Investigating the influence of standard staining procedures on the copper distribution and concentration in Wilson's disease liver samples by laser ablation-inductively coupled plasma-mass spectrometry.

PubMed

Hachmöller, Oliver; Aichler, Michaela; Schwamborn, Kristina; Lutz, Lisa; Werner, Martin; Sperling, Michael; Walch, Axel; Karst, Uwe

2017-12-01

The influence of rhodanine and haematoxylin and eosin (HE) staining on the copper distribution and concentration in liver needle biopsy samples originating from patients with Wilson's disease (WD), a rare autosomal recessive inherited disorder of the copper metabolism, is investigated. In contemporary diagnostic of WD, rhodanine staining is used for histopathology, since rhodanine and copper are forming a red to orange-red complex, which can be recognized in the liver tissue using a microscope. In this paper, a laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) method is applied for the analysis of eight different WD liver samples. Apart from a spatially resolved elemental detection as qualitative information, this LA-ICP-MS method offers also quantitative information by external calibration with matrix-matched gelatine standards. The sample set of this work included an unstained and a rhodanine stained section of each WD liver sample. While unstained sections of WD liver samples showed very distinct structures of the copper distribution with high copper concentrations, rhodanine stained sections revealed a blurred copper distribution with significant decreased concentrations in a range from 20 to more than 90%. This implies a copper removal from the liver tissue by complexation during the rhodanine staining. In contrast to this, a further HE stained sample of one WD liver sample did not show a significant decrease in the copper concentration and influence on the copper distribution in comparison to the unstained section. Therefore, HE staining can be combined with the analysis by means of LA-ICP-MS in two successive steps from one thin section of a biopsy specimen. This allows further information to be gained on the elemental distribution by LA-ICP-MS additional to results obtained by histological staining. Copyright © 2017 Elsevier GmbH. All rights reserved.

Copper-2 Ingestion, Plus Increased Meat Eating Leading to Increased Copper Absorption, Are Major Factors Behind the Current Epidemic of Alzheimer's Disease.

PubMed

Brewer, George J

2015-12-02

It has become clear that copper toxicity is playing a major role in Alzheimer's disease; but why is the brain copper toxicity with cognition loss in Alzheimer's disease so much different clinically than brain copper toxicity in Wilson's disease, which results in a movement disorder? Furthermore, why is the inorganic copper of supplement pills and in drinking water so much more damaging to cognition than the organic copper in food? A recent paper, which shows that almost all food copper is copper-1, that is the copper-2 of foods reverts to the reduced copper-1 form at death or harvest, gives new insight into these questions. The body has an intestinal transport system for copper-1, Ctr1, which channels copper-1 through the liver and into safe channels. Ctr1 cannot absorb copper-2, and some copper-2 bypasses the liver, ends up in the blood quickly, and is toxic to cognition. Humans evolved to handle copper-1 safely, but not copper-2. Alzheimer's is at least in part, a copper-2 toxicity disease, while Wilson's is a general copper overload disease. In this review, we will show that the epidemiology of the Alzheimer's epidemic occurring in developed, but not undeveloped countries, fits with the epidemiology of exposure to copper-2 ingestion leached from copper plumbing and from copper supplement pill ingestion. Increased meat eating in developed countries is also a factor, because it increases copper absorption, and thus over all copper exposure.

Insights from Genome-Wide Association Analyses of Nonalcoholic Fatty Liver Disease

PubMed Central

Kahali, Bratati; Halligan, Brian; Speliotes, Elizabeth K.

2016-01-01

Nonalcoholic fatty liver disease (NAFLD) is caused by hepatic steatosis, which can progress to nonalcoholic steatohepatitis, fibrosis/cirrhosis, and hepatocellular carcinoma in the absence of excessive alcohol consumption. Nonalcoholic fatty liver disease will become the number one cause of liver disease worldwide by 2020. Nonalcoholic fatty liver disease is correlated albeit imperfectly with obesity and other metabolic diseases such as diabetes, hyperlipidemia, and cardiovascular disease, but exactly how having one of these diseases contributes to the development of other metabolic diseases is only now being elucidated. Development of NAFLD and related metabolic diseases is genetically influenced in the population, and recent genome-wide association studies (GWASs) have discovered genetic variants that associate with these diseases. These GWAS-associated variants cannot only help us to identify individuals at high risk of developing NAFLD, but also to better understand its pathophysiology so that we can develop more effective treatments for this disease and related metabolic diseases in the future. PMID:26676813

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

PubMed

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

2017-09-01

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

The association of coffee intake with liver cancer incidence and chronic liver disease mortality in male smokers.

PubMed

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

2013-09-03

Coffee intake is associated with reduced risk of liver cancer and chronic liver disease as reported in previous studies, including prospective ones conducted in Asian populations where hepatitis B viruses (HBVs) and hepatitis C viruses (HCVs) are the dominant risk factors. Yet, prospective studies in Western populations with lower HBV and HCV prevalence are sparse. Also, although preparation methods affect coffee constituents, it is unknown whether different methods affect disease associations. We evaluated the association of coffee intake with incident liver cancer and chronic liver disease mortality in 27,037 Finnish male smokers, aged 50-69, in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study, who recorded their coffee consumption and were followed up to 24 years for incident liver cancer or chronic liver disease mortality. Multivariate relative risks (RRs) and 95% confidence intervals (CIs) were estimated by Cox proportional hazard models. Coffee intake was inversely associated with incident liver cancer (RR per cup per day=0.82, 95% CI: 0.73-0.93; P-trend across categories=0.0007) and mortality from chronic liver disease (RR=0.55, 95% CI: 0.48-0.63; P-trend<0.0001). Inverse associations persisted in those without diabetes, HBV- and HCV-negative cases, and in analyses stratified by age, body mass index, alcohol and smoking dose. We observed similar associations for those drinking boiled or filtered coffee. These findings suggest that drinking coffee may have benefits for the liver, irrespective of whether coffee was boiled or filtered.

Divalent Copper as a Major Triggering Agent in Alzheimer's Disease.

PubMed

Brewer, George J

2015-01-01

Alzheimer's disease (AD) is at epidemic proportions in developed countries, with a steady increase in the early 1900 s, and then exploding over the last 50 years. This epidemiology points to something causative in the environment of developed countries. This paper will review the considerable evidence that that something could be inorganic copper ingestion. The epidemic parallels closely the spread of copper plumbing, with copper leached from the plumbing into drinking water being a main causal feature, aided by the increasingly common use of supplement pills containing copper. Inorganic copper is divalent copper, or copper-2, while we now know that organic copper, or copper in foods, is primarily monovalent copper, or copper-1. The intestinal transport system, Ctr1, absorbs copper-1 and the copper moves to the liver, where it is put into safe channels. Copper-2 is not absorbed by Ctr1, and some of it bypasses the liver and goes directly into the blood, where it appears to be exquisitely toxic to brain cognition. Thus, while aggregation of amyloid-β has been postulated to be the cause of AD under current dogma, the great increase in prevalence over the last century appears to be due to ingestion of copper-2, which may be causing the aggregation, and/or increasing the oxidant toxicity of the aggregates. An alternative hypothesis proposes that oxidant stress is the primary injuring agent, and under this hypothesis, copper-2 accumulation in the brain may be a causal factor of the oxidant injury. Thus, irrespective of which hypothesis is correct, AD can be classified, at least in part, as a copper-2 toxicity disease. It is relatively easy to avoid copper-2 ingestion, as discussed in this review. If most people begin avoiding copper-2 ingestion, perhaps the epidemic of this serious disease can be aborted.

Copper-2 Ingestion, Plus Increased Meat Eating Leading to Increased Copper Absorption, Are Major Factors Behind the Current Epidemic of Alzheimer’s Disease

PubMed Central

Brewer, George J.

2015-01-01

It has become clear that copper toxicity is playing a major role in Alzheimer’s disease; but why is the brain copper toxicity with cognition loss in Alzheimer’s disease so much different clinically than brain copper toxicity in Wilson’s disease, which results in a movement disorder? Furthermore, why is the inorganic copper of supplement pills and in drinking water so much more damaging to cognition than the organic copper in food? A recent paper, which shows that almost all food copper is copper-1, that is the copper-2 of foods reverts to the reduced copper-1 form at death or harvest, gives new insight into these questions. The body has an intestinal transport system for copper-1, Ctr1, which channels copper-1 through the liver and into safe channels. Ctr1 cannot absorb copper-2, and some copper-2 bypasses the liver, ends up in the blood quickly, and is toxic to cognition. Humans evolved to handle copper-1 safely, but not copper-2. Alzheimer’s is at least in part, a copper-2 toxicity disease, while Wilson’s is a general copper overload disease. In this review, we will show that the epidemiology of the Alzheimer’s epidemic occurring in developed, but not undeveloped countries, fits with the epidemiology of exposure to copper-2 ingestion leached from copper plumbing and from copper supplement pill ingestion. Increased meat eating in developed countries is also a factor, because it increases copper absorption, and thus over all copper exposure. PMID:26633489

High-throughput T-cell receptor sequencing across chronic liver diseases reveals distinct disease-associated repertoires.

PubMed

Liaskou, Evaggelia; Klemsdal Henriksen, Eva Kristine; Holm, Kristian; Kaveh, Fatemeh; Hamm, David; Fear, Janine; Viken, Marte K; Hov, Johannes Roksund; Melum, Espen; Robins, Harlan; Olweus, Johanna; Karlsen, Tom H; Hirschfield, Gideon M

2016-05-01

Hepatic T-cell infiltrates and a strong genetic human leukocyte antigen association represent characteristic features of various immune-mediated liver diseases. Conceptually the presence of disease-associated antigens is predicted to be reflected in T-cell receptor (TCR) repertoires. Here, we aimed to determine if disease-associated TCRs could be identified in the nonviral chronic liver diseases primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), and alcoholic liver disease (ALD). We performed high-throughput sequencing of the TCRβ chain complementarity-determining region 3 of liver-infiltrating T cells from PSC (n = 20), PBC (n = 10), and ALD (n = 10) patients, alongside genomic human leukocyte antigen typing. The frequency of TCRβ nucleotide sequences was significantly higher in PSC samples (2.53 ± 0.80, mean ± standard error of the mean) compared to PBC samples (1.13 ± 0.17, P < 0.0001) and ALD samples (0.62 ± 0.10, P < 0.0001). An average clonotype overlap of 0.85% was detected among PSC samples, significantly higher compared to the average overlap of 0.77% seen within the PBC (P = 0.024) and ALD groups (0.40%, P < 0.0001). From eight to 42 clonotypes were uniquely detected in each of the three disease groups (≥30% of the respective patient samples). Multiple, unique sequences using different variable family genes encoded the same amino acid clonotypes, providing additional support for antigen-driven selection. In PSC and PBC, disease-associated clonotypes were detected among patients with human leukocyte antigen susceptibility alleles. We demonstrate liver-infiltrating disease-associated clonotypes in all three diseases evaluated, and evidence for antigen-driven clonal expansions. Our findings indicate that differential TCR signatures, as determined by high-throughput sequencing, may represent an imprint of distinctive antigenic repertoires present in the different chronic liver diseases

Association between liver fibrosis and coronary heart disease risk in patients with nonalcoholic fatty liver disease.

PubMed

Dogan, Serkan; Celikbilek, Mehmet; Yilmaz, Yunus K; Sarikaya, Savas; Zararsiz, Gokmen; Serin, Halil I; Borekci, Elif; Akyol, Lütfi; Pirti, Ilyas; Davarci, Sena E

2015-03-01

Nonalcoholic fatty liver disease (NAFLD) is being increasingly recognized as the most common cause of chronic liver disease worldwide. It has been shown that NAFLD in adults is associated with increased risk of coronary heart disease (CHD). Because of the limitations of liver biopsy, noninvasive scoring indexes such as the NAFLD fibrosis score (NFS) were developed. The Framingham risk score (FRS) provides an estimate of CHD risk. In our study we aimed to investigate whether the severity of liver fibrosis estimated with the NFS is associated with a higher risk of CHD among individuals with ultrasonography-diagnosed NAFLD. A total of 155 patients and controls (81 patients with NAFLD and 74 controls) with ages ranging from 18 to 70 years were enrolled in this cross-sectional prospective study. Demographic, anthropometric, clinical, and laboratory data were obtained from each individual. The NAFLD patients were divided into subgroups on the basis of the severity of fatty liver. The FRS and NFS were adopted to predict the risk of CHD and the severity of hepatic fibrosis. In our study, we found that the FRS was higher in NAFLD patients than in controls (P<0.05). According to the FRS category, NFSs were higher in the intermediate/high probability CHD risk group in NAFLD (P<0.05). In multiple models, only age, sex, cholesterol, and HDL were independently associated with intermediate/high CHD risk (P<0.05). We also found a positive correlation between the NFS and the FRS (r=0.373, P<0.001). The optimum NFS cutoff point for identifying intermediate/high CHD risk in NAFLD patients was -2.1284, with a sensitivity and specificity of 95.20 and 48.30%, respectively. The predictive performance of the NFS in the determination of intermediate/high CHD risk in NAFLD patients was found to be 72% based on the area under the curve value. The FRS is associated with the NFS in NAFLD. The assessment of liver fibrosis may be useful for the risk stratification of CHD in the absence of liver

Liver disease - resources

MedlinePlus

Resources - liver disease ... The following organizations are good resources for information on liver disease : American Liver Foundation -- www.liverfoundation.org Children's Liver Association for Support Services (C.L.A.S.S.) -- www. ...

Using XAS and SXRF to Study Copper in Wilson Disease at the Molecular and Tissue Level

NASA Astrophysics Data System (ADS)

Ralle, Martina; Blackburn, Ninian J.; Lutsenko, Svetlana

2007-02-01

Wilson disease (WD) is a genetic disorder of copper metabolism associated with severe hepatic, neurological, and psychiatric abnormalities. In WD, the billiary copper excretion is impaired and copper accumulates in tissues, particularly in the liver and the brain. The affected gene, ATP7B, encodes the copper transporting ATPase, Wilson disease protein (WNDP). WNDP has six copper binding sites in the N-terminal portion of the molecule. Each site includes the conserved amino acid sequence MXCXXC, and binds 1 Cu(I) through its 2 cysteine residues. We performed X-ray absorption studies at the Cu Kα-edge on the recombinant N-terminal domain of WNDP (N-WNDP). Copper was bound to N-WNDP either in vivo or in vitro in the presence of different reducing agents. We found that in N-WNDP copper is predominantly coordinated in a linear fashion by two cysteines, with the appearance of a Cu-Cu interaction when all metal binding sites are filled. Increasing amounts of reducing agents containing sulfide or phosphine groups led to binding of the exogenous ligands to copper thereby increasing the coordination number of copper from two to three. To better understand the role of copper in WD, we utilized livers of the 6-weeks-old Atp7b-/- mice (an animal model for WD) in which the copper concentration was 10-20-fold higher compared to that of the control mice. The distribution of copper in hepatocytes was evaluated by synchrotron based X-ray fluorescence microprobe (SXRF). We demonstrate that we can prepare liver slices that retain copper and can detect copper with subcellular resolution. On the same sections μ-XANES (spot size: 5 micron) was used to determine the oxidation state of copper.

Valproic acid and nonalcoholic fatty liver disease: A possible association?

PubMed Central

Farinelli, Edoardo; Giampaoli, David; Cenciarini, Anja; Cercado, Ephraim; Verrotti, Alberto

2015-01-01

Valproic acid (VPA) is one of the most prescribed drugs in children with newly diagnosed epilepsy. Weight gain and obesity have been observed as side effects of VPA. These are often linked with other metabolic disturbances such as development of insulin resistance, dyslipidemia, metabolic syndrome (MetS) and non-alcoholic fatty liver disease or nonalcoholic fatty liver disease (NAFLD). NAFLD refers to a group of liver disorders with marked hepatic steatosis. It is associated with an increased incidence of cardiovascular diseases and overall reduced life expectancy. NAFLD occurs in 20%-25% of the general population and it is known to be the most common cause of chronic liver disease. NAFLD therefore represents a major public health issue worldwide. This study reviews and summarizes relevant literature that supports the existence of an association between VPA therapy and the development of NAFLD in children. Long-term VPA-therapy appears to be associated with an increased risk of developing NAFLD. Further studies are needed to clarify the pathogenic mechanisms that lie behind this association and to standardize the options for the use of this drug in overweight patients and in those with risks for developing MetS and NAFLD. PMID:26019740

[Nutritional Assessment and Management for Patients with Chronic Liver Disease].

PubMed

Lee, Tae Hee

2018-04-25

When liver disease is severe, the prognosis can be worse if the patient is malnourished. Adequate nutritional support for patients with liver diseases can improve the patient's condition and prognosis. In the case of liver cirrhosis, malnutrition can occur due to a variety of causes, including poor oral intake, maldigestion, malabsorption, associated renal disease, and metabolic abnormalities. For a nutritional assessment, it is important to check the dietary intake, change in body composition, including anthropometry, and a functional assessment of muscle. Counselling and oral or enteral nutrition is preferred over parenteral nutrition as in other diseases. If esophageal varices are present, care should be taken when installing a feeding tube, but if there are ascites, percutaneous endoscopic gastrostomy is contraindicated because of the risk of complications. Calories of 30-35 kcal/kg/day and protein from 1.2 to 1.5 g/kg/day are appropriate. Protein restriction is unnecessary unless the hepatic encephalopathy is severe. A late evening snack and branched chain amino acids can be helpful. In the case of cholestasis, the supply of manganese and copper should be restricted. Sarcopenia in patients with liver cirrhosis is also prevalent and associated with the prognosis.

[MRT of the liver in Wilson's disease].

PubMed

Vogl, T J; Steiner, S; Hammerstingl, R; Schwarz, S; Kraft, E; Weinzierl, M; Felix, R

1994-01-01

To show that Wilson's disease is one likely cause of multiple low-intensity nodules of the liver we obtained MR images in 16 patients with clinically and histopathologically confirmed Wilson's disease. Corresponding to morphological changes MRI enabled the subdivision of the patients into two groups. Using a T2-weighted spin-echo sequence (TR/TE = 2000/45-90) liver parenchyma showed multiple tiny low-intensity-nodules surrounded by high-intensity septa in 10 out of 16 patients. 5 patients had also low-intensity nodules in T1-weighted images (TR/TE = 600/20). In patients of this group histopathology revealed liver cirrhosis (n = 7) and fibrosis (n = 2). Common feature of this patient group was marked inflammatory cell infiltration into fibrous septa, increase of copper concentration in liver parenchyma and distinct pathological changes of laboratory data. In the remaining 6 patients no pathological change of liver morphology was demonstrated by MRI corresponding to slight histopathological changes of parenchyma and normal laboratory data. As low-intensity nodules surrounded by high intensity septa can be demonstrated in patients with marked inflammatory infiltration of liver parenchyma MRI may help to define Wilson patients with poorer prognosis. In patients with low-intensity nodules of the liver and unknown cause of liver cirrhosis laboratory data and histopathology should be checked when searching for disorders of copper metabolism.

Library of molecular associations: curating the complex molecular basis of liver diseases.

PubMed

Buchkremer, Stefan; Hendel, Jasmin; Krupp, Markus; Weinmann, Arndt; Schlamp, Kai; Maass, Thorsten; Staib, Frank; Galle, Peter R; Teufel, Andreas

2010-03-20

Systems biology approaches offer novel insights into the development of chronic liver diseases. Current genomic databases supporting systems biology analyses are mostly based on microarray data. Although these data often cover genome wide expression, the validity of single microarray experiments remains questionable. However, for systems biology approaches addressing the interactions of molecular networks comprehensive but also highly validated data are necessary. We have therefore generated the first comprehensive database for published molecular associations in human liver diseases. It is based on PubMed published abstracts and aimed to close the gap between genome wide coverage of low validity from microarray data and individual highly validated data from PubMed. After an initial text mining process, the extracted abstracts were all manually validated to confirm content and potential genetic associations and may therefore be highly trusted. All data were stored in a publicly available database, Library of Molecular Associations http://www.medicalgenomics.org/databases/loma/news, currently holding approximately 1260 confirmed molecular associations for chronic liver diseases such as HCC, CCC, liver fibrosis, NASH/fatty liver disease, AIH, PBC, and PSC. We furthermore transformed these data into a powerful resource for molecular liver research by connecting them to multiple biomedical information resources. Together, this database is the first available database providing a comprehensive view and analysis options for published molecular associations on multiple liver diseases.

The Features of Copper Metabolism in the Rat Liver during Development

PubMed Central

2015-01-01

Strong interest in copper homeostasis is due to the fact that copper is simultaneously a catalytic co-factor of the vital enzymes, a participant in signaling, and a toxic agent provoking oxidative stress. In mammals, during development copper metabolism is conformed to two types. In embryonic type copper metabolism (ETCM), newborns accumulate copper to high level in the liver because its excretion via bile is blocked; and serum copper concentration is low because ceruloplasmin (the main copper-containing protein of plasma) gene expression is repressed. In the late weaning, the ETCM switches to the adult type copper metabolism (ATCM), which is manifested by the unlocking of copper excretion and the induction of ceruloplasmin gene activity. The considerable progress has been made in the understanding of the molecular basis of copper metabolic turnover in the ATCM, but many aspects of the copper homeostasis in the ETCM remain unclear. The aim of this study was to investigate the copper metabolism during transition from the ETCM (up to 12-days-old) to the ATCM in the rats. It was shown that in the liver, copper was accumulated in the nuclei during the first 5 days of life, and then it was re-located to the mitochondria. In parallel with the mitochondria, copper bulk bound with cytosolic metallothionein was increased. All compartments of the liver cells rapidly lost most of their copper on the 13th day of life. In newborns, serum copper concentration was low, and its major fraction was associated with holo-Cp, however, a small portion of copper was bound to extracellular metallothionein and a substance that was slowly eluted during gel-filtration. In adults, serum copper concentration increased by about a factor of 3, while metallothionein-bound copper level decreased by a factor of 2. During development, the expression level of Cp, Sod1, Cox4i1, Atp7b, Ctr1, Ctr2, Cox17, and Ccs genes was significantly increased, and metallothionein was decreased. Atp7a gene�

Association of PNPLA3 I148M Variant With Chronic Viral Hepatitis, Autoimmune Liver Diseases and Outcomes of Liver Transplantation

PubMed Central

Geng, Ning; Xin, Yong-Ning; Xia, Harry Hua-Xiang; Jiang, Man; Wang, Jian; Liu, Yang; Chen, Li-Zhen; Xuan, Shi-Ying

2015-01-01

Context: The PNPLA3 I148M variant has been recognized as a genetic determinant of liver fat content and a genetic risk factor of liver damage progression associated with steatohepatitis. The I148M variant is associated with many chronic liver diseases. However, its potential association with inflammatory and autoimmune liver diseases has not been established. Evidence Acquisition: We systemically reviewed the potential associations of I148M variant with chronic viral hepatitis, autoimmune liver diseases and the outcome of liver transplantation, explored the underlying molecular mechanisms and tried to translate them into more individualized decision-making and personalized medicine. Results: There were associations between I148M variant and chronic viral hepatitis and autoimmune liver diseases and differential associations of I148M variant in donors and recipients with post-liver transplant outcomes. I148M variant may activate the development of steatosis caused by host metabolic disorders in chronic viral hepatitis, but few researches were found to illustrate the mechanisms in autoimmune liver diseases. The peripherally mediated mechanism (via extrahepatic adipose tissue) may play a principal role in triglyceride accumulation regardless of adiponutrin activity in the graft liver. Conclusions: Evidences have shown the associations between I148M variant and mentioned diseases. I148M variant induced steatosis may be involved in the mechanism of chronic viral hepatitis and genetic considered personalized therapies, especially for PSC male patients. It is also crucial to pay attention to this parameter in donor selection and prognosis estimation in liver transplantation. PMID:26034504

Does Dietary Copper Supplementation enhance or diminish PCB126 Toxicity in Rodent Liver?

PubMed Central

Lai, Ian K.; Klaren, William D.; Li, Miao; Wels, Brian; Simmons, Donald L.; Olivier, Alicia K.; Haschek, Wanda M.; Wang, Kai; Ludewig, Gabriele; Robertson, Larry W.

2013-01-01

Copper is essential for the function of the mitochondrial electron transport chain and several antioxidant proteins. However, in its free form copper can participate in Fenton-like reactions that produce reactive hydroxyl radicals. Aryl-hydrocarbon receptor (AhR) agonists, including the most potent polychlorinated biphenyl (PCB) congener, 3,3',4,4',5-pentachlorobiphenyl (PCB126), increase copper levels in rodent livers. This is accompanied by biochemical and toxic changes. To assess the involvement of copper in PCB toxicity, male Sprague Dawley rats were fed an AIN-93G diet with differing dietary copper levels: low (2 ppm), adequate (6 ppm), and high (10 ppm). After three weeks, rats from each group were given a single ip injection of corn oil (control), 1, or 5 μmol/kg body weight PCB126. Two weeks following injections, biochemical and morphological markers of hepatic toxicity, trace metal status, and hepatic gene expression of metalloproteins were evaluated. Increasing dietary copper was associated with elevated tissue levels of copper and ceruloplasmin. In the livers of PCB126-treated rats the hallmark signs of AhR activation were present, including increased cytochrome P-450 and lipid levels, and decreased glutathione. In addition a doubling of hepatic copper levels was seen and overall metals homeostasis was disturbed, resulting in decreased hepatic selenium, manganese, zinc and iron. Expression of key metalloproteins was either decreased (cytochrome c oxidase), unchanged (ceruloplasmin and CuZnSOD) or increased (tyrosinase, metallothionein 1 and 2) with exposure to PCB126. Increases in metallothionein may contribute/reflect the increased copper seen. Alterations in dietary copper did not amplify or abrogate the hepatic toxicity of PCB126. PCB126 toxicity, i.e. oxidative stress and steatosis, is clearly associated with disturbed metals homeostasis. Understanding the mechanisms of this disturbance may provide tools to prevent liver toxicity by other Ah

Gut microbiota and liver diseases

PubMed Central

Minemura, Masami; Shimizu, Yukihiro

2015-01-01

Several studies revealed that gut microbiota are associated with various human diseases, e.g., metabolic diseases, allergies, gastroenterological diseases, and liver diseases. The liver can be greatly affected by changes in gut microbiota due to the entry of gut bacteria or their metabolites into the liver through the portal vein, and the liver-gut axis is important to understand the pathophysiology of several liver diseases, especially non-alcoholic fatty liver disease and hepatic encephalopathy. Moreover, gut microbiota play a significant role in the development of alcoholic liver disease and hepatocarcinogenesis. Based on these previous findings, trials using probiotics have been performed for the prevention or treatment of liver diseases. In this review, we summarize the current understanding of the changes in gut microbiota associated with various liver diseases, and we describe the therapeutic trials of probiotics for those diseases. PMID:25684933

Hepatic concentrations of copper and other metals in dogs with and without chronic hepatitis.

PubMed

Cedeño, Y; López-Alonso, M; Miranda, M

2016-12-01

Defects in copper metabolism have been described in several dog breeds, and recently, it has been suggested that changes in other essential trace elements could be involved in the pathogenesis of hepatic disease. This study measured hepatic copper accumulation and its interactions with other essential trace and toxic metals in dogs diagnosed with chronic hepatitis. Liver samples of 20 chronic hepatitis and 20 healthy dogs were collected. Samples were acid digested, and essential metals (cobalt, copper, iron, manganese, molibdenum, selenium and zinc) and toxic metals (arsenic, cadmium, mercury and lead) were analysed by inductively-coupled plasma mass spectrometry. Copper concentrations were significantly higher in dogs affected by hepatic disease than in controls. Dogs having chronic hepatitis with liver copper concentration greater than 100 mg/kg wet weight showed statistically higher cobalt, manganese and zinc concentrations than dogs having chronic hepatitis with liver copper concentrations less than 100 mg/kg wet weight and controls. Toxic metal concentrations were low - in all cases below the threshold associated with toxicity in dogs. Dogs with chronic hepatitis not only have increased concentrations of copper in the liver but also increased concentrations of cobalt, manganese and zinc; measurement of these elements may perhaps aid in diagnosis of liver disease in dogs. © 2016 British Small Animal Veterinary Association.

Maternal choline modifies fetal liver copper, gene expression, DNA methylation, and neonatal growth in the tx-j mouse model of Wilson disease.

PubMed

Medici, Valentina; Shibata, Noreene M; Kharbanda, Kusum K; Islam, Mohammad S; Keen, Carl L; Kim, Kyoungmi; Tillman, Brittany; French, Samuel W; Halsted, Charles H; LaSalle, Janine M

2014-02-01

Maternal diet can affect fetal gene expression through epigenetic mechanisms. Wilson disease (WD), which is caused by autosomal recessive mutations in ATP7B encoding a biliary copper transporter, is characterized by excessive hepatic copper accumulation, but variability in disease severity. We tested the hypothesis that gestational supply of dietary methyl groups modifies fetal DNA methylation and expression of genes involved in methionine and lipid metabolism that are impaired prior to hepatic steatosis in the toxic milk (tx-j) mouse model of WD. Female C3H control and tx-j mice were fed control (choline 8 mmol/Kg of diet) or choline-supplemented (choline 36 mmol/Kg of diet) diets for 2 weeks throughout mating and pregnancy to gestation day 17. A second group of C3H females, half of which were used to cross foster tx-j pups, received the same diet treatments that extended during lactation to 21 d postpartum. Compared with C3H, fetal tx-j livers had significantly lower copper concentrations and significantly lower transcript levels of Cyclin D1 and genes related to methionine and lipid metabolism. Maternal choline supplementation prevented the transcriptional deficits in fetal tx-j liver for multiple genes related to cell growth and metabolism. Global DNA methylation was increased by 17% in tx-j fetal livers after maternal choline treatment (P<0.05). Maternal dietary choline rescued the lower body weight of 21 d tx-j mice. Our results suggest that WD pathogenesis is modified by maternal in utero factors, including dietary choline.

Maternal choline modifies fetal liver copper, gene expression, DNA methylation, and neonatal growth in the tx-j mouse model of Wilson disease

PubMed Central

Medici, Valentina; Shibata, Noreene M; Kharbanda, Kusum K; Islam, Mohammad S; Keen, Carl L; Kim, Kyoungmi; Tillman, Brittany; French, Samuel W; Halsted, Charles H; LaSalle, Janine M

2014-01-01

Maternal diet can affect fetal gene expression through epigenetic mechanisms. Wilson disease (WD), which is caused by autosomal recessive mutations in ATP7B encoding a biliary copper transporter, is characterized by excessive hepatic copper accumulation, but variability in disease severity. We tested the hypothesis that gestational supply of dietary methyl groups modifies fetal DNA methylation and expression of genes involved in methionine and lipid metabolism that are impaired prior to hepatic steatosis in the toxic milk (tx-j) mouse model of WD. Female C3H control and tx-j mice were fed control (choline 8 mmol/Kg of diet) or choline-supplemented (choline 36 mmol/Kg of diet) diets for 2 weeks throughout mating and pregnancy to gestation day 17. A second group of C3H females, half of which were used to cross foster tx-j pups, received the same diet treatments that extended during lactation to 21 d postpartum. Compared with C3H, fetal tx-j livers had significantly lower copper concentrations and significantly lower transcript levels of Cyclin D1 and genes related to methionine and lipid metabolism. Maternal choline supplementation prevented the transcriptional deficits in fetal tx-j liver for multiple genes related to cell growth and metabolism. Global DNA methylation was increased by 17% in tx-j fetal livers after maternal choline treatment (P < 0.05). Maternal dietary choline rescued the lower body weight of 21 d tx-j mice. Our results suggest that WD pathogenesis is modified by maternal in utero factors, including dietary choline. PMID:24220304

Coffee and Liver Disease.

PubMed

Wadhawan, Manav; Anand, Anil C

2016-03-01

Coffee is the most popular beverage in the world. Consumption of coffee has been shown to benefit health in general, and liver health in particular. This article reviews the effects of coffee intake on development and progression of liver disease due to various causes. We also describe the putative mechanisms by which coffee exerts the protective effect. The clinical evidence of benefit of coffee consumption in Hepatitis B and C, as well as nonalcoholic fatty liver disease and alcoholic liver disease, has also been presented. Coffee consumption is associated with improvement in liver enzymes (ALT, AST, and GGTP), especially in individuals with risk for liver disease. Coffee intake more than 2 cups per day in patients with preexisting liver disease has been shown to be associated with lower incidence of fibrosis and cirrhosis, lower hepatocellular carcinoma rates, as well as decreased mortality.

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

PubMed

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

2016-03-01

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

Alcoholic Liver Disease and Liver Transplantation.

PubMed

Gallegos-Orozco, Juan F; Charlton, Michael R

2016-08-01

Excessive alcohol use is a common health care problem worldwide and is associated with significant morbidity and mortality. Alcoholic liver disease represents the second most frequent indication for liver transplantation in North America and Europe. The pretransplant evaluation of patients with alcoholic liver disease should aim at identifying those at high risk for posttransplant relapse of alcohol use disorder, as return to excessive drinking can be deleterious to graft and patient survival. Carefully selected patients with alcoholic liver disease, including those with severe alcoholic hepatitis, will have similar short-term and long-term outcomes when compared with other indications for liver transplantation. Copyright © 2016 Elsevier Inc. All rights reserved.

Disease Modeling and Gene Therapy of Copper Storage Disease in Canine Hepatic Organoids.

PubMed

Nantasanti, Sathidpak; Spee, Bart; Kruitwagen, Hedwig S; Chen, Chen; Geijsen, Niels; Oosterhoff, Loes A; van Wolferen, Monique E; Pelaez, Nicolas; Fieten, Hille; Wubbolts, Richard W; Grinwis, Guy C; Chan, Jefferson; Huch, Meritxell; Vries, Robert R G; Clevers, Hans; de Bruin, Alain; Rothuizen, Jan; Penning, Louis C; Schotanus, Baukje A

2015-11-10

The recent development of 3D-liver stem cell cultures (hepatic organoids) opens up new avenues for gene and/or stem cell therapy to treat liver disease. To test safety and efficacy, a relevant large animal model is essential but not yet established. Because of its shared pathologies and disease pathways, the dog is considered the best model for human liver disease. Here we report the establishment of a long-term canine hepatic organoid culture allowing undifferentiated expansion of progenitor cells that can be differentiated toward functional hepatocytes. We show that cultures can be initiated from fresh and frozen liver tissues using Tru-Cut or fine-needle biopsies. The use of Wnt agonists proved important for canine organoid proliferation and inhibition of differentiation. Finally, we demonstrate that successful gene supplementation in hepatic organoids of COMMD1-deficient dogs restores function and can be an effective means to cure copper storage disease. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

High fructose feeding induces copper deficiency in Sprague-Dawley rats: A novel mechanism for obesity related fatty liver

USDA-ARS?s Scientific Manuscript database

Dietary copper deficiency is associated with a variety of manifestations of the metabolic syndrome, including hyperlipidemia and fatty liver. Fructose feeding has been reported to exacerbate complications of copper deficiency. In this study, we investigated whether copper deficiency plays a role in ...

Aberrant expression of copper associated genes after copper accumulation in COMMD1-deficient dogs.

PubMed

Favier, Robert P; Spee, Bart; Fieten, Hille; van den Ingh, Ted S G A M; Schotanus, Baukje A; Brinkhof, Bas; Rothuizen, Jan; Penning, Louis C

2015-01-01

COMMD1-deficient dogs progressively develop copper-induced chronic hepatitis. Since high copper leads to oxidative damage, we measured copper metabolism and oxidative stress related gene products during development of the disease. Five COMMD1-deficient dogs were studied from 6 months of age over a period of five years. Every 6 months blood was analysed and liver biopsies were taken for routine histological evaluation (grading of hepatitis), rubeanic acid copper staining and quantitative copper analysis. Expression of genes involved in copper metabolism (COX17, CCS, ATOX1, MT1A, CP, ATP7A, ATP7B, ) and oxidative stress (SOD1, catalase, GPX1 ) was measured by qPCR. Due to a sudden death of two animals, the remaining three dogs were treated with d-penicillamine from 43 months of age till the end of the study. Presented data for time points 48, 54, and 60 months was descriptive only. A progressive trend from slight to marked hepatitis was observed at histology, which was clearly preceded by an increase in semi-quantitative copper levels starting at 12 months until 42 months of age. During the progression of hepatitis most gene products measured were transiently increased. Most prominent was the rapid increase in the copper binding gene product MT1A mRNA levels. This was followed by a transient increase in ATP7A and ATP7B mRNA levels. In the sequence of events, copper accumulation induced progressive hepatitis followed by a transient increase in gene products associated with intracellular copper trafficking and temporal activation of anti-oxidative stress mechanisms. Copyright © 2014 Elsevier GmbH. All rights reserved.

An epidemiological study of the association of coffee with chronic liver disease.

PubMed

Walton, H B; Masterton, G S; Hayes, P C

2013-11-01

Chronic liver disease affects 855 people per million in the UK. Previous studies have reported that coffee appears protective against the development of abnormal liver enzymes, hepatic fibrosis and cirrhosis. The aim of this study, the first in a Scottish population, was to compare coffee consumption in patients with liver disease and that of control populations to determine correlations between coffee intake and the incidence of non-cancerous liver disease and with Child's-Pugh and model for end-stage liver disease (MELD) scores. Two hundred and eighty-six patients attending the liver outpatient department at the Royal Infirmary of Edinburgh completed a questionnaire regarding coffee consumption and lifestyle factors. Control questionnaires were also completed by 100 orthopaedic outpatients and 120 medical students. Patients with cirrhosis (n = 95) drank significantly less coffee than those without cirrhosis (p = <0.001). There was no correlation between Child's-Pugh (-0.018) and MELD scores (-0.132) with coffee consumption. Coffee drinking is associated with a reduced prevalence of cirrhosis in patients with chronic liver disease. However, there was no significant difference in the amount of coffee drunk by liver patients and the control groups. It is possible that by changing the amount of coffee drunk, the development of cirrhosis in liver disease could be postponed.

Evolution of Exchangeable Copper and Relative Exchangeable Copper through the Course of Wilson's Disease in the Long Evans Cinnamon Rat

PubMed Central

Schmitt, Françoise; Podevin, Guillaume; Poupon, Joël; Roux, Jérôme; Legras, Pierre; Trocello, Jean-Marc; Woimant, France; Laprévote, Olivier; NGuyen, Tuan Huy; Balkhi, Souleiman El

2013-01-01

Background Wilson's disease (WD) is an inherited disorder of copper metabolism leading to liver failure and/or neurological impairment. Its diagnosis often remains difficult even with genetic testing. Relative exchangeable copper (REC) has recently been described as a reliable serum diagnostic marker for WD. Methodology/Principal Findings The aim of this study was to validate the use of REC in the Long Evans Cinnamon (LEC) rat, an animal model for WD, and to study its relevance under different conditions in comparison with conventional markers. Two groups of LEC rats and one group of Long-Evans (LE) rats were clinically and biologically monitored from 6 to 28 weeks of age. One group of LEC rats was given copper-free food. The other groups had normal food. Blood samples were collected each month and different serum markers for WD (namely ceruloplasmin oxidase activity, exchangeable copper (CuEXC), total serum copper and REC) and acute liver failure (serum transaminases and bilirubinemia) were tested. Every LEC rat under normal food developed acute liver failure (ALF), with 40% global mortality. Serum transaminases and bilirubinemia along with total serum copper and exchangeable copper levels increased with the onset of acute liver failure. A correlation was observed between CuEXC values and the severity of ALF. Cut-off values were different between young and adult rats and evolved because of age and/or liver failure. Only REC, with values >19%, was able to discriminate LEC groups from the LE control group at every time point in the study. REC sensitivity and specificity reached 100% in adults rats. Conclusions/Significance REC appears to be independent of demographic or clinical data in LEC rats. It is a very simple and reliable blood test for the diagnosis of copper toxicosis owing to a lack of ATP7B function. CuEXC can be used as an accurate biomarker of copper overload. PMID:24358170

Nonalcoholic fatty liver disease - A multisystem disease?

PubMed Central

Mikolasevic, Ivana; Milic, Sandra; Turk Wensveen, Tamara; Grgic, Ivana; Jakopcic, Ivan; Stimac, Davor; Wensveen, Felix; Orlic, Lidija

2016-01-01

Non-alcoholic fatty liver disease (NAFLD) is one of the most common comorbidities associated with overweight and metabolic syndrome (MetS). Importantly, NAFLD is one of its most dangerous complications because it can lead to severe liver pathologies, including fibrosis, cirrhosis and hepatic cellular carcinoma. Given the increasing worldwide prevalence of obesity, NAFLD has become the most common cause of chronic liver disease and therefore is a major global health problem. Currently, NAFLD is predominantly regarded as a hepatic manifestation of MetS. However, accumulating evidence indicates that the effects of NAFLD extend beyond the liver and are negatively associated with a range of chronic diseases, most notably cardiovascular disease (CVD), diabetes mellitus type 2 (T2DM) and chronic kidney disease (CKD). It is becoming increasingly clear that these diseases are the result of the same underlying pathophysiological processes associated with MetS, such as insulin resistance, chronic systemic inflammation and dyslipidemia. As a result, they have been shown to be independent reciprocal risk factors. In addition, recent data have shown that NAFLD actively contributes to aggravation of the pathophysiology of CVD, T2DM, and CKD, as well as several other pathologies. Thus, NAFLD is a direct cause of many chronic diseases associated with MetS, and better detection and treatment of fatty liver disease is therefore urgently needed. As non-invasive screening methods for liver disease become increasingly available, detection and treatment of NAFLD in patients with MetS should therefore be considered by both (sub-) specialists and primary care physicians. PMID:27920470

Secondhand tobacco exposure is associated with nonalcoholic fatty liver disease in children

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

Lin, Connie; Rountree, Carl B.; Department of Pediatrics, Bon Secour St. Mary's Hospital, 5801 Bremo Rd, Richmond, VA 23226

Background: Nonalcoholic fatty liver disease (NAFLD) is the leading cause of liver disease in children in the United States, and prevalence rates are rising. Smoking is associated with NAFLD, but the association of secondhand smoke exposure with NAFLD is unknown. Aims: To investigate the association of secondhand tobacco exposure with NAFLD in children. Methods: We surveyed parents/guardians of 304 children aged 3–12 years who had received an abdominal ultrasound at Penn State Hershey Medical Center. The survey addressed demographics, medical history, secondhand tobacco exposure, activity level, screen viewing time and other environmental exposures. A pediatric radiologist and sonographer reviewed themore » ultrasounds to grade the presence of bight liver compatible with NAFLD. We conducted logistic regression analysis to assess the association of secondhand tobacco exposure and NAFLD. Results: 54% of eligible potential participants responded to the survey. Fatty liver was present in 3% of the children. Increasing child age was associated with increased odds of NAFLD (OR 1.63 95% CI 1.1, 2.4). Reported child obesity was associated with increased odds of NAFLD (OR 44.5 95% CI 5.3, 371.7). The rate of NAFLD was higher in the smoke exposed group (6.7% vs. 1.7%). For every extra pack per day smoked at home, the odds of a child having NAFLD increased 1.8 times (AOR 1.8, 95% CI 1.2, 2.8), and any exposure increased a child's odds of NAFLD four-fold (AOR 4.0, 95% CI 1.02, 15.8). Conclusion: We found an association of secondhand smoke exposure and NAFLD in children. This may represent an area for future prevention efforts. - Highlights: • We evaluated the relation of tobacco exposure with nonalcoholic fatty liver disease. • Tobacco smoke exposure was associated with nonalcoholic fatty liver disease. • Tobacco smoke exposure may be an addressable risk factor.« less

Dysregulation of iron and copper homeostasis in nonalcoholic fatty liver

PubMed Central

Aigner, Elmar; Weiss, Günter; Datz, Christian

2015-01-01

Elevated iron stores as indicated by hyperferritinemia with normal or mildly elevated transferrin saturation and mostly mild hepatic iron deposition are a characteristic finding in subjects with non-alcoholic fatty liver disease (NAFLD). Excess iron is observed in approximately one third of NAFLD patients and is commonly referred to as the “dysmetabolic iron overload syndrome”. Clinical evidence suggests that elevated body iron stores aggravate the clinical course of NAFLD with regard to liver-related and extrahepatic disease complications which relates to the fact that excess iron catalyses the formation of toxic hydroxyl-radicals subsequently resulting in cellular damage. Iron removal improves insulin sensitivity, delays the onset of type 2 diabetes mellitus, improves pathologic liver function tests and likewise ameliorates NAFLD histology. Several mechanisms contribute to pathologic iron accumulation in NAFLD. These include impaired iron export from hepatocytes and mesenchymal Kupffer cells as a consequence of imbalances in the concentrations of iron regulatory factors, such as hepcidin, cytokines, copper or other dietary factors. This review summarizes the knowledge about iron homeostasis in NAFLD and the rationale for its therapeutic implications. PMID:25729473

[Various pathways leading to the progression of chronic liver diseases].

PubMed

Egresi, Anna; Lengyel, Gabriella; Somogyi, Anikó; Blázovics, Anna; Hagymási, Krisztina

2016-02-21

As the result of various effects (viruses, metabolic diseases, nutritional factors, toxic agents, autoimmune processes) abnormal liver function, liver steatosis and connective tissue remodeling may develop. Progression of this process is complex including various pathways and a number of factors. The authors summarize the factors involved in the progression of chronic liver disease. They describe the role of cells and the produced inflammatory mediators and cytokines, as well as the relationship between the disease and the intestinal flora. They emphasize the role of oxidative stress, mitochondrial dysfunction and cell death in disease progression. Insulin resistance and micro-elements (iron, copper) in relation to liver damage are also discussed, and genetic and epigenetic aspects underlying disease progression are summarized. Discovery of novel treatment options, assessment of the effectiveness of treatment, as well as the success and proper timing of liver transplantation may depend on a better understanding of the process of disease progression.

Nonalcoholic fatty liver disease, association with cardiovascular disease and treatment (II). The treatment of nonalcoholic fatty liver disease.

PubMed

Brea, Ángel; Pintó, Xavier; Ascaso, Juan F; Blasco, Mariano; Díaz, Ángel; González-Santos, Pedro; Hernández-Mijares, Antonio; Mantilla, Teresa; Millán, Jesús; Pedro-Botet, Juan

Disease nonalcoholic fatty liver disease (NAFLD) comprises a series of histologically similar to those induced by alcohol consumption in people with very little or no liver damage same. The importance of NAFLD is its high prevalence in our Western societies, from the point of view liver in its progressive evolution from steatosis to steatohepatitis, cirrhosis and liver cancer. During the last decade it has been observed that NAFLD leads to an increased cardiovascular risk with accelerated atherosclerosis and cardiovascular events, the leading cause of morbidity and mortality. This updated January 2016 revision consists of two parts. In this second part, the treatment of NAFLD and its influence on cardiovascular disease and drugs used in the control of cardiovascular risk factors showing a beneficial effect on the liver disease will be reviewed. Copyright © 2016 Sociedad Española de Arteriosclerosis. Publicado por Elsevier España, S.L.U. All rights reserved.

Liver steatosis is associated with insulin resistance in skeletal muscle rather than in the liver in Japanese patients with non-alcoholic fatty liver disease.

PubMed

Kato, Ken-Ichiro; Takeshita, Yumie; Misu, Hirofumi; Zen, Yoh; Kaneko, Shuichi; Takamura, Toshinari

2015-03-01

To examine the association between liver histological features and organ-specific insulin resistance indices calculated from 75-g oral glucose tolerance test data in patients with non-alcoholic fatty liver disease. Liver biopsy specimens were obtained from 72 patients with non-alcoholic fatty liver disease, and were scored for steatosis, grade and stage. Hepatic and skeletal muscle insulin resistance indices (hepatic insulin resistance index and Matsuda index, respectively) were calculated from 75-g oral glucose tolerance test data, and metabolic clearance rate was measured using the euglycemic hyperinsulinemic clamp method. The degree of hepatic steatosis, and grade and stage of non-alcoholic steatohepatitis were significantly correlated with Matsuda index (steatosis r = -0.45, P < 0.001; grade r = -0.54, P < 0.001; stage r = -0.37, P < 0.01), but not with hepatic insulin resistance index. Multiple regression analyses adjusted for age, sex, body mass index and each histological score showed that the degree of hepatic steatosis (coefficient = -0.22, P < 0.05) and grade (coefficient = -0.40, P < 0.01) were associated with Matsuda index, whereas the association between stage and Matsuda index (coefficient = -0.07, P = 0.593) was no longer significant. A similar trend was observed for the association between steatosis and metabolic clearance rate (coefficient = -0.62, P = 0.059). Liver steatosis is associated with insulin resistance in skeletal muscle rather than in the liver in patients with non-alcoholic fatty liver disease, suggesting a central role of fatty liver in the development of peripheral insulin resistance and the existence of a network between the liver and skeletal muscle.

Genome-Wide Associations Related to Hepatic Histology in Nonalcoholic Fatty Liver Disease in Hispanic Boys.

PubMed

Wattacheril, Julia; Lavine, Joel E; Chalasani, Naga P; Guo, Xiuqing; Kwon, Soonil; Schwimmer, Jeffrey; Molleston, Jean P; Loomba, Rohit; Brunt, Elizabeth M; Chen, Yii-Der Ida; Goodarzi, Mark O; Taylor, Kent D; Yates, Katherine P; Tonascia, James; Rotter, Jerome I

2017-11-01

To identify genetic loci associated with features of histologic severity of nonalcoholic fatty liver disease in a cohort of Hispanic boys. There were 234 eligible Hispanic boys age 2-17 years with clinical, laboratory, and histologic data enrolled in the Nonalcoholic Steatohepatitis Clinical Research Network included in the analysis of 624 297 single nucleotide polymorphisms (SNPs). After the elimination of 4 outliers and 22 boys with cryptic relatedness, association analyses were performed on 208 DNA samples with corresponding liver histology. Logistic regression analyses were carried out for qualitative traits and linear regression analyses were applied for quantitative traits. The median age and body mass index z-score were 12.0 years (IQR, 11.0-14.0) and 2.4 (IQR, 2.1-2.6), respectively. The nonalcoholic fatty liver disease activity score (scores 1-4 vs 5-8) was associated with SNP rs11166927 on chromosome 8 in the TRAPPC9 region (P = 8.7 -07 ). Fibrosis stage was associated with SNP rs6128907 on chromosome 20, near actin related protein 5 homolog (p = 9.9 -07 ). In comparing our results in Hispanic boys with those of previously reported SNPs in adult nonalcoholic steatohepatitis, 2 of 26 susceptibility loci were associated with nonalcoholic fatty liver disease activity score and 2 were associated with fibrosis stage. In this discovery genome-wide association study, we found significant novel gene effects on histologic traits associated with nonalcoholic fatty liver disease activity score and fibrosis that are distinct from those previously recognized by adult nonalcoholic fatty liver disease genome-wide association studies. Copyright © 2017 Elsevier Inc. All rights reserved.

Parenteral nutrition-associated liver disease and lipid emulsions.

PubMed

Zugasti Murillo, Ana; Petrina Jáuregui, Estrella; Elizondo Armendáriz, Javier

2015-01-01

Parenteral nutrition-associated liver disease (PNALD) is a particularly important problem in patients who need this type of nutritional support for a long time. Prevalence of the condition is highly variable depending on the series, and its clinical presentation is different in adults and children. The etiology of PNALD is not well defined, and participation of several factors at the same time has been suggested. When a bilirubin level >2 mg/dl is detected for a long time, other causes of liver disease should be ruled out and risk factors should be minimized. The composition of lipid emulsions used in parenteral nutrition is one of the factors related to PNALD. This article reviews the different types of lipid emulsions and the potential benefits of emulsions enriched with omega-3 fatty acids. Copyright © 2014 SEEN. Published by Elsevier España, S.L.U. All rights reserved.

Copper-associated hepatitis in a patient with chronic myeloid leukemia following hematopoietic stem cell transplantation: A case report.

PubMed

Lee, Ching-Fen; Chen, Chi-Hua; Wen, Yu-Chuan; Chang, Tsung-Yen; Lai, Ming-Wei; Jaing, Tang-Her

2017-12-01

We report a complicated case of cholestatic hepatitis with suspected autoimmune hemolytic anemia (AIHA) and copper toxicity syndrome after HSCT and donor lymphocyte infusion (DLI). A 19-year-1-month-old girl presented with a history of CML. She underwent matched unrelated donor HSCT and donor lymphocyte infusion subsequently. Three months later, yellowish discoloration of the skin was found, which was accompanied by progressive itchy skin, easy fatigability, insomnia, and dark urine output. After admission, liver function disorders were observed. Methylprednisolone was administered for suspected hepatic GVHD. Although abdominal sonography revealed no evidence of biliary tract obstruction and the viral hepatitis survey disclosed unremarkable findings; silymarin and ursodeoxycholic acid were administered to preserve the liver function. In addition, rituximab was prescribed for suspected AIHA. Because hyperbilirubinemia was progressive, mycophenolate and high-dose intravenous immunoglobulin were accordingly administered. As drug-induced liver injury cannot be excluded, all potential unconfirmed causes of drug-related hepatoxicity were discontinued. In this case, the patient's history of shrimps and chocolate consumption led us to strongly suspect cholestatic hepatitis associated with copper toxicity syndrome. High 24-hour urine copper excretion and low serum zinc levels were also confirmed. Accordingly, D-penicillamine and zinc gluconate were administered. She succumbed to progressive hepatic failure and eventual multisystem organ failure 14 months after HSCT. No autopsy was performed. This report described the combined effects of hepatic GVHD, AIHA, drugs, and copper toxicity on liver damage, and demonstrated the potential diagnostic challenges and treatment dilemmas associated with this disease.

Canine Models for Copper Homeostasis Disorders.

PubMed

Wu, Xiaoyan; Leegwater, Peter A J; Fieten, Hille

2016-02-04

Copper is an essential trace nutrient metal involved in a multitude of cellular processes. Hereditary defects in copper metabolism result in disorders with a severe clinical course such as Wilson disease and Menkes disease. In Wilson disease, copper accumulation leads to liver cirrhosis and neurological impairments. A lack in genotype-phenotype correlation in Wilson disease points toward the influence of environmental factors or modifying genes. In a number of Non-Wilsonian forms of copper metabolism, the underlying genetic defects remain elusive. Several pure bred dog populations are affected with copper-associated hepatitis showing similarities to human copper metabolism disorders. Gene-mapping studies in these populations offer the opportunity to discover new genes involved in copper metabolism. Furthermore, due to the relatively large body size and long life-span of dogs they are excellent models for development of new treatment strategies. One example is the recent use of canine organoids for disease modeling and gene therapy of copper storage disease. This review addresses the opportunities offered by canine genetics for discovery of genes involved in copper metabolism disorders. Further, possibilities for the use of dogs in development of new treatment modalities for copper storage disorders, including gene repair in patient-derived hepatic organoids, are highlighted.

Canine Models for Copper Homeostasis Disorders

PubMed Central

Wu, Xiaoyan; Leegwater, Peter A. J.; Fieten, Hille

2016-01-01

Copper is an essential trace nutrient metal involved in a multitude of cellular processes. Hereditary defects in copper metabolism result in disorders with a severe clinical course such as Wilson disease and Menkes disease. In Wilson disease, copper accumulation leads to liver cirrhosis and neurological impairments. A lack in genotype-phenotype correlation in Wilson disease points toward the influence of environmental factors or modifying genes. In a number of Non-Wilsonian forms of copper metabolism, the underlying genetic defects remain elusive. Several pure bred dog populations are affected with copper-associated hepatitis showing similarities to human copper metabolism disorders. Gene-mapping studies in these populations offer the opportunity to discover new genes involved in copper metabolism. Furthermore, due to the relatively large body size and long life-span of dogs they are excellent models for development of new treatment strategies. One example is the recent use of canine organoids for disease modeling and gene therapy of copper storage disease. This review addresses the opportunities offered by canine genetics for discovery of genes involved in copper metabolism disorders. Further, possibilities for the use of dogs in development of new treatment modalities for copper storage disorders, including gene repair in patient-derived hepatic organoids, are highlighted. PMID:26861285

Diagnosis of abnormal biliary copper excretion by positron emission tomography with targeting of 64Copper-asialofetuin complex in LEC rat model of Wilson’s disease

PubMed Central

Bahde, Ralf; Kapoor, Sorabh; Bhargava, Kuldeep K; Palestro, Christopher J; Gupta, Sanjeev

2014-01-01

Identification by molecular imaging of key processes in handling of transition state metals, such as copper (Cu), will be of considerable clinical value. For instance, the ability to diagnose Wilson’s disease with molecular imaging by identifying copper excretion in an ATP7B-dependent manner will be very significant. To develop highly effective diagnostic approaches, we hypothesized that targeting of radiocopper via the asialoglycoprotein receptor will be appropriate for positron emission tomography, and examined this approach in a rat model of Wilson’s disease. After complexing 64Cu to asialofetuin we studied handling of this complex compared with 64Cu in healthy LEA rats and diseased homozygous LEC rats lacking ATP7B and exhibiting hepatic copper toxicosis. We analyzed radiotracer clearance from blood, organ uptake, and biliary excretion, including sixty minute dynamic positron emission tomography recordings. In LEA rats, 64Cu-asialofetuin was better cleared from blood followed by liver uptake and greater biliary excretion than 64Cu. In LEC rats, 64Cu-asialofetuin activity cleared even more rapidly from blood followed by greater uptake in liver, but neither 64Cu-asialofetuin nor 64Cu appeared in bile. Image analysis demonstrated rapid visualization of liver after 64Cu-asialofetuin administration followed by decreased liver activity in LEA rats while liver activity progressively increased in LEC rats. Image analysis resolved this difference in hepatic activity within one hour. We concluded that 64Cu-asialofetuin complex was successfully targeted to the liver and radiocopper was then excreted into bile in an ATP7B-dependent manner. Therefore, hepatic targeting of radiocopper will be appropriate for improving molecular diagnosis and for developing drug/cell/gene therapies in Wilson’s disease. PMID:25250203

Spatial investigation of the elemental distribution in Wilson's disease liver after d-penicillamine treatment by LA-ICP-MS.

PubMed

Hachmöller, Oliver; Zibert, Andree; Zischka, Hans; Sperling, Michael; Groba, Sara Reinartz; Grünewald, Inga; Wardelmann, Eva; Schmidt, Hartmut H-J; Karst, Uwe

2017-12-01

At present, the copper chelator d-penicillamine (DPA) is the first-line therapy of Wilson's disease (WD), which is characterized by an excessive copper overload. Lifelong DPA treatments aim to reduce the amount of detrimental excess copper retention in the liver and other organs. Although DPA shows beneficial effect in many patients, it may cause severe adverse effects. Despite several years of copper chelation therapy, discontinuation of DPA therapy can be linked to a rapidly progressing liver failure, indicating a high residual liver copper load. In order to investigate the spatial distribution of remaining copper and additional elements, such as zinc and iron, in rat and human liver samples after DPA treatment, a high resolution (spotsize of 10μm) laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) imaging method was applied. Untreated LPP -/- rats, an established animal model for WD, appeared with a high overall copper concentration and a copper distribution of hotspots distributed over the liver tissue. In contrast, a low (>2-fold decreased) overall copper concentration was detected in liver of DPA treated animals. Importantly, however, copper distribution was highly inhomogeneous with lowest concentrations in direct proximity to blood vessels, as observed using novel zonal analysis. A human liver needle biopsy of a DPA treated WD patient substantiated the finding of an inhomogeneous copper deposition upon chelation therapy. In contrast, comparatively homogenous distributions of zinc and iron were observed. Our study indicates that a high resolution LA-ICP-MS analysis of liver samples is excellently suited to follow efficacy of chelator therapy in WD patients. Copyright © 2017 Elsevier GmbH. All rights reserved.

Copper excess in liver HepG2 cells interferes with apoptosis and lipid metabolic signaling at the protein level.

PubMed

Liu, Yu; Yang, Huarong; Song, Zhi; Gu, Shaojuan

2014-12-01

Copper is an essential trace element that serves as an important catalytic cofactor for cuproenzymes, carrying out major biological functions in growth and development. Although Wilson's disease (WD) is unquestionably caused by mutations in the ATP7B gene and subsequent copper overload, the precise role of copper in inducing pathological changes remains poorly understood. Our study aimed to explore, in HepG2 cells exposed to copper, the cell viability and apoptotic cells was tested by MTT and Hoechst 33342 stainning respectively, and the signaling pathways involved in oxidative stress response, apoptosis and lipid metabolism were determined by real time RT-PCR and Western blot analysis. The results demonstrate dose- and time-dependent cell viability and apoptosis in HepG2 cells following treatment with 10 μM, 200 μM and 500 μM of copper sulfate for 8 and 24 h. Copper overload significantly induced the expression of HSPA1A (heat shock 70 kDa protein 1A), an oxidative stress-responsive signal gene, and BAG3 (BCL2 associated athanogene3), an anti-apoptotic gene, while expression of HMGCR (3-hydroxy-3-methylglutaryl-CoA reductase), a lipid biosynthesis and lipid metabolism gene, was inhibited. These findings provide new insights into possible mechanisms accounting for the development of liver apoptosis and steatosis in the early stages of Wilson's disease.

The nutritional geometry of liver disease including non-alcoholic fatty liver disease.

PubMed

Simpson, Stephen J; Raubenheimer, David; Cogger, Victoria C; Macia, Laurence; Solon-Biet, Samantha M; Le Couteur, David G; George, Jacob

2018-02-01

Nutrition has a profound effect on chronic liver disease, especially non-alcoholic fatty liver disease (NAFLD). Most observational studies and clinical trials have focussed on the effects of total energy intake, or the intake of individual macronutrients and certain micronutrients, such as vitamin D, on liver disease. Although these studies have shown the importance of nutrition on hepatic outcomes, there is not yet any unifying framework for understanding the relationship between diet and liver disease. The Geometric Framework for Nutrition (GFN) is an innovative model for designing nutritional experiments or interpreting nutritional data that can determine the effects of nutrients and their interactions on animal behaviour and phenotypes. Recently the GFN has provided insights into the relationship between dietary energy and macronutrients on obesity and ageing in mammals including humans. Mouse studies using the GFN have disentangled the effects of macronutrients on fatty liver and the gut microbiome. The GFN is likely to play a significant role in disentangling the effects of nutrients on liver disease, especially NAFLD, in humans. Copyright © 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

In utero copper treatment for Menkes disease associated with a severe ATP7A mutation

PubMed Central

Haddad, Marie Reine; Macri, Charles J.; Holmes, Courtney S.; Goldstein, David S.; Jacobson, Beryl E.; Centeno, Jose A.; Popek, Edwina J.; Gahl, Willam A.; Kaler, Stephen G.

2012-01-01

Menkes disease is a lethal X-linked recessive neurodegenerative disorder of copper transport caused by mutations in ATP7A, which encodes a copper-transporting ATPase. Early postnatal treatment with copper injections often improves clinical outcomes in affected infants. While Menkes disease newborns appear normal neurologically, analyses of fetal tissues including placenta indicate abnormal copper distribution and suggest a prenatal onset of the metal transport defect. In an affected fetus whose parents found termination unacceptable and who understood the associated risks, we began in utero copper histidine treatment at 31.5 weeks gestational age. Copper histidine (900 μg per dose) was administered directly to the fetus by intramuscular injection (fetal quadriceps or gluteus) under ultrasound guidance. Percutaneous umbilical blood sampling enabled serial measurement of fetal copper and ceruloplasmin levels that were used to guide therapy over a four-week period. Fetal copper levels rose from 17 μg/dL prior to treatment to 45 μg/dL, and ceruloplasmin levels from 39 mg/L to 122 mg/L. After pulmonary maturity was confirmed biochemically, the baby was delivered at 35.5 weeks and daily copper histidine therapy (250 μg sc b.i.d.) was begun. Despite this very early intervention with copper, the infant showed hypotonia, developmental delay, and electroencephalographic abnormalities and died of respiratory failure at 5.5 months of age. The patient’s ATP7A mutation, which severely disrupted mRNA splicing, resulted in complete absence of ATP7A protein on Western blots. These investigations suggest that prenatally initiated copper replacement is inadequate to correct Menkes disease caused by severe loss-of-function mutations, and that postnatal ATP7A gene addition represents a rational approach in such circumstances. PMID:22695177

Association of nonalcoholic fatty liver disease with low bone mass in postmenopausal women.

PubMed

Moon, Seong-Su; Lee, Young-Sil; Kim, Sung Woo

2012-10-01

Osteoporosis is a disease associated with insulin resistant states such as central obesity, diabetes, and metabolic syndrome. Non-alcoholic fatty liver disease (NAFLD) is also increased in such conditions. However, little is known about whether osteoporosis and nonalcoholic fatty liver disease are etiologically related to each other or not. We examined whether bone mineral density (BMD) is associated with NAFLD in pre- and postmenopausal women. Four hundred eighty-one female subjects (216 premenopausal and 265 postmenopausal) were enrolled. Lumbar BMD was measured using dual-energy X-ray absorptiometry. Liver ultrasonography was done to check the severity of fatty liver. We excluded subjects with a secondary cause of liver disease. Blood pressure, lipid profile, fasting plasma glucose, alanine aminotransferase (ALT), aspartate aminotransferase, and body mass index were measured in every subject. Mean lumbar BMD was lower in subjects with NAFLD than those without NAFLD in postmenopausal women (0.98 ± 0.01 vs. 1.01 ± 0.02 g/cm², P = 0.046). Multiple correlation analysis revealed a significant association between mean lumbar BMD and NAFLD in postmenopausal subjects after adjusting for age, body mass index, ALT, smoking status, and alcohol consumption (β coefficient -0.066, 95% CI -0.105 to -0.027, P = 0.001). Even after adjusting the presence of metabolic syndrome, the significance was maintained (β coefficient -0.043, 95% CI -0.082 to -0.004, P = 0.031). Lumbar BMD is related with NAFLD in postmenopausal females. We suggest that postmenopausal women with NAFLD may have a higher risk of osteoporosis than those without.

Chronic copper poisoning in Angora kids.

PubMed

Belford, C J; Raven, C R; Black, H

1989-12-01

The investigation of five field cases of chronic copper poisoning in a group of 100 Angora kids is reported. Toxicity was confirmed by the demonstration of Heinz body anaemias, necrotizing liver disease, haemoglobinuric nephrosis and excessive levels of copper in blood, livers and kidneys. The dietary history of the kids is described. Tissue levels of copper and reported interactions between selenium, zinc and copper are discussed. Therapeutic and preventative measures are suggested.

Concentrations of strontium, barium, cadmium, copper, zinc, manganese, chromium, antimony, selenium, and lead in the liver and kidneys of dogs according to age, gender, and the occurrence of chronic kidney disease

PubMed Central

Mainzer, Barbara; Lahrssen-Wiederholt, Monika; Schafft, Helmut; Palavinskas, Richard; Breithaupt, Angele; Zentek, Jürgen

2015-01-01

This study was conducted to measure the concentrations of strontium (Sr), barium (Ba), cadmium (Cd), copper (Cu), zinc (Zn), manganese (Mn), chromium (Cr), antimony (Sb), selenium (Se), and lead (Pb) in canine liver, renal cortex, and renal medulla, and the association of these concentrations with age, gender, and occurrence of chronic kidney disease (CKD). Tissues from 50 dogs were analyzed using inductively coupled plasma mass spectrometry. Cu, Zn, and Mn levels were highest in the liver followed by the renal cortex and renal medulla. The highest Sr, Cd, and Se concentrations were measured in the renal cortex while lower levels were found in the renal medulla and liver. Female dogs had higher tissue concentrations of Sr (liver and renal medulla), Cd (liver), Zn (liver and renal cortex), Cr (liver, renal cortex, and renal medulla), and Pb (liver) than male animals. Except for Mn and Sb, age-dependent variations were observed for all element concentrations in the canine tissues. Hepatic Cd and Cr concentrations were higher in dogs with CKD. In conclusion, the present results provide new knowledge about the storage of specific elements in canine liver and kidneys, and can be considered important reference data for diagnostic methods and further investigations. PMID:25234328

Temporal trends in population-based death rates associated with chronic liver disease and liver cancer in the United States over the last 30 years.

PubMed

Kim, Yuhree; Ejaz, Aslam; Tayal, Amit; Spolverato, Gaya; Bridges, John F P; Anders, Robert A; Pawlik, Timothy M

2014-10-01

The health and economic burden from liver disease in the United States is substantial and rising. The objective of this study was to characterize temporal trends in mortality from chronic liver disease and liver cancer and the incidence of associated risk factors using population-based data over the past 30 years. Population-based mortality data were obtained from the National Vital Statistics System, and population estimates were derived from the national census for US adults (aged >45 years). Crude death rates (CDRs), age-adjusted death rates (ADRs), and average annual percentage change (AAPC) statistics were calculated. In total, 690,414 deaths (1.1%) were attributable to chronic liver disease, whereas 331,393 deaths (0.5%) were attributable to liver cancer between 1981 and 2010. The incidence of liver cancer was estimated at 7.1 cases per 100,000 population. Mortality rates from chronic liver disease and liver cancer increased substantially over the past 3 decades, with ADRs of 23.7 and 16.6 per 100,000 population in 2010, respectively. The AAPC from 2006 to 2010 demonstrated an increased ADR for chronic liver disease (AAPC, 1.5%; 95% confidence interval, 0.3%-2.8%) and liver cancer (AAPC, 2.6%; 95% confidence interval, 2.4%-2.7%). A comprehensive approach that involves primary and secondary prevention, increased access to treatment, and more funding for liver-related research is needed to address the high death rates associated with chronic liver disease and liver cancer in the United States. © 2014 American Cancer Society.

Liver fibrosis markers in alcoholic liver disease.

PubMed

Chrostek, Lech; Panasiuk, Anatol

2014-07-07

Alcohol is one of the main factors of liver damage. The evaluation of the degree of liver fibrosis is of great value for therapeutic decision making in patients with alcoholic liver disease (ALD). Staging of liver fibrosis is essential to define prognosis and management of the disease. Liver biopsy is a gold standard as it has high sensitivity and specificity in fibrosis diagnostics. Taking into account the limitations of liver biopsy, there is an exigency to introduce non-invasive serum markers for fibrosis that would be able to replace liver biopsy. Ideal serum markers should be specific for the liver, easy to perform and independent to inflammation and fibrosis in other organs. Serum markers of hepatic fibrosis are divided into direct and indirect. Indirect markers reflect alterations in hepatic function, direct markers reflect extracellular matrix turnover. These markers should correlate with dynamic changes in fibrogenesis and fibrosis resolution. The assessment of the degree of liver fibrosis in alcoholic liver disease has diagnostic and prognostic implications, therefore noninvasive assessment of fibrosis remains important. There are only a few studies evaluating the diagnostic and prognostic values of noninvasive biomarkers of fibrosis in patients with ALD. Several noninvasive laboratory tests have been used to assess liver fibrosis in patients with alcoholic liver disease, including the hyaluronic acid, FibroTest, FibrometerA, Hepascore, Forns and APRI indexes, FIB4, an algorithm combining Prothrombin index (PI), α-2 macroglobulin and hyaluronic acid. Among these tests, Fibrotest, FibrometerA and Hepascore demonstrated excellent diagnostic accuracy in identifying advanced fibrosis and cirrhosis, and additionally, Fibrotest was independently associated with survival. Therefore, the use of biomarkers may reduce the need for liver biopsy and permit an earlier treatment of alcoholic patients.

Folate, Alcohol, and Liver Disease

PubMed Central

Medici, Valentina; Halsted, Charles H.

2013-01-01

Alcoholic liver disease (ALD) is typically associated with folate deficiency, which is the result of reduced dietary folate intake, intestinal malabsorption, reduced liver uptake and storage, and increased urinary folate excretion. Folate deficiency favors the progression of liver disease through mechanisms that include its effects on methionine metabolism with consequences for DNA synthesis and stability and the epigenetic regulation of gene expression involved in pathways of liver injury. This paper reviews the pathogenesis of alcoholic liver disease with particular focus on ethanol-induced alterations in methionine metabolism which may act in synergy with folate deficiency to decrease antioxidant defense as well as DNA stability while regulating epigenetic mechanisms of relevant gene expressions. We also review the current evidence available on potential treatments of alcoholic liver disease based on correcting abnormalities in methionine metabolism and the methylation regulation of relevant gene expressions. PMID:23136133

The Relationship Between Fatty Liver Disease and Periodontal Disease

DTIC Science & Technology

2017-03-22

Periodontitis is a highly prevalent and destructive chronic disease. Numerous studies support an association between periodontal disease and other...systemic diseases (diabetes, cardiovascular disease, chronic kidney disease, adverse pregnancy outcome, etc.). Non-alcoholic fatty liver disease is a... chronic inflammatory disease that is characterized by accumulation of triglycerides and fat in the liver which may lead to fibrosis and even cirrhosis

Autoimmune liver disease 2007.

PubMed

Muratori, Paolo; Granito, Alessandro; Pappas, Georgios; Muratori, Luigi; Lenzi, Marco; Bianchi, Francesco B

2008-01-01

Autoimmune liver disease (ALD) includes a spectrum of diseases which comprises both cholestatic and hepatitic forms: autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC) and the so called "overlap" syndromes where hepatitic and cholestatic damage coexists. All these diseases are characterized by an extremely high heterogeneity of presentation, varying from asymptomatic, acute (as in a subset of AIH) or chronic (with aspecific symptoms such as fatigue and myalgia in AIH or fatigue and pruritus in PBC and PSC). The detection and characterization of non organ specific autoantibodies plays a major role in the diagnostic approach of autoimmune liver disease; anti nuclear reactivities (ANA) and anti smooth muscle antibodies (SMA) mark type 1 AIH, liver kidney microsomal antibody type 1 (LKM1) and liver cytosol type 1 (LC1) are the serological markers of type 2 AIH; antimitochondrial antibodies (AMA) are associated with PBC, while no specific marker is found in PSC, since anticytoplasmic neutrophil antibodies with perinuclear pattern (atypical p-ANCA or p-ANNA) are also detected in a substantial proportion of type 1 AIH cases. Treatment options rely on immunosoppressive therapy (steroids and azathioprine) in AIH and on ursodeoxycholic acid in cholestatic conditions; in all these diseases liver transplantation remains the only therapeutical approach for the end stage of liver disease.

PNPLA3 gene in liver diseases.

PubMed

Trépo, Eric; Romeo, Stefano; Zucman-Rossi, Jessica; Nahon, Pierre

2016-08-01

Genome-wide association studies (GWAS) in the field of liver diseases have revealed previously unknown pathogenic loci and generated new biological hypotheses. In 2008, a GWAS performed in a population-based sample study, where hepatic liver fat content was measured by magnetic spectroscopy, showed a strong association between a variant (rs738409 C>G p.I148M) in the patatin-like phospholipase domain containing 3 (PNPLA3) gene and nonalcoholic fatty liver disease. Further replication studies have shown robust associations between PNPLA3 and steatosis, fibrosis/cirrhosis, and hepatocellular carcinoma on a background of metabolic, alcoholic, and viral insults. The PNPLA3 protein has lipase activity towards triglycerides in hepatocytes and retinyl esters in hepatic stellate cells. The I148M substitution leads to a loss of function promoting triglyceride accumulation in hepatocytes. Although PNPLA3 function has been extensively studied, the molecular mechanisms leading to hepatic fibrosis and carcinogenesis remain unclear. This unsuspected association has highlighted the fact that liver fat metabolism may have a major impact on the pathophysiology of liver diseases. Conversely, alone, this locus may have limited predictive value with regard to liver disease outcomes in clinical practice. Additional studies at the genome-wide level will be required to identify new variants associated with liver damage and cancer to explain a greater proportion of the heritability of these phenotypes. Thus, incorporating PNPLA3 and other genetic variants in combination with clinical data will allow for the development of tailored predictive models. This attractive approach should be evaluated in prospective cohorts. Copyright © 2016 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Late onset of Wilson's disease in a family with genetic haemochromatosis.

PubMed

Dib, Nina; Valsesia, Emmanuelle; Malinge, Marie Claire; Mauras, Yves; Misrahi, Micheline; Calès, Paul

2006-01-01

We report the coexistence of Wilson's disease and genetic haemochromatosis in one family. The diagnosis of genetic haemochromatosis was established in a 52-year-old man. Among his siblings, one 57-year-old sister and one 55-year-old brother had decreased copper and ceruloplasmin levels in serum and increased urinary copper excretion. The sister shared the same human leucocyte antigen haplotypes and was homozygous for the HFE mutation C282Y, like the propositus. However, she had normal liver iron content and increased liver copper content. Her dietary copper intake was probably excessive. The association of Wilson's disease and genetic haemochromatosis is rare and has only been described twice. The onset of Wilson's disease after 50 years of age is rare; Wilson's disease should be considered in any patient with unexplained chronic liver disease; an excess in liver copper content might be induced by excessive dietary input in a susceptible individual.

Gut microbiome and liver diseases.

PubMed

Tilg, Herbert; Cani, Patrice D; Mayer, Emeran A

2016-12-01

The gut microbiota has recently evolved as a new important player in the pathophysiology of many intestinal and extraintestinal diseases. The liver is the organ which is in closest contact with the intestinal tract, and is exposed to a substantial amount of bacterial components and metabolites. Various liver disorders such as alcoholic liver disease, non-alcoholic liver disease and primary sclerosing cholangitis have been associated with an altered microbiome. This dysbiosis may influence the degree of hepatic steatosis, inflammation and fibrosis through multiple interactions with the host's immune system and other cell types. Whereas few results from clinical metagenomic studies in liver disease are available, evidence is accumulating that in liver cirrhosis an oral microbiome is overrepresented in the lower intestinal tract, potentially contributing to disease process and severity. A major role for the gut microbiota in liver disorders is also supported by the accumulating evidence that several complications of severe liver disease such as hepatic encephalopathy are efficiently treated by various prebiotics, probiotics and antibiotics. A better understanding of the gut microbiota and its components in liver diseases might provide a more complete picture of these complex disorders and also form the basis for novel therapies. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Neutrophil gelatinase‐associated lipocalin level is a prognostic factor for survival in rat and human chronic liver diseases

PubMed Central

Yoshikawa, Kyoko; Iwasa, Motoh; Kojima, Shinichi; Yoshizawa, Naohiko; Tempaku, Mina; Sugimoto, Ryosuke; Yamamoto, Norihiko; Sugimoto, Kazushi; Kobayashi, Yoshinao; Hasegawa, Hiroshi; Takei, Yoshiyuki

2017-01-01

Chronic liver disease patients often have complications, such as hepatocellular carcinoma (HCC) and acute bacterial infection. Model for end‐stage liver disease and Child‐Pugh scores are useful prognostic factors for chronic liver diseases but not for all chronic conditions, such as HCC. Our investigative aim targeted the prognostic abilities of neutrophil gelatinase‐associated lipocalin (NGAL) in rat and human chronic liver diseases. Blood NGAL levels were measured by enzyme‐linked immunosorbent assay in rats with cirrhosis and 96 patients with chronic liver disease and HCC. We examined the correlation between blood NGAL levels and liver functions as well as survival. In our rat model, liver NGAL expression was assessed by immunostaining, real‐time quantitative polymerase chain reaction, and immunoblot. In rats with cirrhosis, blood NGAL levels were continuously and significantly elevated in the deceased group and were significantly correlated with liver functions. Liver NGAL, toll‐like receptor 4, and interleukin‐6 levels were increased in the deceased group compared to the survival group. Blood NGAL levels were significantly correlated with liver NGAL levels, indicating blood NGAL was derived from the liver. In patients with chronic liver disease, blood NGAL levels were associated with liver function and renal function. Blood NGAL levels were significantly increased in patients with chronic liver disease with HCC compared to without HCC. For the survival group, 38 out of 96 patients were dead in the average follow‐up period of 9.9 months. The patients with blood NGAL ≤119 ng/mL had significantly longer rates of survival compared to patients with blood NGAL >119 ng/mL. Conclusion: Blood NGAL predicts the survival rate in rat and human chronic liver diseases. Our findings suggest blood NGAL may be prognostic of survival in chronic liver diseases complicated by HCC. (Hepatology Communications 2017;1:946–956) PMID:29404502

Discharge Disposition After Stroke in Patients With Liver Disease.

PubMed

Parikh, Neal S; Merkler, Alexander E; Schneider, Yecheskel; Navi, Babak B; Kamel, Hooman

2017-02-01

Liver disease is associated with both hemorrhagic and thrombotic processes, including an elevated risk of intracranial hemorrhage. We sought to assess the relationship between liver disease and outcomes after stroke, as measured by discharge disposition. Using administrative claims data, we identified a cohort of patients hospitalized with stroke in California, Florida, and New York from 2005 to 2013. The predictor variable was liver disease. All diagnoses were defined using validated diagnosis codes. Ordinal logistic regression was used to analyze the association between liver disease and worsening discharge disposition: home, nursing/rehabilitation facility, or death. Secondarily, multiple logistic regression was used to analyze the association between liver disease and in-hospital mortality. Models were adjusted for demographics, vascular risk factors, and comorbidities. We identified 121 428 patients with intracerebral hemorrhage and 703 918 with ischemic stroke. Liver disease was documented in 13 584 patients (1.7%). Liver disease was associated with worse discharge disposition after both intracerebral hemorrhage (global odds ratio, 1.28; 95% confidence interval, 1.19-1.38) and ischemic stroke (odds ratio, 1.23; 95% confidence interval, 1.17-1.29). Similarly, liver disease was associated with in-hospital death after both intracerebral hemorrhage (odds ratio, 1.33; 95% confidence interval, 1.23-1.44) and ischemic stroke (odds ratio, 1.60; 95% confidence interval, 1.51-1.71). Liver disease was associated with worse hospital discharge disposition and in-hospital mortality after stroke, suggesting worse functional outcomes. © 2016 American Heart Association, Inc.

A Systematic Review and Meta-Analysis on the Strength and Consistency of the Associations between Dupuytren Disease and Diabetes Mellitus, Liver Disease, and Epilepsy.

PubMed

Broekstra, Dieuwke C; Groen, Henk; Molenkamp, Sanne; Werker, Paul M N; van den Heuvel, Edwin R

2018-03-01

The role of diabetes mellitus, liver disease, and epilepsy as risk factors for Dupuytren disease remains unclear. In this systematic review and meta-analysis, the strength and consistency of these associations were examined. The MEDLINE, EMBASE, and Web of Science databases were searched for articles reporting an association between Dupuytren disease and diabetes mellitus, liver disease, and epilepsy published before September 26, 2016. The frequencies of Dupuytren disease and diabetes mellitus, liver disease, and epilepsy were extracted, as was information on potential confounders. Generalized linear mixed models were applied to estimate pooled odds ratios, adjusted for confounders. Heterogeneity between studies was quantified using an intraclass correlation coefficient and was accounted for by a random effect for study. One thousand two hundred sixty unique studies were identified, of which 32 were used in the meta-analyses. An association between Dupuytren disease and diabetes mellitus was observed (OR, 3.06; 95 percent CI, 2.69 to 3.48, adjusted for age), which was stronger for type 1 diabetes mellitus than for type 2 diabetes mellitus but was not statistically significant (p = 0.24). An association between Dupuytren disease and liver disease was observed (OR, 2.92; 95 percent CI, 2.08 to 4.12, adjusted for sex). Dupuytren disease and epilepsy were associated, yielding an OR of 2.80 (95 percent CI, 2.49 to 3.15). Heterogeneity between studies was moderate to low. These findings demonstrate an association between Dupuytren disease and diabetes mellitus, liver disease, and epilepsy. Prospective, longitudinal studies are needed to elucidate the pathways causing these associations.

Liver transplant for cholestatic liver diseases.

PubMed

Carrion, Andres F; Bhamidimarri, Kalyan Ram

2013-05-01

Cholestatic liver diseases include a group of diverse disorders with different epidemiology, pathophysiology, clinical course, and prognosis. Despite significant advances in the clinical care of patients with cholestatic liver diseases, liver transplant (LT) remains the only definitive therapy for end-stage liver disease, regardless of the underlying cause. As per the United Network for Organ Sharing database, the rate of cadaveric LT for cholestatic liver disease was 18% in 1991, 10% in 2000, and 7.8% in 2008. This review summarizes the available evidence on various common and rare cholestatic liver diseases, disease-specific issues, and pertinent aspects of LT. Copyright © 2013 Elsevier Inc. All rights reserved.

Non-hepatic tumors change the activity of genes encoding copper trafficking proteins in the liver

PubMed Central

Babich, Polina S.; Skvortsov, Alexey N; Rusconi, Paolo; Tsymbalenko, Nadezhda V.; Mutanen, Marja; Puchkova, Ludmila V.; Broggini, Massimo

2013-01-01

To assess the statistical relationship between tumor growth and copper metabolism, we performed a metaanalysis of studies in which patients with neoplasms were characterized according to any of the copper status indexes (atomic copper serum concentration, serum oxidase activity, ceruloplasmin protein content). Our metaanalysis shows that in the majority of cases (more than 3100 patients), tumor growth positively correlates with the copper status indexes. Nude athymic CD-1 nu/nu mice with subcutaneous tumors of human origin, C57Bl/6J mice with murine melanoma and ApcMin mice with spontaneously developing adenomas throughout the intestinal tract were studied to experimentally determine the relationship between tumor progression, liver copper metabolism, and copper status indexes. We showed that the copper status indexes increased significantly during tumor growth. In the liver tissue of tumor-bearing mice, ceruloplasmin gene expression, as well as the expression of genes related to ceruloplasmin metallation (CTR1 and ATP7B), increased significantly. Moreover, the presence of an mRNA splice variant encoding a form of ceruloplasmin anchored to the plasma membrane by glycosylphosphatidyl inositol, which is atypical for hepatocytes, was also detected. The ATP7A copper transporter gene, which is normally expressed in the liver only during embryonic copper metabolism, was also activated. Depletion of holo-ceruloplasmin resulted in retardation of human HCT116 colon carcinoma cell growth in nude mice and induced DNA fragmentation in tumor cells. In addition, the concentration of cytochrome c increased significantly in the cytosol, while decreasing in the mitochondria. We discuss a possible trans-effect of developing tumors on copper metabolism in the liver. PMID:23792645

Alcohol consumption in late adolescence is associated with an increased risk of severe liver disease later in life.

PubMed

Hagström, Hannes; Hemmingsson, Tomas; Discacciati, Andrea; Andreasson, Anna

2018-03-01

High alcohol consumption is associated with an increased risk of severe liver disease. Current recommendations suggest it is safe for men to consume 30 grams of alcohol per day. We investigated the association between alcohol consumption early in life and later development of severe liver disease. We used data on alcohol consumption at conscription to military service from 43,296 men (18-20 years) in Sweden between 1969 and 1970. Outcomes were defined as incident diagnoses of severe liver disease from systematic national registration of clinical events until the end of 2009. A Cox regression model adjusted for body mass index, smoking, use of narcotics, cognitive ability and cardiovascular capacity was applied. During a mean follow-up of 37.8 years, 383 men developed severe liver disease. Alcohol consumption was associated with an increased risk of development of severe liver disease in a dose-response pattern (adjusted hazard ratio for every one gram/day increase 1.02; 95% CI 1.01-1.02). No evidence of a threshold effect was found. Importantly, a clear trend pointed towards an increased risk of severe liver disease in men who consumed less than 30 grams of alcohol per day. Alcohol consumption in young men is associated with an increased risk of severe liver disease, up to 39 years later in life. The risk was dose-dependent, with no sign of a threshold effect. Current guidelines for safe alcohol intake in men might have to be revised. We investigated more than 43,000 Swedish men in their late teens enlisted for conscription in 1969-1970. After almost 40 years of follow-up, we found that alcohol consumption was a significant risk factor for developing severe liver disease, independent of confounders. This risk was dose-dependent, and was most pronounced in men consuming two drinks per day or more. Copyright © 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Hepatitis A and B superimposed on chronic liver disease: vaccine-preventable diseases.

PubMed

Keeffe, Emmet B

2006-01-01

A number of studies have demonstrated that the acquisition of hepatitis A or hepatitis B in patients with chronic liver disease is associated with high rates of morbidity and mortality. Superimposition of acute hepatitis A in patients with chronic hepatitis C has been associated with a particularly high mortality rate, and chronic hepatitis B virus coinfection with hepatitis C virus is associated with an accelerated progression of chronic liver disease to cirrhosis, decompensated liver disease and hepatocellular carcinoma. With the availability of vaccines against hepatitis B and hepatitis A since 1981 and 1995, respectively, these are vaccine-preventable diseases. Studies have confirmed that hepatitis A and hepatitis B vaccines are safe and immunogenic in patients with mild to moderate chronic liver disease. However, hepatitis A and B vaccination is less effective in patients with advanced liver disease and after liver transplantation. These observations have led to the recommendation that patients undergo hepatitis A and B vaccination early in the natural history of their chronic liver disease. Vaccination rates are low in clinical practice, and public health and educational programs are needed to overcome barriers to facilitate timely implementation of these recommendations.

Hepatitis A and B Superimposed on Chronic Liver Disease: Vaccine-Preventable Diseases

PubMed Central

Keeffe, Emmet B

2006-01-01

A number of studies have demonstrated that the acquisition of hepatitis A or hepatitis B in patients with chronic liver disease is associated with high rates of morbidity and mortality. Superimposition of acute hepatitis A in patients with chronic hepatitis C has been associated with a particularly high mortality rate, and chronic hepatitis B virus coinfection with hepatitis C virus is associated with an accelerated progression of chronic liver disease to cirrhosis, decompensated liver disease and hepatocellular carcinoma. With the availability of vaccines against hepatitis B and hepatitis A since 1981 and 1995, respectively, these are vaccine-preventable diseases. Studies have confirmed that hepatitis A and hepatitis B vaccines are safe and immunogenic in patients with mild to moderate chronic liver disease. However, hepatitis A and B vaccination is less effective in patients with advanced liver disease and after liver transplantation. These observations have led to the recommendation that patients undergo hepatitis A and B vaccination early in the natural history of their chronic liver disease. Vaccination rates are low in clinical practice, and public health and educational programs are needed to overcome barriers to facilitate timely implementation of these recommendations. PMID:18528476

Liver disease

MedlinePlus

... Coccidioidomycosis Delta agent (hepatitis D) Drug-induced cholestasis Fatty liver disease Hemochromatosis Hepatitis A Hepatitis B Hepatitis C ... abscess Reye syndrome Sclerosing cholangitis Wilson disease Images Fatty liver, CT scan Liver with disproportional fattening, CT scan ...

Parenteral Nutrition-Associated Liver Disease: The Role of the Gut Microbiota.

PubMed

Cahova, Monika; Bratova, Miriam; Wohl, Petr

2017-09-07

Parenteral nutrition (PN) provides life-saving nutritional support in situations where caloric supply via the enteral route cannot cover the necessary needs of the organism. However, it does have serious adverse effects, including parenteral nutrition-associated liver disease (PNALD). The development of liver injury associated with PN is multifactorial, including non-specific intestine inflammation, compromised intestinal permeability, and barrier function associated with increased bacterial translocation, primary and secondary cholangitis, cholelithiasis, short bowel syndrome, disturbance of hepatobiliary circulation, lack of enteral nutrition, shortage of some nutrients (proteins, essential fatty acids, choline, glycine, taurine, carnitine, etc.), and toxicity of components within the nutrition mixture itself (glucose, phytosterols, manganese, aluminium, etc.). Recently, an increasing number of studies have provided evidence that some of these factors are directly or indirectly associated with microbial dysbiosis in the intestine. In this review, we focus on PN-induced changes in the taxonomic and functional composition of the microbiome. We also discuss immune cell and microbial crosstalk during parenteral nutrition, and the implications for the onset and progression of PNALD. Finally, we provide an overview of recent advances in the therapeutic utilisation of pro- and prebiotics for the mitigation of PN-associated liver complications.

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.

Progression of liver fibrosis is associated with non‐liver‐related mortality in patients with nonalcoholic fatty liver disease

PubMed Central

Kumada, Takashi; Toyoda, Hidenori; Mizuno, Kazuyuki; Sone, Yasuhiro; Akita, Tomoyuki; Tanaka, Junko

2017-01-01

In patients with nonalcoholic fatty liver disease (NAFLD), prognosis and outcome, especially non‐liver‐related mortality, remain incompletely elucidated. We clarified the mortality from all causes in patients with NAFLD. A total of 4,073 patients with NAFLD diagnosed by ultrasonography were enrolled. We investigated the causes of death and analyzed the mortality from non‐liver‐related diseases according to the degrees of steatosis and fibrosis using the competing risk method. We used the NAFLD fibrosis score (NFS) to assess fibrosis severity and the ultrasonography fatty liver score to evaluate steatosis severity. The numbers of patients with NFS indicating low, intermediate, and high probabilities of advanced fibrosis were 2,451 (60.2%), 1,462 (35.9%), and 160 (3.9%), respectively. Of the 4,073 patients, 179 died during follow‐up, but only nine deaths were due to liver‐related diseases. Of the remaining 170 patients who died due to non‐liver‐related diseases, 83 (48.8%), 42 (24.7%), and 45 (26.5%) patients died due to malignancies, cerebrovascular and cardiovascular diseases, and benign diseases (excluding cerebrovascular and cardiovascular diseases), respectively. Multivariate analysis showed that the intermediate and high NFS groups were independently associated with each disease category: hazard ratio (HR) 2.163 (95% confidence interval [CI], 1.354‐3.457) and HR 4.814 (95% CI, 2.323‐9.977) for malignancies; HR 2.265 (95% CI, 1.141‐4.497) and HR 8.482 (95% CI, 3.558‐20.220) for cerebrovascular and cardiovascular diseases; and HR 3.216 (95% CI, 1.641‐6.303) and HR 5.558 (95% CI, 1.923‐16.070) for benign diseases, respectively. Conversely, the status of steatosis was not associated with risk of mortality in multivariate analysis. Conclusion: Progression of liver fibrosis severity was associated with mortality from various non‐liver‐related causes in patients with NAFLD. (Hepatology Communications 2017;1:928–945) PMID:29404500

Clinical epidemiology and disease burden of nonalcoholic fatty liver disease

PubMed Central

Perumpail, Brandon J; Khan, Muhammad Ali; Yoo, Eric R; Cholankeril, George; Kim, Donghee; Ahmed, Aijaz

2017-01-01

Nonalcoholic fatty liver disease (NAFLD) is defined as the presence of hepatic fat accumulation after the exclusion of other causes of hepatic steatosis, including other causes of liver disease, excessive alcohol consumption, and other conditions that may lead to hepatic steatosis. NAFLD encompasses a broad clinical spectrum ranging from nonalcoholic fatty liver to nonalcoholic steatohepatitis (NASH), advanced fibrosis, cirrhosis, and finally hepatocellular carcinoma (HCC). NAFLD is the most common liver disease in the world and NASH may soon become the most common indication for liver transplantation. Ongoing persistence of obesity with increasing rate of diabetes will increase the prevalence of NAFLD, and as this population ages, many will develop cirrhosis and end-stage liver disease. There has been a general increase in the prevalence of NAFLD, with Asia leading the rise, yet the United States is following closely behind with a rising prevalence from 15% in 2005 to 25% within 5 years. NAFLD is commonly associated with metabolic comorbidities, including obesity, type II diabetes, dyslipidemia, and metabolic syndrome. Our understanding of the pathophysiology of NAFLD is constantly evolving. Based on NAFLD subtypes, it has the potential to progress into advanced fibrosis, end-stage liver disease and HCC. The increasing prevalence of NAFLD with advanced fibrosis, is concerning because patients appear to experience higher liver-related and non-liver-related mortality than the general population. The increased morbidity and mortality, healthcare costs and declining health related quality of life associated with NAFLD makes it a formidable disease, and one that requires more in-depth analysis. PMID:29307986

The Menkes and Wilson disease genes counteract in copper toxicosis in Labrador retrievers: a new canine model for copper-metabolism disorders

PubMed Central

Fieten, Hille; Gill, Yadvinder; Martin, Alan J.; Concilli, Mafalda; Dirksen, Karen; van Steenbeek, Frank G.; Spee, Bart; van den Ingh, Ted S. G. A. M.; Martens, Ellen C. C. P.; Festa, Paola; Chesi, Giancarlo; van de Sluis, Bart; Houwen, Roderick H. J. H.; Watson, Adrian L.; Aulchenko, Yurii S.; Hodgkinson, Victoria L.; Zhu, Sha; Petris, Michael J.; Polishchuk, Roman S.; Leegwater, Peter A. J.; Rothuizen, Jan

2016-01-01

ABSTRACT The deleterious effects of a disrupted copper metabolism are illustrated by hereditary diseases caused by mutations in the genes coding for the copper transporters ATP7A and ATP7B. Menkes disease, involving ATP7A, is a fatal neurodegenerative disorder of copper deficiency. Mutations in ATP7B lead to Wilson disease, which is characterized by a predominantly hepatic copper accumulation. The low incidence and the phenotypic variability of human copper toxicosis hamper identification of causal genes or modifier genes involved in the disease pathogenesis. The Labrador retriever was recently characterized as a new canine model for copper toxicosis. Purebred dogs have reduced genetic variability, which facilitates identification of genes involved in complex heritable traits that might influence phenotype in both humans and dogs. We performed a genome-wide association study in 235 Labrador retrievers and identified two chromosome regions containing ATP7A and ATP7B that were associated with variation in hepatic copper levels. DNA sequence analysis identified missense mutations in each gene. The amino acid substitution ATP7B:p.Arg1453Gln was associated with copper accumulation, whereas the amino acid substitution ATP7A:p.Thr327Ile partly protected against copper accumulation. Confocal microscopy indicated that aberrant copper metabolism upon expression of the ATP7B variant occurred because of mis-localization of the protein in the endoplasmic reticulum. Dermal fibroblasts derived from ATP7A:p.Thr327Ile dogs showed copper accumulation and delayed excretion. We identified the Labrador retriever as the first natural, non-rodent model for ATP7B-associated copper toxicosis. Attenuation of copper accumulation by the ATP7A mutation sheds an interesting light on the interplay of copper transporters in body copper homeostasis and warrants a thorough investigation of ATP7A as a modifier gene in copper-metabolism disorders. The identification of two new functional variants in

Alcoholic liver disease.

PubMed

Penny, Steven M

2013-01-01

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

Interaction between periodontitis and liver diseases

PubMed Central

Han, Pengyu; Sun, Dianxing; Yang, Jie

2016-01-01

Periodontitis is an oral disease that is highly prevalent worldwide, with a prevalence of 30–50% of the population in developed countries, but only ~10% present with severe forms. It is also estimated that periodontitis results in worldwide productivity losses amounting to ~54 billion USD yearly. In addition to the damage it causes to oral health, periodontitis also affects other types of disease. Numerous studies have confirmed the association between periodontitis and systemic diseases, such as diabetes, respiratory disease, osteoporosis and cardiovascular disease. Increasing evidence also indicated that periodontitis may participate in the progression of liver diseases, such as non-alcoholic fatty liver disease, cirrhosis and hepatocellular carcinoma, as well as affecting liver transplantation. However, to the best of our knowledge, there are currently no reviews elaborating upon the possible links between periodontitis and liver diseases. Therefore, the current review summarizes the human trials and animal experiments that have been conducted to investigate the correlation between periodontitis and liver diseases. Furthermore, in the present review, certain mechanisms that have been postulated to be responsible for the role of periodontitis in liver diseases (such as bacteria, pro-inflammatory mediators and oxidative stress) are considered. The aim of the review is to introduce the hypothesis that periodontitis may be important in the progression of liver disease, thus providing dentists and physicians with an improved understanding of this issue. PMID:27588170

Nonalcoholic fatty liver disease is associated with cognitive function in adults

PubMed Central

Gottesman, Rebecca F.; Clark, Jeanne M.; Hernaez, Ruben; Chang, Yoosoo; Kim, Changsoo; Ha, Kyoung Hwa; Guallar, Eliseo; Lazo, Mariana

2016-01-01

Objective: We hypothesized that nonalcoholic fatty liver disease (NAFLD) is independently associated with cognitive impairment in a representative sample of the general US population regardless of the presence of cardiovascular disease (CVD) or its risk factors. Methods: This was a cross-sectional study of 4,472 adults aged 20–59 years who participated in the Third National Health and Nutritional Examination Survey. The participants underwent assessment of liver enzyme activity and hepatic steatosis by ultrasound, and underwent cognitive evaluation using the following computer-administered tests: the Simple Reaction Time Test (SRTT), the Symbol-Digit Substitution Test (SDST), and the Serial Digit Learning Test (SDLT). We defined NAFLD as moderate/severe steatosis as determined by ultrasound in the absence of hepatitis B or C or excessive alcohol consumption. We used multiple linear regression models to examine the association between NAFLD and cognitive function while controlling for potential confounders. Results: Participants with NAFLD showed lower overall performance on the SDLT (β = 0.726, 95% confidence interval [CI] 0.105–1.347), while associations with SRTT and SDST did not reach significance. Increased activity of the liver enzymes alanine aminotransferase (β = 0.018, 95% CI 0.006–0.030) and aspartate aminotransferase (β = 0.021, 95% CI 0.005–0.037) correlated with lower performance on the SDLT, while increased alanine aminotransferase was also correlated with lower performance in the SDST (β = 0.002, 95% CI 0.0001–0.004). Conclusions: NAFLD was independently associated with lower cognitive performance independent of CVD and its risk factors. Given the scarcity of risk factors associated with age-related cognitive decline, these findings may have significant implications. PMID:26911638

Nonalcoholic fatty liver disease is associated with cognitive function in adults.

PubMed

Seo, Sang Won; Gottesman, Rebecca F; Clark, Jeanne M; Hernaez, Ruben; Chang, Yoosoo; Kim, Changsoo; Ha, Kyoung Hwa; Guallar, Eliseo; Lazo, Mariana

2016-03-22

We hypothesized that nonalcoholic fatty liver disease (NAFLD) is independently associated with cognitive impairment in a representative sample of the general US population regardless of the presence of cardiovascular disease (CVD) or its risk factors. This was a cross-sectional study of 4,472 adults aged 20-59 years who participated in the Third National Health and Nutritional Examination Survey. The participants underwent assessment of liver enzyme activity and hepatic steatosis by ultrasound, and underwent cognitive evaluation using the following computer-administered tests: the Simple Reaction Time Test (SRTT), the Symbol-Digit Substitution Test (SDST), and the Serial Digit Learning Test (SDLT). We defined NAFLD as moderate/severe steatosis as determined by ultrasound in the absence of hepatitis B or C or excessive alcohol consumption. We used multiple linear regression models to examine the association between NAFLD and cognitive function while controlling for potential confounders. Participants with NAFLD showed lower overall performance on the SDLT (β = 0.726, 95% confidence interval [CI] 0.105-1.347), while associations with SRTT and SDST did not reach significance. Increased activity of the liver enzymes alanine aminotransferase (β = 0.018, 95% CI 0.006-0.030) and aspartate aminotransferase (β = 0.021, 95% CI 0.005-0.037) correlated with lower performance on the SDLT, while increased alanine aminotransferase was also correlated with lower performance in the SDST (β = 0.002, 95% CI 0.0001-0.004). NAFLD was independently associated with lower cognitive performance independent of CVD and its risk factors. Given the scarcity of risk factors associated with age-related cognitive decline, these findings may have significant implications. © 2016 American Academy of Neurology.

Fatty Liver Disease

MedlinePlus

... fatty liver disease that is not related to heavy alcohol use. There are two kinds: Simple fatty ... disease? Alcoholic fatty liver disease is due to heavy alcohol use. Your liver breaks down most of ...

Neurologic Manifestations of Chronic Liver Disease and Liver Cirrhosis.

PubMed

Sureka, Binit; Bansal, Kalpana; Patidar, Yashwant; Rajesh, S; Mukund, Amar; Arora, Ankur

2015-01-01

The normal functioning of brain is intimately as well as intricately interrelated with normal functioning of the liver. Liver plays a critical role of not only providing vital nutrients to the brain but also of detoxifying the splanchnic blood. Compromised liver function leads to insufficient detoxification thus allowing neurotoxins (such as ammonia, manganese, and other chemicals) to enter the cerebral circulation. In addition, portosystemic shunts, which are common accompaniments of advanced liver disease, facilitate free passage of neurotoxins into the cerebral circulation. The problem is compounded further by additional variables such as gastrointestinal tract bleeding, malnutrition, and concurrent renal failure, which are often associated with liver cirrhosis. Neurologic damage in chronic liver disease and liver cirrhosis seems to be multifactorial primarily attributable to the following: brain accumulation of ammonia, manganese, and lactate; altered permeability of the blood-brain barrier; recruitment of monocytes after microglial activation; and neuroinflammation, that is, direct effects of circulating systemic proinflammatory cytokines such as tumor necrosis factor, IL-1β, and IL-6. Radiologist should be aware of the conundrum of neurologic complications that can be encountered in liver disease, which include hepatic encephalopathy, hepatocerebral degeneration, hepatic myelopathy, cirrhosis-related parkinsonism, cerebral infections, hemorrhage, and osmotic demyelination. In addition, neurologic complications can be exclusive to certain disorders, for example, Wilson disease, alcoholism (Wernicke encephalopathy, alcoholic cerebellar degeneration, Marchiafava-Bignami disease, etc). Radiologist should be aware of their varied clinical presentation and radiological appearances as the diagnosis is not always straightforward. Copyright © 2015 Mosby, Inc. All rights reserved.

The association between serum copper concentrations and cardiovascular disease risk factors in children and adolescents in NHANES.

PubMed

Zang, Xiaodong; Huang, Hesuyuan; Zhuang, Zhulun; Chen, Runsen; Xie, Zongyun; Xu, Cheng; Mo, Xuming

2018-06-01

Copper is an essential element in human beings, alterations in serum copper levels could potentially have effect on human health. To date, no data are available regarding how serum copper affects cardiovascular disease (CVD) risk factors in children and adolescents. We examined the association between serum copper levels and CVD risk factors in children and adolescents. We analyzed data consisting of 1427 subjects from a nationally representative sample of the US population in the National Health and Nutrition Examination Survey (NHANES) from 2011 to 2014. The CVD risk factors included total cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides, fasting glucose, glycohemoglobin, fasting insulin, and blood pressure. Multivariate and generalized linear regressions were performed to investigate associations adjusted for age, gender, ethnicity, poverty:income ratio (PIR), BMI, energy intake, and physical activity. We found significant associations between serum copper and total cholesterol (coefficient = 0.132; 95% CI 0.081, 0.182; P for trend < 0.001), glycohemoglobin (coefficient = 0.044; 95% CI 0.020, 0.069; P < 0.001), and fasting insulin (coefficient = 0.730; 95% CI 0.410, 1.050; P < 0.001) among the included participants. Moreover, in the generalized linear models, subjects with the highest copper levels demonstrated a 0.83% (95% CI 0.44%, 1.24%) greater increase in serum total cholesterol (p for trend < 0.001) when compared to participants with the lowest copper concentrations. Our results provide the first epidemiological evidence that serum copper concentrations are associated with total cholesterol concentrations in children and adolescents. However, the underlying mechanisms still need further exploration.

Genetics of liver disease: From pathophysiology to clinical practice.

PubMed

Karlsen, Tom H; Lammert, Frank; Thompson, Richard J

2015-04-01

Paralleling the first 30 years of the Journal of Hepatology we have witnessed huge advances in our understanding of liver disease and physiology. Genetic advances have played no small part in that. Initial studies in the 1970s and 1980s identified the strong major histocompatibility complex associations in autoimmune liver diseases. During the 1990 s, developments in genomic technologies drove the identification of genes responsible for Mendelian liver diseases. Over the last decade, genome-wide association studies have allowed for the dissection of the genetic susceptibility to complex liver disorders, in which also environmental co-factors play important roles. Findings have allowed the identification and elaboration of pathophysiological processes, have indicated the need for reclassification of liver diseases and have already pointed to new disease treatments. In the immediate future genetics will allow further stratification of liver diseases and contribute to personalized medicine. Challenges exist with regard to clinical implementation of rapidly developing technologies and interpretation of the wealth of accumulating genetic data. The historical perspective of genetics in liver diseases illustrates the opportunities for future research and clinical care of our patients. Copyright © 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Endocannabinoids in liver disease and hepatic encephalopathy.

PubMed

Magen, Iddo; Avraham, Yosefa; Berry, Elliot; Mechoulam, Raphael

2008-01-01

Chronic liver disease results from a variety of causes such as hepatitis virus infections, autoimmune processes and alcohol consumption. Its complications include fat deposition, hemodynamic changes and fibrosis. Clinically there may be progression to portal-hypertension and porto-systemic encephalopathy. Pioneering research from the laboratory of Kunos at NIH has stressed the importance of endocannabinoids (ECs) as mediators of some of the pathological processes in chronic liver disease. The present review summarizes the literature on the association between ECs and liver disease, as well as the therapeutic potential of ECs and exogenous cannabinoids in liver disease with emphasis on hepatic encephalopathy.

Non-alcoholic fatty liver disease is not associated with a lower health perception.

PubMed

Mlynarsky, Liat; Schlesinger, Dalit; Lotan, Roni; Webb, Muriel; Halpern, Zamir; Santo, Erwin; Shibolet, Oren; Zelber-Sagi, Shira

2016-05-07

To examine the association between non-alcoholic fatty liver disease (NAFLD) and general health perception. This cross sectional and prospective follow-up study was performed on a cohort of a sub-sample of the first Israeli national health and nutrition examination survey, with no secondary liver disease or history of alcohol abuse. On the first survey, in 2003-2004, 349 participants were included. In 2009-2010 participants from the baseline survey were invited to participate in a follow-up survey. On both baseline and follow-up surveys the data collected included: self-reported general health perception, physical activity habits, frequency of physician's visits, fatigue impact scale and abdominal ultrasound. Fatty liver was diagnosed by abdominal ultrasonography using standardized criteria and the ratio between the median brightness level of the liver and the right kidney was calculated to determine the Hepato-Renal Index. Out of 349 eligible participants in the first survey, 213 volunteers participated in the follow-up cohort and were included in the current analysis, NAFLD was diagnosed in 70/213 (32.9%). The prevalence of "very good" self-reported health perception was lower among participants diagnosed with NAFLD compared to those without NAFLD. However, adjustment for BMI attenuated the association (OR = 0.73, 95%CI: 0.36-1.50, P = 0.392). Similar results were observed for the hepato-renal index; it was inversely associated with "very good" health perception but adjustment for BMI attenuated the association. In a full model of multivariate analysis, that included all potential predictors for health perception, NAFLD was not associated with the self-reported general health perception (OR = 0.86, 95%CI: 0.40-1.86, P = 0.704). The odds for "very good" self-reported general health perception (compared to "else") increased among men (OR = 2.42, 95%CI: 1.26-4.66, P = 0.008) and those with higher performance of leisure time physical activity (OR = 1.01, 95%CI: 1

Tyrosine levels are associated with insulin resistance in patients with nonalcoholic fatty liver disease

PubMed Central

Kawanaka, Miwa; Nishino, Ken; Oka, Takahito; Urata, Noriyo; Nakamura, Jun; Suehiro, Mitsuhiko; Kawamoto, Hirofumi; Chiba, Yasutaka; Yamada, Gotaro

2015-01-01

Objective Amino acid imbalance is often found in patients with cirrhosis, and this imbalance is associated with insulin resistance. However, the mechanism underlying the relationship between amino acid imbalance and insulin resistance remains unclear. We evaluated serum amino acid concentrations in patients with nonalcoholic fatty liver disease to determine if any of the levels of amino acids were associated with the biochemical markers and fibrosis stage of nonalcoholic steatohepatitis (NASH). Methods In 137 patients with nonalcoholic fatty liver disease who underwent liver biopsy, plasma levels of branched-chain amino acid (BCAA), tyrosine (Tyr), and the BCAA-to-Tyr ratio values were determined using mass spectroscopy. These values were then assessed for associations with fibrosis stage, anthropometric markers (age, sex, and body mass index), biochemical markers (alanine aminotransferase, aspartate aminotransferase, γ-glutamyl transpeptidase, albumin, platelet count, total cholesterol, triglycerides, low-density lipoprotein cholesterol, and glycosylated hemoglobin), and relevant disease-specific biomarkers (homeostasis model assessment of insulin resistance [HOMA-IR], serum iron, ferritin, leptin, adiponectin, high-sensitivity C-reactive protein, and hyaluronic acid). Results Serum albumin levels, plasma BCAA levels, and BCAA-to-Tyr ratio values were negatively associated with the fibrosis stage. In contrast, Tyr levels increased with increasing fibrotic staging. Tyr levels were also correlated with HOMA-IR results. Conclusion Plasma BCAA levels in patients with NASH decreased with increasing liver fibrosis, while Tyr levels increased with increasing fibrotic stage. These results suggest that amino acid imbalance and insulin resistance are intimately involved in a complex pathogenic mechanism for NASH. PMID:26082668

Recurrent viral liver disease (hepatitis B and C) after liver transplantation.

PubMed

Olivera-Martínez, Marco Antonio; Gallegos-Orozco, Juan F

2007-08-01

Hepatitis C represents more than 35% of liver transplant candidates worldwide. Meanwhile, hepatitis B continues to be an important cause of end-stage liver disease and hepatocellular carcinoma in Asia and Africa. Recurrent viral liver disease is a significant event after liver transplantation and continues to be one of the main causes of graft dysfunction and loss in the middle and long-term follow-up. Mechanisms of liver reinfection and disease recurrence vary between these two viruses and pre-emptive as well as the therapeutic approaches are different. Hepatitis B patients can be managed with immune globulin immediately after liver transplant and various agents such as nucleotide and nucleoside analogues can be associated. As a result, disease recurrence has been delayed or prevented in these patients. Individuals transplanted for hepatitis C are known to have universal reinfection and a high rate of disease recurrence has been reported in the literature. Strategies to treat hepatitis C recurrence are limited to the use of pegylated interferon and ribavirin when disease is demonstrated histologically and biochemically, although other strategies have been described with limited or no success. We herein review the mechanisms of disease recurrence and the current as well as the future therapeutic approaches to prevent and to treat these diseases.

Non-alcoholic fatty liver disease is associated with high prevalence of gastro-oesophageal reflux symptoms.

PubMed

Miele, Luca; Cammarota, Giovanni; Vero, Vittoria; Racco, Simona; Cefalo, Consuelo; Marrone, Giuseppe; Pompili, Maurizio; Rapaccini, Gianlodovico; Bianco, Alessandro; Landolfi, Raffaele; Gasbarrini, Antonio; Grieco, Antonio

2012-12-01

Gastro-oesophageal reflux symptoms are usually reported by patients with obesity and metabolic syndrome. Aim of this study was to assess the prevalence and clinical characteristics of gastro-oesophageal reflux symptoms in subjects with non-alcoholic fatty liver disease. Cross-sectional, case-control study of 185 consecutive patients with non-alcoholic fatty liver disease and an age- and sex-matched control group of 112 healthy volunteers. Participants were interviewed with the aid of a previously validated questionnaire to assess lifestyle and reflux symptoms in the 3 months preceding enrolment. Odds ratios were determined before and after adjustment for body mass index, increased waist circumference, physical activity, metabolic syndrome and proton pump inhibitors and/or antiacid medication. The prevalence of heartburn and/or regurgitation and of at least one of gastro-oesophageal reflux symptoms was significantly higher in the non-alcoholic fatty liver disease group. Non-alcoholic fatty liver disease subjects were associated to higher prevalence of heartburn (adjusted odds ratios: 2.17, 95% confidence intervals: 1.16-4.04), regurgitation (adjusted odds ratios: 2.61, 95% confidence intervals: 1.24-5.48) and belching (adjusted odds ratios: 2.01, 95% confidence intervals: 1.12-3.59) and had higher prevalence of at least one GER symptom (adjusted odds ratios: 3.34, 95% confidence intervals: 1.76-6.36). Non-alcoholic fatty liver disease is associated with a higher prevalence of gastro-oesophageal reflux symptoms. Copyright © 2012 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

Accuracy of the radioactive copper incorporation test in the diagnosis of Wilson disease.

PubMed

Członkowska, Anna; Rodo, Maria; Wierzchowska-Ciok, Agata; Smolinski, Lukasz; Litwin, Tomasz

2018-02-08

In Wilson disease (WD), copper accumulates in the liver and other tissues because of mutations in the ATP7B copper transporter gene. Early and effective anticopper treatment is crucial. However, routine diagnostic methods based on clinical findings, copper metabolism tests, liver biopsies and DNA analyses do not always provide a conclusive diagnosis. The aim was to evaluate radioactive copper incorporation as a diagnostic test. We included cases with a diagnosis of WD supported by radiocopper testing and later, when available, confirmed by DNA analysis. Incorporation of 64 Cu was measured at 2, 24 and 48 hours following intravenous injection. Diagnostic accuracy (area under the receiver operating characteristic curve [AUC]), sensitivity, specificity and predictive value were assessed for 24 hours/2 hours and 48 hours/2 hours 64 Cu ratios and compared with serum measurements of ceruloplasmin, copper, non-ceruloplasmin-bound copper and urinary 24-hours copper excretion. Patients having two pathogenic ATP7B mutations (homozygotes/compound heterozygotes) (n = 74) had significantly lower 24 hours/2 hours and 48 hours/2 hours 64 Cu ratios than heterozygote controls (n = 21) (mean 0.14 and 0.12 vs 0.49 and 0.63, respectively; both P < .001). Of note, 24 hours/2 hours and 48 hours/2 hours 64 Cu ratios had excellent diagnostic accuracy, with AUCs approaching 1, and only 24-hours urinary copper excretion displayed similar positive features. Other copper metabolism tests studied had lower accuracy, specificity and sensitivity. The radioactive copper test had excellent diagnostic accuracy and may be useful in the evaluation of new therapies aimed at restoring ATP7B function. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Association of Sleep Disorders with Nonalcoholic Fatty Liver Disease (NAFLD): A Population-based Study.

PubMed

Mir, Heshaam M; Stepanova, Maria; Afendy, Hena; Cable, Rebecca; Younossi, Zobair M

2013-09-01

Nonalcoholic fatty liver disease (NAFLD) is a major cause of chronic liver disease. In smaller studies, sleep apnea has been previously associated with NAFLD. The aim of this study was to assess the prevalence and independent associations of sleep disorders in patients with NAFLD using recent population-based data. Three cycles of the National Health and Nutrition Examination Survey (NHANES) conducted between 2005 and 2010 were used. The diagnosis of NAFLD was established as elevated liver enzymes in the absence of all other causes of chronic liver disease. Sleep disorders were diagnosed using sleep disorder questionnaires completed by NHANES participants, and included self-reported history of sleep apnea, insomnia, and restless leg syndrome. The prevalence of sleep disorders was compared between those with and without NAFLD. A total of 10,541 adult NHANES participants with complete demographic, clinical, and laboratory data were included. Of those, 15.0% had NAFLD and 7.2% reported having sleep disorders. Of those with sleep disorders, 64.7% reported history of sleep apnea, 16.0% had history of insomnia, and 4.0% had restless leg syndrome. Individuals with NAFLD were more likely to be male (53.8% vs. 45.7%, P < 0.0001), obese (50.1% vs. 33.4%, P < 0.0001) and had higher prevalence of sleep disorders (9.1% vs. 6.9%, P = 0.0118). In multivariate analysis, having any sleep disorder, sleep apnea and insomnia were all independently associated with NAFLD [OR (95% CI) = 1.40 (1.11-1.76), OR = 1.39 (0.98-1.97), and OR = 2.17 (1.19-3.95); respectively)]. This large population-based data suggests that NAFLD is associated with sleep disorders. Although the exact mechanism is unknown, this association is most likely through metabolic conditions associated with NAFLD.

Association of Sleep Disorders with Nonalcoholic Fatty Liver Disease (NAFLD): A Population-based Study

PubMed Central

Mir, Heshaam M.; Stepanova, Maria; Afendy, Hena; Cable, Rebecca; Younossi, Zobair M.

2013-01-01

Background Nonalcoholic fatty liver disease (NAFLD) is a major cause of chronic liver disease. In smaller studies, sleep apnea has been previously associated with NAFLD. The aim of this study was to assess the prevalence and independent associations of sleep disorders in patients with NAFLD using recent population-based data. Methods Three cycles of the National Health and Nutrition Examination Survey (NHANES) conducted between 2005 and 2010 were used. The diagnosis of NAFLD was established as elevated liver enzymes in the absence of all other causes of chronic liver disease. Sleep disorders were diagnosed using sleep disorder questionnaires completed by NHANES participants, and included self-reported history of sleep apnea, insomnia, and restless leg syndrome. The prevalence of sleep disorders was compared between those with and without NAFLD. Results A total of 10,541 adult NHANES participants with complete demographic, clinical, and laboratory data were included. Of those, 15.0% had NAFLD and 7.2% reported having sleep disorders. Of those with sleep disorders, 64.7% reported history of sleep apnea, 16.0% had history of insomnia, and 4.0% had restless leg syndrome. Individuals with NAFLD were more likely to be male (53.8% vs. 45.7%, P < 0.0001), obese (50.1% vs. 33.4%, P < 0.0001) and had higher prevalence of sleep disorders (9.1% vs. 6.9%, P = 0.0118). In multivariate analysis, having any sleep disorder, sleep apnea and insomnia were all independently associated with NAFLD [OR (95% CI) = 1.40 (1.11–1.76), OR = 1.39 (0.98–1.97), and OR = 2.17 (1.19–3.95); respectively)]. Conclusions This large population-based data suggests that NAFLD is associated with sleep disorders. Although the exact mechanism is unknown, this association is most likely through metabolic conditions associated with NAFLD. PMID:25755498

[Liver involvement in coeliac disease].

PubMed

Riestra, S; Fernández, E; Rodrigo, L

1999-12-01

Coeliac disease is a gluten-sensitive enteropathy in which, genetic, immunologic and environmental factors are implied. Several extradigestive diseases have been described in association with coeliac disease, which share most of the times an immunologic mechanism. The liver is damaged in coeliac disease, and it has been considered by some authors as an extraintestinal manifestation of the disease. In the present revision we discuss the different hepatic diseases related with the coeliac disease, as well as the best approach to diagnosis and therapy of choice. At diagnosis, it is very frequent to find an asymptomatic hipertransaminasemia, which frequently disappears after gluten suppression; the morphological substratum found in this alteration is a non-specific reactive hepatitis in the majority of cases. Coeliac disease is a demonstrated cause of cryptogenic hipertransaminasemia. In a small percentage of patient with coeliac disease an association has been found with other immunological liver diseases, such as primary biliary cirrhosis, primary sclerosing cholangitis and autoimmune hepatitis. Few studies exist that include a large number of patient, and the results on occasions are discordant. Nevertheless, the strongest association is with autoimmune hepatitis and with primary biliary cirrhosis. Several communications of isolated cases of rare hepatic diseases, which probably, only reflect a fortuitous association, have been cited in the literature.

Functional characterization of liver-associated lymphocytes in patients with liver metastasis.

PubMed

Winnock, M; Garcia-Barcina, M; Huet, S; Bernard, P; Saric, J; Bioulac-Sage, P; Gualde, N; Balabaud, C

1993-10-01

The liver-associated lymphocytes (LAL) population is mainly composed of cells with natural killer (NK) activity expressing the CD3+/-CD56+ phenotype. No evident difference has been found in the phenotypic data between patients with benign or malignant liver disease. In this study, the cytotoxic pattern of this population has been characterized from patients who underwent an operation for benign or metastatic liver disease. LAL were isolated by sinusoidal high-pressure lavage from partial hepatectomies. Phenotype was characterized by flow cytometry, and cytotoxicity was evaluated by standard 4-hour 51Cr release assays against NK and lymphokine-activated killer (LAK)-sensitive targets. In patients with benign liver disease, LAL showed spontaneous high levels of NK activity and LAK activity compared with peripheral blood lymphocytes. In patients with metastatic liver disease, no difference was observed in the levels of NK activity between LAL and peripheral blood, and the level of LAK activity was far lower than that expressed in patients with benign liver disease. These results show that the cytotoxic pattern of peripheral blood lymphocytes does not mirror that of LAL. In patients with benign liver disease, LAL are in a state of activation, whereas the decreased level of LAL cytotoxicity in patients with metastatic liver disease suggests that the cytotoxic activity of these cells could be inhibited by the presence of suppressive factors.

Liver Diseases

MedlinePlus

Your liver is the largest organ inside your body. It helps your body digest food, store energy, and remove poisons. There are many kinds of liver diseases: Diseases caused by viruses, such as hepatitis ...

Administration of high doses of copper to capuchin monkeys does not cause liver damage but induces transcriptional activation of hepatic proliferative responses.

PubMed

Araya, Magdalena; Núñez, Héctor; Pavez, Leonardo; Arredondo, Miguel; Méndez, Marco; Cisternas, Felipe; Pizarro, Fernando; Sierralta, Walter; Uauy, Ricardo; González, Mauricio

2012-02-01

Liver cells respond to copper loading upregulating protective mechanisms. However, to date, except for liver content, there are no good indicators that identify individuals with excess liver copper. We hypothesized that administering high doses of copper to young (5.5 mg Cu · kg⁻¹ . d⁻¹) and adult (7.5 mg Cu · kg⁻¹ . d⁻¹) capuchin monkeys would induce detectable liver damage. Study groups included adult monkeys (2 females, 2 males) 3-3.5 y old at enrollment treated with copper for 36 mo (ACu); age-matched controls (1 female, 3 males) that did not receive additional copper (AC); young monkeys (2 female, 2 males) treated from birth with copper for 36 mo (YCu); and young age-matched controls (2 female, 2 males) that did not receive additional copper (YC). We periodically assessed clinical, blood biochemical, and liver histological indicators and at 36 mo the hepatic mRNA abundance of MT2a, APP, DMT1, CTR1, HGF, TGFβ, and NFκΒ only in adult monkeys. After 36 mo, the liver copper concentration was 4-5 times greater in treated monkeys relative to controls. All monkeys remained healthy with normal routine serum biochemical indices and there was no evidence of liver tissue damage. Relative mRNA abundance of HGF, TGFβ and NFκB was significantly greater in ACu than in AC monkeys. In conclusion, capuchin monkeys exposed to copper at doses up to 50 times the current upper level enhanced expression of genes related to inflammation and injury without clinical, blood biochemical, or histological evidence of liver damage.

Inverse Association between Hepatitis B Virus Infection and Fatty Liver Disease: A Large-Scale Study in Populations Seeking for Check-Up

PubMed Central

Cheng, Yuan-Lung; Wang, Yuan-Jen; Kao, Wei-Yu; Chen, Ping-Hsien; Huo, Teh-Ia; Huang, Yi-Hsiang; Lan, Keng-Hsin; Su, Chien-Wei; Chan, Wan-Leong; Lin, Han-Chieh; Lee, Fa-Yauh; Wu, Jaw-Ching

2013-01-01

Background Although many studies have attempted to clarify the association between hepatitis B virus (HBV) infection and fatty liver disease, no prior studies have emphasized the relationship of HBV and fatty liver regarding different demographics of age and body mass index (BMI). Aim To investigate the correlation of HBV and fatty liver in the different demographics of age and BMI. Methods We enrolled consecutive subjects who had received health check-up services at the Taipei Veterans General Hospital from 2002 to 2009 and ultrasonography was used to diagnose fatty liver according to the practice guidelines of the American Gastroenterological Association. Results Among the 33,439 subjects enrolled in this study, fatty liver was diagnosed in 43.9% of the population and 38.9% of patients with chronic HBV infection. Multivariate analysis showed that BMI, age, waist circumference, systolic blood pressure, fasting glucose, cholesterol, alanine aminotransferase (ALT) levels, and platelet counts were positively associated, while hepatitis B surface antigen (HBsAg) positivity was inversely associated with fatty liver, especially for subjects with BMI>22.4 kg/m2 and age>50 years. On the contrary, HBV infection was positively correlated with the presence of elevated serum ALT levels in subjects with fatty liver disease regardless of their age and BMI. Conclusions Metabolic factors are important determinants for the prevalence of fatty liver. Patients with HBV infection were inversely associated with fatty liver disease than the general population, especially in older and obese patients. Furthermore, metabolic factors and HBV infection were associated with elevated serum ALT levels in fatty liver disease. PMID:23991037

Serum adipokine levels in chronic liver diseases: association of resistin levels with fibrosis severity.

PubMed

Tsochatzis, Emmanuel; Papatheodoridis, George V; Hadziyannis, Emilia; Georgiou, Anastasia; Kafiri, Georgia; Tiniakos, Dina G; Manesis, Emanuel K; Archimandritis, Athanasios J

2008-01-01

Leptin and adiponectin have been implicated in the pathogenesis and progression of non-alcoholic steatohepatitis (NASH) and chronic hepatitis C (CHC), but little is known about the role of resistin in chronic liver diseases. The objective of this study was to investigate serum levels of the above three adipokines in relation to the etiology of liver disease and to determine their associations with histological severity. We prospectively evaluated 146 patients (HBeAg-negative chronic hepatitis B (CHB): 52, CHC: 70, NASH: 24) who consecutively underwent liver biopsy. Detailed epidemiological, anthropometric and laboratory data were recorded. Histological lesions were evaluated blindly according to the Ishak and the Brunt classifications for CHB/CHC and NASH, respectively. Serum adipokine levels were similar between CHB and CHC patients, while CHB/CHC patients had significantly lower leptin levels compared with NASH patients (8.3+/-7.3 versus 17.6+/-16.6 ng/ml, p=0.012) and higher adiponectin (10.2+/-5.1 versus 7.5+/-4 microg/ml, p=0.018) and resistin levels (7.1+/-2.5 versus 5.7+/-2.8 ng/ml, p=0.016). In CHB/CHC, there was no significant association between steatosis or necroinflammation and levels of adipokines, while the presence of moderate/severe fibrosis (stages 4-6) was associated with higher leptin and adiponectin levels in male but not in female patients and with lower resistin levels irrespective of gender or other factors (adjusted odds ratio=0.788, p=0.035). Serum adipokine levels depend on the etiology of liver disease differing between chronic viral hepatitis and NASH, but not between CHB and CHC. In CHB/CHC, resistin levels are independently associated with fibrosis severity, whereas in the association of leptin and adiponectin levels with fibrosis, it seems to be a gender effect.

Non-alcoholic fatty liver disease is not associated with a lower health perception

PubMed Central

Mlynarsky, Liat; Schlesinger, Dalit; Lotan, Roni; Webb, Muriel; Halpern, Zamir; Santo, Erwin; Shibolet, Oren; Zelber-Sagi, Shira

2016-01-01

AIM: To examine the association between non-alcoholic fatty liver disease (NAFLD) and general health perception. METHODS: This cross sectional and prospective follow-up study was performed on a cohort of a sub-sample of the first Israeli national health and nutrition examination survey, with no secondary liver disease or history of alcohol abuse. On the first survey, in 2003-2004, 349 participants were included. In 2009-2010 participants from the baseline survey were invited to participate in a follow-up survey. On both baseline and follow-up surveys the data collected included: self-reported general health perception, physical activity habits, frequency of physician's visits, fatigue impact scale and abdominal ultrasound. Fatty liver was diagnosed by abdominal ultrasonography using standardized criteria and the ratio between the median brightness level of the liver and the right kidney was calculated to determine the Hepato-Renal Index. RESULTS: Out of 349 eligible participants in the first survey, 213 volunteers participated in the follow-up cohort and were included in the current analysis, NAFLD was diagnosed in 70/213 (32.9%). The prevalence of "very good" self-reported health perception was lower among participants diagnosed with NAFLD compared to those without NAFLD. However, adjustment for BMI attenuated the association (OR = 0.73, 95%CI: 0.36-1.50, P = 0.392). Similar results were observed for the hepato-renal index; it was inversely associated with "very good" health perception but adjustment for BMI attenuated the association. In a full model of multivariate analysis, that included all potential predictors for health perception, NAFLD was not associated with the self-reported general health perception (OR = 0.86, 95%CI: 0.40-1.86, P = 0.704). The odds for "very good" self-reported general health perception (compared to "else") increased among men (OR = 2.42, 95%CI: 1.26-4.66, P = 0.008) and those with higher performance of leisure time physical activity

Alpha-1-antitrypsin phenotypes in adult liver disease patients

PubMed Central

Alempijevic, Tamara; Milutinovic, Aleksandra Sokic; Kovacevic, Nada

2009-01-01

Alpha-1-antitrypsin (AAT) is an important serine protease inhibitor in humans. Hereditary alpha-1-antitrypsin deficiency (AATD) affects lungs and liver. Liver disease caused by AATD in paediatric patients has been previously well documented. However, the association of liver disease with alpha-1-antitrypsin gene polymorphisms in adults is less clear. Therefore, we aimed to study AAT polymorphisms in adults with liver disease. We performed a case-control study. AAT polymorphisms were investigated by isoelectric focusing in 61 patients with liver cirrhosis and 9 patients with hepatocellular carcinoma. The control group consisted of 218 healthy blood donors. A significant deviation of observed and expected frequency of AAT phenotypes from Hardy-Weinberg equilibrium (chi-square = 34.77, df 11, P = 0.000) in the patient group was caused by a higher than expected frequency of Pi ZZ homozygotes (f = 0.0143 and f = 0.0005, respectively, P = 0.000). In addition, Pi M homozygotes were more frequent in patients than in controls (63% and 46%, respectively, P = 0.025). Our study results show that Pi ZZ homozygosity in adults could be associated with severe liver disease. Presence of Pi M homozygosity could be associated with liver disease via some mechanism different from Z allele-induced liver damage through accumulation of AAT polymers. PMID:19961268

Interactions Between the Intestinal Microbiome and Liver Diseases

PubMed Central

Schnabl, Bernd; Brenner, David A.

2014-01-01

The human intestine harbors a diverse community of microbes that promote metabolism and digestion in their symbiotic relationship with the host. Disturbance of its homeostasis can result in disease. We review factors that disrupt intestinal homeostasis and contribute to non-alcoholic fatty liver disease (NAFLD), steatohepatitis (NASH), alcoholic liver disease, and cirrhosis. Liver disease has long been associated with qualitative and quantitative (overgrowth) dysbiotic changes in the intestinal microbiota. Extrinsic factors, such as the Western diet and alcohol, contribute to these changes. Dysbiosis results in intestinal inflammation, a breakdown of the intestinal barrier, and translocation of microbial products in animal models. However, the contribution of the intestinal microbiome to liver disease goes beyond simple translocation of bacterial products that promote hepatic injury and inflammation. Microbial metabolites produced in a dysbiotic intestinal environment and host factors are equally important in the pathogenesis of liver disease. We review how the combination of liver insult and disruptions in intestinal homeostasis contribute to liver disease. PMID:24440671

Periodontal disease and liver cirrhosis: A systematic review

PubMed Central

2015-01-01

Objectives: Studies suggest that periodontal disease, a source of subclinical and persistent infection, may be associated with various systemic conditions, including liver cirrhosis. The aim of this study was to examine the literature and determine the relationship between periodontal disease and liver cirrhosis and to identify opportunities and directions for future research in this area. Methods: A systematic review of English articles in the PubMed, EMBASE, and Scopus databases was conducted using search terms including ‘liver cirrhosis’, ‘end-stage liver disease’, ‘liver diseases’, ‘oral health’, ‘periodontal disease’, ‘mouth disease’, ‘gingivitis’, and ‘periodontitis’. Results: Thirteen studies published between 1981 and 2014 were found to include data on oral health and periodontal disease in cirrhotic patients. Studies indicated an increased incidence of periodontal disease in patients with liver cirrhosis, measured with several different periodontal indices. The reported prevalence of periodontal disease in cirrhosis patients ranged from 25.0% to 68.75% in four studies and apical periodontitis was found in 49%–79% of the patients. One study found that mortality was lower among patients who underwent dental treatment versus non-treated patients. Another study suggested an association between periodontal disease and the progression of liver cirrhosis, but data are sparse and conflicting as to whether periodontal disease is correlated to cirrhosis aetiology and severity. Conclusion: Despite the clinical reality of periodontal disease in liver cirrhosis patients, there are few published studies. Before clinical implications can be addressed, more data on the prevalence of and correlation between periodontal disease and liver cirrhosis aetiology, duration, and progression are needed. PMID:26770799

Gut-Liver Axis, Nutrition, and Non Alcoholic Fatty Liver Disease

PubMed Central

Kirpich, Irina A.; Marsano, Luis S.; McClain, Craig J.

2015-01-01

Nonalcoholic fatty liver disease (NAFLD) represents a spectrum of diseases involving hepatic fat accumulation, inflammation with the potential progression to fibrosis and cirrhosis over time. NAFLD is often associated with obesity, insulin resistance, and diabetes. The interactions between the liver and the gut, the so-called ”gut-liver axis”, play a critical role in NAFLD onset and progression. Compelling evidence links the gut microbiome, intestinal barrier integrity, and NAFLD. The dietary factors may alter the gut microbiota and intestinal barrier function, favoring the occurrence of metabolic endotoxemia and low grade inflammation, thereby contributing to the development of obesity and obesity-associated fatty liver disease. Therapeutic manipulations with prebiotics and probiotics to modulate the gut microbiota and maintain intestinal barrier integrity are potential agents for NAFLD management. This review summarizes the current knowledge regarding the complex interplay between the gut microbiota, intestinal barrier, and dietary factors in NAFLD pathogenesis. The concepts addressed in this review have important clinical implications, although more work needs to be done to understand how dietary factors affect the gut barrier and microbiota, and to comprehend how microbe-derived components may interfere with the host’s metabolism contributing to NAFLD development. PMID:26151226

Progression of Liver Disease

MedlinePlus

... Liver Function Tests Clinical Trials Liver Transplant FAQs Medical Terminology Diseases of the Liver Alagille Syndrome Alcohol-Related ... the Liver The Progression of Liver Disease FAQs Medical Terminology HOW YOU CAN HELP Sponsorship Ways to Give ...

Nutritional Needs and Support for Children with Chronic Liver Disease

PubMed Central

Yang, Christine H.; Yoo, Eric R.; Kerner, John A.

2017-01-01

Malnutrition has become a dangerously common problem in children with chronic liver disease, negatively impacting neurocognitive development and growth. Furthermore, many children with chronic liver disease will eventually require liver transplantation. Thus, this association between malnourishment and chronic liver disease in children becomes increasingly alarming as malnutrition is a predictor of poorer outcomes in liver transplantation and is often associated with increased morbidity and mortality. Malnutrition requires aggressive and appropriate management to correct nutritional deficiencies. A comprehensive review of the literature has found that infants with chronic liver disease (CLD) are particularly susceptible to malnutrition given their low reserves. Children with CLD would benefit from early intervention by a multi-disciplinary team, to try to achieve nutritional rehabilitation as well as to optimize outcomes for liver transplant. This review explains the multifactorial nature of malnutrition in children with chronic liver disease, defines the nutritional needs of these children, and discusses ways to optimize their nutritional. PMID:29035331

Gastrointestinal effects associated with soluble and insoluble copper in drinking water.

PubMed Central

Pizarro, F; Olivares, M; Araya, M; Gidi, V; Uauy, R

2001-01-01

The aim of this study was to determine whether total copper or soluble copper concentration is associated with gastrointestinal signs and symptoms. Forty-five healthy adult women (18-55 years of age), living in Santiago, Chile, ingested tap water with 5 mg/L of copper containing different ratios of soluble copper (copper sulfate) and insoluble copper (copper oxide) over a 9-week period. Three randomized sequences of the different copper ratios (0:5, 1:4, 2:3, 3:2, and 5:0 mg/L) were followed. Subjects recorded their water consumption and gastrointestinal symptoms daily on a special form. Mean water consumption was similar among groups. Serum copper levels, ceruloplasmin, and activities of liver enzymes were within normal limits. No differences were detected between the means of biochemical parameters at the beginning and at the end of the study. Twenty subjects presented gastrointestinal disturbances at least once during the study, 9 suffered diarrhea (with or without abdominal pain and vomiting), and the other 11 subjects reported abdominal pain, nausea, or vomiting. No differences were found in incidence of abdominal pain, nausea, vomiting, and diarrhea regardless of the ratio of copper sulfate to copper oxide. In conclusion, both copper sulfate (a soluble compound) and copper oxide (an insoluble compound) have comparable effects on the induction of gastrointestinal manifestations, implying that similar levels of ionic copper were present in the stomach. PMID:11673125

[Copper intake and blood levels as risk factors for atheromatous disease].

PubMed

Albala, C; Salazar, G; Vío, F; Araya, F; Feuerhacke, W; Olivares, S; Alvarez, G

1997-08-01

Copper is part of antioxidant enzymes and could have a cardiovascular protective effect. A higher cardiovascular risk has been associated with high as well as low plasma copper levels. To search for differences in copper intake and plasma levels between patients with coronary artery or cerebrovascular diseases and normal subjects. Zinc and copper intake, plasma levels and serum lipid levels were measured in 20 patients with cerebrovascular disease, 20 patients with an acute myocardial infarction and 40 subjects hospitalized for elective surgery, that served as controls. Copper and zinc intake was below recommended allowances in all subjects. Serum zinc and copper levels did not differ in the three study groups. In patients with myocardial infarction a weak correlation was found between serum copper and total cholesterol (r = 0.24; p < 0.05) and LDL cholesterol (r = 0.31; p < 0.05). No differences in copper levels were found in subjects with atherosclerosis and controls. The correlation between serum copper and cholesterol deserves further investigation.

Overexpression of copper transporter CTR1 in the brain barrier of North Ronaldsay sheep: implications for the study of neurodegenerative disease.

PubMed

Haywood, S; Vaillant, C

2014-01-01

Age-related regulatory failure of the brain barrier towards the influx of redox metals such as copper and iron may be associated with the pathological changes that characterize dementias such as Alzheimer's diseases (ADs) and amyotrophic lateral sclerosis (ALS). The integrity of the brain barrier to regulate copper in the brain is maintained by the complex interplay of membrane-located transporters, of which copper transporter 1 (CTR1) exerts a defining role. North Ronaldsay (NR) sheep are a primitive breed that have adapted to a copper-deficient environment by an enhanced uptake of the metal, resulting in copper overload in the liver and brain. This study reports that CTR1 is overexpressed in both the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCB) of adult NR sheep when compared with a domesticated breed. The excess copper is stored ultimately in astrocytes as non-injurious copper-metallothionein (MT). NR sheep have apparently retained an immature regulatory setting for CTR1 in the BBB, promoting facilitated copper uptake into the brain. This putative failure of maturation of CTR1 allows insight into the regulatory control of brain copper homeostasis, whereby the BBB and BCB act in concert to sequester excess copper and protect neurons from injury. The elevated copper content of the ageing human brain may derive from a dysregulation of CTR1 at the brain barrier, with a return to the default (immature) setting and implications for neurodegenerative disease. Copyright © 2013 Elsevier Ltd. All rights reserved.

Wilson Disease

MedlinePlus

Wilson disease is a rare inherited disorder that prevents your body from getting rid of extra copper. You need ... copper into bile, a digestive fluid. With Wilson disease, the copper builds up in your liver, and ...

Physicians’ practices for diagnosing liver fibrosis in chronic liver diseases: A nationwide, Canadian survey

PubMed Central

Sebastiani, Giada; Ghali, Peter; Wong, Philip; Klein, Marina B; Deschenes, Marc; Myers, Robert P

2014-01-01

OBJECTIVE: To determine practices among physicians in Canada for the assessment of liver fibrosis in patients with chronic liver diseases. METHODS: Hepatologists, gastroenterologists, infectious diseases specialists, members of the Canadian Gastroenterology Association and/or the Canadian HIV Trials Network who manage patients with liver diseases were invited to participate in a web-based, national survey. RESULTS: Of the 237 physicians invited, 104 (43.9%) completed the survey. Routine assessment of liver fibrosis was requested by the surveyed physicians mostly for chronic hepatitis C (76.5%), followed by autoimmune/cholestatic liver disease (59.6%) and chronic hepatitis B (52.9%). Liver biopsy was the main diagnostic tool for 46.2% of the respondents, Fibroscan (Echosens, France) for 39.4% and Fibrotest (LabCorp, USA) for 7.7%. Etiology-specific differences were observed: noninvasive methods were mostly used for hepatitis C (63% versus 37% liver biopsy) and hepatitis B (62.9% versus 37.1% liver biopsy). For 42.7% of respondents, the use of noninvasive methods reduced the need for liver biopsy by >50%. Physicians’ characteristics associated with higher use of noninvasive methods were older age and being based at a university hospital or in private practice versus community hospital. Physicians’ main concerns regarding noninvasive fibrosis assessment methods were access/availability (42.3%), lack of guidelines for clinical use (26.9%) and cost/lack of reimbursement (14.4%). CONCLUSIONS: Physicians who manage patients with chronic liver diseases in Canada require routine assessment of liver fibrosis stage. Although biopsy remains the primary diagnostic tool for almost one-half of respondents, noninvasive methods, particularly Fibroscan, have significantly reduced the need for liver biopsy in Canada. Limitations in access to and availability of the noninvasive methods represent a significant barrier. Finally, there is a need for clinical guidelines and a better

Nonalcoholic fatty liver disease in patients with type 2 diabetes mellitus and its association with cardiovascular disease.

PubMed

Vanjiappan, Sivabal; Hamide, Abdoul; Ananthakrishnan, Ramesh; Periyasamy, Senthilkumar Gandhipuram; Mehalingam, Vadivelan

2018-01-31

Non-alcoholic fatty liver disease (NAFLD) encompasses a wide spectrum of liver disease that ranges from hepatic steatosis to non-alcoholic steatohepatitis. Obesity and diabetes mellitus are the prime risk factors for NAFLD. The aim of this study was to find out the prevalence of NAFLD among patients with type 2 diabetes mellitus and to detect the association of NAFLD with cardiovascular disease in them. Prospective observational study. The study was conducted on 300 patients with type 2 diabetes mellitus attending the outpatient department of a tertiary care teaching hospital. All patients underwent hepatic ultrasonography to look for hepatic steatosis. Among the 300 patients, 124 were divided into NAFLD and non-NAFLD groups based on the ultrasound findings. These patients were subjected to electrocardiogram, 2D echocardiogram, carotid intima media thickness (CIMT) measurement and ankle brachial pressure index measurement along with measurement of markers of oxidative stress. Hepatic steatosis was present in 61% of diabetic patients in this study. Cardiovascular disease was not found to be significantly associated in diabetic patients with NAFLD. However, cardiovascular risk factors like CIMT, high sensitivity c-reactive protein (hs-CRP) and malondialdehyde (MDA) were elevated in these patients. hs-CRP and MDA levels were found to be significantly associated with the severity of NAFLD. There is a high prevalence of NAFLD in type 2 diabetic patients. No correlation was detected between the presence of NAFLD and cardiovascular disease in them; although there was an association between cardiovascular risk factors and NAFLD. Copyright © 2018. Published by Elsevier Ltd.

Vitamin D deficiency is associated with severity of liver disease in HIV/HCV coinfected patients.

PubMed

Guzmán-Fulgencio, María; García-Álvarez, Mónica; Berenguer, Juan; Jiménez-Sousa, M Ángeles; Cosín, Jaime; Pineda-Tenor, Daniel; Carrero, Ana; Aldámiz, Teresa; Alvarez, Emilio; López, Juan Carlos; Resino, Salvador

2014-02-01

To study the association of plasma 25-hydroxy vitamin D (25(OH)D) levels in HIV/HCV coinfected patients with severity of liver disease and virological response to hepatitis C virus (HCV) therapy with pegylated-interferon-alpha plus ribavirin (pegIFNα/RBV). A cross-sectional study in 174 HIV/HCV coinfected patients that underwent a liver biopsy previously to start HCV therapy and a retrospective study of 125 of them. Plasma 25(OH)D levels were quantified by enzyme immunoassay. Liver biopsies were evaluated by METAVIR score. A sustained virological response (SVR) was defined as an undetectable serum HCV viral load (<10 IU/mL) up through 24 weeks after the end of HCV treatment. The median of plasma 25(OH)D level was 48 nmol/L (p25th: 32.5; p75th: 56.1) and 27 (15.5%) had 25(OH)D deficiency (<25 nmol/L). The percentage of 25(OH)D deficiency was higher in patients with significant fibrosis (F ≥ 2) (92.6% vs. 57.1%; p = 0.010) and moderate necroinflammatory activity grade (A ≥ 2) (85.2% vs. 60%; p = 0.043). However, adjusted logistic regression analyses showed that 25(OH)D deficiency was only associated with severity of liver disease [F ≥ 2 (OR = 8.47 (95% of confidence interval (CI) = 1.88; 38.3); p = 0.005) and A ≥ 2 (OR = 3.25 (95%CI = 1.06; 10.1); p = 0.040)]. Moreover, any significant relationship was found between 25(OH)D deficiency and SVR after HCV therapy. Plasma 25(OH)D deficiency was associated with liver disease severity in HIV/HCV coinfected patients, but it was not associated with HCV treatment failure. Copyright © 2013 The British Infection Association. Published by Elsevier Ltd. All rights reserved.

Cirrhosis and autoimmune liver disease: Current understanding

PubMed Central

Liberal, Rodrigo; Grant, Charlotte R

2016-01-01

Primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC) and autoimmune hepatitis (AIH) constitute the classic autoimmune liver diseases (AILDs). While AIH target the hepatocytes, in PBC and PSC the targets of the autoimmune attack are the biliary epithelial cells. Persistent liver injury, associated with chronic AILD, leads to un-resolving inflammation, cell proliferation and the deposition of extracellular matrix proteins by hepatic stellate cells and portal myofibroblasts. Liver cirrhosis, and the resultant loss of normal liver function, inevitably ensues. Patients with cirrhosis have higher risks or morbidity and mortality, and that in the decompensated phase, complications of portal hypertension and/or liver dysfunction lead to rapid deterioration. Accurate diagnosis and monitoring of cirrhosis is, therefore of upmost importance. Liver biopsy is currently the gold standard technique, but highly promising non-invasive methodology is under development. Liver transplantation (LT) is an effective therapeutic option for the management of end-stage liver disease secondary to AIH, PBC and PSC. LT is indicated for AILD patients who have progressed to end-stage chronic liver disease or developed intractable symptoms or hepatic malignancy; in addition, LT may also be indicated for patients presenting with acute liver disease due to AIH who do not respond to steroids. PMID:27729952

Non-Alcoholic Fatty Liver Disease in HIV Infection.

PubMed

Macías, Juan; Pineda, Juan A; Real, Luis M

2017-01-01

Non-alcoholic fatty liver disease is one of the most frequent chronic hepatic conditions worldwide. The spectrum of non-alcoholic fatty liver disease goes from hepatic steatosis to steatohepatitis, cirrhosis, and hepatocellular carcinoma. Risk factors for non-alcoholic fatty liver disease are metabolic, mainly obesity and the accompanying consequences. Treatment and prevention of non-alcoholic fatty liver disease should target those metabolic abnormalities. The frequency of and the factors associated with hepatic steatosis in HIV infection seem to be similar to those reported in the general population, though direct comparisons are lacking. Hepatic steatosis in HIV infection may also be secondary to antiretroviral drugs or HCV-related factors in HCV-coinfected subjects. However, more recent data suggest that hepatic steatosis in HIV infection represents true non-alcoholic fatty liver disease. As such, management of non-alcoholic fatty liver disease in HIV infection should follow the same principles as in the general population.

Alcoholic liver disease: The gut microbiome and liver crosstalk

PubMed Central

Hartmann, Phillipp; Seebauer, Caroline T.; Schnabl, Bernd

2015-01-01

Alcoholic liver disease is a leading cause of morbidity and mortality worldwide. Alcoholic fatty liver disease can progress to steatohepatitis, alcoholic hepatitis, fibrosis, and cirrhosis. Patients with alcohol abuse show quantitative and qualitative changes in the composition of the intestinal microbiome. Furthermore, patients with alcoholic liver disease have increased intestinal permeability and elevated systemic levels of gut-derived microbial products. Maintaining eubiosis, stabilizing the mucosal gut barrier or preventing cellular responses to microbial products protect from experimental alcoholic liver disease. Therefore, intestinal dysbiosis and pathological bacterial translocation appear fundamental for the pathogenesis of alcoholic liver disease. This review highlights causes for intestinal dysbiosis and pathological bacterial translocation, their relationship and consequences for alcoholic liver disease. We also discuss how the liver affects the intestinal microbiota. PMID:25872593

Association between non-alcoholic fatty liver disease and peripheral artery disease in patients with type 2 diabetes.

PubMed

Zou, Yaowu; Li, Xinde; Wang, Can; Wang, Jing; Wang, Fei; Ma, Lidan; You, Wenjun; Li, Changgui

2017-10-01

Non-alcoholic fatty liver disease (NAFLD) is associated with the risk of coronary heart diseases; however, the relationship between NAFLD and peripheral artery disease (PAD) in patients with type 2 diabetes has not been investigated. To investigate the association between NAFLD and PAD in patients with type 2 diabetes. We carried out a cross-sectional study on 2646 type 2 diabetes patients ≥ 40 years. All patients provided fasting blood samples and underwent a liver ultrasonography and ankle-brachial index (ABI) test. PAD was defined as an ABI <0.9. Multiple logistic regression analyses were performed to investigate the odds ratio (OR) for PAD associated with NAFLD. Our analyses showed that patients with NAFLD had a significantly higher prevalence of PAD compared with those without NAFLD (12.8% vs 7.8%). NAFLD was associated with a 75% (OR 1.75, 95% confidence interval (CI) 1.35-2.28) increased risk of PAD after adjustment for demographic factors. Addition of various metabolic risk factors as confounders attenuated the association (OR 1.49, 95% CI 1.12-2.00). Further adjustment for C-reactive protein led the association to be marginally significant (OR 1.33, 95% CI 0.99-1.80). Analyses stratified by gender suggested the association was much stronger among women than among men. Type 2 diabetes patients with NAFLD had a higher prevalence of PAD, and this association was partly, but not entirely, explained by metabolic risk factors and inflammation. © 2017 Royal Australasian College of Physicians.

Liver Disease in Sri Lanka.

PubMed

Wijewantha, Hasitha S

2017-01-01

Liver disease in Sri Lanka is mainly due to alcoholic liver disease and nonalcoholic fatty liver disease. In contrast to other South Asian countries, the prevalence of hepatitis B and C is low in Sri Lanka and prevalence of hepatitis A is intermediate. The few reported cases of hepatitis E in Sri Lanka are mainly in people who have traveled to neighboring South Asian countries. Wilson's disease, autoimmune hepatitis, hemochromatosis, drug-induced liver disease, and primary biliary cirrhosis are recognized causes of liver disease in Sri Lanka. Pyogenic and amebic liver abscesses and dengue infection are the other causes of liver disease. Some of the commonly used plants as traditional herbal medicine in Sri Lanka have been shown to have deleterious effects on the liver in animal studies. Considering the high popularity of traditional herbal medicine in the country, it is likely that herbal medicine is an etiological factor for liver disease in Sri Lanka, but no published data are available. Address reprint requests to: Wijewantha HS. Liver Disease in Sri Lanka. Euroasian J Hepato-Gastroenterol 2017;7(1):78-81.

MARS variant associated with both recessive interstitial lung and liver disease and dominant Charcot-Marie-Tooth disease.

PubMed

Rips, Jonathan; Meyer-Schuman, Rebecca; Breuer, Oded; Tsabari, Reuven; Shaag, Avraham; Revel-Vilk, Shoshana; Reif, Shimon; Elpeleg, Orly; Antonellis, Anthony; Harel, Tamar

2018-04-12

Aminoacyl-tRNA synthetases (ARSs) are ubiquitously expressed enzymes responsible for charging tRNA with cognate amino acids during protein translation. Non-canonical functions are increasingly recognized, and include transcription and translation control and extracellular signaling. Monoallelic mutations in genes encoding several ARSs have been identified in axonal Charcot-Marie-Tooth (CMT2) disease, whereas biallelic mutations in ARS loci have been associated with multi-tissue syndromes, variably involving the central nervous system, lung, and liver. We report a male infant of non-consanguineous origin, presenting with successive onset of transfusion-dependent anemia, hypothyroidism, cholestasis, interstitial lung disease, and developmental delay. Whole-exome sequencing (WES) revealed compound heterozygosity for two variants (p.Tyr307Cys and p.Arg618Cys) in MARS, encoding methionyl-tRNA synthetase. Biallelic MARS mutations are associated with interstitial lung and liver disease (ILLD). Interestingly, the p.Arg618Cys variant, inherited from an unaffected father, was previously reported in a family with autosomal dominant late-onset CMT2. Yeast complementation assays confirmed pathogenicity of p.Arg618Cys, yet suggested retained function of p.Tyr307Cys. Our findings underscore the phenotypic variability associated with ARS mutations, and suggest genetic or environmental modifying factors in the onset of monoallelic MARS-associated CMT2. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Cannabis use is associated with reduced prevalence of progressive stages of alcoholic liver disease.

PubMed

Adejumo, Adeyinka C; Ajayi, Tokunbo O; Adegbala, Oluwole M; Adejumo, Kelechi L; Alliu, Samson; Akinjero, Akintunde M; Onyeakusi, Nnaemeka E; Ojelabi, Ogooluwa; Bukong, Terence N

2018-01-17

Abusive alcohol use has well-established health risks including causing liver disease (ALD) characterized by alcoholic steatosis (AS), steatohepatitis (AH), fibrosis, cirrhosis (AC) and hepatocellular carcinoma (HCC). Strikingly, a significant number of individuals who abuse alcohol also use Cannabis, which has seen increased legalization globally. While cannabis has demonstrated anti-inflammatory properties, its combined use with alcohol and the development of liver disease remain unclear. The aim of this study was to determine the effects of cannabis use on the incidence of liver disease in individuals who abuse alcohol. We analysed the 2014 Healthcare Cost and Utilization Project-Nationwide Inpatient Sample (NIS) discharge records of patients 18 years and older, who had a past or current history of abusive alcohol use (n = 319 514). Using the International Classification of Disease, Ninth Edition codes, we studied the four distinct phases of progressive ALD with respect to three cannabis exposure groups: non-cannabis users (90.39%), non-dependent cannabis users (8.26%) and dependent cannabis users (1.36%). We accounted for the complex survey sampling methodology and estimated the adjusted odds ratio (AOR) for developing AS, AH, AC and HCC with respect to cannabis use (SAS 9.4). Our study revealed that among alcohol users, individuals who additionally use cannabis (dependent and non-dependent cannabis use) showed significantly lower odds of developing AS, AH, AC and HCC (AOR: 0.55 [0.48-0.64], 0.57 [0.53-0.61], 0.45 [0.43-0.48] and 0.62 [0.51-0.76]). Furthermore, dependent users had significantly lower odds than non-dependent users for developing liver disease. Our findings suggest that cannabis use is associated with a reduced incidence of liver disease in alcoholics. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Effects of rutin supplementation on antioxidant status and iron, copper, and zinc contents in mouse liver and brain.

PubMed

Gao, Zhonghong; Xu, Huibi; Huang, Kaixun

2002-09-01

The effect of rutin on total antioxidant status as well as on trace elements such as iron, copper, and zinc in mouse liver and brain were studied. Mice were administrated with 0.75 g/kg or 2.25 g/kg P. O. of rutin for 30 d consecutively. Following the treatment, the activity of total antioxidant status, catalase, Cu,Zn-superoxide dismutase, Mn-superoxide dismutase, zinc, copper, and iron were measured in mouse liver and brain. The results showed that rutin significantly increased the antioxidant status and Mn-superoxide dismutase activities in mouse liver, but it had no effect on these variables in the brain. Treatment with a higher concentration of rutin significantly decreased catalase activity and iron, zinc, and copper contents in mouse liver; it also resulted in a slower weight gain for the first 20 d. These results indicate that rutin taken in proper amount can effectively improve antioxidant status, whereas at an increased dosage, it may cause trace element (such as iron, zinc, and copper) deficiencies and a decrease in the activities of related metal-containing enzymes.

Leptospira Exposure and Patients with Liver Diseases: A Case-Control Seroprevalence Study

PubMed Central

Alvarado-Esquivel, Cosme; Sánchez-Anguiano, Luis Francisco; Hernández-Tinoco, Jesús; Ramos-Nevárez, Agar; Margarita Cerrillo-Soto, Sandra; Alberto Guido-Arreola, Carlos

2016-01-01

The seroepidemiology of Leptospira infection in patients suffering from liver disease has been poorly studied. Information about risk factors associated with infection in liver disease patients may help in the optimal planning of preventive measures. We sought to determine the association of Leptospira IgG seroprevalence and patients with liver diseases, and to determine the characteristics of the patients with Leptospira exposure. We performed a case-control study of 75 patients suffering from liver diseases and 150 age- and gender-matched control subjects. Diagnoses of liver disease included liver cirrhosis, steatosis, chronic hepatitis, acute hepatitis, and amoebic liver abscess. Sera of participants were analyzed for the presence of anti- Leptospira IgG antibodies using a commercially available enzyme immunoassay. Anti-Leptospira IgG antibodies were found in 17 (22.7%) of 75 patients and in 15 (10.0%) of 150 control subjects (OR = 2.32; 95% CI: 1.09-4.94; P=0.03). This is the first age- and gender-matched case control study about Leptospira seroprevalence in patients with liver diseases. Results indicate that Leptospira infection is associated with chronic and acute liver diseases. Results warrants for additional studies on the role of Leptospira exposure in chronic liver disease. PMID:27493589

Molecular insights into the mechanisms of liver-associated diseases in early-lactating dairy cows: hypothetical role of endoplasmic reticulum stress.

PubMed

Ringseis, R; Gessner, D K; Eder, K

2015-08-01

The transition period represents the most critical period in the productive life of high-yielding dairy cows due to both metabolic and inflammatory stimuli, which challenge the liver and predispose dairy cows to develop liver-associated diseases such as fatty liver and ketosis. Despite the fact that all high-yielding dairy cows are affected by marked metabolic stress due to a severe negative energy balance (NEB) during early lactation, not all cows develop liver-associated diseases. Although the reason for this is largely unknown, this indicates that the capacity of the liver to cope with metabolic and inflammatory challenges varies between individual high-yielding dairy cows. Convincing evidence exists that endoplasmic reticulum (ER) stress plays a key role in the development of fatty liver, and it has been recently shown that ER stress occurs in the liver of high-yielding dairy cows. This indicates that ER stress may be involved in the development of liver-associated diseases in dairy cows. The present review shows that the liver of dairy cows during early lactation is exposed to several metabolic and inflammatory challenges, such as non-esterified fatty acids, tumour necrosis factor α, interleukin-1β, reactive oxygen species and lipopolysaccharides, which are known inducers of ER stress. Thus, ER stress may represent a molecular basis for fatty liver development and account for the frequent occurrence of fatty liver and ketosis in high-yielding dairy cows. Interindividual differences between dairy cows in the activation of hepatic stress response pathways, such as nuclear factor E2-related factor 2, which is activated during ER stress and reduces the sensitivity of tissues to oxidative and inflammatory damage, might provide an explanation at the molecular level for differences in the capacity to cope with pathological inflammatory challenges during early lactation and the susceptibility to develop liver-associated diseases between early-lactating dairy cows

Non-alcoholic fatty liver disease and type 2 diabetes mellitus: The liver disease of our age?

PubMed Central

Firneisz, Gábor

2014-01-01

Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease that might affect up to one-third of the adult population in industrialised countries. NAFLD incorporates histologically and clinically different non-alcoholic entities; fatty liver (NAFL, steatosis hepatis) and steatohepatitis (NASH-characterised by hepatocyte ballooning and lobular inflammation ± fibrosis) might progress to cirrhosis and rarely to hepatocellular cancer. NAFL increasingly affects children (paediatric prevalence is 4.2%-9.6%). Type 2 diabetes mellitus (T2DM), insulin resistance (IR), obesity, metabolic syndrome and NAFLD are particularly closely related. Increased hepatic lipid storage is an early abnormality in insulin resistant women with a history of gestational diabetes mellitus. The accumulation of triacylglycerols in hepatocytes is predominantly derived from the plasma nonesterified fatty acid pool supplied largely by the adipose tissue. A few NAFLD susceptibility gene variants are associated with progressive liver disease, IR, T2DM and a higher risk for hepatocellular carcinoma. Although not approved, pharmacological approaches might be considered in NASH patients. PMID:25083080

Non-alcoholic fatty liver disease and type 2 diabetes mellitus: the liver disease of our age?

PubMed

Firneisz, Gábor

2014-07-21

Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease that might affect up to one-third of the adult population in industrialised countries. NAFLD incorporates histologically and clinically different non-alcoholic entities; fatty liver (NAFL, steatosis hepatis) and steatohepatitis (NASH-characterised by hepatocyte ballooning and lobular inflammation ± fibrosis) might progress to cirrhosis and rarely to hepatocellular cancer. NAFL increasingly affects children (paediatric prevalence is 4.2%-9.6%). Type 2 diabetes mellitus (T2DM), insulin resistance (IR), obesity, metabolic syndrome and NAFLD are particularly closely related. Increased hepatic lipid storage is an early abnormality in insulin resistant women with a history of gestational diabetes mellitus. The accumulation of triacylglycerols in hepatocytes is predominantly derived from the plasma nonesterified fatty acid pool supplied largely by the adipose tissue. A few NAFLD susceptibility gene variants are associated with progressive liver disease, IR, T2DM and a higher risk for hepatocellular carcinoma. Although not approved, pharmacological approaches might be considered in NASH patients.

Diabetes mellitus and renal involvement in chronic viral liver disease.

PubMed

Iovanescu, V F; Streba, C T; Ionescu, M; Constantinescu, A F; Vere, C C; Rogoveanu, I; Moța, E

2015-01-01

Chronic viral liver disease is often associated with other conditions. Diabetes mellitus (DM) is frequently reported in this context and may play a role in the progression of the liver disease to hepatocellular carcinoma (HCC). Renal disease is also an important extrahepatic manifestation of hepatitis viral infection and its presence is associated with poor prognosis and management issues. Our study had multiple purposes: to determine the frequency of the association between chronic viral liver disease and diabetes mellitus, evaluate the potential of diabetes mellitus as a risk factor for HCC and assess an eventual renal involvement. We included in our study a number of 246 patients with chronic liver disease, from whom 136 were diagnosed with chronic viral hepatitis and 110 with viral liver cirrhosis. These patients were assessed by using a clinical examination and a series of tests, including serum transaminase levels, serum bilirubin, serum albumin, markers of cholestasis, fasting plasma glucose levels, serum creatinine, urea, albuminuria, Addis-Hamburger test, electrophoresis of urinary proteins, abdominal ultrasound and, in some cases, CT examination. We obtained the following results: diabetes mellitus is often associated with chronic liver disease of viral etiology, having been identified in 18.29% of the patients in our study. Age above 60 in patients with chronic hepatitis (p=0.013<0.05) and presence of hepatitis C virus were particularly correlated with the presence of diabetes mellitus. Renal disease was present in 13.4% of the patients with chronic liver disease and it was especially associated with liver cirrhosis and hepatitis C virus. The most common form of renal injury was glomerulonephritis. Acute kidney injury was diagnosed only in cirrhotic patients as hepatorenal syndrome, occurring in 7.27% of the subjects, while chronic kidney disease was identified only in two cases of chronic viral hepatitis. Four patients in our study were diagnosed with

Sarcopenia in patients with advanced liver disease.

PubMed

Ponziani, Francesca Romana; Gasbarrini, Antonio

2017-04-28

Sarcopenia is the loss of muscle mass and function, affecting up to 70% of patients with advanced liver disease. Liver cirrhosis is characterized by an altered glucose metabolism, lipid oxidation, ketogenesis and protein catabolism, leading to the loss of adipose and muscle tissue. The gastrointestinal dysfunction of cirrhotic patients results in inadequate nutrients intake and is responsible for muscle weakness thus limiting physical exercise and perpetuating the reduction of muscle mass. Recently, alterations of hormonal pathways involved in muscle growth, increased intestinal permeability and changes in the gut microbiota composition have been reported in cirrhotic patients. Interestingly, a role of intestinal bacteria in maintaining muscle health has been hypothesized through the translocation of bacteria and bacterial products into the bloodstream triggering the production of muscle wasting-associated cytokines. Sarcopenia is associated with severe outcomes in patients with liver cirrhosis, mostly due to the incidence of disease complications. Furthermore, sarcopenia may represent an important prognostic factor for patients with hepatocellular carcinoma and for those undergoing liver transplantation and can be considered a useful additional tool in the global assessment of patients with advanced liver disease. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

The Effects of Physical Exercise on Fatty Liver Disease

PubMed Central

van der Windt, Dirk J.; Sud, Vikas; Zhang, Hongji; Tsung, Allan; Huang, Hai

2018-01-01

The increasing prevalence of obesity has made nonalcoholic fatty liver disease (NAFLD) the most common chronic liver disease. As a consequence, NAFLD and especially its inflammatory form nonalcoholic steatohepatitis (NASH) are the fastest increasing etiology of end-stage liver disease and hepatocellular carcinoma. Physical inactivity is related to the severity of fatty liver disease irrespective of body weight, supporting the hypothesis that increasing physical activity through exercise can improve fatty liver disease. This review summarizes the evidence for the effects of physical exercise on NAFLD and NASH. Several clinical trials have shown that both aerobic and resistance exercise reduce the hepatic fat content. From clinical and basic scientific studies, it is evident that exercise affects fatty liver disease through various pathways. Improved peripheral insulin resistance reduces the excess delivery of free fatty acids and glucose for free fatty acid synthesis to the liver. In the liver, exercise increases fatty acid oxidation, decreases fatty acid synthesis, and prevents mitochondrial and hepatocellular damage through a reduction of the release of damage-associated molecular patterns. In conclusion, physical exercise is a proven therapeutic strategy to improve fatty liver disease. PMID:29212576

[Liver diseases in the elderly].

PubMed

Bruguera, Miguel

2014-11-01

Liver diseases in the elderly have aroused less interest than diseases of other organs, since the liver plays a limited role in aging. There are no specific liver diseases of old age, but age-related anatomical and functional modifications of the liver cause changes in the frequency and clinical behavior of some liver diseases compared with those in younger patients. This review discusses the most important features of liver function in the healthy elderly population, as well as the features of the most prevalent liver diseases in this age group, especially the diagnostic approach to the most common liver problems in the elderly: asymptomatic elevation of serum transaminases and jaundice. Copyright © 2014 Elsevier España, S.L.U. and AEEH y AEG. All rights reserved.

Hepatic steatosis and non-alcoholic fatty liver disease are not associated with decline in renal function in people with Type 2 diabetes.

PubMed

Jenks, S J; Conway, B R; Hor, T J; Williamson, R M; McLachlan, S; Robertson, C; Morling, J R; Strachan, M W J; Price, J F

2014-09-01

We aimed to determine whether the presence of hepatic steatosis and/or non-alcoholic fatty liver disease was associated with decline in renal function or onset of microalbuminuria in a cohort of people with Type 2 diabetes, including those managed in both primary and secondary care. Nine hundred and thirty-three patients from the Edinburgh Type 2 Diabetes Study, a cohort of Scottish men and women aged 60-74 years with Type 2 diabetes, underwent assessment for hepatic steatosis by liver ultrasonography 1 year after recruitment. Non-alcoholic fatty liver disease was defined as the presence of steatosis following exclusion of secondary causes of liver disease. Patients were followed for 4 years and decline in renal function was assessed by the change in estimated glomerular filtration rate over time. Of the 933 subjects, 530 had hepatic steatosis and, of those with hepatic steatosis, 388 had non-alcoholic fatty liver disease. Neither hepatic steatosis nor non-alcoholic fatty liver disease were significantly associated with rate of decline in renal function, with the mean rate of decline in estimated glomerular filtration rate being -1.55 ml min(-1) 1.73 m(-2) per year for participants with hepatic steatosis compared with -1.84 ml min(-1) 1.73 m(-2) for those without steatosis (P = 0.19). Similar results were obtained when the analysis was restricted to participants with and without non-alcoholic fatty liver disease (-1.44 vs. -1.64 ml min(-1) 1.73 m(-2) per year, respectively; P = 0.44). Additionally, neither hepatic steatosis nor non-alcoholic fatty liver disease were associated with the onset or regression of albuminuria during follow-up (all P ≥ 0.05). The presence of hepatic steatosis/non-alcoholic fatty liver disease was not associated with decline in renal function during a 4-year follow-up in our cohort of older people with Type 2 diabetes. © 2014 The Authors. Diabetic Medicine © 2014 Diabetes UK.

Intestinal fungi contribute to development of alcoholic liver disease.

PubMed

Yang, An-Ming; Inamine, Tatsuo; Hochrath, Katrin; Chen, Peng; Wang, Lirui; Llorente, Cristina; Bluemel, Sena; Hartmann, Phillipp; Xu, Jun; Koyama, Yukinori; Kisseleva, Tatiana; Torralba, Manolito G; Moncera, Kelvin; Beeri, Karen; Chen, Chien-Sheng; Freese, Kim; Hellerbrand, Claus; Lee, Serene Ml; Hoffman, Hal M; Mehal, Wajahat Z; Garcia-Tsao, Guadalupe; Mutlu, Ece A; Keshavarzian, Ali; Brown, Gordon D; Ho, Samuel B; Bataller, Ramon; Stärkel, Peter; Fouts, Derrick E; Schnabl, Bernd

2017-06-30

Chronic liver disease with cirrhosis is the 12th leading cause of death in the United States, and alcoholic liver disease accounts for approximately half of all cirrhosis deaths. Chronic alcohol consumption is associated with intestinal bacterial dysbiosis, yet we understand little about the contribution of intestinal fungi, or mycobiota, to alcoholic liver disease. Here we have demonstrated that chronic alcohol administration increases mycobiota populations and translocation of fungal β-glucan into systemic circulation in mice. Treating mice with antifungal agents reduced intestinal fungal overgrowth, decreased β-glucan translocation, and ameliorated ethanol-induced liver disease. Using bone marrow chimeric mice, we found that β-glucan induces liver inflammation via the C-type lectin-like receptor CLEC7A on Kupffer cells and possibly other bone marrow-derived cells. Subsequent increases in IL-1β expression and secretion contributed to hepatocyte damage and promoted development of ethanol-induced liver disease. We observed that alcohol-dependent patients displayed reduced intestinal fungal diversity and Candida overgrowth. Compared with healthy individuals and patients with non-alcohol-related cirrhosis, alcoholic cirrhosis patients had increased systemic exposure and immune response to mycobiota. Moreover, the levels of extraintestinal exposure and immune response correlated with mortality. Thus, chronic alcohol consumption is associated with an altered mycobiota and translocation of fungal products. Manipulating the intestinal mycobiome might be an effective strategy for attenuating alcohol-related liver disease.

Extracorporeal Bioartificial Liver for Treating Acute Liver Diseases

PubMed Central

Kumar, Ashok; Tripathi, Anuj; Jain, Shivali

2011-01-01

Abstract: Liver is a vital organ of the human body performing myriad of essential functions. Liver-related ailments are often life-threatening and dramatically deteriorate the quality of life of patients. Management of acute liver diseases requires adequate support of various hepatic functions. Thus far, liver transplantation has been proven as the only effective solution for acute liver diseases. However, broader application of liver transplantation is limited by demand for lifelong immunosuppression, shortage of organ donors, relative high morbidity, and high cost. Therefore, research has been focused on attempting to develop alternative support systems to treat liver diseases. Earlier attempts have been made to use nonbiological therapies based on the use of conventional detoxification procedures such as filtration and dialysis. However, the absence of liver cells in such techniques reduced the overall survival rate of the patients and led to inadequate essential liver-specific functions. As a result, there has been growing interest in the development of biological therapy-based extracorporeal liver support systems as a bridge to liver transplantation or to support the ailing liver. A bioartificial liver support is an extracorporeal device through which plasma is circulated over living and functionally active hepatocytes packed in a bioreactor with the aim to aid the diseased liver until it regenerates or until a suitable graft for transplantation is available. This review article gives a brief overview of efficacy of various liver support systems that are currently available. Also, the development of advanced liver support systems, which has been analyzed for improving the important system component such as cell source and other culture and circulation conditions for the maintenance of the liver-specific functions, have been described. PMID:22416599

Nutritional Considerations for Dogs and Cats with Liver Disease.

PubMed

Norton, Rebecca D; Lenox, Catherine E; Manino, Paul; Vulgamott, James C

2016-01-01

The goals of nutritional management of liver disease in the dog and cat are directed at treating the clinical manifestations as opposed to treating the underlying cause. Specifically, the clinician strives to avoid overwhelming the remaining metabolic capacities of the damaged liver while providing sufficient nutrients for regeneration. A brief overview of liver diseases and associated clinical signs encountered in the dog and cat and a review of specific nutrients are discussed as well as amounts and sources of nutrients recommended to meet nutritional goals in the diseased liver.

Review article: Probiotics in gastrointestinal and liver diseases.

PubMed

Jonkers, D; Stockbrügger, R

2007-12-01

Probiotics, defined as live micro-organisms with beneficial effects for the host, are widely applied in gastrointestinal and liver diseases. To review the available evidence of clinical trials on probiotics in gastrointestinal and liver diseases, with a major focus on irritable bowel syndrome, inflammatory bowel disease, pancreatitis and chronic liver diseases. Evidence for the therapeutic or preventive application of particular probiotic strains is available for antibiotic-associated diarrhoea, rota-virus-associated diarrhoea and pouchitis. Results are encouraging for irritable bowel syndrome, ulcerative colitis and for reducing side effects by Helicobacter pylori eradication therapies, but are less clear for Crohn's disease, lactose intolerance and constipation. In general, for most of these patient groups, more placebo-controlled methodologically well-designed studies that pay attention to both clinical outcome and mechanistic aspects are required. The application in liver disease and pancreatitis is promising, but more human trials have to be awaited. Possible mechanisms of probiotics include modulation of the intestinal microbiota and the immune system, but different bacterial may have different effects. Further insight into disease entities and the functioning of probiotic strains is required to be able to select disease-specific strains, which have to be tested in well-designed placebo-controlled studies.

Mechanistic insights of rapid liver regeneration after associating liver partition and portal vein ligation for stage hepatectomy.

PubMed

Moris, Demetrios; Vernadakis, Spyridon; Papalampros, Alexandros; Vailas, Michail; Dimitrokallis, Nikolaos; Petrou, Athanasios; Dimitroulis, Dimitrios

2016-09-07

To highlight the potential mechanisms of regeneration in the Associating Liver Partition and Portal vein ligation for Stage hepatectomy models (clinical and experimental) that could unlock the myth behind the extraordinary capability of the liver for regeneration, which would help in designing new therapeutic options for the regenerative drive in difficult setup, such as chronic liver diseases. Associating Liver Partition and Portal vein ligation for Stage hepatectomy has been recently advocated to induce rapid future liver remnant hypertrophy that significantly shortens the time for the second stage hepatectomy. The introduction of Associating Liver Partition and Portal vein ligation for Stage hepatectomy in the surgical armamentarium of therapeutic tools for liver surgeons represented a real breakthrough in the history of liver surgery. A comprehensive literature review of Associating Liver Partition and Portal vein ligation for Stage hepatectomy and its utility in liver regeneration is performed. Liver regeneration after Associating Liver Partition and Portal vein ligation for Stage hepatectomy is a combination of portal flow changes and parenchymal transection that generate a systematic response inducing hepatocyte proliferation and remodeling. Associating Liver Partition and Portal vein ligation for Stage hepatectomy represents a real breakthrough in the history of liver surgery because it offers rapid liver regeneration potential that facilitate resection of liver tumors that were previously though unresectable. The jury is still out though in terms of safety, efficacy and oncological outcomes. As far as Associating Liver Partition and Portal vein ligation for Stage hepatectomy -induced liver regeneration is concerned, further research on the field should focus on the role of non-parenchymal cells in liver regeneration as well as on the effect of Associating Liver Partition and Portal vein ligation for Stage hepatectomy in liver regeneration in the setup of

Preclinical Models for Investigation of Herbal Medicines in Liver Diseases: Update and Perspective

PubMed Central

Tan, Hor-Yue; San-Marina, Serban; Wang, Ning; Hong, Ming; Li, Sha; Li, Lei; Cheung, Fan; Wen, Xiao-Yan; Feng, Yibin

2016-01-01

Liver disease results from a dynamic pathological process associated with cellular and genetic alterations, which may progress stepwise to liver dysfunction. Commonly, liver disease begins with hepatocyte injury, followed by persistent episodes of cellular regeneration, inflammation, and hepatocyte death that may ultimately lead to nonreversible liver failure. For centuries, herbal remedies have been used for a variety of liver diseases and recent studies have identified the active compounds that may interact with liver disease-associated targets. Further study on the herbal remedies may lead to the formulation of next generation medicines with hepatoprotective, antifibrotic, and anticancer properties. Still, the pharmacological actions of vast majority of herbal remedies remain unknown; thus, extensive preclinical studies are important. In this review, we summarize progress made over the last five years of the most commonly used preclinical models of liver diseases that are used to screen for curative herbal medicines for nonalcoholic fatty liver disease, liver fibrosis/cirrhosis, and liver. We also summarize the proposed mechanisms associated with the observed liver-protective, antifibrotic, and anticancer actions of several promising herbal medicines and discuss the challenges faced in this research field. PMID:26941826

SLC31 (CTR) Family of Copper Transporters in Health and Disease

PubMed Central

Kim, Heejeong; Wu, Xiaobin; Lee, Jaekwon

2012-01-01

Copper is a vital mineral for many organisms, yet it is highly toxic as demonstrated by serious health concerns associated with its deficiency or excess accumulation. The SLC31 (CTR) family of copper transporters is a major gateway of copper acquisition in eukaryotes, ranging from yeast to humans. Characterization of the function, modes of action, and regulation of CTR and other molecular factors that functionally cooperate with CTR for copper transport, compartmentalization, incorporation into cuproproteins, and detoxification has revealed that organisms have evolved fascinating mechanisms for tight control of copper metabolism. This research progress further indicates the significance of copper in health and disease and opens avenues for therapeutic control of copper bioavailability and its metabolic pathways. PMID:23506889

The Impact of Liver Cell Injury on Health-Related Quality of Life in Patients with Chronic Liver Disease

PubMed Central

Alt, Yvonne; Grimm, Anna; Schlegel, Liesa; Grambihler, Annette; Kittner, Jens M.; Wiltink, Jörg; Galle, Peter R.; Wörns, Marcus A.; Schattenberg, Jörn M.

2016-01-01

Background Patients with chronic liver disease often suffer from unspecific symptoms and report severe impairment in the quality of life. The underlying mechanisms are multifactorial and include disease-specific but also liver related causes. The current analysis evaluated the association of hepatocellular apoptosis in non-viral chronic liver disease and health-related quality of life (HRQL). Furthermore we examined factors, which influence patient's physical and mental well-being. Methods A total of 150 patients with non-infectious chronic liver disease were included between January 2014 and June 2015. The German version of the Chronic Liver Disease Questionnaire (CLDQ-D), a liver disease specific instrument to assess HRQL, was employed. Hepatocellular apoptosis was determined by measuring Cytokeratin 18 (CK18, M30 Apoptosense ELISA). Results Female gender (5.24 vs. 5.54, p = 0.04), diabetes mellitus type II (4.75 vs. 5.46, p<0.001) and daily drug intake (5.24 vs. 6.01, p = 0.003) were associated with a significant impairment in HRQL. HRQL was not significantly different between the examined liver diseases. Levels of CK18 were the highest in patients with NASH compared to all other disease entities (p<0.001). Interestingly, CK18 exhibited significant correlations with obesity (p<0.001) and hyperlipidemia (p<0.001). In patients with cirrhosis levels of CK18 correlated with the MELD score (r = 0.18, p = 0.03) and were significantly higher compared to patients without existing cirrhosis (265.5 U/l vs. 186.9U/l, p = 0.047). Additionally, CK18 showed a significant correlation with the presence and the degree of hepatic fibrosis (p = 0.003) and inflammation (p<0.001) in liver histology. Finally, there was a small negative association between CLDQ and CK18 (r = -0.16, p = 0.048). Conclusion Different parameters are influencing HRQL and CK18 levels in chronic non-viral liver disease and the amount of hepatocellular apoptosis correlates with the impairment in HRQL in

Cadmium Exposure and Liver Disease among US Adults

PubMed Central

Hyder, Omar; Chung, Michael; Cosgrove, David; Herman, Joseph M.; Li, Zhiping; Firoozmand, Amin; Gurakar, Ahmet; Koteish, Ayman; Pawlik, Timothy M.

2014-01-01

Background Effects of chronic cadmium exposure on liver disease and liver-related mortality are unknown. We evaluated the association of creatinine-corrected urinary cadmium levels with hepatic necroinflammation, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), liver-related mortality, and liver cancer mortality in the US general population. Methods We analyzed the relationship of individuals in the top quartile for urinary cadmium measured in 12,732 adults who participated in the Third National Health and Nutrition Examination Survey in 1988–1994 (NHANES III), and hepatic necroinflammation, NAFLD, and NASH. Associations between cadmium, liver-related mortality, and liver cancer mortality were evaluated in the NHANES III mortality follow-up study. Results The cutoffs for highest quartile of urinary cadmium per gram of urinary creatinine were 0.65 and 0.83 μg/g for men and women, respectively (P<0.001). After multivariate adjustment for other factors including smoking, the odds ratios [95 % confidence intervals (CI)] for hepatic necroinflammation, NAFLD, and NASH associated with being in the top quartile of cadmium levels by gender, were 2.21 (95 % CI, 1.64–3.00), 1.30 (95 % CI, 1.01–1.68) and 1.95 (95 % CI, 1.11–3.41) for men and 1.26 (95 % CI, 1.01–1.57), 1.11 (95 % CI, 0.88–1.41) and 1.34 (95 % CI, 0.72–2.50) for women, respectively. The hazard ratios for liver-related mortality and liver cancer mortality for both genders were 3.42 (95 % CI, 1.12–10.47) and 1.25 (95 % CI, 0.37–4.27). Conclusions Environmental cadmium exposure was associated with hepatic necroinflammation, NAFLD, and NASH in men, and hepatic necroinflammation in women. Individuals in the top quartile of creatinine-corrected urinary cadmium had over a threefold increased risk of liver disease mortality but not in liver cancer related mortality. PMID:23636881

Increased risk of non-alcoholic fatty liver disease after diagnosis of celiac disease.

PubMed

Reilly, Norelle R; Lebwohl, Benjamin; Hultcrantz, Rolf; Green, Peter H R; Ludvigsson, Jonas F

2015-06-01

Non-alcoholic fatty liver disease is a common cause of chronic liver disease. Celiac disease alters intestinal permeability and treatment with a gluten-free diet often causes weight gain, but so far there are few reports of non-alcoholic fatty liver disease in patients with celiac disease. Population-based cohort study. We compared the risk of non-alcoholic fatty liver disease diagnosed from 1997 to 2009 in individuals with celiac disease (n = 26,816) to matched reference individuals (n = 130,051). Patients with any liver disease prior to celiac disease were excluded, as were individuals with a lifetime diagnosis of alcohol-related disorder to minimize misclassification of non-alcoholic fatty liver disease. Cox regression estimated hazard ratios for non-alcoholic fatty liver disease were determined. During 246,559 person-years of follow-up, 53 individuals with celiac disease had a diagnosis of non-alcoholic fatty liver disease (21/100,000 person-years). In comparison, we identified 85 reference individuals diagnosed with non-alcoholic fatty liver disease during 1,488,413 person-years (6/100,000 person-years). This corresponded to a hazard ratio of 2.8 (95% CI 2.0-3.8), with the highest risk estimates seen in children (HR = 4.6; 95% CI 2.3-9.1). The risk increase in the first year after celiac disease diagnosis was 13.3 (95% CI 3.5-50.3) but remained significantly elevated even beyond 15 years after the diagnosis of celiac disease (HR = 2.5; 95% CI 1.0-5.9). Individuals with celiac disease are at increased risk of non-alcoholic fatty liver disease compared to the general population. Excess risks were highest in the first year after celiac disease diagnosis, but persisted through 15 years after diagnosis with celiac disease. Copyright © 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Rheumatic Disease Autoantibodies in Autoimmune Liver Diseases.

PubMed

Utiyama, Shirley R R; Zenatti, Katiane B; Nóbrega, Heloisa A J; Soares, Juliana Z C; Skare, Thelma L; Matsubara, Caroline; Muzzilo, Dominique A; Nisihara, Renato M

2016-08-01

Autoimmune liver diseases (ALDs) are known to be associated with systemic autoimmune rheumatic diseases (SARDs) and their autoantibodies. We aimed to study the prevalence of SARDs and related autoantibodies, as well as their prognostic implications in a group of patients with ALDs. This was a cross-sectional study. Sixty patients with ALDs (38.3% with autoimmune hepatitis; 11.7% with primary biliary cirrhosis; 25% with primary sclerosing cholangitis and 25% with overlap syndrome) were studied for the presence of SARDs and their autoantibodies. There was autoimmune rheumatic disease in 20% of the studied sample. Systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) were the commonest (11.6% and 5%, respectively). Antinuclear antibodies (ANAs) were present in 35% of the patients, followed by anti-Ro (20.0%); anti-nucleosome (18.3%); rheumatoid factor (10%) anti-CCP (8.3%); anti-RNP (8.3%); anti-ds-DNA (6.6%); anti-La (3.3%); anti-Sm (3.3%), anti-ribosomal P (3.3%). Anti-Ro (p = 0.0004), anti-La (p = 0.03), anti-RNP (p = 0.04) and anti-Sm (p = 0.03) were commonly found in patients with SARD, but not anti-DNA, anti-nucleosome and anti-ribosomal P. No differences were found in liver function tests regarding to the presence of autoantibodies. There was a high prevalence of SARD and their autoantibodies in ALD patients. Anti-Ro, anti-La, anti-RNP and anti-Sm positivity points to an association with systemic autoimmune rheumatic diseases. The presence of autoantibodies was not related to liver function tests.

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

Serum adipokines might predict liver histology findings in non-alcoholic fatty liver disease.

PubMed

Jamali, Raika; Razavizade, Mohsen; Arj, Abbas; Aarabi, Mohammad Hossein

2016-06-07

To assess significance of serum adipokines to determine the histological severity of non-alcoholic fatty liver disease. Patients with persistent elevation in serum aminotransferase levels and well-defined characteristics of fatty liver at ultrasound were enrolled. Individuals with a history of alcohol consumption, hepatotoxic medication, viral hepatitis or known liver disease were excluded. Liver biopsy was performed to confirm non-alcoholic liver disease (NAFLD). The degrees of liver steatosis, lobular inflammation and fibrosis were determined based on the non-alcoholic fatty liver activity score (NAS) by a single expert pathologist. Patients with a NAS of five or higher were considered to have steatohepatitis. Those with a NAS of two or lower were defined as simple fatty liver. Binary logistic regression was used to determine the independent association of adipokines with histological findings. Receiver operating characteristic (ROC) analysis was employed to determine cut-off values of serum adipokines to discriminate the grades of liver steatosis, lobular inflammation and fibrosis. Fifty-four participants aged 37.02 ± 9.82 were enrolled in the study. Higher serum levels of visfatin, IL-8, TNF-α levels were associated independently with steatosis grade of more than 33% [β = 1.08 (95%CI: 1.03-1.14), 1.04 (95%CI: 1.008-1.07), 1.04 (95%CI: 1.004-1.08), P < 0.05]. Elevated serum IL-6 and IL-8 levels were associated independently with advanced lobular inflammation [β = 1.4 (95%CI: 1.09-1.8), 1.07 (95%CI: 1.003-1.15), P < 0.05]. Similarly, higher TNF-α, resistin, and hepcidin levels were associated independently with advanced fibrosis stage [β = 1.06 (95%CI: 1.002-1.12), 19.86 (95%CI: 2.79-141.19), 560.72 (95%CI: 5.98-5255.33), P < 0.05]. Serum IL-8 and TNF-α values were associated independently with the NAS score, considering a NAS score of 5 as the reference value [β = 1.05 (95%CI: 1.01-1.1), 1.13 (95%CI: 1.04-1.22), P < 0.05]. Certain adipokines may

Metabonomics Research Progress on Liver Diseases.

PubMed

Yu, Mengqian; Zhu, Ying; Cong, Qingwei; Wu, Chunyan

2017-01-01

Metabolomics as the new omics technique develops after genomics, transcriptomics, and proteomics and has rapid development at present. Liver diseases are worldwide public health problems. In China, chronic hepatitis B and its secondary diseases are the common liver diseases. They can be diagnosed by the combination of history, virology, liver function, and medical imaging. However, some patients seldom have relevant physical examination, so the diagnosis may be delayed. Many other liver diseases, such as drug-induced liver injury (DILI), alcoholic liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD), and autoimmune liver diseases, still do not have definite diagnostic markers; the diagnosis consists of history, medical imaging, and the relevant score. As a result, the clinical work becomes very complex. So it has broad prospects to explore the specific and sensitive biomarkers of liver diseases with metabolomics. In this paper, there are several summaries which are related to the current research progress and application of metabolomics on biomarkers of liver diseases.

Risk of seizures and status epilepticus in older patients with liver disease.

PubMed

Alkhachroum, Ayham M; Rubinos, Clio; Kummer, Benjamin R; Parikh, Neal S; Chen, Monica; Chatterjee, Abhinaba; Reynolds, Alexandra; Merkler, Alexander E; Claassen, Jan; Kamel, Hooman

2018-06-06

Seizures can be provoked by systemic diseases associated with metabolic derangements, but the association between liver disease and seizures remains unclear. We performed a retrospective cohort study using inpatient and outpatient claims between 2008 and 2015 from a nationally representative 5% sample of Medicare beneficiaries. The primary exposure variable was cirrhosis, and the secondary exposure was mild, noncirrhotic liver disease. The primary outcome was seizure, and the secondary outcome was status epilepticus. Diagnoses were ascertained using validated International Classification of Diseases, Ninth Edition, Clinical Modification codes. Survival statistics were used to calculate incidence rates, and Cox proportional hazards models were used to examine the association between exposures and outcomes while adjusting for seizure risk factors. Among 1 782 402 beneficiaries, we identified 10 393 (0.6%) beneficiaries with cirrhosis and 19 557 (1.1%) with mild, noncirrhotic liver disease. Individuals with liver disease were older and had more seizure risk factors than those without liver disease. Over 4.6 ± 2.2 years of follow-up, 49 843 (2.8%) individuals were diagnosed with seizures and 25 patients (0.001%) were diagnosed with status epilepticus. Cirrhosis was not associated with seizures (hazard ratio [HR] = 1.1, 95% confidence interval [CI] = 1.0-1.3), but there was an association with status epilepticus (HR = 1.9, 95% CI = 1.3-2.8). Mild liver disease was not associated with a higher risk of seizures (HR = 0.8, 95% CI = 0.6-0.9) or status epilepticus (HR = 1.1, 95% CI = 0.7-1.5). In a large, population-based cohort, we found an association between cirrhosis and status epilepticus, but no overall association between liver disease and seizures. Wiley Periodicals, Inc. © 2018 International League Against Epilepsy.

Management of alcohol misuse in patients with liver diseases

PubMed Central

Peng, Jennifer L; Patel, Milan Prakash; McGee, Breann; Liang, Tiebing; Chandler, Kristina; Tayarachakul, Sucharat; O’Connor, Sean; Liangpunsakul, Suthat

2017-01-01

Excessive alcohol use not only causes alcoholic liver disease (ALD) but also increases the risk of liver-related mortality in patients who already have other chronic liver diseases. Screening for alcohol misuse or alcohol use disorder (AUD) among patients with underlying liver disease is essential. This clinical review covers what is known about ALD, the impact of alcohol in patients with underlying liver diseases, current management of alcohol misuse and AUD, and the management of alcohol misuse and AUD specifically in patients with liver diseases. Several treatment options for alcohol misuse and AUD exist such as psychosocial intervention and behavioral and pharmacological therapies. The strategies used in the treatment of alcohol misuse and AUD are still applicable in those who consume alcohol and have underlying liver disease. However, certain medications still need to be carefully used due to potentially worsening already compromised liver function. Screening of ongoing alcohol use in subjects with liver disease is important, and prompt intervention is needed to prevent the associated morbidity and mortality from the detrimental effects of continued alcohol use on underlying liver disease. Considering alcoholism is a complex disease, probably a multidisciplinary approach combining psychotherapy and comprehensive medical care will be the most effective. Future research could focus on identifying additional treatment options for addressing the psychotherapy component since the self-determination and will to quit drinking alcohol can play such a crucial role in promoting abstinence. PMID:27940551

Limited yield of diagnoses of intrahepatic infectious causes of canine granulomatous hepatitis from archival liver tissue.

PubMed

Hutchins, Rae G; Breitschwerdt, Edward B; Cullen, John M; Bissett, Sally A; Gookin, Jody L

2012-09-01

Canine granulomatous hepatitis is an uncommon morphologic diagnosis that has been associated with a variety of diseases, including a number of systemic infectious etiologies. Formalin-fixed, paraffin-embedded (FFPE) tissues are typically the only source of liver tissue remaining for additional testing for the presence of infectious disease within granulomas. It is unclear if the more common infectious culprits of granulomatous hepatitis can be identified from such specimens. The aim of the current study was to retrospectively investigate archival FFPE liver tissue from dogs with granulomatous hepatitis for the presence of infectious agents. Semiquantitative analysis of copper accumulation in liver specimens was also performed. Medical records were examined for recorded evidence of systemic infectious disease diagnosis. Formalin-fixed, paraffin-embedded liver was prospectively evaluated for infectious agents via differential staining techniques (n = 13), eubacterial fluorescent in situ hybridization (n = 11), and Bartonella polymerase chain reaction assays (n = 15). An infectious cause of granulomatous hepatitis was not identified within liver tissue from any dog using these diagnostic methodologies. Six out of 25 (24%) dogs were diagnosed with concurrent systemic or localized bacterial infections at the time of presentation. Nine out of 17 (53%) dogs had excessive hepatic copper accumulation when evaluated by a semiquantitative histologic grading scheme or quantitative copper analysis. As definitive infectious causes of granulomatous hepatitis were not identified within archival liver biopsy samples, it was concluded that investigation of infectious etiologies within FFPE liver specimens using these diagnostic approaches may be of low yield.

Pyogenic Liver Abscess as Endemic Disease, Taiwan

PubMed Central

Tsai, Feng-Chiao; Huang, Yu-Tsung; Chang, Luan-Yin

2008-01-01

Pyogenic liver abscess has become a health problem in Taiwanese society. However, the extent of this problem has remained unclear because of the lack of a population-based study. We therefore performed a nationwide analysis of pyogenic liver abscess in Taiwan from 1996 through 2004. We analyzed 29,703 cases from the Taiwan National Health Insurance database and 506 cases from National Taiwan University Hospital. Our analysis showed that the annual incidence of pyogenic liver abscess increased steadily from 11.15/100,000 population in 1996 to 17.59/100,000 in 2004. Diabetes, malignancy, renal disease, and pneumonia were associated with a higher risk for the disease. By contrast, death due to pyogenic liver abscess decreased over time, although population-based abscess-related death increased slightly. Renal disease, malignancy, pneumonia, and heart disease correlated with higher death rates; Klebsiella pneumoniae infection and therapeutic procedures were related to lower death rates. Diabetes did not significantly change death rates for the 506 patients from the hospital. PMID:18826824

Cu,Zn-superoxide dismutase is lower and copper chaperone CCS is higher in erythrocytes of copper-deficient rats and mice.

PubMed

West, Elizabeth C; Prohaska, Joseph R

2004-09-01

Discovery of a sensitive blood biochemical marker of copper status would be valuable for assessing marginal copper intakes. Rodent models were used to investigate whether erythrocyte concentrations of copper,zinc-superoxide dismutase (SOD), and the copper metallochaperone for SOD (CCS) were sensitive to dietary copper changes. Several models of copper deficiency were studied in postweanling male Holtzman rats, male Swiss Webster mice offspring, and both rat and mouse dams. Treatment resulted in variable but significantly altered copper status as evaluated by the presence of anemia, and lower liver copper and higher liver iron concentrations in copper-deficient compared with copper-adequate animals. Associated with this copper deficiency were consistent reductions in immunoreactive SOD and robust enhancements in CCS. In most cases, the ratio of CCS:SOD was several-fold higher in red blood cell extracts from copper-deficient compared with copper-adequate rodents. Determination of red cell CCS:SOD may be useful for assessing copper status of humans.

To screen or not to screen? Celiac antibodies in liver diseases

PubMed Central

Narciso-Schiavon, Janaína Luz; Schiavon, Leonardo Lucca

2017-01-01

Celiac disease (CD) is a systemic immune-mediated disorder triggered by dietary gluten in genetically predisposed individuals. The typical symptoms are anemia, diarrhea, fatigue, weight loss, and abdominal pain. CD has been reported in patients with primary sclerosing cholangitis, primary biliary cholangitis, autoimmune hepatitis, aminotransferase elevations, nonalcoholic fatty liver disease, hepatitis B, hepatitis C, portal hypertension and liver cirrhosis. We evaluate recommendations for active screening for CD in patients with liver diseases, and the effect of a gluten-free diet in these different settings. Active screening for CD is recommended in patients with liver diseases, particularly in those with autoimmune disorders, steatosis in the absence of metabolic syndrome, noncirrhotic intrahepatic portal hypertension, cryptogenic cirrhosis, and in the context of liver transplantation. In hepatitis C, diagnosis of CD can be important as a relative contraindication to interferon use. Gluten-free diet ameliorates the symptoms associated with CD; however, the associated liver disease may improve, remain the same, or progress. PMID:28223722

Epigenetic Events in Liver Cancer Resulting From Alcoholic Liver Disease

PubMed Central

French, Samuel W.

2013-01-01

Epigenetic mechanisms play an extensive role in the development of liver cancer (i.e., hepatocellular carcinoma [HCC]) associated with alcoholic liver disease (ALD) as well as in liver disease associated with other conditions. For example, epigenetic mechanisms, such as changes in the methylation and/or acetylation pattern of certain DNA regions or of the histone proteins around which the DNA is wrapped, contribute to the reversion of normal liver cells into progenitor and stem cells that can develop into HCC. Chronic exposure to beverage alcohol (i.e., ethanol) can induce all of these epigenetic changes. Thus, ethanol metabolism results in the formation of compounds that can cause changes in DNA methylation and interfere with other components of the normal processes regulating DNA methylation. Alcohol exposure also can alter histone acetylation/deacetylation and methylation patterns through a variety of mechanisms and signaling pathways. Alcohol also acts indirectly on another molecule called toll-like receptor 4 (TLR4) that is a key component in a crucial regulatory pathway in the cells and whose dysregulation is involved in the development of HCC. Finally, alcohol use regulates an epigenetic mechanism involving small molecules called miRNAs that control transcriptional events and the expression of genes important to ALD. PMID:24313165

Screening for Wilson disease in acute liver failure: a comparison of currently available diagnostic tests.

PubMed

Korman, Jessica D; Volenberg, Irene; Balko, Jody; Webster, Joe; Schiodt, Frank V; Squires, Robert H; Fontana, Robert J; Lee, William M; Schilsky, Michael L

2008-10-01

Acute liver failure (ALF) due to Wilson disease (WD) is invariably fatal without emergency liver transplantation. Therefore, rapid diagnosis of WD should aid prompt transplant listing. To identify the best method for diagnosis of ALF due to WD (ALF-WD), data and serum were collected from 140 ALF patients (16 with WD), 29 with other chronic liver diseases and 17 with treated chronic WD. Ceruloplasmin (Cp) was measured by both oxidase activity and nephelometry and serum copper levels by atomic absorption spectroscopy. In patients with ALF, a serum Cp <20 mg/dL by the oxidase method provided a diagnostic sensitivity of 21% and specificity of 84% while, by nephelometry, a sensitivity of 56% and specificity of 63%. Serum copper levels exceeded 200 microg/dL in all ALF-WD patients measured (13/16), but were also elevated in non-WD ALF. An alkaline phosphatase (AP) to total bilirubin (TB) ratio <4 yielded a sensitivity of 94%, specificity of 96%, and a likelihood ratio of 23 for diagnosing fulminant WD. In addition, an AST:ALT ratio >2.2 yielded a sensitivity of 94%, a specificity of 86%, and a likelihood ratio of 7 for diagnosing fulminant WD. Combining the tests provided a diagnostic sensitivity and specificity of 100%. Conventional WD testing utilizing serum ceruloplasmin and/or serum copper levels are less sensitive and specific in identifying patients with ALF-WD than other available tests. More readily available laboratory tests including alkaline phosphatase, bilirubin and serum aminotransferases by contrast provides the most rapid and accurate method for diagnosis of ALF due to WD.

Coeliac disease in autoimmune liver disease: a cross-sectional study and a systematic review.

PubMed

Mirzaagha, Foroozandeh; Azali, Sepideh Hagh; Islami, Farhad; Zamani, Farhad; Khalilipour, Elias; Khatibian, Morteza; Malekzadeh, Reza

2010-09-01

Several studies have reported an association between coeliac disease and autoimmune liver disease, but there is little information on the prevalence of coeliac disease in certain autoimmune liver diseases, particularly from non-European, non-American countries. To investigate prevalence of coeliac disease in autoimmune liver disease in Iran and to summarize previous literature. We investigated prevalence of coeliac disease among 100 autoimmune liver disease patients and compared it with the prevalence in healthy individuals. We also performed an extensive search of the English literature in PubMed Database. We found substantially elevated prevalence of coeliac disease in patients with overlap syndrome (10-15%) compared to the general population (0.1-1%). To a lesser extent, the prevalence was high in patients with autoimmune hepatitis (2-4%). In our systematic review, prevalence of coeliac disease in autoimmune hepatitis in the majority of studies was 4% or more; several studies also reported such prevalence in primary biliary cirrhosis. Since coeliac disease is common among patients with autoimmune liver disease, screening autoimmune liver disease patients for coeliac disease is indicated. Although the magnitude of benefit from a gluten-free diet in reversing autoimmune liver disease in patients with coeliac disease is controversial, it may reduce the risk of further complications of coeliac disease. Copyright (c) 2010 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

Association of hepatic insulin resistance indexes to nonalcoholic fatty liver disease and related biomarkers.

PubMed

Sesti, G; Fiorentino, T V; Hribal, M L; Sciacqua, A; Perticone, F

2013-12-01

Nonalcoholic fatty liver disease (NAFLD) is linked with insulin resistance, however, if it is differentially associated with surrogate hepatic insulin resistance indexes is still undefined. We examined the relationship between these indexes, NAFLD and its related biomarkers (alanine aminotransferase [ALT], aspartate aminotransferase [AST], gamma-glutamyltransferase [GGT], alkaline phosphatase [ALK], high-sensitive C reactive protein [hsCRP], insulin-like growth factor-1 [IGF-1]). 473 Caucasians subjects underwent liver ultrasonography and oral glucose tolerance tests; homeostasis model assessment (HOMA), glucose(0-30) (area under the curve [AUC]) × insulin(0-30) (AUC) and liver insulin resistance (liver IR) indexes were computed. Liver IR index correlated more strongly than HOMA with GGT, ALK, hsCRP, ALT and AST and more strongly than glucose(0-30) (AUC) × insulin(0-30) (AUC) index with ALT, AST, GGT, ALK, hsCRP, and IGF-1. The ability of these indexes to identify NAFLD was evaluated by the area under the ROC curve; the ROC AUC for liver IR index was higher (0.733) than the ones for HOMA (0.685) and glucose(0-30) (AUC) × insulin(0-30) (AUC) (0.663) indexes. In a logistic regression model subjects in the highest quartile of the three indexes had a higher risk of having NAFLD than those in the lowest quartile (9.85-, 5.12- or 3.99-fold higher for liver IR index, HOMA, glucose(0-30) (AUC) × insulin(0-30) (AUC) index respectively). we documented significant cross-sectional associations of NAFLD and liver biomarkers with three validated indexes of hepatic insulin resistance, with liver IR index showing the stronger correlation. © 2013 Elsevier B.V. All rights reserved.

Steatorrhea in patients with liver disease

PubMed Central

Williams, C. N.; Sidorov, J. J.

1971-01-01

Intestinal function was studied in 26 patients with seven types of acute and chronic liver disease, documented by liver biopsy. Steatorrhea, defined by a stool fat higher than 6 g. per day, was present in 18 of 23 consecutive patients studied, an incidence of 78.3%. Two patients with infectious hepatitis associated with steatorrhea studied previously were added and the 20 cases were analyzed. The malabsorption found was confined to fat and fat-soluble vitamins; stool excretion varied from 6.1 to 22 g. per day in the seven groups studied. No histological abnormality was seen on jejunal biopsy, serum vitamin B12, D-xylose and Schilling tests were normal, and no radiological findings associated with malabsorption were detected in the small bowel. It is concluded that steatorrhea is a common finding in a wide variety of acute and chronic liver diseases and cannot be attributed to a primary defect of the small bowel. PMID:5150072

Association of serum retinoic acid with hepatic steatosis and liver injury in nonalcoholic fatty liver disease.

PubMed

Liu, Yan; Chen, Hongen; Wang, Jingjing; Zhou, Wenjing; Sun, Ruifang; Xia, Min

2015-07-01

Retinoic acid (RA), an active metabolite of vitamin A (retinol), has been implicated in the regulation of lipid metabolism and hepatic steatosis in animal models. However, the relation between RA and liver histology in patients with nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) is unknown. This study aimed at examining the association of RA with NAFLD and NASH in Chinese subjects. Serum RA concentration was determined by ELISA in 41 control subjects, 45 patients with NAFLD, and 38 patients with NASH. The associations of RA with adiposity, serum glucose, lipid profiles, and markers of liver damage were studied. Moreover, both mRNA and protein levels of retinoic X receptor α (RXRα) in the liver were analyzed in subjects with different degrees of hepatic steatosis. Serum RA concentrations in patients with NAFLD (1.42 ± 0.47 ng/mL) and NASH (1.14 ± 0.26 ng/mL) were significantly lower than those in control subjects (2.70 ± 0.52 ng/mL) (P < 0.01). Furthermore, serum RA concentrations were significantly different between subjects with normal glucose tolerance and those with type 2 diabetes in control [2.87 ± 0.52 (n = 28) vs. 2.32 ± 0.44 ng/mL (n = 13)], NAFLD [1.61 ± 0.37 (n = 29) vs. 1.28 ± 0.41 ng/mL (n = 16)], and NASH [1.35 ± 0.34 (n = 24) vs. 1.07 ± 0.29 ng/mL (n = 14)] groups. In human liver tissue, RXRα mRNA expression was inversely correlated with the exacerbation of hepatic steatosis. Both serum RA concentrations and RXRα mRNA levels were inversely correlated with intrahepatic triglyceride content (r = -0.700, P < 0.001, and r = -0.611, P = 0.002, respectively). Compared with grade 0 severity, the concentration of RXRα protein was lower in more severe grades in patients with NAFLD. These results show that circulating RA concentrations were lower in subjects with NAFLD and were associated with hepatic lipid metabolism and insulin resistance. This trial was registered at clinicaltrials.gov as NCT01940263. © 2015

Nonalcoholic fatty liver disease and hepatic cirrhosis: Comparison with viral hepatitis-associated steatosis.

PubMed

Haga, Yuki; Kanda, Tatsuo; Sasaki, Reina; Nakamura, Masato; Nakamoto, Shingo; Yokosuka, Osamu

2015-12-14

Nonalcoholic fatty liver disease (NAFLD) including nonalcoholic steatohepatitis (NASH) is globally increasing and has become a world-wide health problem. Chronic infection with hepatitis B virus or hepatitis C virus (HCV) is associated with hepatic steatosis. Viral hepatitis-associated hepatic steatosis is often caused by metabolic syndrome including obesity, type 2 diabetes mellitus and/or dyslipidemia. It has been reported that HCV genotype 3 exerts direct metabolic effects that lead to hepatic steatosis. In this review, the differences between NAFLD/NASH and viral hepatitis-associated steatosis are discussed.

A Different Perspective for Management of Diabetes Mellitus: Controlling Viral Liver Diseases.

PubMed

Zhao, Yingying; Xing, Huichun

2017-01-01

Knowing how to prevent and treat diabetes mellitus (DM) earlier is essential to improving outcomes. Through participating in synthesis and catabolism of glycogen, the liver helps to regulate glucose homeostasis. Viral related liver diseases are associated with glycometabolism disorders, which means effective management of viral liver diseases may be a therapeutic strategy for DM. The present article reviews the correlation between DM and liver diseases to give an update of the management of DM rooted by viral liver diseases.

Gut Microbiota and Complications of Liver Disease

PubMed Central

Acharya, Chathur; Bajaj, Jasmohan

2016-01-01

Synopsis The epidemic of chronic liver disease and how to combat its complications has been a challenging aspect for many years. New laboratory techniques have made analysis of the human intestinal microbiome easier and also more detailed. With insight into dysbiosis and how this dysbiosis impacts liver disease, scientists have new targets in the intestine and liver. Dysbiosis is associated with endotoxemia and propagates liver injury in NASH and alcoholic cirrhosis. The composition of the microbiota changes with the development of cirrhosis and decompensation Apart from microbes, the role that bile acids play in this arena are also being discovered and newer treatments like FXR receptor agonists are coming into the picture. Altered gut microbiota plays an important role in cirrhosis and its modulation to prevent disease progression changes, and concomitantly bile acid physiology must be regulated or augmented to help prevent cirrhosis and its complications. PMID:28164848

The global burden of liver disease: the major impact of China.

PubMed

Wang, Fu-Sheng; Fan, Jian-Gao; Zhang, Zheng; Gao, Bin; Wang, Hong-Yang

2014-12-01

Liver disease is a major cause of illness and death worldwide. In China alone, liver diseases, primarily viral hepatitis (predominantly hepatitis B virus [HBV]), nonalcoholic fatty liver disease, and alcoholic liver disease, affect approximately 300 million people. The establishment of the Expanded Program on Immunization in 1992 has resulted in a substantial decline in the number of newly HBV-infected patients; however, the number of patients with alcoholic and nonalcoholic fatty liver diseases is rising at an alarming rate. Liver cancer, one of the most deadly cancers, is the second-most common cancer in China. Approximately 383,000 people die from liver cancer every year in China, which accounts for 51% of the deaths from liver cancer worldwide. Over the past 10 years, China has made some significant efforts to shed its "leader in liver diseases" title by investing large amounts of money in funding research, vaccines, and drug development for liver diseases and by recruiting many Western-trained hepatologists and scientists. Over the last two decades, hepatologists and scientists in China have made significant improvements in liver disease prevention, diagnosis, management, and therapy. They have been very active in liver disease research, as shown by the dramatic increase in the number of publications in Hepatology. Nevertheless, many challenges remain that must be tackled collaboratively. In this review, we discuss the epidemiology and characteristics of liver diseases and liver-related research in China. © 2014 by the American Association for the Study of Liver Diseases.

The effect of copper deficiency on fetal growth and liver anti-oxidant capacity in the Cohen diabetic rat model

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

Ergaz, Zivanit, E-mail: zivanit@hadassah.org.il; Shoshani-Dror, Dana; Guillemin, Claire

High sucrose low copper diet induces fetal growth restriction in the three strains of the Cohen diabetic rats: an inbred copper deficient resistant (CDr), an inbred copper deficient sensitive (CDs that become diabetic on high sucrose low copper diet -HSD) and an outbred Wistar derived Sabra rats. Although those growth restricted fetuses also exhibit increased oxidative stress, antioxidants do not restore normal growth. In the present study, we evaluated the role of copper deficiency in the HSD induced fetal growth restriction by adding to the drinking water of the rats 1 ppm or 2 ppm of copper throughout their pregnancy.more » Fetal and placental growth in correlation with fetal liver copper content and anti-oxidant capacity was evaluated on day 21 of pregnancy. HSD compared to regular chow induced fetal growth restriction, which was most significant in the Cohen diabetic sensitive animals. The addition of 1 ppm and 2 ppm copper to the drinking water normalized fetal growth in a dose dependent manner and reduced the degree of hyperglycemia in the diabetes sensitive rats. The CDs fetuses responded to the HSD with lower catalase like activity, and less reduced superoxide dismutase levels compared to the Sabra strain, and had high malondialdehyde levels even when fed regular chow. Immunostaining was higher for nitrotyrosine among the CDr and higher for hypoxia factor 1 α among the CDs. We conclude that in our model of dietary-induced fetal growth restriction, copper deficiency plays a major etiologic role in the decrease of fetal growth and anti-oxidant capacity. -- Highlights: ► High sucrose low copper diet restricted fetal growth in the Cohen diabetic rat model ► Maternal copper blood levels directly correlated with fetal liver copper content ► Copper supplementation decreased embryonic resorption in the inbred strains ► Copper supplementation reduced hyperglycemia in the sucrose sensitive inbred strain ► Copper supplementation alleviated growth

Aortic sudanophilia an zinc-copper ratios in the liver of vervet monkeys fed different types of dietary fibre.

PubMed

Klevay, L M; Mendelsohn, D; Vanderwatt, J J; Davidson, L M; Kritchevsky, D

1981-04-18

Vervet monkeys (Cercopithecus aethiops pygerethrus) were fed a semipurified diet containing 40% sucrose, 25% casein, 14% hydrogenated coconut oil and 15% fibre for 6 months. Alfalfa, cellulose, or wheat straw was the source of the fibre. All the diets led to aortic sudanophilia, but the group fed wheat straw had the highest copper level in the liver and the least sudanophilia. The order to severity of the sudanophilia, the ratio of zinc to copper in the fibers, and the ratio of zinc to copper in the liver were: alfalfa-fed group greater than cellulose-fed group greater than wheat straw-fed group. These findings, which may have resulted from the relatively large amount of copper in the wheat straw, are consonant with observations on lipid metabolism in other species.

[Wilsons disease].

PubMed

Mareček, Z; Brůha, R

2013-07-01

Wilsons disease is an autosomal recessive genetic disorder in which copper accumulates in tissues, especially in the liver and the brain. The genetic defect affects the P type ATPase gene (ATP7B). More than 500 mutations causing Wilsons disease have been described. The most common mutation in Central Europe concerns H1069Q. The symptoms of Wilsons disease include hepatic or neurological conditions. The hepatic condition is manifested as steatosis, acute or chronic hepatitis or cirrhosis. The neurological conditions are most often manifested after the age of 20 as motor disorders (tremor, speech and writing disorders), which may result in severe extrapyramidal syndrome with rigidity, dysarthria and muscle contractions. The dia-gnosis is based on clinical and laboratory assessments (neurological signs, liver lesions, low ceruloplasmin, increased free serum copper, high Cu volumes in urine, KayserFleischer ring). The dia-gnosis is confirmed by a high Cu level in liver tissue or genetic proof. Untreated Wilsons disease causes death of the patient. If treated properly the survival rate approximates to the survival rate of the common population. The treatment concerns either removal of copper from the body using chelating agents excreted into the urine (Penicillamine, Trientine) or limitation of copper absorption from the intestine and reducing the toxicity of copper (zinc, ammonium tetrathiomolybdate). In the Czech Republic, Penicillamine or zinc is used. A liver transplant is indicated in patients with fulminant hepatic failure or decompensated liver cirrhosis. In the family all siblings of the affected individual need to be screened in order to treat any asymptomatic subjects.

Role of folate in nonalcoholic fatty liver disease.

PubMed

Sid, Victoria; Siow, Yaw L; O, Karmin

2017-10-01

Nonalcoholic fatty liver disease (NAFLD) is a spectrum of chronic liver conditions that are characterized by steatosis, inflammation, fibrosis, and liver injury. The global prevalence of NAFLD is rapidly increasing in proportion to the rising incidence of obesity and type 2 diabetes. Because NAFLD is a multifaceted disorder with many underlying metabolic abnormalities, currently, there is no pharmacological agent that is therapeutically approved for the treatment of this disease. Folate is a water-soluble B vitamin that plays an essential role in one-carbon transfer reactions involved in nucleic acid biosynthesis, methylation reactions, and sulfur-containing amino acid metabolism. The liver is the primary organ responsible for storage and metabolism of folates. Low serum folate levels have been observed in patients with obesity and diabetes. It has been reported that a low level of endogenous folates in rodents perturbs folate-dependent one-carbon metabolism, and may be associated with development of metabolic diseases such as NAFLD. This review highlights the biological role of folate in the progression of NAFLD and its associated metabolic complications including obesity and type 2 diabetes. Understanding the role of folate in metabolic disease may position this vitamin as a potential therapeutic for NAFLD.

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

PubMed

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

2009-11-01

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

From the liver to the heart: Cardiac dysfunction in obese children with non-alcoholic fatty liver disease

PubMed Central

Di Sessa, Anna; Umano, Giuseppina Rosaria; Miraglia del Giudice, Emanuele; Santoro, Nicola

2017-01-01

In the last decades the prevalence of non-alcoholic fatty liver disease (NAFLD) has increased as a consequence of the childhood obesity world epidemic. The liver damage occurring in NAFLD ranges from simple steatosis to steatohepatitis, fibrosis and cirrhosis. Recent findings reported that fatty liver disease is related to early atherosclerosis and cardiac dysfunction even in the pediatric population. Moreover, some authors have shown an association between liver steatosis and cardiac abnormalities, including rise in left ventricular mass, systolic and diastolic dysfunction and epicardial adipose tissue thickness. In this editorial, we provide a brief overview of the current knowledge concerning the association between NAFLD and cardiac dysfunction. PMID:28144387

From the liver to the heart: Cardiac dysfunction in obese children with non-alcoholic fatty liver disease.

PubMed

Di Sessa, Anna; Umano, Giuseppina Rosaria; Miraglia Del Giudice, Emanuele; Santoro, Nicola

2017-01-18

In the last decades the prevalence of non-alcoholic fatty liver disease (NAFLD) has increased as a consequence of the childhood obesity world epidemic. The liver damage occurring in NAFLD ranges from simple steatosis to steatohepatitis, fibrosis and cirrhosis. Recent findings reported that fatty liver disease is related to early atherosclerosis and cardiac dysfunction even in the pediatric population. Moreover, some authors have shown an association between liver steatosis and cardiac abnormalities, including rise in left ventricular mass, systolic and diastolic dysfunction and epicardial adipose tissue thickness. In this editorial, we provide a brief overview of the current knowledge concerning the association between NAFLD and cardiac dysfunction.

The intersection of nonalcoholic fatty liver disease and obesity.

PubMed

Woo Baidal, Jennifer A; Lavine, Joel E

2016-01-27

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

Nonalcoholic fatty liver disease and vascular disease: State-of-the-art

PubMed Central

Fargion, Silvia; Porzio, Marianna; Fracanzani, Anna Ludovica

2014-01-01

Nonalcoholic fatty liver disease (NAFLD), the most common of chronic liver disease in Western Country, is closely related to insulin resistance and oxidative stress and includes a wide spectrum of liver diseases ranging from steatosis alone, usually a benign and non-progressive condition, to nonalcoholic steatohepatitis (NASH), which may progress to liver fibrosis and cirrhosis. NAFLD is considered the hepatic manifestation of the metabolic syndrome with which shares several characteristics, however recent data suggest that NAFLD is linked to increased cardiovascular risk independently of the broad spectrum of risk factors of metabolic syndrome. Accumulating evidence suggests that the clinical burden of NAFLD is not restricted to liver-related morbidity and mortality, with the majority of deaths in NAFLD patients related to cardiovascular disease and cancer and not to the progression of liver disease. Retrospective and prospective studies provide evidence of a strong association between NAFLD and subclinical manifestation of atherosclerosis (increased intima-media thickness, endothelial dysfunction, arterial stiffness, impaired left ventricular function and coronary calcification). A general agreement emerging from these studies indicates that patients with NASH are at higher risk of cardiovascular diseases than those with simple steatosis, emphasizing the role of chronic inflammation in the pathogenesis of atherosclerosis of these patients. It is very likely that the different mechanisms involved in the pathogenesis of atherosclerosis in patients with NAFLD have a different relevance in the patients according to individual genetic background. In conclusion, in the presence of NAFLD patients should undergo a complete cardiovascular evaluation to prevent future atherosclerotic complications. Specific life-style modification and aggressive pharmaceutical modification will not only reduce the progression of liver disease, but also reduce morbidity for cardiovascular

Role of scavenger receptors in the pathophysiology of chronic liver diseases.

PubMed

Armengol, Carolina; Bartolí, Ramon; Sanjurjo, Lucía; Serra, Isabel; Amézaga, Núria; Sala, Margarita; Sarrias, Maria-Rosa

2013-01-01

Scavenger receptors comprise a large family of structurally diverse proteins that are involved in many homeostatic functions. They recognize a wide range of ligands, from pathogen-associated molecular patterns (PAMPs) to endogenous, as well as modified host-derived molecules (DAMPs). The liver deals with blood micro-organisms and DAMPs released from injured organs, thus performing vital metabolic and clearance functions that require the uptake of nutrients and toxins. Many liver cell types, including hepatocytes and Kupffer cells, express scavenger receptors that play key roles in hepatitis C virus entry, lipid uptake, and macrophage activation, among others. Chronic liver disease causes high morbidity and mortality worldwide. Hepatitis virus infection, alcohol abuse, and non-alcoholic fatty liver are the main etiologies associated with this disease. In this context, continuous inflammation as a result of liver damage leads to hepatic fibrosis, which frequently brings about cirrhosis and ultimately hepatocellular carcinoma. In this review, we will summarize the role of scavenger receptors in the pathophysiology of chronic liver diseases. We will also emphasize their potential as biomarkers of advanced liver disease, including cirrhosis and cancer.

Novel associations of bile acid diarrhoea with fatty liver disease and gallstones: a cohort retrospective analysis.

PubMed

Appleby, Richard N; Nolan, Jonathan D; Johnston, Ian M; Pattni, Sanjeev S; Fox, Jessica; Walters, Julian Rf

2017-01-01

Bile acid diarrhoea (BAD) is a common cause of chronic diarrhoea with a population prevalence of primary BAD around 1%. Previous studies have identified associations with low levels of the ileal hormone fibroblast growth factor 19 (FGF19), obesity and hypertriglyceridaemia. The aim of this study was to identify further associations of BAD. A cohort of patients with chronic diarrhoea who underwent 75 selenohomocholic acid taurate (SeHCAT) testing for BAD was further analysed retrospectively. Additional clinical details available from the electronic patient record, including imaging, colonoscopy, chemistry and histopathology reports were used to calculate the prevalence of fatty liver disease, gallstones, colonic neoplasia and microscopic colitis, which was compared for BAD, the primary BAD subset and control patients with diarrhoea. Of 578 patients, 303 (52%) had BAD, defined as a SeHCAT 7d retention value <15%, with 179 (31%) having primary BAD. 425 had an alanine aminotransferase (ALT) recorded, 184 had liver imaging and 176 had both. Overall, SeHCAT values were negatively associated with ALT (r s =-0.19, p<0.0001). Patients with BAD had an OR of 3.1 for an ALT >31 ng/mL with imaging showing fatty liver (p<0.001); similar figures occurred in the primary BAD group. FGF19 was not significantly related to fatty liver but low levels were predictive of ALT >40 IU/L. In 176 subjects with gallbladder imaging, 27% had gallstones, 7% had a prior cholecystectomy and 34% either of these. The median SeHCAT values were lower in those with gallstones (3.8%, p<0.0001), or gallstones/cholecystectomy (7.2%, p<0.001), compared with normal gallbladder imaging (14%). Overall, BAD had an OR of 2.0 for gallstones/cholecystectomy (p<0.05). BAD was not significantly associated with colonic adenoma/carcinoma or with microscopic colitis. The diagnosis of BAD is associated with fatty liver disease and with gallstones. The reasons for these associations require further investigation into

Novel associations of bile acid diarrhoea with fatty liver disease and gallstones: a cohort retrospective analysis

PubMed Central

Appleby, Richard N; Nolan, Jonathan D; Johnston, Ian M; Pattni, Sanjeev S; Fox, Jessica; Walters, Julian RF

2017-01-01

Background Bile acid diarrhoea (BAD) is a common cause of chronic diarrhoea with a population prevalence of primary BAD around 1%. Previous studies have identified associations with low levels of the ileal hormone fibroblast growth factor 19 (FGF19), obesity and hypertriglyceridaemia. The aim of this study was to identify further associations of BAD. Methods A cohort of patients with chronic diarrhoea who underwent 75selenohomocholic acid taurate (SeHCAT) testing for BAD was further analysed retrospectively. Additional clinical details available from the electronic patient record, including imaging, colonoscopy, chemistry and histopathology reports were used to calculate the prevalence of fatty liver disease, gallstones, colonic neoplasia and microscopic colitis, which was compared for BAD, the primary BAD subset and control patients with diarrhoea. Findings Of 578 patients, 303 (52%) had BAD, defined as a SeHCAT 7d retention value <15%, with 179 (31%) having primary BAD. 425 had an alanine aminotransferase (ALT) recorded, 184 had liver imaging and 176 had both. Overall, SeHCAT values were negatively associated with ALT (rs=−0.19, p<0.0001). Patients with BAD had an OR of 3.1 for an ALT >31 ng/mL with imaging showing fatty liver (p<0.001); similar figures occurred in the primary BAD group. FGF19 was not significantly related to fatty liver but low levels were predictive of ALT >40 IU/L. In 176 subjects with gallbladder imaging, 27% had gallstones, 7% had a prior cholecystectomy and 34% either of these. The median SeHCAT values were lower in those with gallstones (3.8%, p<0.0001), or gallstones/cholecystectomy (7.2%, p<0.001), compared with normal gallbladder imaging (14%). Overall, BAD had an OR of 2.0 for gallstones/cholecystectomy (p<0.05). BAD was not significantly associated with colonic adenoma/carcinoma or with microscopic colitis. Interpretation The diagnosis of BAD is associated with fatty liver disease and with gallstones. The reasons for these

Donation after cardiac death liver transplantation is associated with increased risk of end-stage renal disease.

PubMed

Ruebner, Rebecca L; Reese, Peter P; Abt, Peter L

2014-12-01

Limited organ supply has led to greater use of liver allografts with higher donor risk indices (DRI) and/or donated after cardiac death (DCD). DCD status is associated with acute kidney injury after liver transplantation; however, less is known about the association between donor quality and end-stage renal disease (ESRD). Using SRTR data, we assembled a cohort of liver transplant recipients from 2/2002 to 12/2010. We fit multivariable Cox regression models for ESRD. Model 1 included total DRI; model 2 included components of DRI, including DCD, as separate variables. Forty thousand four hundred and sixty-three liver transplant recipients were included. Median DRI was 1.40 (IQR 1.14, 1.72); 1822 (5%) received DCD livers. During median follow-up of 3.93 years, ESRD occurred in 2008 (5%) and death in 11 075 (27%) subjects. There was a stepwise increase in ESRD risk with higher DRI (DRI ≥1.14 and <1.40: HR 1.17, P = 0.06; DRI ≥1.40 and <1.72: HR 1.29, P = 0.003; DRI ≥1.72: HR 1.39, P < 0.001, compared with DRI <1.14). Adjusting for DRI components separately, DCD status was most strongly associated with ESRD (HR 1.40, P = 0.008). Higher DRI is associated with ESRD after liver transplantation, driven in part by DCD status. Donor quality is an important predictor of long-term renal outcomes in liver transplant recipients. © 2014 Steunstichting ESOT.

Clinical approaches to non-alcoholic fatty liver disease

PubMed Central

Schwenger, Katherine JP; Allard, Johane P

2014-01-01

Non-alcoholic fatty liver disease (NAFLD) ranges from simple steatosis to nonalcoholic steatohepatitis (NASH), leading to fibrosis and potentially cirrhosis, and it is one of the most common causes of liver disease worldwide. NAFLD is associated with other medical conditions such as metabolic syndrome, obesity, cardiovascular disease and diabetes. NASH can only be diagnosed through liver biopsy, but noninvasive techniques have been developed to identify patients who are most likely to have NASH or fibrosis, reducing the need for liver biopsy and risk to patients. Disease progression varies between individuals and is linked to a number of risk factors. Mechanisms involved in the pathogenesis are associated with diet and lifestyle, influx of free fatty acids to the liver from adipose tissue due to insulin resistance, hepatic oxidative stress, cytokines production, reduced very low-density lipoprotein secretion and intestinal microbiome. Weight loss through improved diet and increased physical activity has been the cornerstone therapy of NAFLD. Recent therapies such as pioglitazone and vitamin E have been shown to be beneficial. Omega 3 polyunsaturated fatty acids and statins may offer additional benefits. Bariatric surgery should be considered in morbidly obese patients. More research is needed to assess the impact of these treatments on a long-term basis. The objective of this article is to briefly review the diagnosis, management and treatment of this disease in order to aid clinicians in managing these patients. PMID:24587650

Association between nocturnal hypoxia and liver injury in the setting of nonalcoholic fatty liver disease.

PubMed

Lin, Qi-Chang; Chen, Li-Da; Chen, Gong-Ping; Zhao, Jian-Ming; Chen, Xiao; Huang, Jie-Feng; Wu, Li-Hua

2015-03-01

Obstructive sleep apnea (OSA) is suggested as a potential risk factor of nonalcoholic fatty liver disease (NAFLD). However, the underlying mechanism is still far from clear. The aim of this observational study was to investigate the influence of OSA-related hypoxia on severity of liver injury in patients with NAFLD. Consecutive patients with ultrasound-diagnosed NAFLD who underwent standard polysomnography were enrolled. Fasting blood samples were obtained from all patients for biological profile measurements, and demographic data were collected. Subjects were divided into control, moderate, and severe groups. A total of 85 subjects with 73 males and 12 females were included (mean age, 44.67 ± 1.28 years; mean body mass index, 27.28 ± 0.33 kg/m(2)). Alanine aminotransferase (ALT), aspartate aminotransferase (AST), ALT/AST, gamma glutamyltransferase, total cholesterol, low density lipoprotein-cholesterol, fasting glucose, and high-sensitivity C-reactive protein significantly increased with the aggravation of OSA. In multivariate analysis, oxygen desaturation index was the major contributing factor for elevated ALT (β = 0.435, p = 0.000), average O2 saturation was the major independent predictor of elevated AST (β = -0.269, p = 0.020). OSA-related hypoxia was independently associated with the biochemical evidence of liver injury in the presence of NAFLD.

Content of total iron, copper and manganese in liver of animals during hypokinesia, muscle activity and process of recovery

NASA Technical Reports Server (NTRS)

Potapovich, G. M.; Taneyeva, G. V.; Uteshev, A. B.

1980-01-01

It is shown that the content of total iron, copper and manganese in the liver of animals is altered depending on the intensity and duration of their swimming. Hypodynamia for 7 days does not alter the concentration of iron, but sufficiently increases the content of copper and manganese. The barometric factor effectively influences the maintenance of constancy in the content of microelements accumulated in the liver after intensive muscle activity.

Nutrigenomics analysis reveals that copper deficiency and dietary sucrose up-regulate inflammation, fibrosis and lipogenic pathways in a mature rat model of nonalcoholic fatty liver disease.

PubMed

Tallino, Savannah; Duffy, Megan; Ralle, Martina; Cortés, María Paz; Latorre, Mauricio; Burkhead, Jason L

2015-10-01

Nonalcoholic fatty liver disease (NAFLD) prevalence is increasing worldwide, with the affected US population estimated near 30%. Diet is a recognized risk factor in the NAFLD spectrum, which includes nonalcoholic steatohepatitis (NASH) and fibrosis. Low hepatic copper (Cu) was recently linked to clinical NAFLD/NASH severity. Simple sugar consumption including sucrose and fructose is implicated in NAFLD, while consumption of these macronutrients also decreases liver Cu levels. Though dietary sugar and low Cu are implicated in NAFLD, transcript-level responses that connect diet and pathology are not established. We have developed a mature rat model of NAFLD induced by dietary Cu deficiency, human-relevant high sucrose intake (30% w/w) or both factors in combination. Compared to the control diet with adequate Cu and 10% (w/w) sucrose, rats fed either high-sucrose or low-Cu diet had increased hepatic expression of genes involved in inflammation and fibrogenesis, including hepatic stellate cell activation, while the combination of diet factors also increased ATP citrate lyase and fatty acid synthase gene transcription (fold change > 2, P < 0.02). Low dietary Cu decreased hepatic and serum Cu (P ≤ 0.05), promoted lipid peroxidation and induced NAFLD-like histopathology, while the combined factors also induced fasting hepatic insulin resistance and liver damage. Neither low Cu nor 30% sucrose in the diet led to enhanced weight gain. Taken together, transcript profiles, histological and biochemical data indicate that low Cu and high sucrose promote hepatic gene expression and physiological responses associated with NAFLD and NASH, even in the absence of obesity or severe steatosis. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Coffee Intake Is Associated with a Lower Liver Stiffness in Patients with Non-Alcoholic Fatty Liver Disease, Hepatitis C, and Hepatitis B.

PubMed

Hodge, Alexander; Lim, Sarah; Goh, Evan; Wong, Ophelia; Marsh, Philip; Knight, Virginia; Sievert, William; de Courten, Barbora

2017-01-10

There is emerging evidence for the positive effects or benefits of coffee in patients with liver disease. We conducted a retrospective cross-sectional study on patients with non-alcoholic fatty liver disease (NAFLD), hepatitis C virus (HCV), and hepatitis B virus (HBV) infection to determine the effects of coffee intake on a non-invasive marker of liver fibrosis: liver stiffness assessed by transient elastography (TE). We assessed coffee and tea intake and measured TE in 1018 patients with NAFLD, HCV, and HBV (155 with NAFLD, 378 with HCV and 485 with HBV). Univariate and multivariate regression models were performed taking into account potential confounders. Liver stiffness was higher in males compared to females ( p < 0.05). Patients with HBV had lower liver stiffness than those with HCV and NAFLD. After adjustment for age, gender, smoking, alcohol consumption, M or XL probe, and disease state (NAFLD, HCV, and HBV status), those who drank 2 or more cups of coffee per day had a lower liver stiffness ( p = 0.044). Tea consumption had no effect ( p = 0.9). Coffee consumption decreases liver stiffness, which may indicate less fibrosis and inflammation, independent of disease state. This study adds further evidence to the notion of coffee maybe beneficial in patients with liver disease.

Coffee Intake Is Associated with a Lower Liver Stiffness in Patients with Non-Alcoholic Fatty Liver Disease, Hepatitis C, and Hepatitis B

PubMed Central

Hodge, Alexander; Lim, Sarah; Goh, Evan; Wong, Ophelia; Marsh, Philip; Knight, Virginia; Sievert, William; de Courten, Barbora

2017-01-01

There is emerging evidence for the positive effects or benefits of coffee in patients with liver disease. We conducted a retrospective cross-sectional study on patients with non-alcoholic fatty liver disease (NAFLD), hepatitis C virus (HCV), and hepatitis B virus (HBV) infection to determine the effects of coffee intake on a non-invasive marker of liver fibrosis: liver stiffness assessed by transient elastography (TE). We assessed coffee and tea intake and measured TE in 1018 patients with NAFLD, HCV, and HBV (155 with NAFLD, 378 with HCV and 485 with HBV). Univariate and multivariate regression models were performed taking into account potential confounders. Liver stiffness was higher in males compared to females (p < 0.05). Patients with HBV had lower liver stiffness than those with HCV and NAFLD. After adjustment for age, gender, smoking, alcohol consumption, M or XL probe, and disease state (NAFLD, HCV, and HBV status), those who drank 2 or more cups of coffee per day had a lower liver stiffness (p = 0.044). Tea consumption had no effect (p = 0.9). Coffee consumption decreases liver stiffness, which may indicate less fibrosis and inflammation, independent of disease state. This study adds further evidence to the notion of coffee maybe beneficial in patients with liver disease. PMID:28075394

Probiotics in Pediatric Liver Disease.

PubMed

Miloh, Tamir

2015-01-01

The gut-liver axis involves complex interaction between the intestinal microbiome and the liver parenchyma. Probiotics are live microorganisms that are used in a variety of diseases. With currently only 2 randomized-controlled studies (one with Lactobacillus GG and the other with VSL #3), data are scarce to support the clinical effect of probiotic use in children with nonalcoholic fatty liver disease. There is evidence that probiotics decrease the risk of necrotizing enterocolitis and thereby reduce the prevalence of total parenteral nutrition-induced chronic liver disease. Probiotics are used with a few reported positive outcomes in patients with cystic fibrosis and familial hypercholesterolemia and may be promising in other liver conditions. Probiotics are generally safe and well tolerated in children, premature infants, and in patients after liver transplantation. Large, prospective, randomized clinical trials are needed to evaluate the benefit of probiotics in children with liver diseases.

Nonalcoholic fatty liver disease is associated with aortic valve sclerosis in patients with type 2 diabetes mellitus.

PubMed

Bonapace, Stefano; Valbusa, Filippo; Bertolini, Lorenzo; Pichiri, Isabella; Mantovani, Alessandro; Rossi, Andrea; Zenari, Luciano; Barbieri, Enrico; Targher, Giovanni

2014-01-01

Recent epidemiological data suggest that non-alcoholic fatty liver disease (NAFLD) is closely associated with aortic valve sclerosis (AVS), an emerging risk factor for adverse cardiovascular outcomes, in nondiabetic and type 2 diabetic individuals. To date, nobody has investigated the association between NAFLD and AVS in people with type 2 diabetes, a group of individuals in which the prevalence of these two diseases is high. We recruited 180 consecutive type 2 diabetic patients without ischemic heart disease, valvular heart disease, hepatic diseases or excessive alcohol consumption. NAFLD was diagnosed by liver ultrasonography whereas AVS was determined by conventional echocardiography in all participants. In the whole sample, 120 (66.7%) patients had NAFLD and 53 (29.4%) had AVS. No patients had aortic stenosis. NAFLD was strongly associated with an increased risk of prevalent AVS (odds ratio [OR] 2.79, 95% CI 1.3-6.1, p<0.01). Adjustments for age, sex, duration of diabetes, diabetes treatment, body mass index, smoking, alcohol consumption, hypertension, dyslipidemia, hemoglobin A1c and estimated glomerular filtration rate did not attenuate the strong association between NAFLD and risk of prevalent AVS (adjusted-OR 3.04, 95% CI 1.3-7.3, p = 0.01). Our results provide the first demonstration of a positive and independent association between NAFLD and AVS in patients with type 2 diabetes mellitus.

Laser ablation inductively coupled plasma mass spectrometry imaging of metals in experimental and clinical Wilson's disease

PubMed Central

Boaru, Sorina Georgiana; Merle, Uta; Uerlings, Ricarda; Zimmermann, Astrid; Flechtenmacher, Christa; Willheim, Claudia; Eder, Elisabeth; Ferenci, Peter; Stremmel, Wolfgang; Weiskirchen, Ralf

2015-01-01

Wilson's disease is an autosomal recessive disorder in which the liver does not properly release copper into bile, resulting in prominent copper accumulation in various tissues. Affected patients suffer from hepatic disorders and severe neurological defects. Experimental studies in mutant mice in which the copper-transporting ATPase gene (Atp7b) is disrupted revealed a drastic, time-dependent accumulation of hepatic copper that is accompanied by formation of regenerative nodes resembling cirrhosis. Therefore, these mice represent an excellent exploratory model for Wilson's disease. However, the precise time course in hepatic copper accumulation and its impact on other trace metals within the liver is yet poorly understood. We have recently established novel laser ablation inductively coupled plasma mass spectrometry protocols allowing quantitative metal imaging in human and murine liver tissue with high sensitivity, spatial resolution, specificity and quantification ability. By use of these techniques, we here aimed to comparatively analyse hepatic metal content in wild-type and Atp7b deficient mice during ageing. We demonstrate that the age-dependent accumulation of hepatic copper is strictly associated with a simultaneous increase in iron and zinc, while the intrahepatic concentration and distribution of other metals or metalloids is not affected. The same findings were obtained in well-defined human liver samples that were obtained from patients suffering from Wilson's disease. We conclude that in Wilson's disease the imbalances of hepatic copper during ageing are closely correlated with alterations in intrahepatic iron and zinc content. PMID:25704483

Copper/MYC/CTR1 interplay: a dangerous relationship in hepatocellular carcinoma

PubMed Central

Barbaro, Barbara; Illi, Barbara; Nasi, Sergio; Martini, Maurizio; Licata, Anna; Miele, Luca; Grieco, Antonio; Balsano, Clara

2018-01-01

Free serum copper correlates with tumor incidence and progression of human cancers, including hepatocellular carcinoma (HCC). Copper extracellular uptake is provided by the transporter CTR1, whose expression is regulated to avoid excessive intracellular copper entry. Inadequate copper serum concentration is involved in the pathogenesis of Non Alcoholic Fatty Liver Disease (NAFLD), which is becoming a major cause of liver damage progression and HCC incidence. Finally, MYC is over-expressed in most of HCCs and is a critical regulator of cellular growth, tumor invasion and metastasis. The purpose of our study was to understand if higher serum copper concentrations might be involved in the progression of NAFLD-cirrhosis toward-HCC. We investigated whether high exogenous copper levels sensitize liver cells to transformation and if it exists an interplay between copper-related proteins and MYC oncogene. NAFLD-cirrhotic patients were characterized by a statistical significant enhancement of serum copper levels, even more evident in HCC patients. We demonstrated that high extracellular copper concentrations increase cell growth, migration, and invasion of liver cancer cells by modulating MYC/CTR1 axis. We highlighted that MYC binds a specific region of the CTR1 promoter, regulating its transcription. Accordingly, CTR1 and MYC proteins expression were progressively up-regulated in liver tissues from NAFLD-cirrhotic to HCC patients. This work provides novel insights on the molecular mechanisms by which copper may favor the progression from cirrhosis to cancer. The Cu/MYC/CTR1 interplay opens a window to refine HCC diagnosis and design new combined therapies. PMID:29507693

Copper/MYC/CTR1 interplay: a dangerous relationship in hepatocellular carcinoma.

PubMed

Porcu, Cristiana; Antonucci, Laura; Barbaro, Barbara; Illi, Barbara; Nasi, Sergio; Martini, Maurizio; Licata, Anna; Miele, Luca; Grieco, Antonio; Balsano, Clara

2018-02-06

Free serum copper correlates with tumor incidence and progression of human cancers, including hepatocellular carcinoma (HCC). Copper extracellular uptake is provided by the transporter CTR1, whose expression is regulated to avoid excessive intracellular copper entry. Inadequate copper serum concentration is involved in the pathogenesis of Non Alcoholic Fatty Liver Disease (NAFLD), which is becoming a major cause of liver damage progression and HCC incidence. Finally, MYC is over-expressed in most of HCCs and is a critical regulator of cellular growth, tumor invasion and metastasis. The purpose of our study was to understand if higher serum copper concentrations might be involved in the progression of NAFLD-cirrhosis toward-HCC. We investigated whether high exogenous copper levels sensitize liver cells to transformation and if it exists an interplay between copper-related proteins and MYC oncogene. NAFLD-cirrhotic patients were characterized by a statistical significant enhancement of serum copper levels, even more evident in HCC patients. We demonstrated that high extracellular copper concentrations increase cell growth, migration, and invasion of liver cancer cells by modulating MYC/CTR1 axis. We highlighted that MYC binds a specific region of the CTR1 promoter, regulating its transcription. Accordingly, CTR1 and MYC proteins expression were progressively up-regulated in liver tissues from NAFLD-cirrhotic to HCC patients. This work provides novel insights on the molecular mechanisms by which copper may favor the progression from cirrhosis to cancer. The Cu/MYC/CTR1 interplay opens a window to refine HCC diagnosis and design new combined therapies.

Dietary fructose in nonalcoholic fatty liver disease.

PubMed

Vos, Miriam B; Lavine, Joel E

2013-06-01

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in adults and children. A number of genetic and environmental factors are known to predispose individuals to NAFLD. Certain dietary sugars, particularly fructose, are suspected to contribute to the development of NAFLD and its progression. The increasing quantity of fructose in the diet comes from sugar additives (most commonly sucrose and high fructose corn syrup) in beverages and processed foods. Substantial links have been demonstrated between increased fructose consumption and obesity, dyslipidemia, and insulin resistance. Growing evidence suggests that fructose contributes to the development and severity of NAFLD. In human studies, fructose is associated with increasing hepatic fat, inflammation, and possibly fibrosis. Whether fructose alone can cause NAFLD or if it serves only as a contributor when consumed excessively in the setting of insulin resistance, positive energy balance, and sedentary lifestyle is unknown. Sufficient evidence exists to support clinical recommendations that fructose intake be limited through decreasing foods and drinks high in added (fructose-containing) sugars. Copyright © 2013 American Association for the Study of Liver Diseases.

Obstructive sleep apnea and hypoxemia are associated with advanced liver histology in pediatric nonalcoholic fatty liver disease.

PubMed

Sundaram, Shikha S; Sokol, Ronald J; Capocelli, Kelley E; Pan, Zhaoxing; Sullivan, Jillian S; Robbins, Kristen; Halbower, Ann C

2014-04-01

To determine whether obstructive sleep apnea (OSA) and/or nocturnal hypoxemia are associated with the severity of liver injury in patients with pediatric nonalcoholic fatty liver disease (NAFLD). Obese children aged 10-18 years with liver biopsy-proven NAFLD were enrolled. Demographic, clinical, and laboratory data were collected, polysomnography was performed, and liver histology was scored. Subjects were divided into those with OSA/hypoxemia and those without OSA/hypoxemia for analysis. Of 25 subjects with NAFLD, OSA/hypoxemia was present in 15 (60%) (mean age, 12.8 ± 1.9 years; 68% male; 88% Hispanic; mean body mass index z-score, 2.3 ± 0.3). Subjects with and without OSA/hypoxemia had similar levels of serum aminotransferases, serum lipids, and inflammatory and insulin resistance markers. Although there were no differences between groups in the histological severity of steatosis, inflammation, ballooning degeneration, NAFLD activity score, or histological grade, subjects with OSA/hypoxemia had significantly more severe hepatic fibrosis. Moreover, oxygen saturation nadir during polysomnography was related to hepatic fibrosis stage (r = -0.49; P = .01) and aspartate aminotransferase level (r = 0.42; P < .05). Increasing percentage of time with oxygen saturation ≤90% was related to NAFLD inflammation grade (r = 0.44; P = .03), degree of hepatic steatosis (r = -0.50; P = .01), NAFLD activity score (r = 0.42; P = .04), aspartate aminotransferase level (r = 0.56; P = .004), and alanine aminotransferase level (r = 0.44; P = .03). Moderate OSA/hypoxemia is common in pediatric patients with biopsy-proven NAFLD. OSA and the severity/duration of hypoxemia are associated with biochemical and histological measures of NAFLD severity. Copyright © 2014 Mosby, Inc. All rights reserved.

Plasma amino acid profile associated with fatty liver disease and co-occurrence of metabolic risk factors.

PubMed

Yamakado, Minoru; Tanaka, Takayuki; Nagao, Kenji; Imaizumi, Akira; Komatsu, Michiharu; Daimon, Takashi; Miyano, Hiroshi; Tani, Mizuki; Toda, Akiko; Yamamoto, Hiroshi; Horimoto, Katsuhisa; Ishizaka, Yuko

2017-11-03

Fatty liver disease (FLD) increases the risk of diabetes, cardiovascular disease, and steatohepatitis, which leads to fibrosis, cirrhosis, and hepatocellular carcinoma. Thus, the early detection of FLD is necessary. We aimed to find a quantitative and feasible model for discriminating the FLD, based on plasma free amino acid (PFAA) profiles. We constructed models of the relationship between PFAA levels in 2,000 generally healthy Japanese subjects and the diagnosis of FLD by abdominal ultrasound scan by multiple logistic regression analysis with variable selection. The performance of these models for FLD discrimination was validated using an independent data set of 2,160 subjects. The generated PFAA-based model was able to identify FLD patients. The area under the receiver operating characteristic curve for the model was 0.83, which was higher than those of other existing liver function-associated markers ranging from 0.53 to 0.80. The value of the linear discriminant in the model yielded the adjusted odds ratio (with 95% confidence intervals) for a 1 standard deviation increase of 2.63 (2.14-3.25) in the multiple logistic regression analysis with known liver function-associated covariates. Interestingly, the linear discriminant values were significantly associated with the progression of FLD, and patients with nonalcoholic steatohepatitis also exhibited higher values.

Multimodal LA-ICP-MS and nanoSIMS imaging enables copper mapping within photoreceptor megamitochondria in a zebrafish model of Menkes disease.

PubMed

Ackerman, Cheri M; Weber, Peter K; Xiao, Tong; Thai, Bao; Kuo, Tiffani J; Zhang, Emily; Pett-Ridge, Jennifer; Chang, Christopher J

2018-03-01

Copper is essential for eukaryotic life, and animals must acquire this nutrient through the diet and distribute it to cells and organelles for proper function of biological targets. Indeed, mutations in the central copper exporter ATP7A contribute to a spectrum of diseases, including Menkes disease, with symptoms ranging from neurodegeneration to lax connective tissue. As such, a better understanding of the fundamental impacts of ATP7A mutations on in vivo copper distributions is of relevance to those affected by these diseases. Here we combine metal imaging and optical imaging techniques at a variety of spatial resolutions to identify tissues and structures with altered copper levels in the Calamity gw71 zebrafish model of Menkes disease. Rapid profiling of tissue slices with LA-ICP-MS identified reduced copper levels in the brain, neuroretina, and liver of Menkes fish compared to control specimens. High resolution nanoSIMS imaging of the neuroretina, combined with electron and confocal microscopies, identified the megamitochondria of photoreceptors as loci of copper accumulation in wildtype fish, with lower levels of megamitochondrial copper observed in Calamity gw71 zebrafish. Interestingly, this localized copper decrease does not result in impaired photoreceptor development or altered megamitochondrial morphology, suggesting the prioritization of copper at sufficient levels for maintaining essential mitochondrial functions. Together, these data establish the Calamity gw71 zebrafish as an optically transparent in vivo model for the study of neural copper misregulation, illuminate a role for the ATP7A copper exporter in trafficking copper to the neuroretina, and highlight the utility of combining multiple imaging techniques for studying metals in whole organism settings with spatial resolution.

Acute hepatitis A and B in patients with chronic liver disease: prevention through vaccination.

PubMed

Keeffe, Emmet B

2005-10-01

Retrospective and prospective studies have demonstrated that the occurrence of acute hepatitis A in patients with chronic liver disease is associated with higher rates of morbidity and mortality than in previously healthy individuals with acute hepatitis A. The mortality associated with acute hepatitis A may be particularly high in patients with preexisting chronic hepatitis C. Although acute hepatitis B in patients with preexisting chronic liver disease is less well studied, worse outcomes than in previously healthy individuals are apparent. However, numerous studies convincingly demonstrate that chronic hepatitis B virus coinfection with hepatitis C virus (or hepatitis D virus) is associated with an accelerated natural history of liver disease and worse outcomes. These observations led to studies that demonstrated the safety and efficacy of hepatitis A and hepatitis B vaccination in patients with mild-to-moderate chronic liver disease. Hepatitis A and B vaccination is less effective in patients with advanced liver disease, especially after decompensation, such as in patients awaiting liver transplantation, and in liver transplant recipients. The emerging lower rates of inherent immunity in younger individuals, higher morbidity and mortality of acute hepatitis A or B superimposed on chronic liver disease, and greater vaccine efficacy in milder forms of chronic liver disease suggest that it is a reasonable policy to recommend hepatitis A and B vaccination in patients early in the natural history of chronic liver disease.

Wilson disease: changes in methionine metabolism and inflammation affect global DNA methylation in early liver disease

PubMed Central

Medici, Valentina; Shibata, Noreene M.; Kharbanda, Kusum K.; LaSalle, Janine M.; Woods, Rima; Liu, Sarah; Engelberg, Jesse A.; Devaraj, Sridevi; Török, Natalie J.; Jiang, Joy X.; Havel, Peter J.; Lönnerdal, Bo; Kim, Kyoungmi; Halsted, Charles H.

2012-01-01

Hepatic methionine metabolism may play an essential role in regulating methylation status and liver injury in Wilson disease (WD) through the inhibition of S-adenosylhomocysteine hydrolase (SAHH) by copper (Cu) and the consequent accumulation of S-adenosylhomocysteine (SAH). We studied the transcript levels of selected genes related to liver injury, levels of SAHH, SAH, DNA methyltransferases genes (Dnmt1, Dnmt3a, Dnmt3b) and global DNA methylation in the tx-j mouse (tx-j), an animal model of WD. Findings were compared to those in control C3H mice, and in response to Cu chelation by penicillamine (PCA) and dietary supplementation of the methyl donor betaine to modulate inflammatory and methylation status. Transcript levels of selected genes related to endoplasmic reticulum stress, lipid synthesis, and fatty acid oxidation were down-regulated at baseline in tx-j mice, further down-regulated in response to PCA, and showed little to no response to betaine. Hepatic Sahh transcript and protein levels were reduced in tx-j mice with consequent increase of SAH levels. Hepatic Cu accumulation was associated with inflammation, as indicated by histopathology and elevated serum ALT and liver tumor necrosis factor alpha (Tnf-α) levels. Dnmt3b was down-regulated in tx-j mice together with global DNA hypomethylation. PCA treatment of tx-j mice reduced Tnf-α and ALT levels, betaine treatment increased S-adenosylmethionine and up-regulated Dnmt3b levels, and both treatments restored global DNA methylation levels. Conclusion: reduced hepatic Sahh expression was associated with increased liver SAH levels in the tx-j model of WD, with consequent global DNA hypomethylation. Increased global DNA methylation was achieved by reducing inflammation by Cu chelation or by providing methyl groups. We propose that increased SAH levels and inflammation affect widespread epigenetic regulation of gene expression in WD. PMID:22945834

The plant decapeptide OSIP108 prevents copper-induced toxicity in various models for Wilson disease

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

Spincemaille, Pieter; Pham, Duc-Hung; Chandhok, Gursimran

2014-10-15

Background: Wilson disease (WD) is caused by accumulation of excess copper (Cu) due to a mutation in the gene encoding the liver Cu transporter ATP7B, and is characterized by acute liver failure or cirrhosis and neuronal cell death. We investigated the effect of OSIP108, a plant derived decapeptide that prevents Cu-induced apoptosis in yeast and human cells, on Cu-induced toxicity in various mammalian in vitro models relevant for WD and in a Cu-toxicity zebrafish larvae model applicable to WD. Methods: The effect of OSIP108 was evaluated on viability of various cell lines in the presence of excess Cu, on livermore » morphology of a Cu-treated zebrafish larvae strain that expresses a fluorescent reporter in hepatocytes, and on oxidative stress levels in wild type AB zebrafish larvae. Results: OSIP108 increased not only viability of Cu-treated CHO cells transgenically expressing ATP7B and the common WD-causing mutant ATP7B{sup H1069Q}, but also viability of Cu-treated human glioblastoma U87 cells. Aberrancies in liver morphology of Cu-treated zebrafish larvae were observed, which were further confirmed as Cu-induced hepatotoxicity by liver histology. Injections of OSIP108 into Cu-treated zebrafish larvae significantly increased the amount of larvae with normal liver morphology and decreased Cu-induced production of reactive oxygen species. Conclusions: OSIP108 prevents Cu-induced toxicity in in vitro models and in a Cu-toxicity zebrafish larvae model applicable to WD. General significance: All the above data indicate the potential of OSIP108 as a drug lead for further development as a novel WD treatment. - Highlights: • Wilson disease (WD) is characterized by accumulation of toxic copper (Cu). • OSIP108 increases viability of Cu-treated cellular models applicable to WD. • OSIP108 injections preserve liver morphology of Cu-treated zebrafish larvae. • OSIP108 injections into zebrafish larvae abrogates Cu-induced oxidative stress.« less

The Role of Celiac Disease in Severity of Liver Disorders and Effect of a Gluten Free Diet on Diseases Improvement

PubMed Central

Rostami-Nejad, Mohammad; Haldane, Thea; AlDulaimi, David; Alavian, Seyed Moayed; Zali, Mohammad Reza; Rostami, Kamran

2013-01-01

Context Celiac disease (CD) is defined as a permanent intolerance to ingested gluten. The intolerance to gluten results in immune-mediated damage of small intestine mucosa manifested by villous atrophy and crypt hyperplasia. These abnormalities resolve with initiationa gluten-free diet. Evidence Acquisition PubMed, Ovid, and Google were searched for full text articles published between 1963 and 2012. The associated keywords were used, and papers described particularly the impact of celiac disease on severity of liver disorder were identified. Results Recently evidence has emerged revealingthat celiac disease not only is associated with small intestine abnormalities and malabsorption, but is also a multisystem disorder affecting other systems outside gastrointestinal tract, including musculo-skeletal, cardiovascular and nervous systems. Some correlations have been assumed between celiac and liver diseases. In particular, celiac disease is associated with changes in liver biochemistry and linked to alter the prognosis of other disorders. This review will concentrate on the effect of celiac disease and gluten-free diets on the severity of liver disorders. Conclusions Although GFD effect on the progression of CD associated liver diseases is not well defined, it seems that GFD improves liver function tests in patients with a hypertransaminasemia. PMID:24348636

Psoriasis and Nonalcoholic Fatty Liver Disease.

PubMed

Carrascosa, J M; Bonanad, C; Dauden, E; Botella, R; Olveira-Martín, A

Nonalcoholic fatty liver disease (NAFLD) is the most prevalent liver condition in the West. The prevalence and severity of NAFLD is higher and the prognosis worse in patients with psoriasis. The pathogenic link between psoriasis and NAFLD is chronic inflammation and peripheral insulin resistance, a common finding in diseases associated with psoriasis. NAFLD should therefore be ruled out during the initial evaluation of patients with psoriasis, in particular if they show signs of metabolic syndrome and require systemic treatment. Concomitant psoriasis and NAFLD and the likelihood of synergy between them place limitations on general recommendations and treatment for these patients given the potential for liver toxicity. As hepatotoxic risk is associated with some of the conventional drugs used in this setting (e.g., acitretin, methotrexate, and ciclosporin), patients prescribed these treatments should be monitored as appropriate. Anti-tumor necrosis factor agents hold the promise of potential benefits based on their effects on the inflammatory process and improving peripheral insulin resistance. However, cases of liver toxicity have also been reported in relation to these biologics. No evidence has emerged to suggest that anti-p40 or anti-interleukin 17 agents provide benefits or have adverse effects. Copyright © 2017 AEDV. Publicado por Elsevier España, S.L.U. All rights reserved.

[Coffee can be beneficial for patients with liver diseases].

PubMed

Kjærgaard, Maria; Thiele, Maja; Krag, Aleksander

2014-10-20

Coffee is one of the most commonly consumed beverages in the world. Consequently, it is important to consider the impact of coffee on health and disease. A daily intake of at least three cups of coffee is likely to have beneficial health effects, especially in patients at risk of liver diseases. Coffee has been associated with decreased liver inflammation, prevention of cirrhosis, reduced steatosis and lower incidence of hepatocellular carcinoma. It is not yet possible to make clear recommendations, but coffee can likely be included as part of a healthy diet for patients with liver diseases.

Non-Alcoholic Fatty Liver Disease.

PubMed

Engin, Atilla

2017-01-01

Non-alcoholic fatty liver disease (NAFLD) is in parallel with the obesity epidemic and it is the most common cause of liver diseases. The development of hepatic steatosis in majority of patients is linked to dietary fat ingestion. NAFLD is characterized by excess accumulation of triglyceride in the hepatocyte due to both increased inflow of free fatty acids and de novo hepatic lipogenesis. Insulin resistance with the deficiency of insulin receptor substrate-2 (IRS-2)-associated phosphatidylinositol 3-kinase (PI3K) activity causes an increase in intracellular fatty acid-derived metabolites such as diacylglycerol, fatty acyl CoA or ceramides. Lipotoxicity-related mechanism of NAFLD could be explained still best by the "double-hit" hypothesis. Insulin resistance is the major mechanism in the development and progression of NAFLD/Non-alcoholic steatohepatitis (NASH). Metabolic oxidative stress, autophagy, and inflammation induce NASH progression. In the "first hit" the hepatic concentrations of diacylglycerol increase with rising saturated liver fat content in human NAFLD. Activities of mitochondrial respiratory chain complexes are decreased in liver tissue of patients with NASH. Furthermore, hepatocyte lipoapoptosis is a critical feature of NASH. In "second hit" reduced glutathione levels due to oxidative stress lead to overactivation of c-Jun N-terminal kinase (JNK)/c-Jun signaling that induces cell death in the steatotic liver. Accumulation of toxic levels of reactive oxygen species (ROS) is caused by the ineffectual cycling of the endoplasmic reticulum (ER) oxidoreductin (Ero1)-protein disulfide isomerase oxidation cycle through the downstream of the inner membrane mitochondrial oxidative metabolism and Kelch like-ECH-associated protein 1 (Keap1)- Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway.

Management of cytomegalovirus infection and disease in liver transplant recipients

PubMed Central

Bruminhent, Jackrapong; Razonable, Raymund R

2014-01-01

Cytomegalovirus (CMV) is one of the most common viral pathogens causing clinical disease in liver transplant recipients, and contributing to substantial morbidity and occasional mortality. CMV causes febrile illness often accompanied by bone marrow suppression, and in some cases, invades tissues including the transplanted liver allograft. In addition, CMV has been significantly associated with an increased predisposition to acute and chronic allograft rejection, accelerated hepatitis C recurrence, and other opportunistic infections, as well as reduced overall patient and allograft survival. To negate the adverse effects of CMV infection on transplant outcome, its prevention, whether through antiviral prophylaxis or preemptive therapy, is an essential component to the management of liver transplant recipients. Two recently updated guidelines have suggested that antiviral prophylaxis or preemptive therapy are similarly effective in preventing CMV disease in modest-risk CMV-seropositive liver transplant recipients, while antiviral prophylaxis is the preferred strategy over preemptive therapy for the prevention of CMV disease in high-risk recipients [CMV-seronegative recipients of liver allografts from CMV-seropositive donors (D+/R-)]. However, antiviral prophylaxis has only delayed the onset of CMV disease in many CMV D+/R- liver transplant recipients, and such occurrence of late-onset CMV disease was significantly associated with increased all-cause and infection-related mortality after liver transplantation. Therefore, a search for better strategies for prevention, such as prolonged duration of antiviral prophylaxis, a hybrid approach (antiviral prophylaxis followed by preemptive therapy), or the use of immunologic measures to guide antiviral prophylaxis has been suggested to prevent late-onset CMV disease. The standard treatment of CMV disease consists of intravenous ganciclovir or oral valganciclovir, and if feasible, reduction in pharmacologic immunosuppression

Role of Gut Microbiota in Liver Disease.

PubMed

Brenner, David A; Paik, Yong-Han; Schnabl, Bernd

2015-01-01

Many lines of research have established a relationship between the gut microbiome and patients with liver disease. For example, patients with cirrhosis have increased bacteremia, increased blood levels of lipopolysaccharide, and increased intestinal permeability. Patients with cirrhosis have bacterial overgrowth in the small intestine. Selective intestinal decontamination with antibiotics is beneficial for patients with decompensated cirrhosis. In experimental models of chronic liver injury with fibrosis, several toll-like receptors (TLR) are required to make mice sensitive to liver fibrosis. The presumed ligand for the TLRs are bacterial products derived from the gut microbiome, and TLR knockout mice are resistant to liver inflammation and fibrosis. We and others have characterized the association between preclinical models of liver disease in mice with the microbial diversity in their gut microbiome. In each model, including intragastric alcohol, bile duct ligation, chronic carbon tetrachloride (CCl4), administration, and genetic obesity, there is a significant change in the gut microbiome from normal control mice. However, there is not a single clear bacterial strain or pattern that distinguish mice with liver injury from controlled mice. So how can the gut microbiota affect liver disease? We can identify at least 6 changes that would result in liver injury, inflammation, and/or fibrosis. These include: (1) changes in caloric yield of diet; (2) regulation of gut permeability to release bacterial products; (3) modulation of choline metabolism; (4) production of endogenous ethanol; (5) regulation of bile acid metabolism; and (6) regulation in lipid metabolism.

Non-alcoholic Fatty Liver Disease (NAFLD)--A Review.

PubMed

Karim, M F; Al-Mahtab, M; Rahman, S; Debnath, C R

2015-10-01

Non-alcoholic fatty liver disease (NAFLD) is an emerging problem in Hepatology clinics. It is closely related to the increased frequency of overweight or obesity. It has recognised association with metabolic syndrome. Central obesity, diabetes mellitus, dyslipidemia are commonest risk factors. Association with hepatitis C genotype 3 is also recognised. NAFLD is an important cause of cyptogenic cirrhosis of liver. It affects all populations and all age groups. Most patients with NAFLD are asymptomatic or vague upper abdominal pain. Liver function tests are mostly normal or mild elevation of aminotranferases. Histological features almost identical to those of alcohol-induced liver damage and can range from mild steatosis to cirrhosis. Two hit hypothesis is prevailing theory for the development of NAFLD. Diagnosis is usually made by imaging tools like ultrasonogram which reveal a bright liver while liver biopsy is gold standard for diagnosis as well as differentiating simple fatty liver and non-alcoholic steatohepatitis (NASH). Prognosis is variable. Simple hepatic steatosis generally has a benign long-term prognosis. However, one to two third of NASH progress to fibrosis or cirrhosis and may have a similar prognosis as cirrhosis from other liver diseases. Treatment is mostly control of underlying disorders and dietary advice, exercise, insulin sensitizers, antioxidants, or cytoprotective agents. The prevalence of NAFLD is increasing. So it needs more research to address this problem.

Crosstalk between the gut and the liver via susceptibility loci: Novel advances in inflammatory bowel disease and autoimmune liver disease.

PubMed

Li, Xinyang; Shen, Jun; Ran, Zhihua

2017-02-01

Inflammatory bowel disease (IBD) is an autoimmune disorder characterized by chronic, relapsing intestinal inflammation. Autoimmune liver disease (AILD) may be involved in IBD as an extra-intestinal manifestation (EIM). Epidemiologic and anatomic evidence have demonstrated an intimate crosstalk between the gut and the liver. In this review, we briefly introduced nine groups of susceptibility loci shared by inflammatory bowel and autoimmune liver disease for the first time. The genome-wide association studies (GWAS) evidence of pathways involving crosstalk between the gut and the liver is clarified and explained. It has been found that HNF4-α, GPR35, MST1R, CARD9, IL2/IL21/IL2R, BACH2, TNFRSF14, MAdCAM-1, and FUT2 are the genes involved in tight junction formation, macrophage function, T helper cell or T reg cell cycle and function, TNF secretion, lymphocyte homing or intestinal dysbiosis, respectively. The intimate crosstalk between the gut and liver in immunity is also highlighted and discussed in this review. Copyright © 2016 Elsevier Inc. All rights reserved.

Long-term Erythrocytapheresis Is Associated With Reduced Liver Iron Concentration in Sickle Cell Disease.

PubMed

Myers, Scott N; Eid, Ryan; Myers, John; Bertolone, Salvatore; Panigrahi, Arun; Mullinax, Jennifer; Raj, Ashok B

2016-01-01

Erythrocytapheresis procedures are increasingly used in sickle cell disease. Serum ferritin and noninvasive magnetic resonance imaging measurements of liver iron concentration (LIC) are frequently used to monitor iron overload secondary to hypertransfusion. There is a paucity of data describing the impact of long-term erythrocytapheresis (LTE) on LIC. We measured magnetic resonance imaging liver and cardiac iron on LTE subjects and stratified them into 2 groups: higher LIC (>3 mg/g) and lower LIC (<3 mg/g). χ(2) and t test were used to test for differences between the 2 groups. Logistic regression and generalized linear mixed-effects models were used to test what impacted LIC. None of 29 sickle cell disease subjects maintained on LTE had high cardiac iron concentration. LIC was associated with serum ferritin (r=0.697, P<0.001) but was not associated with the total number of LTE procedures (r=-0.088, P=0.656) or total number of simple transfusions (r=0.316, P=0.108). The total number of LTE procedures was not associated with serum ferritin (r=0.040, P=0.838), the total number of simple transfusions (r=-0.258, P=0.184), or LIC group (r=-0.111, P=0.566). There was no significant correlation between duration of LTE maintenance and LIC.

Sugar-sweetened beverage, diet soda, and fatty liver disease in the Framingham Heart Study cohorts.

PubMed

Ma, Jiantao; Fox, Caroline S; Jacques, Paul F; Speliotes, Elizabeth K; Hoffmann, Udo; Smith, Caren E; Saltzman, Edward; McKeown, Nicola M

2015-08-01

Non-alcoholic fatty liver disease affects ∼30% of US adults, yet the role of sugar-sweetened beverages and diet soda on these diseases remains unknown. We examined the cross-sectional association between intake of sugar-sweetened beverages or diet soda and fatty liver disease in participants of the Framingham Offspring and Third Generation cohorts. Fatty liver disease was defined using liver attenuation measurements generated from computed tomography in 2634 participants. Alanine transaminase concentration, a crude marker of fatty liver disease, was measured in 5908 participants. Sugar-sweetened beverage and diet soda intake were estimated using a food frequency questionnaire. Participants were categorized as either non-consumers or consumers (3 categories: 1 serving/month to <1 serving/week, 1 serving/week to <1 serving/day, and ⩾1 serving/day) of sugar-sweetened beverages or diet soda. After adjustment for age, sex, smoking status, Framingham cohort, energy intake, alcohol, dietary fiber, fat (% energy), protein (% energy), diet soda intake, and body mass index, the odds ratios of fatty liver disease were 1, 1.16 (0.88, 1.54), 1.32 (0.93, 1.86), and 1.61 (1.04, 2.49) across sugar-sweetened beverage consumption categories (p trend=0.04). Sugar-sweetened beverage consumption was also positively associated with alanine transaminase levels (p trend=0.007). We observed no significant association between diet soda intake and measures of fatty liver disease. In conclusion, we observed that regular sugar-sweetened beverage consumption was associated with greater risk of fatty liver disease, particularly in overweight and obese individuals, whereas diet soda intake was not associated with measures of fatty liver disease. Copyright © 2015 European Association for the Study of the Liver. All rights reserved.

Nutrigenomics analysis reveals that copper deficiency and dietary sucrose up-regulate inflammation, fibrosis and lipogenic pathways in a mature rat model of non-alcoholic fatty-liver disease

PubMed Central

Tallino, Savannah; Duffy, Megan; Ralle, Martina; Cortés, María Paz; Latorre, Mauricio; Burkhead, Jason L.

2015-01-01

Nonalcoholic fatty-liver disease (NAFLD) prevalence is increasing worldwide, with the affected US population estimated near 30%. Diet is a recognized risk factor in the NAFLD spectrum, which includes non-alcoholic steatohepatitis (NASH) and fibrosis. Low hepatic copper (Cu) was recently linked to clinical NAFLD/NASH severity. Simple sugar consumption including sucrose and fructose is implicated in NAFLD, while consumption of these macronutrients also decrease liver Cu levels. Though dietary sugar and low Cu are implicated in NAFLD, transcript-level responses that connect diet and pathology are not established. We have developed a mature rat model of NAFLD induced by dietary Cu deficiency, human-relevant high sucrose intake (30% w/w), or both factors in combination. Compared to the control diet with adequate Cu and 10% (w/w) sucrose, rats fed either high sucrose or low Cu diets had increased hepatic expression of genes involved in inflammation and fibrogenesis, including hepatic stellate cell activation, while the combination of diet factors also increased ATP citrate lyase (Acly) and fatty-acid synthase (Fasn) gene transcription (Fold change >2, p <0.02). Low dietary Cu decreased hepatic and serum Cu (p ≤0.05), promoted lipid peroxidation, and induced NAFLD-like histopathology, while the combined factors also induced fasting hepatic insulin resistance and liver damage. Neither low Cu nor 30% sucrose in the diet led to enhanced weight gain. Taken together, transcript profiles, histological and biochemical data indicate that low Cu and high sucrose promote hepatic gene expression and physiological responses associated with NAFLD and NASH, even in the absence of obesity or severe steatosis. PMID:26033743

Impaired copper and iron metabolism in blood cells and muscles of patients affected by copper deficiency myeloneuropathy.

PubMed

Spinazzi, Marco; Sghirlanzoni, Angelo; Salviati, Leonardo; Angelini, Corrado

2014-12-01

Severe copper deficiency leads in humans to a treatable multisystem disease characterized by anaemia and degeneration of spinal cord and nerves, but its mechanisms have not been investigated. We tested whether copper deficit leads to alterations in fundamental copper-dependent proteins and in iron metabolism in blood and muscles of patients affected by copper deficiency myeloneuropathy, and if these metabolic abnormalities are associated with compensatory mechanisms for copper maintenance. We evaluated the expression of critical copper enzymes, of iron-related proteins, and copper chaperones and transporters in blood and muscles from five copper-deficient patients presenting with subacute sensory ataxia, muscle paralysis, liver steatosis and variable anaemia. Severe copper deficiency was caused by chronic zinc intoxication in all of the patients, with an additional history of gastrectomy in two cases. The antioxidant enzyme SOD1 and subunit 2 of cytochrome c oxidase were significantly decreased in blood cells and in muscles of copper-deficient patients compared with controls. In muscle, the iron storage protein ferritin was dramatically reduced despite normal serum ferritin, and the expression of the haem-proteins cytochrome c and myoglobin was impaired. Muscle expression of the copper transporter CTR1 and of the copper chaperone CCS, was strikingly increased, while antioxidant protein 1 was diminished. copper-dependent enzymes with critical functions in antioxidant defences, in mitochondrial energy production, and in iron metabolism are affected in blood and muscles of patients with profound copper deficiency leading to myeloneuropathy. Homeostatic mechanisms are strongly activated to increase intracellular copper retention. © 2013 British Neuropathological Society.

Chronic Liver Diseases in Children: Clinical Profile and Histology.

PubMed

Dhole, Sachin Devidas; Kher, Archana S; Ghildiyal, Radha G; Tambse, Manjusha P

2015-07-01

The main aim of the study is to study the clinical profile of disorders of the liver and hepatobiliary system in paediatric patients and to correlate the histopathology findings of liver biopsy in chronic liver disease. Another aim being to assess the prognosis and to know the outcome and the effects of treatment in chronic liver diseases in paediatric age group. It was a prospective study, included the clinical profile of Chronic Liver Diseases (CLD) in children and the histopathological correlation. A total of 55 children were thoroughly investigated by doing relevant investigations and liver biopsy. A male predominance (60%) was noted with maximum incidence in the age group of 6-12 years. The incidence of CLD was 1.1% of total admissions. The most common presenting complaint was jaundice and abdominal distension. Hepatic encephalopathy was noted in 29% patients. Hepatomegaly was seen in 63% patients and spleenomegaly was seen in 60% patients. The incidence of cirrhosis on liver biopsy was 42% (23cases) in CLD patients. The most common diagnosis on histopathology was Wilson's disease (22%), followed by hepatitis and autoimmune hepatitis. The predominant spectrum of CLD was metabolic liver disease and also the predominant cause of death. As the incidence of CLD is quite low, a very high index of suspicion is required for its diagnosis. Some uncommon causes of CLD in children were seen in our study like neutral lipid storage disease, α1-Antitrypsin deficiency disease, lupus hepatitis, Alagille syndrome and Budd-Chiari syndrome. A patient of CLD with jaundice and hepatomegaly should be treated aggressively as those are the poor prognostic indicators of the disease. Hepatic encephalopathy and cirrhosis are also associated with poor outcome in patients with CLD. Liver biopsy histopathology by an expert and its correlation with laboratory investigations plays an important role in the diagnosis of CLD. The major cause of deaths in patients with CLD is due to end stage

The Natural Course of Non-Alcoholic Fatty Liver Disease

PubMed Central

Calzadilla Bertot, Luis; Adams, Leon Anton

2016-01-01

Non-alcoholic fatty liver disease (NAFLD) is the most prevalent form of chronic liver disease in the world, paralleling the epidemic of obesity and Type 2 diabetes mellitus (T2DM). NAFLD exhibits a histological spectrum, ranging from “bland steatosis” to the more aggressive necro-inflammatory form, non-alcoholic steatohepatitis (NASH) which may accumulate fibrosis to result in cirrhosis. Emerging data suggests fibrosis, rather than NASH per se, to be the most important histological predictor of liver and non-liver related death. Nevertheless, only a small proportion of individuals develop cirrhosis, however the large proportion of the population affected by NAFLD has led to predictions that NAFLD will become a leading cause of end stage liver disease, hepatocellular carcinoma (HCC), and indication for liver transplantation. HCC may arise in non-cirrhotic liver in the setting of NAFLD and is associated with the presence of the metabolic syndrome (MetS) and male gender. The MetS and its components also play a key role in the histological progression of NAFLD, however other genetic and environmental factors may also influence the natural history. The importance of NAFLD in terms of overall survival extends beyond the liver where cardiovascular disease and malignancy represents additional important causes of death. PMID:27213358

Role of the Gut Microbiome in Nonalcoholic Fatty Liver Disease.

PubMed

Aqel, Bashar; DiBaise, John K

2015-12-01

The incidence of nonalcoholic fatty liver disease (NAFLD) continues to increase with prevalence estimates ranging from 17%-33%, making it is the most common cause of chronic liver disease in North America. Its importance is due to not only its prevalence but also its association with increased cardiovascular morbidity and progression to cirrhosis in a subset of patients. NAFLD encompasses a pathologic spectrum of disease, from relatively benign accumulation of lipid (steatosis) to progressive nonalcoholic steatohepatitis associated with inflammation, fibrosis, and necrosis. Nonalcoholic steatohepatitis remains an important phenotypic state because this subgroup of patients is deemed at high risk for developing cirrhosis and progressing to liver failure requiring transplantation or to death. Gut microbiota has recently been identified as regulators of energy homeostasis and fat deposition, thereby implicating them in the development of obesity and associated metabolic diseases. The growing evidence that alteration in gut microbiota (dysbiosis) may affect liver pathology may allow for a better understanding of its role in the pathogenesis of NAFLD, help to identify patients at risk of progression, and expose a microbial target for prevention and therapeutic intervention. In this review, we discuss the growing evidence that highlights the relationship between gut microbiota and its association with NAFLD. © 2015 American Society for Parenteral and Enteral Nutrition.

Inorganic arsenic causes fatty liver and interacts with ethanol to cause alcoholic liver disease in zebrafish

PubMed Central

Zhang, Chi; Austin, Christine; Amarasiriwardena, Chitra; Arora, Manish

2018-01-01

ABSTRACT The rapid increase in fatty liver disease (FLD) incidence is attributed largely to genetic and lifestyle factors; however, environmental toxicants are a frequently overlooked factor that can modify the effects of more common causes of FLD. Chronic exposure to inorganic arsenic (iAs) is associated with liver disease in humans and animal models, but neither the mechanism of action nor the combinatorial interaction with other disease-causing factors has been fully investigated. Here, we examined the contribution of iAs to FLD using zebrafish and tested the interaction with ethanol to cause alcoholic liver disease (ALD). We report that zebrafish exposed to iAs throughout development developed specific phenotypes beginning at 4 days post-fertilization (dpf), including the development of FLD in over 50% of larvae by 5 dpf. Comparative transcriptomic analysis of livers from larvae exposed to either iAs or ethanol revealed the oxidative stress response and the unfolded protein response (UPR) caused by endoplasmic reticulum (ER) stress as common pathways in both these models of FLD, suggesting that they target similar cellular processes. This was confirmed by our finding that arsenic is synthetically lethal with both ethanol and a well-characterized ER-stress-inducing agent (tunicamycin), suggesting that these exposures work together through UPR activation to cause iAs toxicity. Most significantly, combined exposure to sub-toxic concentrations of iAs and ethanol potentiated the expression of UPR-associated genes, cooperated to induce FLD, reduced the expression of as3mt, which encodes an arsenic-metabolizing enzyme, and significantly increased the concentration of iAs in the liver. This demonstrates that iAs exposure is sufficient to cause FLD and that low doses of iAs can potentiate the effects of ethanol to cause liver disease. This article has an associated First Person interview with the first author of the paper. PMID:29361514

Intestinal microbiota in liver disease.

PubMed

Haque, Tanvir R; Barritt, A Sidney

2016-02-01

The intestinal microbiota have emerged as a topic of intense interest in gastroenterology and hepatology. The liver is on the front line as the first filter of nutrients, toxins and bacterial metabolites from the intestines and we are becoming increasingly aware of interactions among the gut, liver and immune system as important mediators of liver health and disease. Manipulating the microbiota with therapeutic intent is a rapidly expanding field. In this review, we will describe what is known about the contribution of intestinal microbiota to liver homeostasis; the role of dysbiosis in the pathogenesis of liver disease including alcoholic and non-alcoholic fatty liver disease, cirrhosis and hepatocellular carcinoma; and the therapeutic manifestations of altering intestinal microbiota via antibiotics, prebiotics, probiotics and fecal microbiota transplantation. Copyright © 2016. Published by Elsevier Ltd.

Liver Disease in Mitochondrial Disorders

PubMed Central

Lee, Way S.; Sokol, Ronald J.

2013-01-01

Liver involvement, a common feature in childhood mitochondrial hepatopathies, particularly in the neonatal period, may manifest as neonatal acute liver failure, hepatic steatohepatitis, cholestasis, or cirrhosis with chronic liver failure of insidious onset. There are usually significant neuromuscular symptoms, multisystem involvement, and lactic acidemia. The liver disease is usually progressive and eventually fatal. Current medical therapy of mitochondrial hepatopathies is largely ineffective, and the prognosis is usually poor. The role of liver transplantation in patients with liver failure remains poorly defined because of the systemic nature of the disease that does not respond to transplantation. Several specific molecular defects (mutations in nuclear genes such as SCO1, BCS1L, POLG, DGUOK, and MPV17 and deletion or rearrangement of mitochondrial DNA) have been identified in recent years. Prospective, longitudinal multicenter studies will be needed to address the gaps in our knowledge in these rare liver diseases. PMID:17682973

GENETIC MODIFIERS OF LIVER DISEASE IN CYSTIC FIBROSIS

PubMed Central

Bartlett, Jaclyn R.; Friedman, Kenneth J.; Ling, Simon C.; Pace, Rhonda G.; Bell, Scott C.; Bourke, Billy; Castaldo, Giuseppe; Castellani, Carlo; Cipolli, Marco; Colombo, Carla; Colombo, John L.; Debray, Dominique; Fernandez, Adriana; Lacaille, Florence; Macek, Milan; Rowland, Marion; Salvatore, Francesco; Taylor, Christopher J.; Wainwright, Claire; Wilschanski, Michael; Zemková, Dana; Hannah, William B.; Phillips, M. James; Corey, Mary; Zielenski, Julian; Dorfman, Ruslan; Wang, Yunfei; Zou, Fei; Silverman, Lawrence M.; Drumm, Mitchell L.; Wright, Fred A.; Lange, Ethan M.; Durie, Peter R.; Knowles, Michael R.

2013-01-01

Context A subset (~3–5%) of patients with cystic fibrosis (CF) develops severe liver disease (CFLD) with portal hypertension. Objective To assess whether any of 9 polymorphisms in 5 candidate genes (SERPINA1, ACE, GSTP1, MBL2, and TGFB1) are associated with severe liver disease in CF patients. Design, Setting, and Participants A 2-stage design was used in this case–control study. CFLD subjects were enrolled from 63 U.S., 32 Canadian, and 18 CF centers outside of North America, with the University of North Carolina at Chapel Hill (UNC) as the coordinating site. In the initial study, we studied 124 CFLD patients (enrolled 1/1999–12/2004) and 843 CF controls (patients without CFLD) by genotyping 9 polymorphisms in 5 genes previously implicated as modifiers of liver disease in CF. In the second stage, the SERPINA1 Z allele and TGFB1 codon 10 genotype were tested in an additional 136 CFLD patients (enrolled 1/2005–2/2007) and 1088 CF controls. Main Outcome Measures We compared differences in distribution of genotypes in CF patients with severe liver disease versus CF patients without CFLD. Results The initial study showed CFLD to be associated with the SERPINA1 (also known as α1-antiprotease and α1-antitrypsin) Z allele (P value=3.3×10−6; odds ratio (OR) 4.72, 95% confidence interval (CI) 2.31–9.61), and with transforming growth factor β-1 (TGFB1) codon 10 CC genotype (P=2.8×10−3; OR 1.53, CI 1.16–2.03). In the replication study, CFLD was associated with the SERPINA1 Z allele (P=1.4×10−3; OR 3.42, CI 1.54–7.59), but not with TGFB1 codon 10. A combined analysis of the initial and replication studies by logistic regression showed CFLD to be associated with SERPINA1 Z allele (P=1.5×10−8; OR 5.04, CI 2.88–8.83). Conclusion The SERPINA1 Z allele is a risk factor for liver disease in CF. Patients who carry the Z allele are at greater odds (OR ~5) to develop severe liver disease with portal hypertension. PMID:19738092

Methods to determine intestinal permeability and bacterial translocation during liver disease

PubMed Central

Wang, Lirui; Llorente, Cristina; Hartmann, Phillipp; Yang, An-Ming; Chen, Peng; Schnabl, Bernd

2015-01-01

Liver disease is often times associated with increased intestinal permeability. A disruption of the gut barrier allows microbial products and viable bacteria to translocate from the intestinal lumen to extraintestinal organs. The majority of the venous blood from the intestinal tract is drained into the portal circulation, which is part of the dual hepatic blood supply. The liver is therefore the first organ in the body to encounter not only absorbed nutrients, but also gut-derived bacteria and pathogen associated molecular patterns (PAMPs). Chronic exposure to increased levels of PAMPs has been linked to disease progression during early stages and to infectious complications during late stages of liver disease (cirrhosis). It is therefore important to assess and monitor gut barrier dysfunction during hepatic disease. We review methods to assess intestinal barrier disruption and discuss advantages and disadvantages. We will in particular focus on methods that we have used to measure increased intestinal permeability and bacterial translocation during experimental liver disease models. PMID:25595554

Review article: the endocannabinoid system in liver disease, a potential therapeutic target.

PubMed

Basu, P P; Aloysius, M M; Shah, N J; Brown, R S

2014-04-01

Endocannabinoids are a family of potent lipid-soluble molecules, acting on the cannabinoid (CB) receptors that mediate the effects of marijuana. The CB receptors, endocannabinoids and the enzymes involved in their synthesis and degradation are located in the brain and peripheral tissues, including the liver. To review the current understanding of the role of the endocannabinoid system in liver disease-associated pathophysiological conditions, and drugs targeting the endocannabinoid system as therapy for liver disease. Original articles and reviews were used to summarise the relevant pre-clinical and clinical research findings relating to this topic. The endocannabinoid system as a whole plays an important role in liver diseases (i.e. non-alcoholic liver disease, alcoholic liver disease, hepatic encephalopathy and autoimmune hepatitis) and related pathophysiological conditions (i.e. altered hepatic haemodynamics, cirrhotic cardiomyopathy, metabolic syndrome and ischaemia/reperfusion disease). Pharmacological targeting of the endocannabinoid system has had success as treatment for patients with liver disease, but adverse events led to withdrawal of marketing approval. However, there is optimism over novel therapeutics targeting the endocannabinoid system currently in the pre-clinical stage of development. The endocannabinoid system plays an important role in the pathophysiology of liver disease and its associated conditions. While some drugs targeting the endocannabinoid system have deleterious neurological adverse events, there is promise for a newer generation of therapies that do not cross the blood-brain barrier. © 2014 John Wiley & Sons Ltd.

Progesterone, prolactin, and gynaecomastia in men with liver disease.

PubMed Central

Farthing, M J; Green, J R; Edwards, C R; Dawson, A M

1982-01-01

Plasma progesterone was raised in 36 of 50 (72%) men with liver disease compared with 20 healthy male control subjects. Plasma progesterone was significantly higher in men with non-alcoholic cirrhosis with gynaecomastia than those without, but no similar relationship was found in men with alcoholic fatty change and alcoholic cirrhosis. Hyperprolactinaemia was found in 14% of men with liver disease but levels were unrelated to the presence of gynaecomastia. Increased circulating levels of progesterone and prolactin alone do not explain the development of gynaecomastia in patients with liver disease, but progesterone may be an additional factor acting in association with the known disturbances of other sex steroids. PMID:7076004

Association of coffee and caffeine consumption with fatty liver disease, nonalcoholic steatohepatitis, and degree of hepatic fibrosis.

PubMed

Molloy, Jeffrey W; Calcagno, Christopher J; Williams, Christopher D; Jones, Frances J; Torres, Dawn M; Harrison, Stephen A

2012-02-01

Coffee caffeine consumption (CC) is associated with reduced hepatic fibrosis in patients with chronic liver diseases, such as hepatitis C. The association of CC with nonalcoholic fatty liver disease (NAFLD) has not been established. The aim of this study was to correlate CC with the prevalence and severity of NAFLD. Patients involved in a previously published NAFLD prevalence study, as well as additional NASH patients identified in the Brooke Army Medical Center Hepatology clinic, were queried about their caffeine intake. A validated questionnaire for CC was utilized to assess for a relationship between caffeine and four groups: ultrasound negative (controls), bland steatosis/not-NASH, NASH stage 0-1, and NASH stage 2-4. A total of 306 patients responded to the CC questionnaire. Average milligrams of total caffeine/coffee CC per day in controls, bland steatosis/not-NASH, NASH stage 0-1, and NASH stage 2-4 were 307/228, 229/160, 351/255, and 252/152, respectively. When comparing patients with bland steatosis/not-NASH to those with NASH stage 0-1, there was a significant difference in CC between the two groups (P = 0.005). Additionally, when comparing patients with NASH stage 0-1 to those with NASH stage 2-4, there was a significant difference in coffee CC (P = 0.016). Spearman's rank correlation analysis further supported a negative relationship between coffee CC and hepatic fibrosis (r = -0.215; P = 0.035). Coffee CC is associated with a significant reduction in risk of fibrosis among NASH patients. Copyright © 2011 American Association for the Study of Liver Diseases.

Liver Disease in Cystic Fibrosis: an Update

PubMed Central

Parisi, Giuseppe Fabio; Di Dio, Giovanna; Franzonello, Chiara; Gennaro, Alessia; Rotolo, Novella; Lionetti, Elena; Leonardi, Salvatore

2013-01-01

Context Cystic fibrosis (CF) is the most widespread autosomal recessive genetic disorder that limits life expectation amongst the Caucasian population. As the median survival has increased related to early multidisciplinary intervention, other manifestations of CF have emergedespecially for the broad spectrum of hepatobiliary involvement. The present study reviews the existing literature on liver disease in cystic fibrosis and describes the key issues for an adequate clinical evaluation and management of patients, with a focus on the pathogenetic, clinical and diagnostic-therapeutic aspects of liver disease in CF. Evidence Acquisition A literature search of electronic databases was undertaken for relevant studies published from 1990 about liver disease in cystic fibrosis. The databases searched were: EMBASE, PubMed and Cochrane Library. Results CF is due to mutations in the gene on chromosome 7 that encodes an amino acidic polypeptide named CFTR (cystic fibrosis transmembrane regulator). The hepatic manifestations include particular changes referring to the basic CFTR defect, iatrogenic lesions or consequences of the multisystem disease. Even though hepatobiliary disease is the most common non-pulmonary cause ofmortalityin CF (the third after pulmonary disease and transplant complications), only about the 33%ofCF patients presents clinically significant hepatobiliary disease. Conclusions Liver disease will have a growing impact on survival and quality of life of cystic fibrosis patients because a longer life expectancy and for this it is important its early recognition and a correct clinical management aimed atdelaying the onset of complications. This review could represent an opportunity to encourage researchers to better investigate genotype-phenotype correlation associated with the development of cystic fibrosis liver disease, especially for non-CFTR genetic polymorphisms, and detect predisposed individuals. Therapeutic trials are needed to find strategies of

Ursodeoxycholic Acid in Treatment of Non-cholestatic Liver Diseases: A Systematic Review.

PubMed

Reardon, Jillian; Hussaini, Trana; Alsahafi, Majid; Azalgara, Vladimir Marquez; Erb, Siegfried R; Partovi, Nilufar; Yoshida, Eric M

2016-09-28

Aims: To systematically evaluate the literature for evidence to support the use of bile acids in non-cholestatic liver conditions. Methods: Searches were conducted on the databases of Medline (1948-March 31, 2015), Embase (1980-March 31, 2015) and the Cochrane Central Register of Controlled Trials, and on Google and Google Scholar to identify articles describing ursodeoxycholic acid (UDCA) and its derivatives for non-cholestatic hepatic indications. Combinations of the following search terms were used: ursodeoxycholic acid, ursodiol, bile acids and/or salts, non alcoholic fatty liver, non alcoholic steatohepatitis, fatty liver, alcoholic hepatitis, alcohol, liver disease, autoimmune, autoimmune hepatitis, liver transplant, liver graft, transplant rejection, graft rejection, ischemic reperfusion injury, reperfusion injury, hepatitis B, hepatitis C, viral hepatitis, chronic hepatitis, acute hepatitis, transaminases, alanine transaminase, liver enzymes, aspartate aminotransferase, gamma-glutamyl transferase, gamma-glutamyl transpeptidase, bilirubin, alkaline phosphatase. No search limits were applied. Additionally, references of the included studies were reviewed to identify additional articles. Results: The literature search yielded articles meeting inclusion criteria for the following indications: non-alcoholic fatty liver disease (n = 5); alcoholic liver disease (n = 2); autoimmune hepatitis (n = 6), liver transplant (n = 2) and viral hepatitis (n = 9). Bile acid use was associated with improved normalization of liver biochemistry in non-alcoholic fatty liver disease, autoimmune hepatitis and hepatitis B and C infections. In contrast, liver biochemistry normalization was inconsistent in alcoholic liver disease and liver transplantation. The majority of studies reviewed showed that normalization of liver biochemistry did not correlate to improvement in histologic disease. In the prospective trials reviewed, adverse effects associated with the bile acids were limited

Ursodeoxycholic Acid in Treatment of Non-cholestatic Liver Diseases: A Systematic Review

PubMed Central

Reardon, Jillian; Hussaini, Trana; Alsahafi, Majid; Azalgara, Vladimir Marquez; Erb, Siegfried R.; Partovi, Nilufar; Yoshida, Eric M.

2016-01-01

Abstract Aims: To systematically evaluate the literature for evidence to support the use of bile acids in non-cholestatic liver conditions. Methods: Searches were conducted on the databases of Medline (1948-March 31, 2015), Embase (1980-March 31, 2015) and the Cochrane Central Register of Controlled Trials, and on Google and Google Scholar to identify articles describing ursodeoxycholic acid (UDCA) and its derivatives for non-cholestatic hepatic indications. Combinations of the following search terms were used: ursodeoxycholic acid, ursodiol, bile acids and/or salts, non alcoholic fatty liver, non alcoholic steatohepatitis, fatty liver, alcoholic hepatitis, alcohol, liver disease, autoimmune, autoimmune hepatitis, liver transplant, liver graft, transplant rejection, graft rejection, ischemic reperfusion injury, reperfusion injury, hepatitis B, hepatitis C, viral hepatitis, chronic hepatitis, acute hepatitis, transaminases, alanine transaminase, liver enzymes, aspartate aminotransferase, gamma-glutamyl transferase, gamma-glutamyl transpeptidase, bilirubin, alkaline phosphatase. No search limits were applied. Additionally, references of the included studies were reviewed to identify additional articles. Results: The literature search yielded articles meeting inclusion criteria for the following indications: non-alcoholic fatty liver disease (n = 5); alcoholic liver disease (n = 2); autoimmune hepatitis (n = 6), liver transplant (n = 2) and viral hepatitis (n = 9). Bile acid use was associated with improved normalization of liver biochemistry in non-alcoholic fatty liver disease, autoimmune hepatitis and hepatitis B and C infections. In contrast, liver biochemistry normalization was inconsistent in alcoholic liver disease and liver transplantation. The majority of studies reviewed showed that normalization of liver biochemistry did not correlate to improvement in histologic disease. In the prospective trials reviewed, adverse effects associated with the bile acids

Epidemiology and Natural History of Non-alcoholic Fatty Liver Disease

PubMed Central

Mishra, Alita; Younossi, Zobair M

2012-01-01

Non-alcoholic fatty liver disease (NAFLD) is an important cause of liver disease burden across the world. By definition, although the histopathologic features of NAFLD are identical to that of alcoholic liver disease, its diagnosis requires absence of significant alcohol use and absence of other causes of chronic liver disease. We now know that NAFLD is not simply a disease of the Western world. It is manifested across the world, in varying rates, across gender, across varying ethnicities, and in its association with other host factors. In this review article, the definition of NAFLD, its spectrum, ranging from mild steatosis to hepatocellular injury and inflammation defined as non-alcoholic steatohepatitis (NASH) is discussed. Mild steatosis is generally a stable disease whereas NASH can be progressive. Based on current published literature, current incidence and prevalence of NAFLD and NASH are discussed. It is also accepted that these processes will continue to increase in prevalence with the rise of obesity, type II diabetes, and associated metabolic syndrome. Some of the risk factors have been well-established and are discussed. In addition, this review also presents emerging associations with other risk factors for NAFLD. Natural history of NAFLD is variable depending upon the histologic subtypes and other underlying comorbidities and is discussed in this review as well. PMID:25755422

Immunology in the liver--from homeostasis to disease.

PubMed

Heymann, Felix; Tacke, Frank

2016-02-01

The liver is a central immunological organ with a high exposure to circulating antigens and endotoxins from the gut microbiota, particularly enriched for innate immune cells (macrophages, innate lymphoid cells, mucosal-associated invariant T (MAIT) cells). In homeostasis, many mechanisms ensure suppression of immune responses, resulting in tolerance. Tolerance is also relevant for chronic persistence of hepatotropic viruses or allograft acceptance after liver transplantation. The liver can rapidly activate immunity in response to infections or tissue damage. Depending on the underlying liver disease, such as viral hepatitis, cholestasis or NASH, different triggers mediate immune-cell activation. Conserved mechanisms such as molecular danger patterns (alarmins), Toll-like receptor signalling or inflammasome activation initiate inflammatory responses in the liver. The inflammatory activation of hepatic stellate and Kupffer cells results in the chemokine-mediated infiltration of neutrophils, monocytes, natural killer (NK) and natural killer T (NKT) cells. The ultimate outcome of the intrahepatic immune response (for example, fibrosis or resolution) depends on the functional diversity of macrophages and dendritic cells, but also on the balance between pro-inflammatory and anti-inflammatory T-cell populations. As reviewed here, tremendous progress has helped to understand the fine-tuning of immune responses in the liver from homeostasis to disease, indicating promising targets for future therapies in acute and chronic liver diseases.

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

PubMed

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

2017-02-01

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

Sugar-sweetened beverage, diet soda, and fatty liver disease in the Framingham Heart Study cohorts

PubMed Central

Ma, Jiantao; Fox, Caroline S.; Jacques, Paul F.; Speliotes, Elizabeth K.; Hoffmann, Udo; Smith, Caren E.; Saltzman, Edward; McKeown, Nicola M.

2016-01-01

Background & Aims Non-alcoholic fatty liver disease affects ~30% of US adults, yet the role of sugar-sweetened beverages and diet soda on these diseases remains unknown. We examined the cross-sectional association between intake of sugar-sweetened beverages or diet soda and fatty liver disease in participants of the Framingham Offspring and Third Generation cohorts. Methods Fatty liver disease was defined using liver attenuation measurements generated from computed tomography in 2634 participants. Alanine transaminase concentration, a crude marker of fatty liver disease, was measured in 5908 participants. Sugar-sweetened beverage and diet soda intake were estimated using a food frequency questionnaire. Participants were categorized as either non-consumers or consumers (3 categories: 1 serving/month to <1 serving/week, 1 serving/week to <1 serving/-day, and ⩾1 serving/day) of sugar-sweetened beverages or diet soda. Results After adjustment for age, sex, smoking status, Framingham cohort, energy intake, alcohol, dietary fiber, fat (% energy), protein (% energy), diet soda intake, and body mass index, the odds ratios of fatty liver disease were 1, 1.16 (0.88, 1.54), 1.32 (0.93, 1.86), and 1.61 (1.04, 2.49) across sugar-sweetened beverage consumption categories (p trend = 0.04). Sugar-sweetened beverage consumption was also positively associated with alanine transaminase levels (p trend = 0.007). We observed no significant association between diet soda intake and measures of fatty liver disease. Conclusion In conclusion, we observed that regular sugar-sweetened beverage consumption was associated with greater risk of fatty liver disease, particularly in overweight and obese individuals, whereas diet soda intake was not associated with measures of fatty liver disease. PMID:26055949

The Pathogenesis of Autoimmune Liver Disease.

PubMed

Arndtz, Katherine; Hirschfield, Gideon M

Autoimmune liver disease (AILD) encompasses 3 main distinct clinical diseases: autoimmune hepatitis, primary biliary cholangitis (formally known as cirrhosis, PBC) and primary sclerosing cholangitis (PSC). These conditions are an important, yet under-appreciated cause of patient morbidity and mortality with ongoing unmet needs for further research and clinical advances. There is observational evidence for genetic predisposition, with all 3 conditions being more common in first degree relatives. AILD is associated with the presence of auto-antibodies and higher risks of other non-hepatic auto-immune conditions. Genetic risk association studies have identified HLA and non-HLA risk loci for the development of disease, with some HLA loci providing prognostic information. This re-enforces the concept that genetic predisposition to autoimmunity is important, likely in the context of environmental exposures. Such environmental triggers are unclear but relevant risks include smoking, drug and xenobiotic exposure as well as the complexities of the microbiome. There is evidence for a loss of immune tolerance to self-antigens playing a part in the development of these conditions. In particular the IL-2 and IL-12 regulatory pathways have been implicated in pre-disposing to an unopposed inflammatory response within the liver. Main immunological themes revolve around loss of immune tolerance leading to T-cell mediated injury, imbalance in the regulation of immune cells and defective immune response to foreign antigens. For PBC and PSC, there is then the added complexity of the consequences of cholestasis on hepato-biliary injury, immune regulation and liver fibrosis. Whilst specific disease causes and triggers are still lacking, AILD arises on the background of collective genetic and environmental risk, leading to chronic and abnormal hepato-biliary immune responses. Effective and more rational therapy will ultimately be developed when the multiple pathways to liver injury are

Non-alcoholic fatty liver disease: an emerging driving force in chronic kidney disease.

PubMed

Targher, Giovanni; Byrne, Christopher D

2017-05-01

Non-alcoholic fatty liver disease (NAFLD) is caused by an accumulation of fat in the liver; the condition can progress over time to increase the risk of developing cirrhosis, end-stage liver disease and hepatocellular carcinoma. The prevalence of NAFLD is increasing rapidly owing to the global epidemics of obesity and type 2 diabetes mellitus (T2DM), and NAFLD has been predicted to become the most important indication for liver transplantation over the next decade. It is now increasingly clear that NAFLD not only affects the liver but can also increase the risk of developing extra-hepatic diseases, including T2DM, cardiovascular disease and chronic kidney disease (CKD), which have a considerable impact on health-care resources. Accumulating evidence indicates that NAFLD exacerbates insulin resistance, predisposes to atherogenic dyslipidaemia and releases a variety of proinflammatory factors, prothrombotic factors and profibrogenic molecules that can promote vascular and renal damage. Furthermore, communication or 'crosstalk' between affected organs or tissues in these diseases has the potential to further harm function and worsen patient outcomes, and increasing amounts of evidence point to a strong association between NAFLD and CKD. Whether a causal relationship between NAFLD and CKD exists remains to be definitively established.

ATP7A-related copper transport diseases-emerging concepts and future trends.

PubMed

Kaler, Stephen G

2011-01-01

This Review summarizes recent advances in understanding copper-transporting ATPase 1 (ATP7A), and examines the neurological phenotypes associated with dysfunction of this protein. Involvement of ATP7A in axonal outgrowth, synapse integrity and neuronal activation underscores the fundamental importance of copper metabolism to neurological function. Defects in ATP7A cause Menkes disease, an infantile-onset, lethal condition. Neonatal diagnosis and early treatment with copper injections enhance survival in patients with this disease, and can normalize clinical outcomes if mutant ATP7A molecules retain small amounts of residual activity. Gene replacement rescues a mouse model of Menkes disease, suggesting a potential therapeutic approach for patients with complete loss-of-function ATP7A mutations. Remarkably, a newly discovered ATP7A disorder-isolated distal motor neuropathy-has none of the characteristic clinical or biochemical abnormalities of Menkes disease or its milder allelic variant occipital horn syndrome (OHS), instead resembling Charcot-Marie-Tooth disease type 2. These findings indicate that ATP7A has a crucial but previously unappreciated role in motor neuron maintenance, and that the mechanism underlying ATP7A-related distal motor neuropathy is distinct from Menkes disease and OHS pathophysiology. Collectively, these insights refine our knowledge of the neurology of ATP7A-related copper transport diseases and pave the way for further progress in understanding ATP7A function.

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

PubMed

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

2015-08-07

To evaluate the nutritional status and its association with proinflammatory cytokines in children with chronic liver disease. 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. The median (25(th)-75(th) 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-Pugh score (P = 0

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

Circulating lipocalin 2 is neither related to liver steatosis in patients with non-alcoholic fatty liver disease nor to residual liver function in cirrhosis.

PubMed

Meier, Elisabeth M; Pohl, Rebekka; Rein-Fischboeck, Lisa; Schacherer, Doris; Eisinger, Kristina; Wiest, Reiner; Krautbauer, Sabrina; Buechler, Christa

2016-09-01

Lipocalin 2 (LCN2) is induced in the injured liver and associated with inflammation. Aim of the present study was to evaluate whether serum LCN2 is a non-invasive marker to assess hepatic steatosis in patients with non-alcoholic fatty liver disease (NAFLD) or residual liver function in patients with liver cirrhosis. Therefore, LCN2 was measured by ELISA in serum of 32 randomly selected patients without fatty liver (controls), 24 patients with ultrasound diagnosed NAFLD and 42 patients with liver cirrhosis mainly due to alcohol. Systemic LCN2 was comparable in patients with liver steatosis, those with liver cirrhosis and controls. LCN2 negatively correlated with bilirubin in both cohorts. In cirrhosis, LCN2 was not associated with more advanced liver injury defined by the CHILD-PUGH score and model for end-stage liver disease score. Resistin but not C-reactive protein or chemerin positively correlated with LCN2. LCN2 levels were not increased in patients with ascites or patients with esophageal varices. Consequently, reduction of portal pressure by transjugular intrahepatic portosystemic shunt did not affect LCN2 levels. Hepatic venous blood (HVS), portal venous blood and systemic venous blood levels of LCN2 were similar. HVS LCN2 was unchanged in patients with end-stage liver cirrhosis compared to those with well-compensated disease arguing against increased hepatic release. Current data exclude that serum LCN2 is of any value as steatosis marker in patients with NAFLD and indicator of liver function in patients with alcoholic liver cirrhosis. Copyright © 2016 Elsevier Ltd. All rights reserved.

Effect of Liver Disease on Hepatic Transporter Expression and Function.

PubMed

Thakkar, Nilay; Slizgi, Jason R; Brouwer, Kim L R

2017-09-01

Liver disease can alter the disposition of xenobiotics and endogenous substances. Regulatory agencies such as the Food and Drug Administration and the European Medicines Evaluation Agency recommend, if possible, studying the effect of liver disease on drugs under development to guide specific dose recommendations in these patients. Although extensive research has been conducted to characterize the effect of liver disease on drug-metabolizing enzymes, emerging data have implicated that the expression and function of hepatobiliary transport proteins also are altered in liver disease. This review summarizes recent developments in the field, which may have implications for understanding altered disposition, safety, and efficacy of new and existing drugs. A brief review of liver physiology and hepatic transporter localization/function is provided. Then, the expression and function of hepatic transporters in cholestasis, hepatitis C infection, hepatocellular carcinoma, human immunodeficiency virus infection, nonalcoholic fatty liver disease and nonalcoholic steatohepatitis, and primary biliary cirrhosis are reviewed. In the absence of clinical data, nonclinical information in animal models is presented. This review aims to advance the understanding of altered expression and function of hepatic transporters in liver disease and the implications of such changes on drug disposition. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Non-alcoholic fatty liver disease and dyslipidemia: An update.

PubMed

Katsiki, Niki; Mikhailidis, Dimitri P; Mantzoros, Christos S

2016-08-01

Non-alcoholic fatty liver (NAFLD) is the most common liver disease worldwide, progressing from simple steatosis to necroinflammation and fibrosis (leading to non-alcoholic steatohepatitis, NASH), and in some cases to cirrhosis and hepatocellular carcinoma. Inflammation, oxidative stress and insulin resistance are involved in NAFLD development and progression. NAFLD has been associated with several cardiovascular (CV) risk factors including obesity, dyslipidemia, hyperglycemia, hypertension and smoking. NAFLD is also characterized by atherogenic dyslipidemia, postprandial lipemia and high-density lipoprotein (HDL) dysfunction. Most importantly, NAFLD patients have an increased risk for both liver and CV disease (CVD) morbidity and mortality. In this narrative review, the associations between NAFLD, dyslipidemia and vascular disease in NAFLD patients are discussed. NAFLD treatment is also reviewed with a focus on lipid-lowering drugs. Finally, future perspectives in terms of both NAFLD diagnostic biomarkers and therapeutic targets are considered. Copyright © 2016 Elsevier Inc. All rights reserved.

End-Stage Liver Disease in Patients with Intracranial Hemorrhage Is Associated with Increased Mortality: A Cohort Study.

PubMed

Lagman, Carlito; Nagasawa, Daniel T; Sheppard, John P; Jacky Chen, Cheng Hao; Nguyen, Thien; Prashant, Giyarpuram N; Niu, Tianyi; Tucker, Alexander M; Kim, Won; Pouratian, Nader; Kaldas, Fady M; Busuttil, Ronald W; Yang, Isaac

2018-05-01

To determine if end-stage liver disease (ESLD) in patients with intracranial hemorrhage (ICH) is associated with increased mortality. This single-center, retrospective cohort study included 53 patients (33 in ESLD cohort and 20 in non-ESLD cohort) who received neurosurgical care between 2006 and 2017. ESLD was defined clinically as severely impaired liver function and at least 1 major complication of liver failure. The primary outcome was mortality. Overall, in-hospital, and 30-day mortality rates were higher in the ESLD cohort versus the non-ESLD cohort (79 vs. 30%, 79 vs. 20%, and 64 vs. 25%, all P ≤ 0.01). We identified a significant difference in overall survival between ESLD and non-ESLD cohorts on Kaplan-Meier analysis (P = 0.004 with log-rank and Wilcoxon tests). Odds of overall, in-hospital, and 30-day mortality in the ESLD cohort were 8.67 (95% confidence interval [CI], 2.44-30.84), 14.86 (95% CI, 3.75-58.90), and 5.25 (95% CI, 1.53-18.08). Other predictors of overall mortality included primary admission diagnosis of liver disease (odds ratio [OR] = 9.60; 95% CI, 3.75-58.90), higher Child-Pugh (OR = 1.64; 95% CI, 2.66-34.67) and Model for End-Stage Liver Disease (OR = 1.12; 95% CI, 1.04-1.20) scores, lower Glasgow Coma Scale score (OR = 0.73; 95% CI, 0.61-0.88), ICH that developed in the hospital (OR = 4.11; 95% CI, 1.21-13.98), and intraparenchymal hemorrhage (OR = 9.23; 95% CI, 1.72-49.56). ESLD in patients with ICH is associated with increased mortality. Copyright © 2018 Elsevier Inc. All rights reserved.

Emerging roles of SIRT1 in fatty liver diseases

PubMed Central

Ding, Ren-Bo; Bao, Jiaolin; Deng, Chu-Xia

2017-01-01

Fatty liver diseases, which are commonly associated with high-fat/calorie diet, heavy alcohol consumption and/or other metabolic disorder causes, lead to serious medical concerns worldwide in recent years. It has been demonstrated that metabolic homeostasis disruption is most likely to be responsible for this global epidemic. Sirtuins are a group of conserved nicotinamide adenine dinucleotide (NAD+) dependent histone and/or protein deacetylases belonging to the silent information regulator 2 (Sir2) family. Among seven mammalian sirtuins, sirtuin 1 (SIRT 1) is the most extensively studied one and is involved in both alcoholic and nonalcoholic fatty liver diseases. SIRT1 plays beneficial roles in regulating hepatic lipid metabolism, controlling hepatic oxidative stress and mediating hepatic inflammation through deacetylating some transcriptional regulators against the progression of fatty liver diseases. Here we summarize the latest advances of the biological roles of SIRT1 in regulating lipid metabolism, oxidative stress and inflammation in the liver, and discuss the potential of SIRT1 as a therapeutic target for treating alcoholic and nonalcoholic fatty liver diseases. PMID:28808418

Liver-brain interactions in inflammatory liver diseases: implications for fatigue and mood disorders.

PubMed

D'Mello, Charlotte; Swain, Mark G

2014-01-01

Chronic inflammatory liver diseases are often accompanied by behavior alterations including fatigue, mood disorders, cognitive dysfunction and sleep disturbances. These altered behaviors can adversely affect patient quality of life. The communication pathways between the inflamed liver and the brain that mediate changes in central neural activity leading to behavior alterations during liver inflammation are poorly understood. Neural and humoral communication pathways have been most commonly implicated as driving peripheral inflammation to brain signaling. Classically, the cytokines TNFα, IL-1β and IL-6 have received the greatest scientific attention as potential mediators of this communication pathway. In mice with liver inflammation we have identified a novel immune-mediated liver-to-brain communication pathway whereby CCR2(+) monocytes found within the peripheral circulation transmigrate into the brain parenchyma in response to MCP-1/CCL2 expressing activated microglia. Inhibition of cerebral monocyte infiltration in these mice significantly improved liver inflammation associated sickness behaviors. Importantly, in recent work we have found that at an earlier time point, when cerebral monocyte infiltration is not evident in mice with liver inflammation, increased monocyte:cerebral endothelial cell adhesive interactions are observed using intravital microscopy of the brain. These monocyte:cerebral endothelial cell adhesive interactions are P-selectin mediated, and inhibition of these interactions attenuated microglial activation and sickness behavior development. Delineating the pathways that the periphery uses to communicate with the brain during inflammatory liver diseases, and the central neurotransmitter systems that are altered through these communication pathways (e.g., serotonin, corticotrophin releasing hormone) to give rise to liver inflammation-associated sickness behaviors, will allow for the identification of novel therapeutic targets to decrease the

Combination therapy with andrographolide and D-penicillamine enhanced therapeutic advantage over monotherapy with D-penicillamine in attenuating fibrogenic response and cell death in the periportal zone of liver in rats during copper toxicosis

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

Roy, Dijendra Nath; Sen, Gargi; Chowdhury, Kaustav Dutta

2011-01-01

Long treatment regime with D-penicillamine is needed before it can exert clinically meaningful benefits in the treatment of copper toxicosis. The consequence of long-term D-penicillamine treatment is associated with numerous side effects. The limitations of D-penicillamine monotherapy prompted us to search for more effective treatment strategies that could decrease the duration of D-penicillamine therapy. The present study was designed to evaluate the therapeutic potential of D-penicillamine in combination with another hepatoprotective drug, andrographolide in treatment of copper toxicosis in rats. D-penicillamine treatment led to the excretion of copper through urine. Addition of andrographolide to D-penicillamine regime appeared to increase protectionmore » of liver by increasing the biliary excretion of copper and reduction in cholestatic injury. The early removal of the causative agent copper during combination treatment was the most effective therapeutic intervention that contributed to the early rectification of fibrosis in liver. Combination treatment reduced Kupffer cells accumulation and TNF{alpha} production in liver of copper exposed rats. In particular, andrographolide mediated the anti-inflammatory effect by inhibiting the cytokine production. However, another possible mechanism of cytoprotection of andrographolide was decreasing mitochondrial production of superoxide anions that resulted in better restoration of mitochondrial dysfunction during combination therapy than monotherapy. Furthermore, ROS inhibition by combination regimen resulted in significant decline in activation of caspase cascade. Inhibition of caspases attenuated apoptosis of hepatocytes, induced by chronic copper exposure. In summary, this study suggested that added benefit of combination treatment over use of either agent alone in alleviating the hepatotoxicity and fibrosis associated with copper toxicosis.« less

A Protein-Truncating HSD17B13 Variant and Protection from Chronic Liver Disease.

PubMed

Abul-Husn, Noura S; Cheng, Xiping; Li, Alexander H; Xin, Yurong; Schurmann, Claudia; Stevis, Panayiotis; Liu, Yashu; Kozlitina, Julia; Stender, Stefan; Wood, G Craig; Stepanchick, Ann N; Still, Matthew D; McCarthy, Shane; O'Dushlaine, Colm; Packer, Jonathan S; Balasubramanian, Suganthi; Gosalia, Nehal; Esopi, David; Kim, Sun Y; Mukherjee, Semanti; Lopez, Alexander E; Fuller, Erin D; Penn, John; Chu, Xin; Luo, Jonathan Z; Mirshahi, Uyenlinh L; Carey, David J; Still, Christopher D; Feldman, Michael D; Small, Aeron; Damrauer, Scott M; Rader, Daniel J; Zambrowicz, Brian; Olson, William; Murphy, Andrew J; Borecki, Ingrid B; Shuldiner, Alan R; Reid, Jeffrey G; Overton, John D; Yancopoulos, George D; Hobbs, Helen H; Cohen, Jonathan C; Gottesman, Omri; Teslovich, Tanya M; Baras, Aris; Mirshahi, Tooraj; Gromada, Jesper; Dewey, Frederick E

2018-03-22

Elucidation of the genetic factors underlying chronic liver disease may reveal new therapeutic targets. We used exome sequence data and electronic health records from 46,544 participants in the DiscovEHR human genetics study to identify genetic variants associated with serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Variants that were replicated in three additional cohorts (12,527 persons) were evaluated for association with clinical diagnoses of chronic liver disease in DiscovEHR study participants and two independent cohorts (total of 37,173 persons) and with histopathological severity of liver disease in 2391 human liver samples. A splice variant (rs72613567:TA) in HSD17B13, encoding the hepatic lipid droplet protein hydroxysteroid 17-beta dehydrogenase 13, was associated with reduced levels of ALT (P=4.2×10 -12 ) and AST (P=6.2×10 -10 ). Among DiscovEHR study participants, this variant was associated with a reduced risk of alcoholic liver disease (by 42% [95% confidence interval {CI}, 20 to 58] among heterozygotes and by 53% [95% CI, 3 to 77] among homozygotes), nonalcoholic liver disease (by 17% [95% CI, 8 to 25] among heterozygotes and by 30% [95% CI, 13 to 43] among homozygotes), alcoholic cirrhosis (by 42% [95% CI, 14 to 61] among heterozygotes and by 73% [95% CI, 15 to 91] among homozygotes), and nonalcoholic cirrhosis (by 26% [95% CI, 7 to 40] among heterozygotes and by 49% [95% CI, 15 to 69] among homozygotes). Associations were confirmed in two independent cohorts. The rs72613567:TA variant was associated with a reduced risk of nonalcoholic steatohepatitis, but not steatosis, in human liver samples. The rs72613567:TA variant mitigated liver injury associated with the risk-increasing PNPLA3 p.I148M allele and resulted in an unstable and truncated protein with reduced enzymatic activity. A loss-of-function variant in HSD17B13 was associated with a reduced risk of chronic liver disease and of progression from

Anesthesia for Patients With Liver Disease

PubMed Central

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

2014-01-01

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

Fatty Liver Index and Lipid Accumulation Product Can Predict Metabolic Syndrome in Subjects without Fatty Liver Disease

PubMed Central

Cheng, Yuan-Lung; Wang, Yuan-Jen; Lan, Keng-Hsin; Huo, Teh-Ia; Hsieh, Wei-Yao; Hou, Ming-Chih; Lee, Fa-Yauh; Wu, Jaw-Ching; Lee, Shou-Dong

2017-01-01

Background. Fatty liver index (FLI) and lipid accumulation product (LAP) are indexes originally designed to assess the risk of fatty liver and cardiovascular disease, respectively. Both indexes have been proven to be reliable markers of subsequent metabolic syndrome; however, their ability to predict metabolic syndrome in subjects without fatty liver disease has not been clarified. Methods. We enrolled consecutive subjects who received health check-up services at Taipei Veterans General Hospital from 2002 to 2009. Fatty liver disease was diagnosed by abdominal ultrasonography. The ability of the FLI and LAP to predict metabolic syndrome was assessed by analyzing the area under the receiver operating characteristic (AUROC) curve. Results. Male sex was strongly associated with metabolic syndrome, and the LAP and FLI were better than other variables to predict metabolic syndrome among the 29,797 subjects. Both indexes were also better than other variables to detect metabolic syndrome in subjects without fatty liver disease (AUROC: 0.871 and 0.879, resp.), and the predictive power was greater among women. Conclusion. Metabolic syndrome increases the cardiovascular disease risk. The FLI and LAP could be used to recognize the syndrome in both subjects with and without fatty liver disease who require lifestyle modifications and counseling. PMID:28194177

Tuberculosis and liver disease: management issues.

PubMed

Sonika, Ujjwal; Kar, Premashis

2012-01-01

Tuberculosis is one of the most common diseases in India and has attained epidemic proportions. Tuberculosis and liver are related in many ways. Liver disease can occur due to hepatic tuberculosis or the treatment with various anti-tubercular drugs may precipitate hepatic injury or patients with chronic liver disease may develop tuberculosis and pose special management problems. Tuberculosis per se can affect liver in three forms. The most common form is the diffuse hepatic involvement, seen along with pulmonary or miliary tuberculosis. The second is granulomatous hepatitis and the third, much rarer form presents as focal/local tuberculoma or abscess. Tubercular disease of liver occurring along with pulmonary involvement as in disseminated tuberculosis is treated with standard regimen for pulmonary tuberculosis. Granulomatous hepatitis and tubercular liver abscess are treated like any other extra-pulmonary tubercular lesions without any extra risk of hepatotoxicity by anti-tubercular drugs. Treatment of tuberculosis in patients who already have a chronic liver disease poses various clinical challenges. There is an increased risk of drug induced hepatitis in these patients and its implications are potentially more serious in these patients as their hepatic reserve is already depleted. However, hepatotoxic anti-tubercular drugs can be safely used in these patients if the number of drugs used is adjusted appropriately. Thus, the main principle is to closely monitor the patient for signs of worsening liver disease and to reduce the number of hepatotoxic drugs in the anti-tubercular regimen according to the severity of underlying liver disease.

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

PubMed Central

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

2015-01-01

Patient: Female, 21 Final Diagnosis: Unresectable liver adenomatosis associated with congenital absence of portal vein Symptoms: — Medication: — Clinical Procedure: Living donor liver transplantation Specialty: Transplantology Objective: Rare disease Background: Abernethy malformation (AM), or congenital absence of portal vein (CAPV), is a very rare disease which tends to be associated with the development of benign or malignant tumors, usually in children or young adults. Case Report: We report the case of a 21-year-old woman diagnosed with type Ib AM (portal vein draining directly into the inferior vena cava) and unresectable liver adenomatosis. The patient presented mild liver dysfunction and was largely asymptomatic. Living donor liver transplantation was performed using a left hemiliver graft from her mother. Postoperatively, the patient attained optimal liver function and at 9-month follow-up has returned to normal life. Conclusions: We consider that living donor liver transplantation is the best therapeutic solution for AM associated with unresectable liver adenomatosis, especially because compared to receiving a whole liver graft, the waiting time on the liver transplantation list is much shorter. PMID:26386552

Inorganic arsenic causes fatty liver and interacts with ethanol to cause alcoholic liver disease in zebrafish.

PubMed

Bambino, Kathryn; Zhang, Chi; Austin, Christine; Amarasiriwardena, Chitra; Arora, Manish; Chu, Jaime; Sadler, Kirsten C

2018-02-26

The rapid increase in fatty liver disease (FLD) incidence is attributed largely to genetic and lifestyle factors; however, environmental toxicants are a frequently overlooked factor that can modify the effects of more common causes of FLD. Chronic exposure to inorganic arsenic (iAs) is associated with liver disease in humans and animal models, but neither the mechanism of action nor the combinatorial interaction with other disease-causing factors has been fully investigated. Here, we examined the contribution of iAs to FLD using zebrafish and tested the interaction with ethanol to cause alcoholic liver disease (ALD). We report that zebrafish exposed to iAs throughout development developed specific phenotypes beginning at 4 days post-fertilization (dpf), including the development of FLD in over 50% of larvae by 5 dpf. Comparative transcriptomic analysis of livers from larvae exposed to either iAs or ethanol revealed the oxidative stress response and the unfolded protein response (UPR) caused by endoplasmic reticulum (ER) stress as common pathways in both these models of FLD, suggesting that they target similar cellular processes. This was confirmed by our finding that arsenic is synthetically lethal with both ethanol and a well-characterized ER-stress-inducing agent (tunicamycin), suggesting that these exposures work together through UPR activation to cause iAs toxicity. Most significantly, combined exposure to sub-toxic concentrations of iAs and ethanol potentiated the expression of UPR-associated genes, cooperated to induce FLD, reduced the expression of as3mt , which encodes an arsenic-metabolizing enzyme, and significantly increased the concentration of iAs in the liver. This demonstrates that iAs exposure is sufficient to cause FLD and that low doses of iAs can potentiate the effects of ethanol to cause liver disease.This article has an associated First Person interview with the first author of the paper. © 2018. Published by The Company of Biologists Ltd.

Characterization of European ancestry nonalcoholic fatty liver disease-associated variants in individuals of African and Hispanic descent.

PubMed

Palmer, Nicholette D; Musani, Solomon K; Yerges-Armstrong, Laura M; Feitosa, Mary F; Bielak, Lawrence F; Hernaez, Ruben; Kahali, Bratati; Carr, J Jeffrey; Harris, Tamara B; Jhun, Min A; Kardia, Sharon L R; Langefeld, Carl D; Mosley, Thomas H; Norris, Jill M; Smith, Albert V; Taylor, Herman A; Wagenknecht, Lynne E; Liu, Jiankang; Borecki, Ingrid B; Peyser, Patricia A; Speliotes, Elizabeth K

2013-09-01

Nonalcoholic fatty liver disease (NAFLD) is an obesity-related condition affecting over 50% of individuals in some populations and is expected to become the number one cause of liver disease worldwide by 2020. Common, robustly associated genetic variants in/near five genes were identified for hepatic steatosis, a quantifiable component of NAFLD, in European ancestry individuals. Here we tested whether these variants were associated with hepatic steatosis in African- and/or Hispanic-Americans and fine-mapped the observed association signals. We measured hepatic steatosis using computed tomography in five African American (n = 3,124) and one Hispanic American (n = 849) cohorts. All analyses controlled for variation in age, age(2) , gender, alcoholic drinks, and population substructure. Heritability of hepatic steatosis was estimated in three cohorts. Variants in/near PNPLA3, NCAN, LYPLAL1, GCKR, and PPP1R3B were tested for association with hepatic steatosis using a regression framework in each cohort and meta-analyzed. Fine-mapping across African American cohorts was conducted using meta-analysis. African- and Hispanic-American cohorts were 33.9/37.5% male, with average age of 58.6/42.6 years and body mass index of 31.8/28.9 kg/m(2) , respectively. Hepatic steatosis was 0.20-0.34 heritable in African- and Hispanic-American families (P < 0.02 in each cohort). Variants in or near PNPLA3, NCAN, GCKR, PPP1R3B in African Americans and PNPLA3 and PPP1R3B in Hispanic Americans were significantly associated with hepatic steatosis; however, allele frequency and effect size varied across ancestries. Fine-mapping in African Americans highlighted missense variants at PNPLA3 and GCKR and redefined the association region at LYPLAL1. Multiple genetic variants are associated with hepatic steatosis across ancestries. This explains a substantial proportion of the genetic predisposition in African- and Hispanic-Americans. Missense variants in PNPLA3 and GCKR are likely

Microbiota-Liver Axis in Hepatic Disease

PubMed Central

Chassaing, Benoit; Etienne-Mesmin, Lucie; Gewirtz, Andrew T.

2014-01-01

Accumulating evidence indicates that the gut microbiota, long appreciated to be a key determinant of intestinal inflammation, is also playing a key role in chronic inflammatory disease of the liver. Such studies have yielded a general central hypothesis whereby microbiota products activate the innate immune system to drive pro-inflammatory gene expression thus promoting chronic inflammatory disease of the liver. This article reviews the background supporting this hypothesis, outlines how it can potentially explain classic and newly emerging epidemiological chronic inflammatory liver disease, and discusses potential therapeutic means to manipulate the microbiota so as to prevent and/or treat liver disease. PMID:23703735

Strategies, models and biomarkers in experimental non-alcoholic fatty liver disease research

PubMed Central

Willebrords, Joost; Pereira, Isabel Veloso Alves; Maes, Michaël; Yanguas, Sara Crespo; Colle, Isabelle; Van Den Bossche, Bert; Da silva, Tereza Cristina; Oliveira, Cláudia P; Andraus, Wellington; Alves, Venâncio Avancini Ferreira; Cogliati, Bruno; Vinken, Mathieu

2015-01-01

Non-alcoholic fatty liver disease encompasses a spectrum of liver diseases, including simple steatosis, steatohepatitis, liver fibrosis and cirrhosis and hepatocellular carcinoma. Non-alcoholic fatty liver disease is currently the most dominant chronic liver disease in Western countries due to the fact that hepatic steatosis is associated with insulin resistance, type 2 diabetes mellitus, obesity, metabolic syndrome and drug-induced injury. A variety of chemicals, mainly drugs, and diets is known to cause hepatic steatosis in humans and rodents. Experimental non-alcoholic fatty liver disease models rely on the application of a diet or the administration of drugs to laboratory animals or the exposure of hepatic cell lines to these drugs. More recently, genetically modified rodents or zebrafish have been introduced as non-alcoholic fatty liver disease models. Considerable interest now lies in the discovery and development of novel non-invasive biomarkers of non-alcoholic fatty liver disease, with specific focus on hepatic steatosis. Experimental diagnostic biomarkers of non-alcoholic fatty liver disease, such as (epi)genetic parameters and ‘-omics’-based read-outs are still in their infancy, but show great promise. . In this paper, the array of tools and models for the study of liver steatosis is discussed. Furthermore, the current state-of-art regarding experimental biomarkers such as epigenetic, genetic, transcriptomic, proteomic and metabonomic biomarkers will be reviewed. PMID:26073454

Management of Neurologic Manifestations in Patients with Liver Disease.

PubMed

Ferro, José M; Viana, Pedro; Santos, Patrícia

2016-08-01

Liver disease, both in its acute and chronic forms, can be associated with a wide spectrum of neurologic manifestations, both central and peripheral, ranging in severity from subclinical changes to neurocritical conditions. Neurologists are frequently consulted to participate in their management. In this review, we present an overview of management strategies for patients with hepatic disease whose clinical course is complicated by neurologic manifestations. Type A hepatic encephalopathy (HE), which occurs in acute liver failure, is a neurologic emergency, and multiple measures should be taken to prevent and treat cerebral edema. In Type C HE, which occurs in chronic liver disease, management should be aimed at correcting precipitant factors and hyperammonemia. There is an increasing spectrum of drug treatments available to minimize ammonia toxicity. Acquired hepatocerebral degeneration is a rare complication of the chronic form of HE, with typical clinical and brain MRI findings, whose most effective treatment is liver transplantation. Epilepsy is frequent and of multifactorial cause in patients with hepatic disease, and careful considerations should be made regarding choice of the appropriate anti-epileptic drugs. Several mechanisms increase the risk of stroke in hepatic disease, but many of the drugs used to treat and prevent stroke are contraindicated in severe hepatic failure. Hepatitis C infection increases the risk of ischemic stroke. Hemorrhagic stroke is more frequent in patients with liver disease of alcoholic etiology. Viral hepatitis is associated with a wide range of immune-mediated complications, mostly in the peripheral nervous system, which respond to different types of immunomodulatory treatment. Several drugs used to treat hepatic disease, such as the classical and the new direct-acting antivirals, may have neurologic complications which in some cases preclude its continued use.

Subacute copper-deficiency myelopathy in a patient with occult celiac disease.

PubMed

Cavallieri, Francesco; Fini, Nicola; Contardi, Sara; Fiorini, Massimo; Corradini, Elena; Valzania, Franco

2017-07-01

Acquired copper deficiency represents a rare cause of progressive myelopathy presenting with sensory ataxia and spastic gait. The time interval from neurological symptoms onset to diagnosis of myelopathy ranges from 2 months to several years in almost all cases, mimicking the clinical course of subacute combined degeneration due to vitamin B12 deficiency. A 60-year-old man, without any gastrointestinal symptoms, developed over the course of one week rapidly progressive gait imbalance, tingling and numbness in his feet and ascending lower limb weakness. Spine magnetic resonance imaging revealed hyperintensity involving cervical and dorsal posterior columns of spinal cord. Blood analysis revealed undetectable serum copper levels, low serum ceruloplasmin and positive serum Immunoglobulin A anti-tissue transglutaminase. Upper gastrointestinal endoscopy was performed revealing duodenal villous atrophy consistent with a malabsorption pattern. A gluten-free diet in association with intravenous then oral copper supplementation prompted sustained normalization of serum copper levels and progressive clinical improvement. We report a rare case of myelopathy induced by copper deficiency secondary to undiagnosed celiac disease, peculiarly presenting with a subacute onset. This case expands the neurological presentation and clinical course of myelopathy due to acquired copper deficiency. We suggest investigation of copper deficiency in patients presenting with subacute or even acute sensory ataxia and spastic gait. Detection of hypocupremia in patients without a previous history of gastric surgery should lead to diagnostic testing for celiac disease even in the absence of any obvious gastrointestinal symptoms.

Nonalcoholic fatty liver disease: Evolving paradigms

PubMed Central

Lonardo, Amedeo; Nascimbeni, Fabio; Maurantonio, Mauro; Marrazzo, Alessandra; Rinaldi, Luca; Adinolfi, Luigi Elio

2017-01-01

In the last years new evidence has accumulated on nonalcoholic fatty liver disease (NAFLD) challenging the paradigms that had been holding the scene over the previous 30 years. NAFLD has such an epidemic prevalence as to make it impossible to screen general population looking for NAFLD cases. Conversely, focusing on those cohorts of individuals exposed to the highest risk of NAFLD could be a more rational approach. NAFLD, which can be diagnosed with either non-invasive strategies or through liver biopsy, is a pathogenically complex and clinically heterogeneous disease. The existence of metabolic as opposed to genetic-associated disease, notably including ”lean NAFLD” has recently been recognized. Moreover, NAFLD is a systemic condition, featuring metabolic, cardiovascular and (hepatic/extra-hepatic) cancer risk. Among the clinico-laboratory features of NAFLD we discuss hyperuricemia, insulin resistance, atherosclerosis, gallstones, psoriasis and selected endocrine derangements. NAFLD is a precursor of type 2 diabetes (T2D) and metabolic syndrome and progressive liver disease develops in T2D patients in whom the course of disease is worsened by NAFLD. Finally, lifestyle changes and drug treatment options to be implemented in the individual patient are also critically discussed. In conclusion, this review emphasizes the new concepts on clinical and pathogenic heterogeneity of NAFLD, a systemic disorder with a multifactorial pathogenesis and protean clinical manifestations. It is highly prevalent in certain cohorts of individuals who are thus potentially amenable to selective screening strategies, intensive follow-up schedules for early identification of liver-related and extrahepatic complications and in whom earlier and more aggressive treatment schedules should be carried out whenever possible. PMID:29085206

Nuclear Receptor Variants in Liver Disease

PubMed Central

Müllenbach, Roman; Weber, Susanne N.; Lammert, Frank

2012-01-01

This review aims to provide a snapshot of the actual state of knowledge on genetic variants of nuclear receptors (NR) involved in regulating important aspects of liver metabolism. It recapitulates recent evidence for the application of NR in genetic diagnosis of monogenic (“Mendelian”) liver disease and their use in clinical diagnosis. Genetic analysis of multifactorial liver diseases such as viral hepatitis or fatty liver disease identifies key players in disease predisposition and progression. Evidence from these analyses points towards a role of NR polymorphisms in common diseases, linking regulatory networks to complex and variable phenotypes. The new insights into NR variants also offer perspectives and cautionary advice for their use as handles towards diagnosis and treatment. PMID:22523693

Effects of Melatonin on Liver Injuries and Diseases

PubMed Central

Zhang, Jiao-Jiao; Meng, Xiao; Li, Ya; Zhou, Yue; Xu, Dong-Ping; Li, Sha; Li, Hua-Bin

2017-01-01

Liver injuries and diseases are serious health problems worldwide. Various factors, such as chemical pollutants, drugs, and alcohol, could induce liver injuries. Liver diseases involve a wide range of liver pathologies, including hepatic steatosis, fatty liver, hepatitis, fibrosis, cirrhosis, and hepatocarcinoma. Despite all the studies performed up to now, therapy choices for liver injuries and diseases are very few. Therefore, the search for a new treatment that could safely and effectively block or reverse liver injuries and diseases remains a priority. Melatonin is a well-known natural antioxidant, and has many bioactivities. There are numerous studies investigating the effects of melatonin on liver injuries and diseases, and melatonin could regulate various molecular pathways, such as inflammation, proliferation, apoptosis, metastasis, and autophagy in different pathophysiological situations. Melatonin could be used for preventing and treating liver injuries and diseases. Herein, we conduct a review summarizing the potential roles of melatonin in liver injuries and diseases, paying special attention to the mechanisms of action. PMID:28333073

Reduction of obesity-associated white adipose tissue inflammation by rosiglitazone is associated with reduced non-alcoholic fatty liver disease in LDLr-deficient mice.

PubMed

Mulder, Petra; Morrison, Martine C; Verschuren, Lars; Liang, Wen; van Bockel, J Hajo; Kooistra, Teake; Wielinga, Peter Y; Kleemann, Robert

2016-08-22

Obesity is associated with chronic low-grade inflammation that drives the development of metabolic diseases, including non-alcoholic fatty liver disease (NAFLD). We recently showed that white adipose tissue (WAT) constitutes an important source of inflammatory factors. Hence, interventions that attenuate WAT inflammation may reduce NAFLD development. Male LDLr-/- mice were fed a high-fat diet (HFD) for 9 weeks followed by 7 weeks of HFD with or without rosiglitazone. Effects on WAT inflammation and NAFLD development were analyzed using biochemical and (immuno)histochemical techniques, combined with gene expression analyses. Nine weeks of HFD feeding induced obesity and WAT inflammation, which progressed gradually until the end of the study. Rosiglitazone fully blocked progression of WAT inflammation and activated PPARγ significantly in WAT. Rosiglitazone intervention did not activate PPARγ in liver, but improved liver histology and counteracted the expression of genes associated with severe NAFLD in humans. Rosiglitazone reduced expression of pro-inflammatory factors in WAT (TNF-α, leptin) and increased expression of adiponectin, which was reflected in plasma. Furthermore, rosiglitazone lowered circulating levels of pro-inflammatory saturated fatty acids. Together, these observations provide a rationale for the observed indirect hepatoprotective effects and suggest that WAT represents a promising therapeutic target for the treatment of obesity-associated NAFLD.

Select tissue mineral concentrations and chronic wasting disease status in mule deer from North-central Colorado.

PubMed

Wolfe, Lisa L; Conner, Mary M; Bedwell, Cathy L; Lukacs, Paul M; Miller, Michael W

2010-07-01

Trace mineral imbalances have been suggested as having a causative or contributory role in chronic wasting disease (CWD), a prion disease of several North American cervid species. To begin exploring relationships between tissue mineral concentrations and CWD in natural systems, we measured liver tissue concentrations of copper, manganese, and molybdenum in samples from 447 apparently healthy, adult (> or = 2 yr old) mule deer (Odocoileus hemionus) culled or vehicle killed from free-ranging populations in north-central Colorado, United States, where CWD occurs naturally; we also measured copper concentrations in brain-stem (medulla oblongata at the obex) tissue from 181 of these deer. Analyses revealed a wide range of concentrations of all three minerals among sampled deer (copper: 5.6-331 ppm in liver, 1.5-31.9 ppm in obex; manganese: 0.1-21.4 ppm in liver; molybdenum: 0.5-4.0 ppm in liver). Bayesian multiple regression analysis revealed a negative association between obex copper (-0.097; 95% credible interval -0.192 to -0.006) and the probability of sampled deer also being infected with CWD, as well as a positive association between liver manganese (0.158; 95% credible interval 0.066 to 0.253) and probability of infection. We could not discern whether the tendencies toward lower brain-stem copper concentrations or higher systemic manganese concentrations in infected deer preceded prion infection or rather were the result of infection and its subsequent effects, although the distribution of trace mineral concentrations in infected deer seemed more suggestive of the latter.

Alcoholic Liver Disease: Pathogenesis and Current Management

PubMed Central

Osna, Natalia A.; Donohue, Terrence M.; Kharbanda, Kusum K.

2017-01-01

Excessive alcohol consumption is a global healthcare problem. The liver sustains the greatest degree of tissue injury by heavy drinking because it is the primary site of ethanol metabolism. Chronic and excessive alcohol consumption produces a wide spectrum of hepatic lesions, the most characteristic of which are steatosis, hepatitis, and fibrosis/cirrhosis. Steatosis is the earliest response to heavy drinking and is characterized by the deposition of fat in hepatocytes. Steatosis can progress to steatohepatitis, which is a more severe, inflammatory type of liver injury. This stage of liver disease can lead to the development of fibrosis, during which there is excessive deposition of extracellular matrix proteins. The fibrotic response begins with active pericellular fibrosis, which may progress to cirrhosis, characterized by excessive liver scarring, vascular alterations, and eventual liver failure. Among problem drinkers, about 35 percent develop advanced liver disease because a number of disease modifiers exacerbate, slow, or prevent alcoholic liver disease progression. There are still no FDA-approved pharmacological or nutritional therapies for treating patients with alcoholic liver disease. Cessation of drinking (i.e., abstinence) is an integral part of therapy. Liver transplantation remains the life-saving strategy for patients with end-stage alcoholic liver disease. PMID:28988570

Acute alcoholic hepatitis, end stage alcoholic liver disease and liver transplantation: An Italian position statement

PubMed Central

Testino, Gianni; Burra, Patrizia; Bonino, Ferruccio; Piani, Francesco; Sumberaz, Alessandro; Peressutti, Roberto; Giannelli Castiglione, Andrea; Patussi, Valentino; Fanucchi, Tiziana; Ancarani, Ornella; De Cerce, Giovanna; Iannini, Anna Teresa; Greco, Giovanni; Mosti, Antonio; Durante, Marilena; Babocci, Paola; Quartini, Mariano; Mioni, Davide; Aricò, Sarino; Baselice, Aniello; Leone, Silvia; Lozer, Fabiola; Scafato, Emanuele; Borro, Paolo

2014-01-01

Alcoholic liver disease encompasses a broad spectrum of diseases ranging from steatosis steatohepatitis, fibrosis, and cirrhosis to hepatocellular carcinoma. Forty-four per cent of all deaths from cirrhosis are attributed to alcohol. Alcoholic liver disease is the second most common diagnosis among patients undergoing liver transplantation (LT). The vast majority of transplant programmes (85%) require 6 mo of abstinence prior to transplantation; commonly referred to as the “6-mo rule”. Both in the case of progressive end-stage liver disease (ESLD) and in the case of severe acute alcoholic hepatitis (AAH), not responding to medical therapy, there is a lack of evidence to support a 6-mo sobriety period. It is necessary to identify other risk factors that could be associated with the resumption of alcohol drinking. The “Group of Italian Regions” suggests that: in a case of ESLD with model for end-stage liver disease < 19 a 6-mo abstinence period is required; in a case of ESLD, a 3-mo sober period before LT may be more ideal than a 6-mo period, in selected patients; and in a case of severe AAH, not responding to medical therapies (up to 70% of patients die within 6 mo), LT is mandatory, even without achieving abstinence. The multidisciplinary transplant team must include an addiction specialist/hepato-alcohologist. Patients have to participate in self-help groups. PMID:25356027

Cell Death and Cell Death Responses in Liver Disease: Mechanisms and Clinical Relevance

PubMed Central

Luedde, Tom; Kaplowitz, Neil; Schwabe, Robert F.

2015-01-01

Summary Hepatocellular death is present in almost all types of human liver disease and is used as a sensitive parameter for the detection of acute and chronic liver disease of viral, toxic, metabolic, or autoimmune origin. Clinical data and animal models suggest that hepatocyte death is the key trigger of liver disease progression, manifested by the subsequent development of inflammation, fibrosis, cirrhosis, and hepatocellular carcinoma. Modes of hepatocellular death differ substantially between liver diseases. Different modes of cell death such as apoptosis, necrosis, and necroptosis trigger specific cell death responses and promote progression of liver disease through distinct mechanisms. In this review, we first discuss molecular mechanisms by which different modes of cell death, damage-associated molecular patterns, and specific cell death responses contribute to the development of liver disease. We then review the clinical relevance of cell death, focusing on biomarkers; the contribution of cell death to drug-induced, viral, and fatty liver disease and liver cancer; and evidence for cell death pathways as therapeutic targets. PMID:25046161

Periodontitis is associated with significant hepatic fibrosis in patients with non-alcoholic fatty liver disease.

PubMed

Alazawi, William; Bernabe, Eduardo; Tai, David; Janicki, Tomasz; Kemos, Polychronis; Samsuddin, Salma; Syn, Wing-Kin; Gillam, David; Turner, Wendy

2017-01-01

Non-alcoholic fatty liver disease (NAFLD) has a bidirectional association with metabolic syndrome. It affects up to 30% of the general population, 70% of individuals with diabetes and 90% with obesity. The main histological hallmark of progressive NAFLD is fibrosis. There is a bidirectional epidemiological link between periodontitis and metabolic syndrome. NAFLD, periodontitis and diabetes share common risk factors, are characterised by inflammation and associated with changes in commensal bacteria. Therefore we tested the hypothesis that periodontitis is associated with NAFLD and with significant fibrosis in two study groups. We analyzed data from a population-based survey and a patient-based study. NHANES III participants with abdominal ultrasound and sociodemographic, clinical, and oral examination data were extracted and appropriate weighting applied. In a separate patient-based study, consenting patients with biopsy-proved NAFLD (or with liver indices too mild to justify biopsy) underwent dental examination. Basic Periodontal Examination score was recorded. In NHANES, periodontitis was significantly associated with steatosis in 8172 adults even after adjusting for sociodemographic factors. However, associations were fully explained after accounting for features of metabolic syndrome. In the patient-based study, periodontitis was significantly more common in patients with biopsy-proven NASH and any fibrosis (F0-F4) than without NASH (p = 0.009). Periodontitis was more common in patients with NASH and significant fibrosis (F2-4) than mild or no fibrosis (F0-1, p = 0.04). Complementary evidence from an epidemiological survey and a clinical study show that NAFLD is associated with periodontitis and that the association is stronger with significant liver fibrosis.

Organ allocation for chronic liver disease: model for end-stage liver disease and beyond.

PubMed

Asrani, Sumeet K; Kim, W Ray

2010-05-01

Implementation of the model for end-stage liver disease (MELD) score has led to a reduction in waiting list registration and waitlist mortality. Prognostic models have been proposed to either refine or improve the current MELD-based liver allocation. The model for end-stage liver disease - sodium (MELDNa) incorporates serum sodium and has been shown to improve the predictive accuracy of the MELD score. However, laboratory variation and manipulation of serum sodium is a concern. Organ allocation in the United Kingdom is now based on a model that includes serum sodium. An updated MELD score is associated with a lower relative weight for serum creatinine coefficient and a higher relative weight for bilirubin coefficient, although the contribution of reweighting coefficients as compared with addition of variables is unclear. The D-MELD, the arithmetic product of donor age and preoperative MELD, proposes donor-recipient matching; however, inappropriate transplantation of high-risk donors is a concern. Finally, the net benefit model ranks patients according to the net survival benefit that they would derive from the transplant. However, complex statistical models are required and unmeasured characteristics may unduly affect the model. Despite their limitations, efforts to improve the current MELD-based organ allocation are encouraging.

Copper storage in the liver of the wild mute swan (Cygnus olor). Its possible relation to pollution of harbor waters by antifouling paints.

PubMed

Molnar, J J

1983-12-01

Postmortem examination of three wild mute swans (Cygnus olor) from a harbor area disclosed an unusual black discoloration of the liver. Chemical, histochemical, and microscopic studies, along with electron-probe microanalysis, showed that cytoplasmic pigment granules in the liver cells contained a copper-protein complex. Similar findings have been reported in Danish and English studies on large numbers of wild mute swans. Two control mute swans from The Bronx Zoo had negligible amounts of hepatic copper. The striking difference between the wild and the captive swans in hepatic copper content suggests that the copper in the wild swans was of environmental origin, most likely from copper-rich antifouling paint used extensively in the marine industry. Flakes of this paint may be ingested by swans searching for food in the sediment of harbor waters.

Nonalcoholic fatty liver disease in Asia: emerging perspectives.

PubMed

Seto, Wai-Kay; Yuen, Man-Fung

2017-02-01

As in the West, nonalcoholic fatty liver disease (NAFLD) is the commonest chronic liver disease in Asia, with a prevalence higher than 40 % in some countries. The risk factors for NAFLD development are similar to those in Western countries, including increased body mass index, diabetes, insulin resistance, and metabolic syndrome. NAFLD in Asians is associated with different extrahepatic manifestations involving the cardiovascular, gastrointestinal, and renal systems. A considerable proportion of Asians with NAFLD are described as having "lean" NAFLD. Present in approximately 20 % of the Asian population, lean NAFLD is closely linked with insulin resistance, diabetes, and other metabolic complications, but its association with disease progression to nonalcoholic steatohepatitis and cirrhosis remains to be defined. There is emerging evidence of the interactions of NAFLD with hepatitis B virus and hepatitis C virus infection in Asia. Unlike in Western countries, NAFLD constitutes only a minority of cirrhosis and hepatocellular carcinoma cases in Asia. Possible explanations are the lower prevalence of obesity and the overwhelming problem of viral hepatitis in Asia. With aging of the obesity cohort in Asia, NAFLD-related liver complications are expected to increase.

Association of Model for End-Stage Liver Disease Score With Mortality in Emergency General Surgery Patients.

PubMed

Havens, Joaquim M; Columbus, Alexandra B; Olufajo, Olubode A; Askari, Reza; Salim, Ali; Christopher, Kenneth B

2016-07-20

Emergency general surgery (EGS) patients have a disproportionate burden of death and complications. Chronic liver disease (CLD) increases the risk of complications following elective surgery. For EGS patients with CLD, long-term outcomes are unknown and risk stratification models do not reflect severity of CLD. To determine whether the Model for End-Stage Liver Disease (MELD) score is associated with increased risk of 90-day mortality following intensive care unit (ICU) admission in EGS patients. We performed a retrospective cohort study of patients with CLD who underwent an EGS procedure based on International Classification of Diseases, Ninth Revision (ICD-9) procedure codes and were admitted to a medical or surgical ICU within 48 hours of surgery between January 1, 1998, and September 20, 2012, at 2 academic medical centers. Chronic liver disease was identified using ICD-9 codes. Multivariable logistic regression was performed. The analysis was conducted from July 1, 2015, to January 1, 2016. The primary outcome was all-cause 90-day mortality. A total of 13 552 EGS patients received critical care; of these, 707 (5%) (mean [SD] age at hospital admission, 56.6 [14.2] years; 64% male; 79% white) had CLD and data to determine MELD score at ICU admission. The median MELD score was 14 (interquartile range, 10-20). Overall 90-day mortality was 30.1%. The adjusted odds ratio of 90-day mortality for each 10-point increase in MELD score was 1.63 (95% CI, 1.34-1.98). A decrease in MELD score of more than 3 in the 48 hours following ICU admission was associated with a 2.2-fold decrease in 90-day mortality (odds ratio = 0.46; 95% CI, 0.22-0.98). In this study, MELD score was associated with 90-day mortality following EGS in patients with CLD. The MELD score can be used as a prognostic factor in this patient population and should be used in preoperative risk prediction models and when counseling EGS patients on the risks and benefits of operative intervention.

Molecular Mediators Governing Iron-Copper Interactions

PubMed Central

Gulec, Sukru; Collins, James F.

2015-01-01

Given their similar physiochemical properties, it is a logical postulate that iron and copper metabolism are intertwined. Indeed, iron-copper interactions were first documented over a century ago, but the homeostatic effects of one on the other has not been elucidated at a molecular level to date. Recent experimental work has, however, begun to provide mechanistic insight into how copper influences iron metabolism. During iron deficiency, elevated copper levels are observed in the intestinal mucosa, liver, and blood. Copper accumulation and/or redistribution within enterocytes may influence iron transport, and high hepatic copper may enhance biosynthesis of a circulating ferroxidase, which potentiates iron release from stores. Moreover, emerging evidence has documented direct effects of copper on the expression and activity of the iron-regulatory hormone hepcidin. This review summarizes current experimental work in this field, with a focus on molecular aspects of iron-copper interplay and how these interactions relate to various disease states. PMID:24995690

Role of autoimmunity in nonviral chronic liver disease.

PubMed

Amarapurkar, D N; Amarapurkar, A D

2000-11-01

To evaluate the prevalence and clinical profile of autoimmune hepatitis (AIH) in patients with chronic liver disease. Four hundred and thirty five consecutive patient with chronic liver disease seen in our department from January 1997 to December 1998 were studied with detailed history and clinical examination. All the patients underwent liver function tests, ultrasonography, isotope liver scanning, viral markers, autoimmune markers ANA, ASMA, LKM1 and AMA (by immunofluorescence technique) and liver histology whenever permissible. Appropriate work up for Wilson's disease was done whenever suspected clinically. Diagnosis of autoimmune hepatitis was made by the composite scoring system by international autoimmune hepatitis group. Twenty out of the 435 patients met the criteria of definite autoimmune hepatitis and seven patient had probable autoimmune hepatitis. Forty out of 408 patients showed markers of autoimmunity positive but did not qualify diagnosis of AIH on composite scores. Demographic profile of 27 patients with autoimmune hepatitis was as follows; male:female ratio 1:8, mean age 39.8 +/- 13 years (Range 4-65 years); mode of presentation as cirrhosis 11/27 (40.7%), chronic hepatitis 12/27 (44.4%) and acute hepatitis 4/27 (14.8%). Elevated serum bilirubin levels were seen in 12 (44.4%) patients while mean serum aminotransferases levels were 249 +/- 343 and 262 +/- 418 respectively. Other disease associations seen were as follows: diabetes in 4 (14.8%), rheumatoid arthritis in 3 (11%), hypothyroidism in 2 (7.4%) and ulcerative colitis in 1 (3.7%). The pattern of autoimmune markers was ANA +ve 23/27 (85%) (+ve titres of ANA > 1:80 in adults and 1:20 in children), ASMA +ve in 16/27 (59.2%) (+ve titres of ASMA > 1:40) and LKM1 in 3 patients. AMA in tires less than 1:80 was found in 3 patients. Liver histology changes seen were lymphoplasmacytic infiltrates (100%), bridging necrosis (93%), liver cell rossetting (80%) and fibrosis with or without cirrhosis (50

ADV36 adipogenic adenovirus in human liver disease

PubMed Central

Trovato, Francesca M; Catalano, Daniela; Garozzo, Adriana; Martines, G Fabio; Pirri, Clara; Trovato, Guglielmo M

2014-01-01

Obesity and liver steatosis are usually described as related diseases. Obesity is regarded as exclusive consequence of an imbalance between food intake and physical exercise, modulated by endocrine and genetic factors. Non-alcoholic fatty liver disease (NAFLD), is a condition whose natural history is related to, but not completely explained by over-nutrition, obesity and insulin resistance. There is evidence that environmental infections, and notably adipogenic adenoviruses (ADV) infections in humans, are associated not only with obesity, which is sufficiently established, but also with allied conditions, such as fatty liver. In order to elucidate the role, if any, of previous ADV36 infection in humans, we investigated association of ADV36-ADV37 seropositivity with obesity and fatty liver in humans. Moreover, the possibility that lifestyle-nutritional intervention in patients with NAFLD and different ADV36 seropositive status, achieves different clinical outcomes on ultrasound bright liver imaging, insulin resistance and obesity was challenged. ADV36 seropositive patients have a more consistent decrease in insulin resistance, fatty liver severity and body weight in comparison with ADV36 seronegative patients, indicating a greater responsiveness to nutritional intervention. These effects were not dependent on a greater pre-interventional body weight and older age. These results imply that no obvious disadvantage - and, seemingly, that some benefit - is linked to ADV36 seropositivity, at least in NAFLD. ADV36 previous infection can boost weight loss and recovery of insulin sensitivity under interventional treatment. PMID:25356033

Liver fat content, non-alcoholic fatty liver disease, and ischaemic heart disease: Mendelian randomization and meta-analysis of 279 013 individuals.

PubMed

Lauridsen, Bo Kobberø; Stender, Stefan; Kristensen, Thomas Skårup; Kofoed, Klaus Fuglsang; Køber, Lars; Nordestgaard, Børge G; Tybjærg-Hansen, Anne

2018-02-01

In observational studies, non-alcoholic fatty liver disease (NAFLD) is associated with high risk of ischaemic heart disease (IHD). We tested the hypothesis that a high liver fat content or a diagnosis of NAFLD is a causal risk factor for IHD. In a cohort study of the Danish general population (n = 94 708/IHD = 10 897), we first tested whether a high liver fat content or a diagnosis of NAFLD was associated observationally with IHD. Subsequently, using Mendelian randomization, we tested whether a genetic variant in the gene encoding the protein patatin-like phospholipase domain containing 3 protein (PNPLA3), I148M (rs738409), a strong and specific cause of high liver fat content and NAFLD, was causally associated with the risk of IHD. We found that the risk of IHD increased stepwise with increasing liver fat content (in quartiles) up to an odds ratio (OR) of 2.41 (1.28-4.51)(P-trend = 0.004). The corresponding OR for IHD in individuals with vs. without NAFLD was 1.65 (1.34-2.04)(P = 3×10-6). PNPLA3 I148M was associated with a stepwise increase in liver fat content of up to 28% in MM vs. II-homozygotes (P-trend = 0.0001) and with ORs of 2.03 (1.52-2.70) for NAFLD (P = 3×10-7), 3.28 (2.37-4.54) for cirrhosis (P = 4×10-12), and 0.95 (0.86-1.04) for IHD (P = 0.46). In agreement, in meta-analysis (N = 279 013/IHD = 71 698), the OR for IHD was 0.98 (0.96-1.00) per M-allele vs. I-allele. The OR for IHD per M-allele higher genetically determined liver fat content was 0.98 (0.94-1.03) vs. an observational estimate of 1.05 (1.02-1.09)(P for comparison = 0.02). Despite confirming the known observational association of liver fat content and NAFLD with IHD, lifelong, genetically high liver fat content was not causally associated with risk of IHD. These results suggest that the observational association is due to confounding or reverse causation. Published on behalf of the European Society of Cardiology. All rights reserved. �

Reactive hyperemia index (RHI) and cognitive performance indexes are associated with histologic markers of liver disease in subjects with non-alcoholic fatty liver disease (NAFLD): a case control study.

PubMed

Tuttolomondo, Antonino; Petta, Salvatore; Casuccio, Alessandra; Maida, Carlo; Corte, Vittoriano Della; Daidone, Mario; Di Raimondo, Domenico; Pecoraro, Rosaria; Fonte, Roberto; Cirrincione, Anna; Zafonte, Rita; Cabibi, Daniela; Cammà, Calogero; Di Marco, Vito; Licata, Anna; Magliozzo, Franco; Marchesini, Giulio; Merlino, Giovanni; Craxì, Antonio; Pinto, Antonio

2018-02-16

No study evaluated vascular health markers in subjects with non-alcoholic fatty liver disease (NAFLD) through a combined analysis of reactive hyperemia peripheral arterial tonometry (RH-PAT) and arterial stiffness indexes. We aimed to assess whether NAFLD and its histological severity are associated with impairment of arterial stiffness and RH-PAT indexes in a mixed cohort of patients with biopsy-proven NAFLD. The Kleiner classification was used to grade NAFLD grade. Pulse wave velocity (PWV) and augmentation index (Aix) were used as markers of arterial stiffness, whereas endothelial function was assessed using reactive hyperemia index (RHI). The mini-mental state examination (MMSE) was administered to test cognitive performance. 80 consecutive patients with biopsy-proven NAFLD and 83 controls without fatty liver disease. NAFLD subjects showed significantly lower mean RHI, higher mean arterial stiffness indexes and lower mean MMSE score. Multivariable analysis after correction for BMI, dyslipidaemia, hypertension, sex, diabetes, age and cardiovascular disease showed that BMI, diastolic blood pressure and RHI are significantly associated to NAFLD. Simple linear regression analysis showed among non-alcoholic steatohepatitis (NASH) subjects a significant negative relationship between ballooning grade and MMSE and a significant positive association between Kleiner steatosis grade and augmentation index. Future research will be addressed to evaluate the relationship between inflammatory markers and arterial stiffness and endothelial function indexes in NAFLD subjects. These study will evaluate association between cardiovascular event incidence and arterial stiffness, endothelial and cognitive markers, and they will address the beneficial effects of cardiovascular drugs such as statins and ACE inhibitors on these surrogate markers in NAFLD subjects.

The Association between Non-Alcoholic Fatty Liver Disease and Cardiovascular Risk in Children.

PubMed

Di Sessa, Anna; Umano, Giuseppina Rosaria; Miraglia Del Giudice, Emanuele

2017-07-07

The rising prevalence of childhood obesity in the past decades has made Non-Alcoholic Fatty Liver Disease (NAFLD) the most common cause of pediatric chronic liver disease worldwide. Currently, a growing body of evidence links NAFLD with cardiovascular disease (CVD) even at an early age. Data on the pediatric population have shown that NAFLD could represent an independent risk factor not only for cardiovascular events but also for early subclinical abnormalities in myocardial structure and function. Briefly, we review the current knowledge regarding the relationship between pediatric NAFLD and cardiovascular risk in an attempt to clarify our understanding of NAFLD as a possible cardiovascular risk factor in childhood.

Targeting Dysbiosis for the Treatment of Liver Disease.

PubMed

Anand, Gobind; Zarrinpar, Amir; Loomba, Rohit

2016-02-01

The gut microbiome is composed of a vast number of microbes in the gastrointestinal tract, which benefit host metabolism, aid in digestion, and contribute to normal immune function. Alterations in microbial composition can result in intestinal dysbiosis, which has been implicated in several diseases including obesity, inflammatory bowel disease, and liver diseases. Over the past several years, significant interactions between the intestinal microbiota and liver have been discovered, with possible mechanisms for the development as well as progression of liver disease and promising therapeutic targets to either prevent or halt the progression of liver disease. In this review the authors examine mechanisms of dysbiosis-induced liver disease; highlight current knowledge regarding the role of dysbiosis in nonalcoholic liver disease, alcoholic liver disease, and cirrhosis; and discuss potential therapeutic targets. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Possible association between Helicobacter pylori infection and nonalcoholic fatty liver disease.

PubMed

Chen, Chang-Xi; Mao, Yu-Shan; Foster, Parker; Zhu, Zhong-Wei; Du, Juan; Guo, Chuan-Yong

2017-03-01

Possible association between Helicobacter pylori infection (HPI) and nonalcoholic fatty liver disease (NAFLD) has been proposed by several studies with inconsistent conclusions. Here, we studied the association between HPI and NAFLD at 3 levels: (i) genetic level; (ii) small molecular level; and (iii) clinical level. Relation data between diseases, genes, and small molecules were acquired from Pathway Studio ResNet Mammalian database. Clinical data were acquired from 2263 elderly South Chinese subjects, including 603 NAFLD patients and 1660 subjects without NAFLD. Results showed that HPI and NAFLD present significantly shared genetic bases (95 genes, p value = 2.5E-72), demonstrating multiple common genetic pathways (enrichment p value ≤ 4.38E-20 for the top 10 pathways). Genetic network analysis suggested that mutual regulation may exist between HPI and NAFLD through 21 out of 95 genes. Furthermore, 85 out of the 95 genes manifested strong interaction with 12 small molecules/drugs that demonstrate effectiveness in treating both diseases. Clinical results showed that HPI rate in the NAFLD group was significantly higher than that in the group without NAFLD (51.9% vs. 43.6%; p value = 4.9E-4). Multivariate logistic regression results supported the observations and suggested that HPI served as a risk factor for NAFLD in the experiment data studied (odds ratio: 1.387, p value = 0.018). Results from this study support the hypothesis that complex biological association may exist between HPI and NAFLD, which partially explains the significant clinical co-incidence in the elderly population of south China.

Challenge of liver disease in systemic lupus erythematosus: Clues for diagnosis and hints for pathogenesis

PubMed Central

Bessone, Fernando; Poles, Natalia; Roma, Marcelo G

2014-01-01

Systemic lupus erythematosus (SLE) encompass a broad spectrum of liver diseases. We propose here to classify them as follows: (1) immunological comorbilities (overlap syndromes); (2) non-immunological comorbilities associated to SLE; and (3) a putative liver damage induced by SLE itself, referred to as “lupus hepatitis”. In the first group, liver injury can be ascribed to overlapping hepatopathies triggered by autoimmune mechanisms other than SLE occurring with higher incidence in the context of lupus (e.g., autoimmune hepatitis, primary biliary cirrhosis). The second group includes non-autoimmune liver diseases, such as esteatosis, hepatitis C, hypercoagulation state-related liver lesions, hyperplasic parenchymal and vascular lesions, porphyria cutanea tarda, and drug-induced hepatotoxicity. Finally, the data in the literature to support the existence of a hepatic disease produced by SLE itself, or the occurrence of a SLE-associated prone condition that increases susceptibility to acquire other liver diseases, is critically discussed. The pathological mechanisms underlying each of these liver disorders are also reviewed. Despite the high heterogeneity in the literature regarding the prevalence of SLE-associated liver diseases and, in most cases, lack of histopathological evidence or clinical studies large enough to support their existence, it is becoming increasingly apparent that liver is an important target of SLE. Consequently, biochemical liver tests should be routinely carried out in SLE patients to discard liver disorders, particularly in those patients chronically exposed to potentially hepatotoxic drugs. Diagnosing liver disease in SLE patients is always challenging, and the systematization of the current information carried out in this review is expected to be of help both to attain a better understanding of pathogenesis and to build an appropriate work-up for diagnosis. PMID:25018850

Performance-based measures associate with frailty in patients with end-stage liver disease

PubMed Central

Lai, Jennifer C.; Volk, Michael L; Strasburg, Debra; Alexander, Neil

2016-01-01

Background Physical frailty, as measured by the Fried Frailty Index, is increasingly recognized as a critical determinant of outcomes in cirrhotics. However, its utility is limited by the inclusion of self-reported components. We aimed to identify performance-based measures associated with frailty in patients with cirrhosis. Methods Cirrhotics ≥50 years underwent: 6-minute walk test (6MWT, cardiopulmonary endurance), chair stands in 30 seconds (muscle endurance), isometric knee extension (lower extremity strength), unipedal stance time (static balance), and maximal step length (dynamic balance/coordination). Linear regression associated each physical performance test with frailty. Principal components exploratory factor analysis evaluated the inter-relatedness of frailty and the 5 physical performance tests. Results Of forty cirrhotics, with a median age of 64 years and Model for End-stage Liver Disease (MELD) MELD of 12,10 (25%) were frail by Fried Frailty Index ≥3. Frail cirrhotics had poorer performance in 6MWT distance (231 vs. 338 meters), 30 second chair stands (7 vs. 10), isometric knee extension (86 vs. 122 Newton meters), and maximal step length (22 vs. 27 inches) [p≤0.02 for each]. Each physical performance test was significantly associated with frailty (p<0.01), even after adjustment for MELD or hepatic encephalopathy. Principal component factor analysis demonstrated substantial, but unique, clustering of each physical performance test to a single factor – frailty. Conclusion Frailty in cirrhosis is a multi-dimensional construct that is distinct from liver dysfunction and incorporates endurance, strength, and balance. Our data provide specific targets for prehabilitation interventions aimed at reducing frailty in cirrhotics in preparation for liver transplantation. PMID:27495749

Performance-Based Measures Associate With Frailty in Patients With End-Stage Liver Disease.

PubMed

Lai, Jennifer C; Volk, Michael L; Strasburg, Debra; Alexander, Neil

2016-12-01

Physical frailty, as measured by the Fried Frailty Index, is increasingly recognized as a critical determinant of outcomes in patients with cirrhosis. However, its utility is limited by the inclusion of self-reported components. We aimed to identify performance-based measures associated with frailty in patients with cirrhosis. Patients with cirrhosis, aged 50 years or older, underwent: 6-minute walk test (cardiopulmonary endurance), chair stands in 30 seconds (muscle endurance), isometric knee extension (lower extremity strength), unipedal stance time (static balance), and maximal step length (dynamic balance/coordination). Linear regression associated each physical performance test with frailty. Principal components exploratory factor analysis evaluated the interrelatedness of frailty and the 5 physical performance tests. Of 40 patients with cirrhosis, with a median age of 64 years and Model for End-stage Liver Disease (MELD) MELD of 12.10 (25%) were frail by Fried Frailty Index ≥3. Frail patients with cirrhosis had poorer performance in 6-minute walk test distance (231 vs 338 m), 30-second chair stands (7 vs 10), isometric knee extension (86 vs 122 Newton meters), and maximal step length (22 vs 27 in. (P ≤ 0.02 for each). Each physical performance test was significantly associated with frailty (P < 0.01), even after adjustment for MELD or hepatic encephalopathy. Principal component factor analysis demonstrated substantial, but unique, clustering of each physical performance test to a single factor-frailty. Frailty in cirrhosis is a multidimensional construct that is distinct from liver dysfunction and incorporates endurance, strength, and balance. Our data provide specific targets for prehabilitation interventions aimed at reducing frailty in patients with cirrhosis in preparation for liver transplantation.

Serum YKL-40 as a marker of liver fibrosis in patients with non-alcoholic fatty liver disease.

PubMed

Kumagai, Erina; Mano, Yohei; Yoshio, Sachiyo; Shoji, Hirotaka; Sugiyama, Masaya; Korenaga, Masaaki; Ishida, Tsuyoshi; Arai, Taeang; Itokawa, Norio; Atsukawa, Masanori; Hyogo, Hideyuki; Chayama, Kazuaki; Ohashi, Tomohiko; Ito, Kiyoaki; Yoneda, Masashi; Kawaguchi, Takumi; Torimura, Takuji; Nozaki, Yuichi; Watanabe, Sumio; Mizokami, Masashi; Kanto, Tatsuya

2016-10-14

Non-alcoholic fatty liver disease (NAFLD) is a common cause of chronic non-viral liver disease. YKL-40, chitinase-like protein expressed in multiple tissues including liver, is involved in cell proliferation, inflammation and remodeling of the extracellular matrix. The aim of this study was to assess whether serum YKL-40 levels are associated with liver fibrosis in NAFLD patients. Serum YKL-40 levels were quantified in 111 NAFLD patients and 23 HCC patients with NAFLD. To identify the source of YKL-40, immunofluorescence staining of liver specimens from NAFLD patients was performed. Serum YKL-40 levels in NAFLD patients increased in accordance with the progression of liver fibrosis. Multivariate analysis revealed that YKL-40 was one of the independent factors significantly associated with severe fibrosis (F3-4). We established a new predictive model for fibrosis of NAFLD, using logistic regression analysis: YKL-40 based fibrosis score = -0.0545 + type IV collagen 7s * 0.3456 + YKL-40 * 0.0024. Serum YKL-40 levels of HCC patients with non-cirrhotic NAFLD were significantly higher than those without HCC. Immunofluorescence staining showed that YKL-40 was expressed by macrophages in liver tissue of NAFLD patients. In conclusion, macrophage-derived YKL-40 is a feasible biomarker of liver fibrosis in NAFLD patients.

Haemolysis and Perturbations in the Systemic Iron Metabolism of Suckling, Copper-Deficient Mosaic Mutant Mice – An Animal Model of Menkes Disease

PubMed Central

Lenartowicz, Małgorzata; Starzyński, Rafał R.; Krzeptowski, Wojciech; Grzmil, Paweł; Bednarz, Aleksandra; Ogórek, Mateusz; Pierzchała, Olga; Staroń, Robert; Gajowiak, Anna; Lipiński, Paweł

2014-01-01

The biological interaction between copper and iron is best exemplified by the decreased activity of multicopper ferroxidases under conditions of copper deficiency that limits the availability of iron for erythropoiesis. However, little is known about how copper deficiency affects iron homeostasis through alteration of the activity of other copper-containing proteins, not directly connected with iron metabolism, such as superoxide dismutase 1 (SOD1). This antioxidant enzyme scavenges the superoxide anion, a reactive oxygen species contributing to the toxicity of iron via the Fenton reaction. Here, we analyzed changes in the systemic iron metabolism using an animal model of Menkes disease: copper-deficient mosaic mutant mice with dysfunction of the ATP7A copper transporter. We found that the erythrocytes of these mutants are copper-deficient, display decreased SOD1 activity/expression and have cell membrane abnormalities. In consequence, the mosaic mice show evidence of haemolysis accompanied by haptoglobin-dependent elimination of haemoglobin (Hb) from the circulation, as well as the induction of haem oxygenase 1 (HO1) in the liver and kidney. Moreover, the hepcidin-ferroportin regulatory axis is strongly affected in mosaic mice. These findings indicate that haemolysis is an additional pathogenic factor in a mouse model of Menkes diseases and provides evidence of a new indirect connection between copper deficiency and iron metabolism. PMID:25247420

Non-alcoholic fatty liver disease: What the clinician needs to know

PubMed Central

Machado, Mariana Verdelho; Cortez-Pinto, Helena

2014-01-01

Non-alcoholic fatty liver disease (NAFLD) is the most frequent cause of liver disease in the Western world. Furthermore, it is increasing worldwide, paralleling the obesity pandemic. Though highly frequent, only about one fifth of affected subjects are at risk of developing the progressive form of the disease, non-alcoholic steatohepatitis with fibrosis. Even in the latter, liver disease is slowly progressive, though, since it is so prevalent, it is already the third cause of liver transplantation in the United States, and it is predicted to get to the top of the ranking in few years. Of relevance, fatty liver is also associated with increased overall mortality and particularly increased cardiovascular mortality. The literature and amount of published papers on NAFLD is increasing as fast as its prevalence, which makes it difficult to keep updated in this topic. This review aims to summarize the latest knowledge on NAFLD, in order to help clinicians understanding its pathogenesis and advances on diagnosis and treatment. PMID:25278691

Repurposing of Copper(II)-chelating Drugs for the Treatment of Neurodegenerative Diseases.

PubMed

Lanza, Valeria; Milardi, Danilo; Di Natale, Giuseppe; Pappalardo, Giuseppe

2018-02-12

There is mounting urgency to find new drugs for the treatment of neurodegenerative disorders. A large number of reviews have exhaustively described either the molecular or clinical aspects of neurodegenerative diseases such as Alzheimer's (AD) and Parkinson's (PD). Conversely, reports outlining how known drugs in use for other diseases can also be effective as therapeutic agents in neurodegenerative diseases are less reported. This review focuses on the current uses of some copper(II) chelating molecules as potential drug candidates in neurodegeneration. Starting from the well-known harmful relationships existing between the dyshomeostasis and mis-management of metals and AD onset, we surveyed the experimental work reported in the literature, which deals with the repositioning of metal-chelating drugs in the field of neurodegenerative diseases. The reviewed papers were retrieved from common literature and their selection was limited to those describing the biomolecular aspects associated with neuroprotection. In particular, we emphasized the copper(II) coordination abilities of the selected drugs. Copper, together with zinc and iron, are known to play a key role in regulating neuronal functions. Changes in copper homeostasis are crucial for several neurodegenerative disorders. The studies included in this review may provide an overview on the current strategies aimed at repurposing copper (II) chelating drugs for the treatment of neurodegenerative disorders. Starting from the exemplary case of clioquinol repurposing, we discuss the challenge and the opportunities that repurposing of other metal-chelating drugs may provide (e.g. PBT-2, metformin and cyclodipeptides) in the treatment of neurodegenerative disease. In order to improve the success rate of drug repositioning, comprehensive studies on the molecular mechanism and therapeutic efficacy are still required. The present review upholds that drug repurposing makes significant advantages over drug discovery since

LIVER ULTRASONOGRAPHY IN DOLPHINS: USE OF ULTRASONOGRAPHY TO ESTABLISH A TECHNIQUE FOR HEPATOBILIARY IMAGING AND TO EVALUATE METABOLIC DISEASE-ASSOCIATED LIVER CHANGES IN BOTTLENOSE DOLPHINS (TURSIOPS TRUNCATUS).

PubMed

Seitz, Kelsey E; Smith, Cynthia R; Marks, Stanley L; Venn-Watson, Stephanie K; Ivančić, Marina

2016-12-01

The objective of this study was to establish a comprehensive technique for ultrasound examination of the dolphin hepatobiliary system and apply this technique to 30 dolphins to determine what, if any, sonographic changes are associated with blood-based indicators of metabolic syndrome (insulin greater than 14 μIU/ml or glucose greater than 112 mg/dl) and iron overload (transferrin saturation greater than 65%). A prospective study of individuals in a cross-sectional population with and without elevated postprandial insulin levels was performed. Twenty-nine bottlenose dolphins ( Tursiops truncatus ) in a managed collection were included in the final data analysis. An in-water ultrasound technique was developed that included detailed analysis of the liver and pancreas. Dolphins with hyperinsulinemia concentrations had larger livers compared with dolphins with nonelevated concentrations. Using stepwise, multivariate regression including blood-based indicators of metabolic syndrome in dolphins, glucose was the best predictor of and had a positive linear association with liver size (P = 0.007, R 2 = 0.24). Bottlenose dolphins are susceptible to metabolic syndrome and associated complications that affect the liver, including fatty liver disease and iron overload. This study facilitated the establishment of a technique for a rapid, diagnostic, and noninvasive ultrasonographic evaluation of the dolphin liver. In addition, the study identified ultrasound-detectable hepatic changes associated primarily with elevated glucose concentration in dolphins. Future investigations will strive to detail the pathophysiological mechanisms for these changes.

Contribution of PNPLA3 gene to the natural history of liver diseases.

PubMed

Trépo, E

2017-01-01

n 2008, a genome-wide association studies (GWAS) showed a strong association between a variant (rs738409 C>G p.I148M) in the PNPLA3 and nonalcoholic fatty liver disease. Further replication studies have shown robust associations between PNPLA3 and steatosis, fibrosis/cirrhosis, and hepatocellular carcinoma on a background of metabolic, alcoholic, and viral insults. The PNPLA3 protein has lipase activity towards triglycerides in hepatocytes and retinyl esters in hepatic stellate cells. The I148M substitution leads to a loss of function promoting triglyceride accumulation in hepatocytes. Although PNPLA3 function has been extensively studied, the molecular mechanisms leading to hepatic fibrosis and carcinogenesis remain unclear. This unsuspected association has highlighted the fact that liver fat metabolism may have a major impact on the pathophysiology of liver disease. Conversely, alone, this locus may have limited predictive value with regard to liver disease outcomes in clinical practice. Additional studies at the genome-wide level will be required to identify new variants associated with liver damage and cancer to explain a greater proportion of the heritability of these phenotypes. Thus, incorporating PNPLA3 and other genetic variants in combination with clinical data will allow for the development of tailored predictive models. This attractive approach should be evaluated in prospective cohorts. (Acta gastroenterol. belg., 2017, 80, 43-51). © Acta Gastro-Enterologica Belgica.

Diagnosis and Management of Alcoholic Liver Disease.

PubMed

Dugum, Mohannad; McCullough, Arthur

2015-06-28

Alcohol is a leading cause of liver disease and is associated with significant morbidity and mortality. Several factors, including the amount and duration of alcohol consumption, affect the development and progression of alcoholic liver disease (ALD). ALD represents a spectrum of liver pathology ranging from fatty change to fibrosis to cirrhosis. Early diagnosis of ALD is important to encourage alcohol abstinence, minimize the progression of liver fibrosis, and manage cirrhosis-related complications including hepatocellular carcinoma. A number of questionnaires and laboratory tests are available to screen for alcohol intake. Liver biopsy remains the gold-standard diagnostic tool for ALD, but noninvasive accurate alternatives, including a number of biochemical tests as well as liver stiffness measurement, are increasingly being utilized in the evaluation of patients with suspected ALD. The management of ALD depends largely on complete abstinence from alcohol. Supportive care should focus on treating alcohol withdrawal and providing enteral nutrition while managing the complications of liver failure. Alcoholic hepatitis (AH) is a devastating acute form of ALD that requires early recognition and specialized tertiary medical care. Assessment of AH severity using defined scoring systems is important to allocate resources and initiate appropriate therapy. Corticosteroids or pentoxifylline are commonly used in treating AH but provide a limited survival benefit. Liver transplantation represents the ultimate therapy for patients with alcoholic cirrhosis, with most transplant centers mandating a 6 month period of abstinence from alcohol before listing. Early liver transplantation is also emerging as a therapeutic measure in specifically selected patients with severe AH. A number of novel targeted therapies for ALD are currently being evaluated in clinical trials.

Prevalence and causes of abnormal liver function in patients with coeliac disease.

PubMed

Casella, Giovanni; Antonelli, Elisabetta; Di Bella, Camillo; Villanacci, Vincenzo; Fanini, Lucia; Baldini, Vittorio; Bassotti, Gabrio

2013-08-01

Coeliac disease patients frequently display mild elevation of liver enzymes and this abnormality usually normalizes after gluten-free diet. To investigate the cause and prevalence of altered liver function tests in coeliac patients, basally and after 1 year of gluten-free diet. Data from 245 untreated CD patients (196 women and 49 men, age range 15-80 years) were retrospectively analysed and the liver function tests before and after diet, as well as associated liver pathologies, were assessed. Overall, 43/245 (17.5%) patients had elevated values of one or both aminotransferases; the elevation was mild (<5 times the upper reference limit) in 41 (95%) and marked (>10 times the upper reference limit) in the remaining 2 (5%) patients. After 1 year of gluten-free diet, aminotransferase levels normalized in all but four patients with HCV infection or primary biliary cirrhosis. In coeliac patients, hypertransaminaseaemia at diagnosis and the lack of normalization of liver enzymes after 12 months of diet suggest coexisting liver disease. In such instance, further evaluation is recommended to exclude the liver disease. Early recognition and treatment of coeliac disease in patients affected by liver disease are important to improve the liver function and prevent complications. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Liver and Cardiovascular Damage in Patients With Lean Nonalcoholic Fatty Liver Disease, and Association With Visceral Obesity.

PubMed

Fracanzani, Anna Ludovica; Petta, Salvatore; Lombardi, Rosa; Pisano, Giuseppina; Russello, Maurizio; Consonni, Dario; Di Marco, Vito; Cammà, Calogero; Mensi, Laura; Dongiovanni, Paola; Valenti, Luca; Craxì, Antonio; Fargion, Silvia

2017-10-01

Lean nonalcoholic fatty liver disease (NAFLD) is defined as NAFLD that develops in patients with a body mass index (BMI) less than 25 kg/m 2 . We investigated the differences between lean NAFLD and NAFLD in overweight and obese persons, factors associated with the severity of liver and cardiovascular disease, and the effects of visceral obesity. We performed a retrospective cohort study of 669 consecutive patients with biopsy-proven NAFLD seen at 3 liver centers in Italy. We collected anthropometric, clinical, and biochemical data, as well as information on carotid atherosclerosis (artery intima-media thickness and plaque), liver histology (nonalcoholic steatohepatitis [NASH] and fibrosis), insulin resistance, and diabetes. Overweight was defined as a BMI of 25 to 29.9 kg/m 2 , and obese was defined as a BMI of 30 kg/m 2 or greater. Patients were assigned to groups based on waist circumference, a marker of visceral obesity (low: men, <94 cm, women <80 cm; medium: men, 94-102 cm, women 80-88 cm; or high: men >102 cm, women >88 cm). DNA samples were analyzed for the rs738409 C>G (I148M in PNPLA3), the rs58542926 C>T (E167K in TM6SF2), and single-nucleotide polymorphisms. Variables in men and women were analyzed using chi-squared analysis and the Mann-Whitney or Kruskal-Wallis tests. Multiple linear or logistic regression analyses were adjusted for all the variables of clinical relevance or statistically significant at univariate analyses. The primary outcome was the difference in liver and cardiovascular disease between lean NAFLD and NAFLD in overweight and obese persons. Secondary outcomes were effects of visceral obesity, based on waist circumference, on hepatic, vascular, and metabolic features. Significantly lower proportions of patients with lean NAFLD (143 patients; 43 women; mean age, 46 ± 13 y) had hypertension (P = .001), diabetes (P = .0001), and metabolic syndrome (P = .0001) than overweight or obese patients with NAFLD (526 patients; 149 women; mean

HIV/HCV Co-infection, Liver Disease Progression, and Age-Related IGF-1 Decline.

PubMed

Quinn, Jeffrey; Astemborski, Jacquie; Mehta, Shruti H; Kirk, Gregory D; Thomas, David L; Balagopal, Ashwin

2017-01-01

We have previously reported that persons co-infected with HIV and hepatitis C virus (HCV) had liver disease stages similar to HIV-uninfected individuals who were approximately 10 years older. Insulin-like growth factor 1(IGF-1) levels have long been known to decline with advancing age in humans and non-humans alike. We examined whether HIV infection affects the expected decline in IGF-1 in persons with chronic hepatitis C virus (HCV) infection and if that alteration in IGF-1 decline contributes to the link between HIV, aging, and liver disease progression. A total of 553 individuals with HCV infection were studied from the AIDS Linked to the Intravenous Experience (ALIVE) cohort for whom more than 10 years of follow-up was available. Serum IGF-1 levels were determined by ELISA and evaluated according to baseline characteristics and over time by HIV status and liver disease progression. Linear regression with generalized estimating equations was used to determine whether IGF-1 decline over time was independently associated with liver disease progression. Baseline IGF-1 levels were strongly associated with age ( P < 0.0001) but not with gender or HIV infection. Levels of IGF-1 declined at a rate of -1.75 ng/mL each year in HCV mono-infected individuals and at a rate of -1.23 ng/mL each year in HIV/HCV co-infected individuals ( P < 0.05). In a multivariable linear regression model, progression of liver fibrosis was associated with HIV infection and age, as well as with a slower rate of IGF-1 decline ( P = 0.001); however, the rate of IGF-1 decline did not alter the strength of the associations between HIV, liver disease, and age. The normal decline in IGF-1 levels with age was attenuated in HIV/HCV co-infected individuals compared to those with HCV mono-infection, and slower IGF-1 decline was independently associated with liver disease progression.

Targeting nuclear receptors for the treatment of fatty liver disease.

PubMed

Tanaka, Naoki; Aoyama, Toshifumi; Kimura, Shioko; Gonzalez, Frank J

2017-11-01

Ligand-activated nuclear receptors, including peroxisome proliferator-activated receptor alpha (PPARα), pregnane X receptor, and constitutive androstane receptor, were first identified as key regulators of the responses against chemical toxicants. However, numerous studies using mouse disease models and human samples have revealed critical roles for these receptors and others, such as PPARβ/δ, PPARγ, farnesoid X receptor (FXR), and liver X receptor (LXR), in maintaining nutrient/energy homeostasis in part through modulation of the gut-liver-adipose axis. Recently, disorders associated with disrupted nutrient/energy homeostasis, e.g., obesity, metabolic syndrome, and non-alcoholic fatty liver disease (NAFLD), are increasing worldwide. Notably, in NAFLD, a progressive subtype exists, designated as non-alcoholic steatohepatitis (NASH) that is characterized by typical histological features resembling alcoholic steatohepatitis (ASH), and NASH/ASH are recognized as major causes of hepatitis virus-unrelated liver cirrhosis and hepatocellular carcinoma. Since hepatic steatosis is basically caused by an imbalance between fat/energy influx and utilization, abnormal signaling of these nuclear receptors contribute to the pathogenesis of fatty liver disease. Standard therapeutic interventions have not been fully established for fatty liver disease, but some new agents that activate or inhibit nuclear receptor signaling have shown promise as possible therapeutic targets. In this review, we summarize recent findings on the roles of nuclear receptors in fatty liver disease and discuss future perspectives to develop promising pharmacological strategies targeting nuclear receptors for NAFLD/NASH. Copyright © 2017 Elsevier Inc. All rights reserved.