Nonalcoholic Fatty Liver Disease

Pouneh S. Mofrad, MD, Arun J. Sanyal, MD


April 16, 2003

In This Article

Natural History

The natural history of NAFLD has not been well defined. The existing literature is almost entirely obtained in a retrospective manner, and is therefore subject to all of the limitations of retrospective data. It is currently believed that there are several histologic stages in the progression of NAFLD to cirrhosis. These progressively include fatty liver alone, steatohepatitis, steatohepatitis with fibrosis, and cirrhosis.

The earliest stage is a simple fatty liver alone. The concept of whether a fatty liver progresses to steatohepatitis remains controversial. The current evidence indicates that such progression does indeed occur, although the frequency with which it does is likely low. Thus, the majority of patients with fatty liver alone have an excellent prognosis. Over time, steatohepatitis may become associated with increasing fibrosis. The pericentral, perisinusoidal fibrosis may extend to portal tracts or other central veins forming central-central or central-portal bridges. Portal-to-portal bridging fibrosis is unusual in NAFLD. Eventually, cirrhosis may develop.

A retrospective study by Matteoni and colleagues[26] provides some assistance in predicting the clinical course of patients with NAFLD. In this report, subjects with NAFLD were grouped into 4 categories based on their liver histology as follows: (1) fatty liver alone; (2) fat + lobular inflammation; (3) fat + ballooning degeneration; and (4) fat + ballooning + Mallory's hyaline or fibrosis. Survival among the patient groups over 18 years of follow-up were 33%, 30%, 26%, and 44%, respectively. Subjects in groups 3 and 4 had the highest number of liver-related deaths, and liver-related diseases were the second most common cause of death, with cancer being the number-one cause. Recent studies indicate that NASH-related cirrhosis is associated with a higher likelihood of developing hepatocellular carcinoma compared with cirrhosis associated with other causes.[27]

The time course over which patients progress from one stage to the next remains unknown. Additionally, the risk factors for progression are not well characterized. However, cross-sectional studies suggest that increasing age, BMI, and the presence of diabetes are associated with higher stages of fibrosis.

Improvement in liver histology has also been observed, mainly in patients with minimal fibrosis. The latter occurs in obese patients who achieve slow but significant weight loss. Conversely, rapid weight loss may promote progression of the disease. Indeed, following severe and rapid weight loss, patients may present with worsening liver failure. This phenomenon has been termed subacute NASH. Therefore, when obese patients are placed on a weight loss program, the rate of weight loss should be monitored and should ideally be between 1 and 2 lb/week.