leptin and Liver-Failure

Estimates of people suffering from overweight (one billion) and obesity (300 million) are increasing. The accumulation of triglycerides in the liver, in the absence of excess alcohol intake, has been described in the early sixties. It was not until 1980, however, that Ludwig et al named this condition nonalcoholic steatohepatitis (NASH). Subsequently, nonalcoholic fatty liver disease (NAFLD) has been used as a general name for conditions ranging from simple steatosis through steatohepatitis to end-stage liver disease (cirrhosis). Many studies have demonstrated the significant correlation with obesity and insulin resistance. Other studies have revealed a significant correlation between hepatic steatosis, cardiovascular disease and increased intima-media thickness. WHO estimated that at least two million patients will develop cirrhosis due to hepatic steatosis in the years to come. Longitudinal cohort studies have demonstrated that those patients with cirrhosis have a similar risk to develop hepatocellular carcinoma as those with other causes of cirrhosis. Taken all together, NAFLD has become the third most important indication for liver transplantation. Therefore, training programmes in internal medicine, gastroenterology and hepatology should stress the importance of diagnosing this entity and treat properly those at risk for developing complications of portal hypertension and concomitant cardiovascular disease. This review will focus on the clinical characteristics, pathophysiology, imaging techniques and the readily available therapeutic options.

Topics: Adipocytes; Fatigue; Fatty Acids, Nonesterified; Fatty Liver; Humans; Insulin Resistance; Leptin; Lipids; Liver; Liver Failure; Pain; Reference Values

Liver fibrosis is the excessive accumulation of extracellular matrix proteins including collagen that occurs in most types of chronic liver diseases. Advanced liver fibrosis results in cirrhosis, liver failure, and portal hypertension and often requires liver transplantation. Our knowledge of the cellular and molecular mechanisms of liver fibrosis has greatly advanced. Activated hepatic stellate cells, portal fibroblasts, and myofibroblasts of bone marrow origin have been identified as major collagen-producing cells in the injured liver. These cells are activated by fibrogenic cytokines such as TGF-beta1, angiotensin II, and leptin. Reversibility of advanced liver fibrosis in patients has been recently documented, which has stimulated researchers to develop antifibrotic drugs. Emerging antifibrotic therapies are aimed at inhibiting the accumulation of fibrogenic cells and/or preventing the deposition of extracellular matrix proteins. Although many therapeutic interventions are effective in experimental models of liver fibrosis, their efficacy and safety in humans is unknown. This review summarizes recent progress in the study of the pathogenesis and diagnosis of liver fibrosis and discusses current antifibrotic strategies.

Topics: Angiotensin II; Animals; Humans; Hypertension, Portal; Leptin; Liver Cirrhosis; Liver Failure; Transforming Growth Factor beta

Knockout of C/EBPalpha causes a severe loss of liver function and, subsequently, neonatal lethality in mice. By using a gene replacement approach, we generated a new C/EBPalpha-null mouse strain in which C/EBPbeta, in addition to its own expression, substituted for C/EBPalpha expression in tissues. The homozygous mutant mice C/ebpalpha(beta/beta) are viable and fertile and show none of the overt liver abnormalities found in the previous C/EBPalpha-null mouse line. Levels of hepatic PEPCK mRNA are not different between C/ebpalpha(beta/beta) and wild-type mice. However, despite their normal growth rate, C/ebpalpha(beta/beta) mice have markedly reduced fat storage in their white adipose tissue (WAT). Expression of two adipocyte-specific factors, adipsin and leptin, is significantly reduced in the WAT of C/ebpalpha(beta/beta) mice. In addition, expression of the non-adipocyte-specific genes for transferrin and cysteine dioxygenase is reduced in WAT but not in liver. Our study demonstrates that when expressed from the C/ebpalpha gene locus, C/EBPbeta can act for C/EBPalpha to maintain liver functions during development. Moreover, our studies with the C/ebpalpha(beta/beta) mice provide new insights into the nonredundant functions of C/EBPalpha and C/EBPbeta on gene regulation in WAT.

Topics: Adipose Tissue; Animals; Blood Glucose; CCAAT-Enhancer-Binding Proteins; Chimera; Complement Factor D; Crosses, Genetic; Cysteine Dioxygenase; Dioxygenases; DNA-Binding Proteins; Female; Fertility; Gene Expression Regulation; Genotype; Leptin; Lipid Metabolism; Liver; Liver Failure; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Nuclear Proteins; Organ Specificity; Oxygenases; Promoter Regions, Genetic; Recombinant Fusion Proteins; RNA, Messenger; Serine Endopeptidases; Transferrin

Leptin, the product of the ob gene, is a postulated feedback regulator of adiposity with appetite suppressant and catabolic effects. Catabolic states are associated with decreased body fat mass as a result of both nutritional and metabolic perturbation. Low serum leptin has been described previously in a number of catabolic states. It has been unclear whether the observed changes in leptin are a cause or consequence of changes in adiposity. Paediatric end-stage liver disease (ESLD) is characterized by decreased body fat mass and poor linear growth. Successful treatment by orthotopic liver transplantation (OLT) is accompanied by increase in fat mass. We investigated the hypothesis that serum leptin would be low in paediatric ESLD and that increase in body fat mass post-OLT would result in increased serum leptin.. Serum leptin and insulin were measured by radioimmunoassay in children with ESLD before and after successful OLT and in age-matched controls.. Twenty-four children with ESLD attending the outpatient department of King's College Hospital, London and 10 age-matched controls.. Anthropometric measurements were performed according to standard techniques and standard deviation (SDS) derived from population standards. Serum leptin and insulin were measured by radioimmunoassay.. Serum leptin pre-OLT, leptin (4.06 micrograms/l, [3.45, 5.68] median, with 25th and 75th interquartile ranges) was significantly lower than controls (6.62 micrograms/l, [4.33, 8.05], P = 0.02). Following OLT, serum leptin fell to levels which were significantly lower than pre-OLT values (3.32 micrograms/l, [2.30, 3.99], P = 0.01). There was no significant difference between boys and girls either pre-OLT (boys; 3.64 micrograms/l, [2.45, 5.57], girls; 4.14 micrograms/l, [3.18, 5.65]) or post-OLT (boys; 3.32 micrograms/l, [2.93, 3.62], girls; 3.69 micrograms/l, [2.23, 4.63]. Neither the age at OLT nor the age at the time of blood sampling was correlated with serum leptin pre-OLT or post-OLT. Pre-OLT the children were significantly malnourished with low measures of body fat mass (mid-arm circumference (MAC) SDS -1.90 [-4.67, -1.07]; triceps skinfold thickness (TSF) SDS -1.53, [-2.23, -0.23]; body mass index (BMI) 16.2, [15.5, 16.9]). Three months post-OLT, there were significant improvements in MAC SDS (-0.77, [-1.08, -0.20], P = 0.02) and TSF SDS (-0.41, [-1.95, -0.38], P = 0.003), but no significant change in BMI (15.9 [15.3, 16.7], P = 0.41. Pre-OLT, log serum leptin did not correlate with BMI, MAC SDS or TSF SDS. In contrast, post-OLT, there was a positive correlation between log serum leptin and BMI (r = 0.59, P = 0.003), MAC SDS (r = 0.49, P = 0.01) and TSF SDS (r = 0.41, P = 0.05). BMI also correlated with log serum leptin in the control children (r = 0.64, P = 0.04).. Serum leptin is low in children with end-stage liver disease but does not show the expected correlation with measures of body fat mass. Surprisingly, following orthotopic liver transplantation serum leptin falls significantly despite significant increases in measures of body fat mass (triceps skinfold thickness standard deviation scores, mid-arm circumference standard deviation scores). Orthotopic liver transplantation restores the expected correlation of serum leptin with measures of body fat mass within the treatment group. The elevation of serum leptin above predicted levels in paediatric end-stage liver disease offers a mechanism for the anorexia and cachexia characteristic of this disease.

Topics: Anthropometry; Biomarkers; Child; Child, Preschool; Female; Humans; Infant; Insulin; Leptin; Liver Failure; Liver Transplantation; Male; Postoperative Period; Proteins; Radioimmunoassay; Regression Analysis; Statistics, Nonparametric