Nonalcoholic fatty liver disease: relationship to insulin sensitivity and oxidative stress. Treatment spproaches using vitamin E, magnesium, and betaine - Fatty Liver

Alternative Medicine Review, August, 2002 by Lyn Patrick

Abstract

Nonalcoholic steatotic hepatitis (NASH), the most prevalent form of progressive liver disease in the United States, is considered to be a manifestation of insulin resistance syndrome. There is increasing evidence that steatosis in NASH is a result of the pathology in fat metabolism occurring in obesity and insulin resistance. For steatosis to progress to necroinflammation and fibrosis, however, the theory of mitochondrial oxidative-stress induced cellular damage is receiving wide acceptance. Treatment approaches that address these etiologies are reviewed: betaine, magnesium, and vitamin E. (Altern Med Rev 2002;7(4):276-291)

Introduction

Nonalcoholic steatotic hepatitis (NASH) is part of the spectrum of nonalcoholic fatty liver disease (NAFLD), a condition becoming increasingly recognized both in the United States and worldwide due to its prevalence in obesity, diabetes, and insulin resistance syndrome. (1) NAFLD can manifest as simple steatosis (fatty liver), which rarely has any sequelae, or can progress to steatosis with inflammation or fibrosis, in which case it is termed NASH. NASH is the most prevalent form of progressive liver disease in the United States. (2) Due to the fact that approximately 50 percent of NASH patients develop liver fibrosis--15-30 percent develop cirrhosis, and three percent may progress to liver failure (3,4)--there is an increasing need to recognize and understand the etiology and treatment of this condition.

Epidemiology

NAFLD is known to affect 10-39 percent of the general global population with an average incidence of 20 percent. (5,6) It is the most common cause of increased liver enzyme levels in adults in the United States. (7) NAFLD occurs commonly in diabetics and the obese: 50 percent of diabetics (ranging between 21 and 78 percent), 57-74 percent of obese persons, (5) and 90 percent of morbidly obese persons (over 200 percent of ideal body weight) (8) are affected.

NAFLD also occurs in children: 2.6 percent of normal weight children and up to 52.8 percent of obese children have been diagnosed with fatty liver disease. (9) Obesity in children is currently an epidemic in the United States; e.g., the National Health and Nutrition Examination Survey from 1988 to 1994 found 20 percent of children aged 12-17 years of age to be overweight and 8-17 percent to be obese. (10) Obesity in children has been directly related to NASH, elevated serum ALT levels, and lower levels of serum antioxidants. (10)

In an urban, hospital-based hepatology practice of 1,226 patients, NASH was the second most common diagnosis after chronic viral hepatitis. (11) In the United States it is estimated that over 30 million adults have NAFLD. Of these, 8.6 million may have NASH. (5) This prevalence far outnumbers that of chronic hepatitis C (4 million adults) and is probably an underestimate since NASH is, for the most part, asymptomatic and is becoming increasingly more prevalent in both children and adolescents.

NAFLD characterized only by stable steatosis has a low risk of progressing. Unlike NAFLD, NASH progresses to fibrosis and cirrhosis in up to 50 percent of patients. (3,4) There are few natural history studies on the progression of NAFLD to NASH and risk of mortality. One retrospective study of 30 NASH patients found a 67-percent 5-year survival rate and a 59-percent 10-year survival rate. (12) The only detailed natural history study as of this writing looked at liver biopsies in 132 patients with NAFLD, including NASH and cirrhosis. (13) The study reviewed up to an 18-year period in which 25 percent of those initially diagnosed with evidence of hepatocyte necrosis (with or without fibrosis) had progressed to cirrhosis. Of those initially diagnosed with cirrhosis, 11 percent died of a liver-related cause, and 80 percent of the patients that developed cirrhosis during the study had previously shown evidence of fibrosis on initial biopsy. Current research suggests NASH is a major contributor to the development of cryptogenic cirrhosis, a diagnosis of cirrhosis that has no other identifiable cause. (14)

Clinical Features

The majority of patients with NASH are asymptomatic, with the exception of discomfort in the right upper quadrant, fatigue, and malaise. Hepatomegaly can occur but does not necessarily accompany symptoms. (15) Acanthosis nigricans (hyperpigmentation) is more commonly found in children with NAFLD. (16) Elevations of aminotransferase levels are common (2-3-fold increases), and recent research identified an AST/ALT ratio of greater than one as a significant predictor of existing fibrosis, unless the patient already has progressed to cirrhosis. (2) Less than 50 percent of patients have elevated alkaline phosphatase levels, and only 10-15 percent have elevated serum conjugated bilirubin levels. (15) Hypoalbuminemia, thrombocytopenia, elevated bilirubin, and prolonged clotting time indicate advanced liver disease. (5) Fibrosis and cirrhosis in newly diagnosed NASH patients are not rare: fibrosis has been found in 66 percent of patients, (5) and cirrhosis in 7-16 percent on initial biopsy. (14) Histopathology on liver biopsy in NASH is identical to the damage in alcohol abuse. The presence of macrovesicular steatosis, inflammatory cell infiltration, hepatocyte ballooning, and necrosis are the main histological features of NASH. (5,14)