State of the Art: Treatment of Nonalcoholic Steatohepatitis

Michelle Pearlman; Rohit Loomba


Curr Opin Gastroenterol. 2014;30(3):223-237. 

In This Article

Abstract and Introduction


Purpose of review: Nonalcoholic fatty liver disease is the most common cause of chronic liver disease in Western countries, and consists of a spectrum of histopathological changes that range in severity from simple steatosis to steatohepatitis to cirrhosis. The use of pharmacological agents as adjunctive therapy to lifestyle modification is crucial, because weight loss is often difficult to achieve and maintain. The purpose of this review is to analyze the most recent literature pertaining to current therapies for nonalcoholic steatohepatitis (NASH), as there are currently no Food and Drug Administration-approved medications.

Recent findings: Recent studies suggest that vitamin E may improve liver histology in NASH without affecting insulin resistance; however, long-term risks remain to be studied. Pioglitazone is beneficial in improving liver histology and insulin resistance, but is associated with weight gain. Emerging data suggest that pentoxifylline may also be beneficial in improving serum aminotransferase and liver histology in patients with biopsy-proven NASH.

Summary: Ongoing research evaluating potential pharmacological agents for NASH is critical, because these patients are at an increased risk for cirrhosis and hepatocellular carcinoma. The current therapies being used for the treatment of NASH include the use of vitamin E and pioglitazone, in addition to dietary counseling and regular exercise.


Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the United States and consists of a spectrum of disease states including nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH). The prevalence of NAFLD varies dramatically depending on the study population and the mode of diagnosis.[1] NAFL is nonprogressive whereas NASH can advance to cirrhosis and hepatocellular carcinoma.[2,3] NASH-induced cirrhosis is the third leading cause of liver transplantation in the United States[4] and is associated with high liver-related morbidity and mortality.[3] Furthermore, patients with NASH have an increased risk of developing fibrosis if they gain more than 5 kg, have significant insulin resistance, or exhibit profound hepatic fatty infiltration.[5]

With the continued rise in obesity in the United States, the prevalence of NAFLD has followed a similar trend. NAFLD is associated with central obesity, dyslipidemia, hypertension, and insulin resistance; a constellation of diseases that comprise metabolic syndrome.[6,7] It is imperative to manage these comorbidities, as the most common cause of death in this patient population is cardiovascular disease.[5] Additionally, elderly patients with NAFLD are more likely to develop NASH and advanced fibrosis compared with nonelderly patients with NAFLD.[5,8] Given the growing elderly population, knowledge of the natural history and available treatment options are of particular importance in this patient population.

The diagnosis of NAFLD is made in a patient without a history of significant alcohol use, after other causes of liver disease or hepatic steatosis have been excluded.[9] The definitive diagnosis for NAFLD is by liver biopsy, with histopathology exhibiting macrovesicular hepatic steatosis predominantly in zone 3 with varying degrees of lobular inflammation, and balloon degeneration, with or without perisinusoidal fibrosis.[10] Some of these histopathological changes including steatosis (grade 0–3), lobular inflammation (grade 0–3), and ballooning (grade 0–2) are used to calculate the NAFLD activity score (NAS with a total summary score of 8), which is used for research purposes to determine the response to therapy in a more objective manner.[1]

The treatment approach for NAFLD and NASH begins with an exercise program and a calorie restricted diet to achieve a normal weight in a gradual manner. We usually recommend a goal of 1–2 lb weight/week to have a gradual weight reduction. The use of pharmacological agents as adjunctive therapy is often necessary, however, as lifestyle modification and weight loss are difficult to maintain,([11] Table 1 ). This review article will examine the most current literature ( Table 2 )[12–21] regarding the treatment of NASH and is based on both the current American Association for the Study of Liver Disease (AASLD) practice guidelines published in 2012 and the practical approaches utilized at UCSD NAFLD clinic.[1] The studies chosen for this review were found on PubMed using search terms NASH, pioglitazone, pentoxifylline, vitamin E, and only include human participants with NAFL or NASH. The effects of surgical weight loss therapies have been discussed elsewhere and are beyond the scope of this review.[1,22] All studies used a P <= 0.05 to denote statistical significance.