The American Journal of Gastroenterology (2003) 98, 955–956; doi:10.1111/j.1572-0241.2003.07485.x

Elevated AST or ALT to nonalcoholic fatty liver disease: accurate predictor of disease prevalence?

Andy S Yu MD and Emmet B Keeffe MD

Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, California, USA

Correspondence: Andy S Yu, MD, Stanford University Medical Center, 750 Welch Road, Suite 210, Palo Alto, CA 94304-1509, USA.

Received 11 February 2003; Accepted 13 February 2003.

Clark et al. (1), in this issue of the American Journal of Gastroenterology, propose that elevated AST or ALT levels are predictive of the presence of nonalcoholic fatty liver disease (NAFLD) if two basic criteria are met: 1) exclusion of alternative chronic liver diseases, e.g., alcoholic liver disease (ALD), hepatitis B or C infection, and hemochromatosis; and 2) presence of features of the metabolic syndrome, i.e., increased body mass index (BMI) or waist circumference, elevated triglyceride or fasting insulin levels, low high density lipoprotein levels, type 2 diabetes mellitus, and hypertension. Analysis of data from the Third National Health and Nutrition Examination Survey (NHANES III) in the United States yielded a 7.9% prevalence rate of elevated AST or ALT (1), which is somewhat higher than the 1–4% rate commonly found in other studies (2). The five most common chronic liver diseases, and thus the usual causes of elevated liver chemistry tests, include NAFLD, chronic hepatitis C, ALD, chronic hepatitis B, and hemochromatosis. Chronic hepatitis C is estimated to affect approximately 2% of the general population (3). The true prevalence of ALD is not readily available, as many affected patients remain asymptomatic and national survey questionnaires are not sufficiently specific to allow accurate classification of liver diseases based on etiology (4). More importantly, not all heavy drinkers develop ALD, despite 7.4% of the Americans meeting the DSM-IV criteria for alcohol abuse and/or dependence (5). However, 1% may be a reasonable estimate of the prevalence of ALD in the general population. The prevalence of the HBsAg carrier ranges from 0.1% to 2% in the western world, but probably averages 0.3% to 0.4% in the Unites States (2). Finally, HFE-linked hereditary hemochromatosis, the most common genetic disease among individuals of northern European descent, has a homozygote frequency of 1:200 to 1:400, although clinical expression may be considerably lower (6).

Other chronic liver diseases occur at a much lower frequency. The autoimmune liver diseases (autoimmune hepatitis, primary biliary cirrhosis, and primary sclerosing cholangitis) are uncommon, with point prevalence rates per 100,000 in a Norwegian population of 17, 15, and nine, respectively (7). alpha1-Antitrypsin deficiency (one per 1,500 to 7,600) and Wilson's disease (one per 30,000) are also uncommon. None of these uncommon chronic liver diseases would be likely to contribute significantly to the cause of elevated AST or ALT levels in the general population. Thus, the "from elevated AST or ALT to NAFLD" hypothesis in the study of Clark et al., which excluded common liver diseases, is likely valid and not undermined by the presence of uncommon chronic liver diseases, all of which are too infrequent to have an impact on the results of this study.

The high prevalence rate of NAFLD inferred from elevated aminotransferase levels in the NHANES database is probably realistic. NAFLD is a clinicopathological syndrome that encompasses a broad spectrum ranging from simple steatosis alone to nonalcoholic steatohepatitis (NASH) (8). This disease entity may be considered as an additional feature of the metabolic, or insulin resistance, syndrome that includes obesity, diabetes mellitus, dyslipidemia, and hypertension (9). The prevalence of NAFLD varies from 10% to 40% based on estimates by various studies, either focused on selected subpopulations or on population-based studies using liver biopsy, autopsy, radiological imaging, or elevated liver chemistry tests (10). NAFLD is an increasingly common liver disease in developed countries because of the rising prevalence of obesity (11).

Steatohepatitis was found in 18.5% of markedly obese versus 2.7% of lean individuals in an autopsy study (12). Furthermore, the risk of steatohepatitis increased by 2.6-fold in those who had a history of type 2 diabetes mellitus. Dyslipidemia was found in >90% of patients with NASH in one study (9). In another study, simple steatosis was found on biopsy in 70% of subjects who were 10% above ideal body weight and in nearly all morbidly obese individuals (13). In the current article, Clark et al. demonstrated that the majority (69%) of aminotransferase elevations in the general U.S. population are unexplained but are strongly associated with central adiposity as well as various features of insulin resistance (1).

A separate analysis of the NHANES III database studying ALT alone found that 2.8% of the population had elevated levels, after eliminating individuals with viral hepatitis, moderate-to-high alcohol consumption, elevated iron saturation, and diabetes mellitus (14). Central adiposity, hyperleptinemia, and hyperinsulinemia were the major determinants of the association between being overweight and having elevated serum ALT levels. The use of ALT alone, without AST, as the sole marker for occult liver disease and the exclusion of patients with diabetes mellitus likely underestimate the disease burden of NAFLD in the general population (15). Nevertheless, even with this potential underestimation, the prevalence of NAFLD is already higher than that of the other common chronic liver diseases, i.e., chronic hepatitis C, ALD, chronic hepatitis B, and hemochromatosis.

The contribution of NASH to cryptogenic cirrhosis also ap- pears to have been underestimated in the past. The features of insulin resistance, such as obesity and diabetes mellitus, were demonstrated to be much more prevalent in patients with cryp- togenic cirrhosis than in those with liver diseases of well-defined etiologies (16, 17). Furthermore, these features are more frequently observed in patients with cryptogenic cirrhosis and hepatocellular carcinoma than in age- and sex-matched patients with hepatocellular carcinoma complicating alcoholic or viral liver disease (18). The classic histology of NASH may disappear after the development of "burnt-out" cirrhosis, leaving behind the clinical presentation as the only clue to the cause of the liver disease. Furthermore, NASH and NAFLD have been shown to develop in liver recipients who underwent transplantation for cryptogenic cirrhosis (19), further suggesting the underestimated prevalence of NAFLD in the pretransplant population.

Several potential limitations to this study should be considered. Some factors might have led to an overestimate of the prevalence of NAFLD. The one-time measurement of aminotransferase levels can overestimate the prevalence of NAFLD, as it may capture merely a transient biochemical abnormality, a laboratory error, or an injury to other organs such as muscle trauma. It should be noted that some causes of chronic liver disease such as Wilson's disease, alpha1-antitrypsin deficiency, or autoimmune liver diseases were not excluded but should not significantly affect the results of this study given their low prevalence rates. Finally, liver biopsy was unavailable to determine the exact etiology of elevated aminotransferases in individual patients.

On the other hand, there are factors that may have underestimated the true prevalence rate of NAFLD in this study. Aminotransferase levels could have been artificially lowered, as chemical analysis was conducted on serum that had been frozen, potentially leading to artificially lower AST or ALT levels and an underestimation of the disease prevalence. One could also speculate that the prevalence rate of NAFLD might even be higher if the upper limits of normal for serum aminotransferases were to reset at lower levels, as has been suggested (20). Finally, patients with NAFLD may have normal AST or ALT levels, which also might underestimate the true prevalence rate of NAFLD.

In summary, the "elevated AST or ALT to NAFLD" hypothesis seems to be valid provided that common alternative chronic liver diseases are excluded and affected patients have one of more features of the metabolic syndrome. Potentially confounding factors that might overestimate or underestimate the prevalence rate of NAFLD probably neutralize one another, leaving intact the validity of this hypothesis.



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