leptin and Hepatitis-C

Numerous investigations have shown that mitochondrial dysfunction is a major mechanism of drug-induced liver injury, which involves the parent drug or a reactive metabolite generated through cytochromes P450. Depending of their nature and their severity, the mitochondrial alterations are able to induce mild to fulminant hepatic cytolysis and steatosis (lipid accumulation), which can have different clinical and pathological features. Microvesicular steatosis, a potentially severe liver lesion usually associated with liver failure and profound hypoglycemia, is due to a major inhibition of mitochondrial fatty acid oxidation (FAO). Macrovacuolar steatosis, a relatively benign liver lesion in the short term, can be induced not only by a moderate reduction of mitochondrial FAO but also by an increased hepatic de novo lipid synthesis and a decreased secretion of VLDL-associated triglycerides. Moreover, recent investigations suggest that some drugs could favor lipid deposition in the liver through primary alterations of white adipose tissue (WAT) homeostasis. If the treatment is not interrupted, steatosis can evolve toward steatohepatitis, which is characterized not only by lipid accumulation but also by necroinflammation and fibrosis. Although the mechanisms involved in this aggravation are not fully characterized, it appears that overproduction of reactive oxygen species by the damaged mitochondria could play a salient role. Numerous factors could favor drug-induced mitochondrial and metabolic toxicity, such as the structure of the parent molecule, genetic predispositions (in particular those involving mitochondrial enzymes), alcohol intoxication, hepatitis virus C infection, and obesity. In obese and diabetic patients, some drugs may induce acute liver injury more frequently while others may worsen the pre-existent steatosis (or steatohepatitis).

Topics: Adiponectin; Adipose Tissue; Alcoholic Intoxication; Animals; Carbohydrate Metabolism; Cell Death; Chemical and Drug Induced Liver Injury; Diabetes Mellitus, Type 2; Energy Metabolism; Fatty Acids; Fatty Liver; Genetic Predisposition to Disease; Genome, Mitochondrial; Hepatitis C; Humans; Insulin Resistance; Leptin; Lipid Metabolism; Mitochondria, Liver; Mitochondrial Membrane Transport Proteins; Mitochondrial Permeability Transition Pore; Models, Biological; Obesity; Oxidation-Reduction; Oxidative Phosphorylation; Reactive Oxygen Species

Topics: Antiviral Agents; Biological Availability; Drug Resistance; Fatty Liver; Hepatitis C; Humans; Immune System; Interferons; Leptin; Liver; Obesity; Treatment Failure

Serum leptin levels are elevated in alcoholic liver cirrhosis and thus might be involved in the anorexia and hypermetabolism often seen in those patients. We hypothesized that the leptin system is modulated in patients with hepatitis C and might be affected by antiviral therapy. The aim of this study was to investigate the different leptin components in serum of patients with hepatitis C before, during and after interferon alpha and ribavirin therapy and in controls.. 25 patients (11 female, 14 male) with chronic hepatitis C were compared with body mass index, gender and age-matched controls (n = 25). Patients were treated with interferon alpha alone (3 MU tiw) or in combination with ribavirin for 6-12 months. Free leptin and bound leptin levels were measured using specific radioimmunoassays before interferon therapy, at 12 weeks of therapy and after 3 months of follow-up.. Free leptin levels were higher in female than in male subjects, both for patients (P < 0.01) and controls (P < 0.05). Bound leptin levels were elevated in both female (P < 0.05) and male (P < 0.001) patients compared to controls. No alteration of free leptin levels was found during therapy, whereas bound leptin levels decreased after 3 months of therapy (P < 0.005) and re-increased to the baseline levels 3 months after therapy was stopped. Responder but not non-responder had decreased bound leptin levels (P < 0.01) comparing pre- and posttreatment levels. However, no significant correlations were determined between any of the leptin components to virus load, ALT, TNF alpha receptor levels (sTNFR-75, sTNFR-55) and histopathology at any time point.. Since no correlation was found between the different leptin components and any of the inflammatory markers, the decrease in bound leptin levels during antiviral therapy suggests either a direct interferon-dependent effect on the leptin system or an alteration of other leptin secretagogues.

Topics: Adult; Age Distribution; Antiviral Agents; Biomarkers; Drug Therapy, Combination; Female; Hepatitis C; Humans; Interferons; Leptin; Male; Middle Aged; Multivariate Analysis; Probability; Prognosis; Radioimmunoassay; Reference Values; Regression Analysis; Ribavirin; Sensitivity and Specificity; Severity of Illness Index; Sex Distribution

To investigate the levels of leptin and adiponectin in prediction of hepatocellular carcinoma (HCC) survival among patients without liver transplantation.. We measured pretreatment plasma leptin and adiponectin in 172 HCC cases who were prospectively followed-up over 7 years.. Gender, hepatitis B virus (HBV) and hepatitis C virus (HCV) infection, high body mass index (BMI), diabetes mellitus (DM) history and Child-Pugh (CP) class were associated with leptin and adiponectin levels, while α-fetoprotein (AFP) and presence of metastasis, being outside the Milan criteria and Barcelona clinic liver cancer (BCLC) stage, were significantly associated with liver transplantation and HCC survival. No significant association was observed for leptin or adiponectin and HCC survival in the overall group. In subgroup analyses among those without liver transplantation, we found significant associations between metastasis, Milan criteria, BCLC stage, hepatitis B surface antigen (HBsAg) and HCC survival. When separately determining the Cox proportional hazard models and Kaplan-Meier survival curves by liver transplantation status, higher adiponectin was significantly associated with an increased hazard ratio (HR) of death of 1.72 (95% confidence interval (CI)=1.12-2.64), i.e. poor survival among patients without liver transplantation. A multivariate Cox proportional hazard model, including adiponectin, CP class, presence of metastasis, tumor outside of Milan criteria, AFP and BCLC stage B/C parameters, also showed significant association with poor HCC survival (likelihood ratio test p<0.0001). No significant impact was observed for leptin on HCC survival regardless of liver transplantation status.. Higher levels of plasma adiponectin may predict poor HCC survival among patients without liver transplantation.

Topics: Adiponectin; alpha-Fetoproteins; Carcinoma, Hepatocellular; Female; Hepatitis B; Hepatitis C; Humans; Leptin; Liver Neoplasms; Liver Transplantation; Male; Middle Aged; Neoplasm Staging; Proportional Hazards Models

The mechanisms underlying steatosis during hepatitis C virus (HCV) infection are complex and multifactorial. The aim of our study was to assess whether host metabolic factors influence the degree of hepatic steatosis and fibrosis in patients infected with hepatitis C virus genotype 4 by investigating the role of adiponectin, leptin and insulin resistance.. Adiponectin and leptin levels, HCV genotypes, HCV-RNA, IR (HOMA-IR), body mass index and liver steatosis and fibrosis were assessed in 74 chronic patients with HCV genotype 4.. Chronic HCV patients with steatosis showed lower serum adiponectin levels and higher levels of leptin, HOMA, alanine aminotransferase, gamma-glutamiltransferase and fibrosis scores. Low adiponectin levels were independently associated with grades of steatosis and HOMA-IR. Adiponectin levels showed significant inverse correlation between adiponectin and steatosis grade, BMI, HOMA and fibrosis stage. The multivariate analysis of factors showed that steatosis was significantly associated with low adiponectin concentration while leptin, insulin, HOMA, ALT, gamma-GT and cholesterol were positively associated with steatosis.. This study stated that patients with HCV genotype-4 suffering from steatosis had a lower adiponectin level which is inversely correlated with insulin resistance. These data support a role for adiponectin in protecting against liver injury and also that hypoadiponectinaemia may contribute to the progression of hepatic steatosis. Further molecular and genetic studies with larger numbers of patients are required to confirm these results.

Topics: Adiponectin; Adult; Alanine Transaminase; Cholesterol; Fatty Liver; Female; Fibrosis; gamma-Glutamyltransferase; Genotype; Hepacivirus; Hepatitis C; Hepatitis C Antibodies; Humans; Leptin; Male; Middle Aged; RNA, Viral; Triglycerides

Mechanisms linking obesity and unfavourable outcomes in patients with viral hepatitis C (HCV) cirrhosis are not well understood. Obesity is associated with insulin resistance, increased leptin, and decreased adiponectin serum levels.. We assessed the predictive value of those factors for the occurrence of hepatocellular carcinoma (HCC) and liver-related death or transplantation in a cohort of 248 patients (mean age 58 (12 years, BMI 25.4 ± 4.4 kg/m(2)) with compensated HCV cirrhosis and persistent infection prospectively followed and screened for HCC.. The mean baseline serum levels of adiponectin and leptin were 16.8 ± 15 mg/L and 16.8 ± 19 ng/ml, respectively. The mean homeostasis model assessment of insulin resistance (HOMA) index was 3.8 ± 3; median 2.9. After a median follow-up of 72 months, 61 patients developed HCC, 58 died of liver causes, and 17 were transplanted. The incidences (Kaplan Meier) of HCC were 7%, 18%, and 27% at 5 years (p=0.017) and of liver-related death or transplantation 15%, 15% and 29% (p=0.002) according to the lowest, middle and highest tertile of HOMA, respectively. In multivariate analysis, the HOMA index was associated with HCC occurrence (HR=1.10, [1.01-1.21] p=0.026) and was a strong predictor of liver-related death or transplantation (HR=1.13, [1.07-1.21] p<0.0001). Serum levels of adiponectin and leptin were not associated with the outcome.. In patients with compensated HCV cirrhosis, insulin resistance but not serum levels of adiponectin and leptin predicted the occurrence of HCC and of liver-related death or transplantation.

Topics: Adiponectin; Adult; Aged; Carcinoma, Hepatocellular; Female; Follow-Up Studies; Hepatitis C; Humans; Insulin Resistance; Leptin; Liver; Liver Cirrhosis; Liver Neoplasms; Male; Middle Aged; Risk Factors

Topics: Adipokines; Hepatitis C; Humans; Insulin Resistance; Interleukin-8; Leptin; Liver

The objectives of this research were to investigate the leptin levels among Chronic Hepatitis B Virus (HBV), Chronic Hepatitis C Virus (HCV) and non-alcoholic steatosis hepatitis (NASH) diseases of Thai patients compared with controls. Twenty of each HBV, HCV and NASH patients compared with sixty people as the control group from the Outpatient Department at the Hospital for Tropical Diseases, Bangkok, Thailand were investigated. Fasting blood samples were collected for investigation of leptin concentration, liver enzyme function tests and hematological variables. The serum leptin concentration of liver patients was significantly higher than that of control subjects. It might be due to the accumulations of fat cells in liver disease patients. However, there is no relationship between leptin level and other parameters such as BMI, ALT, AST, ALP and hematological variables. Liver enzyme functions levels are much higher in patients groups. White blood cells counts, platelets and hematocrit values are slightly lower in liver disease patients. Therefore, it is concluded that physiological regulation of leptin maintains in relation to body fat, even in chronic viral liver diseases. This finding and the apparent stage suggest the possibility that in the course of chronic viral diseases, serum leptin levels may reflect the extent of liver dysfunction.

Topics: Adult; Aged; Case-Control Studies; Chronic Disease; Fatty Liver; Female; Hepatitis B; Hepatitis C; Humans; Leptin; Male; Middle Aged; Thailand

Leptin, the Ob gene product, is an adipocyte hormone that centrally regulates weight control. In addition, other effects of leptin in peripheral tissues have been described. Thus, leptin has been found to regulate reproduction, haematopoiesis and immune function. We have found recently that leptin has a stimulatory effect on human peripheral blood mononuclear cells (PBMC). Monocytes are activated by leptin alone whereas T lymphocytes need a suboptimal stimulus of PHA or ConA before further activation by leptin. These effects are mediated by the long isoform of the leptin receptor, which has been shown to trigger signalling in PBMC. In fact, we have found that human leptin stimulates Janus kinase (JAK)-signal transducer and activator of transcription (STAT), phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways in PBMC. In order to assess possible regulation of the long isoform of the leptin receptor (Ob-R) in mononuclear cells upon activation, we have studied the expression of Ob-R by RT-PCR and Western blotting in PBMC activated in vitro by PHA or ConA and in vivo in HIV-infected patients. We have found that in vitro activation and in vivo HIV infection correlates with an increase in leptin receptor expression in PBMC. Moreover, the leptin receptor is tyrosine phosphorylated in PBMC from HIV-infected patients, suggesting that the leptin receptor is activated. These results are consistent with the suggested role of leptin in modulating the immune response.

Topics: Adolescent; Adult; Carrier Proteins; Cells, Cultured; Child; Concanavalin A; Female; Gene Expression Regulation; Hepatitis C; HIV Infections; Humans; Leptin; Lymphocyte Activation; Male; Phosphorylation; Phytohemagglutinins; Protein Isoforms; Protein Processing, Post-Translational; Receptors, Cell Surface; Receptors, Leptin; Recombinant Proteins; RNA, Messenger; Signal Transduction; T-Lymphocytes

Little information is available on the involvement of leptin in clinical conditions associated with malnutrition, such as liver cirrhosis. The behaviour of serum leptin in patients with different Child-Pugh score, post-hepatitis liver cirrhosis and insulin sensitivity has therefore been investigated and compared with that in alcoholic Child C patients.. Sixty-four patients, aged 51 to 62 years, with different degrees of post-hepatitis cirrhosis or Child C alcoholic cirrhosis were compared with 15 age-matched control subjects. Body composition was estimated by skinfold thickness. Serum leptin, glucose and insulin were assayed.. In post-hepatitis patients a significant reduction in leptin levels was observed as the Child-Pugh score worsened (men: 2.94+/-1.61 in Child C vs 6.78+/-2.49 ng/ml in controls, p<0.001; women: 4.14+/-0.66 in Child C vs 16.16+/-3.90 ng/ml in controls, p<0.02). Conversely, only the men with alcoholic liver cirrhosis showed a significant difference in leptin concentration compared to controls (8.5+/-2.1 vs 16.4+/-7.9 kg, p<0.05). In particular, Child C, alcoholic cirrhotic women had a significantly (p=0.03) higher level of leptin than post-hepatitis matched women. A positive correlation was observed between leptin and fat mass (men R2=0.59, p<0.0001 and women R2=0.65, p<0.0001). While fasting levels of serum leptin correlated significantly with insulin concentrations in controls, a similar relationship was not observed in the cirrhotic population, which displayed higher insulin concentrations than controls.. In contrast to findings in alcoholic cirrhotic women, low leptin values in post-hepatitis cirrhotic patients mainly represent the expression of a reduced fat mass.

Topics: Adipose Tissue; Fasting; Female; Hepatitis B; Hepatitis C; Humans; Insulin Resistance; Leptin; Liver Cirrhosis; Liver Cirrhosis, Alcoholic; Male; Middle Aged; Organ Size; Reference Values