leptin and Hepatitis--Autoimmune

Lipodystrophies are hypoleptinemic conditions characterized by fat loss, severe insulin resistance, hypertriglyceridemia, and ectopic fat accumulation. Non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) are also features of this condition. We studied the spectrum of liver disease in lipodystrophy and the effects of leptin replacement.. This was an open-label, prospective study of leptin therapy in patients with inherited and acquired lipodystrophy at the National Institutes of Health. Liver biopsies were performed at baseline (N=50) and after leptin replacement (N=27). NASH activity was assessed using the NASH Clinical Research Network (CRN) scoring system. Fasting blood glucose, triglyceride, hemoglobin A1c and liver enzymes were measured at baseline and at the time of the final liver biopsy.. In leptin-treated patients, 86% met criteria for NASH at baseline, while only 33% had NASH after leptin replacement for 25.8 ± 3.7 months (mean ± SE, p=0.0003). There were significant improvements in steatosis grade (reduction of mean score from 1.8 to 0.9) and ballooning injury scores (from 1.2 to 0.4), with a 44.2% reduction in mean NAFLD activity score (p<0.0001). Patients who already had fibrosis remained stable on leptin replacement. We observed significant improvement in metabolic profile, ALT and AST. In addition to NASH, four patients with acquired generalized lipodystrophy (AGL) had autoimmune hepatitis.. The fundamental liver disease of lipodystrophy is NASH, although autoimmune hepatitis was observed in some patients with AGL. Leptin appears to be a highly effective therapy for NASH in hypoleptinemic lipodystrophic patients.

Topics: Adolescent; Adult; Aged; Alanine Transaminase; Aspartate Aminotransferases; Child; Cohort Studies; Fatty Liver; Female; Hepatitis, Autoimmune; Humans; Leptin; Lipodystrophy; Liver; Male; Metabolome; Middle Aged; Non-alcoholic Fatty Liver Disease; Prospective Studies; Recombinant Proteins; Young Adult

Leptin has a particular profibrogenic role in the liver. We investigated whether IFN-alpha influences leptin production in patients with chronic hepatitis B (CHB) and C (CHC). Leptin was determined in serial samples from 63 CHB and 42 CHC IFN-alpha treated patients. Furthermore, we evaluated whether leptin alterations were associated with patients' characteristics.. Sera were investigated at serial time-points using an enzyme-linked-immunosorbent-assay. Controls consisted of 36 patients with autoimmune liver diseases and 44 healthy patients.. Leptin levels before IFN-alpha administration were higher in CHB and CHC compared to healthy (P<0.004) and diseased controls (P=0.0001). In CHB patients, we observed a significant reduction of leptin during IFN-alpha treatment and lasting for up to 6 months after the end of treatment, followed by an increase reaching pretreatment levels at 1.5 years after stopping therapy. The pattern of leptin alterations was similar in CHC patients where leptin's decrease was more pronounced at 6 months after the end of treatment. Biochemical or virological response to treatment was not associated with leptin reduction in both groups.. This study provides information on leptin kinetics during IFN-alpha treatment and follow-up in CHB and CHC patients and suggests IFN-alpha as a potential inhibitor of leptin production.

Topics: Adult; Aged; Antiviral Agents; Female; Follow-Up Studies; Hepatitis B, Chronic; Hepatitis C, Chronic; Hepatitis, Autoimmune; Humans; Interferon-alpha; Leptin; Liver Cirrhosis; Male; Middle Aged; Prospective Studies; Sex Characteristics; Treatment Outcome

A high prevalence of obesity is reported in children and adolescents with autoimmune hepatitis (AIH). Adipokines participate in inflammatory processes. The objective of this study was to examine the relationship between excess weight and systemic inflammation, adipokines, and ghrelin in adolescents with AIH.. This case-controlled study included 27 adolescents with AIH (13 with excess weight and 14 with normal weight) and a control group. Excess weight was defined by a body mass index/age Z score >+1 standard deviation. Adipokines (adiponectin, leptin, tumor necrosis factor alpha, interleukin 6 [IL-6], and IL-10) and ghrelin were measured with Luminex technology.. Adiponectin (μg/mL) was higher (P < 0.001) in AIH adolescents with and without excess weight (median: 35.0 and 42.1, respectively) than in normal-weight (17.5) and excess-weight (17.0) controls. Leptin was higher (P < 0.001) in excess-weight AIH patients (18.0 ng/mL) and controls (19.8 ng/mL) than in normal-weight AIH (7.7 ng/mL) and control (7.0 ng/mL) adolescents. IL-6 levels were higher in excess-weight (3.8 pg/mL) and normal-weight (3.8 pg/mL) AIH patients than in excess-weight (1.1 pg/mL) and normal-weight (0.5 pg/mL) controls. IL-10 levels were higher (5.2 pg/mL) in normal-weight AIH patients than in excess-weight (1.8 pg/mL) and normal-weight (2.1 pg/mL) controls. Ferritin levels were lower in patients with AIH than in controls.. Independent of body weight, AIH patients had higher levels of adipokines, especially adiponectin and IL-6. Leptin levels were associated with body weight and were not influenced by AIH. IL-10 levels were associated with lean tissue in AIH.

Topics: Adipokines; Adiponectin; Adolescent; Body Weight; Child; Hepatitis, Autoimmune; Humans; Leptin

Acquired generalized lipodystrophy (AGL) is associated with leptin deficiency as a result of adipose tissue loss and hypertriglyceridemia, insulin resistance, and hepatic steatosis. It may coexist with other autoimmune diseases such as Hashimoto's thyroiditis, rheumatoid arthritis, hemolytic anemia, and chronic active hepatitis. Metreleptin therapy has been shown to improve metabolic abnormalities in lipodystrophy, but the effect on AGL patients with active autoimmune disease is unknown.. We report 3 cases of pediatric patients with AGL and distinct active autoimmune diseases who were treated with metreleptin over a period of 4-6 years. Case 1 is a 9-year-old girl with active juvenile dermatomyositis, who was successfully treated with leptin with no worsening of her dermatomoysitis. Case 2 is a 16-year-old female with Graves' disease, who could discontinue all her antidiabetic medication completely with improved triglyceride levels. Case 3 is an 11-year-old boy with active autoimmune hepatitis and chronic urticaria, whose hyperphagia has resolved and his liver enzymes and hepatosplenomegaly have improved.. Metreleptin therapy is of considerable clinical benefit to reduce insulin resistance and hypertriglyceridemia and did not appear to alter the clinical course of autoimmune disease nor clinical efficacy of immunosuppressive treatments. Our observations suggest that risk or presence of autoimmune disease should not lead to withholding of metreleptin treatment from patients with AGL, but should prompt close clinical follow up in light of cautionary preclinical data.

Topics: Adolescent; Autoimmune Diseases; Child; Compassionate Use Trials; Dermatomyositis; Female; Graves Disease; Hepatitis, Autoimmune; Humans; Hypoglycemic Agents; Hypolipidemic Agents; Leptin; Lipodystrophy; Male; Severity of Illness Index; Treatment Outcome; Urticaria

To determine the metabolic and immunological effects of the oral administration of DT56a, an enzymatic isolate of soybeans.. DT56a was orally administered to mice in three animal models: leptin deficiency, high-fat diet (HFD) supplementation and immune-mediated hepatitis. Liver damage and immunological status were assessed.. Oral administration of DT56a to leptin-deficient (ob/ob) and HFD mice led to a significant reduction in serum triglyceride (TG) and total cholesterol (TC) levels. DT56a-treated mice in both models exhibited a significant reduction in hepatic levels of TG and marked alleviation of glycemic control as indicated by significant decreases in fasting blood glucose levels and glucose tolerance tests. The levels of liver enzymes were reduced. These metabolic effects were associated with altered distributions of regulatory T (Tregs) and natural killer T (NKT) cells. DT56a suppressed the immune-mediated liver damage induced by concanavalin A indicated by decreased liver enzymes and serum interferon-γ levels and by improved histology and decreased hepatic apoptosis. Oral administration of DT56a also alleviated immune-mediated hepatitis and affected Tregs and NKT cells.. Oral administration of DT56a promotes a hepatoprotective effect associated with an alteration in the distribution of Tregs and NKT cells.

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; Blood Glucose; Cholesterol; Concanavalin A; Dietary Fats; Fatty Liver; Glucose Tolerance Test; Hepatitis, Autoimmune; Interferon-gamma; Leptin; Liver; Lymphocyte Count; Male; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Mice, Knockout; Natural Killer T-Cells; Plant Extracts; T-Lymphocytes, Regulatory; Triglycerides

Cytokines may play an important role as inflammatory factors in liver diseases. There is some evidence suggesting a link between adiponectin-biliary function and liver disease. The aim of this study was to clarify the behavior of adipokines in autoimmune hepatitis type 1.. We assessed the circulating levels of adiponectin, tumor necrosis factor-alpha, resistin and leptin in 42 patients with autoimmune hepatitis, comparing them with 42 healthy subjects who were matched for age and sex and with 31 patients with nonalcoholic steatohepatitis (NASH), evaluating the associations with markers of cytolysis, cholestasis, and histological severity.. Adiponectin and TNF-alpha values were higher in patients compared to controls. The patients showed significantly higher Homeostasis Model Assessment values, suggesting an increased insulin resistance and serum levels of adiponectin positively correlated with gamma-glutamyltranspeptidase and alkaline phosphatase values after a simple regression analysis. Serum levels of resistin positively correlated with elevated aminotransferases and bilirubin values, and serum levels of TNF-alpha positively correlated with elevated alanine-aminotransferase and resistin values. The concentration of adiponectin increased significantly with staging of the disease. Patients with NASH showed lower levels of adiponectin and higher levels of resistin than AIH patients and controls.. Patients with AIH showed significantly higher adiponectin concentrations than controls despite their higher HOMA-IR values. The significant correlation between adiponectin levels and serological features of cholestasis suggested an association with biliary function. Our results indicate that adiponectin may be a possible marker for disease progression in AIH.

Topics: Adipokines; Adiponectin; Adult; Aged; Biomarkers; Cholestasis; Disease Progression; Fatty Liver; Female; Hepatitis, Autoimmune; Humans; Insulin; Insulin Resistance; Leptin; Male; Middle Aged; Resistin; Transaminases; Tumor Necrosis Factor-alpha