiretroviral therapy for long periods of time, human immunodeficiency virus (HIV)-infected patients have several non-acquired immunodeficiency syndrome (AIDS) related co-morbidities, including liver disease, cardiovascular disease and neurocognitive decline, which have a clear impact on survival. It has been considered that persistent innate and acquired immune activation contributes to the pathogenesis of these non-AIDS related diseases. Immune activation has been related with several conditions, remarkably with the bacterial translocation related with the intestinal barrier damage by the HIV or by hepatitis C virus (HCV)-related liver cirrhosis. Consequently, increased morbidity and mortality must be expected in HIV-HCV coinfected patients. Disrupted gut barrier lead to an increased passage of microbial products and to an activation of the mucosal immune system and secretion of inflammatory mediators, which in turn might increase barrier dysfunction. In the present review, the intestinal barrier structure, measures of intestinal barrier dysfunction and the modifications of them in HIV monoinfection and in HIV-HCV coinfection will be considered. Both pathogenesis and the consequences for the progression of liver disease secondary to gut microbial fragment leakage and immune activation will be assessed.

Iodine-131 induced hepatotoxicity in previously healthy patients with Grave's disease.

PubMed

Jhummon, Navina Priya; Tohooloo, Bhavna; Qu, Shen

2013-01-01

To describe the association of the rare and serious complication of liver toxicity in previously healthy Grave's disease (GD) patients after the treatment with radioactive iodine (131)I (RAI). We report the clinical, laboratory and pathologic findings of 2 cases of severe liver toxicity associated with the treatment with RAI in previously healthy patients with GD. Clinical examination and laboratory investigations excluded viral hepatitis, autoimmune hepatitis, granulomatous disease, primary biliary disease, extrahepatic biliary obstruction, and heart failure. Case 1: A previously healthy 52-years old man reportedly having a typical GD but following RAI treatment, concomitantly developed severe liver toxicity that required 1 week of treatment in hospital. Case 2: A previously healthy 34-years old woman is reported as having a typical GD but developed jaundice following RAI treatment that required several weeks of in hospital treatment in the hepato-biliary department. In both cases, the liver dysfunction resolved after intensive treatment with hepato-protective agents. In this report the therapeutic considerations as well as the pathogenetic possibilities are reviewed. To the best of our knowledge, this is the first description of the association observed, which is rare but may be severe and should be considered in any case of thyrotoxicosis where a liver dysfunction develops after the treatment with radioactive iodine (131)I.

The Emerging Role of Disturbed CoQ Metabolism in Nonalcoholic Fatty Liver Disease Development and Progression

PubMed Central

Botham, Kathleen M.; Napolitano, Mariarosaria; Bravo, Elena

2015-01-01

Although non-alcoholic fatty liver disease (NAFLD), characterised by the accumulation of triacylglycerol in the liver, is the most common liver disorder, the causes of its development and progression to the more serious non-alcoholic steatohepatitis (NASH) remain incompletely understood. Oxidative stress has been implicated as a key factor in both these processes, and mitochondrial dysfunction and inflammation are also believed to play a part. Coenzyme Q (CoQ) is a powerful antioxidant found in all cell membranes which has an essential role in mitochondrial respiration and also has anti-inflammatory properties. NAFLD has been shown to be associated with disturbances in plasma and liver CoQ concentrations, but the relationship between these changes and disease development and progression is not yet clear. Dietary supplementation with CoQ has been found to be hepatoprotective and to reduce oxidative stress and inflammation as well as improving mitochondrial dysfunction, suggesting that it may be beneficial in NAFLD. However, studies using animal models or patients with NAFLD have given inconclusive results. Overall, evidence is now emerging to indicate that disturbances in CoQ metabolism are involved in NAFLD development and progression to NASH, and this highlights the need for further studies with human subjects to fully clarify its role. PMID:26633474

Advanced MRI Methods for Assessment of Chronic Liver Disease

PubMed Central

Taouli, Bachir; Ehman, Richard L.; Reeder, Scott B.

2010-01-01

MRI plays an increasingly important role for assessment of patients with chronic liver disease. MRI has numerous advantages, including lack of ionizing radiation and the possibility of performing multiparametric imaging. With recent advances in technology, advanced MRI methods such as diffusion-, perfusion-weighted MRI, MR elastography, chemical shift based fat-water separation and MR spectroscopy can now be applied to liver imaging. We will review the respective roles of these techniques for assessment of chronic liver disease. PMID:19542391

Liver Dysfunction and Phosphatidylinositol-3-Kinase Signalling in Early Sepsis: Experimental Studies in Rodent Models of Peritonitis

PubMed Central

Westermann, Martin; Lambeck, Sandro; Lupp, Amelie; Rudiger, Alain; Dyson, Alex; Carré, Jane E.; Kortgen, Andreas; Krafft, Christoph; Popp, Jürgen; Sponholz, Christoph; Fuhrmann, Valentin; Hilger, Ingrid; Claus, Ralf A.; Riedemann, Niels C.; Wetzker, Reinhard; Singer, Mervyn; Trauner, Michael; Bauer, Michael

2012-01-01

Background Hepatic dysfunction and jaundice are traditionally viewed as late features of sepsis and portend poor outcomes. We hypothesized that changes in liver function occur early in the onset of sepsis, yet pass undetected by standard laboratory tests. Methods and Findings In a long-term rat model of faecal peritonitis, biotransformation and hepatobiliary transport were impaired, depending on subsequent disease severity, as early as 6 h after peritoneal contamination. Phosphatidylinositol-3-kinase (PI3K) signalling was simultaneously induced at this time point. At 15 h there was hepatocellular accumulation of bilirubin, bile acids, and xenobiotics, with disturbed bile acid conjugation and drug metabolism. Cholestasis was preceded by disruption of the bile acid and organic anion transport machinery at the canalicular pole. Inhibitors of PI3K partially prevented cytokine-induced loss of villi in cultured HepG2 cells. Notably, mice lacking the PI3Kγ gene were protected against cholestasis and impaired bile acid conjugation. This was partially confirmed by an increase in plasma bile acids (e.g., chenodeoxycholic acid [CDCA] and taurodeoxycholic acid [TDCA]) observed in 48 patients on the day severe sepsis was diagnosed; unlike bilirubin (area under the receiver-operating curve: 0.59), these bile acids predicted 28-d mortality with high sensitivity and specificity (area under the receiver-operating curve: CDCA: 0.77; TDCA: 0.72; CDCA+TDCA: 0.87). Conclusions Liver dysfunction is an early and commonplace event in the rat model of sepsis studied here; PI3K signalling seems to play a crucial role. All aspects of hepatic biotransformation are affected, with severity relating to subsequent prognosis. Detected changes significantly precede conventional markers and are reflected by early alterations in plasma bile acids. These observations carry important implications for the diagnosis of liver dysfunction and pharmacotherapy in the critically ill. Further clinical work is necessary to extend these concepts into clinical practice. Please see later in the article for the Editors' Summary PMID:23152722

Functional restoration of HCV-specific CD8 T cells by PD-1 blockade is defined by PD-1 expression and compartmentalization.

PubMed

Nakamoto, Nobuhiro; Kaplan, David E; Coleclough, Jennifer; Li, Yun; Valiga, Mary E; Kaminski, Mary; Shaked, Abraham; Olthoff, Kim; Gostick, Emma; Price, David A; Freeman, Gordon J; Wherry, E John; Chang, Kyong-Mi

2008-06-01

The immunoinhibitory receptor programmed death-1 (PD-1) is up-regulated on dysfunctional virus-specific CD8 T cells during chronic viral infections, and blockade of PD-1/PD-ligand (PD-L) interactions can restore their function. As hepatitis C virus (HCV) persists in the liver with immune-mediated disease pathogenesis, we examined the role of PD-1/PD-L pathway in antigen-specific CD8 T-cell dysfunction in the liver and blood of HCV-infected patients. PD-1 expression and function of circulating CD8 T cells specific for HCV, Epstein-Barr virus, and influenza virus were examined ex vivo and following antigenic stimulation in vitro in patients with acute, chronic, and resolved HCV infection using class I tetramers and flow cytometry. Intrahepatic CD8 T cells were examined from liver explants of chronically HCV-infected transplant recipients. Intrahepatic HCV-specific CD8 T cells from chronically HCV-infected patients were highly PD-1 positive, profoundly dysfunctional, and unexpectedly refractory to PD-1/PD-L blockade, contrasting from circulating PD-1-intermediate HCV-specific CD8 T cells with responsiveness to PD-1/PD-L blockade. This intrahepatic functional impairment was HCV-specific and directly associated with the level of PD-1 expression. Highly PD-1-positive intrahepatic CD8 T cells were more phenotypically exhausted with increased cytotoxic T-lymphocyte antigen 4 and reduced CD28 and CD127 expression, suggesting that active antigen-specific stimulation in the liver induces a profound functional exhaustion not reversible by PD-1/PD-L blockade alone. HCV-specific CD8 T-cell dysfunction and responsiveness to PD-1/PD-L blockade are defined by their PD-1 expression and compartmentalization. These findings provide new and clinically relevant insight to differential antigen-specific CD8 T-cell exhaustion and their functional restoration.

Functional restoration of HCV-specific CD8 T-cells by PD1 blockade is defined by PD1 expression and compartmentalization

PubMed Central

Nakamoto, Nobuhiro; Kaplan, David E.; Coleclough, Jennifer; Li, Yun; Kaminski, Mary; Shaked, Abraham; Olthoff, Kim; Gostick, Emma; Price, David A.; Freeman, Gordon J.; Wherry, E. John; Chang, Kyong-Mi

2008-01-01

Background & Aims The immuno-inhibitory receptor Programmed Death-1 (PD-1) is upregulated on dysfunctional virus-specific CD8 T-cells during chronic viral infections and blockade of PD-1:PD-ligand (PD-L) interactions can restore their function. As hepatitis C virus (HCV) persists in the liver with immune-mediated disease pathogenesis, we examined the role of PD1/PD-L pathway in antigen-specific CD8 T-cell dysfunction in the liver and blood of HCV-infected patients. Methods PD-1 expression and function of circulating CD8 T-cells specific for HCV, EBV and Flu were examined ex vivo and following antigenic stimulation in vitro in patients with acute, chronic and resolved HCV infection using class I tetramers and flow cytometry. Intrahepatic CD8 T-cells were examined from liver explants of chronically HCV-infected transplant recipients. Results Intrahepatic HCV-specific CD8 T-cells from chronically HCV-infected patients were highly PD-1-positive, profoundly dysfunctional and unexpectedly refractory to PD-1:PD-L blockade, contrasting from circulating PD-1-intermediate HCV-specific CD8 T-cells with responsiveness to PD-1:PD-L blockade. This intrahepatic functional impairment was HCV-specific and directly associated with the level of PD-1 expression. Highly PD-1-positive intrahepatic CD8 T-cells were more phenotypically exhausted with increased cytotoxic T-lymphocyte antigen 4 (CTLA-4) and reduced CD28 and CD127 expression, suggesting that active antigen-specific stimulation in the liver induces a profound functional exhaustion not reversible by PD-1:PD-L blockade alone. Conclusion HCV-specific CD8 T-cell dysfunction and responsiveness to PD-1:PD-L blockade are defined by their PD-1 expression and compartmentalization. These findings provide new and clinically relevant insight to differential antigen-specific CD8 T-cell exhaustion and their functional restoration. PMID:18549878

Accuracy of the Enhanced Liver Fibrosis Test vs FibroTest, Elastography, and Indirect Markers in Detection of Advanced Fibrosis in Patients With Alcoholic Liver Disease.

PubMed

Thiele, Maja; Madsen, Bjørn Stæhr; Hansen, Janne Fuglsang; Detlefsen, Sönke; Antonsen, Steen; Krag, Aleksander

2018-04-01

Alcohol is the leading cause of cirrhosis and liver-related mortality, but we lack serum markers to detect compensated disease. We compared the accuracy of the Enhanced Liver Fibrosis test (ELF), the FibroTest, liver stiffness measurements (made by transient elastography and 2-dimensional shear-wave elastography), and 6 indirect marker tests in detection of advanced liver fibrosis (Kleiner stage ≥F3). We performed a prospective study of 10 liver fibrosis markers (patented and not), all performed on the same day. Patients were recruited from primary centers (municipal alcohol rehabilitation, n = 128; 6% with advanced fibrosis) and secondary health care centers (hospital outpatient clinics, n = 161; 36% with advanced fibrosis) in the Region of Southern Denmark from 2013 through 2016. Biopsy-verified fibrosis stage was used as the reference standard. The primary aim was to validate ELF in detection of advanced fibrosis in patients with alcoholic liver disease recruited from primary and secondary health care centers, using the literature-based cutoff value of 10.5. Secondary aims were to assess the diagnostic accuracy of ELF for significant fibrosis and cirrhosis and to determine whether combinations of fibrosis markers increase diagnostic yield. The ELF identified patients with advanced liver fibrosis with an area under the receiver operating characteristic curve (AUROC) of 0.92 (95% confidence interval 0.89-0.96); findings did not differ significantly between patients from primary vs secondary care (P = .917). ELF more accurately identified patients with advanced liver fibrosis than indirect marker tests, but ELF and FibroTest had comparable diagnostic accuracies (AUROC of FibroTest, 0.90) (P = .209 for comparison with ELF). Results from the ELF and FibroTest did not differ significantly from those of liver stiffness measurement in intention-to-diagnose analyses (AUROC for transient elastography, 0.90), but did differ in the per-protocol analysis (AUROC for transient elastography, 0.97) (P = .521 and .004 for comparison with ELF). Adding a serum marker to transient elastography analysis did not increase accuracy. For patients in primary care, ELF values below 10.5 and FibroTest values below 0.58 had negative predictive values for advanced liver fibrosis of 98% and 94%, respectively. In a prospective, direct comparison of tests, ELF and FibroTest identified advanced liver fibrosis in alcoholic patients from primary and secondary care with high diagnostic accuracy (AUROC values of 0.90 or higher using biopsy as reference). Advanced fibrosis can be ruled out in primary health care patients based on an ELF value below 10.5 or a FibroTest value below 0.58. Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.

Inhibiting Autophagy During Interleukin 2 (IL-2) Immunotherapy Promotes Long Term Tumor Regression

PubMed Central

Liang, Xiaoyan; De Vera, Michael E.; Buchser, William J.; Romo de Vivar Chavez, Antonio; Loughran, Patricia; Stolz, Donna Beer; Basse, Per; Wang, Tao; Van Houten, Bennett; Zeh, Herbert J.; Lotze, Michael T.

2012-01-01

Administration of high dose interleukin 2 (HDIL-2) has durable antitumor effects in 5-10% patients with melanoma and renal cell carcinoma. However, treatment is often limited by side effects, including reversible, multi-organ dysfunction and characterized by a cytokine-induced ‘systemic autophagic syndrome’. Here we hypothesized that the autophagy inhibitor chloroquine (CQ) would enhance IL-2 immunotherapeutic efficacy and limit toxicity. In an advanced murine metastatic liver tumor model, IL-2 inhibited tumor growth in a dose-dependent fashion, and these anti-tumor effects were significantly enhanced upon addition of CQ. The combination of IL-2 with CQ increased long term survival, decreased toxicity associated with vascular leakage, and enhanced immune cell proliferation and infiltration in the liver and spleen. HDIL-2 alone increased serum levels of IFN-γ, IL-6 and IL-18 and also induced autophagy within the liver and translocation of HMGB1 from the nucleus to the cytosol in hepatocytes, effects that were inhibited by combined administration with CQ. In tumor cells, CQ increased autophagic vacuoles and LC3-II levels inhibited oxidative phosphorylation and ATP production and promoted apoptosis, which was associated with increased Annexin V+/PI- cells, cleaved-PARP, cleaved-caspase 3, and cytochrome C release from mitochondria. Taken together, our findings provide a novel clinical strategy to enhance the efficacy of HDIL-2 immunotherapy for cancer patients. PMID:22472122

The Enhanced liver fibrosis score is associated with clinical outcomes and disease progression in patients with chronic liver disease.

PubMed

Irvine, Katharine M; Wockner, Leesa F; Shanker, Mihir; Fagan, Kevin J; Horsfall, Leigh U; Fletcher, Linda M; Ungerer, Jacobus P J; Pretorius, Carel J; Miller, Gregory C; Clouston, Andrew D; Lampe, Guy; Powell, Elizabeth E

2016-03-01

Current tools for risk stratification of chronic liver disease subjects are limited. We aimed to determine whether the serum-based ELF (Enhanced Liver Fibrosis) test predicted liver-related clinical outcomes, or progression to advanced liver disease, and to compare the performance of ELF to liver biopsy and non-invasive algorithms. Three hundred patients with ELF scores assayed at the time of liver biopsy were followed up (median 6.1 years) for liver-related clinical outcomes (n = 16) and clear evidence of progression to advanced fibrosis (n = 18), by review of medical records and clinical data. Fourteen of 73 (19.2%) patients with ELF score indicative of advanced fibrosis (≥9.8, the manufacturer's cut-off) had a liver-related clinical outcome, compared to only two of 227 (<1%) patients with ELF score <9.8. In contrast, the simple scores APRI and FIB-4 would only have predicted subsequent decompensation in six and four patients respectively. A unit increase in ELF score was associated with a 2.53-fold increased risk of a liver-related event (adjusted for age and stage of fibrosis). In patients without advanced fibrosis on biopsy at recruitment, 55% (10/18) with an ELF score ≥9.8 showed clear evidence of progression to advanced fibrosis (after an average 6 years), whereas only 3.5% of those with an ELF score <9.8 (8/207) progressed (average 14 years). In these subjects, a unit increase in ELF score was associated with a 4.34-fold increased risk of progression. The ELF score is a valuable tool for risk stratification of patients with chronic liver disease. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Increased concentrations of plasma IL-18 in patients with hepatic dysfunction after hepatectomy.

PubMed

Shibata, M; Hirota, M; Nozawa, F; Okabe, A; Kurimoto, M; Ogawa, M

2000-10-01

We investigated the dynamic aspects of circulatory IL-18 and other inflammatory cytokines in patients who underwent a hepatectomy. In patients with post-operative hepatic dysfunction, plasma concentrations of these cytokines increased, reflecting severe surgical trauma. IL-6, IL-10 and IFN-gamma increased in the early phase, while IL-18 increased in the later phase after 1 week. Interestingly, the increase in the plasma IL-18 concentration was correlated with that in serum bilirubin levels in hepatectomized patients. Hence, the decrease in the hepatic metabolism of IL-18 may cause the plasma accumulation of IL-18. This mechanism was confirmed using rat experiments. Intravenously administered human IL-18 was excreted into bile. Furthermore, the plasma clearance of human IL-18 was prolonged in bile duct-ligated rats. These results suggest that IL-18 is metabolized in the liver and excreted into bile, and an increase in plasma IL-18 in patients with hepatic dysfunction reflects the decreased metabolism in the liver. Copyright 2000 Academic Press.

Comparative Study of Reproductive Development in Wild and Captive-Reared Greater Amberjack Seriola dumerili (Risso, 1810)

PubMed Central

Zupa, Rosa; Rodríguez, Covadonga; Mylonas, Constantinos C.; Rosenfeld, Hanna; Fakriadis, Ioannis; Papadaki, Maria; Pérez, José A.; Pousis, Chrysovalentinos; Basilone, Gualtiero

2017-01-01

The greater amberjack Seriola dumerili is a large teleost fish with rapid growth and excellent flesh quality, whose domestication represents an ambitious challenge for aquaculture. The occurrence of reproductive dysfunctions in greater amberjack reared in captivity was investigated by comparing reproductive development of wild and captive-reared individuals. Wild and captive-reared breeders were sampled in the Mediterranean Sea during three different phases of the reproductive cycle: early gametogenesis (EARLY, late April-early May), advanced gametogenesis (ADVANCED, late May-early June) and spawning (SPAWNING, late June-July). Fish reproductive state was evaluated using the gonado-somatic index (GSI), histological analysis of the gonads and determination of sex steroid levels in the plasma, and correlated with leptin expression in the liver and gonad biochemical composition. The GSI and sex steroid levels were lower in captive-reared than in wild fish. During the ADVANCED period, when the wild greater amberjack breeders were already in spawning condition, ovaries of captive-reared breeders showed extensive atresia of late vitellogenic oocytes and spermatogenic activity ceased in the testes of half of the examined males. During the SPAWNING period, all captive-reared fish had regressed gonads, while wild breeders still displayed reproductive activity. Liver leptin expression and gonad proximate composition of wild and captive greater amberjack were similar. However, the gonads of captive-reared fish showed different total polar lipid contents, as well as specific lipid classes and fatty acid profiles with respect to wild individuals. This study underlines the need for an improvement in rearing technology for this species, which should include minimum handling during the reproductive season and the formulation of a specific diet to overcome the observed gonadal decrements of phospholipids, DHA (22:6n-3) and ARA (20:4n-6), compared to wild breeders. PMID:28056063

Non-alcoholic fatty liver disease is associated with left ventricular diastolic dysfunction in essential hypertension.

PubMed

Fallo, F; Dalla Pozza, A; Sonino, N; Lupia, M; Tona, F; Federspil, G; Ermani, M; Catena, C; Soardo, G; Di Piazza, L; Bernardi, S; Bertolotto, M; Pinamonti, B; Fabris, B; Sechi, L A

2009-11-01

Insulin resistance is recognized as the pathophysiological hallmark of non-alcoholic fatty liver disease (NAFLD). A relation between insulin sensitivity and left ventricular morphology and function has been reported in essential hypertension, where a high prevalence of NAFLD has been recently found. We investigated the inter-relationship between left ventricular morphology/function, metabolic parameters and NAFLD in 86 never-treated essential hypertensive patients subdivided in two subgroups according to the presence (n = 48) or absence (n = 38) of NAFLD at ultrasonography. The two groups were similar as to sex, age and blood pressure levels. No patient had diabetes mellitus, obesity, hyperlipidemia, or other risk factors for liver disease. Body mass index, waist circumference, triglycerides, glucose, insulin, homeostasis model of assessment index for insulin resistance (HOMA-IR), aspartate aminotransferase and alanine aminotransferase were higher and adiponectin levels were lower in patients with NAFLD than in patients without NAFLD, and were associated with NAFLD at univariate analysis. Patients with NAFLD had similar prevalence of left ventricular hypertrophy compared to patients without NAFLD, but a higher prevalence of diastolic dysfunction (62.5 vs 21.1%, P < 0.001), as defined by E/A ratio <1 and E-wave deceleration time >220 ms. Diastolic dysfunction (P = 0.040) and HOMA-IR (P = 0.012) remained independently associated with NAFLD at backward multivariate analysis. Non-alcoholic fatty liver disease was associated with insulin resistance and abnormalities of left ventricular diastolic function in a cohort of patients with essential hypertension, suggesting a concomitant increase of metabolic and cardiac risk in this condition.

Anesthetic management during the first combined heart-liver transplant performed in Korea: a case report.

PubMed

Park, Hyejin; Park, Jungchan; Lee, Jonghwan; Kim, Gaabsoo

2017-10-01

Herein, we describe the anesthetic management during the first combined heart-liver transplant (CHLT) performed in Korea. Though CHLT is a rare procedure, accumulating evidence suggests that it is a feasible option for patients with coexisting heart and liver failure. A 45-year-old female patient presented with severe cardiac dysfunction requiring extracorporeal membrane oxygenation (ECMO) support and secondary congestive hepatopathy. The patient underwent consecutive heart and liver transplantation using extracorporeal circulatory devices-heart transplant with cardiopulmonary bypass, and liver transplant with peripheral ECMO. In this case report, we focus on the specific anesthetic considerations for CHLT pertaining to the challenges associated with dual pathophysiology.

Feline hepatic lipidosis.

PubMed

Dimski, D S

1997-02-01

Hepatic lipidosis occurs when lipid mobilized to the liver exceeds lipid leaving the liver via formation of very-low-density lipoproteins or by oxidation. Hepatic lipidosis in cats is associated with overt liver dysfunction. In affected cats, excess lipid is mobilized to the liver because of starvation. Removal of hepatic lipid may be impaired because of protein malnutrition, a relative carnitine deficiency, or oxidative damage to peroxisomes and other hepatic organelles. Hepatic lipidosis occurs in adult cats, and is manifest by signs of weight loss, depression, vomiting, and icterus. Diagnosis is achieved by evaluating laboratory and diagnostic imaging data, in conjunction with a liver biopsy. Aggressive tube feeding is the treatment of choice. With this treatment, survival rates are 60% to 80%.

Basic and advanced echocardiographic evaluation of myocardial dysfunction in sepsis and septic shock.

PubMed

Vallabhajosyula, S; Pruthi, S; Shah, S; Wiley, B M; Mankad, S V; Jentzer, J C

2018-01-01

Sepsis continues to be a leading cause of mortality and morbidity in the intensive care unit. Cardiovascular dysfunction in sepsis is associated with worse short- and long-term outcomes. Sepsis-related myocardial dysfunction is noted in 20%-65% of these patients and manifests as isolated or combined left or right ventricular systolic or diastolic dysfunction. Echocardiography is the most commonly used modality for the diagnosis of sepsis-related myocardial dysfunction. With the increasing use of ultrasonography in the intensive care unit, there is a renewed interest in sepsis-related myocardial dysfunction. This review summarises the current scope of literature focused on sepsis-related myocardial dysfunction and highlights the use of basic and advanced echocardiographic techniques for the diagnosis of sepsis-related myocardial dysfunction and the management of sepsis and septic shock.

[Development of new therapeutic strategy for transporter-related diseases].

PubMed

Hayashi, Hisamitsu

2014-01-01

Significant technological advances in gene sequence analysis and construction of genetically-modified animals during the last two decades made it possible to reveal that many transporters are associated with diseases. The bile salt export pump (BSEP/ABCB11), a member of the family of ATP-binding cassette transporters, is localized on the canalicular membrane of hepatocytes and predominantly mediates the biliary excretion of bile salts. A hereditary defect of BSEP results in severe cholestasis called progressive familial intrahepatic cholestasis type 2 (PFIC2). Without liver transplantation, this disease progresses to liver failure and death before adulthood; therefore the development of new, less invasive medical therapy for PFIC2 is of the highest priority. We have previously shown that in many cases of PFIC2 patients, the dysfunction of BSEP is attributable to decreased BSEP expression on the hepatocanalicular membrane and that 4-phenylbutyrate (4PB), an approved drug for urea cycle disorder, may be a compound with potential to restore BSEP expression. This drug inhibits ubiquitination of cell surface-resident BSEP and thereby its clathrin-mediated endocytosis through the AP2 adaptor complex, leading to increase in BSEP expression on the canalicular membrane. Clinical studies to investigate the efficacy of 4PB in the treatment of PFIC2 revealed that 4PB therapy biochemically and histologically improved liver function without any side effect. Therefore, 4PB therapy may become the preferred choice, instead of liver transplantation, for PFIC2 patients. The strategy employed and findings in this study would be valuable for the drug development of transporter-related disorders.

Chinese Herbal Formulation PHY906 and Sorafenib Tosylate in Treating Patients With Advanced Liver Cancer

ClinicalTrials.gov

2018-05-07

Adult Primary Hepatocellular Carcinoma; Advanced Adult Primary Liver Cancer; Advanced Adult Hepatocellular Carcinoma; BCLC Stage B Adult Hepatocellular Carcinoma; BCLC Stage C Adult Hepatocellular Carcinoma

[A Case of Hyperammonemia Caused by Urinary Tract Infection Due to Urease-Producing Bacteria].

PubMed

Emura, Masahiro; Tsuchihashi, Kazunari; Shimizu, Yosuke; Kanamaru, Sojun; Matoba, Shun; Ito, Noriyuki

2016-08-01

We present here a rare case of hyperammonemia without liver dysfunction or portal-systemic shunting. The patient was an 80-year-old woman with a history of neurogenic bladder. She was admitted to a nearby hospital for vomiting, diarrhea and consciousness disturbance. Two days after admission, she was transferred to our hospital because of persistant consciousness disturbance. Laboratory data revealed hyperammonemia, but there was no indication of liver dysfunction. Moreover abdominal computed tomography did not reveal any clear finding of liver disease or portal-systemic shunting, but we noted multiple large bladder diverticula. Antibiotic therapy, tracheal intubation, ventilator management and bladder catheterization were performed. The patient's level of consciousness improved rapidly. Urinary culture revealed Bacteroides ureolyticus (urease-producing bacteria). The patient was diagnosed with hyperammonemia and a urinary tract infection due to urease-producing bacteria. Thus, physicians should be aware that obstructive urinary tract infections due to urease-producing bacteria can also be the cause of hyperammonemia.

Heart transplantation in adults with congenital heart disease.

PubMed

Houyel, Lucile; To-Dumortier, Ngoc-Tram; Lepers, Yannick; Petit, Jérôme; Roussin, Régine; Ly, Mohamed; Lebret, Emmanuel; Fadel, Elie; Hörer, Jürgen; Hascoët, Sébastien

2017-05-01

With the advances in congenital cardiac surgery and postoperative care, an increasing number of children with complex congenital heart disease now reach adulthood. There are already more adults than children living with a congenital heart defect, including patients with complex congenital heart defects. Among these adults with congenital heart disease, a significant number will develop ventricular dysfunction over time. Heart failure accounts for 26-42% of deaths in adults with congenital heart defects. Heart transplantation, or heart-lung transplantation in Eisenmenger syndrome, then becomes the ultimate therapeutic possibility for these patients. This population is deemed to be at high risk of mortality after heart transplantation, although their long-term survival is similar to that of patients transplanted for other reasons. Indeed, heart transplantation in adults with congenital heart disease is often challenging, because of several potential problems: complex cardiac and vascular anatomy, multiple previous palliative and corrective surgeries, and effects on other organs (kidney, liver, lungs) of long-standing cardiac dysfunction or cyanosis, with frequent elevation of pulmonary vascular resistance. In this review, we focus on the specific problems relating to heart and heart-lung transplantation in this population, revisit the indications/contraindications, and update the long-term outcomes. Copyright © 2017. Published by Elsevier Masson SAS.

Somatotropic Axis Dysfunction in Non-Alcoholic Fatty Liver Disease: Beneficial Hepatic and Systemic Effects of Hormone Supplementation

PubMed Central

Cabrera, Daniel; Solís, Nancy; San Martín, Diego; Cofré, Catalina; Pizarro, Margarita; Abrigo, Johanna; Campos, Fabián; Irigoyen, Betzabé; Carrasco-Avino, Gonzalo; Bezares, Katiuska; Riquelme, Valentina; Riquelme, Arnoldo; Arrese, Marco; Barrera, Francisco

2018-01-01

Background: Somatotropic axis dysfunction associated with non-alcoholic fatty liver disease (NAFLD) has potential multisystemic detrimental effects. Here, we analysed the effects of growth hormone (GH) and insulin-like growth factor-1 (IGF-1) supplementation on liver histology, adipokine profile and muscle function in an NAFLD model. Methods: C57BL/6 mice were fed with a high fat diet (HFD) for 12 weeks and were separated into three groups treated for 4 weeks with: (1) High fat diet (HFD) (n = 10); (2) HFD + GH 9 μg/g/d (n = 10); (3) HFD + IGF-1 0.02 µg/g/d (n = 9). A control group fed a chow diet was included (n = 6). Liver histology, liver triglycerides content, serum alanine aminotransferase (ALT) activity, adiponectin and leptin serum levels, in vivo muscle strength, tetanic force and muscle fibre cross-sectional area (CSA) were measured. Results: HFD + GH and HFD + IGF-1 groups showed significantly lower ALT activity compared to HFD (p < 0.01). Liver triglyceride content in HFD + GH was decreased compared to HFD (p < 0.01). Histologic steatosis score was increased in HFD and HFD + GH group (p < 0.01), whereas HFD + IGF-1 presented no difference compared to the chow group (p = 0.3). HFD + GH group presented lower serum leptin and adiponectin levels compared to HFD. GH and IGF-1 supplementation therapy reverted HFD-induced reduction in muscle strength and CSA (sarcopenia). Conclusions: GH and IGF-1 supplementation induced significant improvement in liver steatosis, aminotransferases and sarcopenia in a diet-induced NAFLD model. PMID:29724029

MELD score measured day 10 after orthotopic liver transplantation predicts death and re-transplantation within the first year.

PubMed

Rostved, Andreas A; Lundgren, Jens D; Hillingsø, Jens; Peters, Lars; Mocroft, Amanda; Rasmussen, Allan

2016-11-01

The impact of early allograft dysfunction on the outcome after liver transplantation is yet to be established. We explored the independent predictive value of the Model for End-Stage Liver Disease (MELD) score measured in the post-transplant period on the risk of mortality or re-transplantation. Retrospective cohort study on adults undergoing orthotopic deceased donor liver transplantation from 2004 to 2014. The MELD score was determined prior to transplantation and daily until 21 days after. The risk of mortality or re-transplantation within the first year was assessed according to quartiles of MELD using unadjusted and adjusted stepwise Cox regression analysis. We included 374 consecutive liver transplant recipients of whom 60 patients died or were re-transplanted. The pre-transplant MELD score was comparable between patients with good and poor outcome, but from day 1 the MELD score significantly diversified and was higher in the poor outcome group (MELD score quartile 4 versus quartile 1-3 at day 10: HR 5.1, 95% CI: 2.8-9.0). This association remained after adjustment for non-identical blood type, autoimmune liver disease and hepatocellular carcinoma (adjusted HR 5.3, 95% CI: 2.9-9.5 for MELD scores at day 10). The post-transplant MELD score was not associated with pre-transplant MELD score or the Eurotransplant donor risk index. Early determination of the MELD score as an indicator of early allograft dysfunction after liver transplantation was a strong independent predictor of mortality or re-transplantation and was not influenced by the quality of the donor, or preoperative recipient risk factors.

Prevention of alcoholic fatty liver and mitochondrial dysfunction in the rat by long-chain polyunsaturated fatty acids

PubMed Central

Song, Byoung-Joon; Moon, Kwan-Hoon; Olsson, Nils U.; Salem, Norman

2008-01-01

Background/Aims We reported that reduced dietary intake of polyunsaturated fatty acids (PUFA) such as arachidonic (AA,20:4n6, omega-6) and docosahexaenoic (DHA,22:6n3, omega-3) acids led to alcohol-induced fatty liver and fibrosis. This study was aimed at studying the mechanisms by which a DHA/AA-supplemented diet prevents alcohol-induced fatty liver. Methods Male Long-Evans rats were fed an ethanol or control liquid-diet with or without DHA/AA for 9 weeks. Plasma transaminase levels, liver histology, oxidative/nitrosative stress markers, and activities of oxidatively-modified mitochondrial proteins were evaluated. Results Chronic alcohol administration increased the degree of fatty liver but fatty liver decreased significantly in rats fed the alcohol-DHA/AA-supplemented diet. Alcohol exposure increased oxidative/nitrosative stress with elevated levels of ethanol-inducible CYP2E1, nitric oxide synthase, nitrite and mitochondrial hydrogen peroxide. However, these increments were normalized in rats fed the alcohol-DHA/AA-supplemented diet. The number of oxidatively-modified mitochondrial proteins was markedly increased following alcohol exposure but significantly reduced in rats fed the alcohol-DHA/AA-supplemented diet. The suppressed activities of mitochondrial aldehyde dehydrogenase, ATP synthase, and 3-ketoacyl-CoA thiolase in ethanol-exposed rats were also recovered in animals fed the ethanol-DHA/AA-supplemented diet. Conclusions Addition of DHA/AA prevents alcohol-induced fatty liver and mitochondrial dysfunction in an animal model by protecting various mitochondrial enzymes most likely through reducing oxidative/nitrosative stress. PMID:18571270

Extended-criteria donors in liver transplantation Part II: reviewing the impact of extended-criteria donors on the complications and outcomes of liver transplantation.

PubMed

Nemes, Balázs; Gámán, György; Polak, Wojciech G; Gelley, Fanni; Hara, Takanobu; Ono, Shinichiro; Baimakhanov, Zhassulan; Piros, Laszlo; Eguchi, Susumu

2016-07-01

Extended-criteria donors (ECDs) have an impact on early allograft dysfunction (EAD), biliary complications, relapse of hepatitis C virus (HCV), and survivals. Early allograft dysfunction was frequently seen in grafts with moderate and severe steatosis. Donors after cardiac death (DCD) have been associated with higher rates of graft failure and biliary complications compared to donors after brain death. Extended warm ischemia, reperfusion injury and endothelial activation trigger a cascade, leading to microvascular thrombosis, resulting in biliary necrosis, cholangitis, and graft failure. The risk of HCV recurrence increased by donor age, and associated with using moderately and severely steatotic grafts. With the administration of protease inhibitors sustained virological response was achieved in majority of the patients. Donor risk index and EC donor scores (DS) are reported to be useful, to assess the outcome. The 1-year survival rates were 87% and 40% respectively, for donors with a DS of 0 and 3. Graft survival was excellent up to a DS of 2, however a DS >2 should be avoided in higher-risk recipients. The 1, 3 and 5-year survival of DCD recipients was comparable to optimal donors. However ECDs had minor survival means of 85%, 78.6%, and 72.3%. The graft survival of split liver transplantation (SLT) was comparable to that of whole liver orthotopic liver transplantation. SLT was not regarded as an ECD factor in the MELD era any more. Full-right-full-left split liver transplantation has a significant advantage to extend the high quality donor pool. Hypothermic oxygenated machine perfusion can be applied clinically in DCD liver grafts. Feasibility and safety were confirmed. Reperfusion injury was also rare in machine perfused DCD livers.

Abnormality of autophagic function and cathepsin expression in the liver from patients with non-alcoholic fatty liver disease.

PubMed

Fukuo, Yuka; Yamashina, Shunhei; Sonoue, Hiroshi; Arakawa, Atsushi; Nakadera, Eisuke; Aoyama, Tomonori; Uchiyama, Akira; Kon, Kazuyoshi; Ikejima, Kenichi; Watanabe, Sumio

2014-09-01

Recent evidences indicate that hepatic steatosis suppresses autophagic proteolysis. The present study evaluated the correlation between autophagic function and cathepsin expression in the liver from patients with non-alcoholic fatty liver disease (NAFLD). Liver biopsy specimens were obtained from patients with chronic liver diseases (chronic hepatitis C [CHC; n = 20], chronic hepatitis B [CHB; n = 16], primary biliary cirrhosis [PBC; n = 23], NAFLD [n = 22] and control [n = 14]). The number of autophagic vesicles in hepatocytes was counted by using transmission electron microscopy. Expression of cathepsin B, D, L and p62 in the liver section was analyzed by immunohistochemical staining. The histological severity of NAFLD is assessed by NAFLD activity score (NAS). The number of autophagic vesicles in hepatocytes was significantly increased in both CHC and NAFLD groups, but not CHB and PBC, more than control. Although hepatocytes with aggregation of p62 were observed in less than 15% of CHC, p62 aggregation was detected in approximately 65% of NAFLD. Cathepsin B, D and L expression was significantly suppressed in the liver from NAFLD patients. Suppression of cathepsin B, D and L expression was not observed in CHB, CHC and PBC. In NAFLD patients, p62 aggregation was correlated with serum alanine aminotransferase value and inflammatory activity by NAS. These results indicate that a decrease in hepatic cathepsin expression in NAFLD is associated with autophagic dysfunction. Hepatic inflammation correlates with autophagic dysfunction in NAFLD. These findings indicate that the suppression of autophagic proteolysis by hepatic steatosis is involved in the pathogenesis of NAFLD. © 2013 The Japan Society of Hepatology.

Extended normothermic extracorporeal perfusion of isolated human liver after warm ischaemia: a preliminary report.

PubMed

Bellomo, Rinaldo; Marino, Bruno; Starkey, Graeme; Fink, Michael; Wang, Bao Zhong; Eastwood, Glenn M; Peck, Leah; Young, Helen; Houston, Shane; Skene, Alison; Opdam, Helen; Jones, Robert

2014-09-01

Donation after circulatory death (DCD) livers are at markedly increased risk of primary graft dysfunction and biliary tract ischaemia. Normothermic extracorporeal liver perfusion (NELP) may increase the ability to transplant DCD livers and may allow their use for artificial extracorporeal liver support of patients with fulminant liver failure. We conducted two proof-of-concept experiments using human livers after DCD to assess the feasibility and functional efficacy of NELP over an extended period. We applied extracorporeal membrane oxygenation, parenteral nutrition, separate hepatic artery and portal vein perfusion and physiological perfusion pressures to two livers obtained after DCD. We achieved NELP and evidence of liver function (bile production, paracetamol removal and maintenance of normal lactate levels) in both livers; one for 24 hours and the other for 43 hours. Histological examination showed areas of patchy ischaemia but preserved biliary ducts and canaliculi. Our experiments justify further investigations of the feasibility and efficacy of extended DCD liver preservation by ex-vivo perfusion.

Immune Dysfunction in Cirrhosis

PubMed Central

Noor, Mohd Talha; Manoria, Piyush

2017-01-01

Abstract Cirrhosis due to any etiology disrupts the homeostatic role of liver in the body. Cirrhosis-associated immune dysfunction leads to alterations in both innate and acquired immunity, due to defects in the local immunity of liver as well as in systemic immunity. Cirrhosis-associated immune dysfunction is a dynamic phenomenon, comprised of both increased systemic inflammation and immunodeficiency, and is responsible for 30% mortality. It also plays an important role in acute as well as chronic decompensation. Immune paralysis can accompany it, which is characterized by increase in anti-inflammatory cytokines and suppression of proinflammatory cytokines. There is also presence of increased gut permeability, reduced gut motility and altered gut flora, all of which leads to increased bacterial translocation. This increased bacterial translocation and consequent endotoxemia leads to increased blood stream bacterial infections that cause systemic inflammatory response syndrome, sepsis, multiorgan failure and death. The gut microbiota of cirrhotic patients has more pathogenic microbes than that of non-cirrhotic individuals, and this disturbs the homeostasis and favors gut translocation. Prompt diagnosis and treatment of such infections are necessary for better survival. We have reviewed the various mechanisms of immune dysfunction and its consequences in cirrhosis. Recognizing the exact pathophysiology of immune dysfunction will help treating clinicians in avoiding its complications in their patients and can lead to newer therapeutic interventions and reducing the morbidity and mortality rates. PMID:28507927

Normothermic extracorporeal perfusion of isolated porcine liver after warm ischaemia: a preliminary report.

PubMed

Bellomo, Rinaldo; Suzuki, Satoshi; Marino, Bruno; Starkey, Graeme K; Chambers, Brenton; Fink, Michael A; Wang, Bao Zhong; Houston, Shane; Eastwood, Glenn; Calzavacca, Paolo; Glassford, Neil; Skene, Alison; Jones, Daryl A; Jones, Robert

2012-09-01

Liver transplantation is a major life-saving procedure, and donation after cardiac death (DCD) has increased the pool of potential liver donors. However, DCD livers are at increased risk of primary graft dysfunction and biliary tract ischaemia. Normothermic extracorporeal liver perfusion (NELP) may increase the ability to protect, evaluate and, in future, transplant DCD livers. We conducted proof-of-concept experiments using a DCD model in the pig to assess the short-term (4 hours) feasibility and functional efficacy of NELP. Using extracorporeal membrane oxygenation, parenteral nutrition, separate hepatic artery and portal vein perfusion, and physiological perfusion pressures, we achieved NELP and evidence of function (bile production, paracetamol removal, maintenance of normal ammonia and lactate levels) for 4 hours in pig livers subjected to 15 and 30 minutes of cardiac arrest before explantation. Our experiments justify further investigations of the feasibility and efficacy of human DCD liver preservation by ex-vivo perfusion.

Antiviral Nucleotide Incorporation by Recombinant Human Mitochondrial RNA Polymerase Is Predictive of Increased In Vivo Mitochondrial Toxicity Risk

PubMed Central

Lin, Xiaodong; Yokokawa, Fumiaki; Sweeney, Zachary; Saunders, Oliver; Xie, Lili; Lim, Siew Pheng; Uteng, Marianne; Uehara, Kyoko; Warne, Robert; Gang, Wang; Jones, Christopher; Yendluri, Satya; Gu, Helen; Mansfield, Keith; Boisclair, Julie; Heimbach, Tycho; Catoire, Alexandre; Bracken, Kathryn; Weaver, Margaret; Moser, Heinz; Zhong, Weidong

2016-01-01

Nucleoside or nucleotide inhibitors are a highly successful class of antivirals due to selectivity, potency, broad coverage, and high barrier to resistance. Nucleosides are the backbone of combination treatments for HIV, hepatitis B virus, and, since the FDA approval of sofosbuvir in 2013, also for hepatitis C virus (HCV). However, many promising nucleotide inhibitors have advanced to clinical trials only to be terminated due to unexpected toxicity. Here we describe the in vitro pharmacology of compound 1, a monophosphate prodrug of a 2′-ethynyluridine developed for the treatment of HCV. Compound 1 inhibits multiple HCV genotypes in vitro (50% effective concentration [EC50], 0.05 to 0.1 μM) with a selectivity index of >300 (50% cytotoxic concentration [CC50], 30 μM in MT-4 cells). The active triphosphate metabolite of compound 1, compound 2, does not inhibit human α, β, or γ DNA polymerases but was a substrate for incorporation by the human mitochondrial RNA polymerase (POLRMT). In dog, the oral administration of compound 1 resulted in elevated serum liver enzymes and microscopic changes in the liver. Transmission electron microscopy showed significant mitochondrial swelling and lipid accumulation in hepatocytes. Gene expression analysis revealed dose-proportional gene signature changes linked to loss of hepatic function and increased mitochondrial dysfunction. The potential of in vivo toxicity through mitochondrial polymerase incorporation by nucleoside analogs has been previously shown. This study shows that even moderate levels of nucleotide analog incorporation by POLRMT increase the risk of in vivo mitochondrial dysfunction. Based on these results, further development of compound 1 as an anti-HCV compound was terminated. PMID:27645237

The basic data for residents aged 16 years or older who received a comprehensive health check examinations in 2011-2012 as a part of the Fukushima Health Management Survey after the great East Japan earthquake.

PubMed

Kawasaki, Yukihiko; Hosoya, Mitsuaki; Yasumura, Seiji; Ohira, Tetsuya; Satoh, Hiroaki; Suzuki, Hitoshi; Sakai, Akira; Ohtsuru, Akira; Takahashi, Atsushi; Ozasa, Kotaro; Kobashi, Gen; Kamiya, Kenji; Yamashita, Shunichi; Abe, Masafumi

2014-01-01

To assist in the long-term health management of residents and evaluate health impacts after the Tokyo Electric Power Company's Fukushima Daiichi Nuclear Power Plant accident in Fukushima Prefecture, the Fukushima prefectural government decided to conduct the Fukushima Health Management Survey. This report describes the results for residents aged 16 years or older who received the health check examinations and evaluates the data obtained from 2011 and 2012. The target group consisted of residents aged 16 years or older who had lived in the evacuation zone. The health check examinations were performed on receipt of an application for a health check examination from any of the residents. The examinations, including measurements of height, weight, abdominal circumference/body mass index (BMI), blood pressure, biochemical laboratory findings, and peripheral blood findings, were performed as required. 1) A total of 56,399 (30.9%) and 47,009 (25.4%) residents aged 16 years or older received health checks in 2011 and 2012, respectively. 2) In both years, a number of male and female residents in the 16-39 year age group were found to suffer obesity, hyperlipidemia, hyperuricemia, or liver dysfunction, and the prevalence of obesity and hyperlipidemia among residents increased with age. Furthermore, the proportion of residents with hypertension, glucose metabolic abnormalities or renal dysfunction was higher in those aged 40 years or older. 3) The frequencies of obesity, hypertension and hyperlipidemia among residents in 2012 were lower than those in 2011. However, the prevalence of liver dysfunction, hyperuricemia, glucose metabolic abnormalities and renal dysfunction among residents was higher in 2012 than in 2011. These results suggested the number of residents who had lived in the evacuation zone with obesity, hyperlipidemia, hyperuricemia, liver dysfunction, hypertension, glucose metabolic abnormalities, or renal dysfunction increased with age in all age groups. Therefore, we think that it is necessary to continue with health check examinations for these residents in order to ameliorate lifestyle-related disease.

Renal function improvement in liver transplant recipients after early everolimus conversion: A clinical practice cohort study in Spain.

PubMed

Bilbao, Itxarone; Salcedo, Magdalena; Gómez, Miguel Angel; Jimenez, Carlos; Castroagudín, Javier; Fabregat, Joan; Almohalla, Carolina; Herrero, Ignacio; Cuervas-Mons, Valentín; Otero, Alejandra; Rubín, Angel; Miras, Manuel; Rodrigo, Juan; Serrano, Trinidad; Crespo, Gonzalo; De la Mata, Manuel; Bustamante, Javier; Gonzalez-Dieguez, M Luisa; Moreno, Antonia; Narvaez, Isidoro; Guilera, Magda

2015-08-01

A national, multicenter, retrospective study was conducted to assess the results obtained for liver transplant recipients with conversion to everolimus in daily practice. The study included 477 recipients (481 transplantations). Indications for conversion to everolimus were renal dysfunction (32.6% of cases), hepatocellular carcinoma (HCC; 30.2%; prophylactic treatment for 68.9%), and de novo malignancy (29.7%). The median time from transplantation to conversion to everolimus was 68.7 months for de novo malignancy, 23.8 months for renal dysfunction, and 7.1 months for HCC and other indications. During the first year of treatment, mean everolimus trough levels were 5.4 (standard deviation [SD], 2.7) ng/mL and doses remained stable (1.5 mg/day) from the first month after conversion. An everolimus monotherapy regimen was followed by 28.5% of patients at 12 months. Patients with renal dysfunction showed a glomerular filtration rate (4-variable Modification of Diet in Renal Disease) increase of 10.9 mL (baseline mean, 45.8 [SD, 25.3] versus 57.6 [SD, 27.6] mL/minute/1.73 m(2) ) at 3 months after everolimus initiation (P < 0.001), and 6.8 mL at 12 months. Improvement in renal function was higher in patients with early conversion (<1 year). Adverse events were the primary reason for discontinuation in 11.2% of cases. The probability of survival at 3 years after conversion to everolimus was 83.0%, 71.1%, and 59.5% for the renal dysfunction, de novo malignancy, and HCC groups, respectively. Everolimus is a viable option for the treatment of renal dysfunction, and earlier conversion is associated with better recovery of renal function. Prospective studies are needed to confirm advantages in patients with malignancy. © 2015 American Association for the Study of Liver Diseases.

New Developments in Hepatorenal Syndrome.

PubMed

Mindikoglu, Ayse L; Pappas, Stephen C

2018-02-01

Hepatorenal syndrome (HRS) continues to be one of the major complications of decompensated cirrhosis, leading to death in the absence of liver transplantation. Challenges in precisely evaluating renal function in the patient with cirrhosis remain because of the limitations of serum creatinine (Cr) alone in estimating glomerular filtration rate (GFR); current GFR estimating models appear to underestimate renal dysfunction. Newer models incorporating renal biomarkers, such as the Cr-Cystatin C GFR Equation for Cirrhosis appear to estimate measured GFR more accurately. A major change in the diagnostic criteria for HRS based on dynamic serial changes in serum Cr that regard HRS type 1 as a special form of acute kidney injury promises the possibility of earlier identification of renal dysfunction in patients with cirrhosis. The diagnostic criteria of HRS still include the exclusion of other causes of kidney injury. Renal biomarkers have been disappointing in assisting with the differentiation of HRS from prerenal azotemia and other kidney disorders. Serum metabolomic profiling may be a more powerful tool to assess renal dysfunction, although the practical clinical significance of this remains unclear. As a result of the difficulties of assessing renal function in cirrhosis and the varying HRS diagnostic criteria and the rigor with which they are applied, the precise incidence and prevalence of HRS is unknown, but it is likely that HRS occurs more commonly than expected. The pathophysiology of HRS is rooted firmly in the setting of progressive reduction in renal blood flow as a result of portal hypertension and splanchnic vasodilation. Progressive marked renal cortical ischemia in patients with cirrhosis parallels the evolution of diuretic-sensitive ascites to diuretic-refractory ascites and HRS, a recognized continuum of renal dysfunction in cirrhosis. Alterations in nitrous oxide production, both increased and decreased, may play a major role in the pathophysiology of this evolution. The inflammatory cascade, triggered by bacterial translocation and endotoxemia, increasingly recognized as important in the manifestation of acute-on-chronic liver failure, also may play a significant role in the pathophysiology of HRS. The mainstay of treatment remains vasopressor therapy with albumin in an attempt to reverse splanchnic vasodilation and improve renal blood flow. Several meta-analyses have confirmed the value of vasopressors, chiefly terlipressin and noradrenaline, in improving renal function and reversing HRS type 1. Other interventions such as renal replacement therapy, transjugular intrahepatic portosystemic shunt, and artificial liver support systems have a very limited role in improving outcomes in HRS. Liver transplantation remains the definitive treatment for HRS. The frequency of simultaneous liver-kidney transplantation has increased dramatically in the Model for End-stage Liver Disease era, with changes in organ allocation policies. This has resulted in a more urgent need to predict native kidney recovery from HRS after liver transplantation alone, to avoid unnecessary simultaneous liver-kidney transplantation. Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.

AISF-SIMTI Position Paper: The appropriate use of albumin in patients with liver cirrhosis.

PubMed

2016-01-01

The use of human albumin is common in hepatology since international scientific societies support its administration to treat or prevent severe complications of cirrhosis, such as the prevention of post-paracentesis circulatory dysfunction after large-volume paracentesis and renal failure induced by spontaneous bacterial peritonitis, and the treatment of hepatorenal syndrome in association with vasoconstrictors. However, these indications are often disregarded, mainly because the high cost of human albumin leads health authorities and hospital administrations to restrict its use. On the other hand, physicians often prescribe human albumin in patients with advanced cirrhosis for indications that are not supported by solid scientific evidence and/or are still under investigation in clinical trials. In order to implement appropriate prescription of human albumin and to avoid its futile use, the Italian Association for the Study of the Liver (AISF) and the Italian Society of Transfusion Medicine and Immunohaematology (SIMTI) nominated a panel of experts, who reviewed the available clinical literature and produced practical clinical recommendations for the use of human albumin in patients with cirrhosis. Copyright © 2015 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

Multidisciplinary Approach in Hepatocellular Carcinoma in a Level II Hospital: The First Decade of Hospital Universitario Fundacion Alcorcon.

PubMed

Loinaz Segurola, C; LIedó Navarro, J L; Burgos, R de la Cruz; Martín Ríos, D; Ochando Cerdán, F; Alonso López, S; Martel Villagrán, J; Gutiérrez Garcia, M L; Fernandez Cebrián, J M; Fernández Rodríguez, C

2015-06-01

Mean survival in hepatocellular carcinoma remains low. Many efforts have been done during the last years through screening, diagnosis and treatment to improve the results. The aim of this work is to present the experience of our hospital multidisciplinary group during the first decade of this century. The patients with hepatocellullar carcinoma presented at the multidisciplinary meeting from 1999 to 2009 were prospectively studied. According to the tumor and functional status they were treated through the current available guidelines by transplant, partial hepatectomy, local/regional procedures, systemic or symptomatic treatment. One hundred and forty two patients were studied. Median tumor size was 3 cm. A single tumor was diagnosed in 64.8% of the patients. Eighteen patients had liver resection (6 transplantation and 12 with partial resection), 53 tumors were not treated due to advanced stage or liver dysfunction, and in the remaining patients radiofrequency, ethanol or embolization treatments were used, single or combined. a multidisciplinary approach of hepatocellular carcinoma in a second level hospital with trained professionals permits a diagnosis in early tumoral and functional stages in the majority of patients, and a variety of possible treatments with adequate survival outcomes.

Gut microbial balance and liver transplantation: alteration, management, and prediction.

PubMed

Tian, Xinyao; Yang, Zhe; Luo, Fangzhou; Zheng, Shusen

2018-04-01

Liver transplantation is a conventional treatment for terminal stage liver diseases. However, several complications still hinder the survival rate. Intestinal barrier destruction is widely observed among patients receiving liver transplant and suffering from ischemia-reperfusion or rejection injuries because of the relationship between the intestine and the liver, both in anatomy and function. Importantly, the resulting alteration of gut microbiota aggravates graft dysfunctions during the process. This article reviews the research progress for gut microbial alterations and liver transplantation. Especially, this work also evaluates research on the management of gut microbial alteration and the prediction of possible injuries utilizing microbial alteration during liver transplantation. In addition, we propose possible directions for research on gut microbial alteration during liver transplantation and offer a hypothesis on the utilization of microbial alteration in liver transplantation. The aim is not only to predict perioperative injuries but also to function as a method of treatment or even inhibit the rejection of liver transplantation.

Drug-Induced Liver Injury Associated with Complementary and Alternative Medicines

PubMed Central

Takahashi, Koji; Kanda, Tatsuo; Yasui, Shin; Haga, Yuki; Kumagai, Junichiro; Sasaki, Reina; Wu, Shuang; Nakamoto, Shingo; Nakamura, Masato; Arai, Makoto; Yokosuka, Osamu

2016-01-01

A 24-year-old man was admitted due to acute hepatitis with unknown etiology. After his condition and laboratory data gradually improved with conservative therapy, he was discharged 1 month later. Two months after his discharge, however, liver dysfunction reappeared. After his mother accidentally revealed that he took complementary and alternative medicine, discontinuation of the therapy caused his condition to improve. Finally, he was diagnosed with a recurrent drug-induced liver injury associated with Japanese complementary and alternative medicine. It is important to take the medical history in detail and consider complementary and alternative medicine as a cause of liver disease. PMID:28100990

Iodine-131 induced hepatotoxicity in previously healthy patients with Grave’s disease

PubMed Central

2013-01-01

Objective To describe the association of the rare and serious complication of liver toxicity in previously healthy Grave’s disease (GD) patients after the treatment with radioactive iodine 131I (RAI). Case presentation We report the clinical, laboratory and pathologic findings of 2 cases of severe liver toxicity associated with the treatment with RAI in previously healthy patients with GD. Clinical examination and laboratory investigations excluded viral hepatitis, autoimmune hepatitis, granulomatous disease, primary biliary disease, extrahepatic biliary obstruction, and heart failure. Case 1: A previously healthy 52-years old man reportedly having a typical GD but following RAI treatment, concomitantly developed severe liver toxicity that required 1 week of treatment in hospital. Case 2: A previously healthy 34-years old woman is reported as having a typical GD but developed jaundice following RAI treatment that required several weeks of in hospital treatment in the hepato-biliary department. In both cases, the liver dysfunction resolved after intensive treatment with hepato-protective agents. In this report the therapeutic considerations as well as the pathogenetic possibilities are reviewed. Conclusion To the best of our knowledge, this is the first description of the association observed, which is rare but may be severe and should be considered in any case of thyrotoxicosis where a liver dysfunction develops after the treatment with radioactive iodine 131I. PMID:23497434

Cordyceps sinensis protects against liver and heart injuries in a rat model of chronic kidney disease: a metabolomic analysis.

PubMed

Liu, Xia; Zhong, Fang; Tang, Xu-long; Lian, Fu-lin; Zhou, Qiao; Guo, Shan-mai; Liu, Jia-fu; Sun, Peng; Hao, Xu; Lu, Ying; Wang, Wei-ming; Chen, Nan; Zhang, Nai-xia

2014-05-01

To test the hypothesis that the traditional Chinese medicine Cordyceps sinensis could improve the metabolic function of extrarenal organs to achieve its anti-chronic kidney disease (CKD) effects. Male SD rats were divided into CKD rats (with 5/6-nephrectomy), CKD rats treated with Cordyceps sinensis (4 mg•kg-1•d-1, po), and sham-operated rats. After an 8-week treatment, metabolites were extracted from the hearts and livers of the rats, and then subjected to (1)H-NMR-based metabolomic analysis. Oxidative stress, energy metabolism, amino acid and protein metabolism and choline metabolism were considered as links between CKD and extrarenal organ dysfunction. Within the experimental period of 8 weeks, the metabolic disorders in the liver were more pronounced than in the heart, suggesting that CKD-related extrarenal organ dysfunctions occurred sequentially rather than simultaneously. Oral administration of Cordyceps sinensis exerted statistically significant rescue effects on the liver and heart by reversely regulating levels of those metabolites that are typically perturbed in CKD. Oral administration of Cordyceps sinensis significantly attenuates the liver and heart injuries in CKD rats. The (1)H NMR-based metabolomic approach has provided a systematic view for understanding of CKD and the drug treatment, which can also be used to elucidate the mechanisms of action of other traditional Chinese medicines.

Cordyceps sinensis protects against liver and heart injuries in a rat model of chronic kidney disease: a metabolomic analysis

PubMed Central

Liu, Xia; Zhong, Fang; Tang, Xu-long; Lian, Fu-lin; Zhou, Qiao; Guo, Shan-mai; Liu, Jia-fu; Sun, Peng; Hao, Xu; Lu, Ying; Wang, Wei-ming; Chen, Nan; Zhang, Nai-xia

2014-01-01

Aim: To test the hypothesis that the traditional Chinese medicine Cordyceps sinensis could improve the metabolic function of extrarenal organs to achieve its anti-chronic kidney disease (CKD) effects. Methods: Male SD rats were divided into CKD rats (with 5/6-nephrectomy), CKD rats treated with Cordyceps sinensis (4 mg•kg-1•d-1, po), and sham-operated rats. After an 8-week treatment, metabolites were extracted from the hearts and livers of the rats, and then subjected to 1H-NMR-based metabolomic analysis. Results: Oxidative stress, energy metabolism, amino acid and protein metabolism and choline metabolism were considered as links between CKD and extrarenal organ dysfunction. Within the experimental period of 8 weeks, the metabolic disorders in the liver were more pronounced than in the heart, suggesting that CKD-related extrarenal organ dysfunctions occurred sequentially rather than simultaneously. Oral administration of Cordyceps sinensis exerted statistically significant rescue effects on the liver and heart by reversely regulating levels of those metabolites that are typically perturbed in CKD. Conclusion: Oral administration of Cordyceps sinensis significantly attenuates the liver and heart injuries in CKD rats. The 1H NMR-based metabolomic approach has provided a systematic view for understanding of CKD and the drug treatment, which can also be used to elucidate the mechanisms of action of other traditional Chinese medicines. PMID:24632844

Factors predicting non-alcoholic steatohepatitis (NASH) and advanced fibrosis in patients with non-alcoholic fatty liver disease (NAFLD).

PubMed

Tasneem, Abbas Ali; Luck, Nasir Hassan; Majid, Zain

2018-04-01

Introduction To determine the factors predicting non-alcoholic steatohepatitis (NASH) and advanced fibrosis in patients with non-alcoholic fatty liver disease (NAFLD). Methodology All patients aged >18 years and having a fatty liver on abdominal ultrasound (US), presenting from January 2011 to January 2017, were included. A liver biopsy was performed on all the patients. Results Of 96 patients undergoing liver biopsy for non-alcoholic fatty liver disease (NAFLD), 76 (79.2%) were men. On liver US, diffuse fatty liver (DFL) was noted in 68 (70.8%) patients. Liver biopsy showed non-alcoholic steatohepatitis (NASH) in 78 (81.3%) patients. Factors associated with NASH were male gender, body mass index (BMI) > 27 kg/m 2 , DFL and raised alanine aminotransferase (ALT). A GULAB score (based on gender, US liver findings, lipid (fasting) levels, ALT level and BMI) of ≥5 predicted NASH with 82.05% sensitivity. Factors associated with advanced fibrosis in NAFLD were age >40 years, diabetes mellitus, AST/ALT ratio > 1 and raised GGT. Conclusion NASH is common in patients with male gender, high BMI, DFL on liver US, raised ALT and GULAB score ≥5.

Protective role of endogenous carbon monoxide in hepatic microcirculatory dysfunction after hemorrhagic shock in rats.

PubMed Central

Pannen, B H; Köhler, N; Hole, B; Bauer, M; Clemens, M G; Geiger, K K

1998-01-01

Maintenance of hepatic microcirculatory flow after ischemia of the liver is essential to prevent hepatic dysfunction. Thus, we determined the differential role of carbon monoxide (CO) and nitric oxide (NO) in the intrinsic control of sinusoidal perfusion, mitochondrial redox state, and bile production in the isolated perfused rat liver after hemorrhagic shock. Administration of tin protoporphyrin-IX (50 microM), a specific inhibitor of the CO generating enzyme heme oxygenase, caused a decrease in sinusoidal flow that was more pronounced after shock compared with sham shock, as determined by in situ epifluorescence microscopy. This was associated with a shift in hepatocellular redox potential to a more reduced state (increased fluorescence intensity of reduced pyridine nucleotides in hepatocytes, decreased acetoacetate/beta-hydroxybutyrate ratio in the perfusate) and a profound reduction in bile flow. In sharp contrast, the preferential inhibitor of the inducible isoform of NO synthase S-methylisothiourea sulfate (100 microM) did not affect sinusoidal flow, hepatic redox state, or function. This indicates that 1.) endogenously generated CO preserves sinusoidal perfusion after hemorrhagic shock, 2.) protection of the hepatic microcirculation by CO may serve to limit shock-induced liver dysfunction, and 3.) in contrast to CO, inducible NO synthase-derived NO is of only minor importance for the intrinsic control of hepatic perfusion and function under these conditions. PMID:9739056

Prognostic factors and monomicrobial necrotizing fasciitis: gram-positive versus gram-negative pathogens

PubMed Central

2011-01-01

Background Monomicrobial necrotizing fasciitis is rapidly progressive and life-threatening. This study was undertaken to ascertain whether the clinical presentation and outcome for patients with this disease differ for those infected with a gram-positive as compared to gram-negative pathogen. Methods Forty-six patients with monomicrobial necrotizing fasciitis were examined retrospectively from November 2002 to January 2008. All patients received adequate broad-spectrum antibiotic therapy, aggressive resuscitation, prompt radical debridement and adjuvant hyperbaric oxygen therapy. Eleven patients were infected with a gram-positive pathogen (Group 1) and 35 patients with a gram-negative pathogen (Group 2). Results Group 2 was characterized by a higher incidence of hemorrhagic bullae and septic shock, higher APACHE II scores at 24 h post-admission, a higher rate of thrombocytopenia, and a higher prevalence of chronic liver dysfunction. Gouty arthritis was more prevalent in Group 1. For non-survivors, the incidences of chronic liver dysfunction, chronic renal failure and thrombocytopenia were higher in comparison with those for survivors. Lower level of serum albumin was also demonstrated in the non-survivors as compared to those in survivors. Conclusions Pre-existing chronic liver dysfunction, chronic renal failure, thrombocytopenia and hypoalbuminemia, and post-operative dependence on mechanical ventilation represent poor prognostic factors in monomicrobial necrotizing fasciitis. Patients with gram-negative monobacterial necrotizing fasciitis present with more fulminant sepsis. PMID:21208438

The postoperative Model for End stage Liver Disease score as a predictor of short-term outcome after transplantation of extended criteria donor livers.

PubMed

Benko, Tamas; Gallinat, Anja; Minor, Thomas; Saner, Fuat H; Sotiropoulos, Georgios C; Paul, Andreas; Hoyer, Dieter P

2017-06-01

Recently, the postoperative Model for End stage Liver Disease score (POPMELD) was suggested as a definition of postoperative graft dysfunction and a predictor of outcome after liver transplantation (LT). The aim of the present study was to validate this concept in the context of extended criteria donor (ECD) organs. Single-center prospectively collected data (OPAL study/01/11-12/13) of 116 ECD LTs were utilized. For each recipient, the Model for End stage Liver Disease (MELD) score was calculated for 7 postoperative days (PODs). The ability of international normalized ratio, bilirubin, aspartate aminotransferase, Donor Risk Index, a recent definition of early allograft dysfunction, and the POPMELD was compared to predict 90-day graft loss. Predictive abilities were compared by receiver operating characteristic curves, sensitivity and specificity, and positive and negative predictive values. The median Donor Risk Index was 1.8. In all, 60.3% of recipients were men [median age of 54 (23-68) years]. The median POD1-7 peak-aspartate aminotransferase value was 1052 (194-17 577) U/l. The rate of early allograft dysfunction was 22.4%. The 90-day graft survival was 89.7%. Out of possible predictors of the 90-day graft loss MELD on POD5 was the best predictor of outcome (area under the curve=0.84). A MELD score of 16 or more on POD5 predicted the 90-day graft loss with a specificity of 80.8%, a sensitivity of 81.8%, and a positive and negative predictive value of 31 and 97.7%. A MELD score of 16 or more on POD5 is an excellent predictor of outcome in ECD donor LT. Routine evaluation of POPMELD scores might support clinical decision-making and should be reported routinely in clinical trials.

Severe Liver Cirrhosis Markedly Reduces AhR-Mediated Induction of Cytochrome P450 in Rats by Decreasing the Transcription of Target Genes

PubMed Central

Floreani, Maura; De Martin, Sara; Gabbia, Daniela; Barbierato, Massimo; Nassi, Alberto; Mescoli, Claudia; Orlando, Rocco; Bova, Sergio; Angeli, Paolo; Gola, Elisabetta; Sticca, Antonietta; Palatini, Pietro

2013-01-01

Although the induction of cytochrome P450 (CYP) has long been investigated in patients with cirrhosis, the question whether liver dysfunction impairs the response to CYP inducers still remains unresolved. Moreover, the mechanism underlying the possible effect of cirrhosis on induction has not been investigated. Since ethical constraints do not permit methodologically rigorous studies in humans, this question was addressed by investigating the effect of the prototypical inducer benzo[a]pyrene (BP) on CYP1A1 and CYP1A2 in cirrhotic rats stratified according to the severity of liver dysfunction. We simultaneously assessed mRNA level, protein expression and enzymatic activity of the CYP1A enzymes, as well as mRNA and protein expressions of the aryl hydrocarbon receptor (AhR), which mediates the BP effect. Basal mRNA and protein expressions of CYP1A1 were virtually absent in both healthy and cirrhotic rats. On the contrary, CYP1A2 mRNA, protein and enzyme activity were constitutively present in healthy rats and decreased significantly as liver function worsened. BP treatment markedly increased the concentrations of mRNA and immunodetectable protein, and the enzymatic activities of both CYP1A enzymes to similar levels in healthy and non-ascitic cirrhotic rats. Induced mRNA levels, protein expressions and enzymatic activities of both CYPs were much lower in ascitic rats and were proportionally reduced. Both constitutive and induced protein expressions of AhR were significantly lower in ascitic than in healthy rats. These results indicate that the inducibility of CYP1A enzymes is well preserved in compensated cirrhosis, whereas it is markedly reduced when liver dysfunction becomes severe. Induction appears to be impaired at the transcriptional level, due to the reduced expression of AhR, which controls the transcription of CYP1A genes. PMID:23626760

Assessment of biochemical liver function tests in relation to age among steady state sickle cell anemia patients.

PubMed

Akuyam, S A; Abubakar, A; Lawal, N; Yusuf, R; Aminu, S M; Hassan, A; Musa, A; Bello, A K; Yahaya, I A; Okafor, P A

2017-11-01

Multiorgan failure including liver dysfunction is a common finding in sickle cell anemia (SCA) patients, the cause of which is multifactorial with advancing age said to be a major determinant. There is a paucity of data on liver function among SCA patients in relation to age in northern Nigerian hospitals, including Ahmadu Bello University Teaching Hospital (ABUTH), Zaria. This study was to assess the biochemical liver function tests (LFTs) as they relate to age among SCA patients in steady state, with a view to improving the overall monitoring of these patients. This study was carried out in ABUTH, Zaria, Northern Nigeria. LFTs were carried out in 100 SCA and 100 apparently healthy participants (controls). The SCA group was made up of fifty adults and fifty children diagnosed of SCA, whereas the control group was made up of fifty adults and fifty children who were apparently healthy and had hemoglobin AA. Paired two-tailed Student's t-test for matched samples and Pearson's linear correlation statistical methods were employed for the data analysis using Microsoft Office Excel 2007. A P ≤ 0.05 was considered as statistically significant. The serum concentrations of total bilirubin (TB), alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), and AST/ALT ratio were significantly higher in SCA patients compared to the controls (P = 0.001, P = 0.001, P = 0.05, P = 0.05 and P = 0.001, respectively). Serum total protein (TP) and ALB were significantly lower (P = 0.01 and P < 0.05, respectively) in SCA patients compared with the controls. The levels of TB, ALT, AST, ALP, and AST/ALT were significantly lower in SCA adults compared to SCA children, whereas TP and ALB were higher in SCA adults compared to the SCA children. There were significant negative correlations between age and each of TB, ALT, AST, ALP, and AST/ALT, and significant positive correlations between age and each of TP and ALB in SCA patients. There are mild LFTs derangements in SCA patients even in steady state with the extent of the abnormalities decreasing with advancing age of the patients.

[Cardio-hepatic Syndrome in Heart Failure: Prevalence, Pathogenesis and Prognostic Significance].

PubMed

Kobalava, Zh D; Villevalde, S V; Soloveva, A E

2016-12-01

In a framework of the concept of organ interactions great attention has been paid during recent years to interaction of the heart and liver. The term cardio-hepatic syndrome (CHS) designates the combination of clinical-laboratory signs of liver dysfunction and acute or chronic cardiac pathology. In this article, we present mechanisms and characteristics of CHS in acute and chronic heart failure (HF), data of large clinical studies and registries on prevalence, associations, and prognostic significance of cardiogenic disturbances of liver function in patients with HF.

Magnetic Resonance Elastography and Other Magnetic Resonance Imaging Techniques in Chronic Liver Disease: Current Status and Future Directions.

PubMed

Tan, Cher Heng; Venkatesh, Sudhakar Kundapur

2016-09-15

Recent advances in the noninvasive imaging of chronic liver disease have led to improvements in diagnosis, particularly with magnetic resonance imaging (MRI). A comprehensive evaluation of the liver may be performed with the quantification of the degree of hepatic steatosis, liver iron concentration, and liver fibrosis. In addition, MRI of the liver may be used to identify complications of cirrhosis, including portal hypertension, ascites, and the development of hepatocellular carcinoma. In this review article, we discuss the state of the art techniques in liver MRI, namely, magnetic resonance elastography, hepatobiliary phase MRI, and liver fat and iron quantification MRI. The use of these advanced techniques in the management of chronic liver diseases, including nonalcoholic fatty liver disease, will be elaborated.

Magnetic Resonance Elastography and Other Magnetic Resonance Imaging Techniques in Chronic Liver Disease: Current Status and Future Directions

PubMed Central

Tan, Cher Heng; Venkatesh, Sudhakar Kundapur

2016-01-01

Recent advances in the noninvasive imaging of chronic liver disease have led to improvements in diagnosis, particularly with magnetic resonance imaging (MRI). A comprehensive evaluation of the liver may be performed with the quantification of the degree of hepatic steatosis, liver iron concentration, and liver fibrosis. In addition, MRI of the liver may be used to identify complications of cirrhosis, including portal hypertension, ascites, and the development of hepatocellular carcinoma. In this review article, we discuss the state of the art techniques in liver MRI, namely, magnetic resonance elastography, hepatobiliary phase MRI, and liver fat and iron quantification MRI. The use of these advanced techniques in the management of chronic liver diseases, including non-alcoholic fatty liver disease, will be elaborated. PMID:27563019

Toxic hepatitis in occupational exposure to solvents

PubMed Central

Malaguarnera, Giulia; Cataudella, Emanuela; Giordano, Maria; Nunnari, Giuseppe; Chisari, Giuseppe; Malaguarnera, Mariano

2012-01-01

The liver is the main organ responsible for the metabolism of drugs and toxic chemicals, and so is the primary target organ for many organic solvents. Work activities with hepatotoxins exposures are numerous and, moreover, organic solvents are used in various industrial processes. Organic solvents used in different industrial processes may be associated with hepatotoxicity. Several factors contribute to liver toxicity; among these are: species differences, nutritional condition, genetic factors, interaction with medications in use, alcohol abuse and interaction, and age. This review addresses the mechanisms of hepatotoxicity. The main pathogenic mechanisms responsible for functional and organic damage caused by solvents are: inflammation, dysfunction of cytochrome P450, mitochondrial dysfunction and oxidative stress. The health impact of exposure to solvents in the workplace remains an interesting and worrying question for professional health work. PMID:22719183

Current Review of Iron Overload and Related Complications in Hematopoietic Stem Cell Transplantation

PubMed Central

Atilla, Erden; Toprak, Selami K.; Demirer, Taner

2017-01-01

Iron overload is an adverse prognostic factor for patients undergoing hematopoietic stem cell transplantation (HSCT). In the HSCT setting, pretransplant and early posttransplant ferritin and transferrin saturation were found to be highly elevated due to high transfusion requirements. In addition to that, post-HSCT iron overload was shown to be related to infections, hepatic sinusoidal obstruction syndrome, mucositis, liver dysfunction, and acute graft-versus-host disease. Hyperferritinemia causes decreased survival rates in both pre- and posttransplant settings. Serum ferritin levels, magnetic resonance imaging, and liver biopsy are diagnostic tools for iron overload. Organ dysfunction due to iron overload may cause high mortality rates and therefore sufficient iron chelation therapy is recommended in this setting. In this review the management of iron overload in adult HSCT is discussed. PMID:27956374

Molecular adsorbent recirculating system (MARS) in acute liver injury and graft dysfunction: Results from a case-control study.

PubMed

Gerth, Hans U; Pohlen, Michele; Thölking, Gerold; Pavenstädt, Hermann; Brand, Marcus; Wilms, Christian; Hüsing-Kabar, Anna; Görlich, Dennis; Kabar, Iyad; Schmidt, Hartmut H J

2017-01-01

The primary therapeutic goals in the treatment of liver injury are to support liver regeneration or bridge the gap to liver transplantation (LT). Molecular adsorbent recirculating system (MARS) therapy has shown beneficial effects for specific symptoms of liver failure; however, general survival advantages have not yet been demonstrated. We studied the effects of MARS therapy compared to standard medical treatment (SMT) in two patient cohorts: in patients with an acute liver injury and in those with graft dysfunction (GD). We report on our experience over a 6.5-year period with 73 patients treated with SMT or with SMT and MARS (MARS group). In total, 53 patients suffered from acute liver injury in their native liver without a preexisting liver disease (SMT: n = 31, MARS: n = 22), and 20 patients showed a severe GD after LT (SMT: n = 10, MARS: n = 10). The entire cohort was predominantly characterized by hemodynamically and respiratorily stable patients with a low hepatic encephalopathy (HE) grade and a model of end-stage liver disease (MELD) score of 20.57 (MARS) or 22.51 (SMT, p = 0.555). Within the MARS group, the median number of extracorporeal therapy sessions was four (range = 3-5 sessions). Independent of the underlying etiology, MARS improved the patients' bilirubin values in the short term compared to SMT alone. In patients with acute liver injury, this response was sustained even after the end of MARS therapy. By contrast, the majority of patients with GD and an initial response to MARS therapy experienced worsened hyperbilirubinemia. No differences in 28-day mortality were observed with respect to acute liver injury (MARS 5.3% (95% CI: 0-15.3); SMT 3.3% (95% CI: 0-9.8), p = 0.754) or GD (MARS 20.0% (95% CI: 0-44.7), SMT 11.1% (95% CI: 0-31.7), p = 0.478). Although it did not improve 28-day mortality, MARS therapy improved the short-term response in patients with acute liver injury as well as in those with GD. In cases of acute hepatic injury, the use of MARS therapy resulted in the sustained stabilization of liver function and improved liver regeneration. A short-term response to MARS may predict the future course of the disease.

Molecular adsorbent recirculating system (MARS) in acute liver injury and graft dysfunction: Results from a case-control study

PubMed Central

Thölking, Gerold; Pavenstädt, Hermann; Brand, Marcus; Wilms, Christian; Hüsing-Kabar, Anna; Görlich, Dennis; Kabar, Iyad; Schmidt, Hartmut H. J.

2017-01-01

Background The primary therapeutic goals in the treatment of liver injury are to support liver regeneration or bridge the gap to liver transplantation (LT). Molecular adsorbent recirculating system (MARS) therapy has shown beneficial effects for specific symptoms of liver failure; however, general survival advantages have not yet been demonstrated. Aim We studied the effects of MARS therapy compared to standard medical treatment (SMT) in two patient cohorts: in patients with an acute liver injury and in those with graft dysfunction (GD). Methods We report on our experience over a 6.5-year period with 73 patients treated with SMT or with SMT and MARS (MARS group). In total, 53 patients suffered from acute liver injury in their native liver without a preexisting liver disease (SMT: n = 31, MARS: n = 22), and 20 patients showed a severe GD after LT (SMT: n = 10, MARS: n = 10). Results The entire cohort was predominantly characterized by hemodynamically and respiratorily stable patients with a low hepatic encephalopathy (HE) grade and a model of end-stage liver disease (MELD) score of 20.57 (MARS) or 22.51 (SMT, p = 0.555). Within the MARS group, the median number of extracorporeal therapy sessions was four (range = 3–5 sessions). Independent of the underlying etiology, MARS improved the patients’ bilirubin values in the short term compared to SMT alone. In patients with acute liver injury, this response was sustained even after the end of MARS therapy. By contrast, the majority of patients with GD and an initial response to MARS therapy experienced worsened hyperbilirubinemia. No differences in 28-day mortality were observed with respect to acute liver injury (MARS 5.3% (95% CI: 0–15.3); SMT 3.3% (95% CI: 0–9.8), p = 0.754) or GD (MARS 20.0% (95% CI: 0–44.7), SMT 11.1% (95% CI: 0–31.7), p = 0.478). Conclusions Although it did not improve 28-day mortality, MARS therapy improved the short-term response in patients with acute liver injury as well as in those with GD. In cases of acute hepatic injury, the use of MARS therapy resulted in the sustained stabilization of liver function and improved liver regeneration. A short-term response to MARS may predict the future course of the disease. PMID:28403210

Rib fractures in chronic alcoholic men: Relationship with feeding habits, social problems, malnutrition, bone alterations, and liver dysfunction.

PubMed

González-Reimers, Emilio; García-Valdecasas-Campelo, Elena; Santolaria-Fernández, Francisco; Milena-Abril, Antonio; Rodríguez-Rodríguez, Eva; Martínez-Riera, Antonio; Pérez-Ramírez, Alina; Alemán-Valls, María Remedios

2005-10-01

Rib fractures are common in alcoholics. This high prevalence might be due to ethanol-associated malnutrition, bone disease, liver dysfunction, or the peculiar lifestyle of the alcoholic with frequent trauma and altercations. In this study we try to discern the role of these factors on rib fracture (assessed on a plain thoracic X-ray film) in 81 consecutive alcoholic patients, 25 of them cirrhotics. Serum albumin, prothrombin aspartate aminotransferase (ASAT), alanine aminotransferase (ALAT), gamma-glutamyl transpeptidase, C-terminal cross-linking telopeptide of type 1 collagen, osteocalcin, insulin growth factor 1, 1,25-dihydroxyvitamin D, parathyroid hormone, estradiol, free testosterone, and corticosterone were measured, and the patients also underwent assessment of bone mineral density by a HOLOGIC QDR-2000 bone densitometer (Waltham, MA, USA). Body mass index, triceps skinfold, and brachial perimeter were also determined, and the patients and their families were asked about tobacco consumption, social and familial links, consumption of ethanol by other members of the family, kind of job, and feeding habits. Forty-two male nondrinker sanitary workers of similar age served as controls. Forty of the 81 patients showed rib fractures. There was a statistically significant association between rib fractures and disruption of social and familial links, irregular feeding habits (in bars or pubs, not at home), ethanol consumption by close relatives, and intensity of tobacco consumption, but not between rib fractures and liver function tests, nutritional parameters, or bone mineral density, besides a nearly significant trend (p = .053) with the presence of osteopenia at the femoral neck. Patients with major withdrawal symptoms at admission also presented more frequent rib fractures. We conclude that rib fractures in alcoholics are related to the peculiar lifestyle of these patients rather than to bone alterations, liver dysfunction, or nutritional status.

Obesity-induced hepatic hypoperfusion primes for hepatic dysfunction after resuscitated hemorrhagic shock.

PubMed

Matheson, Paul J; Hurt, Ryan T; Franklin, Glen A; McClain, Craig J; Garrison, R Neal

2009-10-01

Obese patients (BMI>35) after blunt trauma are at increased risk compared to non-obese for organ dysfunction, prolonged hospital stay, infection, prolonged mechanical ventilation, and mortality. Obesity and non-alcoholic fatty liver disease (NAFLD) produce a low grade systemic inflammatory response syndrome (SIRS) with compromised hepatic blood flow, which increases with body mass index. We hypothesized that obesity further aggravates liver dysfunction by reduced hepatic perfusion following resuscitated hemorrhagic shock (HEM). Age-matched Zucker rats (Obese, 314-519 g & Lean, 211-280 g) were randomly assigned to 4 groups (n = 10-12/group): (1) Lean-Sham; (2) Lean, HEM, and resuscitation (HEM/RES); (3) Obese-Sham; and (4) Obese-HEM/RES. HEM was 40% of mean arterial pressure (MAP) for 60 min; RES was return of shed blood/5 min and 2 volumes of saline/25 min. Hepatic blood flow (HBF) using galactose clearance, liver enzymes and complete metabolic panel were measured over 4 h after completion of RES. Obese rats had increased MAP, heart rate, and fasting blood glucose and BUN concentrations compared to lean controls, required less blood withdrawal (mL/g) to maintain 40% MAP, and RES did not restore BL MAP. Obese rats had decreased HBF at BL and during HEM/RES, which persisted 4 h post RES. ALT and BUN were increased compared to Lean-HEM/RES at 4 h post-RES. These data suggest that obesity significantly contributes to trauma outcomes through compromised vascular control or through fat-induced sinusoidal compression to impair hepatic blood flow after HEM/RES resulting in a greater hepatic injury. The pro-inflammatory state of NAFLD seen in obesity appears to prime the liver for hepatic ischemia after resuscitated hemorrhagic shock, perhaps intensified by insidious and ongoing hepatic hypoperfusion established prior to the traumatic injury or shock.

Arachidonic acid metabolites and endothelial dysfunction of portal hypertension.

PubMed

Sacerdoti, David; Pesce, Paola; Di Pascoli, Marco; Brocco, Silvia; Cecchetto, Lara; Bolognesi, Massimo

2015-07-01

Increased resistance to portal flow and increased portal inflow due to mesenteric vasodilatation represent the main factors causing portal hypertension in cirrhosis. Endothelial cell dysfunction, defined as an imbalance between the synthesis, release, and effect of endothelial mediators of vascular tone, inflammation, thrombosis, and angiogenesis, plays a major role in the increase of resistance in portal circulation, in the decrease in the mesenteric one, in the development of collateral circulation. Reduced response to vasodilators in liver sinusoids and increased response in the mesenteric arterioles, and, viceversa, increased response to vasoconstrictors in the portal-sinusoidal circulation and decreased response in the mesenteric arterioles are also relevant to the pathophysiology of portal hypertension. Arachidonic acid (AA) metabolites through the three pathways, cyclooxygenase (COX), lipoxygenase, and cytochrome P450 monooxygenase and epoxygenase, are involved in endothelial dysfunction of portal hypertension. Increased thromboxane-A2 production by liver sinusoidal endothelial cells (LSECs) via increased COX-1 activity/expression, increased leukotriens, increased epoxyeicosatrienoic acids (EETs) (dilators of the peripheral arterial circulation, but vasoconstrictors of the portal-sinusoidal circulation), represent a major component in the increased portal resistance, in the decreased portal response to vasodilators and in the hyper-response to vasoconstrictors. Increased prostacyclin (PGI2) via COX-1 and COX-2 overexpression, and increased EETs/heme-oxygenase-1/K channels/gap junctions (endothelial derived hyperpolarizing factor system) play a major role in mesenteric vasodilatation, hyporeactivity to vasoconstrictors, and hyper-response to vasodilators. EETs, mediators of liver regeneration after hepatectomy and of angiogenesis, may play a role in the development of regenerative nodules and collateral circulation, through stimulation of vascular endothelial growth factor (VEGF) inside the liver and in the portal circulation. Pharmacological manipulation of AA metabolites may be beneficial for cirrhotic portal hypertension. Copyright © 2015 Elsevier Inc. All rights reserved.

High Dose Atorvastatin Associated with Increased Risk of Significant Hepatotoxicity in Comparison to Simvastatin in UK GPRD Cohort

PubMed Central

Clarke, Alan T.; Johnson, Paul C. D.; Hall, Gillian C.; Ford, Ian; Mills, Peter R.

2016-01-01

Background & Aims Occasional risk of serious liver dysfunction and autoimmune hepatitis during atorvastatin therapy has been reported. We compared the risk of hepatotoxicity in atorvastatin relative to simvastatin treatment. Methods The UK GPRD identified patients with a first prescription for simvastatin [164,407] or atorvastatin [76,411] between 1997 and 2006, but with no prior record of liver disease, alcohol-related diagnosis, or liver dysfunction. Incident liver dysfunction in the following six months was identified by biochemical value and compared between statin groups by Cox regression model adjusting for age, sex, year treatment started, dose, alcohol consumption, smoking, body mass index and comorbid conditions. Results Moderate to severe hepatotoxicity [bilirubin >60μmol/L, AST or ALT >200U/L or alkaline phosphatase >1200U/L] developed in 71 patients on atorvastatin versus 101 on simvastatin. Adjusted hazard ratio [AHR] for all atorvastatin relative to simvastatin was 1.9 [95% confidence interval 1.4–2.6]. High dose was classified as 40–80mg daily and low dose 10–20mg daily. Hepatotoxicity occurred in 0.44% of 4075 patients on high dose atorvastatin [HDA], 0.07% of 72,336 on low dose atorvastatin [LDA], 0.09% of 44,675 on high dose simvastatin [HDS] and 0.05% of 119,732 on low dose simvastatin [LDS]. AHRs compared to LDS were 7.3 [4.2–12.7] for HDA, 1.4 [0.9–2.0] for LDA and 1.5 [1.0–2.2] for HDS. Conclusions The risk of hepatotoxicity was increased in the first six months of atorvastatin compared to simvastatin treatment, with the greatest difference between high dose atorvastatin and low dose simvastatin. The numbers of events in the analyses were small. PMID:26983033

Matrix metalloproteinases in liver injury, repair and fibrosis

PubMed Central

Duarte, Sergio; Baber, John; Fujii, Takehiro; Coito, Ana J.

2015-01-01

The liver is a large highly vascularized organ with a central function in metabolic homeostasis, detoxification, and immunity. Due to its roles, the liver is frequently exposed to various insults which can cause cell death and hepatic dysfunction. Alternatively, the liver has a remarkable ability to self-repair and regenerate after injury. Liver injury and regeneration have both been linked to complex extracellular matrix (ECM) related pathways. While normal degradation of ECM components is an important feature of tissue repair and remodeling, irregular ECM turnover contributes to a variety of liver diseases. Matrix metalloproteinases (MMPs) are the main enzymes implicated in ECM degradation. MMPs not only remodel the ECM, but also regulate immune responses. In this review, we highlight some of the MMP-attributed roles in acute and chronic liver injury and emphasize the need for further experimentation to better understand their functions during hepatic physiological conditions and disease progression. PMID:25599939

[Perioperative management of the pancreaticoduoden-ectomy: fluid administration and nutritional support based on complication prevention and treatment].

PubMed

Peng, Jun-sheng; Chen, Shi

2013-11-01

Pancreaticoduodenectomy(PD) has been widely accepted as one of the most complicated operation in abdominal surgery. The patients who receive PD operation always have other concurrent conditions, such as jaundice, diabetes, liver dysfunction, and malnutrition. Pancreatic fistula, biliary fistula and gastrointestinal dysfunction are common complications after PD. Proper perioperative management and fluid administration can reduce postoperative complications and the mortality.

3-Tesla MRI Response to TACE in HCC (Liver Cancer)

ClinicalTrials.gov

2016-08-22

Adult Primary Hepatocellular Carcinoma; Advanced Adult Primary Liver Cancer; Localized Resectable Adult Primary Liver Cancer; Localized Unresectable Adult Primary Liver Cancer; Stage A Adult Primary Liver Cancer (BCLC); Stage B Adult Primary Liver Cancer (BCLC)

Invasive liver abscess syndrome caused by Klebsiella pneumoniae with definite K2 serotyping in Japan: a case report.

PubMed

Seo, Ryota; Kudo, Daisuke; Gu, Yoshiaki; Yano, Hisakazu; Aoyagi, Tetsuji; Omura, Taku; Irino, Shigemi; Kaku, Mitsuo; Kushimoto, Shigeki

2016-12-01

Klebsiella pneumonia is a well-known human pathogen, and recently, a distinct invasive syndrome caused by K. pneumoniae serotypes K1 and K2 has been recognized in Southeast Asia. This syndrome is characterized by primary liver abscess and extrahepatic complications resulting from bacteremic dissemination. We report the first adult case of primary liver abscess caused by the definite K2 serotyped pathogen, with endogenous endophthalmitis in Japan. A 64-year-old woman was admitted to a nearby hospital for a high fever and diarrhea. She had visual loss of her right eye, renal dysfunction, and thrombocytopenia within 24 h from admission. She was transferred to our institution. On admission, she had no alteration of mental status and normal vital signs; however, she had almost complete ablepsia of the right eye. Laboratory data showed severe inflammation, liver dysfunction, thrombocytopenia, an increased serum creatinine level, and coagulopathy. Computed tomography showed a low density area in the right lobe of the liver. Invasive liver abscess syndrome probably caused by K. pneumonia was highly suspected and immediately administered broad-spectrum antibiotics for severe sepsis. Concurrently, endogenous endophthalmitis was diagnosed, and we performed vitrectomy on the day of admission. The blood culture showed K. pneumoniae infection. Percutaneous drainage of the liver abscess was also performed. Although she was discharged in a good general condition on day 22, she had complete ablepsia of the right eye. The K2A gene was detected by polymerase chain reaction (PCR), which is consistent with the K2 serotype. PCR was also positive for the virulence-associated gene rmpA. Final diagnosis was invasive liver abscess syndrome caused by K2 serotype K. pneumonia. Although the primary liver abscess caused by K. pneumoniae with a hypermucoviscous phenotype is infrequently reported outside Southeast Asia, physicians should recognize this syndrome, and appropriate diagnosis and treatment is essential for saving patients' lives and preserving organ function, especially for visual acuity.

Liver failure with coagulopathy, hyperammonemia and cyclic vomiting in a toddler revealed to have combined heterozygosity for genes involved with ornithine transcarbamylase deficiency and Wilson disease.

PubMed

Mira, Valerie; Boles, Richard G

2012-01-01

A girl with a 2 month history of cyclic episodes of vomiting, diarrhea, and lethargy lasting 2-3 days each presented with acute hepatopathy (ALT 3,500 IU/L) with coagulopathy (PT 55 s) and hyperammonemia (207 μmol/L) at age 1½ years. Biochemical and molecular analyzes revealed ornithine transcarbamylase (OTC) deficiency. While laboratory signs of mild hepatocellular dysfunction are common in OTC deficiency, substantial liver failure with coagulopathy is generally not seen, although four others cases have been reported, three of which presented with cyclic vomiting. Further evaluation in our case revealed elevated urine (198.8 μg/g creatinine) and liver (103 μg/g dry weight) copper content, and a heterozygous mutation in the Wilson disease gene, ATP7B. Our patient, now aged 5 years, has remained in excellent health with normal growth and development on fasting avoidance, a modified vegan diet, and sodium phenylbutyrate.These five cases demonstrate that generalized liver dysfunction/failure is a potential serious complication of OTC deficiency, although not a common one, and suggests that an ALT and PT should be obtained in OTC patients during episodes of hyperammonemia. Cyclic vomiting is a known presentation of OTC deficiency; it is not known if comorbid liver failure predisposes toward this phenotype. We propose that the heterozygote state in ATP7B increases the liver copper content, thus predisposing our patient with OTC deficiency to develop liver failure during a hyperammonemic episode. Our present case is an example of the opportunity of molecular diagnostics to identify putative modifier genes in patients with atypical presentations of genetic disorders.

Functional restoration of cirrhotic liver after partial hepatectomy in the rat.

PubMed

Hashimoto, Masaji; Watanabe, Goro

2005-01-01

Although cirrhosis is the terminal stage of various liver diseases, thanks to recent advances one might eliminate some causes of liver damage. Liver has a potent regeneration capacity. It is important to evaluate the regenerating cirrhotic liver after partial hepatectomy, morphologically and functionally, in the long term. We evaluated the functional capacity of the rat liver rendered cirrhotic by orally administered thioacetamide, and examined the correlation between morphological and functional restoration after 2/3 hepatectomy in comparison with hepatectomized normal rats and sham-operated cirrhotic rats. Morphological restoration was evaluated by remnant liver weight, proliferating cell nuclear antigen labeling index, and fibrosis ratio. Functional restoration was evaluated by the indocyanine green disappearance rate and aminopyrine clearance. Cirrhotic rats were functionally deteriorated in comparison with the normal rats. Morphological restoration in cirrhotic rats was delayed in comparison with normal rats. Functional restoration after 2/3 hepatectomy was advanced in comparison with morphological restoration. In comparison with sham-operated cirrhotic rats, functional restoration of the cirrhotic liver was accelerated by partial hepatectomy. In cirrhotic rats, functional restoration of the liver after 2/3 hepatectomy was advanced in comparison with morphological restoration. Partial hepatectomy seemed to promote functional restoration of the cirrhotic liver.

 High prevalence of undiagnosed liver cirrhosis and advanced fibrosis in type 2 diabetic patients.

PubMed

Arab, Juan P; Barrera, Francisco; Gallego, Consuelo; Valderas, Juan P; Uribe, Sergio; Tejos, Cristian; Serrano, Cristóbal; Serrano, Cristóbal; Huete, Álvaro; Liberona, Jessica; Labbé, Pilar; Quiroga, Teresa; Benítez, Carlos; Irarrázaval, Pablo; Riquelme, Arnoldo; Arrese, Marco

2016-01-01

 Background. Patients with type 2 diabetes mellitus (T2DM) are at risk for developing end-stage liver disease due to nonalcoholic steatohepatitis (NASH), the aggressive form of non-alcoholic fatty liver disease (NAFLD). Data on prevalence of advanced fibrosis among T2DM patients is scarce. To evaluate prevalence of steatosis, advanced fibrosis and cirrhosis using non-invasive methods in T2DM patients. 145 consecutive T2DM patients (> 55 years-old) were prospectively recruited. Presence of cirrhosis and advanced fibrosis was evaluated by magnetic resonance imaging (MRI) and NAFLD fibrosis score (NFS) respectively. Exclusion criteria included significant alcohol consumption, markers of viral hepatitis infection or other liver diseases. Results are expressed in percentage or median (interquartile range). 52.6% of patients were women, the median age was 60 years old (57-64), mean BMI was 29.6 ± 4.7 kg/m2 and diabetes duration was 7.6 ± 6.9 years. A high prevalence of liver steatosis (63.9%), advanced fibrosis assessed by NFS (12.8%) and evidence of liver cirrhosis in MRI (6.0%) was observed. In a multivariate analysis GGT > 82 IU/L (P = 0.004) and no alcohol intake (P = 0.032) were independently associated to advanced fibrosis. A high frequency of undiagnosed advanced fibrosis and cirrhosis was observed in non-selected T2DM patients. Screening of these conditions may be warranted in this patient population.

[Hypersensitivity to dacarbazine in patients with metastatic malignant melanoma].

PubMed

Levy, A; Guitera, P; Kerob, D; Ollivaud, L; Archimbaud, A; Dubertret, L; Basset-Seguin, N

2006-02-01

Dacarbazine (DTIC) is the first-line chemotherapy for metastatic malignant melanoma without cerebral metastasis. Its clinical and hematological safety is usually good. Hypersensitivity in hepatic failure patients is the most serious side effect described. This was a retrospective study of the prevalence of hypersensitivity in patients treated with DTIC for metastatic melanoma between 11/01/2002 and 10/31/2003. Hypersensitivity was diagnosed in the event of fever, hypereosinophilia (> 500/mm3) with or without liver dysfunction (> twice pre-therapeutic values). Clinical data, DTIC administration modalities, number of courses and clinical and laboratory safety data were recorded. Twenty patients were included, 11 women and 9 men of median age 58.6 years (22-82 years) with multiple metastases in all cases. DTIC was the first-line treatment for 19 patients, being administered for 4 days to 10 patients and for 1 day to the other 10 patients, depending on their overall health status. Five hypersensitivity-like manifestations were observed, all in the 4-day treatment group. In 3 patients, fever and hypereosinophilia were seen without liver dysfunction at D3 of the second course of treatment. In 2 patients, treatment was stopped after the second course because of disease progression. In the third patient, 4 courses were given with recurrence of symptoms, although the latter were controlled during the fifth course with corticosteroids and antihistamines given 15 minutes before the start of treatment. Two patients experienced severe forms of hypersensitivity with fever, hypereosinophilia, liver dysfunction (cytolysis and cholestasis) and delayed medullar aplasia, after the first and second course respectively. In one patient, bone marrow examination showed a block at the promyelocytic stage consistent with a toxic etiology. Treatment with DTIC was stopped, and all signs regressed with symptomatic treatment. Hypersensitivity with DTIC seems to be frequent, being observed in 20% of our patients, with early onset (after the first or second course) and absence of dose-dependence. We describe for the first time two cases of medullar aplasia occurring in association with DTIC hypersensitivity. During phase I studies, the hematologic toxicity of DTIC was moderate, rarely affecting red cells, and was observed with higher doses than those used in metastatic malignant melanoma. We suggest that this aplasia forms part of the signs of hypersensitivity because of the bone marrow morphology, the existence of anemia and concomitant resolution with all the others signs of hypersensitivity. Laboratory monitoring (NFS, liver enzymes) is thus justified, particularly after the first and second courses of DTIC. In case of fever and hypereosinophilia without liver dysfunction, DTIC may be continued together with symptomatic treatment. In the event of hepatic dysfunction, and of course severe hematological disorders, potentially fatal complications can occur and treatment must be stopped.

IGFBP-1 and IGF-I as markers for advanced fibrosis in NAFLD - a pilot study.

PubMed

Hagström, Hannes; Stål, Per; Hultcrantz, Rolf; Brismar, Kerstin; Ansurudeen, Ishrath

2017-12-01

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease globally. Advanced fibrosis (stage 3-4) is the most robust marker for future mortality, but diagnosis requires liver biopsy. Current non-invasive scoring systems aimed to identify advanced fibrosis are imperfect. Insulin-like growth factor I (IGF-I) and its binding protein IGFBP-1 are liver derived proteins, that are involved in various liver disorders. The aim of this study was to examine the possible association between advanced fibrosis and IGF-I and IGFBP-1 in NAFLD. Fasting blood samples were obtained from 52 patients diagnosed with NAFLD by liver biopsy. Total IGF-I and IGFBP-1 concentrations were determined in serum by in-house radio-immuno-assays. IGF-I levels were age-standardized (IGF-SD). A logistic regression model was used to investigate the association of IGF-SD and IGFBP-1 with advanced fibrosis (stage 3-4). Patients with advanced fibrosis (stage 3-4 vs. 0-2) had lower IGF-SD (-1.17 vs. 0.11, p = .01) and higher mean levels of IGFBP-1 (29.9 vs. 18.8 µg/l, p = .02). IGFBP-1 was associated with presence of advanced fibrosis (OR 1.04 per unit increase, 95%CI 1.0-1.07, p = .05), while IGF-1 was negatively associated with advanced fibrosis (OR 0.63 per standard deviation, 95%CI 0.44-0.92, p = .02). This pilot study suggests an association between serum IGFBP-1 and IGF-I levels with advanced fibrosis in NAFLD patients. IGFBP1 and IGF-1 could be of interest as future biomarkers. Similar studies in larger cohorts are needed.

Management of chronic spinal cord dysfunction.

PubMed

Abrams, Gary M; Ganguly, Karunesh

2015-02-01

Both acute and chronic spinal cord disorders present multisystem management problems to the clinician. This article highlights key issues associated with chronic spinal cord dysfunction. Advances in symptomatic management for chronic spinal cord dysfunction include use of botulinum toxin to manage detrusor hyperreflexia, pregabalin for management of neuropathic pain, and intensive locomotor training for improved walking ability in incomplete spinal cord injuries. The care of spinal cord dysfunction has advanced significantly over the past 2 decades. Management and treatment of neurologic and non-neurologic complications of chronic myelopathies ensure that each patient will be able to maximize their functional independence and quality of life.

Abnormal liver function in common variable immunodeficiency disorders due to nodular regenerative hyperplasia.

PubMed

Ward, C; Lucas, M; Piris, J; Collier, J; Chapel, H

2008-09-01

Patients with common variable immunodeficiency disorders are monitored for liver function test abnormalities. A proportion of patients develop deranged liver function and some also develop hepatomegaly. We investigated the prevalence of abnormalities and types of liver disease, aiming to identify those at risk and determine outcomes. The local primary immunodeficiency database was searched for patients with a common variable immunodeficiency disorder and abnormal liver function and/or a liver biopsy. Patterns of liver dysfunction were determined and biopsies reviewed. A total of 47 of 108 patients had deranged liver function, most commonly raised alkaline phosphatase levels. Twenty-three patients had liver biopsies. Nodular regenerative hyperplasia was found in 13 of 16 with unexplained pathology. These patients were more likely to have other disease-related complications of common variable immunodeficiency disorders, in particular non-coeliac (gluten insensitive) lymphocytic enteropathy. However, five had no symptoms of liver disease and only one died of liver complications. Nodular regenerative hyperplasia is a common complication of common variable immunodeficiency disorders but was rarely complicated by portal hypertension.

Enteric-coated mycophenolate sodium experience in liver transplant patients.

PubMed

Cantisani, G P C; Zanotelli, M L; Gleisner, A L M; de Mello Brandão, A; Marroni, C A

2006-04-01

Mycophenolate sodium (EC-MPS) has been shown to be as effective and as safe as mycophenolate mofetil (MMF) in renal transplant patients. Nevertheless, compared to MMF its use in liver transplant patients has been limited. The purpose of this study was to analyze the efficacy of EC-MPS as a primary immunosuppressant or as a replacement for MMF in liver transplant patients. Ninety among 470 liver transplant recipients were receiving or had added an antimetabolite to their immunosuppressant therapy. The most common reason for this change was renal dysfunction (47.8%) or diabetes (32.2%). EC-MPS was started at a median of 30 months after liver transplantation. The mean administered daily dose was 720 mg/d. At least one gastrointestinal symptom was reported by 25 patients. Abdominal pain (16.6%) and diarrhea (14.5%) were the most frequent. EC-MPS had to be discontinued in two patients, while six others required dose reduction to resolve the symptoms. Hematological adverse events were infrequent: three patients had leukopenia and one, anemia, all of which responded to dosage reduction. There was a creatinine reduction within 6 months of drug commencement and maintenance of the lower creatinine levels at 1 year among patients who began EC-MPS for renal dysfunction. Serum low-density lipoprotein cholesterol and triglyceride levels were significantly lower among patients on EC-MPS than on MMF. In conclusion, EC-MPS appears to have a similar efficacy and safety profile as MMF in liver transplant patients. Hematological and gastrointestinal adverse events were infrequent; seldom had the drug to be discontinued.

Early allograft dysfunction in liver transplantation with donation after cardiac death donors results in inferior survival.

PubMed

Lee, David D; Singh, Amandeep; Burns, Justin M; Perry, Dana K; Nguyen, Justin H; Taner, C Burcin

2014-12-01

Donation after cardiac death (DCD) liver allografts have been associated with increased morbidity from primary nonfunction, biliary complications, early allograft failure, cost, and mortality. Early allograft dysfunction (EAD) after liver transplantation has been found to be associated with inferior patient and graft survival. In a cohort of 205 consecutive liver-only transplant patients with allografts from DCD donors at a single center, the incidence of EAD was found to be 39.5%. The patient survival rates for those with no EAD and those with EAD at 1, 3, and 5 years were 97% and 89%, 79% and 79%, and 61% and 54%, respectively (P = 0.009). Allograft survival rates for recipients with no EAD and those with EAD at 1, 3, and 5 years were 90% and 75%, 72% and 64%, and 53% and 43%, respectively (P = 0.003). A multivariate analysis demonstrated a significant association between the development of EAD and the cold ischemia time [odds ratio (OR) = 1.26, 95% confidence interval (CI) = 1.01-1.56, P = 0.037] and hepatocellular cancer as a secondary diagnosis in recipients (OR = 2.26, 95% CI = 1.11-4.58, P = 0.025). There was no correlation between EAD and the development of ischemic cholangiopathy. In conclusion, EAD results in inferior patient and graft survival in recipients of DCD liver allografts. Understanding the events that cause EAD and developing preventive or early therapeutic approaches should be the focus of future investigations. © 2014 American Association for the Study of Liver Diseases.

Neonatal cholestatic hepatitis from carbamazepine exposure during pregnancy and breast feeding.

PubMed

Frey, Bernhard; Braegger, Christian P; Ghelfi, Daniela

2002-04-01

To report a case of transient cholestatic hepatitis occurring in an infant between the third and seventh weeks of life, most likely due to carbamazepine exposure during pregnancy and breast feeding. A boy, born to an epileptic mother who had been treated with carbamazepine monotherapy throughout pregnancy and breast feeding, experienced asphyxia at birth with transient hepatic dysfunction in the first week of life. After full recovery from asphyxia, he experienced a second period of liver dysfunction, presenting as cholestatic hepatitis that lasted approximately 5 weeks. Infectious and metabolic etiologies as well as extrahepatic biliary atresia were excluded. Carbamazepine is known to induce hepatic damage in children and adults. As the drug crosses the placenta and is excreted into breast milk, infants of mothers taking carbamazepine might also develop liver dysfunction. In addition to the present case, there are 2 well-documented case reports of cholestasis in association with transplacental and transmammary carbamazepine exposure. Carbamazepine-induced hepatitis may occur in association with prenatal exposure and breast feeding. This may expose infants to unnecessary diagnostic procedures, and should therefore be mentioned in the company's product information.

Cediranib Maleate and Combination Chemotherapy in Treating Patients With Advanced Biliary Cancers

ClinicalTrials.gov

2017-02-10

Adult Primary Cholangiocellular Carcinoma; Advanced Adult Primary Liver Cancer; Cholangiocarcinoma of the Extrahepatic Bile Duct; Cholangiocarcinoma of the Gallbladder; Localized Unresectable Adult Primary Liver Cancer; Periampullary Adenocarcinoma; Recurrent Adult Primary Liver Cancer; Recurrent Extrahepatic Bile Duct Cancer; Recurrent Gallbladder Cancer; Unresectable Extrahepatic Bile Duct Cancer; Unresectable Gallbladder Cancer

Bortezomib in Treating Patients With Unresectable Locally Advanced or Metastatic Adenocarcinoma of the Bile Duct or Gallbladder

ClinicalTrials.gov

2017-06-13

Adenocarcinoma of the Extrahepatic Bile Duct; Adenocarcinoma of the Gallbladder; Advanced Adult Primary Liver Cancer; Gastrointestinal Cancer; Localized Unresectable Adult Primary Liver Cancer; Recurrent Adult Primary Liver Cancer; Recurrent Extrahepatic Bile Duct Cancer; Recurrent Gallbladder Cancer; Unresectable Extrahepatic Bile Duct Cancer; Unresectable Gallbladder Cancer

CPI-613 in Treating Patients With Advanced or Metastatic Bile Duct Cancer That Cannot Be Removed By Surgery

ClinicalTrials.gov

2018-05-22

Adult Primary Cholangiocellular Carcinoma; Advanced Adult Primary Liver Cancer; Cholangiocarcinoma of the Extrahepatic Bile Duct; Cholangiocarcinoma of the Gallbladder; Localized Unresectable Adult Primary Liver Cancer; Metastatic Extrahepatic Bile Duct Cancer; Recurrent Adult Primary Liver Cancer; Recurrent Extrahepatic Bile Duct Cancer; Unresectable Extrahepatic Bile Duct Cancer

A switch in the source of ATP production and a loss in capacity to perform glycolysis are hallmarks of hepatocyte failure in advance liver disease.

PubMed

Nishikawa, Taichiro; Bellance, Nadège; Damm, Aaron; Bing, Han; Zhu, Zhen; Handa, Kan; Yovchev, Mladen I; Sehgal, Vasudha; Moss, Tyler J; Oertel, Michael; Ram, Prahlad T; Pipinos, Iraklis I; Soto-Gutierrez, Alejandro; Fox, Ira J; Nagrath, Deepak

2014-06-01

The cause of hepatic failure in the terminal stages of chronic injury is unknown. Cellular metabolic adaptations in response to the microenvironment have been implicated in cellular breakdown. To address the role of energy metabolism in this process we studied mitochondrial number, respiration, and functional reserve, as well as cellular adenosine-5'-triphosphate (ATP) production, glycolytic flux, and expression of glycolysis related genes in isolated hepatocytes from early and terminal stages of cirrhosis using a model that produces hepatic failure from irreversible cirrhosis in rats. To study the clinical relevance of energy metabolism in terminal stages of chronic liver failure, we analyzed glycolysis and energy metabolism related gene expression in liver tissue from patients at different stages of chronic liver failure according to Child-Pugh classification. Additionally, to determine whether the expression of these genes in early-stage cirrhosis (Child-Pugh Class A) is related to patient outcome, we performed network analysis of publicly available microarray data obtained from biopsies of 216 patients with hepatitis C-related Child-Pugh A cirrhosis who were prospectively followed up for a median of 10years. In the early phase of cirrhosis, mitochondrial function and ATP generation are maintained by increasing energy production from glycolytic flux as production from oxidative phosphorylation falls. At the terminal stage of hepatic injury, mitochondria respiration and ATP production are significantly compromised, as the hepatocytes are unable to sustain the increased demand for high levels of ATP generation from glycolysis. This impairment corresponds to a decrease in glucose-6-phosphatase catalytic subunit and phosphoglucomutase 1. Similar decreased gene expression was observed in liver tissue from patients at different stages of chronic liver injury. Further, unbiased network analysis of microarray data revealed that expression of these genes was down regulated in the group of patients with poor outcome. An adaptive metabolic shift, from generating energy predominantly from oxidative phosphorylation to glycolysis, allows maintenance of energy homeostasis during early stages of liver injury, but leads to hepatocyte dysfunction during terminal stages of chronic liver disease because hepatocytes are unable to sustain high levels of energy production from glycolysis. Copyright © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Relationship of antioxidant and oxidative stress markers in different organs following copper toxicity in a rat model

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kumar, Vijay; Kalita, Jayantee, E-mail: jayanteek@yahoo.com; Bora, Himangsu K.

Copper (Cu) at a higher level becomes toxic and it can catalyze the formation of highly reactive hydroxyl radical. We report the vulnerability of liver, kidney and brain to different dose of copper sulfate (CuSO{sub 4}) induced oxidative stress at different time duration. Fifty-four male Wistar rats (weight range = 205 ± 10 g) were equally divided into three groups. CuSO{sub 4} was administered orally to the experimental groups (Group-II and III) up to 90 days in a dose of 100 and 200 mg/Kg body weight per day. Saline water was given to the control group (Group-I). At the endmore » of 30, 60 and 90 days of administration, neurobehavioral studies were done and six rats from each group were sacrificed. Their liver, kidney and brain tissues were subjected for Cu, glutathione (GSH), malondialdehyde (MDA) and total antioxidant capacity (TAC) assay. Blood urea nitrogen (BUN), serum creatinine, bilirubin and transaminases were measured. GSH, TAC and MDA levels were correlated with the markers of respective organ dysfunction. Administration of CuSO{sub 4} resulted in increased free Cu and MDA level, and decrease GSH and TAC levels in group-II and III compared with group-I. In experimental groups, the reduction in TAC and GSH levels was maximum in liver tissue followed by brain and kidney; whereas increase in MDA level was highest in liver followed by brain and kidney at 30, 60 and 90 days. TAC and GSH levels in the liver inversely correlated with serum transaminases and bilirubin, and tissue free Cu, and positively correlated with MDA levels. Free Cu level in kidney tissue and BUN inversely correlated with TAC and GSH, and positively with MDA level. Grip-strength, rotarod and Y-maze findings were inversely correlated with brain free Cu and MDA levels and positively with GSH and TAC levels. The oxidative stress was highest in liver followed by brain and kidney after oral CuSO{sub 4} exposure in a rat model. These levels correlated with the respective organ dysfunction and tissue free Cu concentration. - Highlights: • Oral dosing of CuSO{sub 4} leads to oxidative stress in liver, brain and kidney. • Liver has maximum oxidative stress followed by brain and kidney. • Oxidative stress correlated with the respective organ dysfunction and tissue Cu concentration.« less

Dicarbonyl stress in clinical obesity.

PubMed

Masania, Jinit; Malczewska-Malec, Malgorzata; Razny, Urszula; Goralska, Joanna; Zdzienicka, Anna; Kiec-Wilk, Beata; Gruca, Anna; Stancel-Mozwillo, Julita; Dembinska-Kiec, Aldona; Rabbani, Naila; Thornalley, Paul J

2016-08-01

The glyoxalase system in the cytoplasm of cells provides the primary defence against glycation by methylglyoxal catalysing its metabolism to D-lactate. Methylglyoxal is the precursor of the major quantitative advanced glycation endproducts in physiological systems - arginine-derived hydroimidazolones and deoxyguanosine-derived imidazopurinones. Glyoxalase 1 of the glyoxalase system was linked to anthropometric measurements of obesity in human subjects and to body weight in strains of mice. Recent conference reports described increased weight gain on high fat diet-fed mouse with lifelong deficiency of glyoxalase 1 deficiency, compared to wild-type controls, and decreased weight gain in glyoxalase 1-overexpressing transgenic mice, suggesting a functional role of glyoxalase 1 and dicarbonyl stress in obesity. Increased methylglyoxal, dicarbonyl stress, in white adipose tissue and liver may be a mediator of obesity and insulin resistance and thereby a risk factor for development of type 2 diabetes and non-alcoholic fatty liver disease. Increased methylglyoxal formation from glyceroneogenesis on adipose tissue and liver and decreased glyoxalase 1 activity in obesity likely drives dicarbonyl stress in white adipose tissue increasing the dicarbonyl proteome and related dysfunction. The clinical significance will likely emerge from on-going clinical evaluation of inducers of glyoxalase 1 expression in overweight and obese subjects. Increased transcapillary escape rate of albumin and increased total body interstitial fluid volume in obesity likely makes levels of glycation of plasma protein unreliable indicators of glycation status in obesity as there is a shift of albumin dwell time from plasma to interstitial fluid, which decreases overall glycation for a given glycemic exposure.

Short-term fructose ingestion affects the brain independently from establishment of metabolic syndrome.

PubMed

Jiménez-Maldonado, Alberto; Ying, Zhe; Byun, Hyae Ran; Gomez-Pinilla, Fernando

2018-01-01

Chronic fructose ingestion is linked to the global epidemic of metabolic syndrome (MetS), and poses a serious threat to brain function. We asked whether a short period (one week) of fructose ingestion potentially insufficient to establish peripheral metabolic disorder could impact brain function. We report that the fructose treatment had no effect on liver/body weight ratio, weight gain, glucose tolerance and insulin sensitivity, was sufficient to reduce several aspects of hippocampal plasticity. Fructose consumption reduced the levels of the neuronal nuclear protein NeuN, Myelin Basic Protein, and the axonal growth-associated protein 43, concomitant with a decline in hippocampal weight. A reduction in peroxisome proliferator-activated receptor gamma coactivator-1 alpha and Cytochrome c oxidase subunit II by fructose treatment is indicative of mitochondrial dysfunction. Furthermore, the GLUT5 fructose transporter was increased in the hippocampus after fructose ingestion suggesting that fructose may facilitate its own transport to brain. Fructose elevated levels of ketohexokinase in the liver but did not affect SIRT1 levels, suggesting that fructose is metabolized in the liver, without severely affecting liver function commensurable to an absence of metabolic syndrome condition. These results advocate that a short period of fructose can influence brain plasticity without a major peripheral metabolic dysfunction. Copyright © 2017 Elsevier B.V. All rights reserved.

Fructose-Rich Diet Affects Mitochondrial DNA Damage and Repair in Rats.

PubMed

Cioffi, Federica; Senese, Rosalba; Lasala, Pasquale; Ziello, Angela; Mazzoli, Arianna; Crescenzo, Raffaella; Liverini, Giovanna; Lanni, Antonia; Goglia, Fernando; Iossa, Susanna

2017-03-24

Evidence indicates that many forms of fructose-induced metabolic disturbance are associated with oxidative stress and mitochondrial dysfunction. Mitochondria are prominent targets of oxidative damage; however, it is not clear whether mitochondrial DNA (mtDNA) damage and/or its lack of repair are events involved in metabolic disease resulting from a fructose-rich diet. In the present study, we evaluated the degree of oxidative damage to liver mtDNA and its repair, in addition to the state of oxidative stress and antioxidant defense in the liver of rats fed a high-fructose diet. We used male rats feeding on a high-fructose or control diet for eight weeks. Our results showed an increase in mtDNA damage in the liver of rats fed a high-fructose diet and this damage, as evaluated by the expression of DNA polymerase γ, was not repaired; in addition, the mtDNA copy number was found to be significantly reduced. A reduction in the mtDNA copy number is indicative of impaired mitochondrial biogenesis, as is the finding of a reduction in the expression of genes involved in mitochondrial biogenesis. In conclusion, a fructose-rich diet leads to mitochondrial and mtDNA damage, which consequently may have a role in liver dysfunction and metabolic diseases.

Age-related Changes in the Hepatic Microcirculation in Mice

PubMed Central

Ito, Yoshiya; Sørensen, Karen K.; Bethea, Nancy W.; Svistounov, Dmitri; McCuskey, Margaret K.; Smedsrød, Bård H.; McCuskey, Robert S.

2007-01-01

Aging of the liver is associated with impaired metabolism of drugs, adverse drug interactions, and susceptibility to toxins. Since reduced hepatic blood flow is suspected to contribute this impairment, we examined age-related alterations in hepatic microcirculation.. Livers of C57Bl/6 mice were examined at 0.8 (pre-pubertal), 3 (young adult), 14 (middle-aged) and 27 (senescent) months of age using in vivo and electron microscopic methods. The results demonstrated a 14% reduction in the numbers of perfused sinusoids between 0.8 and 27 month mice associated with 35% reduction in sinusoidal blood flow. This was accompanied by an inflammatory response evidenced by a 5-fold increase in leukocyte adhesion in 27 month mice, up-regulated expression of ICAM-1, and increases in intrahepatic macrophages. Sinusoidal diameter decreased 6-10%. Liver sinusoidal endothelial cell (LSEC) dysfunction was seen as early as 14 months when there was a 3-fold increase in the numbers of swollen LSEC. The endocytotic capacity of LSEC also was found to be reduced in older animals. The sinusoidal endothelium in 27 month old mice exhibited pseudocapillarization. In conclusion, the results suggest that leukocyte accumulation in the sinusoids and narrowing of sinusoidal lumens due to pseudocapillarization and dysfunction of LSEC reduce sinusoidal blood flow in aged livers. PMID:17582718

Protective and Curative Effects of the Sea Cucumber Holothuria atra Extract against DMBA-Induced Hepatorenal Diseases in Rats

PubMed Central

Dakrory, Ahmed I.; Fahmy, Sohair R.; Soliman, Amel M.; Mohamed, Ayman S.; Amer, Sayed A. M.

2015-01-01

Oxidative stress is a common mechanism contributing to the initiation and progression of hepatic damage. Hence there is a great demand for the development of agents with potent antioxidant effect. The aim of the present study is to evaluate the efficacy of Holothuria atra extract (HaE) as an antioxidant against 7,12-dimethylbenz[a]anthracene- (DMBA-) induced hepatorenal dysfunction. Experimental animals were divided into two main groups: protective and curative. Each group was then divided into five subgroups pre- or posttreated either with distilled water (DMBA subgroups) or with HaE (200 mg/kg body weight) for seven and fourteen days. Single oral administration of DMBA (15 mg/kg body weight) to Wistar rats resulted in a significant increase in the serum liver enzymes and kidney function's parameters. DMBA increased level of liver malondialdehyde (MDA), decreased levels of reduced glutathione (GSH), glutathione-S-transferase (GST), superoxide dismutase (SOD), and catalase (CAT) in the liver tissue, and induced liver histopathological alterations. Pre- or posttreatment with HaE orally for 14 days significantly reversed the hepatorenal alterations induced following DMBA administration. In conclusion, HaE exhibits good hepatoprotective, curative, and antioxidant potential against DMBA-induced hepatorenal dysfunction in rats that might be due to decreased free radical generation. PMID:25821811

Is intestinal inflammation linking dysbiosis to gut barrier dysfunction during liver disease?

PubMed Central

Brandl, Katharina

2016-01-01

Changes in the intestinal microbiota composition contribute to the pathogenesis of many disorders including gastrointestinal and liver diseases. Recent studies have broadened our understanding of the “gut-liver” axis. Dietary changes, other environmental and genetic factors can lead to alterations in the microbiota. Dysbiosis can further disrupt the integrity of the intestinal barrier leading to pathological bacterial translocation and the initiation of an inflammatory response in the liver. In this article, the authors dissect the different steps involved in disease pathogenesis to further refine approaches for the medical management of liver diseases. The authors will specifically discuss the role of dysbiosis in inducing intestinal inflammation and increasing intestinal permeability. PMID:26088524

Extracorporeal albumin dialysis in patients with Amanita phalloides poisoning.

PubMed

Faybik, Peter; Hetz, Hubert; Baker, Amir; Bittermann, Clemens; Berlakovich, Gabriela; Werba, Alois; Krenn, Claus-Georg; Steltzer, Heinz

2003-01-01

Ingestion of Amanita phalloides is the most common cause of lethal mushroom poisoning. The relative late onset of symptoms is a distinct diagnostic feature of Amanita intoxication and also the main reason of failure for extracorporeal removal of Amanita-specific toxins from the gut and circulation. Extracorporeal albumin dialysis (ECAD) has been used on six consecutive patients admitted after A. phalloides poisoning with acute liver failure (ALF). Six patients, with mean age of 46 years (range: 9-70 years), underwent one to three ECAD treatments. The mean time from mushroom ingestion until the first ECAD treatment was 76 h. Two patients regenerated spontaneously under ECAD treatment and orthotopic liver transplantation (OLT) could be avoided. Two patients were successfully bridged to OLT and one patient died because of cerebral herniation. One patient was treated with ECAD immediately after OLT because of the graft dysfunction and survived without re-transplantation. ECAD appeared to be a successful treatment perspective in supporting liver regeneration or in sufficient bridging to OLT and also in treatment of graft dysfunction after OLT in patients with A. phalloides poisoning.

Hepatic Steatosis as a Marker of Metabolic Dysfunction

PubMed Central

Fabbrini, Elisa; Magkos, Faidon

2015-01-01

Nonalcoholic fatty liver disease (NAFLD) is the liver manifestation of the complex metabolic derangements associated with obesity. NAFLD is characterized by excessive deposition of fat in the liver (steatosis) and develops when hepatic fatty acid availability from plasma and de novo synthesis exceeds hepatic fatty acid disposal by oxidation and triglyceride export. Hepatic steatosis is therefore the biochemical result of an imbalance between complex pathways of lipid metabolism, and is associated with an array of adverse changes in glucose, fatty acid, and lipoprotein metabolism across all tissues of the body. Intrahepatic triglyceride (IHTG) content is therefore a very good marker (and in some cases may be the cause) of the presence and the degree of multiple-organ metabolic dysfunction. These metabolic abnormalities are likely responsible for many cardiometabolic risk factors associated with NAFLD, such as insulin resistance, type 2 diabetes mellitus, and dyslipidemia. Understanding the factors involved in the pathogenesis and pathophysiology of NAFLD will lead to a better understanding of the mechanisms responsible for the metabolic complications of obesity, and hopefully to the discovery of novel effective treatments for their reversal. PMID:26102213

Pathogenesis of liver cirrhosis.

PubMed

Zhou, Wen-Ce; Zhang, Quan-Bao; Qiao, Liang

2014-06-21

Liver cirrhosis is the final pathological result of various chronic liver diseases, and fibrosis is the precursor of cirrhosis. Many types of cells, cytokines and miRNAs are involved in the initiation and progression of liver fibrosis and cirrhosis. Activation of hepatic stellate cells (HSCs) is a pivotal event in fibrosis. Defenestration and capillarization of liver sinusoidal endothelial cells are major contributing factors to hepatic dysfunction in liver cirrhosis. Activated Kupffer cells destroy hepatocytes and stimulate the activation of HSCs. Repeated cycles of apoptosis and regeneration of hepatocytes contribute to pathogenesis of cirrhosis. At the molecular level, many cytokines are involved in mediation of signaling pathways that regulate activation of HSCs and fibrogenesis. Recently, miRNAs as a post-transcriptional regulator have been found to play a key role in fibrosis and cirrhosis. Robust animal models of liver fibrosis and cirrhosis, as well as the recently identified critical cellular and molecular factors involved in the development of liver fibrosis and cirrhosis will facilitate the development of more effective therapeutic approaches for these conditions.

Pathogenesis of liver cirrhosis

PubMed Central

Zhou, Wen-Ce; Zhang, Quan-Bao; Qiao, Liang

2014-01-01

Liver cirrhosis is the final pathological result of various chronic liver diseases, and fibrosis is the precursor of cirrhosis. Many types of cells, cytokines and miRNAs are involved in the initiation and progression of liver fibrosis and cirrhosis. Activation of hepatic stellate cells (HSCs) is a pivotal event in fibrosis. Defenestration and capillarization of liver sinusoidal endothelial cells are major contributing factors to hepatic dysfunction in liver cirrhosis. Activated Kupffer cells destroy hepatocytes and stimulate the activation of HSCs. Repeated cycles of apoptosis and regeneration of hepatocytes contribute to pathogenesis of cirrhosis. At the molecular level, many cytokines are involved in mediation of signaling pathways that regulate activation of HSCs and fibrogenesis. Recently, miRNAs as a post-transcriptional regulator have been found to play a key role in fibrosis and cirrhosis. Robust animal models of liver fibrosis and cirrhosis, as well as the recently identified critical cellular and molecular factors involved in the development of liver fibrosis and cirrhosis will facilitate the development of more effective therapeutic approaches for these conditions. PMID:24966602

Targeting the gut microbiota with inulin-type fructans: preclinical demonstration of a novel approach in the management of endothelial dysfunction.

PubMed

Catry, Emilie; Bindels, Laure B; Tailleux, Anne; Lestavel, Sophie; Neyrinck, Audrey M; Goossens, Jean-François; Lobysheva, Irina; Plovier, Hubert; Essaghir, Ahmed; Demoulin, Jean-Baptiste; Bouzin, Caroline; Pachikian, Barbara D; Cani, Patrice D; Staels, Bart; Dessy, Chantal; Delzenne, Nathalie M

2018-02-01

To investigate the beneficial role of prebiotics on endothelial dysfunction, an early key marker of cardiovascular diseases, in an original mouse model linking steatosis and endothelial dysfunction. We examined the contribution of the gut microbiota to vascular dysfunction observed in apolipoprotein E knockout (Apoe -/- ) mice fed an n-3 polyunsaturated fatty acid (PUFA)-depleted diet for 12 weeks with or without inulin-type fructans (ITFs) supplementation for the last 15 days. Mesenteric and carotid arteries were isolated to evaluate endothelium-dependent relaxation ex vivo. Caecal microbiota composition (Illumina Sequencing of the 16S rRNA gene) and key pathways/mediators involved in the control of vascular function, including bile acid (BA) profiling, gut and liver key gene expression, nitric oxide and gut hormones production were also assessed. ITF supplementation totally reverses endothelial dysfunction in mesenteric and carotid arteries of n-3 PUFA-depleted Apoe -/- mice via activation of the nitric oxide (NO) synthase/NO pathway. Gut microbiota changes induced by prebiotic treatment consist in increased NO-producing bacteria, replenishment of abundance in Akkermansia and decreased abundance in bacterial taxa involved in secondary BA synthesis. Changes in gut and liver gene expression also occur upon ITFs suggesting increased glucagon-like peptide 1 production and BA turnover as drivers of endothelium function preservation. We demonstrate for the first time that ITF improve endothelial dysfunction, implicating a short-term adaptation of both gut microbiota and key gut peptides. If confirmed in humans, prebiotics could be proposed as a novel approach in the prevention of metabolic disorders-related cardiovascular diseases. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Prevalence of non-alcoholic fatty liver disease and risk factors for advanced fibrosis and mortality in the United States.

PubMed

Le, Michael H; Devaki, Pardha; Ha, Nghiem B; Jun, Dae Won; Te, Helen S; Cheung, Ramsey C; Nguyen, Mindie H

2017-01-01

In the United States, non-alcoholic fatty liver disease (NAFLD) is the most common liver disease and associated with higher mortality according to data from earlier National Health and Nutrition Examination Survey (NHANES) 1988-1994. Our goal was to determine the NAFLD prevalence in the recent 1999-2012 NHANES, risk factors for advanced fibrosis (stage 3-4) and mortality. NAFLD was defined as having a United States Fatty Liver Index (USFLI) > 30 in the absence of heavy alcohol use and other known liver diseases. The probability of low/high risk of having advanced fibrosis was determined by the NAFLD Fibrosis Score (NFS). In total, 6000 persons were included; of which, 30.0% had NAFLD and 10.3% of these had advanced fibrosis. Five and eight-year overall mortality in NAFLD subjects with advanced fibrosis was significantly higher than subjects without NAFLD ((18% and 35% vs. 2.6% and 5.5%, respectively) but not NAFLD subjects without advanced fibrosis (1.1% and 2.8%, respectively). NAFLD with advanced fibrosis (but not those without) is an independent predictor for mortality on multivariate analysis (HR = 3.13, 95% CI 1.93-5.08, p<0.001). In conclusion, in this most recent NHANES, NAFLD prevalence remains at 30% with 10.3% of these having advanced fibrosis. NAFLD per se was not a risk factor for increased mortality, but NAFLD with advanced fibrosis was. Mexican American ethnicity was a significant risk factor for NAFLD but not for advanced fibrosis or increased mortality.

Renal Liver-Type Fatty Acid Binding Protein (L-FABP) Attenuates Acute Kidney Injury in Aristolochic Acid Nephrotoxicity

PubMed Central

Matsui, Katsuomi; Kamijo-Ikemorif, Atsuko; Sugaya, Takeshi; Yasuda, Takashi; Kimura, Kenjiro

2011-01-01

Injection of aristolochic acid (AA) in mice causes AA-induced nephrotoxicity, in which oxidative stress contributes to development of tubulointerstitial damage (TID). Liver-type fatty acid binding protein (L-FABP) is expressed in human proximal tubules and has an endogenous antioxidative function. The renoprotection of renal L-FABP was examined in a model of AA-induced nephrotoxicity. Established human L-FABP (hL-FABP) transgenic (Tg) mice and wild-type (WT) mice were treated with AA for up to 5 days. Mice were sacrificed on days 1, 3, and 5 after the start of AA injection. Although mouse L-FABP was not expressed in proximal tubules of WT mice, hL-FABP was expressed in proximal tubules of Tg mice. The expression of renal hL-FABP was significantly increased in Tg mice administered AA (Tg-AA), compared with the control (saline-treated Tg mice). In WT-AA mice, there was high urinary excretion of Nε-(hexanoyl)-lysine, the production of heme oxygenase-1 and receptor for advanced glycation end products increased, and TID was provoked. In contrast, renal hL-FABP in Tg-AA mice suppressed production of Nε-(hexanoyl)lysine, heme oxygenase-1, and receptor for advanced glycation end products. Renal dysfunction was significantly milder in Tg-AA mice than in WT-AA mice. The degree of TID was significantly attenuated in Tg-AA mice, compared with WT-AA. In conclusion, renal hL-FABP reduced the oxidative stress in AA-induced nephrotoxicity and attenuated TID. PMID:21356355

Carboxylesterase 1 Is Regulated by Hepatocyte Nuclear Factor 4α and Protects Against Alcohol- and MCD diet-induced Liver Injury.

PubMed

Xu, Jiesi; Xu, Yang; Li, Yuanyuan; Jadhav, Kavita; You, Min; Yin, Liya; Zhang, Yanqiao

2016-04-14

The liver is a major organ that controls hepatic and systemic homeostasis. Dysregulation of liver metabolism may cause liver injury. Previous studies have demonstrated that carboxylesterase 1 (CES1) regulates hepatic triglyceride metabolism and protects against liver steatosis. In the present study, we investigated whether CES1 played a role in the development of alcoholic liver disease (ALD) and methionine and choline-deficient (MCD) diet-induced liver injury. Both hepatocyte nuclear factor 4α (HNF4α) and CES1 were markedly reduced in patients with alcoholic steatohepatitis. Alcohol repressed both HNF4α and CES1 expression in primary hepatocytes. HNF4α regulated CES1 expression by directly binding to the proximal promoter of CES1. Global inactivation of CES1 aggravated alcohol- or MCD diet-induced liver inflammation and liver injury, likely as a result of increased production of acetaldehyde and reactive oxygen species and mitochondrial dysfunctions. Knockdown of hepatic CES1 exacerbated ethanol-induced steatohepatitis. These data indicate that CES1 plays a crucial role in protection against alcohol- or MCD diet-induced liver injury.

Major Challenges Limiting Liver Transplantation in the United States

PubMed Central

Wertheim, Jason A.; Petrowsky, Henrik; Saab, Sammy; Kupiec-Weglinski, Jerzy W.; Busuttil, Ronald W.

2011-01-01

Liver transplantation is the gold standard of care in patients with end-stage liver disease and those with tumors of hepatic origin in the setting of liver dysfunction. From 1988 to 2009, liver transplantation in the United States grew 3.7-fold from 1713 to 6320 transplants annually. The expansion of liver transplantation is chiefly driven by scientific breakthroughs that have extended patient and graft survival well beyond those expected 50 years ago. The success of liver transplantation is now its primary obstacle, as the pool of donor livers fails to keep pace with the growing number of patients added to the national liver transplant waiting list. This review focuses on three major challenges facing liver transplantation in the United States and discusses new areas of investigation that address each issue: 1) the need for an expanded number of useable donor organs, 2) the need for improved therapies to treat recurrent hepatitis C after transplantation and 3) the need for improved detection, risk stratification based upon tumor biology and molecular inhibitors to combat hepatocellular carcinoma. PMID:21672146

The intersection of nonalcoholic fatty liver disease and obesity.

PubMed

Woo Baidal, Jennifer A; Lavine, Joel E

2016-01-27

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide and recently emerged as the most rapidly increasing indication for liver transplant. Although obesity is a risk factor for NAFLD, overlap between these two entities is incompletely understood. We highlight recent insights into the pathogenesis of human NAFLD in relation to obesity and discuss advances in the diagnosis and treatment of NAFLD. Copyright © 2016, American Association for the Advancement of Science.

Reduced Uptake of FDOPA PET in End-Stage Liver Disease with Elevated Manganese Levels

PubMed Central

Criswell, Susan R; Perlmutter, Joel S; Crippin, Jeffrey S; Videen, Tom O; Moerlein, Stephen M; Flores, Hubert P; Birke, Angela M; Racette, Brad A

2013-01-01

Objective To investigate whether manganese toxicity secondary to end state liver disease is associated with nigrastriatal dysfunction as measured by 6-[18F]fluoro-L-DOPA (FDOPA) PET imaging. Design Observational case report. Setting The Movement Disorder Center at Washington University in St. Louis. Patients An individual with manganese toxicity secondary to end stage liver disease. His FDOPA PET was compared with those of 10 idiopathic Parkinson disease patients and 10 age- and sex-matched healthy controls. Main Outcome Measure The average estimated net FDOPA uptake by Patlak graphical analysis for caudate, anterior putamen and posterior putamen. Results The FDOPA uptake for the patient with secondary manganese toxicity was reduced across all regions by more than 2 SDs compared with healthy controls: caudate (reduced 24.7%), anterior putamen (28.0%), and posterior putamen (29.3%). The ratio of uptake between the caudate/posterior putamen was 0.99 and was different from that of idiopathic Parkinson disease patients, in whom the greatest reduction of FDOPA was in the posterior putamen (mean [SD] ratio, 1.65 [0.41]). Conclusions Reduce striatal uptake of FDOPA uptake indicates dysfunction of the nigrostriatal pathways in manganese toxicity secondary to end stage liver disease. The pattern of striatal involvement with equal reduction of FDOPA uptake in the caudate compared with posterior putamen appears different from those previously reported in individuals with occupational manganese toxicity and idiopathic Parkinson disease and may be specific to manganese toxicity secondary to end stage liver disease. PMID:22410448

Ursodeoxycholic acid in the treatment of liver diseases.

PubMed Central

Saksena, S.; Tandon, R. K.

1997-01-01

Ursodeoxycholic acid is a dihydroxy bile acid with a rapidly expanding spectrum of usage in acute and chronic liver diseases. The various mechanisms of action of this hydrophilic bile acid include direct cytoprotection, detergent action on dysfunctional microtubules, immunomodulation and induction of hypercholeresis. Its efficacy in primary biliary cirrhosis and primary sclerosing cholangitis as an adjunct to medical therapy has been well established. Newer indications include its use in the management of chronic hepatitis, cirrhosis, post liver transplant rejection, graft-versus-host disease and acute viral hepatitis, where it not only relieves symptoms of cholestasis but also arrests ongoing hepatocyte necrosis. PMID:9122101

Pearson disease in an infant presenting with severe hypoplastic anemia, normal pancreatic function, and progressive liver failure.

PubMed

Shapira, Adi; Konopnicki, Muriel; Hammad-Saied, Mohammed; Shabad, Evelyn

2014-07-01

Pearson disease is a rare, usually fatal, mitochondrial disorder affecting primarily the bone marrow and the exocrine pancreas. We report a previously healthy 10-week-old girl who presented with profound macrocytic anemia followed by pancytopenia, synthetic liver dysfunction with liver steatosis, and metabolic acidosis with high lactate levels. She had no pancreatic involvement. Multiple cytoplasmic vacuoles in myelocytes and monocytes were seen upon microscopic evaluation of the bone marrow. Genetic analysis of the mitochondrial genome revealed a 5 kbp deletion, thus establishing the diagnosis of Pearson disease.

THE NATURAL HISTORY OF NONALCOHOLIC FATTY LIVER DISEASE WITH ADVANCED FIBROSIS OR CIRRHOSIS: AN INTERNATIONAL COLLABORATIVE STUDY

PubMed Central

Bhala, Neeraj; Angulo, Paul; van der Poorten, David; Lee, Eric; Hui, Jason M.; Saracco, Giorgio; Adams, Leon A.; Charatcharoenwitthaya, Punchai; Topping, Joanne H.; Bugianesi, Elisabetta; Day, Christopher P.; George, Jacob

2011-01-01

Information on the long-term prognosis of nonalcoholic fatty liver disease (NAFLD) is limited. We sought to describe the long-term morbidity and mortality of patients with NAFLD with advanced fibrosis or cirrhosis. We conducted this prospective cohort study including 247 patients with NAFLD and 264 patients with HCV infection that were either naïve or non-responders to treatment. Both cohorts were Child-Pugh class A and had advanced (stage 3) fibrosis or cirrhosis (stage 4) confirmed by liver biopsy at enrolment. In the NAFLD cohort, followed-up for 85.6 months mean (range 6-297), there were 48 (19.4%) liver-related complications and 33 (13.4%) deaths or liver transplants. In the HCV cohort, followed-up for 74.9 months mean (range 6-238), there were 47 (16.7%) liver-related complications and 25 (9.4%) deaths or liver transplants. When adjusting for baseline differences in age and gender, the cumulative incidence of liver-related complications was lower in the NAFLD than the HCV cohort (p=0.03), including incident hepatocellular cancer (6 vs 18; p=0.03), but that of cardiovascular events (p=0.17) and overall mortality (p=0.6) was similar in both groups. In the NAFLD cohort, platelet count, stage 4 fibrosis, and serum levels of cholesterol and ALT were associated with liver-related complications; an AST/ALT ratio >1 and older age were associated with overall mortality; and higher serum bilirubin levels and stage 4 fibrosis were associated with liver-related mortality. Conclusions Patients with NAFLD with advanced fibrosis or cirrhosis have lower rates of liver-related complications and hepatocellular cancer than corresponding patients with HCV infection, but similar overall mortality. Some clinical and laboratory features predict outcomes in patients with NAFLD. PMID:21688282

[A case of chronic active Epstein-Barr virus infection with a pharyngeal ulcer].

PubMed

Nagano, Hiromi; Iuchi, Hiroyuki; Yoshifuku, Kosuke; Morizono, Kensuke; Kurono, Yuichi

2013-07-01

Chronic active Epstein-Barr virus infection (CAEBV) is characterized by chronic or recurrent infectious mononucleosis-like symptoms, such as fever, extensive lymphadenopathy, and hepatosplenomegaly. A 44-year-old women visited our ENT clinic with a four-month history of fever and throat pain. She was diagnosed as having CAEBV based on the findings of fever, liver dysfunction, lymphadenopathy, pharyngeal ulcer, the titer for IgG to the EBV capsid and pathological findings. The whole-blood EBV DNA levels were high and above 3.7 x 10(3) copies/mL. After administration of intravenous predonine (1000 mg/day for 3 days) and oral predonine (1.5 mg/kg. 60 mg/day), the liver dysfunction and pharyngeal ulcer improved. Since the prognosis is poor in adult cases of CAEBV, chemotherapy is scheduled for this case.

Calcium and ER stress mediate hepatic apoptosis after burn injury

PubMed Central

Gauglitz, Gerd G.; Song, Juquan; Kulp, Gabriela A.; Finnerty, Celeste C.; Cox, Robert A.; Barral, José M.; Herndon, David N.; Boehning, Darren

2009-01-01

Abstract A hallmark of the disease state following severe burn injury is decreased liver function, which results in gross metabolic derangements that compromise patient survival. The underlying mechanisms leading to hepatocyte dysfunction after burn are essentially unknown. The aim of the present study was to determine the underlying mechanisms leading to hepatocyte dysfunction and apoptosis after burn. Rats were randomized to either control (no burn) or burn (60% total body surface area burn) and sacrificed at various time‐points. Liver was either perfused to isolate primary rat hepatocytes, which were used for in vitro calcium imaging, or liver was harvested and processed for immunohistology, transmission electron microscopy, mitochondrial isolation, mass spectroscopy or Western blotting to determine the hepatic response to burn injury in vivo. We found that thermal injury leads to severely depleted endoplasmic reticulum (ER) calcium stores and consequent elevated cytosolic calcium concentrations in primary hepatocytes in vitro. Burn‐induced ER calcium depletion caused depressed hepatocyte responsiveness to signalling molecules that regulate hepatic homeostasis, such as vasopressin and the purinergic agonist ATP. In vivo, thermal injury resulted in activation of the ER stress response and major alterations in mitochondrial structure and function – effects which may be mediated by increased calcium release by inositol 1,4,5‐trisphosphate receptors. Our results reveal that thermal injury leads to dramatic hepatic disturbances in calcium homeostasis and resultant ER stress leading to mitochondrial abnormalities contributing to hepatic dysfunction and apoptosis after burn injury. PMID:20141609

Heme oxygenase-1 prevents hyperthyroidism induced hepatic damage via an antioxidant and antiapoptotic pathway.

PubMed

Giriş, Murat; Erbil, Yeşim; Depboylu, Bilge; Mete, Ozgür; Türkoğlu, Umit; Abbasoğlu, Semra Doğru; Uysal, Müjdat

2010-12-01

The exact pathogenesis of hepatic dysfunction in hyperthyroidism is still unknown. We aimed to investigate the pathogenesis of liver dysfunction caused by hyperthyroidism through inducing heme oxygenase-1 (HO-1) expression, which has antioxidant and anti-apoptotic properties. Rats were divided into six groups: untreated (group 1), treated with zinc protoporphyrin (ZnPP) (group 2), treated with hemin (group 3), treated with tri-iodothyronine (T3) (group 4), treated with T3 and ZnPP (group 5), and treated with T3 and hemin (group 6). After 22 d, oxidative stress and antioxidant enzymes and the expression of HO-1, mitochondrial permeability transition, cytochrome c, Bax, Bcl-2, caspase-3, caspase-8, and caspase-3 activity, and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay were examined. Hyperthyroidism induced oxidative stress of liver tissue was ameliorated by HO-1 induction. Administration of hemin (HO-1 inducer) increased Bcl-2 expression. Decreased expression of cytochrome c was accompanied by a decrease in caspase-3, caspase-8, Bax expression, and caspase-3 activity. The apoptotic activity and oxidative damage were found to be increased by the administration of ZnPP (HO-1 inhibitor). Immunohistochemistry findings supported these results. HO-1 induction plays a protective role in the pathogenesis of the liver dysfunction in hyperthyroidism. This effect is dependent on modulation of the antiapoptotic and antioxidative pathways by HO-1 expression. Copyright © 2010 Elsevier Inc. All rights reserved.

Long-term culture of human liver tissue with advanced hepatic functions.

PubMed

Ng, Soon Seng; Xiong, Anming; Nguyen, Khanh; Masek, Marilyn; No, Da Yoon; Elazar, Menashe; Shteyer, Eyal; Winters, Mark A; Voedisch, Amy; Shaw, Kate; Rashid, Sheikh Tamir; Frank, Curtis W; Cho, Nam Joon; Glenn, Jeffrey S

2017-06-02

A major challenge for studying authentic liver cell function and cell replacement therapies is that primary human hepatocytes rapidly lose their advanced function in conventional, 2-dimensional culture platforms. Here, we describe the fabrication of 3-dimensional hexagonally arrayed lobular human liver tissues inspired by the liver's natural architecture. The engineered liver tissues exhibit key features of advanced differentiation, such as human-specific cytochrome P450-mediated drug metabolism and the ability to support efficient infection with patient-derived inoculums of hepatitis C virus. The tissues permit the assessment of antiviral agents and maintain their advanced functions for over 5 months in culture. This extended functionality enabled the prediction of a fatal human-specific hepatotoxicity caused by fialuridine (FIAU), which had escaped detection by preclinical models and short-term clinical studies. The results obtained with the engineered human liver tissue in this study provide proof-of-concept determination of human-specific drug metabolism, demonstrate the ability to support infection with human hepatitis virus derived from an infected patient and subsequent antiviral drug testing against said infection, and facilitate detection of human-specific drug hepatotoxicity associated with late-onset liver failure. Looking forward, the scalability and biocompatibility of the scaffold are also ideal for future cell replacement therapeutic strategies.

Mechanistic Modelling of Drug-Induced Liver Injury: Investigating the Role of Innate Immune Responses.

PubMed

Shoda, Lisl Km; Battista, Christina; Siler, Scott Q; Pisetsky, David S; Watkins, Paul B; Howell, Brett A

2017-01-01

Drug-induced liver injury (DILI) remains an adverse event of significant concern for drug development and marketed drugs, and the field would benefit from better tools to identify liver liabilities early in development and/or to mitigate potential DILI risk in otherwise promising drugs. DILIsym software takes a quantitative systems toxicology approach to represent DILI in pre-clinical species and in humans for the mechanistic investigation of liver toxicity. In addition to multiple intrinsic mechanisms of hepatocyte toxicity (ie, oxidative stress, bile acid accumulation, mitochondrial dysfunction), DILIsym includes the interaction between hepatocytes and cells of the innate immune response in the amplification of liver injury and in liver regeneration. The representation of innate immune responses, detailed here, consolidates much of the available data on the innate immune response in DILI within a single framework and affords the opportunity to systematically investigate the contribution of the innate response to DILI.

Intrahepatic vascular changes in non-alcoholic fatty liver disease: Potential role of insulin-resistance and endothelial dysfunction.

PubMed

Pasarín, Marcos; Abraldes, Juan G; Liguori, Eleonora; Kok, Beverley; La Mura, Vincenzo

2017-10-07

Metabolic syndrome is a cluster of several clinical conditions characterized by insulin-resistance and high cardiovascular risk. Non-alcoholic fatty liver disease is the liver expression of the metabolic syndrome, and insulin resistance can be a frequent comorbidity in several chronic liver diseases, in particular hepatitis C virus infection and/or cirrhosis. Several studies have demonstrated that insulin action is not only relevant for glucose control, but also for vascular homeostasis. Insulin regulates nitric oxide production, which mediates to a large degree the vasodilating, anti-inflammatory and antithrombotic properties of a healthy endothelium, guaranteeing organ perfusion. The effects of insulin on the liver microvasculature and the effects of IR on sinusoidal endothelial cells have been studied in animal models of non-alcoholic fatty liver disease. The hypotheses derived from these studies and the potential translation of these results into humans are critically discussed in this review.

[Various pathways leading to the progression of chronic liver diseases].

PubMed

Egresi, Anna; Lengyel, Gabriella; Somogyi, Anikó; Blázovics, Anna; Hagymási, Krisztina

2016-02-21

As the result of various effects (viruses, metabolic diseases, nutritional factors, toxic agents, autoimmune processes) abnormal liver function, liver steatosis and connective tissue remodeling may develop. Progression of this process is complex including various pathways and a number of factors. The authors summarize the factors involved in the progression of chronic liver disease. They describe the role of cells and the produced inflammatory mediators and cytokines, as well as the relationship between the disease and the intestinal flora. They emphasize the role of oxidative stress, mitochondrial dysfunction and cell death in disease progression. Insulin resistance and micro-elements (iron, copper) in relation to liver damage are also discussed, and genetic and epigenetic aspects underlying disease progression are summarized. Discovery of novel treatment options, assessment of the effectiveness of treatment, as well as the success and proper timing of liver transplantation may depend on a better understanding of the process of disease progression.

[Epidemiology, risk factors and molecular pathogenesis of primary liver cancer].

PubMed

Hagymási, Krisztina; Tulassay, Zsolt

2008-03-23

Primary liver cancer is the fifth most common cancer worldwide. Hepatocellular carcinoma accounts for 85-90% of primary liver cancers. Distribution of hepatocellular carcinoma shows variations among geographic regions and ethnic groups. Males have higher liver cancer rates than females. Hepatocellular carcinoma occurs within an established background of chronic liver disease and cirrhosis (70-90%). Major causes (80%) of hepatocellular carcinoma are hepatitis B, C virus infection, and aflatoxin exposition. Its development is a multistep process. We have a growing understanding on the molecular pathogenesis. Genetic and epigenetic changes activate oncogenes, inhibit tumorsuppressor genes, which result in autonomous cell proliferation. The chromosomal instability caused by telomere dysfunction, the growth-retrained environment and the alterations of the micro- and macroenvironment help the expansion of the malignant cells. Understanding the molecular mechanisms could improve the screening of patients with chronic liver disease, or cirrhosis, and the prevention as well as treatment of hepatocellular carcinoma.

Role of aramchol in steatohepatitis and fibrosis in mice

PubMed Central

Iruarrizaga‐Lejarreta, Marta; Varela‐Rey, Marta; Fernández‐Ramos, David; Martínez‐Arranz, Ibon; Delgado, Teresa C; Simon, Jorge; Gutiérrez‐de Juan, Virginia; delaCruz‐Villar, Laura; Azkargorta, Mikel; Lavin, José L.; Mayo, Rebeca; Van Liempd, Sebastiaan M.; Aurrekoetxea, Igor; Buqué, Xabier; Delle Cave, Donatella; Peña, Arantza; Rodríguez‐Cuesta, Juan; Aransay, Ana M.; Elortza, Felix; Falcón‐Pérez, Juan M.; Aspichueta, Patricia; Hayardeny, Liat; Noureddin, Mazen; Sanyal, Arun J.; Alonso, Cristina; Anguita, Juan; Martínez‐Chantar, María Luz; Lu, Shelly C.

2017-01-01

Nonalcoholic steatohepatitis (NASH) is the advanced form of nonalcoholic fatty liver disease (NAFLD) that sets the stage for further liver damage. The mechanism for the progression of NASH involves multiple parallel hits, including oxidative stress, mitochondrial dysfunction, inflammation, and others. Manipulation of any of these pathways may be an approach to prevent NASH development and progression. Arachidyl‐amido cholanoic acid (Aramchol) is presently in a phase IIb NASH study. The aim of the present study was to investigate Aramchol's mechanism of action and its effect on fibrosis using the methionine‐ and choline‐deficient (MCD) diet model of NASH. We collected liver and serum from mice fed an MCD diet containing 0.1% methionine (0.1MCD) for 4 weeks; these mice developed steatohepatitis and fibrosis. We also collected liver and serum from mice receiving a control diet, and metabolomes and proteomes were determined for both groups. The 0.1MCD‐fed mice were given Aramchol (5 mg/kg/day for the last 2 weeks), and liver samples were analyzed histologically. Aramchol administration reduced features of steatohepatitis and fibrosis in 0.1MCD‐fed mice. Aramchol down‐regulated stearoyl‐coenyzme A desaturase 1, a key enzyme involved in triglyceride biosynthesis and the loss of which enhances fatty acid β‐oxidation. Aramchol increased the flux through the transsulfuration pathway, leading to a rise in glutathione (GSH) and the GSH/oxidized GSH ratio, the main cellular antioxidant that maintains intracellular redox status. Comparison of the serum metabolomic pattern between 0.1MCD‐fed mice and patients with NAFLD showed a substantial overlap. Conclusion: Aramchol treatment improved steatohepatitis and fibrosis by 1) decreasing stearoyl‐coenyzme A desaturase 1 and 2) increasing the flux through the transsulfuration pathway maintaining cellular redox homeostasis. We also demonstrated that the 0.1MCD model resembles the metabolic phenotype observed in about 50% of patients with NAFLD, which supports the potential use of Aramchol in NASH treatment. (Hepatology Communications 2017;1:911–927) PMID:29159325

Living Donor Liver Transplantation for Unresectable Liver Adenomatosis Associated with Congenital Absence of Portal Vein: A Case Report and Literature Review

PubMed Central

Brasoveanu, Vladislav; Ionescu, Mihnea Ioan; Grigorie, Razvan; Mihaila, Mariana; Bacalbasa, Nicolae; Dumitru, Radu; Herlea, Vlad; Iorgescu, Andreea; Tomescu, Dana; Popescu, Irinel

2015-01-01

Patient: Female, 21 Final Diagnosis: Unresectable liver adenomatosis associated with congenital absence of portal vein Symptoms: — Medication: — Clinical Procedure: Living donor liver transplantation Specialty: Transplantology Objective: Rare disease Background: Abernethy malformation (AM), or congenital absence of portal vein (CAPV), is a very rare disease which tends to be associated with the development of benign or malignant tumors, usually in children or young adults. Case Report: We report the case of a 21-year-old woman diagnosed with type Ib AM (portal vein draining directly into the inferior vena cava) and unresectable liver adenomatosis. The patient presented mild liver dysfunction and was largely asymptomatic. Living donor liver transplantation was performed using a left hemiliver graft from her mother. Postoperatively, the patient attained optimal liver function and at 9-month follow-up has returned to normal life. Conclusions: We consider that living donor liver transplantation is the best therapeutic solution for AM associated with unresectable liver adenomatosis, especially because compared to receiving a whole liver graft, the waiting time on the liver transplantation list is much shorter. PMID:26386552

Preclinical Models for Investigation of Herbal Medicines in Liver Diseases: Update and Perspective

PubMed Central

Tan, Hor-Yue; San-Marina, Serban; Wang, Ning; Hong, Ming; Li, Sha; Li, Lei; Cheung, Fan; Wen, Xiao-Yan; Feng, Yibin

2016-01-01

Liver disease results from a dynamic pathological process associated with cellular and genetic alterations, which may progress stepwise to liver dysfunction. Commonly, liver disease begins with hepatocyte injury, followed by persistent episodes of cellular regeneration, inflammation, and hepatocyte death that may ultimately lead to nonreversible liver failure. For centuries, herbal remedies have been used for a variety of liver diseases and recent studies have identified the active compounds that may interact with liver disease-associated targets. Further study on the herbal remedies may lead to the formulation of next generation medicines with hepatoprotective, antifibrotic, and anticancer properties. Still, the pharmacological actions of vast majority of herbal remedies remain unknown; thus, extensive preclinical studies are important. In this review, we summarize progress made over the last five years of the most commonly used preclinical models of liver diseases that are used to screen for curative herbal medicines for nonalcoholic fatty liver disease, liver fibrosis/cirrhosis, and liver. We also summarize the proposed mechanisms associated with the observed liver-protective, antifibrotic, and anticancer actions of several promising herbal medicines and discuss the challenges faced in this research field. PMID:26941826

A stepwise algorithm using an at-a-glance first-line test for the non-invasive diagnosis of advanced liver fibrosis and cirrhosis.

PubMed

Boursier, Jérôme; de Ledinghen, Victor; Leroy, Vincent; Anty, Rodolphe; Francque, Sven; Salmon, Dominique; Lannes, Adrien; Bertrais, Sandrine; Oberti, Frederic; Fouchard-Hubert, Isabelle; Calès, Paul

2017-06-01

Chronic liver diseases (CLD) are common, and are therefore mainly managed by non-hepatologists. These physicians lack access to the best non-invasive tests of liver fibrosis, and consequently cannot accurately determine the disease severity. Referral to a hepatologist is then needed. We aimed to implement an algorithm, comprising a new first-line test usable by all physicians, for the detection of advanced liver fibrosis in all CLD patients. Diagnostic study: 3754 CLD patients with liver biopsy were 2:1 randomized into derivation and validation sets. Prognostic study: longitudinal follow-up of 1275 CLD patients with baseline fibrosis tests. Diagnostic study: the easy liver fibrosis test (eLIFT), an "at-a-glance" sum of points attributed to age, gender, gamma-glutamyl transferase, aspartate aminotransferase (AST), platelets and prothrombin time, was developed for the diagnosis of advanced fibrosis. In the validation set, eLIFT and fibrosis-4 (FIB4) had the same sensitivity (78.0% vs. 76.6%, p=0.470) but eLIFT gave fewer false positive results, especially in patients ≥60years old (53.8% vs. 82.0%, p<0.001), and was thus more suitable as screening test. FibroMeter with vibration controlled transient elastography (VCTE) was the most accurate among the eight fibrosis tests evaluated. The sensitivity of the eLIFT-FM VCTE algorithm (first-line eLIFT, second-line FibroMeter VCTE ) was 76.1% for advanced fibrosis and 92.1% for cirrhosis. Prognostic study: patients diagnosed as having "no/mild fibrosis" by the algorithm had excellent liver-related prognosis with thus no need for referral to a hepatologist. The eLIFT-FM VCTE algorithm extends the detection of advanced liver fibrosis to all CLD patients and reduces unnecessary referrals of patients without significant CLD to hepatologists. Blood fibrosis tests and transient elastography accurately diagnose advanced liver fibrosis in the large population of patients having chronic liver disease, but these non-invasive tests are only currently available in specialized centers. We have developed an algorithm including the easy liver fibrosis test (eLIFT), a new simple and widely available blood test. It is used as a first-line procedure that selects at-risk patients who need further evaluation with the FibroMeter VCTE , an accurate fibrosis test combining blood markers and transient elastography result. This new algorithm, called the eLIFT-FM VCTE , accurately identifies the patients with advanced chronic liver disease who need referral to a specialist, and those with no or mild liver lesions who can remain under the care of their usual physician. No registration (analysis of pooled data from previously published diagnostic studies). Copyright © 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Recent advancement of molecular mechanisms of liver fibrosis.

PubMed

Seki, Ekihiro; Brenner, David A

2015-07-01

Liver fibrosis occurs in response to any etiology of chronic liver injury including hepatitis B and C, alcohol consumption, fatty liver disease, cholestasis, and autoimmune hepatitis. Hepatic stellate cells (HSCs) are the primary source of activated myofibroblasts that produce extracellular matrix (ECM) in the liver. Various inflammatory and fibrogenic pathways contribute to the activation of HSCs. Recent studies also discovered that liver fibrosis is reversible and activated HSCs can revert to quiescent HSCs when causative agents are removed. Although the basic research for liver fibrosis has progressed remarkably, sensitive and specific biomarkers as non-invasive diagnostic tools, and effective anti-fibrotic agents have not been developed yet. This review highlights the recent advances in cellular and molecular mechanisms of liver fibrosis, especially focusing on origin of myofibroblasts, inflammatory signaling, autophagy, cellular senescence, HSC inactivation, angiogenesis, and reversibility of liver fibrosis. © 2015 Japanese Society of Hepato-Biliary-Pancreatic Surgery.

Elevated liver stiffness is linked to increased biomarkers of inflammation and immune activation in HIV/hepatitis C virus-coinfected patients.

PubMed

Medrano, Luz M; Garcia-Broncano, Pilar; Berenguer, Juan; González-García, Juan; Jiménez-Sousa, Ma Ángeles; Guardiola, Josep M; Crespo, Manuel; Quereda, Carmen; Sanz, José; Canorea, Isabel; Carrero, Ana; Hontañón, Victor; Muñoz-Fernández, Ma Ángeles; Resino, Salvador

2018-06-01

Immune dysregulation is a hallmark of HIV and hepatitis C virus (HCV) infections. We aimed to evaluate the relationship between liver stiffness measurement (LSM) and biomarkers of T-cell activation, bacterial translocation, inflammation, endothelial dysfunction, and coagulopathy in HIV/HCV-coinfected patients. Cross-sectional study. We studied 238 HIV/HCV-coinfected patients, 32 healthy controls, and 39 HIV-monoinfected patients. Patients were stratified according to LSM into four groups: less than 12.5, 12.5-25, 25-40, and more than 40 kPa. T-cell subsets were measured using flow cytometry and plasma biomarkers using immunoassays. HIV/HCV-coinfected patients had higher biomarker levels of immune activation in peripheral blood [T-cell activation (CD4CD38 and CD8CD38), bacterial translocation (soluble CD14), inflammation [IL-1b, IL-6, IL-8, IL-18, IFN-γ-inducible protein 10 (IP-10)] endothelial dysfunction [soluble vascular cell adhesion molecule 1 (sVCAM1), soluble intercellular cell adhesion molecule 1 (sICAM1), and soluble tumor necrosis factor receptor 1 (sTNFR1)], and coagulopathy (plasminogen activator inhibitor-1)] than healthy controls and HIV-monoinfected patients. Moreover, in HIV/HCV-coinfected patients, a direct relationship between LSM and immune activation [T-cell activation (CD8CD38 bacterial translocation (lipopolysaccharide), inflammation (IL-8, IP-10), endothelial dysfunction (sVCAM1, sICAM1, and sTNFR1), and coagulopathy (D-dimer)] was found. Subsequently, patients were stratified into different fibrosis stages, finding that patients with cirrhosis who had LSM at least 40 kPa showed higher biomarker values of immune activation [T-cell activation (CD4CD38 and CD8CD38), bacterial translocation (lipopolysaccharide), inflammation (IL-8, IL-6, IP-10), endothelial dysfunction (sVCAM1, sICAM1, and sTNFR1), and coagulopathy (D-dimer)] than patients from the other three groups (<12.5, 12.5-25, and 25-40 kPa). T-cell activation, bacterial translocation, inflammation, endothelial dysfunction, and coagulopathy increased with the severity of liver fibrosis in HIV/HCV-coinfected patients, particularly in patients who had LSM at least 40 kPa.

Cirrhotic cardiomyopathy

PubMed Central

Ruiz-del-Árbol, Luis; Serradilla, Regina

2015-01-01

During the course of cirrhosis, there is a progressive deterioration of cardiac function manifested by the disappearance of the hyperdynamic circulation due to a failure in heart function with decreased cardiac output. This is due to a deterioration in inotropic and chronotropic function which takes place in parallel with a diastolic dysfunction and cardiac hypertrophy in the absence of other known cardiac disease. Other findings of this specific cardiomyopathy include impaired contractile responsiveness to stress stimuli and electrophysiological abnormalities with prolonged QT interval. The pathogenic mechanisms of cirrhotic cardiomyopathy include impairment of the b-adrenergic receptor signalling, abnormal cardiomyocyte membrane lipid composition and biophysical properties, ion channel defects and overactivity of humoral cardiodepressant factors. Cirrhotic cardiomyopathy may be difficult to determine due to the lack of a specific diagnosis test. However, an echocardiogram allows the detection of the diastolic dysfunction and the E/e′ ratio may be used in the follow-up progression of the illness. Cirrhotic cardiomyopathy plays an important role in the pathogenesis of the impairment of effective arterial blood volume and correlates with the degree of liver failure. A clinical consequence of cardiac dysfunction is an inadequate cardiac response in the setting of vascular stress that may result in renal hypoperfusion leading to renal failure. The prognosis is difficult to establish but the severity of diastolic dysfunction may be a marker of mortality risk. Treatment is non-specific and liver transplantation may normalize the cardiac function. PMID:26556983

Evaluating the Risks of High Altitude Travel in Chronic Liver Disease Patients.

PubMed

Luks, Andrew M; Swenson, Erik R

2015-06-01

Luks, Andrew M., and Erik R. Swenson. Clinician's Corner: Evaluating the risks of high altitude travel in chronic liver disease patients. High Alt Med Biol 16:80-88, 2015.--With improvements in the quality of health care, people with chronic medical conditions are experiencing better quality of life and increasingly participating in a wider array of activities, including travel to high altitude. Whenever people with chronic diseases travel to this environment, it is important to consider whether the physiologic responses to hypobaric hypoxia will interact with the underlying medical condition such that the risk of acute altitude illness is increased or the medical condition itself may worsen. This review considers these questions as they pertain to patients with chronic liver disease. While the limited available evidence suggests there is no evidence of liver injury or dysfunction in normal individuals traveling as high as 5000 m, there is reason to suspect that two groups of cirrhosis patients are at increased risk for problems, hepatopulmonary syndrome patients, who are at risk for severe hypoxemia following ascent, and portopulmonary hypertension patients who may be at risk for high altitude pulmonary edema and acute right ventricular dysfunction. While liver transplant patients may tolerate high altitude exposure without difficulty, no information is available regarding the risks of long-term residence at altitude with chronic liver disease. All travelers with cirrhosis require careful pre-travel evaluation to identify conditions that might predispose to problems at altitude and develop risk mitigation strategies for these issues. Patients also require detailed counseling about recognition, prevention, and treatment of acute altitude illness and may require different medication regimens to prevent or treat altitude illness than used in healthy individuals.

The Influence of the Severity of Chronic Virus-Related Liver Disease on Propofol Requirements during Propofol-Remifentanil Anesthesia

PubMed Central

Wu, Jian; Huang, Su-Qin; Chen, Qing-Lian

2013-01-01

Purpose The purpose of this study was to investigate the influence of chronic virus-related liver disease severity on propofol requirements. Materials and Methods In this study, 48 male patients with chronic hepatitis B infection were divided into three groups according to Child-Turcotte-Pugh classification of liver function (groups A, B, and C with mild, moderate and severe liver disease, respectively). After intubation, propofol concentration was adjusted by ±0.3 µg/mL increments to maintain bispectral index in the range of 40-60. Target propofol concentrations at anesthesia initiation, pre-intubation and pre-incision were recorded. Results The initial concentration used in group C was significantly lower than that used in group A or B (p<0.05), whereas no difference was observed between groups A and B. At pre-intubation, the actual required concentration of propofol increased significantly (3.2 µg/mL) in group A (p<0.05), which lead to significant differences between the groups (p<0.05). At pre-incision, the requirements for propofol decreased significantly in both groups A and B (3.0 µg/mL and 2.7 µg/mL, respectively) compared with those at pre-intubation (p<0.05), and were significantly different for all three groups (p<0.05), with group C demonstrating the lowest requirement (2.2 µg/mL). The required concentrations of propofol at pre-incision were similar to those at induction. Conclusion In this study, propofol requirements administered by target-controlled infusion to maintain similar depths of hypnosis were shown to depend on the severity of chronic virus-related liver dysfunction. In other words, patients with the most severe liver dysfunction required the least amount of propofol. PMID:23225825

Treatment with a Catalytic Superoxide Dismutase (SOD) Mimetic Improves Liver Steatosis, Insulin Sensitivity, and Inflammation in Obesity-Induced Type 2 Diabetes

PubMed Central

Delmastro-Greenwood, Meghan M.; Marré, Meghan L.; O’Connor, Erin C.; Novak, Elizabeth A.; Vincent, Garret; Mollen, Kevin P.; Lee, Sojin; Dong, H. Henry; Piganelli, Jon D.

2017-01-01

Oxidative stress and persistent inflammation are exaggerated through chronic over-nutrition and a sedentary lifestyle, resulting in insulin resistance. In type 2 diabetes (T2D), impaired insulin signaling leads to hyperglycemia and long-term complications, including metabolic liver dysfunction, resulting in non-alcoholic fatty liver disease (NAFLD). The manganese metalloporphyrin superoxide dismustase (SOD) mimetic, manganese (III) meso-tetrakis (N-ethylpyridinium-2-yl) porphyrin (MnP), is an oxidoreductase known to scavenge reactive oxygen species (ROS) and decrease pro-inflammatory cytokine production, by inhibiting nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation. We hypothesized that targeting oxidative stress-induced inflammation with MnP would assuage liver complications and enhance insulin sensitivity and glucose tolerance in a high-fat diet (HFD)-induced mouse model of T2D. During 12 weeks of feeding, we saw significant improvements in weight, hepatic steatosis, and biomarkers of liver dysfunction with redox modulation by MnP treatment in HFD-fed mice. Additionally, MnP treatment improved insulin sensitivity and glucose tolerance, while reducing serum insulin and leptin levels. We attribute these effects to redox modulation and inhibition of hepatic NF-κB activation, resulting in diminished ROS and pro-inflammatory cytokine production. This study highlights the importance of controlling oxidative stress and secondary inflammation in obesity-mediated insulin resistance and T2D. Our data confirm the role of NF-κB-mediated inflammation in the development of T2D, and demonstrate the efficacy of MnP in preventing the progression to disease by specifically improving liver pathology and hepatic insulin resistance in obesity. PMID:29104232

Liver proteomics for therapeutic drug discovery: inhibition of the cyclophilin receptor CD147 attenuates sepsis-induced acute renal failure

PubMed Central

Dear, James W.; Leelahavanichkul, Asada; Aponte, Angel; Hu, Xuzhen; Constant, Stephanie L.; Hewitt, Stephen M.; Yuen, Peter S.T.; Star, Robert A.

2008-01-01

Objective Sepsis-induced multi-organ failure continues to have a high mortality. The liver is an organ central to the disease pathogenesis. The objective of this study was to identify the liver proteins that change in abundance with sepsis and, therefore, identify new drug targets. Design Proteomic discovery study and drug target validation Setting Research institute laboratory Subjects Three month old C57BL/6 mice Interventions We used a mouse model of sepsis based on cecal ligation and puncture (CLP) but with fluid and antibiotic resuscitation. Liver proteins that changed in abundance were identified by difference in-gel electrophoresis (DIGE). We compared liver proteins from 6 hr post-CLP to sham-operated mice (‘early proteins’) and 24 hr post-CLP with 6 hr post-CLP (‘late proteins’). Proteins that changed in abundance were identified by tandem mass spectrometry. We then inhibited the receptor for one protein and determined the effect on sepsis-induced organ dysfunction. Results The liver proteins that changed in abundance after sepsis had a range of functions such as acute phase proteins, coagulation, ER stress, oxidative stress, apoptosis, mitochondrial proteins and nitric oxide metabolism. We found that cyclophilin increased in abundance after CLP. When the receptor for this protein, CD147, was inhibited sepsis-induced renal dysfunction was reduced. There was also a significant reduction in serum cytokine production when CD147 was inhibited. Conclusion By applying proteomics to a clinically relevant mouse model of sepsis we identified a number of novel proteins that changed in abundance. The inhibition of the receptor for one of these proteins, cyclophilin, attenuated sepsis-induced acute renal failure. The application of proteomics to sepsis research can facilitate the discovery of new therapeutic targets. PMID:17944020

Low level arsenic promotes progressive inflammatory angiogenesis and liver blood vessel remodeling in mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Straub, Adam C.; Stolz, Donna B.; Vin, Harina

2007-08-01

The vascular effects of arsenic in drinking water are global health concerns contributing to human disease worldwide. Arsenic targets the endothelial cells lining blood vessels, and endothelial cell activation or dysfunction may underlie the pathogenesis of both arsenic-induced vascular diseases and arsenic-enhanced tumorigenesis. The purpose of the current studies was to demonstrate that exposing mice to drinking water containing environmentally relevant levels of arsenic promoted endothelial cell dysfunction and pathologic vascular remodeling. Increased angiogenesis, neovascularization, and inflammatory cell infiltration were observed in Matrigel plugs implanted in C57BL/6 mice following 5-week exposures to 5-500 ppb arsenic [Soucy, N.V., Mayka, D., Klei,more » L.R., Nemec, A.A., Bauer, J.A., Barchowsky, A., 2005. Neovascularization and angiogenic gene expression following chronic arsenic exposure in mice. Cardiovasc.Toxicol 5, 29-42]. Therefore, functional in vivo effects of arsenic on endothelial cell function and vessel remodeling in an endogenous vascular bed were investigated in the liver. Liver sinusoidal endothelial cells (LSEC) became progressively defenestrated and underwent capillarization to decrease vessel porosity following exposure to 250 ppb arsenic for 2 weeks. Sinusoidal expression of PECAM-1 and laminin-1 proteins, a hallmark of capillarization, was also increased by 2 weeks of exposure. LSEC caveolin-1 protein and caveolae expression were induced after 2 weeks of exposure indicating a compensatory change. Likewise, CD45/CD68-positive inflammatory cells did not accumulate in the livers until after LSEC porosity was decreased, indicating that inflammation is a consequence and not a cause of the arsenic-induced LSEC phenotype. The data demonstrate that the liver vasculature is an early target of pathogenic arsenic effects and that the mouse liver vasculature is a sensitive model for investigating vascular health effects of arsenic.« less

Influence of preformed donor-specific antibodies and C4d on early liver allograft function.

PubMed

Perera, M T; Silva, M A; Murphy, N; Briggs, D; Mirza, D F; Neil, D A H

2013-12-01

INTRODUCTION. The impact of preformed donor-specific antibodies (DSA) is incompletely understood in liver transplantation. The incidence and impact of preformed DSA on early post liver transplant were assessed and these were correlated with compliment fragment C4d on allograft biopsy. METHODS. Pretransplant serum from 41 consecutive liver transplant recipients (brain dead donors; DBD = 27 and cardiac death donors; DCD = 14) were tested for class-specific anti-human leukocyte antigen (HLA) and compared against donor HLA types. Liver biopsies were taken during cold storage (t-1) and post-reperfusion (t0) stained with C4d and graded for preservation-reperfusion injury (PRI). RESULTS. Of the 41 recipients, 8 (20%) had anti-HLA class I/II antibodies pretransplant, 3 (7%) were confirmed preformed DSA; classes I and II (n=1) and class I only (n=2). No biopsies showed definite evidence of antibody-mediated rejection. Graft biopsies in overall showed only mild PRI with ischemic hepatocyte C4d pattern similar in both positive and negative DSA patients. One DSA-positive (33%) compared with four DSA-negative patients (10%) had significant early graft dysfunction; severe PRI causing graft loss from primary nonfunction was seen only in DSA-negative group. Allograft biopsy of preformed DSA-positive patient demonstrated only minimal PRI; however, no identifiable cause could be attributed to graft dysfunction other than preformed DSA. CONCLUSION. Preformed DSA are present in 5-10% liver transplant recipients. There is no association between anti-HLA DSA and PRI and C4d, but preformed DSA may cause early morbidity. Larger studies on the impact of DSA with optimization of C4d techniques are required.

Pharmacokinetics and Safety of Bortezomib in Patients with Advanced Malignancies and Varying Degrees of Liver Dysfunction: Phase 1 NCI Organ Dysfunction Working Group Study NCI-6432

PubMed Central

LoRusso, Patricia M; Venkatakrishnan, Karthik; Ramanathan, Ramesh K; Sarantopoulos, John; Mulkerin, Daniel; Shibata, Stephen I; Hamilton, Anne; Dowlati, Afshin; Mani, Sridhar; Rudek, Michelle A; Takimoto, Chris H; Neuwirth, Rachel; Esseltine, Dixie-Lee; Ivy, Percy

2013-01-01

Purpose The proteasome inhibitor bortezomib undergoes oxidative hepatic metabolism. This study (NCI-6432; NCT00091117) was conducted to evaluate bortezomib pharmacokinetics and safety in patients with varying degrees of hepatic impairment, to inform dosing recommendations in these special populations. Methods Patients received bortezomib on days 1, 4, 8, and 11 of 21-day cycles. Patients were assigned to four hepatic function groups based on the National Cancer Institute Organ Dysfunction Working Group classification. Those with normal function received bortezomib at the 1.3 mg/m2 standard dose. Patients with severe, moderate, and mild impairment received escalating doses from 0.5, 0.7, and 1.0 mg/m2, respectively, up to a 1.3 mg/m2 maximum. Serial blood samples were collected for 24 hours post-dose on days 1 and 8, cycle 1, for bortezomib plasma concentration measurements. Results Sixty-one patients were treated, including 14 with normal hepatic function and 17, 12, and 18 with mild, moderate, and severe impairment, respectively. Mild hepatic impairment did not alter dose-normalized bortezomib exposure (AUC0-tlast) or Cmax compared with patients with normal function. Mean dose-normalized AUC0-tlast was increased by approximately 60% on day 8 in patients with moderate or severe impairment. Conclusions Patients with mild hepatic impairment do not require a starting dose adjustment of bortezomib. Patients with moderate or severe hepatic impairment should be started at a reduced dose of 0.7 mg/m2. PMID:22394984

Sustained virologic response to interferon-free therapies ameliorates HCV-induced portal hypertension.

PubMed

Mandorfer, Mattias; Kozbial, Karin; Schwabl, Philipp; Freissmuth, Clarissa; Schwarzer, Rémy; Stern, Rafael; Chromy, David; Stättermayer, Albert Friedrich; Reiberger, Thomas; Beinhardt, Sandra; Sieghart, Wolfgang; Trauner, Michael; Hofer, Harald; Ferlitsch, Arnulf; Ferenci, Peter; Peck-Radosavljevic, Markus

2016-10-01

We aimed to investigate the impact of sustained virologic response (SVR) to interferon (IFN)-free therapies on portal hypertension in patients with paired hepatic venous pressure gradient (HVPG) measurements. One hundred and four patients with portal hypertension (HVPG ⩾6mmHg) who underwent HVPG and liver stiffness measurement before IFN-free therapy (baseline [BL]) were retrospectively studied. Among 100 patients who achieved SVR, 60 patients underwent HVPG and transient elastography (TE) after antiviral therapy (follow-up [FU]). SVR to IFN-free therapies significantly decreased HVPG across all BL HVPG strata: 6-9mmHg (BL: 7.37±0.28 vs. FU: 5.11±0.38mmHg; -2.26±0.42mmHg; p<0.001), 10-15mmHg (BL: 12.2±0.4 vs. FU: 8.91±0.62mmHg; -3.29±0.59mmHg; p<0.001) and ⩾16mmHg (BL: 19.4±0.73 vs. FU: 17.1±1.21mmHg; -2.3±0.89mmHg; p=0.018). In the subgroup of patients with BL HVPG of 6-9mmHg, HVPG normalized (<6mmHg) in 63% (12/19) of patients, while no patient progressed to ⩾10mmHg. Among patients with BL HVPG ⩾10mmHg, a clinically relevant HVPG decrease ⩾10% was observed in 63% (26/41); 24% (10/41) had a FU HVPG <10mmHg. Patients with Child-Pugh stage B were less likely to have a HVPG decrease (hazard ratio [HR]: 0.103; 95% confidence interval [CI]: 0.02-0.514; p=0.006), when compared to Child-Pugh A patients. In the subgroup of patients with BL CSPH, the relative change in liver stiffness (per %; HR: 0.972; 95% CI: 0.945-0.999; p=0.044) was a predictor of a HVPG decrease ⩾10%. The area under the receiver operating characteristic curve for the diagnosis of FU CSPH by FU liver stiffness was 0.931 (95% CI: 0.865-0.997). SVR to IFN-free therapies might ameliorate portal hypertension across all BL HVPG strata. However, changes in HVPG seemed to be more heterogeneous among patients with BL HVPG of ⩾16mmHg and a HVPG decrease was less likely in patients with more advanced liver dysfunction. TE might be useful for the non-invasive evaluation of portal hypertension after SVR. We investigated the impact of curing hepatitis C using novel interferon-free treatments on portal hypertension, which drives the development of liver-related complications and mortality. Cure of hepatitis C decreased portal pressure, but a decrease was less likely among patients with more pronounced hepatic dysfunction. Transient elastography, which is commonly used for the non-invasive staging of liver disease, might identify patients without clinically significant portal hypertension after successful treatment. Copyright © 2016 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Oral Anticoagulation in Patients With Liver Disease.

PubMed

Qamar, Arman; Vaduganathan, Muthiah; Greenberger, Norton J; Giugliano, Robert P

2018-05-15

Patients with liver disease are at increased risks of both thrombotic and bleeding complications. Many have atrial fibrillation (AF) or venous thromboembolism (VTE) necessitating oral anticoagulant agents (OACs). Recent evidence has contradicted the assumption that patients with liver disease are "auto-anticoagulated" and thus protected from thrombotic events. Warfarin and non-vitamin K-antagonist OACs have been shown to reduce thrombotic events safely in patients with either AF or VTE. However, patients with liver disease have largely been excluded from trials of OACs. Because all currently approved OACs undergo metabolism in the liver, hepatic dysfunction may cause increased bleeding. Thus, the optimal anticoagulation strategy for patients with AF or VTE who have liver disease remains unclear. This review discusses pharmacokinetic and clinical studies evaluating the efficacy and safety of OACs in patients with liver disease and provides a practical, clinically oriented approach to the management of OAC therapy in this population. Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Elevated renin levels in patients with liver cirrhosis and hepatocellular carcinoma.

PubMed

Lotfy, Mahmoud; El-Kenawy, Ayman El-Meghawry; Abdel-Aziz, Mohamed M; El-Kady, Ibrahim; Talaat, Ayman

2010-01-01

Liver fibrosis is the common consequence of chronic liver injury of any etiology, disrupting the normal architecture,and causing hepatocellular dysfunction and portal hypertension. Since the renin-angiotensin system (RAS) may be involved in chronic liver diseases, in the present study we assayed renin levels using ELISA in groups of Egyptian patients with liver cirrhosis (N=32) and hepatocellular carcinoma (HCC) (N=67), for comparison with twenty five healthy controls. The results showed significant differences between the control and liver cirrhosis patients (P<0.001) and also the controls and HCC patients (P<0.001), without significant variation between the patient groups. Furthermore, in HCC patients, it was found that the renin levels negatively correlated with serum albumin and prothrombin time (P=0.003 for each) and positively with α-fetoprotein (P=0.04). Thus, it is concluded that renin levels are elevated in patients with liver cirrhosis and HCC and suitable medical intervention should be placed for management of such alteration. Moreover, further studies are warranted to explore its prognostic significance.

Vinpocetine protects liver against ischemia-reperfusion injury.

PubMed

Zaki, Hala Fahmy; Abdelsalam, Rania Mohsen

2013-12-01

Hepatic ischemia-reperfusion (IR) injury is a clinical problem that leads to cellular damage and organ dysfunction mediated mainly via production of reactive oxygen species and inflammatory cytokines. Vinpocetine has long been used in cerebrovascular disorders. This study aimed to explore the protective effect of vinpocetine in IR injury to the liver. Ischemia was induced in rats by clamping the common hepatic artery and portal vein for 30 min followed by 30 min of reperfusion. Serum transaminases and liver lactate dehydrogenase (LDH) activities, liver inflammatory cytokines, oxidative stress biomarkers, and liver histopathology were assessed. IR resulted in marked histopathology changes in liver tissues coupled with elevations in serum transaminases and liver LDH activities. IR also increased the production of liver lipid peroxides, nitric oxide, and inflammatory cytokines interleukin-1β and interleukin-6, in parallel with a reduction in reduced glutathione and interleukin-10 in the liver. Pretreatment with vinpocetine protected against liver IR-induced injury, in a dose-dependent manner, as evidenced by the attenuation of oxidative stress as well as inflammatory and liver injury biomarkers. The effects of vinpocetine were comparable with that of curcumin, a natural antioxidant, and could be attributed to its antioxidant and anti-inflammatory properties.

Cirrhosis and autoimmune liver disease: Current understanding

PubMed Central

Liberal, Rodrigo; Grant, Charlotte R

2016-01-01

Primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC) and autoimmune hepatitis (AIH) constitute the classic autoimmune liver diseases (AILDs). While AIH target the hepatocytes, in PBC and PSC the targets of the autoimmune attack are the biliary epithelial cells. Persistent liver injury, associated with chronic AILD, leads to un-resolving inflammation, cell proliferation and the deposition of extracellular matrix proteins by hepatic stellate cells and portal myofibroblasts. Liver cirrhosis, and the resultant loss of normal liver function, inevitably ensues. Patients with cirrhosis have higher risks or morbidity and mortality, and that in the decompensated phase, complications of portal hypertension and/or liver dysfunction lead to rapid deterioration. Accurate diagnosis and monitoring of cirrhosis is, therefore of upmost importance. Liver biopsy is currently the gold standard technique, but highly promising non-invasive methodology is under development. Liver transplantation (LT) is an effective therapeutic option for the management of end-stage liver disease secondary to AIH, PBC and PSC. LT is indicated for AILD patients who have progressed to end-stage chronic liver disease or developed intractable symptoms or hepatic malignancy; in addition, LT may also be indicated for patients presenting with acute liver disease due to AIH who do not respond to steroids. PMID:27729952

Regulation of Mammalian Physiology by Interconnected Circadian and Feeding Rhythms

PubMed Central

Atger, Florian; Mauvoisin, Daniel; Weger, Benjamin; Gobet, Cédric; Gachon, Frédéric

2017-01-01

Circadian clocks are endogenous timekeeping systems that adapt in an anticipatory fashion the physiology and behavior of most living organisms. In mammals, the master pacemaker resides in the suprachiasmatic nucleus and entrains peripheral clocks using a wide range of signals that differentially schedule physiology and gene expression in a tissue-specific manner. The peripheral clocks, such as those found in the liver, are particularly sensitive to rhythmic external cues like feeding behavior, which modulate the phase and amplitude of rhythmic gene expression. Consequently, the liver clock temporally tunes the expression of many genes involved in metabolism and physiology. However, the circadian modulation of cellular functions also relies on multiple layers of posttranscriptional and posttranslational regulation. Strikingly, these additional regulatory events may happen independently of any transcriptional oscillations, showing that complex regulatory networks ultimately drive circadian output functions. These rhythmic events also integrate feeding-related cues and adapt various metabolic processes to food availability schedules. The importance of such temporal regulation of metabolism is illustrated by metabolic dysfunctions and diseases resulting from circadian clock disruption or inappropriate feeding patterns. Therefore, the study of circadian clocks and rhythmic feeding behavior should be of interest to further advance our understanding of the prevention and therapy of metabolic diseases. PMID:28337174

Abnormal permeability of inner and outer mitochondrial membranes contributes independently to mitochondrial dysfunction in the liver during acute endotoxemia.

PubMed

Crouser, Elliott D; Julian, Mark W; Huff, Jennifer E; Joshi, Mandar S; Bauer, John A; Gadd, Martha E; Wewers, Mark D; Pfeiffer, Douglas R

2004-02-01

This study was designed to determine the role played by the mitochondrial permeability transition in the pathogenesis of mitochondrial damage and dysfunction in a representative systemic organ during the acute phase of endotoxemia. A well-established, normotensive feline model was employed to determine whether pretreatment with cyclosporine A, a potent inhibitor of the mitochondrial permeability transition, normalizes mitochondrial ultrastructural injury and dysfunction in the liver during acute endotoxemia. The Ohio State University Medical Center research laboratory. Random source, adult, male conditioned cats. Hemodynamic resuscitation and maintenance of acid-base balance and tissue oxygen availability were provided, as needed, to minimize the potentially confounding effects of tissue hypoxia and/or acidosis on the experimental results. Treatment groups received isotonic saline vehicle (control; n = 6), lipopolysaccharide (3.0 mg/kg, intravenously; n = 8), or cyclosporine A (6.0 mg/kg, intravenously; n = 6) or tacrolimus (FK506, 0.1 mg/kg, intravenously; n = 4) followed in 30 mins by lipopolysaccharide (3.0 mg/kg, intravenously). Liver samples were obtained 4 hrs posttreatment, and mitochondrial ultrastructure, function, and cytochrome c, Bax, and ceramide contents were assessed. As expected, significant mitochondrial injury was apparent in the liver 4 hrs after lipopolysaccharide treatment, despite maintenance of regional tissue oxygen availability. Namely, mitochondria demonstrated high-amplitude swelling and exhibited altered respiratory function. Cyclosporine A pretreatment attenuated lipopolysaccharide-induced mitochondrial ultrastructural abnormalities and normalized mitochondrial respiratory control, reflecting protection against inner mitochondrial membrane damage. However, an abnormal permeability of outer mitochondrial membranes to cytochrome c was observed in all lipopolysaccharide-treated groups and was associated with increased mitochondrial concentrations of Bax and ceramide. These studies confirm that liver mitochondria are early targets of injury during endotoxemia and that inner and outer mitochondrial membrane damage occurs through different mechanisms. Inner mitochondrial membrane damage appears to relate to the mitochondrial permeability transition, whereas outer mitochondrial membrane damage can occur independent of the mitochondrial permeability transition. Preliminary evidence suggests that Bax may participate in lipopolysaccharide-induced outer mitochondrial membrane damage, but further investigations are needed to confirm this.

Downregulation of Glutathione Biosynthesis Contributes to Oxidative Stress and Liver Dysfunction in Acute Kidney Injury

PubMed Central

Siow, Yaw L.; Isaak, Cara K.

2016-01-01

Ischemia-reperfusion is a common cause for acute kidney injury and can lead to distant organ dysfunction. Glutathione is a major endogenous antioxidant and its depletion directly correlates to ischemia-reperfusion injury. The liver has high capacity for producing glutathione and is a key organ in modulating local and systemic redox balance. In the present study, we investigated the mechanism by which kidney ischemia-reperfusion led to glutathione depletion and oxidative stress. The left kidney of Sprague-Dawley rats was subjected to 45 min ischemia followed by 6 h reperfusion. Ischemia-reperfusion impaired kidney and liver function. This was accompanied by a decrease in glutathione levels in the liver and plasma and increased hepatic lipid peroxidation and plasma homocysteine levels. Ischemia-reperfusion caused a significant decrease in mRNA and protein levels of hepatic glutamate-cysteine ligase mediated through the inhibition of transcription factor Nrf2. Ischemia-reperfusion inhibited hepatic expression of cystathionine γ-lyase, an enzyme responsible for producing cysteine (an essential precursor for glutathione synthesis) through the transsulfuration pathway. These results suggest that inhibition of glutamate-cysteine ligase expression and downregulation of the transsulfuration pathway lead to reduced hepatic glutathione biosynthesis and elevation of plasma homocysteine levels, which, in turn, may contribute to oxidative stress and distant organ injury during renal ischemia-reperfusion. PMID:27872680

Clinical outcomes of transfusion-associated iron overload in patients with refractory chronic anemia.

PubMed

Gao, Chong; Li, Li; Chen, Baoan; Song, Huihui; Cheng, Jian; Zhang, Xiaoping; Sun, Yunyu

2014-01-01

The purpose of this study was to evaluate the clinical outcomes of transfusion-associated iron overload in patients with chronic refractory anemia. Clinical manifestations, main organ function, results of computed tomography (CT), endocrine evaluation, and serum ferritin levels were analyzed retrospectively in 13 patients who were transfusion-dependent for more than 1 year (receiving >50 units of red blood cells) to determine the degree of iron overload and efficacy of iron-chelating therapy. Serum ferritin levels increased to 1,830-5,740 ng/mL in all patients. Ten patients had abnormal liver function. The CT Hounsfield units in the liver increased significantly in eleven patients, and were proportional to their serum ferritin levels. Skin pigmentation, liver dysfunction, and endocrine dysfunction were observed in nine patients with serum ferritin >3,500 ng/mL, eight of whom have since died. Interestingly, serum ferritin levels did not decrease significantly in nine transfusion-dependent patients who had received 15-60 days of iron-chelating therapy. Transfusion-dependent patients may progress to secondary iron overload with organ impairment, which may be fatal in those who are heavily iron-overloaded. The CT Hounsfield unit is a sensitive indicator of iron overload in the liver. Iron chelation therapy should be initiated when serum ferritin is >1,000 ng/mL and continued until it is <1,000 ng/mL in transfusional iron-overloaded patients.

Glycogen synthase kinase 3-mediated voltage-dependent anion channel phosphorylation controls outer mitochondrial membrane permeability during lipid accumulation.

PubMed

Martel, Cecile; Allouche, Maya; Esposti, Davide Degli; Fanelli, Elena; Boursier, Céline; Henry, Céline; Chopineau, Joel; Calamita, Giuseppe; Kroemer, Guido; Lemoine, Antoinette; Brenner, Catherine

2013-01-01

Nonalcoholic steatosis is a liver pathology characterized by fat accumulation and severe metabolic alterations involving early mitochondrial impairment and late hepatocyte cell death. However, mitochondrial dysfunction mechanisms remain elusive. Using four models of nonalcoholic steatosis, i.e., livers from patients with fatty liver disease, ob/ob mice, mice fed a high-fat diet, and in vitro models of lipotoxicity, we show that outer mitochondrial membrane permeability is altered and identified a posttranslational modification of voltage-dependent anion channel (VDAC), a membrane channel and NADH oxidase, as a cause of early mitochondrial dysfunction. Thus, in nonalcoholic steatosis VDAC exhibits reduced threonine phosphorylation, which increases the influx of water and calcium into mitochondria, sensitizes the organelle to matrix swelling, depolarization, and cytochrome c release without inducing cell death. This also amplifies VDAC enzymatic and channel activities regulation by calcium and modifies its interaction with proteic partners. Moreover, lipid accumulation triggers a rapid lack of VDAC phosphorylation by glycogen synthase kinase 3 (GSK3). Pharmacological and genetic manipulations proved GSK3 to be responsible for VDAC phosphorylation in normal cells. Notably, VDAC phosphorylation level correlated with steatosis severity in patients. VDAC acts as an early sensor of lipid toxicity and its GSK3-mediated phosphorylation status controls outer mitochondrial membrane permeabilization in hepatosteatosis. Copyright © 2012 American Association for the Study of Liver Diseases.

Food Poisonings by Ingestion of Cyprinid Fish

PubMed Central

Asakawa, Manabu; Noguchi, Tamao

2014-01-01

Raw or dried gallbladders of cyprinid fish have long been ingested as a traditional medicine in the Asian countries, particularly in China, for ameliorating visual acuity, rheumatism, and general health; however, sporadic poisoning incidences have occurred after their ingestion. The poisoning causes complex symptoms in patients, including acute renal failure, liver dysfunction, paralysis, and convulsions of limbs. The causative substance for the poisoning was isolated, and its basic properties were examined. The purified toxin revealed a minimum lethal dose of 2.6 mg/20 g in mouse, when injected intraperitoneally. The main symptoms were paralysis and convulsions of the hind legs, along with other neurological signs. Liver biopsy of the euthanized mice clearly exhibited hepatocytes necrosis and infiltration of neutrophils and lymphocytes, suggesting the acute dysfunction of the liver. Blood tests disclosed the characteristics of acute renal failure and liver injury. Infrared (IR) spectrometry, fast atom bombardment (FAB) mass spectrometry, and 1H- and 13C-nuclear magnetic resonance (NMR) analysis indicated, a molecular formula of C27H48O8S, containing a sulfate ester group for the toxin. Thus, we concluded that the structure of carp toxin to be 5α-cyprinol sulfate (5α-cholestane-3α, 7α, 12α, 26, 27-pentol 26-sulfate). This indicated that carp toxin is a nephro- and hepato- toxin, which could be the responsible toxin for carp bile poisoning in humans. PMID:24476713

High-volume plasma exchange in a patient with acute liver failure due to non-exertional heat stroke in a sauna.

PubMed

Chen, Kuan-Jung; Chen, Tso-Hsiao; Sue, Yuh-Mou; Chen, Tzay-Jinn; Cheng, Chung-Yi

2014-10-01

Heat stroke is a life-threatening condition characterized by an increased core body temperature (over 40°C) and a systemic inflammatory response, which may lead to a syndrome of multiple organ dysfunction. Heat stroke may be due to either strenuous exercise or non-exercise-induced exposure to a high environmental temperature. Current management of heat stroke is mostly supportive, with an emphasis on cooling the core body temperature and preventing the development of multiple organ dysfunction. Prognosis of heat stroke depends on the severity of organ involvement. Here, we report a rare case of non-exercise-induced heat stroke in a 73-year-old male patient who was suffering from acute liver failure after prolonged exposure in a hot sauna room. We successfully managed this patient by administering high-volume plasma exchange, and the patient recovered completely after treatment. © 2014 Wiley Periodicals, Inc.

[A case of loxoprofen-induced pulmonary eosinophilia].

PubMed

Ii, T; Doutsu, Y; Ashitani, J; Taniguchi, H; Mizuta, M; Toshimori, H; Matsukura, S

1992-05-01

A 65-year-old female suffering from lumbago, headache, and hypertension had been treated with nonsteroidal anti-inflammatory drugs (NSAIDs) and antihypertensive drugs. On June 13, 1990, 2 weeks after the commencement of loxoprofen administration, she developed cough and low grade fever. She was treated with antibiotics and NSAIDs without improvement. Laboratory data showed marked eosinophilia (2200/mm3), elevation of IgE (3090 IU/ml), and liver dysfunction. Her chest X-ray revealed no active lesion, but the percentage of eosinophils in BALF was elevated (38%). Because drug-induced eosinophilic pneumonia was suspected, all drugs were discontinued. Her symptoms improved and the abnormalities of laboratory data normalized. The lymphocyte stimulation test was weakly positive with three NSAIDs (loxoprofen, pranoprofen, and alminoprofen). The challenge test by loxoprofen reproduced eosinophilia and liver dysfunction, suggesting that she had loxoprofen-induced eosinophilic pneumonia. To our knowledge, this is the first reported case of loxoprofen-induced lung injury.

Solid organ transplantation following end-organ failure in recipients of hematopoietic stem cell transplantation in children.

PubMed

Upadhyay, Kiran; Fine, Richard N

2014-08-01

Hematopoietic stem cell transplantation (HSCT) is an accepted treatment modality for various malignant and non-malignant disorders of the lympho-hematopoietic system. Patient survival rate has increased significantly with the use of this procedure. However, with the increase in disease-free patient survival rates, complications including various organ toxicities are also common. Kidney, liver, lung, heart, and skin are among those solid organs that are commonly affected and frequently lead to organ dysfunction and eventually end-organ disease. Conservative measures may or may not be successful in managing the organ failure in these patients. Solid organ transplantation has been shown to be promising in those patients who fail conservative management. This review will summarize the causes of solid organ (kidney, liver, and lung) dysfunction and the available data on transplantation of these solid organs in post-HSCT recipients.

Physiological Aging: Links Among Adipose Tissue Dysfunction, Diabetes, and Frailty

PubMed Central

Stout, Michael B.; Justice, Jamie N.; Nicklas, Barbara J.; Kirkland, James L.

2016-01-01

Advancing age is associated with progressive declines in physiological function that lead to overt chronic disease, frailty, and eventual mortality. Importantly, age-related physiological changes occur in cellularity, insulin-responsiveness, secretory profiles, and inflammatory status of adipose tissue, leading to adipose tissue dysfunction. Although the mechanisms underlying adipose tissue dysfunction are multifactorial, the consequences result in secretion of proinflammatory cytokines and chemokines, immune cell infiltration, an accumulation of senescent cells, and an increase in senescence-associated secretory phenotype (SASP). These processes synergistically promote chronic sterile inflammation, insulin resistance, and lipid redistribution away from subcutaneous adipose tissue. Without intervention, these effects contribute to age-related systemic metabolic dysfunction, physical limitations, and frailty. Thus adipose tissue dysfunction may be a fundamental contributor to the elevated risk of chronic disease, disability, and adverse health outcomes with advancing age. PMID:27927801

Evaluation of Hepatoprotective Effect of Curcumin on Liver Cirrhosis Using a Combination of Biochemical Analysis and Magnetic Resonance-Based Electrical Conductivity Imaging

PubMed Central

Kyung, Eun Jung; Kim, Hyun Bum; Hwang, Eun Sang; Lee, Seok; Choi, Bup Kyung; Lim, Sang Moo; Kwon, Oh In

2018-01-01

In oriental medicine, curcumin is used to treat inflammatory diseases, and its anti-inflammatory effect has been reported in recent research. In this feasibility study, the hepatoprotective effect of curcumin was investigated using a rat liver cirrhosis model, which was induced with dimethylnitrosamine (DMN). Together with biochemical analysis, we used a magnetic resonance-based electrical conductivity imaging method to evaluate tissue conditions associated with a protective effect. The effects of curcumin treatment and lactulose treatment on liver cirrhosis were compared. Electrical conductivity images indicated that liver tissues damaged by DMN showed decreased conductivity compared with normal liver tissues. In contrast, cirrhotic liver tissues treated with curcumin or lactulose showed increased conductivity than tissues in the DMN-only group. Specifically, conductivity of cirrhotic liver after curcumin treatment was similar to that of normal liver tissues. Histological staining and immunohistochemical examination showed significant levels of attenuated fibrosis and decreased inflammatory response after both curcumin and lactulose treatments compared with damaged liver tissues by DMN. The conductivity imaging and biochemical examination results indicate that curcumin's anti-inflammatory effect can prevent the progression of irreversible liver dysfunction. PMID:29887757

Hepatocyte transplants improve liver function and encephalopathy in portacaval shunted rats.

PubMed

Fogel, Wieslawa Agnieszka; Stasiak, Anna; Maksymowicz, Michał; Kobos, Jozef; Unzeta, Mercedes; Mussur, Miroslaw

2014-07-01

Rats with portacaval shunt (PCS) are useful experimental models of human hepatic encephalopathy in chronic liver dysfunction. We have previously shown that PCS modifies amine neurotransmitter systems in the CNS and increases voluntary alcohol intake by rats. Hepatocyte transplantation, used in acute liver failure, has recently also been applied to chronic liver diseases, which prompted us to investigate whether the altered brain amine system and the drinking behavior in long-term shunted rats could be normalized by hepatocyte transplants. Hepatocytes, isolated from syngeneic donors by collagenase digestion, were injected (3 × 10(6) cells/rat) into the pancreatic tail region, 6 months after PCS. Hepatic function was evaluated by measuring urine urea and plasma L-histidine concentrations. A free choice test with two bottles (tap water and 10% ethyl alcohol) was performed for 3 days to assess the rats' preference for alcohol. The rats were euthanized 2 months posttransplantation. Brain histamine and 5-hydroxyindoleacetic acid (5-HIAA) levels were measured by radioenzymatic assay and by HPLC-EC, respectively, N-tele-methylhistamine by GC/MS while MAOA and MAOB activities by isotopic procedures. Portacaval shunt rats with hepatocyte transplants gave more urea than before transplantation, with lower plasma L-His levels and higher body weight versus the PCS counterparts. Also, those rats consumed less alcohol. The CNS amines and 5-HIAA concentrations, as well as MAO-B activity, being abnormally high in untreated PCS rats, significantly reduced after PCS hepatocyte treatment. The results support the therapeutic values of hepatocyte transplants in chronic liver diseases and the temporary character of PCS-exerted CNS dysfunctions. © 2014 John Wiley & Sons Ltd.

Neutrophil depletion improves diet-induced non-alcoholic fatty liver disease in mice.

PubMed

Ou, Rongying; Liu, Jia; Lv, Mingfen; Wang, Jingying; Wang, Jinmeng; Zhu, Li; Zhao, Liang; Xu, Yunsheng

2017-07-01

Non-alcoholic fatty liver disease is highly associated with morbidity and mortality in population. Although studies have already demonstrated that the immune response plays a pivotal role in the development of non-alcoholic fatty liver disease, the comprehensive regulation is unclear. Therefore, present study was carried out to investigate the non-alcoholic fatty liver disease development under neutrophil depletion. To achieve the aim of the study, C57BL/6 J mice were fed with high fat diet for 6 weeks before treated with neutrophil deplete antibody 1A8 or isotype control (200 μg/ mouse every week) for another 4 weeks. Treated with 1A8 antibody, obese mice exhibited better whole body metabolic parameters, including reduction of body weight gain and fasting blood glucose levels. Neutrophil depletion also effectively reduced hepatic structural disorders, dysfunction and lipid accumulation. Lipid β-oxidative markers, phosphorylated-AMP-activated protein kinase α and phosphorylated-acetyl-CoA carboxylase levels were increased in 1A8 antibody-treated obese mouse group. The mitochondrial number and function were also reversed after 1A8 antibody treatment, including increased mitochondrial number, reduced lipid oxidative damage and enhanced mitochondrial activity. Furthermore, the expression of inflammatory cytokines, tumor necrosis factor-α, interleukin-6, and monocyte chemoattractant protein-1 were obviously reduced after neutrophil depletion, accompanied with decreased F4/80 mRNA level and macrophage percentage in liver. The decreased NF-κB signaling activity was also involved in the beneficial effect of neutrophil depletion. Taken together, neutrophil depletion could attenuate metabolic syndromes and hepatic dysfunction.

Enhanced Production of Adenosine Triphosphate by Pharmacological Activation of Adenosine Monophosphate-Activated Protein Kinase Ameliorates Acetaminophen-Induced Liver Injury

PubMed Central

Hwang, Jung Hwan; Kim, Yong-Hoon; Noh, Jung-Ran; Choi, Dong-Hee; Kim, Kyoung-Shim; Lee, Chul-Ho

2015-01-01

The hepatic cell death induced by acetaminophen (APAP) is closely related to cellular adenosine triphosphate (ATP) depletion, which is mainly caused by mitochondrial dysfunction. Adenosine monophosphate (AMP)-activated protein kinase (AMPK) is a key sensor of low energy status. AMPK regulates metabolic homeostasis by stimulating catabolic metabolism and suppressing anabolic pathways to increase cellular energy levels. We found that the decrease in active phosphorylation of AMPK in response to APAP correlates with decreased ATP levels, in vivo. Therefore, we hypothesized that the enhanced production of ATP via AMPK stimulation can lead to amelioration of APAP-induced liver failure. A769662, an allosteric activator of AMPK, produced a strong synergistic effect on AMPK Thr172 phosphorylation with APAP in primary hepatocytes and liver tissue. Interestingly, activation of AMPK by A769662 ameliorated the APAP-induced hepatotoxicity in C57BL/6N mice treated with APAP at a dose of 400 mg/kg intraperitoneally. However, mice treated with APAP alone developed massive centrilobular necrosis, and APAP increased their serum alanine aminotransferase and aspartate aminotransferase levels. Furthermore, A769662 administration prevented the loss of intracellular ATP without interfering with the APAP-mediated reduction of mitochondrial dysfunction. In contrast, inhibition of glycolysis by 2-deoxy-glucose eliminated the beneficial effects of A769662 on APAP-mediated liver injury. In conclusion, A769662 can effectively protect mice against APAP-induced liver injury through ATP synthesis by anaerobic glycolysis. Furthermore, stimulation of AMPK may have potential therapeutic application for APAP overdose. PMID:26434492

Prenatal iron deficiency causes sex-dependent mitochondrial dysfunction and oxidative stress in fetal rat kidneys and liver.

PubMed

Woodman, Andrew G; Mah, Richard; Keddie, Danae; Noble, Ronan M N; Panahi, Sareh; Gragasin, Ferrante S; Lemieux, Hélène; Bourque, Stephane L

2018-06-01

Prenatal iron deficiency alters fetal developmental trajectories, which results in persistent changes in organ function. Here, we studied the effects of prenatal iron deficiency on fetal kidney and liver mitochondrial function. Pregnant Sprague-Dawley rats were fed partially or fully iron-restricted diets to induce a state of moderate or severe iron deficiency alongside iron-replete control rats. We assessed mitochondrial function via high-resolution respirometry and reactive oxygen species generation via fluorescence microscopy on gestational d 21. Hemoglobin levels were reduced in dams in the moderate (-31%) and severe groups (-54%) compared with controls, which was accompanied by 55% reductions in fetal hemoglobin levels in both moderate and severe groups versus controls. Male iron-deficient kidneys exhibited globally reduced mitochondrial content and respiration, as well as increased cytosolic superoxide and decreased NO. Female iron-deficient kidneys exhibited complex II down-regulation and increased mitochondrial oxidative stress. Male iron-deficient livers exhibited reduced complex IV respiration and increased cytosolic superoxide, whereas female liver tissues exhibited no alteration in oxidant levels or mitochondrial function. These findings indicate that prenatal iron deficiency causes changes in mitochondrial content and function as well as oxidant status in a sex- and organ-dependent manner, which may be an important mechanism that underlies the programming of cardiovascular disease.-Woodman, A. G., Mah, R., Keddie, D., Noble, R. M. N., Panahi, S., Gragasin, F. S., Lemieux, H., Bourque, S. L. Prenatal iron deficiency causes sex-dependent mitochondrial dysfunction and oxidative stress in fetal rat kidneys and liver.

Ipragliflozin Improves Hepatic Steatosis in Obese Mice and Liver Dysfunction in Type 2 Diabetic Patients Irrespective of Body Weight Reduction.

PubMed

Komiya, Chikara; Tsuchiya, Kyoichiro; Shiba, Kumiko; Miyachi, Yasutaka; Furuke, Shunsaku; Shimazu, Noriko; Yamaguchi, Shinobu; Kanno, Kazuo; Ogawa, Yoshihiro

2016-01-01

Type 2 diabetes mellitus (T2DM) is associated with a high incidence of non-alcoholic fatty liver disease (NAFLD) related to obesity and insulin resistance. Currently, medical interventions for NAFLD have focused on diet control and exercise to reduce body weight, and there is a requirement for effective pharmacological therapies. Sodium-glucose cotransporter 2 (SGLT2) inhibitors are oral antidiabetic drugs that promote the urinary excretion of glucose by blocking its reabsorption in renal proximal tubules. SGLT2 inhibitors lower blood glucose independent of insulin action and are expected to reduce body weight because of urinary calorie loss. Here we show that an SGLT2 inhibitor ipragliflozin improves hepatic steatosis in high-fat diet-induced and leptin-deficient (ob/ob) obese mice irrespective of body weight reduction. In the obese mice, ipragliflozin-induced hyperphagia occurred to increase energy intake, attenuating body weight reduction with increased epididymal fat mass. There is an inverse correlation between weights of liver and epididymal fat in ipragliflozin-treated obese mice, suggesting that ipragliflozin treatment promotes normotopic fat accumulation in the epididymal fat and prevents ectopic fat accumulation in the liver. Despite increased adiposity, ipragliflozin ameliorates obesity-associated inflammation and insulin resistance in epididymal fat. Clinically, ipragliflozin improves liver dysfunction in patients with T2DM irrespective of body weight reduction. These findings provide new insight into the effects of SGLT2 inhibitors on energy homeostasis and fat accumulation and indicate their potential therapeutic efficacy in T2DM-associated hepatic steatosis.

Enhanced Production of Adenosine Triphosphate by Pharmacological Activation of Adenosine Monophosphate-Activated Protein Kinase Ameliorates Acetaminophen-Induced Liver Injury.

PubMed

Hwang, Jung Hwan; Kim, Yong-Hoon; Noh, Jung-Ran; Choi, Dong-Hee; Kim, Kyoung-Shim; Lee, Chul-Ho

2015-10-01

The hepatic cell death induced by acetaminophen (APAP) is closely related to cellular adenosine triphosphate (ATP) depletion, which is mainly caused by mitochondrial dysfunction. Adenosine monophosphate (AMP)-activated protein kinase (AMPK) is a key sensor of low energy status. AMPK regulates metabolic homeostasis by stimulating catabolic metabolism and suppressing anabolic pathways to increase cellular energy levels. We found that the decrease in active phosphorylation of AMPK in response to APAP correlates with decreased ATP levels, in vivo. Therefore, we hypothesized that the enhanced production of ATP via AMPK stimulation can lead to amelioration of APAP-induced liver failure. A769662, an allosteric activator of AMPK, produced a strong synergistic effect on AMPK Thr172 phosphorylation with APAP in primary hepatocytes and liver tissue. Interestingly, activation of AMPK by A769662 ameliorated the APAP-induced hepatotoxicity in C57BL/6N mice treated with APAP at a dose of 400 mg/kg intraperitoneally. However, mice treated with APAP alone developed massive centrilobular necrosis, and APAP increased their serum alanine aminotransferase and aspartate aminotransferase levels. Furthermore, A769662 administration prevented the loss of intracellular ATP without interfering with the APAP-mediated reduction of mitochondrial dysfunction. In contrast, inhibition of glycolysis by 2-deoxy-glucose eliminated the beneficial effects of A769662 on APAP-mediated liver injury. In conclusion, A769662 can effectively protect mice against APAP-induced liver injury through ATP synthesis by anaerobic glycolysis. Furthermore, stimulation of AMPK may have potential therapeutic application for APAP overdose.

Aldolase-B knockout in mice phenocopies hereditary fructose intolerance in humans.

PubMed

Oppelt, Sarah A; Sennott, Erin M; Tolan, Dean R

2015-03-01

The rise in fructose consumption, and its correlation with symptoms of metabolic syndrome (MBS), has highlighted the need for a better understanding of fructose metabolism. To that end, valid rodent models reflecting the same metabolism as in humans, both biochemically and physiologically, are critical. A key to understanding any type of metabolism comes from study of disease states that affect such metabolism. A serious defect of fructose metabolism is the autosomal recessive condition called hereditary fructose intolerance (HFI), caused by mutations in the human aldolase B gene (Aldob). Those afflicted with HFI experience liver and kidney dysfunction after fructose consumption, which can lead to death, particularly during infancy. With very low levels of fructose exposure, HFI patients develop non-alcoholic fatty acid liver disease and fibrosis, sharing liver pathologies also seen in MBS. A major step toward establishing that fructose metabolism in mice mimics that of humans is reported by investigating the consequences of targeting the mouse aldolase-B gene (Aldo2) for deletion in mice (Aldo2(-/-)). The Aldo2(-/-) homozygous mice show similar pathology following exposure to fructose as humans with HFI such as failure to thrive, liver dysfunction, and potential morbidity. Establishing that this mouse reflects the symptoms of HFI in humans is critical for comparison of rodent studies to the human condition, where this food source is increasing, and increasingly controversial. This animal should provide a valuable resource for answering remaining questions about fructose metabolism in HFI, as well as help investigate the biochemical mechanisms leading to liver pathologies seen in MBS from high fructose diets. Copyright © 2015 Elsevier Inc. All rights reserved.

Ammonia-induced brain swelling and neurotoxicity in an organotypic slice model

PubMed Central

Back, Adam; Tupper, Kelsey Y.; Bai, Tao; Chiranand, Paulpoj; Goldenberg, Fernando D.; Frank, Jeffrey I.; Brorson, James R.

2013-01-01

Objectives Acute liver failure produces cerebral dysfunction and edema, mediated in part by elevated ammonia concentrations, often leading to coma and death. The pathophysiology of cerebral edema in acute liver failure is incompletely understood. In vitro models of the cerebral effects of acute liver failure have predominately consisted of dissociated astrocyte cultures or acute brain slices. We describe a stable long-term culture model incorporating both neural and glial elements in a three-dimensional tissue structure offering significant advantages to the study of astrocytic-neuronal interactions in the pathophysiology of cerebral edema and dysfunction in acute liver failure. Methods We utilized chronic organotypic slice cultures from mouse forebrain, applying ammonium acetate in iso-osmolar fashion for 72 hours. Imaging of slice thickness to assess for tissue swelling was accomplished in living slices with optical coherence tomography, and confocal microscopy of fluorescence immunochemical and histochemical staining served to assess astrocyte and neuronal numbers, morphology, and volume in the fixed brain slices. Results Ammonia exposure at 1–10 mM produced swelling of immunochemically-identified astrocytes, and at 10 mM resulted in macroscopic tissue swelling, with slice thickness increasing by about 30%. Astrocytes were unchanged in number. In contrast, 10 mM ammonia treatment severely disrupted neuronal morphology and reduced neuronal survival at 72 hours by one-half. Discussion Elevated ammonia produces astrocytic swelling, tissue swelling, and neuronal toxicity in cerebral tissues. Ammonia-treated organotypic brain slice cultures provide an in vitro model of cerebral effects of conditions relevant to acute liver failure, applicable to pathophysiological investigations. PMID:22196764

Cardiac and Noncardiac Causes of Long-Term Mortality in ST-Segment-Elevation Acute Myocardial Infarction Patients Who Underwent Primary Percutaneous Coronary Intervention.

PubMed

Yamashita, Yugo; Shiomi, Hiroki; Morimoto, Takeshi; Yaku, Hidenori; Furukawa, Yutaka; Nakagawa, Yoshihisa; Ando, Kenji; Kadota, Kazushige; Abe, Mitsuru; Nagao, Kazuya; Shizuta, Satoshi; Ono, Koh; Kimura, Takeshi

2017-01-01

In patients with ST-segment-elevation acute myocardial infarction (STEMI) who underwent primary percutaneous coronary intervention, long-term risks for cardiac and noncardiac death beyond acute phase of STEMI have not been thoroughly evaluated yet. We identified 3942 STEMI patients who had primary percutaneous coronary intervention within 24 hours after onset between January 2005 and December 2007 in the CREDO-Kyoto AMI registry (Coronary Revascularization Demonstrating Outcome study in Kyoto Acute Myocardial Infarction) and evaluated their short-term (within 6-month) and long-term (beyond 6-month) incidences and causes of deaths. The cumulative 5-year incidence of all-cause death in the current study population was 20.4% (cardiac death, 12.2% and noncardiac death, 9.4%, respectively). The vast majority of deaths were cardiac in origin within 6-month (cardiac death, 8.0% and noncardiac death, 0.9%), whereas noncardiac death accounted for nearly two thirds of all-cause death beyond 6-month (cardiac death, 4.6% and noncardiac death, 8.5%). In the stratified analysis according to age, the proportion of noncardiac death was similar regardless of age although the absolute mortality rate was higher with increasing age. By the multivariable Cox regression models, the independent risk factors of all-cause death were advanced age, cardiogenic shock, renal dysfunction, large infarct size, and anterior wall infarction within 6 months after STEMI, and advanced age, previous heart failure, renal dysfunction, and liver cirrhosis beyond 6 months after STEMI, respectively. In STEMI patients who underwent primary percutaneous coronary intervention, the long-term risk for cardiac death was relatively low compared with that for noncardiac death, which accounted for nearly two thirds of all-cause death beyond 6 months. © 2017 American Heart Association, Inc.

Endothelial dysfunction in the regulation of portal hypertension

PubMed Central

Iwakiri, Yasuko

2013-01-01

Portal hypertension is caused by an increased intrahepatic resistance, a major consequence of cirrhosis. Endothelial dysfunction in liver sinusoidal endothelial cells (LSECs) decreases the production of vasodilators, such as nitric oxide (NO) and favors vasoconstriction. This contributes to an increased vascular resistance in the intrahepatic/sinusoidal microcirculation. Portal hypertension, once developed, causes endothelial cell (EC) dysfunction in the extrahepatic, i.e. splanchnic and systemic, circulation. Unlike LSEC dysfunction, EC dysfunction in the splanchnic and systemic circulation overproduces vasodilator molecules, leading to arterial vasodilatation. In addition, portal hypertension leads to the formation of portosystemic collateral vessels. Both arterial vasodilatation and portosystemic collateral vessel formation exacerbate portal hypertension by increasing the blood flow through the portal vein. Pathologic consequences, such as esophageal varices and ascites, result. While the sequence of pathological vascular events in cirrhosis and portal hypertension have been elucidated, the underlying cellular and molecular mechanisms causing EC dysfunctions are not yet fully understood. This review article summarizes the current cellular and molecular studies on EC dysfunctions found during the development of cirrhosis and portal hypertension with a focus on intra- and extrahepatic circulation. The article ends by discussing future directions of study for EC dysfunctions. PMID:21745318

Loss of sirtuin 1 and mitofusin 2 contributes to enhanced ischemia/reperfusion injury in aged livers.

PubMed

Chun, Sung Kook; Lee, Sooyeon; Flores-Toro, Joseph; U, Rebecca Y; Yang, Ming-Jim; Go, Kristina L; Biel, Thomas G; Miney, Catherine E; Pierre Louis, Schiley; Law, Brian K; Law, Mary E; Thomas, Elizabeth M; Behrns, Kevin E; Leeuwenburgh, Christiaan; Kim, Jae-Sung

2018-05-17

Ischemia/reperfusion (I/R) injury is a causative factor contributing to morbidity and mortality during liver resection and transplantation. Livers from elderly patients have a poorer recovery from these surgeries, indicating reduced reparative capacity with aging. Mechanisms underlying this age-mediated hypersensitivity to I/R injury remain poorly understood. Here, we investigated how sirtuin 1 (SIRT1) and mitofusin 2 (MFN2) are affected by I/R in aged livers. Young (3 months) and old (23-26 months) male C57/BL6 mice were subjected to hepatic I/R in vivo. Primary hepatocytes isolated from each age group were also exposed to simulated in vitro I/R. Biochemical, genetic, and imaging analyses were performed to assess cell death, autophagy flux, mitophagy, and mitochondrial function. Compared to young mice, old livers showed accelerated liver injury following mild I/R. Reperfusion of old hepatocytes also showed necrosis, accompanied with defective autophagy, onset of the mitochondrial permeability transition, and mitochondrial dysfunction. Biochemical analysis indicated a near-complete loss of both SIRT1 and MFN2 after I/R in old hepatocytes, which did not occur in young cells. Overexpression of either SIRT1 or MFN2 alone in old hepatocytes failed to mitigate I/R injury, while co-overexpression of both proteins promoted autophagy and prevented mitochondrial dysfunction and cell death after reperfusion. Genetic approaches with deletion and point mutants revealed that SIRT1 deacetylated K655 and K662 residues in the C-terminus of MFN2, leading to autophagy activation. The SIRT1-MFN2 axis is pivotal during I/R recovery and may be a novel therapeutic target to reduce I/R injury in aged livers. © 2018 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

Ultrasonic diagnosis of patients with clonorchiasis and preliminary study of pathogenic mechanism.

PubMed

Fan, Mei; Lu, Lin; Su, Chun; Xue, Mei; Dou, Ji-Mei; Li, Pei; Feng, Han-Qi; Fan, Yan-Bing

2016-07-01

To discuss the liver function damage mechanism of patients with clonorchiasis by analyzing the ultrasound characteristics, liver function, change of the serum inflammatory factors and cell apoptosis factors. Color Doppler ultrasound technique was adopted to detect the portal vein and blood flow change of patients with clonorchiasis; ELISA was used to determine the level of different serum inflammatory factors. The levels of serum total bilirubin, serum albumin and glutamic-pyruvic transaminase were detected by automatic biochemical analyzer. Western blot was used to determine the expression of proteins relevant to apoptosis. Compared with the health control group, the trunk diameter of portal vein and the thickness of spleen, as well as the hepatic artery pulsation index of clonorchiasis patients increased obviously, the mean blood flow velocity of portal vein (P < 0.05 or P < 0.01) decreased. The content of total bilirubin and transaminase in plasma increased significantly, but albumin decreased (P < 0.05). Levels of TNF-α, IL-6 and IFN-γ increased remarkably, and the level of every factor was significantly different among patients with Child-Pugh , Child-Pugh II and Child-Pugh III classification of liver function (P < 0.05 or P < 0.01). With the exacerbation of liver dysfunction, levels of TNF-α, IL-6 and IFN-γ gradually increased (P < 0.05). Compared with the healthy control group, the expression quantity of apoptosis protein Fas, FasL, Bax and Caspase-3 increased significantly (P < 0.05 or P < 0.01), but Bcl-2 decreased (P < 0.05). Changes of ultrasonic characteristics and liver dysfunction, caused by liver fluke infection, may be related to that both inflammatory response and apoptosis response have participated in the pathogenic process and liver damage course of clonorchiasis. Copyright © 2016 Hainan Medical College. Production and hosting by Elsevier B.V. All rights reserved.

Interaction of Gender and Hepatitis C in Risk of Chronic Renal Failure After Liver Transplantation.

PubMed

Ip, Stephen; Hussaini, Trana; Daulat, Aliya; Partovi, Nilufar; Erb, Siegfried R; Yoshida, Eric M; Marquez, Vladimir

2017-01-01

Chronic renal failure (CRF) is a significant cause of morbidity and mortality in post-liver transplantation (LT) recipients. The risk factors associated with the development of renal dysfunction are not clearly elucidated. To examine the risk factors in the development of CRF in these patients. Retrospective case-cohort of liver transplant patients without baseline kidney dysfunction who developed chronic renal failure during their follow-up. Of 370 patients, 254 met the inclusion criteria. 30% (76) of these patients had CRF of which 57% (43) were male. Age, estimated glomerular filtration rate (eGFR) at discharge, and HCV infection were found to be risk factors for CRF post-LT. The odds ratio of developing CRF was 1.4 (0.6-3.3) in males with HCV, 1.6 (0.7-3.9) in females without HCV and 4.4 (1.5-13.2) among females with HCV when compared to men without HCV. In this cohort of LT receipients of a major Canadian city, age, eGFR, and HCV infection were risk factors for CRF. Female gender and HCV increased this odds by a factor of more than 4.

Antibiotic tigecycline enhances cisplatin activity against human hepatocellular carcinoma through inducing mitochondrial dysfunction and oxidative damage

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tan, Jun; Song, Meijun; Zhou, Mi

Targeting mitochondrial metabolism has been recently demonstrated to be a promising therapeutic strategy for the treatment of various cancer. In this work, we demonstrate that antibiotic tigecycline is selectively against hepatocellular carcinoma (HCC) through inducing mitochondrial dysfunction and oxidative damage. Tigecycline is more effective in inhibiting proliferation and inducing apoptosis of HCC than normal liver cells. Importantly, tigecycline significantly enhances the inhibitory effects of chemotherapeutic drug cisplatin in HCC in vitro and in vivo. Mechanistically, tigecycline specifically inhibits mitochondrial translation as shown by the decreased protein levels of Cox-1 and -2 but not Cox-4 or Grp78, and increased mRNA levels of Cox-1more » and -2 but not Cox-4 in HCC cells exposed to tigecycline. In addition, tigecycline significantly induces mitochondrial dysfunction in HCC cells via decreasing mitochondrial membrane potential, complex I and IV activities, mitochondrial respiration and ATP levels. Tigecycline also increases levels of mitochondrial superoxide, hydrogen peroxide and ROS levels. Consistent with oxidative stress, oxidative damage on DNA, protein and lipid are also observed in tigecycline-treated cells. Importantly, antioxidant N-acetyl-L-cysteine (NAC) reverses the effects of tigecycline, suggesting that oxidative stress is required for the action of tigecycline in HCC cells. We further show that HCC cells have higher level of mitochondrial biogenesis than normal liver cells which might explain the different sensitivity to tigecycline between HCC and normal liver cells. Our work is the first to demonstrate that tigecycline is a promising candidate for HCC treatment and highlight the therapeutic value of targeting mitochondrial metabolism in HCC. - Highlights: • Tigecycline selectively targets HCC in vitro and in vivo. • Tigecycline enhances HCC cell response to chemotherapeutic drug. • Tigecycline inhibits mitochondrial translation and functions in HCC cells. • Tigecycline induces oxidative stress and damage in HCC cells. • Mitochondrial biogenesis and respiration is higher in HCC than normal liver cells.« less

Structural and functional abnormalities of hepatic tissues in male Wistar rats fed hyperwhey and super amino anabolic protein.

PubMed

Ali, Doaa A; El-Sayyad, Hassan I H; Moftah, Osama A; Chilibeck, Phil D

2016-01-01

Athletes and bodybuilders consume high-protein supplements to obtain energy and enhance the development and strength of their muscles. Over time, different investigations have revealed dysfunctions of their body organs. There are contradictions among scientists concerning the benefits and the alarm of developing body dysfunction. The aim of this study was to illustrate the effects on consumption of two anabolic protein supplements on body weight and structure and function of hepatocytes in male albino Wistar rats. We assigned male Wistar albino rats into three groups (n = 10 each): control, hyperwhey protein (Nutrabolics, Richmond, Canada) (2.5 g/kg body weight), and super amino 2500 (SA) (APN, Ft. Launderale, FL, USA) (2.5 g/kg body weight). The applied dose was orally administered daily in tap water for 14 wk. Body weight was regularly measured. At 14 wk, animals were sacrificed and dissected. Blood was collected from a puncture of the heart and the liver was removed and weighed. Biochemical analysis of liver function tests, lipidogram, hematology, histopathology, transmission electron microscopy, immunohistochemistry of proliferating cell nuclear antigen, B-cell lymphoma 2 and 70 kd heat shock proteins, and flow-cytometry of hepatocyte cell cycle were performed. Hyperwhey- and SA-supplemented rats had lower body weight gain compared with the control group and developed hepatic dysfunction manifested by apparent congestion of blood vessel, increased apoptosis, and breakdown of hepatocytes. The SA group had thickening of the liver capsule and more drastic damage of hepatocytes. The level of transaminases was markedly increased. Insulin level was also markedly decreased in parallel with increase cholesterol, low-density lipoprotein, and triacylglycerols. Hyperwhey and SA protein formula administration dramatically altered the liver function and increased hepatic damage similar to the development of suspected diabetes. Copyright © 2016 Elsevier Inc. All rights reserved.

Living donor liver transplantation in children: should the adult donor be operated on by an adult or pediatric surgeon? Experience of a single pediatric center.

PubMed

Andrade, Wagner de Castro; Velhote, Manoel Carlos Prieto; Ayoub, Ali Ahman; Silva, Marcos Marques; Gibelli, Nelson Elias M; Tannuri, Ana Cristina A; Santos, Maria Merces; Pinho-Apezzato, Maria Lucia; de Barros, Fabio; Moreira, Daniel Rangel; Miyatani, Helena T; Pereira, Raimundo Renato; Tannuri, Uenis

2014-04-01

Living donor liver transplantation has become a cornerstone for the treatment of children with end-stage hepatic dysfunction, especially within populations or countries with low rates of organ utilization from deceased donors. The objective is to report our experience with 185 living donors operated on by a team pediatric surgeons in a tertiary center for pediatric liver transplantation. Retrospective analysis of medical records of donors of hepatic grafts for transplant undergoing surgery between June 1998 and March 2013. Over the last 14 years, 185 liver transplants were performed in pediatric recipients of grafts from living donors. Among the donors, 166 left lateral segments (89.7%), 18 left lobes without the caudate lobe (9.7%) and 1 right lobe (0.5%) were harvested. The donor age ranged from 16 to 53 years, and the weight ranged from 47 to 106 kg. In 10 donors, an additional graft of the donor inferior mesenteric vein was harvested to substitute for a hypoplastic recipient portal vein. The transfusion of blood products was required in 15 donors (8.1%). The mean hospital stay was 5 days. No deaths occurred, but complications were identified in 23 patients (12.4%): 9 patients experienced abdominal pain and severe gastrointestinal symptoms and 3 patients required reoperations. Eight donors presented with minor bile leaks that were treated conservatively, and 3 patients developed extra-peritoneal infections (1 wound collection, 1 phlebitis and 1 pneumonia). Eight grafts (4.3%) showed primary dysfunction resulting in recipient death (3 cases of fulminant hepatitis, 1 patient with metabolic disease, 1 patient with Alagille syndrome and 3 cases of biliary atresia in infants under 1 year old). There was no relation between donor complications and primary graft dysfunction (P=0.6). Living donor transplantation is safe for the donor and presents a low morbidity. The donor surgery may be performed by a team of trained pediatric surgeons. © 2014.

Rat liver mitochondrial dysfunction by addition of copper(II) or iron(III) ions.

PubMed

Saporito-Magriñá, Christian; Musacco-Sebio, Rosario; Acosta, Juan M; Bajicoff, Sofía; Paredes-Fleitas, Paola; Boveris, Alberto; Repetto, Marisa G

2017-01-01

Increased copper (Cu) and iron (Fe) levels in liver and brain are associated to oxidative stress and damage with increased phospholipid oxidation process. The aim of this work was to assess the toxic effects of Cu 2+ and Fe 3+ addition to rat liver mitochondria by determining mitochondrial respiration in states 3 (active respiration) and 4 (resting respiration), and phospholipid peroxidation. Both, Cu 2+ and Fe 3+ produced decreases in O 2 consumption in a concentration-dependent manner in active state 3: both ions by 42% with malate-glutamate as complex I substrate (concentration for half maximal response (C 50 ) 60μM Cu 2+ and 1.25mM Fe 3+ ), and with succinate as complex II substrate: 64-69% with C 50 of 50μM Cu 2+ and with C 50 of 1.25mM of Fe 3+ . Respiratory control decreased with Cu 2+ (C 50 50μM) and Fe 3+ (C 50 1.25-1-75mM) with both substrates. Cu 2+ produced a 2-fold increase and Fe 3+ a 5-fold increase of thiobarbituric acid-reactive substances (TBARS) content from 25μM Cu 2+ (C 50 40μM) and from 100μM Fe 3+ (C 50 1.75mM). Supplementations with Cu 2+ and Fe 3+ ions induce mitochondrial dysfunction with phospholipid peroxidation in rat liver mitochondria. Although is proved that a Fenton/Haber Weiss mechanism of oxidative damage occurs in metal-ion induced mitochondrial toxicity, slightly different responses to the metal ions suggest some differences in the mechanism of intracellular toxicity. The decreased rates of mitochondrial respiration and the alteration of mitochondrial function by phospholipid and protein oxidations lead to mitochondrial dysfunction, cellular dyshomeostasis and cell death. Copyright © 2016 Elsevier Inc. All rights reserved.

Influence of polymorphisms within the methotrexate pathway genes on the toxicity and efficacy of methotrexate in patients with juvenile idiopathic arthritis

PubMed Central

Yanagimachi, Masakatsu; Naruto, Takuya; Hara, Takuma; Kikuchi, Masako; Hara, Ryoki; Miyamae, Takako; Imagawa, Tomoyuki; Mori, Masaaki; Kaneko, Tetsuji; Morita, Satoshi; Goto, Hiroaki; Yokota, Shumpei

2011-01-01

AIMS We investigated whether several polymorphisms within the methotrexate (MTX) pathway genes were related to the toxicity and efficacy of MTX in 92 Japanese patients with articular-type juvenile idiopathic arthritis (JIA). METHODS Eight gene polymorphisms within the MTX pathway genes, namely, RFC, BCRP, MTHFR (two), FPGS, γ-glutamyl hydrolase (GGH; two) and ATIC, were genotyped using TaqMan assays. Liver dysfunction was defined as an increase in alanine transaminase to five times the normal upper limit. Non-responders to MTX were defined as patients refractory to MTX and were therefore treated with biologics. RESULTS The non-TT genotype at GGH T16C was associated with a high risk of liver dysfunction (P = 0.028, odds ratio = 6.90, 95% confidence interval 1.38–34.5), even after adjustment for the duration of MTX treatment. A longer interval from disease onset to treatment (8.5 and 21.3 months, P = 0.029) and rheumatoid factor positivity (P = 0.026, odds ratio = 2.87, 95% confidence interval 1.11–7.39) were associated with lower efficacy of MTX. CONCLUSIONS The non-TT genotype at GGH T16C was associated with a high risk of liver dysfunction, presumably because the C allele of GGH C16T may reduce the activity of GGH. The time interval before MTX treatment and rheumatoid factor positivity were associated with the efficacy of MTX treatment. The pharmacogenetics of the MTX pathway genes affects the toxicity and efficacy of MTX in Japanese JIA patients. PMID:21219404

Early obesity leads to increases in hepatic arginase I and related systemic changes in nitric oxide and L-arginine metabolism in mice.

PubMed

Ito, Tatsuo; Kubo, Masayuki; Nagaoka, Kenjiro; Funakubo, Narumi; Setiawan, Heri; Takemoto, Kei; Eguchi, Eri; Fujikura, Yoshihisa; Ogino, Keiki

2018-02-01

Obesity is a risk factor for vascular endothelial cell dysfunction characterized by low-grade, chronic inflammation. Increased levels of arginase I and concomitant decreases in L-arginine bioavailability are known to play a role in the pathogenesis of vascular endothelial cell dysfunction. In the present study, we focused on changes in the systemic expression of arginase I as well as L-arginine metabolism in the pre-disease state of early obesity prior to the onset of atherosclerosis. C57BL/6 mice were fed a control diet (CD; 10% fat) or high-fat diet (HFD; 60% fat) for 8 weeks. The mRNA expression of arginase I in the liver, adipose tissue, aorta, and muscle; protein expression of arginase I in the liver and plasma; and systemic levels of L-arginine bioavailability and NO 2 - were assessed. HFD-fed mice showed early obesity without severe disease symptoms. Arginase I mRNA and protein expression levels in the liver were significantly higher in HFD-fed obese mice than in CD-fed mice. Arginase I levels were slightly increased, whereas L-arginine levels were significantly reduced, and these changes were followed by reductions in NO 2 - levels. Furthermore, hepatic arginase I levels positively correlated with plasma arginase I levels and negatively correlated with L-arginine bioavailability in plasma. These results suggested that increases in the expression of hepatic arginase I and reductions in plasma L-arginine and NO 2 - levels might lead to vascular endothelial dysfunction in the pre-disease state of early obesity.

Glucose fluctuation increased hepatocyte apoptosis under lipotoxicity and the involvement of mitochondrial permeability transition opening.

PubMed

Yin, Xueyao; Zheng, Fenping; Pan, Qianqian; Zhang, Saifei; Yu, Dan; Xu, Zhiye; Li, Hong

2015-12-01

Oxidative stress is considered to be an important factor in producing lethal hepatocyte injury associated with nonalcoholic fatty liver disease (NAFLD). Glucose fluctuation, more pronounced in patients with diabetes, has been recognized as an even stronger oxidative stress inducer than the sustained hyperglycemia. Here, we investigated the role of glucose variability in the development of the NAFLD based on hepatocyte apoptosis and possible mechanisms. To achieve this goal we studied C57BL/6J mice that were maintained on a high fat diet (HFD) and injected with glucose (3 g/kg) twice daily to induce intermittent high glucose (IHG). We also studied hepatic L02 cells incubated with palmitic acid (PA) to induce steatosis. The following experimental groups were compared: normal glucose (NG), sustained high glucose (SHG) and IHG with or without PA. We found that, although hepatic enzyme levels and liver lipid deposition were comparable between HFD mice injected with glucose or saline, the glucose injected mice displayed marked hepatocyte apoptosis and inflammation, accompanied by increased lipid peroxide in liver. In vitro, in the presence of PA, IHG increased L02 cell apoptosis and oxidative stress and produced pronounced mitochondrial dysfunction relative to the NG and SHG groups. Furthermore, treatment with the mitochondrial permeability transition (MPT) inhibitor, cyclosporin A (1.5 μmol/l), prevented mitochondrial dysfunction, oxidative stress and hepatocyte apoptosis. Our data suggests that IHG under lipotoxicity might contribute to the development of NAFLD by increasing oxidative stress and hepatocyte apoptosis via MPT and its related mitochondrial dysfunction. © 2015 Society for Endocrinology.

Current Status of Herbal Medicines in Chronic Liver Disease Therapy: The Biological Effects, Molecular Targets and Future Prospects

PubMed Central

Hong, Ming; Li, Sha; Tan, Hor Yue; Wang, Ning; Tsao, Sai-Wah; Feng, Yibin

2015-01-01

Chronic liver dysfunction or injury is a serious health problem worldwide. Chronic liver disease involves a wide range of liver pathologies that include fatty liver, hepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma. The efficiency of current synthetic agents in treating chronic liver disease is not satisfactory and they have undesirable side effects. Thereby, numerous medicinal herbs and phytochemicals have been investigated as complementary and alternative treatments for chronic liver diseases. Since some herbal products have already been used for the management of liver diseases in some countries or regions, a systematic review on these herbal medicines for chronic liver disease is urgently needed. Herein, we conducted a review describing the potential role, pharmacological studies and molecular mechanisms of several commonly used medicinal herbs and phytochemicals for chronic liver diseases treatment. Their potential toxicity and side effects were also discussed. Several herbal formulae and their biological effects in chronic liver disease treatment as well as the underlying molecular mechanisms are also summarized in this paper. This review article is a comprehensive and systematic analysis of our current knowledge of the conventional medicinal herbs and phytochemicals in treating chronic liver diseases and on the potential pitfalls which need to be addressed in future study. PMID:26633388

Current Status of Herbal Medicines in Chronic Liver Disease Therapy: The Biological Effects, Molecular Targets and Future Prospects.

PubMed

Hong, Ming; Li, Sha; Tan, Hor Yue; Wang, Ning; Tsao, Sai-Wah; Feng, Yibin

2015-12-02

Chronic liver dysfunction or injury is a serious health problem worldwide. Chronic liver disease involves a wide range of liver pathologies that include fatty liver, hepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma. The efficiency of current synthetic agents in treating chronic liver disease is not satisfactory and they have undesirable side effects. Thereby, numerous medicinal herbs and phytochemicals have been investigated as complementary and alternative treatments for chronic liver diseases. Since some herbal products have already been used for the management of liver diseases in some countries or regions, a systematic review on these herbal medicines for chronic liver disease is urgently needed. Herein, we conducted a review describing the potential role, pharmacological studies and molecular mechanisms of several commonly used medicinal herbs and phytochemicals for chronic liver diseases treatment. Their potential toxicity and side effects were also discussed. Several herbal formulae and their biological effects in chronic liver disease treatment as well as the underlying molecular mechanisms are also summarized in this paper. This review article is a comprehensive and systematic analysis of our current knowledge of the conventional medicinal herbs and phytochemicals in treating chronic liver diseases and on the potential pitfalls which need to be addressed in future study.

Donation after cardio-circulatory death liver transplantation

PubMed Central

Le Dinh, Hieu; de Roover, Arnaud; Kaba, Abdour; Lauwick, Séverine; Joris, Jean; Delwaide, Jean; Honoré, Pierre; Meurisse, Michel; Detry, Olivier

2012-01-01

The renewed interest in donation after cardio-circulatory death (DCD) started in the 1990s following the limited success of the transplant community to expand the donation after brain-death (DBD) organ supply and following the request of potential DCD families. Since then, DCD organ procurement and transplantation activities have rapidly expanded, particularly for non-vital organs, like kidneys. In liver transplantation (LT), DCD donors are a valuable organ source that helps to decrease the mortality rate on the waiting lists and to increase the availability of organs for transplantation despite a higher risk of early graft dysfunction, more frequent vascular and ischemia-type biliary lesions, higher rates of re-listing and re-transplantation and lower graft survival, which are obviously due to the inevitable warm ischemia occurring during the declaration of death and organ retrieval process. Experimental strategies intervening in both donors and recipients at different phases of the transplantation process have focused on the attenuation of ischemia-reperfusion injury and already gained encouraging results, and some of them have found their way from pre-clinical success into clinical reality. The future of DCD-LT is promising. Concerted efforts should concentrate on the identification of suitable donors (probably Maastricht category III DCD donors), better donor and recipient matching (high risk donors to low risk recipients), use of advanced organ preservation techniques (oxygenated hypothermic machine perfusion, normothermic machine perfusion, venous systemic oxygen persufflation), and pharmacological modulation (probably a multi-factorial biologic modulation strategy) so that DCD liver allografts could be safely utilized and attain equivalent results as DBD-LT. PMID:22969222

Liver transplantation for hepatocellular carcinoma: a surgical perspective.

PubMed

Fortune, Brett E; Umman, Veysel; Gilliland, Thomas; Emre, Sukru

2013-07-01

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality in the world. Early detection and timely treatment of HCC is critical for better patient outcomes. Curative therapy consists of surgical hepatic resection or liver transplantation (LTx); however, both are restricted to explicit selective criteria. Liver resection is the gold standard of treatment for noncirrhotic patients but can be done in only a small fraction of cirrhotic patients depending on synthetic dysfunction, degree of portal hypertension, and number and location(s) of tumor(s). Therefore, the best treatment modality in cirrhotic patients with HCC is LTx as it will cure both HCC and the underlying cirrhosis. The limitation to offer transplant to all cirrhotic patients with HCC is the shortage of available donor organs. While these patients are waiting for transplant, their tumors may progress and develop distant metastases and may lead to patients losing their candidacy for LTx. Various ablation therapies can be used to treat HCC, prevent tumor progression, and thus, avoid patients losing the option of LTx. Future directions to improve HCC patient outcomes include advancement in tumor gene analysis and histopathology for better prediction of tumor behavior, improved immunosuppression regimens to reduce tumor recurrence in the posttransplant setting, and efficient use of an expanded donor pool that includes living donor organs. This paper will review the current methods of HCC diagnosis, selection for either hepatic resection or LTx, and will also summarize posttreatment outcomes. We will suggest future directions for the field as we strive to improve outcomes for our HCC patients.

Advanced heart failure due to cancer therapy.

PubMed

Shah, Sachin; Nohria, Anju

2015-01-01

Certain chemotherapeutic agents and mediastinal irradiation can be cardiotoxic and place cancer survivors at risk for developing advanced heart failure (HF). Anthracyclines are the prototypical agents associated with left ventricular (LV) dysfunction. Newer agents including trastuzumab and certain tyrosine kinase inhibitors such as sunitinib can also cause cardiomyopathy. Cancer survivors with advanced HF refractory to standard medical management should be considered for advanced therapies, including mechanical circulatory support (MCS) and transplantation. While overall outcomes after MCS and transplantation are similar in cancer survivors compared to other etiologies of HF, patients with radiation-induced restrictive cardiomyopathy have a significantly worse prognosis after transplantation. The increased need for right ventricular (RV) support after MCS in cancer survivors necessitates a careful evaluation for pre-operative RV dysfunction. Special consideration must also be given to the risk for recurrent malignancy, neurocognitive dysfunction, and increased psychological needs in this patient population.

PET-CT in Determining the Radioembolization Dose Delivered to Patients With Liver Metastasis, Primary Liver Cancer, or Biliary Cancer

ClinicalTrials.gov

2018-02-08

Adult Primary Hepatocellular Carcinoma; Advanced Adult Primary Liver Cancer; Metastatic Extrahepatic Bile Duct Cancer; Recurrent Adult Primary Liver Cancer; Recurrent Extrahepatic Bile Duct Cancer; Stage D Adult Primary Liver Cancer (BCLC); Unspecified Adult Solid Tumor, Protocol Specific

Spontaneous acute subdural hematoma and intracerebral hemorrhage in a patient with thrombotic microangiopathy during pregnancy.

PubMed

Wayhs, Sâmia Yasin; Wottrich, Joise; Uggeri, Douglas Prestes; Dias, Fernando Suparregui

2013-01-01

Preeclampsia, HELLP syndrome (hemolysis, elevated liver enzymes, and low-platelet count), and acute fatty liver of pregnancy are the main causes of thrombotic microangiopathy and evere liver dysfunction during pregnancy and represent different manifestations of the same pathological continuum. The case of a 35-week pregnant woman who was admitted to an intensive care unit immediately after a Cesarean section due to fetal death and the presence of nausea, vomiting, and jaundice is reported. Postpartum preeclampsia and acute fatty liver of pregnancy were diagnosed. The patient developed an acute subdural hematoma and an intracerebral hemorrhage, which were subjected to neurosurgical treatment. The patient died from refractory hemolytic anemia and spontaneous bleeding of multiple organs. Preeclampsia HELLP syndrome, and acute fatty liver of pregnancy might overlap and be associated with potentially fatal complications, including intracranial hemorrhage, as in the present case. Early detection and diagnosis are crucial to ensure management and treatment success.

Overextended Criteria Donors: Experience of an Italian Transplantation Center.

PubMed

Nure, E; Lirosi, M C; Frongillo, F; Bianco, G; Silvestrini, N; Fiorillo, C; Sganga, G; Agnes, S

2015-09-01

The increasing gap between the number of patients who could benefit from liver transplantation and the number of available donors has fueled efforts to maximize the donor pool using marginal grafts that usually were discarded for transplantation. This study included data of all patients who received decreased donor liver grafts between January 2004 and January 2013 (n = 218) with the use of a prospectively collected database. Patients with acute liver failure, retransplantation, pediatric transplantation, and split liver transplantation were excluded. Donors were classified as standard donor (SD), extended criteria donor (ECD), and overextended criteria donor (OECD). The primary endpoints of the study were early allograft primary dysfunction (PDF), primary nonfunction (PNF), and patient survival (PS), whereas incidence of major postoperative complications was the secondary endpoint. In our series we demonstrated that OECD have similar outcome in terms of survival and incidence of complication after liver transplantation as ideal grafts. Copyright © 2015 Elsevier Inc. All rights reserved.

Complications of cirrhosis. A 50 years flashback.

PubMed

Møller, Søren; Bendtsen, Flemming

2015-06-01

In patients with cirrhosis and portal hypertension, it is largely the frequency and severity of complications relating to the diseased liver, degree of portal hypertension and hemodynamic derangement that determine the prognosis. It can be considered as a multiple organ failure that apart from the liver involves the heart, lungs, kidneys, the immune systems and other organ systems. Progressive fibrosis of the liver and subsequent metabolic impairment leads to a systemic and splanchnic arteriolar vasodilatation. With the progression of the disease development of portal hypertension leads to formation of esophageal varices and ascites. The circulation becomes hyperdynamic with cardiac, pulmonary as well as renal consequences for dysfunction and reduced survival. Infections and a changed cardiac function known as cirrhotic cardiomyopathy may be involved in further aggravation of other complications such as renal failure precipitating the hepatorenal syndrome. Patients with end-stage liver disease and related complications as for example the hepatopulmonary syndrome can only radically be treated by liver transplantation.

Isoorientin induces apoptosis through mitochondrial dysfunction and inhibition of PI3K/Akt signaling pathway in HepG2 cancer cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yuan, Li; Wang, Jing; Xiao, Haifang

Isoorientin (ISO) is a flavonoid compound that can be extracted from several plant species, such as Phyllostachys pubescens, Patrinia, and Drosophyllum lusitanicum; however, its biological activity remains poorly understood. The present study investigated the effects and putative mechanism of apoptosis induced by ISO in human hepatoblastoma cancer (HepG2) cells. The results showed that ISO induced cell death in a dose-dependent manner in HepG2 cells, but no toxicity in human liver cells (HL-7702) and buffalo rat liver cells (BRL-3A) treated with ISO at the indicated concentrations. ISO-induced cell death included apoptosis which characterized by the appearance of nuclear shrinkage, the cleavagemore » of poly (ADP-ribose) polymerase (PARP) and DNA fragmentation. ISO significantly (p < 0.01) increased the Bax/Bcl-2 ratio, disrupted the mitochondrial membrane potential (MMP), increased the release of cytochrome c, activated caspase-3, and enhanced intracellular levels of reactive oxygen species (ROS) and nitric oxide (NO). In addition, ISO effectively inhibited the phosphorylation of Akt and increased FoxO4 expression. The PI3K/Akt inhibitor LY294002 enhanced the apoptosis-inducing effect of ISO. However, LY294002 markedly quenched ROS and NO generation and diminished the protein expression of heme peroxidase enzyme (HO-1) and inducible nitric oxide synthase (iNOS). Furthermore, the addition of a ROS inhibitor (N-acetyl cysteine, NAC) or iNOS inhibitor (N-[3-(aminomethyl) benzyl] acetamidine, dihydrochloride, 1400W) significantly diminished the apoptosis induced by ISO and also blocked the phosphorylation of Akt. These results demonstrated for the first time that ISO induces apoptosis in HepG2 cells and indicate that this apoptosis might be mediated through mitochondrial dysfunction and PI3K/Akt signaling pathway, and has no toxicity in normal liver cells, suggesting that ISO may have good potential as a therapeutic and chemopreventive agent for liver cancer. Highlights: ► Isoorientin induced apoptosis in HepG2 cells. ► Isoorientin disordered mitochondrial function and inhibited PI3K/AKt pathway. ► PI3K/Akt pathway mediated mitochondrial dysfunction via Bcl-2 family members. ► Isoorientin stimulated the intracellular ROS and NO generation in HepG2 cells. ► ROS and NO initiated mitochondria dysfunction and involved in PI3K/Akt pathway.« less

Long-Term Follow-Up After Successful Transjugular Intrahepatic Portosystemic Shunt Placement in a Pediatric Patient with Budd-Chiari Syndrome

DOE Office of Scientific and Technical Information (OSTI.GOV)

Carnevale, Francisco Cesar, E-mail: fcarnevale@uol.com.br; Szejnfeld, Denis, E-mail: denis@cura.com.br; Moreira, Airton Mota

Orthotopic liver transplantation is the standard of care in patients with Budd-Chiari syndrome (BCS), and transjugular intrahepatic portosystemic shunt (TIPS) has become an important adjunct procedure while the patient is waiting for a liver. No long-term follow up of TIPS in BCS patients has been published in children. We report successful 10-year follow-up of a child with BCS and iatrogenic TIPS dysfunction caused by oral contraceptive use.

A novel 2-step approach combining the NAFLD fibrosis score and liver stiffness measurement for predicting advanced fibrosis.

PubMed

Chan, Wah-Kheong; Nik Mustapha, Nik Raihan; Mahadeva, Sanjiv

2015-10-01

The non-alcoholic fatty liver disease (NAFLD) fibrosis score (NFS) is indeterminate in a proportion of NAFLD patients. Combining the NFS with liver stiffness measurement (LSM) may improve prediction of advanced fibrosis. We aim to evaluate the NFS and LSM in predicting advanced fibrosis in NAFLD patients. The NFS was calculated and LSM obtained for consecutive adult NAFLD patients scheduled for liver biopsy. The accuracy of predicting advanced fibrosis using either modality and in combination were assessed. An algorithm combining the NFS and LSM was developed from a training cohort and subsequently tested in a validation cohort. There were 101 and 46 patients in the training and validation cohort, respectively. In the training cohort, the percentages of misclassifications using the NFS alone, LSM alone, LSM alone (with grey zone), both tests for all patients and a 2-step approach using LSM only for patients with indeterminate and high NFS were 5.0, 28.7, 2.0, 2.0 and 4.0 %, respectively. The percentages of patients requiring liver biopsy were 30.7, 0, 36.6, 36.6 and 18.8 %, respectively. In the validation cohort, the percentages of misclassifications were 8.7, 28.3, 2.2, 2.2 and 8.7 %, respectively. The percentages of patients requiring liver biopsy were 28.3, 0, 41.3, 43.5 and 19.6 %, respectively. The novel 2-step approach further reduced the number of patients requiring a liver biopsy whilst maintaining the accuracy to predict advanced fibrosis. The combination of NFS and LSM for all patients provided no apparent advantage over using either of the tests alone.

Prospective comparison of magnetic resonance imaging to transient elastography and serum markers for liver fibrosis detection.

PubMed

Dyvorne, Hadrien A; Jajamovich, Guido H; Bane, Octavia; Fiel, M Isabel; Chou, Hsin; Schiano, Thomas D; Dieterich, Douglas; Babb, James S; Friedman, Scott L; Taouli, Bachir

2016-05-01

Establishing accurate non-invasive methods of liver fibrosis quantification remains a major unmet need. Here, we assessed the diagnostic value of a multiparametric magnetic resonance imaging (MRI) protocol including diffusion-weighted imaging (DWI), dynamic contrast-enhanced (DCE)-MRI and magnetic resonance elastography (MRE) in comparison with transient elastography (TE) and blood tests [including ELF (Enhanced Liver Fibrosis) and APRI] for liver fibrosis detection. In this single centre cross-sectional study, we prospectively enrolled 60 subjects with liver disease who underwent multiparametric MRI (DWI, DCE-MRI and MRE), TE and blood tests. Correlation was assessed between non-invasive modalities and histopathologic findings including stage, grade and collagen content, while accounting for covariates such as age, sex, BMI, HCV status and MRI-derived fat and iron content. ROC curve analysis evaluated the performance of each technique for detection of moderate-to-advanced liver fibrosis (F2-F4) and advanced fibrosis (F3-F4). Magnetic resonance elastography provided the strongest correlation with fibrosis stage (r = 0.66, P < 0.001), inflammation grade (r = 0.52, P < 0.001) and collagen content (r = 0.53, P = 0.036). For detection of moderate-to-advanced fibrosis (F2-F4), AUCs were 0.78, 0.82, 0.72, 0.79, 0.71 for MRE, TE, DCE-MRI, DWI and APRI, respectively. For detection of advanced fibrosis (F3-F4), AUCs were 0.94, 0.77, 0.79, 0.79 and 0.70, respectively. Magnetic resonance elastography provides the highest correlation with histopathologic markers and yields high diagnostic performance for detection of advanced liver fibrosis and cirrhosis, compared to DWI, DCE-MRI, TE and serum markers. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Long-term management of cirrhosis. Appropriate supportive care is both critical and difficult.

PubMed

Habib, A; Bond, W M; Heuman, D M

2001-03-01

Orthotopic liver transplantation has emerged as an important treatment option for patients with advanced liver disease. However, each year the number of new cases of cirrhosis exceeds the number of livers available for transplantation by a factor of 5 to 10. This translates into long waiting lists and restrictive criteria for selecting transplant recipients. Until advances in surgical technique or biotechnology increase the availability of organs for transplantation, the majority of patients with advanced liver disease will have to be managed medically for years--perhaps indefinitely. Early consultation with a liver transplant center can be helpful. The transplant hepatologist and surgeon can help with triage decisions, guide workup, provide advice about patient care, optimize the timing of transplantation, offer specialized diagnostic and therapeutic options, and help the treating physician stay abreast of the continuous changes in this complex field. In the final analysis, however, it is often the skill and diligence of the primary care physician in diagnosing liver disease, identifying and treating correctable causes, optimizing the patient's health and nutrition, and anticipating and preventing catastrophic complications that determine whether the patient lives or dies.

Serum gastrin concentrations in dogs with liver disorders.

PubMed

Mazaki-Tovi, M; Segev, G; Yas-Natan, E; Lavy, E

2012-07-07

Dogs with liver disorders often display gastrointestinal signs that may be triggered by ulceration. The liver is important for inactivation of some forms of gastrin. Therefore, hypergastrinaemia has been implicated in the pathogenesis of gastrointestinal ulcerations related to liver dysfunction. The aim of this study was to determine serum gastrin concentrations in dogs with liver disease. Fasted blood samples were collected from 15 dogs with newly diagnosed liver disease and 18 healthy dogs. Gastrin concentrations were significantly lower in dogs with congenital portosystemic shunt compared with healthy dogs (P=0.003). No significant difference (P=0.6) in gastrin concentration was revealed between dogs with hepatocellular disease and healthy dogs. Serum gastrin concentrations were not significantly associated with the occurrence of vomiting, anorexia, diarrhoea, or melaena in dogs with liver disorders. These findings did not provide support for the role of hypergastrinaemia in the development of gastrointestinal signs associated with liver disease in dogs. Decreased serum concentrations of gastrin in a dog with liver disease may suggest the presence of portosystemic shunt. Further investigation is warranted to determine the importance of hyopogastrinaemia in congenital postosystemic shunts in dogs and to evaluate potential alterations in serum gastrin concentrations in specific hepatocellular diseases.

Silymarin/Silybin and Chronic Liver Disease: A Marriage of Many Years.

PubMed

Federico, Alessandro; Dallio, Marcello; Loguercio, Carmelina

2017-01-24

Silymarin is the extract of Silybum marianum , or milk thistle, and its major active compound is silybin, which has a remarkable biological effect. It is used in different liver disorders, particularly chronic liver diseases, cirrhosis and hepatocellular carcinoma, because of its antioxidant, anti-inflammatory and antifibrotic power. Indeed, the anti-oxidant and anti-inflammatory effect of silymarin is oriented towards the reduction of virus-related liver damages through inflammatory cascade softening and immune system modulation. It also has a direct antiviral effect associated with its intravenous administration in hepatitis C virus infection. With respect to alcohol abuse, silymarin is able to increase cellular vitality and to reduce both lipid peroxidation and cellular necrosis. Furthermore, silymarin/silybin use has important biological effects in non-alcoholic fatty liver disease. These substances antagonize the progression of non-alcoholic fatty liver disease, by intervening in various therapeutic targets: oxidative stress, insulin resistance, liver fat accumulation and mitochondrial dysfunction. Silymarin is also used in liver cirrhosis and hepatocellular carcinoma that represent common end stages of different hepatopathies by modulating different molecular patterns. Therefore, the aim of this review is to examine scientific studies concerning the effects derived from silymarin/silybin use in chronic liver diseases, cirrhosis and hepatocellular carcinoma.

Enhanced liver fibrosis test using ELISA assay accurately discriminates advanced stage of liver fibrosis as determined by transient elastography fibroscan in treatment naïve chronic HCV patients.

PubMed

Omran, Dalia; Yosry, Ayman; Darweesh, Samar K; Nabeel, Mohammed M; El-Beshlawey, Mohammed; Saif, Sameh; Fared, Azza; Hassany, Mohamed; Zayed, Rania A

2018-02-01

Evaluation of liver fibrosis stage is crucial in the assessment of chronic HCV patients, regarding decision to start treatment and during follow-up. Our aim was to assess the validity of the enhanced liver fibrosis (ELF) score in discrimination of advanced stage of liver fibrosis in naïve chronic HCV patients. We prospectively evaluated liver fibrosis stage in one hundred eighty-one naïve chronic HCV Egyptian patients by transient elastography (TE)-FibroScan. Patients were categorized into mild to moderate fibrosis (≤F2) group and advanced fibrosis (≥F3) group. The ELF score components, hyaluronic acid (HA), amino-terminal propeptide of type-III-procollagen (PIIINP) and tissue inhibitor of metalloproteinase type-1 (TIMP-1), were done using ELISA test. The mean values of ELF and its individual components significantly correlated with the hepatic fibrosis stage as measured by TE-FibroScan (P value 0.001). ELF cutoff value of 9.8 generated a sensitivity of 77.8%, specificity of 67.1%, area under the receiver operator characteristic curve (AUROC) of 0.76 with 95% confidence interval [CI] (0.68-0.83) for detecting advanced fibrosis (F ≥ 3). ELF panel is a good, reliable noninvasive test and showed comparable results to TE-FibroScan in detecting liver fibrosis stage in treatment naïve chronic HCV patients.

Physiological Aging: Links Among Adipose Tissue Dysfunction, Diabetes, and Frailty.

PubMed

Stout, Michael B; Justice, Jamie N; Nicklas, Barbara J; Kirkland, James L

2017-01-01

Advancing age is associated with progressive declines in physiological function that lead to overt chronic disease, frailty, and eventual mortality. Importantly, age-related physiological changes occur in cellularity, insulin-responsiveness, secretory profiles, and inflammatory status of adipose tissue, leading to adipose tissue dysfunction. Although the mechanisms underlying adipose tissue dysfunction are multifactorial, the consequences result in secretion of proinflammatory cytokines and chemokines, immune cell infiltration, an accumulation of senescent cells, and an increase in senescence-associated secretory phenotype (SASP). These processes synergistically promote chronic sterile inflammation, insulin resistance, and lipid redistribution away from subcutaneous adipose tissue. Without intervention, these effects contribute to age-related systemic metabolic dysfunction, physical limitations, and frailty. Thus adipose tissue dysfunction may be a fundamental contributor to the elevated risk of chronic disease, disability, and adverse health outcomes with advancing age. ©2017 Int. Union Physiol. Sci./Am. Physiol. Soc.

Repopulation of the fibrotic/cirrhotic rat liver by transplanted hepatic stem/progenitor cells and mature hepatocytes

PubMed Central

Yovchev, Mladen I.; Xue, Yuhua; Shafritz, David A.; Locker, Joseph; Oertel, Michael

2013-01-01

Background & Aim Considerable progress has been made in developing anti-fibrotic agents and other strategies to treat liver fibrosis; however, significant long-term restoration of functional liver mass has not yet been achieved. Therefore, we investigated whether transplanted hepatic stem/progenitor cells can effectively repopulate the liver with advanced fibrosis/cirrhosis. Methods Stem/progenitor cells derived from fetal livers or mature hepatocytes from DPPIV+ F344 rats were transplanted into DPPIV− rats with thioacetamide (TAA)-induced fibrosis/cirrhosis; rats were sacrificed 1, 2, or 4 months later. Liver tissues were analyzed by histochemistry, hydroxyproline determination, RT-PCR, and immunohistochemistry. Results After chronic TAA administration, DPPIV− F344 rats exhibited progressive fibrosis, cirrhosis and severe hepatocyte damage. Besides stellate cell activation, increased numbers of stem/progenitor cells (Dlk-1+, AFP+, CD133+, Sox-9+, FoxJ1+) were observed. In conjunction with partial hepatectomy (PH), transplanted stem/progenitor cells engrafted, proliferated competitively compared to host hepatocytes, differentiated into hepatocytic and biliary epithelial cells, and generated new liver mass with extensive long-term liver repopulation (40.8 ± 10.3%). Remarkably, more than 20% liver repopulation was achieved in the absence of PH, associated with reduced fibrogenic activity (e.g., expression of α-SMA, PDGFRβ, desmin, vimentin, TIMP1) and fibrosis (reduced collagen). Furthermore, hepatocytes can also replace liver mass with advanced fibrosis/cirrhosis, but to a lesser extent than FLSPCs. Conclusions This study is a Proof of Principle demonstration that transplanted epithelial stem/progenitor cells can restore injured parenchyma in a liver environment with advanced fibrosis/cirrhosis and exhibit anti-fibrotic effects. PMID:23840008

Small for Size and Flow (SFSF) syndrome: An alternative description for posthepatectomy liver failure.

PubMed

Golriz, Mohammad; Majlesara, Ali; El Sakka, Saroa; Ashrafi, Maryam; Arwin, Jalal; Fard, Nassim; Raisi, Hanna; Edalatpour, Arman; Mehrabi, Arianeb

2016-06-01

Small for Size Syndrome (SFSS) syndrome is a recognizable clinical syndrome occurring in the presence of a reduced mass of liver, which is insufficient to maintain normal liver function. A definition has yet to be fully clarified, but it is a common clinical syndrome following partial liver transplantation and extended hepatectomy, which is characterized by postoperative liver dysfunction with prolonged cholestasis and coagulopathy, portal hypertension, and ascites. So far, this syndrome has been discussed with focus on the remnant size of the liver after partial liver transplantation or extended hepatectomy. However, the current viewpoints believe that the excessive flow of portal vein for the volume of the liver parenchyma leads to over-pressure, sinusoidal endothelial damages and haemorrhage. The new hypothesis declares that in both extended hepatectomy and partial liver transplantation, progression of Small for Size Syndrome is not determined only by the "size" of the liver graft or remnant, but by the hemodynamic parameters of the hepatic circulation, especially portal vein flow. Therefore, we suggest the term "Small for Size and Flow (SFSF)" for this syndrome. We believe that it is important for liver surgeons to know the pathogenesis and manifestation of this syndrome to react early enough preventing non-reversible tissue damages. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Epidermal growth factor receptor restoration rescues the fatty liver regeneration in mice.

PubMed

Zimmers, Teresa A; Jin, Xiaoling; Zhang, Zongxiu; Jiang, Yanlin; Koniaris, Leonidas G

2017-10-01

Hepatic steatosis is a common histological finding in obese patients. Even mild steatosis is associated with delayed hepatic regeneration and poor outcomes following liver resection or transplantation. We sought to identify and target molecular pathways that mediate this dysfunction. Lean mice and mice made obese through feeding of a high-fat, hypercaloric diet underwent 70 or 80% hepatectomy. After 70% resection, obese mice demonstrated 100% survival but experienced increased liver injury, reduced energy stores, reduced mitoses, increased necroapoptosis, and delayed recovery of liver mass. Increasing liver resection to 80% was associated with mortality of 40% in lean and 80% in obese mice ( P < 0.05). Gene expression profiling showed decreased epidermal growth factor receptor (EGFR) in fatty liver. Meta-analysis of expression studies in mice, rats, and patients also demonstrated reduction of EGFR in fatty liver. In mice, both EGFR and phosphorylated EGFR decreased with increasing percent body fat. Hydrodynamic transfection of EGFR plasmids in mice corrected fatty liver regeneration, reducing liver injury, increasing proliferation, and improving survival after 80% resection. Loss of EGFR expression is rate limiting for liver regeneration in obesity. Therapies directed at increasing EGFR in steatosis might promote liver regeneration and survival following hepatic resection or transplantation. Copyright © 2017 the American Physiological Society.

Early Allograft Dysfunction After Liver Transplantation Is Associated With Short- and Long-Term Kidney Function Impairment.

PubMed

Wadei, H M; Lee, D D; Croome, K P; Mai, M L; Golan, E; Brotman, R; Keaveny, A P; Taner, C B

2016-03-01

Early allograft dysfunction (EAD) after liver transplantation (LT) is related to ischemia-reperfusion injury and may lead to a systemic inflammatory response and extrahepatic organ dysfunction. We evaluated the effect of EAD on new-onset acute kidney injury (AKI) requiring renal replacement therapy within the first month and end-stage renal disease (ESRD) within the first year post-LT in 1325 primary LT recipients. EAD developed in 358 (27%) of recipients. Seventy-one (5.6%) recipients developed AKI and 38 (2.9%) developed ESRD. Compared with those without EAD, recipients with EAD had a higher risk of AKI and ESRD (4% vs. 9% and 2% vs. 6%, respectively, p < 0.001 for both). Multivariate logistic regression analysis showed an independent relationship between EAD and AKI as well as ESRD (odds ratio 3.5, 95% confidence interval 1.9-6.4, and odds ratio 3.1, 95% confidence interval 11.9-91.2, respectively). Patients who experienced both EAD and AKI had inferior 1-, 3-, 5-, and 10-year patient and graft survival compared with those with either EAD or AKI alone, while those who had neither AKI nor EAD had the best outcomes (p < 0.001). Post-LT EAD is a risk factor for both AKI and ESRD and should be considered a target for future intervention to reduce post-LT short- and long-term renal dysfunction. © Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.

Liver regenerative medicine: advances and challenges.

PubMed

Chistiakov, Dimitry A

2012-01-01

Liver transplantation is the standard care for many end-stage liver diseases. However, donor organs are scarce and some people succumb to liver failure before a donor is found. Liver regenerative medicine is a special interdisciplinary field of medicine focused on the development of new therapies incorporating stem cells, gene therapy and engineered tissues in order to repair or replace the damaged organ. In this review we consider the emerging progress achieved in the hepatic regenerative medicine within the last decade. The review starts with the characterization of liver organogenesis, fetal and adult stem/progenitor cells. Then, applications of primary hepatocytes, embryonic and adult (mesenchymal, hematopoietic and induced pluripotent) stem cells in cell therapy of liver diseases are considered. Current advances and challenges in producing mature hepatocytes from stem/progenitor cells are discussed. A section about hepatic tissue engineering includes consideration of synthetic and natural biomaterials in engineering scaffolds, strategies and achievements in the development of 3D bioactive matrices and 3D hepatocyte cultures, liver microengineering, generating bioartificial liver and prospects for fabrication of the bioengineered liver. Copyright © 2012 S. Karger AG, Basel.

FIB-4 stage of liver fibrosis predicts incident heart failure among HIV-infected and uninfected patients.

PubMed

So-Armah, Kaku A; Lim, Joseph K; Lo Re, Vincent; Tate, Janet P; Chang, Chung-Chou H; Butt, Adeel A; Gibert, Cynthia L; Rimland, David; Marconi, Vincent C; Goetz, Matthew B; Rodriguez-Barradas, Maria C; Budoff, Matthew J; Tindle, Hilary A; Samet, Jeffrey H; Justice, Amy C; Freiberg, Matthew S

2017-10-01

Liver fibrosis is common, particularly in individuals who are infected with human immunodeficiency virus (HIV). HIV-infected individuals have excess congestive heart failure (CHF) risk compared with uninfected people. It remains unknown whether liver fibrosis stage influences the CHF risk or if HIV or hepatitis C virus (HCV) infection modifies this association. Our objectives were to assess whether 1) stage of liver fibrosis is independently associated with incident CHF and 2) the association between stage of liver fibrosis and incident CHF is modified by HIV/HCV status. Participants alive on or after April 1, 2003, in the Veterans Aging Cohort Study were included. Those without prevalent cardiovascular disease were followed until their first CHF event, death, last follow-up date, or December 31, 2011. Liver fibrosis was measured using the fibrosis 4 index (FIB-4), which is calculated using age, aminotransferases, and platelets. Cox proportional hazards regression models were adjusted for cardiovascular disease risk factors. Among 96,373 participants over 6.9 years, 3844 incident CHF events occurred. FIB-4 between 1.45 and 3.25 (moderate fibrosis) and FIB-4 > 3.25 (advanced fibrosis/cirrhosis) were associated with CHF (hazard ratio [95% confidence interval], 1.17 [1.07-1.27] and 1.65 [1.43-1.92], respectively). The association of advanced fibrosis/cirrhosis and incident CHF persisted regardless of HIV/HCV status. Moderate and advanced liver fibrosis/cirrhosis are associated with an increased risk of CHF. The association for advanced fibrosis/cirrhosis persists even among participants without hepatitis C and/or HIV infection. Assessing liver health may be important for reducing the risk of future CHF events, particularly among HIV and hepatitis C infected people among whom cardiovascular disease risk is elevated and liver disease is common. (Hepatology 2017;66:1286-1295). © 2017 by the American Association for the Study of Liver Diseases.

Association of diabetes and PNPLA3 genetic variants with disease severity of patients with chronic hepatitis C virus infection.

PubMed

Huang, Chung-Feng; Dai, Chia-Yen; Yeh, Ming-Lun; Huang, Ching-I; Tai, Chi-Ming; Hsieh, Meng-Hsuan; Liang, Po-Cheng; Lin, Yi-Hung; Hsieh, Ming-Yen; Yang, Hua-Ling; Huang, Jee-Fu; Lin, Zu-Yau; Chen, Shinn-Cherng; Yu, Ming-Lung; Chuang, Wan-Long

2015-03-01

Genetic variants of patatin-like phospholipase domain-containing 3 (PNPLA3) and diabetes are associated with liver disease severity, in patients with chronic hepatitis C (CHC) infection. We aimed at exploring their interaction in determining hepatitis C virus (HCV)-related liver fibrosis. The PNPLA3 genetic polymorphism at rs738409 was verified in 1077 biopsy-proven CHC patients. Other clinical variables, including diabetes status, were analysed for factors associated with bridging fibrosis. Patients with advanced liver fibrosis had higher proportions of the GG genotype (14.5% vs. 10.4%, p=0.06 in recessive model) and GG/GC genotype carriage (64.0% vs. 56.8%, p=0.03 in dominant model). Stepwise logistic regression analysis revealed that factors predictive of advanced liver fibrosis included age (odds ratio [OR]: 1.02, 95% confidence intervals [CI]: 1.008-1.037, p=0.002), diabetes (OR: 1.81, CI: 1.236-2.653, p=0.002), α-fetoprotein (OR: 1.006, CI: 1.001-1.01, p=0.01), platelet counts (OR: 1.009, CI: 1.006-1.012, p<0.001), and PNPLA3 rs738409 CG/GG genotype (OR: 1.34, CI: 1.006-1.785, p=0.046). When patients were grouped according to their diabetes status, the PNPLA3 genetic variants were associated with advanced liver fibrosis in diabetic patients only, but not in non-diabetic patients. The PNPLA3 gene was the most important predictive factor of bridging fibrosis in diabetic patients, using the recessive model (OR: 4.53, CI: 1.356-15.106, p=0.014) or the dominant model (OR: 2.20, CI: 1.026-4.734, p=0.04). Compared to non-diabetic patients, patients with the diabetes/GG genotype were more likely to have advanced liver fibrosis (OR: 8.79, CI: 2.889-26.719, p<0.001), followed by those with diabetes/non-GG genotype (OR: 1.55, CI: 1.048-2.286, p=0.03). The effect of PNPLA3 genetic variants in HCV-related advanced liver fibrosis was enhanced in diabetic patients. The strong genetic-environmental interaction contributed to the high risk of advanced liver disease in CHC patients. Copyright © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Phenocopy of warfarin syndrome in an infant born to a mother with sickle cell anemia and severe transfusional iron overload.

PubMed

Xie, Yi; Pivnick, Eniko K; Cohen, Harris L; Adams-Graves, Patricia E; Pourcyrous, Massroor; Aygun, Banu; Hankins, Jane S

2013-08-01

Neonatal chondrodysplasia punctata (CDP) is characterized by epiphyseal stippling and midfacial hypoplasia. CDP is usually inherited, but can be acquired because of maternal vitamin K deficiency. We describe an infant with CDP born to a teenager with sickle cell anemia and transfusional iron overload. The mother had severe liver fibrosis, elevated liver iron concentration (34 mg Fe/g), and coagulopathy, but no gestational use of warfarin. Fetal abnormalities were attributed to vitamin K deficiency secondary to liver dysfunction from iron toxicity. Treatment of iron overload among women with sickle cell anemia of childbearing potential is important to avoid possible CDP in newborns.

Focus on autonomic dysfunction in familial amyloidotic polyneuropathy (FAP).

PubMed

Obayashi, Konen; Ando, Yukio

2012-06-01

It is well known that autonomic dysfunction in familial amyloidotic polyneuropathy (FAP) is the most serious problem, because it restricts the daily life of these patients. The detail mechanisms of the onset are not well understood in FAP and domino liver transplantation-induced amyloid neuropathy. As autonomic disturbances play an important role in the symptomatology of FAP, further studies of autonomic dysfunction in these patients may lead the pathogenesis of FAP. Autonomic dysfunction is often observed before sensory and motor nerve dysfunction in FAP. This can be attributed to the morphological characteristics of the nerves. Unmyelinated, small myelinated, and large myelinated fibers tend to become impaired in that order. Although the reasons of susceptibility to amyloid infiltration and injury are not known, studies of autopsied FAP patients have revealed heavy infiltration of amyloid in autonomic ganglions. Moreover, spinal ganglion and posterior loot of the spine had severe amyloid deposits than did the anterior root of the spine or the motor nerves. It is well known that autonomic dysfunction is the most serious problem, because it restricts the daily life of FAP patients. However, we have four major questions about autonomic dysfunction in clinical. In this manuscript, we discuss about the answers of these questions.

Hepatic protoporphyrin metabolism in patients with advanced protoporphyric liver disease.

PubMed Central

Bloomer, J. R.

1997-01-01

Protoporphyria is a genetic disorder in which liver damage is caused by the toxic effect of protoporphyrin accumulation in the liver. In this study protoporphyrin was measured in the resected livers of 7 patients who had liver transplantation and an additional patient from whom liver tissue was obtained post mortem. Comparison of liver, erythrocyte and serum protoporphyrin levels demonstrated a marked gradient between these compartments: erythrocyte, 5781 +/- 655 micrograms/dl; serum, 384 +/- 102 micrograms/dl; liver 377,238 +/- 55,568 micrograms/100 gm wet weight, (mean +/- SE). Protoporphyrin levels in bile of 3 patients were 55,559, and 1,153 micrograms/dl, indicating a gradient between liver and bile as well. Examination of the livers by polarization microscopy and electron microscopy demonstrated protoporphyrin pigment crystals. In one patient who had recurrent liver disease after transplantation, the protoporphyrin concentration in the graft at the time of death was similar to that in the resected liver. These data indicate that liver protoporphyrin levels in patients with advanced protoporphyric liver disease are much higher than levels in blood and bile, in part because protoporphyrin forms crystalline deposits in liver tissue. Thus, progressive hepatic accumulation of protoporphyrin occurs in the face of impaired biliary excretion. An intrinsic defect in hepatic excretion of protoporphyrin is probably not necessary for this condition to develop because liver disease can occur in the graft following transplantation. PMID:9626752

Impact of beta-blockers on cardiopulmonary exercise testing in patients with advanced liver disease.

PubMed

Wallen, M P; Hall, A; Dias, K A; Ramos, J S; Keating, S E; Woodward, A J; Skinner, T L; Macdonald, G A; Arena, R; Coombes, J S

2017-10-01

Patients with advanced liver disease may develop portal hypertension that can result in variceal haemorrhage. Beta-blockers reduce portal pressure and minimise haemorrhage risk. These medications may attenuate measures of cardiopulmonary performance, such as the ventilatory threshold and peak oxygen uptake measured via cardiopulmonary exercise testing. To determine the effect of beta-blockers on cardiopulmonary exercise testing variables in patients with advanced liver disease. This was a cross-sectional analysis of 72 participants who completed a cardiopulmonary exercise test before liver transplantation. All participants remained on their usual beta-blocker dose and timing prior to the test. Variables measured during cardiopulmonary exercise testing included the ventilatory threshold, peak oxygen uptake, heart rate, oxygen pulse, the oxygen uptake efficiency slope and the ventilatory equivalents for carbon dioxide slope. Participants taking beta-blockers (n = 28) had a lower ventilatory threshold (P <.01) and peak oxygen uptake (P = .02), compared to participants not taking beta-blockers. After adjusting for age, the model of end-stage liver-disease score, liver-disease aetiology, presence of refractory ascites and ventilatory threshold remained significantly lower in the beta-blocker group (P = .04). The oxygen uptake efficiency slope was not impacted by beta-blocker use. Ventilatory threshold is reduced in patients with advanced liver disease taking beta-blockers compared to those not taking the medication. This may incorrectly risk stratify patients on beta-blockers and has implications for patient management before and after liver transplantation. The oxygen uptake efficiency slope was not influenced by beta-blockers and may therefore be a better measure of cardiopulmonary performance in this patient population. © 2017 John Wiley & Sons Ltd.

FIB-4 Index is a Predictor of Background Liver Fibrosis and Long-Term Outcomes After Curative Resection of Hepatocellular Carcinoma.

PubMed

Okamura, Yukiyasu; Ashida, Ryo; Yamamoto, Yusuke; Ito, Takaaki; Sugiura, Teiichi; Uesaka, Katsuhiko

2016-08-01

The FIB-4 index is a simple formula for predicting the degree of liver fibrosis. This study aimed to examine the relationship between the preoperative FIB-4 index and liver fibrosis in non-tumor regions of surgical specimens and to investigate whether the FIB-4 index is a useful predictor for long-term outcomes experienced by hepatocellular carcinoma (HCC) patients after curative resection. This study retrospectively analyzed 493 HCC patients treated with curative resection. The utility of the FIB-4 index as a predictor of advanced liver fibrosis (F3 or F4) was assessed. The cutoff value for the FIB-4 index was determined using a receiver operating characteristic curve analysis, and the impact of the FIB-4 index on overall and recurrence-free survival after surgery was evaluated. Advanced liver fibrosis was found in 236 patients (47.9 %). The FIB-4 index was significantly higher for the patients with advanced liver fibrosis than for those without this condition (P < 0.001). An FIB-4 index of 2.87 was the optimal cutoff point for predicting advanced liver fibrosis. The multivariate analysis showed the FIB-4 index to be an independent prognostic factor for recurrence-free and overall survival after curative resection only for patients who underwent hepatectomy as initial treatment (hazard ratio, 1.47 and 1.59; 95 % confidence interval, 1.12-1.93 and 1.09-2.32; P = 0.006 and 0.016, respectively). The study showed the FIB4-index to be a predictor of background liver fibrosis and long-term outcomes for HCC patients who underwent hepatectomy as their initial treatment.

Review article: scoring systems for assessing prognosis in critically ill adult cirrhotics.

PubMed

Cholongitas, E; Senzolo, M; Patch, D; Shaw, S; Hui, C; Burroughs, A K

2006-08-01

Cirrhotic patients admitted to intensive care units (ICU) still have poor outcomes. Some current ICU prognostic models [Acute Physiology and Chronic Health Evaluation (APACHE), Organ System Failure (OSF) and Sequential Organ Failure Assessment (SOFA)] were used to stratify cirrhotics into risk categories, but few cirrhotics were included in the original model development. Liver-specific scores [Child-Turcotte-Pugh (CTP) and model for end-stage liver disease (MELD)] could be useful in this setting. To evaluate whether ICU prognostic models perform better compared with liver-disease specific ones in cirrhotics admitted to ICU. We performed a structured literature review identifying clinical studies focusing on prognosis and risk factors for mortality in adult cirrhotics admitted to ICU. We found 21 studies (five solely dealing with gastrointestinal bleeding) published during the last 20 years (54-420 patients in each). APACHE II and III, SOFA and OSF had better discrimination for correctly predicting death compared with the CTP score. The MELD score was evaluated only in one study and had good predictive accuracy [receiver operator characteristic (ROC) curve: 0.81). Organ dysfunction models (OSF, SOFA) were superior compared with APACHE II and III (ROC curve: range 0.83-0.94 vs. 0.66-0.88 respectively). Cardiovascular, liver and renal system dysfunction were more frequently independently associated with mortality. General-ICU models had better performance in cirrhotic populations compared with CTP score; OSF and SOFA had the best predictive ability. Further prospective and validation studies are needed.

[A case of advanced gastric cancer with multiple liver metastases completely responding long term to paclitaxel plus S-1 therapy].

PubMed

Kanou, Mikihiro; Kurisu, Yoshihiro; Akagi, Shinji; Tanaka, Tomoko; Toge, Kunio

2010-01-01

A 69-year-old man was admitted to our hospital with complaints of loss of appetite, fatigue and dysphasia. Upper gastroscopy revealed advanced gastric cancer. Abdominal CT suggested liver metastases. At first we thought the liver metastases has been completely resected, but we found multiple liver metastases unexpectedly. So only total gastric resection and liver biopsy were performed. The pathological diagnosis was metastatic carcinoma. Paclitaxel (PTX) and S-1 combination chemotherapy was started after operation and was continued for 42 courses. A CT scan showed a complete response, and he has been well without tumor re-growth ever since. The combination of PTX and S-1 not only may be an effective regimen for gastric cancer with liver metastases, but also can be used without side effects for a long time.

Gamma-glutamyl-transpeptidase to platelet ratio is not superior to APRI,FIB-4 and RPR for diagnosing liver fibrosis in CHB patients in China.

PubMed

Huang, Rui; Wang, Guiyang; Tian, Chen; Liu, Yong; Jia, Bei; Wang, Jian; Yang, Yue; Li, Yang; Sun, Zhenhua; Yan, Xiaomin; Xia, Juan; Xiong, Yali; Song, Peixin; Zhang, Zhaoping; Ding, Weimao; Wu, Chao

2017-08-17

The gamma-glutamyl transpeptidase to platelet ratio (GPR) is a novel index to estimate liver fibrosis in chronic hepatitis B (CHB). Few studies compared diagnostic accuracy of GPR with other non-invasive fibrosis tests based on blood parameters. We analyzed diagnostic values of GPR for detecting liver fibrosis and compared diagnostic performances of GPR with APRI (aspartate aminotransferase-to-platelet ratio index), FIB-4 (fibrosis index based on the four factors), NLR (neutrophil-to-lymphocyte ratio), AAR (aspartate aminotransferase/alanine aminotransferase ratio) and RPR (red cell distribution width-to-platelet ratio) in HBeAg positive CHB and HBeAg negative CHB. We found AUROCs of GPR in predicting significant liver fibrosis, advanced liver fibrosis and liver cirrhosis were 0.732 (95% CI 0.663 to 0.801), 0.788 (95% CI 0.729 to 0.847) and 0.753 (95% CI 0.692 to 0.814), respectively. Further comparisons showed the diagnostic performance of GPR was not significantly different with APRI, FIB-4 and RPR in identifying significant fibrosis, advanced fibrosis and cirrhosis, but it was significantly superior to AAR and NLR in both HBeAg positive CHB and HBeAg negative CHB. In conclusion, GPR does not show advantages than APRI, FIB-4 and RPR in identifying significant liver fibrosis, advanced liver fibrosis and liver cirrhosis in both HBeAg positive CHB and HBeAg negative CHB in China.

Role of Oxygen Free Radicals, Nitric Oxide and Mitochondria in Mediating Cardiac Alterations During Liver Cirrhosis Induced by Thioacetamide.

PubMed

Amirtharaj, G Jayakumar; Natarajan, Sathish Kumar; Pulimood, Anna; Balasubramanian, K A; Venkatraman, Aparna; Ramachandran, Anup

2017-04-01

Thioacetamide (TAA) administration is widely used for induction of liver cirrhosis in rats, where reactive oxygen radicals (ROS) and nitric oxide (NO) participate in development of liver damage. Cardiac dysfunction is an important complication of liver cirrhosis, but the role of ROS or NO in cardiac abnormalities during liver cirrhosis is not well understood. This was investigated in animals after TAA-induced liver cirrhosis and temporal changes in oxidative stress, NO and mitochondrial function in the heart evaluated. TAA induced elevation in cardiac levels of nitrate before development of frank liver cirrhosis, without gross histological alterations. This was accompanied by an early induction of P38 MAP kinase, which is influenced by ROS and plays an important signaling role for induction of iNOS. Increased nitrotyrosine, protein oxidation and lipid peroxidation in the heart and cardiac mitochondria, suggestive of oxidative stress, also preceded frank liver cirrhosis. However, compromised cardiac mitochondrial function with a decrease in respiratory control ratio and increased mitochondrial swelling was seen later, when cirrhosis was evident. In conclusion, TAA induces elevations in ROS and NO in the heart in parallel to early liver damage. This leads to later development of functional deficits in cardiac mitochondria after development of liver cirrhosis.

FGF7 is a functional niche signal required for stimulation of adult liver progenitor cells that support liver regeneration

PubMed Central

Takase, Hinako M.; Itoh, Tohru; Ino, Seitaro; Wang, Ting; Koji, Takehiko; Akira, Shizuo; Takikawa, Yasuhiro; Miyajima, Atsushi

2013-01-01

The liver is a unique organ with a remarkably high potential to regenerate upon injuries. In severely damaged livers where hepatocyte proliferation is impaired, facultative liver progenitor cells (LPCs) proliferate and are assumed to contribute to regeneration. An expansion of LPCs is often observed in patients with various types of liver diseases. However, the underlying mechanism of LPC activation still remains largely unknown. Here we show that a member of the fibroblast growth factor (FGF) family, FGF7, is a critical regulator of LPCs. Its expression was induced concomitantly with LPC response in the liver of mouse models as well as in the serum of patients with acute liver failure. Fgf7-deficient mice exhibited markedly depressed LPC expansion and higher mortality upon toxin-induced hepatic injury. Transgenic expression of FGF7 in vivo led to the induction of cells with characteristics of LPCs and ameliorated hepatic dysfunction. We revealed that Thy1+ mesenchymal cells produced FGF7 and appeared in close proximity to LPCs, implicating a role for those cells as the functional LPC niche in the regenerating liver. These findings provide new insights into the cellular and molecular basis for LPC regulation and identify FGF7 as a potential therapeutic target for liver diseases. PMID:23322300

SIMULTANEOUS LIVER KIDNEY TRANSPLANTATION IN LIVER TRANSPLANT CANDIDATES WITH RENAL DYSFUNCTION: IMPORTANCE OF CREATININE LEVELS, DIALYSIS, AND ORGAN QUALITY IN SURVIVAL

PubMed Central

Tanriover, Bekir; MacConmara, Malcolm P.; Parekh, Justin; Arce, Cristina; Zhang, Song; Gao, Ang; Mufti, Arjmand; Levea, Swee-Ling; Sandikci, Burhaneddin; Ayvaci, Mehmet U.S.; Ariyamuthu, Venketash K.; Hwang, Christine; Mohan, Sumit; Mete, Mutlu; Vazquez, Miguel A.; Marrero, Jorge A.

2016-01-01

Background The survival benefit from simultaneous liver-kidney transplantation (SLK) over liver transplant alone (LTA) in recipients with moderate renal dysfunction is not well understood. Moreover, the impact of deceased donor organ quality in SLK transplant survival has not been well described in the literature. Methods The Scientific Registry of Transplant Recipients was studied for adult recipients receiving LTA (N=2,700) or SLK (N=1,361) transplantation with moderate renal insufficiency between 2003 and 2013. The study cohort was stratified into four groups based on serum creatinine (Scr< 2 mg/dL versus Scr≥ 2 mg/dL) and dialysis status at listing and at transplant. The patients with end-stage renal disease and requiring acute dialysis more than three months before transplantation were excluded. A propensity score (PS)-matching was performed in each stratified groups to factor out imbalances between the SLK and LTA regarding covariates distribution and to reduce measured confounding. Donor quality was assessed with liver-donor risk index (L-DRI). The primary outcome of interest was post-transplant mortality. Results On multivariable PS-matched Cox proportional hazard models, SLK led to decrease in post-transplant mortality compared to LTA across all four groups, but only reached statistical significance (HR 0.77; 95% CI, 0.62–0.96) in the recipients not exposed to dialysis and Scr≥ 2 mg/dL at transplant (mortality incidence rate per patient-year 5.7% in SLK vs. 7.6% in LTA, p=0.005). The decrease in mortality was observed among SLK recipients with better quality donors (L-DRI<1.5). Conclusions Exposure to pre-transplantation dialysis and donor quality affected overall survival among SLK recipients. PMID:27942610

Role for Neutrophil Extracellular Traps (NETs) and Platelet Aggregation in Early Sepsis-induced Hepatic Dysfunction.

PubMed

Sakurai, Kentaro; Miyashita, Tomoharu; Okazaki, Mitsuyoshi; Yamaguchi, Takahisa; Ohbatake, Yoshinao; Nakanuma, Shinichi; Okamoto, Koichi; Sakai, Seisho; Kinoshita, Jun; Makino, Isamu; Nakamura, Keishi; Hayashi, Hironori; Oyama, Katsunobu; Tajima, Hidehiro; Takamura, Hiroyuki; Ninomiya, Itasu; Fushida, Sachio; Harada, Kenichi; Harmon, John W; Ohta, Tetsuo

2017-01-01

Severe sepsis is associated with high morbidity and mortality rates. Inflammation and coagulation play pivotal roles in the pathogenesis of sepsis leading to multiple organ failure, especially in the liver. The aim of the present study was to assess the mechanism from sepsis to liver damage in a mouse model. We created a sepsis model by injecting lipopolysaccharide (LPS) intraperitoneally in mice. At 0, 6, 12, and 24 h following intraperitoneal injection of LPS, mice were euthanised and analyzed. Primary antibodies against myeloperoxidase (MPO), hepatic sinusoidal endothelial cells (SE-1), and P-selectin (CD62p) were used. Expression and localization in neutrophil, sinusoidal endothelial, and platelet cells were assessed by immunohistochemistry. Immunohistochemical analyses revealed a positive staining for MPO, most abundantly in neutrophil granulocytes, within the hepatic sinusoids immediately after injection. Neutrophil extracellular trap (NET)-like structures stained for MPO, indicating the presence of neutrophils undergoing NETosis, were confirmed at 6 h after LPS administration. SE-1 staining for liver sinusoidal endothelial cells was significantly reduced at 12 h post-LPS administration through sinusoidal endothelial injury or detachment. Furthermore, the presence of extravasated platelets was confirmed in the space of Disse at 24 h after LPS administration. Blood sample analyses showed that white blood cell counts and platelet counts decreased gradually, while MPO amounts increased until 12 h after LPS administration. We conclude that NET formation and intravasated platelet aggregation are the first steps from sepsis to liver damage, and that extravasated platelet aggregation promoted by NET-facilitated detachment of sinusoidal endothelial cells is the origin of sepsis-induced liver dysfunction. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Adenoviral bcl-2 transfer improves survival and early graft function after ischemia and reperfusion in rat liver transplantation.

PubMed

Rentsch, Markus; Kienle, Klaus; Mueller, Thomas; Vogel, Mandy; Jauch, Karl Walter; Püllmann, Kerstin; Obed, Aiman; Schlitt, Hans J; Beham, Alexander

2005-11-27

Primary graft dysfunction due to ischemia and reperfusion injury represents a major problem in liver transplantation. The related cell stress may induce apoptosis, which can be suppressed by bcl-2. The purpose of the study was to investigate the effect of adenoviral bcl-2 gene transfer on early graft function and survival in rat liver transplantation. An adenoviral construct that transfers bcl-2 under the control of a tetracycline inducible promoter was generated (advTetOn bcl-2) and used with a second adenovirus that transfers the repressor protein (advCMV Rep). Forty-eight hours before explantation, donor rats were treated with advTetOn bcl-2/ advCMV Rep (n=7) and doxycyclin, with the control adenoviral construct advCMV GFP (n=8) or with doxycyclin alone (n=8). Liver transplantation was performed following 16 hours of cold storage (UW). Bcl-2 expression and intrahepatic apoptosis was assessed. Bile flow was monitored 90 min posttransplantation. The endpoint for survival was 7 days. Bcl-2 was expressed in hepatocytes and sinusoidal lining cells. This was associated with a significant reduction of apoptotic sinusoidal lining cells and hepatocytes after 24 hours and 7 days. Bile production was significantly higher following bcl-2 pretreatment. Furthermore, bcl-2 transfer resulted in significantly improved survival (100% vs. 50% both control groups). Adenoviral bcl-2 transfer results in protein expression in hepatocytes and sinusoidal lining cells resulting in early graft function and survival enhancement after prolonged ischemia and reperfusion injury. The inhibition of apoptosis in the context of liver transplantation might be a reasonable approach in the treatment of graft dysfunction.

Mitochondrial dysfunction and tissue injury by alcohol, high fat, nonalcoholic substances and pathological conditions through post-translational protein modifications

PubMed Central

Song, Byoung-Joon; Akbar, Mohammed; Abdelmegeed, Mohamed A.; Byun, Kyunghee; Lee, Bonghee; Yoon, Seung Kew; Hardwick, James P.

2014-01-01

Mitochondria are critically important in providing cellular energy ATP as well as their involvement in anti-oxidant defense, fat oxidation, intermediary metabolism and cell death processes. It is well-established that mitochondrial functions are suppressed when living cells or organisms are exposed to potentially toxic agents including alcohol, high fat diets, smoking and certain drugs or in many pathophysiological states through increased levels of oxidative/nitrative stress. Under elevated nitroxidative stress, cellular macromolecules proteins, DNA, and lipids can undergo different oxidative modifications, leading to disruption of their normal, sometimes critical, physiological functions. Recent reports also indicated that many mitochondrial proteins are modified via various post-translation modifications (PTMs) and primarily inactivated. Because of the recently-emerging information, in this review, we specifically focus on the mechanisms and roles of five major PTMs (namely oxidation, nitration, phosphorylation, acetylation, and adduct formation with lipid-peroxides, reactive metabolites, or advanced glycation end products) in experimental models of alcoholic and nonalcoholic fatty liver disease as well as acute hepatic injury caused by toxic compounds. We also highlight the role of the ethanol-inducible cytochrome P450-2E1 (CYP2E1) in some of these PTM changes. Finally, we discuss translational research opportunities with natural and/or synthetic anti-oxidants, which can prevent or delay the onset of mitochondrial dysfunction, fat accumulation and tissue injury. PMID:25465468

Clinical epidemiology and disease burden of nonalcoholic fatty liver disease

PubMed Central

Perumpail, Brandon J; Khan, Muhammad Ali; Yoo, Eric R; Cholankeril, George; Kim, Donghee; Ahmed, Aijaz

2017-01-01

Nonalcoholic fatty liver disease (NAFLD) is defined as the presence of hepatic fat accumulation after the exclusion of other causes of hepatic steatosis, including other causes of liver disease, excessive alcohol consumption, and other conditions that may lead to hepatic steatosis. NAFLD encompasses a broad clinical spectrum ranging from nonalcoholic fatty liver to nonalcoholic steatohepatitis (NASH), advanced fibrosis, cirrhosis, and finally hepatocellular carcinoma (HCC). NAFLD is the most common liver disease in the world and NASH may soon become the most common indication for liver transplantation. Ongoing persistence of obesity with increasing rate of diabetes will increase the prevalence of NAFLD, and as this population ages, many will develop cirrhosis and end-stage liver disease. There has been a general increase in the prevalence of NAFLD, with Asia leading the rise, yet the United States is following closely behind with a rising prevalence from 15% in 2005 to 25% within 5 years. NAFLD is commonly associated with metabolic comorbidities, including obesity, type II diabetes, dyslipidemia, and metabolic syndrome. Our understanding of the pathophysiology of NAFLD is constantly evolving. Based on NAFLD subtypes, it has the potential to progress into advanced fibrosis, end-stage liver disease and HCC. The increasing prevalence of NAFLD with advanced fibrosis, is concerning because patients appear to experience higher liver-related and non-liver-related mortality than the general population. The increased morbidity and mortality, healthcare costs and declining health related quality of life associated with NAFLD makes it a formidable disease, and one that requires more in-depth analysis. PMID:29307986

Fibrosis Assessment in Nonalcoholic Fatty Liver Disease (NAFLD) in 2016.

PubMed

Kaswala, Dharmesh H; Lai, Michelle; Afdhal, Nezam H

2016-05-01

Nonalcoholic fatty liver disease (NAFLD) is a spectrum of liver pathologies characterized by hepatic steatosis with a history of little to no alcohol consumption or secondary causes of hepatic steatosis. The prevalence of NAFLD is 20-25 % of the general population in the Western countries and is associated with metabolic risk factors such as obesity, diabetes mellitus, and dyslipidemia. The spectrum of disease ranges from simple steatosis to nonalcoholic steatohepatitis, fibrosis, and cirrhosis. Advanced fibrosis is the most significant predictor of mortality in NAFLD. It is crucial to assess for the presence and degree of hepatic fibrosis in order to make therapeutic decisions and predict clinical outcomes. Liver biopsy, the current gold standard to assess the liver fibrosis, has a number of drawbacks such as invasiveness, sampling error, cost, and inter-/intra-observer variability. There are currently available a number of noninvasive tests as an alternative to liver biopsy for fibrosis staging. These noninvasive fibrosis tests are increasingly used to rule out advanced fibrosis and help guide disease management. While these noninvasive tests perform relatively well for ruling out advanced fibrosis, they also have limitations. Understanding the strengths and limitations of liver biopsy and the noninvasive tests is necessary for deciding when to use the appropriate tests in the evaluation of patients with NAFLD.

The role of hepatocyte nuclear factor 4-alpha in perfluorooctanoic and perfluorooctanesulfonic acid-induced hepatocellular dysfunction

EPA Science Inventory

Perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS), chemicals present in a multitude of consumer products, are persistent organic pollutants. Both compounds induce hepatotoxic effects in rodents, including steatosis, hepatomegaly and liver cancer. The mechani...

Acute kidney injury in acute liver failure: a review.

PubMed

Moore, Joanna K; Love, Eleanor; Craig, Darren G; Hayes, Peter C; Simpson, Kenneth J

2013-11-01

Acute liver failure is a rare and often devastating condition consequent on massive liver cell necrosis that frequently affects young, previously healthy individuals resulting in altered cognitive function, coagulopathy and peripheral vasodilation. These patients frequently develop concurrent acute kidney injury (AKI). This abrupt and sustained decline in renal function, through a number of pathogenic mechanisms such as renal hypoperfusion, direct drug-induced nephrotoxicity or sepsis/systemic inflammatory response contributes to increased morbidity and is strongly associated with a worse prognosis. Improved understanding of the pathophysiology AKI in the context of acute liver failure may be beneficial in a number of areas; the development of new and sensitive biomarkers of renal dysfunction, refining prognosis and organ allocation, and ultimately leading to the development of novel treatment strategies, these issues are discussed in more detail in this expert review.

Obesity Increases Sensitivity to Endotoxin Liver Injury: Implications for the Pathogenesis of Steatohepatitis

NASA Astrophysics Data System (ADS)

Yang, Shi Qi; Zhi Lin, Hui; Lane, M. Daniel; Clemens, Mark; Diehl, Anna Mae

1997-03-01

Genetically obese fatty/fatty rats and obese/obese mice exhibit increased sensitivity to endotoxin hepatotoxicity, quickly developing steatohepatitis after exposure to low doses of lipopolysaccharide (LPS). Among obese animals, females are more sensitive to endotoxin liver injury than males. LPS induction of tumor necrosis factor α (TNFα ), the proven affecter of endotoxin liver injury, is no greater in the livers, white adipose tissues, or sera of obese animals than in those of lean controls. Indeed, the lowest serum concentrations of TNF occur in female obese rodents, which exhibit the most endotoxin-induced liver injury. Several cytokines that modulate the biological activity of TNF are regulated abnormally in the livers of obese animals. After exposure to LPS, mRNA of interferon γ , which sensitizes hepatocytes to TNF toxicity, is overexpressed, and mRNA levels of interleukin 10, a TNF inhibitor, are decreased. The phagocytic activity of liver macrophages and the hepatic expression of a gene encoding a macrophage-specific receptor are also decreased in obesity. This new animal model of obesity-associated liver disease demonstrates that hepatic macrophage dysfunction occurs in obesity and suggests that this might promote steatohepatitis by sensitizing hepatocytes to endotoxin.

The FXR agonist PX20606 ameliorates portal hypertension by targeting vascular remodelling and sinusoidal dysfunction.

PubMed

Schwabl, Philipp; Hambruch, Eva; Seeland, Berit A; Hayden, Hubert; Wagner, Michael; Garnys, Lukas; Strobel, Bastian; Schubert, Tim-Lukas; Riedl, Florian; Mitteregger, Dieter; Burnet, Michael; Starlinger, Patrick; Oberhuber, Georg; Deuschle, Ulrich; Rohr-Udilova, Nataliya; Podesser, Bruno K; Peck-Radosavljevic, Markus; Reiberger, Thomas; Kremoser, Claus; Trauner, Michael

2017-04-01

Steroidal farnesoid X receptor (FXR) agonists demonstrated potent anti-fibrotic activities and lowered portal hypertension in experimental models. The impact of the novel non-steroidal and selective FXR agonist PX20606 on portal hypertension and fibrosis was explored in this study. In experimental models of non-cirrhotic (partial portal vein ligation, PPVL, 7days) and cirrhotic (carbon tetrachloride, CCl 4 , 14weeks) portal hypertension, PX20606 (PX,10mg/kg) or the steroidal FXR agonist obeticholic acid (OCA,10mg/kg) were gavaged. We then measured portal pressure, intrahepatic vascular resistance, liver fibrosis and bacterial translocation. PX decreased portal pressure in non-cirrhotic PPVL (12.6±1.7 vs. 10.4±1.1mmHg; p=0.020) and cirrhotic CCl 4 (15.2±0.5 vs. 11.8±0.4mmHg; p=0.001) rats. In PPVL animals, we observed less bacterial translocation (-36%; p=0.041), a decrease in lipopolysaccharide binding protein (-30%; p=0.024) and splanchnic tumour necrosis factor α levels (-39%; p=0.044) after PX treatment. In CCl 4 rats, PX decreased fibrotic Sirius Red area (-43%; p=0.005), hepatic hydroxyproline (-66%; p<0.001), and expression of profibrogenic proteins (Col1a1, α smooth muscle actin, transforming growth factor β). CCl 4 -PX rats had significantly lower transaminase levels and reduced hepatic macrophage infiltration. Moreover, PX induced sinusoidal vasodilation (upregulation of cystathionase, dimethylaminohydrolase (DDAH)1, endothelial nitric oxide synthase (eNOS), GTP-cyclohydrolase1) and reduced intrahepatic vasoconstriction (downregulation of endothelin-1, p-Moesin). In cirrhosis, PX improved endothelial dysfunction (decreased von-Willebrand factor) and normalized overexpression of vascular endothelial growth factor, platelet-derived growth factor and angiopoietins. While short-term 3-day PX treatment reduced portal pressure (-14%; p=0.041) by restoring endothelial function, 14week PX therapy additionally inhibited sinusoidal remodelling and decreased portal pressure to a greater extent (-22%; p=0.001). In human liver sinusoidal endothelial cells, PX increased eNOS and DDAH expression. The non-steroidal FXR agonist PX20606 ameliorates portal hypertension by reducing liver fibrosis, vascular remodelling and sinusoidal dysfunction. The novel drug PX20606 activates the bile acid receptor FXR and shows beneficial effects in experimental liver cirrhosis: In the liver, it reduces scarring and inflammation, and also widens blood vessels. Thus, PX20606 leads to an improved blood flow through the liver and decreases hypertension of the portal vein. Additionally, PX20606 improves the altered intestinal barrier and decreases bacterial migration from the gut. Copyright © 2016 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Real-time monitoring of metabolic function in liver-on-chip microdevices tracks the dynamics of mitochondrial dysfunction

PubMed Central

Bavli, Danny; Prill, Sebastian; Ezra, Elishai; Levy, Gahl; Cohen, Merav; Vinken, Mathieu; Vanfleteren, Jan; Jaeger, Magnus; Nahmias, Yaakov

2016-01-01

Microfluidic organ-on-a-chip technology aims to replace animal toxicity testing, but thus far has demonstrated few advantages over traditional methods. Mitochondrial dysfunction plays a critical role in the development of chemical and pharmaceutical toxicity, as well as pluripotency and disease processes. However, current methods to evaluate mitochondrial activity still rely on end-point assays, resulting in limited kinetic and prognostic information. Here, we present a liver-on-chip device capable of maintaining human tissue for over a month in vitro under physiological conditions. Mitochondrial respiration was monitored in real time using two-frequency phase modulation of tissue-embedded phosphorescent microprobes. A computer-controlled microfluidic switchboard allowed contiguous electrochemical measurements of glucose and lactate, providing real-time analysis of minute shifts from oxidative phosphorylation to anaerobic glycolysis, an early indication of mitochondrial stress. We quantify the dynamics of cellular adaptation to mitochondrial damage and the resulting redistribution of ATP production during rotenone-induced mitochondrial dysfunction and troglitazone (Rezulin)-induced mitochondrial stress. We show troglitazone shifts metabolic fluxes at concentrations previously regarded as safe, suggesting a mechanism for its observed idiosyncratic effect. Our microfluidic platform reveals the dynamics and strategies of cellular adaptation to mitochondrial damage, a unique advantage of organ-on-chip technology. PMID:27044092

The relationship between liver histology and noninvasive markers in primary biliary cirrhosis.

PubMed

Olmez, Sehmus; Sayar, Suleyman; Avcioglu, Ufuk; Tenlik, İlyas; Ozaslan, Ersan; Koseoglu, Hasan T; Altiparmak, Emin

2016-07-01

Primary biliary cirrhosis (PBC) is a disease that affects liver with various severity and progression rates. It is important to diagnose advanced stage of the disease to lower liver-related morbidity and mortality. Since liver biopsy is an invasive method, liver biopsy tends to be replaced by noninvasive methods. In this study, we aim to show the role of aminotransferase to platelet ratio index (APRI) and fibrosis index on the basis of the four factors (FIB-4) scores, laboratory values, and their effectiveness in predicting advanced disease. PBC patients diagnosed pathologically at Numune Education and Research Hospital were included in the study between the years 1995 and 2013. Patients were grouped according to their fibrosis level: group 1 (early stage) included 18 patients with F1 and F2 fibrosis and group 2 (advanced stage) included 22 patients with F3 and F4 fibrosis. APRI and FIB-4 scores, routine laboratory values, and their proportions were compared. The effectiveness of parameters showing advanced stage was further compared. There were statistically significant differences in APRI, FIB-4 scores, and aspartate aminotransferase (AST) levels between the groups with early and advanced stages of disease. Receiver operating curve analysis was used to determine APRI, FIB-4 and AST levels. The most effective parameters for diagnosing an advanced stage were APRI, AST levels, and FIB-4 scores, respectively. In conclusion, APRI and FIB-4 scores can be calculated simply and easily by routine laboratory tests at low cost and also these scores may be a predictor of advanced stage of the disease in PBC. These tests may be reproducible and may be used to monitor disease progression.

(p-ClPhSe)2 stimulates carbohydrate metabolism and reverses the metabolic alterations induced by high fructose load in rats.

PubMed

Quines, Caroline B; Rosa, Suzan G; Chagas, Pietro M; Velasquez, Daniela; Prado, Vinicius C; Nogueira, Cristina W

2017-09-01

The modern life leads to excess consumption of food rich in fructose; however, the long-term changes in carbohydrate and lipid metabolism could lead to metabolic dysfunction in humans. The present study evaluated the in vitro insulin-mimetic action of p-chloro-diphenyl diselenide (p-ClPhSe) 2 . The second aim of this study was to investigate if (p-ClPhSe) 2 reverses metabolic dysfunction induced by fructose load in Wistar rats. The insulin-mimetic action of (p-ClPhSe) 2  at concentrations of 50 and 100 μM was determined in slices of rat skeletal muscle. (p-ClPhSe) 2  at a concentration of 50 μM stimulated the glucose uptake by 40% in skeletal muscle. A dose-response curve revealed that (p-ClPhSe) 2  at a dose of 25 mg/kg reduced (∼20%) glycemia in rats treated with fructose (5 g/kg, i.g.). The administration of fructose impaired the liver homeostasis and (p-ClPhSe) 2 (25 mg/kg) protected against the increase (∼25%) in the G-6-Pase and isocitrate dehydrogenase activities and reduced the triglyceride content (∼25%) in the liver. (p-ClPhSe) 2 regulated the liver homeostasis by stimulating hexokinase activity (∼27%), regulating the TCA cycle activity (increased the ATP and citrate synthase activity (∼15%)) and increasing the glycogen levels (∼67%). In conclusion, (p-ClPhSe) 2 stimulated carbohydrate metabolism and reversed metabolic dysfunction in rats fed with fructose. Copyright © 2017 Elsevier Ltd. All rights reserved.

Sirtuin signaling controls mitochondrial function in glycogen storage disease type Ia.

PubMed

Cho, Jun-Ho; Kim, Goo-Young; Mansfield, Brian C; Chou, Janice Y

2018-05-08

Glycogen storage disease type Ia (GSD-Ia) deficient in glucose-6-phosphatase-α (G6Pase-α) is a metabolic disorder characterized by impaired glucose homeostasis and a long-term complication of hepatocellular adenoma/carcinoma (HCA/HCC). Mitochondrial dysfunction has been implicated in GSD-Ia but the underlying mechanism and its contribution to HCA/HCC development remain unclear. We have shown that hepatic G6Pase-α deficiency leads to downregulation of sirtuin 1 (SIRT1) signaling that underlies defective hepatic autophagy in GSD-Ia. SIRT1 is a NAD + -dependent deacetylase that can deacetylate and activate peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α), a master regulator of mitochondrial integrity, biogenesis, and function. We hypothesized that downregulation of hepatic SIRT1 signaling in G6Pase-α-deficient livers impairs PGC-1α activity, leading to mitochondrial dysfunction. Here we show that the G6Pase-α-deficient livers display defective PGC-1α signaling, reduced numbers of functional mitochondria, and impaired oxidative phosphorylation. Overexpression of hepatic SIRT1 restores PGC-1α activity, normalizes the expression of electron transport chain components, and increases mitochondrial complex IV activity. We have previously shown that restoration of hepatic G6Pase-α expression normalized SIRT1 signaling. We now show that restoration of hepatic G6Pase-α expression also restores PGC-1α activity and mitochondrial function. Finally, we show that HCA/HCC lesions found in G6Pase-α-deficient livers contain marked mitochondrial and oxidative DNA damage. Taken together, our study shows that downregulation of hepatic SIRT1/PGC-1α signaling underlies mitochondrial dysfunction and that oxidative DNA damage incurred by damaged mitochondria may contribute to HCA/HCC development in GSD-Ia.

Effects of gabexate mesilate on coagulopathy and organ dysfunction in rats with endotoxemia: a potential use of thrombelastography in endotoxin-induced sepsis.

PubMed

Tsai, Hsin-Jung; Ding, Chen; Tsao, Cheng-Ming; Liao, Mei-Hui; Ka, Shuk-Man; Liaw, Wen-Jinn; Wu, Chin-Chen

2015-03-01

Sepsis and its associated multiple organ failure are related to high mortality in critical patients. Several studies have reported that gabexate mesilate, a synthetic inhibitor of trypsin-like serine protease, protects tissues/organs against injury in the models of endotoxemia. The aim of this study was to examine whether gabexate mesilate could attenuate coagulopathy and organ dysfunction in lipopolysaccharide (LPS)-induced sepsis model by using thrombelastography (TEG). LPS (7.5  mg/kg/h, intravenouly for 4  h) was administered to male adult Wistar rats. Some of the LPS rats received a continuous infusion of gabexate mesilate (10  mg/kg/h, intravenously for 8.5  h) for 30  min before the LPS administration. Variable parameters of hemodynamics, biochemistry, hemostasis and inflammatory response were measured for 6  h after the LPS infusion. TEG variables (R-time, K-time, α-angle, and maximal amplitude) were also measured. The pretreatment of LPS rats with gabexate mesilate significantly attenuated the lung, liver and kidney dysfunction, consumptive coagulopathy, the increases in serum tumor necrosis factor-α, interleukin-6, plasma thrombin-antithrombin complex and plasminogen activator inhibitor-1, and neutrophils infiltration score in lung, liver and kidney, compared with the LPS alone group. In addition, TEG parameters correlated with tissue and liver injury in the late phase of endotoxemia. In particular, a strong negative correlation between maximal amplitude at 4  h and Ln (lactate dehydrogenase) at 6  h after LPS infusion was noted (r = -0.752, P < 0.001, R = 0.566). These results indicate that beneficial effects of anticoagulants (e.g. gabexate mesilate) in endotoxemia could be monitored by TEG per se.

Vildagliptin and its metabolite M20.7 induce the expression of S100A8 and S100A9 in human hepatoma HepG2 and leukemia HL-60 cells

PubMed Central

Asakura, Mitsutoshi; Karaki, Fumika; Fujii, Hideaki; Atsuda, Koichiro; Itoh, Tomoo; Fujiwara, Ryoichi

2016-01-01

Vildagliptin is a potent, orally active inhibitor of dipeptidyl peptidase-4 (DPP-4) for the treatment of type 2 diabetes mellitus. It has been reported that vildagliptin can cause hepatic dysfunction in patients. However, the molecular-mechanism of vildagliptin-induced liver dysfunction has not been elucidated. In this study, we employed an expression microarray to determine hepatic genes that were highly regulated by vildagliptin in mice. We found that pro-inflammatory S100 calcium-binding protein (S100) a8 and S100a9 were induced more than 5-fold by vildagliptin in the mouse liver. We further examined the effects of vildagliptin and its major metabolite M20.7 on the mRNA expression levels of S100A8 and S100A9 in human hepatoma HepG2 and leukemia HL-60 cells. In HepG2 cells, vildagliptin, M20.7, and sitagliptin – another DPP-4 inhibitor – induced S100A9 mRNA. In HL-60 cells, in contrast, S100A8 and S100A9 mRNAs were significantly induced by vildagliptin and M20.7, but not by sitagliptin. The release of S100A8/A9 complex in the cell culturing medium was observed in the HL-60 cells treated with vildagliptin and M20.7. Therefore, the parental vildagliptin- and M20.7-induced release of S100A8/A9 complex from immune cells, such as neutrophils, might be a contributing factor of vildagliptin-associated liver dysfunction in humans. PMID:27759084

Vildagliptin and its metabolite M20.7 induce the expression of S100A8 and S100A9 in human hepatoma HepG2 and leukemia HL-60 cells.

PubMed

Asakura, Mitsutoshi; Karaki, Fumika; Fujii, Hideaki; Atsuda, Koichiro; Itoh, Tomoo; Fujiwara, Ryoichi

2016-10-19

Vildagliptin is a potent, orally active inhibitor of dipeptidyl peptidase-4 (DPP-4) for the treatment of type 2 diabetes mellitus. It has been reported that vildagliptin can cause hepatic dysfunction in patients. However, the molecular-mechanism of vildagliptin-induced liver dysfunction has not been elucidated. In this study, we employed an expression microarray to determine hepatic genes that were highly regulated by vildagliptin in mice. We found that pro-inflammatory S100 calcium-binding protein (S100) a8 and S100a9 were induced more than 5-fold by vildagliptin in the mouse liver. We further examined the effects of vildagliptin and its major metabolite M20.7 on the mRNA expression levels of S100A8 and S100A9 in human hepatoma HepG2 and leukemia HL-60 cells. In HepG2 cells, vildagliptin, M20.7, and sitagliptin - another DPP-4 inhibitor - induced S100A9 mRNA. In HL-60 cells, in contrast, S100A8 and S100A9 mRNAs were significantly induced by vildagliptin and M20.7, but not by sitagliptin. The release of S100A8/A9 complex in the cell culturing medium was observed in the HL-60 cells treated with vildagliptin and M20.7. Therefore, the parental vildagliptin- and M20.7-induced release of S100A8/A9 complex from immune cells, such as neutrophils, might be a contributing factor of vildagliptin-associated liver dysfunction in humans.

Influence of polymorphisms within the methotrexate pathway genes on the toxicity and efficacy of methotrexate in patients with juvenile idiopathic arthritis.

PubMed

Yanagimachi, Masakatsu; Naruto, Takuya; Hara, Takuma; Kikuchi, Masako; Hara, Ryoki; Miyamae, Takako; Imagawa, Tomoyuki; Mori, Masaaki; Kaneko, Tetsuji; Morita, Satoshi; Goto, Hiroaki; Yokota, Shumpei

2011-02-01

We investigated whether several polymorphisms within the methotrexate (MTX) pathway genes were related to the toxicity and efficacy of MTX in 92 Japanese patients with articular-type juvenile idiopathic arthritis (JIA). Eight gene polymorphisms within the MTX pathway genes, namely, RFC, BCRP, MTHFR (two), FPGS, γ-glutamyl hydrolase (GGH; two) and ATIC, were genotyped using TaqMan assays. Liver dysfunction was defined as an increase in alanine transaminase to five times the normal upper limit. Non-responders to MTX were defined as patients refractory to MTX and were therefore treated with biologics. The non-TT genotype at GGH T16C was associated with a high risk of liver dysfunction (P=0.028, odds ratio=6.90, 95% confidence interval 1.38-34.5), even after adjustment for the duration of MTX treatment. A longer interval from disease onset to treatment (8.5 and 21.3 months, P=0.029) and rheumatoid factor positivity (P=0.026, odds ratio=2.87, 95% confidence interval 1.11-7.39) were associated with lower efficacy of MTX. The non-TT genotype at GGH T16C was associated with a high risk of liver dysfunction, presumably because the C allele of GGH C16T may reduce the activity of GGH. The time interval before MTX treatment and rheumatoid factor positivity were associated with the efficacy of MTX treatment. The pharmacogenetics of the MTX pathway genes affects the toxicity and efficacy of MTX in Japanese JIA patients. © 2011 The Authors. British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society.

(p-ClPhSe)2 Reduces Hepatotoxicity Induced by Monosodium Glutamate by Improving Mitochondrial Function in Rats.

PubMed

Quines, Caroline B; Chagas, Pietro M; Hartmann, Diane; Carvalho, Nélson R; Soares, Félix A; Nogueira, Cristina W

2017-09-01

It is has been demonstrated that mitochondrial dysfunction, oxidative stress, and chronic inflammatory process are associated with progress of morbid obesity in human patients. For this reason, the searching for safe and effective antiobesity drugs has been the subject of intense research. In this context, the organic selenium compounds have attracted much attention due to their pharmacological properties, such as antihyperglycemic, antioxidant, and anti-inflammatory. The aim of this study was to evaluate the hepatoprotective action of p-chloro-diphenyl diselenide (p-ClPhSe) 2 , an organic selenium compound, in a model of obesity induced by monosodium glutamate (MSG) administration in rats. Wistar rats were treated during the first ten postnatal days with MSG (4 g/kg by subcutaneous injections) and received (p-ClPhSe) 2 (10 mg/kg, intragastrically) from 90th to 97th postnatal day. Mitochondrial function, purine content and the levels of proteins involved in apoptotic (poly [ADP-ribose] polymerase [PARP]) and inflammatory processes (inducible nitric oxide synthases [iNOS] and p38) were determined in the liver of rats. The present study, demonstrated that postnatal administration of MSG to male rats induced a mitochondrial dysfunction, accompanied by oxidative stress and an increase in the ADP levels, without altering the efficiency of phosphorylation in the liver of adult rats. Furthermore, the MSG administration also induces hepatotoxicity, through an increase in PARP, iNOS, and p38 levels. (p-ClPhSe) 2 treatment had beneficial effects against mitochondrial dysfunction, oxidative stress, and modulated protein markers of apoptosis and inflammation in the liver of MSG-treated rats. J. Cell. Biochem. 118: 2877-2886, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Advances in bioartificial liver assist devices.

PubMed

Patzer, J F

2001-11-01

Rapid advances in development of bioartificial liver assist devices (BLADs) are exciting clinical interest in the application of BLAD technology for support of patients with acute liver failure. Four devices (Circe Biomedical HepatAssist, Vitagen ELAD, Gerlach BELS, and Excorp Medical BLSS) that rely on hepatocytes cultured in hollow-fiber membrane technology are currently in various stages of clinical evaluation. Several alternative approaches for culture and perfusion of hepatocytes have been evaluated in preclinical, large animal models of liver failure, or at a laboratory scale. Engineering design issues with respect to xenotransplantation, BLAD perfusion, hepatocyte functionality and culture maintenance, and ultimate distribution of a BLAD to a clinical site are delineated.

Renal outcomes of simultaneous liver-kidney transplantation compared to liver transplant alone for candidates with renal dysfunction.

PubMed

Brennan, Todd V; Lunsford, Keri E; Vagefi, Parsia A; Bostrom, Alan; Ma, Michael; Feng, Sandy

2015-01-01

It is unclear whether a concomitant kidney transplant grants survival benefit to liver transplant (LT) candidates with renal dysfunction (RD). We retrospectively studied LT candidates without RD (n = 714) and LT candidates with RD who underwent either liver transplant alone (RD-LTA; n = 103) or simultaneous liver-kidney transplant (RD-SLKT; n = 68). RD was defined as renal replacement therapy (RRT) requirement or modification of diet in renal disease (MDRD)-glomerular filtration rate (GFR) <25 mL/min/1.73 m(2) . RD-LTAs had worse one-yr post-transplant survival compared to RD-SLKTs (79.6% vs. 91.2%, p = 0.05). However, RD-LTA recipients more often had hepatitis C (60.2% vs. 41.2%, p = 0.004) and more severe liver disease (MELD 37.9 ± 8.1 vs. 32.7 ± 9.1, p = 0.0001). Twenty RD-LTA recipients died in the first post-transplant year. Evaluation of the cause and timing of death relative to native renal recovery revealed that only four RD-LTA recipients might have derived survival benefit from RD-SLKT. Overall, 87% of RD-LTA patients recovered renal function within one month of transplant. One yr after RD-LTA or RD-SLKT, serum creatinine (1.5 ± 1.2 mg/dL vs. 1.4 ± 0.5 mg/dL, p = 0.63) and prevalence of stage 4 or 5 chronic kidney disease (CKD; 5.9% vs. 6.8%, p = 0.11) were comparable. Our series provides little evidence that RD-SLKT would have yielded substantial short-term survival benefit to RD-LTA recipients. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Pro-Brain Natriuretic Peptide and Troponin T-Hypersensitivity Levels Correlate With the Severity of Liver Dysfunction in Liver Cirrhosis.

PubMed

Zhao, Jiancheng; Li, Sai; Ren, Linan; Guo, Xiaozhong; Qi, Xingshun

2017-08-01

Increased pro-brain natriuretic peptide (pro-BNP) or troponin T-hypersensitivity (TnT-HSST) levels are common in liver cirrhosis. We conducted a retrospective observational study aimed to evaluate the correlation of pro-BNP and TnT-HSST levels with the clinical characteristics, laboratory data and in-hospital outcomes of patients with liver cirrhosis. We selected cirrhotic patients admitted to our hospital between January 2011 and June 2014. All eligible patients had pro-BNP or TnT-HSST data, or both. The pro-BNP and TnT-HSST data were further divided according to the presence of cardiac diseases. The prevalence of pro-BNP level >900pg/mL was 41.72% (63 of 151 patients). The prevalence of TnT-HSST level >0.05ng/mL was 11.22% (45 of 401 patients). In the overall analysis, pro-BNP level significantly correlated with red blood cell (RBC), platelet, ascites, blood urea nitrogen (BUN), creatinine (Cr), Child-Pugh score, model for end-stage liver disease (MELD) score and in-hospital death; TnT-HSST level significantly correlated with white blood cell, ascites, albumin (ALB), BUN, Cr, Child-Pugh score, MELD score and in-hospital death. In patients with cardiac diseases, pro-BNP level significantly correlated with RBC, ascites, BUN, Cr, Child-Pugh score and MELD score; TnT-HSST level significantly correlated with sex, ascites, white blood cell, ALB, BUN, Cr, Child-Pugh score, MELD score and in-hospital death. In patients without cardiac diseases, pro-BNP level significantly correlated with ascites, RBC, platelet, BUN, Cr, MELD score and in-hospital death; TnT-HSST level significantly correlated with age, ascites, RBC, ALB, BUN, Cr, Child-Pugh score, MELD score and in-hospital death. Pro-BNP and TnT-HSST levels significantly correlated with the severity of liver dysfunction and in-hospital mortality in cirrhosis. Copyright © 2017 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.

A score model for the continuous grading of early allograft dysfunction severity.

PubMed

Pareja, Eugenia; Cortes, Miriam; Hervás, David; Mir, José; Valdivieso, Andrés; Castell, José V; Lahoz, Agustín

2015-01-01

Early allograft dysfunction (EAD) dramatically influences graft and patient outcomes. A lack of consensus on an EAD definition hinders comparisons of liver transplant outcomes and management of recipients among and within centers. We sought to develop a model for the quantitative assessment of early allograft function [Model for Early Allograft Function Scoring (MEAF)] after transplantation. A retrospective study including 1026 consecutive liver transplants was performed for MEAF score development. Multivariate data analysis was used to select a small number of postoperative variables that adequately describe EAD. Then, the distribution of these variables was mathematically modeled to assign a score for each actual variable value. A model, based on easily obtainable clinical parameters (ie, alanine aminotransferase, international normalized ratio, and bilirubin) and scoring liver function from 0 to 10, was built. The MEAF score showed a significant association with patient and graft survival at 3-, 6- and 12-month follow-ups. Hepatic steatosis and age for donors; cold/warm ischemia times and postreperfusion syndrome for surgery; and intensive care unit and hospital stays, Model for End-Stage Liver Disease and Child-Pugh scores, body mass index, and fresh frozen plasma transfusions for recipients were factors associated significantly with EAD. The model was satisfactorily validated by its application to an independent set of 200 patients who underwent liver transplantation at a different center. In conclusion, a model for the quantitative assessment of EAD severity has been developed and validated for the first time. The MEAF provides a more accurate graft function assessment than current categorical classifications and may help clinicians to make early enough decisions on retransplantation benefits. Furthermore, the MEAF score is a predictor of recipient and graft survival. The standardization of the criteria used to define EAD may allow reliable comparisons of recipients' treatments and transplant outcomes among and within centers. © 2014 American Association for the Study of Liver Diseases.

Gut Microbiome-Based Metagenomic Signature for Non-invasive Detection of Advanced Fibrosis in Human Nonalcoholic Fatty Liver Disease.

PubMed

Loomba, Rohit; Seguritan, Victor; Li, Weizhong; Long, Tao; Klitgord, Niels; Bhatt, Archana; Dulai, Parambir Singh; Caussy, Cyrielle; Bettencourt, Richele; Highlander, Sarah K; Jones, Marcus B; Sirlin, Claude B; Schnabl, Bernd; Brinkac, Lauren; Schork, Nicholas; Chen, Chi-Hua; Brenner, David A; Biggs, William; Yooseph, Shibu; Venter, J Craig; Nelson, Karen E

2017-05-02

The presence of advanced fibrosis in nonalcoholic fatty liver disease (NAFLD) is the most important predictor of liver mortality. There are limited data on the diagnostic accuracy of gut microbiota-derived signature for predicting the presence of advanced fibrosis. In this prospective study, we characterized the gut microbiome compositions using whole-genome shotgun sequencing of DNA extracted from stool samples. This study included 86 uniquely well-characterized patients with biopsy-proven NAFLD, of which 72 had mild/moderate (stage 0-2 fibrosis) NAFLD, and 14 had advanced fibrosis (stage 3 or 4 fibrosis). We identified a set of 40 features (p < 0.006), which included 37 bacterial species that were used to construct a Random Forest classifier model to distinguish mild/moderate NAFLD from advanced fibrosis. The model had a robust diagnostic accuracy (AUC 0.936) for detecting advanced fibrosis. This study provides preliminary evidence for a fecal-microbiome-derived metagenomic signature to detect advanced fibrosis in NAFLD. Copyright © 2017 Elsevier Inc. All rights reserved.

A new hypothesis on the manifestation of cerebral malaria: the secret is in the liver.

PubMed

Martins, Yuri Chaves; Daniel-Ribeiro, Cláudio Tadeu

2013-11-01

Despite the abundance of information on cerebral malaria (CM), the pathogenesis of this disease is not completely understood. At present, two nonexclusive dominant hypotheses exist to explain how the neurological syndrome manifests: the sequestration (or mechanical) hypothesis and the inflammatory hypothesis. The sequestration hypothesis states that sequestration of Plasmodium falciparum-parasitized red blood cells (pRBCs) to brain capillary endothelia causes obstruction of capillary blood flow followed by brain tissue anoxia and coma. The inflammatory hypothesis postulates that P. falciparum infection releases toxic molecules in the circulation, inducing an imbalanced systemic inflammatory response that leads to coagulopathy, brain endothelial cell dysfunction, accumulation of leukocytes in the brain microcirculation, blood brain barrier (BBB) leakage, cerebral vasoconstriction, edema, and coma. However, both hypotheses, even when considered together, are not sufficient to fully explain the pathogenesis of CM. Here, we propose that the development of acute liver failure (ALF) together with BBB breakdown are the necessary and sufficient conditions for the genesis of CM. ALF is characterized by coagulopathy and hepatic encephalopathy (HE) in a patient without pre-existing liver disease. Signs of hepatic dysfunction have been shown to occur in 2.5-40% of CM patients. In addition, recent studies with murine models demonstrated that mice presenting experimental cerebral malaria (ECM) had hepatic damage and brain metabolic changes characteristic of HE. However, the occurrence of CM in patients with mild or without apparent hepatocellular liver damage and the presence of liver damage in non-CM murine models indicate that the development of ALF during malaria infection is not the single factor responsible for neuropathology. To solve this problem, we also propose that BBB breakdown contributes to the pathogenesis of CM and synergizes with hepatic failure to cause neurological signs and symptoms. BBB dysfunction would thus occur in CM by a mechanism similar to the one occurring in sepsis and is in agreement with the inflammatory hypothesis. Nevertheless, differently from in the inflammatory hypothesis, BBB leakage would facilitate the penetration of ammonia and other toxins into the brain parenchyma, but would not be sufficient to cause CM when occurring alone. We believe our hypothesis better explains the pathogenesis of CM, does not have problems to deal with the exception data not explained by the previous hypotheses, and reveals new targets for adjunctive therapy. Copyright © 2013 Elsevier Ltd. All rights reserved.

Building shared experience to advance practical application of pathway-based toxicology: liver toxicity mode-of-action.

PubMed

Willett, Catherine; Caverly Rae, Jessica; Goyak, Katy O; Minsavage, Gary; Westmoreland, Carl; Andersen, Melvin; Avigan, Mark; Duché, Daniel; Harris, Georgina; Hartung, Thomas; Jaeschke, Hartmut; Kleensang, Andre; Landesmann, Brigitte; Martos, Suzanne; Matevia, Marilyn; Toole, Colleen; Rowan, Andrew; Schultz, Terry; Seed, Jennifer; Senior, John; Shah, Imran; Subramanian, Kalyanasundaram; Vinken, Mathieu; Watkins, Paul

2014-01-01

A workshop sponsored by the Human Toxicology Project Consortium (HTPC), "Building Shared Experience to Advance Practical Application of Pathway-Based Toxicology: Liver Toxicity Mode-of-Action" brought together experts from a wide range of perspectives to inform the process of pathway development and to advance two prototype pathways initially developed by the European Commission Joint Research Center (JRC): liver-specific fibrosis and steatosis. The first half of the workshop focused on the theory and practice of pathway development; the second on liver disease and the two prototype pathways. Participants agreed pathway development is extremely useful for organizing information and found that focusing the theoretical discussion on a specific AOP is extremely helpful. In addition, it is important to include several perspectives during pathway development, including information specialists, pathologists, human health and environmental risk assessors, and chemical and product manufacturers, to ensure the biology is well captured and end use is considered.

Lipidomics comparing DCD and DBD liver allografts uncovers lysophospholipids elevated in recipients undergoing early allograft dysfunction.

PubMed

Xu, Jin; Casas-Ferreira, Ana M; Ma, Yun; Sen, Arundhuti; Kim, Min; Proitsi, Petroula; Shkodra, Maltina; Tena, Maria; Srinivasan, Parthi; Heaton, Nigel; Jassem, Wayel; Legido-Quigley, Cristina

2015-12-04

Finding specific biomarkers of liver damage in clinical evaluations could increase the pool of available organs for transplantation. Lipids are key regulators in cell necrosis and hence this study hypothesised that lipid levels could be altered in organs suffering severe ischemia. Matched pre- and post-transplant biopsies from donation after circulatory death (DCD, n = 36, mean warm ischemia time = 2 min) and donation after brain death (DBD, n = 76, warm ischemia time = none) were collected. Lipidomic discovery and multivariate analysis (MVA) were applied. Afterwards, univariate analysis and clinical associations were conducted for selected lipids differentiating between these two groups. MVA grouped DCD vs. DBD (p = 6.20 × 10(-12)) and 12 phospholipids were selected for intact lipid measurements. Two lysophosphatidylcholines, LysoPC (16:0) and LysoPC (18:0), showed higher levels in DCD at pre-transplantation (q < 0.01). Lysophosphatidylcholines were associated with aspartate aminotransferase (AST) 14-day post-transplantation (q < 0.05) and were more abundant in recipients undergoing early allograft dysfunction (EAD) (p < 0.05). A receiver-operating characteristics (ROC) curve combining both lipid levels predicted EAD with 82% accuracy. These findings suggest that LysoPC (16:0) and LysoPC (18:0) might have a role in signalling liver tissue damage due to warm ischemia before transplantation.

Nicotinamide mononucleotide (NMN) supplementation ameliorates the impact of maternal obesity in mice: comparison with exercise.

PubMed

Uddin, Golam Mezbah; Youngson, Neil A; Doyle, Bronte M; Sinclair, David A; Morris, Margaret J

2017-11-08

Maternal overnutrition increases the risk of long-term metabolic dysfunction in offspring. Exercise improves metabolism partly by upregulating mitochondrial biogenesis or function, via increased levels of nicotinamide adenine dinucleotide (NAD + ). We have shown that the NAD + precursor, nicotinamide mononucleotide (NMN) can reverse some of the negative consequences of high fat diet (HFD) consumption. To investigate whether NMN can impact developmentally-set metabolic deficits, we compared treadmill exercise and NMN injection in offspring of obese mothers. Five week old lean and obese female C57BL6/J mice were mated with chow fed males. Female offspring weaned onto HFD were given treadmill exercise for 9 weeks, or NMN injection daily for 18 days. Maternal obesity programmed increased adiposity and liver triglycerides, with decreased glucose tolerance, liver NAD + levels and citrate synthase activity in offspring. Both interventions reduced adiposity, and showed a modest improvement in glucose tolerance and improved markers of mitochondrial function. NMN appeared to have stronger effects on liver fat catabolism (Hadh) and synthesis (Fasn) than exercise. The interventions appeared to exert the most global benefit in mice that were most metabolically challenged (HFD-consuming offspring of obese mothers). This work encourages further study to confirm the suitability of NMN for use in reversing metabolic dysfunction linked to programming by maternal obesity.

Specific Etiologies Associated With the Multiple Organ Dysfunction Syndrome in Children: Part 2.

PubMed

Upperman, Jeffrey S; Bucuvalas, John C; Williams, Felicia N; Cairns, Bruce A; Cox, Charles S; Doctor, Allan; Tamburro, Robert F

2017-03-01

To describe a number of conditions and therapies associated with multiple organ dysfunction syndrome presented as part of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Multiple Organ Dysfunction Workshop (March 26-27, 2015). In addition, the relationship between burn injuries and multiple organ dysfunction syndrome is also included although it was not discussed at the workshop. Literature review, research data, and expert opinion. Not applicable. Moderated by an expert from the field, issues relevant to the association of multiple organ dysfunction syndrome with a variety of conditions and therapies were presented, discussed, and debated with a focus on identifying knowledge gaps and the research priorities. Summary of presentations and discussion supported and supplemented by relevant literature. Sepsis and trauma are the two conditions most commonly associated with multiple organ dysfunction syndrome both in children and adults. However, many other pathophysiologic processes may result in multiple organ dysfunction syndrome. In this article, we discuss conditions such as liver failure and pancreatitis, pathophysiologic processes such as ischemia and hypoxia, and injuries such as trauma and burns. Additionally, therapeutic interventions such as medications, blood transfusions, transplantation may also precipitate and contribute to multiple organ dysfunction syndrome. The purpose of this article is to describe the association of multiple organ dysfunction syndrome with a variety of conditions and therapies in an attempt to identify similarities, differences, and opportunities for therapeutic intervention.

Veliparib, Paclitaxel, and Carboplatin in Treating Patients With Solid Tumors That Are Metastatic or Cannot Be Removed by Surgery and Liver or Kidney Dysfunction

ClinicalTrials.gov

2017-07-25

Breast Carcinoma; Carcinoma of Unknown Primary Origin; Endometrial Carcinoma; Esophageal Carcinoma; Lung Carcinoma; Malignant Head and Neck Neoplasm; Melanoma; Ovarian Carcinoma; Renal Pelvis and Ureter Urothelial Carcinoma; Testicular Lymphoma

Pharmacological inhibition of soluble epoxide hydrolase ameliorates diet-induced metabolic syndrome in rats.

PubMed

Iyer, Abishek; Kauter, Kathleen; Alam, Md Ashraful; Hwang, Sung Hee; Morisseau, Christophe; Hammock, Bruce D; Brown, Lindsay

2012-01-01

The signs of metabolic syndrome following chronic excessive macronutrient intake include body weight gain, excess visceral adipose deposition, hyperglycaemia, glucose and insulin intolerances, hypertension, dyslipidaemia, endothelial damage, cardiovascular hypertrophy, inflammation, ventricular contractile dysfunction, fibrosis, and fatty liver disease. Recent studies show increased activity of soluble epoxide hydrolase (sEH) during obesity and metabolic dysfunction. We have tested whether sEH inhibition has therapeutic potential in a rat model of diet-induced metabolic syndrome. In these high-carbohydrate, high-fat-fed rats, chronic oral treatment with trans-4-[4-(3-adamantan-1-ylureido)-cyclohexyloxy]-benzoic acid (t-AUCB), a potent sEH inhibitor, alleviated the signs of metabolic syndrome in vivo including glucose, insulin, and lipid abnormalities, changes in pancreatic structure, increased systolic blood pressure, cardiovascular structural and functional abnormalities, and structural and functional changes in the liver. The present study describes the pharmacological responses to this selective sEH inhibitor in rats with the signs of diet-induced metabolic syndrome.

MECHANISMS IN ENDOCRINOLOGY: The sexually dimorphic role of androgens in human metabolic disease.

PubMed

Schiffer, Lina; Kempegowda, Punith; Arlt, Wiebke; O'Reilly, Michael W

2017-09-01

Female androgen excess and male androgen deficiency manifest with an overlapping adverse metabolic phenotype, including abdominal obesity, insulin resistance, type 2 diabetes mellitus, non-alcoholic fatty liver disease and an increased risk of cardiovascular disease. Here, we review the impact of androgens on metabolic target tissues in an attempt to unravel the complex mechanistic links with metabolic dysfunction; we also evaluate clinical studies examining the associations between metabolic disease and disorders of androgen metabolism in men and women. We conceptualise that an equilibrium between androgen effects on adipose tissue and skeletal muscle underpins the metabolic phenotype observed in female androgen excess and male androgen deficiency. Androgens induce adipose tissue dysfunction, with effects on lipid metabolism, insulin resistance and fat mass expansion, while anabolic effects on skeletal muscle may confer metabolic benefits. We hypothesise that serum androgen concentrations observed in female androgen excess and male hypogonadism are metabolically disadvantageous, promoting adipose and liver lipid accumulation, central fat mass expansion and insulin resistance. © 2017 The authors.

MECHANISMS IN ENDOCRINOLOGY: The sexually dimorphic role of androgens in human metabolic disease

PubMed Central

Schiffer, Lina; Kempegowda, Punith; Arlt, Wiebke

2017-01-01

Female androgen excess and male androgen deficiency manifest with an overlapping adverse metabolic phenotype, including abdominal obesity, insulin resistance, type 2 diabetes mellitus, non-alcoholic fatty liver disease and an increased risk of cardiovascular disease. Here, we review the impact of androgens on metabolic target tissues in an attempt to unravel the complex mechanistic links with metabolic dysfunction; we also evaluate clinical studies examining the associations between metabolic disease and disorders of androgen metabolism in men and women. We conceptualise that an equilibrium between androgen effects on adipose tissue and skeletal muscle underpins the metabolic phenotype observed in female androgen excess and male androgen deficiency. Androgens induce adipose tissue dysfunction, with effects on lipid metabolism, insulin resistance and fat mass expansion, while anabolic effects on skeletal muscle may confer metabolic benefits. We hypothesise that serum androgen concentrations observed in female androgen excess and male hypogonadism are metabolically disadvantageous, promoting adipose and liver lipid accumulation, central fat mass expansion and insulin resistance. PMID:28566439

Feasibility of using marginal liver grafts in living donor liver transplantation

PubMed Central

Lan, Xiang; Zhang, Hua; Li, Hong-Yu; Chen, Ke-Fei; Liu, Fei; Wei, Yong-Gang; Li, Bo

2018-01-01

Liver transplantation (LT) is one of the most effective treatments for end-stage liver disease caused by related risk factors when liver resection is contraindicated. Additionally, despite the decrease in the prevalence of hepatitis B virus (HBV) over the past two decades, the absolute number of HBsAg-positive people has increased, leading to an increase in HBV-related liver cirrhosis and hepatocellular carcinoma. Consequently, a large demand exists for LT. While the wait time for patients on the donor list is, to some degree, shorter due to the development of living donor liver transplantation (LDLT), there is still a shortage of liver grafts. Furthermore, recipients often suffer from emergent conditions, such as liver dysfunction or even hepatic encephalopathy, which can lead to a limited choice in grafts. To expand the pool of available liver grafts, one option is the use of organs that were previously considered “unusable” by many, which are often labeled “marginal” organs. Many previous studies have reported on the possibilities of using marginal grafts in orthotopic LT; however, there is still a lack of discussion on this topic, especially regarding the feasibility of using marginal grafts in LDLT. Therefore, the present review aimed to summarize the feasibility of using marginal liver grafts for LDLT and discuss the possibility of expanding the application of these grafts. PMID:29930466

AMELIORATIVE ROLE OF Vernonia cinerea IN CARBON TETRACHLORIDE INDUCED HEPATIC DYSFUNCTION IN RATS.

PubMed

Gokilaveni, C; Nishadh, A; Selvi, V

2006-01-01

The ameliorative activity of herbal powder prepared from Veronia cinerea leaves on CCl(4) (0.2ml/kg body wt. intraperitoneally (ip) and liquid paraffin (0.2 ml / kg body wt:ip) induced hepatotoxicity was studied in rats. The liver marker enzymes namely alanine transmainase (ALT), aspartate transaminase (AST), acid phosphatase and alkaline phosphatase (ALP) activities were decreased in 10% w/v liver homogenates of hepatotoxicity induced rats. The results of both post treated and pre treated groups suggest the hepatoprotective activity of Veronia cinerea in CCl(4) induced rats.

Mechanisms of bile acid mediated inflammation in the liver.

PubMed

Li, Man; Cai, Shi-Ying; Boyer, James L

2017-08-01

Bile acids are synthesized in the liver and are the major component in bile. Impaired bile flow leads to cholestasis that is characterized by elevated levels of bile acid in the liver and serum, followed by hepatocyte and biliary injury. Although the causes of cholestasis have been extensively studied, the molecular mechanisms as to how bile acids initiate liver injury remain controversial. In this chapter, we summarize recent advances in the pathogenesis of bile acid induced liver injury. These include bile acid signaling pathways in hepatocytes as well as the response of cholangiocytes and innate immune cells in the liver in both patients with cholestasis and cholestatic animal models. We focus on how bile acids trigger the production of molecular mediators of neutrophil recruitment and the role of the inflammatory response in this pathological process. These advances point to a number of novel targets where drugs might be judged to be effective therapies for cholestatic liver injury. Copyright © 2017 Elsevier Ltd. All rights reserved.

Modified CLIP with objective liver reserve assessment retains prognosis prediction for patients with advanced hepatocellular carcinoma.

PubMed

Shao, Yu-Yun; Liu, Tsung-Hao; Lee, Ying-Hui; Hsu, Chih-Hung; Cheng, Ann-Lii

2016-07-01

The Cancer of the Liver Italian Program (CLIP) score is a commonly used staging system for hepatocellular carcinoma (HCC) helpful with predicting prognosis of advanced HCC. CLIP uses the Child-Turcotte-Pugh (CTP) score to evaluate liver reserve. A new scoring system, the albumin-bilirubin (ALBI) grade, has been proposed as they objectively evaluate liver reserve. We examined whether the modification of CLIP with ALBI retained its prognosis prediction for patients with advanced HCC. We included patients who received first-line antiangiogenic therapy for advanced HCC. Liver reserve was assessed using CTP and ALBI scores, which were then incorporated into CLIP and ALBI-CLIP, respectively. To assess their efficacies of prognostic prediction, the Cox's proportional hazard model and concordance indexes were used. A total of 142 patients were included; 137 of them were classified CTP A and 5 patients CTP B. Patients could be divided into four or five groups with different prognosis according to CLIP and ALBI-CLIP, respectively. Higher R(2) (0.249 vs 0.216) and lower Akaike information criterion (995.0 vs 1001.1) were observed for ALBI-CLIP than for CLIP in the Cox's model predicting overall survival. ALBI-CLIP remained an independent predictor for overall survival when CLIP and ALBI-CLIP were simultaneously incorporated in Cox's models allowing variable selection with adjustment for hepatitis etiology, treatment, and performance status. The concordance index was also higher for ALBI-CLIP than for CLIP (0.724 vs 0.703). Modification of CLIP scoring with ALBI, which objectively assesses liver reserve, retains and might have improved prognosis prediction for advanced HCC. © 2016 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.

Sexual dysfunction in 2013: Advances in epidemiology, diagnosis and treatment.

PubMed

Lee, King Chien Joe; Fahmy, Nader; Brock, Gerald B

2013-09-01

To provide a contemporary review of the epidemiology, diagnosis and treatment of premature ejaculation (PE) and erectile dysfunction (ED). We searched for English-language articles published in the past 12 months using the PubMed database. Relevant articles on the subjects of sexual dysfunction, ED and PE were selected for review. Recent studies on male sexual dysfunction have provided new therapeutic possibilities. Tramadol, a well-used analgesic, has a new role in the treatment of PE. Super-selective targeting of dorsal penile nerves by surgery or cryoablative technologies might become a viable treatment option for refractory PE in the future. The role of ED as a harbinger of important comorbidities allows for the early detection and intervention of these conditions, which can optimise therapeutic outcomes. The long-term effect of chronic phosphodiesterase-5 inhibitors on endothelial dysfunction, the angiogenic potential of low-intensity extracorporeal shock wave therapy, and further advances in drug-eluting endovascular stents might in future allow clinicians to treat ED more definitively.

Phase I clinical study of personalized peptide vaccination combined with radiotherapy for advanced hepatocellular carcinoma

PubMed Central

Shen, Jie; Wang, Li-Feng; Zou, Zheng-Yun; Kong, Wei-Wei; Yan, Jing; Meng, Fan-Yan; Chen, Fang-Jun; Du, Juan; Shao, Jie; Xu, Qiu-Ping; Ren, Hao-Zhen; Li, Ru-Tian; Wei, Jia; Qian, Xiao-Ping; Liu, Bao-Rui

2017-01-01

AIM To assess the efficacy and safety of a new treatment modality, cellular immune therapy based on personalized peptide vaccination (PPV-DC-CTL) combined with radiotherapy, for treating advanced hepatocellular carcinoma (HCC). METHODS A total of nine patients with advanced HCC were enrolled. Multidisciplinary consultation confirmed that all the patients definitely had no opportunity of surgery, because four patients had multiple liver metastases (the number of liver lesions > 3), one patient had liver metastases and portal vein tumor thrombosis, one patient had lung and bone metastases, two patients had liver and lung metastases and one patient had liver metastasis and peritoneal metastasis. Patients with metastasis were treated with precise radiotherapy combined with PPV-DC-CTL. RESULTS Following radiotherapy and one to three cycles of PPV-DC-CTL treatment, AFP levels were significantly decreased in six patients and imaging assessment of the lesions showed a partial response (PR) in three patients and stable disease in the other three patients. The response rate was 33% and disease control rate was 66%. This regimen was found to be safe and well tolerated. None of the patients developed liver or kidney side effects. Only one patient developed grade II bone marrow suppression and the remaining patients had no significant hematological side effects. CONCLUSION Radiotherapy combined with PPV-DC-CTL provides a new therapeutic strategy for patients with advanced HCC, which is well tolerated, safe, feasible and effective. PMID:28839440

[Chronic rejection: Differences and similarities in various solid organ transplants].

PubMed

Suhling, H; Gottlieb, J; Bara, C; Taubert, R; Jäckel, E; Schiffer, M; Bräsen, J H

2016-01-01

In this paper, chronic rejections after transplantation of the lungs, heart, liver, and kidney are described. Chronic allograft dysfunction (CAD) plays an important role in all of these transplantations and has a significant influence on patient survival. The pathophysiological reasons for CAD varies greatly in the various organs.Chronic lung allograft dysfunction (CLAD) is the most important determinant of survival and quality of life after lung transplantation. Diagnosis is based on lung function, especially forced expiratory flow in 1 s (FEV1) decline. Prevention, early detection, and rapid treatment are extremely important. Azithromycin and extracorporeal photopheresis are commonly used for treatment because they usually positively influence the progression of lung remodeling.The expression for chronic rejection of the heart is cardiac allograft vasculopathy (CAV). Immunological and nonimmunological factors are important for its development. Due to limited therapeutic options, prevention is of utmost importance (administration of mTOR inhibitors and minimizing cardiovascular risk factors).The mid- and long-term survival rates after liver transplantation have hardly changed in recent decades, which is an indication of the difficulty in diagnosing chronic graft dysfunction. Chronic ductopenic rejection accounts for a small proportion of late graft dysfunction. Idiopathic posttransplant hepatitis and de novo autoimmune hepatitis are important in addition to recurrence of the underlying disease that led to transplantation.Chronic allograft nephropathy is the result of severe rejection which cumulates in increasing fibrosis with remodeling. The earliest possible diagnosis and therapy is currently the only option. Diagnosis is based on evidence of donor-specific antibodies and histological findings.

Spontaneous acute subdural hematoma and intracerebral hemorrhage in a patient with thrombotic microangiopathy during pregnancy

PubMed Central

Wayhs, Sâmia Yasin; Wottrich, Joise; Uggeri, Douglas Prestes; Dias, Fernando Suparregui

2013-01-01

Preeclampsia, HELLP syndrome (hemolysis, elevated liver enzymes, and low-platelet count), and acute fatty liver of pregnancy are the main causes of thrombotic microangiopathy and severe liver dysfunction during pregnancy and represent different manifestations of the same pathological continuum. The case of a 35-week pregnant woman who was admitted to an intensive care unit immediately after a Cesarean section due to fetal death and the presence of nausea, vomiting, and jaundice is reported. Postpartum preeclampsia and acute fatty liver of pregnancy were diagnosed. The patient developed an acute subdural hematoma and an intracerebral hemorrhage, which were subjected to neurosurgical treatment. The patient died from refractory hemolytic anemia and spontaneous bleeding of multiple organs. Preeclampsia, HELLP syndrome, and acute fatty liver of pregnancy might overlap and be associated with potentially fatal complications, including intracranial hemorrhage, as in the present case. Early detection and diagnosis are crucial to ensure appropriate management and treatment success. PMID:23917984

Pathogenesis of Zika Virus-Associated Embryopathy.

PubMed

Mawson, Anthony R

2016-01-01

A strong causal association has become evident between Zika virus (ZIKV) infection during pregnancy and the occurrence of fetal growth restriction, microcephaly and eye defects. Circumstantial evidence is presented in this paper in support of the hypothesis that these effects, as well as the Guillain-Barré syndrome, are due to an endogenous form of hypervitaminosis A resulting from ZIKV infection-induced damage to the liver and the spillage of stored vitamin A compounds ("retinoids") into the maternal and fetal circulation in toxic concentrations. Retinoids are mainly stored in the liver (about 80%) and are essential for numerous biological functions. In higher concentration, retinoids are potentially cytotoxic, pro-oxidant, mutagenic and teratogenic, especially if sudden shifts occur in their bodily distribution. Although liver involvement has not been mentioned specifically in recent reports, conventional liver enzyme tests underestimate the true extent of liver dysfunction. The proposed model could be tested by comparing retinoid concentration and expression profiles in microcephalic newborns of ZIKV-infected mothers and nonmicrocephalic newborn controls, and by correlating these profiles with measures of clinical severity.

Nonalcoholic fatty liver disease: diagnosis, pathogenesis, and management.

PubMed

Başaranoğlu, Metin; Örmeci, Necati

2014-04-01

Nonalcoholic fatty liver disease (NAFLD) is an umbrella term that covers both a relatively benign condition, which is simple steatosis, and nonalcoholic steatohepatitis (NASH). NASH is characterized by a chronic and progressive liver pathology that may progress to cirrhosis, end-stage liver disease, hepatocellular carcinoma, and liver transplantation. Despite the growing body of evidence, one of the important and unresolved problems is the pathogenesis of NASH. It might be a metabolic disturbance as a primary abnormality in NAFLD. Insulin resistance is at the center of these metabolic abnormalities. Then, hepatocyte injury might be induced by oxidative stress. This ongoing process progresses to NASH, even to cirrhosis in some patients. In addition to oxidative stress, possibilities for the next hit are lipid peroxidation, reactive metabolites, adipose tissue products, transforming growth factor-β₁, Fas ligand, mitochondrial dysfunction, respiratory chain deficiency, and intestinal microbiota. Currently, there is no well-established and approved therapy. Recommendations are to improve existing co-morbidities, such as obesity, hyperlipidemia, or type 2 diabetes, and lifestyle modification with weight loss and exercise.

Methods to determine intestinal permeability and bacterial translocation during liver disease

PubMed Central

Wang, Lirui; Llorente, Cristina; Hartmann, Phillipp; Yang, An-Ming; Chen, Peng; Schnabl, Bernd

2015-01-01

Liver disease is often times associated with increased intestinal permeability. A disruption of the gut barrier allows microbial products and viable bacteria to translocate from the intestinal lumen to extraintestinal organs. The majority of the venous blood from the intestinal tract is drained into the portal circulation, which is part of the dual hepatic blood supply. The liver is therefore the first organ in the body to encounter not only absorbed nutrients, but also gut-derived bacteria and pathogen associated molecular patterns (PAMPs). Chronic exposure to increased levels of PAMPs has been linked to disease progression during early stages and to infectious complications during late stages of liver disease (cirrhosis). It is therefore important to assess and monitor gut barrier dysfunction during hepatic disease. We review methods to assess intestinal barrier disruption and discuss advantages and disadvantages. We will in particular focus on methods that we have used to measure increased intestinal permeability and bacterial translocation during experimental liver disease models. PMID:25595554

Hepatitis A complicated with acute renal failure and high hepatocyte growth factor: A case report.

PubMed

Oe, Shinji; Shibata, Michihiko; Miyagawa, Koichiro; Honma, Yuichi; Hiura, Masaaki; Abe, Shintaro; Harada, Masaru

2015-08-28

A 58-year-old man was admitted to our hospital. Laboratory data showed severe liver injury and that the patient was positive for immunoglobulin M anti-hepatitis A virus (HAV) antibodies. He was also complicated with severe renal dysfunction and had an extremely high level of serum hepatocyte growth factor (HGF). Therefore, he was diagnosed with severe acute liver failure with acute renal failure (ARF) caused by HAV infection. Prognosis was expected to be poor because of complications by ARF and high serum HGF. However, liver and renal functions both improved rapidly without intensive treatment, and he was subsequently discharged from our hospital on the 21(st) hospital day. Although complication with ARF and high levels of serum HGF are both important factors predicting poor prognosis in acute liver failure patients, the present case achieved a favorable outcome. Endogenous HGF might play an important role as a regenerative effector in injured livers and kidneys.

Severe chronic hepatitis secondary to prolonged use of ecstasy and cocaine.

PubMed

Payancé, Audrey; Scotto, Béatrice; Perarnau, Jean-Marc; de Muret, Anne; Bacq, Yannick

2013-11-01

Severe acute hepatotoxicity is a well known complication following the ingestion of ecstasy (3,4-methylenedioxymethamphetamine [MDMA] ecstasy). Hepatic dysfunction has also been reported after acute cocaine intoxication. However, chronic hepatitis after prolonged use of ecstasy and/or cocaine has rarely been reported. We report the case of a 27-year-old woman hospitalized with edema, ascites and severe liver failure (prothrombin rate 33%), following the use of ecstasy and cocaine over the previous 9 months. Clinical, biological, radiological and pathology findings were recorded at admission and over 8 years' follow-up. Liver biopsy showed architectural distortion caused by bridging fibrosis, proliferation of cholangioles, and lesions of active interface hepatitis. Other causes of acute and chronic liver disease were excluded. Magnetic resonance imaging showed marked liver fibrosis. After withdrawal of both substances clinical examination and liver function tests progressively normalized. Long-term monitoring with magnetic resonance imaging showed progressive regression of fibrosis. Use of ecstasy and cocaine may cause chronic hepatitis leading to marked liver fibrosis, which may regress after withdrawal of both substances. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

Hepatocyte polyploidization and its association with pathophysiological processes.

PubMed

Wang, Min-Jun; Chen, Fei; Lau, Joseph T Y; Hu, Yi-Ping

2017-05-18

A characteristic cellular feature of the mammalian liver is the progressive polyploidization of the hepatocytes, where individual cells acquire more than two sets of chromosomes. Polyploidization results from cytokinesis failure that takes place progressively during the course of postnatal development. The proportion of polyploidy also increases with the aging process or with cellular stress such as surgical resection, toxic stimulation, metabolic overload, or oxidative damage, to involve as much as 90% of the hepatocytes in mice and 40% in humans. Hepatocyte polyploidization is generally considered an indicator of terminal differentiation and cellular senescence, and related to the dysfunction of insulin and p53/p21 signaling pathways. Interestingly, the high prevalence of hepatocyte polyploidization in the aged mouse liver can be reversed when the senescent hepatocytes are serially transplanted into young mouse livers. Here we review the current knowledge on the mechanism of hepatocytes polyploidization during postnatal growth, aging, and liver diseases. The biologic significance of polyploidization in senescent reversal, within the context of new ways to think of liver aging and liver diseases is considered.

Ischaemia–reperfusion injury in liver transplantation—from bench to bedside

PubMed Central

Zhai, Yuan; Petrowsky, Henrik; Hong, Johnny C.; Busuttil, Ronald W.; Kupiec-Weglinski, Jerzy W.

2013-01-01

Ischaemia–reperfusion injury (IRI) in the liver, a major complication of haemorrhagic shock, resection and transplantation, is a dynamic process that involves the two interrelated phases of local ischaemic insult and inflammation-mediated reperfusion injury. This Review highlights the latest mechanistic insights into innate–adaptive immune crosstalk and cell activation cascades that lead to inflammation-mediated injury in livers stressed by ischaemia–reperfusion, discusses progress in large animal experiments and examines efforts to minimize liver IRI in patients who have received a liver transplant. The interlinked signalling pathways in multiple hepatic cell types, the IRI kinetics and positive versus negative regulatory loops at the innate–adaptive immune interface are discussed. The current gaps in our knowledge and the pathophysiology aspects of IRI in which basic and translational research is still required are stressed. An improved appreciation of cellular immune events that trigger and sustain local inflammatory responses, which are ultimately responsible for organ injury, is fundamental to developing innovative strategies for treating patients who have received a liver transplant and developed ischaemia–reperfusion inflammation and organ dysfunction. PMID:23229329

Hepatocyte polyploidization and its association with pathophysiological processes

PubMed Central

Wang, Min-Jun; Chen, Fei; Lau, Joseph T Y; Hu, Yi-Ping

2017-01-01

A characteristic cellular feature of the mammalian liver is the progressive polyploidization of the hepatocytes, where individual cells acquire more than two sets of chromosomes. Polyploidization results from cytokinesis failure that takes place progressively during the course of postnatal development. The proportion of polyploidy also increases with the aging process or with cellular stress such as surgical resection, toxic stimulation, metabolic overload, or oxidative damage, to involve as much as 90% of the hepatocytes in mice and 40% in humans. Hepatocyte polyploidization is generally considered an indicator of terminal differentiation and cellular senescence, and related to the dysfunction of insulin and p53/p21 signaling pathways. Interestingly, the high prevalence of hepatocyte polyploidization in the aged mouse liver can be reversed when the senescent hepatocytes are serially transplanted into young mouse livers. Here we review the current knowledge on the mechanism of hepatocytes polyploidization during postnatal growth, aging, and liver diseases. The biologic significance of polyploidization in senescent reversal, within the context of new ways to think of liver aging and liver diseases is considered. PMID:28518148

Erlotinib in Treating Patients With Unresectable Liver, Bile Duct, or Gallbladder Cancer

ClinicalTrials.gov

2013-06-03

Adult Primary Cholangiocellular Carcinoma; Adult Primary Hepatocellular Carcinoma; Advanced Adult Primary Liver Cancer; Cholangiocarcinoma of the Extrahepatic Bile Duct; Cholangiocarcinoma of the Gallbladder; Localized Unresectable Adult Primary Liver Cancer; Recurrent Adult Primary Liver Cancer; Recurrent Extrahepatic Bile Duct Cancer; Recurrent Gallbladder Cancer; Unresectable Extrahepatic Bile Duct Cancer; Unresectable Gallbladder Cancer

Prevalence of elevated liver enzymes in children with cystic fibrosis diagnosed by newborn screen.

PubMed

Woodruff, Samantha A; Sontag, Marci K; Accurso, Frank J; Sokol, Ronald J; Narkewicz, Michael R

2017-01-01

Prevalence and risks for elevated liver enzymes have not been studied systematically in children with CF identified by newborn screen. 298 CF children identified by newborn screen since 1982. AST, ALT and GGT tested at annual visits. Percent of children with 1 or ≥2 values of elevated AST, ALT and GGT determined. Relationship of liver enzymes to clinical factors or subsequent liver disease was analyzed RESULTS: At least one abnormal value for AST (63%), ALT (93%) and ALT ≥1.5× ULN (52%) occurred by 21years of age. Liver enzyme elevations were not correlated with CFTR mutation, meconium ileus or ethnicity. AST and GGT ≥1.5× ULN were associated with later advanced liver disease HR (CI) 6.53 (2.02-21.1) and 4.03 (1.15-13.45), respectively. Elevated liver enzymes are common during childhood in CF patients identified by newborn screen. Elevated AST and GGT may be markers for risk of advanced liver disease. Copyright © 2016 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

Clinical and histological determinants of nonalcoholic steatohepatitis and advanced fibrosis in elderly patients.

PubMed

Noureddin, Mazen; Yates, Katherine P; Vaughn, Ivana A; Neuschwander-Tetri, Brent A; Sanyal, Arun J; McCullough, Arthur; Merriman, Raphael; Hameed, Bilal; Doo, Edward; Kleiner, David E; Behling, Cynthia; Loomba, Rohit

2013-11-01

The characteristics of nonalcoholic fatty liver disease (NAFLD) in elderly patients are unknown. Therefore, we aimed to examine the differences between elderly and nonelderly patients with NAFLD and to identify determinants of nonalcoholic steatohepatitis (NASH) and advanced fibrosis (bridging fibrosis or cirrhosis) in elderly patients. This is a cross-sectional analysis of adult participants who were prospectively enrolled in the NASH Clinical Research Network studies. Participants were included based on availability of the centrally reviewed liver histology data within 1 year of enrollment, resulting in 61 elderly (age ≥65 years) and 735 nonelderly (18-64 years) participants. The main outcomes were the presence of NASH and advanced fibrosis. Compared to nonelderly patients with NAFLD, elderly patients had a higher prevalence of NASH (56% versus 72%, P = 0.02), and advanced fibrosis (25% versus 44%, P = 0.002). Compared to nonelderly patients with NASH, elderly patients with NASH had higher rates of advanced fibrosis (35% versus 52%, P = 0.03), as well as other features of severe liver disease including the presence of ballooning degeneration, acidophil bodies, megamitochondria, and Mallory-Denk bodies (P ≤ 0.05 for each). In multiple logistic regression analyses, independent determinants of NASH in elderly patients included higher aspartate aminotransferase (AST) (odds ratio [OR] = 1.12, P = 0.007) and lower platelets (OR = 0.98, P = 0.02); and independent determinants of advanced fibrosis included higher AST (OR = 1.08, P = 0.007), lower alanine aminotransferase value (OR = 0.91, P = 0.002), and an increased odds of having low high-density lipoprotein (OR = 8.35, P = 0.02). Elderly patients are more likely to have NASH and advanced fibrosis than nonelderly patients with NAFLD. Liver biopsy may be considered in elderly patients and treatment should be initiated in those with NASH and advanced fibrosis. © 2013 by the American Association for the Study of Liver Diseases.

Acetaminophen-induced liver injury in rats and mice: Comparison of protein adducts, mitochondrial dysfunction, and oxidative stress in the mechanism of toxicity

DOE Office of Scientific and Technical Information (OSTI.GOV)

McGill, Mitchell R.; Williams, C. David; Xie, Yuchao

2012-11-01

Acetaminophen (APAP) overdose is the most common cause of acute liver failure in the West. In mice, APAP hepatotoxicity can be rapidly induced with a single dose. Because it is both clinically relevant and experimentally convenient, APAP intoxication has become a popular model of liver injury. Early data demonstrated that rats are resistant to APAP toxicity. As a result, mice are the preferred species for mechanistic studies. Furthermore, recent work has shown that the mechanisms of APAP toxicity in humans are similar to mice. Nevertheless, some investigators still use rats. New mechanistic information from the last forty years invites amore » reevaluation of the differences between these species. Comparison may provide interesting insights and confirm or exclude the rat as an option for APAP studies. To this end, we treated rats and mice with APAP and measured parameters of liver injury, APAP metabolism, oxidative stress, and activation of the c-Jun N-terminal kinase (JNK). Consistent with earlier data, we found that rats were highly resistant to APAP toxicity. Although overall APAP metabolism was similar in both species, mitochondrial protein adducts were significantly lower in rats. Accordingly, rats also had less oxidative stress. Finally, while mice showed extensive activation and mitochondrial translocation of JNK, this could not be detected in rat livers. These data support the hypothesis that mitochondrial dysfunction is critical for the development of necrosis after APAP treatment. Because mitochondrial damage also occurs in humans, rats are not a clinically relevant species for studies of APAP hepatotoxicity. Highlights: ► Acetaminophen overdose causes severe liver injury only in mice but not in rats. ► APAP causes hepatic GSH depletion and protein adduct formation in rats and mice. ► Less protein adducts were measured in rat liver mitochondria compared to mouse. ► No oxidant stress, peroxynitrite formation or JNK activation was present in rats. ► The limited mitochondrial adducts in rats are insufficient to trigger cell necrosis.« less

BMS-247550 in Treating Patients With Liver or Gallbladder Cancer

ClinicalTrials.gov

2014-05-13

Adult Primary Cholangiocellular Carcinoma; Adult Primary Hepatocellular Carcinoma; Advanced Adult Primary Liver Cancer; Cholangiocarcinoma of the Extrahepatic Bile Duct; Cholangiocarcinoma of the Gallbladder; Localized Extrahepatic Bile Duct Cancer; Localized Gallbladder Cancer; Localized Resectable Adult Primary Liver Cancer; Localized Unresectable Adult Primary Liver Cancer; Recurrent Adult Primary Liver Cancer; Recurrent Extrahepatic Bile Duct Cancer; Recurrent Gallbladder Cancer; Unresectable Extrahepatic Bile Duct Cancer; Unresectable Gallbladder Cancer

46 CFR 197.560 - Medical surveillance.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 46 Shipping 7 2014-10-01 2014-10-01 false Medical surveillance. 197.560 Section 197.560 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) MARINE OCCUPATIONAL SAFETY AND HEALTH STANDARDS..., and abnormal functions of formed blood elements, a history of renal or liver dysfunction, a history of...

46 CFR 197.560 - Medical surveillance.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 46 Shipping 7 2011-10-01 2011-10-01 false Medical surveillance. 197.560 Section 197.560 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) MARINE OCCUPATIONAL SAFETY AND HEALTH STANDARDS..., and abnormal functions of formed blood elements, a history of renal or liver dysfunction, a history of...

46 CFR 197.560 - Medical surveillance.

Code of Federal Regulations, 2012 CFR

2012-10-01

... 46 Shipping 7 2012-10-01 2012-10-01 false Medical surveillance. 197.560 Section 197.560 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) MARINE OCCUPATIONAL SAFETY AND HEALTH STANDARDS..., and abnormal functions of formed blood elements, a history of renal or liver dysfunction, a history of...

46 CFR 197.560 - Medical surveillance.

Code of Federal Regulations, 2013 CFR

2013-10-01

... 46 Shipping 7 2013-10-01 2013-10-01 false Medical surveillance. 197.560 Section 197.560 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) MARINE OCCUPATIONAL SAFETY AND HEALTH STANDARDS..., and abnormal functions of formed blood elements, a history of renal or liver dysfunction, a history of...

46 CFR 197.560 - Medical surveillance.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 46 Shipping 7 2010-10-01 2010-10-01 false Medical surveillance. 197.560 Section 197.560 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) MARINE OCCUPATIONAL SAFETY AND HEALTH STANDARDS..., and abnormal functions of formed blood elements, a history of renal or liver dysfunction, a history of...

Hyperammonemic encephalopathy due to suture line breakdown after bladder operation.

PubMed

Boogerd, W; Zoetmulder, F A; Moffie, D

1990-01-01

A patient is described with a severe encephalopathy and hyperammonemia in absence of liver dysfunction, attributed to urine absorption into the systemic circulation due to suture line breakdown after bladder dome resection. At autopsy characteristic Alzheimer type II astrocytes were found in the basal ganglia.

Magnetic resonance imaging and liver histology as biomarkers of hepatic steatosis in children with nonalcoholic fatty liver disease.

PubMed

Schwimmer, Jeffrey B; Middleton, Michael S; Behling, Cynthia; Newton, Kimberly P; Awai, Hannah I; Paiz, Melissa N; Lam, Jessica; Hooker, Jonathan C; Hamilton, Gavin; Fontanesi, John; Sirlin, Claude B

2015-06-01

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in children. In order to advance the field of NAFLD, noninvasive imaging methods for measuring liver fat are needed. Advanced magnetic resonance imaging (MRI) has shown great promise for the quantitative assessment of hepatic steatosis but has not been validated in children. Therefore, this study was designed to evaluate the correlation and diagnostic accuracy of MRI-estimated liver proton density fat fraction (PDFF), a biomarker for hepatic steatosis, compared to histologic steatosis grade in children. The study included 174 children with a mean age of 14.0 years. Liver PDFF estimated by MRI was significantly (P < 0.01) correlated (0.725) with steatosis grade. The correlation of MRI-estimated liver PDFF and steatosis grade was influenced by both sex and fibrosis stage. The correlation was significantly (P < 0.01) stronger in girls (0.86) than in boys (0.70). The correlation was significantly (P < 0.01) weaker in children with stage 2-4 fibrosis (0.61) than children with no fibrosis (0.76) or stage 1 fibrosis (0.78). The diagnostic accuracy of commonly used threshold values to distinguish between no steatosis and mild steatosis ranged from 0.69 to 0.82. The overall accuracy of predicting the histologic steatosis grade from MRI-estimated liver PDFF was 56%. No single threshold had sufficient sensitivity and specificity to be considered diagnostic for an individual child. Advanced magnitude-based MRI can be used to estimate liver PDFF in children, and those PDFF values correlate well with steatosis grade by liver histology. Thus, magnitude-based MRI has the potential for clinical utility in the evaluation of NAFLD, but at this time no single threshold value has sufficient accuracy to be considered diagnostic for an individual child. © 2015 by the American Association for the Study of Liver Diseases.

Hepatic encephalopathy in acute-on-chronic liver failure.

PubMed

Lee, Guan-Huei

2015-10-01

The presence of hepatic encephalopathy (HE) within 4 weeks is part of the criteria for defining acute-on-chronic liver failure (ACLF). The pathophysiology of HE is complex, and hyperammonemia and cerebral hemodynamic dysfunction appear to be central in the pathogenesis of encephalopathy. Recent data also suggest that inflammatory mediators may have a significant role in modulating the cerebral effect of ammonia. Multiple prospective and retrospective studies have shown that hepatic encephalopathy in ACLF patients is associated with higher mortality, especially in those with grade III-IV encephalopathy, similar to that of acute liver failure (ALF). Although significant cerebral edema detected by CT in ACLF patients appeared to be less common, specialized MRI imaging was able to detect cerebral edema even in low grade HE. Ammonia-focused therapy constitutes the basis of current therapy, as in the treatment of ALF. Emerging treatment strategies focusing on modulating the gut-liver-circulation-brain axis are discussed.

Non-alcoholic fatty liver disease and dyslipidemia: An update.

PubMed

Katsiki, Niki; Mikhailidis, Dimitri P; Mantzoros, Christos S

2016-08-01

Non-alcoholic fatty liver (NAFLD) is the most common liver disease worldwide, progressing from simple steatosis to necroinflammation and fibrosis (leading to non-alcoholic steatohepatitis, NASH), and in some cases to cirrhosis and hepatocellular carcinoma. Inflammation, oxidative stress and insulin resistance are involved in NAFLD development and progression. NAFLD has been associated with several cardiovascular (CV) risk factors including obesity, dyslipidemia, hyperglycemia, hypertension and smoking. NAFLD is also characterized by atherogenic dyslipidemia, postprandial lipemia and high-density lipoprotein (HDL) dysfunction. Most importantly, NAFLD patients have an increased risk for both liver and CV disease (CVD) morbidity and mortality. In this narrative review, the associations between NAFLD, dyslipidemia and vascular disease in NAFLD patients are discussed. NAFLD treatment is also reviewed with a focus on lipid-lowering drugs. Finally, future perspectives in terms of both NAFLD diagnostic biomarkers and therapeutic targets are considered. Copyright © 2016 Elsevier Inc. All rights reserved.

Noni juice is not hepatotoxic

PubMed Central

West, Brett J; Jensen, C Jarakae; Westendorf, Johannes

2006-01-01

Noni juice (Morinda citrifolia) has been approved for use as a safe food within the European Union, following a review of safety. Since approval, three cases of acute hepatitis in Austrian noni juice consumers have been published, where a causal link is suggested between the liver dysfunction and ingestion of anthraquinones from the plant. Measurements of liver function in a human clinical safety study of TAHITIAN NONI® Juice, as well as subacute and subchronic animal toxicity tests revealed no evidence of adverse liver effects at doses many times higher than those reported in the case studies. Additionally, M. citrifolia anthraquinones occur in the fruit in quantities too small to be of any toxicological significance. Further, these do not have chemical structures capable of being reduced to reactive anthrone radicals, which were implicated in previous cases of herbal hepototoxicity. The available data reveals no evidence of liver toxicity. PMID:16773722

Green tea extracts reduce leukocyte cell-Derived chemotaxin 2 and selenoprotein P levels in the livers of C57BL/6J mice fed a high-fat diet.

PubMed

Onishi, Shintaro; Kitazawa, Hidefumi; Meguro, Shinichi; Tokimitsu, Ichiro

2018-05-31

Epidemiological studies suggest that green tea extracts (GTEs), including catechins such as epigallocatechin gallate and epicatechin gallate, have a beneficial effect on obesity, hyperglycemia, insulin resistance, endothelial dysfunction, and inflammation. Although several studies have shown that catechins directly modulate the cellular and molecular alterations in the liver tissue, the contributions of indirect mechanisms underlying these systemic effects of catechins remain unclear. In this study, we report that, in the C57BL/6J mouse liver, GTEs reduce high-fat diet-induced increases in the levels of hepatokines, liver-derived secretary proteins such as leukocyte cell-derived chemotaxin 2 and selenoprotein P production, which have been shown to induce systemic adverse effects, including several metabolic diseases. These findings suggest that the systemic effects of GTEs involve the regulation of hepatokine production as an indirect mechanism.

[Ammonia as a cause for hepatic encephalopathy].

PubMed

Naimushin, Alexey; Livneh, Avi

2010-02-01

In a patient with cirrhosis of the liver, associated with hepatitis B virus, who was admitted for confusion and acute elevation of liver enzymes, a diagnosis of hepatic encephalopathy was made. A serum ammonia level of 54 (normal less than 33) microgram/liter, supported the diagnosis, but puzzled the medical staff regarding the possibility that ammonia may directly induce the confusion. While it is widely accepted that the ammonia level is a marker that usually parallels the amount of toxins and metabolites that bypasses the liver, its role in causing brain dysfunction is debated. However, since ammonia may directly hinder the metabolism of neuro-transmitters, and drugs and treatments specifically aimed at reducing ammonia levels may minimize the time interval for recovery from the acute brain insult, it is assumed that ammonia by itself had a role in bringing about the encephalopathy manifestations in our patients and other patients with cirrhosis of the liver.

Serum immunoglobulin levels predict fibrosis in patients with non-alcoholic fatty liver disease.

PubMed

McPherson, Stuart; Henderson, Elsbeth; Burt, Alastair D; Day, Christopher P; Anstee, Quentin M

2014-05-01

A third of the population are estimated to have NAFLD of varying severity. Serum immunoglobulins are frequently elevated in patients with chronic liver disease, but little is known about serum immunoglobulin levels in patients with NAFLD. Aim of this study was to evaluate serum immunoglobulin levels (IgA, IgG, and IgM) in a large cohort of patients with biopsy-proven NAFLD and determine if immunoglobulin levels are associated with clinical or histological features. Patients seen in a tertiary fatty liver clinic between 1999 and 2009 were included. Liver biopsies were assessed using the Kleiner score. Immunoglobulin levels and other blood tests were taken at time of biopsy. 285 patients (110 simple steatosis and 175 NASH) had serum immunoglobulins measured within 6months of liver biopsy. 130 (46%) patients had elevated (>1× upper limit of normal) serum IgA levels, 28 (10%) patients had elevated IgG and 22 (8%) raised IgM. Serum IgA levels were elevated more frequently in patients with NASH compared with subjects with simple steatosis (55% vs. 31%, p<0.001). Overall, 55 (19%) patients had advanced liver fibrosis (Kleiner stage 3-4). There was a significant positive association between serum IgA levels and the stage of fibrosis (p<0.001). Serum IgA, age, platelets, AST/ALT ratio and BMI were all independently with advanced fibrosis following multivariate analysis. A model constructed from these independent predictors accurately predicted advanced fibrosis (AUROC 0.87). The serum IgA level was frequently elevated in patients with NAFLD and was an independent predictor of advanced fibrosis. Copyright © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Childhood obesity-related endothelial dysfunction: an update on pathophysiological mechanisms and diagnostic advancements.

PubMed

Bruyndonckx, Luc; Hoymans, Vicky Y; Lemmens, Katrien; Ramet, José; Vrints, Christiaan J

2016-06-01

Childhood obesity jeopardizes a healthy future for our society's children as it is associated with increased cardiovascular morbidity and mortality later on in life. Endothelial dysfunction, the first step in the development of atherosclerosis, is already present in obese children and may well represent a targetable risk factor. Technological advancements in recent years have facilitated noninvasive measurements of endothelial homeostasis in children. Thereby this topic ultimately starts to get the attention it deserves. In this paper, we aim to summarize the latest insights on endothelial dysfunction in childhood obesity. We discuss methodological advancements in peripheral endothelial function measurement and newly identified diagnostic markers of vascular homeostasis. Finally, future challenges and perspectives are set forth on how to efficiently tackle the catastrophic rise in cardiovascular morbidity and mortality that will be inflicted on obese children if they are not treated optimally.

The proteome of methylmalonic acidemia (MMA): the elucidation of altered pathways in patient livers.

PubMed

Caterino, Marianna; Chandler, Randy J; Sloan, Jennifer L; Dorko, Kenneth; Cusmano-Ozog, Kristina; Ingenito, Laura; Strom, Stephen C; Imperlini, Esther; Scolamiero, Emanuela; Venditti, Charles P; Ruoppolo, Margherita

2016-02-01

Methylmalonic acidemia (MMA) is a heterogeneous and severe autosomal recessive inborn error of metabolism most commonly caused by the deficient activity of the vitamin B12 dependent enzyme, methylmalonyl-CoA mutase (MUT). The main treatment for MMA patients is the dietary restriction of propiogenic amino acids and carnitine supplementation. Despite treatment, the prognosis for vitamin B12 non-responsive patients remains poor and is associated with neonatal lethality, persistent morbidity and decreased life expectancy. While multi-organ pathology is a feature of MMA, the liver is severely impacted by mitochondrial dysfunction which likely underlies the metabolic instability experienced by the patients. Liver and/or combined liver/kidney transplantation is therefore sometimes performed in severely affected patients. Using liver specimens from donors and MMA patients undergoing elective liver transplantation collected under a dedicated natural history protocol (clinicaltrials.gov: NCT00078078), we employed proteomics to characterize the liver pathology and impaired hepatic metabolism observed in the patients. Pathway analysis revealed perturbations of enzymes involved in energy metabolism, gluconeogenesis and Krebs cycle anaplerosis. Our findings identify new pathophysiologic and therapeutic targets that could be valuable for designing alternative therapies to alleviate clinical manifestations seen in this disorder.

Atherogenic diet induced lipid accumulation induced NFκB level in heart, liver and brain of Wistar rat and diosgenin as an anti-inflammatory agent.

PubMed

Binesh, Ambika; Devaraj, Sivasithamparam Niranjali; Halagowder, Devaraj

2018-03-01

Atherogenic Diet (AD) was given to rats to understand the key role of inflammatory mediators in atherosclerotic lesion formation, as a serendipitous study, the diet induced inflammatory mediators in liver and brain, whereas pancreas, kidney and spleen were not affected. The efficacy of diosgenin in ameliorating atherosclerotic progression in heart and suppression of inflammatory mediators in liver and brain of Wistar rat fed on AD diet was investigated. Atherogenic diet triggered inflammatory mediators in heart, liver and brain by upregulating TNF-α, COX-2 and NFkBp65 which are the inflammatory hub, played a key role in pathophysiologic conditions. Endothelial dysfunction, liver tissue with prominent steatosis and the stress evoked in the brain by the atherogenic diet triggered these inflammatory mediators. TNF-α and COX-2 expression was upregulated and its elevation was associated with NFkBp65 activation in heart, liver and brain of atherogenic diet induced rat. Diosgenin downregulated these inflammatory mediators, thereby prevented the atherosclerotic disease progression and concomitant suppression of inflammatory mediators in liver and brain. Copyright © 2018. Published by Elsevier Inc.

Genetics of liver disease: From pathophysiology to clinical practice.

PubMed

Karlsen, Tom H; Lammert, Frank; Thompson, Richard J

2015-04-01

Paralleling the first 30 years of the Journal of Hepatology we have witnessed huge advances in our understanding of liver disease and physiology. Genetic advances have played no small part in that. Initial studies in the 1970s and 1980s identified the strong major histocompatibility complex associations in autoimmune liver diseases. During the 1990 s, developments in genomic technologies drove the identification of genes responsible for Mendelian liver diseases. Over the last decade, genome-wide association studies have allowed for the dissection of the genetic susceptibility to complex liver disorders, in which also environmental co-factors play important roles. Findings have allowed the identification and elaboration of pathophysiological processes, have indicated the need for reclassification of liver diseases and have already pointed to new disease treatments. In the immediate future genetics will allow further stratification of liver diseases and contribute to personalized medicine. Challenges exist with regard to clinical implementation of rapidly developing technologies and interpretation of the wealth of accumulating genetic data. The historical perspective of genetics in liver diseases illustrates the opportunities for future research and clinical care of our patients. Copyright © 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Inhibition of mTOR improves the impairment of acidification in autophagic vesicles caused by hepatic steatosis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nakadera, Eisuke; Yamashina, Shunhei, E-mail: syamashi@juntendo.ac.jp; Izumi, Kousuke

Recent investigations revealed that dysfunction of autophagy involved in the progression of chronic liver diseases such as alcoholic and nonalcoholic steatohepatitis and hepatocellular neoplasia. Previously, it was reported that hepatic steatosis disturbs autophagic proteolysis via suppression of both autophagic induction and lysosomal function. Here, we demonstrate that autophagic acidification was altered by a decrease in lysosomal proton pump vacuolar-ATPase (V-ATPase) in steatohepatitis. The number of autophagic vesicles was increased in hepatocytes from obese KKAy mice as compared to control. Similarly, autophagic membrane protein LC3-II and lysosomal protein LAMP-2 expression were enhanced in KKAy mice liver. Nevertheless, both phospho-mTOR and p62more » expression were augmented in KKAy mice liver. More than 70% of autophagosomes were stained by LysoTracker Red (LTR) in hepatocytes from control mice; however, the percentage of acidic autolysosomes was decreased in hepatocytes from KKAy mice significantly (40.1 ± 3.48%). Both protein and RNA level of V-ATPase subunits ATP6v1a, ATP6v1b, ATP6v1d in isolated lysosomes were suppressed in KKAy mice as compared to control. Interestingly, incubation with mTOR inhibitor rapamycin increased in the rate of LTR-positive autolysosomes in hepatocytes from KKAy mice and suppressed p62 accumulation in the liver from KKAy mice which correlated to an increase in the V-ATPase subunits expression. These results indicate that down-regulation of V-ATPase due to hepatic steatosis causes autophagic dysfunction via disruption of lysosomal and autophagic acidification. Moreover, activation of mTOR plays a pivotal role on dysregulation of lysosomal and autophagic acidification by modulation of V-ATPase expression and could therefore be a useful therapeutic target to ameliorate dysfunction of autophagy in NAFLD. - Highlights: • Hepatic steatosis causes accumulation of autophagic vesicles in hepatocytes. • Hepatic steatosis disturbs acidification of autophagic vesicles. • Lipid accumulation suppresses the expression of lysosomal V-ATPase subunits. • Rapamycin upregulates the expression of lysosomal V-ATPase suppressed in NAFLD. • Rapamycin ameliorates the acidification of autolysosomes impaired in NAFLD.« less

The Origin of New-Onset Diabetes After Liver Transplantation: Liver, Islets, or Gut?

PubMed

Ling, Qi; Xu, Xiao; Wang, Baohong; Li, Lanjuan; Zheng, Shusen

2016-04-01

New-onset diabetes is a frequent complication after solid organ transplantation. Although a number of common factors are associated with the disease, including recipient age, body mass index, hepatitis C infection, and use of immunosuppressive drugs, new-onset diabetes after liver transplantation (NODALT) has the following unique aspects and thus needs to be considered its own entity. First, a liver graft becomes the patient's primary metabolic regulator after liver transplantation, but this would not be the case for kidney or other grafts. The metabolic states, as well as the genetics of the graft, play crucial roles in the development of NODALT. Second, dysfunction of the islets of Langerhans is common in cirrhotic patients and would be exacerbated by immunosuppressive agents, particularly calcineurin inhibitors. On the other hand, minimized immunosuppressive protocols have been widely advocated in liver transplantation because of liver tolerance (immune privilege). Third and last, through the "gut-liver axis," graft function is closely linked to gut microbiota, which is now considered an important metabolic organ and known to independently influence the host's metabolic homeostasis. Liver transplant recipients present with specific gut microbiota that may be prone to trigger metabolic disorders. In this review, we proposed 3 possible sites for the origin of NODALT, which are liver, islets, and gut, to help elucidate the underlying mechanism of NODALT.

Improvement of Liver Cell Therapy in Rats by Dietary Stearic Acid

PubMed Central

Goradel, Nasser Hashemi; Eghbal, Mohammad Ali; Darabi, Masoud; Roshangar, Leila; Asadi, Maryam; Zarghami, Nosratollah; Nouri, Mohammad

2016-01-01

Background: Stearic acid is known as a potent anti-inflammatory lipid. This fatty acid has profound and diverse effects on liver metabolism. The aim of this study was to investigate the effect of stearic acid on markers of hepatocyte transplantation in rats with acetaminophen (APAP)-induced liver damage. Methods: Wistar rats were randomly assigned to 10-day treatment. Stearic acid was administered to the rats with APAP-induced liver damage. The isolated liver cells were infused intraperitoneally into rats. Blood samples were obtained to evaluate the changes in the serum liver enzymes, including activities of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP) and the level of serum albumin. To assess the engraftment of infused hepatocytes, rats were euthanized, and the liver DNA was used for PCR using sex-determining region Y (SRY) primers. Results: The levels of AST, ALT and ALP in the serum of rats with APAP-induced liver injury were significantly increased and returned to the levels in control group by day six. The APAP-induced decrease in albumin was significantly improved in rats through cell therapy, when compared with that in the APAP-alone treated rats. SRY PCR analysis showed the presence of the transplanted cells in the liver of transplanted rats. Conclusion: Stearic acid-rich diet in combination with cell therapy accelerates the recovering of hepatic dysfunction in a rat model of liver injury. PMID:27090202

Resolution of donor non-alcoholic fatty liver disease following liver transplantation.

PubMed

Posner, Andrew D; Sultan, Samuel T; Zaghloul, Norann A; Twaddell, William S; Bruno, David A; Hanish, Steven I; Hutson, William R; Hebert, Laci; Barth, Rolf N; LaMattina, John C

2017-09-01

Transplant surgeons conventionally select against livers displaying high degrees (>30%) of macrosteatosis (MaS), out of concern for primary non-function or severe graft dysfunction. As such, there is relatively limited experience with such livers, and the natural history remains incompletely characterized. We present our experience of transplanted livers with high degrees of MaS and microsteatosis (MiS), with a focus on the histopathologic and clinical outcomes. Twenty-nine cases were identified with liver biopsies available from both the donor and the corresponding liver transplant recipient. Donor liver biopsies displayed either MaS or MiS ≥15%, while all recipients received postoperative liver biopsies for cause. The mean donor MaS and MiS were 15.6% (range 0%-60%) and 41.3% (7.5%-97.5%), respectively. MaS decreased significantly from donor (M=15.6%) to recipient postoperative biopsies (M=0.86%), P<.001. Similarly, MiS decreased significantly from donor biopsies (M=41.3%) to recipient postoperative biopsies (M=1.8%), P<.001. At a median of 68 days postoperatively (range 4-384), full resolution of MaS and MiS was observed in 27 of 29 recipients. High degrees of MaS and MiS in donor livers resolve in recipients following liver transplantation. Further insight into the mechanisms responsible for treating fatty liver diseases could translate into therapeutic targets. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Selumetinib and Akt Inhibitor MK-2206 in Treating Patients With Refractory or Advanced Gallbladder or Bile Duct Cancer That Cannot Be Removed By Surgery

ClinicalTrials.gov

2014-09-08

Adenocarcinoma of the Gallbladder; Adenocarcinoma With Squamous Metaplasia of the Gallbladder; Adult Primary Cholangiocellular Carcinoma; Advanced Adult Primary Liver Cancer; Cholangiocarcinoma of the Extrahepatic Bile Duct; Localized Unresectable Adult Primary Liver Cancer; Metastatic Extrahepatic Bile Duct Cancer; Recurrent Adult Primary Liver Cancer; Recurrent Extrahepatic Bile Duct Cancer; Stage II Gallbladder Cancer; Stage IIIA Gallbladder Cancer; Stage IIIB Gallbladder Cancer; Stage IVA Gallbladder Cancer; Stage IVB Gallbladder Cancer; Unresectable Extrahepatic Bile Duct Cancer

Antiangiogenic treatment in hepatocellular carcinoma: the balance of efficacy and safety

PubMed Central

Welker, Martin-Walter; Trojan, Joerg

2013-01-01

Hepatocellular carcinoma (HCC) is a severe complication of advanced liver disease with a worldwide incidence of more than 600,000 patients per year. Liver function, clinical performance status, and tumor size are considered in the Barcelona Clinic Liver Cancer (BCLC) system. While curative treatment options are available for early stages, most patients present with intermediate- or advanced-stage HCC, burdened with a poor prognosis, substantially influenced by the degree of liver-function impairment. Hypervascularization is a major characteristic of HCC, and antiangiogenic treatments are the basis of treatment in noncurative stages, including interventional and pharmacological treatments. Currently, the tyrosine-kinase inhibitor sorafenib is still the only approved drug for HCC. Further improvements in survival in patients with intermediate- and advanced-stage HCC may be anticipated by both multimodal approaches, such as combination of interventional and systemic treatments, and new systemic treatment options. Until now, the Phase III development of other tyrosine-kinase inhibitors in patients with advanced HCC has failed due to minor efficacy and/or increased toxicity compared to sorafenib. However, promising Phase II data have been reported with MET inhibitors in this hard-to-treat population. This review gives a critical overview of antiangiogenic drugs and strategies in intermediate- and advanced-stage HCC, with a special focus on safety. PMID:24204170

Mechanisms of decompensation and organ failure in cirrhosis: From peripheral arterial vasodilation to systemic inflammation hypothesis.

PubMed

Bernardi, Mauro; Moreau, Richard; Angeli, Paolo; Schnabl, Bernd; Arroyo, Vicente

2015-11-01

The peripheral arterial vasodilation hypothesis has been most influential in the field of cirrhosis and its complications. It has given rise to hundreds of pathophysiological studies in experimental and human cirrhosis and is the theoretical basis of life-saving treatments. It is undisputed that splanchnic arterial vasodilation contributes to portal hypertension and is the basis for manifestations such as ascites and hepatorenal syndrome, but the body of research generated by the hypothesis has revealed gaps in the original pathophysiological interpretation of these complications. The expansion of our knowledge on the mechanisms regulating vascular tone, inflammation and the host-microbiota interaction require a broader approach to advanced cirrhosis encompassing the whole spectrum of its manifestations. Indeed, multiorgan dysfunction and failure likely result from a complex interplay where the systemic spread of bacterial products represents the primary event. The consequent activation of the host innate immune response triggers endothelial molecular mechanisms responsible for arterial vasodilation, and also jeopardizes organ integrity with a storm of pro-inflammatory cytokines and reactive oxygen and nitrogen species. Thus, the picture of advanced cirrhosis could be seen as the result of an inflammatory syndrome in contradiction with a simple hemodynamic disturbance. Copyright © 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Water-soluble C60 fullerenes reduce manifestations of acute cholangitis in rats

NASA Astrophysics Data System (ADS)

Kuznietsova, H. M.; Lynchak, O. V.; Dziubenko, N. V.; Osetskyi, V. L.; Ogloblya, O. V.; Prylutskyy, Yu I.; Rybalchenko, V. K.; Ritter, U.; Scharff, P.

2018-03-01

Sclerosing cholangitis is the liver disease of uncertain etiology, extremely unfavorable prognosis and lack of effective medication therapy. Therefore, the effect of water-soluble biocompatible C60 fullerenes (C60FAS) on the liver functional state on rat acute-cholangitis model was aimed to be discovered. Acute cholangitis was simulated by single α-naphthyl isothiocyanate (ANIT, 100 mg/kg) per os administration; C60FAS (0.5 mg/kg) was administered either per os or intraperitoneally in 24 and 48 h after ANIT ingestion, and in 72 h the animals were sacrificed. The activities of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), the total and direct bilirubin, creatinine and urea in the blood serum were determined, and the liver morphological state was assessed. In animals experienced ANIT-induced acute cholangitis, the total and direct bilirubin, creatinine, ALT, AST, ALP and LDH 1.5-4-fold increase were observed, indicating cytolysis of hepatocytes, cholestasis, and renal dysfunction. The features of periductal fibrosis, biliary epithelium atrophy, and portal-portal linking septa formation were detected, confirming the sclerosing cholangitis development. C60FAS promoted to the normalization of direct and total bilirubin levels, the ALT activity and diminution of fibrotic features. In addition, C60FAS intraperitoneal administration also normalized the ALP activity, indicating the attenuation of disease symptoms. However, the AST activity and creatinine level remained unchanged, and the LDH activity even increased, manifesting the partial persistence of cholestasis and renal dysfunction. Thus, the therapeutic application of C60FAS promotes a partial protection of liver against cholangitis.

Extracorporeal liver assist device to exchange albumin and remove endotoxin in acute liver failure: Results of a pivotal pre-clinical study.

PubMed

Lee, Karla C L; Baker, Luisa A; Stanzani, Giacomo; Alibhai, Hatim; Chang, Yu Mei; Jimenez Palacios, Carolina; Leckie, Pamela J; Giordano, Paola; Priestnall, Simon L; Antoine, Daniel J; Jenkins, Rosalind E; Goldring, Christopher E; Park, B Kevin; Andreola, Fausto; Agarwal, Banwari; Mookerjee, Rajeshwar P; Davies, Nathan A; Jalan, Rajiv

2015-09-01

In acute liver failure, severity of liver injury and clinical progression of disease are in part consequent upon activation of the innate immune system. Endotoxaemia contributes to innate immune system activation and the detoxifying function of albumin, critical to recovery from liver injury, is irreversibly destroyed in acute liver failure. University College London-Liver Dialysis Device is a novel artificial extracorporeal liver assist device, which is used with albumin infusion, to achieve removal and replacement of dysfunctional albumin and reduction in endotoxaemia. We aimed to test the effect of this device on survival in a pig model of acetaminophen-induced acute liver failure. Pigs were randomised to three groups: Acetaminophen plus University College London-Liver Dialysis Device (n=9); Acetaminophen plus Control Device (n=7); and Control plus Control Device (n=4). Device treatment was initiated two h after onset of irreversible acute liver failure. The Liver Dialysis Device resulted in 67% reduced risk of death in acetaminophen-induced acute liver failure compared to Control Device (hazard ratio=0.33, p=0.0439). This was associated with 27% decrease in circulating irreversibly oxidised human non-mercaptalbumin-2 throughout treatment (p=0.046); 54% reduction in overall severity of endotoxaemia (p=0.024); delay in development of vasoplegia and acute lung injury; and delay in systemic activation of the TLR4 signalling pathway. Liver Dialysis Device-associated adverse clinical effects were not seen. The survival benefit and lack of adverse effects would support clinical trials of University College London-Liver Dialysis Device in acute liver failure patients. Copyright © 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Immediate postoperative tracheal extubation in a liver transplant recipient with encephalopathy and the Mayo end-stage liver disease score of 41: A CARE-compliant case report revealed meaningful challenge in recovery after surgery (ERAS) for liver transplantation.

PubMed

Li, Jianbo; Wang, Chengdi; Chen, Nan; Song, Jiulin; Sun, Yan; Yao, Qin; Yan, Lunan; Yang, Jiayin

2017-11-01

Immediate postoperative tracheal extubation (IPTE) is one of the most important subject in recovery after surgery (ERAS) for liver transplantation. However, the criteria for IPTE is not uniform at present. We reported a successful IPTE in a liver transplant recipient with encephalopathy and a high Mayo end-stage liver disease (MELD) score of 41, which beyond the so-called criteria reported in the literature. The patient was 48-year-old man, admitted in September 2016 for end-stage liver cirrhosis secondary to hepatitis B. End-stage liver cirrhosis secondary to hepatitis B with encephalopathy and a high MELD score of 41. He was involved in our ERAS project and was extubated at the end of the liver transplantation in the operating room. As a result, the patient was not reintubated and had an excellent postoperative recovery, staying in intensive care unit (ICU) for just 2 days and discharged home on day 10. We believed IPTE in liver transplant recipients with severe liver dysfunction is a meaningful challenge in ERAS for liver transplantation. Our case and literature review suggest 3 things: IPTE in liver transplantation is generally feasible and safe; the encephalopathy or high MELD score should not be the only limiting factor; and a more systematic predicting system for IPTE in liver transplantation should be addressed in future studies. Copyright © 2017 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.

Advances in the treatment of erectile dysfunction: what’s new and upcoming?

PubMed Central

Patel, Chintan K.; Bennett, Nelson

2016-01-01

Erectile dysfunction adversely affects up to 20% of all men and is the most commonly treated sexual disorder. The public health implications of this condition are significant and represent a challenge for our healthcare system. The physiological pathways responsible for erections have been extensively studied, and much advancement has been made since the introduction of phosphodiesterase 5 inhibitors. Newer agents, such as dopaminergic and melanocortin receptor agonists, which target central erectogenic pathways, are under investigation. Newer formulations and delivery methods of existing medications such as alprostadil will also be introduced in the near future. Furthermore, low-intensity shockwave lithotripsy and stem cell regenerative techniques are innovative approaches to the treatment of erectile dysfunction. PMID:27516878

Quantitative Assessment of Liver Fat with Magnetic Resonance Imaging and Spectroscopy

PubMed Central

Reeder, Scott B.; Cruite, Irene; Hamilton, Gavin; Sirlin, Claude B.

2011-01-01

Hepatic steatosis is characterized by abnormal and excessive accumulation of lipids within hepatocytes. It is an important feature of diffuse liver disease, and the histological hallmark of non-alcoholic fatty liver disease (NAFLD). Other conditions associated with steatosis include alcoholic liver disease, viral hepatitis, HIV and genetic lipodystrophies, cystic fibrosis liver disease, and hepatotoxicity from various therapeutic agents. Liver biopsy, the current clinical gold standard for assessment of liver fat, is invasive and has sampling errors, and is not optimal for screening, monitoring, clinical decision making, or well-suited for many types of research studies. Non-invasive methods that accurately and objectively quantify liver fat are needed. Ultrasound (US) and computed tomography (CT) can be used to assess liver fat but have limited accuracy as well as other limitations. Magnetic resonance (MR) techniques can decompose the liver signal into its fat and water signal components and therefore assess liver fat more directly than CT or US. Most magnetic resonance (MR) techniques measure the signal fat-fraction (the fraction of the liver MR signal attributable to liver fat), which may be confounded by numerous technical and biological factors and may not reliably reflect fat content. By addressing the factors that confound the signal fat-fraction, advanced MR techniques measure the proton density fat-fraction (the fraction of the liver proton density attributable to liver fat), which is a fundamental tissue property and a direct measure of liver fat content. These advanced techniques show promise for accurate fat quantification and are likely to be commercially available soon. PMID:22025886

Efficacy and safety of selective internal radiotherapy with yttrium-90 resin microspheres compared with sorafenib in locally advanced and inoperable hepatocellular carcinoma (SARAH): an open-label randomised controlled phase 3 trial.

PubMed

Vilgrain, Valérie; Pereira, Helena; Assenat, Eric; Guiu, Boris; Ilonca, Alina Diana; Pageaux, Georges-Philippe; Sibert, Annie; Bouattour, Mohamed; Lebtahi, Rachida; Allaham, Wassim; Barraud, Hélène; Laurent, Valérie; Mathias, Elodie; Bronowicki, Jean-Pierre; Tasu, Jean-Pierre; Perdrisot, Rémy; Silvain, Christine; Gerolami, René; Mundler, Olivier; Seitz, Jean-Francois; Vidal, Vincent; Aubé, Christophe; Oberti, Frédéric; Couturier, Olivier; Brenot-Rossi, Isabelle; Raoul, Jean-Luc; Sarran, Anthony; Costentin, Charlotte; Itti, Emmanuel; Luciani, Alain; Adam, René; Lewin, Maïté; Samuel, Didier; Ronot, Maxime; Dinut, Aurelia; Castera, Laurent; Chatellier, Gilles

2017-12-01

Sorafenib is the recommended treatment for patients with advanced hepatocellular carcinoma. We aimed to compare the efficacy and safety of sorafenib to that of selective internal radiotherapy (SIRT) with yttrium-90 ( 90 Y) resin microspheres in patients with hepatocellular carcinoma. SARAH was a multicentre, open-label, randomised, controlled, investigator-initiated, phase 3 trial done at 25 centres specialising in liver diseases in France. Patients were eligible if they were aged at least 18 years with a life expectancy greater than 3 months, had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, Child-Pugh liver function class A or B score of 7 or lower, and locally advanced hepatocellular carcinoma (Barcelona Clinic Liver Cancer [BCLC] stage C), or new hepatocellular carcinoma not eligible for surgical resection, liver transplantation, or thermal ablation after a previously cured hepatocellular carcinoma (cured by surgery or thermoablative therapy), or hepatocellular carcinoma with two unsuccessful rounds of transarterial chemoembolisation. Patients were randomly assigned (1:1) by a permutated block method with block sizes two and four to receive continuous oral sorafenib (400 mg twice daily) or SIRT with 90 Y-loaded resin microspheres 2-5 weeks after randomisation. Patients were stratified according to randomising centre, ECOG performance status, previous transarterial chemoembolisation, and presence of macroscopic vascular invasion. The primary endpoint was overall survival. Analyses were done on the intention-to-treat population; safety was assessed in all patients who received at least one dose of sorafenib or underwent at least one of the SIRT work-up exams. This study has been completed and the final results are reported here. The trial is registered with ClinicalTrials.gov, number NCT01482442. Between Dec 5, 2011, and March 12, 2015, 467 patients were randomly assigned; after eight patients withdrew consent, 237 were assigned to SIRT and 222 to sorafenib. In the SIRT group, 53 (22%) of 237 patients did not receive SIRT; 26 (49%) of these 53 patients were treated with sorafenib. Median follow-up was 27·9 months (IQR 21·9-33·6) in the SIRT group and 28·1 months (20·0-35·3) in the sorafenib group. Median overall survival was 8·0 months (95% CI 6·7-9·9) in the SIRT group versus 9·9 months (8·7-11·4) in the sorafenib group (hazard ratio 1·15 [95% CI 0·94-1·41] for SIRT vs sorafenib; p=0·18). In the safety population, at least one serious adverse event was reported in 174 (77%) of 226 patients in the SIRT group and in 176 (82%) of 216 in the sorafenib group. The most frequent grade 3 or worse treatment-related adverse events were fatigue (20 [9%] vs 41 [19%]), liver dysfunction (25 [11%] vs 27 [13%]), increased laboratory liver values (20 [9%] vs 16 [7%]), haematological abnormalities (23 [10%] vs 30 [14%]), diarrhoea (three [1%] vs 30 [14%]), abdominal pain (six [3%] vs 14 [6%]), increased creatinine (four [2%] vs 12 [6%]), and hand-foot skin reaction (one [<1%] vs 12 [6%]). 19 deaths in the SIRT group and 12 in the sorafenib group were deemed to be treatment related. In patients with locally advanced or intermediate-stage hepatocellular carcinoma after unsuccessful transarterial chemoembolisation, overall survival did not significantly differ between the two groups. Quality of life and tolerance might help when choosing between the two treatments. Sirtex Medical Inc. Copyright © 2017 Elsevier Ltd. All rights reserved.

Cardiovascular alterations and multi organ dysfunction after birth asphyxia

PubMed Central

Polglase, Graeme R.; Ong, Tracey; Hillman, Noah H

2016-01-01

Synopsis The cardiovascular response to asphyxia involves redistribution of cardiac output to maintain oxygen delivery to critical organs such as the adrenal gland, heart and brain, at the expense of other organs such as the gut, kidneys and skin. This results in reduced perfusion and localized hypoxia/ischemia in these organs, which if severe, can result in multi-organ failure. Liver injury, coagulopathy, bleeding, thrombocytopenia, renal dysfunction, pulmonary and gastrointestinal injury all result from hypoxia, under-perfusion or both. Current clinical therapies need to be considered together with therapeutic hypothermia and cardiovascular recovery. PMID:27524448

Spontaneous and induced tolerance for liver transplant recipients.

PubMed

Feng, Sandy

2016-02-01

Transformative medical and surgical advances have remarkably improved short-term survival after liver transplantation. There is, however, pervasive concern that the cumulative toxicities of modern immunosuppression regimens severely compromise both quality and quantity of life for liver transplant recipients. The inherently tolerogenic nature of the liver offers the tantalizing opportunity to change the current paradigm of nonspecific and lifelong immunosuppression. Safe minimization or discontinuation of immunosuppression without damage to the liver allograft is an attractive strategy to improve long-term survival after liver transplantation. Recent prospective, multicenter clinical trials have demonstrated that immunosuppression can be safely withdrawn from selected liver transplant recipients with preservation of allograft histology. These successes have spurred multiple avenues of investigation to identify peripheral blood and/or tissue biomarkers and delineate mechanisms of tolerance. Concomitant advances in the ability to expand regulatory T cells in the laboratory have spawned clinical trials to facilitate immunosuppression minimization and/or discontinuation. This review will delineate the unique liver immunobiology that has driven the recent clinical trials to unmask spontaneous tolerance or induce tolerance for liver transplant recipients. The emerging results of these trials over the next 5 years hold promise to reduce the burden of lifelong immunosuppression and thereby optimize the long-term health of liver transplant recipients.

Surgery for Intermediate and Advanced Hepatocellular Carcinoma: A Consensus Report from the 5th Asia-Pacific Primary Liver Cancer Expert Meeting (APPLE 2014).

PubMed

Ho, Ming-Chih; Hasegawa, Kiyoshi; Chen, Xiao-Ping; Nagano, Hiroaki; Lee, Young-Joo; Chau, Gar-Yang; Zhou, Jian; Wang, Chih-Chi; Choi, Young Rok; Poon, Ronnie Tung-Ping; Kokudo, Norihiro

2016-10-01

The Barcelona Clinic Liver Cancer (BCLC) staging and treatment strategy does not recommended surgery for treating BCLC stage B and C hepatocellular carcinoma (HCC). However, numerous Asia-Pacific institutes still perform surgery for this patient group. This consensus report from the 5th Asia-Pacific Primary Liver Cancer Expert Meeting aimed to share opinions and experiences pertaining to liver resection for intermediate and advanced HCCs and to provide evidence to issue recommendations for surgery in this patient group. Thirteen experts from five Asia-Pacific regions were invited to the meeting; 10 of them (Japan: 2, Taiwan: 3, South Korea: 2, Hong Kong: 1, and China: 2) voted for the final consensus. The discussion focused on evaluating the preoperative liver functional reserve and surgery for large tumors, multiple tumors, HCCs with vascular invasion, and HCCs with distant metastasis. The feasibility of future prospective randomized trials comparing surgery with transarterial chemoembolization for intermediate HCC and with sorafenib for advanced HCC was also discussed. The Child-Pugh score (9/10 experts) and indocyanine green retention rate at 15 min (8/10) were the most widely accepted methods for evaluating the preoperative liver functional reserve. All (10/10) experts agreed that portal hypertension, tumor size >5 cm, portal venous invasion, hepatic venous invasion, and extrahepatic metastasis are not absolute contraindications for the surgical resection of HCC. Furthermore, 9 of the 10 experts agreed that tumor resection may be performed for patients with >3 tumors. The limitations of surgery are associated with a poor liver functional reserve, incomplete tumor resection, and a high probability of recurrence. Surgery provides significant survival benefits for Asian-Pacific patients with intermediate and advanced HCCs, particularly when the liver functional reserve is favorable. However, prospective randomized controlled trials are difficult to conduct because of technical and ethical considerations.

Recurrent viral liver disease (hepatitis B and C) after liver transplantation.

PubMed

Olivera-Martínez, Marco Antonio; Gallegos-Orozco, Juan F

2007-08-01

Hepatitis C represents more than 35% of liver transplant candidates worldwide. Meanwhile, hepatitis B continues to be an important cause of end-stage liver disease and hepatocellular carcinoma in Asia and Africa. Recurrent viral liver disease is a significant event after liver transplantation and continues to be one of the main causes of graft dysfunction and loss in the middle and long-term follow-up. Mechanisms of liver reinfection and disease recurrence vary between these two viruses and pre-emptive as well as the therapeutic approaches are different. Hepatitis B patients can be managed with immune globulin immediately after liver transplant and various agents such as nucleotide and nucleoside analogues can be associated. As a result, disease recurrence has been delayed or prevented in these patients. Individuals transplanted for hepatitis C are known to have universal reinfection and a high rate of disease recurrence has been reported in the literature. Strategies to treat hepatitis C recurrence are limited to the use of pegylated interferon and ribavirin when disease is demonstrated histologically and biochemically, although other strategies have been described with limited or no success. We herein review the mechanisms of disease recurrence and the current as well as the future therapeutic approaches to prevent and to treat these diseases.