Sir,
Leptin is a peptide hormone produced by the ob gene of adipocytes1. In experimental animals hyperleptinemia increases insulin resistance and hepatic triglyceride content which may lead to hepatic steatosis and steatohepatitis. This suggests that leptin may have a role in the aetiopathogenesis of non-alcoholic steatohepatitis (NASH)1,2,3,4. Leptin levels in NASH patients have been studied in western population. We therefore, measured serum leptin levels in Indian patients and correlated it with their body mass index (BMI) and histologic features in patients with NASH.
The aims of this study were to compare serum leptin levels in patients with NASH and matched controls, and to correlate serum leptin levels with clinical, biochemical and histological features to elucidate the role of leptin in the pathogenesis of NASH. Inclusion criteria were elevated alanine aminotransferase (ALT) levels more than 1.5 times normal for >6 months, alcohol intake <20 g/day, fatty liver on ultrasonography (USG) or MRI, and adequate liver biopsy for histological examination. Patients were excluded if they had any systemic illness, were taking any medication like estrogens, methotrexate, corticosteroids, tamoxifen and amiodarone in the last one year, were following any dietary regimen or receiving any treatment for NASH.
Twenty one consecutive patients presenting to Gastrointestinal out-patient department of our hospital from January 2009 to March 2009 and an equal number of age, sex and BMI matched controls (recruited from the staff of the hospital) were included in the study. Chronic liver disease was excluded in controls by physical examination, viral serology and abdominal USG scan. In the patients, anthropometric data were recorded and laboratory tests were done to exclude viral and autoimmune aetiology. Serum leptin was measured by enzyme linked immunosorbant assay kit (Titerzyme EIA, ELISA kit, Assay designs’ Inc, USA). Liver biopsies were graded and staged according to the criteria given by Brunt et al5.
The mean age of the patients was 31 ± 7 yr and mean BMI was 25.1 ± 1.2 kg/m2. One patient had diabetes mellitus, 19 had hypertriglyceridaemia, and 11 had insulin resistance (Table). Serum leptin was significantly (P<0.05) higher in NASH patients compared to controls. On univariate analysis, BMI (r = 0.934, P<0.001), necroinflammatory activity (P=0.019) and fibrosis stage (P=0.042) correlated with serum leptin levels. On multivariate regression analysis, BMI was the only independent predictor of serum leptin levels (P<0.001). On univariate analysis, serum leptin levels (P=0.047), BMI (P=0.004), serum ALT levels (P=0.012), steatosis (P=0.001) and lobular inflammation (P=0.005) correlated with necroinflammatory grade of NASH. On multivariate regression analysis only ALT levels (P=0.027) and lobular inflammation (P=0.038) were independent predictor of necroinflammatory grade. Further multivariate regression analysis did not show leptin to be an independent predictor of steatosis, lobular inflammation, portal inflammation or fibrosis.
Table.
Anthropometric and biochemical parameters of patients with NASH and matched controls
Our study confirmed the earlier findings6,7 reporting significantly higher serum leptin levels in patients with NASH as compared to controls. In our study serum leptin levels showed disproportionately greater increase with BMI in NASH patients as compared to matched controls. Thus, the increases in leptin levels in NASH is not explained by obesity alone but is also due to peripheral leptin resistance. In NASH leptin receptors become resistant to its effect leading to hyperleptinemia which alters insulin signaling and promotes accumulation of intracellular fatty acids in hepatocytes thereby increasing hepatic steatosis and steatohepatitis7,8,9,10,12. Our study indicates that serum leptin increases the severity of necroinflammation and fibrosis in NASH but it is not an independent predictor of disease severity.
In our study serum leptin was not found to be an independent predictor of liver fibrosis. Chitturi et al6 (47 patients) and Chalasani et al10 (26 patients) also did not find any correlation between serum leptin levels and fibrosis stage. Kim et al11 found that serum leptin levels correlated with hepatic fibrosis, but serum leptin was not an independent predictor on univariate analysis.
In conclusion, this study suggests that serum leptin levels are increased in NASH patients disproportionate to increase in BMI, however, leptin levels do not predict histologic severity of NASH (necroinflammation or fibrosis) on liver biopsy. Further studies are needed to determine clearly the role of leptin and other adipokines in causing hepatic steatosis and steatohepatitis.
References
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