The therapeutic efficacy of angiotensin II receptor antagonist, losartan, was studied in patients with nonalcoholic steatohepatitis (NASH). Seven patients with both NASH and hypertension were treated with losartan (50 mg/d) for 48 weeks. Treatment with losartan resulted in a significant decrease in blood markers of hepatic fibrosis, plasma TGF-␤1 and serum ferritin concentration concurrently with an improvement in serum aminotransferase levels. Histological assessment showed improvement of hepatic necroinflammation in five patients, reduction of hepatic fibrosis in four patients, and disappearance of iron deposition in two patients. No side effect of treatment was noted at any time during the study. In conclusion, the present data raise the possibility that an angiotensin II receptor antagonist may be therapeutically efficacious for NASH. (HEPATOLOGY 2004;40:1222-1225 N onalcoholic steatohepatitis (NASH) is a distinct clinical entity characterized by varying degrees of progressive steatosis, lobular inflammation and fibrosis of the liver. 1,2 Although the causes of NASH are not well defined and several therapies including diet, 3 antioxidants, 4 and approaches that improve insulin resistance 5 have been tried, no commonly accepted therapeutic protocol has yet been established. Recent studies have demonstrated a crucial role of angiotensin II in the pathogenesis of hepatic fibrosis, 6 and this peptide has been shown to enhance insulin resistance and tissue iron deposition. 7,8 Administration of an antagonist of angiotensin II type 1 receptor has been shown to decrease hepatic fibrosis in rats. 6 In the present study, the effects of losartan, a selective angiotensin II type I receptor antagonist, were investigated in patients with NASH. Patients and MethodsEight patients (two men and six women), aged 41-65 (median 57) years, with both NASH and hypertension, were entered into this study. All patients consumed less than 40 g of alcohol per week. Four patients were obese (body mass index Ͻ 25), four had diabetes mellitus, four had hyperlipidemia, and one had hyperuricemia. At the time of the study, some of the patients had already been on medication, including benzodiazepines, calcium antagonists or anticoagulants for at least 12 months. These therapeutic regimens were not changed after the start of the study. None of the patients were taking any angiotensin-converting enzyme inhibitors or angiotensin II receptor antagonists before the study.Baseline laboratory assessment revealed abnormally high serum transaminase and ␥-glutamyl transpeptidase concentrations in all patients. Five patients showed high serum ferritin concentrations. Homeostasis model assessment (HOMA)-R was abnormally high in all patients. Liver biopsies were performed prior to entry the study, and revealed moderate to severe lobular steatosis, and various degrees of hepatic necroinflammation and fibrosis in all patients. In two patients, iron deposition in hepatocytes was noted (Table 1).

Ursodeoxycholic acid (UDCA) has been shown to have beneficial effects on patients with primary biliary cirrhosis, suggesting that UDCA has immunomodulating effects. We investigated the effect of UDCA in patients with autoimmune hepatitis (AIH) which is characterized by immunological abnormalities. Eight patients with type 1 AIH were treated with 600 mg of UDCA per day for 2 years. Based on the criteria of the International Autoimmune Hepatitis Group, five patients were diagnosed as definite and three as probable type 1 AIH. Liver function tests were performed every 4 weeks, before and during UDCA therapy and the serum levels of anti-nuclear antibodies (ANA), smooth muscle antibodies (SMA), immunoglobulin G and gamma globulin were determined every 3 months. The levels of serum aspartate aminotransferase and alanine aminotransferase significantly decreased from 154 +/- 24 IU/L and 170 +/- 17 IU/L before UDCA therapy to 31 +/- 3 IU/L and 25 +/- 5 IU/L (P < 0.001) after 1 year of treatment and 28 +/- 2 IU/L and 23 +/- 4 IU/L (P < 0.001) after 2 years of treatment. After 2 years of treatment, the levels of serum immunoglobulin G and gamma globulin significantly decreased (P < 0.05) and ANA titres (5/8 patients) were reduced and SMA (3/5 patients) became negative. Furthermore, hepatic histopathological changes of four patients were assessed after 1 year of treatment, and an improvement of intrahepatic inflammation, but not fibrosis, was observed. In conclusion, these results suggest that UDCA has a beneficial therapeutic effect in patients with type 1 autoimmune hepatitis.

The present results suggest that high molecular weight but not low molecular weight HA prevents liver injury by reducing proinflammatory cytokines in a T-cell-mediated liver injury model. The extracellular matrix component hyaluronan (HA) modulates the production of various cytokines and chemokines by activated inflammatory cells. In this study, we investigated whether exogenous administration of HA influences T-cell-mediated liver injury and cytokine production.

Our data suggest the crucial involvement of HSCs in anti-fibrotic effect of angiotensin II receptor antagonist on patients with NASH.

These findings suggest that Con A induces TNF-alpha release, and this TNF-alpha stimulates MIP-2 induction, at least partially contributing to the liver injury mediated through the recruitment of neutrophils.