Association of pro-inflammatory cytokines, adipokines & oxidative stress with insulin resistance & non-alcoholic fatty liver disease.

Background & objectives: The cytokines, adipokines, and oxidative stress have been implicated in the pathogenesis of non-alcoholic fatty liver disease (NAFLD); however, such data remain scarce in India. The present study evaluated pro-inflammatory cytokines, adipokines, and markers of oxidative stress in patients with non-alcoholic fatty liver disease (NAFLD), and their association with degree of adiposity, insulin resistance and markers of disease severity. Methods: The present prospective cross-sectional pilot study included 79 subjects; 34 NAFLD, 22 chronic hepatitis B (CH-B) and 23 healthy controls (HC). The parameters studied were adiponectin, leptin, tumour necrosis factor α (TNFα), interleukin-1 and 6 (IL-1, IL-6), and systemic markers of oxidative stress. Results: The mean body mass index (kg/m2) in NAFLD patients, CHB, and HC were 26.4±3.7, 21.3±2.3, and 22.3±2.7, respectively. The median serum levels of all pro-inflammatory cytokines were significantly higher (P<0.001) in NAFLD compared to control groups. Compared to HC, levels of adiponectin and leptin were significantly (P<0.05, P<0.01) reduced in both NAFLD and CHB. IL-6 showed marked and selective increase only in NAFLD patients. The levels of IL-6 were significantly (P<0.02) higher in NAFLD patients with advanced histology grade and correlated with IR (r=0.42, P=0.02). In a sub-group, markers of oxidative stress were significantly higher, and that of antioxidant potential were significantly lower among NAFLD patients compared to control subjects. Interpretation & conclusions: Patients with NAFLD revealed significantly elevated levels of pro-inflammatory cytokines, increased oxidative stress, and a significant association of IL-6 with IR and advanced histopathology.

Pathogenesis of non alcoholic fatty liver disease: Present concepts.

Non alcoholic fatty liver disease has become a common cause for the chronic liver disease, a clinicopathological entity characterised by excessive triglyceride accumulation in hepatocytes. The spectrum of non alcoholic fatty liver disease varies from simple steatosis, a relatively benign condition, to steatohepatitis which may ultimately progress to cirrhosis and end stage liver disease. Its pathophysiology is complex, but visceral adipose tissue and insulin resistance are the key initiating and perpetuating factors. Adipose tissue is now considered as an endocrine organ, and crosstalk between adipocytes and hepatocytes, through adipokines plays an important role in governing the sensitivity of insulin on glucose and lipid metabolism. Once hepatic steatosis develops, various intracellular mechanisms, like oxidative stress and endoplasmic reticulum stress lead to progression to steatohepatitis and cirrhosis. The different natural history in various ethnic groups suggest that genetic and environmental factors may play a crucial role in the development of the ultimate phenotype.

Impact and management of hepatitis B and hepatitis C virus co-infection in HIV patients.

Individuals at risk of HIV are concomitantly at risk of acquiring parenterally or sexually transmitted viruses, including HBV and HCV. After the introduction of highly active antiretroviral therapy (ART), liver disease has emerged as a major cause of morbidity and mortality in HIV-infected persons. HBV, HCV and HIV share common routes of transmission, but the differential efficiency of these viruses to the types of exposures underlies difference in their prevalence by geographic region. Coinfection alters the natural history of each of these viruses in a peculiar way; furthermore coinfection with viral hepatitis may complicate the delivery of ART by increasing the risk of drug-related hepatoxicity and impacting the selection of specific agents (e.g., those dually active against HIV and HBV). The treatment of HBV in HIV co-infection is complex because the drug(s) used is/are associated with drug-resistance, cross-resistance, hepatotoxicity and suboptimal response. The aim is to achieve long-term sustained viral (HBV) suppression. HBV should be treated in coinfected patients with elevated HBV DNA or significant hepatic fibrosis (Metavir score = A2 or F2). The HBV DNA threshold for initiation of HBV treatment should be lower than in patients with HBV monoinfection. Anti HBV therapy should also be considered in those receiving ART irrespective of viral load and fibrosis, in order to prevent hepatitis of immune reconstitution. Selection of drug(s) depends on whether coinfected patients require treatment of only HBV or both HBV and HIV. In patients requiring only HBV treatment, drugs with dual antiviral activity should not be used in order to avoid early HIV resistance. When both HIV and HBV meet criteria for the treatment, agents with dual activity should be included in the anti-retroviral regimen. Treatment should be monitored by measuring the ALT and HBV DNA levels 3 to 6 monthly. The required duration of HBV treatment in coinfected induviduals is not known and may possibly be life long. Every coinfected person with compensated chronic HCV should be considered for HCV treatment. However, treatment should be avoided in decompensated cirrhosis and in the presence of active opportunistic infection. In patients with CD4 counts <200 cells/il and/or plasma HIV-RNA above 100,000 copies/mI, it may be better to consider anti HIV treatment before HCV treatment. The standard treatment in coinfected patients is pegylated interferon alfa-2a (Pegasys) or -2b (Peg-Intron) plus ribavirin for 48 weeks. Several studies have shown an overall sustained vwal response rate of 14% to 29% in genotype 1 and 53% to 73% in genotypes 2 and 3. The other concern with treatment is drug interaction with anti retroviral drugs necessitating avoidance of certain drugs from ART regimen. The coinfected persons with decompensated liver cirrhosis should not be denied HAART and should be evaluated for liver transplantation. Finally, management of patients not responding to standared therapy is not known.