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Sample records for chronic liver impairment

  1. Generalized Liver- and Blood-Derived CD8+ T-Cell Impairment in Response to Cytokines in Chronic Hepatitis C Virus Infection.

    PubMed

    Burke Schinkel, Stephanie C; Carrasco-Medina, Lorna; Cooper, Curtis L; Crawley, Angela M

    2016-01-01

    Generalized CD8+ T-cell impairment in chronic hepatitis C virus (HCV) infection and the contribution of liver-infiltrating CD8+ T-cells to the immunopathogenesis of this infection remain poorly understood. It is hypothesized that this impairment is partially due to reduced CD8+ T-cell activity in response to cytokines such as IL-7, particularly within the liver. To investigate this, the phenotype and cytokine responsiveness of blood- and liver-derived CD8+ T-cells from healthy controls and individuals with HCV infection were compared. In blood, IL-7 receptor α (CD127) expression on bulk CD8+ T-cells in HCV infection was no different than controls yet was lower on central memory T-cells, and there were fewer naïve cells. IL-7-induced signalling through phosphorylated STAT5 was lower in HCV infection than in controls, and differed between CD8+ T-cell subsets. Production of Bcl-2 following IL-7 stimulation was also lower in HCV infection and inversely related to the degree of liver fibrosis. In liver-derived CD8+ T-cells, STAT5 activation could not be increased with cytokine stimulation and basal Bcl-2 levels of liver-derived CD8+ T-cells were lower than blood-derived counterparts in HCV infection. Therefore, generalized CD8+ T-cell impairment in HCV infection is characterized, in part, by impaired IL-7-mediated signalling and survival, independent of CD127 expression. This impairment is more pronounced in the liver and may be associated with an increased potential for apoptosis. This generalized CD8+ T-cell impairment represents an important immune dysfunction in chronic HCV infection that may alter patient health.

  2. Osteoporosis in chronic liver disease.

    PubMed

    Yadav, Anitha; Carey, Elizabeth J

    2013-02-01

    Osteoporosis is a common skeletal complication seen in patients with chronic liver disease. Osteoporosis is usually asymptomatic and, if untreated, can result in fractures and impaired quality of life. For this review, we performed a systematic search of the PubMed database, and all recent peer-reviewed articles regarding the prevalence, pathophysiology, diagnosis, and management of osteoporosis in chronic liver disease were included. The prevalence of osteoporosis varies between 11% and 58% in patients with chronic liver disease and in transplant recipients. The etiology of osteoporosis is multifactorial and only partially understood. Various factors linked to the pathogenesis of bone loss are vitamin D, calcium, insulin growth factor-1, receptor activation of nuclear factor-κB ligand (RANKL), bilirubin, fibronectin, leptin, proinflammatory cytokines, and genetic polymorphisms. Management of osteoporosis involves early diagnosis, identifying and minimizing risk factors, general supportive care, nutrition therapy, and pharmacotherapy. Osteoporosis is diagnosed based on the bone mineral density (BMD) assessment using dual-energy X-ray absorptiometry scan. Measurement of BMD should be considered in all patients with advanced liver disease and in transplant recipients. Vitamin D and calcium supplementation is recommended for all patients with osteoporosis. Specific agents used for treatment of osteoporosis include bisphosphonates, calcitonin, hormonal therapy, and raloxifene. Bisphosphonates have become the mainstay of therapy for osteoporosis prevention and treatment. Prolonged suppression of bone remodeling resulting in atypical fractures has emerged as a significant complication with long-term use of bisphosphonates. Newer treatment agents and better fracture prevention strategies are necessary to prevent and treat osteoporosis.

  3. Chronic Liver Disease and Hispanic Americans

    MedlinePlus

    ... Population Profiles > Hispanic/Latino > Chronic Liver Disease Chronic Liver Disease and Hispanic Americans Among the Hispanic/Latino population, chronic liver disease is a leading cause of death. While ...

  4. Chronic Hyponatremia Causes Neurologic and Psychologic Impairments

    PubMed Central

    Fujisawa, Haruki; Takagi, Hiroshi; Mizoguchi, Hiroyuki; Takeuchi, Hideyuki; Izumida, Hisakazu; Nakashima, Kohtaro; Ochiai, Hiroshi; Takeuchi, Seiji; Kiyota, Atsushi; Fukumoto, Kazuya; Iwama, Shintaro; Takagishi, Yoshiko; Hayashi, Yoshitaka; Arima, Hiroshi; Komatsu, Yukio; Murata, Yoshiharu; Oiso, Yutaka

    2016-01-01

    Hyponatremia is the most common clinical electrolyte disorder. Once thought to be asymptomatic in response to adaptation by the brain, recent evidence suggests that chronic hyponatremia may be linked to attention deficits, gait disturbances, risk of falls, and cognitive impairments. Such neurologic defects are associated with a reduction in quality of life and may be a significant cause of mortality. However, because underlying diseases such as adrenal insufficiency, heart failure, liver cirrhosis, and cancer may also affect brain function, the contribution of hyponatremia alone to neurologic manifestations and the underlying mechanisms remain unclear. Using a syndrome of inappropriate secretion of antidiuretic hormone rat model, we show here that sustained reduction of serum sodium ion concentration induced gait disturbances; facilitated the extinction of a contextual fear memory; caused cognitive impairment in a novel object recognition test; and impaired long-term potentiation at hippocampal CA3–CA1 synapses. In vivo microdialysis revealed an elevated extracellular glutamate concentration in the hippocampus of chronically hyponatremic rats. A sustained low extracellular sodium ion concentration also decreased glutamate uptake by primary astrocyte cultures, suggesting an underlying mechanism of impaired long-term potentiation. Furthermore, gait and memory performances of corrected hyponatremic rats were equivalent to those of control rats. Thus, these results suggest chronic hyponatremia in humans may cause gait disturbance and cognitive impairment, but these abnormalities are reversible and careful correction of this condition may improve quality of life and reduce mortality. PMID:26376860

  5. Gallstones in Patients with Chronic Liver Diseases

    PubMed Central

    2017-01-01

    With prevalence of 10–20% in adults in developed countries, gallstone disease (GSD) is one of the most prevalent and costly gastrointestinal tract disorders in the world. In addition to gallstone disease, chronic liver disease (CLD) is also an important global public health problem. The reported frequency of gallstone in chronic liver disease tends to be higher. The prevalence of gallstone disease might be related to age, gender, etiology, and severity of liver disease in patients with chronic liver disease. In this review, the aim was to identify the epidemiology, mechanisms, and treatment strategies of gallstone disease in chronic liver disease patients. PMID:28251162

  6. Counseling the Chronically Health Impaired Student.

    ERIC Educational Resources Information Center

    Dale, Brian, Comp.; And Others

    The role of counselors in working with chronically health impaired students is examined, and illustrations of the Chronic Health Impaired/Sickle Cell Anemia Program in Baltimore (MD) are presented. The importance of setting goals with the student is underlined, as is the necessity for counselors to have proper flexibility and time to devote to…

  7. Chronic Liver Disease and Asian Americans/Pacific Islanders

    MedlinePlus

    ... Population Profiles > Asian American > Chronic Liver Disease Chronic Liver Disease and Asian Americans/Pacific Islanders Among Asian Americans, chronic liver disease is a leading cause of death. While ...

  8. Chronic Liver Disease and Native Hawaiian/Pacific Islanders

    MedlinePlus

    ... Hawaiian/Other Pacific Islander > Chronic Liver Disease Chronic Liver Disease and Native Hawaiian/Pacific Islander Native Hawaiian/ ... times more likely to be diagnosed with chronic liver disease in 2006. American Samoans were 8 times ...

  9. Chronic Liver Disease and American Indians/Alaska Natives

    MedlinePlus

    ... American Indian/Alaska Native > Chronic Liver Disease Chronic Liver Disease and American Indians/Alaska Natives Among American Indians and Alaska Natives, chronic liver disease is a leading cause of death. While ...

  10. Acute-on-chronic liver failure.

    PubMed

    Bernal, William; Jalan, Rajiv; Quaglia, Alberto; Simpson, Kenneth; Wendon, Julia; Burroughs, Andrew

    2015-10-17

    Acute-on-chronic liver failure combines an acute deterioration in liver function in an individual with pre-existing chronic liver disease and hepatic and extrahepatic organ failures, and is associated with substantial short-term mortality. Common precipitants include bacterial and viral infections, alcoholic hepatitis, and surgery, but in more than 40% of patients, no precipitating event is identified. Systemic inflammation and susceptibility to infection are characteristic pathophysiological features. A new diagnostic score, the Chronic Liver Failure Consortium (CLIF-C) organ failure score, has been developed for classification and prognostic assessment of patients with acute-on-chronic liver failure. Disease can be reversed in many patients, and thus clinical management focuses upon the identification and treatment of the precipitant while providing multiorgan-supportive care that addresses the complex pattern of physiological disturbance in critically ill patients with liver disease. Liver transplantation is a highly effective intervention in some specific cases, but recipient identification, organ availability, timing of transplantation, and high resource use are barriers to more widespread application. Recognition of acute-on-chronic liver failure as a clinically and pathophysiologically distinct syndrome with defined diagnostic and prognostic criteria will help to encourage the development of new management pathways and interventions to address the unacceptably high mortality.

  11. Disposition of nitrendipine in patients with chronic liver diseases.

    PubMed

    Zilly, W; Rämsch, K D; Gothe, M

    1988-01-01

    Metabolism of nitrendipine occurs principally in the liver. Therefore, an alteration of pharmacokinetics has to be discussed in patients with hepatic impairment. To evaluate steady-state plasma concentrations and pharmacokinetics, a low dose of nitrendipine (5 mg/day for 3 weeks) was administered orally to patients with different chronic liver diseases (fatty liver, n = 3; chronic hepatitis, n = 2; and cirrhosis of the liver, n = 5). Nitrendipine plasma concentrations were analyzed by using a gas-liquid chromatography procedure. Twenty-two days after beginning the study, steady-state plasma concentrations were lower than 1.0 microgram/L in one patient without liver disease and in seven patients with chronic liver diseases, in contrast to three patients with alcoholic cirrhosis (5.5, 1.3, and 2.9 micrograms/L). The maximum concentration (Cmax) was 2.3 micrograms/L in the patient without liver disease and 8.3 +/- 3.9 micrograms/L in the hepatic patients. The elimination half-life was prolonged in three of five patients with cirrhosis of the liver (35, 67, and 43 h), whereas in the other patients the half-life was in a normal range (4.2-21.3 h). The area under the concentration-time curve (AUC) was enhanced in three patients with liver cirrhosis (387, 69, and 126 h/micrograms/L); in the other seven hepatic patients, results were normal (35-49 h/micrograms/L). There were no alterations observed in any patient in blood pressure and laboratory data. Oral administration of a low dose of nitrendipine resulted in slightly enhanced steady state plasma concentrations only in patients with advanced cirrhosis of the liver. The half-life, AUC, and bioavailability also seem to be altered only in a more severe state of liver disease.

  12. Vitamin D deficiency in chronic liver disease

    PubMed Central

    Iruzubieta, Paula; Terán, Álvaro; Crespo, Javier; Fábrega, Emilio

    2014-01-01

    Vitamin D is an important secosteroid hormone with known effect on calcium homeostasis, but recently there is increasing recognition that vitamin D also is involved in cell proliferation and differentiation, has immunomodulatory and anti-inflammatory properties. Vitamin D deficiency has been frequently reported in many causes of chronic liver disease and has been associated with the development and evolution of non-alcoholic fatty liver disease (NAFLD) and chronic hepatitis C (CHC) virus infection. The role of vitamin D in the pathogenesis of NAFLD and CHC is not completely known, but it seems that the involvement of vitamin D in the activation and regulation of both innate and adaptive immune systems and its antiproliferative effect may explain its importance in these liver diseases. Published studies provide evidence for routine screening for hypovitaminosis D in patients with liver disease. Further prospectives studies demonstrating the impact of vitamin D replacement in NAFLD and CHC are required. PMID:25544877

  13. Vitamin D deficiency in chronic liver disease.

    PubMed

    Iruzubieta, Paula; Terán, Álvaro; Crespo, Javier; Fábrega, Emilio

    2014-12-27

    Vitamin D is an important secosteroid hormone with known effect on calcium homeostasis, but recently there is increasing recognition that vitamin D also is involved in cell proliferation and differentiation, has immunomodulatory and anti-inflammatory properties. Vitamin D deficiency has been frequently reported in many causes of chronic liver disease and has been associated with the development and evolution of non-alcoholic fatty liver disease (NAFLD) and chronic hepatitis C (CHC) virus infection. The role of vitamin D in the pathogenesis of NAFLD and CHC is not completely known, but it seems that the involvement of vitamin D in the activation and regulation of both innate and adaptive immune systems and its antiproliferative effect may explain its importance in these liver diseases. Published studies provide evidence for routine screening for hypovitaminosis D in patients with liver disease. Further prospectives studies demonstrating the impact of vitamin D replacement in NAFLD and CHC are required.

  14. Renal tubular acidosis in chronic liver disease

    PubMed Central

    Golding, Peter L.

    1975-01-01

    Renal tubular acidosis of the gradient or classic type, thought to be due to a disorder of the distal tubule, has been found to occur in 32% of 117 patients with chronic liver disease. Whilst the cause of this disorder is probably multifactorial, immunological mechanisms are considered to play a major role. The presence of this disorder might well be a cause, rather than the result of, the various electrolyte abnormalities seen in patients with chronic liver disease. ImagesFig. 1Fig. 6 PMID:1234340

  15. Chronic hepatitis C and liver transplantation.

    PubMed

    Davis, Gary L

    2004-01-01

    Chronic hepatitis C virus (HCV) is a worldwide health problem. Approximately 4 million people in the United States are chronically infected with HCV. The incidence of infection peaked between 2 and 3 decades ago, and we are now beginning to see an increase in the complications of cirrhosis from HCV. This trend is expected to continue for another 2 to 3 decades. Survival is poor once complications of cirrhosis, such as liver failure or hepatocellular carcinoma, ensue, and liver transplantation is often the only option. Complications of chronic HCV are the most common indication for liver transplantation, accounting for more than 40% of transplants performed in the United States and Europe. HCV recurs in all patients and rapid development of hepatic fibrosis is very common. Several strategies have been proposed to reduce the risk of graft loss from recurrent HCV infection after transplantation, as the progression of the resulting liver disease is rapid. Although antiviral treatment is successful in some patients, it is extremely difficult to administer and requires dose reductions in the majority of cases. Retransplantation in the current era of the Model for End-Stage Liver Disease (MELD) system for prioritizing listing for transplant is associated with very low survival rates at a high cost. Furthermore, the system raises difficult ethical issues of utilization of limited resources and fairness to other transplant candidates.

  16. Ursodeoxycholic acid in chronic liver disease.

    PubMed Central

    de Caestecker, J S; Jazrawi, R P; Petroni, M L; Northfield, T C

    1991-01-01

    The hydrophilic bile acid ursodeoxycholic acid has recently been shown to reduce biochemical markers of both cholestasis and hepatocellular damage in patients with chronic liver diseases. The most compelling evidence available is for chronic cholestatic liver diseases, in particular primary biliary cirrhosis, primary sclerosing cholangitis, and cholestasis associated with cystic fibrosis. The effects may be less beneficial in patients with advanced liver disease from these conditions. Data from placebo controlled trials are now available in support of earlier uncontrolled observations, but it is not yet clear whether short term benefit results in an improvement in longterm prognosis. The mechanism of action of the compound seems to reside in its displacement of toxic hydrophobic bile acids from both the bile acid pool and hepatocellular membranes. There may be an independent effect on bile flow, which could be of particular importance in cystic fibrosis, and possibly an effect on the immune system. Ursodeoxycholic acid should now be regarded as occupying a central place in the medical management of chronic cholestatic liver diseases, in particular primary biliary cirrhosis, because it improves cholestasis and reduces hepatocellular damage and it is not toxic. Research should now be targeted on whether treatment with ursodeoxycholic acid, initiated early in cholestatic liver conditions, improves the long-term outcome. PMID:1916492

  17. Can paracetamol (acetaminophen) be administered to patients with liver impairment?

    PubMed

    Hayward, Kelly L; Powell, Elizabeth E; Irvine, Katharine M; Martin, Jennifer H

    2016-02-01

    Although 60 years have passed since it became widely available on the therapeutic market, paracetamol dosage in patients with liver disease remains a controversial subject. Fulminant hepatic failure has been a well documented consequence of paracetamol overdose since its introduction, while short and long term use have both been associated with elevation of liver transaminases, a surrogate marker for acute liver injury. From these reports it has been assumed that paracetamol use should be restricted or the dosage reduced in patients with chronic liver disease. We review the factors that have been purported to increase risk of hepatocellular injury from paracetamol and the pharmacokinetic alterations in different pathologies of chronic liver disease which may affect this risk. We postulate that inadvertent under-dosing may result in concentrations too low to enable efficacy. Specific research to improve the evidence base for prescribing paracetamol in patients with different aetiologies of chronic liver disease is needed.

  18. Can paracetamol (acetaminophen) be administered to patients with liver impairment?

    PubMed Central

    Hayward, Kelly L.; Powell, Elizabeth E.; Irvine, Katharine M.

    2015-01-01

    Although 60 years have passed since it became widely available on the therapeutic market, paracetamol dosage in patients with liver disease remains a controversial subject. Fulminant hepatic failure has been a well documented consequence of paracetamol overdose since its introduction, while short and long term use have both been associated with elevation of liver transaminases, a surrogate marker for acute liver injury. From these reports it has been assumed that paracetamol use should be restricted or the dosage reduced in patients with chronic liver disease. We review the factors that have been purported to increase risk of hepatocellular injury from paracetamol and the pharmacokinetic alterations in different pathologies of chronic liver disease which may affect this risk. We postulate that inadvertent under‐dosing may result in concentrations too low to enable efficacy. Specific research to improve the evidence base for prescribing paracetamol in patients with different aetiologies of chronic liver disease is needed. PMID:26460177

  19. Complement activation in chronic liver disease.

    PubMed Central

    Munoz, L E; De Villiers, D; Markham, D; Whaley, K; Thomas, H C

    1982-01-01

    Patients with HBsAg positive chronic active liver disease (CALD) and primary biliary cirrhosis (PBC) exhibit increased C3d concentrations and changes in the serum concentrations of the complement components consistent with activation of the classical and alternative pathways. In these patients the concentrations of the regulatory proteins, C3b inactivator (C3bINA) and beta IH globulin, are normal. Patients with HBsAg negative CALD and alcohol induced liver disease (ALD) exhibit no evidence of an increased level of complement system activation. In these patients diminished serum concentrations of complement components appear to be related to diminished hepatic synthetic function. C4 synthesis may be specifically reduced in autoimmune chronic active liver disease. PMID:7083631

  20. FastStats: Chronic Liver Disease and Cirrhosis

    MedlinePlus

    ... Submit What's this? Submit Button NCHS Home Chronic Liver Disease and Cirrhosis Recommend on Facebook Tweet Share ... Services Administration American Association for the Study of Liver Diseases American Liver Foundation Get Email Updates To ...

  1. Nutrition in cirrhosis and chronic liver disease.

    PubMed

    Juakiem, Wassem; Torres, Dawn M; Harrison, Stephen A

    2014-02-01

    Nutrition has not been a primary focus of many medical conditions despite its importance in the development and the severity of these diseases. This is certainly the case with nutrition and end-stage liver disease despite the well-established association of nutritional deficiencies and increased rates of complications and mortality in cirrhosis. This review provides an overview of nutrition in chronic liver disease with an emphasis on its pathogenesis as well as ways to assess nutritional status and intervene in an effort to improve nutrition.

  2. Acute-on-chronic Liver Failure.

    PubMed

    Sarin, Shiv Kumar; Choudhury, Ashok

    2016-12-01

    Acute-on-chronic liver failure (ACLF) is a distinct entity that differs from acute liver failure and decompensated cirrhosis in timing, presence of treatable acute precipitant, and course of disease, with a potential for self-recovery. The core concept is acute deterioration of existing liver function in a patient of chronic liver disease with or without cirrhosis in response to an acute insult. The insult should be a hepatic one and presentation in the form of liver failure (jaundice, encephalopathy, coagulopathy, ascites) with or without extrahepatic organ failure in a defined time frame. ACLF is characterized by a state of deregulated inflammation. Initial cytokine burst presenting as SIRS, progression to CARS and associated immunoparalysis leads to sepsis and multi-organ failure. Early identification of the acute insult and mitigation of the same, use of nucleoside analogue in HBV-ACLF, steroid in severe alcoholic hepatitis, steroid in severe autoimmune hepatitis and/or bridging therapy lead to recovery, with a 90-day transplant-free survival rate of up to 50 %. First-week presentation is crucial concerning SIRS/sepsis, development, multiorgan failure and consideration of transplant. A protocol-based multi-disciplinary approach including critical care hepatology, early liver transplant before multi-organ involvement, or priority for organ allocation may improve the outcome. Presentation with extrahepatic organ involvement or inclusion of sepsis as an acute insult in definition restricts the therapy, i.e., liver transplant or bridging therapy, and needs serious consideration. Augmentation of regeneration, cell-based therapy, immunotherapy, and gut microbiota modulation are the emerging areas and need further research.

  3. Acute-on-chronic liver failure

    PubMed Central

    Asrani, Sumeet K; Simonetto, Douglas A; Kamath, Patrick S

    2015-01-01

    Over the last two decades, the concept of acute-on-chronic liver failure (ACLF) has been proposed as an alternate path in the natural history of decompensated cirrhosis. ACLF is thus characterized by the presence of a precipitating event (identified or unidentified) in subjects with underlying chronic liver disease leading to rapid progression of liver injury and ending in multi-organ dysfunction characterized by high short term mortality. Multiple organ failure and increased risk for mortality are key to diagnosis of ACLF. The prevalence of ACLF ranges from 24–40% in hospitalized patients. The pathophysiological basis of ACLF can be explained using a 4 part model of predisposing event, injury due to precipitating event, response to injury and organ failure. Though several mathematical scores have been proposed for identifying outcomes with ACLF, it is yet unclear whether these organ failure scores are truly prognostic or are only reflective of the dying process. Treatment paradigms continue to evolve but consist of early recognition, supportive intensive care, and consideration of liver transplantation prior to onset of irreversible multiple organ failure. PMID:26188138

  4. Hemorheological Alteration in Patients Clinically Diagnosed with Chronic Liver Diseases

    PubMed Central

    2016-01-01

    Since liver function is changed by chronic liver diseases, chronic liver disease can lead to different hemorheological alterations during the course of the progression. This study aims to compare alterations in whole blood viscosity in patients with chronic liver disease, focusing on the gender effect. Chronic liver diseases were classified into three categories by patient’s history, serologic markers, and radiologic findings: nonalcoholic fatty liver disease (NAFLD) (n = 63), chronic viral hepatitis B and C (n = 50), and liver cirrhosis (LC) (n = 35). Whole blood viscosity was measured by automated scanning capillary tube viscometer, while liver stiffness was measured by transient elastography using FibroScan®. Both systolic and diastolic whole blood viscosities were significantly lower in patients with LC than NAFLD and chronic viral hepatitis (P < 0.001) in male patients, but not in female patients. In correlation analysis, there were inverse relationships between both systolic and diastolic whole blood viscosity and liver stiffness (systolic: r = −0.25, diastolic: r = −0.22). Whole blood viscosity was significantly lower in male patients with LC than NAFLD or chronic viral hepatitis. Our data suggest that whole blood viscosity test can become a useful tool for classifying chronic liver disease and determining the prognosis for different types of chronic liver diseases. PMID:27822933

  5. Hemorheological Alteration in Patients Clinically Diagnosed with Chronic Liver Diseases.

    PubMed

    Jang, Bohyun; Han, Ji Won; Sung, Pil Soo; Jang, Jeong Won; Bae, Si Hyun; Choi, Jong Young; Cho, Young I; Yoon, Seung Kew

    2016-12-01

    Since liver function is changed by chronic liver diseases, chronic liver disease can lead to different hemorheological alterations during the course of the progression. This study aims to compare alterations in whole blood viscosity in patients with chronic liver disease, focusing on the gender effect. Chronic liver diseases were classified into three categories by patient's history, serologic markers, and radiologic findings: nonalcoholic fatty liver disease (NAFLD) (n = 63), chronic viral hepatitis B and C (n = 50), and liver cirrhosis (LC) (n = 35). Whole blood viscosity was measured by automated scanning capillary tube viscometer, while liver stiffness was measured by transient elastography using FibroScan®. Both systolic and diastolic whole blood viscosities were significantly lower in patients with LC than NAFLD and chronic viral hepatitis (P < 0.001) in male patients, but not in female patients. In correlation analysis, there were inverse relationships between both systolic and diastolic whole blood viscosity and liver stiffness (systolic: r = -0.25, diastolic: r = -0.22). Whole blood viscosity was significantly lower in male patients with LC than NAFLD or chronic viral hepatitis. Our data suggest that whole blood viscosity test can become a useful tool for classifying chronic liver disease and determining the prognosis for different types of chronic liver diseases.

  6. Acute-on-chronic and Decompensated Chronic Liver Failure: Definitions, Epidemiology, and Prognostication.

    PubMed

    Olson, Jody C

    2016-07-01

    Chronic liver disease is the fifth leading cause of death worldwide and represents a major burden for the health care community. Cirrhosis is a progressive disease resulting in end-stage liver failure, which in the absence of liver transplantation is fatal. Acute-on-chronic liver failure carries high short-term mortality but is potentially reversible. Viral hepatitis, alcohol, and nonalcoholic fatty liver disease remain the principal causes of liver disease. Though treatments exist for hepatitis B and C, they remain unavailable to many with these diseases. This article reviews the epidemiology of advanced liver disease and the concept of acute-on-chronic liver failure.

  7. Impaired hepatitis C virus (HCV)-specific effector CD8+ T cells undergo massive apoptosis in the peripheral blood during acute HCV infection and in the liver during the chronic phase of infection.

    PubMed

    Radziewicz, Henry; Ibegbu, Chris C; Hon, Huiming; Osborn, Melissa K; Obideen, Kamil; Wehbi, Mohammad; Freeman, Gordon J; Lennox, Jeffrey L; Workowski, Kimberly A; Hanson, Holly L; Grakoui, Arash

    2008-10-01

    A majority of patients infected with hepatitis C virus (HCV) do not sustain an effective T-cell response, and viremia persists. The mechanism leading to failure of the HCV-specific CD8(+) T-cell response in patients developing chronic infection is unclear. We investigated apoptosis susceptibility of HCV-specific CD8(+) T cells during the acute and chronic stages of infection. Although HCV-specific CD8(+) T cells in the blood during the acute phase of infection and in the liver during the chronic phase were highly activated and expressed an effector phenotype, the majority was undergoing apoptosis. In contrast, peripheral blood HCV-specific CD8(+) T cells during the chronic phase expressed a resting memory phenotype. Apoptosis susceptibility of HCV-specific CD8(+) T cells was associated with very high levels of programmed death-1 (PD-1) and low CD127 expression and with significant functional T-cell deficits. Further evaluation of the "death phase" of HCV-specific CD8(+) T cells during acute HCV infection showed that the majority of cells were dying by a process of cytokine withdrawal, mediated by activated caspase 9. Contraction during the acute phase occurred rapidly via this process despite the persistence of the virus. Remarkably, in the chronic phase of HCV infection, at the site of infection in the liver, a substantial frequency of caspase 9-mediated T-cell death was also present. This study highlights the importance of cytokine deprivation-mediated apoptosis with consequent down-modulation of the immune response to HCV during acute and chronic infections.

  8. Growth Differentiation Factor 15 Predicts Chronic Liver Disease Severity

    PubMed Central

    Lee, Eaum Seok; Kim, Seok Hyun; Kim, Hyun Jin; Kim, Kyung Hee; Lee, Byung Seok; Ku, Bon Jeong

    2017-01-01

    Background/Aims Growth differentiation factor 15 (GDF-15) belongs to the transforming growth factor-β superfamily. GDF-15 is emerging as a biomarker for several diseases. The aim of this study was to determine the clinical performances of GDF-15 for the prediction of liver fibrosis and severity in chronic liver disease. Methods The serum GDF-15 levels were examined via enzyme immunoassay in 145 patients with chronic liver disease and 101 healthy individuals. The patients with chronic liver disease consisted of 54 patients with chronic hepatitis, 44 patients with compensated liver cirrhosis, and 47 patients with decompensated liver cirrhosis. Results Of the patients with chronic liver diseases, the decompensated liver cirrhosis patients had an increased serum GDF-15 (3,483 ng/L) level compared with the patients with compensated liver cirrhosis (1,861 ng/L) and chronic hepatitis (1,232 ng/L). The overall diagnostic accuracies of GDF-15, as determined by the area under the receiver operating characteristic curves, were as follows: chronic hepatitis=0.656 (>574 ng/L, sensitivity, 53.7%; specificity, 79.2%), compensated liver cirrhosis=0.886 (>760 ng/L, sensitivity, 75.6%; specificity, 92.1%), and decompensated liver cirrhosis=0.984 (>869 ng/L, sensitivity, 97.9%; specificity, 94.1%). Conclusions This investigation represents the first study to demonstrate the availability of GDF-15 in chronic liver disease. GDF-15 comprised a useful biomarker for the prediction of liver fibrosis and severity in chronic liver disease. PMID:27728964

  9. Brain cholinergic impairment in liver failure

    PubMed Central

    García-Ayllón, María-Salud; Cauli, Omar; Silveyra, María-Ximena; Rodrigo, Regina; Candela, Asunción; Compañ, Antonio; Jover, Rodrigo; Pérez-Mateo, Miguel; Martínez, Salvador; Felipo, Vicente

    2008-01-01

    The cholinergic system is involved in specific behavioural responses and cognitive processes. Here, we examined potential alterations in the brain levels of key cholinergic enzymes in cirrhotic patients and animal models with liver failure. An increase (∼30%) in the activity of the acetylcholine-hydrolyzing enzyme, acetylcholinesterase (AChE) is observed in the brain cortex from patients deceased from hepatic coma, while the activity of the acetylcholine-synthesizing enzyme, choline acetyltransferase, remains unaffected. In agreement with the human data, AChE activity in brain cortical extracts of bile duct ligated (BDL) rats was increased (∼20%) compared to controls. A hyperammonemic diet did not result in any further increase of AChE levels in the BDL model, and no change was observed in hyperammonemic diet rats without liver disease. Portacaval shunted rats which display increased levels of cerebral ammonia did not show any brain cholinergic abnormalities, confirming that high ammonia levels do not play a role in brain AChE changes. A selective increase of tetrameric AChE, the major AChE species involved in hydrolysis of acetylcholine in the brain, was detected in both cirrhotic humans and BDL rats. Histological examination of BDL and non-ligated rat brains shows that the subcellular localization of both AChE and choline acetyltransferase, and thus the accessibility to their substrates, appears unaltered by the pathological condition. The BDL-induced increase in AChE activity was not parallelled by an increase in mRNA levels. Increased AChE in BDL cirrhotic rats leads to a pronounced decrease (∼50–60%) in the levels of acetylcholine. Finally, we demonstrate that the AChE inhibitor rivastigmine is able to improve memory deficits in BDL rats. One week treatment with rivastigmine (0.6 mg/kg; once a day, orally, for a week) resulted in a 25% of inhibition in the enzymatic activity of AChE with no change in protein composition, as assessed by sucrose density

  10. Chronic Alcohol Ingestion in Rats Alters Lung Metabolism, Promotes Lipid Accumulation, and Impairs Alveolar Macrophage Functions

    PubMed Central

    Romero, Freddy; Shah, Dilip; Duong, Michelle; Stafstrom, William; Hoek, Jan B.; Kallen, Caleb B.; Lang, Charles H.

    2014-01-01

    Chronic alcoholism impairs pulmonary immune homeostasis and predisposes to inflammatory lung diseases, including infectious pneumonia and acute respiratory distress syndrome. Although alcoholism has been shown to alter hepatic metabolism, leading to lipid accumulation, hepatitis, and, eventually, cirrhosis, the effects of alcohol on pulmonary metabolism remain largely unknown. Because both the lung and the liver actively engage in lipid synthesis, we hypothesized that chronic alcoholism would impair pulmonary metabolic homeostasis in ways similar to its effects in the liver. We reasoned that perturbations in lipid metabolism might contribute to the impaired pulmonary immunity observed in people who chronically consume alcohol. We studied the metabolic consequences of chronic alcohol consumption in rat lungs in vivo and in alveolar epithelial type II cells and alveolar macrophages (AMs) in vitro. We found that chronic alcohol ingestion significantly alters lung metabolic homeostasis, inhibiting AMP-activated protein kinase, increasing lipid synthesis, and suppressing the expression of genes essential to metabolizing fatty acids (FAs). Furthermore, we show that these metabolic alterations promoted a lung phenotype that is reminiscent of alcoholic fatty liver and is characterized by marked accumulation of triglycerides and free FAs within distal airspaces, AMs, and, to a lesser extent, alveolar epithelial type II cells. We provide evidence that the metabolic alterations in alcohol-exposed rats are mechanistically linked to immune impairments in the alcoholic lung: the elevations in FAs alter AM phenotypes and suppress both phagocytic functions and agonist-induced inflammatory responses. In summary, our work demonstrates that chronic alcohol ingestion impairs lung metabolic homeostasis and promotes pulmonary immune dysfunction. These findings suggest that therapies aimed at reversing alcohol-related metabolic alterations might be effective for preventing and

  11. Impaired Physical Function Following Pediatric Liver Transplantation

    PubMed Central

    Feldman, Amy G.; Neighbors, Katie; Mukherjee, Shubra; Rak, Melanie; Varni, James W.; Alonso, Estella M.

    2016-01-01

    Objective Investigate the spectrum of physical function of pediatric liver transplant (LT) recipients 12–24 months post-LT. Study design Review data collected through the Functional Outcomes Group, an ancillary study of Studies of Pediatric Liver Transplantation registry. Patients were eligible if they had survived LT by 12–24 months. Children ≥ 8 years and parents completed the Pediatric Quality of Life Inventory™ 4.0 Generic Core Scales, which includes 8 questions assessing physical function. Scores were compared to a matched healthy child population (n=1658), and between survivors with optimal versus non-optimal health. Results A total of 263 patients were included. Median age at transplant and survey was 4.8 years (IQR 1.3–11.4) and 5.9 years (IQR 2.6–13.1), respectively. The mean Physical Functioning Score on child and parent reports were 81.2± 17.3 and 77.1± 23.7, respectively. Compared to a matched healthy population, transplant survivors and their parents reported lower physical function scores (p<0.01). 32.9% of patients and 35.0% of parents reported a physical function score <75, which is >1 SD below the mean of a healthy population. Physical Function Scores were significantly higher in survivors with optimal health than those with non-optimal health (p<0.01). There was a significant relationship between Emotional Functioning and Physical Functioning Scores for LT recipients (r=0.69, p<0.001). In multivariate analysis, primary disease, height Z score<−1.64 at long term follow-up (LTF) visit, ≥4 days of hospitalization since LTF visit, and not listed as Status 1 were predictors of poor physical function. Conclusions Pediatric LT recipients 1–2 years post-LT and their parents report lower physical function than a healthy population. Findings suggest practitioners need to routinely assess physical function, and development of rehabilitation programs may be important. PMID:26850789

  12. Chronic stress impairs collateral blood flow recovery in aged mice.

    PubMed

    Lassance-Soares, Roberta M; Sood, Subeena; Chakraborty, Nabarun; Jhamnani, Sunny; Aghili, Nima; Nashin, Hajra; Hammamieh, Rasha; Jett, Marti; Epstein, Stephen E; Burnett, Mary Susan

    2014-11-01

    Chronic stress is associated with increased risk of cardiovascular diseases. Aging is also associated with vascular dysfunction. We hypothesize that chronic stress accelerates collateral dysfunction in old mice. Mice were subjected to either chronic social defeat (CSD) or chronic cold stress (CCS). The CSD mice were housed in a box inside an aggressor's cage and exposed to the aggressor. The CCS group was placed in iced water. After chronic stress, mice underwent femoral artery ligation (FAL) and flow recovery was measured. For the CSD group, appearance and use scores of the foot and a behavioral test were performed. CSD impaired collateral flow recovery after FAL. Further, stressed mice had greater ischemic damage, impaired foot function, and altered behavior. The CCS mice also showed impaired collateral flow recovery. Chronic stress causes hind limb collateral dysfunction in old mice, a conclusion reinforced by the fact that two types of stress produced similar changes.

  13. Cognitive Impairment in Chronic Obstructive Pulmonary Disease

    PubMed Central

    Crişan, Alexandru F.; Oancea, Cristian; Timar, Bogdan; Fira-Mladinescu, Ovidiu; Crişan, Alexandru; Tudorache, Voicu

    2014-01-01

    Background/Purpose Chronic obstructive pulmonary disease (COPD), especially in severe forms, is commonly associated with multiple cognitive problems. Montreal Cognitive Assessment test (MoCA) is used to detect cognitive impairment evaluating several areas: visuospatial, memory, attention and fluency. Our study aim was to evaluate the impact of stable COPD and exacerbation (AECOPD) phases on cognitive status using MoCA questionnaire. Methods We enrolled 39 patients (pts), smokers with COPD group D (30 stable and 9 in AECOPD) and 13 healthy subjects (control group), having similar level of education and no significant differences regarding the anthropometric measurements. We analyzed the differences in MoCA score between these three groups and also the correlation between this score and inflammatory markers. Results Patients with AECOPD had a significant (p<0.001) decreased MoCA score (14.6±3.4) compared to stable COPD (20.2±2.4) and controls (24.2±5.8). The differences between groups were more accentuated for the language abstraction and attention (p<0.001) and delayed recall and orientation (p<0.001) sub-topics. No significant variance of score was observed between groups regarding visuospatial and naming score (p = 0.095). The MoCA score was significantly correlated with forced expiratory volume (r = 0.28) and reverse correlated with C-reactive protein (CRP) (r = −0.57), fibrinogen (r = −0.58), erythrocyte sedimentation rate (ESR) (r = −0.55) and with the partial pressure of CO2 (r = −0.47). Conclusions According to this study, COPD significantly decreases the cognitive status in advanced and acute stages of the disease. PMID:25033379

  14. How to Face Chronic Liver Disease: The Sinusoidal Perspective

    PubMed Central

    Fernández-Iglesias, Anabel; Gracia-Sancho, Jordi

    2017-01-01

    Liver microcirculation plays an essential role in the progression and aggravation of chronic liver disease. Hepatic sinusoid environment, mainly composed by hepatocytes, liver sinusoidal endothelial cells, Kupffer cells, and hepatic stellate cells, intimately cooperate to maintain global liver function and specific phenotype of each cell type. However, continuous liver injury significantly deregulates liver cells protective phenotype, leading to parenchymal and non-parenchymal dysfunction. Recent data have enlightened the molecular processes that mediate hepatic microcirculatory injury, and consequently, opened the possibility to develop new therapeutic strategies to ameliorate liver circulation and viability. The present review summarizes the main cellular components of the hepatic sinusoid, to afterward focus on non-parenchymal cells phenotype deregulation due to chronic injury, in the specific clinical context of liver cirrhosis and derived portal hypertension. Finally, we herein detail new therapies developed at the bench-side with high potential to be translated to the bedside. PMID:28239607

  15. Gut microbiota and probiotics in chronic liver diseases.

    PubMed

    Cesaro, Claudia; Tiso, Angelo; Del Prete, Anna; Cariello, Rita; Tuccillo, Concetta; Cotticelli, Gaetano; Del Vecchio Blanco, Camillo; Loguercio, Carmelina

    2011-06-01

    There is a strong relationship between liver and gut: the portal system receives blood from the gut, and intestinal blood content activates liver functions. The liver, in turn, affects intestinal functions through bile secretion into the intestinal lumen. Alterations of intestinal microbiota seem to play an important role in induction and promotion of liver damage progression, in addition to direct injury resulting from different causal agents. Bacterial overgrowth, immune dysfunction, alteration of the luminal factors, and altered intestinal permeability are all involved in the pathogenesis of complications of liver cirrhosis, such as infections, hepatic encephalopathy, spontaneous bacterial peritonitis, and renal failure. Probiotics have been suggested as a useful integrative treatment of different types of chronic liver damage, for their ability to augment intestinal barrier function and prevent bacterial translocation. This review summarizes the main literature findings about the relationships between gut microbiota and chronic liver disease, both in the pathogenesis and in the treatment by probiotics of the liver damage.

  16. Decreased S100B expression in chronic liver diseases

    PubMed Central

    Baik, Su Jung; Kim, Tae Hun; Yoo, Kwon; Moon, Il Hwan; Choi, Ju Young; Chung, Kyu Won; Song, Dong Eun

    2017-01-01

    Background/Aims Hepatic innervation in liver diseases is not fully understood. We here evaluated S100B expression as a marker of hepatic nerves in patients with various chronic liver diseases, topographically and semi-quantitatively. Methods Liver specimens were obtained from 70 subjects (three controls, and 32 chronic hepatitis B, 14 chronic hepatitis C, 14 liver cirrhosis, and seven hepatocellular carcinoma patients). The hepatic nerve density was calculated based on immunohistochemical staining of S100B protein in the portal tracts and hepatic lobules. S100B mRNA levels were semi-quantitatively assessed as the S100B/glyceraldehyde 3-phosphate dehydrogenase (GAPDH) mRNA ratio. Results The densities of the hepatic nerves in portal tracts of chronic liver diseases were not significantly different from those of normal controls but the hepatic nerve densities in lobular areas of liver cirrhosis were significantly decreased (p = 0.025). Compared to the control, the S100B/GAPDH mRNA ratio was significantly decreased in chronic liver diseases (p = 0.006) and most decreased in chronic hepatitis C patients (p = 0.023). In chronic liver diseases, The S100B/GAPDH mRNA ratio tended to decrease as the fibrosis score > 0 (p = 0.453) but the overall correlation between the S100B/GAPDH mRNA ratio and fibrosis score was not statistically significant (r = 0.061, p = 0.657). Conclusions Hepatic innervation is decreased in cirrhotic regenerating nodules compared to the control group and seems to decrease in early stages of fibrosis progression. Further studies are needed to clarify the association between changes of hepatic innervation and chronic liver disease progression. PMID:27255110

  17. Chronic liver injury induced by drugs: a systematic review.

    PubMed

    Stine, Jonathan G; Chalasani, Naga

    2015-11-01

    To examine the available literature and summarize what is known about chronic drug-induced liver injury. We reviewed PubMed/MEDLINE through March 2015. We developed a MEDLINE search strategy using PubMed medical subject heading terms chronic liver injury, hepatotoxicity, drug-induced liver injury, cirrhosis and chronic liver disease. We reviewed the reference list of included articles to identify articles missed in the database search. Chronic liver injury from drugs is more common than once thought with prevalence as high as 18% based on large national registries. Patients with cholestatic injury, age ≤65 years, and a long latency period (>365 days) are at increased risk. Of the most common drugs associated with drug-induced liver injury, antibiotics (amoxicillin-clavulanic acid, trimethoprim-sulfamethoxazole, azithromycin) are most likely to cause chronic injury. The presence of autoantibodies is common with chronic DILI, however, it is not diagnostic nor is it specific to autoimmune-like drug-induced liver injury. Immunosuppressive therapy may be necessary for individual cases of autoimmune-like drug-induced liver injury where cessation of the drug alone does not result in resolution of injury, however, the lowest dose should be used for the shortest duration with careful attention to the development of side effects. The effectiveness of treament of cholestatic liver injury with corticosteroids or ursodiol remains unclear. Cases of drug-induced fatty liver, nodular regenerative hyperplasia and peliosis hepatitis are less common subtypes of chronic drug-induced liver injury that deserve special consideration. A high degree of clinical suspicion is required for the diagnosis of chronic drug-induced liver injury and should be suspected in any patient with liver associated enzyme abnormalities that persist out past 6 months of initial presentation. Treatment with drug removal and/or immunosuppressive therapy appears to be effective for the majority of cases

  18. Study on Assessment of Renal Function in Chronic Liver Disease

    PubMed Central

    Das, Nupur; Paria, Baishakhi; Sarkar, Sujoy

    2015-01-01

    Introduction: Renal dysfunction is common in chronic liver disease. The cause of this renal dysfunction is either multi-organ involvement in acute conditions or secondary to advanced liver disease. Objectives: The study was undertaken to assess the renal function in chronic liver diseases and find out the association of alteration of renal function with gradation of liver disease. (assessed by child-pugh criteria) and to find out the association of alteration of renal function among the cases of chronic liver disease of different aetiology. Materials and Methods: This cross-sectional, observational study was undertaken in Department of General Medicine, Calcutta National Medical College & Hospital, Kolkata during March 2012 to July 2013 with 50 admitted patients of chronic liver disease after considering the exclusion criteria. The patients were interviewed with a pre-designed and pre-tested schedule, examined clinically, followed by some laboratory investigations relevant to diagnose the aetiology of chronic liver disease, and to assess the severity of liver and renal dysfunction. Data was analysed by standard statistical method. Results: Eighty six percent of the patients were male and the mean age of study population was 43.58 y, 68% patients suffered from alcoholic liver disease, followed by 14% patients had chronic Hepatitis-B, 10% patients developed acute kidney injury, 20% had hepato renal syndrome and 14% had IgA deposition. The distribution of serum urea and creatinine across the categories of Child Pugh classification tested by Mann-Whitney test and the distribution was statistically significant. Conclusion: The present study has found significant association between severity of liver dysfunction and certain parameters of renal dysfunction. PMID:25954647

  19. Tempol prevents chronic sleep-deprivation induced memory impairment.

    PubMed

    Alzoubi, Karem H; Khabour, Omar F; Albawaana, Amal S; Alhashimi, Farah H; Athamneh, Rabaa Y

    2016-01-01

    Sleep deprivation is associated with oxidative stress that causes learning and memory impairment. Tempol is a nitroxide compound that promotes the metabolism of many reactive oxygen species (ROS) and has antioxidant and neuroprotective effect. The current study investigated whether chronic administration of tempol can overcome oxidative stress and prevent learning and memory impairment induced by sleep deprivation. Sleep deprivation was induced in rats using multiple platform model. Tempol was administered to rats via oral gavages. Behavioral studies were conducted to test the spatial learning and memory using radial arm water maze. The hippocampus was dissected; antioxidant biomarkers (GSH, GSSG, GSH/GSSG ratio, GPx, SOD, and catalase) were assessed. The result of this project revealed that chronic sleep deprivation impaired both short and long term memory (P<0.05), while tempol treatment prevented such effect. Furthermore, tempol normalized chronic sleep deprivation induced reduction in the hippocampus activity of catalase, GPx, and SOD (P<0.05). Tempol also enhanced the ratio of GSH/GSSG in chronically sleep deprived rats treated with tempol as compared with only sleep deprived rats (P<0.05). In conclusion chronic sleep deprivation induced memory impairment, and treatment with tempol prevented this impairment probably through normalizing antioxidant mechanisms in the hippocampus.

  20. Simulation of Chronic Liver Injury Due to Environmental Chemicals

    EPA Science Inventory

    US EPA Virtual Liver (v-Liver) is a cellular systems model of hepatic tissues to predict the effects of chronic exposure to chemicals. Tens of thousands of chemicals are currently in commerce and hundreds more are introduced every year. Few of these chemicals have been adequate...

  1. Liver transplantation for chronic liver disease: advances and controversies in an era of organ shortages

    PubMed Central

    Prince, M; Hudson, M

    2002-01-01

    Since liver transplantation was first performed in 1968 by Starzl et al, advances in case selection, liver surgery, anaesthetics, and immunotherapy have significantly increased the indications for and success of this operation. Liver transplantation is now a standard therapy for many end stage liver disorders as well as acute liver failure. However, while demand for cadaveric organ grafts has increased, in recent years the supply of organs has fallen. This review addresses current controversies resulting from this mismatch. In particular, methods for increasing graft availability and difficulties arising from transplantation in the context of alcohol related cirrhosis, primary liver tumours, and hepatitis C are reviewed. Together these three indications accounted for 42% of liver transplants performed for chronic liver disease in the UK in 2000. Ethical frameworks for making decisions on patients' suitability for liver transplantation have been developed in both the USA and the UK and these are also reviewed. PMID:11884694

  2. Hydrogen peroxide impairs autophagic flux in a cell model of nonalcoholic fatty liver disease

    SciTech Connect

    Jiang, Pengtao; Huang, Zhen; Zhao, Hong; Wei, Taotao

    2013-04-19

    Highlights: •Free fatty acids exposure induces elevated autophagy. •H{sub 2}O{sub 2} inhibits autophagic flux through impairing the fusion between autophagosomes and lysosomes. •Inhibition of autophagy potentiates H{sub 2}O{sub 2}-induced cell death. -- Abstract: Nonalcoholic fatty liver disease (NAFLD) has become the leading cause of chronic liver disease, but the pathogenesis of NAFLD is not fully clear. The aim of this study was to determine whether autophagy plays a role in the pathogenesis of NAFLD. We found that the levels of autophagy were elevated in hepatoma cells upon exposure to free fatty acids, as confirmed by the increase in the number of autophagosomes. However, exposure of hepatoma cells to H{sub 2}O{sub 2} and TNF-α, two typical “second hit” factors, increased the initiation of autophagy but inhibited the autophagic flux. The inhibition of autophagy sensitized cells to pro-apoptotic stimuli. Taken together, our results suggest that autophagy acts as a protective mechanism in the pathogenesis of NAFLD and that impairment of autophagy might induce more severe lesions of the liver. These findings will be a benefit to the understanding of the pathogenesis of NAFLD and might suggest a strategy for the prevention and cure of NAFLD.

  3. Impaired liver function attenuates liver regeneration and hypertrophy after portal vein embolization

    PubMed Central

    Kageyama, Yumiko; Kokudo, Takashi; Amikura, Katsumi; Miyazaki, Yoshihiro; Takahashi, Amane; Sakamoto, Hirohiko

    2016-01-01

    AIM To clarify the clinical factors associated with liver regeneration after major hepatectomy and the hypertrophic rate after portal vein embolization (PVE). METHODS A total of 63 patients who underwent major hepatectomy and 13 patients who underwent PVE in a tertiary care hospital between January 2012 and August 2015 were included in the analysis. We calculated the remnant liver volume following hepatectomy using contrast-enhanced computed tomography (CT) performed before and approximately 3-6 mo after hepatectomy. Furthermore, we calculated the liver volume using CT performed 2-4 wk after PVE. Preoperative patient characteristics and laboratory data were analyzed to identify factors affecting postoperative liver regeneration or hypertrophy rate following PVE. RESULTS The remnant liver volume/total liver volume ratio negatively correlated with the liver regeneration rate after hepatectomy (ρ = -0.850, P < 0.001). The regeneration rate was significantly lower in patients with an indocyanine green retention rate at 15 min (ICG-R15) of ≥ 20% in the right hepatectomy group but not in the left hepatectomy group. The hypertrophic rate after PVE positively correlated with the regeneration rate after hepatectomy (ρ = 0.648, P = 0.017). In addition, the hypertrophic rate after PVE was significantly lower in patients with an ICG-R15 ≥ 20% and a serum total bilirubin ≥ 1.5 mg/dL. CONCLUSION The regeneration rate after major hepatectomy correlated with hypertrophic rate after PVE. Both of them were attenuated in the presence of impaired liver function. PMID:27729956

  4. Chronic Antidepressant Treatment Impairs the Acquisition of Fear Extinction

    PubMed Central

    Burghardt, Nesha S.; Sigurdsson, Torfi; Gorman, Jack M.; McEwen, Bruce S.; LeDoux, Joseph E.

    2012-01-01

    Background Like fear conditioning, the acquisition phase of extinction involves new learning that is mediated by the amygdala. During extinction training, the conditioned stimulus is repeatedly presented in the absence of the unconditioned stimulus and the expression of previously learned fear gradually becomes suppressed. Our previous study revealed that chronic treatment with a selective serotonin reuptake inhibitor (SSRI) impairs the acquisition of auditory fear conditioning. To gain further insight into how SSRIs affect fear learning, we tested the effects of chronic SSRI treatment on the acquisition of extinction. Methods Rats were treated chronically (22 days) or subchronically (9 days) with the SSRI citalopram (10 mg/kg/day) before extinction training. The results were compared to those following chronic and subchronic treatment with tianeptine (10 mg/kg/day), an antidepressant with a different method of action. The expression of the NR2B subunit of the NMDA receptor in the amygdala was examined after behavioral testing. Results Chronic but not subchronic administration of citalopram impaired the acquisition of extinction and downregulated the NR2B subunit of the NMDA receptor in the lateral and basal nuclei of the amygdala. Similar behavioral and molecular changes were found with tianeptine treatment. Conclusions These results provide further evidence that chronic antidepressant treatment can impair amygdala-dependent learning. Our findings are consistent with a role for glutamatergic neurotransmission in the final common pathway of antidepressant treatment. PMID:23260230

  5. The pathophysiology of thrombocytopenia in chronic liver disease

    PubMed Central

    Mitchell, Oscar; Feldman, David M; Diakow, Marla; Sigal, Samuel H

    2016-01-01

    Thrombocytopenia is the most common hematological abnormality encountered in patients with chronic liver disease (CLD). In addition to being an indicator of advanced disease and poor prognosis, it frequently prevents crucial interventions. Historically, thrombocytopenia has been attributed to hypersplenism, which is the increased pooling of platelets in a spleen enlarged by congestive splenomegaly secondary to portal hypertension. Over the past decade, however, there have been significant advances in the understanding of thrombopoiesis, which, in turn, has led to an improved understanding of thrombocytopenia in cirrhosis. Multiple factors contribute to the development of thrombocytopenia and these can broadly be divided into those that cause decreased production, splenic sequestration, and increased destruction. Depressed thrombopoietin levels in CLD, together with direct bone marrow suppression, result in a reduced rate of platelet production. Thrombopoietin regulates both platelet production and maturation and is impaired in CLD. Bone marrow suppression can be caused by viruses, alcohol, iron overload, and medications. Splenic sequestration results from hypersplenism. The increased rate of platelet destruction in cirrhosis also occurs through a number of pathways: increased shear stress, increased fibrinolysis, bacterial translocation, and infection result in an increased rate of platelet aggregation, while autoimmune disease and raised titers of antiplatelet immunoglobulin result in the immunologic destruction of platelets. An in-depth understanding of the complex pathophysiology of the thrombocytopenia of CLD is crucial when considering treatment strategies. This review outlines the recent advances in our understanding of thrombocytopenia in cirrhosis and CLD. PMID:27186144

  6. Delayed Liver Function Impairment Secondary to Interferon β-1a Use in Multiple Sclerosis

    PubMed Central

    Liao, Ming-Feng; Yen, Su-Chen; Chun-Yen, Lin; Rong-Kuo, Lyu

    2013-01-01

    Interferon β-1a is a widely used immunomodulation treatment for multiple sclerosis. Liver function impairment is a common side effect and usually develops in the first 6 months after interferon use. Here, we describe 2 multiple sclerosis patients who developed delayed liver function impairment 5 years after receiving interferon β-1a treatment. Their liver function recovered after discontinuing interferon use, and further detailed hepatological evaluations excluded other etiologies of liver function impairment. Our case reports illustrate that liver function impairment induced by interferon β-1a can be delayed for 5 years after starting treatment and, probably, this is an idiosyncratic reaction. Regular liver function monitoring in multiple sclerosis patients who receive interferon β is necessary even after the first 6 months of treatment, especially in those patients with concomitant use of other liver-toxic medications. PMID:23904853

  7. Chronic liver disease: evaluation by magnetic resonance

    SciTech Connect

    Stark, D.D.; Goldberg, H.I.; Moss, A.A.; Bass, N.M.

    1984-01-01

    Magnetic resonance (MR) imaging distinguished hepatitis from fatty liver and cirrhosis in a woman with a history of alcohol abuse. Anatomic and physiologic manifestations of portal hypertension were also demonstrated by MR.

  8. 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.

  9. Acute-on-chronic liver failure: a review

    PubMed Central

    Zamora Nava, Luis Eduardo; Aguirre Valadez, Jonathan; Chávez-Tapia, Norberto C; Torre, Aldo

    2014-01-01

    There is no universally accepted definition of acute-on-chronic liver failure; however, it is recognized as an entity characterized by decompensation from an underlying chronic liver disease associated with organ failure that conveys high short-term mortality, with alcoholism and infection being the most frequent precipitating events. The pathophysiology involves inflammatory processes associated with a trigger factor in susceptible individuals (related to altered immunity in the cirrhotic population). This review addresses the different definitions developed by leading research groups, epidemiological and pathophysiological aspects, and the latest treatments for this entity. PMID:24790454

  10. Current Concepts in Diabetes Mellitus and Chronic Liver Disease: Clinical Outcomes, Hepatitis C Virus Association, and Therapy.

    PubMed

    García-Compeán, Diego; González-González, José Alberto; Lavalle-González, Fernando Javier; González-Moreno, Emmanuel Irineo; Villarreal-Pérez, Jesús Zacarías; Maldonado-Garza, Héctor J

    2016-02-01

    Hereditary type 2 diabetes mellitus is a risk factor for chronic liver disease, and ~30 % of patients with liver cirrhosis develop diabetes. Diabetes mellitus has been associated with cirrhotic and non-cirrhotic hepatitis C virus liver infection, can aggravate the course the liver infection, and can induce a lower sustained response to antiviral treatment. Evidences that HCV may induce metabolic and autoimmune disturbances leading to hypobetalipoproteinemia, steatosis, insulin resistance, impaired glucose tolerance, thyroid disease, and gonadal dysfunction have been found. Prospective studies have demonstrated that diabetes increases the risk of liver complications and death in patients with cirrhosis. However, treatment of diabetes in these patients is complex, as antidiabetic drugs can promote hypoglycemia and lactic acidosis. There have been few therapeutic studies evaluating antidiabetic treatments in patients with liver cirrhosis published to date; thus, the optimal treatment for diabetes and the impact of treatment on morbidity and mortality are not clearly known. As numbers of patients with chronic liver disease and diabetes mellitus are increasing, largely because of the global epidemics of obesity and nonalcoholic fatty liver disease, evaluation of treatment options is becoming more important. This review discusses new concepts on hepatogenous diabetes, the diabetes mellitus–hepatitis C virus association, and clinical implications of diabetes mellitus in patients with chronic liver disease. In addition, the effectiveness and safety of old and new antidiabetic drugs, including incretin-based therapies, will be described.

  11. Dapagliflozin-Induced Acute-on-Chronic Liver Injury

    PubMed Central

    Levine, Joshua A.; Ann Lo, Amy; Wallia, Amisha; Rogers, Melinda

    2016-01-01

    Sodium-glucose cotransporter 2 inhibitors are a new class of oral hypoglycemic agents, and thus safety data are limited. We present a 48-year-old woman with type 2 diabetes mellitus and Child’s Class A cirrhosis secondary to nonalcoholic steatohepatitis presenting with jaundice and acute cholestatic liver injury. Other than starting dapagliflozin, she reported no medication changes or supplement use. Before treatment, her total bilirubin was 1.2 mg/dL. On admission, her liver values were elevated and liver biopsy was consistent with drug-induced liver injury. This report raises awareness about the potential hepatotoxic effects of dapagliflozin, particularly in patients with chronic liver disease. PMID:28008402

  12. Acute-on-chronic liver failure: terminology, mechanisms and management.

    PubMed

    Sarin, Shiv K; Choudhury, Ashok

    2016-03-01

    Acute-on-chronic liver failure (ACLF) is a distinct clinical entity and differs from acute liver failure and decompensated cirrhosis in timing, presence of acute precipitant, course of disease and potential for unaided recovery. The definition involves outlining the acute and chronic insults to include a homogenous patient group with liver failure and an expected outcome in a specific timeframe. The pathophysiology of ACLF relates to persistent inflammation, immune dysregulation with initial wide-spread immune activation, a state of systematic inflammatory response syndrome and subsequent sepsis due to immune paresis. The disease severity and outcome can be predicted by both hepatic and extrahepatic organ failure(s). Clinical recovery is expected with the use of nucleoside analogues for hepatitis B, and steroids for severe alcoholic hepatitis and, possibly, severe autoimmune hepatitis. Artificial liver support systems help remove toxins and metabolites and serve as a bridge therapy before liver transplantation. Hepatic regeneration during ongoing liver failure, although challenging, is possible through the use of growth factors. Liver transplantation remains the definitive treatment with a good outcome. Pre-emptive antiviral agents for hepatitis B before chemotherapy to prevent viral reactivation and caution in using potentially hepatotoxic drugs can prevent the development of ACLF.

  13. Autophagy in chronic liver diseases: the two faces of Janus.

    PubMed

    Gual, Philippe; Gilgenkrantz, Hélène; Lotersztajn, Sophie

    2017-03-01

    Alcoholic liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD) are the leading causes of cirrhosis and increase the risk of hepatocellular carcinoma and liver-related death. ALD and NAFLD share common pathogenic features extending from isolated steatosis to steatohepatitis and steatofibrosis, which can progress to cirrhosis and hepatocellular carcinoma. The pathophysiological mechanisms of the progression of NAFLD and ALD are complex and still unclear. Important links between the regulation of autophagy (macroautophagy and chaperone-mediated autophagy) and chronic liver diseases have been reported. Autophagy may protect against steatosis and progression to steatohepatitis by limiting hepatocyte injury and reducing M1 polarization, as well as promoting liver regeneration. Its role in fibrosis and hepatocarcinogenesis is more complex. It has pro- and antifibrogenic properties depending on the hepatic cell type concerned, and beneficial and deleterious effects on hepatocarcinogenesis at initiating and late phases, respectively. This review summarizes the latest advances on the role of autophagy in different stages of fatty liver disease progression and describes its divergent and cell-specific effects during chronic liver injury.

  14. Hydrogen peroxide impairs autophagic flux in a cell model of nonalcoholic fatty liver disease.

    PubMed

    Jiang, Pengtao; Huang, Zhen; Zhao, Hong; Wei, Taotao

    2013-04-19

    Nonalcoholic fatty liver disease (NAFLD) has become the leading cause of chronic liver disease, but the pathogenesis of NAFLD is not fully clear. The aim of this study was to determine whether autophagy plays a role in the pathogenesis of NAFLD. We found that the levels of autophagy were elevated in hepatoma cells upon exposure to free fatty acids, as confirmed by the increase in the number of autophagosomes. However, exposure of hepatoma cells to H2O2 and TNF-α, two typical "second hit" factors, increased the initiation of autophagy but inhibited the autophagic flux. The inhibition of autophagy sensitized cells to pro-apoptotic stimuli. Taken together, our results suggest that autophagy acts as a protective mechanism in the pathogenesis of NAFLD and that impairment of autophagy might induce more severe lesions of the liver. These findings will be a benefit to the understanding of the pathogenesis of NAFLD and might suggest a strategy for the prevention and cure of NAFLD.

  15. Role of spleen elastography in patients with chronic liver diseases

    PubMed Central

    Giunta, Mariangela; Conte, Dario; Fraquelli, Mirella

    2016-01-01

    The development of liver cirrhosis and portal hypertension (PH), one of its major complications, are structural and functional alterations of the liver, occurring in many patients with chronic liver diseases (CLD). Actually the progressive deposition of hepatic fibrosis has a key role in the prognosis of CLD patients. The subsequent development of PH leads to its major complications, such as ascites, hepatic encephalopathy, variceal bleeding and decompensation. Liver biopsy is still considered the reference standard for the assessment of hepatic fibrosis, whereas the measurement of hepatic vein pressure gradient is the standard to ascertain the presence of PH and upper endoscopy is the method of choice to detect the presence of oesophageal varices. However, several non-invasive tests, including elastographic techniques, are currently used to evaluate the severity of liver disease and predict its prognosis. More recently, the measurement of the spleen stiffness has become particularly attractive to assess, considering the relevant role accomplished by the spleen in splanchnic circulation in the course of liver cirrhosis and in the PH. Moreover, spleen stiffness as compared with liver stiffness better represents the dynamic changes occurring in the advanced stages of cirrhosis and shows higher diagnostic performance in detecting esophageal varices. The aim of this review is to provide an exhaustive overview of the actual role of spleen stiffness measurement as assessed by several elastographic techniques in evaluating both liver disease severity and the development of cirrhosis complications, such as PH and to highlight its potential and possible limitations. PMID:27672283

  16. Chronic Glucocorticoid-Rich Milieu and Liver Dysfunction

    PubMed Central

    Castro, María Cecilia

    2016-01-01

    We investigated the impact of chronic hypercorticosteronemia (due to neonatal monosodium L-glutamate, MSG, and treatment) on liver oxidative stress (OS), inflammation, and carbohydrate/lipid metabolism in adult male rats. We evaluated the peripheral concentrations of several metabolic and OS markers and insulin resistance indexes. In liver we assessed (a) OS (GSH and protein carbonyl groups) and inflammatory (IL-1b, TNFa, and PAI-1) biomarkers and (b) carbohydrate and lipid metabolisms. MSG rats displayed degenerated optic nerves, hypophagia, low body and liver weights, and enlarged adipose tissue mass; higher peripheral levels of glucose, triglycerides, insulin, uric acid, leptin, corticosterone, transaminases and TBARS, and peripheral and liver insulin resistance; elevated liver OS, inflammation markers, and glucokinase (mRNA/activity) and fructokinase (mRNA). Additionally, MSG liver phosphofructokinase-2, glucose-6-phosphatase (mRNA and activity) and glucose-6-phosphate dehydrogenase, Chrebp, Srebp1c, fatty acid synthase, and glycerol-3-phosphate (mRNAs) were increased. In conclusion adult MSG rats developed an insulin-resistant state and increased OS and serious hepatic dysfunction characterized by inflammation and metabolic signs suggesting increased lipogenesis. These features, shared by both metabolic and Cushing's syndrome human phenotypes, support that a chronic glucocorticoid-rich endogenous environment mainly impacts on hepatic glucose cycle, displacing local metabolism to lipogenesis. Whether correcting the glucocorticoid-rich environment ameliorates such dysfunctions requires further investigation. PMID:27597864

  17. Chronic Glucocorticoid-Rich Milieu and Liver Dysfunction.

    PubMed

    Villagarcía, Hernán Gonzalo; Sabugo, Vanesa; Castro, María Cecilia; Schinella, Guillermo; Castrogiovanni, Daniel; Spinedi, Eduardo; Massa, María Laura; Francini, Flavio

    2016-01-01

    We investigated the impact of chronic hypercorticosteronemia (due to neonatal monosodium L-glutamate, MSG, and treatment) on liver oxidative stress (OS), inflammation, and carbohydrate/lipid metabolism in adult male rats. We evaluated the peripheral concentrations of several metabolic and OS markers and insulin resistance indexes. In liver we assessed (a) OS (GSH and protein carbonyl groups) and inflammatory (IL-1b, TNFa, and PAI-1) biomarkers and (b) carbohydrate and lipid metabolisms. MSG rats displayed degenerated optic nerves, hypophagia, low body and liver weights, and enlarged adipose tissue mass; higher peripheral levels of glucose, triglycerides, insulin, uric acid, leptin, corticosterone, transaminases and TBARS, and peripheral and liver insulin resistance; elevated liver OS, inflammation markers, and glucokinase (mRNA/activity) and fructokinase (mRNA). Additionally, MSG liver phosphofructokinase-2, glucose-6-phosphatase (mRNA and activity) and glucose-6-phosphate dehydrogenase, Chrebp, Srebp1c, fatty acid synthase, and glycerol-3-phosphate (mRNAs) were increased. In conclusion adult MSG rats developed an insulin-resistant state and increased OS and serious hepatic dysfunction characterized by inflammation and metabolic signs suggesting increased lipogenesis. These features, shared by both metabolic and Cushing's syndrome human phenotypes, support that a chronic glucocorticoid-rich endogenous environment mainly impacts on hepatic glucose cycle, displacing local metabolism to lipogenesis. Whether correcting the glucocorticoid-rich environment ameliorates such dysfunctions requires further investigation.

  18. Defective liver disposal of free fatty acids in patients with impaired glucose tolerance.

    PubMed

    Iozzo, Patricia; Turpeinen, Anu K; Takala, Teemu; Oikonen, Vesa; Bergman, Jörgen; Grönroos, Tove; Ferrannini, Ele; Nuutila, Pirjo; Knuuti, Juhani

    2004-07-01

    The liver exchanges high fluxes of glucose and free fatty acids (FFA) and is one main site of their reciprocal regulation. Acute exposure to hyperglycemia and hyperinsulinemia has been shown to reduce splanchnic beta-oxidation in healthy humans. We investigated whether a spontaneous condition of chronic mild hyperglycemia and hyperinsulinemia affects liver FFA uptake. Hepatic FFA influx rate constant (LKi) was measured after a 12-15-h fast in 10 patients with impaired glucose tolerance (IGT) and eight control subjects using positron emission tomography in combination with the long-chain FFA analog 14(R,S)-[18F]fluoro-6-thia-heptadecanoic acid. Compared with controls, IGT patients had higher serum insulin, glucose, and triglyceride levels (1.71 +/- 0.24 vs. 0.59 +/- 0.06 mmol/liter, P < 0.001), lower high-density lipoprotein (1.04 +/- 0.11 vs. 1.42 +/- 0.13 mmol/liter, P < 0.05), and similar FFA levels (0.59 +/- 0.06 vs. 0.56 +/- 0.05 mmol/liter(-1), P = not significant). LKi was significantly reduced in IGT (0.288 +/- 0.014 min(-1)) compared with control subjects (0.341 +/- 0.014 min(-1), P < 0.02). LKi was negatively correlated with plasma glucose (r = 0.51, P < 0.03), glycosylated hemoglobin (r = 0.55, P < 0.02), and blood lactate levels (r = 0.52, P < 0.03). We conclude that, in IGT patients, the ability of the liver to extract FFA from the circulation appears to be impaired. The reciprocal relationship between hepatic FFA extraction and glucose/lactate flux may derive from intrahepatic substrate competition.

  19. Impaired Hepatic Adaptation to Chronic Cholestasis induced by Primary Sclerosing Cholangitis

    PubMed Central

    Milkiewicz, Malgorzata; Klak, Marta; Kempinska-Podhorodecka, Agnieszka; Wiechowska-Kozlowska, Anna; Urasinska, Elzbieta; Blatkiewicz, Malgorzata; Wunsch, Ewa; Elias, Elwyn; Milkiewicz, Piotr

    2016-01-01

    Pathogenesis of primary sclerosing cholangitis (PSC) may involve impaired bile acid (BA) homeostasis. We analyzed expressions of factors mediating enterohepatic circulation of BA using ileal and colonic (ascending and sigmoid) biopsies obtained from patients with PSC with and without ulcerative colitis (UC) and explanted PSC livers. Two-fold increase of BA-activated farnesoid X receptor (FXR) protein levels were seen in ascending and sigmoid colon of PSC patients with correspondingly decreased apical sodium-dependent BA transporter (ASBT) gene expression. This was associated with increased OSTβ protein levels in each part of analyzed gut. An intestinal fibroblast growth factor (FGF19) protein expression was significantly enhanced in ascending colon. Despite increased hepatic nuclear receptors (FXR, CAR, SHP), and FGF19, neither CYP7A1 suppression nor CYP3A4 induction were observed. The lack of negative regulation of BA synthesis may be accountable for lower levels of cholesterol observed in PSC in comparison to primary biliary cholangitis (PBC). In conclusion, chronic cholestasis in PSC induces adaptive changes in expression of BA transporters and FXR in the intestine. However hepatic impairment of expected in chronic cholestasis downregulation of CYP7A1 and upregulation of CYP3A4 may promote BA-induced liver injury in PSC. PMID:28008998

  20. Chronic hepatitis C virus infection: Serum biomarkers in predicting liver damage

    PubMed Central

    Valva, Pamela; Ríos, Daniela A; De Matteo, Elena; Preciado, Maria V

    2016-01-01

    Currently, a major clinical challenge in the management of the increasing number of hepatitis C virus (HCV) infected patients is determining the best means for evaluating liver impairment. Prognosis and treatment of chronic hepatitis C (CHC) are partly dependent on the assessment of histological activity, namely cell necrosis and inflammation, and the degree of liver fibrosis. These parameters can be provided by liver biopsy; however, in addition to the risks related to an invasive procedure, liver biopsy has been associated with sampling error mostly due to suboptimal biopsy size. To avoid these pitfalls, several markers have been proposed as non-invasive alternatives for the diagnosis of liver damage. Distinct approaches among the currently available non-invasive methods are (1) the physical ones based on imaging techniques; and (2) the biological ones based on serum biomarkers. In this review, we discuss these approaches with special focus on currently available non-invasive serum markers. We will discuss: (1) class I serum biomarkers individually and as combined panels, particularly those that mirror the metabolism of liver extracellular matrix turnover and/or fibrogenic cell changes; (2) class II biomarkers that are indirect serum markers and are based on the evaluation of common functional alterations in the liver; and (3) biomarkers of liver cell death, since hepatocyte apoptosis plays a significant role in the pathogenesis of HCV infection. We highlight in this review the evidence behind the use of these markers and assess the diagnostic accuracy as well as advantages, limitations, and application in clinical practice of each test for predicting liver damage in CHC. PMID:26819506

  1. Telomere and telomerase in chronic liver disease and hepatocarcinoma.

    PubMed

    Carulli, Lucia; Anzivino, Claudia

    2014-05-28

    The pathogenesis of liver cirrhosis is not completely elucidated. Although in the majority of patients, the risk factors may be identified in B and C viral hepatitis, alcohol intake, drugs or fatty liver disease, there is a small percentage of patients with no apparent risk factors. In addition, the evolution of chronic liver disease is highly heterogeneous from one patient to another. Among patient with identical risk factors, some rapidly progress to cirrhosis and hepatocellular carcinoma (HCC) whereas others have a benign course. Therefore, a genetic predisposition may contribute to the development of cirrhosis and HCC. Evidence supporting the role of genetic factors as a risk for cirrhosis has been accumulating during the past years. In addition to the results from epidemiological studies, polymorphisms studies and data on twins, the concept of telomere shortening as a genetic risk factor for chronic liver disease and HCC has been proposed. Here we review the literature on telomerase mutations, telomere shortening and liver disease including hepatocellular carcinoma.

  2. Chronic permanent hypoxemia predisposes to mild elevation of liver stiffness

    PubMed Central

    Tahiri, Mohamed; Drighil, Abdenasser; Jalal, Yasmine; Ghellab, Dounia; Hliwa, Wafaa; Fouad, Haddad; Badre, Wafaa; Bellabah, Ahmad; Habbal, Rachida; Alaoui, Rhimou

    2014-01-01

    AIM: To evaluate the impact of long term permanent hypoxemia noticed in patients with non operated congenital cyanogenic cyanotic cardiopathy on liver stiffness. METHODS: We included ten adult patients with non operated inoperate cyanotic cardiopathy and ten matched patients for age and gender admitted to the gastroenterology department for proctologic diseases; Clinical and laboratory data were collected [age, gender, body mass index, oxygen saturation, glutamate oxaloacetate transaminase (GOT), glutamate pyruvate transaminase (GPT), glycemia and cholesterol]. Measurement of hepatic stiffness by transient elastography was carried out in all patients using the Fibroscan device. All patients underwent an echocardiography to eliminate congestive heart failure. RESULTS: Among the patients with cyanotic cardiopathy, median liver stiffness 5.9 ± 1.3 kPa was greater than control group (4.7 ± 0.4 kPa) (P = 0.008). Median levels of GOT, GPT, gamma-glutamyltransferase, glycemia and cholesterol were comparable in cardiopathy and control group. In regression analysis including age, gender, body mass index, oxygen saturation, GOT, GPT, glycemia, cholesterol showed that only oxygen saturation was related to liver stiffness (r = -0.63 P = 0.002). CONCLUSION: Chronic permanent hypoxemia can induce mild increase of liver stiffness, but further studies are needed to explore the histological aspects of liver injury induced by chronic permanent hypoxemia. PMID:25132776

  3. Cryoglobulins in acute and chronic liver diseases

    PubMed Central

    Florin-Christensen, A.; Roux, María E. B.; Arana, R. M.

    1974-01-01

    Cryoglobulins were detected in the sera of thirteen patients with acute viral hepatitis and of twelve with chronic hepatic diseases (active chronic hepatitis, primary biliary cirrhosis and cryptogenic cirrhosis). Their nature and antibody activity was studied. In both groups, most of them consisted of mixed cryoimmunoglobulins (IgM, IgG and/or IgA), but some were single-class immunoglobulins with one or both types of light chains. Unusual components were also found. α1-fetoprotein was present in four cryoprecipitates: in two as the single constituent and in two associated to immunoglobulins; hepatitis-associated antigen co-existed in one of the latter. Some cryoglobulins showed antibody activity against human IgG, smooth muscle and mitochondrial antigens. In one case, the IgM-kappa of the cryoprecipitate had antibody activity against α1-fetoprotein; this antigen was also present in the cryoprecipitate, suggesting immune-complex formation. Autoantibodies were also looked for in the sera of the twenty-five patients; apart from the most common ones, antibodies to α1-fetoprotein were found in two patients. PMID:4143195

  4. Chronic Low Quality Sleep Impairs Postural Control in Healthy Adults

    PubMed Central

    Gonçalves, Bruno da Silva B.; Abranches, Isabela Lopes Laguardia; Abrantes, Ana Flávia

    2016-01-01

    The lack of sleep, both in quality and quantity, is an increasing problem in modern society, often related to workload and stress. A number of studies have addressed the effects of acute (total) sleep deprivation on postural control. However, up to date, the effects of chronic sleep deficits, either in quantity or quality, have not been analyzed. Thirty healthy adults participated in the study that consisted of registering activity with a wrist actigraph for more than a week before performing a series of postural control tests. Sleep and circadian rhythm variables were correlated and the sum of activity of the least active 5-h period, L5, a rhythm variable, obtained the greater coefficient value with sleep quality variables (wake after sleep onset WASO and efficiency sleep). Cluster analysis was performed to classify subjects into two groups based on L5 (low and high). The balance tests scores used to asses postural control were measured using Biodex Balance System and were compared between the two groups with different sleep quality. The postural tests were divided into dynamic (platform tilt with eyes open, closed and cursor) and static (clinical test of sensory integration). The results showed that during the tests with eyes closed, the group with worse sleep quality had also worse postural control performance. Lack of vision impairs postural balance more deeply in subjects with chronic sleep inefficiency. Chronic poor sleep quality impairs postural control similarly to total sleep deprivation. PMID:27732604

  5. Chronic Low Quality Sleep Impairs Postural Control in Healthy Adults.

    PubMed

    Furtado, Fabianne; Gonçalves, Bruno da Silva B; Abranches, Isabela Lopes Laguardia; Abrantes, Ana Flávia; Forner-Cordero, Arturo

    2016-01-01

    The lack of sleep, both in quality and quantity, is an increasing problem in modern society, often related to workload and stress. A number of studies have addressed the effects of acute (total) sleep deprivation on postural control. However, up to date, the effects of chronic sleep deficits, either in quantity or quality, have not been analyzed. Thirty healthy adults participated in the study that consisted of registering activity with a wrist actigraph for more than a week before performing a series of postural control tests. Sleep and circadian rhythm variables were correlated and the sum of activity of the least active 5-h period, L5, a rhythm variable, obtained the greater coefficient value with sleep quality variables (wake after sleep onset WASO and efficiency sleep). Cluster analysis was performed to classify subjects into two groups based on L5 (low and high). The balance tests scores used to asses postural control were measured using Biodex Balance System and were compared between the two groups with different sleep quality. The postural tests were divided into dynamic (platform tilt with eyes open, closed and cursor) and static (clinical test of sensory integration). The results showed that during the tests with eyes closed, the group with worse sleep quality had also worse postural control performance. Lack of vision impairs postural balance more deeply in subjects with chronic sleep inefficiency. Chronic poor sleep quality impairs postural control similarly to total sleep deprivation.

  6. Enhanced Liver Fibrosis (ELF) test accurately identifies liver fibrosis in patients with chronic hepatitis C.

    PubMed

    Parkes, J; Guha, I N; Roderick, P; Harris, S; Cross, R; Manos, M M; Irving, W; Zaitoun, A; Wheatley, M; Ryder, S; Rosenberg, W

    2011-01-01

    Assessment of liver fibrosis is important in determining prognosis and evaluating interventions. Due to limitations of accuracy and patient hazard of liver biopsy, non-invasive methods have been sought to provide information on liver fibrosis, including the European liver fibrosis (ELF) test, shown to have good diagnostic accuracy for the detection of moderate and severe fibrosis. Access to independent cohorts of patients has provided an opportunity to explore if this test could be simplified. This paper reports the simplification of the ELF test and its ability to identity severity of liver fibrosis in external validation studies in patients with chronic hepatitis C (CHC). Paired biopsy and serum samples from 347 naïve patients with CHC in three independent cohorts were analysed. Diagnostic performance characteristics were derived (AUROC, sensitivity and specificity, predictive values), and clinical utility modelling performed to determine the proportion of biopsies that could have been avoided if ELF test was used in this patient group. It was possible to simplify the original ELF test without loss of performance and the new algorithm is reported. The simplified ELF test was able to predict severe fibrosis [pooled AUROC of 0.85 (95% CI 0.81-0.89)] and using clinical utility modelling to predict severe fibrosis (Ishak stages 4-6; METAVIR stages 3 and 4) 81% of biopsies could have been avoided (65% correctly). Issues of spectrum effect in diagnostic test evaluations are discussed. In chronic hepatitis C a simplified ELF test can detect severe liver fibrosis with good accuracy.

  7. Management of Acute-on-Chronic Liver Failure.

    PubMed

    Durand, Francois; Nadim, Mitra K

    2016-05-01

    Acute-on-chronic liver failure (ACLF) is defined by the occurrence of organ failure(s) other than the liver in patients with cirrhosis. Even though mortality rates are high, there should no longer be reluctance to admit patients with ACLF in the intensive care unit. The prevalence of multidrug-resistant bacteria is high and broad spectrum antibiotics should be initiated as soon as infection is suspected. In patients with circulatory failure, the assessment of circulatory status is challenging due to the hyperkinetic state and an imbalance between the splanchnic and systemic blood volume. Acute kidney injury is common in patients with ACLF. Acute tubular necrosis should be differentiated from hepatorenal syndrome, which justifies vasoconstrictive agents. Renal replacement therapy and mechanical ventilation should be decided on clinical grounds. Recent trials on extracorporeal liver support failed to demonstrate a survival benefit. Aggressive management may serve as a bridge to transplantation provided patients are likely to survive after transplantation.

  8. 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.

  9. Chronic cholestatic liver diseases: clues from histopathology for pathogenesis.

    PubMed

    Pollheimer, Marion J; Fickert, Peter; Stieger, Bruno

    2014-06-01

    Chronic cholestatic liver diseases include fibrosing cholangiopathies such as primary biliary cirrhosis or primary sclerosing cholangitis. These and related cholangiopathies clearly display pathologies associated with (auto)immunologic processes. As the cholangiocyte's apical membrane is exposed to the toxic actions of the bile fluid, the interaction of bile with cholangiocytes and the biliary tree in general must be considered to completely understand the pathogenesis of cholangiopathies. While the molecular processes involved in the hepatocellular formation of bile are well understood in both normal and pathophysiologic conditions, those in the bile ducts of normal liver and in livers with cholangiopathies lag behind. This survey highlights key mechanisms known to date that are important for the formation of bile by hepatocytes and its modification by the biliary tree. It also delineates the clinical pathophysiologic findings for cholangiopathies and puts them in perspective with current experimental models to reveal the pathogenesis of cholangiopathies and develop novel therapeutic approaches.

  10. Chronic Liver Disease in Peru: Role of Viral Hepatitis

    DTIC Science & Technology

    1994-01-01

    ceruloplasmin, ferritin, iron, antinuclear anti- by one-third of subjects) in 48% of chronic liver bodies (ANA), and antimitochondrial antibodies to rule...Rebagliati (R.F.) and Naval Medical Research Institute Detachment (I.A.P.), Lima, Peru The prevalence of antibodies to hepatitis C virus 19921. To...development of serologic assays for the abuse, defined as being repeatedly intoxicated at least detection of antibody to hepatitis C virus (anti-HCV

  11. Impaired orofacial motor functions on chronic temporomandibular disorders.

    PubMed

    Ferreira, Cláudia Lúcia Pimenta; Machado, Bárbara Cristina Zanandréa; Borges, Carina Giovana Pissinatti; Rodrigues Da Silva, Marco Antonio M; Sforza, Chiarella; De Felício, Cláudia Maria

    2014-08-01

    Because temporomandibular disorders (TMDs) rehabilitation continues to be a challenge, a more comprehensive picture of the orofacial functions in patients with chronic pain is required. This study assessed the orofacial functions, including surface electromyography (EMG) of dynamic rhythmic activities, in patients with moderate-severe signs and symptoms of chronic TMD. It was hypothesized that orofacial motor control differs between patients with moderate-severe chronic TMD and healthy subjects. Seventy-six subjects (46 with TMD and 30 control) answered questionnaires of severity of TMD and chewing difficulties. Orofacial functions and EMG during chewing were assessed. Standardized EMG indices were obtained by quantitative analysis of the differential EMG signals of the paired masseter and temporal muscles, and used to describe muscular action during chewing. TMD patients showed significant greater difficulty in chewing; worse orofacial scores; longer time for free mastication; a less accurate recruitment of the muscles on the working and balancing sides, reduced symmetrical mastication index (SMI) and increased standardized activity during EMG test than healthy subjects. SMI, TMD severity and orofacial myofunctional scores were correlated (P<0.01). Impaired orofacial functions and increased activity of the muscles of balancing sides during unilateral chewing characterized the altered orofacial motor control in patients with moderate-severe chronic TMD. Implications for rehabilitation are discussed.

  12. Intrahepatic synthese of immunoglobulin G in chronic liver disease.

    PubMed

    Kronborg, I J; Knopf, P M

    1980-04-01

    A method has been developed to measure the in vitro production of immunoglobulin (Ig) by liver biopsy specimens. Five to 30 mg of liver tissue was cultured for 24 h in Dulbecco's modified Eagle's medium/10% foetal calf serum (FCS) containing radiolabelled leucine (L-[4,5-3H] leucine). The culture medium was collected, centrifuged and the supernatant dialysed to remove labelled leucine. The residual radioactivity was a measure of newly synthesized 3H-labelled proteins released into the medium. The quantity of IgG was determined by immunoprecipitation with monospecific antisera to IgG heavy chains. The presence of IgG in the supernatant was confirmed by chromatography on protein-A Sepharose column. In 6 biopsies without evidence of active inflammation (4 normal and 2 fatty liver by histological criteria) less than 1% of the protein synthesized was IgG. In contrast in the presence of active inflammation in 4 cases of alcoholic hepatitis the IgG percentage ranged from 2 to 6%. Maximal levels of IgG production were detected in 3 cases of chronic active hepatitis (CAH) and ranged from 5 to 30%. The increased Ig synthesis by the liver in alcoholic hepatitis and CAH is presumed to be an index of the intrahepatic host response and may have important implications for mechanisms of liver damage in these diseases.

  13. Chronic jet lag impairs startle-induced locomotion in Drosophila.

    PubMed

    Vaccaro, Alexandra; Birman, Serge; Klarsfeld, André

    2016-12-01

    Endogenous circadian clocks with ~24-h periodicity are found in most organisms from cyanobacteria to humans. Daylight synchronizes these clocks to solar time. In humans, shift-work and jet lag perturb clock synchronization, and such perturbations, when repeated or chronic, are strongly suspected to be detrimental to healthspan. Here we investigated locomotor aging and longevity in Drosophila melanogaster with genetically or environmentally disrupted clocks. We compared two mutations in period (per, a gene essential for circadian rhythmicity in Drosophila), after introducing them in a common reference genetic background: the arrhythmic per(01), and per(T) which displays robust short 16-h rhythms. Compared to the wild type, both per mutants showed reduced longevity and decreased startle-induced locomotion in aging flies, while spontaneous locomotor activity was not impaired. The per(01) phenotypes were generally less severe than those of per(T), suggesting that chronic jet lag is more detrimental to aging than arrhythmicity in Drosophila. Interestingly, the adjustment of environmental light-dark cycles to the endogenous rhythms of the per(T) mutant fully suppressed the acceleration in the age-related decline of startle-induced locomotion, while it accelerated this decline in wild-type flies. Overall, our results show that chronic jet lag accelerates a specific form of locomotor aging in Drosophila, and that this effect can be alleviated by environmental changes that ameliorate circadian rhythm synchronization.

  14. Rat liver mitochondrial damage under acute or chronic carbon tetrachloride-induced intoxication: Protection by melatonin and cranberry flavonoids

    SciTech Connect

    Cheshchevik, V.T.; Lapshina, E.A.; Dremza, I.K.; Zabrodskaya, S.V.; Reiter, R.J.; Prokopchik, N.I.; Zavodnik, I.B.

    2012-06-15

    In current societies, the risk of toxic liver damage has markedly increased. The aim of the present work was to carry out further research into the mechanism(s) of liver mitochondrial damage induced by acute (0.8 g/kg body weight, single injection) or chronic (1.6 g/ kg body weight, 30 days, biweekly injections) carbon tetrachloride – induced intoxication and to evaluate the hepatoprotective potential of the antioxidant, melatonin, as well as succinate and cranberry flavonoids in rats. Acute intoxication resulted in considerable impairment of mitochondrial respiratory parameters in the liver. The activity of mitochondrial succinate dehydrogenase (complex II) decreased (by 25%, p < 0.05). Short-term melatonin treatment (10 mg/kg, three times) of rats did not reduce the degree of toxic mitochondrial dysfunction but decreased the enhanced NO production. After 30-day chronic intoxication, no significant change in the respiratory activity of liver mitochondria was observed, despite marked changes in the redox-balance of mitochondria. The activities of the mitochondrial enzymes, succinate dehydrogenase and glutathione peroxidase, as well as that of cytoplasmic catalase in liver cells were inhibited significantly. Mitochondria isolated from the livers of the rats chronically treated with CCl{sub 4} displayed obvious irreversible impairments. Long-term melatonin administration (10 mg/kg, 30 days, daily) to chronically intoxicated rats diminished the toxic effects of CCl{sub 4}, reducing elevated plasma activities of alanine aminotransferase and aspartate aminotransferase and bilirubin concentration, prevented accumulation of membrane lipid peroxidation products in rat liver and resulted in apparent preservation of the mitochondrial ultrastructure. The treatment of the animals by the complex of melatonin (10 mg/kg) plus succinate (50 mg/kg) plus cranberry flavonoids (7 mg/kg) was even more effective in prevention of toxic liver injury and liver mitochondria damage

  15. Chronic exercise increases insulin binding in muscles but not liver

    SciTech Connect

    Bonen, A.; Clune, P.A.; Tan, M.H.

    1986-08-01

    It has been postulated that the improved glucose tolerance provoked by chronic exercise is primarily attributable to increased insulin binding in skeletal muscle. Therefore, the authors investigated the effects of progressively increased training (6 wk) on insulin binding by five hindlimb skeletal muscles and in liver. In the trained animals serum insulin levels at rest were lower either in a fed or fasted state and after an oral glucose tolerance test. Twenty-four hours after the last exercise bout sections of the liver, soleus (S), plantaris (P), extensor digitorum longus (EDL), and red (RG) and white gastrocnemius (WG) muscles were pooled from four to six rats. Insulin binding to plasma membranes increased in S, P, and EDL but not in WG or in liver. There were insulin binding differences among muscles. Comparison of rank orders of insulin binding data with published glucose transport data for the same muscles revealed that these parameters do not correspond well. In conclusion, insulin binding to muscle is shown to be heterogeneous and training can increase insulin binding to selected muscles but not liver.

  16. Association between inherited monogenic liver disorders and chronic hepatitis C

    PubMed Central

    Piekuse, Linda; Kreile, Madara; Zarina, Agnese; Steinberga, Zane; Sondore, Valentina; Keiss, Jazeps; Lace, Baiba; Krumina, Astrida

    2014-01-01

    AIM: To determine the frequencies of mutations that cause inherited monogenic liver disorders in patients with chronic hepatitis C. METHODS: This study included 86 patients with chronic hepatitis C (55 men, 31 women; mean age at diagnosis, 38.36 ± 14.52 years) who had undergone antiviral therapy comprising pegylated interferon and ribavirin. Viral load, biochemical parameter changes, and liver biopsy morphological data were evaluated in all patients. The control group comprised 271 unrelated individuals representing the general population of Latvia for mutation frequency calculations. The most frequent mutations that cause inherited liver disorders [gene (mutation): ATP7B (H1069Q), HFE (C282Y, H63D), UGT1A1 (TA)7, and SERPINA1 (PiZ)] were detected by polymerase chain reaction (PCR), bidirectional PCR allele-specific amplification, restriction fragment length polymorphism analysis, and sequencing. RESULTS: The viral genotype was detected in 80 of the 86 patients. Viral genotypes 1, 2, and 3 were present in 61 (76%), 7 (9%), and 12 (15%) patients, respectively. Among all 86 patients, 50 (58%) reached an early viral response and 70 (81%) reached a sustained viral response. All 16 patients who did not reach a sustained viral response had viral genotype 1. Case-control analysis revealed a statistically significant difference in only the H1069Q mutation between patients and controls (patients, 0.057; controls, 0.012; odds ratio, 5.514; 95%CI: 1.119-29.827, P = 0.022). However, the H1069Q mutation was not associated with antiviral treatment outcomes or biochemical indices. The (TA) 7 mutation of the UGT1A1 gene was associated with decreased ferritin levels (beta regression coefficient = -295.7, P = 0.0087). CONCLUSION: Genetic mutations that cause inherited liver diseases in patients with hepatitis C should be studied in detail. PMID:24575168

  17. Impaired Pancreatic Beta Cell Function by Chronic Intermittent Hypoxia

    PubMed Central

    Wang, Ning; Khan, Shakil A.; Prabhakar, Nanduri R.; Nanduri, Jayasri

    2013-01-01

    Breathing disorders with recurrent apnea produce periodic decreases in arterial blood O2 or chronic intermittent hypoxia (CIH). Recurrent apnea patients and CIH-exposed rodents exhibit several co-morbidities including diabetes. However, the effects of CIH on pancreatic beta cell function are not known. In the present study, we investigated pancreatic beta cell function in C57BL6 mice exposed to 30 days of CIH. CIH-exposed mice exhibited elevated levels of fasting plasma insulin, but comparable glucose levels, and higher homeostasis model assessment (HOMA), indicating insulin resistance. Pancreatic beta cell morphology was unaltered in CIH- exposed mice. Insulin content was decreased in CIH-exposed beta cells, and this effect was associated with increased proinsulin levels. mRNA and protein levels of the enzyme pro-hormone convertase 1 (PC1) which converts proinsulin to insulin were down regulated in CIH-treated islets. More importantly, glucose-stimulated insulin secretion (GSIS) was impaired in CIH-exposed mice and in isolated islets. Mitochondrial reactive oxygen species (ROS) levels were elevated in CIH-exposed pancreatic islets. Treatment of mice with mito-tempol, a scavenger of mitochondrial ROS during CIH exposure, prevented the augmented insulin secretion and restored the proinsulin as well as HOMA values to control levels. These results demonstrate that CIH leads to pancreatic beta cell dysfunction manifested by augmented basal insulin secretion, insulin resistance, defective proinsulin processing, impaired GSIS and mitochondrial ROS mediates the effects of CIH on pancreatic beta cell function. PMID:23709585

  18. Hypercalcemia of advanced chronic liver disease: a forgotten clinical entity!

    PubMed

    Kuchay, Mohammad Shafi; Mishra, Sunil Kumar; Farooqui, Khalid Jamal; Bansal, Beena; Wasir, Jasjeet Singh; Mithal, Ambrish

    2016-01-01

    Hypercalcemia caused by advanced chronic liver disease (CLD) without hepatic neoplasia is uncommonly reported and poorly understood condition. We are reporting two cases of advanced CLD who developed hypercalcemia in the course of the disease. This diagnosis of exclusion was made only after meticulous ruling out of all causes of hypercalcemia. The unique feature of this type of hypercalcemia is its transient nature that may or may not require treatment. This clinical condition in patients with CLD should be kept in mind while evaluating the cause of hypercalcemia in them.

  19. Hypercalcemia of advanced chronic liver disease: a forgotten clinical entity!

    PubMed Central

    Kuchay, Mohammad Shafi; Mishra, Sunil Kumar; Farooqui, Khalid Jamal; Bansal, Beena; Wasir, Jasjeet Singh; Mithal, Ambrish

    2016-01-01

    Summary Hypercalcemia caused by advanced chronic liver disease (CLD) without hepatic neoplasia is uncommonly reported and poorly understood condition. We are reporting two cases of advanced CLD who developed hypercalcemia in the course of the disease. This diagnosis of exclusion was made only after meticulous ruling out of all causes of hypercalcemia. The unique feature of this type of hypercalcemia is its transient nature that may or may not require treatment. This clinical condition in patients with CLD should be kept in mind while evaluating the cause of hypercalcemia in them. PMID:27252737

  20. Herbal Products: Benefits, Limits, and Applications in Chronic Liver Disease

    PubMed Central

    Del Prete, Anna; Scalera, Antonella; Iadevaia, Maddalena Diana; Miranda, Agnese; Zulli, Claudio; Gaeta, Laura; Tuccillo, Concetta; Federico, Alessandro; Loguercio, Carmelina

    2012-01-01

    Complementary and alternative medicine soughts and encompasses a wide range of approaches; its use begun in ancient China at the time of Xia dynasty and in India during the Vedic period, but thanks to its long-lasting curative effect, easy availability, natural way of healing, and poor side-effects it is gaining importance throughout the world in clinical practice. We conducted a review describing the effects and the limits of using herbal products in chronic liver disease, focusing our attention on those most known, such as quercetin or curcumin. We tried to describe their pharmacokinetics, biological properties, and their beneficial effects (as antioxidant role) in metabolic, alcoholic, and viral hepatitis (considering that oxidative stress is the common pathway of chronic liver diseases of different etiology). The main limit of applicability of CAM comes from the lacking of randomized, placebo-controlled clinical trials giving a real proof of efficacy of those products, so that anecdotal success and personal experience are frequently the driving force for acceptance of CAM in the population. PMID:22991573

  1. Herbal products: benefits, limits, and applications in chronic liver disease.

    PubMed

    Del Prete, Anna; Scalera, Antonella; Iadevaia, Maddalena Diana; Miranda, Agnese; Zulli, Claudio; Gaeta, Laura; Tuccillo, Concetta; Federico, Alessandro; Loguercio, Carmelina

    2012-01-01

    Complementary and alternative medicine soughts and encompasses a wide range of approaches; its use begun in ancient China at the time of Xia dynasty and in India during the Vedic period, but thanks to its long-lasting curative effect, easy availability, natural way of healing, and poor side-effects it is gaining importance throughout the world in clinical practice. We conducted a review describing the effects and the limits of using herbal products in chronic liver disease, focusing our attention on those most known, such as quercetin or curcumin. We tried to describe their pharmacokinetics, biological properties, and their beneficial effects (as antioxidant role) in metabolic, alcoholic, and viral hepatitis (considering that oxidative stress is the common pathway of chronic liver diseases of different etiology). The main limit of applicability of CAM comes from the lacking of randomized, placebo-controlled clinical trials giving a real proof of efficacy of those products, so that anecdotal success and personal experience are frequently the driving force for acceptance of CAM in the population.

  2. Sub-chronically exposing mice to a polycyclic aromatic hydrocarbon increases lipid accumulation in their livers.

    PubMed

    Jin, Yuanxiang; Miao, Wenyu; Lin, Xiaojian; Wu, Tao; Shen, Hangjie; Chen, Shan; Li, Yanhong; Pan, Qiaoqiao; Fu, Zhengwei

    2014-09-01

    The potential for exposing humans and wildlife to environmental polycyclic aromatic hydrocarbons (PAHs) has increased. Risk assessments describing how PAHs disturb lipid metabolism and induce hepatotoxicity have only received limited attention. In the present study, seven-week-old male ICR mice received intraperitoneal injections of 0, 0.01, 0.1 or 1mg/kg body weight 3-methylcholanthrene (3MC) per week for 10 weeks. A high-fat diet was provided during the exposure. Histopathological lipid accumulation and lipid metabolism-related genes were measured. We observed that sub-chronic 3MC exposure significantly increased lipid droplet and triacylglycerol (TG) levels in the livers. A low dose of 3MC activated the aryl hydrocarbon receptor, which negatively regulated lipid synthesis in the livers. The primary genes including acetyl-CoA carboxylase (Acc), fatty acid synthase (Fas) and stearoyl-CoA desaturase 1 (Scd1) decreased significantly when compared with those in the control group, indicating that de novo fatty acid synthesis in the hepatocytes was significantly inhibited by the sub-chronic 3MC exposure. However, the free fatty acid (FFA) synthesis in the adipose tissue was greatly enhanced by up-regulating the expression of peroxisome proliferator-activated receptor γ (PPARγ) and sterol regulatory element binding protein-1c (SREBP1C) and target genes including Acc, Fas and Scd1. The synthesized FFA was released into the blood and then transported into the liver by the up-regulation of Fat and Fatp2, which resulted in the gradual accumulation of lipids in the liver. In conclusion, histological examinations and molecular level analyses highlighted the development of lipid accumulation and confirmed that 3MC significantly impaired lipid metabolism in mice.

  3. Impaired lipid accumulation in the liver of Tsc2-heterozygous mice during liver regeneration

    SciTech Connect

    Obayashi, Yoko; Campbell, Jean S.; Fausto, Nelson; Yeung, Raymond S.

    2013-07-19

    Highlights: •Tuberin phosphorylation correlated with mTOR activation in early liver regeneration. •Liver regeneration in the Tsc2+/− mice was not enhanced. •The Tsc2+/− livers failed to accumulate lipid bodies during liver regeneration. •Mortality rate increased in Tsc2+/− mice after partial hepatectomy. •Tuberin plays a critical role in hepatic lipid accumulation to support regeneration. -- Abstract: Tuberin is a negative regulator of mTOR pathway. To investigate the function of tuberin during liver regeneration, we performed 70% hepatectomy on wild-type and Tsc2+/− mice. We found the tuberin phosphorylation correlated with mTOR activation during early liver regeneration in wild-type mice. However, liver regeneration in the Tsc2+/− mice was not enhanced. Instead, the Tsc2+/− livers failed to accumulate lipid bodies, and this was accompanied by increased mortality. These findings suggest that tuberin plays a critical role in liver energy balance by regulating hepatocellular lipid accumulation during early liver regeneration. These effects may influence the role of mTORC1 on cell growth and proliferation.

  4. Chronic hepatitis C infection–induced liver fibrogenesis is associated with M2 macrophage activation

    PubMed Central

    Bility, Moses T.; Nio, Kouki; Li, Feng; McGivern, David R.; Lemon, Stanley M.; Feeney, Eoin R.; Chung, Raymond T.; Su, Lishan

    2016-01-01

    The immuno-pathogenic mechanisms of chronic hepatitis C virus (HCV) infection remain to be elucidated and pose a major hurdle in treating or preventing chronic HCV-induced advanced liver diseases such as cirrhosis. Macrophages are a major component of the inflammatory milieu in chronic HCV–induced liver disease, and are generally derived from circulating inflammatory monocytes; however very little is known about their role in liver diseases. To investigate the activation and role of macrophages in chronic HCV–induced liver fibrosis, we utilized a recently developed humanized mouse model with autologous human immune and liver cells, human liver and blood samples and cell culture models of monocyte/macrophage and/or hepatic stellate cell activation. We showed that M2 macrophage activation was associated with liver fibrosis during chronic HCV infection in the livers of both humanized mice and patients, and direct-acting antiviral therapy attenuated M2 macrophage activation and associated liver fibrosis. We demonstrated that supernatant from HCV-infected liver cells activated human monocytes/macrophages with M2-like phenotypes. Importantly, HCV-activated monocytes/macrophages promoted hepatic stellate cell activation. These results suggest a critical role for M2 macrophage induction in chronic HCV-associated immune dysregulation and liver fibrosis. PMID:28000758

  5. Chronic hepatitis C infection-induced liver fibrogenesis is associated with M2 macrophage activation.

    PubMed

    Bility, Moses T; Nio, Kouki; Li, Feng; McGivern, David R; Lemon, Stanley M; Feeney, Eoin R; Chung, Raymond T; Su, Lishan

    2016-12-21

    The immuno-pathogenic mechanisms of chronic hepatitis C virus (HCV) infection remain to be elucidated and pose a major hurdle in treating or preventing chronic HCV-induced advanced liver diseases such as cirrhosis. Macrophages are a major component of the inflammatory milieu in chronic HCV-induced liver disease, and are generally derived from circulating inflammatory monocytes; however very little is known about their role in liver diseases. To investigate the activation and role of macrophages in chronic HCV-induced liver fibrosis, we utilized a recently developed humanized mouse model with autologous human immune and liver cells, human liver and blood samples and cell culture models of monocyte/macrophage and/or hepatic stellate cell activation. We showed that M2 macrophage activation was associated with liver fibrosis during chronic HCV infection in the livers of both humanized mice and patients, and direct-acting antiviral therapy attenuated M2 macrophage activation and associated liver fibrosis. We demonstrated that supernatant from HCV-infected liver cells activated human monocytes/macrophages with M2-like phenotypes. Importantly, HCV-activated monocytes/macrophages promoted hepatic stellate cell activation. These results suggest a critical role for M2 macrophage induction in chronic HCV-associated immune dysregulation and liver fibrosis.

  6. Drug dosage recommendations in patients with chronic liver disease.

    PubMed

    Periáñez-Párraga, Leonor; Martínez-López, Iciar; Ventayol-Bosch, Pere; Puigventós-Latorre, Francesc; Delgado-Sánchez, Olga

    2012-04-01

    Chronic liver diseases (CLD) alter the kinetics of drugs. Despite dosage adjustment is based on Child-Pugh scores, there are no available recommendations and/or algorithms of reference to facilitate dosage regimens. A literature review about dose adjustment of the drugs from the hospital guide -which are included in the list of the WHO recommended drugs to be avoided or used with caution in patients with liver disease- was carried out. The therapeutic novelties from the last few years were also included. In order to do so, the summary of product characteristics (SPC), the database DrugDex-Micromedex, the WHO recommendations and the review articles from the last 10 years in Medline were reviewed. Moreover, the kinetic parameters of each drug were calculated with the aim of establishing a theoretical recommendation based on the proposal of Delcò and Huet. Recommendations for 186 drugs are presented according to the SPC (49.5%), DrugDex-Micromedex (26.3%) and WHO (18.8%) indications; six recommendations were based on specific publications; the theoretical recommendation based on pharmacokinetic parameters was proposed in four drugs. The final recommendations for clinical management were: dosage modification (26.9%), hepatic/analytical monitoring of the patient (8.6%), contraindication (18.8%), use with caution (19.3%) and no adjustment required (26.3%). In this review, specific recommendations for the practical management of patients with chronic liver disease are presented. It has been elaborated through a synthesis of the published bibliography and completed by following a theoretical methodology.

  7. Chronic ethanol-induced impairment of Wnt/β-catenin signaling is attenuated by PPAR-δ agonist

    PubMed Central

    Xu, Chelsea Q.; de la Monte, Suzanne M.; Tong, Ming; Huang, Chiung-Kuei; Kim, Miran

    2015-01-01

    Background The Wnt/β-catenin pathway regulates liver growth, repair, and regeneration. Chronic ethanol exposure blunts normal liver regenerative responses, in part by inhibiting insulin/IGF signaling, and correspondingly, previous studies showed that ethanol-impaired liver regeneration could be restored by insulin sensitizer (PPAR-δ agonist) treatment. Since Wnt/β-catenin functions overlap and crosstalk with insulin/IGF pathways, we investigated the effects of ethanol exposure and PPAR-δ agonist treatment on Wnt pathway gene expression in relation to liver regeneration. Methods Adult male Long Evans rats were fed with isocaloric liquid diets containing 0% or 37% ethanol for 8 weeks, and also treated with vehicle or a PPAR-δ agonist during the last 3 weeks of the feeding regimen. The rats were then subjected to 70% partial hepatectomy (PH) and livers harvested at various post-PH time points were used to quantify expression of 19 Wnt pathway genes using Quantigene 2.0 Multiplex Assay. Results Ethanol broadly inhibited expression of Wnt/β-catenin signaling-related genes, including down-regulation of Wnt1, Fzd3, Lef1, and Bcl9 throughout the post-PH time course (0-72 h), and suppression of Wnt7a, Ccnd1, Fgf4, Wif1, Sfrp2, and Sfrp5 at 18, 24 hours post-PH time points. PPAR-δ agonist treatments rescued the ethanol-induced suppression of Wnt1, Wnt7a, Fzd3, Lef1, Bcl9, Ccnd1, and Sfrp2 gene expression in liver, corresponding with the improvements in DNA synthesis and restoration of hepatic architecture. Conclusions Chronic high-dose ethanol exposures inhibit Wnt signaling, which likely contributes to the impairments in liver regeneration. Therapeutic effects of PPAR-δ agonists extend beyond restoration of insulin/IGF signaling mechanisms and are mediated in part by enhancement of Wnt pathway signaling. Future studies will determine the degree to which targeted restoration of Wnt signaling is sufficient to improve liver regeneration and remodeling in the context of

  8. Carnitine metabolism in patients with chronic liver disease.

    PubMed

    Krähenbühl, S; Reichen, J

    1997-01-01

    Carnitine metabolism was studied in 79 patients with chronic liver disease, including 22 patients with noncirrhotic liver disease and 57 patients with different types of cirrhosis (22 patients with hepatitis B- or C-associated cirrhosis, 15 patients with alcohol-induced cirrhosis, 15 patients with primary biliary cirrhosis [PBC], and 5 patients with cryptogenic cirrhosis), and compared with 28 control subjects. In comparison with control subjects, patients with noncirrhotic liver disease showed no change in the plasma carnitine pool, whereas patients with cirrhosis had a 29% increase in the long-chain acylcarnitine concentration. Analysis of subgroups of patients with cirrhosis showed that patients with alcohol-induced cirrhosis had an increase in the total plasma carnitine concentration (67.8 +/- 29.5 vs. 55.2 +/- 9.9 micromol/L in control subjects), resulting from increases in both the short-chain and long-chain acylcarnitine concentration. In this group of patients, the acylcarnitine concentrations showed a close correlation with the total carnitine concentration, and the total carnitine concentration with the serum bilirubin concentration. Urinary excretion of carnitine was not different between patients with noncirrhotic or cirrhotic liver disease and control patients. However, patients with PBC showed an increased urinary excretion of total carnitine (52.5 +/- 40.0 vs. 28.0 +/- 16.7 micromol carnitine/mmol creatinine), resulting from an increase in the fractional excretion of both free carnitine and short-chain acylcarnitine. The current studies show that patients with cirrhosis are normally not carnitine deficient. Patients with alcohol-induced cirrhosis have increased plasma carnitine concentrations, which may result from increased carnitine biosynthesis because of increased skeletal muscle protein turnover. The increase in the fractional carnitine excretion in patients with primary biliary cirrhosis may result from competition of bile acids and

  9. Peripheral neuropathy in chronic liver disease: clinical, electrodiagnostic, and nerve biopsy findings

    PubMed Central

    Knill-Jones, R. P.; Goodwill, C. J.; Dayan, A. D.; Williams, Roger

    1972-01-01

    In a prospective study of 70 unselected patients with chronic liver disease, clinical signs of a peripheral neuropathy were observed in 13 patients. Abnormal nerve conduction was demonstrated in nine of these and in one further patient who had no abnormal neurological signs. The occurrence of a neuropathy (in patients with cryptogenic cirrhosis, haemochromatosis, active chronic hepatitis as well as in alcoholic cirrhosis) could not be related to liver function, although it was associated with higher IgA and IgM values. Clinical diabetes was present in six of the 14 patients with neuropathy but there was no relation in the non-diabetic patients between neuropathy and minor impairment of carbohydrate tolerance. Those with neuropathy had a significantly higher incidence of oesophageal varices and there was also a relationship to a history of previous encephalopathy. Sural nerve biopsy was carried out on 14 patients, eight of whom had clinical or electrodiagnostic evidence of neuropathy. Single nerve fibres were examined by teasing and in all nerves histological evidence was found of an indolent process which had damaged whole Schwann cells and which resulted in demyelination and remyelination. Diabetic angiopathy was not seen and axonal degeneration, which was never severe, was found in all disease groups equally. Images PMID:4337271

  10. Chronic exposure to environmental levels of tribromophenol impairs zebrafish reproduction

    SciTech Connect

    Deng Jun; Liu Chunsheng; Yu Liqin; Zhou Bingsheng

    2010-02-15

    Tribromophenol (2,4,6-TBP) is ubiquitously found in aquatic environments and biota. In this study, we exposed zebrafish embryos (F{sub 0}; 2'''' days post-fertilization, dpf) to environmental concentration (0.3 mug/L) and a higher concentration (3.0 mug/L) of TBP and assessed the impact of chronic exposure (120 dpf) on reproduction. TBP exposure did not cause a significant increase in the malformation and reduction in the survival in the F{sub 0}-generation fish. After TBP exposure, the plasma testosterone and estradiol levels significantly increased in males and decreased in females. The transcription of steroidogenic genes (3beta-HSD, 17beta-HSD, CYP17, CYP19A, CYP19B) was significantly upregulated in the brain and testes in males and downregulated in the brain and ovary in females. TBP exposure significantly downregulated and upregulated the expression of VTG in the liver of female and male fish, respectively. Meanwhile, TBP exposure altered the sex ratio toward a male-dominant state. The F{sub 1}-generation larvae exhibited increased malformation, reduced survival, and retarded growth, suggesting that TBP in the aquatic environment has significant adverse effects on fish population.

  11. Liver-specific magnetic resonance contrast medium in the evaluation of chronic liver disease

    PubMed Central

    dos Reis, Marcio Augusto Correia Rodrigues; Baroni, Ronaldo Hueb

    2015-01-01

    ABSTRACT The hepatobiliary-specific contrast medium (gadoxetic acid – Primovist®) is primarily used to improve detection and characterization of focal hepatic lesions, such as in chronic liver disease patients with suspected hepatocellular carcinoma. Since the contrast medium is selectively taken up by functioning hepatocytes in the late hepatobiliary phase, it helps to detect typical hepatocellular carcinoma, which show low signal intensity on this phase. This imaging feature also assists in differentiating regenerative/dysplastic nodules from early hepatocellular carcinomas (with over 90% accuracy), as well as hypervascular hepatocellular carcinomas from arterial pseudo-enhancement foci. Future perspectives include its use in quantification of hepatic function and fibrosis. PMID:26154554

  12. A comparison of the fibrotic potential of nonalcoholic fatty liver disease and chronic hepatitis C.

    PubMed

    Charlotte, Fréderic; Le Naour, Gilles; Bernhardt, Carole; Poynard, Thierry; Ratziu, Vlad

    2010-08-01

    In nonalcoholic fatty liver disease the amount of fibrosis for individual histologic stages is unknown. To better understand the fibrotic potential of nonalcoholic fatty liver disease, we compared the amount of fibrosis in nonalcoholic fatty liver disease versus chronic hepatitis C virus patients. The area of fibrosis for equivalent fibrosis stages was measured by micromorphometry in 70 nonalcoholic fatty liver disease and 70 matched, untreated, chronic hepatitis C virus controls. The area of fibrosis correlated with Brunt stage (r = 0.71; P < .001) in nonalcoholic fatty liver disease and METAVIR stage (r = 0.58; P < .001) in chronic hepatitis C virus. Mean area of fibrosis was similar in nonalcoholic fatty liver disease and chronic hepatitis C virus patients (7.77% versus 7.70%). Although chronic hepatitis C virus patients displayed higher area of fibrosis in early disease (no or mild fibrosis), nonalcoholic fatty liver disease and chronic hepatitis C virus patients had similar area of fibrosis in more advanced disease (7.83% versus 8.06%, respectively; P = .86 for bridging fibrosis; and 16.62% versus 12.98%, respectively; P = .29 for cirrhosis). The area of fibrosis was similar in Brunt stage 3 nonalcoholic fatty liver disease and METAVIR stage 2 chronic hepatitis C virus, the usual threshold for initiating therapy. The area of steatosis declined with increasing fibrosis stages confirming the early loss of liver fat with progressive fibrosis in nonalcoholic fatty liver disease. Fibrosis is as abundant in nonalcoholic fatty liver disease as in chronic hepatitis C virus, especially in the advanced stages of the disease. The fibrotic potential of nonalcoholic fatty liver disease is as severe as that of chronic hepatitis C virus.

  13. Loss of p21 Permits Carcinogenesis from Chronically Damaged Liver and Kidney Epithelial Cells Despite Unchecked Apoptosis

    PubMed Central

    Willenbring, Holger; Sharma, Amar Deep; Vogel, Arndt; Lee, Andrew Young; Rothfuss, Andreas; Wang, Zhongya; Finegold, Milton; Grompe, Markus

    2008-01-01

    SUMMARY Accumulation of toxic metabolites in tyrosinemia type I (HT1) patients leads to chronic DNA damage and the highest risk for hepatocellular carcinomas (HCCs) of any human disease. Here we show that hepatocytes of HT1 mice exhibit a profound cell cycle arrest which, despite concomitant apoptosis resistance, causes mortality from impaired liver regeneration. However, additional loss of p21 in HT1 mice restores the proliferative capabilities of hepatocytes and renal proximal tubular cells. This growth response compensates cell loss due to uninhibited apoptosis and enables animal survival but rapidly leads to HCCs, renal cysts and renal carcinomas. Thus, p21’s antiproliferative function is indispensable for the suppression of carcinogenesis from chronically injured liver and renal epithelial cells and cannot be compensated by apoptosis. PMID:18598944

  14. Noninvasive assessment of liver fibrosis in patients with chronic hepatitis B

    PubMed Central

    Enomoto, Masaru; Morikawa, Hiroyasu; Tamori, Akihiro; Kawada, Norifumi

    2014-01-01

    Infection with hepatitis B virus is an important health problem worldwide: it affects more than 350 million people and is a leading cause of liver-related morbidity, accounting for 1 million deaths annually. Hepatic fibrosis is a consequence of the accumulation of extracellular matrix components in the liver. An accurate diagnosis of liver fibrosis is essential for the management of chronic liver disease. Liver biopsy has been considered the gold standard for diagnosing disease, grading necroinflammatory activity, and staging fibrosis. However, liver biopsy is unsuitable for repeated evaluations because it is invasive and can cause major complications, including death. Several noninvasive evaluations have been introduced for the assessment of liver fibrosis: serum biomarkers, combined indices or scores, and imaging techniques including transient elastography, acoustic radiation force impulse, real-time tissue elastography, and magnetic resonance elastography. Here, we review the recent progress of noninvasive assessment of liver fibrosis in patients with chronic hepatitis B. Most noninvasive evaluations for liver fibrosis have been validated first in patients with chronic hepatitis C, and later in those with chronic hepatitis B. The establishment of a noninvasive assessment of liver fibrosis is urgently needed to aid in the management of this leading cause of chronic liver disease. PMID:25232240

  15. Management of adults with paediatric-onset chronic liver disease: strategic issues for transition care.

    PubMed

    Vajro, Pietro; Ferrante, Lorenza; Lenta, Selvaggia; Mandato, Claudia; Persico, Marcello

    2014-04-01

    Advances in the management of children with chronic liver disease have enabled many to survive into adulthood with or without their native livers, so that the most common of these conditions are becoming increasingly common in adult hepatology practice. Because the aetiologies of chronic liver disease in children may vary significantly from those in adulthood, adults with paediatric-onset chronic liver disease may often present with clinical manifestations unfamiliar to their adulthood physician. Transition of medical care to adult practice requires that the adulthood medical staff (primary physicians and subspecialists) have a comprehensive knowledge of childhood liver disease and their implications, and of the differences in caring for these patients. Pending still unavailable Scientific Society guidelines, this article examines causes, presentation modes, evaluation, management, and complications of the main paediatric-onset chronic liver diseases, and discusses key issues to aid in planning a program of transition from paediatric to adult patients.

  16. Pharmacokinetics of isradipine in patients with chronic liver disease.

    PubMed

    Cotting, J; Reichen, J; Kutz, K; Laplanche, R; Nüesch, E

    1990-01-01

    The pharmacokinetics of the dihydropyridine calcium antagonist isradipine has been examined in 8 healthy volunteers, 7 patients with non-cirrhotic chronic liver disease (CLD), and 8 patients with biopsy-proven cirrhosis (CIR). Isradipine was simultaneously given orally (12C 5 mg) and i.v. (13C 1 mg). Systemic availability was significantly increased from 17% to 16% in controls and CLD, respectively, to 37% in CIR. The corresponding systemic clearances averaged 1.1, 0.9 and 0.6 l.min-1, the reduction in cirrhotics being significant. Both aminopyrine demethylation capacity, a measure of hepatic microsomal function, and indocyanine green disappearance, a measure of hepatic perfusion, were correlated with the reduction in systemic clearance, and the reduction in oral clearance was correlated with the reciprocal of the serum bile acid concentration. The loss of first-pass extraction should be considered when this calcium antagonist is given perorally in patients with hepatic cirrhosis.

  17. Role of Infections in Acute-on-Chronic Liver Failure.

    PubMed

    Moreau, Richard

    2015-01-01

    Patients with cirrhosis are prone to developing bacterial infections. Moreover, bacterial infection is the most common identifiable trigger of acute-on-chronic liver failure (ACLF), which is characterized by organ failures and a high risk of death. There is evidence of an excessive immune response of the host as a major mechanism leading to the development of organ failures in patients with cirrhosis. However, a role for direct tissue damage caused by bacterial toxins and virulence factors cannot be excluded. Failed tolerance mechanisms may also contribute to organ failures, although the involved mechanisms are unclear. A proportion of patients with infection-related ACLF have a prolonged stay in the intensive care unit. These patients have immune suppression, increased risk of superinfection and poor outcome. Immune suppression might be a consequence of the first infection episode that has led patients to be admitted to hospital.

  18. Decompensation of chronic stable alcoholic liver disease by severe exfoliative dermatitis.

    PubMed

    Shawcross, Debbie L; Mookerjee, Rajeshwar P; Jalan, Rajiv

    2003-04-01

    Of the numerous precipitants of hepatic decompensation in chronic liver disease, there are no reports in the literature documenting an acute decompensation following an acute episode of severe dermatitis. This case highlights the haemodynamic consequences of a severe flare up of exfoliative dermatitis in a patient with stable chronic alcoholic liver disease, speculates on the mechanism by which this may provoke clinical decompensation and the impact this may have upon liver failure.

  19. Hepatitis B antigen in hepatocytes of chronic active liver disease.

    PubMed

    Kawanishi, H

    1979-04-01

    To study the morphologic interrelation of hepatocytes with the replication of hepatitis B vius (HBV) and immunocompetent cells in chronic active liver disease(CALD), organ cultures were prepared from liver biopsy specimens. Replication of hepatitis B core antigen (HBcAg) appears to occur in the nucleus of the hepatocyte in close association with intranuclear electron-dense strands and sometimes intranucleolar matrixes (likely HBcAg genomes), and cytoplasmic maturation of the HBcAg takes place in the preautolytic condition of host hepatocytes. Immunocompetent cells became progressively autolyzed in the early period of cultures. No difference in progression of hepatocyte injury in tissues from normal subjects and from hepatitis B surface antigen (HBsAg)-positive and HBsAg-negative patients with CALD may suggest that intracellular synthesis of HBV alone is not cytopathic to host hepatocytes. This model is promising for the study of HBV replication and development, and also for testing the efficacy of new antiviral agents against the virus.

  20. Progressive induction of hepatocyte progenitor cells in chronically injured liver

    PubMed Central

    Tanimizu, Naoki; Ichinohe, Norihisa; Yamamoto, Masahiro; Akiyama, Haruhiko; Nishikawa, Yuji; Mitaka, Toshihiro

    2017-01-01

    Differentiated epithelial cells show substantial lineage plasticity upon severe tissue injuries. In chronically injured mouse livers, part of hepatocytes become Sry-HMG box containing 9 (Sox9) (+) epithelial cell adhesion molecule (−) hepatocyte nuclear factor 4 α (+) biphenotypic hepatocytes. However, it is not clear whether all Sox9+ hepatocytes uniformly possess cellular properties as hepatocyte progenitors. Here, we examined the microarray data comparing Sox9+ hepatocytes with mature hepatocytes and identified CD24 as a novel marker for biphenotypic hepatocytes. Immunohistochemical analyses showed that part of Sox9+ hepatocytes near expanded ductular structures expressed CD24 in the liver injured by 3,5-diethoxycarbonyl-1,4-dihydro-collidine (DDC) diet and by bile duct ligation. Indeed, Sox9+ hepatocytes could be separated into CD24− and CD24+ cells by fluorescence activated cell sorting. The ratio of CD24+ cells against CD24− ones in Sox9+ hepatocytes gradually increased while DDC-injury progressed and colony-forming capability mostly attributed to CD24+ cells. Although hepatocyte markers were remarkably downregulated in of Sox9+ CD24+ hepatocytes, they re-differentiated into mature hepatocytes in vitro and in vivo. Our current results demonstrate that the emergence of biphenotypic hepatocytes is a sequential event including the transition from CD24− and CD24+ status, which may be a crucial step for hepatocytes to acquire progenitor properties. PMID:28051157

  1. Chronic liver inflammation modifies DNA methylation at the precancerous stage of murine hepatocarcinogenesis.

    PubMed

    Stoyanov, Evgeniy; Ludwig, Guy; Mizrahi, Lina; Olam, Devorah; Schnitzer-Perlman, Temima; Tasika, Elena; Sass, Gabriele; Tiegs, Gisa; Jiang, Yong; Nie, Ting; Kohler, James; Schinazi, Raymond F; Vertino, Paula M; Cedar, Howard; Galun, Eithan; Goldenberg, Daniel

    2015-05-10

    Chronic liver inflammation precedes the majority of hepatocellular carcinomas (HCC). Here, we explore the connection between chronic inflammation and DNA methylation in the liver at the late precancerous stages of HCC development in Mdr2(-/-) (Mdr2/Abcb4-knockout) mice, a model of inflammation-mediated HCC. Using methylated DNA immunoprecipitation followed by hybridization with "CpG islands" (CGIs) microarrays, we found specific CGIs in 76 genes which were hypermethylated in the Mdr2(-/-) liver compared to age-matched healthy controls. The observed hypermethylation resulted mainly from an age-dependent decrease of methylation of the specific CGIs in control livers with no decrease in mutant mice. Chronic inflammation did not change global levels of DNA methylation in Mdr2(-/-) liver, but caused a 2-fold decrease of the global 5-hydroxymethylcytosine level in mutants compared to controls. Liver cell fractionation revealed, that the relative hypermethylation of specific CGIs in Mdr2(-/-) livers affected either hepatocyte, or non-hepatocyte, or both fractions without a correlation between changes of gene methylation and expression. Our findings demonstrate that chronic liver inflammation causes hypermethylation of specific CGIs, which may affect both hepatocytes and non-hepatocyte liver cells. These changes may serve as useful markers of an increased regenerative activity and of a late precancerous stage in the chronically inflamed liver.

  2. The Role of Iron and Iron Overload in Chronic Liver Disease

    PubMed Central

    Milic, Sandra; Mikolasevic, Ivana; Orlic, Lidija; Devcic, Edita; Starcevic-Cizmarevic, Nada; Stimac, Davor; Kapovic, Miljenko; Ristic, Smiljana

    2016-01-01

    The liver plays a major role in iron homeostasis; thus, in patients with chronic liver disease, iron regulation may be disturbed. Higher iron levels are present not only in patients with hereditary hemochromatosis, but also in those with alcoholic liver disease, nonalcoholic fatty liver disease, and hepatitis C viral infection. Chronic liver disease decreases the synthetic functions of the liver, including the production of hepcidin, a key protein in iron metabolism. Lower levels of hepcidin result in iron overload, which leads to iron deposits in the liver and higher levels of non-transferrin-bound iron in the bloodstream. Iron combined with reactive oxygen species leads to an increase in hydroxyl radicals, which are responsible for phospholipid peroxidation, oxidation of amino acid side chains, DNA strain breaks, and protein fragmentation. Iron-induced cellular damage may be prevented by regulating the production of hepcidin or by administering hepcidin agonists. Both of these methods have yielded successful results in mouse models. PMID:27332079

  3. GRPR antagonist protects from drug-induced liver injury by impairing neutrophil chemotaxis and motility.

    PubMed

    Czepielewski, Rafael S; Jaeger, Natália; Marques, Pedro E; Antunes, Maísa M; Rigo, Maurício M; Alvarenga, Débora M; Pereira, Rafaela V; da Silva, Rodrigo D; Lopes, Tiago G; da Silva, Vinícius D; Porto, Bárbara N; Menezes, Gustavo B; Bonorino, Cristina

    2017-04-01

    Drug-induced liver injury (DILI) is a major cause of acute liver failure (ALF), where hepatocyte necrotic products trigger liver inflammation, release of CXC chemokine receptor 2 (CXCR2) ligands (IL-8) and other neutrophil chemotactic molecules. Liver infiltration by neutrophils is a major cause of the life-threatening tissue damage that ensues. A GRPR (gastrin-releasing peptide receptor) antagonist impairs IL-8-induced neutrophil chemotaxis in vitro. We investigated its potential to reduce acetaminophen-induced ALF, neutrophil migration, and mechanisms underlying this phenomenon. We found that acetaminophen-overdosed mice treated with GRPR antagonist had reduced DILI and neutrophil infiltration in the liver. Intravital imaging and cell tracking analysis revealed reduced neutrophil mobility within the liver. Surprisingly, GRPR antagonist inhibited CXCL2-induced migration in vivo, decreasing neutrophil activation through CD11b and CD62L modulation. Additionally, this compound decreased CXCL8-driven neutrophil chemotaxis in vitro independently of CXCR2 internalization, induced activation of MAPKs (p38 and ERK1/2) and downregulation of neutrophil adhesion molecules CD11b and CD66b. In silico analysis revealed direct binding of GRPR antagonist and CXCL8 to the same binding spot in CXCR2. These findings indicate a new potential use for GRPR antagonist for treatment of DILI through a mechanism involving adhesion molecule modulation and possible direct binding to CXCR2.

  4. Inhibition of VEGF- and NO-dependent angiogenesis does not impair liver regeneration

    PubMed Central

    Shergill, U.; Das, A.; Langer, D.; Adluri, RS.; Maulik, N.

    2010-01-01

    Angiogenesis occurs through a convergence of diverse signaling mechanisms with prominent pathways that include autocrine effects of endothelial nitric oxide (NO) synthase (eNOS)-derived NO and vascular endothelial growth factor (VEGF). However, the redundant and distinct roles of NO and VEGF in angiogenesis remain incompletely defined. Here, we use the partial hepatectomy model in mice genetically deficient in eNOS to ascertain the influence of eNOS-derived NO on the angiogenesis that accompanies liver regeneration. While sinusoidal endothelial cell (SEC) eNOS promotes angiogenesis in vitro, surprisingly the absence of eNOS did not influence the angiogenesis that occurs after partial hepatectomy in vivo. While this observation could not be attributed to induction of alternate NOS isoforms, it was associated with induction of VEGF signaling as evidenced by enhanced levels of VEGF ligand in regenerating livers from mice genetically deficient in eNOS. However, surprisingly, mice that were genetically heterozygous for deficiency in the VEGF receptor, fetal liver kinase-1, also maintained unimpaired capacity for liver regeneration. In summary, inhibition of VEGF- and NO-dependent angiogenesis does not impair liver regeneration, indicating signaling redundancies that allow liver regeneration to continue in the absence of this canonical vascular pathway. PMID:20421635

  5. Deceleration of liver regeneration by knockdown of augmenter of liver regeneration gene is associated with impairment of mitochondrial DNA synthesis in mice.

    PubMed

    Han, Li-hong; Dong, Ling-yue; Yu, Hao; Sun, Guang-yong; Wu, Yuan; Gao, Jian; Thasler, Wolfgang; An, Wei

    2015-07-15

    Hepatic stimulator substance, also known as augmenter of liver regeneration (ALR), is a novel hepatic mitogen that stimulates liver regeneration after partial hepatectomy (PH). Recent work has indicated that a lack of ALR expression inhibited liver regeneration in rats, and the mechanism seems to be related to increased cell apoptosis. The mitochondria play an important role during liver regeneration. Adequate ATP supply, which is largely dependent on effective mitochondrial biogenesis, is essential for progress of liver regeneration. However, ALR gene expression during liver regeneration, particularly its function with mitochondrial DNA synthesis, remains poorly understood. In this study, ALR expression in hepatocytes of mice was suppressed with ALR short-hairpin RNA interference or ALR deletion (knockout, KO). The ALR-defective mice underwent PH, and the liver was allowed to regenerate for 1 wk. Analysis of liver growth and its correlation with mitochondrial biogenesis showed that both ALR mRNA and protein levels increased robustly in control mice with a maximum at days 3 and 4 post-PH. However, ALR knockdown inhibited hepatic DNA synthesis and decelerated liver regeneration after PH. Furthermore, both in the ALR-knockdown and ALR-KO mice, expression of mitochondrial transcription factor A and peroxisome proliferator-activated receptor-γ coactivator-1α were reduced, resulting in impaired mitochondrial biogenesis. In conclusion, ALR is apparently required to ensure appropriate liver regeneration following PH in mice, and deletion of the ALR gene may delay liver regeneration in part due to impaired mitochondrial biogenesis.

  6. Is liver biopsy still needed in children with chronic viral hepatitis?

    PubMed Central

    Pokorska-Śpiewak, Maria; Kowalik-Mikołajewska, Barbara; Aniszewska, Małgorzata; Pluta, Magdalena; Marczyńska, Magdalena

    2015-01-01

    Liver biopsy is a standard method used for obtaining liver tissue for histopathological evaluation. Since reliable serological and virological tests are currently available, liver biopsy is no longer needed for the etiological diagnosis of chronic hepatitis B and C. However, liver histology remains the gold standard as a prognostic tool, providing information about the liver disease progression (grading of necroinflammatory activity and staging of fibrosis) and serving clinicians in the management and therapeutic decisions. In general, histopathological evaluation is indicated before starting the antiviral treatment. Main limitations of the liver biopsy include its invasive and painful procedure, sampling errors and the inter- and intra-observer variability. In addition, indications for the liver biopsy in pediatric patients with chronic viral hepatitis were questioned recently, and efforts have been made toward the development of non-invasive methods as an alternative to the liver biopsy. The most commonly used methods are novel imaging studies (elastography) and combinations of biomarkers. However, to date, none of these tests was validated in children with chronic viral hepatitis. In this review, we present the current status of the liver biopsy in the management of chronic viral hepatitis B and C in pediatric population, including specific indications, complications, contraindications, problems, limitations, and alternative non-invasive methods. PMID:26576098

  7. Is liver biopsy still needed in children with chronic viral hepatitis?

    PubMed

    Pokorska-Śpiewak, Maria; Kowalik-Mikołajewska, Barbara; Aniszewska, Małgorzata; Pluta, Magdalena; Marczyńska, Magdalena

    2015-11-14

    Liver biopsy is a standard method used for obtaining liver tissue for histopathological evaluation. Since reliable serological and virological tests are currently available, liver biopsy is no longer needed for the etiological diagnosis of chronic hepatitis B and C. However, liver histology remains the gold standard as a prognostic tool, providing information about the liver disease progression (grading of necroinflammatory activity and staging of fibrosis) and serving clinicians in the management and therapeutic decisions. In general, histopathological evaluation is indicated before starting the antiviral treatment. Main limitations of the liver biopsy include its invasive and painful procedure, sampling errors and the inter- and intra-observer variability. In addition, indications for the liver biopsy in pediatric patients with chronic viral hepatitis were questioned recently, and efforts have been made toward the development of non-invasive methods as an alternative to the liver biopsy. The most commonly used methods are novel imaging studies (elastography) and combinations of biomarkers. However, to date, none of these tests was validated in children with chronic viral hepatitis. In this review, we present the current status of the liver biopsy in the management of chronic viral hepatitis B and C in pediatric population, including specific indications, complications, contraindications, problems, limitations, and alternative non-invasive methods.

  8. Amelioration of Liver Injury by Continuously Targeted Intervention against TNFRp55 in Rats with Acute-on-Chronic Liver Failure

    PubMed Central

    Bao, Shishan; Tabassam, Fazal; Cai, Wei; Xiang, Xiaogang; Zhao, Gangde; Wu, Haiqing; Gao, Ting; Li, Hai; Xie, Qing

    2013-01-01

    Background Acute-on-chronic liver failure (ACLF) is an acute deterioration of established liver disease. Blocking the TNF (tumor necrosis factor)/TNFR (tumor necrosis factor receptor) 1 pathway may reduce hepatocyte apoptosis/necrosis, and subsequently decrease mortality during development of ACLF. We demonstrated that a long-acting TNF antagonist (soluble TNF receptor: IgG Fc [sTNFR:IgG-Fc]) prevented/reduced development of acute liver failure by blocking the TNF/TNFR1 (TNFRp55) pathway. However, it is still unclear if sTNFR:IgG-Fc can inhibit hepatocyte damage during development of ACLF. Methodology Chronic liver disease (liver fibrosis/cirrhosis) was induced in Wistar rats by repeatedly challenging with human serum albumin (HSA), and confirmed by histopathology. ACLF was induced with D-galactosamine (D-GalN)/lipopolysaccharide (LPS) i.p. in the rats with chronic liver disease. Serum and liver were collected for biochemical, pathological and molecular biological examinations. Principal Findings Reduced mortality was observed in sTNFR:IgG-Fc treated ACLF rats, consistent with reduced interleukin (IL)-6 levels in serum and liver, as well as reduced hepatic caspase-3 activity, compared to that of mock treated group. Reduced hepatic damage was confirmed with histopathology in the sTNFR:IgG-Fc treated group, which is consistent with reduced Bcl-2 and Bax, at mRNA and protein levels, but increased hepatocyte proliferation (PCNA). This is also supported by the findings that caspase-3 production was up-regulated significantly in ACLF group compared to the mock treated group. Moreover, up-regulated caspase-3 was inhibited following sTNFR:IgG-Fc treatment. Finally, there was up-regulation of hepatic IL-22R in sTNFR:IgG-Fc treated ACLF rats. Conclusions sTNFR:IgG-Fc improved survival rate during development of ACLF via ameliorating liver injury with a potential therapeutic value. PMID:23874752

  9. Repeated exposure to modern volatile anaesthetics may cause chronic hepatitis as well as acute liver injury.

    PubMed

    Nicoll, Amanda; Moore, David; Njoku, Dolores; Hockey, Brad

    2012-11-06

    Volatile anaesthetic agents are known to cause acute hepatitis and fulminant hepatic failure in susceptible individuals. Four patients were identified with prolonged liver injury due to volatile anaesthetic-induced hepatitis. Three had liver biopsy confirmation and all gave blood for specific diagnostic tests (TFA and CYP 2E1 IgG4 antibodies). The Roussel Uclaf Causality Assessment Method (RUCAM) drug causality scale was used to determine the likelihood of volatile anaesthetics causing the chronic liver injury. We describe four cases of volatile anaesthetic hepatitis in which three evolved into chronic hepatitis. The fourth followed a more typical pattern of acute hepatitis; however, resolution took a few months. These cases all occurred with modern volatile anaesthetics, predominantly sevoflurane, and all cases were proven with specific antibody tests, liver histology and a drug causality scale. This is the first report of chronic liver injury due to volatile anaesthetic exposure.

  10. Repeated exposure to modern volatile anaesthetics may cause chronic hepatitis as well as acute liver injury

    PubMed Central

    Nicoll, Amanda; Moore, David; Njoku, Dolores; Hockey, Brad

    2012-01-01

    Volatile anaesthetic agents are known to cause acute hepatitis and fulminant hepatic failure in susceptible individuals. Four patients were identified with prolonged liver injury due to volatile anaesthetic-induced hepatitis. Three had liver biopsy confirmation and all gave blood for specific diagnostic tests (TFA and CYP 2E1 IgG4 antibodies). The Roussel Uclaf Causality Assessment Method (RUCAM) drug causality scale was used to determine the likelihood of volatile anaesthetics causing the chronic liver injury. We describe four cases of volatile anaesthetic hepatitis in which three evolved into chronic hepatitis. The fourth followed a more typical pattern of acute hepatitis; however, resolution took a few months. These cases all occurred with modern volatile anaesthetics, predominantly sevoflurane, and all cases were proven with specific antibody tests, liver histology and a drug causality scale. This is the first report of chronic liver injury due to volatile anaesthetic exposure. PMID:23131606

  11. Impaired Functional Connectivity in the Prefrontal Cortex: A Mechanism for Chronic Stress-Induced Neuropsychiatric Disorders

    PubMed Central

    Negrón-Oyarzo, Ignacio; Aboitiz, Francisco; Fuentealba, Pablo

    2016-01-01

    Chronic stress-related psychiatric diseases, such as major depression, posttraumatic stress disorder, and schizophrenia, are characterized by a maladaptive organization of behavioral responses that strongly affect the well-being of patients. Current evidence suggests that a functional impairment of the prefrontal cortex (PFC) is implicated in the pathophysiology of these diseases. Therefore, chronic stress may impair PFC functions required for the adaptive orchestration of behavioral responses. In the present review, we integrate evidence obtained from cognitive neuroscience with neurophysiological research with animal models, to put forward a hypothesis that addresses stress-induced behavioral dysfunctions observed in stress-related neuropsychiatric disorders. We propose that chronic stress impairs mechanisms involved in neuronal functional connectivity in the PFC that are required for the formation of adaptive representations for the execution of adaptive behavioral responses. These considerations could be particularly relevant for understanding the pathophysiology of chronic stress-related neuropsychiatric disorders. PMID:26904302

  12. Procalcitonin Impairs Liver Cell Viability and Function In Vitro: A Potential New Mechanism of Liver Dysfunction and Failure during Sepsis?

    PubMed Central

    Ehler, Johannes; Wagner, Nana-Maria

    2017-01-01

    Purpose. Liver dysfunction and failure are severe complications of sepsis and result in poor outcome and increased mortality. The underlying pathologic mechanisms of hepatocyte dysfunction and necrosis during sepsis are only incompletely understood. Here, we investigated whether procalcitonin, a biomarker of sepsis, modulates liver cell function and viability. Materials and Methods. Employing a previously characterized and patented biosensor system evaluating hepatocyte toxicity in vitro, human hepatocellular carcinoma cells (HepG2/C3A) were exposed to 0.01–50 ng/mL procalcitonin for 2 × 72 h and evaluated for proliferation, necrosis, metabolic activity, cellular integrity, microalbumin synthesis, and detoxification capacity. Acetaminophen served as positive control. For further standardization, procalcitonin effects were confirmed in a cellular toxicology assay panel employing L929 fibroblasts. Data were analyzed using ANOVA/Tukey's test. Results. Already at concentrations as low as 0.25 ng/mL, procalcitonin induced HepG2/C3A necrosis (P < 0.05) and reduced metabolic activity, cellular integrity, synthesis, and detoxification capacity (all P < 0.001). Comparable effects were obtained employing L929 fibroblasts. Conclusion. We provide evidence for procalcitonin to directly impair function and viability of human hepatocytes and exert general cytotoxicity in vitro. Therapeutical targeting of procalcitonin could thus display a novel approach to reduce incidence of liver dysfunction and failure during sepsis and lower morbidity and mortality of septic patients. PMID:28255555

  13. Procalcitonin Impairs Liver Cell Viability and Function In Vitro: A Potential New Mechanism of Liver Dysfunction and Failure during Sepsis?

    PubMed

    Sauer, Martin; Doß, Sandra; Ehler, Johannes; Mencke, Thomas; Wagner, Nana-Maria

    2017-01-01

    Purpose. Liver dysfunction and failure are severe complications of sepsis and result in poor outcome and increased mortality. The underlying pathologic mechanisms of hepatocyte dysfunction and necrosis during sepsis are only incompletely understood. Here, we investigated whether procalcitonin, a biomarker of sepsis, modulates liver cell function and viability. Materials and Methods. Employing a previously characterized and patented biosensor system evaluating hepatocyte toxicity in vitro, human hepatocellular carcinoma cells (HepG2/C3A) were exposed to 0.01-50 ng/mL procalcitonin for 2 × 72 h and evaluated for proliferation, necrosis, metabolic activity, cellular integrity, microalbumin synthesis, and detoxification capacity. Acetaminophen served as positive control. For further standardization, procalcitonin effects were confirmed in a cellular toxicology assay panel employing L929 fibroblasts. Data were analyzed using ANOVA/Tukey's test. Results. Already at concentrations as low as 0.25 ng/mL, procalcitonin induced HepG2/C3A necrosis (P < 0.05) and reduced metabolic activity, cellular integrity, synthesis, and detoxification capacity (all P < 0.001). Comparable effects were obtained employing L929 fibroblasts. Conclusion. We provide evidence for procalcitonin to directly impair function and viability of human hepatocytes and exert general cytotoxicity in vitro. Therapeutical targeting of procalcitonin could thus display a novel approach to reduce incidence of liver dysfunction and failure during sepsis and lower morbidity and mortality of septic patients.

  14. Prognostic factors for the evolution and reversibility of chronic rejection in pediatric liver transplantation

    PubMed Central

    Tannuri, Ana Cristina Aoun; Lima, Fabiana; de Mello, Evandro Sobroza; Tanigawa, Ryan Yukimatsu; Tannuri, Uenis

    2016-01-01

    OBJECTIVE: Chronic rejection remains a major cause of graft failure with indication for re-transplantation. The incidence of chronic rejection remains high in the pediatric population. Although several risk factors have been implicated in adults, the prognostic factors for the evolution and reversibility of chronic rejection in pediatric liver transplantation are not known. Hence, the current study aimed to determine the factors involved in the progression or reversibility of pediatric chronic rejection by evaluating a series of chronic rejection cases following liver transplantation. METHODS: Chronic rejection cases were identified by performing liver biopsies on patients based on clinical suspicion. Treatment included maintaining high levels of tacrolimus and the introduction of mofetil mycophenolate. The children were divided into 2 groups: those with favorable outcomes and those with adverse outcomes. Multivariate analysis was performed to identify potential risk factors in these groups. RESULTS: Among 537 children subjected to liver transplantation, chronic rejection occurred in 29 patients (5.4%). In 10 patients (10/29, 34.5%), remission of chronic rejection was achieved with immunosuppression (favorable outcomes group). In the remaining 19 patients (19/29, 65.5%), rejection could not be controlled (adverse outcomes group) and resulted in re-transplantation (7 patients, 24.1%) or death (12 patients, 41.4%). Statistical analysis showed that the presence of ductopenia was associated with worse outcomes (risk ratio=2.08, p=0.01). CONCLUSION: The presence of ductopenia is associated with poor prognosis in pediatric patients with chronic graft rejection. PMID:27166772

  15. Impaired erythropoietin production in liver transplant recipients: the role of calcineurin inhibitors.

    PubMed

    Bardet, Valérie; Junior, Alcindo Pissaia; Coste, Joël; Lecoq-Lafon, Carinne; Chouzenoux, Sandrine; Bernard, Denis; Soubrane, Olivier; Lacombe, Catherine; Calmus, Yvon; Conti, Filoména

    2006-11-01

    Anemia is common following liver transplantation. Because cyclosporine inhibits erythropoietin (Epo) production in experimental models, we investigated whether Epo production was impaired in liver transplant recipients receiving a cyclosporine- or tacrolimus-based immunosuppressive regimen. First, serum Epo levels were measured before and 1 year after transplantation in 35 liver transplant recipients. Second, serum Epo levels were compared in a large series of liver transplant recipients with stable graft and renal functions: 27 receiving a cyclosporine-based and 31 receiving a tacrolimus-based immunosuppressive regimen. A reference group was made up of 22 blood donors and 21 nontransplanted subjects with iron-deficiency anemia. Serum Epo levels were significantly lower after than before liver transplantation, especially in cyclosporine-treated patients. Serum Epo concentrations correlated with hematocrit values in both transplant recipients and control subjects. Using multiple linear regression models, the polynomial relationship between hematocrit and serum Epo values was similar to the control group in patients under tacrolimus, whereas Epo production was significantly reduced in patients under cyclosporine-based immunosuppression. Hematocrit values and the type of calcineurin inhibitor were the only parameters independently related to Epo levels. In conclusion, cyclosporine, but not tacrolimus, inhibits Epo production at the doses used in clinical practice.

  16. Chronic Stress Impairs Collateral Blood Flow Recovery in Aged Mice

    DTIC Science & Technology

    2014-10-15

    factor associated with atherosclerosis [19, 20]. Chronic stress, mental disorders, and non-pathological psychological stress states are associat- ed...Grahame-Clarke, C., Shanks, N., et al. (2003). Chronic stress accelerates atherosclerosis in the apolipoprotein E deficient mouse. Stress, 6(4), 297–299. 4...of oxidative stress in atherosclerosis . American of Journal in Cardiology, 91, 7A–11A. 11. Balkaya, M., Prinz, V., Custodis, F., et al. (2011

  17. Acute stress does not affect the impairing effect of chronic stress on memory retrieval

    PubMed Central

    Ozbaki, Jamile; Goudarzi, Iran; Salmani, Mahmoud Elahdadi; Rashidy-Pour, Ali

    2016-01-01

    Objective(s): Due to the prevalence and pervasiveness of stress in modern life and exposure to both chronic and acute stresses, it is not clear whether prior exposure to chronic stress can influence the impairing effects of acute stress on memory retrieval. This issue was tested in this study. Materials and Methods: Adult male Wistar rats were randomly assigned to the following groups: control, acute, chronic, and chronic + acute stress groups. The rats were trained with six trials per day for 6 consecutive days in the water maze. Following training, the rats were either kept in control conditions or exposed to chronic stress in a restrainer 6 hr/day for 21 days. On day 22, a probe test was done to measure memory retention. Time spent in target and opposite areas, platform location latency, and proximity were used as indices of memory retention. To induce acute stress, 30 min before the probe test, animals received a mild footshock. Results: Stressed animals spent significantly less time in the target quadrant and more time in the opposite quadrant than control animals. Moreover, the stressed animals showed significantly increased platform location latency and proximity as compared with control animals. No significant differences were found in these measures among stress exposure groups. Finally, both chronic and acute stress significantly increased corticosterone levels. Conclusion: Our results indicate that both chronic and acute stress impair memory retrieval similarly. Additionally, the impairing effects of chronic stress on memory retrieval were not influenced by acute stress. PMID:27635201

  18. Chronic administration of fluoxetine or clozapine induces oxidative stress in rat liver: a histopathological study.

    PubMed

    Zlatković, Jelena; Todorović, Nevena; Tomanović, Nada; Bošković, Maja; Djordjević, Snežana; Lazarević-Pašti, Tamara; Bernardi, Rick E; Djurdjević, Aleksandra; Filipović, Dragana

    2014-08-01

    Chronic exposure to stress contributes to the etiology of mood disorders, and the liver as a target organ of antidepressant and antipsychotic drug metabolism is vulnerable to drug-induced toxicity. We investigated the effects of chronic administration of fluoxetine (15mg/kg/day) or clozapine (20mg/kg/day) on liver injury via the measurement of liver enzymes, oxidative stress and histopathology in rats exposed to chronic social isolation (21days), an animal model of depression, and controls. The activity of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST), the liver content of carbonyl groups, malonyldialdehyde (MDA), reduced glutathione (GSH), cytosolic glutathione S-transferase (GST) and nitric oxide (NO) metabolites were determined. We also characterized nuclear factor-κB (NF-κB), cyclooxygenase-2 (COX-2) and CuZn-superoxide dismutase (CuZnSOD) protein expression as well as histopathological changes. Increased serum ALT activity in chronically-isolated and control animals treated with both drugs was found while increased AST activity was observed only in fluoxetine-treated rats (chronically-isolated and controls). Increased carbonyl content, MDA, GST activity and decreased GSH levels in drug-treated controls/chronically-isolated animals suggest a link between drugs and hepatic oxidative stress. Increased NO levels associated with NF-κB activation and the concomitant increased COX-2 expression together with compromised CuZnSOD expression in clozapine-treated chronically-isolated rats likely reinforce oxidative stress, observed by increased lipid peroxidation and GSH depletion. In contrast, fluoxetine reduced NO levels in chronically-isolated rats. Isolation induced oxidative stress but histological changes were similar to those observed in vehicle-treated controls. Chronic administration of fluoxetine in both chronically-isolated and control animals resulted in more or less normal hepatic architecture, while clozapine in both groups

  19. Liver steatosis in children with chronic hepatitis B and C

    PubMed Central

    Pokorska-Śpiewak, Maria; Kowalik-Mikołajewska, Barbara; Aniszewska, Małgorzata; Pluta, Magdalena; Walewska-Zielecka, Bożena; Marczyńska, Magdalena

    2017-01-01

    Abstract Only scarce data on liver steatosis in children with chronic hepatitis B and C (CHB and CHC) are available. The objective of this study was to evaluate the prevalence, predictors, and impact of hepatic steatosis on children with CHB and CHC. A total of 78 patients aged 11.5 ± 3.4 years were included: 30 (38%) had CHB, and 48 (62%) had CHC. Steatosis was scored on a 5-point scale, as follows: absent; minimal (≤5% hepatocytes affected), mild (6–33%), moderate (34–66%), and severe (>66%). Stepwise logistic regression was used to determine the factors associated with steatosis and moderate-to-severe steatosis. Steatosis was observed in 4/30 (13%) patients with CHB and 13/48 (27%) patients with CHC (P = 0.17). Moderate-to-severe steatosis was observed in 6/78 (8%) patients: 1/30 (3%) had CHB and 5/48 (10%) had CHC (P = 0.40). The body mass index (BMI) z-score was positively associated with the presence of steatosis in children with CHB (odds ratio [OR] = 3.3, 95% confidence interval [CI]: 1.02–10.64). In CHC, steatosis occurred more frequently in patients with hepatitis C virus genotype 3 compared with other genotypes (P = 0.002). In patients with non-3 genotype hepatitis C virus, steatosis was associated with the stage of fibrosis (OR = 3.35, 95% CI: 1.01–11.07) and inversely associated with the duration of infection (OR = 0.74, 95% CI: 0.55–0.97). Moderate-to-severe steatosis was positively associated with the BMI z-score (OR = 3.62, 95% CI: 1.22–10.75) and stage of fibrosis (OR = 3.89, 95% CI: 1.05–14.47). Steatosis is a common finding in children with chronic viral hepatitis. It is associated with metabolic factors in CHB, whereas in patients with CHC, metabolic and viral factors may have a combined effect, leading to more advanced grades of steatosis in children with higher BMI z-scores. Moderate-to-severe steatosis is a predictor of advanced fibrosis in children with CHC. PMID:28099338

  20. Crude extract of cyanobacteria (Radiocystis fernandoi, strain R28) induces liver impairments in fish.

    PubMed

    Paulino, M G; Tavares, D; Bieczynski, F; Pedrão, P G; Souza, N E S; Sakuragui, M M; Luquet, C M; Terezan, A P; Fernandes, J B; Giani, A; Fernandes, M N

    2017-01-01

    Radiocystis fernandoi R28 strain is a cyanobacterium which produces mostly the RR and YR microcystin variants (MC-RR and MC-YR, respectively). The effects of crude extract of the R. fernandoi strain R28 were evaluated on the protein phosphatases and on the structure and ultrastructure of the liver of the Neotropical fish, Hoplias malabaricus, after acute and subchronic exposure. Concomitantly, the accumulation of the majority of MCs was determined in the liver and muscle. The fish were exposed to 120.60 MC-RR+MC-LR kg-fish(-1) (=100μg MC-LReq kg-fish(-1)) for 12 and 96h (one single dose, acute exposure) and 30days (one similar dose every 72h, subchronic exposure). MCs did not accumulate in the muscle but, in the liver, MC-YR accumulated after acute exposure and MC-RR and MC-YR accumulation occurred after subchronic exposure. Protein phosphatase 2A (PP2A) activity was inhibited only after subchronic exposure. Acute exposure induced liver hyperemia, hemorrhage, changes in hepatocytes and cord-like disorganization. At the ultrastructural level, the decreasing of glycogen and lipid levels, the swelling of mitochondria and whirling of endoplasmic reticulum suggested hepatocyte necrosis. Subchronic exposure resulted in a complete disarrangement of cord-like hepatocytes, some recovery of mitochondria and whirling endoplasmic reticulum and extensive connective tissues containing fibrous materials in the liver parenchyma. Despite microcystin toxicity and liver alterations, no tumor was induced by MCs. In conclusion, the increased algal mass of R. fernandoi in tropical freshwater, producing mainly MC-RR and MC-YR variants, results in fish liver impairments.

  1. Loss of Survivin influences liver regeneration and is associated with impaired Aurora B function

    PubMed Central

    Hagemann, S; Wohlschlaeger, J; Bertram, S; Levkau, B; Musacchio, A; Conway, E M; Moellmann, D; Kneiseler, G; Pless-Petig, G; Lorenz, K; Sitek, B; Baba, H A

    2013-01-01

    The chromosomal passenger complex (CPC) acts as a key regulator of mitosis, preventing asymmetric segregation of chromosomal material into daughter cells. The CPC is composed of three non-enzymatic components termed Survivin, the inner centromere protein (INCENP) and Borealin, and an enzymatic component, Aurora B kinase. Survivin is necessary for the appropriate separation of sister chromatids during mitosis and is involved in liver regeneration, but its role in regenerative processes is incompletely elucidated. Whether Survivin, which is classified as an inhibitor of apoptosis protein (IAP) based on domain composition, also has a role in apoptosis is controversial. The present study examined the in vivo effects of Survivin ablation in the liver and during liver regeneration after 70% hepatectomy in a hepatocyte-specific knockout mouse model. The absence of Survivin caused a reduction in the number of hepatocytes in the liver, together with an increase in cell volume, macronucleation and polyploidy, but no changes in apoptosis. During liver regeneration, mitosis of hepatocytes was associated with mislocalization of the members of the CPC, which were no longer detectable at the centromere despite an unchanged protein amount. Furthermore, the loss of survivin in regenerating hepatocytes was associated with reduced levels of phosphorylated Histone H3 at serine 28 and abolished phosphorylation of CENP-A and Hec1 at serine 55, which is a consequence of decreased Aurora B kinase activity. These data indicate that Survivin expression determines hepatocyte number during liver development and liver regeneration. Lack of Survivin causes mislocalization of the CPC members in combination with reduced Aurora B activity, leading to impaired phosphorylation of its centromeric target proteins and inappropriate cytokinesis. PMID:23519077

  2. Quantitative comparison of transient elastography (TE), shear wave elastography (SWE) and liver biopsy results of patients with chronic liver disease.

    PubMed

    Kim, Hyun-Jin; Lee, Hae-Kag; Cho, Jae-Hwan; Yang, Han-Jun

    2015-08-01

    [Purpose] The purpose of this study was to carry out a comparitive analysis of hepatic fibrosis results of the liver hardness of patients with chronic liver disease as measured by elastography (TE), shear wave elastography (SWE), and liver biopsy. [Subjects and Methods] This study was a retrospective analysis of 304 patients who underwent SWE and TE before and after liver biopsy, taken from among patients who had been checked for liver fibrosis by liver biopsy between August 2013 and August 2014. We used receiver operating characteristic (ROC) curve to prove the diagnostic significance of liver stiffness, and then analyzed the sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of SWE and TE, as well as the kappa index through cross-analysis of SWE, TE, and liver biopsy. [Results] For liver hardness, the sensitivity of SWE was 84.39%, the specificity of SWE was 97.92%, the accuracy of SWE was 87.33%, the positive predictive value of SWE was 99.32%, and the negative predictive value of SWE was 63.51%. The sensitivity of TE was 94.80%, the specificity of TE was 77.08%, the accuracy of TE was 90.95%, the positive predictive value of TE was 93.97%, and the negative predictive value of TE was 80.43%. [Conclusion] It is our opinion that SWE and TE are non-invasive methods that are more effective than the invasive methods used for diagnosing liver hardness. Invasive methods cover only a section of liver tissue, and are more likely to cause side effects during biopsy.

  3. Complementary and Alternative Medicine Use in Chronic Liver Disease Patients

    PubMed Central

    Ferrucci, Leah M.; Bell, Beth P.; Dhotre, Kathy B.; Manos, M. Michele; Terrault, Norah A.; Zaman, Atif; Murphy, Rosemary C.; VanNess, Grace R.; Thomas, Ann R.; Bialek, Stephanie R.; Desai, Mayur M.; Sofair, Andre N.

    2013-01-01

    Goals To examine a wide range of sociodemographic and clinical characteristics as potential predictors of complementary and alternative medicine (CAM) use among chronic liver disease (CLD) patients, with a focus on CAM therapies with the greatest potential for hepatotoxicity and interactions with conventional treatments. Background There is some evidence that patients with CLD commonly use CAM to address general and CLD-specific health concerns. Study Patients enrolled in a population-based surveillance study of persons newly diagnosed with CLD between 1999 and 2001 were asked about current use of CAM specifically for CLD. Socio-demographic and clinical information was obtained from interviews and medical records. Predictors of CAM use were examined using univariate and multivariate logistic regression analysis. Results Of the 1040 participants, 284 (27.3%) reported current use of at least 1 of 3 CAM therapies of interest. Vitamins or other dietary supplements were the most commonly used therapy, reported by 188 (18.1%) patients. This was followed by herbal medicine (175 patients, 16.8%) and homeopathy (16 patients, 1.5%). Several characteristics were found to be independent correlates of CAM use: higher education and family income, certain CLD etiologies (alcohol, hepatitis C, hepatitis C and alcohol, and hepatitis B), and prior hospitalization for CLD. Conclusions Use of CAM therapies that have the potential to interact with conventional treatments for CLD was quite common among this population-based sample of patients with CLD. There is a need for patient and practitioner education and communication regarding CAM use in the context of CLD. PMID:19779363

  4. Chronic hepatitis E virus infection in a pediatric female liver transplant recipient.

    PubMed

    Passos-Castilho, Ana Maria; Porta, Gilda; Miura, Irene K; Pugliese, Renata P S; Danesi, Vera L B; Porta, Adriana; Guimarães, Teresa; Seda, João; Antunes, Eduardo; Granato, Celso F H

    2014-12-01

    We describe a case of chronic hepatitis E virus (HEV) infection in a 13-year-old female liver transplant recipient with recurrent increased aminotransferase levels and acute cellular rejection. This finding demonstrates that chronic HEV infection can occur and should be further investigated in immunocompromised patients in Latin America.

  5. Serum γ-glutamyl Transferase Levels, Insulin Resistance and Liver Fibrosis in Patients with Chronic Liver Diseases

    PubMed Central

    Petta, Salvatore; Macaluso, Fabio Salvatore; Barcellona, Maria Rosa; Cammà, Calogero; Cabibi, Daniela; Di Marco, Vito; Craxì, Antonio

    2012-01-01

    Background and Aims Serum levels of γ-glutamyl-transpeptidase(γ-GT) were associated with liver disease severity and metabolic alterations, which in turn are able to affect hepatic damage. In patients with nonalcoholic fatty liver disease (NAFLD), genotype 1 chronic hepatitis C (G1CHC) and chronic hepatitis B (CHB), we assessed the link between liver fibrosis and γ-GT serum levels, and we evaluated if normal or high γ-GT serum levels affect the association between insulin resistance (IR) and severity of liver fibrosis. Methods 843 consecutive patients with chronic liver disease (CLD)(193 NAFLD, 481 G1CHC, 169 CHB) were evaluated by liver biopsy (Kleiner and Scheuer scores) and clinical and metabolic measurements. IR was diagnosed if HOMA>3. A serum γ-GT concentration of >36 IU/L in females and >61 IU/L in males was considered the threshold value for identifying high levels of γ-GT. Results By multivariate logistic regression analysis, abnormal γ-GT serum levels were independently linked to severe liver fibrosis in patients with NAFLD (OR2.711,CI1.120–6.564,p = 0.02), G1CHC (OR3.461,CI2.138–5.603,p<0.001) and CHB (OR2.778,CI1.042–7.414,p = 0.04), together with IR and liver necroinflammation, and with a negative predictive value>80%. Interestingly, among patients with high or normal γ-GT values, even if IR prevalence was significantly higher in patients with severe fibrosis compared to those without, IR remained significantly associated with severe fibrosis in patients with abnormal γ-GT values only (OR4.150,CI1.079–15.970,p = 0.03 for NAFLD; OR2.250,CI1.211–4.181,p = 0.01 for G1CHC; OR3.096,CI2.050–34.220,p = 0.01 for CHB). Conclusions In patients with CLD, IR is independently linked to liver fibrosis only in patients with abnormal γ-GT values, without differences according to liver disease etiology, and suggesting a role of γ-GT as a marker of metabolic-induced liver damage. These data could be useful for the clinical and

  6. Management of Thrombocytopenia in Chronic Liver Disease: Focus on Pharmacotherapeutic Strategies.

    PubMed

    Maan, Raoel; de Knegt, Robert J; Veldt, Bart J

    2015-11-01

    Thrombocytopenia (platelet count <150 × 10(9)/L) often complicates chronic liver disease, impeding optimal management of these patients. The prevalence of this manifestation ranges from 6% among non-cirrhotic patients with chronic liver disease to 70% among patients with liver cirrhosis. It has also been shown that the severity of liver disease is associated with both prevalence and level of thrombocytopenia. Its development is often multifactorial, although thrombopoietin is thought to be a major factor. The discovery of and ability to clone thrombopoietin led to new treatment opportunities for this clinical manifestation. This review discusses data on the three most important thrombopoietin receptor agonists: eltrombopag, avatrombopag, and romiplostim. Currently, only eltrombopag is approved for usage among patients with thrombocytopenia and chronic hepatitis C virus infection in order to initiate and maintain interferon-based antiviral treatment. Nevertheless, the optimal management of hematologic abnormalities among patients with chronic liver disease, and its risk for bleeding complications, is still a matter of discussion. Thrombocytopenia definitely contributes to hemostatic defects but is often counterbalanced by the enhanced presence of procoagulant factors. Therefore, a thorough assessment of the patient's risk for thrombotic events is essential when the use of thrombopoietin receptor agonists is considered among patients with chronic liver disease and thrombocytopenia.

  7. Effect of chronic heroin and cocaine administration on global DNA methylation in brain and liver.

    PubMed

    Fragou, Domniki; Zanos, Panos; Kouidou, Sofia; Njau, Samuel; Kitchen, Ian; Bailey, Alexis; Kovatsi, Leda

    2013-04-26

    Drug abuse is associated with epigenetic changes, such as histone modifications and DNA methylation. The purpose of the present study was to examine the effect of chronic cocaine and heroin administration on global DNA methylation in brain and liver. Male, 8 week old, C57BL/6J mice received heroin in a chronic 'intermittent' escalating dose paradigm, or cocaine in a chronic escalating dose 'binge' paradigm, which mimic the human pattern of opioid or cocaine abuse respectively. Following sacrifice, livers and brains were removed and DNA was extracted from them. The extracted DNA was hydrolyzed and 2'-deoxycytidine and 5-methyl-2'-deoxycytidine were determined by HPLC-UV. The % 5-methyl-2'-deoxycytidine content of DNA was significantly higher in the brain compared to the liver. There were no differences between the control animals and the cocaine or heroin treated animals in neither of the tissues examined, which is surprising since cocaine administration induced gross morphological changes in the liver. Moreover, there was no difference in the % 5-methyl-2'-deoxycytidine content of DNA between the cocaine and the heroin treated animals. The global DNA methylation status in the brain and liver of mice chronically treated with cocaine or heroin remains unaffected, but this finding cannot exclude the existence of anatomical region or gene-specific methylation differences. This is the first time that global DNA methylation in the liver and whole brain has been studied following chronic cocaine or heroin treatment.

  8. A case of Hodgkin’s lymphoma with severely impaired liver function treated successfully with gemcitabine followed by ABVD

    PubMed Central

    Chakraborty, Rajshekhar; Mukkamalla, Shiva Kumar Reddy; Gutzmore, Garfield; Chan, Hon Cheung

    2015-01-01

    Hodgkin’s lymphoma (HL) originates from clonal B cells and is the most common malignancy in the second decade of life. Liver involvement is uncommon at presentation in patients with HL and there is a paucity of data for treatment of patients with severely impaired liver function. We present an unusual case of HL with severe hepatic impairment, splenomegaly and multiple chromosomal abnormalities that was treated initially with gemcitabine and steroids. Once liver function tests improved, six cycles of Adriamycin, bleomycin, vinblastine, and dacarbazine were administered. The patient remains in remission at 3.5 years of follow-up. PMID:25848330

  9. MicroRNA function in the profibrogenic interplay upon chronic liver disease.

    PubMed

    Huang, Jia; Yu, Xiaojie; Fries, Jochen W U; Zhang, Li'ang; Odenthal, Margarete

    2014-05-27

    In chronic liver disease leading to fibrosis, hepatic stellate cells (HSC) differentiate into myofibroblasts. Myofibroblastic HSC have taken center stage during liver fibrogenesis, due to their remarkable synthesis of extracellular matrix proteins, their secretion of profibrogenic mediators and their contribution to hypertension, due to elevated contractility. MicroRNAs (miRNAs) are small, noncoding RNA molecules of 19-24 nucleotides in length. By either RNA interference or inhibition of translational initiation and elongation, each miRNA is able to inhibit the gene expression of a wide panel of targeted transcripts. Recently, it was shown that altered miRNA patterns after chronic liver disease highly affect the progression of fibrosis by their potential to target the expression of extracellular matrix proteins and the synthesis of mediators of profibrogenic pathways. Here, we underline the role of miRNAs in the interplay of the profibrogenic cell communication pathways upon myofibroblastic differentiation of hepatic stellate cells in the chronically injured liver.

  10. Multiparametric magnetic resonance imaging predicts clinical outcomes in patients with chronic liver disease

    PubMed Central

    Pavlides, Michael; Banerjee, Rajarshi; Sellwood, Joanne; Kelly, Catherine J.; Robson, Matthew D.; Booth, Jonathan C.; Collier, Jane; Neubauer, Stefan; Barnes, Eleanor

    2016-01-01

    Background & Aims Multiparametric magnetic resonance (MR) imaging has been demonstrated to quantify hepatic fibrosis, iron, and steatosis. The aim of this study was to determine if MR can be used to predict negative clinical outcomes in liver disease patients. Methods Patients with chronic liver disease (n = 112) were recruited for MR imaging and data on the development of liver related clinical events were collected by medical records review. The median follow-up was 27 months. MR data were analysed blinded for the Liver Inflammation and Fibrosis score (LIF; <1, 1–1.99, 2–2.99, and ⩾3 representing normal, mild, moderate, and severe liver disease, respectively), T2∗ for liver iron content and proportion of liver fat. Baseline liver biopsy was performed in 102 patients. Results Liver disease aetiologies included non-alcoholic fatty liver disease (35%) and chronic viral hepatitis (30%). Histologically, fibrosis was mild in 54 (48%), moderate in 17 (15%), and severe in 31 (28%) patients. Overall mortality was 5%. Ten patients (11%) developed at least one liver related clinical event. The negative predictive value of LIF <2 was 100%. Two patients with LIF 2–2.99 and eight with LIF ⩾3 had a clinical event. Patients with LIF ⩾3 had a higher cumulative risk for developing clinical events, compared to those with LIF <1 (p = 0.02) and LIF 1–1.99 (p = 0.03). Cox regression analysis including all 3 variables (fat, iron, LIF) resulted in an enhanced LIF predictive value. Conclusions Non-invasive standardised multiparametric MR technology may be used to predict clinical outcomes in patients with chronic liver disease. PMID:26471505

  11. A guide to the management of tuberculosis in patients with chronic liver disease.

    PubMed

    Dhiman, Radha K; Saraswat, Vivek A; Rajekar, Harshal; Reddy, Chandrasekhar; Chawla, Yogesh K

    2012-09-01

    Tuberculosis remains one of the 'Captains of the Men of Death' even today, particularly in the developing world. Its frequency is increased 14-fold in patients with chronic liver diseases (CLD) and liver cirrhosis, more so in those with decompensated disease, probably due to the cirrhosis-associated immune dysfunction syndrome, and case-fatality rates are high. The diagnosis of tuberculosis, particularly the interpretation of the Mantoux test, is also fraught with difficulties in CLD, especially after previous BCG vaccination. However, the greatest challenge in the patient with CLD or liver cirrhosis and tuberculosis is managing their therapy since the best first-line anti-tuberculosis drugs are hepatotoxic and baseline liver function is often deranged. Frequency of hepatotoxicity is increased in those with liver cirrhosis, chronic hepatitis B and chronic hepatitis C, possibly related to increased viral loads and may be decreased following antiviral therapy. If hepatotoxicity develops in those with liver cirrhosis, particularly decompensated cirrhosis, the risk of severe liver failure is markedly increased. Currently, there are no established guidelines for anti-tuberculosis therapy (ATT) in CLD and liver cirrhosis although the need for such guidelines is self-evident. It is proposed that ATT should include no more than 2 hepatotoxic drugs (RIF and INH) in patients with CLD or liver cirrhosis and stable liver function [Child-Turcotte-Pugh (CTP) ≤7], only a single hepatotoxic drug (RIF or INH) in those with advanced liver dysfunction (CTP 8-10) and no hepatotoxic drugs with very advanced liver dysfunction (CTP ≥11). A standard protocol should be followed for monitoring ATT-related hepatotoxicity and for stop rules and reintroduction rules in all these patients, on the lines proposed here. It is hoped that these proposals will introduce uniformity and result in streamlining the management of these difficult patients.

  12. 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.

  13. 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

  14. IDH1 deficiency attenuates gluconeogenesis in mouse liver by impairing amino acid utilization

    PubMed Central

    Ye, Jing; Gu, Yu; Zhang, Feng; Zhao, Yuanlin; Yuan, Yuan; Hao, Zhenyue; Sheng, Yi; Li, Wanda Y.; Wakeham, Andrew; Cairns, Rob A.; Mak, Tak W.

    2017-01-01

    Although the enzymatic activity of isocitrate dehydrogenase 1 (IDH1) was defined decades ago, its functions in vivo are not yet fully understood. Cytosolic IDH1 converts isocitrate to α-ketoglutarate (α-KG), a key metabolite regulating nitrogen homeostasis in catabolic pathways. It was thought that IDH1 might enhance lipid biosynthesis in liver or adipose tissue by generating NADPH, but we show here that lipid contents are relatively unchanged in both IDH1-null mouse liver and IDH1-deficient HepG2 cells generated using the CRISPR-Cas9 system. Instead, we found that IDH1 is critical for liver amino acid (AA) utilization. Body weights of IDH1-null mice fed a high-protein diet (HPD) were abnormally low. After prolonged fasting, IDH1-null mice exhibited decreased blood glucose but elevated blood alanine and glycine compared with wild-type (WT) controls. Similarly, in IDH1-deficient HepG2 cells, glucose consumption was increased, but alanine utilization and levels of intracellular α-KG and glutamate were reduced. In IDH1-deficient primary hepatocytes, gluconeogenesis as well as production of ammonia and urea were decreased. In IDH1-deficient whole livers, expression levels of genes involved in AA metabolism were reduced, whereas those involved in gluconeogenesis were up-regulated. Thus, IDH1 is critical for AA utilization in vivo and its deficiency attenuates gluconeogenesis primarily by impairing α-KG–dependent transamination of glucogenic AAs such as alanine. PMID:28011762

  15. Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) procedure for hepatocellular carcinoma with chronic liver disease: a case report and review of literature

    PubMed Central

    Pizanias, Michail; Yip, Vincent; Prassas, Evangellos; Prachalias, Andreas; Quaglia, Alberto; Peddu, Praveen; Heaton, Nigel; Srinivasan, Parthi

    2016-01-01

    The incidence of complications after liver resection is closely related to functional future liver remnant (FLR). The standard approach to augment FLR is surgical or radiological occlusion of the artery or portal vein on the tumor side. Associated liver partition and portal vein ligation for staged hepatectomy (ALLPS) has been introduced as an alternative method to augment FLR. It offers rapid and effective hypertrophy for resecting liver metastases. However, data regarding its application in patients with hepatocellular carcinoma (HCC) with a background of chronic liver disease are limited. Here we describe the use of ALPPS procedure to manage a large solitary HCC with a background of chronic liver disease. The rising incidence of HCC has increased the number of surgical resections in patients with advanced stage liver disease not considered for liver transplantation. We reviewed reported experience of ALPPS in established chronic liver disease and current therapeutic modalities for HCC on a background of chronic liver disease in patients with potential liver insufficiency where tumor burden is beyond liver transplant criteria. PMID:27212995

  16. Usefulness of Non-invasive Markers for Predicting Significant Fibrosis in Patients with Chronic Liver Disease

    PubMed Central

    Lee, Han Hyo; Seo, Yeon Seok; Won, Nam Hee; Yoo, Hanna; Jung, Eun Suk; Kwon, Yong Dae; Park, Sanghoon; Keum, Bora; Kim, Yong Sik; Yim, Hyung Joon; Jeen, Yoon Tae; Chun, Hoon Jai; Kim, Chang Duck; Ryu, Ho Sang

    2010-01-01

    The purpose of this prospective study was to verify and compare the strengths of various blood markers and fibrosis models in predicting significant liver fibrosis. One hundred fifty-eight patients with chronic liver disease who underwent liver biopsy were enrolled. The mean age was 41 yr and male patients accounted for 70.2%. The common causes of liver disease were hepatitis B (67.7%) and C (16.5%) and fatty liver (9.5%). Stages of liver fibrosis (F0-4) were assessed according to the Batts and Ludwig scoring system. Significant fibrosis was defined as ≥F2. Sixteen blood markers were measured along with liver biopsy, and estimates of hepatic fibrosis were calculated using various predictive models. Predictive accuracy was evaluated with a receiver-operating characteristics (ROC) curve. Liver biopsy revealed significant fibrosis in 106 cases (67.1%). On multivariate analysis, α2-macroglobulin, hyaluronic acid, and haptoglobin were found to be independently related to significant hepatic fibrosis. A new predictive model was constructed based on these variables, and its area under the ROC curve was 0.91 (95% confidence interval, 0.85-0.96). In conclusion, α2-macroglobulin, hyaluronic acid, and haptoglobin levels are independent predictors for significant hepatic fibrosis in chronic liver disease. PMID:20052350

  17. Trace element analysis by PIXE in liver samples from dogs with chronic active hepatitis and liver cirrhosis

    NASA Astrophysics Data System (ADS)

    Andersson, Marianne; Ekholm, Ann-Kristin; Sevelius, Ewa

    1990-04-01

    Trace element levels of liver samples obtained from necropsied dogs suffering from hepatitis and/or liver cirrhosis were determined by PIXE. Two different techniques for preparation of the samples were compared: the pellet press method and wet digestion. Both methods gave similar results, but the pellet press method was chosen for the subsequent routine analyses because of its simplicity due to few preparation steps and little risk of contamination. Preliminary results indicate elevated levels of Cu in chronic hepatitis and cirrhosis. In hereditary copper-induced hepatitis (Bedlington hepatitis) Fe and Br levels were increased as well.

  18. Impaired neutrophil directional chemotactic accuracy in chronic periodontitis patients

    PubMed Central

    Roberts, Helen M; Ling, Martin R; Insall, Robert; Kalna, Gabriela; Spengler, Julia; Grant, Melissa M; Chapple, Iain LC

    2015-01-01

    Aim To investigate the chemotactic accuracy of peripheral blood neutrophils from patients with chronic periodontitis compared with matched healthy controls, before and after non-surgical periodontal therapy. Material & Methods Neutrophils were isolated from patients and controls (n = 18) by density centrifugation. Using the Insall chamber and video microscopy, neutrophils were analysed for directional chemotaxis towards N-formyl-methionyl-leucyl-phenylalanine [fMLP (10 nM), or CXCL8 (200 ng/ml)]. Circular statistics were utilized for the analysis of cell movement. Results Prior to treatment, neutrophils from patients with chronic periodontitis had significantly reduced speed, velocity and chemotactic accuracy compared to healthy controls for both chemoattractants. Following periodontal treatment, patient neutrophils continued to display reduced speed in response to both chemoattractants. However, velocity and accuracy were normalized for the weak chemoattractant CXCL8 while they remained significantly reduced for fMLP. Conclusions Chronic periodontitis is associated with reduced neutrophil chemotaxis, and this is only partially restored by successful treatment. Dysfunctional neutrophil chemotaxis may predispose patients with periodontitis to their disease by increasing tissue transit times, thus exacerbating neutrophil-mediated collateral host tissue damage. PMID:25360483

  19. Complication Rate of Percutaneous Liver Biopsies among Persons with Advanced Chronic Liver Disease in the HALT-C Trial

    PubMed Central

    Seeff, Leonard B.; Everson, Gregory T.; Morgan, Timothy R.; Curto, Teresa M.; Lee, William M.; Ghany, Marc G.; Shiffman, Mitchell L.; Fontana, Robert J.; Di Bisceglie, Adrian M.; Bonkovsky, Herbert L.; Dienstag, Jules L.

    2013-01-01

    Background & Aims Although percutaneous liver biopsy is a standard diagnostic procedure, it has drawbacks, including risk of serious complications. It is not known whether persons with advanced chronic liver disease have a greater risk of complications from liver biopsy than patients with more mild, chronic liver disease. The safety and complications of liver biopsy were examined in patients with hepatitis C-related bridging fibrosis or cirrhosis that were enrolled in the Hepatitis C Antiviral Long-Term Treatment against Cirrhosis (HALT-C) Trial. Methods Standard case report forms from 2,740 liver biopsies performed at 10 study sites between 2000 and 2006 were reviewed for serious adverse events, along with information from questionnaires completed by investigators about details of biopsy techniques used at each hospital. Results There were 29 serious adverse events (1.1%); the most common was bleeding (16 cases, 0.6%). There were no biopsy-related deaths. The bleeding rate was higher among patients with platelet counts ≤60,000/mm3 and among those with an international normalized ratio (INR) ≥1.3, although none of the patients with an INR >1.5 bled. Excluding subjects with a platelet count ≤60,000/mm3 would have reduced the bleeding rate by 25% (4/16), eliminating only 2.8% (77/2740) of biopsies. Operator experience, the type of needle used, or the performance of the biopsy under ultrasound guidance did not influence the frequencies of adverse events. Conclusions Approximately 0.5% of persons with hepatitis C and advanced fibrosis experienced potentially serious bleeding after liver biopsy; risk increased significantly in patients with platelet counts ≤60,000/mm3.(K2). PMID:20362695

  20. An intensive drug monitoring study suggesting possible clinical irrelevance of impaired drug disposition in liver disease.

    PubMed Central

    Naranjo, C A; Busto, U; Janecek, E; Ruiz, I; Roach, C A; Kaplan, K

    1983-01-01

    1 Liver disease can alter the disposition and clinical effects of drugs. However, even though altered drug disposition occurs, there is no clinical evidence relating it to an increased susceptibility to adverse drug reactions (ADRs). 2 An intensive prospective drug monitoring study of 2,582 hospitalized patients was conducted. The adverse drug reactions probability scale (APS) was used to assess ADRs. Only non-mild, definite or probable ADRs (APS greater than or equal to 5) were included. Severity of liver dysfunction was assessed by a composite clinical and laboratory index (CCLI). 3 The frequency of ADRs was higher in 402 patients with cirrhosis (27.4%) than in 661 with renal dysfunction (22.8%) and in 249 with other parenchymatous liver diseases (13.7%) or in 1,270 patients with neither liver diseases nor renal dysfunction (10.9%) (chi 2 3 = 85.53, P less than 0.001). The frequency of ADRs in cirrhotics was highly correlated with the severity of the liver dysfunction measured by CCLI (r = 0.82, P less than 0.001). 4 Drugs predominantly eliminated by liver metabolism were not among those most commonly inducing ADRs or those causing severe reactions in cirrhotics. Thus, frusemide caused the most common and the most severe ADRs, whereas reactions induced by sedatives were uncommon. Drug-induced hepatic encephalopathy was more common in cirrhotics receiving diuretics (13.3%) than in those receiving sedatives (1.8%) (chi 2 y.c. = 5.29, P less than 0.025). Patients with alcoholic liver disease had more drug-induced hepatic encephalopathy (7.7%) than those with non-alcoholic liver disease (1.2%) (chi 2 y.c. = 11.86, P less than 0.001). 5 These results indicate that susceptibility to ADRs is increased only in severe cirrhosis and that the most common and severe ADRs seem more likely related to enhanced pharmacodynamic action than to impaired drug disposition. PMID:6849781

  1. Liver transient elastography (Fibroscan): a place in the management algorithms of chronic viral hepatitis.

    PubMed

    Scott, David R; Levy, Miriam T

    2010-01-01

    Treatment guidelines are continuously evolving in chronic viral hepatitis, taking into consideration our greater understanding of natural history and therapeutic efficacy and safety. Key in the decision making process is an assessment of liver injury. Traditionally, liver biopsy has provided this information; however, this is an invasive procedure and not completely reliable. Liver transient elastography (Fibroscan) is exciting new technology that allows estimation of hepatic fibrosis through measurement of liver stiffness. It is acceptably accurate, safe, cheap, quick and widely applicable, and can reduce the need for liver biopsy in chronic hepatitis. In chronic hepatitis C, it can identify those most likely to benefit from treatment, as well as those with cirrhosis who require more specific care. In chronic hepatitis B, it could screen groups previously excluded from treatment (normal alanine aminotransferase and low DNA) to identify the subgroup that would benefit from therapy. It cannot replace biopsy in all settings, but it will narrow the group who do require biopsy, and provide information on liver damage in patients for whom biopsy would probably not have been considered.

  2. Non invasive assessment of liver fibrosis in chronic hemodialysis patients with viral hepatitis C

    PubMed Central

    Arrayhani, Mohamed; Sqalli, Tarik; Tazi, Nada; El Youbi, Randa; Chaouch, Safae; Aqodad, Nourdin; Ibrahimi, Sidi Adil

    2015-01-01

    The liver biopsy has long been the "gold standard" for assessing liver fibrosis in patients with hepatitis C. It's an invasive procedure which is associated with an elevated bleeding, especially in chronic hemodialysis patients. Main goal is to assess liver fibrosis in chronic hemodialysis with HCV by Fibroscan and by biological scores (APRI, Forns and Fib-4), and to measure the correlation between these tests. Cross-sectional study including all chronic hemodialysis patients with hepatitis C virus, in two public hemodialysis centers of Fez. All patients were evaluated for liver fibrosis using noninvasive methods (FibroScan and laboratory tests). Subsequently, the correlation between different tests has been measured. 95 chronic hemodialysis were studied, twenty nine patients (30.5%) with chronic hepatitis C. The average age was 52.38 ± 16.8 years. Nine liver fibrosis cases have been concluded by forns score. Fibroscan has objectified significant fibrosis in 6 cases. On the other side APRI has objectified sgnifivant fibrosis only in 3 cases. The Fib-4 showed severe fibrosis in five cases. The results have been most consistent between APRI and Fib-4, followed by Fibroscan and Forns, then APRI and FibroScan. PMID:26958136

  3. Non invasive assessment of liver fibrosis in chronic hemodialysis patients with viral hepatitis C.

    PubMed

    Arrayhani, Mohamed; Sqalli, Tarik; Tazi, Nada; El Youbi, Randa; Chaouch, Safae; Aqodad, Nourdin; Ibrahimi, Sidi Adil

    2015-01-01

    The liver biopsy has long been the "gold standard" for assessing liver fibrosis in patients with hepatitis C. It's an invasive procedure which is associated with an elevated bleeding, especially in chronic hemodialysis patients. Main goal is to assess liver fibrosis in chronic hemodialysis with HCV by Fibroscan and by biological scores (APRI, Forns and Fib-4), and to measure the correlation between these tests. Cross-sectional study including all chronic hemodialysis patients with hepatitis C virus, in two public hemodialysis centers of Fez. All patients were evaluated for liver fibrosis using noninvasive methods (FibroScan and laboratory tests). Subsequently, the correlation between different tests has been measured. 95 chronic hemodialysis were studied, twenty nine patients (30.5%) with chronic hepatitis C. The average age was 52.38 ± 16.8 years. Nine liver fibrosis cases have been concluded by forns score. Fibroscan has objectified significant fibrosis in 6 cases. On the other side APRI has objectified sgnifivant fibrosis only in 3 cases. The Fib-4 showed severe fibrosis in five cases. The results have been most consistent between APRI and Fib-4, followed by Fibroscan and Forns, then APRI and FibroScan.

  4. Association of serum α-tocopherol, β-carotene, and retinol with liver cancer incidence and chronic liver disease mortality

    PubMed Central

    Lai, G Y; Weinstein, S J; Albanes, D; Taylor, P R; Virtamo, J; McGlynn, K A; Freedman, N D

    2014-01-01

    Background: Micronutrients may influence the development or progression of liver cancer and liver disease. We evaluated the association of serum α-tocopherol, β-carotene, and retinol with incident liver cancer and chronic liver disease (CLD) mortality in a prospective cohort of middle-aged Finnish male smokers. Methods: Baseline and 3-year follow-up serum were available from 29 046 and 22 805 men, respectively. After 24 years of follow-up, 208 men were diagnosed with liver cancer and 237 died from CLD. Hazards ratios and 95% confidence intervals were calculated for highest vs lowest quartiles from multivariate proportional hazards models. Results: Higher β-carotene and retinol levels were associated with less liver cancer (β-carotene: 0.35, 0.22–0.55, P-trend <0.0001; retinol: 0.58, 0.39–0.85, P-trend=0.0009) and CLD mortality (β-carotene: 0.47, 0.30–0.75, P-trend=0.001; retinol: 0.55, 0.38–0.78, P-trend=0.0007). α-Tocopherol was associated with CLD mortality (0.63, 0.40–0.99, P-trend=0.06), but not with liver cancer (1.06, 0.64–1.74, P-trend=0.77). Participants with higher levels of β-carotene and retinol, but not α-tocopherol, at both baseline and year 3 had lower risk of each outcome than those with lower levels. Conclusions: Our findings suggest that higher concentrations of β-carotene and retinol are associated with incident liver cancer and CLD. However, such data do not indicate that supplementation should be considered for these diseases. PMID:25314058

  5. Chronic aspartame intake causes changes in the trans-sulphuration pathway, glutathione depletion and liver damage in mice.

    PubMed

    Finamor, Isabela; Pérez, Salvador; Bressan, Caroline A; Brenner, Carlos E; Rius-Pérez, Sergio; Brittes, Patricia C; Cheiran, Gabriele; Rocha, Maria I; da Veiga, Marcelo; Sastre, Juan; Pavanato, Maria A

    2017-04-01

    No-caloric sweeteners, such as aspartame, are widely used in various food and beverages to prevent the increasing rates of obesity and diabetes mellitus, acting as tools in helping control caloric intake. Aspartame is metabolized to phenylalanine, aspartic acid, and methanol. Our aim was to study the effect of chronic administration of aspartame on glutathione redox status and on the trans-sulphuration pathway in mouse liver. Mice were divided into three groups: control; treated daily with aspartame for 90 days; and treated with aspartame plus N-acetylcysteine (NAC). Chronic administration of aspartame increased plasma alanine aminotransferase (ALT) and aspartate aminotransferase activities and caused liver injury as well as marked decreased hepatic levels of reduced glutathione (GSH), oxidized glutathione (GSSG), γ-glutamylcysteine ​​(γ-GC), and most metabolites of the trans-sulphuration pathway, such as cysteine, S-adenosylmethionine (SAM), and S-adenosylhomocysteine ​​(SAH). Aspartame also triggered a decrease in mRNA and protein levels of the catalytic subunit of glutamate cysteine ligase (GCLc) and cystathionine γ-lyase, and in protein levels of methionine adenosyltransferase 1A and 2A. N-acetylcysteine prevented the aspartame-induced liver injury and the increase in plasma ALT activity as well as the decrease in GSH, γ-GC, cysteine, SAM and SAH levels and GCLc protein levels. In conclusion, chronic administration of aspartame caused marked hepatic GSH depletion, which should be ascribed to GCLc down-regulation and decreased cysteine levels. Aspartame triggered blockade of the trans-sulphuration pathway at two steps, cystathionine γ-lyase and methionine adenosyltransferases. NAC restored glutathione levels as well as the impairment of the trans-sulphuration pathway.

  6. Maternal saturated-fat-rich diet promotes leptin resistance in fetal liver lipid catabolism and programs lipid homeostasis impairments in the liver of rat offspring.

    PubMed

    Mazzucco, María Belén; Fornes, Daiana; Capobianco, Evangelina; Higa, Romina; Jawerbaum, Alicia; White, Verónica

    2016-01-01

    We aimed to analyze if an overload of saturated fat in maternal diet induced lipid metabolic impairments in livers from rat fetuses that persist in the offspring and to identify potential mechanisms involving fetal leptin resistance. Female rats were fed either a diet enriched in 25% of saturated fat (SFD rats) or a regular diet (controls). Fetuses of 21days of gestation and offspring of 21 and 140days of age were obtained and plasma and liver were kept for further analysis. Livers from a group of control and SFD fetuses were cultured in the presence or absence of leptin. Leptin or vehicle was administered to control fetuses during the last days of gestation and, on day 21, fetal livers and plasma were obtained. Lipid levels were assessed by thin-layer chromatography and mRNA gene expression of CPT1, ACO and PPARα by RT-PCR. Liver lipid levels were increased and CPT1 and ACO were down-regulated in fetuses and offspring from SFD rats compared to controls. After the culture with leptin, control fetal livers showed increased ACO and CPT1 expression and decreased lipid levels, while fetal livers from SFD rats showed no changes. Fetal administration of leptin induced a decrease in ACO and no changes in CPT1 expression. In summary, our results suggest that a saturated fat overload in maternal diet induces fetal leptin resistance in liver lipid catabolism, which might be contributing to liver lipid alterations that are sustained in the offspring.

  7. Ameliorating effect and potential mechanism of Rehmannia glutinosa oligosaccharides on the impaired glucose metabolism in chronic stress rats fed with high-fat diet.

    PubMed

    Zhang, Ruxue; Zhou, Jun; Li, Maoxing; Ma, Haigang; Qiu, Jianguo; Luo, Xiaohong; Jia, Zhengping

    2014-04-15

    The aim of this study was to determine whether the Rehmannia glutinosa oligosaccharides (ROS) ameliorate the impaired glucose metabolism and the potential mechanism in chronic stress rats fed with high-fat diet. The rats were fed by a high-fat diet and simultaneously stimulated by chronic stress over 5 weeks. Body weight, fasting plasma glucose, intraperitoneal glucose tolerance test (IPGTT), plasma lipids, gluconeogenesis test (GGT), glycogen content, and corticosterone, insulin and leptin levels were measured. The results showed that ROS administration (100, 200 mg/kg, i.g.) for 5 weeks exerted the effects of increasing the organ weights of thymus and spleen, lowering the fasting plasma glucose level, improving impaired glucose tolerance, increasing the contents of liver and muscle glycogen, decreasing the gluconeogenesis ability, plasma-free fatty acid's level, as well as plasma triglyceride and total cholesterol levels in chronic stress and high-fat fed rats, especially in the group of 200mg/kg; while the plasma corticosterone level was decreased, and plasma leptin level was increased. These results suggest that ROS exert an ameliorating effect of impaired glucose metabolism in chronic stress rats fed with high-fat diet, and the potential mechanism may be mediated through rebuilding the glucose homeostasis in the neuroendocrine immuno-modulation (NIM) network through multilinks and multitargets.

  8. Regulatory T cells: Mechanisms of suppression and impairment in autoimmune liver disease.

    PubMed

    Liberal, Rodrigo; Grant, Charlotte R; Longhi, Maria Serena; Mieli-Vergani, Giorgina; Vergani, Diego

    2015-02-01

    There are three classic liver diseases with probable autoimmune etiology: primary biliary cirrhosis, primary sclerosing cholangitis, and autoimmune hepatitis. The occurrence of these autoimmune conditions is determined by the breakdown of immune-regulatory mechanisms that in health are responsible for maintaining immunological tolerance against self-antigens. Among the multiple T cell subsets with suppressive function, the regulatory T cells (Tregs), defined by the expression of CD4, the IL-2 receptor α chain (CD25), and the transcription factor FOXP3, have emerged as having a central role in maintaining immune-tolerance to autoantigens. Tregs are equipped with an array of mechanisms of suppression, including the modulation of antigen presenting cell maturation and function, the killing of target cells, the disruption of metabolic pathways, and the production of anti-inflammatory cytokines. In all the three autoimmune liver diseases mentioned above, there is evidence pointing for either a reduced frequency and/or function of Tregs. Here, we review the definition, phenotypic characteristics, and mechanisms of suppression employed by Tregs and then we discuss the evidence available pointing to their impairment in patients with autoimmune liver disease.

  9. Assessment of School Readiness in Chronic Cholestatic Liver Disease: A Pilot Study Examining Children with and without Liver Transplantation

    PubMed Central

    Rogers, Alaine; Rankin, Stephanie; Parmar, Arpita; Kamath, Binita M.; Avitzur, Yaron; Ng, Vicky Lee

    2017-01-01

    Background. Assessment of school readiness evaluates physical, social-emotional, and neuropsychological domains essential for educational success. Cognitive testing of preschool aged children with chronic liver disease may guide more timely interventions and focused efforts by health care providers. Patients and Methods. Children with chronic cholestatic liver disease diagnosed as an infant and still with their native liver (NL) and children who received a liver transplant (LT) before age of 2 years underwent testing with a battery of well-validated pediatric psychometric measures. Results. Eighteen (13 LT, 5 NL) patients (median age of 4.45 and 4.05 years, resp.) were tested. Median Full-Scale IQ was 98 (range 102–116) for LT and 116 [(range 90–106), p = 0.35, NS] for NL subjects. LT recipients had significantly greater visual based difficulties, poorer caregiver rated daily living skills (p = 0.04), and higher levels of executive function based difficulties (e.g., inattention, inhibition). Conclusion. This pilot study highlights the risk of neuropsychological difficulties in early school age children who were under 2 years of age at time of LT. Comprehensive early school age assessment should integrate psychometric measures to identify children at greatest risk, thus allowing for proactive educational intervention. PMID:28194394

  10. Do people with chronic pain have impaired executive function? A meta-analytical review.

    PubMed

    Berryman, Carolyn; Stanton, Tasha R; Bowering, K Jane; Tabor, Abby; McFarlane, Alexander; Moseley, G Lorimer

    2014-11-01

    A widely held belief within the clinical community is that chronic pain is associated with cognitive impairment, despite the absence of a definitive systematic review or meta-analysis on the topic. The current systematic review and meta-analysis aimed to establish the current evidence concerning the difference in executive function between people with chronic pain and healthy controls. Six databases were searched for citations related to executive function and chronic pain from inception to June 24, 2013. Two reviewers independently assessed studies for eligibility and extracted relevant data according to the Cochrane Collaboration and Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Twenty five studies were included in the review and twenty two studies in the meta-analysis. A small to moderate impairment in executive function performance was found in people with chronic pain across cognitive components, although all studies had a high risk of bias. The current evidence suggests impairment of executive function in people with chronic pain, however, important caveats exist. First, executive function involves many cognitive components and there is no standard test for it. Second, moderators of executive function, such as medication and sleep, were seldom controlled for in studies of executive function performance.

  11. Impairment of the liver insulin receptor autoactivation cascade at full-term pregnancy in the rat.

    PubMed

    Martinez, C; Molero, J C; Ruiz, P; Del Arco, A; Andres, A; Carrascosa, J M

    1995-10-15

    Partially purified liver insulin receptors from full-term pregnant rats show decreased autophosphorylation rates if compared with receptors from virgins. We studied the molecular mechanism of this phenomenon, looking at possible structural and functional changes of several domains. The ATP-binding domain seems to be unaltered in receptors from pregnant rats since Km for ATP was similar to that observed in virgins. In contrast, the Vmax. is decreased some 45%, suggesting changes in the kinase domain. Truncation of a fragment of 10 kDa from the C-terminal tail does not normalize the kinase activity in receptors from pregnant rats, suggesting that this domain is not involved in the inhibitory regulation. Treatment with alkaline phosphatase increases the [32P]Pi incorporation into receptors from pregnant rats; however, the autophosphorylation remains lower than that observed in virgin rats. Tryptic phosphopeptide maps of phosphorylated receptors show that the same phosphopeptides are present in receptors from virgin and pregnant rats. However, the progression through the autoactivation cascade in the kinase domain is impaired in receptors from pregnant rats. Differences in the cleavage by trypsin at the two alternative sites in the kinase domain were observed, indicating possible structural changes in receptors from pregnant rats that could be related to the impairment of the autoactivation cascade. Integrity of the alpha- and beta-subunits, as well as differential expression of the two receptor isotypes, were shown to be unaltered. We conclude that (1) the decreased autophosphorylation rate of the liver insulin receptor from pregnant rats is associated with the impairment of its autoactivation cascade, probably as a consequence of the basal Ser/Thr phosphorylation; and (2) the inhibition of the autoactivation cascade does not account for the overall inhibition of autophosphorylation observed in receptors from pregnant rats.

  12. Living with Tics: Reduced Impairment and Improved Quality of Life for Youth with Chronic Tic Disorders

    PubMed Central

    McGuire, Joseph F.; Arnold, Elysse; Park, Jennifer M.; Nadeau, Joshua M.; Lewin, Adam B.; Murphy, Tanya K.; Storch, Eric A.

    2014-01-01

    Pharmacological and behavioral interventions have focused on reducing tic severity to alleviate tic-related impairment for youth with chronic tic disorders (CTDs), with no existing intervention focused on the adverse psychosocial consequences of tics. This study examined the preliminary efficacy of a modularized cognitive behavioral intervention ("Living with Tics", LWT) in reducing tic-related impairment and improving quality of life relative to a waitlist control of equal duration. Twenty-four youth (ages 7–17 years) with Tourette Disorder or Chronic Motor Tic Disorder and psychosocial impairment participated. A treatment-blind evaluator conducted all pre- and post-treatment clinician-rated measures. Youth were randomly assigned to receive the LWT intervention (n=12) or a 10-week waitlist (n=12). The LWT intervention consisted of up to 10 weekly sessions targeted at reducing tic-related impairment and developing skills to manage psychosocial consequences of tics. Youth in the LWT condition experienced significantly reduced clinician-rated tic-impairment, and improved child-rated quality of life. Ten youth (83%) in the LWT group were classified as treatment responders compared to four youth in the waitlist condition (33%). Treatment gains were maintained at one-month follow-up. Findings provide preliminary data that the LWT intervention reduces tic-related impairment and improves quality of life for youth with CTDs. PMID:25500348

  13. Living with tics: reduced impairment and improved quality of life for youth with chronic tic disorders.

    PubMed

    McGuire, Joseph F; Arnold, Elysse; Park, Jennifer M; Nadeau, Joshua M; Lewin, Adam B; Murphy, Tanya K; Storch, Eric A

    2015-02-28

    Pharmacological and behavioral interventions have focused on reducing tic severity to alleviate tic-related impairment for youth with chronic tic disorders (CTDs), with no existing intervention focused on the adverse psychosocial consequences of tics. This study examined the preliminary efficacy of a modularized cognitive behavioral intervention ("Living with Tics", LWT) in reducing tic-related impairment and improving quality of life relative to a waitlist control of equal duration. Twenty-four youth (ages 7-17 years) with Tourette Disorder or Chronic Motor Tic Disorder and psychosocial impairment participated. A treatment-blind evaluator conducted all pre- and post-treatment clinician-rated measures. Youth were randomly assigned to receive the LWT intervention (n=12) or a 10-week waitlist (n=12). The LWT intervention consisted of up to 10 weekly sessions targeted at reducing tic-related impairment and developing skills to manage psychosocial consequences of tics. Youth in the LWT condition experienced significantly reduced clinician-rated tic-impairment, and improved child-rated quality of life. Ten youth (83%) in the LWT group were classified as treatment responders compared to four youth in the waitlist condition (33%). Treatment gains were maintained at one-month follow-up. Findings provide preliminary data that the LWT intervention reduces tic-related impairment and improves quality of life for youth with CTDs.

  14. Hepatocyte Tissue Factor Contributes to the Hypercoagulable State in a Mouse Model of Chronic Liver Injury

    PubMed Central

    Rautou, Pierre-Emmanuel; Tatsumi, Kohei; Antoniak, Silvio; Owens, A. Phillip; Sparkenbaugh, Erica; Holle, Lori A.; Wolberg, Alisa S.; Kopec, Anna K.; Pawlinski, Rafal; Luyendyk, James P.; Mackman, Nigel

    2015-01-01

    Summary Background & Aims Patients with chronic liver disease and cirrhosis have a dysregulated coagulation system and are prone to thrombosis. The basis for this hypercoagulable state is not completely understood. Tissue factor (TF) is the primary initiator of coagulation in vivo. Patients with cirrhosis have increased TF activity in white blood cells and circulating microparticles. The aim of our study was to determine the contribution of TF to the hypercoagulable state in a mouse model of chronic liver injury. Methods We measured levels of TF activity in the liver, white blood cells and circulating microparticles, and a marker of activation of coagulation [thrombinantithrombin complexes (TATc)] in the plasma of mice subjected to bile duct ligation for 12 days. We used wild-type mice, mice with a global TF deficiency (low TF mice), and mice deficient for TF in either myeloid cells (TFflox/flox, LysMCre mice) or in hepatocytes (TFflox/flox, AlbCre). Results Wild-type mice with liver injury had increased levels of white blood cell, microparticle TF activity and TATc compared to sham mice. Low TF mice and mice lacking TF in hepatocytes had reduced levels of TF in the liver and in microparticles and exhibited reduced activation of coagulation without a change in liver fibrosis. In contrast, mice lacking TF in myeloid cells had reduced white blood cell TF but no change in microparticle TF activity or TATc. Conclusions Hepatocyte TF activates coagulation in a mouse model of chronic liver injury. TF may contribute to the hypercoagulable state associated with chronic liver diseases in patients. PMID:26325534

  15. Hepatitis B antigen and auto-antibodies in chronic liver diseases in Hong Kong.

    PubMed

    Lee, A K

    1975-06-01

    The frequency of occurrence of hepatitis B antigen (HBAg) and certain tissue autoantibodies [antinuclear antibody (ANA), smooth muscle antibody (SMA) and mitochondrial antibody (MIA)] were studied with the microtiter complement fixation and immunofluorescence techniques respectively in a group of patients suffering from chronic liver diseases. These were chronic hepatitis (30), cirrhosis of the liver (66) and hepatocellular carcinoma, mostly with underlying cirrhosis (100). A group of closely matched hospital in-patients served as controls. HBAg was found in high frequency in the patients with liver disease (60% in chronic hepatitis, 36.4% in cirrhosis and 49% in hepatocellular carcinoma) whereas tissue auto-antibodies were found in lower frequencies (16.7%, 10.6% and 13% in the three groups respectively). However, in both the frequency was significantly higher than that in the controls (9.2% for HBAg and 0.8% for auto-antibodies). There was a negative correlation between HBAg and tissue auto-antibodies in the group of patients with liver disease when taken as a whole (x2=14.3, P less than 0.001). These results suggest a possible aetiological role played by hepatitis virus B in hepatocellular carcinoma through chronic hepatitis and cirrhosis in Hong Kong while the mutual exclusion between HBAg and auto-antibodies supports the hypothesis of heterogeneity in the aetiology of chronic liver diseases. The patients with auto-antibodies may belong to the auto-immune category but no definate conclusion can be reached until the role played by hepatitis virus A in chronic liver diseases is clarified when more reliable techniques for its identification are available.

  16. Peripubertal anxiety profile can predict predisposition to spatial memory impairments following chronic stress.

    PubMed

    Bellani, Rudy; Luecken, Linda J; Conrad, Cheryl D

    2006-01-30

    We tested the hypothesis that peripubertal anxiety levels are predictive of the detrimental effects of chronic stress on hippocampal-dependent spatial memory. The anxiety levels of peripubertal male Sprague-Dawley rats (43 days old) were characterized using open field and elevated plus mazes, followed by chronic restraint stress for 6 h/day/21 days beginning in young adulthood (75 days). Following chronic stress treatment, rats were tested on the spatial Y-maze using two inter-trial interval levels of difficulty (4 h: 1 day post-chronic stress; 1 min: 2 days post-chronic stress). As expected, all groups displayed intact spatial memory in the less difficult 1 min version of the Y-maze. However, in the 4 h version of the Y-maze, chronically stressed high anxiety rats showed impaired spatial memory, while chronically stressed low anxiety and control (low and high anxiety) rats displayed intact spatial memory. Moreover, a month after chronic stress ended, high anxiety rats had significantly higher basal corticosterone levels than low anxiety rats (control and stress). These results indicate that peripubertal anxiety and chronic stress interact to influence hippocampal-dependent spatial memory in adulthood.

  17. Vortioxetine restores reversal learning impaired by 5-HT depletion or chronic intermittent cold stress in rats.

    PubMed

    Wallace, Ashley; Pehrson, Alan L; Sánchez, Connie; Morilak, David A

    2014-10-01

    Current treatments for depression, including serotonin-specific reuptake inhibitors (SSRIs), are only partially effective, with a high incidence of residual symptoms, relapse, and treatment resistance. Loss of cognitive flexibility, a component of depression, is associated with dysregulation of the prefrontal cortex. Reversal learning, a form of cognitive flexibility, is impaired by chronic stress, a risk factor for depression, and the stress-induced impairment in reversal learning is sensitive to chronic SSRI treatment, and is mimicked by serotonin (5-HT) depletion. Vortioxetine, a novel, multimodal-acting antidepressant, is a 5-HT3, 5-HT7 and 5-HT1D receptor antagonist, a 5-HT1B receptor partial agonist, a 5-HT1A receptor agonist, and inhibits the 5-HT transporter. Using adult male rats, we first investigated the direct effects of vortioxetine, acting at post-synaptic 5-HT receptors, on reversal learning that was compromised by 5-HT depletion using 4-chloro-DL-phenylalanine methyl ester hydrochloride (PCPA), effectively eliminating any contribution of 5-HT reuptake blockade. PCPA induced a reversal learning impairment that was alleviated by acute or sub-chronic vortioxetine administration, suggesting that post-synaptic 5-HT receptor activation contributes to the effects of vortioxetine. We then investigated the effects of chronic dietary administration of vortioxetine on reversal learning that had been compromised in intact animals exposed to chronic intermittent cold (CIC) stress, to assess vortioxetine's total pharmacological effect. CIC stress impaired reversal learning, and chronic vortioxetine administration prevented the reversal-learning deficit. Together, these results suggest that the direct effect of vortioxetine at 5-HT receptors may contribute to positive effects on cognitive flexibility deficits, and may enhance the effect of 5-HT reuptake blockade.

  18. Clinical Benefits of Biochemical Markers of Fibrosis in Egyptian Children With Chronic Liver Diseases

    PubMed Central

    Abdel-Ghaffar, Tawhida Y.; Behairy, Behairy E.; El-Shaheed, Azza Abd; Mahdy, Karam; El-Batanony, Mohamed; Hussein, Mohsen H.; Sira, Mostafa M.

    2010-01-01

    Background The need for repetition of liver biopsy, especially in assessing the degree of fibrosis and follow-up of treatment protocols, justifies an intensive search for non-invasive alternatives. We attempted to investigate the clinical usefulness of serum fibrogenesis markers in pediatric chronic liver diseases. Methods We measured serum levels of TGF-β1, collagen IV, laminin, MMP-2 and EGF-R, in 50 children with chronic liver disease (HBV, HCV and Bilharziasis) and 30 healthy controls, and determined their relationship to frequently used liver function tests and liver biopsy findings in patients. Results TGF-β1, collagen IV, laminin and MMP-2, but not EGF-R, were significantly higher in patients than in controls (P < 0.01). None of these markers correlated with the histological fibrosis stage, whereas laminin correlated with necroinflammatory activity (P < 0.01). TGF-β1, collagen IV, laminin and MMP-2 had the ability to discriminate patients with significant fibrosis, while only collagen IV and laminin were able to discriminate those with cirrhosis. Among these markers, collagen IV had the best predictive accuracy for significant fibrosis (AUROC 0.94; PPV 91.5%) and cirrhosis (AUROC 0.85; PPV 80%). Conclusions In conclusion, these markers may be useful in reducing but not replacing the need for liver biopsy in the monitoring of disease progression and treatment effectiveness and might be an inseparable part of assessment of chronic hepatopathies. PMID:27942306

  19. Cyclooxygenase-2 Inhibitor Reduces Hepatic Stiffness in Pediatric Chronic Liver Disease Patients Following Kasai Portoenterostomy

    PubMed Central

    Chang, Hye Kyung; Chang, Eun Young; Ryu, Seonae

    2016-01-01

    Purpose The purpose of this study was to define the role of cyclooxygenase-2 inhibitors (COX-2i) in reducing hepatic fibrosis in pediatric patients with chronic liver disease. Materials and Methods From September 2009 to September 2010, patients over 2 years old who visited our outpatient clinic for follow-up to manage their chronic liver disease after Kasai portoenterostomy for biliary atresia, were included in this study. Volunteers were assigned to the study or control groups, according to their preference. A COX-2i was given to only the study group after obtaining consent. The degree of hepatic fibrosis (liver stiffness score, LSS) was prospectively measured using FibroScan, and liver function was examined using serum analysis before and after treatment. After 1 year, changes in LSSs and liver function were compared between the two groups. Results Twenty-five patients (18 females and 7 males) were enrolled in the study group. The control group included 44 patients (26 females and 18 males). After 1 year, the least square mean values for the LSSs were significantly decreased by 3.91±0.98 kPa (p=0.004) only in the study group. Serum total bilirubin did not decrease significantly in either group. Conclusion COX-2i treatment improved the LSS in patients with chronic liver disease after Kasai portoenterostomy for biliary atresia. PMID:27189282

  20. Liver Apparent Diffusion Coefficient Changes during Telaprevir-Based Therapy for Chronic Hepatitis C

    PubMed Central

    Gürcan, Nagihan İnan; Sakçı, Zakir; Akhan, Sıla; Altunok, Elif Sargın; Aynıoğlu, Aynur; Gürbüz, Yeşim; Sarisoy, Hasan Tahsin; Akansel, Gür

    2016-01-01

    Background Diffusion-weighted imaging (DWI) has become an established diagnostic modality for the evaluation of liver parenchymal changes in diseases such as diffuse liver fibrosis. Aims To evaluate the parenchymal apparent diffusion coefficient value (ADC) changes using diffusion-weighted imaging (DWI) during telaprevir-based triple therapy. Study Design Diagnostic accuracy study. Methods Seventeen patients with chronic hepatitis C virus (HCV) virus and twenty-five normal volunteers were included. All of the patients took 12-weeks of telaprevir-based triple therapy followed by 12-weeks of PEGylated interferon and ribavirin therapy. They were examined before treatment (BT), as well as 12-weeks (W12) and 24-weeks (W24) after treatment by 3 Tesla magnetic resonance imaging (MRI). DWI was obtained using a breath-hold single-shot echo-planar spin echo sequence. Histopathologically, liver fibrosis was classified in accordance with the modified Knodell score described by Ishak. Quantitatively, liver ADCs were compared between patients and normal volunteers to detect the contribution of DWI in the detection of fibrosis. In addition, liver ADCs were compared during the therapy to analyze the effect of antiviral medication on liver parenchyma. Results The liver ADC values of fibrotic liver parenchyma were significantly lower than those of the healthy liver parenchyma (p<0.001). However, we were not able to reach a sufficiently discriminative threshold value. The ADC values showed a declining trend with increasing fibrotic stage. No statistically significant correlation (p=0.204) was observed. Compared with those before treatment, the liver ADC values after telaprevir-based triple therapy were significantly decreased at W12. A significant increase in the liver ADC values was also observed after the cessation of telaprevir therapy at W24 with a return to initial values. Conclusion Liver ADC values appear to indicate the present but not the stage of liver fibrosis. DWI may be

  1. Chronic ethanol feeding alters miRNA expression dynamics during liver regeneration

    PubMed Central

    Dippold, Rachael P.; Vadigepalli, Rajanikanth; Gonye, Gregory E.; Patra, Biswanath; Hoek, Jan B.

    2012-01-01

    Background Adaptation to chronic ethanol treatment of rats results in a changed functional state of the liver and greatly inhibits its regenerative ability, which may contribute to the progression of alcoholic liver disease. Methods In this study we investigated the effect of chronic ethanol intake on hepatic miRNA expression in male Sprague-Dawley rats during the initial 24 hrs of liver regeneration following 70% partial hepatectomy (PHx) using microRNA (miRNA) microarrays. miRNA expression during adaptation to ethanol was investigated using RT-qPCR. Nuclear Factor kappa B (NFκB) binding at target miRNA promoters was investigated with chromatin immunoprecipitation. Results Unsupervised clustering of miRNA expression profiles suggested that miRNA expression was more affected by chronic ethanol feeding than by the acute challenge of liver regeneration after PHx. Several miRNAs that were significantly altered by chronic ethanol feeding, including miRs-34a, -103, -107, and -122 have been reported to play a role in regulating hepatic metabolism and the onset of these miRNA changes occurred gradually during the time course of ethanol feeding. Chronic ethanol feeding also altered the dynamic miRNA profile during liver regeneration. Promoter analysis predicted a role for Nuclear Factor kappa B (NFκB) in the immediate early miRNA response to PHx. NFκB binding at target miRNA promoters in the chronic ethanol-fed group was significantly altered and these changes directly correlated with the observed expression dynamics of the target miRNA. Conclusions Chronic ethanol consumption alters the hepatic miRNA expression profile such that the response of the metabolism-associated miRNAs occurs during long-term adaptation to ethanol rather than as an acute transient response to ethanol metabolism. Additionally, the dynamic miRNA program during liver regeneration in response to PHx is altered in the chronically ethanol-fed liver and these differences reflect, in part, differences

  2. Caloric Restriction Chronically Impairs Metabolic Programming in Mice

    PubMed Central

    Kirchner, Henriette; Hofmann, Susanna M.; Fischer-Rosinský, Antje; Hembree, Jazzminn; Abplanalp, William; Ottaway, Nickki; Donelan, Elizabeth; Krishna, Radha; Woods, Stephen C.; Müller, Timo D.; Spranger, Joachim; Perez-Tilve, Diego; Pfluger, Paul T.; Tschöp, Matthias H.; Habegger, Kirk M.

    2012-01-01

    Although obesity rates are rapidly rising, caloric restriction remains one of the few safe therapies. Here we tested the hypothesis that obesity-associated disorders are caused by increased adipose tissue as opposed to excess dietary lipids. Fat mass (FM) of lean C57B6 mice fed a high-fat diet (HFD; FMC mice) was “clamped” to match the FM of mice maintained on a low-fat diet (standard diet [SD] mice). FMC mice displayed improved glucose and insulin tolerance as compared with ad libitum HFD mice (P < 0.001) or SD mice (P < 0.05). These improvements were associated with fewer signs of inflammation, consistent with the less-impaired metabolism. In follow-up studies, diet-induced obese mice were food restricted for 5 weeks to achieve FM levels identical with those of age-matched SD mice. Previously, obese mice exhibited improved glucose and insulin tolerance but showed markedly increased fasting-induced hyperphagia (P < 0.001). When mice were given ad libitum access to the HFD, the hyperphagia of these mice led to accelerated body weight gain as compared with otherwise matched controls without a history of obesity. These results suggest that although caloric restriction on a HFD provides metabolic benefits, maintaining those benefits may require lifelong continuation, at least in individuals with a history of obesity. PMID:22787140

  3. [Chronic Budd-Chiari syndrome can cause liver cirrhosis].

    PubMed

    Karlsen, Stine; Nielsen, Dennis Tønner; Grønbæk, Henning

    2012-06-11

    Budd-Chiari syndrome (BCS) is a rare disease defined by congestive hepatopathy with obstruction of the hepatic venous outflow tract. Classical symptoms and signs include ascites, hepatomegaly, abdominal pain and various degrees of liver dysfunction. BCS is predominantly caused by thrombosis, malformations and venous compression. We present a case, in which BCS was the cause of liver cirrhosis complicated with refractory ascites and which can be misinterpreted as hepatocellular carcinoma nodules. The diagnosis was confirmed during the transjugular intrahepatic portosystemic shunt procedure with successful vascular stenting resolving the ascites formation.

  4. Carbamazepine suppresses calpain-mediated autophagy impairment after ischemia/reperfusion in mouse livers

    SciTech Connect

    Kim, Jae-Sung Wang, Jin-Hee Biel, Thomas G. Kim, Do-Sung Flores-Toro, Joseph A. Vijayvargiya, Richa Zendejas, Ivan Behrns, Kevin E.

    2013-12-15

    Onset of the mitochondrial permeability transition (MPT) plays a causative role in ischemia/reperfusion (I/R) injury. Current therapeutic strategies for reducing reperfusion injury remain disappointing. Autophagy is a lysosome-mediated, catabolic process that timely eliminates abnormal or damaged cellular constituents and organelles such as dysfunctional mitochondria. I/R induces calcium overloading and calpain activation, leading to degradation of key autophagy-related proteins (Atg). Carbamazepine (CBZ), an FDA-approved anticonvulsant drug, has recently been reported to increase autophagy. We investigated the effects of CBZ on hepatic I/R injury. Hepatocytes and livers from male C57BL/6 mice were subjected to simulated in vitro, as well as in vivo I/R, respectively. Cell death, intracellular calcium, calpain activity, changes in autophagy-related proteins (Atg), autophagic flux, MPT and mitochondrial membrane potential after I/R were analyzed in the presence and absence of 20 μM CBZ. CBZ significantly increased hepatocyte viability after reperfusion. Confocal microscopy revealed that CBZ prevented calcium overloading, the onset of the MPT and mitochondrial depolarization. Immunoblotting and fluorometric analysis showed that CBZ blocked calpain activation, depletion of Atg7 and Beclin-1 and loss of autophagic flux after reperfusion. Intravital multiphoton imaging of anesthetized mice demonstrated that CBZ substantially reversed autophagic defects and mitochondrial dysfunction after I/R in vivo. In conclusion, CBZ prevents calcium overloading and calpain activation, which, in turn, suppresses Atg7 and Beclin-1 depletion, defective autophagy, onset of the MPT and cell death after I/R. - Highlights: • A mechanism of carbamazepine (CBZ)-induced cytoprotection in livers is proposed. • Impaired autophagy is a key event contributing to lethal reperfusion injury. • The importance of autophagy is extended and confirmed in an in vivo model. • CBZ is a potential

  5. Primary Hepatic Amyloidosis Presenting as Acute-on-Chronic Liver Failure

    PubMed Central

    Rangegowda, Devaraja; Vyas, Tanmay; Kulkarni, Anand; Grover, Shrruti; Mahiwall, Rakhi; Sarin, Shiv Kumar

    2017-01-01

    Systemic amyloidosis of amyloid light chain associated protein (AL), also called primary amyloidosis, frequently involves the liver, but rarely causes clinically apparent liver disease. The more common presentation is with acute renal failure. Hepatomegaly and mild elevation of alkaline phosphatase are the most common clinical and biochemical findings, respectively. We report a case of systemic amyloidosis of AL that clinically presented as acute-on-chronic liver failure and resulted in a fatal clinical course in a 56-year-old man. PMID:28286788

  6. 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

  7. Effect of chronic carbon monoxide exposure on experimental alcoholic liver injury in rats

    SciTech Connect

    Nanji, A.A. ); Jui, L.T.; French, S.W. )

    1989-01-01

    Two groups of experimental animals with pair-fed controls were studied to evaluate the effect of chronic carbon monoxide (CO) exposure on progression of experimental alcoholic liver injury. Eight pairs of male Wistar rats were continuously infused liquid diet and ethanol or isocaloric dextrose for four months. Four pairs were also exposed to CO. Liver damage was followed monthly by serum ALT and morphologic assessment of liver biopsy. Serum levels of ALT were significantly higher in the CO-ethanol group compared to other groups. Electron microscopy revealed a greater degree of cell necrosis in the CO exposed group which explained the significantly higher ALT activity in these animals. Both experimental groups had significantly greater liver damage than controls. Carboxyhemoglobin levels were not different in the ethanol-fed and control group. Our results show that chronic CO exposure enhances liver cell necrosis in ethanol-fed rats thereby lending support to the hypothesis that ethanol and hypoxia enhance cellular disruption in the liver which could be important in the pathogenesis of alcoholic liver disease in rats.

  8. A20 prevents chronic liver inflammation and cancer by protecting hepatocytes from death

    PubMed Central

    Catrysse, L; Farhang Ghahremani, M; Vereecke, L; Youssef, S A; Mc Guire, C; Sze, M; Weber, A; Heikenwalder, M; de Bruin, A; Beyaert, R; van Loo, G

    2016-01-01

    An important regulator of inflammatory signalling is the ubiquitin-editing protein A20 that acts as a break on nuclear factor-κB (NF-κB) activation, but also exerts important cytoprotective functions. A20 knockout mice are cachectic and die prematurely due to excessive multi-organ inflammation. To establish the importance of A20 in liver homeostasis and pathology, we developed a novel mouse line lacking A20 specifically in liver parenchymal cells. These mice spontaneously develop chronic liver inflammation but no fibrosis or hepatocellular carcinomas, illustrating an important role for A20 in normal liver tissue homeostasis. Hepatocyte-specific A20 knockout mice show sustained NF-κB-dependent gene expression in the liver upon tumor necrosis factor (TNF) or lipopolysaccharide injection, as well as hepatocyte apoptosis and lethality upon challenge with sublethal doses of TNF, demonstrating an essential role for A20 in the protection of mice against acute liver failure. Finally, chronic liver inflammation and enhanced hepatocyte apoptosis in hepatocyte-specific A20 knockout mice was associated with increased susceptibility to chemically or high fat-diet-induced hepatocellular carcinoma development. Together, these studies establish A20 as a crucial hepatoprotective factor. PMID:27253414

  9. Chronic effects of berberine on blood, liver glucolipid metabolism and liver PPARs expression in diabetic hyperlipidemic rats.

    PubMed

    Zhou, Ji Yin; Zhou, Shi Wen; Zhang, Ke Bin; Tang, Jian Lin; Guang, Li Xia; Ying, Yi; Xu, Ying; Zhang, Le; Li, Dan Dan

    2008-06-01

    Berberine is one of the main alkaloids of Rhizoma coptidis which has been used as a folk medicine to treat diabetes mellitus for more than 1400 years in China. To investigate the chronic effect of berberine on diabetic hyperlipidemic rats, fasted rats were intraperitoneally injected 35 mg/kg streptozotocin. Diabetic rats were admitted after 2 weeks and given a high-carbohydrate/high-fat diet to induce hyperlipidemia. The rats were divided into 7 groups at the end of week 16: normal and diabetic rats received no drug, 5 treatment groups were administered with either 75, 150, 300 mg/kg berberine, 100 mg/kg fenofibrate or 4 mg/kg rosiglitazone per day for 16 weeks, respectively. The blood glucose, hemoglobin A1c, lipid metabolic parameters and hepatic glycogen and triglyceride were measured, and histopathology and peroxisome proliferator-activated receptors (PPARs) alpha/delta/gamma expression of liver were determined by hematoxylin eosin and immunohistochemical staining. Berberine reduced diabetic rats' body weight, liver weight and liver to body weight ratio. Berberine restored the increased blood glucose, hemoglobin A1c, total cholesterol, triglyceride, low density lipoprotein-cholesterol, apolipoprotein B and the decreased high density lipoprotein-cholesterol, apolipoprotein AI levels in diabetic rats to near the control ones. Berberine alleviated the pathological progression of liver and reverted the increased hepatic glycogen and triglyceride to near the control levels. Berberine increased PPARalpha/delta expression and reduced PPARgamma expression in liver of diabetic rat to near the control ones. Berberine improved glucolipid metabolism both in blood and liver in diabetic rats possibly through modulating the metabolic related PPARalpha/delta/gamma protein expression in liver.

  10. 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

  11. 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.

  12. Successful pregnancy outcome in decompensated chronic liver disease with portal vein thrombosis: case report and review of literature.

    PubMed

    Kumar, Mukesh; Kamani, Lubna; Hussain, Riaz; Siddique, Shoaib

    2011-07-01

    Pregnancy is rare in women with decompensated chronic liver disease. In this case report, we describe a case of a young woman who presented with hepatitis B-related decompensated chronic liver disease with portal vein thrombosis having successful full-term uneventful pregnancy.

  13. Liver Monocytes and Kupffer Cells Remain Transcriptionally Distinct during Chronic Viral Infection

    PubMed Central

    van de Garde, Martijn D. B.; Movita, Dowty; van der Heide, Marieke; Herschke, Florence; De Jonghe, Sandra; Gama, Lucio; Boonstra, Andre

    2016-01-01

    Due to the scarcity of immunocompetent animal models for chronic viral hepatitis, little is known about the role of the innate intrahepatic immune system during viral replication in the liver. These insights are however fundamental for the understanding of the inappropriate adaptive immune responses during the chronic phase of the infection. We apply the Lymphocytic Choriomenigitis Virus (LCMV) clone 13 mouse model to examine chronic virus-host interactions of Kupffer cells (KC) and infiltrating monocytes (IM) in an infected liver. LCMV infection induced overt clinical hepatitis, with rise in ALT and serum cytokines, and increased intrahepatic F4/80 expression. Despite ongoing viral replication, whole liver transcriptome showed baseline expression levels of inflammatory cytokines, interferons, and interferon induced genes during the chronic infection phase. Transcriptome analyses of sorted KC and IMs using NanoString technology revealed two unique phenotypes with only minimal overlap. At the chronic viral infection phase, KC showed no increased transcription of activation markers Cd80 and Cd86, but an increased expression of genes related to antigen presentation, whereas monocytes were more activated and expressed higher levels of Tnf transcripts. Although both KCs and intrahepatic IM share the surface markers F4/80 and CD11b, their transcriptomes point towards distinctive roles during virus-induced chronic hepatitis. PMID:27812182

  14. Chronic stress impairs learning and hippocampal cell proliferation in senescence-accelerated prone mice.

    PubMed

    Yan, Weihong; Zhang, Ting; Jia, Weiping; Sun, Xiaojiang; Liu, Xueyuan

    2011-02-25

    Chronic stress can induce cognitive impairment. It is unclear whether a higher susceptibility to chronic stress is associated with the progression of pathological brain aging. Senescence-accelerated prone mouse 8 (SAMP8) is a naturally occurring animal model of accelerated brain aging. Senescence-accelerated resistant mouse 1 (SAMR1) is usually used as the normal control. In this study, we examined the effects of chronic restraint stress (CRS) on learning in the Y-maze, hippocampal cell proliferation, and the expression of brain-derived neurotrophic factor (BDNF) in the hippocampus of 4-month-old SAMP8 and SAMR1. The results showed that exposure to CRS impaired learning and hippocampal cell proliferation in SAMP8 and SAMR1 but to a much greater extent in SAMP8. Furthermore, CRS significantly decreased the expression of BDNF protein and mRNA in the hippocampus of SAMP8 and SAMR1. These data indicated that SAMP8 is more sensitive to the deleterious effects of CRS on learning than SAMR1. A greater decrease in hippocampal cell proliferation caused by chronic stress may be part of the underlying mechanism for the more severe learning deficit observed in SAMP8. In addition, our findings suggested a role of BDNF in the stress-induced impairment of learning and hippocampal cell proliferation in both strains.

  15. Micro-RNA-122 levels in acute liver failure and chronic hepatitis C.

    PubMed

    Dubin, Perry H; Yuan, Hejun; Devine, Robert K; Hynan, Linda S; Jain, Mamta K; Lee, William M

    2014-09-01

    MicroRNA-122 (miR-122) is the foremost liver-related micro-RNA, but its role in the hepatocyte is not fully understood. To evaluate whether circulating levels of miR-122 are elevated in chronic-HCV for a reason other than hepatic injury, we compared serum level in patients with chronic hepatitis C to other forms of liver injury including patients with acute liver failure and healthy controls. MiR-122 was quantitated using sera from 35 acute liver failure patients (20 acetaminophen-induced, 15 other etiologies), 39 chronic-HCV patients and 12 controls. In parallel, human genomic DNA (hgDNA) levels were measured to reflect quantitatively the extent of hepatic necrosis. Additionally, six HIV-HCV co-infected patients, who achieved viral clearance after undergoing therapy with interferon and ribavirin, had serial sera miR-122 and hgDNA levels measured before and throughout treatment. Serum miR-122 levels were elevated approximately 100-fold in both acute liver failure and chronic-HCV sera as compared to controls (P < 0.001), whereas hgDNA levels were only elevated in acute liver failure patients as compared to both chronic-HCV and controls (P < 0.001). Subgroup analysis showed that chronic-HCV sera with normal aminotransferase levels showed elevated miR-122 despite low levels of hepatocyte necrosis. All successfully treated HCV patients showed a significant Log10 decrease in miR-122 levels ranging from 0.16 to 1.46, after sustained viral response. Chronic-HCV patients have very elevated serum miR-122 levels in the range of most patients with severe hepatic injury leading to acute liver failure. Eradication of HCV was associated with decreased miR-122 but not hgDNA. An additional mechanism besides hepatic injury may be active in chronic-HCV to explain the exaggerated circulating levels of miR-122 observed.

  16. Macrophage derived Wnt signalling opposes Notch signalling in a Numb mediated manner to specify HPC fate in chronic liver disease in human and mouse

    PubMed Central

    Boulter, Luke; Govaere, Olivier; Bird, Tom G; Radulescu, Sorina; Ramachandran, Prakash; Pellicoro, Antonella; Ridgway, Rachel A; Seo, Sang Soo; Spee, Bart; Van Rooijen, Nico; Sansom, Owen J.; Iredale, John P; Lowell, Sally; Roskams, Tania; Forbes, Stuart J

    2012-01-01

    During chronic injury, regeneration of the adult liver becomes impaired. In this context bipotent Hepatic Progenitor Cells (HPCs) become activated and can regenerate both cholangiocytes and hepatocytes. Notch and Wnt signalling during hepatic ontogeny are described, but their roles in HPC mediated liver regeneration are unclear. Here we show in human diseased liver and murine models of the ductular reaction with biliary and hepatocyte regeneration that Notch and Wnt signalling direct HPC specification within the activated myofibroblasts and macrophages HPC niche. During biliary regeneration, Numb is downregulated in HPCs, Jagged1 promotes biliary specification within HPCs. During hepatocyte regeneration, macrophage derived canonical Wnt signalling maintains Numb within HPCs, and Notch signalling is reduced promoting hepatocyte specification. This dominant Wnt state is stimulated through engulfment of hepatocyte debris by niche macrophages and can directly influence the HPCs. Macrophage Wnt3a expression in turn facilitates hepatocyte regeneration – thus exemplifying a novel positive feedback mechanism in adult parenchymal regeneration. PMID:22388089

  17. For Better or Worse, Iron Overload by Superparamagnetic Iron Oxide Nanoparticles as a MRI Contrast Agent for Chronic Liver Diseases.

    PubMed

    Zhou, Qibing; Wei, Yushuang

    2017-01-17

    Superparamagnetic iron oxide nanoparticles (SPIONs) have recently been used as an effective magnetic resonance imaging (MRI) contrast agent for the noninvasive diagnosis of chronic liver diseases including nonalcohol fatty liver diseases, nonalcohol steatohepatitis, and cirrhosis as well as liver tumors. However, the potential risk of the iron overload by SPIONs has been highly underestimated in chronic liver diseases. While most of SPIONs have been shown safe in the healthy group, significant toxicity potential by the iron overload has been revealed through immunotoxicity, lipid peroxidation, and fatty acid and cholesterol metabolism in cirrhosis as a high risk factor. As a result, the systems toxicology assessments of SPIONs are crucial in both healthy ones and chronic liver disease models to determine the margin of safety. In addition, the challenge of the iron overload by SPIONs requires better designed SPIONs as MRI contrast agents for chronic liver diseases such as the biodegradable nanocluster assembly with urine clearance.

  18. Low-dose, Chronic Exposure to Silver Nanoparticles Causes Mild Mitochondrial Alterations in the Liver of Sprague-Dawley Rat

    DTIC Science & Technology

    2014-05-10

    AFRL-AFOSR-UK-TR-2014-0032 Low-dose, chronic exposure to silver nanoparticles causes mild mitochondrial alterations in the liver ...TITLE AND SUBTITLE Low-dose, chronic exposure to silver nanoparticles causes mild mitochondrial alterations in the liver of Sprague-Dawley rat 5a...alterations were found in heart and kidney levels, and despite the fact that the alterations found in liver mitochondria did not appear to compromise ATP

  19. Chronic Intake of Japanese Sake Mediates Radiation-Induced Metabolic Alterations in Mouse Liver

    PubMed Central

    Nakajima, Tetsuo; Vares, Guillaume; Wang, Bing; Nenoi, Mitsuru

    2016-01-01

    Sake is a traditional Japanese alcoholic beverage that is gaining popularity worldwide. Although sake is reported to have beneficial health effects, it is not known whether chronic sake consumption modulates health risks due to radiation exposure or other factors. Here, the effects of chronic administration of sake on radiation-induced metabolic alterations in the livers of mice were evaluated. Sake (junmai-shu) was administered daily to female mice (C3H/He) for one month, and the mice were exposed to fractionated doses of X-rays (0.75 Gy/day) for the last four days of the sake administration period. For comparative analysis, a group of mice were administered 15% (v/v) ethanol in water instead of sake. Metabolites in the liver were analyzed by capillary electrophoresis-time-of-flight mass spectrometry one day following the last exposure to radiation. The metabolite profiles of mice chronically administered sake in combination with radiation showed marked changes in purine, pyrimidine, and glutathione (GSH) metabolism, which were only partially altered by radiation or sake administration alone. Notably, the changes in GSH metabolism were not observed in mice treated with radiation following chronic administration of 15% ethanol in water. Changes in several metabolites, including methionine and valine, were induced by radiation alone, but were not detected in the livers of mice who received chronic administration of sake. In addition, the chronic administration of sake increased the level of serum triglycerides, although radiation exposure suppressed this increase. Taken together, the present findings suggest that chronic sake consumption promotes GSH metabolism and anti-oxidative activities in the liver, and thereby may contribute to minimizing the adverse effects associated with radiation. PMID:26752639

  20. Impaired acclimatization to chronic hypoxia in adult male and female rats following neonatal hypoxia.

    PubMed

    Lumbroso, Delphine; Joseph, Vincent

    2009-08-01

    We tested the hypothesis that neonatal exposure to hypoxia alters acclimatization to chronic hypoxia later in life. Rat pups were exposed to normobaric hypoxia (12% O(2); nHx group) in a sealed chamber, or to normoxia (21% O(2); nNx group) from the day before birth to postnatal day 10. The animals were then raised in normal conditions until reaching 12 wk of age. At this age, we assessed ventilatory and hematological acclimatization to chronic hypoxia by exposing male and female nHx and nNx rats for 2 wk to 10% O(2). Minute ventilation, metabolic rate, hypoxic ventilatory response, hematocrit, and hemoglobin levels were measured both before and after acclimatization. We also quantified right ventricular hypertrophy as an index of pulmonary hypertension both before and after acclimatization. There was a significant effect of neonatal hypoxia that decreases ventilatory response (relative to metabolic rate, VE/VCO(2)) to acute hypoxia before acclimatization in males but not in females. nHx rats had an impaired acclimatization to chronic hypoxia characterized by altered respiratory pattern and elevated hematocrit and hemoglobin levels after acclimatization, in both males and females. Right ventricular hypertrophy was present before and after acclimatization in nHx rats, indicating that neonatal hypoxia results in pulmonary hypertension in adults. We conclude that neonatal hypoxia impairs acclimatization to chronic hypoxia in adults and may be a factor contributing to the establishment of chronic mountain sickness in humans living at high altitude.

  1. Quantitative assessment of fibrosis and steatosis in liver biopsies from patients with chronic hepatitis C

    PubMed Central

    Zaitoun, A; Al, M; Awad, S; Ukabam, S; Makadisi, S; Record, C

    2001-01-01

    Backgrounds—Hepatic fibrosis is one of the main consequences of liver disease. Both fibrosis and steatosis may be seen in some patients with chronic hepatitis C and alcoholic liver disease (ALD). Aims—To quantitate fibrosis and steatosis by stereological and morphometric techniques in patients with chronic hepatitis C and compare the results with a control group of patients with ALD. In addition, to correlate the quantitative features of fibrosis with the Ishak modified histological score. Materials and methods—Needle liver biopsies from 86 patients with chronic hepatitis C and from 32 patients with alcoholic liver disease (disease controls) were analysed by stereological and morphometric analyses using the Prodit 5.2 system. Haematoxylin and eosin and Picro-Mallory stained sections were used. The area fractions (AA) of fibrosis, steatosis, parenchyma, and other structures (bile duct and central vein areas) were assessed by stereological method. The mean diameters of fat globules were determined by morphometric analysis. Results—Significant differences were found in the AA of fibrosis, including fibrosis within portal tract areas, between chronic hepatitis C patients and those with ALD (mean (SD): 19.14 (10.59) v 15.97 (12.51)). Portal and periportal (zone 1) fibrosis was significantly higher (p = 0.00004) in patients with chronic hepatitis C compared with the control group (mean (SD): 9.04 (6.37) v 3.59 (3.16)). Pericentral fibrosis (zone 3) occurred in both groups but was significantly more pronounced in patients with ALD. These results correlate well with the modified Ishak scoring system. However, in patients with cirrhosis (stage 6) with chronic hepatitis C the AA of fibrosis varied between 20% and 74%. The diameter of fat globules was significantly lower in patients with hepatitis C (p = 0.00002) than the ALD group (mean (SD): 14.44 (3.45) v 18.4 (3.32)). Microglobules were more frequent in patients with chronic hepatitis C than in patients with ALD

  2. [Clinical and immunological features of acute hepatitis B in patients with concomitant chronic toxic liver damage].

    PubMed

    Furyk, E; Ryabokon, E

    2013-02-01

    The article presents information obtained during the survey in 64 patients with acute hepatitis B. We show that acute hepatitis B in patients with concomitant chronic toxic liver characterized by a marked imbalance of cytokine status due to a lower level of interleukin-2 and a higher content of interleukin-8, the highest levels of nitrite content, spontaneous oxidative modifications of blood proteins and the lowest content of L -arginine in the blood serum in the dynamics of disease compared with patients without this concomitant factor. In the period of convalescence these changes in patients with acute hepatitis B with concomitant chronic toxic liver characterized combined with higher cytolysis of liver cells, often circulating in the blood of HBsAg seroconversion and less frequently with the advent of anti-HBeAg.

  3. Sarcopenia in Patients with Chronic Liver Disease: Can It Be Altered by Diet and Exercise?

    PubMed

    Kappus, Matthew R; Mendoza, Mardeli Saire; Nguyen, Douglas; Medici, Valentina; McClave, Stephen A

    2016-08-01

    Sarcopenia, a loss of muscle mass, is being increasingly recognized to have a deleterious effect on outcomes in patients with chronic liver disease. Factors related to diet and the inflammatory nature of chronic liver disease contribute to the occurrence of sarcopenia in these patients. Sarcopenia adversely influences quality of life, performance, morbidity, success of transplantation, and even mortality. Specific deficiencies in macronutrients (protein, polyunsaturated fatty acids) and micronutrients (vitamins C, D, and E, carotenoids, and selenium) have been linked to sarcopenia. Lessons learned from nutritional therapy in geriatric patient populations may provide strategies to manage sarcopenia in patients with liver disease. Combining diet modification and nutrient supplementation with an organized program of exercise may help ameliorate or even reverse the effects of sarcopenia on an already complex disease process.

  4. 1,2-Dichloroethane impairs glucose and lipid homeostasis in the livers of NIH Swiss mice.

    PubMed

    Wang, Ting; Xu, Dandan; Fan, Qiming; Rong, Weifeng; Zheng, Jiewei; Gao, Chen; Li, Guoliang; Zeng, Ni; Guo, Tao; Zeng, Lihai; Wang, Fei; Xiao, Chen; Cai, Li; Tang, Shangqing; Deng, Xinlei; Yin, Xiao; Huang, Manqi; Lu, Fengrong; Hu, Qiansheng; Chen, Wen; Huang, Zhenlie; Wang, Qing

    2017-04-01

    Excessive exposure to 1,2-Dichloroethane (1,2-DCE), a chlorinated organic toxicant, can lead to liver dysfunction. To fully explore the mechanism of 1,2-DCE-induced hepatic abnormalities, 30 male National Institutes of Health (NIH) Swiss mice were exposed to 0, 350, or 700mg/m(3) of 1,2-DCE, via inhalation, 6h/day for 28days. Increased liver/body weight ratios, as well as serum AST and serum ALT activity were observed in the 350 and 700mg/m(3) 1,2-DCE exposure group mice, compared with the control group mice. In addition, decreased body weights were observed in mice exposed to 700mg/m(3) 1,2-DCE, compared with control mice. Exposure to 350 and 700mg/m(3) 1,2-DCE also led to significant accumulation of hepatic glycogen, free fatty acids (FFA) and triglycerides, elevation of blood triglyceride and FFA levels, and decreases in blood glucose levels. Results from microarray analysis indicated that the decreases in glucose-6-phosphatase catalytic subunit (G6PC) and liver glycogen phosphorylase (PYGL) expression, mediated by the activation of AKT serine/threonine kinase 1 (Akt1), might be responsible for the hepatic glycogen accumulation and steatosis. Further in vitro study demonstrated that 2-chloroacetic acid (1,2-DCE metabolite), rather than 1,2-DCE, up-regulated Akt1 phosphorylation and suppressed G6PC and PYGL expression, resulting in hepatocellular glycogen accumulation. These results suggest that hepatic glucose and lipid homeostasis are impaired by 1,2-DCE exposure via down-regulation of PYGL and G6PC expression, which may be primarily mediated by the 2-chloroacetic acid-activated Akt1 pathway.

  5. Chronic Opisthorchis viverrini Infection Changes the Liver Microbiome and Promotes Helicobacter Growth

    PubMed Central

    Itthitaetrakool, Upsornsawan; Pinlaor, Porntip; Pinlaor, Somchai; Chomvarin, Chariya; Dangtakot, Rungtiwa; Chaidee, Apisit; Wilailuckana, Chotechana; Sangka, Arunnee; Lulitanond, Aroonlug; Yongvanit, Puangrat

    2016-01-01

    Adults of Opisthorchis viverrini reside in the biliary system, inducing inflammation of bile ducts and cholangitis, leading to hepatobiliary disease (HBD) including cholangiocarcinoma. O. viverrini infection also has major implications for the bacterial community in bile ducts and liver. To investigate this in chronic O. viverrini infection (≥ 8 months p.i.), bacterial genomic DNA from livers of hamsters and from worms was investigated using culture techniques, PCR for Helicobacter spp. and high-throughput next-generation sequencing targeting the V3-V4 hypervariable regions of prokaryotic 16S rRNA gene. Of a total of 855,046 DNA sequence reads, 417,953 were useable after filtering. Metagenomic analyses assigned these to 93 operational taxonomic units (OTUs) consisting of 80 OTUs of bacteria, including 6 phyla and 42 genera. In the chronic O. viverrini-infected group, bacterial community composition and diversity were significantly increased compared to controls. Sequences of Fusobacterium spp. were the most common (13.81%), followed by Streptococcus luteciae (10.76%), Escherichia coli (10.18%), and Bifidobacterium spp. (0.58%). In addition, Helicobacter pylori (0.17% of sequences) was also identified in the liver of chronic O. viverrini infections, but not in normal liver. The presence of H. pylori was confirmed by PCR and by use of an antibody against bacterial antigen, supporting the metagenomics data. The identities of bacteria cultured for enrichment suggested that chronic O. viverrini infection changes the liver microbiome and promotes Helicobacter spp. growth. There may be synergy between O. viverrini and the liver microbiome in enhancing immune response-mediated hepatobiliary diseases. PMID:27806126

  6. Elastography in Chronic Liver Disease: Modalities, Techniques, Limitations, and Future Directions.

    PubMed

    Srinivasa Babu, Aparna; Wells, Michael L; Teytelboym, Oleg M; Mackey, Justin E; Miller, Frank H; Yeh, Benjamin M; Ehman, Richard L; Venkatesh, Sudhakar K

    2016-01-01

    Chronic liver disease has multiple causes, many of which are increasing in prevalence. The final common pathway of chronic liver disease is tissue destruction and attempted regeneration, a pathway that triggers fibrosis and eventual cirrhosis. Assessment of fibrosis is important not only for diagnosis but also for management, prognostic evaluation, and follow-up of patients with chronic liver disease. Although liver biopsy has traditionally been considered the reference standard for assessment of liver fibrosis, noninvasive techniques are the emerging focus in this field. Ultrasound-based elastography and magnetic resonance (MR) elastography are gaining popularity as the modalities of choice for quantifying hepatic fibrosis. These techniques have been proven superior to conventional cross-sectional imaging for evaluation of fibrosis, especially in the precirrhotic stages. Moreover, elastography has added utility in the follow-up of previously diagnosed fibrosis, the assessment of treatment response, evaluation for the presence of portal hypertension (spleen elastography), and evaluation of patients with unexplained portal hypertension. In this article, a brief overview is provided of chronic liver disease and the tools used for its diagnosis. Ultrasound-based elastography and MR elastography are explored in depth, including a brief glimpse into the evolution of elastography. Elastography is based on the principle of measuring tissue response to a known mechanical stimulus. Specific elastographic techniques used to exploit this principle include MR elastography and ultrasonography-based static or quasistatic strain imaging, one-dimensional transient elastography, point shear-wave elastography, and supersonic shear-wave elastography. The advantages, limitations, and pitfalls of each modality are emphasized. (©)RSNA, 2016.

  7. 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.

  8. Cardiopulmonary response to exercise in patients with liver cirrhosis and impaired pulmonary gas exchange.

    PubMed

    Lemyze, Malcolm; Dharancy, Sébastien; Nevière, Remy; Wallaert, Benoît

    2011-10-01

    Maximal exercise capacity and pulmonary gas exchange are both commonly impaired in liver cirrhosis. Apart from rare cases of hepatopulmonary syndrome, it is still unknown whether these moderate pulmonary gas exchange abnormalities can alter aerobic capacity of cirrhotic patients. Resting pulmonary function tests and symptom-limited cardiopulmonary exercise testing were prospectively investigated in 30 patients with liver cirrhosis exhibiting a widened alveolar-arterial oxygen gradient (P(A-a)O(2) > 30 mm Hg at peak exercise) without pulmonary vascular dilatations at contrast-enhanced echocardiography. Data were compared with those of 30 normoxemic cirrhotic controls (matched for age, gender, body mass index, etiology and severity of liver disease, smoking habits, hemoglobin level, and beta-blocker therapy). Resting cardiopulmonary parameters were within normal range in both groups except carbon monoxide lung transfer (TLCO, 60.4 ± 2.9 vs 74.3 ± 2.8% in controls, p = 0.0004) and P(A-a)O(2) (28.8 ± 2 vs 15.3 ± 2 mm Hg in controls, p < 0.0001). Cirrhotics with impaired gas exchange during exercise exhibited a significant reduction in maximal oxygen uptake (VO(2)max, 1.18 ± 0.07 (53% predicted) vs 1.41 ± 0.07 L/min (62% predicted), p = 0.004), a higher ventilation level at ventilatory threshold (V(E)/VO(2), 39.2 ± 1.5 vs 35.3 ± 1.5, p = 0.01) without ventilatory limitation, and a greater dead space to tidal volume ratio (V(D)/V(T)max, 0.32 ± 0.01 vs 0.25 ± 0.01, p = 0.01). VO(2)max correlates negatively with V(D)/V(T)max (r(2) = 0.36; p < 0.0001). There were no differences in cardiac or metabolic response to exercise between groups. Taken together these findings suggest that clinically undetectable pulmonary vascular disorders can slightly contribute to further reduce exercise capacity of cirrhotic patients.

  9. PNPLA3 polymorphism increases risk for and severity of chronic hepatitis C liver disease

    PubMed Central

    Salameh, Habeeb; Masadeh, Maen; Al Hanayneh, Muhannad; Petros, Vincent; Maslonka, Matthew; Nanda, Arjun; Singal, Ashwani K

    2016-01-01

    AIM To examine the association of PNPLA3 polymorphisms in chronic hepatitis C patients and development of liver disease spectrum. METHODS Literature was searched systematically from PubMed/MEDLINE, EMBASE, and Cochrane search engines for full-length articles written in English that examined PNPLA3 polymorphism in chronic hepatitis C (CHC) patients. Studies evaluating the association of PNPLA3 polymorphism spectrum (fatty liver, steatohepatitis, cirrhosis, and hepatocellular carcinoma) of CHC were included. Pooled data are reported as OR with 95%CI. Our study endpoint was the risk of the entire liver disease spectrum including: Steatosis/fatty liver, cirrhosis, and hepatocellular carcinoma in CHC patients with PNPLA3 polymorphisms. RESULTS Of 380 studies identified, a total of 53 studies were included for full-text review. Nineteen on chronic hepatitis C were eligible for analysis. Pooled ORs for rs738409 GG compared to CC and CG among patients with fatty liver was 2.214 (95%CI: 1.719-2.853). ORs among advanced fibrosis/cirrhosis were 1.762 (95%CI: 1.258-2.468). Similar odds ratios among hepatocellular carcinoma patients were 2.002 (95%CI: 1.519-2.639). Pooled ORs for rs738409 GG and CG compared to CC among patients with fatty liver were 1.750 (95%CI: 1.542-1.986). Pooled ORs for advanced fibrosis/cirrhosis patients were 1.613 (95%CI: 1.211-2.147). All analyses were homogenous and without publication bias except one. The associations were maintained after adjusting for publication bias and heterogeneity. CONCLUSION PNPLA3 polymorphisms have strong association with increased risk and severity of the liver disease spectrum in CHC patients. PMID:28050240

  10. Impaired resistance to Listeria monocytogenes in mice chronically exposed to cadmium.

    PubMed Central

    Simonet, M; Berche, P; Fauchere, J L; Veron, M

    1984-01-01

    It is shown in this work that resistance to Listeria monocytogenes is greatly impaired in C57BL/6 mice chronically exposed to cadmium (Cd) chloride. Animals received 0.5 mg/kg Cd by an intraperitoneal route three times a week during a 4-week period and were then infected with L. monocytogenes. Susceptibility to this pathogenic bacteria was not due to a defect of the specific immune response, since mice developed normal levels of anti-Listeria T cell-mediated immunity and did not show any impairment of macrophage activation. In fact, bacterial growth in organs was rapid in Cd-exposed mice during the early phase of infection, suggesting an impairment of non-specific defence mechanisms. Experimental data indicate that the susceptibility to L. monocytogenes might be due to a defect of macrophage recruitment in sites of infection during the early phase of the host response. PMID:6332063

  11. Increased susceptibility to liver injury after hemorrhagic shock in rats chronically fed ethanol: role of nuclear factor-kappa B, interleukin-6, and granulocyte colony-stimulating factor.

    PubMed

    Ono, Masafumi; Yu, Bi; Hardison, Edith G; Mastrangelo, Mary-Ann A; Tweardy, David J

    2004-06-01

    Chronic ethanol use preceding severe trauma and hemorrhagic shock (HS) is associated with an increased incidence of multiorgan failure (MOF) and death; however, the molecular basis for this increased susceptibility is unknown. We previously demonstrated that production of interleukin-6 (IL-6) and granulocyte colony-stimulating factor (G-CSF), mediated by nuclear factor-kappa B (NF-kappa B), each make essential contributions to organ injury and inflammation in a rodent model of controlled HS, and we proposed in this study to examine the hypothesis that the increased susceptibility to MOF after shock/trauma in the setting of chronic ethanol use is due to an exaggerated activation of NF-kappa B and production of these proinflammatory cytokines. We observed increased HS-induced liver injury 4 h after resuscitation in rats fed the ethanol-containing Lieber-DeCarli liquid diet for 8 weeks compared with rats fed the control liquid diet (3-fold increase in serum alanine aminotransferase [ALT], P = 0.008, and 2-fold increase in focal liver necrosis, P = 0.005). The increased liver injury in the ethanol-fed HS rats was accompanied by a 70% increase in liver NF-kappa B activation (P < 0.05), a 3- to 5-fold increase in hepatocyte and Kupffer cell production of IL-6 and G-CSF (P < 0.05 for each), and a 2-fold increase in neutrophil infiltration (P < 0.005) compared with the control diet-fed HS rats. Thus, increased susceptibility to HS-induced liver injury in the setting of chronic ethanol use may be mediated, at least in part, by increased NF-kappa B activation resulting in increased local production of IL-6 and G-CSF and increased infiltration of neutrophils, which can damage liver cells directly and contribute to impaired sinusoidal blood flow.

  12. Balance impairment limits ability to increase walking speed in individuals with chronic stroke.

    PubMed

    Middleton, Addie; Braun, Carty H; Lewek, Michael D; Fritz, Stacy L

    2017-03-01

    Purpose Determine the relationship between balance impairments and the ability to increase walking speed (WS) on demand in individuals with chronic stroke. Methods WS and Berg Balance Scale (BBS) data were collected on 124 individuals with chronic stroke (>6 months). The ability to increase WS on demand (walking speed reserve, WSR) was quantified as the difference between participants' self-selected (SSWS) and maximal (MWS) walking speeds. Correlation, regression and receiver operating characteristic (ROC) analyses were performed to investigate the relationship between balance and the ability to increase WS. Results Of sample, 58.9% were unable to increase WS on demand (WSR < 0.2 m/s). BBS scores were associated with WSR values (rs=0.74, 0.65-0.81) and were predictive of 'able/unable' to increase WS [odds ratio (OR) = 0.75, 0.67-0.84]. The AUC for the ROC curve constructed to assess the accuracy of BBS to discriminate between able/unable to increase WS was 0.85 (0.78-0.92). A BBS cutscore of 47 points was identified [sensitivity: 72.6%, specificity: 90.2%, +likelihood ratio (LR): 7.41, -LR: 0.30]. Conclusions The inability to increase WS on demand is common in individuals with chronic stroke, and balance appears to be a significant contributor to this difficulty. A BBS cutscore of 47 points can identify individuals who may benefit from balance interventions to improve the ability to increase their WS. Implications for Rehabilitation A majority of individuals with chronic stroke may be unable to increase their walking speed beyond their self-selected speed on demand. This may limit functional ambulation, as these individuals are walking "at capacity". Balance impairments contribute to the inability to increase walking speed. A Berg Balance Scale score <47 points can be used to identify individuals with chronic stroke walking "at capacity" due to balance impairments.

  13. Serum proinflammatory cytokines and nutritional status in pediatric chronic liver disease

    PubMed Central

    Santetti, Daniele; de Albuquerque Wilasco, Maria Inês; Dornelles, Cristina Toscani Leal; Werlang, Isabel Cristina Ribas; Fontella, Fernanda Urruth; Kieling, Carlos Oscar; dos Santos, Jorge Luiz; Vieira, Sandra Maria Gonçalves; Goldani, Helena Ayako Sueno

    2015-01-01

    AIM: To evaluate the nutritional status and its association with proinflammatory cytokines in children with chronic liver disease. METHODS: We performed a cross-sectional study with 43 children and adolescents, aged 0 to 17 years, diagnosed with chronic liver disease. All patients regularly attended the Pediatric Hepatology Unit and were under nutritional follow up. The exclusion criteria were fever from any etiology at the time of enrollment, inborn errors of the metabolism and any chronic illness. The severity of liver disease was assessed by Child-Pugh, Model for End-stage Liver Disease (MELD) and Pediatric End Stage Liver Disease (PELD) scores. Anthropometric parameters were height/age, body mass index/age and triceps skinfold/age according to World Health Organization standards. The cutoff points for nutritional status were risk of malnutrition (Z-score < -1.00) and malnutrition (Z-score < -2.00). Interleukin-1β (IL-1β), IL-6 and tumor necrosis factor-α levels were assessed by commercial ELISA kits. For multivariate analysis, linear regression was applied to assess the association between cytokine levels, disease severity and nutritional status. RESULTS: The median (25th-75th centile) age of the study population was 60 (17-116)-mo-old, and 53.5% were female. Biliary atresia was the main cause of chronic liver disease (72%). With respect to Child-Pugh score, cirrhotic patients were distributed as follows: 57.1% Child-Pugh A, a mild presentation of the disease, 34.3% Child-Pugh B, a moderate stage of cirrhosis and 8.6% Child-Pugh C, were considered severe cases. PELD and MELD scores were only above the cutoff point in 5 cases. IL-6 values ​​were increased in patients at nutritional risk (34.9%) compared with those who were well-nourished [7.12 (0.58-34.23) pg/mL vs 1.63 (0.53-3.43) pg/mL; P = 0.02], correlating inversely with triceps skinfold-for-age z-score (rs = -0.61; P < 0.001). IL-6 levels were associated with liver disease severity assessed by Child

  14. Chronic kidney disease accelerates cognitive impairment in a mouse model of Alzheimer's disease, through angiotensin II.

    PubMed

    Nakagawa, Takashi; Hasegawa, Yu; Uekawa, Ken; Kim-Mitsuyama, Shokei

    2017-01-01

    Epidemiological studies suggest that chronic kidney disease (CKD) is a significant risk factor in the development of cognitive decline. However, the exact role of CKD in cognitive impairment or dementia is unclear. This work was performed to examine the potential impact of CKD on cognitive impairment in Alzheimer's disease (AD), focusing on angiotensin II. (1) CKD was induced in 5XFAD mice, an AD model mouse, and wild-type mice by feeding an adenine-containing diet and the effect on cognitive function was compared between both strains. There was no significant difference regarding the severity of CKD induced by adenine between the strains. In 5XFAD mice, the CKD group exhibited significant cognitive impairment while the control group (control diet-fed group) did not, as evidenced by a passive avoidance test. On the other hand, in wild-type mice, neither the CKD group nor the control group showed cognitive impairment. Thus, CKD itself appears to accelerate cognitive impairment in AD mice. (2) We also examined the effect of olmesartan, an angiotensin II receptor blocker, on 5XFAD mice with CKD to elucidate the potential involvement of angiotensin II. As evidenced by the findings of the water maze test, olmesartan treatment significantly ameliorated the impairment of spatial learning and memory function induced by CKD in 5XFAD mice. Olmesartan treatment significantly ameliorated blood-brain barrier (BBB) disruption induced by CKD in 5XFAD mice. Furthermore, olmesartan reduced hippocampal oxidative stress in 5XFAD with CKD to similar levels to the control group of 5XFAD fed standard diet. Hence, the amelioration of CKD-induced cognitive impairment in 5XFAD mice by olmesartan appears to be mediated by the suppression of BBB disruption or oxidative stress. In conclusion, we obtained the evidence suggesting that CKD itself accelerates cognitive impairment in AD mice, through angiotensin II. Thus, our work provides a novel insight into the underlying mechanism of the link

  15. Small hepatocellular carcinomas in chronic liver disease: Detection with SPECT

    SciTech Connect

    Kudo, M.; Hirasa, M.; Takakuwa, H.; Ibuki, Y.; Fujimi, K.; Miyamura, M.; Tomita, S.; Komori, H.; Todo, A.; Kitaura, Y.

    1986-06-01

    Single-photon emission computed tomography (SPECT) performed using a rotating gamma camera was compared with ..cap alpha../sub 1/-fetoprotein (AFP) assay, conventional liver scintigraphy, ultrasound (US) imaging, computed tomography (CT), and selective celiac angiography in 40 patients with a total of 50 small hepatocellular carcinomas (HCCs;<5 cm). The detection rates of US and CT were determined on an initial screening study and on a second, more precisely focused study. The detection rate of small HCCs by the various modalities was as follows: AFP, 13%; liver scintigraphy, 36%; SPECT, 72%; initial screening US, 80%; second, more precise US studies, 94%; initial screening CT, 64%; second, more precise CT study, 82%; angiography, 88%. Although SPECT was inferior to the initial screening US examination in detecting HCCs less than 2 cm in size, its sensitivity was identical to that of the initial screening US study for detecting HCCs of 2-5 cm. The combination of SPECT and US was an excellent method for the early detection of HCCs, yielding a detection rate of 94%.

  16. Caffeine prevents cognitive impairment induced by chronic psychosocial stress and/or high fat-high carbohydrate diet.

    PubMed

    Alzoubi, K H; Abdul-Razzak, K K; Khabour, O F; Al-Tuweiq, G M; Alzubi, M A; Alkadhi, K A

    2013-01-15

    Caffeine alleviates cognitive impairment associated with a variety of health conditions. In this study, we examined the effect of caffeine treatment on chronic stress- and/or high fat-high carbohydrate Western diet (WD)-induced impairment of learning and memory in rats. Chronic psychosocial stress, WD and caffeine (0.3 g/L in drinking water) were simultaneously administered for 3 months to adult male Wistar rats. At the conclusion of the 3 months, and while the previous treatments continued, rats were tested in the radial arm water maze (RAWM) for learning, short-term and long-term memory. This procedure was applied on a daily basis to all animals for 5 consecutive days or until the animal reaches days to criterion (DTC) in the 12th learning trial and memory tests. DTC is the number of days that the animal takes to make zero error in two consecutive days. Chronic stress and/or WD groups caused impaired learning, which was prevented by chronic caffeine administration. In the memory tests, chronic caffeine administration also prevented memory impairment during chronic stress conditions and/or WD. Furthermore, DTC value for caffeine treated stress, WD, and stress/WD groups indicated that caffeine normalizes memory impairment in these groups. These results showed that chronic caffeine administration prevented stress and/or WD-induced impairment of spatial learning and memory.

  17. Transketolase-TPP-effect in chronic alcoholics with various degrees of liver cirrhosis.

    PubMed

    Somogyi, J C; Kopp, P M; Filippini, L; Monnat, A

    1980-01-01

    A re-investigation of the use of the transketolase-TPP-effect for the assessment of the thiamine status of chronic alcoholics with various degrees of liver cirrhosis was carried out on 36 alcoholics. The extent of the liver damage in these patients was established by clinical examinations and biochemical tests. Fourteen persons showed no significant hepatic abnormalities, 5 patients had compensated liver cirrhosis, 7 slightly decompensated, and 10 patients suffered from severely decompensated liver cirrhosis. This investigation shows that the transketolase-TPP-effect is also present in patients even with severe liver cirrhosis and that a decrease of the TPP-effect can be observed after oral thiamine administration in these subjects. The TPP-effect of patients with compensated liver cirrhosis was markedly smaller than that of the subjects with slightly or severely decompensated cirrhosis. Accordingly a relationship exists between the TPP-effect and the degree of liver damage. No other correlations however could be established in this respect.

  18. Fructose supplementation impairs rat liver autophagy through mTORC activation without inducing endoplasmic reticulum stress.

    PubMed

    Baena, Miguel; Sangüesa, Gemma; Hutter, Natalia; Sánchez, Rosa M; Roglans, Núria; Laguna, Juan C; Alegret, Marta

    2015-02-01

    Supplementation with 10% liquid fructose to female rats for 2weeks caused hepatic steatosis through increased lipogenesis and reduced peroxisome proliferator activated receptor (PPAR) α activity and fatty acid catabolism, together with increased expression of the spliced form of X-binding protein-1 (Rebollo et al., 2014). In the present study, we show that some of these effects are preserved after sub-chronic (8weeks) fructose supplementation, specifically increased hepatic expression of lipid synthesis-related genes (stearoyl-CoA desaturase, ×6.7-fold; acetyl-CoA carboxylase, ×1.6-fold; glycerol-3-phosphate acyltransferase, ×1.65-fold), and reduced fatty acid β-oxidation (×0.77-fold), resulting in increased liver triglyceride content (×1.69-fold) and hepatic steatosis. However, hepatic expression of PPARα and its target genes was not modified and, further, livers of 8-week fructose-supplemented rats showed no sign of unfolded protein response activation, except for an increase in p-IRE1 levels. Hepatic mTOR phosphorylation was enhanced (×1.74-fold), causing an increase in the phosphorylation of UNC-51-like kinase 1 (ULK-1) (×2.8-fold), leading to a decrease in the ratio of LC3B-II/LC3B-I protein expression (×0.39-fold) and an increase in the amount of the autophagic substrate p62, indicative of decreased autophagy activity. A harmful cycle may be established in the liver of 8-week fructose-supplemented rats where lipid accumulation may cause defective autophagy, and reduced autophagy may result in decreased free fatty acid formation from triglyceride depots, thus reducing the substrates for β-oxidation and further increasing hepatic steatosis. In summary, the length of supplementation is a key factor in the metabolic disturbances induced by fructose: in short-term studies, PPARα inhibition and ER stress induction are critical events, whereas after sub-chronic supplementation, mTOR activation and autophagy inhibition are crucial.

  19. Brain impairment in well-nourished chronic alcoholics is related to ethanol intake.

    PubMed

    Nicolás, J M; Estruch, R; Salamero, M; Orteu, N; Fernandez-Solà, J; Sacanella, E; Urbano-Márquez, A

    1997-05-01

    To determine the influence of chronic ethanol intake on the central nervous system, we studied 40 asymptomatic, well-nourished, chronic alcoholics (mean age, 42.6 +/- 9.1 years) and 20 age-, sex-, and education-matched control subjects. Studies included neuropsychological testing, visual and short-latency auditory evoked potentials, and morphometric analysis of computed tomography scans. The mean daily ethanol consumption of the alcoholics was 204 gm over an average of 26.4 years. Compared to control subjects, chronic alcoholics exhibited a significant prolongation of the P100 latency of visual evoked potentials, and a prolongation and reduction in the amplitude of the latency of the V wave of short-latency auditory evoked potentials. These abnormalities were related to the lifetime dose of ethanol consumed. Brain morphometric analysis showed that alcoholics had a significantly greater degree of brain shrinkage with age, compared to control subjects. The cortical atrophy index correlated significantly with the lifetime ethanol consumption. Neuropsychological testing in alcoholics compared to controls revealed a significant impairment of frontal skills that was related to age, degree of scholarship, and the presence of frontal atrophy. In conclusion, well-nourished chronic alcoholics exhibited significant brain impairment, as demonstrated by neuropsychological testing, evoked potentials, and brain morphometric analysis, which was correlated with the lifetime dose of ethanol consumed.

  20. Impaired contractility of colonic muscle cells in a patient with chronic intestinal pseudo-obstruction.

    PubMed

    Guarino, M P L; Carotti, S; Cogliandro, R; Stanghellini, V; De Giorgio, R; Barbara, G; Alloni, R; Altomare, A; Tarquini, E; Coppola, R; Corinaldesi, R; Cicala, M

    2008-03-01

    Chronic intestinal pseudo-obstruction represents a cause of persistent functional intestinal failure either "secondary" to specific conditions or "chronic intestinal idiopathic pseudo-obstruction" in origin. The diagnosis is mainly clinical, supported by radiological and/or endoscopic findings excluding any mechanical cause of intestinal obstruction. We reported a case of a 39-year-old woman with chronic intestinal idiopathic pseudo-obstruction, who underwent colectomy with ileorectal anastomosis; histological examination of the surgical specimen did not reveal myogenic or neurogenic defects or other pathological abnormalities indicative of an underlying neuromuscular impairment. Because of the apparent integrity of the gut neuromuscular layer, we tested whether a functional impairment affected colonic single smooth muscle cells. Muscle cells were isolated from the right colon and their contractile response to a receptor-dependent agonist evaluated in comparison to that obtained from controls. The cell contraction induced by acetylcholine in a dose response manner was markedly decreased in the patient affected by chronic intestinal idiopathic pseudo-obstruction compared with cells from controls (percentage of cell shortening with maximal dose of acetylcholine [10(-6)M]: 10.7+/-3% versus 34.2+/-4%, respectively). The present findings indicate a specific defect of colonic smooth muscle cells likely related to an ineffective response to acetylcholine.

  1. Expression and function of the atypical cadherin FAT1 in chronic liver disease

    SciTech Connect

    Valletta, Daniela; Czech, Barbara; Thasler, Wolfgang E.; Mueller, Martina; Bosserhoff, Anja-Katrin; Hellerbrand, Claus

    2012-09-28

    Highlights: Black-Right-Pointing-Pointer The expression of the atypical cadherin FAT1 is increased in chronic liver disease. Black-Right-Pointing-Pointer FAT1 expression goes up during the activation of hepatic stellate cells (HSCs). Black-Right-Pointing-Pointer Activated HSCs are the cellular source of enhanced FAT1 expression in diseased livers. Black-Right-Pointing-Pointer FAT1 enhanced NFkB activity and resistance to apoptosis in activated HSCs. Black-Right-Pointing-Pointer FAT1 is a new therapeutic target for prevention and treatment of hepatic fibrosis. -- Abstract: Hepatic fibrosis can be considered as wound healing process in response to hepatocellular injury. Activation of hepatic stellate cells (HSCs) is a key event of hepatic fibrosis since activated HSCs are the cellular source of enhanced extracellular matrix deposition, and reversion of liver fibrosis is accompanied by clearance of activated HSCs by apoptosis. The atypical cadherin FAT1 has been shown to regulate diverse biological functions as cell proliferation and planar cell polarity, and also to affect wound healing. Here, we found increased FAT1 expression in different murine models of chronic liver injury and in cirrhotic livers of patients with different liver disease. Also in hepatic tissue of patients with non-alcoholic steatohepatitis FAT1 expression was significantly enhanced and correlated with collagen alpha I(1) expression. Immunohistochemistry revealed no significant differences in staining intensity between hepatocytes in normal and cirrhotic liver tissue but myofibroblast like cells in fibrotic septa of cirrhotic livers showed a prominent immunosignal. Furthermore, FAT1 mRNA and protein expression markedly increased during in vitro activation of primary human and murine HSCs. Together, these data indicated activated HSCs as cellular source of enhanced FAT1 expression in diseased livers. To gain insight into the functional role of FAT1 in activated HSCs we suppressed FAT1 in these

  2. Colchicine reduces procollagen III and increases pseudocholinesterase in chronic liver disease

    PubMed Central

    Muntoni, Sergio; Rojkind, Marcos; Muntoni, Sandro

    2010-01-01

    AIM: To test whether colchicine would be an effective antifibrotic agent for treatment of chronic liver diseases in patients who could not be treated with α-interferon. METHODS: Seventy-four patients (46 males, 28 females) aged 40-66 years (mean 53 ± 13 years) participated in the study. The patients were affected by chronic liver diseases with cirrhosis which was proven histologically (n = 58); by chronic active hepatitis C (n = 4), chronic active hepatitis B (n = 2), and chronic persistent hepatitis C (n = 6). In the four patients lacking histology, cirrhosis was diagnosed from anamnesis, serum laboratory tests, esophageal varices and ascites. Patients were assigned to colchicine (1 mg/d) or standard treatment as control in a randomized, double-blind trial, and followed for 4.4 years with clinical and laboratory evaluation. RESULTS: Survival at the end of the study was 94.6% in the colchicine group and 78.4% in the control group (P = 0.001). Serum N-terminal peptide of type III procollagen levels fell from 34.0 to 18.3 ng/mL (P = 0.0001), and pseudocholinesterase levels rose from 4.900 to 5.610 mU/mL (P = 0.0001) in the colchicine group, while no significant change was seen in controls. Best results were obtained in patients with chronic hepatitis C and in alcoholic cirrhotics. CONCLUSION: Colchicine is an effective and safe antifibrotic drug for long-term treatment of chronic liver disease in which fibrosis progresses towards cirrhosis. PMID:20556834

  3. Liver regeneration after partial hepatectomy in rat is more impaired in a steatotic liver induced by dietary fructose compared to dietary fat

    SciTech Connect

    Tanoue, Shirou; Uto, Hirofumi; Kumamoto, Ryo; Arima, Shiho; Hashimoto, Shinichi; Nasu, Yuichiro; Takami, Yoichiro; Moriuchi, Akihiro; Sakiyama, Toshio; Oketani, Makoto; Ido, Akio; Tsubouchi, Hirohito

    2011-04-01

    Highlights: {yields} Hepatic steatosis in rats fed a high fructose diet was less severe than that in rats fed a high fat diet. {yields} Liver regeneration was more impaired in rats fed a high fructose diet than in rats fed a high fat diet. {yields} Dysregulation of genes associated with metabolism may contribute to impairment of liver regeneration. {yields} Regulation of the TGF-{beta}1 level after partial hepatectomy may be impaired in rats fed a high fructose diet. -- Abstract: Hepatic steatosis (HS) has a negative effect on liver regeneration, but different pathophysiologies of HS may lead to different outcomes. Male Sprague-Dawley rats were fed a high fructose (66% fructose; H-fruc), high fat (54% fat; H-fat), or control chow diet for 4 weeks. Based on hepatic triglyceride content and oil red O staining, HS developed in the H-fruc group, but was less severe compared to the H-fat group. Hepatic mRNA expression levels of fatty acid synthase and fructokinase were increased and those of carnitine palmitoyltransferase-1 and peroxisome proliferator-activated receptor-{alpha} were decreased in the H-fruc group compared to the H-fat group. Liver regeneration after 70% partial hepatectomy (PHx) was evaluated by measuring the increase in postoperative liver mass and PCNA-positive hepatocytes, and was impaired in the H-fruc group compared to the H-fat and control groups on days 3 and 7. Serum levels of tumor necrosis factor-{alpha}, interleukin-6 and hepatocyte growth factor did not change significantly after PHx. In contrast, serum TGF-{beta}1 levels were slightly but significantly lower in the control group on day 1 and in the H-fat group on day 3 compared to the level in each group on day 0, and then gradually increased. However, the serum TGF-{beta}1 level did not change after PHx in the H-fruc group. These results indicate that impairment of liver regeneration after PHx in HS is related to the cause, rather than the degree, of steatosis. This difference may result

  4. Liver and kidney lesions and associated enzyme changes induced in rabbits by chronic cyanide exposure.

    PubMed

    Okolie, N P; Osagie, A U

    1999-07-01

    The effect of prolonged chronic cyanide exposure on liver and kidney integrity, as well as some associated enzyme and metabolite changes, were investigated in New Zealand white rabbits (initial mean weight 1.52 kg) using a combination of colorimetric, spectrophotometric, enzymatic, gravimetric and histological procedures. Two groups of rabbits were fed for 40 weeks on either pure growers' mash or growers' mash containing 702 ppm inorganic cyanide. Results obtained indicate that the cyanide-fed rabbits had significantly decreased liver activities of alkaline phosphatase, glutamate pyruvate transaminase and sorbitol dehydrogenase relative to controls (P<0.05). On the other hand, there were significant increases (P<0.05) in the serum activities of these enzymes in the cyanide-treated group. Kidney alkaline phosphatase activity was significantly decreased (P<0.05), while serum urea and creatinine were significantly higher (P<0.05) in the cyanide group relative to controls. The cyanide treatment led to significant increases in both tissue and serum activities of lactate dehydrogenase. In addition, liver and kidney rhodanese activities were significantly raised in the cyanide-fed group. There were marked degenerative changes in the liver and kidney sections from the cyanide-treated rabbits. These results suggest that chronic cyanide exposure may be deleterious to liver and kidney functions.

  5. Selective protein depletion impairs bone growth and causes liver fatty infiltration in female rats: prevention by Spirulina alga.

    PubMed

    Fournier, C; Rizzoli, R; Bouzakri, K; Ammann, P

    2016-11-01

    Chronic protein malnutrition leads to child mortality in developing countries. Spirulina alga (Spi), being rich in protein and growing easily, is a good candidate as supplementation. We showed that Spi completely prevents bone growth retardation and liver disturbances observed in young rats fed a low protein diet. This supports Spi as a useful source of vegetable protein to fight against protein malnutrition.

  6. Chronic overexpression of PNPLA3I148M in mouse liver causes hepatic steatosis

    PubMed Central

    Li, John Zhong; Huang, Yongcheng; Karaman, Ruchan; Ivanova, Pavlina T.; Brown, H. Alex; Roddy, Thomas; Castro-Perez, Jose; Cohen, Jonathan C.; Hobbs, Helen H.

    2012-01-01

    A genetic variant in PNPLA3 (PNPLA3I148M), a triacylglycerol (TAG) hydrolase, is a major risk factor for nonalcoholic fatty liver disease (NAFLD); however, the mechanism underlying this association is not known. To develop an animal model of PNPLA3-induced fatty liver disease, we generated transgenic mice that overexpress similar amounts of wild-type PNPLA3 (PNPLA3WT) or mutant PNPLA3 (PNPLA3I148M) either in liver or adipose tissue. Overexpression of the transgenes in adipose tissue did not affect liver fat content. Expression of PNPLA3I148M, but not PNPLA3WT, in liver recapitulated the fatty liver phenotype as well as other metabolic features associated with this allele in humans. Metabolic studies provided evidence for 3 distinct alterations in hepatic TAG metabolism in PNPLA3I148M transgenic mice: increased formation of fatty acids and TAG, impaired hydrolysis of TAG, and relative depletion of TAG long-chain polyunsaturated fatty acids. These findings suggest that PNPLA3 plays a role in remodeling TAG in lipid droplets, as they accumulate in response to food intake, and that the increase in hepatic TAG levels associated with the I148M substitution results from multiple changes in hepatic TAG metabolism. The development of an animal model that recapitulates the metabolic phenotype of the allele in humans provides a new platform in which to elucidate the role of PNLPA3I148M in NAFLD. PMID:23023705

  7. Dynamic Adaptation of Liver Mitochondria to Chronic Alcohol Feeding in Mice

    PubMed Central

    Han, Derick; Ybanez, Maria D.; Johnson, Heather S.; McDonald, Jeniece N.; Mesropyan, Lusine; Sancheti, Harsh; Martin, Gary; Martin, Alanna; Lim, Atalie M; Dara, Lily; Cadenas, Enrique; Tsukamoto, Hidekazu; Kaplowitz, Neil

    2012-01-01

    Liver mitochondria undergo dynamic alterations following chronic alcohol feeding to mice. Intragastric alcohol feeding to mice resulted in 1) increased state III respiration (109% compared with control) in isolated liver mitochondria, probably due to increased levels of complexes I, IV, and V being incorporated into the respiratory chain; 2) increased mitochondrial NAD+ and NADH levels (∼2-fold), with no change in the redox status; 3) alteration in mitochondrial morphology, with increased numbers of elongated mitochondria; and 4) enhanced mitochondrial biogenesis in the liver, which corresponded with an up-regulation of PGC-1α (peroxisome proliferator-activated receptor γ coactivator-1α). Oral alcohol feeding to mice, which is associated with less liver injury and steatosis, slightly enhanced respiration in isolated liver mitochondria (30.8% compared with control), lower than the striking increase caused by intragastric alcohol feeding. Mitochondrial respiration increased with both oral and intragastric alcohol feeding despite extensive N-acetylation of mitochondrial proteins. The alcohol-induced mitochondrial alterations are probably an adaptive response to enhance alcohol metabolism in the liver. Isolated liver mitochondria from alcohol-treated mice had a greater rate of acetaldehyde metabolism and respiration when treated with acetaldehyde than control. Aldehyde dehydrogenase-2 levels were unaltered in response to alcohol, suggesting that the greater acetaldehyde metabolism by isolated mitochondria from alcohol-treated mice was due to increased mitochondrial respiration that regenerated NAD+, the rate-limiting substrate in alcohol/acetaldehyde metabolism. Overall, our work suggests that mitochondrial plasticity in the liver may be an important adaptive response to the metabolic stress caused by alcohol intake and could potentially play a role in many other vital functions performed by the liver. PMID:23086958

  8. Reelin Expression in Human Liver of Patients with Chronic Hepatitis C Infection

    PubMed Central

    Carotti, Simone; Perrone, Giuseppe; Amato, Michelina; Gentilucci, Umberto Vespasiani; Righi, Daniela; Francesconi, Maria; Pellegrini, Claudio; Zalfa, Francesca; Zingariello, Maria; Picardi, Antonio; Muda, Andrea Onetti; Morini, Sergio

    2017-01-01

    Reelin is a secreted extracellular glyco-protein that plays a critical role during brain development. Several studies have described Reelin expression in hepatic stellate cells of the human liver. In order to investigate the possible role of Reelin in the process of hepatic fibrogenesis, in this study we investigated Reelin expression in the liver tissue of patients infected with the Hepatitis C Virus (HCV). On this basis, Reelin expression was analysed by immunohistochemistry during liver biopsies of 81 patients with HCV-related chronic hepatitis. A Knodell score was used to stage liver fibrosis. Hepatic stellate cells/myofibroblast immunohistochemical markers (CRBP-1, alpha-SMA) were also evaluated. As further confirmed by colocalization experiments (Reelin +CRBP-1), Reelin protein was expressed by hepatic stellate cells/myofibroblasts, and a significant positive correlation was found between Reelin expression and the stage of liver fibrosis (P=0.002). Moreover, Reelin correlated with CRBP-1 positive cells (P=0.002), but not with alpha-SMA, suggesting that Reelin should not be regarded as a marker of hepatic stellate cells/myofibroblasts differentiation but rather as a functional protein expressed during some phases of liver fibrosis. Furthermore, Disabled-1 (Dab1), a Reelin adaptor protein, was expressed in cells of ductular reaction suggesting a paracrine role for Reelin with regards these elements. In conclusion, Reelin was expressed by human hepatic stellate cells/myofibroblasts and the number of these cells increased significantly in the lobule as the liver fibrosis progressed, suggesting a role for Reelin in the activation of hepatic stellate cells/myofibroblasts during liver injury. Reelin may potentially be incorporated into liver injury evaluations in combination with other histological data. PMID:28348420

  9. Chronic stress impairs prefrontal cortex-dependent response inhibition and spatial working memory.

    PubMed

    Mika, Agnieszka; Mazur, Gabriel J; Hoffman, Ann N; Talboom, Joshua S; Bimonte-Nelson, Heather A; Sanabria, Federico; Conrad, Cheryl D

    2012-10-01

    Chronic stress leads to neurochemical and structural alterations in the prefrontal cortex (PFC) that correspond to deficits in PFC-mediated behaviors. The present study examined the effects of chronic restraint stress on response inhibition (using a response-withholding task, the fixed-minimum interval schedule of reinforcement, or FMI), and working memory (using a radial arm water maze, RAWM). Adult male Sprague-Dawley rats were first trained on the RAWM and subsequently trained on FMI. After acquisition of FMI, rats were assigned to a restraint stress (6h/d/28d in wire mesh restrainers) or control condition. Immediately after chronic stress, rats were tested on FMI and subsequently on RAWM. FMI results suggest that chronic stress reduces response inhibition capacity and motivation to initiate the task on selective conditions when sucrose reward was not obtained on the preceding trial. RAWM results suggest that chronic stress produces transient deficits in working memory without altering previously consolidated reference memory. Behavioral measures from FMI failed to correlate with metrics from RAWM except for one in which changes in FMI timing imprecision negatively correlated with changes in RAWM working memory errors for the controls, a finding that was not observed following chronic stress. Fisher's r-to-z transformation revealed no significant differences between control and stress groups with correlation coefficients. These findings are the first to show that chronic stress impairs both response inhibition and working memory, two behaviors that have never been directly compared within the same animals after chronic stress, using FMI, an appetitive task, and RAWM, a nonappetitive task.

  10. Age exacerbates chronic catecholamine-induced impairments in contractile reserve in the rat.

    PubMed

    Liles, John T; Ida, Kevin K; Joly, Kristin M; Chapo, Joseph; Plato, Craig F

    2011-08-01

    Contractile reserve decreases with advancing age and chronic isoproterenol (ISO) administration is a well-characterized model of cardiac hypertrophy known to impair cardiovascular function. This study evaluated whether nonsenescent, mature adult rats are more susceptible to detrimental effects of chronic ISO administration than younger adult rats. Rats received daily injections of ISO (0.1 mg/kg sc) or vehicle for 3 wk. ISO induced a greater impairment in contractile reserve [maximum of left ventricular pressure development (Δ+dP/dt(max))] in mature adult ISO-treated (MA-ISO) than in young adult ISO-treated rats (YA-ISO) in response to infusions of mechanistically distinct inotropes (digoxin, milrinone; 20-200 μl·kg(-1)·min(-1)), while basal and agonist-induced changes in heart rate and systolic arterial pressure (SAP) were not different across groups. ISO decreased expression of the calcium handling protein, sarco(endo)plasmic reticulum Ca(2+)-ATPase-2a, in MA-ISO compared with YA, YA-ISO, and MA rats. Chronic ISO also induced greater increases in cardiac hypertrophy [left ventricular (LV) index: 33 ± 3 vs. 22 ± 5%] and caspase-3 activity (34 vs. 5%) in MA-ISO relative to YA-ISO rats. Moreover, β-myosin heavy chain (β-MHC) and atrial natriuretic factor (ANF) mRNA expression was significantly elevated in MA-ISO. These results demonstrate that adult rats develop greater impairments in systolic performance than younger rats when exposed to chronic catecholamine excess. Reduced contractile reserve may result from calcium dysregulation, increased caspase-3 activity, or increased β-MHC and ANF expression. Although several studies report age-related declines in systolic performance in older and senescent animals, the present study demonstrates that catecholamine excess induces reductions in systolic performance significantly earlier in life.

  11. Removal of bile acids by two different extracorporeal liver support systems in acute-on-chronic liver failure.

    PubMed

    Stadlbauer, Vanessa; Krisper, Peter; Beuers, Ulrich; Haditsch, Bernd; Schneditz, Daniel; Jung, Aleksandra; Putz-Bankuti, Csilla; Holzer, Herwig; Trauner, Michael; Stauber, Rudolf E

    2007-01-01

    Acute-on-chronic liver failure (ACLF) is accompanied by marked intrahepatic cholestasis leading to accumulation of cytotoxic bile acids. Extracorporeal liver support systems efficiently remove bile acids, but their effect on bile acid composition in ACLF is unknown. The aim of the present study was to compare elimination of individual plasma bile acids by albumin dialysis (Molecular Adsorbents Recirculating System, MARS) and fractionated plasma separation (Prometheus). Eight consecutive patients with ACLF underwent alternating 6-hour sessions with MARS or Prometheus in a randomized, cross-over design. Serum samples were obtained before, during, and after each treatment, and individual bile acids including cholic acid and chenodeoxycholic acid (CDCA) were measured by gas chromatography. MARS and Prometheus removed total bile acids to a similar extent (reduction ratio, 45% and 46%, respectively). Both devices cleared cholic acid more efficiently than did CDCA. The molar fraction of CDCA (fCDCA) was elevated at baseline and correlated with the degree of liver dysfunction. Prometheus but not MARS treatments further increased fCDCA. Although both devices eliminate total bile acids to a similar extent, clearance of individual bile acids is different, leading to a slight change of the bile acid profile toward hydrophobic bile acids during Prometheus treatments.

  12. Treatment of chronic hepatitis C in liver transplant candidates and recipients: Where do we stand?

    PubMed Central

    Pipili, Chrysoula; Cholongitas, Evangelos

    2015-01-01

    The first generation direct antiviral agents (DAAs) highlighted substantial prognosis improvement among liver transplant (LT) candidates and recipients with recurrent hepatitis C virus (HCV) infection. During 2014, second generation DAAs are associated with high sustained virological response rates (> 95%), shortened duration courses and relatively few toxicities. In keeping with the currently available data, patients with decompensated cirrhosis awaiting LT is preferable to be treated with interferon-free, new generation DAAs, with or without ribavirin combinations. Although data about the safety of new DAAs combinations in this patient population are limited, sofosbuvir and daclatasvir pharmacokinetics do not appear to change significantly in moderate or severe liver impairment, while other new DAAs (simeprevir, asunaprevir) seem to be contraindicated in patients with severe liver impairment (Child-Pugh class C). On the other hand, sofosbuvir should not be given in patients with glomerular filtration rate ≤ 30 mL/min, but ongoing trials will clarify better this issue. With the objective that newer antiviral combinations will yield safer and more efficient manipulation of HCV recurrence post-transplant, the European Association for the Study of the Liver has recently updated its recommendations towards this direction. Nevertheless the new antivirals’ high cost may be the biggest challenge to their implementation worldwide. PMID:26140081

  13. Impairment and Coping in Children and Adolescents with Chronic Fatigue Syndrome: A Comparative Study with Other Paediatric Disorders

    ERIC Educational Resources Information Center

    Garralda, M. Elena; Rangel, Luiza

    2004-01-01

    Background: Functional impairment is a key feature of chronic fatigue syndrome (CFS) of childhood. Aim: To compare impairment, illness attitudes and coping mechanisms in childhood CFS and in other paediatric disorders. Method: Participants were 28 children and adolescents with CFS, 30 with juvenile idiopathic arthritis (JIA) and 27 with emotional…

  14. Circulating vascular endothelial growth factor and its soluble receptors in patients with liver cirrhosis: possible association with hepatic function impairment.

    PubMed

    Jaroszewicz, Jerzy; Januszkiewicz, Marcin; Flisiak, Robert; Rogalska, Magdalena; Kalinowska, Alicja; Wierzbicka, Iwona

    2008-10-01

    Recent studies provided in vivo evidences of an increased angiogenesis in animal model of portal hypertension and cirrhosis which was linked to increased expression of vascular endothelial growth factor. The aim of study was to evaluate the plasma concentration of VEGF and its receptors in liver cirrhosis and the possible association with the degree of liver insufficiency. Methods. Vascular endothelial growth factor (VEGF) and its soluble receptors: sVEGF-R1, sVEGF-R2 were measured in plasma of 78 patients with liver cirrhosis by ELISA. Results. The significant increase of plasma VEGF and sVEGF-R1 was observed in liver cirrhosis compared to healthy individuals (153.1+/-51.9 vs. 46.8+/-4.1pg/mL, P<0.05; 279.8+/-34.3 vs. 105.1+/-5.9pg/mL, P<0.001, respectively). Plasma VEGF and foremost sVEGF R1 showed significant associations with biochemical indices of liver function. Among clinical parameters, only ascites revealed significant association with plasma VEGR and sVEGF-R1. VEGF and sVEGF-R1 were increased respectively to the degree of liver insufficiency. It was demonstrated through a significant positive correlation with Child-Pugh score and MELD classification. In conclusion, our study suggests that serum VEGF and VEGF-R1 may reflect the hepatic function impairment in liver cirrhosis and seems to be associated with portal hypertension symptoms.

  15. 5-Fluorouracil catabolism to 5-fluoro-5,6-dihydrouracil is reduced by acute liver impairment in mice

    SciTech Connect

    Innocenti, Federico; Danesi, Romano; Bocci, Guido; Natale, Gianfranco . E-mail: gianfranco.natale@anist.med.unipi.it; Del Tacca, Mario

    2005-03-01

    This study investigated the effect of acute liver damage on the inactivation of 5-fluorouracil (5-FU) to its main catabolite 5-fluoro-5,6-dihydrouracil (5-FUH{sub 2}) in mice. Plasma pharmacokinetics of 5-FU and 5-FUH{sub 2} in mice receiving 5-FU (10, 30, and 90 mg/kg) were compared to those in mice pretreated with carbon tetrachloride and receiving the same 5-FU doses. Carbon tetrachloride-induced hepatic damage was histopathologically examined under light microscopy and serum transaminases and dihydropyrimidine dehydrogenase activities were also measured. Liver histopathology and elevated aminotransferase activity levels confirmed the presence of liver damage. 5-FU C{sub max} and AUC both increased up to 71% in mice with liver damage. This was reflected by decreased 5-FUH{sub 2} production, since 5-FUH{sub 2} C{sub max} and AUC levels decreased up to 47% and 61%, respectively. Metabolic ratios between 5-FUH{sub 2} and 5-FU AUCs were considerably decreased as well, further suggesting that liver damage caused a reduction in 5-FU catabolism. DPD activity was not altered in damaged livers. The present results indicate that 5-FU disposition in mice could be profoundly altered in the presence of severe liver impairment, potentially leading to enhanced anabolic activation of 5-FU. This effect seems to be ascribed to a reduction of viable hepatocytes, rather than to an inactivation of DPD activity.

  16. Acute kidney injury in patients with chronic liver disease

    PubMed Central

    Rognant, Nicolas

    2015-01-01

    Acute kidney injury (AKI) is a frequent clinical event in patients with liver disease, compounding their prognosis. Furthermore, it is likely that the occurrence of AKI has a detrimental impact on the subsequent renal function and the long-term survival of these patients. Recently, some authors advocated the use of new diagnostic criteria for detecting acute kidney injury in patients with cirrhosis. These criteria are based on the rapidity and extent of the creatinine increase comparing to the basal creatinine and also on the kinetics of diuresis decrease. Although their validity in this population requires further studies to be clearly established, these new criteria could have two advantages: (1) to allow earlier diagnosis of AKI and, thus, hepatorenal syndrome for which earlier intervention could improve patients’ survival; and (2) to promote more intensive monitoring of renal function in these patients with high risk of AKI. Finally, recent practice guidelines about the prevention and treatment of general AKI have been published which should be useful in optimising the management of AKI in cirrhotic patients. PMID:25954481

  17. Association between chronic liver and colon inflammation during the development of murine syngeneic graft-versus-host disease

    PubMed Central

    Brandon, J. Anthony; Perez, Jacqueline; Jennings, C. Darrell; Cohen, Donald A.; Sindhava, V. J.; Bondada, S.; Kaplan, Alan M.

    2010-01-01

    The murine model of cyclosporine A (CsA)-induced syngeneic graft-versus-host disease (SGVHD) is a bone marrow (BM) transplantation model that develops chronic colon inflammation identical to other murine models of CD4+ T cell-mediated colitis. Interestingly, SGVHD animals develop chronic liver lesions that are similar to the early peribiliary inflammatory stages of clinical chronic liver disease, which is frequently associated with inflammatory bowel disease (IBD). Therefore, studies were initiated to investigate the chronic liver inflammation that develops in the SGVHD model. To induce SGVHD, mice were lethally irradiated, reconstituted with syngeneic BM, and treated with CsA. All of the SGVHD animals that developed colitis also develop chronic liver inflammation. Liver samples from control and SGVHD animals were monitored for tissue pathology, RNA for inflammatory mediators, and phenotypic analysis and in vitro reactivity of the inflammatory infiltrate. Diseased animals developed lesions of intrahepatic and extrahepatic bile ducts. Elevated levels of mRNA for molecules associated with chronic liver inflammation, including mucosal cellular adhesion molecule −1, the chemokines CCL25, CCL28, CCR9, and TH1- and TH17-associated cytokines were observed in livers of SGVHD mice. CD4+ T cells were localized to the peribiliary region of the livers of diseased animals, and an enhanced proliferative response of liver-associated mononuclear cells against colonic bacterial antigens was observed. The murine model of SGVHD colitis may be a valuable tool to study the entero-hepatic linkage between chronic colon inflammation and inflammatory liver disease. PMID:20634434

  18. Serum Golgi Protein 73 (GP73) is a Diagnostic and Prognostic Marker of Chronic HBV Liver Disease

    PubMed Central

    Xu, Zhengju; Liu, Liguan; Pan, Xingnan; Wei, Kaipeng; Wei, Meijuan; Liu, Lifei; Yang, Huanwen; Liu, Qian

    2015-01-01

    Abstract Alanine aminotransferase (ALT) is the most commonly used marker of liver injury, but normal ALT levels are seen in a proportion of chronic hepatitis B virus (HBV)-infected patients with severe liver injury. Golgi protein 73 (GP73) is a promising alternative marker of liver injury. This study assessed the relation between GP73 levels and liver disease severity, monitored the kinetic changes in GP73 levels in chronic HBV patients receiving entecavir (ETV) therapy, and investigated the potential diagnostic and prognostic values of serum GP73 as a new liver injury biomarker in chronic HBV infections. This study enrolled 1150 patients with chronic HBV infections, 200 of whom were retrospectively enrolled in this study after receiving 1 year of ETV treatment. GP73 expression in liver tissue was detected by immunohistochemistry. GP73 levels in single or serial serum samples were measured by enzyme-linked immunosorbent assay. Immunohistochemical analysis indicated that GP73 protein expression in the liver increased progressively with pathologic progression from nonexistent or mild hepatitis to severe hepatitis and cirrhosis during chronic HBV infection. Serum GP73 levels were positively correlated with the disease severity of chronic HBV infections (r = 0.58, P < 0.001). In patients with normal ALT levels, serum GP73 concentrations were significantly higher in patients with prominent hepatic inflammatory injury and fibrosis than in patients without hepatic inflammatory injury or fibrosis. Serum GP73 concentrations and GP73 protein expression were decreased in the liver tissues of patients whose ALT levels normalized after 1 year of ETV antiviral therapy. Changes in serum GP73 levels were closely associated with changes in liver injury severity, and, therefore, GP73 may be an effective new liver inflammatory injury biomarker, and could be useful for monitoring the prognosis of chronic HBV infectious patients with normal ALT levels. PMID:25816035

  19. Liver p53 expression in patients with HCV-related chronic hepatitis.

    PubMed

    Loguercio, C; Cuomo, A; Tuccillo, C; Gazzerro, P; Cioffi, M; Molinari, A M; Del Vecchio Blanco, C

    2003-07-01

    Mutated p53 acts as a dominant oncogene and alterations in the p53 gene are described in a large number of patients with hepatocellular carcinoma (HCC). It has been demonstrated that hepatitis C virus (HCV)-core protein regulates transcriptionally cellular genes, as well as cell growth and apoptosis. This study was undertaken to evaluate whether p53 may be expressed also in a precocious stage of HCV-related liver damage. We studied p53 expression by immunoluminometric assay on liver samples from 40 patients (M/F 18/ 22, median age 44 years, range 13-64 years) with biopsy-proven HCV-related chronic hepatitis. We considered the following factors: degree of liver damage, liver iron content and HCV-RNA titre. We also evaluated as possible co-factors alcohol and food intake in the last 3 years. p53 was over-expressed in seven of 40 (17.5%) patients. Liver histology documented the presence of unexpected cirrhosis in two patients among the p53 positive subjects. The p53 positive group had a daily ethanol intake significantly higher in respect to that of the p53 negative group (P < 0.05). Alimentary history documented that patients with a p53 over-expression had a lower intake of total calories, monounsaturated fatty acids, vitamin C and riboflavin. Data indicate that p53 over-expression can occur even in initial stages of HCV-related liver disease.

  20. [Interferon-alpha and liver fibrosis in patients with chronic damage due to hepatitis C virus].

    PubMed

    Gonzalez-Huezo, María Sarai; Gallegos-Orozco, Juan Fernando

    2003-01-01

    The present review focuses on the published information published regarding the effects of interferon alpha therapy on liver fibrosis in patients with chronic liver damage secondary to hepatitis C infection. Data reviewed included results of the in vitro effects of interferon on hepatic cell line cultures with regards to indirect markers of fibrosis, activation of hepatic stellate cells and oxidative stress response. In the clinical arena, there is current clear evidence of a favorable histological outcome in patients with sustained viral response to interferon therapy. For this reason, the current review focuses more on the histological outcomes regarding liver fibrosis in patients who have not attained viral response to therapy (non-responders) or who already have biopsy defined cirrhosis. Data in these patients were analyzed according to the results of objective testing of fibrosis through the assessment of liver biopsy and its change during time, specially because the morbidity and mortality of this disease is directly related to the complications of liver cirrhosis and not necessarily to the persistence of the hepatitis C virus. Lastly, it is concluded that the process of liver fibrosis/cirrhosis is a dynamic one and that there is some evidence to support the usefulness of interferon alpha therapy as a means to halt or retard the progression of hepatic fibrosis. The result of current clinical trials in which interferon therapy is being used to modify the progression of fibrosis in non-responders or cirrhotic patients is eagerly awaited.

  1. Impairment of energy metabolism in intact residual myocardium of rat hearts with chronic myocardial infarction.

    PubMed Central

    Neubauer, S; Horn, M; Naumann, A; Tian, R; Hu, K; Laser, M; Friedrich, J; Gaudron, P; Schnackerz, K; Ingwall, J S

    1995-01-01

    The purpose of this study was to test the hypothesis that energy metabolism is impaired in residual intact myocardium of chronically infarcted rat heart, contributing to contractile dysfunction. Myocardial infarction (MI) was induced in rats by coronary artery ligation. Hearts were isolated 8 wk later and buffer-perfused isovolumically. MI hearts showed reduced left ventricular developed pressure, but oxygen consumption was unchanged. High-energy phosphate contents were measured chemically and by 31P-NMR spectroscopy. In residual intact left ventricular tissue, ATP was unchanged after MI, while creatine phosphate was reduced by 31%. Total creatine kinase (CK) activity was reduced by 17%, the fetal CK isoenzymes BB and MB increased, while the "adult" mitochondrial CK isoenzyme activity decreased by 44%. Total creatine content decreased by 35%. Phosphoryl exchange between ATP and creatine phosphate, measured by 31P-NMR magnetization transfer, fell by 50% in MI hearts. Thus, energy reserve is substantially impaired in residual intact myocardium of chronically infarcted rats. Because phosphoryl exchange was still five times higher than ATP synthesis rates calculated from oxygen consumption, phosphoryl transfer via CK may not limit baseline contractile performance 2 mo after MI. In contrast, when MI hearts were subjected to acute stress (hypoxia), mechanical recovery during reoxygenation was impaired, suggesting that reduced energy reserve contributes to increased susceptibility of MI hearts to acute metabolic stress. PMID:7883957

  2. Resting state interhemispheric motor connectivity and white matter integrity correlate with motor impairment in chronic stroke.

    PubMed

    Chen, Joyce L; Schlaug, Gottfried

    2013-01-01

    Functional and structural reorganization in the brain occurs after stroke. The ability to predict motor outcomes may depend on patterns of brain functional and structural connectivity. We tested the hypothesis that alterations in motor transcallosal and corticospinal connections correlate with motor impairment in patients with chronic stroke. Eleven ischemic stroke patients underwent the Upper Extremity Fugl-Meyer (UE-FM) assessment, resting state functional magnetic resonance imaging, and diffusion tensor imaging (DTI). Twelve healthy control subjects underwent DTI. We assessed the temporal coupling in neural activity between interhemispheric motor cortex, and white matter integrity by means of fractional anisotropy (FA), in the transcallosal motor fibers and corticospinal tract. Partial correlation analyses were performed to determine whether these connectivity measures correlate with Upper UE-FM scores. Patients compared to controls had reduced FA in common voxels of transcallosal motor and ipsilesional corticospinal fibers. Within the patient group those with higher interhemispheric motor cortex connectivity and higher FA in the transcallosal motor fibers were less impaired. The results show that markers of functional and structural motor cortex connectivity correlate with motor impairment in the chronic stage of stroke.

  3. MDMA Pretreatment Leads to Mild Chronic Unpredictable Stress-induced Impairments in Spatial Learning

    PubMed Central

    Cunningham, Jacobi I.; Raudensky, Jamie; Tonkiss, John; Yamamoto, Bryan K.

    2009-01-01

    3,4-Methylenedioxymethamphetamine (MDMA) is a drug of abuse world-wide and a selective serotonin (5-HT) neurotoxin. An important factor in the risk of drug abuse and relapse is stress. Although multiple parallels exist between MDMA abuse and stress including effects on 5-HTergic neurotransmission, few studies have investigated the consequences of combined exposure to MDMA and chronic stress. Therefore, rats were pretreated with MDMA and exposed 7 days later to 10 days of mild chronic unpredictable stress (CUS). MDMA pretreatment was hypothesized to enhance the effects of CUS leading to enhanced 5-HT transporter (SERT) depletion in the hippocampus and increased anxiety and cognitive impairment. While MDMA alone increased anxiety-like behavior on the elevated plus maze, CUS alone or in combination with MDMA pretreatment did not increase anxiety-like behavior. In contrast, MDMA pretreatment led to CUS-induced learning impairment in the Morris water maze but not an enhanced depletion of hippocampal SERT protein. These results show that prior exposure to MDMA leads to stress-induced impairments in learning behavior that is not otherwise observed with stress alone and appear unrelated to an enhanced depletion of SERT. PMID:19824774

  4. Acoustic radiation force impulse elastography for chronic liver disease: comparison with ultrasound-based scores of experienced radiologists, Child-Pugh scores and liver function tests.

    PubMed

    Kim, Ji Eun; Lee, Jae Young; Kim, Yoon Jun; Yoon, Jung Hwan; Kim, Se Hyung; Lee, Jeong Min; Han, Joon Koo; Choi, Byung Ihn

    2010-10-01

    The purpose of our study was to investigate whether acoustic radiation force impulse (ARFI) elastography provides better diagnostic performance for diagnosis of chronic liver disease and correlates better with Child-Pugh scores and liver function tests, compared with an ultrasound (US) scoring system based on visual assessment of conventional B-mode US images by experienced radiologists. Five hundred and twenty-one patients with clinically proven chronic liver disease (n = 293), fatty liver (n = 95) or normal liver (n = 133) were included in this study. B-mode liver US and ARFI elastography were performed in all patients. ARFI elastography was performed at least five times, with each measurement obtained at a different area of the right hepatic lobe; mean shear wave velocity (SWV) was calculated for each patient. The mean SWV was compared with US-based scores from two radiologists (based on liver surface nodularity, parenchyma echotexture and hepatic vein contour), Child-Pugh scores and liver function tests. The mean SWV of the normal liver group was 1.08 m/s ± 0.15; of the fatty liver group, 1.02 m/s ± 0.16; and of the chronic liver disease group, 1.66 m/s ± 0.60 (p < 0.001). The area under the receiver operating characteristics curve of the mean SWV in ARFI elastography was significantly higher than that of the conventional B-mode US-based scores by two radiologists (0.89 vs. 0.74 and 0.77, p < 0.05), with a sensitivity of 75.4% and a specificity of 89.5% at the cut-off value of 1.22 m/s. The sensitivity of the mean SWV was significantly higher than the US-based scores (p < 0.001), although the specificity was not (p > 0.05). The mean SWV was better correlated with Child-Pugh scores and all liver function tests (except total protein) than the US-based scores from two radiologists. In conclusion, ARFI elastography showed better diagnostic performance than visual assessment of experienced radiologists for diagnosis of chronic liver disease, as well as for

  5. Impaired Gallbladder Motility and Increased Gallbladder Wall Thickness in Patients with Nonalcoholic Fatty Liver Disease

    PubMed Central

    Colak, Yasar; Bozbey, Gulcin; Erim, Tolga; Caklili, Ozge Telci; Ulasoglu, Celal; Senates, Ebubekir; Mutlu, Hasan Huseyin; Mesci, Banu; Doğan, Mehmet Sait; Tasan, Guralp; Enc, Feruze Yilmaz; Tuncer, Ilyas

    2016-01-01

    Background/Aims Nonalcoholic fatty liver disease (NAFLD) is currently the most common chronic liver disease worldwide. Along with the increase in the incidence of NAFLD and associated obesity, an increase in gallbladder disease (GD) has been noted. This has led to the identification of a new disease entity called fatty GD. There is a gap in the literature on the dynamics of gallbladder function in patients with NAFLD. Methods An observational case-control study, a total of 50 patients with biopsy proven NAFLD without gallbladder stone/sludge and 38 healthy comparison subjects were enrolled. Fasting, postprandial gallbladder volumes (PGV), gallbladder ejection fraction (GEF), and fasting gallbladder wall thickness (FGWT) were measured by real-time 2-dimensional ultrasonography. Results Fasting gallbladder wall thickness, fasting gallbladder volumes and PGV were significantly higher in patients with NAFLD than control subjects (P < 0.001, P = 0.006, and P < 0.001, respectively). Gallbladder ejection fraction was significantly lower in the NAFLD group than the controls (P = 0.008). The presence of NAFLD was an independent predictor for GEF, PGV, and FGWT. Also, steatosis grade was an independent predictor for GEF, and GEF was significantly lower in the nonalcoholic steatohepatitis (NASH) subgroup than the controls. Conclusions Gallbladder dysfunction and increase in gallbladder wall thickness exists in asymptomatic (without stone/sludge and related symptoms) patients with NAFLD and are useful in identifying fatty GD. Measurement of these variables in NAFLD patients may be useful in identifying those at higher risk for GD. PMID:26932908

  6. When to consider liver transplant during the management of chronic liver disease.

    PubMed

    Fox, Rena K

    2014-01-01

    The decision to perform liver transplantation for a particular patient is never the decision of one single individual, although a single individual could preclude transplant as an option if the opportunity for referral is missed. Every physician treating patients with cirrhosis, including primary care physicians and primary gastroenterologists, should watch for the essential turning points at which a patient may become eligible for a transplant referral. Timing of referral could be assessed according to either the type of liver disease or non–disease-specific measures of disease severity. Although the MELD score is an easily accessible and convenient tool it is not as well known as CTP classification, and many cirrhotic patients under long-term management may not be being allocated a MELD score regularly calculated by their primary physicians. Because a slow progression in MELD score may occur without a change in symptoms, reaching the MELD score acceptable for transplant referral may go unrecognized. As generalists face the rising prevalence of NAFLD and the rising prevalence of cirrhosis and HCC from HCV, there will be an increasing need for education in the management of liver disease. It will be necessary for specialists and health care systems to better inform primary care physicians about the recommendations on criteria for transplant referral and the critical windows of opportunity within which they can act. Although there is a recognized knowledge gap that needs to be addressed, once a patient is in medical care, inadequate physician knowledge should never be the cause for late timing or missing the opportunity for referral.

  7. DNA-binding antibodies and hepatitis B markers in acute and chronic liver disease.

    PubMed Central

    Kingham, J G; Rassam, S; Ganguly, N; Mcguire, M J; Nasrat, B; Holgate, S T; Triger, D R; Wright, R

    1978-01-01

    A Farr technique has been used to assay antibodies to double-stranded DNA in the serum of patients with acute and chronic liver disease and carriers of HBsAg from the United Kingdom and Iraq. These antibodies were found in all groups from both countries. The highest levels were found in chronic active hepatitis and cirrhosis. In the Iraqi patients there was a strongly positive correlation between DNA-binding antibody levels and the presence of hepatitis B markers but not with disease activity. In the patients from the United Kingdom there was little correlation with disease activity and none with autoantibodies. Ninety-five per cent of asymptomatic carriers of HBsAG had elevated DNA-binding antibodies. It is suggested that hepatitis B-specific DNA might be one trigger to DNA antibody formation, though in liver disease a variety of factors are clearly operative. PMID:309808

  8. Cellular and humoral immune reactions in chronic active liver disease. II. Lymphocyte subsets and viral antigens in liver biopsies of patients with acute and chronic hepatitis B.

    PubMed Central

    Eggink, H F; Houthoff, H J; Huitema, S; Wolters, G; Poppema, S; Gips, C H

    1984-01-01

    The characteristics and distribution of the inflammatory infiltrate in liver biopsies of 25 patients with hepatitis B viral (HBV) infection were studied in relation to the distribution and expression of HBV antigens. Mononuclear subsets were characterized with monoclonal (OKT, OKM, Leu) antibodies to surface antigens. For the demonstration of viral antigens directly conjugated antibodies to surface (HBsAg), core (HBcAg) and 'e' (HBeAg) antigen were used. For the study of mutual relations all methods were performed on serial cut tissue sections. In chronic active hepatitis B (CAH-B, n = 12) OKT8+ lymphocytes of T cell origin were the only cell type present in areas with liver cell degeneration and T cell cytotoxicity appears to be the only immune mechanism. In chronic persistent hepatitis B (CPH-B, n = 7) the only conspicuous feature was the presence of many Leu 3+ lymphocytes of the helper/inducer population in the portal tracts. In acute hepatitis B (AHB, n = 6) OKT8+ cells of non-T origin (OKT1-,3-) and Leu 7+ cells of presumed natural killer (NK) potential predominated in the areas with liver cell necrosis, and non-T cell cytotoxicity appears to be the predominant immune mechanism. In none of these disease entities a positive spatial relation could be established between the cytotoxic cells and the demonstrable expression of HBV antigens in hepatocytes. It is concluded that differences in immunological reaction pattern may explain the different course in the three forms of HBV infection studied. Images Fig. 1 Fig. 2 PMID:6713726

  9. Chronic stress impairs GABAergic control of amygdala through suppressing the tonic GABAA receptor currents

    PubMed Central

    2014-01-01

    Background Chronic stress is generally known to exacerbate the development of numerous neuropsychiatric diseases such as fear and anxiety disorders, which is at least partially due to the disinhibition of amygdala subsequent to the prolonged stress exposure. GABA receptor A (GABAAR) mediates the primary component of inhibition in brain and its activation produces two forms of inhibition: the phasic and tonic inhibition. While both of them are critically engaged in limiting the activity of amygdala, their roles in the amygdala disinhibition subsequent to chronic stress exposure are largely unknown. Results We investigated the possible alterations of phasic and tonic GABAAR currents and their roles in the amygdala disinhibition subsequent to chronic stress. We found that both chronic immobilization and unpredictable stress led to long lasting loss of tonic GABAAR currents in the projection neurons of lateral amygdala. By contrast, the phasic GABAAR currents, as measured by the spontaneous inhibitory postsynaptic currents, were virtually unaltered. The loss of tonic inhibition varied with the duration of daily stress and the total days of stress exposure. It was prevented by pretreatment with metyrapone to block corticosterone synthesis or RU 38486, a glucocorticoid receptor antagonist, suggesting the critical involvement of glucocorticoid receptor activation. Moreover, chronic treatment with corticosterone mimicked the effect of chronic stress and reduced the tonic inhibition in lateral amygdala of control mice. The loss of tonic inhibition resulted in the impaired GABAergic gating on neuronal excitability in amygdala, which was prevented by metyrapone pretreatment. Conclusions Our study suggests that enduring loss of tonic but not phasic GABAAR currents critically contributes to the prolonged amygdala disinhibition subsequent to chronic stress. We propose that the preferential loss of tonic inhibition may account for the development of stress

  10. Impaired SNX9 Expression in Immune Cells during Chronic Inflammation: Prognostic and Diagnostic Implications.

    PubMed

    Ish-Shalom, Eliran; Meirow, Yaron; Sade-Feldman, Moshe; Kanterman, Julia; Wang, Lynn; Mizrahi, Olga; Klieger, Yair; Baniyash, Michal

    2016-01-01

    Chronic inflammation is associated with immunosuppression and downregulated expression of the TCR CD247. In searching for new biomarkers that could validate the impaired host immune status under chronic inflammatory conditions, we discovered that sorting nexin 9 (SNX9), a protein that participates in early stages of clathrin-mediated endocytosis, is downregulated as well under such conditions. SNX9 expression was affected earlier than CD247 by the generated harmful environment, suggesting that it is a potential marker sensing the generated immunosuppressive condition. We found that myeloid-derived suppressor cells, which are elevated in the course of chronic inflammation, are responsible for the observed SNX9 reduced expression. Moreover, SNX9 downregulation is reversible, as its expression levels return to normal and immune functions are restored when the inflammatory response and/or myeloid-derived suppressor cells are neutralized. SNX9 downregulation was detected in numerous mouse models for pathologies characterized by chronic inflammation such as chronic infection (Leishmania donovani), cancer (melanoma and colorectal carcinoma), and an autoimmune disease (rheumatoid arthritis). Interestingly, reduced levels of SNX9 were also observed in blood samples from colorectal cancer patients, emphasizing the feasibility of its use as a diagnostic and prognostic biomarker sensing the host's immune status and inflammatory stage. Our new discovery of SNX9 as being regulated by chronic inflammation and its association with immunosuppression, in addition to the CD247 regulation under such conditions, show the global impact of chronic inflammation and the generated immune environment on different cellular pathways in a diverse spectrum of diseases.

  11. Evidence of Impaired Proprioception in Chronic, Idiopathic Neck Pain: Systematic Review and Meta-Analysis

    PubMed Central

    Leake, Hayley B.; Chalmers, K. Jane; Moseley, G. Lorimer

    2016-01-01

    Background Despite common use of proprioceptive retraining interventions in people with chronic, idiopathic neck pain, evidence that proprioceptive dysfunction exists in this population is lacking. Determining whether proprioceptive dysfunction exists in people with chronic neck pain has clear implications for treatment prescription. Purpose The aim of this study was to synthesize and critically appraise all evidence evaluating proprioceptive dysfunction in people with chronic, idiopathic neck pain by completing a systematic review and meta-analysis. Data Sources MEDLINE, CINAHL, PubMed, Allied and Complementary Medicine, EMBASE, Academic Search Premier, Scopus, Physiotherapy Evidence Database (PEDro), and Cochrane Collaboration databases were searched. Study Selection All published studies that compared neck proprioception (joint position sense) between a chronic, idiopathic neck pain sample and asymptomatic controls were included. Data Extraction Two independent reviewers extracted relevant population and proprioception data and assessed methodological quality using a modified Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement. Data Synthesis Thirteen studies were included in the present review. Meta-analysis on 10 studies demonstrated that people with chronic neck pain perform significantly worse on head-to-neutral repositioning tests, with a moderate standardized mean difference of 0.44 (95% confidence interval=0.25, 0.63). Two studies evaluated head repositioning using trunk movement (no active head movement thus hypothesized to remove vestibular input) and showed conflicting results. Three studies evaluated complex or postural repositioning tests; postural repositioning was no different between groups, and complex movement tests were impaired only in participants with chronic neck pain if error was continuously evaluated throughout the movement. Limitations A paucity of studies evaluating complex or postural repositioning

  12. Proteomic Analysis of Liver Proteins in a Rat Model of Chronic Restraint Stress-Induced Depression

    PubMed Central

    Li, Cong; Guo, Zhengguang; Sun, Wei

    2017-01-01

    Depression is a global mental disorder disease and greatly threatened human health and stress is considered to be one of the important factors that lead to depression. In this study, we used newly developed iTRAQ labeling and high performance liquid chromatography (HPLC) and mass spectrum united analysis technology obtained the 2176 accurate proteins. Successively, we used the GO analysis and IPA software to analyze the 98 differentially expressed proteins of liver in depression rats due to chronic restraint stress, showing a map of proteomics analysis of liver proteins from the aspects of related functions, disease and function analysis, canonical pathway analysis, and associated network. This study provide important information for comprehensively understanding the mechanisms of dysfunction or injury in the liver in depression. PMID:28293639

  13. Pylephlebitis with Liver Abscess Secondary to Chronic Appendicitis: A Radiological Conundrum

    PubMed Central

    Santosh, Divya; Low, Gavin

    2016-01-01

    Septic thrombophlebitis of the portal vein and/or its intra-hepatic branches (pylephlebitis) with associated liver abscess formation is a rare and potentially fatal complication of intra-abdominal infection. We present such a case that was caused by missed chronic appendicitis. Imaging findings can be complex and mimic other diseases leading to a diagnostic conundrum. Radiologists need to be knowledgeable of this challenging condition to prevent misdiagnosis and because prompt treatment is often life-saving. PMID:27833779

  14. Clinical observation of salvianolic acid B in treatment of liver fibrosis in chronic hepatitis B

    PubMed Central

    Liu, Ping; Hu, Yi-Yang; Liu, Cheng; Zhu, Da-Yuan; Xue, Hui-Ming; Xu, Zhi-Qiang; Xu, Lie- Ming; Liu, Cheng-Hai; Gu, Hong-Tu; Zhang, Zhi-Qing

    2002-01-01

    AIM: To evaluate the clinical efficacy of salvianolic acid B (SA-B) on liver fibrosis in chronic hepatitis B. METHODS: Sixty patients with definite diagnosis of liver fibrosis with hepatitis B were included in the trial. Interferon-γ (IFN-γ) was used as control drug. The patients took orally SA-B tablets or received muscular injection of IFN-γ in the double blind randomized test. The complete course lasted 6 mo. The histological changes of liver biopsy specimen before and after the treatment were the main evidence in evaluation, in combination with the results of contents of serum HA, LN, IV-C, P-III-P, liver ultrasound imaging, and symptoms and signs. RESULTS: Reverse rate of fibrotic stage was 36.67% in SA-B group and 30.0% in IFN-γ group. Inflammatory alleviating rate was 40.0% in SA-B group and 36.67% in IFN-γ group. The average content of HA and IV-C was significantly lower than that before treatment. The abnormal rate also decreased remarkably. Overall analysis of 4 serological fibrotic markers showed significant improvement in SA-B group as compared with the IFN-γ group. Score of liver ultrasound imaging was lower in SA-B group than in IFN-γ group (HA 36.7% vs 80%, IV-C 3.3% vs 23.2%). Before the treatment, ALT AST activity and total bilirubin content of patients who had regression of fibrosis after oral administration of SA-B, were significantly lower than those of patients who had aggravation of fibrosis after oral administration of SA-B. IFN-γ showed certain side effects (fever and transient decrease of leukocytes, occurrence rates were 50% and 3.23%), but SA-B showed no side effects. CONCLUSION: SA-B could effectively reverse liver fibrosis in chronic hepatitis B. SA-B was better than IFN-γ in reduction of serum HA content, overall decrease of 4 serum fibrotic markers, and decrease of ultrasound imaging score. Liver fibrosis in chronic hepatitis B with slight liver injury was more suitable to SA-B in anti-fibrotic treatment. SA-B showed no

  15. Chronic Hepatitis with Liver Granulomas in a Patient with Granuloma Annulare: A Case Report and Review of the Literature

    PubMed Central

    AlJasser, Mohammed I.; Kalia, Sunil; Yang, H. M.; Ramji, Alnoor

    2017-01-01

    Granuloma annulare (GA) is a benign granulomatous skin disorder of unknown etiology. GA is rarely associated with liver diseases. We report a unique case of chronic hepatitis with liver granulomas in a patient with GA. Despite an extensive workup, no clear etiology for the hepatitis was found. Based on the possible immune pathophysiology of GA and the presence of liver granulomas, the patient was treated with prednisone and azathioprine which resulted in complete normalization of the liver enzymes and concurrent improvement of GA. The association between liver diseases and GA is reviewed. PMID:28326206

  16. Multiomics reveal non-alcoholic fatty liver disease in rats following chronic exposure to an ultra-low dose of Roundup herbicide

    PubMed Central

    Mesnage, Robin; Renney, George; Séralini, Gilles-Eric; Ward, Malcolm; Antoniou, Michael N.

    2017-01-01

    The impairment of liver function by low environmentally relevant doses of glyphosate-based herbicides (GBH) is still a debatable and unresolved matter. Previously we have shown that rats administered for 2 years with 0.1 ppb (50 ng/L glyphosate equivalent dilution; 4 ng/kg body weight/day daily intake) of a Roundup GBH formulation showed signs of enhanced liver injury as indicated by anatomorphological, blood/urine biochemical changes and transcriptome profiling. Here we present a multiomic study combining metabolome and proteome liver analyses to obtain further insight into the Roundup-induced pathology. Proteins significantly disturbed (214 out of 1906 detected, q < 0.05) were involved in organonitrogen metabolism and fatty acid β-oxidation. Proteome disturbances reflected peroxisomal proliferation, steatosis and necrosis. The metabolome analysis (55 metabolites altered out of 673 detected, p < 0.05) confirmed lipotoxic conditions and oxidative stress by showing an activation of glutathione and ascorbate free radical scavenger systems. Additionally, we found metabolite alterations associated with hallmarks of hepatotoxicity such as γ-glutamyl dipeptides, acylcarnitines, and proline derivatives. Overall, metabolome and proteome disturbances showed a substantial overlap with biomarkers of non-alcoholic fatty liver disease and its progression to steatohepatosis and thus confirm liver functional dysfunction resulting from chronic ultra-low dose GBH exposure. PMID:28067231

  17. Multiomics reveal non-alcoholic fatty liver disease in rats following chronic exposure to an ultra-low dose of Roundup herbicide.

    PubMed

    Mesnage, Robin; Renney, George; Séralini, Gilles-Eric; Ward, Malcolm; Antoniou, Michael N

    2017-01-09

    The impairment of liver function by low environmentally relevant doses of glyphosate-based herbicides (GBH) is still a debatable and unresolved matter. Previously we have shown that rats administered for 2 years with 0.1 ppb (50 ng/L glyphosate equivalent dilution; 4 ng/kg body weight/day daily intake) of a Roundup GBH formulation showed signs of enhanced liver injury as indicated by anatomorphological, blood/urine biochemical changes and transcriptome profiling. Here we present a multiomic study combining metabolome and proteome liver analyses to obtain further insight into the Roundup-induced pathology. Proteins significantly disturbed (214 out of 1906 detected, q < 0.05) were involved in organonitrogen metabolism and fatty acid β-oxidation. Proteome disturbances reflected peroxisomal proliferation, steatosis and necrosis. The metabolome analysis (55 metabolites altered out of 673 detected, p < 0.05) confirmed lipotoxic conditions and oxidative stress by showing an activation of glutathione and ascorbate free radical scavenger systems. Additionally, we found metabolite alterations associated with hallmarks of hepatotoxicity such as γ-glutamyl dipeptides, acylcarnitines, and proline derivatives. Overall, metabolome and proteome disturbances showed a substantial overlap with biomarkers of non-alcoholic fatty liver disease and its progression to steatohepatosis and thus confirm liver functional dysfunction resulting from chronic ultra-low dose GBH exposure.

  18. Survival Benefits of Small Anatomical Resection of the Liver for Patients with Hepatocellular Carcinoma and Impaired Liver Function, Based on New-Era Imaging Studies

    PubMed Central

    Sakoda, Masahiko; Ueno, Shinichi; Iino, Satoshi; Hiwatashi, Kiyokazu; Minami, Koji; Kawasaki, Yota; Kurahara, Hiroshi; Mataki, Yuko; Maemura, Kosei; Shinchi, Hiroyuki; Natsugoe, Shoji

    2016-01-01

    Background: It has been reported that anatomical resection of the liver may be preferred for primary hepatocellular carcinoma (HCC), and is at least recommended for systematic removal of a segment confined by tumor-bearing portal tributaries. However, nonanatomical resection (NAR) is often selected because of the patient's background, impairment of liver function, and tumor factors. The aims of the present study were to retrospectively compare the recurrence-free survival (RFS) rates for cases of partial resection (PR) and for small anatomical resection (SAR), which is regarded as NAR for primary HCC with impaired liver function. Patients and Methods: So-called NAR was performed for a primary and solitary (≤ 5cm) HCC in 47 patients; the patients were classified into PR (n=25) and SAR (n=22) groups. Clinicopathological factors, survival data, and recurrence patterns were compared between groups. Results: There were no significant differences in the preoperative characteristics between the two groups. Operative time was significantly longer in the SAR group than in the PR group. There was no significant difference in the postoperative morbidity and tumor pathological characteristics between the two groups. The RFS of the SAR group was significantly better than those of the PR group. Although there was no significant difference in the pattern of recurrence between the two groups, the rate of intrahepatic recurrence in the same segment as the initial tumor tended to be higher in the PR group than in the SAR group. Multivariate analysis revealed that only the PR operative procedure was significant independent risk factor for poorer RFS. Conclusion: Compared with PR, SAR effectively improves the rate of RFS after surgery for a primary and solitary HCC with impaired liver function. PMID:27326244

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

    PubMed Central

    Gadd, Victoria L.; Patel, Preya J.; Jose, Sara; Horsfall, Leigh

    2016-01-01

    Background and Aims 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. Methods 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. Results 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. Conclusions 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

  20. Urea impairs β cell glycolysis and insulin secretion in chronic kidney disease

    PubMed Central

    Koppe, Laetitia; Nyam, Elsa; Vivot, Kevin; Manning Fox, Jocelyn E.; Dai, Xiao-Qing; Nguyen, Bich N.; Attané, Camille; Moullé, Valentine S.; MacDonald, Patrick E.; Ghislain, Julien

    2016-01-01

    Disorders of glucose homeostasis are common in chronic kidney disease (CKD) and are associated with increased mortality, but the mechanisms of impaired insulin secretion in this disease remain unclear. Here, we tested the hypothesis that defective insulin secretion in CKD is caused by a direct effect of urea on pancreatic β cells. In a murine model in which CKD is induced by 5/6 nephrectomy (CKD mice), we observed defects in glucose-stimulated insulin secretion in vivo and in isolated islets. Similarly, insulin secretion was impaired in normal mouse and human islets that were cultured with disease-relevant concentrations of urea and in islets from normal mice treated orally with urea for 3 weeks. In CKD mouse islets as well as urea-exposed normal islets, we observed an increase in oxidative stress and protein O-GlcNAcylation. Protein O-GlcNAcylation was also observed in pancreatic sections from CKD patients. Impairment of insulin secretion in both CKD mouse and urea-exposed islets was associated with reduced glucose utilization and activity of phosphofructokinase 1 (PFK-1), which could be reversed by inhibiting O-GlcNAcylation. Inhibition of O-GlcNAcylation also restored insulin secretion in both mouse models. These results suggest that insulin secretory defects associated with CKD arise from elevated circulating levels of urea that increase islet protein O-GlcNAcylation and impair glycolysis. PMID:27525435

  1. Chronic Arsenic Exposure-Induced Oxidative Stress is Mediated by Decreased Mitochondrial Biogenesis in Rat Liver.

    PubMed

    Prakash, Chandra; Kumar, Vijay

    2016-09-01

    The present study was executed to study the effect of chronic arsenic exposure on generation of mitochondrial oxidative stress and biogenesis in rat liver. Chronic sodium arsenite treatment (25 ppm for 12 weeks) decreased mitochondrial complexes activity in rat liver. There was a decrease in mitochondrial superoxide dismutase (MnSOD) activity in arsenic-treated rats that might be responsible for increased protein and lipid oxidation as observed in our study. The messenger RNA (mRNA) expression of mitochondrial and nuclear-encoded subunits of complexes I (ND1 and ND2) and IV (COX I and COX IV) was downregulated in arsenic-treated rats only. The protein and mRNA expression of MnSOD was reduced suggesting increased mitochondrial oxidative damage after arsenic treatment. There was activation of Bax and caspase-3 followed by release of cytochrome c from mitochondria suggesting induction of apoptotic pathway under oxidative stress. The entire phenomenon was associated with decrease in mitochondrial biogenesis as evident by decreased protein and mRNA expression of nuclear respiratory factor 1 (NRF-1), nuclear respiratory factor 2 (NRF-2), peroxisome proliferator activator receptor gamma-coactivator 1α (PGC-1α), and mitochondrial transcription factor A (Tfam) in arsenic-treated rat liver. The results of the present study indicate that arsenic-induced mitochondrial oxidative stress is associated with decreased mitochondrial biogenesis in rat liver that may present one of the mechanisms for arsenic-induced hepatotoxicity.

  2. Novel bile acid therapeutics for the treatment of chronic liver diseases

    PubMed Central

    Hegade, Vinod S.; Speight, R. Alexander; Etherington, Rachel E.; Jones, David E. J.

    2016-01-01

    Recent developments in understanding the role of bile acids (BAs) as signalling molecules in human metabolism and inflammation have opened new avenues in the field of hepatology research. BAs are no longer considered as simple molecules helping in fat digestion but as agents with real therapeutic value in treating complex autoimmune and metabolic liver diseases. BAs and their receptors such as farnesoid X receptor, transmembrane G protein-coupled receptor 5 and peroxisome proliferator-activated receptor have been identified as novel targets for drug development. Some of these novel pharmaceuticals are already in clinical evaluation with the most advanced drugs having reached phase III trials. Chronic liver diseases such as primary biliary cholangitis, primary sclerosing cholangitis and nonalcoholic fatty liver disease, for which there is no or limited pharmacotherapy, are most likely to gain from these developments. In this review we discuss recent and the most relevant basic and clinical research findings related to BAs and their implications for novel therapy for chronic liver diseases. PMID:27134666

  3. LIVER BIOPSY: IMPORTANCE OF SPECIMEN SIZE IN THE DIAGNOSIS AND STAGING OF CHRONIC VIRAL HEPATITIS

    PubMed Central

    CORAL, Gabriela P.; ANTUNES, Aline Dal Pozzo; SERAFINI, Ana Paula Almeida; ARAUJO, Fernanda B.; de MATTOS, Angelo Alves

    2016-01-01

    Liver biopsy is the gold standard method for the grading and staging of chronic viral hepatitis, but optimal biopsy specimen size remains controversial. The aim of this study was to evaluate the quality of liver specimen (number of portal tracts) and to evaluate the impact of the number of portal tracts in the staging of chronic hepatitis. Material and Methods: 468 liver biopsies from consecutive patients with hepatitis C virus and hepatitis B virus infection from 2009 to 2010 were evaluated. Results: The length of fragment was less than 10 mm in 43 cases (9.3%), between 10 and 14 mm in 114 (24.3%), and ≥ 15 mm in 311 (64.4%); of these, in 39 (8.3%) cases were ≥ 20 mm. The mean representation of portal tracts was 17.6 ± 2.1 (5-40); in specimens ≥ 15 mm the mean portal tract was 13.5 ± 4.7 and in cases ≤ 15 mm was 11.4 ± 5.0 (p = 0.002). Cases with less than 11 portal tracts were associated with F3, and cases with 11 or more portal tracts with F2 (p = 0.001). Conclusion: this study demonstrated the good quality of liver biopsy and a relationship between the macroscopic size of the fragment and the number of portal tracts. PMID:26910447

  4. Hepatotoxicity associated with glucosamine and chondroitin sulfate in patients with chronic liver disease.

    PubMed

    Cerda, Cristian; Bruguera, Miguel; Parés, Albert

    2013-08-28

    Glucosamine and chondroitin sulfate are molecules involved in the formation of articular cartilage and are frequently used for symptom relief in patients with arthrosis. These molecules are well tolerated with scarce secondary effects. Very few cases of possible hepatotoxicity due to these substances have been described. The aim of this paper is to report the frequency of presumed glucosamine hepatotoxicity in patients with liver disease. A questionnaire was given to 151 consecutive patients with chronic liver disease of different etiology (mean age 59 years, 56.9% women) attended in an outpatient clinic with the aim of evaluating the frequency of consumption of these drugs and determine whether their use coincided with a worsening in liver function test results. Twenty-three patients (15.2%) recognized having taken products containing glucosamine or chondroitin sulfate previously or at the time of the questionnaire. Review of the clinical records and liver function tests identified 2 patients presenting an elevation in aminotransferase values temporarily associated with glucosamine treatment; one of the cases simultaneously presented a skin rash attributed to the drug. Review of these two patients and the cases described in the literature suggest toxicity of glucosamine and chondroitin sulfate. The clinical spectrum is variable, and the mechanism of toxicity is not clear but may involve reactions of hypersensitivity. The consumption of products containing glucosamine and/or chondroitin sulfate is frequent among patients with chronic liver diseases and should be taken into account on the appearance of alterations in liver function tests not explained by the underlying disease.

  5. Vascular pathobiology in chronic liver disease and cirrhosis - current status and future directions.

    PubMed

    Iwakiri, Yasuko; Shah, Vijay; Rockey, Don C

    2014-10-01

    Chronic liver disease is associated with remarkable alterations in the intra- and extrahepatic vasculature. Because of these changes, the fields of liver vasculature and portal hypertension have recently become closely integrated within the broader vascular biology discipline. As developments in vascular biology have evolved, a deeper understanding of vascular processes has led to a better understanding of the mechanisms of the dynamic vascular changes associated with portal hypertension and chronic liver disease. In this context, hepatic vascular cells, such as sinusoidal endothelial cells and pericyte-like hepatic stellate cells, are closely associated with one another, where they have paracrine and autocrine effects on each other and themselves. These cells play important roles in the pathogenesis of liver fibrosis/cirrhosis and portal hypertension. Further, a variety of signaling pathways have recently come to light. These include growth factor pathways involving cytokines such as transforming growth factor β, platelet derived growth factor, and others as well as a variety of vasoactive peptides and other molecules. An early and consistent feature of liver injury is the development of an increase in intra-hepatic resistance; this is associated with changes in hepatic vascular cells and their signaling pathway that cause portal hypertension. A critical concept is that this process aggregates signals to the extrahepatic circulation, causing derangement in this system's cells and signaling pathways, which ultimately leads to the collateral vessel formation and arterial vasodilation in the splanchnic and systemic circulation, which by virtue of the hydraulic derivation of Ohm's law (pressure = resistance × flow), worsens portal hypertension. This review provides a detailed review of the current status and future direction of the basic biology of portal hypertension with a focus on the physiology, pathophysiology, and signaling of cells within the liver, as well

  6. Vascular pathobiology in chronic liver disease and cirrhosis – Current status and future directions

    PubMed Central

    Iwakiri, Yasuko; Shah, Vijay; Rockey, Don C.

    2015-01-01

    Summary Chronic liver disease is associated with remarkable alterations in the intra- and extrahepatic vasculature. Because of these changes, the fields of liver vasculature and portal hypertension have recently become closely integrated within the broader vascular biology discipline. As developments in vascular biology have evolved, a deeper understanding of vascular processes has led to a better understanding of the mechanisms of the dynamic vascular changes associated with portal hypertension and chronic liver disease. In this context, hepatic vascular cells, such as sinusoidal endothelial cells and pericyte-like hepatic stellate cells, are closely associated with one another, where they have paracrine and autocrine effects on each other and themselves. These cells play important roles in the pathogenesis of liver fibrosis/cirrhosis and portal hypertension. Further, a variety of signaling pathways have recently come to light. These include growth factor pathways involving cytokines such as transforming growth factor β, platelet derived growth factor, and others as well as a variety of vasoactive peptides and other molecules. An early and consistent feature of liver injury is the development of an increase in intra-hepatic resistance; this is associated with changes in hepatic vascular cells and their signaling pathway that cause portal hypertension. A critical concept is that this process aggregates signals to the extrahepatic circulation, causing derangement in this system’s cells and signaling pathways, which ultimately leads to the collateral vessel formation and arterial vasodilation in the splanchnic and systemic circulation, which by virtue of the hydraulic derivation of Ohm’s law (pressure = resistance × flow), worsens portal hypertension. This review provides a detailed review of the current status and future direction of the basic biology of portal hypertension with a focus on the physiology, pathophysiology, and signaling of cells within the

  7. Modulation of TGF-beta signaling during progression of chronic liver diseases.

    PubMed

    Matsuzaki, Koichi

    2009-01-01

    A large body of work has established roles for epithelial cells as important mediators of progressive fibrosis and carcinogenesis. Transforming growth factor-beta (TGF-beta) and pro-inflammatory cytokines are important inducers of fibro-carcinogenesis. TGF-beta signaling involves phosphorylation of Smad3 at middle linker and/or C-terminal regions. Reversible shifting of Smad3-dependent signaling between tumor-suppression and oncogenesis in hyperactive Ras-expressing epithelial cells indicates that Smad3 phosphorylated at the C-terminal region (pSmad3C) transmits a tumor-suppressive TGF-beta signal, while oncogenic activities such as cell proliferation and invasion are promoted by Smad3 phosphorylated at the linker region (pSmad3L). Notably, pSmad3L-mediated signaling promotes extracellular matrix deposition by activated mesenchymal cells. During progression of chronic liver diseases, hepatic epithelial hepatocytes undergo transition from the tumor-suppressive pSmad3C pathway to the fibrogenic/oncogenic pSmad3L pathway, accelerating liver fibrosis and increasing risk of hepatocellular carcinoma. c-Jun N-terminal kinase activated by pro-inflammatory cytokines is mediating this perturbed hepatocytic TGF-beta signaling. Thus, TGF-beta signaling of hepatocytes affected by chronic inflammation offers a general framework for understanding the molecular mechanisms of human fibro-carcinogenesis during progression of chronic liver diseases.

  8. Nonalcoholic Fatty Liver Disease in Chronic Hepatitis B and C Patients from Western Amazon

    PubMed Central

    Nascimento, A. C. M.; Maia, D. R.; Neto, S. M.; Lima, E. M.; Twycross, M.; Baquette, R. F.; Lobato, C. M. O.

    2012-01-01

    Nonalcoholic fatty liver disease (NAFLD) includes a wide spectrum of histological conditions, extending from simple steatosis to end-stage liver failure. The aim of this study was to examine the prevalence of NAFLD and its associations in chronic hepatitis B and C patients. Methods. We included all patients diagnosed with chronic hepatitis B and C who underwent a liver biopsy between January 2010 and October 2011 (n = 104). Parameters studied included hepatitis type, anthropometric data, histologic, hepatic, metabolic and lipid assessments, presence of hypertension and viral load. Results. Hepatitis B was presented in 28.8% (n = 30) of patients, while hepatitis C was presented in 71.2% (n = 74). In addition, hepatic steatosis was present in 25% (n = 26) of the patients. Steatosis was frequently found in hepatitis C patients (31.1%; 25% n = 23), but infrequently in hepatitis B patients (10%; n = 3) (P = 0.024). It was also found that steatosis was frequently present in hepatitis C patients with intense fibrosis (52.94%) (P = 0.025). Discussion. Our results suggest that steatosis is a common feature in patients with viral chronic hepatitis, and that it plays a different role in each type of hepatitis. PMID:22934189

  9. Multicenter clinical study on Fuzhenghuayu capsule against liver fibrosis due to chronic hepatitis B

    PubMed Central

    Liu, Ping; Hu, Yi-Yang; Liu, Cheng; Xu, Lie-Ming; Liu, Cheng-Hai; Sun, Ke-Wei; Hu, De-Chang; Yin, You-Kuan; Zhou, Xia-Qiu; Wan, Mo-Bin; Cai, Xiong; Zhang, Zhi-Qing; Ye, Jun; Zhou, Ren-Xing; He, Jia; Tang, Bao-Zhang

    2005-01-01

    AIM: To study the efficacy and safety of Fuzhenghuayu capsule (FZHY capsule, a capsule for strengthening body resistance to remove blood stasis) against liver fibrosis due to chronic hepatitis B. METHODS: Multicenter, randomized, double blinded and parallel control experiment was conducted in patients (aged from 18 to 65 years) with liver fibrosis due to chronic hepatitis B. Hepatic histologic changes and HBV markers were examined at wk 0 and 24 during treatment. Serologic parameters (HA, LM, P-III-P, IV-C) were determined and B ultrasound examination of the spleen and liver was performed at wk 0, 12 and 24. Liver function (liver function and serologic parameters for liver fibrosis) was observed at wk 0, 6, 12, 18 and 24. Blood and urine routine test, renal function and ECG were examined before and after treatment. RESULTS: There was no significant difference between experimental group (110 cases) and control group (106 cases) in demographic features, vital signs, course of illness, history for drug anaphylaxis and previous therapy, liver function, serologic parameters for liver fibrosis, liver histologic examination (99 cases in experimental group, 96 cases in control group), HBV markers, and renal function. According to the criteria for liver fibrosis staging, mean score of fibrotic stage(s) in experimental group after treatment (1.80) decreased significantly compared to the previous treatment (2.33, P<0.05), but there was no significant difference in mean score of fibrotic stage(s) (2.11 and 2.14 respectively). There was a significant difference in reverse rate between experimental group (52%) and control group (23.3%) in liver biopsy. With marked effect on decreasing the mean value of inflammatory activity and score of inflammation (P<0.05), Fuzhenghuayu capsule had rather good effects on inhibiting inflammatory activity and was superior to that of Heluoshugan capsule. Compared to that of pretreatment, there was a significant decrease in HA, LM, P-III-P and IV

  10. Latent toxoplasmosis is associated with neurocognitive impairment in young adults with and without chronic HIV infection.

    PubMed

    Ene, L; Marcotte, T D; Umlauf, A; Grancea, C; Temereanca, A; Bharti, A; Achim, C L; Letendre, S; Ruta, S M

    2016-10-15

    We evaluated the impact of latent toxoplasmosis (LT) on neurocognitive (NC) and neurobehavioural functioning in young adults with and without chronic HIV infection, using a standardised NC test battery, self-reported Beck Depression Inventory, Frontal System Behavior Scale, MINI-International Neuropsychiatric Interview and risk-assessment battery. 194 young adults (median age 24years, 48.2% males) with chronic HIV infection (HIV+) since childhood and 51 HIV seronegative (HIV-) participants were included. HIV+ individuals had good current immunological status (median CD4: 479 cells/μl) despite a low CD4 nadir (median: 93 cells/μl). LT (positive anti-Toxoplasma IgG antibodies) was present in one third of participants. The impairment rates in the HIV- with and without Toxo were not significantly different (p=0.17). However, we observed an increasing trend (p<0.001) in impairment rates with HIV and LT status: HIV-/LT- (6.1%); HIV-/LT+ (22%), HIV+/LT- (31%), HIV+/LT+ (49%). In a multivariable analysis using the entire study group there were main effects on cognition for HIV and also for LT. Within the HIV+ group LT was associated with worse performance globally (p=0.006), in memory (p=0.009), speed of information processing (p=0.01), verbal (p=0.02) and learning (p=0.02) domains. LT was not associated with depressive symptoms, frontal systems dysfunction or risk behaviors in any of the groups. HIV participants with lower Toxoplasma antibody concentration had worse NC performance, with higher GDS values (p=0.03) and worse learning (p=0.002), memory (p=0.006), speed of information processing (p=0.01) T scores. Latent Toxoplasmosis may contribute to NC impairment in young adults, including those with and without chronic HIV infection.

  11. White matter changes in chronic alcoholic liver disease: Hypothesized association and putative biochemical mechanisms.

    PubMed

    Hathout, Leith; Huang, Jimmy; Zamani, Amir; Morioka, Craig; El-Saden, Suzie

    2015-12-01

    Advanced liver disease has long been associated with cerebral abnormalities. These abnormalities, termed acquired hepatocerebral degeneration, are typically visualized as T1 weighted hyperintensity on MRI in the deep gray matter of the basal ganglia. Recent reports, however, have demonstrated that a subset of patients with chronic alcoholic liver disease may also develop white matter abnormalities. Thus far, the morphology of these changes is not well characterized. Previous studies have described these changes as patchy, sporadic white matter abnormalities but have not posited localization of these changes to any particular white matter tracts. This paper hypothesizes that the white matter findings associated with advanced alcoholic liver disease localize to the corticocerebellar tracts. As an initial investigation of this hypothesis, 78 patients with a diagnosis of liver cirrhosis and an MRI showing clearly abnormal T1 weighted hyperintensity in the bilateral globus pallidus, characteristic of chronic liver disease, were examined for white matter signal abnormalities in the corticocerebellar tracts using FLAIR and T2 weighted images. The corticocerebellar tracts were subdivided into two regions: periventricular white matter (consisting of the sum of the centrum-semiovale and corona radiata), and lower white matter (consisting of the corona radiata, internal capsules, middle cerebral peduncles, middle cerebellar peduncles and cerebellum). As compared to matched controls, significantly greater signal abnormalities in both the periventricular white matter and lower white matter regions of the corticocerebellar tracts were observed in patients with known liver cirrhosis and abnormal T1 W hyperintensity in the globi pallidi. This difference was most pronounced in the lower white matter region of the corticocerebellar tract, with statistical significance of p<0.0005. Furthermore, the pathophysiologic mechanism underlying these changes remains unknown. This paper

  12. Role of nutrition in liver transplantation for end-stage chronic liver disease.

    PubMed

    Stickel, Felix; Inderbitzin, Daniel; Candinas, Daniel

    2008-01-01

    Patients with end-stage liver disease often reveal significant protein-energy malnutrition, which may deteriorate after listing for transplantation. Since malnutrition affects post-transplant survival, precise assessment must be an integral part of pre- and post-surgical management. While there is wide agreement that aggressive treatment of nutritional deficiencies is required, strong scientific evidence supporting nutritional therapy is sparse. In practice, oral nutritional supplements are preferred over parenteral nutrition, but enteral tube feeding may be necessary to maintain adequate calorie intake. Protein restriction should be avoided and administration of branched-chain amino acids may help yield a sufficient protein supply. Specific problems such as micronutrient deficiency, fluid balance, cholestasis, encephalopathy, and comorbid conditions need attention in order to optimize patient outcome.

  13. Noninvasive fat quantification of the liver and pancreas may provide potential biomarkers of impaired glucose tolerance and type 2 diabetes

    PubMed Central

    Dong, Zhi; Luo, Yanji; Cai, Huasong; Zhang, Zhongwei; Peng, Zhenpeng; Jiang, Mengjie; Li, Yanbing; Li, Chang; Li, Zi-Ping; Feng, Shi-Ting

    2016-01-01

    Abstract The aim of the study is to investigate if the fat content of the liver and pancreas may indicate impaired glucose tolerance (IGT) or type 2 diabetes mellitus (T2DM). A total of 83 subjects (34 men; aged 46.5 ± 13.5 years) were characterized as T2DM, IGT, or normal glucose tolerant (NGT). NGT individuals were stratified as <40 or ≥40 years. Standard laboratory tests were conducted for insulin resistance and β-cell dysfunction. The magnetic resonance imaging Dixon technique was used to determine fat distribution in the liver and pancreas. Correlations among liver and pancreatic fat volume fractions (LFVFs and PFVFs, respectively) and laboratory parameters were analyzed. Among the groups, fat distribution was consistent throughout sections of the liver and pancreas, and LFVFs closely correlated with PFVFs. LFVFs correlated more closely than PFVFs with insulin resistance and β-cell function. Both the LFVFs and PFVFs were the highest in the T2DM patients, less in the IGT, and least in the NGT; all differences were significant. The PFVFs of the NGT subjects ≥40 years were significantly higher than that of those <40 years. The fat content of the liver and pancreas, particularly the liver, may be a biomarker for IGT and T2DM. PMID:27281097

  14. Vitamin D3 protects against prednisolone-induced liver injury associated with the impairment of the hepatic NF-κB/iNOS/NO pathway.

    PubMed

    Lisakovska, Olha; Shymanskyy, Ihor; Mazanova, Anna; Khomenko, Anna; Veliky, Mykola

    2017-04-01

    The study was carried out to define whether prednisolone-induced damage to hepatic cells is accompanied by excessive nitric oxide (NO) levels associated with nuclear factor kappa B (NF-κB)/inducible NO synthase (iNOS) activation and evaluate the efficacy of the treatment with vitamin D3. Histopathological examination, activities of liver transaminases (alanine aminotransferase and aspartate aminotransferase), and cell death assays consistently showed that prednisolone (5 mg/kg body weight, 30 days) induces chronic liver injury in female Wistar rats. Specifically, increased hepatocellular necrosis and caspase-3-dependent apoptosis were observed. Prednisolone enhanced iNOS protein expression, NO generation, and tyrosine nitration in liver cells. Despite unchanged hepatic level of the NF-κB/p65 protein, prednisolone increased inhibitory κB-α (IκB-α) degradation, nuclear translocation, and phosphorylation of NF-κB/p65 at Ser311, indicating that NF-κB activation can be involved in the induction of iNOS/NO. All changes were associated with a 2.9-fold decrease in the serum content of 25-hydroxyvitamin D3 and significant reduction of hepatic vitamin D3 receptor (VDR) expression that points reliably to vitamin D3 deficiency and failures in VDR signaling. Vitamin D3 co-administration (100 IU/rat, 30 days) prevented glucocorticoid-evoked abnormalities in hepatic tissue. In conclusion, prednisolone-induced liver disturbances were associated with the impairment of NF-κB/iNOS/NO responses that can be ameliorated by vitamin D3 treatment through VDR-mediated mechanisms.

  15. Prevalence and characteristics of hypoxic hepatitis in the largest single-centre cohort of avian influenza A(H7N9) virus-infected patients with severe liver impairment in the intensive care unit

    PubMed Central

    Zhang, YiMin; Liu, JiMin; Yu, Liang; Zhou, Ning; Ding, Wei; Zheng, ShuFa; Shi, Ding; Li, LanJuan

    2016-01-01

    Avian influenza A(H7N9) virus (A(H7N9)) emerged in February 2013. Liver impairment of unknown cause is present in 29% of patients with A(H7N9) infection, some of whom experience severe liver injury. Hypoxic hepatitis (HH) is a type of acute severe liver injury characterized by an abrupt, massive increase in serum aminotransferases resulting from anoxic centrilobular necrosis of liver cells. In the intensive care unit (ICU), the prevalence of HH is ∼1%–2%. Here, we report a 1.8% (2/112) incidence of HH in the largest single-centre cohort of ICU patients with A(H7N9) infection. Both HH patients presented with multiple organ failure (MOF) involving respiratory, cardiac, circulatory and renal failure and had a history of chronic heart disease. On admission, severe liver impairment was found. Peak alanine aminotransferase (ALT) and aspartate aminotransferase (AST) values were 937 and 1281 U/L, and 3117 and 3029 U/L, respectively, in the two patients. Unfortunately, both patients died due to deterioration of MOF. A post-mortem biopsy in case 1 confirmed the presence of centrilobular necrosis of the liver, and real-time reverse transcription polymerase chain reaction of A(H7N9)-specific genes was negative, which excluded A(H7N9)-related hepatitis. The incidence of HH in A(H7N9) patients is similar to that in ICU patients with other aetiologies. It seems that patients with A(H7N9) infection and a history of chronic heart disease with a low left ventricular ejection fraction on admission are susceptible to HH, which presents as a marked elevation in ALT at the time of admission. PMID:26733380

  16. Prevalence and characteristics of hypoxic hepatitis in the largest single-centre cohort of avian influenza A(H7N9) virus-infected patients with severe liver impairment in the intensive care unit.

    PubMed

    Zhang, YiMin; Liu, JiMin; Yu, Liang; Zhou, Ning; Ding, Wei; Zheng, ShuFa; Shi, Ding; Li, LanJuan

    2016-01-06

    Avian influenza A(H7N9) virus (A(H7N9)) emerged in February 2013. Liver impairment of unknown cause is present in 29% of patients with A(H7N9) infection, some of whom experience severe liver injury. Hypoxic hepatitis (HH) is a type of acute severe liver injury characterized by an abrupt, massive increase in serum aminotransferases resulting from anoxic centrilobular necrosis of liver cells. In the intensive care unit (ICU), the prevalence of HH is ∼1%-2%. Here, we report a 1.8% (2/112) incidence of HH in the largest single-centre cohort of ICU patients with A(H7N9) infection. Both HH patients presented with multiple organ failure (MOF) involving respiratory, cardiac, circulatory and renal failure and had a history of chronic heart disease. On admission, severe liver impairment was found. Peak alanine aminotransferase (ALT) and aspartate aminotransferase (AST) values were 937 and 1281 U/L, and 3117 and 3029 U/L, respectively, in the two patients. Unfortunately, both patients died due to deterioration of MOF. A post-mortem biopsy in case 1 confirmed the presence of centrilobular necrosis of the liver, and real-time reverse transcription polymerase chain reaction of A(H7N9)-specific genes was negative, which excluded A(H7N9)-related hepatitis. The incidence of HH in A(H7N9) patients is similar to that in ICU patients with other aetiologies. It seems that patients with A(H7N9) infection and a history of chronic heart disease with a low left ventricular ejection fraction on admission are susceptible to HH, which presents as a marked elevation in ALT at the time of admission.

  17. Chronic sleep curtailment impairs the flexible implementation of task goals in new parents.

    PubMed

    Plessow, Franziska; Kiesel, Andrea; Petzold, Antje; Kirschbaum, Clemens

    2011-06-01

    Chronic sleep curtailment is a major concern for health in Western societies. Yet, research on potential consequences of long-term sleep curtailment on cognitive functions is still scarce. The present study investigated the link between chronic sleep limitation and executive functions that enable adaptation to changing environmental demands, i.e. the ability to flexibly implement task goals. To address the effects of chronic sleep restriction under real-life conditions, we considered a sample of adults who often suffer from reduced sleep durations over many months. One-hundred and six new parents (infant's age: 6-18months) were assigned to a sleep-curtailed group (<7h of nighttime sleep) and a non-sleep-curtailed group (≥7h of nighttime sleep), respectively, based on their self-reported average nighttime sleep duration over the preceding 6months. The ability to implement task goals was addressed applying a task-switching paradigm in which participants randomly switched between two tasks. While the two groups did not differ with regard to overall performance level, number of nighttime awakenings, naps during the day, daytime sleepiness, mood, chronic stress level and subjectively perceived cognitive capability, sleep-curtailed new parents showed higher costs for switching between tasks compared with repeating a task than non-sleep-curtailed new parents. This finding on the group level was further substantiated by a negative correlation between nighttime sleep duration and switch costs. With this study, we provide the first evidence for an impairment of the ability to flexibly implement task goals in chronically sleep-deprived new parents and, thus, for a link between chronic sleep curtailment and executive functions.

  18. Impaired emotional-like behavior and serotonergic function during protracted abstinence from chronic morphine

    PubMed Central

    Goeldner, Celia; Lutz, Pierre-Eric; Darcq, Emmanuel; Halter, Thomas; Clesse, Daniel; Ouagazzal, Abdel-Mouttalib; Kieffer, Brigitte L.

    2010-01-01

    Background Opiate abuse is a chronic relapsing disorder and maintaining prolonged abstinence remains a major challenge. Protracted abstinence is characterized by lowered mood and clinical studies show elevated co-morbidity between addiction and depressive disorders. At present, their relationship remains unclear and has been little studied in animal models. Here we investigated emotional alterations during protracted abstinence, in mice with a history of chronic morphine exposure. Methods C57BL6J mice were exposed to a chronic intermittent escalating morphine regimen (20-100mg/kg). Physical dependence (naloxone-precipitated withdrawal), despair-related (tail suspension test) and social behaviors were examined after 1 or 4 weeks of abstinence. Stress hormones and forebrain bioamine levels were analyzed at the end of morphine regimen and after 4 weeks abstinence. Finally, we examined the effects of chronic fluoxetine during abstinence on morphine-induced behavioral deficits. Results Acute naloxone-induced withdrawal was clearly measurable after 1 week, and became undetectable after 4 weeks. In contrast, social and despair-related were unchanged after 1 week, but low sociability and despair-like behavior became significant after 4 weeks. Chronic morphine regimen increased both corticosterone levels and forebrain serotonin turnover, but only serotonergic activity in the dorsal raphe remained impaired after 4 weeks. Remarkably, chronic fluoxetine prevented depressive-like behavioral deficits in 4-week abstinent mice. Conclusions During protracted abstinence, the immediate consequences of morphine exposure attenuate while fluoxetine-sensitive emotional alterations strengthen with time. Our study establishes a direct link between morphine abstinence and depressive-like symptoms, and strongly suggests that serotonin dysfunction represents a main mechanism contributing to mood disorders in opiate abstinence. PMID:20947067

  19. Hepatogenous diabetes: Is it a neglected condition in chronic liver disease?

    PubMed Central

    García-Compeán, Diego; González-González, José Alberto; Lavalle-González, Fernando Javier; González-Moreno, Emmanuel Irineo; Villarreal-Pérez, Jesús Zacarías; Maldonado-Garza, Héctor Jesús

    2016-01-01

    Diabetes mellitus (DM) that occurs because of chronic liver disease (CLD) is known as hepatogenous diabetes (HD). Although the association of diabetes and liver cirrhosis was described forty years ago, it was scarcely studied for long time. Patients suffering from this condition have low frequency of risk factors of type 2 DM. Its incidence is higher in CLD of viral, alcoholic and cryptogenic etiology. Its pathophysiology relates to liver damage, pancreatic dysfunction, interactions between hepatitis C virus (HCV) and glucose metabolism mechanisms and genetic susceptibility. It associates with increased rate of liver complications and hepatocellular carcinoma, and decreased 5-year survival rate. It reduces sustained virological response in HCV infected patients. In spite of these evidences, the American Diabetes Association does not recognize HD. In addition, the impact of glucose control on clinical outcomes of patients has not been evaluated. Treatment of diabetes may be difficult due to liver insufficiency and hepatotoxicity of antidiabetic drugs. Notwithstanding, no therapeutic guidelines have been implemented up to date. In this editorial, authors discuss the reasons why they think that HD may be a neglected pathological condition and call attention to the necessity for more clinical research on different fields of this disease. PMID:26973383

  20. Factors associated with significant liver necroinflammation in chronic hepatitis B patients with cirrhosis

    PubMed Central

    Chen, Sheng-Sen; Yu, Kang-Kang; Ling, Qing-Xia; Huang, Chong; Li, Ning; Zheng, Jian-Ming; Bao, Su-Xia; Cheng, Qi; Zhu, Meng-Qi; Chen, Ming-Quan

    2016-01-01

    We determined the association between various clinical parameters and significant liver necroinflammation in patients with chronic hepatitis B (CHB) related cirrhosis. Two hundred patients with CHB related cirrhosis were recruited in the final analysis. Clinical laboratory values and characteristics were obtained from the medical record. We performed analyses of the relationships between independent variables and significant liver necroinflammation by using binary logistic regression analysis and discriminant analysis. Significant liver necroinflammation (grade≥2) was found in 58.0% (80/138) of antiviral therapy patients and 48.4% (30/62) of non antiviral therapy patients respectively. Also, there were some significant differences in serum hepatitis B surface antigen (HBsAg), serum hepatitis B e antigen (HBeAg) and serum hepatitis B virus (HBV) DNA between antiviral therapy and non antiviral therapy patients. After that, aspartate aminotransferase (AST), total bilirubin (TBIL), total bile acid (TBA), prothrombin time (PT), aspartate aminotransferase to platelet ratio index (APRI) and serum HBV DNA were confirmed as independent predictors of significant liver necroinflammation in CHB patients with cirrhosis by univariate analysis and multivariate analysis (p = 0.002, 0.044, 0.001, 0.014, 0.01 and 0.02 respectively). Finally, receiver operating characteristic (ROC) curve analysis and discriminant analysis validated that these six variables together have strong predictive power to evaluate significant liver necroinflammation. PMID:27615602

  1. Immunohistochemical study for the origin of ductular reaction in chronic liver disease

    PubMed Central

    Lee, Sun-Jae; Park, Jae-Bok; Kim, Kyung-Hyun; Lee, Woo-Ram; Kim, Jung-Yeon; An, Hyun-Jin; Park, Kwan-Kyu

    2014-01-01

    The appearance of proliferating bile ductular structures, which is called the “atypical ductular reaction” is frequently observed in various chronic liver diseases associated. However, the origin of these increased bile ductules has been a matter of controversy. In this study, we investigated the origin of ductular cells as an aspect of relation between epithelial to mesenchymal transition (EMT) and epithelial members of liver parenchyme, such as hepatocyte and cholangiocyte by immunohistochemical staining of human liver. Thirteen specimens of surgically resected liver with biliary cirrhosis were selected. Three sets of double immunohistochemical stains were done; Hep-Par 1 - cytokeratin 19 (CK19), Hep-Par 1 - α-sm ooth mus cle actin (α-SMA) and CK19 - α-SMA. As a result, we investigated the dual expression of the markers of hepatocyte and cholangiocyte in the same cell; in ductular cell and surrounding hepatocyte. However, there seems to be no dual expression of markers for EMT with epithelial markers. This study suggests a possibility of phenotypic change of mature hepatocyte into cholangiocyte. Future studies will be necessary to determine the role that proliferating cholangiocytes play in the pathogenesis of biliary fibrosis and how cholangiocytes interact with other cell types of the liver such as hepatic stellate cells or Kupffer cells. PMID:25120786

  2. The association between indirect bilirubin levels and liver fibrosis due to chronic hepatitis C virus infection.

    PubMed

    Cengiz, Mustafa; Yılmaz, Guldal; Ozenirler, Seren

    2014-08-01

    We proposed to evaluate the association between serum indirect bilirubin levels and liver fibrosis in patients with chronic hepatitis C (CHC) genotype 1b. Biopsy proven CHC genotype 1b patients' demographics, clinical and histopathological characteristics were evaluated. Logistic regression analysis was done to evaluate the clinical, laboratory and demographic features of the histologically proven liver fibrosis in CHC patients. A total of 112 biopsy proven CHC genotype 1b patients were enrolled into the study. Liver fibrosis scores were measured by using Ishak fibrosis scores and were divided into two groups; fibrosis scores ≤ 2 were categorized as mild fibrosis, 82 patients (73.2%), whereas fibrosis scores >2 were categorized as advanced fibrosis group, 30 patients (26.8%). Patients with advanced fibrosis had lower indirect bilirubin levels than the mild fibrosis group (0.28 ± 0.02 mg/dl vs. 0.44 ± 0.032 mg/dl, p<0.001, respectively). Indirect bilirubin level was negatively correlated with advanced fibrosis scores (r=-0.416 and p<0.001). In multivariate logistic regression analysis, low indirect bilirubin level was an independent predicting factor of advanced liver fibrosis (OR: 0.001, 95% CI: 0.0-0.005, p<0.001). There is an inverse relationship between indirect bilirubin levels and advanced liver fibrosis caused by CHC genotype 1b.

  3. Impairment of lipoglycoprotein metabolism in rat liver cells induced by 1,2-dichloroethane.

    PubMed Central

    Cottalasso, D; Barisione, G; Fontana, L; Domenicotti, C; Pronzato, M A; Nanni, G

    1994-01-01

    BACKGROUND--1,2-Dichloroethane (DCE) is a volatile liquid readily absorbed through dermal, digestive, or inhalatory routes. After inhalation or oral administration to rats, death occurs within a narrow range of concentrations (six hour LC50 = 5100 mg/m3). Exposure to single high doses of DCE resulted in adverse effects on the central nervous system, liver, kidneys, adrenals, and lungs. The liver showed fatty changes and hepatocellular necrosis with haemorrhage. These injuries are probably related to changes in several cell functions and constituents. Therefore, it was decided to investigate whether DCE was capable of impairing the secretion of hepatocellular lipoglycoproteins acting both at the level of the Golgi apparatus and endoplasmic reticulum. METHODS--Isolated hepatocytes of Wistar rats were prelabelled with two precursors of lipoglycoproteins 3H-Na-palmitate and 14C-glucosamine, and then exposed to concentrations of DCE from mean (SD) 4.4 (0.03) to 6.5 (0.02) mM for different durations ranging from five to 60 minutes. To measure lipid and sugar bound radioactivity, a preliminary separation of cell homogenate, cytosol, total microsomes, Golgi apparatus, and lipoglycoproteins secreted into cell suspension medium was carried out. RESULTS--After five minutes of exposure, DCE did not induce obvious changes in cell viability or lactic dehydrogenase leakage, but a significant (p < 0.01) depletion of reduced glutathione content was seen (40.10 (4.3) nM/10(6) cells). Furthermore, the cells poisoned by DCE started to show noticeable accumulation of 3H-Na-palmitate in the Golgi apparatus after five minutes (5103 (223) dpm/10(6) cells) and in the microsomes after 15 minutes (85,470 (7190) dpm/10(6) cells). There was a simultaneous significant increase in 14C-glucosamine content in the Golgi apparatus (690 (55) dpm/10(6) cells) and the microsomes (15,975 (2035) dpm/10(6) cells). The specific radioactivity of lipid and sugar moieties incorporated in secreted

  4. Association between Noninvasive Fibrosis Markers and Chronic Kidney Disease among Adults with Nonalcoholic Fatty Liver Disease

    PubMed Central

    Sesti, Giorgio; Fiorentino, Teresa Vanessa; Arturi, Franco; Perticone, Maria; Sciacqua, Angela; Perticone, Francesco

    2014-01-01

    Evidence suggests that nonalcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are associated with an increased risk of chronic kidney disease (CKD). In this study we aimed to evaluate whether the severity of liver fibrosis estimated by NAFLD fibrosis score is associated with higher prevalence of CKD in individuals with NAFLD. To this end NAFLD fibrosis score and estimated glomerular filtration rate (eGFR) were assessed in 570 White individuals with ultrasonography-diagnosed NAFLD. As compared with subjects at low probability of liver fibrosis, individuals at high and intermediate probability showed an unfavorable cardio-metabolic risk profile having significantly higher values of waist circumference, insulin resistance, high sensitivity C-reactive protein, fibrinogen, uric acid and lower insulin-like growth factor-1 levels. Individuals at high and intermediate probability of liver fibrosis have lower eGFR after adjustment for gender, smoking, glucose tolerance status, homeostasis model assessment index of insulin resistance (HOMA-IR index), diagnosis of metabolic syndrome, statin therapy, anti-diabetes and anti-hypertensive treatments (P = 0.001). Individuals at high probability of liver fibrosis had a 5.1-fold increased risk of having CKD (OR 5.13, 95%CI 1.13–23.28; P = 0.03) as compared with individuals at low probability after adjustment for age, gender, and BMI. After adjustment for glucose tolerance status, statin therapy, and anti-hypertensive treatment in addition to gender, individuals at high probability of liver fibrosis had a 3.9-fold increased risk of CKD (OR 3.94, 95%CI 1.11–14.05; P = 0.03) as compared with individuals at low probability. In conclusion, advanced liver fibrosis, determined by noninvasive fibrosis markers, is associated with CKD independently from other known factors. PMID:24520400

  5. Liver-Specific PGC-1beta Deficiency Leads to Impaired Mitochondrial Function and Lipogenic Response to Fasting-Refeeding

    PubMed Central

    Chambers, Kari T.; Chen, Zhouji; Crawford, Peter A.; Fu, Xiaorong; Burgess, Shawn C.; Lai, Ling; Leone, Teresa C.; Kelly, Daniel P.; Finck, Brian N.

    2012-01-01

    PGC-1β plays pleiotropic roles in regulating intermediary metabolism and has been shown to regulate both catabolic and anabolic processes in liver. We sought to evaluate the effects of PGC-1β on liver energy metabolism by generating mice with postnatal, liver-specific deletion of PGC-1β (LS-PGC-1β−/− mice). LS-PGC-1β−/− mice were outwardly normal, but exhibited a significant increase in hepatic triglyceride content at 6 weeks of age. Hepatic steatosis was due, at least in part, to impaired capacity for fatty acid oxidation and marked mitochondrial dysfunction. Mitochondrial DNA content and the expression of genes encoding multiple steps in mitochondrial fatty acid oxidation and oxidative phosphorylation pathways were significantly diminished in LS-PGC-1β−/− mice. Liquid chromatography mass spectrometry-based analyses also revealed that acetylcarnitine and butyrylcarnitine levels were depleted whereas palmitoylcarnitine content was increased in LS-PGC-1β−/− liver, which is consistent with attenuated rates of fatty acid oxidation. Interestingly, loss of PGC-1β also significantly impaired inducible expression of glycolytic and lipogenic enzymes that occurs with high carbohydrate diet refeeding after a prolonged fast. These results suggest that PGC-1β plays dual roles in regulating hepatic fatty acid metabolism by controlling the expression of programs of genes involved in both fatty acid oxidation and de novo fatty acid synthesis. PMID:23285128

  6. Mild Traumatic Brain Injury (mTBI) and chronic cognitive impairment: A scoping review.

    PubMed

    McInnes, Kerry; Friesen, Christopher L; MacKenzie, Diane E; Westwood, David A; Boe, Shaun G

    2017-01-01

    Mild traumatic brain injury (mTBI), or concussion, is the most common type of traumatic brain injury. With mTBI comes symptoms that include headaches, fatigue, depression, anxiety and irritability, as well as impaired cognitive function. Symptom resolution is thought to occur within 3 months post-injury, with the exception of a small percentage of individuals who are said to experience persistent post-concussion syndrome. The number of individuals who experience persistent symptoms appears to be low despite clear evidence of longer-term pathophysiological changes resulting from mTBI. In light of the incongruency between these longer-term changes in brain pathology and the number of individuals with longer-term mTBI-related symptoms, particularly impaired cognitive function, we performed a scoping review of the literature that behaviourally assessed short- and long-term cognitive function in individuals with a single mTBI, with the goal of identifying the impact of a single concussion on cognitive function in the chronic stage post-injury. CINAHL, Embase, and Medline/Ovid were searched July 2015 for studies related to concussion and cognitive impairment. Data relating to the presence/absence of cognitive impairment were extracted from 45 studies meeting our inclusion criteria. Results indicate that, in contrast to the prevailing view that most symptoms of concussion are resolved within 3 months post-injury, approximately half of individuals with a single mTBI demonstrate long-term cognitive impairment. Study limitations notwithstanding, these findings highlight the need to carefully examine the long-term implications of a single mTBI.

  7. Impaired glucose tolerance and predisposition to the fasted state in liver glycogen synthase knock-out mice.

    PubMed

    Irimia, Jose M; Meyer, Catalina M; Peper, Caron L; Zhai, Lanmin; Bock, Cheryl B; Previs, Stephen F; McGuinness, Owen P; DePaoli-Roach, Anna; Roach, Peter J

    2010-04-23

    Conversion to glycogen is a major fate of ingested glucose in the body. A rate-limiting enzyme in the synthesis of glycogen is glycogen synthase encoded by two genes, GYS1, expressed in muscle and other tissues, and GYS2, primarily expressed in liver (liver glycogen synthase). Defects in GYS2 cause the inherited monogenic disease glycogen storage disease 0. We have generated mice with a liver-specific disruption of the Gys2 gene (liver glycogen synthase knock-out (LGSKO) mice), using Lox-P/Cre technology. Conditional mice carrying floxed Gys2 were crossed with mice expressing Cre recombinase under the albumin promoter. The resulting LGSKO mice are viable, develop liver glycogen synthase deficiency, and have a 95% reduction in fed liver glycogen content. They have mild hypoglycemia but dispose glucose less well in a glucose tolerance test. Fed, LGSKO mice also have a reduced capacity for exhaustive exercise compared with mice carrying floxed alleles, but the difference disappears after an overnight fast. Upon fasting, LGSKO mice reach within 4 h decreased blood glucose levels attained by control floxed mice only after 24 h of food deprivation. The LGSKO mice maintain this low blood glucose for at least 24 h. Basal gluconeogenesis is increased in LGSKO mice, and insulin suppression of endogenous glucose production is impaired as assessed by euglycemic-hyperinsulinemic clamp. This observation correlates with an increase in the liver gluconeogenic enzyme phosphoenolpyruvate carboxykinase expression and activity. This mouse model mimics the pathophysiology of glycogen storage disease 0 patients and highlights the importance of liver glycogen stores in whole body glucose homeostasis.

  8. Is the neutrophil to lymphocyte ratio associated with liver fibrosis in patients with chronic hepatitis B?

    PubMed Central

    Kekilli, Murat; Tanoglu, Alpaslan; Sakin, Yusuf Serdar; Kurt, Mevlut; Ocal, Serkan; Bagci, Sait

    2015-01-01

    AIM: To determine the association between the neutrophil to lymphocyte (N/L) ratio and the degree of liver fibrosis in patients with chronic hepatitis B (CHB) infection. METHODS: Between December 2011 and February 2013, 129 consecutive CHB patients who were admitted to the study hospitals for histological evaluation of chronic hepatitis B-related liver fibrosis were included in this retrospective study. The patients were divided into two groups based on the fibrosis score: individuals with a fibrosis score of F0 or F1 were included in the “no/minimal liver fibrosis” group, whereas patients with a fibrosis score of F2, F3, or F4 were included in the “advanced liver fibrosis” group. The Statistical Package for Social Sciences 18.0 for Windows was used to analyze the data. A P value of < 0.05 was accepted as statistically significant. RESULTS: Three experienced and blinded pathologists evaluated the fibrotic status and inflammatory activity of 129 liver biopsy samples from the CHB patients. Following histopathological examination, the “no/minimal fibrosis” group included 79 individuals, while the “advanced fibrosis” group included 50 individuals. Mean (N/L) ratio levels were notably lower in patients with advanced fibrosis when compared with patients with no/minimal fibrosis. The mean value of the aspartate aminotransferase-platelet ratio index was markedly higher in cases with advanced fibrosis compared to those with no/minimal fibrosis. CONCLUSION: Reduced levels of the peripheral blood N/L ratio were found to give high sensitivity, specificity and predictive values in CHB patients with significant fibrosis. The prominent finding of our research suggests that the N/L ratio can be used as a novel noninvasive marker of fibrosis in patients with CHB. PMID:25987782

  9. Losartan may inhibit the progression of liver fibrosis in chronic HCV patients

    PubMed Central

    Salama, Zakaria A.; Sadek, Ahmed; Abdelhady, Ahmed M.; Morsy, Shereif Ahmed; Esmat, Gamal

    2016-01-01

    Background Abundant experimental evidence indicates overproduction of angiotensin II in the injured liver, and a role in stimulation of hepatic stellate cell (HSC) activation and fibrogenesis thereby, representing an attractive antifibrotic target. The aim of this study was to examine the antifibrotic effect of losartan on histopathologic level in chronic HCV patients. Methods A prospective study on fifty patients with chronic HCV and liver fibrosis proved by liver biopsy was conducted. They included patients who did not respond (n=36) or comply (n=2) or receive therapy due to established cirrhosis (n=10), or refused to receive (n=2) combined interferon and ribavirin therapy. They were divided randomly into 2 groups. The 1st group (n=25) was given losartan 50 mg OD for 1 year and the 2nd group (25 patients) was given silymarin, 140 mg t.i.d., (silymarin group). Liver biopsy was done at baseline and 1 year from the onset of treatment (end of study). Results In the second liver biopsy after 1 year, the decrease in fibrosis stage was significantly different between losartan group and silymarin group (a decrease of 1.88±0.96 (50.9%) vs. 0.45±0.93 (11.7%), respectively; P<0.01). In patients treated with losartan, regression in fibrosis stage was observed in 14/16 patients vs. 2/11 in silymarin group (P<0.01). No differences were observed in inflammation grades in both groups. A significant increase in albumin and prothrombin levels and a decrease in systolic blood pressure were found in losartan but not in silymarin group (P=0.009, 0.001 & 0.018 respectively and P=0.158, 0.603 & 0.288, respectively). Conclusions Histopathological scores showed that losartan had an inhibitory effect on progression and even led to regression of fibrosis stage but had no effect on the grade of inflammation. PMID:27275467

  10. Occurrence and significance of antibody to liver-specific membrane lipoprotein by double-antibody immunoprecipitation method in sera of patients with acute and chronic liver diseases.

    PubMed

    Kakumu, S; Arakawa, Y; Goji, H; Kashio, T; Yata, K

    1979-04-01

    A double-antibody immunoprecipitation method was developed for detecting antibody to liver-specific membrane lipoprotein (anti-LSP) in sera of patients with various liver diseases and primary nonhepatic autoimmune diseases. Liver-specific membrane lipoprotein prepared from normal rat livers was labeled with 125I (chloramine-T) and monospecific antibody raised in rabbits. Cross-reactivity and absorption studies demonstrated that the assay used was highly specific. The frequency and titer of anti-LSP were similar for HBsAg-positive and -negative patients with both acute and chronic liver diseases. Patients with chronic active hepatitis had the highest frequenzy (25 of 44 cases, 57%) when compared with those with chronic persistent hepatitis (5 of 23 cases, 22%) and nonalcoholic cirrhosis (8 of 21 cases, 38%). Of the anti-LSP positive cases, the mean titer in patients with chronic active hepatitis tended to be the highest. In patients recovered from acute viral hepatitis, anti-LSP was transiently positive (7 of 20 cases, 35%) in the acute phase. In those who progressed to chronic hepatitis, a late rise as well as an early rise occurred in 6 of 10 patients before the diagnosis was made. Two of 6 patients with primary biliary cirrhosis had anti-LSP, but none of 41 patients with other nonviral liver diseases and none of 60 patients with primary nonhepatic autoimmune diseases. These data indicate that an autoimmune reaction directed against LSP can be initiated during the acute phase of viral hepatitis and it may persist in chronic hepatitis in both HBsAg-positive and -negative cases.

  11. The unique alterations of hippocampus and cognitive impairment in chronic obstructive pulmonary disease

    PubMed Central

    2013-01-01

    Background Cognitive impairment has been found in chronic obstructive pulmonary disease (COPD) patients. However, the structural alteration of the brain and underlying mechanisms are poorly understood. Methods Thirty-seven mild-to-moderate COPD patients, forty-eight severe COPD patients, and thirty-one control subjects were recruited for cognitive test and neuroimaging studies. Serum levels of S100B,pulmonary function and arterial blood gas levels were also evaluated in each subject. Results The hippocampal volume was significantly smaller in COPD patients compared to the control group. It is positively correlated with a mini mental state examination (MMSE) score, SaO2 in mild-to-moderate COPD patients, the levels of PaO2 in both mild-to-moderate and severe COPD patients. Higher S100B concentrations were observed in mild-to-moderate COPD patients, while the highest S100B level was found in severe COPD patients when compared to the control subjects. S100B levels are negatively associated with MMSE in both mild-to-moderate and severe COPD patients and also negatively associated with the hippocampal volume in the total COPD patients. Conclusions Hippocampal atrophy based on quantitative assessment by magnetic resonance imaging does occur in COPD patients, which may be associated with cognitive dysfunction and the most prevalent mechanism accountable for hippocampal atrophy is chronic hypoxemia in COPD. Higher serum S100B levels may be peripheral biochemical marker for cognitive impairment in COPD. PMID:24359080

  12. Efficacy of Rho kinase inhibitor on cognitive impairment induced by chronic cerebral hypoperfusion in rats

    PubMed Central

    Zhang, Qiang; Zhang, Jun-Jian; Han, Zhong-Mou

    2015-01-01

    This work aims to explore the efficacy of Rho kinase inhibitor Fasudil on cognitive impairment induced by chronic cerebral hypoperfusion in rats. A total of 32 male adult Sprague Dawley (SD) rats were randomly divided into three groups: treatment group, control group and sham-operated group for severe carotid artery stenosis model. After two weeks, 8.35 mg/kg Fasudil and physiological saline were intraperitoneally applied twice per day in treatment group and control group, respectively. Morris water maze test was performed in each group to detect the changes of cognitive function and observe the hippocampal pathomorphology in rats after eight weeks. The average escape latency distinctly shortened (P < 0.01) and the percentage of swimming distance in the platform quadrant significantly increased (P < 0.01) in treatment group compared with those at corresponding time points in control group. The rate of carotid artery stenosis in rats had no statistical difference between treatment and control groups (P > 0.05). Fasudil effectively improved hippocampal pathomorphology. Rho kinase inhibitor obviously ameliorated cognitive impairment induced by chronic cerebral hypoperfusion in rats. PMID:25932185

  13. Assessing cardiac and liver iron overload in chronically transfused patients with sickle cell disease.

    PubMed

    Badawy, Sherif M; Liem, Robert I; Rigsby, Cynthia K; Labotka, Richard J; DeFreitas, R Andrew; Thompson, Alexis A

    2016-11-01

    Transfusional iron overload represents a substantial challenge in the management of patients with sickle cell disease (SCD) who receive chronic or episodic red blood cell transfusions. Iron-induced cardiomyopathy is a leading cause of death in other chronically transfused populations but rarely seen in SCD. Study objectives were to: (i) examine the extent of myocardial and hepatic siderosis using magnetic resonance imaging (MRI) in chronically transfused SCD patients, and (ii) evaluate the relationship between long-term (over the 5 years prior to enrolment) mean serum ferritin (MSF), spot-ferritin values and liver iron content (LIC) measured using MRI and liver biopsy. Thirty-two SCD patients (median age 15 years) with transfusional iron overload were recruited from two U.S. institutions. Long-term MSF and spot-ferritin values significantly correlated with LIC by MRI-R2* (r = 0·77, P < 0·001; r = 0·82, P < 0·001, respectively). LIC by MRI-R2* had strong positive correlation with LIC by liver biopsy (r = 0·98, P < 0·001) but modest inverse correlation with cardiac MRI-T2* (r = -0·41, P = 0·02). Moderate to severe transfusional iron overload in SCD was not associated with aberrations in other measures of cardiac function based on echocardiogram or serum biomarkers. Our results suggest that SCD patients receiving chronic transfusions may not demonstrate significant cardiac iron loading irrespective of ferritin trends, LIC and erythropoiesis suppression.

  14. Population-representative Incidence of Acute-On-Chronic Liver Failure

    PubMed Central

    Shao, Jian-Guo; Zhu, Yong-Chang; Xu, Ai-Dong; Yao, Jian-Hua; Wang, Xu-Lin; Qian, Yin-Kun; Wang, Hua-Yu; Shen, Yi; Lu, Peng; Wang, Lu-Jun

    2016-01-01

    Background: Acute-on-chronic liver failure (ACLF) is a major cause of hepatic death in the world, but no population-based studies have evaluated the incidence of ACLF. This study was conducted to determine the incidence and short-term outcomes of ACLF in a region of Eastern China. Methods: In this prospective cross-sectional study, we collected data from public hospitals in Nantong city between January 1, 2005, and December 31, 2014. All hospitals with admission potential for ACLF patients were included. The primary outcome was ACLF defined as severe jaundice and coagulopathy with underlying chronic liver disease, according to diagnostic and laboratory criteria suggested by Chinese Society for Hepatology (CSH). Results: During the 10-year period, a consecutive sample of 1934 ACLF patients was included in this study. The overall ACLF incidence rate over the 10-year period was 2.53 (95% confidence interval, 2.16-2.91) per 100,000 population per year, decreasing from 3.35 in 2005 to 2.06 in 2014. Chronic hepatitis B virus (HBV) infection was the leading cause of chronic liver disease and HBV reactivation was the most common cause of acute hepatic event. The 28-day mortality for the ACLF patients had a clear decline during the study period, form 50.39% in 2005 to 35.44% in 2014. Conclusions: In the Eastern China population, the incidence of ACLF is decreasing and the prognosis improving. Short-term mortality was associated with the presence of cirrhosis and growing age. While ACLF remains a life-threatening disorder, our findings suggest that nationwide and long-term cohorts should be conducted for the natural history of ACLF. PMID:27136963

  15. High antigen levels induce an exhausted phenotype in a chronic infection without impairing T cell expansion and survival

    PubMed Central

    Alfei, Francesca; Roelli, Patrick; Delorenzi, Mauro; Pinschewer, Daniel D.

    2016-01-01

    Chronic infections induce T cells showing impaired cytokine secretion and up-regulated expression of inhibitory receptors such as PD-1. What determines the acquisition of this chronic phenotype and how it impacts T cell function remain vaguely understood. Using newly generated recombinant antigen variant-expressing chronic lymphocytic choriomeningitis virus (LCMV) strains, we uncovered that T cell differentiation and acquisition of a chronic or exhausted phenotype depend critically on the frequency of T cell receptor (TCR) engagement and less significantly on the strength of TCR stimulation. In fact, we noted that low-level antigen exposure promotes the formation of T cells with an acute phenotype in chronic infections. Unexpectedly, we found that T cell populations with an acute or chronic phenotype are maintained equally well in chronic infections and undergo comparable primary and secondary expansion. Thus, our observations contrast with the view that T cells with a typical chronic infection phenotype are severely functionally impaired and rapidly transition into a terminal stage of differentiation. Instead, our data unravel that T cells primarily undergo a form of phenotypic and functional differentiation in the early phase of a chronic LCMV infection without inheriting a net survival or expansion deficit, and we demonstrate that the acquired chronic phenotype transitions into the memory T cell compartment. PMID:27455951

  16. Progenitor cell expansion and impaired hepatocyte regeneration in explanted livers from alcoholic hepatitis

    PubMed Central

    Dubuquoy, Laurent; Louvet, Alexandre; Lassailly, Guillaume; Truant, Stéphanie; Boleslawski, Emmanuel; Artru, Florent; Maggiotto, François; Gantier, Emilie; Buob, David; Leteurtre, Emmanuelle; Cannesson, Amélie; Dharancy, Sébastien; Moreno, Christophe; Pruvot, François-René; Bataller, Ramon; Mathurin, Philippe

    2015-01-01

    Objective In alcoholic hepatitis (AH), development of targeted therapies is crucial and requires improved knowledge of cellular and molecular drivers in liver dysfunction. The unique opportunity of using explanted livers from patients with AH having undergone salvage liver transplantation allowed to perform more in-depth molecular translational studies. Design We studied liver explants from patients with AH submitted to salvage transplantation (n=16), from patients with alcoholic cirrhosis without AH (n=12) and fragments of normal livers (n=16). Hepatic cytokine content was quantified. Hepatocyte function and proliferation and the presence of hepatic progenitor cells (HPCs) were evaluated by immunohistochemistry, western blot or quantitative PCR. Mitochondrial morphology was evaluated by electron microscopy. Results Livers from patients with AH showed decreased cytokine levels involved in liver regeneration (tumour necrosis factor α and interleukin-6), as well as a virtual absence of markers of hepatocyte proliferation compared with alcoholic cirrhosis and normal livers. Electron microscopy revealed obvious mitochondrial abnormalities in AH hepatocytes. Importantly, livers from patients with AH showed substantial accumulation of HPCs that, unexpectedly, differentiate only into biliary cells. AH livers predominantly express laminin (extracellular matrix protein favouring cholangiocyte differentiation); consequently, HPC expansion is inefficient at yielding mature hepatocytes. Conclusions AH not responding to medical therapy is associated with lack of expression of cytokines involved in liver regeneration and profound mitochondrial damage along with lack of proliferative hepatocytes. Expansion of HPCs is inefficient to yield mature hepatocytes. Manoeuvres aimed at promoting differentiation of HPCs into mature hepatocytes should be tested in AH. PMID:25731872

  17. General intellectual impairment in chronic right hemisphere damaged patients with anosognosia: a group study.

    PubMed

    Mattioli, F; Gialanella, B; Stampatori, C; Scarpazza, C

    2012-01-01

    The study evaluates the possible relations between cognitive impairment, persisting anosognosia for hemiplegia and peripersonal neglect. Thirty eight chronic right hemisphere stroke patients were divided in three age- and education-matched groups: A (n = 13) patients with left hemiparesis, peripersonal neglect, and anosognosia for hemiplegia; B (n = 12) patients with left hemiparesis and peripersonal neglect, and C (n = 13) patients with left hemiparesis only. We used MMSE and WAIS Verbal IQ and verbal subtests to assess cognitive impairment in patients, in order to avoid a bias due to visuospatial deficit, which is common in patients with neglect. VIQ, Information, Digit Span and Vocabulary WAIS subtests as well as MMSE were found to be significantly lower in group A versus group B. No difference was found in any test between groups B and C, indicating a general worse cognition in patients compared to those without anosognosia for hemiplegia. Patients with anosognosia for hemiplegia also showed larger brain lesions and, more frequently, frontal, parietal, temporal and basal ganglia involvement, particularly if they had low verbal IQ, indicating a relationship between cognitive impairment, persisting anosognosia for hemiplegia and large right hemisphere lesions.

  18. Protective effect of l-theanine on chronic restraint stress-induced cognitive impairments in mice.

    PubMed

    Tian, Xia; Sun, Lingyan; Gou, Lingshan; Ling, Xin; Feng, Yan; Wang, Ling; Yin, Xiaoxing; Liu, Yi

    2013-03-29

    The present work was aimed to study the protective effect of l-theanine on chronic restraint stress (CRS)-induced cognitive impairments in mice. The stress was produced by restraining the animals in well-ventilated polypropylene tubes (3.2 cm in diameter ×10.5 cm in length) for 8h once daily for 21 consecutive days. L-theanine (2 and 4 mg/kg) was administered 30 min before the animals subjected to acute immobilized stress. At week 4, mice were subjected to Morris water maze and step-through tests to measure the cognitive function followed by oxidative parameters and corticosterone as well as catecholamines (norepinephrine and dopamine) subsequently. Our results showed that the cognitive performances in CRS group were markedly deteriorated, accompanied by noticeable alterations in oxidative parameters and catecholamine levels in the hippocampus and the cerebral cortex as well as corticosterone and catecholamine levels in the serum. However, not only did l-theanine treatment exhibit a reversal of the cognitive impairments and oxidative damage induced by CRS, but also reversed the abnormal level of corticosterone in the serum as well as the abnormal levels of catecholamines in the brain and the serum. This study indicated the protective effect of l-theanine against CRS-induced cognitive impairments in mice.

  19. Impaired early visual response modulations to spatial information in chronic schizophrenia

    PubMed Central

    Knebel, Jean-François; Javitt, Daniel C.; Murray, Micah M.

    2011-01-01

    Early visual processing stages have been demonstrated to be impaired in schizophrenia patients and their first-degree relatives. The amplitude and topography of the P1 component of the visual evoked potential (VEP) are both affected; the latter of which indicates alterations in active brain networks between populations. At least two issues remain unresolved. First, the specificity of this deficit (and suitability as an endophenotype) has yet to be established, with evidence for impaired P1 responses in other clinical populations. Second, it remains unknown whether schizophrenia patients exhibit intact functional modulation of the P1 VEP component; an aspect that may assist in distinguishing effects specific to schizophrenia. We applied electrical neuroimaging analyses to VEPs from chronic schizophrenia patients and healthy controls in response to variation in the parafoveal spatial extent of stimuli. Healthy controls demonstrated robust modulation of the VEP strength and topography as a function of the spatial extent of stimuli during the P1 component. By contrast, no such modulations were evident at early latencies in the responses from patients with schizophrenia. Source estimations localized these deficits to the left precuneus and medial inferior parietal cortex. These findings provide insights on potential underlying low-level impairments in schizophrenia. PMID:21764264

  20. From the prodrome to chronic schizophrenia: the neurobiology underlying psychotic symptoms and cognitive impairments.

    PubMed

    Howes, O D; Fusar-Poli, P; Bloomfield, M; Selvaraj, S; McGuire, P

    2012-01-01

    Schizophrenia is a chronic psychotic disorder that remains a considerable cause of global disease burden. Cognitive impairments are common and contribute significantly to the morbidity of the disorder. Over the last two decades or so molecular imaging studies have refined understanding of the pathophysiology underlying the development of psychosis and cognitive impairments. Firstly they have consistently implicated presynaptic dopaminergic dysfunction in the disorder, finding that dopamine synthesis capacity, dopamine release and baseline dopamine levels are increased in the illness. Secondly recent findings show that dopamine synthesis capacity is elevated in those that go on to develop psychosis in the following year, but not in those that do not, and appears to increase further with the development of psychosis. Thirdly evidence links greater dopamine synthesis capacity to poorer cognitive performance and altered frontal cortical function measured using functional imaging during cognitive tasks. Finally they have provided data on the nature of other neurofunctional alterations in the disorder, in particular in the serotonergic system and neuroinflammation. We review these findings and discuss their implications for understanding the neurobiology of psychosis and cognitive impairments in schizophrenia.

  1. Impaired cerebral haemodynamic function associated with chronic traumatic brain injury in professional boxers.

    PubMed

    Bailey, Damian M; Jones, Daniel W; Sinnott, Andrew; Brugniaux, Julien V; New, Karl J; Hodson, Danielle; Marley, Christopher J; Smirl, Jonathan D; Ogoh, Shigehiko; Ainslie, Philip N

    2013-02-01

    The present study examined to what extent professional boxing compromises cerebral haemodynamic function and its association with CTBI (chronic traumatic brain injury). A total of 12 male professional boxers were compared with 12 age-, gender- and physical fitness-matched non-boxing controls. We assessed dCA (dynamic cerebral autoregulation; thigh-cuff technique and transfer function analysis), CVRCO₂ (cerebrovascular reactivity to changes in CO₂: 5% CO₂ and controlled hyperventilation), orthostatic tolerance (supine to standing) and neurocognitive function (psychometric tests). Blood flow velocity in the middle cerebral artery (transcranial Doppler ultrasound), mean arterial blood pressure (finger photoplethysmography), end-tidal CO₂ (capnography) and cortical oxyhaemoglobin concentration (near-IR spectroscopy) were continuously measured. Boxers were characterized by fronto-temporal neurocognitive dysfunction and impaired dCA as indicated by a lower rate of regulation and autoregulatory index (P<0.05 compared with controls). Likewise, CVRCO₂ was also reduced resulting in a lower CVRCO₂ range (P<0.05 compared with controls). The latter was most marked in boxers with the highest CTBI scores and correlated against the volume and intensity of sparring during training (r=-0.84, P<0.05). These impairments coincided with more marked orthostatic hypotension, cerebral hypoperfusion and corresponding cortical de-oxygenation during orthostatic stress (P<0.05 compared with controls). In conclusion, these findings provide the first comprehensive evidence for chronically impaired cerebral haemodynamic function in active boxers due to the mechanical trauma incurred by repetitive, sub-concussive head impact incurred during sparring training. This may help explain why CTBI is a progressive disease that manifests beyond the active boxing career.

  2. Analysis of hepatic gene expression during fatty liver change due to chronic ethanol administration in mice

    SciTech Connect

    Yin, H.-Q.; Je, Young-Tae; Kim, Mingoo; Kim, Ju-Han; Kong, Gu; Kang, Kyung-Sun; Kim, Hyung-Lae; Yoon, Byung-IL; Lee, Mi-Ock; Lee, Byung-Hoon

    2009-03-15

    Chronic consumption of ethanol can cause cumulative liver damage that can ultimately lead to cirrhosis. To explore the mechanisms of alcoholic steatosis, we investigated the global intrahepatic gene expression profiles of livers from mice administered alcohol. Ethanol was administered by feeding the standard Lieber-DeCarli diet, of which 36% (high dose) and 3.6% (low dose) of the total calories were supplied from ethanol for 1, 2, or 4 weeks. Histopathological evaluation of the liver samples revealed fatty changes and punctate necrosis in the high-dose group and ballooning degeneration in the low-dose group. In total, 292 genes were identified as ethanol responsive, and several of these differed significantly in expression compared to those of control mice (two-way ANOVA; p < 0.05). Specifically, the expression levels of genes involved in hepatic lipid transport and metabolism were examined. An overall net increase in gene expression was observed for genes involved in (i) glucose transport and glycolysis, (ii) fatty acid influx and de novo synthesis, (iii) fatty acid esterification to triglycerides, and (iv) cholesterol transport, de novo cholesterol synthesis, and bile acid synthesis. Collectively, these data provide useful information concerning the global gene expression changes that occur due to alcohol intake and provide important insights into the comprehensive mechanisms of chronic alcoholic steatosis.

  3. Relationships between NOS2 and HO-1 in liver of rats with chronic bile duct ligation.

    PubMed

    Flores, Olga; Criado, Manuela; Sánchez-Rodríguez, Angel; Hidalgo, Froilán; Collía, Francisco; López-Novoa, José Miguel; Esteller, Alejandro

    2005-05-01

    An increased expression and activity of the heme oxygenase-1 (HO-1) in the liver has been observed in models of hepatic damage. Nitric oxide (NO) seems to be involved in HO-1 regulation. The aim of this work is to assess HO-1 induction and heme oxygenase (HO) activity in rats with bile duct ligation (BDL). We have assessed the effect of chronic inhibition of the NO synthesis by N(G)-nitro-l-arginine methyl ester (l-NAME) on HO-1 induction and HO activity. In the BDL animals, compared with sham-operated ones, we found an increased plasma nitrite and bilirubin concentration, and a marked liver expression of inducible nitric oxide synthase and HO-1, assessed by both Western blot and immunohistochemistry. Chronic l-NAME treatment prevented plasma nitrite increase in animals subjected to BDL. BDL animals treated with l-NAME, compared with untreated BDL rats, showed an important decrease in HO-1 expression and in HO activity (assessed as a decreased plasma bilirubin and bilirubin excretion). In conclusion, our experiments show parallel changes in expression and activity of HO-1 and NOS2 activity in the BDL model of liver damage and suggest that increased NO production is involved in HO-1 overexpression.

  4. Fibro markers for prediction of hepatocellular carcinoma in egyptian patients with chronic liver disease.

    PubMed

    Mobarak, Lamiaa; Omran, Dalia; Nabeel, Mohammed M; Zakaria, Zeinab

    2016-10-21

    It is well known that hepatocellular carcinoma (HCC) develops as a consequence of hepatic fibrosis progression. In this study, we aimed to evaluate the inflammatory and fibrosis markers as predictors for HCC development among patients with hepatitis C virus (HCV) related chronic liver disease to help in early diagnosis and management of HCC. A total of 280 patients with chronic liver disease were included in this retrospective study, out of them 140 had liver cirrhosis with HCC and 140 had cirrhosis without HCC. Eight readily available blood indices King score, Fibro Q, AST-ALT ratio (AAR), APRI, LOK index, Goteborg University Cirrhosis Index (GUCI), fibro alpha, and Biotechnology Research Center (BRC) were constructed to compare the accuracies of these non invasive scores in predicting HCC development. All fibrosis scores except APRI were significantly higher in HCC. We found that Fibro alpha and BRC had superior diagnostic performance in prediction of HCC based on area under curve of 0.91 and 0.93, respectively compared to other scores with area under curve ranged from poor to failure (0.59-0.66). Almost all cirrhotic cases were secondary to HCV (93.6%), while HBV was detected in 2.1% of cases only. Anti-HCV positive was reported in 100% of HCC cases (P = 0.002). Fibro alpha and BRC scores can be used for prediction of HCC. J. Med. Virol. © 2016 Wiley Periodicals, Inc.

  5. Transfer factor in the attempted treatment of patients with HBsAg-positive chronic liver disease.

    PubMed Central

    Jain, S; Thomas, H C; Sherlock, S

    1977-01-01

    Six patients with hepatitis B surface antigen-positive (HBsAg-pos) chronic liver disease have been treated with transfer factor (TF) prepared from leucocytes of normal blood donors with no history of hepatitis, and with TF from subjects recently recovered from type B hepatitis. In three patients there were transient elevations of aspartate transaminase (AsT) after 'specific' TF, representing damage or destruction of hepatocytes, and in two of these patients there was coincidental complement consumption, suggesting that TF had stimulated production of antibody. In one other patient there was an increase in E-rosetting lymphocyte (ERL) concentration representing a change in T-lymphocyte reactivity. One of the two patients who had no measured response to TF had a primary liver cell carcinoma and was receiving prednisolone therapy. TF prepared from subjects who have recently recovered from type B hepatitis may have temporarily altered the immunological status of patients with HBsAg-pos chronic liver disease, but it did not have a beneficial therapeutic effect. PMID:606432

  6. Chronic hyperprolactinemia evoked by disruption of lactotrope dopamine D2 receptors impacts on liver and adipocyte genes related to glucose and insulin balance.

    PubMed

    Luque, Guillermina María; Lopez-Vicchi, Felicitas; Ornstein, Ana María; Brie, Belén; De Winne, Catalina; Fiore, Esteban; Perez-Millan, Maria Inés; Mazzolini, Guillermo; Rubinstein, Marcelo; Becu-Villalobos, Damasia

    2016-12-01

    We studied the impact of high prolactin titers on liver and adipocyte gene expression related to glucose and insulin homeostasis in correlation with obesity onset. To that end we used mutant female mice that selectively lack dopamine type 2 receptors (D2Rs) from pituitary lactotropes (lacDrd2KO), which have chronic high prolactin levels associated with increased body weight, marked increments in fat depots, adipocyte size, and serum lipids, and a metabolic phenotype that intensifies with age. LacDrd2KO mice of two developmental ages, 5 and 10 mo, were used. In the first time point, obesity and increased body weight are marginal, although mice are hyperprolactinemic, whereas at 10 mo there is marked adiposity with a 136% increase in gonadal fat and a 36% increase in liver weight due to lipid accumulation. LacDrd2KO mice had glucose intolerance, hyperinsulinemia, and impaired insulin response to glucose already in the early stages of obesity, but changes in liver and adipose tissue transcription factors were time and tissue dependent. In chronic hyperprolactinemic mice liver Prlr were upregulated, there was liver steatosis, altered expression of the lipogenic transcription factor Chrebp, and blunted response of Srebp-1c to refeeding at 5 mo of age, whereas no effect was observed in the glycogenesis pathway. On the other hand, in adipose tissue a marked decrease in lipogenic transcription factor expression was observed when morbid obesity was already settled. These adaptive changes underscore the role of prolactin signaling in different tissues to promote energy storage.

  7. Correlations of Hepatic Hemodynamics, Liver Function, and Fibrosis Markers in Nonalcoholic Fatty Liver Disease: Comparison with Chronic Hepatitis Related to Hepatitis C Virus.

    PubMed

    Shigefuku, Ryuta; Takahashi, Hideaki; Nakano, Hiroyasu; Watanabe, Tsunamasa; Matsunaga, Kotaro; Matsumoto, Nobuyuki; Kato, Masaki; Morita, Ryo; Michikawa, Yousuke; Tamura, Tomohiro; Hiraishi, Tetsuya; Hattori, Nobuhiro; Noguchi, Yohei; Nakahara, Kazunari; Ikeda, Hiroki; Ishii, Toshiya; Okuse, Chiaki; Sase, Shigeru; Itoh, Fumio; Suzuki, Michihiro

    2016-09-14

    The progression of chronic liver disease differs by etiology. The aim of this study was to elucidate the difference in disease progression between chronic hepatitis C (CHC) and nonalcoholic fatty liver disease (NAFLD) by means of fibrosis markers, liver function, and hepatic tissue blood flow (TBF). Xenon computed tomography (Xe-CT) was performed in 139 patients with NAFLD and 152 patients with CHC (including liver cirrhosis (LC)). The cutoff values for fibrosis markers were compared between NAFLD and CHC, and correlations between hepatic TBF and liver function tests were examined at each fibrosis stage. The cutoff values for detection of the advanced fibrosis stage were lower in NAFLD than in CHC. Although portal venous TBF (PVTBF) correlated with liver function tests, PVTBF in initial LC caused by nonalcoholic steatohepatitis (NASH-LC) was significantly lower than that in hepatitis C virus (C-LC) (p = 0.014). Conversely, the liver function tests in NASH-LC were higher than those in C-LC (p < 0.05). It is important to recognize the difference between NAFLD and CHC. We concluded that changes in hepatic blood flow occurred during the earliest stage of hepatic fibrosis in patients with NAFLD; therefore, patients with NAFLD need to be followed carefully.

  8. Correlations of Hepatic Hemodynamics, Liver Function, and Fibrosis Markers in Nonalcoholic Fatty Liver Disease: Comparison with Chronic Hepatitis Related to Hepatitis C Virus

    PubMed Central

    Shigefuku, Ryuta; Takahashi, Hideaki; Nakano, Hiroyasu; Watanabe, Tsunamasa; Matsunaga, Kotaro; Matsumoto, Nobuyuki; Kato, Masaki; Morita, Ryo; Michikawa, Yousuke; Tamura, Tomohiro; Hiraishi, Tetsuya; Hattori, Nobuhiro; Noguchi, Yohei; Nakahara, Kazunari; Ikeda, Hiroki; Ishii, Toshiya; Okuse, Chiaki; Sase, Shigeru; Itoh, Fumio; Suzuki, Michihiro

    2016-01-01

    The progression of chronic liver disease differs by etiology. The aim of this study was to elucidate the difference in disease progression between chronic hepatitis C (CHC) and nonalcoholic fatty liver disease (NAFLD) by means of fibrosis markers, liver function, and hepatic tissue blood flow (TBF). Xenon computed tomography (Xe-CT) was performed in 139 patients with NAFLD and 152 patients with CHC (including liver cirrhosis (LC)). The cutoff values for fibrosis markers were compared between NAFLD and CHC, and correlations between hepatic TBF and liver function tests were examined at each fibrosis stage. The cutoff values for detection of the advanced fibrosis stage were lower in NAFLD than in CHC. Although portal venous TBF (PVTBF) correlated with liver function tests, PVTBF in initial LC caused by nonalcoholic steatohepatitis (NASH-LC) was significantly lower than that in hepatitis C virus (C-LC) (p = 0.014). Conversely, the liver function tests in NASH-LC were higher than those in C-LC (p < 0.05). It is important to recognize the difference between NAFLD and CHC. We concluded that changes in hepatic blood flow occurred during the earliest stage of hepatic fibrosis in patients with NAFLD; therefore, patients with NAFLD need to be followed carefully. PMID:27649152

  9. Chronic intermittent hypoxia causes hepatitis in a mouse model of diet-induced fatty liver.

    PubMed

    Savransky, Vladimir; Bevans, Shannon; Nanayakkara, Ashika; Li, Jianguo; Smith, Philip L; Torbenson, Michael S; Polotsky, Vsevolod Y

    2007-10-01

    Obstructive sleep apnea (OSA) causes chronic intermittent hypoxia (CIH) during sleep. OSA is associated with nonalcoholic steatohepatitis (NASH) in obese individuals and may contribute to progression of nonalcoholic fatty liver disease from steatosis to NASH. The purpose of this study was to examine whether CIH induces inflammatory changes in the liver in mice with diet-induced hepatic steatosis. C57BL/6J mice (n = 8) on a high-fat, high-cholesterol diet were exposed to CIH for 6 mo and were compared with mice on the same diet exposed to intermittent air (control; n = 8). CIH caused liver injury with an increase in serum ALT (461 +/- 58 U/l vs. 103 +/- 16 U/l in the control group; P < 0.01) and AST (637 +/- 37 U/l vs. 175 +/- 13 U/l in the control group; P < 0.001), whereas alkaline phosphatase and total bilirubin levels were unchanged. Histology revealed hepatic steatosis in both groups, with mild accentuation of fat staining in the zone 3 hepatocytes in mice exposed to CIH. Animals exposed to CIH exhibited lobular inflammation and fibrosis in the liver, which were not evident in control mice. CIH caused significant increases in lipid peroxidation in serum and liver tissue; significant increases in hepatic levels of myeloperoxidase and proinflammatory cytokines IL-1beta, IL-6, and CXC chemokine MIP-2; a trend toward an increase in TNF-alpha; and an increase in alpha1(I)-collagen mRNA. We conclude that CIH induces lipid peroxidation and inflammation in the livers of mice on a high-fat, high-cholesterol diet.

  10. Impaired maraviroc and raltegravir clearance in a human immunodeficiency virus-infected patient with end-stage liver disease and renal impairment: a management dilemma.

    PubMed

    Pau, Alice K; Penzak, Scott R; Boyd, Sarita D; McLaughlin, Mary; Morse, Caryn G

    2012-01-01

    Current product labels for maraviroc and raltegravir provide no dosing guidance for patients with end-stage liver disease and worsening renal function. We describe a 41-year-old man with human immunodeficiency virus (HIV) infection and rapidly progressive liver failure and vanishing bile duct syndrome at presentation. Despite discontinuation of all potential offending drugs, the patient's liver function continued to deteriorate. To achieve and maintain HIV suppression while awaiting liver transplantation, a regimen consisting of maraviroc, raltegravir, and enfuvirtide was started. These agents were chosen because the patient was not exposed to them before the onset of liver failure. While receiving product label-recommended twice-daily dosing of these drugs, he achieved and maintained HIV suppression. During a complicated and prolonged hospitalization, the patient also developed renal dysfunction. As hepatic metabolism is the primary route of clearance of maraviroc and raltegravir, we predicted that using approved doses of these drugs could result in significant drug accumulation. Since the safety profiles of supratherapeutic concentrations of these agents are not well defined, we chose to use therapeutic drug monitoring to guide further dosing. The reported concentrations showed severely impaired metabolic clearance of both drugs, with markedly prolonged elimination half-lives of 189 hours for maraviroc and 61 hours for raltegravir. Previously reported half-lives for maraviroc and raltegravir in HIV-infected patients with normal hepatic and renal function are 14-18 hours and 9-12 hours, respectively. Based on these results, the dosing intervals were extended from twice/day to twice/week for maraviroc and every 48 hours for raltegravir. Unfortunately, the patient's clinical condition continued to deteriorate, and he eventually died of complications related to end-stage liver disease. This case illustrates the difficulties in managing antiretroviral therapy in

  11. Neuroprotective effect of Celastrus paniculatus on chronic stress-induced cognitive impairment

    PubMed Central

    Bhagya, V.; Christofer, Thomas; Shankaranarayana Rao, B. S.

    2016-01-01

    Objective: Several studies report that chronic stress results in impaired spatial learning and working memory and enhanced anxiety-like behavior. However, not many studies have looked into the possible ways of reversing stress-induced deficits. Celastrus paniculatus (CP), a traditional ayurvedic herbal medicine, was used to treat cognitive deficits in mentally retarded children. CP oil has been reported to have neuroprotective and antioxidant activities. However, the effects of CP oil on chronic stress-induced cognitive deficits are unclear. In the present study, we intended to analyze the neuroprotective effects of CP oil on stress-associated cognitive dysfunctions. Materials and Methods: Chronic stress was induced by subjecting rats to restrainers for 6 h a day for 21 days. CP oil (400, 600 mg/kg) or vehicle was administered intraperitoneally (i.p.) after stress protocol once a day over the next 14 days. Groups used in the present study: normal control, stress, stress + vehicle, stress + CP oil at 2 different doses (400 and 600 mg/kg, i.p.). After the drug treatment, open field and elevated plus maze (EPM) were used to analyze anxiety-like behavior, and partially baited radial arm maze (RAM) and T-maze were used to evaluate spatial learning and memory capabilities. Analysis has been done using two-way ANOVA followed by Bonferroni's post hoc test and one-way ANOVA followed by Tukey's post hoc test. Results: Stressed rats showed enhanced anxiety-like behavior in EPM (P < 0.001) and impaired performance in RAM (P < 0.001) and T-maze tasks (P < 0.001) compared to normal animals. In contrast, CP oil treatment to these rats improved their performance in both RAM (P < 0.001) and T-maze (P < 0.001). In addition, CP oil significantly reduced stress-induced anxiety behavior (P < 0.001). Conclusion: Chronic treatment with CP oil is to improve cognitive abilities in chronically stressed rats. The current study provides a novel perspective on beneficial effect of herbal

  12. Prior chronic nicotine impairs cued fear extinction but enhances contextual fear conditioning in rats.

    PubMed

    Tian, S; Gao, J; Han, L; Fu, J; Li, C; Li, Z

    2008-06-02

    Clinical observations have shown a link for the high comorbid rate between smoking and psychiatric disorders, including anxiety disorders. However, little is known about the neural mechanism underlying the progression from nicotine dependence to an anxiety disorder. A deficit in fear extinction in general is considered to contribute to anxiety disorders. The aim of the present study is to investigate the effects of chronic nicotine on fear extinction in rats. Rats were administrated s.c. nicotine twice per day for 14 days. Two weeks after the last injection rats received a cued or contextual fear conditioning session. Twenty-four hours and 48 h after conditioning, rats received an extinction training session and an extinction test session, respectively. Percent freezing was assessed during all phases of training. In the cued task, prior chronic nicotine did not affect the acquisition of fear response or the within-session fear extinction, but impaired the between-session fear extinction. In the contextual task, the same nicotine treatment schedule did not affect the acquisition of fear response or the within- and between-session fear extinction, but enhanced the retention of fear conditioning. This prior chronic nicotine-induced deficit in cued fear extinction and/or enhanced fear to context may be one of the critical components that contribute to the progression from nicotine dependence to an anxiety disorder.

  13. Increasing orthostatic stress impairs neurocognitive functioning in chronic fatigue syndrome with postural tachycardia syndrome.

    PubMed

    Ocon, Anthony J; Messer, Zachary R; Medow, Marvin S; Stewart, Julian M

    2012-03-01

    CFS (chronic fatigue syndrome) is commonly co-morbid with POTS (postural tachycardia syndrome). Individuals with CFS/POTS experience unrelenting fatigue, tachycardia during orthostatic stress and ill-defined neurocognitive impairment, often described as 'mental fog'. We hypothesized that orthostatic stress causes neurocognitive impairment in CFS/POTS related to decreased CBFV (cerebral blood flow velocity). A total of 16 CFS/POTS and 20 control subjects underwent graded tilt table testing (at 0, 15, 30, 45, 60 and 75°) with continuous cardiovascular, cerebrovascular, and respiratory monitoring and neurocognitive testing using an n-back task at each angle. The n-back task tests working memory, concentration, attention and information processing. The n-back task imposes increasing cognitive challenge with escalating (0-, 1-, 2-, 3- and 4-back) difficulty levels. Subject dropout due to orthostatic presyncope at each angle was similar between groups. There were no n-back accuracy or RT (reaction time) differences between groups while supine. CFS/POTS subjects responded less correctly during the n-back task test and had greater nRT (normalized RT) at 45, 60 and 75°. Furthermore, at 75° CFS/POTS subjects responded less correctly and had greater nRT than controls during the 2-, 3- and 4-back tests. Changes in CBFV were not different between the groups and were not associated with n-back task test scores. Thus we conclude that increasing orthostatic stress combined with a cognitive challenge impairs the neurocognitive abilities of working memory, accuracy and information processing in CFS/POTS, but that this is not related to changes in CBFV. Individuals with CFS/POTS should be aware that orthostatic stress may impair their neurocognitive abilities.

  14. Deregulation of Regulatory T Cells in Acute-on-Chronic Liver Failure: A Rat Model

    PubMed Central

    Ni, Shunlan; Li, Shanshan; Yang, Naibin; Tang, Xinyue; Zhang, Shengguo; Hu, Danping

    2017-01-01

    Aims. Acute-on-chronic liver failure (ACLF) and acute liver failure (ALF) are similar in many respects during their acute exacerbation; however, ACLF generally has a poorer prognosis. We aimed to investigate the role and dynamic changes of regulatory T cell (Treg) and T helper 17 (Th17) cell proportions during ACLF progress. Methods. All rats were classified into two groups randomly: ACLF group and ALF group (control group). The rat model of ACLF was preestablished by intraperitoneal injection of carbon tetrachloride for 2 months. Then acute liver injury was induced by combined D-galactosamine and lipopolysaccharide. Six time points were examined before or after acute induction. Liver samples were performed with hematoxylin-eosin and Masson staining; circulatory Treg and Th17 cell frequencies were determined using flow cytometry assays; serum levels of alanine aminotransferase, aspartate aminotransferase, interleukin-10 (IL-10), and interferon-γ (IFN-γ) were examined. Results. In group ACLF, both Th17 cell proportion and IFN-γ level presented upgrade firstly and then descend latter tendency; the trends of Treg cell proportion and IL-10 level were observed to gradually decrease and became stable. Conclusion. The Treg cells played an important role in the immunologic mechanism during the process of ACLF. And the function of Treg cells in ACLF was defective. PMID:28194045

  15. Analysis of T cell repertoire in the liver of patients with chronic hepatitis C

    PubMed Central

    Umemura, T; Yoshizawa, K; Ota, M; Katsuyama, Y; Inada, H; Tanaka, E; Kiyosawa, K

    2000-01-01

    Many T cells infiltrate into the liver of patients with chronic hepatitis C (CH-C). They are believed to play a crucial role in the immunopathogenesis of hepatic inflammation, but their clonality and specificity are unknown. The aim of this study was to clarify the characteristics of these T cells. We analysed the complementarity-determining region (CDR)3 size lengths of T cell receptor (TCR) β-chains by size spectratyping, and determined the sequences of Vβ CDR3 after subcloning Vβ-specific polymerase chain reaction products. Spectratyping showed clonal expansions in all liver specimens, most of which showed more than two T cell clones. Moreover, many non-clonal T cells also accumulated in the liver. Clonality of the T cells suspected by spectratyping was confirmed by CDR3 sequencing. Although the sequences revealed no whole CDR3-shared clones among different patients, some common motif sequences were observed. Our data suggest that T cells are stimulated by several hepatitis C virus (HCV) epitopes, then accumulate in the liver of CH-C patients. Shared motifs of expanded T cell clones suggest that they might recognize the same regions of HCV peptides, but have differences due to HCV peptide mutational changes. These clones might also interact with non-clonal T cells and play a crucial role in the immunopathogenesis of CH-C. PMID:10886248

  16. Fibrosis assessment: impact on current management of chronic liver disease and application of quantitative invasive tools.

    PubMed

    Wang, Yan; Hou, Jin-Lin

    2016-05-01

    Fibrosis, a common pathogenic pathway of chronic liver disease (CLD), has long been indicated to be significantly and most importantly associated with severe prognosis. Nowadays, with remarkable advances in understanding and/or treatment of major CLDs such as hepatitis C, B, and nonalcoholic fatty liver disease, there is an unprecedented requirement for the diagnosis and assessment of liver fibrosis or cirrhosis in various clinical settings. Among the available approaches, liver biopsy remains the one which possibly provides the most direct and reliable information regarding fibrosis patterns and changes in the parenchyma at different clinical stages and with different etiologies. Thus, many endeavors have been undertaken for developing methodologies based on the strategy of quantitation for the invasive assessment. Here, we analyze the impact of fibrosis assessment on the CLD patient care based on the data of recent clinical studies. We discuss and update the current invasive tools regarding their technological features and potentials for the particular clinical applications. Furthermore, we propose the potential resolutions with application of quantitative invasive tools for some major issues in fibrosis assessment, which appear to be obstacles against the nowadays rapid progress in CLD medicine.

  17. IRAKM-Mincle axis links cell death to inflammation: Pathophysiological implications for chronic alcoholic liver disease.

    PubMed

    Zhou, Hao; Yu, Minjia; Zhao, Junjie; Martin, Bradley N; Roychowdhury, Sanjoy; McMullen, Megan R; Wang, Emily; Fox, Paul L; Yamasaki, Sho; Nagy, Laura E; Li, Xiaoxia

    2016-12-01

    Lipopolysaccharide (LPS)-mediated activation of Toll-like receptors (TLRs) in hepatic macrophages and injury to hepatocytes are major contributors to the pathogenesis of alcoholic liver disease. However, the mechanisms by which TLR-dependent inflammatory responses and alcohol-induced hepatocellular damage coordinately lead to alcoholic liver disease are not completely understood. In this study, we found that mice deficient in interleukin-1 receptor-associated kinase M (IRAKM), a proximal TLR pathway molecule typically associated with inhibition of TLR signaling, were actually protected from chronic ethanol-induced liver injury. In bone marrow-derived macrophages challenged with low concentrations of LPS, which reflect the relevant pathophysiological levels of LPS in both alcoholic patients and ethanol-fed mice, the IRAKM Myddosome was preferentially formed. Further, the IRAKM Myddosome mediated the up-regulation of Mincle, a sensor for cell death. Mincle-deficient mice were also protected from ethanol-induced liver injury. The endogenous Mincle ligand spliceosome-associated protein 130 (SAP130) is a danger signal released by damaged cells; culture of hepatocytes with ethanol increased the release of SAP130. Ex vivo studies in bone marrow-derived macrophages suggested that SAP130 and LPS synergistically activated inflammatory responses, including inflammasome activation.

  18. Acute on Chronic Liver Failure-What is in a 'Definition'?

    PubMed

    Anand, Anil C; Dhiman, Radha K

    2016-09-01

    Acute on chronic liver failure (ACLF) is a recently recognized syndrome and its definition has been evolving over last two decades. Currently, there is no universal consensus about the definition as kind of cases being seen in the Western world appear to be somewhat different from those that are seen in Asia Pacific region. But every one agrees that definition of ACLF should include following components. (a) The status of pre-existing liver disease, (b) defining the acute insult that leads to rapid deterioration of liver status, (c) time frame during which the acute insult can lead to rapid deterioration, (d) the quantification and definition of liver failure status after deterioration, which will determine the severity of ACLF, and (e) prediction of prognosis after analyzing first four components in the short and long terms. There is some consensus that number of organ failures may be the main determinant of prognosis. Whatever the definition is being used, the central role that superadded infections play in ACLF cannot be denied and need to be tackled aggressively. Apart from that, recovery may be possible if the acute insult or the baseline disease is curable, i.e. with the use of nucleoside analogs for hepatitis B, and corticosteroids for severe autoimmune hepatitis. Development of dynamic criteria with observations in Hospital may improve our understanding of prognosis as well as our approach to the management of ACLF.

  19. The End-Organ Impairment in Liver Cirrhosis: Appointments for Critical Care

    PubMed Central

    Figueiredo, Antonio; Romero-Bermejo, Francisco; Perdigoto, Rui; Marcelino, Paulo

    2012-01-01

    Liver cirrhosis (LC) can lead to a clinical state of liver failure, which can exacerbate through the course of the disease. New therapies aimed to control the diverse etiologies are now more effective, although the disease may result in advanced stages of liver failure, where liver transplantation (LT) remains the most effective treatment. The extended lifespan of these patients and the extended possibilities of liver support devices make their admission to an intensive care unit (ICU) more probable. In this paper the LC is approached from the point of view of the pathophysiological alterations present in LC patients previous to ICU admission, particularly cardiovascular, but also renal, coagulopathic, and encephalopathic. Infections and available liver detoxifications devices also deserve mentioning. We intend to contribute towards ICU physician readiness to the care for this particular type of patients, possibly in dedicated ICUs. PMID:22666568

  20. Antibodies to liver membrane antigens in chronic active hepatitis (CAH). II. Specificity for autoimmune CAH.

    PubMed Central

    Frazer, I H; Kronborg, I J; Mackay, I R

    1983-01-01

    An immunoradiometric assay for IgG class autoantibody to liver membrane antigens, based on serum binding to glutaraldehyde treated monkey hepatocytes, was used to examine sera from patients with chronic active hepatitis (CAH) and other acute and chronic liver diseases. All sera from normals and patients showed binding, up to a titre of 1/2,048. For comparison of assays, results were normalized by selecting two reference sera, one with a high degree of binding, and one from a healthy subject with a low degree of binding: at a dilution of 1/2,048, these sera were given binding values of 100% and 0%. The values for the binding of unknown sera at the same dilution were calculated from these two reference values. For 26 patients with autoimmune CAH, the mean (+/- s.d.) percentage binding value (70 +/- 33%) was significantly higher than the mean value for 26 healthy subjects (10 +/- 15%), and high binding values were significantly associated with biochemically active hepatitis. The mean percentage binding value was moderately increased for eight patients with HBsAg associated CAH (42 +/- 12%), 13 patients with alcoholic hepatitis with cirrhosis (37 +/- 25%) and 45 patients with acute viral hepatitis A (40 +/- 27%) or B (52 +/- 37%). At a cut-off binding value of 65%, the assay as a single diagnostic procedure was shown to have a 70% sensitivity and a 95% specificity for the diagnosis of autoimmune CAH. Better understanding of the pathogenetic significance of antibodies to liver membrane antigens in CAH and other liver diseases will depend upon biochemical analysis of the presumably multiple antigenic determinants on the hepatocyte membrane. PMID:6616969

  1. Chronic exposure to ethanol causes steatosis and inflammation in zebrafish liver

    PubMed Central

    Schneider, Ana Claudia Reis; Gregório, Cleandra; Uribe-Cruz, Carolina; Guizzo, Ranieli; Malysz, Tais; Faccioni-Heuser, Maria Cristina; Longo, Larisse; da Silveira, Themis Reverbel

    2017-01-01

    AIM To evaluate the effects of chronic exposure to ethanol in the liver and the expression of inflammatory genes in zebrafish. METHODS Zebrafish (n = 104), wild type, adult, male and female, were divided into two groups: Control and ethanol (0.05 v/v). The ethanol was directly added into water; tanks water were changed every two days and the ethanol replaced. The animals were fed twice a day with fish food until satiety. After two and four weeks of trial, livers were dissected, histological analysis (hematoxilin-eosin and Oil Red staining) and gene expression assessment of adiponectin, adiponectin receptor 2 (adipor2), sirtuin-1 (sirt-1), tumor necrosis factor-alpha (tnf-a), interleukin-1b (il-1b) and interleukin-10 (il-10) were performed. Ultrastructural evaluations were conducted at fourth week. RESULTS Exposing zebrafish to 0.5% ethanol developed intense liver steatosis after four weeks, as demonstrated by oil red staining. In ethanol-treated animals, the main ultrastructural changes were related to cytoplasmic lipid particles and droplets, increased number of rough endoplasmic reticulum cisterns and glycogen particles. Between two and four weeks, hepatic mRNA expression of il-1b, sirt-1 and adipor2 were upregulated, indicating that ethanol triggered signaling molecules which are key elements in both hepatic inflammatory and protective responses. Adiponectin was not detected in the liver of animals exposed and not exposed to ethanol, and il-10 did not show significant difference. CONCLUSION Data suggest that inflammatory signaling and ultrastructural alterations play a significant role during hepatic steatosis in zebrafish chronically exposed to ethanol. PMID:28357029

  2. Cirrhotic cardiomyopathy: is there any correlation between the stage of cardiac impairment and the severity of liver disease?

    PubMed Central

    Hammami, Rania; Boudabbous, Mouna; Jdidi, Jihen; Trabelsi, Fatma; Mroua, Fakher; Kallel, Rahma; Amouri, Ali; Abid, Dorra; Tahri, Nabil; Abid, Leila; Kammoun, Samir

    2017-01-01

    ABSTRACT Cirrhotic cardiomyopathy is associated with poor prognosis and risk of acute heart failure after liver transplantation or interventional procedures. We aimed to assess the relationship between the severity of cardiac impairment and hepatic disease. Eighty patients and eighty controls underwent echocardiography, tissue Doppler imaging and speckle tracking measures. We assess the correlation between echocardiographic parameters and Child and MELD scores. Systolic parameters function (s wave, p < 0.001) and global longitudinal strain (p < 0.001) as well as diastolic parameters were significantly more impaired in cirrhotic patients compared to controls. There were no differences among the different groups in ‘Child score’ regarding systolic function as well as diastolic function. Paradoxically, the left atrium size correlated positively to both Child (p = 0.01, r = 0.26) and MELD scores (p = 0.02, r = 0.24). Left ventricular ejection fraction was significantly lower in decompensated patients as compared to compensated patients(p = 0.02).. We did not identify any association between severity of liver disease and cardiac dysfunction. Therefore, a transthoracic echocardiography should be performed in all cirrhotic patients before interventional and surgical procedures regardless of the severity of liver disease. PMID:28245727

  3. Antibodies to hepatitis A virus in Italian patients with chronic liver disease.

    PubMed

    Sagnelli, E; Rossi, G; Coppola, N; Scolastico, C; Onofrio, M; Filippini, P; Chiaramonte, M; Pizzigall, E; Aceti, A; Spadaro, A; Raimondo, G; Piccinino, F

    2001-10-01

    To improve our knowledge for future hepatitis A virus (HAV) vaccination strategies we carried out a multicentre study on naturally acquired immunological protection against HAV in patients with chronic hepatitis in Italy. We enrolled 830 consecutive patients with chronic hepatitis on their first observation at one of the six Italian liver units participating in the study. Six hundred and fifty-eight patients (79.3%) were positive for total anti-HAV and 172 (20.7%) were negative. The anti-HAV negative patients were younger (median age 33, range 11-78) than the anti-HAV positive (median age 56, 18-87). There was a higher prevalence of cases with circulating anti-HAV among the 508 patients residing in southern Italy than in the 322 residing in northern Italy (88.8% vs. 64%, P < 0.001). No significant difference in the anti-HAV prevalence was observed between patients from northern Italy and those from southern Italy aged 0-30 years or in those over 60 years, while in those 31-60 years old there was a higher prevalence of anti-HAV positive patients from southern Italy (90.2% vs. 65.8%, P < 0.0001). Of the patients with liver cirrhosis in this study, only 3 of the 26 (11.5%) from northern Italy and 8 of the 228 (3.5%) from southern Italy had no immunological protection against HAV infection. The data suggest that the number of patients with chronic liver disease without naturally acquired immunity against HAV is substantial in Italy, particularly in the north of the country, and that new vaccination strategies are needed.

  4. Transcriptional Dysregulation of Upstream Signaling of IFN Pathway in Chronic HCV Type 4 Induced Liver Fibrosis

    PubMed Central

    Ibrahim, Marwa K.; Salum, Ghada Maher; Bader El Din, Noha G.; Dawood, Reham M.; Barakat, Ahmed; Khairy, Ahmed; El Awady, Mostafa K.

    2016-01-01

    IFN orchestrates the expression of various genes to halt hepatitis C virus (HCV) replication with the possibility of either reduced or increased liver fibrosis; due to controlled viral replication or overproduction of inflammatory mediators, repectively. In this study, we examined the transcriptional profiling of type I IFN related genes in HCV-chronically infected patients with varying degrees of liver fibrosis. PCR array was used to examine the expression of 84 type I IFN related genes in peripheral blood mononuclear cells (PBMCs) RNA from 12 treatment-naïve chronic HCV patients (5 F0-F1 and 7 F2-F4) and 5 healthy subjects. We further validated our results by quantitative real time PCR (qRT-PCR) in 103 treatment-naïve chronic HCV patients (43 F0-F1 and 60 F2-F4) and 15 controls. PCR array data revealed dysregulation in TLR7 pathway. The expression of TLR7 was decreased by 4 folds and MyD88 was increased by 3 folds in PBMCs of F2-F4 patients when compared to the healthy volunteers (p = 0.03 and 0.002, respectively). In addition, IRF7 and TLR7 showed dramatic downregulation (6 and 8 folds, respectively) in F2-F4 patients when compared to F0-F1 ones. qRT-PCR confirmed the altered expression patterns of TLR7 and MyD88 in F2-F4 patients when compared to either controls or F0-F1 patients. However, by qRT-PCR, IRF7 and NF-κB1 (TLR7 pathway transcription factors) exhibited similar mRNA abundance among F2-F4 and F0-F1 patients. These results suggest that TLR7 and MyD88 are possible candidates as biomarkers for the progression of HCV-induced liver fibrosis and/ or targets for therapeutic intervention. PMID:27135246

  5. Transcriptional Dysregulation of Upstream Signaling of IFN Pathway in Chronic HCV Type 4 Induced Liver Fibrosis.

    PubMed

    Ibrahim, Marwa K; Salum, Ghada Maher; Bader El Din, Noha G; Dawood, Reham M; Barakat, Ahmed; Khairy, Ahmed; El Awady, Mostafa K

    2016-01-01

    IFN orchestrates the expression of various genes to halt hepatitis C virus (HCV) replication with the possibility of either reduced or increased liver fibrosis; due to controlled viral replication or overproduction of inflammatory mediators, repectively. In this study, we examined the transcriptional profiling of type I IFN related genes in HCV-chronically infected patients with varying degrees of liver fibrosis. PCR array was used to examine the expression of 84 type I IFN related genes in peripheral blood mononuclear cells (PBMCs) RNA from 12 treatment-naïve chronic HCV patients (5 F0-F1 and 7 F2-F4) and 5 healthy subjects. We further validated our results by quantitative real time PCR (qRT-PCR) in 103 treatment-naïve chronic HCV patients (43 F0-F1 and 60 F2-F4) and 15 controls. PCR array data revealed dysregulation in TLR7 pathway. The expression of TLR7 was decreased by 4 folds and MyD88 was increased by 3 folds in PBMCs of F2-F4 patients when compared to the healthy volunteers (p = 0.03 and 0.002, respectively). In addition, IRF7 and TLR7 showed dramatic downregulation (6 and 8 folds, respectively) in F2-F4 patients when compared to F0-F1 ones. qRT-PCR confirmed the altered expression patterns of TLR7 and MyD88 in F2-F4 patients when compared to either controls or F0-F1 patients. However, by qRT-PCR, IRF7 and NF-κB1 (TLR7 pathway transcription factors) exhibited similar mRNA abundance among F2-F4 and F0-F1 patients. These results suggest that TLR7 and MyD88 are possible candidates as biomarkers for the progression of HCV-induced liver fibrosis and/ or targets for therapeutic intervention.

  6. Comparison of Current Diagnostic Criteria for Acute-On-Chronic Liver Failure

    PubMed Central

    Han, Tao; Nie, CaiYun; Cai, JunJun; Liu, Hua; Liu, Ying

    2015-01-01

    Background and Aims Currently, acute-on-chronic liver failure (ACLF) has been defined differently by Asia–Pacific Association for the Study of the Liver (APASL) and Chinese Medical Association (CMA) in the East, as well as EASL-Chronic Liver Failure (EASL-CLIF) Consortium in the West. This study aimed to compare current different diagnostic criteria for ACLF and to determine predictors of the progression into post-enrollment EASL-CLIF ACLF from ACLF at enrollment defined by APASL alone or by both APASL and CMA but not by EASL-CLIF Consortium. Methods We retrospectively analyzed clinical data from 394 eligible cirrhotic patients fulfilling at least APASL criteria for ACLF at enrollment. Patient survival was estimated by Kaplan-Meier analysis and subsequently compared by log-rank test. Independent predictors of disease progression were determined using univariate analysis and multivariate Cox regression analysis. Results The 90-day mortality rate was 13.1% in patients with ACLF at enrollment defined by APASL alone, 25.3% in patients with ACLF at enrollment defined by both APASL and CMA but not EASL-CLIF Consortium, and 59.3% in patients with ACLF at enrollment defined by EASL-CLIF Consortium in addition to APASL. Baseline Chronic Liver Failure-Sequential Organ Failure Assessment (CLIF-SOFA) score, and the maximum rising rates of CLIF-SOFA score, Model for End-Stage Liver Disease-Sodium (MELD-Na) score and total bilirubin were independent predictors of progression into post-enrollment EASL-CLIF ACLF from ACLF at enrollment defined by APASL alone or by both APASL and CMA but not by EASL-CLIF Consortium. Conclusion Different diagnostic criteria for ACLF caused different patient prognosis. So, it is imperative to formulate a unifying diagnostic criteria for ACLF worldwide, thus attaining early identification and treatment, and eventual improvement in survival of ACLF patients. Baseline CLIF-SOFA score, and the maximum rising rates of CLIF-SOFA score, MELD-Na score and

  7. Chronic Exposure to Low Doses of Dioxin Promotes Liver Fibrosis Development in the C57BL/6J Diet-Induced Obesity Mouse Model

    PubMed Central

    Duval, Caroline; Teixeira-Clerc, Fatima; Leblanc, Alix F.; Touch, Sothea; Emond, Claude; Guerre-Millo, Michèle; Lotersztajn, Sophie; Barouki, Robert; Aggerbeck, Martine; Coumoul, Xavier

    2016-01-01

    Background: Exposure to persistent organic pollutants (POPs) has been associated with the progression of chronic liver diseases, yet the contribution of POPs to the development of fibrosis in non-alcoholic fatty liver disease (NAFLD), a condition closely linked to obesity, remains poorly documented. Objectives: We investigated the effects of subchronic exposure to low doses of the POP 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), an aryl hydrocarbon receptor ligand, on NAFLD progression in diet-induced obese C57BL/6J mice. Methods: Male C57BL/6J mice were fed either a 10% low-fat (LFD) or a 45% high-fat (HFD) purified diet for 14 weeks and TCDD-exposed groups were injected once a week with 5 μg/kg TCDD or the vehicle for the last 6 weeks of the diet. Results: Liver histology and triglyceride levels showed that exposure of HFD fed mice to TCDD worsened hepatic steatosis, as compared to either HFD alone or LFD plus TCDD and the mRNA levels of key genes of hepatic lipid metabolism were strongly altered in co-treated mice. Further, increased liver collagen staining and serum transaminase levels showed that TCDD induced liver fibrosis in the HFD fed mice. TCDD in LFD fed mice increased the expression of several inflammation and fibrosis marker genes with no additional effect from a HFD. Conclusions: Exposure to TCDD amplifies the impairment of liver functions observed in mice fed an enriched fat diet as compared to a low fat diet. The results provide new evidence that environmental pollutants promote the development of liver fibrosis in obesity-related NAFLD in C57BL/6J mice. Citation: Duval C, Teixeira-Clerc F, Leblanc AF, Touch S, Emond C, Guerre-Millo M, Lotersztajn S, Barouki R, Aggerbeck M, Coumoul X. 2017. Chronic exposure to low doses of dioxin promotes liver fibrosis development in the C57BL/6J diet-induced obesity mouse model. Environ Health Perspect 125:428–436; http://dx.doi.org/10.1289/EHP316 PMID:27713108

  8. Spleen Stiffness Is Superior to Liver Stiffness for Predicting Esophageal Varices in Chronic Liver Disease: A Meta-Analysis

    PubMed Central

    Ma, Xiaowen; Wang, Le; Wu, Hao; Feng, Yuemin; Han, Xibiao; Bu, Haoran; Zhu, Qiang

    2016-01-01

    Background and Aims Liver stiffness (LS) and spleen stiffness (SS) are two most widely accessible non-invasive parameters for predicting esophageal varices (EV), but the reported accuracy of the two predictors have been inconsistent across studies. This meta-analysis aims to evaluate the diagnostic performance of LS and SS measurement for detecting EV in patients with chronic liver disease (CLD), and compare their accuracy. Methods Pubmed/Medline, Embase, Cochrane Library and Ovid were searched for all studies assessing SS and LS simultaneously in EV diagnosis. A total of 16 studies including 1892 patients were included in this meta-analysis, and the pooled statistical parameters were calculated using the bivariate mixed effects models. Results In detection of any EV, for LS measurement, the summary sensitivity was 0.83 (95% confidence interval [CI]: 0.78–0.87), and the specificity was 0.66 (95% CI: 0.60–0.72). While for SS measurement, the pooled sensitivity and specificity was 0.88 (95% CI: 0.83–0.92) and 0.78 (95% CI: 0.73–0.83). The summary receiver operating characteristic (SROC) curve values of LS and SS were 0.81 (95% CI: 0.77–0.84) and 0.88 (95% CI: 0.85–0.91) respectively, and the results had statistical significance (P<0.01). The diagnostic odds ratio (DOR) of SS (25.73) was significantly higher than that of LS (9.54), with the relative DOR value was 2.48 (95%CI: 1.10–5.60), P<0.05. Conclusions Under current techniques, SS is significantly superior to LS for identifying the presence of EV in patients with CLD. SS measurement may help to select patients for endoscopic screening. PMID:27829057

  9. [The algorithm for the medical maintenance of the aircraft personnel suffering from chronic sensorineural impairment of hearing].

    PubMed

    Pankova, V B; Skryabina, L Yu; Barkhatova, O A

    2016-01-01

    The present study was designed to systematize the causes underlying the development of chronic sensorineural impairment of hearing in the aircraft personnel engaged in commercial aviation of the Russian Federation. A detailed clinical and audiological picture of chronic sensorineural loss of hearing in the aircraft personnel is presented with special reference to the criteria accepted in the civil aviationfor the evaluation of professional suitability and occupational selection in terms of hearing conditions. The study has demonstrated the paramount importance of the aviation medical expertise for the flight safety control in civil aviation. We analyzed the results of the audiological examination of the aircraft personnel suffering from chronic sensorineural impairment of hearing and proposed the algorithm for the rehabilitation of such subjects taking into consideration the stage of the chronic process.

  10. Soluble complement receptor type 1 (sCR1) in chronic liver diseases: serum levels at different stages of liver diseases.

    PubMed

    Di Bona, D; Montalto, G; Clemenza, L; Bascone, F; Accardo, P; Bellavia, D; Craxì, A; Brai, M

    1998-10-01

    Complement receptor type 1 (CR1) is an integral membrane protein of many haematopoietic cells and plays an important role in the clearance of complement-associated immune complexes, favouring their transport to liver and spleen macrophages. A small amount of soluble CR1 (sCR1) is also found in plasma and might originate directly from release of leucocytes and other circulating cells. In previous studies, an increase in serum sCR1 level has been observed in liver cirrhosis and end-stage renal failure. High levels have also been found in patients with some haematologic malignancies. sCR1 serum levels were measured using a specific double sandwich ELISA assay. The present study demonstrates the correlation between mean serum sCR1 concentrations and disease severity in patients with chronic liver disease. In patients with liver cirrhosis, grouped according to the Child-Pugh classification, sCR1 rose as liver function decreased. The presence of neoplastic growth in the liver apparently does not play a role in the increase of sCR1. Serum sCR1 was not elevated in other solid malignancies. Since sCR1 accumulates in liver diseases, evaluation of its serum levels could be useful as a liver function test.

  11. (14C)Aminopyrine breath test in chronic liver disease: preliminary diagnostic implications

    SciTech Connect

    Burnstein, A.V.; Galambos, J.T.

    1981-12-01

    The (14C)aminopyrine breath test (APBT) score, an estimate of hepatic mixed-oxidase function, was evaluated in 21 consecutive patients wih active nonalcoholic chronic liver diseases. Ten had primary biliary cirrhosis (PBC) and 11 had chronic active hepatitis (CAH). The APBT score was normal or elevated in patients with PBC (P less than 0.001), and lower than normal in CAH patients (P less than 0.01); 10.5 +/- 1.6 and 3.5 +/- 1.86, respectively, vs control 7.65 +/- 1.15 (mean +/- SD). The 11 patients with CAH included two middle-aged women who displayed ambiguous severe intrahepatic cholestasis. There was no overlap between the APBT scores of the 10 PBC and 11 CAH patients. These initial data suggest that the APBT may be helpful in the differentiation of PBC and CAH, including misleading cholestatic forms of CAH.

  12. Assessment of the "fish tumors or other deformities" beneficial use impairment in brown bullhead (Ameiurus nebulosus): II. Liver neoplasia

    USGS Publications Warehouse

    Blazer, V.S.; Rafferty, S.D.; Baumman, P.C.; Smith, S.B.; Obert, E.C.

    2009-01-01

    Liver pathology of fishes, including neoplastic and preneoplastic lesions, is widely used as an indicator of exposure to anthropogenic contaminants. By definition, the "fish tumor or other deformities" beneficial use impairment (BUI) at Great Lakes Areas of Concern (AOC) includes neoplastic and preneoplastic liver lesions in brown bullhead (Ameiurus nebulosus) or suckers. Unfortunately, adequate guidelines for defining neoplastic and preneoplastic liver lesions or determining rates at unimpacted control sites were not provided and different criteria have been used. In some cases, only neoplastic changes were used to calculate tumor prevalence, in some both neoplastic and preneoplastic changes and in some it is difficult to determine which changes were included. Using standardized criteria, the prevalence of liver neoplasia was compared at eight AOC during 1998-2000. The Cuyahoga River had the highest prevalence (25.0%), while the Maumee River had the lowest (3.9%). The Buffalo (4.8%), Detroit (5.9%), Ashtabula (6.8%), Niagara (7.5%) and Black (8.9%) rivers were intermediate, as was Presque Isle Bay (7.1%). From 2002 to 2007 the prevalence of liver neoplasia at Presque Isle Bay ranged from a low of 2.1% (2002) to a high of 12.0% (2007). Non-AOC sites, as potential reference sites, also were monitored during this time. By combining years and sites, the prevalence of liver neoplasia in bullhead (aged 2 to 12 years) at inland lakes was 0.7%, at bays/harbors was 1.6% and at tributary sites was 4.1%. This is the same trend (inland lakes < bays/harbors < tributaries < Presque Isle Bay) noted for orocutaneous neoplasms.

  13. Impaired Clearance of Apoptotic Cells in Chronic Inflammatory Diseases: Therapeutic Implications

    PubMed Central

    Szondy, Zsuzsa; Garabuczi, Éva; Joós, Gergely; Tsay, Gregory J.; Sarang, Zsolt

    2014-01-01

    In healthy individuals, billions of cells die by apoptosis every day. Removal of the dead cells by phagocytosis (a process called efferocytosis) must be efficient to prevent secondary necrosis and the consequent release of pro-inflammatory cell contents that damages the tissue environment and provokes autoimmunity. In addition, detection and removal of apoptotic cells generally induces an anti-inflammatory response. As a consequence improper clearance of apoptotic cells, being the result of either genetic anomalies and/or a persistent disease state, contributes to the establishment and progression of a number of human chronic inflammatory diseases such as autoimmune and neurological disorders, inflammatory lung diseases, obesity, type 2 diabetes, or atherosclerosis. During the past decade, our knowledge about the mechanism of efferocytosis has significantly increased, providing therapeutic targets through which impaired phagocytosis of apoptotic cells and the consequent inflammation could be influenced in these diseases. PMID:25136342

  14. Crepidiastrum denticulatum Extract Protects the Liver Against Chronic Alcohol-Induced Damage and Fat Accumulation in Rats

    PubMed Central

    Yoo, Ji-Hye; Kang, Kyungsu; Yun, Ji Ho; Kim, Mi Ae

    2014-01-01

    Abstract Alcohol is a severe hepatotoxicant that causes liver abnormalities such as steatosis, cirrhosis, and hepatocarcinoma. Crepidiastrum denticulatum (CD) is a well-known, traditionally consumed vegetable in Korea, which was recently reported to have bioactive compounds with detoxification and antioxidant properties. In this study, we report the hepatoprotective effect of CD extract against chronic alcohol-induced liver damage in vivo. The rats that were given CD extract exhibited decreased alanine aminotransferase, aspartate aminotransferase, and γ-glutamyl transpeptidase activities, which are liver damage markers that are typically elevated by alcohol consumption. The results were confirmed by histopathology with hematoxylin and eosin staining. Chronic alcohol consumption induced the formation of alcoholic fatty liver. However, treatment with CD extract dramatically decreased the hepatic lipid droplets. Treatment with CD extract also restored the antioxidative capacity and lipid peroxidation of the liver that had been changed by alcohol consumption. Furthermore, treatment with CD extract normalized the activities of the antioxidative enzymes superoxide dismutase, catalase, glutathione reductase, and glutathione peroxidase, which had been decreased by alcohol consumption. The results indicate that CD extract has protective effects against chronic alcohol hepatotoxicity in rats by increasing the liver's antioxidant capacity, and has potential as a dietary supplement intervention for patients with alcohol-induced liver damage. PMID:24650230

  15. NK cells lacking FcεRIγ are associated with reduced liver damage in chronic hepatitis C virus infection.

    PubMed

    Oh, Jun S; Ali, Alaa K; Kim, Sungjin; Corsi, Daniel J; Cooper, Curtis L; Lee, Seung-Hwan

    2016-04-01

    A novel subset of human natural killer (NK) cells, which displays potent and broad antiviral responsiveness in concert with virus-specific antibodies, was recently uncovered in cytomegalovirus (CMV)+ individuals. This NK-cell subset (g-NK) was characterized by a deficiency in the expression of FcεRIγ adaptor protein and the long-lasting memory-like NK-cell phenotype, suggesting a role in chronic infections. This study investigates whether the g-NK-cell subset is associated with the magnitude of liver disease during chronic hepatitis C virus (HCV) infection. Analysis of g-NK-cell proportions and function in the PBMCs of healthy controls and chronic HCV subjects showed that chronic HCV subjects had slightly lower proportions of the g-NK-cell subset having similarly enhanced antibody-dependent cellular cytotoxicity responses compared to conventional NK cells. Notably, among CMV+ chronic HCV patients, lower levels of liver enzymes and fibrosis were found in those possessing g-NK cells. g-NK cells were predominant among the CD56(neg) NK cell population often found in chronic HCV patients, suggesting their involvement in immune response during HCV infection. For the first time, our findings indicate that the presence of the g-NK cells in CMV+ individuals is associated with amelioration of liver disease in chronic HCV infection, suggesting the beneficial roles of g-NK cells during a chronic infection.

  16. SERUM MARKERS FOR ASSESSING LIVER FIBROSIS IN EGYPTIAN PA- TIENTS WITH CHRONIC HEPATITIS B AND C CO-INFECTION VERSUS CHRONIC HEPATITIS C.

    PubMed

    Mobarak, Lamiaa

    2016-04-01

    Chronic hepatitis B and C can progress to hepatic fibrosis and cirrhosis. The stage of liver fibrosis is critical for decision of treatment and prediction of outcomes, as life threatening complications highly develop in cirrhotic patients. The aim of this study was to evaluate the diagnostic accuracy of non-invasive serum markers in the assessment of liver fibrosis in patients with combined chronic hepatitis B and C versus those with chronic hepatitis C. This study included 2 groups; Gl: combined chronic hepatitis B & C, which included 71 patients and G2: chronic hepatitis C, which included 70 patients. Liver biopsy results from both groups were recorded. Three validated blood indices Fibro Q, Fibro alpha, and Biotechnology Research Center (BRC) were tested for optimal cut off values for assessing liver fibrosis in both groups. The results showed that the area under receiver operating characteristic curves (AUROC) for Fibro Q in differentiating significant fibrosis (> F2) from non-significant fibrosis (≤ F2) was 0.79 (95% CI: 0.60-0.89) in the first group and 0.85 (95% CI: 0.71-0.98) in the second group. AUROC for BRC was 0.76 (95% CI: 0.63-0.89) in the first group and 0.75 (CI: 0.60-0.89) in the second group. Fibro alpha performed less in both groups based on AUROC 0.69 and 0.68 in the first and second group respectively.

  17. Hepcidin as a Biomarker of Impaired Renal Function in Rat Models for Chronic Allograft Nephropathy.

    PubMed

    Xue, Dong; Zhou, Cuixing; Shi, Yunbo; Lu, Hao; He, Xiaozhou

    2016-02-23

    BACKGROUND To explore the use of hepcidin as a marker of impaired renal function in a rat model for chronic allograft nephropathy (CAN). MATERIAL AND METHODS Twenty-four models were developed and 20 models were included in this study, using Fisher (F344) rats (donors) and Lewis rats (recipients). Renal function tests were performed preoperatively and postoperatively. Hepcidin, interleukin-6 (IL-6), and erythropoietin levels in serum and urine were measured by enzyme-linked immunosorbent assay (ELISA). To observe pathological changes in the kidneys, 10 rats each were sacrificed at 2 months and 4 months after surgery. RESULTS After transplantation, the serum hepcidin and IL-6 levels increased, while urine hepcidin levels decreased. Erythropoietin levels showed a similar trend; all P<0.05. Serum creatinine (SCr) and blood urea nitrogen significantly increased post-operatively, with SCr positively correlating with serum hepcidin. Serum hepcidin positively correlated with IL-6 and negatively correlated with EPO. Histopathological results were consistent with CAN, after transplantation. CONCLUSIONS Hepcidin may be considered as a potential marker of impaired renal function.

  18. Olfactory Impairment in Chronic Rhinosinusitis Using Threshold, Discrimination, and Identification Scores.

    PubMed

    Soler, Zachary M; Kohli, Preeti; Storck, Kristina A; Schlosser, Rodney J

    2016-07-28

    Differences in testing modalities and cut-points used to define olfactory dysfunction contribute to the wide variability in estimating the prevalence of olfactory dysfunction in chronic rhinosinusitis (CRS). The aim of this study is to report the prevalence of olfactory impairment using each component of the Sniffin' Sticks test (threshold, discrimination, identification, and total score) with age-adjusted and ideal cut-points from normative populations. Patients meeting diagnostic criteria for CRS were enrolled from rhinology clinics at a tertiary academic center. Olfaction was assessed using the Sniffin' Sticks test. The study population consisted of 110 patients. The prevalence of normosmia, hyposmia, and anosmia using total Sniffin' Sticks score was 41.8%, 20.0%, and 38.2% using age-appropriate cut-points and 20.9%, 40.9%, and 38.2% using ideal cut-points. Olfactory impairment estimates for each dimension mirrored these findings, with threshold yielding the highest values. Threshold, discrimination, and identification were also found to be significantly correlated to each other (P < 0.001). In addition, computed tomography scores, asthma, allergy, and diabetes were found to be associated with olfactory dysfunction. In conclusion, the prevalence of olfactory dysfunction is dependent upon olfactory dimension and if age-adjusted cut-points are used. The method of olfactory testing should be chosen based upon specific clinical and research goals.

  19. Robotic therapy for chronic stroke: general recovery of impairment or improved task-specific skill?

    PubMed Central

    Goldsmith, Jeff; Harran, Michelle; Kane, Leslie; Berard, Jessica; Huang, Sylvia; Ryan, Sophia L.; Mazzoni, Pietro; Krakauer, John W.; Huang, Vincent S.

    2015-01-01

    There is a great need to develop new approaches for rehabilitation of the upper limb after stroke. Robotic therapy is a promising form of neurorehabilitation that can be delivered in higher doses than conventional therapy. Here we sought to determine whether the reported effects of robotic therapy, which have been based on clinical measures of impairment and function, are accompanied by improved motor control. Patients with chronic hemiparesis were trained for 3 wk, 3 days a week, with titrated assistive robotic therapy in two and three dimensions. Motor control improvements (i.e., skill) in both arms were assessed with a separate untrained visually guided reaching task. We devised a novel PCA-based analysis of arm trajectories that is sensitive to changes in the quality of entire movement trajectories without needing to prespecify particular kinematic features. Robotic therapy led to skill improvements in the contralesional arm. These changes were not accompanied by changes in clinical measures of impairment or function. There are two possible interpretations of these results. One is that robotic therapy only leads to small task-specific improvements in motor control via normal skill-learning mechanisms. The other is that kinematic assays are more sensitive than clinical measures to a small general improvement in motor control. PMID:26180120

  20. Impaired bactericidal but not fungicidal activity of polymorphonuclear neutrophils in patients with chronic lymphocytic leukemia.

    PubMed

    Kontoyiannis, Dimitrios P; Georgiadou, Sarah P; Wierda, William G; Wright, Susan; Albert, Nathaniel D; Ferrajoli, Alessandra; Keating, Michael; Lewis, Russell E

    2013-08-01

    We examined the qualitative polymorphonuclear neutrophil (PMN)-associated immune impairment in patients with chronic lymphocytic leukemia (CLL) by characterizing phagocytic killing of key non-opsonized bacterial (Staphylococcus aureus and Pseudomonas aeruginosa) and fungal (Candida albicans and Aspergillus fumigatus) pathogens. Neutrophils were collected from 47 non-neutropenic patients with CLL (PMN count > 1000/mm(3)) and age-matched and young healthy controls (five each). A subset of patients (13%) had prior or subsequent infections. We found that the patients with CLL had diminished PMN microbicidal response against bacteria but not against fungi compared with the controls. Compared to patients with effective PMN responses, we did not identify differences of basal PMN pathogen-associated molecular pattern receptor gene expression, soluble pathogen-associated molecular pattern gene expression or inflammatory cytokine signatures in patients with impaired PMN responses when PMNs were analyzed in multiplex real-time polymerase chain reaction assays. However, differences in PMN microbicidal response against A. fumigatus in patients with CLL were associated with the degree of hypogammaglobulinemia.

  1. Impaired bactericidal but not fungicidal activity of polymorphonuclear neutrophils in patients with chronic lymphocytic leukemia

    PubMed Central

    Kontoyiannis, Dimitrios P.; Georgiadou, Sarah P.; Wierda, William G.; Wright, Susan; Albert, Nathaniel D.; Ferrajoli, Alessandra; Keating, Michael; Lewis, Russell E.

    2013-01-01

    We examined the qualitative polymorphonuclear neutrophil (PMN)-associated immune impairment in patients with chronic lymphocytic leukemia (CLL) by characterizing phagocytic killing of key nonopsonized bacterial (Staphylococcus aureus and Pseudomonas aeruginosa) and fungal (Candida albicans and Aspergillus fumigatus) pathogens. Neutrophils were collected from 47 nonneutropenic CLL patients (PMN count > 1000/mm3), and age-matched and young healthy controls (five each). A subset of patients (13%) had prior or subsequent infections. We found that the CLL patients had diminished PMN microbicidal response against bacteria but not against fungi than did the controls. Compared to patients with effective PMN responses, we did not identify differences of basal PMN pathogen-associated molecular pattern receptor gene expression, soluble pathogen-associated molecular pattern gene expression, or inflammatory cytokine signatures in patients with impaired PMN responses when PMNs were analyzed in multiplex real-time polymerase chain reaction assays. However, differences in PMN microbicidal response against A. fumigatus in CLL patients were associated with the degree of hypogammaglobulinemia. PMID:23163595

  2. Robotic therapy for chronic stroke: general recovery of impairment or improved task-specific skill?

    PubMed

    Kitago, Tomoko; Goldsmith, Jeff; Harran, Michelle; Kane, Leslie; Berard, Jessica; Huang, Sylvia; Ryan, Sophia L; Mazzoni, Pietro; Krakauer, John W; Huang, Vincent S

    2015-09-01

    There is a great need to develop new approaches for rehabilitation of the upper limb after stroke. Robotic therapy is a promising form of neurorehabilitation that can be delivered in higher doses than conventional therapy. Here we sought to determine whether the reported effects of robotic therapy, which have been based on clinical measures of impairment and function, are accompanied by improved motor control. Patients with chronic hemiparesis were trained for 3 wk, 3 days a week, with titrated assistive robotic therapy in two and three dimensions. Motor control improvements (i.e., skill) in both arms were assessed with a separate untrained visually guided reaching task. We devised a novel PCA-based analysis of arm trajectories that is sensitive to changes in the quality of entire movement trajectories without needing to prespecify particular kinematic features. Robotic therapy led to skill improvements in the contralesional arm. These changes were not accompanied by changes in clinical measures of impairment or function. There are two possible interpretations of these results. One is that robotic therapy only leads to small task-specific improvements in motor control via normal skill-learning mechanisms. The other is that kinematic assays are more sensitive than clinical measures to a small general improvement in motor control.

  3. Fibrinogen plasma concentration is an independent marker of haemodynamic impairment in chronic thromboembolic pulmonary hypertension

    PubMed Central

    Hennigs, Jan K.; Baumann, Hans Jörg; Lüneburg, Nicole; Quast, Gesine; Harbaum, Lars; Heyckendorf, Jan; Sydow, Karsten; Schulte-Hubbert, Bernhard; Halank, Michael; Klose, Hans

    2014-01-01

    Fibrinogen has a crucial role in both inflammation and coagulation, two processes pivotal for the pathogenesis of pulmonary hypertension. We therefore aimed to investigate whether fibrinogen plasma concentrations a) are elevated in pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) and b) may serve as a novel biomarker for haemodynamic impairment. In a dual-centre, retrospective analysis including 112 patients with PAH (n = 52), CTEPH (n = 49) and a control cohort of patients with suspected PAH ruled out by right heart catheterisation (n = 11), we found fibrinogen plasma concentrations to be increased in patients with PAH (4.1 ± 1.4 g/l) and CTEPH (4.3 ± 1.2 g/l) compared to control patients (3.4 ± 0.5 g/l, p = 0.0035 and p = 0.0004, respectively). In CTEPH patients but not in PAH patients fibrinogen was associated with haemodynamics (p < 0.036) and functional parameters (p < 0.041). Furthermore, fibrinogen was linked to disease severity (WHO functional class, p = 0.017) and independently predicted haemodynamic impairment specifically in CTEPH (p < 0.016). Therefore, fibrinogen seems to represent an important factor in CTEPH pathophysiology and may have the potential to guide clinical diagnosis and therapy. PMID:24770447

  4. Serum microRNA-124 is a novel biomarker for liver necroinflammation in patients with chronic hepatitis B virus infection.

    PubMed

    Wang, J-Y; Mao, R-C; Zhang, Y-M; Zhang, Y-J; Liu, H-Y; Qin, Y-L; Lu, M-J; Zhang, J-M

    2015-02-01

    Patients with chronic hepatitis B virus (HBV) infection and normal or mildly increased transaminases may have sustained significant liver damage, as verified by liver biopsy. However, no suitable noninvasive method exists for identifying liver necroinflammation in such patients. We aimed to investigate the power of microRNA-124 as a novel biomarker for liver necroinflammation. A total of 131 recruited patients with chronic HBV infection underwent liver biopsy for grading of necroinflammation (G) and staging of fibrosis (S). Thirty healthy individuals were included as controls (HCs). Serum microRNA-124 and microRNA-122 levels were measured using qRT-PCR. Forty-five patients from the study population receiving entecavir therapy were monitored for changes in serum microRNA-124 levels in association with improved liver histology. The capacity of serum microRNA-124 levels in discriminating the grade of liver necroinflammation was compared with alanine aminotransferase (ALT) with liver biopsy validation. Serum microRNA-124 levels were significantly higher in patients with chronic HBV infection than in HCs (P < 0.0001). Patients with considerable liver necroinflammation (G ≥ 2) had significantly higher serum miRNA-124 levels than those without or with mild necroinflammation (P < 0.0001). After 48 weeks of antiviral therapy, serum microRNA-124 levels considerably declined in 45 patients (P < 0.0001), which were associated with histological improvement. In patients with normal ALT and a serum HBV DNA load >10(4) copies/mL, receiver operating characteristic (ROC) curve of serum microRNA-124 levels yielded an area under ROC curve (AUC) of 0.840, with 58.3% sensitivity and 91.7% specificity in discriminating between moderate-to-severe liver necroinflammation (G ≥ 2).

  5. Metabolic syndrome in childhood from impaired carbohydrate metabolism to nonalcoholic fatty liver disease.

    PubMed

    Manco, Melania

    2011-10-01

    Compelling evidence supports the concept that nonalcoholic fatty liver disease (NAFLD) represents the hepatic component of metabolic syndrome (MetS). Intrahepatic fat seems to predict more strongly than does visceral adiposity an individual's cardiovascular risk and the likelihood that metabolic abnormalities are present in youth. Young individuals with fatty liver are more insulin resistant and present with a higher prevalence of metabolic abnormalities than do individuals without intrahepatic fat accumulation. They also present with a certain endothelial dysfunction and greater carotid intima-media thickness. Conversely, youth with MetS seem to have an increased risk of developing liver inflammation, a condition termed nonalcoholic steatohepatitis (NASH), and fibrosis. In the context of MetS, the liver is central in that it can drive both hepatic and systemic insulin resistance, trigger low-grade inflammation, and promote atherogenic processes. In the context of MetS, NAFLD and altered carbohydrate metabolism track from childhood to adulthood. Thus, prevention, recognition, and effective treatment of these two abnormalities may limit the burden of morbidity and mortality associated with obesity and may delay onset of cardiovascular disease in early adulthood. The present review aims at systematically presenting evidence of the critical interplay of fatty liver and altered glucose metabolism in youth. It attempts to provide pathogenetic explanations for such an association and the rationale for its treatment, with particular regard to nutritional interventions. Key teaching points: Overweight and obese youth should be screened for fatty liver disease once after puberty by liver function tests and ultrasonography. Screening for fatty liver should be accurately performed in young patients with features of metabolic syndrome. Obese patients with fatty liver are at increased risk for altered glucose metabolism, thus they should undergo an oral glucose tolerance test

  6. Persistent p55TNFR expression impairs T cell responses during chronic tuberculosis and promotes reactivation

    PubMed Central

    Dambuza, Ivy M.; Keeton, Roanne; Hsu, Nai-Jen; Allie, Nasiema; Quesniaux, Valérie F. J.; Ryffel, Bernhard; Jacobs, Muazzam

    2016-01-01

    The pleiotropic activities of TNF are mediated by two structurally related but functionally distinct type I transmembrane receptors, p55TNFR and p75TNFR expressed in most cell types, that can be cleaved and act as TNF scavengers. Here, we investigated the effect of persistent p55TNFR cell surface expression during aerosol inhalation challenge with virulent M. tuberculosis H37Rv. We demonstrated that persistency of p55TNFR in macrophage cultures increased the synthesis of soluble TNF, p75TNFR and NO, however, had no effects on bacteria killing ability. Furthermore, it did not facilitate enhanced protection to primary acute M. tuberculosis infection in p55∆NS mice. Without exacerbated lung inflammation, we found a compensatory increase in p75TNFR shedding and decrease in bioactive TNF in BAL of p55∆NS mice after M. tuberculosis challenge. Defective expressions of CD44 and INFγ attributed to an impaired T cell response during persistent p55TNFR expression that caused marginal transient susceptibility during chronic infection. Moreover, persistent p55TNFR expression induced early reactivation during latent tuberculosis infection. These data indicate a prominent role of p55TNFR shedding in Th1 mediated protection against chronic and latent tuberculosis infection. PMID:27995986

  7. Muscle wasting and impaired muscle regeneration in a murine model of chronic pulmonary inflammation.

    PubMed

    Langen, Ramon C J; Schols, Annemie M W J; Kelders, Marco C J M; van der Velden, Jos L J; Wouters, Emiel F M; Janssen-Heininger, Yvonne M W

    2006-12-01

    Muscle wasting and increased circulating levels of inflammatory cytokines, including TNF-alpha, are common features of chronic obstructive pulmonary disease. To investigate whether inflammation of the lung is responsible for systemic inflammation and muscle wasting, we adopted a mouse model of pulmonary inflammation resulting from directed overexpression of a TNF-alpha transgene controlled by the surfactant protein C (SP-C) promoter. Compared with wild-type mice, SP-C/TNF-alpha mice exhibited increased levels of TNF-alpha in the circulation and increased endogenous TNF-alpha expression in skeletal muscle, potentially reflecting an amplificatory response to circulating TNF-alpha. Decreased muscle and body weights observed in SP-C/TNF-alpha mice were indicative of muscle wasting. Further evaluation of the SP-C/TNF-alpha mouse musculature revealed a decreased muscle regenerative capacity, shown by attenuated myoblast proliferation and differentiation in response to reloading of disuse-atrophied muscle, which may contribute to skeletal muscle wasting. Importantly, incubation of cultured myoblasts with TNF-alpha also resulted in elevated TNF-alpha mRNA levels and inhibition of myoblast differentiation. Collectively, our results demonstrate that chronic pulmonary inflammation results in muscle wasting and impaired muscle regeneration in SP-C/TNF-alpha mice, possibly as a consequence of an amplificatory TNF-alpha expression circuit extending from the lung to skeletal muscle.

  8. Bumblebee learning and memory is impaired by chronic exposure to a neonicotinoid pesticide.

    PubMed

    Stanley, Dara A; Smith, Karen E; Raine, Nigel E

    2015-11-16

    Bumblebees are exposed to pesticides applied for crop protection while foraging on treated plants, with increasing evidence suggesting that this sublethal exposure has implications for pollinator declines. The challenges of navigating and learning to manipulate many different flowers underline the critical role learning plays for the foraging success and survival of bees. We assessed the impacts of both acute and chronic exposure to field-realistic levels of a widely applied neonicotinoid insecticide, thiamethoxam, on bumblebee odour learning and memory. Although bees exposed to acute doses showed conditioned responses less frequently than controls, we found no difference in the number of individuals able to learn at field-realistic exposure levels. However, following chronic pesticide exposure, bees exposed to field-realistic levels learnt more slowly and their short-term memory was significantly impaired following exposure to 2.4 ppb pesticide. These results indicate that field-realistic pesticide exposure can have appreciable impacts on learning and memory, with potential implications for essential individual behaviour and colony fitness.

  9. Persistent p55TNFR expression impairs T cell responses during chronic tuberculosis and promotes reactivation.

    PubMed

    Dambuza, Ivy M; Keeton, Roanne; Hsu, Nai-Jen; Allie, Nasiema; Quesniaux, Valérie F J; Ryffel, Bernhard; Jacobs, Muazzam

    2016-12-20

    The pleiotropic activities of TNF are mediated by two structurally related but functionally distinct type I transmembrane receptors, p55TNFR and p75TNFR expressed in most cell types, that can be cleaved and act as TNF scavengers. Here, we investigated the effect of persistent p55TNFR cell surface expression during aerosol inhalation challenge with virulent M. tuberculosis H37Rv. We demonstrated that persistency of p55TNFR in macrophage cultures increased the synthesis of soluble TNF, p75TNFR and NO, however, had no effects on bacteria killing ability. Furthermore, it did not facilitate enhanced protection to primary acute M. tuberculosis infection in p55(∆NS) mice. Without exacerbated lung inflammation, we found a compensatory increase in p75TNFR shedding and decrease in bioactive TNF in BAL of p55(∆NS) mice after M. tuberculosis challenge. Defective expressions of CD44 and INFγ attributed to an impaired T cell response during persistent p55TNFR expression that caused marginal transient susceptibility during chronic infection. Moreover, persistent p55TNFR expression induced early reactivation during latent tuberculosis infection. These data indicate a prominent role of p55TNFR shedding in Th1 mediated protection against chronic and latent tuberculosis infection.

  10. Expression and integrity of dermatopontin in chronic cutaneous wounds: a crucial factor in impaired wound healing.

    PubMed

    Krishnaswamy, Venkat Raghavan; Manikandan, Mayakannan; Munirajan, Arasambattu Kannan; Vijayaraghavan, Doraiswamy; Korrapati, Purna Sai

    2014-12-01

    Chronic cutaneous wound (CCW) is a major health care burden wherein the healing process is slow or rather static resulting in anatomical and functional restriction of the damaged tissue. Dysregulated expression and degradation of matrix proteins, growth factors and cytokines contribute to the disrupted and uncoordinated healing process of CCW. Therefore, therapeutic approaches for effective management of CCW should be focused towards identifying and manipulating the molecular defects, such as reduced bioavailability of the pro-healing molecules and elevated activity of proteases. This study essentially deals with assessing the expression and integrity of an extracellular matrix protein, Dermatopontin (DPT), in CCW using real-time quantitative reverse transcriptase PCR and immunological techniques. The results indicate that, despite DPT's high mRNA expression, the protein levels are markedly reduced in both CCW tissue and its exudate. To elucidate the cause for this contradiction in mRNA and protein levels, the stability of DPT is analyzed in the presence of wound exudates and various proteases that are naturally elevated in CCW. DPT was observed to be degraded at higher rates when incubated with certain recombinant proteases or chronic wound exudate. In conclusion, the susceptibility of DPT protein to specific proteases present at high levels in the wound milieu resulted in the degradation of DPT, thus leading to impaired healing response in CCW.

  11. Relationship between ambulatory capacity and cardiorespiratory fitness in chronic stroke: Influence of stroke-specific impairments

    PubMed Central

    Pang, Marco YC; Eng, Janice J; Dawson, Andrew S

    2016-01-01

    Study Objectives To identify in individuals with chronic stroke (1) the relationship between the maximal oxygen uptake (VO2max) during cycle ergometry and the distance covered in the Six Minute Walk Test (6MWT), and (2) the stroke-specific impairments which are important determinants for the 6MWT distance. Design Cross-sectional study using a convenience sample. Setting Exercise testing laboratory in a tertiary rehabilitation center. Participants Sixty-three older adults (mean age ± standard deviation, 65.3 ± 8.7) with an average post-stroke interval of 5.5 ± 4.9 years. Intervention Not applicable Main Outcome Measures Each subject underwent a maximal cycle ergometer test and a 6MWT. Oxygen consumption (VO2) was measured during both tests. Subjects were also evaluated for Berg Balance Scale, Modified Ashworth Scale of Spasticity, isometric knee extension strength and percent body fat. Results The 6MW distance had a low correlation with the VO2max (r=0.402). Balance, knee extension strength and spasticity were all significant determinants for the 6MWT distance, with balance being the major contributor for the 6MWT distance, accounting for 66.5% of its variance. Conclusions Factors other than the cardiorespiratory status considerably influenced the ambulatory capacity as measured by the 6MWT. The 6MWT distance alone should not be used to indicate cardiorespiratory fitness in individuals with chronic stroke. PMID:15705987

  12. Resveratrol prevents impaired cognition induced by chronic unpredictable mild stress in rats.

    PubMed

    Liu, Dexiang; Zhang, Qingrui; Gu, Jianhua; Wang, Xueer; Xie, Kai; Xian, Xiuying; Wang, Jianmei; Jiang, Hong; Wang, Zhen

    2014-03-03

    Depression is one of the most common neuropsychiatric disorders and has been associated with impaired cognition, as well as causing neuroendocrine systems and brain proteins alterations. Resveratrol is a natural polyphenol enriched in polygonum cuspidatum and has diverse biological activities, including potent antidepressant-like effects. The aim of this study was to determine whether resveratrol administration influences chronic unpredictable mild stress (CUMS)-induced cognitive deficits and explores underlying mechanisms. The results showed that CUMS (5weeks) was effective in producing cognitive deficits in rats as indicated by Morris water maze and novel object recognition task. Additionally, CUMS exposure significantly elevated serum corticosterone levels and decreased BDNF levels in the prefrontal cortex (PFC) and hippocampus, accompanied by decreased phosphorylation of extracellular signal-regulated kinase (pERK) and cAMP response element-binding protein (pCREB). Chronic administration of resveratrol (80mg/kg, i.p., 5weeks) significantly prevented all these CUMS-induced behavioral and biochemical alterations. In conclusion, our study shows that resveratrol may be an effective therapeutic agent for cognitive disturbances as was seen within the stress model and its neuroprotective effect was mediated in part by normalizing serum corticosterone levels, up-regulating of the BDNF, pCREB and pERK levels.

  13. Bumblebee learning and memory is impaired by chronic exposure to a neonicotinoid pesticide

    PubMed Central

    Stanley, Dara A.; Smith, Karen E.; Raine, Nigel E.

    2015-01-01

    Bumblebees are exposed to pesticides applied for crop protection while foraging on treated plants, with increasing evidence suggesting that this sublethal exposure has implications for pollinator declines. The challenges of navigating and learning to manipulate many different flowers underline the critical role learning plays for the foraging success and survival of bees. We assessed the impacts of both acute and chronic exposure to field-realistic levels of a widely applied neonicotinoid insecticide, thiamethoxam, on bumblebee odour learning and memory. Although bees exposed to acute doses showed conditioned responses less frequently than controls, we found no difference in the number of individuals able to learn at field-realistic exposure levels. However, following chronic pesticide exposure, bees exposed to field-realistic levels learnt more slowly and their short-term memory was significantly impaired following exposure to 2.4 ppb pesticide. These results indicate that field-realistic pesticide exposure can have appreciable impacts on learning and memory, with potential implications for essential individual behaviour and colony fitness. PMID:26568480

  14. Pathology of chronic hepatitis C in children. Child Liver Study Group of Japan.

    PubMed

    Kage, M; Fujisawa, T; Shiraki, K; Tanaka, T; Fujisawa, T; Kimura, A; Shimamatsu, K; Nakashima, E; Kojiro, M; Koike, M; Tazawa, Y; Abukawa, D; Okaniwa, M; Takita, H; Matsui, A; Hayashi, T; Etou, T; Terasawa, S; Sugiyama, K; Tajiri, H; Yoden, A; Kajiwara, Y; Sata, M; Uchimura, Y

    1997-09-01

    Limited information is available regarding the histology of hepatitis C virus infection in children. The aim of this study was to determine the histological pattern of chronic hepatitis C (CHC) in children, and liver biopsy specimens from 109 pediatric patients with CHC were examined. Each biopsy specimen was evaluated based on a numerical scoring system for the stage of fibrosis (1-4), the grade of portal/periportal necroinflammation (0-4), the grade of lobular necroinflammation (0-4), and their sum (final grade). The histological lesions considered to be characteristic of chronic hepatitis were also evaluated. None of the children had liver cirrhosis, and 105 cases (97%) were stage 1 or 2. Only 4 children were stage 3. Two of these 4 cases showed hemosiderosis. A significant correlation was observed between the staging score and the final grade in the pediatric patients (r = .59; P < .0001). The histological characteristics of adult CHC, such as lymphoid aggregate, bile duct injury, and fatty changes, were also observed in the children. In conclusion, the majority of children with CHC presented with mild fibrosis, but a few showed CHC with lobular distortion and hemosiderosis. Frequent blood transfusion may aggravate hepatic lesions in pediatric CHC.

  15. Association between plasma fibrinogen levels and mortality in acute-on-chronic hepatitis B liver failure.

    PubMed

    Shao, Zhexin; Zhao, Ying; Feng, Limin; Feng, Guofang; Zhang, Juanwen; Zhang, Jie

    2015-01-01

    Acute-on-chronic liver failure (AoCLF) is the most common type of liver failure and is associated with high mortality. Fibrinogen is critical in maintaining primary and secondary hemostasis. Therefore, we prospectively analyzed the association between fibrinogen and outcomes in AoCLF patients. Plasma fibrinogen was measured in 169 AoCLF, 173 chronic hepatitis B (CHB), and 171 healthy patients using a coagulation method. The predictive ability of fibrinogen for 3-month mortality in AoCLF patients was assessed using receiver operating characteristic (ROC) curve and multivariable logistic regression analyses. Plasma fibrinogen was significantly lower in nonsurvivor AoCLF patients compared with survivor AoCLF, CHB, and control patients. The sensitivity, specificity, and area under the ROC curve of 1/fibrinogen predicting mortality in AoCLF patients were 66.7%, 72.5%, and 0.746 (95% confidence interval (CI): 0.672-0.820, P < 0.001), and the fibrinogen cutoff value was 0.90 g/L. On multivariate logistic regression analysis, low fibrinogen was an independent factor predicting mortality (odds ratio: 0.304; 95% CI: 0.094-0.983; P = 0.047). Nonsurvivor AoCLF patients had significantly decreased fibrinogen levels, suggesting that low plasma fibrinogen may be a useful predictor of poor prognosis in AoCLF patients.

  16. Serum sialic acid in malignant tumors, bacterial infections, and chronic liver diseases.

    PubMed

    Stefenelli, N; Klotz, H; Engel, A; Bauer, P

    1985-01-01

    The total serum sialic acid concentration was determined in 2,264 persons with various malignant tumors, bacterial infections, rheumatic diseases, and chronic liver diseases, and in a control group. The thiobarbiturate method according to Warren was used. The upper limit (95% percentile) in the control group was 2.23 mumol/ml. Higher values were found in the groups with neoplasms (mean: 3.04 mumol/ml), inflammatory diseases (e.g., pneumonia: 3.02 mumol/ml), and active rheumatoid arthritis (3.05 mumol/ml). In the group with malignant diseases, the sialic acid concentration at the time of diagnosis was highest for bronchial carcinoma (3.29 mumol/ml) and lowest for breast cancer (2.58 mumol/ml). In chronic liver diseases the mean sialic acid level was lower than in a heterogeneous group of noninflammatory and nonneoplastic diseases. The estimation of the serum sialic acid concentration could be useful in the detection of tumor burden and metastases, and in the evaluation of the later course and prognosis of malignant neoplasms if bacterial/inflammatory and active rheumatoid processes can be excluded.

  17. Immunohistochemical expression of growth factors in the exocrine pancreas of patients with chronic liver diseases.

    PubMed

    Mateescu, Garofiţa; Comănescu, Maria; Mehedinţi, Rodica; Niculescu, Zizi; Bold, Adriana; Panduru, Laurenţia; Cernea, Daniela

    2010-01-01

    Acute viral hepatitis has been reported to cause acute pancreatitis. It was also reported that exocrine pancreatic function is damaged in chronic liver disease (CLD). Growth factors stored in the extracellular matrix and released in the course of pancreatic degradation are major mediators of inductive processes. The immunostaining technique was used to evidence the changes of the expression of the growth factors in different pancreatic cells. VEGF and FGF-beta are involved in the angiogenesis processes and in the evolution of the pancreatic interstitial tissue in case of chronic pancreatitis. Theses markers can also be used for the diagnosis of pancreatitis, but their value is variable. They stimulate the pancreatic star cells, the myofibroblasts and play an important role in the genesis of the extracellular matrix and in the repairing of the tissue after the aggression. TGF beta is important for its role in cellular differentiation and growth and in the development of the fibrosis in liver and other organs. The present paper studies the immunohistochemical expression of these growth factors in pancreatic cells.

  18. Meta-analyses of FibroTest diagnostic value in chronic liver disease

    PubMed Central

    Poynard, Thierry; Morra, Rachel; Halfon, Philippe; Castera, Laurent; Ratziu, Vlad; Imbert-Bismut, Françoise; Naveau, Sylvie; Thabut, Dominique; Lebrec, Didier; Zoulim, Fabien; Bourliere, Marc; Cacoub, Patrice; Messous, Djamila; Munteanu, Mona; de Ledinghen, Victor

    2007-01-01

    Background FibroTest (FT) is a biomarker of liver fibrosis initially validated in patients with chronic hepatitis C (CHC). The aim was to test two hypotheses, one, that the FT diagnostic value was similar in the three other frequent fibrotic diseases: chronic hepatitis B (CHB), alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD); and the other, that the FT diagnostic value was similar for intermediate and extreme fibrosis stages. Methods The main end points were the FT area under the ROC curves (AUROCs) for the diagnosis of bridging fibrosis (F2F3F4 vs. F0F1), standardized for the spectrum of fibrosis stages, and the comparison of FT AUROCs between adjacent stages. Two meta-analyses were performed: one combining all the published studies (random model), and one of an integrated data base combining individual data. Sensitivity analysis integrated the independency of authors, lenght of biopsy, prospective design, respect of procedures, comorbidities, and duration between biopsy and serum sampling. Results A total of 30 studies were included which pooled 6,378 subjects with both FT and biopsy (3,501 HCV, 1,457 HBV, 267 NAFLD, 429 ALD, and 724 mixed). Individual data were analyzed in 3,282 patients. The mean standardized AUROC was 0.84 (95% CI, 0.83–0.86), without differences between causes of liver disease: HCV 0.85 (0.82–0.87), HBV 0.80 (0.77–0.84), NAFLD 0.84 (0.76–0.92), ALD 0.86 (0.80–0.92), mixed 0.85 (0.80–0.93). The AUROC for the diagnosis of the intermediate adjacent stages F2 vs. F1 (0.66; 0.63–0.68, n = 2,055) did not differ from that of the extreme stages F3 vs. F4 (0.69; 0.65–0.72, n = 817) or F1 vs. F0 (0.62; 0.59–0.65, n = 1788). Conclusion FibroTest is an effective alternative to biopsy in patients with chronic hepatitis C and B, ALD and NAFLD. The FT diagnostic value is similar for the diagnosis of intermediate and extreme fibrosis stages. PMID:17937811

  19. Hepatitis A and B screening and vaccination rates among patients with chronic liver disease.

    PubMed

    Ramirez, Jonathan C; Ackerman, Kimberly; Strain, Sasha C; Ahmed, Syed T; de Los Santos, Mario J; Sears, Dawn

    2016-01-01

    Vaccinations against hepatitis A virus (HAV) and hepatitis B virus (HBV) are recommended for patients with chronic liver disease (CLD), yet implementation of these recommendations is lacking. This study reviewed HAV and HBV antibody testing and vaccination status of patients with CLD. In 2008, we began using pre-printed liver order sets, which included vaccination options. We compared Scott & White liver clinic CLD patient records from 2005 (238) with patient records from 2008 (792). Screening rates for immunity and vaccination rates of those lacking immunity were calculated. In 2005, 66% of CLD patients were screened for HAV immunity. In 2008, 56% of CLD patients were screened. The HAV vaccination completion rate was 37% in 2005, while in 2008, the rate was 46%. In 2005, 66% of CLD patients were screened for HBV immunity; in 2008, 56 % CLD patients were screened. The HBV vaccination completion rate was 26% in 2005 compared with 36% in 2008. Although there was a lower percentage of screening in 2008, the overall number of patients tripled between 2005 and 2008. There was a significant increase in the total number of patients screened and vaccinated in 2008. Some physicians may have vaccinated their patients without checking for immunity. In January 2008, we implemented pre-printed order sets with checkboxes to help remind providers to order labs to screen for immunity against HAV and HBV and to order vaccinations for those who lacked immunity. The use of these sets may have aided in the increase of vaccination completion rates.

  20. Impact of preoperative chronic renal failure on liver transplantation: a population-based cohort study

    PubMed Central

    Chung, Peter Chi-Ho; Chen, Hsiu-Pin; Lin, Jr-Rung; Liu, Fu-Chao; Yu, Huang-Ping

    2016-01-01

    Purpose The purpose of this study was to assess whether preoperative chronic renal failure (CRF) affects the rates of postoperative complications and survival after liver transplantation. Methods This population-based retrospective cohort study included 2,931 recipients of liver transplantation performed between 1998 and 2012, enrolled from the Taiwan National Health Insurance Research Database. Patients were divided into two groups, based on the presence or absence of preoperative CRF. Results The overall estimated survival rate of liver transplantation recipients (LTRs) with preoperative CRF was significantly lower than that of patients without preoperative CRF (P=0.0085). There was no significant difference between the groups in terms of duration of intensive care unit stay, total hospital stay, bacteremia, postoperative bleeding, and pneumonia during hospitalization. Long-term adverse effects, including cerebrovascular disease and coronary heart disease, were not different between patients with versus without CRF. Conclusion These findings suggest that LTRs with preoperative CRF have a higher rate of mortality. PMID:28008264

  1. [Central neurobiological mechanism of liver depression and spleen deficiency syndrome based on chronic stress: a review].

    PubMed

    Li, Xiao-hong; Li, Jing-jing; Liu, Yue-yun; Chen, Jia-xu

    2012-01-01

    Some researchers focus on research of the nature of syndromes. The methods of combining traditional Chinese medicine syndrome and diseases and the correspondence between formulas and syndromes may be used in research of the nature of syndromes. According to combined theories of zang-organ state and seven emotions in traditional Chinese medicine with stress theory in modern medicine, the authors applied the methods of chronic immobilization stress to induce liver depression and spleen deficiency syndrome in rats based on the thinking of relativity on formula and syndrome. The research showed that the central neurobiology mechanism of liver depression and spleen deficiency syndrome closely correlates to the hypothalamic-pituitary-adrenal axis, brain-gut axis, myriad central neurotrophic factors, neurotransmitters, neuropeptides and hormones and their receptors, involving in many encephalic regions such as the hypothalamus, hippocampus, cortex, amygdale, etc. The authors will combine their previous work with multi-disciplinary research, such as genomics, proteomics, metabolomics and bioinformatics in future studies, to reveal the scientific connotations of liver depression and spleen deficiency syndrome.

  2. Acute-on-chronic liver failure: A new syndrome that will re-classify cirrhosis.

    PubMed

    Arroyo, Vicente; Moreau, Richard; Jalan, Rajiv; Ginès, Pere

    2015-04-01

    Acute-on-chronic liver failure (ACLF) is a recently recognized syndrome characterized by acute decompensation (AD) of cirrhosis and organ/system failure(s) (organ failure: liver, kidney, brain, coagulation, circulation and/or respiration) and extremely poor survival (28-day mortality rate 30-40%). ACLF occurs in relatively young patients. It is especially frequent in alcoholic- and untreated hepatitis B associated-cirrhosis, in addition it is related to bacterial infections and active alcoholism, although in 40% of cases no precipitating event can be identified. It may develop at any time during the course of the disease in the patient (from compensated to long-standing cirrhosis). The development of ACLF occurs in the setting of a systemic inflammation, the severity of which correlates with the number of organ failures and mortality. Systemic inflammation may cause ACLF through complex mechanisms including an exaggerated inflammatory response and systemic oxidative stress to pathogen- or danger/damage-associated molecular patterns (immunopathology) and/or alteration of tissue homeostasis to inflammation caused either by the pathogen itself or through a dysfunction of tissue tolerance. A scoring system composed of three scores (CLIF-C OFs, CLIF-C AD, and CLIF-C ACLFs) specifically designed for patients with AD, with and without ACLF, allows a step-wise algorithm for a rational indication of therapy. The management of ACLF should be carried out in enhanced or intensive care units. Current therapeutic measures comprise the treatment for associated complications, organ failures support and liver transplantation.

  3. S100 protein positive dendritic cells in primary biliary cirrhosis and other chronic inflammatory liver diseases. Relevance to pathogenesis?

    PubMed Central

    Demetris, A. J.; Sever, C.; Kakizoe, S.; Oguma, S.; Starzl, T. E.; Jaffe, R.

    1989-01-01

    A study to determine the location of dendritic cells, in chronic inflammatory liver disease was performed. S100 protein positivity and dendritic cytoplasmic morphology were used to identify dendritic cells. S100 protein positive dendritic cells (S100 + DC) were found inside the basement membrane between biliary epithelial cells of septal bile ducts of livers affected by early stage PBC, but were not present at later stages. S100 + DC also were seen in areas of piecemeal necrosis in chronic active hepatitis of various etiologies. In contrast, intra-epithelial S100 + DC were not found with any consistency in sclerosing cholangitis, secondary biliary cirrhosis, extrahepatic biliary atresia, or chronic liver allograft rejection, all of which are characterized by inflammatory bile duct damage. The possible relevance of DC in the pathogenesis of PBC is discussed. Images Figure 1 Figure 2 Figure 3 Figure 4 PMID:2705505

  4. Identification of differentially expressed genes in the livers of chronically i-As-treated hamsters.

    PubMed

    Hernández, Alba; Sampayo-Reyes, Adriana; Marcos, Ricard

    2011-08-01

    Inorganic arsenic (i-As) is a human carcinogen causing skin, lung, urinary bladder, liver and kidney tumors. Chronic exposure to this naturally occurring contaminant, mainly via drinking water, is a significant worldwide environmental health concern. To explore the molecular mechanisms of arsenic hepatic injury, a differential display polymerase chain reaction (DD-PCR) screening was undertaken to identify genes with distinct expression patterns between the liver of low i-As-exposed and control animals. Golden Syrian hamsters (5-6 weeks of age) received drinking water containing 15 mg i-As/L as sodium arsenite, or unaltered water for 18 weeks. The in vivo MN test was carried out, and the frequency of micronucleated reticulocytes (MN-RETs) was scored as a measure of exposure and As-related genotoxic/carcinogenic risk. A total of 68 differentially expressed bands were identified in our initial screen, 41 of which could be assigned to specific genes. Differential level of expression of a selected number of genes was verified using real-time RT-PCR with gene-specific primers. Arsenic-altered gene expression included genes related to stress response, cellular metabolism, cell cycle regulation, telomere maintenance, cell-cell communication and signal transduction. Significant differences of MN-RET were found between treated (8.70 ± 0.02 MN/1000RETs) and control (2.5 ± 0.70 MN/1000RETs) groups (P<0.001), demonstrating both the exposure and the i-As genotoxic/carcinogenic risk. Overall, this paper reveals some possible networks involved in hepatic arsenic-related genotoxicity, carcinogenesis and diabetogenesis. Additional studies to explore further the potential implications of each candidate gene are of especial interest. The present work opens the door to new prospects for the study of i-As mechanisms taking place in the liver under chronic settings.

  5. Performance of Enhanced Liver Fibrosis test and comparison with transient elastography in the identification of liver fibrosis in patients with chronic hepatitis B infection.

    PubMed

    Trembling, P M; Lampertico, P; Parkes, J; Tanwar, S; Viganò, M; Facchetti, F; Colombo, M; Rosenberg, W M

    2014-06-01

    Assessment of liver fibrosis is important in determining prognosis, disease progression and need for treatment in patients with chronic hepatitis B (CHB). Limitations to the use of liver biopsy in assessing fibrosis are well recognized, and noninvasive tests are being increasingly evaluated including transient elastography (TE) and serum markers such as the Enhanced Liver Fibrosis (ELF) test. We assessed performance of ELF and TE in detecting liver fibrosis with reference to liver histology in a cohort of patients with CHB (n = 182), and compared the performance of these modalities. Median age was 46 and mean AST 70 IU/L. Cirrhosis was reported in 20% of liver biopsies. Both modalities performed well in assessing fibrosis at all stages. Area under receiver operator characteristic (AUROC) curves for detecting METAVIR fibrosis stages F ≥ 1, F ≥ 2, F ≥ 3 and F4 were 0.77, 0.82, 0.80 and 0.83 for ELF and 0.86, 0.86, 0.90 and 0.95 for TE. TE performed significantly better in the assessment of severe fibrosis (AUROC 0.80 for ELF and 0.90 for TE, P < 0.01) and cirrhosis (0.83 for ELF and 0.95 for TE, P < 0.01). This study demonstrates that ELF has good performance in detection of liver fibrosis in patients with CHB, and when compared, TE performs better in detection of severe fibrosis/cirrhosis.

  6. Performance of Enhanced Liver Fibrosis test and comparison with transient elastography in the identification of liver fibrosis in patients with chronic hepatitis B infection

    PubMed Central

    Trembling, P M; Lampertico, P; Parkes, J; Tanwar, S; Viganò, M; Facchetti, F; Colombo, M; Rosenberg, W M

    2014-01-01

    Assessment of liver fibrosis is important in determining prognosis, disease progression and need for treatment in patients with chronic hepatitis B (CHB). Limitations to the use of liver biopsy in assessing fibrosis are well recognized, and noninvasive tests are being increasingly evaluated including transient elastography (TE) and serum markers such as the Enhanced Liver Fibrosis (ELF) test. We assessed performance of ELF and TE in detecting liver fibrosis with reference to liver histology in a cohort of patients with CHB (n = 182), and compared the performance of these modalities. Median age was 46 and mean AST 70 IU/L. Cirrhosis was reported in 20% of liver biopsies. Both modalities performed well in assessing fibrosis at all stages. Area under receiver operator characteristic (AUROC) curves for detecting METAVIR fibrosis stages F ≥ 1, F ≥ 2, F ≥ 3 and F4 were 0.77, 0.82, 0.80 and 0.83 for ELF and 0.86, 0.86, 0.90 and 0.95 for TE. TE performed significantly better in the assessment of severe fibrosis (AUROC 0.80 for ELF and 0.90 for TE, P < 0.01) and cirrhosis (0.83 for ELF and 0.95 for TE, P < 0.01). This study demonstrates that ELF has good performance in detection of liver fibrosis in patients with CHB, and when compared, TE performs better in detection of severe fibrosis/cirrhosis. PMID:24750297

  7. Protective effects of ginsenoside Rg1 on chronic restraint stress induced learning and memory impairments in male mice.

    PubMed

    Wang, Yuchan; Kan, Hongwei; Yin, Yanyan; Wu, Wangyang; Hu, Wen; Wang, Mingming; Li, Weiping; Li, Weizu

    2014-05-01

    Alzheimer's disease (AD) is one of the major neurological diseases of the elderly. Chronic stress, which can induce atrophy and functional impairments in several key brain areas such as the frontal cortex and hippocampus, plays an important role in the generation and progression of AD. Currently, there are no effective drug treatment options for preventing chronic stress induced learning and memory impairments and neuronal damage. Ginsenoside Rg1 (Rg1) is a steroidal saponin abundantly contained in ginseng. This study explored the neuroprotective effects of Rg1 on chronic restraint stress (CRS) induced learning and memory impairments in a mouse model. Our results showed that Rg1 (5mg/kg) significantly protected against learning and memory impairments induced by CRS in a Morris water maze. Besides, Rg1 (2, 5mg/kg) was able to decrease ROS generation and attenuate the neuronal oxidative damage in the frontal cortex and hippocampus CA1 in mice. Additionally, the inhibition of NOX2, p47phox and RAC1 expression is also involved in the action mechanisms of Rg1 in this experimental model. This study provided an experimental basis for the clinical application of Rg1 in chronic stress induced neuronal oxidative damage.

  8. Chronic Portal Vein Thrombosis After Liver Transplantation in a Child Treated by a Combined Minimally Invasive Approach

    SciTech Connect

    Carnevale, Francisco Cesar Santos, Aline Cristine Barbosa; Zurstrassen, Charles Edouard; Moreira, Airton Mota; Neto, Joao Seda; Filho, Eduardo Carone; Chapchap, Paulo

    2009-09-15

    Portal vein thrombosis (PVT) after orthotopic liver transplantation is an infrequent complication, and when it is present surgical treatment is considered for traditional management. Percutaneous transhepatic portal vein angioplasty has been described as an option to treat PVT with a lower morbidity than conventional surgical treatments. This article describes a case of chronic PVT in a child after a living donor liver transplantation managed by percutaneous transhepatic and surgical approaches.

  9. Loss of discoidin domain receptor 2 promotes hepatic fibrosis after chronic carbon tetrachloride through altered paracrine interactions between hepatic stellate cells and liver-associated macrophages.

    PubMed

    Olaso, Elvira; Arteta, Beatriz; Benedicto, Aitor; Crende, Olatz; Friedman, Scott L

    2011-12-01

    Hepatic stellate cells (HSCs) interact with fibrillar collagen through the discoidin domain receptor 2 (DDR2) in acute hepatic injury, generating increased fibrosis. However, the contribution of DDR2 signaling to chronic liver fibrosis in vivo is unclear, despite its relevance to chronic human liver disease. We administered carbon tetrachloride (CCl(4)) to DDR2(+/+) and DDR2(-/-) mice twice weekly, and liver tissues and isolated HSCs were analyzed. In contrast to changes seen in acute injury, after chronic CCl(4) administration, DDR2(-/-) livers had increased collagen deposition, gelatinolytic activity, and HSC density. Increased basal gene expression of osteopontin, transforming growth factor-β1, monocyte chemoattractant protein-1, and IL-10 and reduced basal gene expression of matrix metalloproteinase-2, matrix metalloproteinase-13, and collagen type I in quiescent DDR2(-/-) HSCs were amplified further after chronic CCl(4). In concordance, DDR2(-/-) HSCs isolated from chronically injured livers had enhanced in vitro migration and proliferation, but less extracellular matrix degradative activity. Macrophages from chronic CCl(4)-treated DDR2(-/-) livers showed stronger chemoattractive activity toward DDR2(-/-) HSCs than DDR2(+/+) macrophages, increased extracellular matrix degradation, and higher cytokine mRNA expression. In conclusion, loss of DDR2 promotes chronic liver fibrosis after CCl(4) injury. The fibrogenic sinusoidal milieu generated in chronic DDR2(-/-) livers recruits more HSCs to injured regions, which enhances fibrosis. Together, these findings suggest that DDR2 normally orchestrates gene programs and paracrine interactions between HSCs and macrophages that together attenuate chronic hepatic fibrosis.

  10. The expression of thymosin β4 in chronic hepatitis B combined nonalcoholic fatty liver disease

    PubMed Central

    Liang, Jing; Cai, Wenjuan; Han, Tao; Jing, Li; Ma, Zhe; Gao, Yingtang

    2016-01-01

    Abstract The aim of the study was to detect the expression level of thymosin β4 (Tβ4) in serum and tissues of patients with chronic hepatitis B (CHB) combined nonalcoholic fatty liver disease (NAFLD). The effects of Tβ4 in hepatic steatosis, chronic inflammation, and fibrosis development in CHB combined NAFLD patients were also discussed. The study included 46 patients in the case group with CHB and NAFLD and 42 patients in the control group with CHB. ELISA was applied to detect serum Tβ4 and TNF-α level. Furthermore, the correlation analysis of Tβ4 levels with biochemical index, pathological index, and TNF-α level was performed. The Tβ4 immunohistochemical levels of different inflammation fibrosis levels were compared, and the correlation analysis with TNF expression was performed. The Tβ4 levels in patients with CHB combined NAFLD showed no statistical difference when compared to the control group. In patients with CHB combined NAFLD group, the Tβ4 level had no correlation with ALT, AST, TG, FGP, hepatitis B virus (HBV)-DNA levels, and fat grading, but had negative correlation with inflammation score and fibrosis score (P <0.01). The immunohistochemical results of hepatic tissues showed that the expression intensity of severe inflammation fibrosis group had statistical significance compared with that of slight group, and the Tβ4 expression both in serum and in liver tissue negatively correlated with TNF-α expression. Tβ4 could be involved in the regulation of chronic inflammation and fibrosis and plays a defense role in the disease progression of CHB combined NAFLD patients. PMID:28033294

  11. The prevalence and magnitude of impaired cutaneous sensation across the hand in the chronic period post-stroke.

    PubMed

    Bowden, Jocelyn L; Lin, Gaven G; McNulty, Penelope A

    2014-01-01

    Sensation is commonly impaired immediately post-stroke but little is known about the long-term changes in cutaneous sensation that have the capacity to adversely impact independence and motor-function. We investigated cutaneous sensory thresholds across the hand in the chronic post-stroke period. Cutaneous sensation was assessed in 42 community-dwelling stroke patients and compared to 36 healthy subjects. Sensation was tested with calibrated monofilaments at 6 sites on the hand that covered the median, ulnar and radial innervation territories and included both glabrous (hairless) and hairy skin. The motor-function of stroke patients was assessed with the Wolf Motor Function Test and the upper-limb motor Fugl-Meyer Assessment. Impaired cutaneous sensation was defined as monofilament thresholds >3 SD above the mean of healthy subjects and good sensation was ≤ 3 SD. Cutaneous sensation was impaired for 33% of patients and was 40-84% worse on the more-affected side compared to healthy subjects depending on the site (p<0.05). When the stroke patient data were pooled cutaneous sensation fell within the healthy range, although ∼ 1/3 of patients were classified with impaired sensation. Classification by motor-function revealed low levels of impaired sensation. The magnitude of sensory loss was only apparent when the sensory-function of stroke patients was classified as good or impaired. Sensation was most impaired on the dorsum of the hand where age-related changes in monofilament thresholds are minimal in healthy subjects. Although patients with both high and low motor-function had poor cutaneous sensation, overall patients with low motor-function had poorer cutaneous sensation than those with higher motor-function, and relationships were found between motor impairments and sensation at the fingertip and palm. These results emphasize the importance of identifying the presence and magnitude of cutaneous sensory impairments in the chronic period after stroke.

  12. Ongoing liver inflammation in patients with chronic hepatitis C and sustained virological response

    PubMed Central

    Welsch, Christoph; Efinger, Mira; von Wagner, Michael; Herrmann, Eva; Zeuzem, Stefan

    2017-01-01

    Background Novel direct-acting antiviral DAA combination therapies tremendously improved sustained virologic response (SVR) rates in patients with chronic HCV infection. SVR is typically accompanied by normalization of liver enzymes, however, hepatic inflammation, i.e. persistently elevated aminotransferase levels may persist despite HCV eradication. Aim: To investigate prevalence and risk factors for ongoing hepatic inflammation after SVR in two large patient cohorts. Methods This post-hoc analysis was based on prospectively collected demographic and clinical data from 834 patients with SVR after HCV treatment with either PegIFN- or DAA-based treatment regimens from the PRAMA trial (n = 341) or patients treated at our outpatient clinic (n = 493). Results We observed an unexpected high prevalence of post-SVR inflammation, including patients who received novel IFN-free DAA-based therapies. Up to 10% of patients had ongoing elevation of aminotransferase levels and another 25% showed aminotransferase activity above the so-called healthy range. Several baseline factors were independently associated with post-SVR aminotransferase elevation. Among those, particularly male gender, advanced liver disease and markers for liver steatosis were strongly predictive for persistent ALT elevation. The use of IFN-based antiviral treatment was independently correlated with post-SVR inflammation, further supporting the overall benefit of IFN-free combination regimens. Conclusion This is the first comprehensive study on a large patient cohort investigating the prevalence and risk factors for ongoing liver inflammation after eradication of HCV. Our data show a high proportion of patients with ongoing hepatic inflammation despite HCV eradication with potential implications for the management of approximately one third of all patients upon SVR. PMID:28196130

  13. Natriuretic hormone—its possible role in fluid and electrolyte disturbances in chronic liver disease

    PubMed Central

    Kramer, Herbert J.

    1975-01-01

    Besides intrarenal physical factors and aldosterone, a natriuretic hormone has been postulated to modulate renal tubular sodium resorption in order to maintain body fluid homeostasis. To investigate the possible role of a natriuretic activity in sodium retention of chronic liver disease, the effects of plasma and plasma fraction IV from patients with cirrhosis of the liver and ascites on sodium transport of the isolated frog skin and on renal sodium excretion in the rat were compared to the antinatriferic and natriuretic effects of plasma from healthy subjects. While plasma from healthy individuals obtained following acute expansion of the extracellular fluid volume (ECV) significantly inhibited potential difference (PD) by -43·8 ± 5·5% and short circuit current (SCC) by -41·3 ± 1·7% when applied to the inner skin surface, control plasma and plasma from patients with liver cirrhosis and ascites affected PD by -3·8 ± 4·7% and -5·2 ± 3·7% and SCC by -7·3 ± 4·6% and -11·7 ± 2·5% respectively. Similar effects on PD and SCC were observed with plasma fractions IV. In contrast to fraction IV from ECV-expanded individuals, which caused marked diuresis and natriuresis when injected in the rat, fraction IV of plasma from cirrhotic patients failed to affect urinary flow rate, free-water clearance or renal sodium excretion. The results suggest that at least some patients with cirrhosis of the liver and sodium retention may lack an adequate humoral natriuretic activity sufficiently to promote renal sodium excretion. PMID:1234337

  14. Risk Factors and Impact of Chronic Obstructive Pulmonary Disease in Candidates for Liver Transplantation

    PubMed Central

    Rybak, Debbie; Fallon, Michael B.; Krowka, Michael J.; Brown, Robert S.; Reinen, Jenna; Stadheim, Linda; Faulk, Dorothy; Nielsen, Carrie; Al-Naamani, Nadine; Roberts, Kari; Zacks, Steven; Perry, Ted; Trotter, James; Kawut, Steven M.

    2010-01-01

    Chronic obstructive pulmonary disease (COPD) may cause significant symptoms and have an impact on survival. Smoking is an important risk factor for COPD and is common in candidates for liver transplantation; however, the risk factors for and outcomes of COPD in this population are unknown. We performed a prospective cohort study of 373 patients being evaluated for liver transplantation at 7 academic centers in the United States. COPD was characterized by expiratory airflow obstruction and defined as follows: prebronchodilator forced expiratory volume in 1 second/forced vital capacity < 0.70. Patients completed the Liver Disease Quality of Life Questionnaire 1.0, which included the Short Form-36. The mean age of the study sample was 53 ± 9 years, and 234 (63%) were male. Sixty-seven patients (18%, 95% confidence interval 14%–22%) had COPD, and 224 (60%) had a history of smoking. Eighty percent of patients with airflow obstruction did not previously carry a diagnosis of COPD, and 27% were still actively smoking. Older age and any smoking (odds ratio = 3.74, 95% confidence interval 1.94–7.23, P < 0.001) were independent risk factors for COPD. Patients with COPD had worse New York Heart Association functional class and lower physical component summary scores on the 36-Item Short Form but had short-term survival similar to that of patients without COPD. In conclusion, COPD is common and often undiagnosed in candidates for liver transplantation. Older age and smoking are significant risk factors of COPD, which has adverse consequences on functional status and quality of life in these patients. PMID:18756494

  15. Risk factors and impact of chronic obstructive pulmonary disease in candidates for liver transplantation.

    PubMed

    Rybak, Debbie; Fallon, Michael B; Krowka, Michael J; Brown, Robert S; Reinen, Jenna; Stadheim, Linda; Faulk, Dorothy; Nielsen, Carrie; Al-Naamani, Nadine; Roberts, Kari; Zacks, Steven; Perry, Ted; Trotter, James; Kawut, Steven M

    2008-09-01

    Chronic obstructive pulmonary disease (COPD) may cause significant symptoms and have an impact on survival. Smoking is an important risk factor for COPD and is common in candidates for liver transplantation; however, the risk factors for and outcomes of COPD in this population are unknown. We performed a prospective cohort study of 373 patients being evaluated for liver transplantation at 7 academic centers in the United States. COPD was characterized by expiratory airflow obstruction and defined as follows: prebronchodilator forced expiratory volume in 1 second/forced vital capacity < 0.70. Patients completed the Liver Disease Quality of Life Questionnaire 1.0, which included the Short Form-36. The mean age of the study sample was 53 +/- 9 years, and 234 (63%) were male. Sixty-seven patients (18%, 95% confidence interval 14%-22%) had COPD, and 224 (60%) had a history of smoking. Eighty percent of patients with airflow obstruction did not previously carry a diagnosis of COPD, and 27% were still actively smoking. Older age and any smoking (odds ratio = 3.74, 95% confidence interval 1.94-7.23, P < 0.001) were independent risk factors for COPD. Patients with COPD had worse New York Heart Association functional class and lower physical component summary scores on the 36-Item Short Form but had short-term survival similar to that of patients without COPD. In conclusion, COPD is common and often undiagnosed in candidates for liver transplantation. Older age and smoking are significant risk factors of COPD, which has adverse consequences on functional status and quality of life in these patients.

  16. Parameters associated with significant liver histological changes in patients with chronic hepatitis B.

    PubMed

    Xiao, Li; Xian, Jianchun; Li, Yang; Geng, Aiwen; Yang, Xiuzhen; Han, Libin; Xu, Hongtao

    2014-01-01

    This study aimed to evaluate factors associated with significant liver histological changes. Liver biopsies from 157 CHB patients were retrospectively analyzed. Only ALB was significantly correlated with advanced liver necroinflammatory (P = 0.001). Age, ALB, GLOB, AST, PLT, and PT were independent predictors of significant fibrosis (P = 0.002, P < 0.001, P = 0.001, P = 0.048, P < 0.001, and P = 0.001, resp.). AST, WBC, and HBV DNA were significantly correlated with advanced fibrosis in normal ALT patients (P < 0.001, P = 0.041, and P = 0.012, resp.) and age, ALB, GLOB, PLT, and PT in patients with abnormal ALT (P = 0.003, P < 0.001, P = 0.004, P < 0.001, and P = 0.002, resp.). Age, AST, GGT, PLT, and PT were significantly associated with advanced fibrosis in HBeAg+ patients (P = 0.01, P = 0.016, P = 0.027, P = 0.016, and P = 0.009, resp.) and ALB, GLOB, WBC, PLT, and PT in HBeAg- patients (P < 0.001, P = 0.004, P = 0.005, P < 0.001, and P = 0.035, resp.). PLT was an excellent predictor for cirrhosis (P < 0.001 and AUROC = 0.805). ALT was not predictive of advanced fibrosis for patients with HBeAg+ or HBeAg- (P = 0.273 and P = 0.599, resp.). PLT was an excellent predictor for cirrhosis in CHB patients. Liver histopathology can be recommended for chronic HBV carriers of older age, with normal ALT, lower PLT, and lower ALB.

  17. Acetaldehyde targets superoxide dismutase 2 in liver cancer cells inducing transient enzyme impairment and a rapid transcriptional recovery.

    PubMed

    Clavijo-Cornejo, Denise; Gutiérrez-Carrera, Mario; Palestino-Domínguez, Mayrel; Dominguez-Perez, Mayra; Nuño, Natalia; Souza, Veronica; Miranda, Roxana U; Kershenobich, David; Gutiérrez-Ruiz, Ma Concepción; Bucio, Leticia; Gómez-Quiroz, Luis E

    2014-07-01

    Alcohol is undoubtedly, the main toxic agent that people consume by recreation and the abuse is associated with liver damage, mainly by the overproduction of reactive oxygen species and the toxic effects of its first metabolite acetaldehyde. It is known that acetaldehyde targets mitochondria inducing redox imbalance and oxidative stress. Mitochondrial superoxide dismutase transforms superoxide radical into hydrogen peroxide, which in addition, is transformed in water by other enzymes. In the present study we demonstrate that acetaldehyde transiently impairs SOD2 activity in HepG2 cells, the decrease in the enzyme activity was associated to a reduction in the protein content, which was rapidly recovered, to basal values, by synthesis de novo in a mechanism mediated by NF-κB and PKC. The SOD2 impairment was not associated with adduct formation. The recovery on SOD2 activity in HepG2 cells can represent survival advantage for cancer cells, the results shown that SOD2 could be considered a therapeutic target in liver cancer.

  18. Potent antiviral therapy improves survival in acute on chronic liver failure due to hepatitis B virus reactivation.

    PubMed

    Philips, Cyriac Abby; Sarin, Shiv Kumar

    2014-11-21

    Acute on chronic liver failure (ACLF) is a disease entity with a high mortality rate. The acute event arises from drugs and toxins, viral infections, bacterial sepsis, interventions (both surgical and non-surgical) and vascular events on top of a known or occult chronic liver disease. ACLF secondary to reactivation of chronic hepatitis B virus is a distinct condition; the high mortality of which can be managed in the wake of new potent antiviral therapy. For example, lamivudine and entecavir use has shown definite short-term survival benefits, even though drug resistance is a concern in the former. The renoprotective effects of telbivudine have been shown in a few studies to be useful in the presence of renal dysfunction. Monotherapy with newer agents such as tenofovir and a combination of nucleos(t)ides is promising for improving survival in this special group of liver disease patients. This review describes the current status of potent antiviral therapy in patient with acute on chronic liver failure due to reactivation of chronic hepatitis B, thereby providing an algorithm in management of such patients.

  19. Complement activation and liver impairment in trichloroethylene-sensitized BALB/c mice.

    PubMed

    Zhang, Jiaxiang; Zha, Wansheng; Wang, Feng; Jiang, Tao; Xu, Shuhai; Yu, Junfeng; Zhou, Chengfan; Shen, Tong; Wu, Changhao; Zhu, Qixing

    2013-01-01

    Our recent studies have shown that trichloroethylene (TCE) was able to induce multisystem injuries in the form of occupational medicamentosa-like dermatitis, including skin, kidney, and liver damages. However, the role of complement activation in the immune-mediated liver injury is not known. This study examined the role of complement activation in the liver injury in a mouse model of TCE-induced sensitization. Treatment of female BALB/c mice with TCE under specific dosing protocols resulted in skin inflammation and sensitization. Skin edema and erythema occurred in TCE-sensitized groups. Trichloroethylene sensitization produced liver histopathological lesions, increased serum alanine aminotransferase, aspartate transaminase activities, and the relative liver weight. The concentrations of serum complement components C3a-desArg, C5a-desArg, and C5b-9 were significantly increased in 24-hour, 48-hour, and 72-hour sensitization-positive groups treated with TCE and peaked in the 72-hour sensitization-positive group. Depositions of C3a, C5a, and C5b-9 into the liver tissue were also revealed by immunohistochemistry. Immunofluorescence further verified high C5b-9 expression in 24-hour, 48-hour, and 72-hour sensitization-positive groups in response to TCE treatment. Reverse transcription-polymerase chain reaction detected C3 messenger RNA expression in the liver, and this was significantly increased in 24-hour and 48-hour sensitization-positive groups with a transient reduction at 72 hours. These results provide the first experimental evidence that complement activation may play a key role in the generation and progression of immune-mediated hepatic injury by exposure to TCE.

  20. Pharmacokinetics in patients with chronic liver disease and hepatic safety of incretin-based therapies for the management of type 2 diabetes mellitus.

    PubMed

    Scheen, André J

    2014-09-01

    Patients with type 2 diabetes mellitus have an increased risk of chronic liver disease (CLD) such as non-alcoholic fatty liver disease and steatohepatitis, and about one-third of cirrhotic patients have diabetes. However, the use of several antidiabetic agents, such as metformin and sulphonylureas, may be a concern in case of hepatic impairment (HI). New glucose-lowering agents targeting the incretin system are increasingly used for the management of type 2 diabetes. Incretin-based therapies comprise oral inhibitors of dipeptidyl peptidase-4 (DPP-4) (gliptins) or injectable glucagon-like peptide-1 (GLP-1) receptor agonists. This narrative review summarises the available data regarding the use of both incretin-based therapies in patients with HI. In contrast to old glucose-lowering agents, they were evaluated in specifically designed acute pharmacokinetic studies in patients with various degrees of HI and their hepatic safety was carefully analysed in large clinical trials. Only mild changes in pharmacokinetic characteristics of DPP-4 inhibitors were observed in patients with different degrees of HI, presumably without major clinical relevance. GLP-1 receptor agonists have a renal excretion rather than liver metabolism. Specific pharmacokinetic data in patients with HI are only available for liraglutide. No significant changes in liver enzymes were reported with DPP-4 inhibitors or GLP-1 receptor agonists, alone or in combination with various other glucose-lowering agents, in clinical trials up to 2 years in length. On the contrary, preliminary data suggested that incretin-based therapies may be beneficial in patients with CLD, more particularly in the presence of non-alcoholic fatty liver disease. Nevertheless, caution should be recommended, especially in patients with advanced cirrhosis, because of a lack of clinical experience with incretin-based therapies in these vulnerable patients.

  1. Etiology of liver cirrhosis in Brazil: chronic alcoholism and hepatitis viruses in liver cirrhosis diagnosed in the state of Espírito Santo

    PubMed Central

    Gonçalves, Patricia Lofego; da Penha Zago-Gomes, Maria; Marques, Carla Couzi; Mendonça, Ana Tereza; Gonçalves, Carlos Sandoval; Pereira, Fausto Edmundo Lima

    2013-01-01

    OBJECTIVES: To report the etiology of liver cirrhosis cases diagnosed at the University Hospital in Vitoria, Espirito Santo, Brazil. METHODS: The medical charts of patients with liver cirrhosis who presented to the University Hospital in Vitoria were reviewed. Chronic alcoholism and the presence of hepatitis B or C infections (HBV and HCV, respectively) were pursued in all cases. RESULTS: The sample consisted of 1,516 cases (male:female ratio 3.5:1, aged 53.2±12.6 years). The following main etiological factors were observed: chronic alcoholism alone (39.7%), chronic alcoholism in association with HBV or HCV (16.1%), HCV alone (14.5%) and in association with alcoholism (8.6%) (total, 23.1%), and HBV alone (13.1%) and in association with alcoholism (7.5%, total 20.6%). The remaining etiologies included cryptogenic cases (9.8%) and other causes (6.0%). The mean patient age was lower and the male-to-female ratio was higher in the cirrhosis cases that were associated with alcoholism or HBV compared with other causes. Intravenous drug abuse and a history of surgery or blood transfusion were significantly associated with HCV infection. Hepatocellular carcinoma was present at the time of diagnosis in 15.4% of cases. Chronic alcoholism associated with HCV infection was significantly associated (p<0.001) with reduced age (at the time of cirrhosis diagnosis) and increased prevalence of hepatocellular carcinoma (p = 0.052). CONCLUSION: Alcoholism, HCV and HBV are the main factors associated with liver cirrhosis in the state of Espirito Santo. Chronic alcoholism associated with HCV infection reduced the age of patients at the time of liver cirrhosis diagnosis. PMID:23644846

  2. MBOAT7 rs641738 increases risk of liver inflammation and transition to fibrosis in chronic hepatitis C

    PubMed Central

    Thabet, Khaled; Asimakopoulos, Anastasia; Shojaei, Maryam; Romero-Gomez, Manuel; Mangia, Alessandra; Irving, William L.; Berg, Thomas; Dore, Gregory J.; Grønbæk, Henning; Sheridan, David; Abate, Maria Lorena; Bugianesi, Elisabetta; Weltman, Martin; Mollison, Lindsay; Cheng, Wendy; Riordan, Stephen; Fischer, Janett; Spengler, Ulrich; Nattermann, Jacob; Wahid, Ahmed; Rojas, Angela; White, Rose; Douglas, Mark W.; McLeod, Duncan; Powell, Elizabeth; Liddle, Christopher; van der Poorten, David; George, Jacob; Eslam, Mohammed; Gallego-Duran, Rocio; Applegate, Tanya; Bassendine, Margaret; Rosso, Chiara; Mezzabotta, Lavinia; Leung, Reynold; Malik, Barbara; Matthews, Gail; Grebely, Jason; Fragomeli, Vincenzo; Jonsson, Julie R.; Santaro, Rosanna

    2016-01-01

    Cirrhosis likely shares common pathophysiological pathways despite arising from a variety of liver diseases. A recent GWAS identified rs641738, a polymorphism in the MBOAT7 locus, as being associated with the development of alcoholic cirrhosis. Here we explore the role of this variant on liver inflammation and fibrosis in two cohorts of patients with chronic hepatitis C. In 2,051 patients, rs641738 associated with severe hepatic inflammation and increased risk of fibrosis, as well as fast fibrosis progression. At functional level, rs641738 associated with MBOAT7 transcript and protein levels in liver and blood, and with serum inflammatory, oxidative stress and macrophage activation markers. MBOAT7 was expressed in immune cell subsets, implying a role in hepatic inflammation. We conclude that the MBOAT7 rs641738 polymorphism is a novel risk variant for liver inflammation in hepatitis C, and thereby for liver fibrosis. PMID:27630043

  3. Physical exercise prevents and mitigates non-alcoholic steatohepatitis-induced liver mitochondrial structural and bioenergetics impairments.

    PubMed

    Gonçalves, Inês O; Passos, Emanuel; Rocha-Rodrigues, Silvia; Diogo, Cátia V; Torrella, Joan R; Rizo, David; Viscor, Ginés; Santos-Alves, Estela; Marques-Aleixo, Inês; Oliveira, Paulo J; Ascensão, António; Magalhães, José

    2014-03-01

    Exercise is considered a non-pharmacological tool against several lifestyle disorders in which mitochondrial dysfunction is involved. The present study aimed to analyze the preventive (voluntary physical activity-VPA) and therapeutic (endurance training-ET) role of exercise against non-alcoholic steatohepatitis (NASH)-induced liver mitochondrial dysfunction. Sixty male Sprague-Dawley rats were divided into standard-diet sedentary (SS, n=20), standard-diet VPA (SVPA, n=10), high-fat diet sedentary (HS, n=20) and high-fat diet VPA (HVPA, n=10). After 9weeks of diet-treatment, half of SS and HS animals were engaged in an ET program (SET and HET) for 8weeks, 5days/week and 60min/day. Liver mitochondrial oxygen consumption and transmembrane-electric potential (ΔΨ) were evaluated in the presence of glutamate-malate (G/M), palmitoyl-malate (P/M) and succinate (S/R). Mitochondrial enzymes activity, lipid and protein oxidation, oxidative phosphorylation (OXPHOS) subunits, cytochrome c, adenine nucleotide translocator (ANT) and uncoupling protein-2 (UCP2) content were assessed. HS groups show the histological features of NASH in parallel with decreased ΔΨ and respiratory control (RCR) and ADP/O ratios (G/M and P/M). A state 3 decrease (G/M and S/R), FCCP-induced uncoupling respiration (S/R) and ANT content were also observed. Both exercise types counteracted oxygen consumption (RCR, ADP/O and FCCP-uncoupling state) impairments and improved ΔΨ (lag-phase). In conclusion, exercise prevented or reverted (VPA and ET, respectively) the bioenergetic impairment induced by NASH, but only ET positively remodeled NASH-induced liver structural damage and abnormal mitochondria. It is possible that alterations in inner membrane integrity and fatty acid oxidation may be related to the observed phenotypes induced by exercise.

  4. Clinical significance of cell population data (CPD) on Sysmex XN-9000 in septic patients with our without liver impairment

    PubMed Central

    Seghezzi, Michela; Vavassori, Mauro; Dominoni, Paola; Apassiti Esposito, Sara; Manenti, Barbara; Mecca, Tommaso; Marchesi, Gianmariano; Castellucci, Enrico; Azzarà, Giovanna; Ottomano, Cosimo; Lippi, Giuseppe

    2016-01-01

    Background This study evaluated the clinical significance of cell population data (CPD) parameters obtained on Sysmex XN-9000 in septic patients admitted to intensive care unit (ICU) and stratified according to liver function. Methods The study population consisted in 84 patients, 44 of whom did not develop sepsis (NS), whereas the remaining 40 developed sepsis (SE) (n=24) or septic shock (SS) (n=16). Two hundred ostensibly healthy blood donors [healthy subjects (HS)], undergoing routine blood testing before a regular blood donation, were studied. Results Except for neutrophils and lymphocytes cell size (NE-FCS and LY-Z), all other CPD values were significantly different in ICU patients compared to HS. Neutrophils and monocytes fluorescence intensity (NE-SFL and MO-X) values were significantly higher in SS compared to sepsis and not develop sepsis patients. The value of many parameters was also different according to liver function. Overall, MO-X and neutrophils fluorescence intensity (NE-SFL) exhibited the best performance for diagnosing sepsis in all patients (AUC, 0.75 and 0.72), as well as in those with (AUC, 0.95 and 0.89) or without (AUC, 0.72 for both) liver impairment. These parameters were also significantly correlated with Sequential Organ Failure Assessment (SOFA) score. Conclusions This study suggested that some novel CPD parameters (namely NE-SFL and MO-X) may provide useful information for diagnosis and management of sepsis. PMID:27942509

  5. Chronic ethanol consumption in mice alters hepatocyte lipid droplet properties

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Background: Hepatosteatosis is a common pathological feature of impaired hepatic metabolism following chronic alcohol consumption. Although often benign and reversible, it is widely believed that steatosis is a risk factor for development of advanced liver pathologies, including steatohepatitis and ...

  6. Nonalcoholic fatty liver disease (NAFLD)--is it a new marker of hyporesponsiveness to recombinant human erythropoietin in patients that are on chronic hemodialysis?

    PubMed

    Orlic, L; Mikolasevic, I; Lukenda, V; Racki, S; Stimac, D; Milic, S

    2014-12-01

    Anemia is a major consequence of chronic kidney disease (CKD) that develops early in the course of illness and affects most patients who exhibit some degree of reduced renal function. Erythropoietin (EPO) deficiency is considered the most important cause of anemia in CKD. Renal anemia has serious clinical consequence. In addition to reducing patient physical capacity and quality of life, anemia induces adaptive cardiovascular mechanisms that increase the risk of cardiovascular disease and death. Thus, treatment of anemia in CKD is very important. While EPO is effective in correcting anemia in most cases, up to 10% of patients however, have an inadequate response to therapy. The two most common and important reasons why patients become relatively unresponsive to EPO therapy are the development of true iron deficiency and the onset of an inflammatory state that impairs the response to EPO. Indeed, the role of inflammation and pro-inflammatory cytokines in resistance to EPO therapy is gaining increasing recognition. On the other hand, the main organ for C-reactive protein (CRP) synthesis is the liver and it is well known that the synthesis of an acute-phase proteins by the liver is up regulated by inflammation. The main consequence of nonalcoholic fatty liver disease (NAFLD) is sub-chronic liver inflammation that leads and contributes to dyslipidemia, inflammation, enhanced oxidative stress and endothelial dysfunction. Considering the recent data about high prevalence of NAFLD in CKD patients, probably due to shared metabolic risk factors, we hypothesized that end-stage renal disease (ESRD) patients with NAFLD will need a much higher dose of EPO to achieve the target hemoglobin levels in comparison with ESRD patients without NAFLD. The possible underlying mechanism is sub-chronic liver inflammation in NAFLD patients that leads and contributes to poor response to EPO. Therefore, we believe that NAFLD could be a new clinical marker of poor response to EPO therapy in

  7. Smad phosphoisoform signals in acute and chronic liver injury: similarities and differences between epithelial and mesenchymal cells.

    PubMed

    Matsuzaki, Koichi

    2012-01-01

    Hepatocellular carcinoma (HCC) usually arises from hepatic fibrosis caused by chronic inflammation. In chronic liver damage, hepatic stellate cells undergo progressive activation to myofibroblasts (MFB), which are important extracellular-matrix-producing mesenchymal cells. Concomitantly, perturbation of transforming growth factor (TGF)-β signaling by pro-inflammatory cytokines in the epithelial cells of the liver (hepatocytes) promotes both fibrogenesis and carcinogenesis (fibro-carcinogenesis). Insights into fibro-carcinogenic effects on chronically damaged hepatocytes have come from recent detailed analyses of the TGF-β signaling process. Smad proteins, which convey signals from TGF-β receptors to the nucleus, have intermediate linker regions between conserved Mad homology (MH) 1 and MH2 domains. TGF-β type I receptor and pro-inflammatory cytokine-activated kinases differentially phosphorylate Smad2 and Smad3 to create phosphoisoforms phosphorylated at the COOH-terminal, linker, or both (L/C) regions. After acute liver injury, TGF-β-mediated pSmad3C signaling terminates hepatocytic proliferation induced by the pro-inflammatory cytokine-mediated mitogenic pSmad3L pathway; TGF-β and pro-inflammatory cytokines synergistically enhance collagen synthesis by activated hepatic stellate cells via pSmad2L/C and pSmad3L/C pathways. During chronic liver disease progression, pre-neoplastic hepatocytes persistently affected by TGF-β together with pro-inflammatory cytokines come to exhibit the same carcinogenic (mitogenic) pSmad3L and fibrogenic pSmad2L/C signaling as do MFB, thereby accelerating liver fibrosis while increasing risk of HCC. This review of Smad phosphoisoform-mediated signals examines similarities and differences between epithelial and mesenchymal cells in acute and chronic liver injuries and considers Smad linker phosphorylation as a potential target for the chemoprevention of fibro-carcinogenesis.

  8. Functional impairment in chronic fatigue syndrome, fibromyalgia, and multiple chemical sensitivity

    PubMed Central

    Lavergne, M. Ruth; Cole, Donald C.; Kerr, Kathleen; Marshall, Lynn M.

    2010-01-01

    ABSTRACT OBJECTIVE To characterize patients diagnosed with multiple chemical sensitivity (MCS), chronic fatigue syndrome (CFS), or fibromyalgia (FM), to compare their level of function with Canadian population average values, and to assess factors associated with function. DESIGN Chart review and abstraction of clinical information. SETTING The Environmental Health Clinic (EHC) at Women’s College Hospital in Toronto, Ont, which is a provincial referral centre for patients with illnesses with suspected environmental links, especially MCS, CFS, and FM. PARTICIPANTS A total of 128 consecutive patients diagnosed with 1 or more of MCS, CFS, or FM, seen between January 2005 and March 2006 at the EHC. MAIN OUTCOME MEASURES Demographic and socioeconomic characteristics, comorbid diagnoses, duration of illness, health services usage, life stresses, helpful therapeutic strategies, and functional impairment measured by the Short Form–36, compared with Canadian population average values. Factors significantly associated with function in bivariate analyses were included in multiple linear and logistic regression models. RESULTS The patient population was predominantly female (86.7%), with a mean age of 44.6 years. Seventy-eight patients had discrete diagnoses of 1 of MCS, CFS, or FM, while the remainder had 2 or 3 overlapping diagnoses. Most (68.8%) had stopped work, and on average this had occurred 3 years after symptom onset. On every Short Form–36 subscale, patients had markedly lower functional scores than population average values, more so when they had 2 or 3 of these diagnoses. Having FM, younger age at onset, and lower socioeconomic status were most consistently associated with poor function. CONCLUSION Patients seen at the EHC demonstrated marked functional impairment, consistent with their reported difficulties working and caring for their homes and families during what should be their peak productive years. Early comprehensive assessment, medical management

  9. Behavioral impairments and serotonin reductions in rats after chronic L-dopa

    PubMed Central

    Stansley, Branden J.; Yamamoto, Bryan K.

    2015-01-01

    Rationale L-dopa, the main therapeutic for Parkinson's disease (PD), has been shown to increase brain dopamine concentrations that are necessary for proper motor control; however, PD patients experience non-motor symptoms that are not improved or could be exacerbated by L-dopa. Objectives The purpose of this study is to determine the effects of L-dopa treatment on cognitive and affective behavioral responses of rats, as well their corresponding monoamine brain concentrations. Methods Rats were treated with L-dopa (6 mg/kg; twice daily) for 10 consecutive days. Sodium ascorbate (400 mg/kg), was co-administered with L-dopa to investigate the effects of antioxidant co-treatment on behavior and monoamine concentrations. Rats underwent cognitive and affective behavioral testing. Monoamine concentrations of several brain regions were analyzed. Results L-dopa treatment resulted in significant impairment in the performance in the Barnes maze and improvement in conditioned fear stress paradigms. Specifically, L-dopa caused an increase in latency to find the goal box during Barnes maze testing, and increased freezing behavior in context-induced conditioned fear testing. Furthermore, the rats in the conditioned fear stress experiments showed corresponding depletions in serotonin (5-HT) and its metabolite, 5-HIAA, in the dorsal DRN and the mPFC. The behavioral impairments as well as monoamine depletions were blocked by ascorbate co-treatment. Conclusions Chronic L-dopa may contribute to non-motor symptoms related to spatial memory and fear. These effects may be attributable to a dysregulation of brain 5-HT caused by L-dopa treatment. The results presented here provide further rationale for investigating adjunctive therapeutics to L-dopa for PD, such as antioxidants. PMID:26037945

  10. Chronic, Severe Hypertension Does Not Impair Spatial Learning and Memory in Sprague-Dawley Rats

    PubMed Central

    Kadish, Inga; van Groen, Thomas; Wyss, J. Michael

    2001-01-01

    This study tested the hypothesis that long-term hypertension impairs spatial learning and memory in rats. In 6-wk-old Sprague-Dawley rats, chronic hypertension was induced by placing one of three sizes of stainless steel clips around the descending aorta (above the renal artery), resulting in a 20–80-mm Hg increase of arterial pressure in all arteries above the clip, that is, the upper trunk and head. Ten months later, the rats were tested for 5 d in a repeated-acquisition water maze task, and on the fifth day, they were tested in a probe trial; that is, there was no escape platform present. At the end of the testing period, the nonsurgical and sham control groups had similar final escape latencies (16 ± 4 sec and 23 ± 9 sec, respectively) that were not significantly different from those of the three hypertensive groups. Rats with mild hypertension (140–160 mm Hg) had a final escape latency of 25 ± 6 sec, whereas severely hypertensive rats (170–199 mm Hg) had a final escape latency of 21 ± 7 sec and extremely hypertensive rats (>200 Hg) had a final escape latency of 19 ± 5 sec. All five groups also displayed a similar preference for the correct quadrant in the probe trial. Together, these data suggest that sustained, severe hypertension for over 10 mo is not sufficient to impair spatial learning and memory deficits in otherwise normal rats. PMID:11274256

  11. Acute and chronic methyl mercury poisoning impairs rat adrenal and testicular function

    SciTech Connect

    Burton, G.V.; Meikle, A.W.

    1980-05-01

    Animals poisoned with methyl mercury (CH/sub 3/Hg) exhibit stress intolerance and decreased sexual activity, which suggest both adrenal and testicular dysfunction. Adrenal and testicular function was studied in male rats after treatment with CH/sub 3/Hg. In animals treated chronically, the adrenal glands were markedly hyperplastic with enlargement of the zona fasciculata. The mean basal serum levels of corticosterone were similar in experimental (17.8 ..mu..g/dl) and control (16.8 ..mu..g/dl) groups. However, with ether stress, experimental animals had a subnormal response, and the mean serum levels of corticosterone increased to only 23.9 ..mu../dl compared to 40.6 ..mu..g/dl in the controls. Exogenous ACTH stimulation produced a mean level of 19.0 ..mu..g/dl in the CH/sub 3/Hg-treated animals and 49.7 ..mu..g/dl in the controls. In vitro studies demonstrated a defect in the conversion of cholesterol to pregnenolone. A profound impairment in swimming was partially reversed with glucocorticoid therapy. In animals treated with CH/sub 3/Hg, serum testosterone was lower than normal in the basal state. Human chorionic gonadotropin stimulation increased the mean serum concentration of testosterone to 23.4 ng/ml in controls, but it was only 4.50 ng/ml in experimental animals. The data indicate that CH/sub 3/Hg poisoning impairs adrenal and testicular steroid hormone secretion, which accounts in part for the diminished stress tolerance and decreased sexual activity observed in CH/sub 3/Hg-intoxicated animals.

  12. Impaired hepatic handling and processing of lysophosphatidylcholine in rats with liver cirrhosis

    SciTech Connect

    Angelico, M.; Alvaro, D.; Cantafora, A.; Masella, R.; Gaudio, E.; Gandin, C.; Ginanni Corradini, S.; Ariosto, F.; Riggio, O.; Capocaccia, L. )

    1991-07-01

    Lysophosphatidylcholine is a major metabolic product in the plasma and cellular turnover of phospholipids, with well-known membrane-toxic and proinflammatory properties. Because the liver plays a key role in plasma lysophosphatidylcholine removal and biotransformation and because virtually nothing is known of these processes in a diseased organ, the hepatobiliary metabolism of lysophosphatidylcholine was investigated in rats with carbon tetrachloride-induced liver cirrhosis. Twelve adult male Wistar rats with histologically confirmed cirrhosis and 8 control animals were fitted with jugular and biliary catheters and allowed to recover. The animals were kept under constant IV infusion of taurocholate (1 mumol/min). Two microcuries of sn-1{sup 14}Cpalmitoyl-lysophosphatidylcholine was administered as a single bolus. The fate of the injected radioactivity, including removal from plasma, uptake, and subcellular location in the liver and molecular and aggregative forms, was studied by combined chromatographic and radiochemical methods. Major findings were (a) that lysophosphatidylcholine has a prolonged permanence in plasma of cirrhotic rats, due both to decreased hepatic clearance and to depressed conversion into phosphatidylcholine; (b) that the rate of lysophosphatidylcholine acylation is much slower in the cirrhotic than in the normal liver, both at the microsomal and at the cytosolic level; (c) that cytosolic lysophosphatidylcholine in the cirrhotic liver, but not in the normal liver, is predominantly non-protein bound; (d) that the strict molecular selectivity of lysophosphatidylcholine acylation observed in controls is partially lost in cirrhosis; and (e) that a consistent fraction of lysophosphatidylcholine is converted into triacylglycerols in cirrhotics but not in controls.

  13. Effects of grape seed polyphenols on oxidative damage in liver tissue of acutely and chronically exercised rats.

    PubMed

    Belviranlı, Muaz; Gökbel, Hakkı; Okudan, Nilsel; Büyükbaş, Sadık

    2013-05-01

    The objective of the present study was to investigate the effects of grape seed extract (GSE) supplementation on oxidative stress and antioxidant defense markers in liver tissue of acutely and chronically exercised rats. Rats were randomly assigned to six groups: Control (C), Control Chronic Exercise (CE), Control Acute Exercise (AE), GSE-supplemented Control (GC), GSE-supplemented Chronic Exercise(GCE) and GSE-supplemented Acute Exercise (GAE). Rats in the chronic exercise groups were subjected to a six-week treadmill running and in the acute exercise groups performed an exhaustive running. Rats in the GSE supplemented groups received GSE (100 mg.kg(-1) .day(-1) ) in drinking water for 6 weeks. Liver tissues of the rats were taken for the analysis of malondialdehyde (MDA), nitric oxide (NO) levels and total antioxidant activity (AOA) and xanthine oxidase (XO) activities. MDA levels decreased with GSE supplementation in control groups but increased in acute and chronic exercise groups compared to their non-supplemented control. NO levels increased with GSE supplementation. XO activities were higher in AE group compared to the CE group. AOA decreased with GSE supplementation. In conclusion, while acute exercise triggers oxidative stress, chronic exercise has protective role against oxidative stress. GSE has a limited antioxidant effect on exercise-induced oxidative stress in liver tissue.

  14. Development of a disease specific questionnaire to measure health related quality of life in patients with chronic liver disease

    PubMed Central

    Younossi, Z; Guyatt, G; Kiwi, M; Boparai, N; King, D

    1999-01-01

    BACKGROUND AND AIMS—To develop and assess a disease specific instrument for measuring health related quality of life (HRQL) in patients with chronic liver disease (CLD).
METHODS—Based on responses from 60 patients with chronic liver disease, from 20 liver experts, and from a Medline search of the literature, items potentially affecting the HRQL of these patients were identified. A separate sample of 75 patients identified which items they found problematic and rated their importance. Results were explored using factor analysis; domains were chosen and items placed within domains. Redundant questions were eliminated and the final questionnaire was pretested in 10 patients. Using this instrument, HRQL was assessed in a further 133 patients with various types and stages of liver disease.
RESULTS—Patients, experts, and the literature search identified 156 items of potential importance. Of these, 35 proved important to over 50% of 75 respondents in the item reduction sample. The factor analysis suggested six domains. After eliminating redundancies, the Chronic Liver Disease Questionnaire (CLDQ) included 29 items in the following domains: fatigue, activity, emotional function, abdominal symptoms, systemic symptoms, and worry. In pretesting, patients found the CLDQ clear and easy to complete in 10 minutes. In another 133 patients, the CLDQ showed a gradient between patients without cirrhosis, Child's A cirrhosis, and those with Child's B or C cirrhosis. CLDQ has evidence for moderate reliability at six months and seems to be responsive.
CONCLUSION—The CLDQ is short, easy to administer, produces both a summary score and domain scores, and correlates with the severity of liver disease.


Keywords: quality of life; liver disease; liver specific quality of life; well being PMID:10403745

  15. Gas6/Axl pathway is activated in chronic liver disease and its targeting reduces fibrosis via hepatic stellate cell inactivation

    PubMed Central

    Bárcena, Cristina; Stefanovic, Milica; Tutusaus, Anna; Joannas, Leonel; Menéndez, Anghara; García-Ruiz, Carmen; Sancho-Bru, Pau; Marí, Montserrat; Caballeria, Joan; Rothlin, Carla V.; Fernández-Checa, José C.; de Frutos, Pablo García; Morales, Albert

    2015-01-01

    Background & Aims Liver fibrosis, an important health concern associated to chronic liver injury that provides a permissive environment for cancer development, is characterized by accumulation of extracellular matrix components mainly derived from activated hepatic stellate cells (HSCs). Axl, a receptor tyrosine kinase, and its ligand Gas6 are involved in cell differentiation, immune response and carcinogenesis. Methods HSCs were obtained from wild type and Axl−/− mice, treated with recombinant Gas6 protein (rGas6), Axl siRNAs or the Axl inhibitor BGB324, and analyzed by western blot and real-time PCR. Experimental fibrosis was studied in CCl4-treated wild type and Axl−/− mice, and in combination with Axl inhibitor. Gas6 and Axl serum levels were measured in alcoholic liver disease (ALD) and hepatitis C virus (HCV) patients. Results In primary mouse HSCs, Gas6 and Axl levels paralleled HSC activation. rGas6 phosphorylated Axl and AKT prior to HSC phenotypic changes, while Axl siRNA silencing reduced HSC activation. Moreover, BGB324 blocked Axl/AKT phosphorylation and diminished HSC activation. In addition, Axl KO mice displayed decreased HSC activation in vitro and liver fibrogenesis after chronic damage by CCl4 administration. Similarly, BGB324 reduced collagen deposition and CCl4-induced liver fibrosis in mice. Importantly, Gas6 and Axl serum levels increased in ALD and HCV patients, inversely correlating with liver functionality. Conclusions: The Gas6/Axl axis is required for full HSC activation. Gas6 and Axl serum levels increase in parallel to chronic liver disease progression. Axl targeting may be a therapeutic strategy for liver fibrosis management. PMID:25908269

  16. Rectification of impaired adipose tissue methylation status and lipolytic response contributes to hepatoprotective effect of betaine in a mouse model of alcoholic liver disease

    PubMed Central

    Dou, Xiaobing; Xia, Yongliang; Chen, Jing; Qian, Ying; Li, Songtao; Zhang, Ximei; Song, Zhenyuan

    2014-01-01

    Background and Purpose Overactive lipolysis in adipose tissue contributes to the pathogenesis of alcoholic liver disease (ALD); however, the mechanisms involved have not been elucidated. We previously reported that chronic alcohol consumption produces a hypomethylation state in adipose tissue. In this study we investigated the role of hypomethylation in adipose tissue in alcohol-induced lipolysis and whether its correction contributes to the well-established hepatoprotective effect of betaine in ALD. Experimental Approach Male C57BL/6 mice were divided into four groups and started on one of four treatments for 5 weeks: isocaloric pair-fed (PF), alcohol-fed (AF), PF supplemented with betaine (BT/AF) and AF supplemented with betaine (BT/AF). Betaine, 0.5% (w v−1), was added to the liquid diet. Both primary adipocytes and mature 3T3-L1 adipocytes were exposed to demethylation reagents and their lipolytic responses determined. Key Results Betaine alleviated alcohol-induced pathological changes in the liver and rectified the impaired methylation status in adipose tissue, concomitant with attenuating lipolysis. In adipocytes, inducing hypomethylation activated lipolysis through a mechanism involving suppression of protein phosphatase 2A (PP2A), due to hypomethylation of its catalytic subunit, leading to increased activation of hormone-sensitive lipase (HSL). In line with in vitro observations, reduced PP2A catalytic subunit methylation and activity, and enhanced HSL activation, were observed in adipose tissue of alcohol-fed mice. Betaine attenuated this alcohol-induced PP2A suppression and HSL activation. Conclusions and Implications In adipose tissue, a hypomethylation state contributes to its alcohol-induced dysfunction and an improvement in its function may contribute to the hepatoprotective effects of betaine in ALD. PMID:24819676

  17. Impaired thymic output in patients with chronic hepatitis C virus infection.

    PubMed

    Hartling, H J; Gaardbo, J C; Ronit, A; Salem, M; Laye, M; Clausen, M R; Skogstrand, K; Gerstoft, J; Ullum, H; Nielsen, S D

    2013-10-01

    Altered T cell homeostasis in chronic hepatitis C virus (HCV) infection has been demonstrated. However, it is unknown whether fibrosis is associated with more perturbed T cell homeostasis in chronic HCV infection. The aim of this study was to examine and compare T cell subsets including recent thymic emigrants (RTE), naive, memory, senescent, apoptotic and IL-7 receptor α (CD127) expressing CD4⁺ and CD8⁺ T cells as well as telomere length and interferon-γ production in HCV-infected patients with (n = 25) and without (n = 26) fibrosis as well as in healthy controls (n = 24). Decreased proportions of CD4⁺ and CD8⁺ RTE were found in HCV-infected patients, especially in HCV-infected patients with fibrosis (14.3% (9.7-23.0) and 28.8% (16.1-40.5), respectively) compared with healthy controls (24.2% (16.3-32.1), P = 0.004 and 39.1% (31.6-55.0), P = 0.010, respectively). Furthermore, HCV-infected patients with fibrosis presented with a higher proportion of CD4⁺ T cells expressing CD127 compared with HCV-infected patients without fibrosis [88.4% (84.5-91.0) versus 83.8% (79.9-86.8), P = 0.016]. Thus, impaired thymic output in HCV infection was found, and high proportion of CD127⁺ T cells may illustrate a compensatory mechanism to preserve T cell counts.

  18. Chronic dietary chlorpyrifos causes long-term spatial memory impairment and thigmotaxic behavior.

    PubMed

    López-Granero, Caridad; Ruiz-Muñoz, Ana M; Nieto-Escámez, Francisco A; Colomina, María T; Aschner, Michael; Sánchez-Santed, Fernando

    2016-03-01

    Little is known about the long-term effects of chronic exposure to low-level organophosphate (OP) pesticides, and the role of neurotransmitter systems, other than the cholinergic system, in mediating OP neurotoxicity. In this study, rats were administered 5mg/kg/day of chlorpyrifos (CPF) for 6 months commencing at 3-months-of-age. The animals were examined 7 months later (at 16-months-of-age) for spatial learning and memory in the Morris water maze (MWM) and locomotor activity. In addition, we assessed the chronic effects of CPF on glutamatergic and gamma-aminobutyric acid (GABAergic) function using pharmacological challenges with dizocilpine (MK801) and diazepam. Impaired performance related to altered search patterns, including thigmotaxis and long-term spatial memory was noted in the MWM in animals exposed to CPF, pointing to dietary CPF-induced behavioral disturbances, such as anxiety. Twenty-four hours after the 31st session of repeated acquisition task, 0.1mg/kg MK801, an N-methyl-d-aspartate (NMDA) antagonist was intraperitoneally (i.p.) injected for 4 consecutive days. Decreased latencies in the MWM in the control group were noted after two sessions with MK801 treatment. Once the MWM assessment was completed, animals were administered 0.1 or 0.2mg/kg of MK801 and 1 or 3mg/kg of diazepam i.p., and tested for locomotor activity. Both groups, the CPF dietary and control, displayed analogous performance in motor activity. In conclusion, our data point to a connection between the long-term spatial memory, thigmotaxic response and CPF long after the exposure ended.

  19. Chronic Cold-Water-Induced Hypothermia Impairs Memory Retrieval and Nepeta menthoides as a Traditional "Hot" Herb Reverses the Impairment.

    PubMed

    Ahmadian-Attar, Mohammad Mahdi; Ahmadiani, Abolhassan; Kamalinejad, Mohammad; Dargahi, Leila; Mosaddegh, Mahmoud

    2014-01-01

    Iranian Traditional Medicine (ITM) describes a kind of dementia with similar signs and symptoms of Alzheimer's disease (AD). It explains the pathology of dementia with cold intemperament of the brain, which means that the brain is colder than its healthy form. ITM strategy for treatment of dementia is to heat the brain up by medical "hot" herbs. Nepeta menthoides (NM) is one of these "hot" herbs. To evaluate the veracity of ITM concept about dementia and its treatment, we first try to examine if coldness of brain can make memory impairment. If so, can NM reverse memory impairment? Rats in cold-water-induced hypothermic (CWH) groups were immersed up to the neck in 3.5 °C water, for 5 min during 14 consecutive days. As a control, rats were forced to swim in warm water at the same conditions. To eliminate the impact of forced swimming stress, a group of intact rats was also added. After last swimming in day 14, some groups received drug (100 or 500 mg/ Kg aqueous extract of NM) or vehicle via i.p. injection. Learning and memory were assessed by Morris water maze, and tau hyperphosphorylation was measured by western blotting. The results showed that CWH impairs learning and memory and induces tau hyperphosphorylation. 100 mg/Kg of NM reversed memory impairment as well as tau hyperphosphorylation. ITM theory about the relationship between brain hypothermia and dementia is in accordance with our findings.

  20. Lipids changes in liver cancer*

    PubMed Central

    Jiang, Jing-ting; Xu, Ning; Zhang, Xiao-ying; Wu, Chang-ping

    2007-01-01

    Liver is one of the most important organs in energy metabolism. Most plasma apolipoproteins and endogenous lipids and lipoproteins are synthesized in the liver. It depends on the integrity of liver cellular function, which ensures homeostasis of lipid and lipoprotein metabolism. When liver cancer occurs, these processes are impaired and the plasma lipid and lipoprotein patterns may be changed. Liver cancer is the fifth common malignant tumor worldwide, and is closely related to the infections of hepatitis B virus (HBV) and hepatitis C virus (HCV). HBV and HCV infections are quite common in China and other Southeast Asian countries. In addition, liver cancer is often followed by a procession of chronic hepatitis or cirrhosis, so that hepatic function is damaged obviously on these bases, which may significantly influence lipid and lipoprotein metabolism in vivo. In this review we summarize the clinical significance of lipid and lipoprotein metabolism under liver cancer. PMID:17565510

  1. Deep Sequencing Reveals Novel Genetic Variants in Children with Acute Liver Failure and Tissue Evidence of Impaired Energy Metabolism

    PubMed Central

    Valencia, C. Alexander; Wang, Xinjian; Wang, Jin; Peters, Anna; Simmons, Julia R.; Moran, Molly C.; Mathur, Abhinav; Husami, Ammar; Qian, Yaping; Sheridan, Rachel; Bove, Kevin E.; Witte, David; Huang, Taosheng; Miethke, Alexander G.

    2016-01-01

    Background & Aims The etiology of acute liver failure (ALF) remains elusive in almost half of affected children. We hypothesized that inherited mitochondrial and fatty acid oxidation disorders were occult etiological factors in patients with idiopathic ALF and impaired energy metabolism. Methods Twelve patients with elevated blood molar lactate/pyruvate ratio and indeterminate etiology were selected from a retrospective cohort of 74 subjects with ALF because their fixed and frozen liver samples were available for histological, ultrastructural, molecular and biochemical analysis. Results A customized next-generation sequencing panel for 26 genes associated with mitochondrial and fatty acid oxidation defects revealed mutations and sequence variants in five subjects. Variants involved the genes ACAD9, POLG, POLG2, DGUOK, and RRM2B; the latter not previously reported in subjects with ALF. The explanted livers of the patients with heterozygous, truncating insertion mutations in RRM2B showed patchy micro- and macrovesicular steatosis, decreased mitochondrial DNA (mtDNA) content <30% of controls, and reduced respiratory chain complex activity; both patients had good post-transplant outcome. One infant with severe lactic acidosis was found to carry two heterozygous variants in ACAD9, which was associated with isolated complex I deficiency and diffuse hypergranular hepatocytes. The two subjects with heterozygous variants of unknown clinical significance in POLG and DGUOK developed ALF following drug exposure. Their hepatocytes displayed abnormal mitochondria by electron microscopy. Conclusion Targeted next generation sequencing and correlation with histological, ultrastructural and functional studies on liver tissue in children with elevated lactate/pyruvate ratio expand the spectrum of genes associated with pediatric ALF. PMID:27483465

  2. The adaptation dynamics of chronic functional impairment: what we can learn from older adults with vision loss.

    PubMed

    Schilling, Oliver K; Wahl, Hans-Werner; Horowitz, Amy; Reinhardt, Joann P; Boerner, Kathrin

    2011-03-01

    This study used vision loss due to age-related macular degeneration to learn about adaptation processes related to chronic functional impairment, focusing on Horowitz and Reinhardt's (1998) concept of Adaptation to Age-related Vision Loss (AVL) as the outcome. We hypothesized that impacts of visual acuity on AVL are mediated by perceived functional vision losses and functional abilities, and tested for "adaptive" weakening of this impact with ongoing loss. Longitudinal data covering a one-year interval from samples with age-related macular degeneration gathered in New York (N = 361) and Heidelberg (Germany, N = 90) were used. We analyzed the hypothesized causal structure by modeling latent change scores, and checked if those with low, medium, and high levels of vision loss at baseline differ in the relations between one-year change scores. Results confirmed that impacts of vision loss on AVL are mediated by decline in functional ability. However, under the most severe levels of vision loss at baseline, functional decline showed only a minor impact on AVL change not explained by a lack of further decline in vision. Findings confirm the effectiveness of adaptation in terms of reduced reactivity to functional losses across increasing level of chronic impairment. Thus, adaptation, weakening the impact of chronic functional impairment on psychological outcomes over time with disease progression, deserves consideration in the study of psychological consequences of chronic physical health conditions in old age.

  3. Genetics and epigenetics in the fibrogenic evolution of chronic liver diseases.

    PubMed

    Zimmer, Vincent; Lammert, Frank

    2011-04-01

    Recent years have seen unprecedented progress in the identification and characterization of genetic information related to chronic liver diseases (CLDs). However, despite the conceptual benefit in early recognition of at-risk populations amenable to pre-emptive treatment and/or surveillance strategies, recent genomic research in the field has placed focus on unravelling the genetic architecture of disease susceptibility, while data on genetic markers anticipating an accelerated fibrogenesis in an individual are still limited. Likewise, sequence variation assigning rapid fibrogenic evolution common to CLDs irrespective of etiology are poorly defined aside from PNPLA3 (adiponutrin) as a prominent exception. The emerging field of epigenetics in hepatology has mostly been studied under the perspective of gene regulation, less so as a heritable alteration in gene activity. In this article we will critically discuss recent findings in genomic hepatology with special focus on the (epi)genetic contribution to the fibrogenic evolution of CLDs.

  4. Acute-on-chronic liver failure: a new syndrome in cirrhosis.

    PubMed

    Moreau, Richard

    2016-03-01

    Patients with cirrhosis who are hospitalized for an acute decompensation (AD) and also have organ failure(s) are at high risk of short-term death. These patients have a syndrome called Acute-on-Chronic Liver Failure (ACLF). ACLF is now considered as a new syndrome that it is distinct from "mere" AD not only because of the presence of organ failure(s) and high short-term mortality but also because of younger age, higher prevalence of alcoholic etiology of cirrhosis, higher prevalence of some precipitants (such as bacterial infections, active alcoholism), and more intense systemic inflammatory response. ACLF is a new syndrome also because severe sepsis or severe alcoholic hepatitis do not account for 100% of the observed cases; in fact, almost 50% of the cases are of "unknown" origin. In other words, severe sepsis, severe alcoholic hepatitis and ACLF of "unknown origin" are subcategories of the syndrome.

  5. Angelica injection reduces cognitive impairment during chronic cerebral hypoperfusion through brain-derived neurotrophic factor and nerve growth factor.

    PubMed

    Zheng, Ping; Zhang, Junjian; Liu, Hanxing; Xu, Xiaojuan; Zhang, Xiaolian

    2008-02-01

    The current study investigated whether chronic cerebral hypoperfusion produced by permanent bilateral common carotid artery occlusion (2-vessel occlusion (2-VO)) induced cognitive impairment and whether angelica injections alleviated the impairment. Furthermore, the study examined whether 2-VO altered the expression patterns of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) in the hippocampus of rats and whether angelica injections attenuated the alteration. Rats were divided into four groups to receive either 2-VO surgery or sham surgery followed by either angelica injections or saline injections for eight weeks. Spatial learning in Morris water maze and the expression patterns of BDNF and NGF in the hippocampus of all rats were examined. The results showed that 2-VO significantly impaired spatial learning and memory, and angelica injections significantly reversed the learning and memory impairment. Furthermore, 2-VO resulted in significantly decreased BDNF protein, NGF protein, and NGF mRNA expression in the hippocampus. Angelica injections significantly attenuated the decreased expression. Moreover, spatial learning in Morris water maze was positively correlated to the expression of BDNF and NGF in the hippocampus. Thus, angelica injections might alleviate cognitive impairment during chronic cerebral hypoperfusion through BDNF and NGF.

  6. Impact of neutrophil apoptosis on haemostatic activation in chronic liver disease patients.

    PubMed

    Essawy, Faiza M; Bekheet, Iman W; Saleh, Abeya F; Madkour, Mona E; Bayoumi, Emad El-Din A

    2008-09-01

    Recent studies suggest the impact of apoptosis on the mechanisms leading to hypercoagulability. We aimed to clarify the potential role of neutrophil apoptosis in neutropenia and hypercoagulable state encountered in chronic liver disease patients. This study was conducted on 15 normal controls and 45 patients with chronic liver disease classified according to modified Child Pugh classification into, Child A, B and C groups (15 cases each). Haemostatic parameters studied include, prothrombin time, partial thromboplastin time, tissue factor, protein C antigen, protein S antigen, and markers of haemostatic activation [prothrombin fragment 1+2 (F1+2), thrombus precursor protein (TpP) and D-dimer]. Flowcytometric study was done for quantitative assay of neutrophil apoptotic subpopulations to detect the percentage of early and late apoptotic, and necrotic neutrophils using Annexin V-FITC/propidium iodide dye. Semiquantitative assay of apoptotic neutrophils showing DNA fragmentation was performed on neutrophil culture using terminal deoxynucleotidyl transferase mediated deoxyuridine triphosphate nick end labelling test. In addition to enzyme-linked immunosorbent assay for soluble Fas (APO-1/CD95) in culture supernatant. The results revealed a rise in the neutrophil apoptotic and necrotic markers with progression of the disease, and they were inversely correlated with the absolute neutrophil count. The apoptotic neutrophil cells showed a significant positive correlation with several haemostatic parameters (tissue factor, prothrombin fragment 1+2, thrombus precursor protein and D-dimer). Regression analysis proved that apoptotic parameters are independent determinants of prothrombotic markers, which further incriminate the apoptotic mechanisms in the hypercoagulable state encountered in this clinical setting.

  7. Presence of TTV DNA in serum, liver and peripheral blood mononuclear cells from patients with chronic hepatitis.

    PubMed

    López-Alcorocho, J M; Mariscal, L F; de Lucas, S; Rodríguez-Iñigo, E; Casqueiro, M; Castillo, I; Bartolomé, J; Herrero, M; Manzano, M L; Pardo, M; Carreño, V

    2000-11-01

    The main site of TT virus (TTV) replication remains unknown. Therefore, we have studied the presence and titres of TTV DNA in paired serum, liver and PBMC samples from 50 patients with liver disease (32 with chronic hepatitis B or C, seven with cryptogenic hepatitis and 11 with nonviral liver disease) were included. TTV DNA was analysed by polymerase chain reaction (PCR) using primers from the open reading frame 1 (ORF 1) and from the untranslated region (UTR) and titres were semiquantified by PCR using an external standard. TTV DNA was detected in 26% of serum, 24% of liver and 14% of PBMC samples with ORF 1 primers. When UTR primers were used, 70% of serum and liver samples and 64% of PBMC were TTV DNA positive. No differences between TTV positive and negative patients were found regarding epidemiological or biochemical parameters. Trypsin treatment and fluorescent in situ hybridization confirm the intracellular location of TTV in PBMC. The mean of TTV DNA titres was statistically higher in liver than in serum or PBMC. TTV titres in serum correlated with those in PBMC but not with those in liver. In conclusion, although the liver seems to be the main site for TTV replication, this virus is also able to infect PBMC.

  8. Frontal Lobe Contusion in Mice Chronically Impairs Prefrontal-Dependent Behavior

    PubMed Central

    Rosi, Susanna

    2016-01-01

    Traumatic brain injury (TBI) is a major cause of chronic disability in the world. Moderate to severe TBI often results in damage to the frontal lobe region and leads to cognitive, emotional, and social behavioral sequelae that negatively affect quality of life. More specifically, TBI patients often develop persistent deficits in social behavior, anxiety, and executive functions such as attention, mental flexibility, and task switching. These deficits are intrinsically associated with prefrontal cortex (PFC) functionality. Currently, there is a lack of analogous, behaviorally characterized TBI models for investigating frontal lobe injuries despite the prevalence of focal contusions to the frontal lobe in TBI patients. We used the controlled cortical impact (CCI) model in mice to generate a frontal lobe contusion and studied behavioral changes associated with PFC function. We found that unilateral frontal lobe contusion in mice produced long-term impairments to social recognition and reversal learning while having only a minor effect on anxiety and completely sparing rule shifting and hippocampal-dependent behavior. PMID:26964036

  9. Metabolic profiling indicates impaired pyruvate dehydrogenase function in myalgic encephalopathy/chronic fatigue syndrome

    PubMed Central

    Mella, Olav; Bruland, Ove; Risa, Kristin; Dyrstad, Sissel E.; Alme, Kine; Rekeland, Ingrid G.; Sapkota, Dipak; Røsland, Gro V.; Fosså, Alexander; Ktoridou-Valen, Irini; Lunde, Sigrid; Sørland, Kari; Lien, Katarina; Herder, Ingrid; Thürmer, Hanne; Gotaas, Merete E.; Baranowska, Katarzyna A.; Bohnen, Louis M.L.J.; Schäfer, Christoph; McCann, Adrian; Sommerfelt, Kristian; Helgeland, Lars; Ueland, Per M.; Dahl, Olav

    2016-01-01

    Myalgic encephalopathy/chronic fatigue syndrome (ME/CFS) is a debilitating disease of unknown etiology, with hallmark symptoms including postexertional malaise and poor recovery. Metabolic dysfunction is a plausible contributing factor. We hypothesized that changes in serum amino acids may disclose specific defects in energy metabolism in ME/CFS. Analysis in 200 ME/CFS patients and 102 healthy individuals showed a specific reduction of amino acids that fuel oxidative metabolism via the TCA cycle, mainly in female ME/CFS patients. Serum 3-methylhistidine, a marker of endogenous protein catabolism, was significantly increased in male patients. The amino acid pattern suggested functional impairment of pyruvate dehydrogenase (PDH), supported by increased mRNA expression of the inhibitory PDH kinases 1, 2, and 4; sirtuin 4; and PPARδ in peripheral blood mononuclear cells from both sexes. Myoblasts grown in presence of serum from patients with severe ME/CFS showed metabolic adaptations, including increased mitochondrial respiration and excessive lactate secretion. The amino acid changes could not be explained by symptom severity, disease duration, age, BMI, or physical activity level among patients. These findings are in agreement with the clinical disease presentation of ME/CFS, with inadequate ATP generation by oxidative phosphorylation and excessive lactate generation upon exertion. PMID:28018972

  10. Impaired JAK-STAT signal transduction contributes to growth hormone resistance in chronic uremia.

    PubMed

    Schaefer, F; Chen, Y; Tsao, T; Nouri, P; Rabkin, R

    2001-08-01

    Chronic renal failure (CRF) is associated with resistance to the growth-promoting and anabolic actions of growth hormone (GH). In rats with CRF induced by partial renal ablation, 7 days of GH treatment had a diminished effect on weight gain and hepatic IGF-1 and IGFBP-1 mRNA levels, compared with sham-operated pair-fed controls. To assess whether GH resistance might be due to altered signal transduction, activation of the JAK-STAT pathway was studied 10 or 15 minutes after intravenous injection of 5 mg/kg GH or vehicle. Hepatic GH receptor (GHR) mRNA levels were significantly decreased in CRF, but GHR protein abundance and GH binding to microsomal and plasma membranes was unaltered. JAK2, STAT1, STAT3, and STAT5 protein abundance was also unchanged. However, GH-induced tyrosine phosphorylation of JAK2, STAT5, and STAT3 was 75% lower in the CRF animals. Phosphorylated STAT5 and STAT3 were also diminished in nuclear extracts. The expression of the suppressor of cytokine signaling-2 (SOCS-2) was increased twofold in GH-treated CRF animals, and SOCS-3 mRNA levels were elevated by 60% in CRF, independent of GH treatment. In conclusion, CRF causes a postreceptor defect in GH signal transduction characterized by impaired phosphorylation and nuclear translocation of GH-activated STAT proteins, which is possibly mediated, at least in part, by overexpression of SOCS proteins.

  11. Frontal Lobe Contusion in Mice Chronically Impairs Prefrontal-Dependent Behavior.

    PubMed

    Chou, Austin; Morganti, Josh M; Rosi, Susanna

    2016-01-01

    Traumatic brain injury (TBI) is a major cause of chronic disability in the world. Moderate to severe TBI often results in damage to the frontal lobe region and leads to cognitive, emotional, and social behavioral sequelae that negatively affect quality of life. More specifically, TBI patients often develop persistent deficits in social behavior, anxiety, and executive functions such as attention, mental flexibility, and task switching. These deficits are intrinsically associated with prefrontal cortex (PFC) functionality. Currently, there is a lack of analogous, behaviorally characterized TBI models for investigating frontal lobe injuries despite the prevalence of focal contusions to the frontal lobe in TBI patients. We used the controlled cortical impact (CCI) model in mice to generate a frontal lobe contusion and studied behavioral changes associated with PFC function. We found that unilateral frontal lobe contusion in mice produced long-term impairments to social recognition and reversal learning while having only a minor effect on anxiety and completely sparing rule shifting and hippocampal-dependent behavior.

  12. Betaine reverses the memory impairments in a chronic cerebral hypoperfusion rat model.

    PubMed

    Nie, Chunjie; Nie, Huijuan; Zhao, Yin; Wu, Jianzhao; Zhang, Xiaojian

    2016-02-26

    Vascular dementia (VaD) is the second reason for the cognitive decline in aged people, but the effective therapy is still missing. The chronic cerebral hypoperfusion (CCH) had been widely found in VaD patients and is thought to be the key reason for cognitive impairment. Betaine is a natural product that had been implicated in many biological processes and had been used for the therapy of some neurodegenerative disease, such as Alzheimer's disease. In this study, we reported that betaine treatment could rescue the memory deficits induced by two-vessel occlusion (2-VO), a widely used CCH rat model. Betaine also restored the expression of PSD93, PSD95 and MAP2 to preserve the synaptic functions. Furthermore, betaine could reduce the oxidative stress by suppressing the MDA and ROS and enhancing the SOD and GSH. Overall, betaine treatment is able to rescue the memory deficits in CCH rats, which provide an experimental basis for the therapy of VaD.

  13. Current status of novel antifibrotic therapies in patients with chronic liver disease

    PubMed Central

    Cohen-Naftaly, Michal; Friedman, Scott L.

    2011-01-01

    Fibrosis accumulation is a dynamic process resulting from a wound-healing response to acute or chronic liver injury of all causes. The cascade starts with hepatocyte necrosis and apoptosis, which instigate inflammatory signaling by chemokines and cytokines, recruitment of immune cell populations, and activation of fibrogenic cells, culminating in the deposition of extracellular matrix. These key elements, along with pathways of transcriptional and epigenetic regulation, represent fertile therapeutic targets. New therapies include drugs specifically designed as antifibrotics, as well as drugs already available with well-established safety profiles, whose mechanism of action may also be antifibrotic. At the same time, the development of noninvasive fibrogenic markers, and techniques (e.g. fibroscan), as well as combined scoring systems incorporating serum and clinical features will allow improved assessment of therapy response. In aggregate, the advances in the elucidation of the biology of fibrosis, combined with improved technologies for assessment will provide a comprehensive framework for design of antifibrotics and their analysis in well-designed clinical trials. These efforts may ultimately yield success in halting the progression of, or reversing, liver fibrosis. PMID:22043231

  14. Recent advances in managing chronic HCV infection: focus on therapy in patients with severe liver disease

    PubMed Central

    Maan, Raoel; van der Meer, Adriaan J.

    2016-01-01

    Chronic hepatitis C virus (HCV) infection still represents a major public health problem, as it is thought to be responsible for more than 350,000 deaths around the globe on a yearly basis. Fortunately, successful eradication of the virus has been associated with improved clinical outcome and reduced mortality rates. In the past few years, treatment has improved considerably by the implementation of direct-acting antivirals (DAAs). From 2014 onwards, sofosbuvir, simeprevir, daclatasvir, ledipasvir, paritaprevir, ombitasvir, and dasabuvir have been approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA). Regimens with various combinations of these new drugs, without the use of interferon (IFN), proved to be very effective and well tolerated, even among patients with advanced liver disease. Moreover, treatment duration could be shortened to 12 weeks in the majority of patients. The high costs of these DAAs, however, limit the availability of IFN-free therapy worldwide. Even in wealthy countries, it is deemed necessary to prioritize DAA treatment in order to limit the immediate impact on the health budget. As patients with advanced liver disease are in most need of HCV clearance, many countries decided to treat those patients first. In the current review, we focus on the currently available IFN-free treatment options for patients with cirrhosis. We discuss the virological efficacy as well as the clinical relevance of these regimens among this specific patient population. PMID:27006761

  15. Therapy of Chronic Hepatitis C in the Era of Nanotechnology: Drug Delivery Systems and Liver Targeting.

    PubMed

    Cuestas, Maria Lujan

    2017-01-01

    Since the British scientist Michael Houghton along with George Kuo, Qui-Lim Choo (Chiron Corporation Emeryville), and Daniel W. Bradley (Centers for Disease Control and Prevention) codiscovered the causative agent of hepatitis C in 1989, so much progress has been made for the screening of blood donors and management of this chronic liver disease. In this regard, direct-acting antiviral agents (DAAs) have emerged as the potential "cure" of this slowly progressing and devastating disease. However, improvements are still clearly required since the anti-hepatitis C drugs currently available in the market are so extremely expensive (i.e. $94,500 for a 12-week course of treatment), that many patients will have a denied access to such drugs by their insurers.

    In the last few years, nanotechnology has emerged as a new platform for drug development, contributing significantly to the improvement of the administration and delivery of many drugs. Additionally, nanotechnologies can provide unique solutions even in poorer societies.

    This manuscript reviews the current knowledges on the available anti-hepatitis C drugs and the new drug candidates being investigated as well, and introduces the recent advances in nanocarrier-based delivery systems. Finally, the challenges in the development of drug delivery systems for the targeting of antiviral drugs to the liver are also discussed.

  16. Chronic kidney disease after liver, cardiac, lung, heart–lung, and hematopoietic stem cell transplant

    PubMed Central

    2008-01-01

    Patient survival after cardiac, liver, and hematopoietic stem cell transplant (HSCT) is improving; however, this survival is limited by substantial pretransplant and treatment-related toxicities. A major cause of morbidity and mortality after transplant is chronic kidney disease (CKD). Although the majority of CKD after transplant is attributed to the use of calcineurin inhibitors, various other conditions such as thrombotic microangiopathy, nephrotic syndrome, and focal segmental glomerulosclerosis have been described. Though the immunosuppression used for each of the transplant types, cardiac, liver and HSCT is similar, the risk factors for developing CKD and the CKD severity described in patients after transplant vary. As the indications for transplant and the long-term survival improves for these children, so will the burden of CKD. Nephrologists should be involved early in the pretransplant workup of these patients. Transplant physicians and nephrologists will need to work together to identify those patients at risk of developing CKD early to prevent its development and progression to end-stage renal disease. PMID:18414901

  17. Chronic Liver Disease: Noninvasive Subharmonic Aided Pressure Estimation of Hepatic Venous Pressure Gradient

    PubMed Central

    Eisenbrey, John R.; Dave, Jaydev K.; Halldorsdottir, Valgerdur G.; Merton, Daniel A.; Miller, Cynthia; Gonzalez, José M.; Machado, Priscilla; Park, Suhyun; Dianis, Scott; Chalek, Carl L.; Kim, Christopher E.; Baliff, Jeffrey P.; Thomenius, Kai E.; Brown, Daniel B.; Navarro, Victor

    2013-01-01

    Purpose: To compare subharmonic aided pressure estimation (SHAPE) with pressure catheter–based measurements in human patients with chronic liver disease undergoing transjugular liver biopsy. Materials and Methods: This HIPAA-compliant study had U.S. Food and Drug Administration and institutional review board approval, and written informed consent was obtained from all participants. Forty-five patients completed this study between December 2010 and December 2011. A clinical ultrasonography (US) scanner was modified to obtain SHAPE data. After transjugular liver biopsy with pressure measurements as part of the standard of care, 45 patients received an infusion of a microbubble US contrast agent and saline. During infusion, SHAPE data were collected from a portal and hepatic vein and were compared with invasive measurements. Correlations between data sets were determined by using the Pearson correlation coefficient, and statistical significance between groups was determined by using the Student t test. Results:- The 45 study patients included 27 men and 18 women (age range, 19–71 years; average age, 55.8 years). The SHAPE gradient between the portal and hepatic veins was in good overall agreement with the hepatic venous pressure gradient (HVPG) (R = 0.82). Patients at increased risk for variceal hemorrhage (HVPG ≥ 12 mm Hg) had a significantly higher mean subharmonic gradient than patients with lower HVPGs (1.93 dB ± 0.61 [standard deviation] vs −1.47 dB ± 0.29, P < .001), with a sensitivity of 100% and a specificity of 81%, indicating that SHAPE may be a useful tool for the diagnosis of clinically important portal hypertension. Conclusion: Preliminary results show SHAPE to be an accurate noninvasive technique for estimating portal hypertension. © RSNA, 2013 Supplemental material: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.13121769/-/DC1 PMID:23525208

  18. Synergistic hepatoprotective effect of Schisandrae lignans with Astragalus polysaccharides on chronic liver injury in rats.

    PubMed

    Yan, Fei; Zhang, Qiao-Yan; Jiao, Lei; Han, Ting; Zhang, Hong; Qin, Lu-Ping; Khalid, Rahman

    2009-09-01

    The aim of this study was to investigate the synergistic hepatoprotective effect of lignans from Fructus Schisandrae chinensis (LFS) with Astragalus polysaccharides (APS) on chronic liver injury in male Sprague-Dawley rats. Subcutaneous injection of 10% CCl(4) twice a week for 3 months resulted in significantly (p<0.001) elevated serum alanine aminotransferase (ALT), asparate aminotransferase (AST), alkaline phosphatase (ALP) activities compared to controls. In the liver, significantly elevated levels (p<0.001) of malondialdehyde (MDA), lowered levels of reduced glutathione (GSH) (p<0.05) and catalase (CAT) (p<0.001), superoxide dismutase (SOD) (p<0.01)were observed following CCl(4) administration. 'LFS+ASP' treatment of rats at doses of 'LFS (45mg/kg)+APS (150mg/kg)' and 'LFS (135mg/kg)+APS (450mg/kg)' displayed hepatoprotective and antioxidative effects than the administration of either LFS or APS, as evident by lower (p<0.005 or 0.001) levels of serum ALT, AST, ALP and hepatic MDA (p<0.001) concentration, as well as higher SOD (p<0.05 or 0.005), CAT activities(p<0.01 or 0.005), GSH concentration (p<0.05 or 0.005) compared to the toxin treated group. Histopathological examinations revealed severe fatty degeneration in the toxin group, and mild damage in groups treated with 'LFS+APS' were observed. The coefficients drug interaction (CDI) between each individual drug and their combination (at the same dose of their single treatment) of these foregoing parameters were all less than 1, indicating that LFS and APS display hepatoprotective and antioxidant properties and act in a synergistic manner in CCl(4) induced liver injury in rats.

  19. PI3K-Akt1 expression and its significance in liver tissues with chronic fluorosis.

    PubMed

    Fan, Bin; Yu, Yanni; Zhang, Ying

    2015-01-01

    This study was to explore the effect and significance of PI3K signal pathway on mechanism of liver injury in chronic fluorosis. We used 48 Sprague-Dawley rats which were randomly divided into 4 groups according to the body weight, 12 in each group, half of male and female. The control group was fed with the solid feed (the fluorine content was 1.5 mg/kg). The fluorosis animals were fed with the corn containing fluorine content of 17 mg/kg from the endemic fluorosis areas. Blocking agent LY294002 was injected in the blocking group and phosphate buffer solution was injected in the blocking control in the caudal vein with 10 mg/kg once every other day in the one week before the end of the experiment. The animals were drunk by tap water freely. The fluoride contents of urinary and skeletal were determined by the F-ion selective electrode method. The mRNA and protein expressions of PI3K, Akt1 in the liver tissues were determined by real-time polymerase chain reaction, and streptavidin-perosidase and Western blot, respectively. Results showed that fluoride contents of the urine and bone were increased in the fluorosis compared to those in the control. The expression of PI3K and Akt1 mRNA and proteins was significantly increased in fluorosis hepatocytes, and lower than that of the fluorosis in the blocking. The apoptosis and the intracellular calcium concentration were increased. Therefore, we conclude that PI3K-Akt signaling pathway may be one of the signaling pathways in the pathogenesis of liver injury caused by fluorosis.

  20. PI3K-Akt1 expression and its significance in liver tissues with chronic fluorosis

    PubMed Central

    Fan, Bin; Yu, Yanni; Zhang, Ying

    2015-01-01

    This study was to explore the effect and significance of PI3K signal pathway on mechanism of liver injury in chronic fluorosis. We used 48 Sprague-Dawley rats which were randomly divided into 4 groups according to the body weight, 12 in each group, half of male and female. The control group was fed with the solid feed (the fluorine content was 1.5 mg/kg). The fluorosis animals were fed with the corn containing fluorine content of 17 mg/kg from the endemic fluorosis areas. Blocking agent LY294002 was injected in the blocking group and phosphate buffer solution was injected in the blocking control in the caudal vein with 10 mg/kg once every other day in the one week before the end of the experiment. The animals were drunk by tap water freely. The fluoride contents of urinary and skeletal were determined by the F-ion selective electrode method. The mRNA and protein expressions of PI3K, Akt1 in the liver tissues were determined by real-time polymerase chain reaction, and streptavidin-perosidase and Western blot, respectively. Results showed that fluoride contents of the urine and bone were increased in the fluorosis compared to those in the control. The expression of PI3K and Akt1 mRNA and proteins was significantly increased in fluorosis hepatocytes, and lower than that of the fluorosis in the blocking. The apoptosis and the intracellular calcium concentration were increased. Therefore, we conclude that PI3K-Akt signaling pathway may be one of the signaling pathways in the pathogenesis of liver injury caused by fluorosis. PMID:25973007

  1. High prevalence of hepatitis C virus (HCV) genotype 2 in Italian patients with chronic liver disease.

    PubMed

    Sartori, M; Andorno, S; Avogadro, E; Ballarè, M; La Terra, G; Leone, F; Quaglia, V; Fortina, G; Aglietta, M

    1996-01-01

    The prevalence of different genotypes of Hepatitis C virus may vary between geographic areas and it is possible that various genotypes have different pathogenic characteristics. Therefore, 90 consecutive Italian patients anti-Hepatitis C Virus positive with a broad spectrum of chronic liver disease, have been analysed to observe prevalence of various genotypes of Hepatitis C Virus. Genotyping was performed by polymerase chain reaction with a set of nested biotinylated primers, located in 5'UTR region. Genotype 1b and genotype 2a were the most commonly encountered (respectively, 50% and 37%) whereas other genotypes were rare. The unexpected high prevalence of genotype 2a allowed direct comparison of clinical characteristics and response to therapy between patients with genotype 2a and those with 1b. Genotype 1b was more prevalent than 2a in patients over 60 years (29 vs 12) and in those with more severe liver disease (34 vs 16). In a univariate analysis, genotype 2a was associated with less severe liver disease (p = 0.02) and younger age (p = 0.018), in comparison with genotype 1b. Patients with genotype 2a responded to interferon alpha therapy better than those with 1b (p = 0.007). In a multivariate analysis, only younger age was associated with genotype 2a. Genotype 2a (in comparison with 1b) and absence of cirrhosis were independent predictors of response to interferon alpha. In conclusion, genotype 2a is playing an emerging role in younger Italian patients and seems more sensitive than 1b to interferon alpha therapy.

  2. Ornicetil on encephalopathy. Effect of ornicetil (ornithine alpha-ketoglutarate) on encephalopathy in patients with acute and chronic liver disease.

    PubMed

    Chainuvati, T; Plengvanit, U; Viranuvatti, V

    1977-12-01

    Di-L (+)-ornithine, alpha ketogluterate infusions were compared with infusions of dextrose water in 27 comatosed patients with acute and chronic liver disease. Of 7 patients with acute liver disease no improvement of conciousness was found in any of these patients. Of 20 patients with chronic liver disease, lowering of blood ammonia level during ornicetil therapy occurred in 8, during the control infusion in 6, and no effect was seen in 4. Improvement of conciousness during ornicetil occurred in 11, during the control infusion in 6 and 3 had no improvement. Among those who improved, 4 in the ornicetil group and 2 in the control group improved after the precipitating causes were controlled or corrected. This study indicated that ornicetil has no beneficial effect on the treatment of coma in various forms of hepatic disease.

  3. Chronic multimorbidity impairs role functioning in middle-aged and older individuals mostly when non-partnered or living alone

    PubMed Central

    Hagedoorn, Mariët; Tuinman, Marrit A.

    2017-01-01

    Background Due to the aging of the population, society includes a growing proportion of older individuals prone to chronic morbidity. This study aimed to investigate the adverse effects of single and multiple chronic morbidity on psychosocial health and whether these effects are more pronounced in individuals who are non-partnered or living alone. Materials and methods Baseline data from the ‘Lifelines Cohort Study’ collected between 2006 and 2013 in the Netherlands were used. Individuals aged 50+ (n = 25,214) were categorized according to their health status (healthy, single chronic morbidity, multiple chronic morbidity), relationship status (partnered, non-partnered), and living arrangement (living with someone, living alone). Analyses of covariance (ANCOVA) were performed to study the main- and the interaction-effects on mental health and role functioning as assessed with the RAND-36. Results Irrespective of having chronic morbidity, having a partner was associated with better mental health when partners shared a home. Individuals with single and especially multiple chronic morbidity had impaired role functioning. Having a partner mitigated the adverse effects of multimorbidity on role functioning, but only in individuals who shared a home with their partner. Non-partnered individuals with multimorbidity and those not sharing a home with their partner demonstrated impaired role functioning. Conclusions The results demonstrate that multimorbidity negatively affects role functioning, but not the mental health, of middle-aged and older individuals. Sharing a home with a partner can mitigate these adverse effects, while other combinations of relationship status and living arrangement do not. Offering intervention to those individuals most vulnerable to impaired functioning may relieve some of the increasing pressure on the health care system. An individual’s relationship status along with one’s living arrangement could foster the identification of a target

  4. Comparison of collagen proportionate areas in liver fibrosis quantification between chronic hepatitis B and C

    PubMed Central

    Chen, Sheng-Hung; Peng, Cheng-Yuan; Chiang, I-Ping; Lai, Hsueh-Chou; Lee, Chiung-Ju; Su, Wen-Pang; Kao, Jung-Ta; Chuang, Po-Heng

    2016-01-01

    Abstract Few studies have compared the distinct hepatic collagen morphometrics of chronic hepatitis B (CHB) and chronic hepatitis C (CHC). This study compared the discrepancies between CHB and CHC in liver fibrosis (F) quantification by using the collagen proportionate area (CPA) and liver stiffness (LS) measured with shear wave velocity (SWV). This study enrolled 274 eligible consecutive patients diagnosed with CHB (n = 137) or CHC (n = 137). Their ages ranged from 20 to 80 years (median = 50). In total, 154 patients (56.2%) were male. Participant LS was measured by using acoustic radiation force impulse elastography preceding an immediate percutaneous liver biopsy. The total proportion of the collagen stained with picrosirius red to the total tissue area was expressed as the CPA percentage, which was stratified into portal–bridging (PB) and perisinusoidal (PS) proportionate areas (PAs). Based on the METAVIR F staging system, 36 (26.3%), 36 (26.3%), 28 (20.4%), and 37 (27.0%) participants in the CHB group and 34 (24.8%), 45 (32.9%), 34 (24.8%), and 24 (17.5%) participants in the CHC group were staged as F1, F2, F3, and F4, respectively. Both the total CPAs and PBPAs were significantly (P < 0.05) higher in the CHC group than in the CHB group within all F-stratified subgroups. The SWVs were significantly (P < 0.05) higher in the CHC group than in the CHB group only within the F2, F3, and F4 subgroups. However, the PSPAs did not differ significantly between the CHC and CHB groups within all subgroups. Multiple regression analysis revealed that viral hepatitis etiology (P < 0.001), METAVIR F stages (P < 0.001), and platelet count (P = 0.007) were independent factors correlated with the CPA (R2 = 0.543, P < 0.001). In conclusion, both the F stage-stratified CPAs and SWVs tended to be higher in cases of CHC than in those of CHB. The type of viral hepatitis significantly affected both the CPA and SWV values. The PBPAs were more

  5. Association of glutathione S-transferase T1 and M1 genotypes with chronic liver diseases among Filipinos.

    PubMed

    Baclig, Michael O; Alvarez, May R; Lozada, Xerxes Morgan R; Mapua, Cynthia A; Lozano-Kühne, Jingky P; Dimamay, Mark Pierre S; Natividad, Filipinas F; Gopez-Cervantes, Juliet; Matias, Ronald R

    2012-01-01

    The glutathione S-transferase (GST) supergene family is made up of four gene families responsible for the biotransformation of drugs and other xenobiotics. Genetic variations in this supergene family influence individual detoxification levels and may contribute to the development of cancer. A hospital-based case-control study was conducted to evaluate the association between GST polymorphism among Filipino patients positive for hepatitis B virus (HBV DNA) and clinically diagnosed as either with chronic active hepatitis, liver cirrhosis, and hepatocellular carcinoma as well as normal individuals negative for HBV infection. Multiplex PCR was used to detect the presence or absence of the GSTT1 and GSTM1 polymorphisms in peripheral blood. DNA sequencing of the S gene region of the virus was used to determine the predominant genotype found among HBV-infected patients. Our results showed that the odds of having a chronic liver disease is only 0.95 (95% CI 0.58-1.57) among those with GSTT1 null genotype compared to those with GSTT1+ genotype. On the other hand, the odds of chronic liver disease is 17.85 times (95% CI 7.34-43.45) for those with GSTM1 null genotype compared to those with GSTM1+ genotype. Using the GSTT1+/GSTM1+ genotype as the reference, both GSTT1+/GSTM1- (OR 16.61; 95% CI 6.69-41.22) and GSTT1-/GSTM1- (OR 11.91; 95% CI 4.48-31.66) genotypes seem to be risk factors for chronic liver disease. From our observations, we conclude that polymorphism in GSTM1 null genotype (OR 17.85; 95% CI 7.34-43.45) seem to be associated with an increased risk of chronic liver disease among Filipinos.

  6. Association of glutathione S-transferase T1 and M1 genotypes with chronic liver diseases among Filipinos

    PubMed Central

    Baclig, Michael O; Alvarez, May R; Lozada, Xerxes Morgan R; Mapua, Cynthia A; Lozano-Kühne, Jingky P; Dimamay, Mark Pierre S; Natividad, Filipinas F; Gopez-Cervantes, Juliet; Matias, Ronald R

    2012-01-01

    The glutathione S-transferase (GST) supergene family is made up of four gene families responsible for the biotransformation of drugs and other xenobiotics. Genetic variations in this supergene family influence individual detoxification levels and may contribute to the development of cancer. A hospital-based case-control study was conducted to evaluate the association between GST polymorphism among Filipino patients positive for hepatitis B virus (HBV DNA) and clinically diagnosed as either with chronic active hepatitis, liver cirrhosis, and hepatocellular carcinoma as well as normal individuals negative for HBV infection. Multiplex PCR was used to detect the presence or absence of the GSTT1 and GSTM1 polymorphisms in peripheral blood. DNA sequencing of the S gene region of the virus was used to determine the predominant genotype found among HBV-infected patients. Our results showed that the odds of having a chronic liver disease is only 0.95 (95% CI 0.58-1.57) among those with GSTT1 null genotype compared to those with GSTT1+ genotype. On the other hand, the odds of chronic liver disease is 17.85 times (95% CI 7.34-43.45) for those with GSTM1 null genotype compared to those with GSTM1+ genotype. Using the GSTT1+/GSTM1+ genotype as the reference, both GSTT1+/GSTM1- (OR 16.61; 95% CI 6.69-41.22) and GSTT1-/GSTM1- (OR 11.91; 95% CI 4.48-31.66) genotypes seem to be risk factors for chronic liver disease. From our observations, we conclude that polymorphism in GSTM1 null genotype (OR 17.85; 95% CI 7.34-43.45) seem to be associated with an increased risk of chronic liver disease among Filipinos. PMID:22724052

  7. Shear-Wave Elastography for the Estimation of Liver Fibrosis in Chronic Liver Disease: Determining Accuracy and Ideal Site for Measurement

    PubMed Central

    Dhyani, Manish; Vij, Abhinav; Bhan, Atul K.; Halpern, Elkan F.; Méndez-Navarro, Jorge; Corey, Kathleen E.; Chung, Raymond T.

    2015-01-01

    Purpose To evaluate the accuracy of shear-wave elastography (SWE) for staging liver fibrosis in patients with diffuse liver disease (including patients with hepatitis C virus [HCV]) and to determine the relative accuracy of SWE measurements obtained from different hepatic acquisition sites for staging liver fibrosis. Materials and Methods The institutional review board approved this single-institution prospective study, which was performed between January 2010 and March 2013 in 136 consecutive patients who underwent SWE before their scheduled liver biopsy (age range, 18–76 years; mean age, 49 years; 70 men, 66 women). Informed consent was obtained from all patients. SWE measurements were obtained at four sites in the liver. Biopsy specimens were reviewed in a blinded manner by a pathologist using METAVIR criteria. SWE measurements and biopsy results were compared by using the Spearman correlation and receiver operating characteristic (ROC) curve analysis. Results SWE values obtained at the upper right lobe showed the highest correlation with estimation of fibrosis (r = 0.41, P < .001). Inflammation and steatosis did not show any correlation with SWE values except for values from the left lobe, which showed correlation with steatosis (r = 0.24, P = .004). The area under the ROC curve (AUC) in the differentiation of stage F2 fibrosis or greater, stage F3 fibrosis or greater, and stage F4 fibrosis was 0.77 (95% confidence interval [CI]: 0.68, 0.86), 0.82 (95% CI: 0.75, 0.91), and 0.82 (95% CI: 0.70, 0.95), respectively, for all subjects who underwent liver biopsy. The corresponding AUCs for the subset of patients with HCV were 0.80 (95% CI: 0.67, 0.92), 0.82 (95% CI: 0.70, 0.95), and 0.89 (95% CI: 0.73, 1.00). The adjusted AUCs for differentiating stage F2 or greater fibrosis in patients with chronic liver disease and those with HCV were 0.84 and 0.87, respectively. Conclusion SWE estimates of liver stiffness obtained from the right upper lobe showed the best

  8. Diethylcarbamazine reduces chronic inflammation and fibrosis in carbon tetrachloride- (CCl₄-) induced liver injury in mice.

    PubMed

    Rocha, Sura Wanessa Santos; de França, Maria Eduarda Rocha; Rodrigues, Gabriel Barros; Barbosa, Karla Patrícia Sousa; Nunes, Ana Karolina Santana; Pastor, André Filipe; Oliveira, Anne Gabrielle Vasconcelos; Oliveira, Wilma Helena; Luna, Rayana Leal Almeida; Peixoto, Christina Alves

    2014-01-01

    This study investigated the anti-inflammatory effects of DEC on the CCl4-induced hepatotoxicity in C57BL/6 mice. Chronic inflammation was induced by i.p. administration of CCl4 0.5 μL/g of body weight through two injections a week for 6 weeks. DEC (50 mg/kg) was administered by gavage for 12 days before finishing the CCl4 induction. Histological analyses of the DEC-treated group exhibited reduced inflammatory process and prevented liver necrosis and fibrosis. Immunohistochemical and immunofluorescence analyses of the DEC-treated group showed reduced COX-2, IL1β, MDA, TGF-β, and αSMA immunopositivity, besides exhibiting decreased IL1β, COX-2, NFκB, IFNγ, and TGFβ expressions in the western blot analysis. The DEC group enhanced significantly the IL-10 expression. The reduction of hepatic injury in the DEC-treated group was confirmed by the COX-2 and iNOS mRNA expression levels. Based on the results of the present study, DEC can be used as a potential anti-inflammatory drug for chronic hepatic inflammation.

  9. Impaired SUMOylation of nuclear receptor LRH-1 promotes nonalcoholic fatty liver disease.

    PubMed

    Stein, Sokrates; Lemos, Vera; Xu, Pan; Demagny, Hadrien; Wang, Xu; Ryu, Dongryeol; Jimenez, Veronica; Bosch, Fatima; Lüscher, Thomas F; Oosterveer, Maaike H; Schoonjans, Kristina

    2017-02-01

    Hepatic steatosis is caused by metabolic imbalances that could be explained in part by an increase in de novo lipogenesis that results from increased sterol element binding protein 1 (SREBP-1) activity. The nuclear receptor liver receptor homolog 1 (LRH-1) is an important regulator of intermediary metabolism in the liver, but its role in regulating lipogenesis is not well understood. Here, we have assessed the contribution of LRH-1 SUMOylation to the development of nonalcoholic fatty liver disease (NAFLD). Mice expressing a SUMOylation-defective mutant of LRH-1 (LRH-1 K289R mice) developed NAFLD and early signs of nonalcoholic steatohepatitis (NASH) when challenged with a lipogenic, high-fat, high-sucrose diet. Moreover, we observed that the LRH-1 K289R mutation induced the expression of oxysterol binding protein-like 3 (OSBPL3), enhanced SREBP-1 processing, and promoted de novo lipogenesis. Mechanistically, we demonstrated that ectopic expression of OSBPL3 facilitates SREBP-1 processing in WT mice, while silencing hepatic Osbpl3 reverses the lipogenic phenotype of LRH-1 K289R mice. These findings suggest that compromised SUMOylation of LRH-1 promotes the development of NAFLD under lipogenic conditions through regulation of OSBPL3.

  10. Glycyrrhizinate reduces portal hypertension in isolated perfused rat livers with chronic hepatitis

    PubMed Central

    Zhao, Xin; Deng, Bo; Xu, Xue-Yan; Yang, Shi-Jun; Zhang, Tao; Song, Yi-Jun; Liu, Xiao-Ting; Wang, Yue-Qi; Cai, Da-Yong

    2013-01-01

    AIM: To investigate the effects of diammonium glycyrrhizinate (Gly) on portal hypertension (PHT) in isolated portal perfused rat liver (IPPRL) with carbon tetrachloride (CCl4)-induced chronic hepatitis. METHODS: PHT model was replicated with CCl4 in rats for 84 d. Model was identified by measuring the ascetic amounts, hepatic function, portal pressure in vivo, splenic index, and pathological alterations. Inducible nitric oxide synthase (iNOS) in liver was assessed by immunohistochemistry. IPPRLs were performed at d0, d28, d56, and d84. After phenylephrine-induced constriction, Gly was geometrically used to reduce PHT. Gly action was expressed as median effective concentration (EC50) and area under the curve (AUC). Underlying mechanism was exploited by linear correlation between AUC values of Gly and existed iNOS in portal triads. RESULTS: PHT model was confirmed with ascites, splenomegaly, serum biomarkers of hepatic injury, and elevated portal pressure. Pathological findings had shown normal hepatic structure at d0, degenerations at d28, fibrosis at d56, cirrhosis at d84 in PHT rats. Pseudo lobule ratios decreased and collagen ratios increased progressively along with PHT development. Gly does dose-dependently reduce PHT in IPPRLs with CCl4-induced chronic hepatitis. Gly potencies were increased gradually along with PHT development, characterized with its EC50 at 2.80 × 10-10, 3.03 × 10-11, 3.77 × 10-11 and 4.65×10-11 mol/L at d0, d28, d56 and d84, respectively. Existed iNOS was located at hepatocyte at d0, stellate cells at d28, stellate cells and macrophages at d56, and macrophages in portal triads at d84. Macrophages infiltrated more into portal triads and expressed more iNOS along with PHT development. AUC values of Gly were positively correlated with existed iNOS levels in portal triads. CONCLUSION: Gly reduces indirectly PHT in IPPRL with CCl4-induced chronic hepatitis. The underlying mechanisms may relate to rescue NO bioavailability from macrophage

  11. Primary lymphoma of the liver in a patient with acquired immune deficiency syndrome and chronic hepatitis B.

    PubMed

    Lisker-Melman, M; Pittaluga, S; Pluda, J M; Kleiner, D E; Thompson, P; Martin, P; Yarchoan, R; Di Bisceglie, A M

    1989-11-01

    We describe the case of a homosexual man with asymptomatic infection with human immunodeficiency virus and hepatitis B virus who developed primary hepatic lymphoma. The lymphoma presented with rapid enlargement of the liver, and ultrasound examination revealed multiple hypoechoic lesions within the liver. Histological examination of the liver showed massive replacement by lymphomatous tissue, as well as changes of chronic active hepatitis B. Immunohistochemical stains for hepatitis B surface and core antigens were strongly positive in almost all hepatocytes, but not in tumor tissue. Whereas the occurrence of lymphoma probably is related to HIV infection, possible interactions between hepatitis B virus and HIV infection are discussed. Thus, the presence of mass lesions within the liver in a patient with HIV infection should raise the possibility of hepatic lymphoma even if there is no evidence of generalized lymphadenopathy.

  12. Assessment of liver fibrosis with 2-D shear wave elastography in comparison to transient elastography and acoustic radiation force impulse imaging in patients with chronic liver disease.

    PubMed

    Gerber, Ludmila; Kasper, Daniela; Fitting, Daniel; Knop, Viola; Vermehren, Annika; Sprinzl, Kathrin; Hansmann, Martin L; Herrmann, Eva; Bojunga, Joerg; Albert, Joerg; Sarrazin, Christoph; Zeuzem, Stefan; Friedrich-Rust, Mireen

    2015-09-01

    Two-dimensional shear wave elastography (2-D SWE) is an ultrasound-based elastography method integrated into a conventional ultrasound machine. It can evaluate larger regions of interest and, therefore, might be better at determining the overall fibrosis distribution. The aim of this prospective study was to compare 2-D SWE with the two best evaluated liver elastography methods, transient elastography and acoustic radiation force impulse (point SWE using acoustic radiation force impulse) imaging, in the same population group. The study included 132 patients with chronic hepatopathies, in which liver stiffness was evaluated using transient elastography, acoustic radiation force impulse imaging and 2-D SWE. The reference methods were liver biopsy for the assessment of liver fibrosis (n = 101) and magnetic resonance imaging/computed tomography for the diagnosis of liver cirrhosis (n = 31). No significant difference in diagnostic accuracy, assessed as the area under the receiver operating characteristic curve (AUROC), was found between the three elastography methods (2-D SWE, transient elastography, acoustic radiation force impulse imaging) for the diagnosis of significant and advanced fibrosis and liver cirrhosis in the "per protocol" (AUROCs for fibrosis stages ≥2: 0.90, 0.95 and 0.91; for fibrosis stage [F] ≥3: 0.93, 0.95 and 0.94; for F = 4: 0.92, 0.96 and 0.92) and "intention to diagnose" cohort (AUROCs for F ≥2: 0.87, 0.92 and 0.91; for F ≥3: 0.91, 0.93 and 0.94; for F = 4: 0.88, 0.90 and 0.89). Therefore, 2-D SWE, ARFI imaging and transient elastography seem to be comparably good methods for non-invasive assessment of liver fibrosis.

  13. Value of the 8-oxodG/dG ratio in chronic liver inflammation of patients with hepatocellular carcinoma

    PubMed Central

    Li, Pengcheng; Ramm, Grant A; Macdonald, Graeme A

    2016-01-01

    The aim of this study was to examine the role of oxidative DNA damage in chronic liver inflammation in the evolution of hepatocellular carcinoma. The accumulated data demonstrated that oxidative DNA damage and chronic liver inflammation are involved in the transformation of normal hepatocytes and their evolution towards hepatocellular carcinoma. However, the levels of 8-oxy-2′-deoxy-guanosine (8-oxodG), a biomarker of oxidative DNA damage, were overestimated and underestimated in previous reports due to various technical limitations. The current techniques are not suitable to analyze the 8-oxodG levels in the non-malignant liver tissues and tumors of hepatocellular carcinoma patients unless they are modified. Therefore, in this study, the protocols for extraction and hydrolysis of DNA were optimized using 54 samples from hepatocellular carcinoma patients with various risk factors, and the 8-oxodG and 2′-deoxyguanosine (dG) levels were measured. The patients enrolled in the study include 23 from The Princess Alexandra Hospital and The Royal Brisbane and Women's Hospitals, Brisbane, Australia, and 31 from South Africa. This study revealed that the 8-oxodG/dG ratios tended to be higher in most non-malignant liver tissues compared to hepatocellular carcinoma tissue (p=0.2887). It also appeared that the ratio was higher in non-malignant liver tissue from Southern African patients (p=0.0479), but there was no difference in the 8-oxodG/dG ratios between non-malignant liver tissues and tumors of Australian hepatocellular carcinoma patients (p=0.7722). Additionally, this study also revealed a trend for a higher 8-oxodG/dG ratio in non-malignant liver tissues compared to tumoural tissues of patients with HBV. Significant differences were not observed in the 8-oxodG/dG ratios between non-cirrhotic and cirrhotic non-malignant liver tissues. PMID:26890046

  14. Chronic developmental lead exposure reduces neurogenesis in adult rat hippocampus but does not impair spatial learning.

    PubMed

    Gilbert, M E; Kelly, M E; Samsam, T E; Goodman, J H

    2005-08-01

    The dentate granule cell (DG) layer of the hippocampal formation has the distinctive property of ongoing neurogenesis that continues throughout adult life. Although the function of these newly generated neurons and the mechanisms that control their birth are unknown, age, activity, diet and psychosocial stress have all been demonstrated to regulate this type of neurogenesis. Little information on the impact of environmental insults on this process has appeared to date. Developmental lead (Pb) exposure has been well documented to impair cognitive function in children and animals and reduce activity-dependent synaptic plasticity in the hippocampus of rodents. Therefore, we examined the effects of this classic environmental neurotoxicant on hippocampal-dependent learning and adult neurogenesis in the hippocampus. Pregnant rats were exposed to a low level of Pb-acetate (0.2%) via the drinking water from late gestation (GD 16) until weaning on postnatal day 21 (PN 21). At weaning, half of the Pb-exposed animals were weaned to control drinking water and the remainder were maintained on Pb water until termination of the study. Animals were paired- housed and on PN 75 were administered a series of injections of a thymidine analog bromodeoxyuridine (BrdU), a marker of DNA synthesis that labels proliferating cells and their progeny. At 12-h intervals for 12 days, rats received an ip injection of BrdU (50 mg/kg). Subjects were sacrificed and perfused 24 h and 28 days after the last injection. Spatial learning was assessed in an independent group of animals beginning on PN 110 using a Morris water maze. No Pb-induced impairments were evident in water maze learning. Immunohistochemistry for the detection of BrdU-labeled cells was performed on 40-microm coronal sections throughout the hippocampus. Continuous exposure to Pb (Life) reduced the total number of BrdU-positive cells at 28 days without affecting the total number of labeled cells evident 24 h after the last injection

  15. The Lung Function Impairment in Non-Atopic Patients With Chronic Rhinosinusitis and Its Correlation Analysis

    PubMed Central

    Zhang, Linghao; Zhang, Lu; Zhang, Chun-Hong; Fang, Xiao-Bi; Huang, Zhen-Xiao; Shi, Qing-Yuan; Wu, Li-Ping; Wu, Peng; Wang, Zhen-Zhen; Liao, Zhi-Su

    2016-01-01

    Objectives Chronic rhinosinusitis (CRS) is common disease in otorhinolaryngology and will lead to lower airway abnormality. However, the only lung function in CRS patients and associated factors have not been much studied. Methods One hundred patients with CRS with nasal polyps (CRSwNP group), 40 patients with CRS without nasal polyps (CRSsNP group), and 100 patients without CRS were enrolled. The difference in lung function was compared. Meanwhile, CRSwNP and CRSsNP group were required to undergo a bronchial provocation or dilation test. Additionally, subjective and objective outcomes were measured by the visual analogue scale (VAS), 20-item Sino-Nasal Outcome Test (SNOT-20), Lund-Mackay score, Lund-Kennedy endoscopic score. The correlation and regression methods were used to analyze the relationship between their lung function and the above parameters. Results The forced expiratory volume in 1 second (FEV1) and forced expiratory flow between 25% and 75% of forced vital capacity (FEF25-75) of CRSwNP group were significantly lower than other groups (P<0.05). On peak expiratory flow, there was no difference between three groups. In CRSwNP group, FEV1 was negatively correlated with peripheral blood eosinophil count (PBEC) and duration of disease (r=–0.348, P=0.013 and r=–0.344, P=0.014, respectively), FEF25-75 negatively with VAS, SNOT-20 (r=–0.490, P=0.028 and r=–0.478, P=0.033, respectively) in CRSsNP group. The incidence of positive bronchial provocation and dilation test was lower in CRSwNP group (10% and 0%, respectively), with both 0% in CRSsNP group. The multiple linear regression analysis indicated that change ratio of FEV1 before and after bronchial provocation or dilation test were correlated with PBEC in CRSwNP group (β=0.403, P=0.006). Conclusion CRS leading to impaired maximum ventilation and small airway is associated with the existence of nasal polyp. Lung function impairments can be reflected by PBEC, duration, VAS, and SNOT-20. In CRSw

  16. Effectiveness of theophylline prophylaxis of renal impairment after coronary angiography in patients with chronic renal insufficiency.

    PubMed

    Huber, Wolfgang; Schipek, Chrysantha; Ilgmann, Kathrin; Page, Michael; Hennig, Michael; Wacker, Annette; Schweigart, Ursula; Lutilsky, Leopoldo; Valina, Christian; Seyfarth, Melchior; Schömig, Albert; Classen, Meinhard

    2003-05-15

    Contrast media can lead to renal impairment that results in longer hospitalization and increased mortality. Adenosine is a crucial mediator of contrast-induced nephropathy (CIN; an increase in serum creatinine of >or=0.5 mg/dl within 48 hours). Therefore, it was the purpose of our study to investigate whether the adenosine antagonist theophylline reduces the incidence of CIN after coronary angiography. We also characterized risk factors for CIN after coronary angiography. One hundred patients with serum creatinine concentrations of >or=1.3 mg/dl randomly received 200 mg IV theophylline or placebo 30 minutes before coronary angiography (amount of contrast medium >or=100 ml). Patients who received theophylline and the controls were comparable with regard to baseline creatinine levels (means +/- SD) (1.65 +/- 0.41 vs 1.72 +/- 0.69 mg/dl) and the amount of contrast medium received (235 +/- 89 vs 261 +/- 139 ml). Theophylline significantly reduced the incidence of CIN (4% vs 20%, p = 0.0138). With placebo, creatinine significantly increased at 12 (1.82 +/- 0.79 mg/dl, p = 0.0057), 24 (1.90 +/- 0.86 mg/dl, p = 0.0001), and 48 hours (1.90 +/- 0.89 mg/dl, p = 0.0007) after administration of contrast medium. With pretreatment with theophylline, mean creatinine only increased 24 hours after contrast medium administration (1.70 +/- 0.40 mg/dl, p = 0.029), but was stable 12 hours (1.65 +/- 0.43 mg/dl, p = 0.99) and 48 hours after contrast medium administration (1.65 +/- 0.41 mg/dl, p = 0.99). The following parameters were significantly associated with contrast-induced renal impairment: Cigarroa quotient >5 (contrast medium [milliters] x serum creatinine/body weight [kg]), elevated troponin T, >300 ml of contrast medium, and emergency angiography. In conclusion, theophylline reduces the incidence of CIN in patients with chronic renal insufficiency undergoing coronary angiography. It should be used especially in patients receiving large amounts of contrast medium, and in

  17. Impairment of liver synthetic function and the production of plasma proteins in primary breast cancer patients on doxorubicincyclophosphamide (AC) protocol.

    PubMed

    Saleem, Zikria; Ahmad, Mobasher; Hashmi, Furqan Khurshid; Saeed, Hamid; Aziz, Muhammad Tahir

    2016-09-01

    Doxorubicin and Cyclophosphamide (AC protocol) combination is usually considered as a first line therapy in newly diagnosed breast cancer patients. Thus, a retrospective observational study was conducted to monitor the effect of AC protocol on liver synthetic functions and production of plasma proteins in breast cancer patients, reporting to specialized cancer care hospital of Lahore, Pakistan. A total of 75 patients (n=75) on AC protocol with breast cancer were observed in this study. The patient data including age, gender, body surface area, dosage, disease status and laboratory biochemical values were recorded by reviewing historical treatment records. Pre-treatment values were taken as baseline values for albumin, globulin, blood urea nitrogen (BUN), albumin/globulin (A/G) ratio and total proteins. The baseline values were compared after each cycle of by applying ANOVA using statistical tool SPSS® version 21. The plasma levels of blood urea nitrogen (BUN), total protein and globulin dropped significantly (p<0.05) in patients of all age groups. However, the albumin levels were not significantly changed (p>0.05). The A/G ratio level increased (p<0.05) as a result of reduction in globulin levels. Significant changes in plasma protein levels were observed in the elderly patients (50 to 65 years) than patients between 20 to 50 years of age. AC protocol impairs liver synthetic functions as observed by decreased blood urea nitrogen (BUN) and plasma protein levels.

  18. Chronic administration of R-flurbiprofen attenuates learning impairments in transgenic amyloid precursor protein mice

    PubMed Central

    Kukar, Thomas; Prescott, Sonya; Eriksen, Jason L; Holloway, Vallie; Murphy, M Paul; Koo, Edward H; Golde, Todd E; Nicolle, Michelle M

    2007-01-01

    Background Long-term use of non-steroidal anti-inflammatory drugs (NSAIDs) is associated with a reduced incidence of Alzheimer's disease (AD). We and others have shown that certain NSAIDs reduce secretion of Aβ42 in cell culture and animal models, and that the effect of NSAIDs on Aβ42 is independent of the inhibition of cyclooxygenase by these compounds. Since Aβ42 is hypothesized to be the initiating pathologic molecule in AD, the ability of these compounds to lower Aβ42 selectively may be associated with their protective effect. We have previously identified R-flurbiprofen (tarenflurbil) as a selective Aβ42 lowering agent with greatly reduced cyclooxygenase activity that shows promise for testing this hypothesis. In this study we report the effect of chronic R-flurbiprofen treatment on cognition and Aβ loads in Tg2576 APP mice. Results A four-month preventative treatment regimen with R-flurbiprofen (10 mg/kg/day) was administered to young Tg2576 mice prior to robust plaque or Aβ pathology. This treatment regimen improved spatial learning as assessed by the Morris water maze, indicated by an increased spatial bias during the third probe trial and an increased utilization of a place strategy to solve the water maze. These results are consistent with an improvement in hippocampal- and medial temporal lobe-dependent memory function. A modest, though not statistically significant, reduction in formic acid-soluble levels of Aβ was also observed. To determine if R-flurbiprofen could reverse cognitive deficits in Tg2576 mice where plaque pathology was already robust, a two-week therapeutic treatment was given to older Tg2576 mice with the same dose of R-flurbiprofen. This approach resulted in a significant decrease in Aβ plaque burden but no significant improvement in spatial learning. Conclusion We have found that chronic administration of R-flurbiprofen is able to attenuate spatial learning deficits if given prior to plaque deposition in Tg2576 mice. Given its

  19. Impaired adult hippocampal neurogenesis and its partial reversal by chronic treatment of fluoxetine in a mouse model of Angelman syndrome.

    PubMed

    Godavarthi, Swetha K; Dey, Parthanarayan; Sharma, Ankit; Jana, Nihar Ranjan

    2015-09-04

    Angelman syndrome (AS) is a neurodevelopmental disorder characterized by severe cognitive and motor deficits, caused by the loss of function of maternally inherited Ube3a. Ube3a-maternal deficient mice (AS model mice) recapitulate many essential features of AS, but how the deficiency of Ube3a lead to such behavioural abnormalities is poorly understood. Here we have demonstrated significant impairment of adult hippocampal neurogenesis in AS mice brain. Although, the number of BrdU and Ki67-positive cell in the hippocampal DG region was nearly equal at early postnatal days among wild type and AS mice, they were significantly reduced in adult AS mice compared to wild type controls. Reduced number of doublecortin-positive immature neurons in this region of AS mice further indicated impaired neurogenesis. Unaltered BrdU and Ki67-positive cells number in the sub ventricular zone of adult AS mice brain along with the absence of imprinted expression of Ube3a in the neural progenitor cell suggesting that Ube3a may not be directly linked with altered neurogenesis. Finally, we show that the impaired hippocampal neurogenesis in these mice can be partially rescued by the chronic treatment of antidepressant fluoxetine. These results suggest that the chronic stress may lead to reduced hippocampal neurogenesis in AS mice and that impaired neurogenesis could contribute to cognitive disturbances observed in these mice.

  20. Impaired adrenergic- and corticotropic-axis outflow during exercise in chronic obstructive pulmonary disease.

    PubMed

    Iranmanesh, Ali; Rochester, Dudley F; Liu, Jing; Veldhuis, Johannes D

    2011-11-01

    Exercise stimulates coordinated release of the sympathoadrenal hormones adrenocorticotropic hormone (ACTH), cortisol, norepinephrine (NE), and epinephrine (Epi). The study hypothesis was that chronic obstructive pulmonary disease (COPD) is marked by heightened sympathoadrenal outflow at comparable relative workloads. The location of the study was at a clinical research unit. Eight healthy men and 9 men with stable COPD (forced expiratory volume at 1 second <75% predicted) were studied. Volunteers rested (baseline) or exercised at individual submaximal (35% ± 5%) or maximal oxygen consumption. Blood was sampled every 2 minutes for 40 minutes concurrently. Two-way analysis of covariance was applied to examine group (healthy/COPD) and exercise (3 levels) effects on ACTH, cortisol, NE, and Epi release and regularity (estimable by approximate entropy). The timing of peak hormone concentrations was Epi, 14 minutes; NE, 16 minutes; ACTH, 22 minutes; and cortisol, 34 minutes in both cohorts. Type of exercise regimen influenced all 4 hormones (each P < .001), and subject group (control vs COPD) affected cortisol (P < .001) and Epi (P = .048) responses. Exercise regimen and group together controlled ACTH, cortisol, and Epi (each P < .001), but not NE, responses. In particular, endocrine responses were attenuated in COPD compared with control subjects. Approximate entropy analysis also identified loss of maximal exercise-induced ACTH-secretory regularity in COPD patients (P = .042). These outcomes demonstrate impaired rather than augmented exercise-associated sympathocorticotropic-axis outflow in patients with COPD even when outcomes are normalized to maximal oxygen consumption, suggesting that factors other than fitness are at work.

  1. Chronic Stress During Adolescence Impairs and Improves Learning and Memory in Adulthood.

    PubMed

    Chaby, Lauren E; Cavigelli, Sonia A; Hirrlinger, Amy M; Lim, James; Warg, Kendall M; Braithwaite, Victoria A

    2015-01-01

    HIGHLIGHTS This study tested the effects of adolescent-stress on adult learning and memory.Adolescent-stressed rats had enhanced reversal learning compared to unstressed rats.Adolescent-stress exposure made working memory more vulnerable to disturbance.Adolescent-stress did not affect adult associative learning or reference memory. Exposure to acute stress can cause a myriad of cognitive impairments, but whether negative experiences continue to hinder individual as they age is not as well understood. We determined how chronic unpredictable stress during adolescence affects multiple learning and memory processes in adulthood. Using male Sprague Dawley rats, we measured learning (both associative and reversal) and memory (both reference and working) starting 110 days after completion of an adolescent-stress treatment. We found that adolescent-stress affected adult cognitive abilities in a context-dependent way. Compared to rats reared without stress, adolescent-stressed rats exhibited enhanced reversal learning, an indicator of behavioral flexibility, but showed no change in associative learning and reference memory abilities. Working memory, which in humans is thought to underpin reasoning, mathematical skills, and reading comprehension, may be enhanced by exposure to adolescent-stress. However, when adolescent-stressed animals were tested after a novel disturbance, they exhibited a 5-fold decrease in working memory performance while unstressed rats continued to exhibit a linear learning curve. These results emphasize the capacity for stress during adolescence to transform the cognitive abilities of adult animals, even after stress exposure has ceased and animals have resided in safe environments for the majority of their lifespans.

  2. Chronic hypernatremia derived from hypothalamic dysfunction: impaired secretion of arginine vasopressin and enhanced renal water handling.

    PubMed

    Fukagawa, A; Ishikawa, S E; Saito, T; Kusaka, I; Nakamura, T; Higashiyama, M; Nagasaka, S; Kusaka, G; Masuzawa, T; Saito, T

    2001-04-01

    We analyzed the disorder of water metabolism in a 32 year-old female with chronic hypernatremia. She had meningitis at 4 years, and ventriculo-peritoneal shunt operation at 13 years because of normal pressure hydrocephalus. At 14 years hypernatremia of 166 mmol/l was initially found and thereafter hypernatremia ranging from 150 to 166 mmol/l has been persisted for the last 18 years. Physical and laboratory findings did not show dehydration. Urine volume was 750-1700 ml per day and urinary osmolality (Uosm) 446-984 mmol/kg, suggesting no urinary concentrating defect. Plasma arginine vasopressin (AVP) levels ranged from 0.4 to 1.2 pmol/l despite hyperosmolality of 298 through 343 mmol/kg under ad libitum water drinking. There was no correlation between plasma osmolality (Posm) and plasma AVP levels, but Uosm had a positive correlation with Posm (r=0.545, P < 0.05). Hypertonic saline (500 NaCl) infusion after a water load increased Uosm from 377 to 679 mmol/kg, and plasma AVP from 0.2 to 1.3 pmol/l. There was a positive correlation between Posm and plasma AVP levels in the hypertonic saline test (r=0.612, P<0.05). In contrast, an acute water load (20 ml/kg BW) verified the presence of impaired water excretion, as the percent excretion of the water load was only 8.5% and the minimal Uosm was as high as 710 mmol/kg. Urinary excretion of aquaporin-2 remained low in concert with plasma AVP levels. No abnormality in pituitary-adrenocortical function was found. These results indicate that marked hypernatremia is derived from partial central diabetes insipidus and elevated threshold of thirst, and that enhanced renal water handling may contribute to maintenance of body water in the present subject.

  3. Chronic kidney disease predicts impaired membrane microviscosity of red blood cells in hypertensive and normotensive subjects.

    PubMed

    Tsuda, Kazushi

    2013-01-01

    Current evidence indicates that abnormalities in physical properties of the cell membranes may be strongly linked to hypertension and other circulatory disorders. Recent studies have shown that chronic kidney disease (CKD) might be a risk factor for cardiovascular and cerebrovascular outcomes. The purpose of the present study was to examine the possible relationship between kidney function and membrane fluidity (a reciprocal value of membrane microviscosity) of red blood cells (RBCs) in hypertensive and normotensive subjects using an electron spin resonance (ESR) and spin-labeling method. The order parameter (S) for the ESR spin-label agent (5-nitroxide stearate) in RBC membranes was significantly higher in hypertensive subjects than in normotensive subjects, indicating that membrane fluidity was decreased in hypertension. The order parameter (S) of RBCs was inversely correlated with estimated glomerular filtration rate (eGFR), suggesting that a decreased eGFR value might be associated with reduced membrane fluidity of RBCs. Multivariate regression analysis also demonstrated that, after adjustment for general risk factors, eGFR might be a significant predictor of membrane fluidity of RBCs. The reduced levels of both membrane fluidity of RBCs and eGFR were associated with increased plasma 8-iso-prostaglandin F2α (an index of oxidative stress) and decreased plasma nitric oxide (NO)-metabolites, suggesting that kidney function could be a determinant of membrane microviscosity of RBCs, at least in part, via oxidative stress- and NO-dependent mechanisms. The ESR study suggests that CKD might have a close correlation with impaired rheologic behavior of RBCs and microcirculatory disorders in hypertensive subjects.

  4. Chronic Stress During Adolescence Impairs and Improves Learning and Memory in Adulthood

    PubMed Central

    Chaby, Lauren E.; Cavigelli, Sonia A.; Hirrlinger, Amy M.; Lim, James; Warg, Kendall M.; Braithwaite, Victoria A.

    2015-01-01

    HIGHLIGHTS This study tested the effects of adolescent-stress on adult learning and memory.Adolescent-stressed rats had enhanced reversal learning compared to unstressed rats.Adolescent-stress exposure made working memory more vulnerable to disturbance.Adolescent-stress did not affect adult associative learning or reference memory. Exposure to acute stress can cause a myriad of cognitive impairments, but whether negative experiences continue to hinder individual as they age is not as well understood. We determined how chronic unpredictable stress during adolescence affects mu