Nonalcoholic fatty liver disease (NAFLD) is the most prevalent liver disease worldwide, and there is no approved pharmacotherapy. The efficacy of vitamin E and pioglitazone has been established in nonalcoholic steatohepatitis (NASH), a progressive form of NAFLD. GLP-1RA and SGLT2 inhibitors, which are currently approved for use in diabetes, have shown early efficacy in NASH, and also have beneficial cardiovascular or renal effects. Innovative NASH therapies include four main pathways. The first approach is targeting hepatic fat accumulation. Medications in this approach include modulation of peroxisome proliferator-activator receptors (e.g., pemafibrate, elafibranor), medications targeting farnesoid X receptor axis [obeticholic acid; OCA)], inhibitors of de novo lipogenesis (aramchol, ACC inhibitor), and fibroblast growth factor-21 analogues. A second target is oxidative stress, inflammation, and apoptosis. This class of drug includes apoptosis signaling kinase 1 (ASK1) inhibitor and emricasan (an irreversible caspase inhibitor). A third target is intestinal microbiomes and metabolic endotoxemia. Several agents are in ongoing trials, including IMMe124, TLR4 antagonist, and solithromycin (macrolide antibiotics). The final target is hepatic fibrosis, which is strongly associated with all-cause or liver-related mortality in NASH. Antifibrotic agents are a cysteine–cysteine motif chemokine receptor-2/5 antagonist (cenicriviroc; CVC) and galectin 3 antagonist. Among a variety of medications in development, four agents such as OCA, elafibranor, ASK1 inhibitor, and CVC are currently being evaluated in an international phase 3 trial for the treatment of NASH. Within the next few years, the availability of therapeutic options for NASH will hopefully curb the rising trend of NASH-related diseases.

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).

Background: Non‐alcoholic steatohepatitis is a distinct entity, characterized by fatty change, lobular inflammation and fibrosis of the liver. Some cases of non‐alcoholic steatohepatitis progress to cirrhosis, but it is not easy to distinguish this disease from non‐alcoholic fatty liver by non‐invasive examinations. No proven therapy for non‐alcoholic steatohepatitis exists. Transforming growth factor‐β1 is implicated in the development of liver fibrosis, and is inhibited by α‐tocopherol (vitamin E) in the liver. Therefore, in this study, the significance of the measurement of the level of plasma transforming growth factor‐β1 and the effect of α‐tocopherol on the clinical course of non‐alcoholic steatohepatitis were investigated. Methods: Twelve patients with non‐alcoholic steatohepatitis and 10 patients with non‐alcoholic fatty liver, with a diagnosis confirmed by liver biopsy, were studied. None of the patients had a history of alcohol abuse, habitual medicine or malignant or inflammatory diseases. All patients were negative for hepatitis B, C and G virus. Patients were given dietary instruction for 6 months, and then α‐tocopherol (300 mg/day) was given for 1 year. Blood chemistries, measurement of plasma transforming growth factor‐β1 level and liver biopsies were undertaken before and after the 1‐year α‐tocopherol treatment. Results: The serum alanine transaminase level decreased in non‐alcoholic fatty liver patients, but not in non‐alcoholic steatohepatitis patients, after 6 months of dietary therapy. Although the serum alanine transaminase level in non‐alcoholic steatohepatitis patients was reduced during the 1‐year α‐tocopherol treatment, α‐tocopherol had no effect on the serum alanine transaminase level in non‐alcoholic fatty liver patients. The histological findings, such as steatosis, inflammation and fibrosis, of the non‐alcoholic steatohepatitis patients were improved after α‐tocopherol treatment. The plasma transforming growth factor‐β1 level in non‐alcoholic steatohepatitis patients was significantly elevated compared with that in non‐alcoholic fatty liver patients and healthy controls, and decreased, accompanied by an improvement in serum alanine transaminase level, with α‐tocopherol treatment. Conclusions: lOur data suggest that the measurement of the level of plasma transforming growth factor‐β1 represents a possible method of distinguishing between non‐alcoholic steatohepatitis and non‐alcoholic fatty liver. Long‐term α‐tocopherol treatment may be safe and effective for non‐alcoholic steatohepatitis. A randomized, controlled, double‐blind trial is needed to confirm the full potential of α‐tocopherol in the management of non‐alcoholic steatohepatitis.