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Fatty Liver When ALT is Normal
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"Clinical and histologic spectrum of nonalcoholic fatty liver disease associated with normal ALT values"
Hepatology, June 2003, Volume 37, Number 6
Pouneh Mofrad
Division of Gastroenterology, Hepatology, and Nutrition, Department of Internal Medicine; Virginia Commonwealth University, Richmond, VA.
Nonalcoholic fatty liver disease (NAFLD) has recently been recognized to be one of the leading causes of chronic liver disease. This histology of this condition is characterized by either predominantly macrovesicular steatosis alone or steatohepatitis. The latter condition includes steatosis along with varying combinations of findings, including cytologic ballooning, Mallory's hyaline, pericellular fibrosis, and scattered inflammatory infiltrate. By definition, nonalcoholic fatty liver and nonalcoholic steatohepatitis (NASH) occur in individuals who do not consume alcohol in amounts generally considered to be harmful to the liver.
The serum ALT value has long been used as a surrogate marker of liver injury. It is, however, well known that the ALT values do not correlate well with the
severity of liver disease noted on liver biopsy in subjects with chronic liver disease. This is particularly true when one considers the stage of fibrosis present in an individual patient. The present study confirms this to be true also for NAFLD
Several published series have provided detailed information on the histologic and clinical spectrum of findings in patients with NAFLD. The majority of subjects in these studies were identified by the presence of elevated liver enzymes. It is, however, known that both fatty liver and NASH may exist without elevation of alanine aminotransferase (ALT). Although the full spectrum of NAFLD is known to occur in the presence of normal ALT levels, there have been no previous studies that have focused on those with NAFLD and normal ALT values or contrasted their clinical and histologic features with those having abnormal ALT levels. Based on an upper limit of normal as 40 IU/L for ALT, a recent study has also suggested that some individuals with high "normal" ALT levels may have underlying NAFLD. We performed a retrospective study to (1) characterize the clinical and histologic features of those with NAFLD and normal ALT values, (2) compare the spectrum of
NAFLD associated with normal versus elevated ALT levels, and (3) determine whether there were differences in the clinical or histologic spectrum of NAFLD between those with a low normal versus high normal ALT value.
ABSTRACT: A retrospective study was performed to (1) characterize the clinical and histologic features of those with nonalcoholic fatty liver disease (NAFLD) and normal alanine aminotransferase (ALT) values, (2) compare the spectrum of NAFLD associated with normal versus elevated ALT levels, and (3) determine whether there were differences in the clinical or histologic spectrum of NAFLD between those with a low normal versus high normal ALT value. A total of 51 subjects with NAFLD and normal ALT were identified and compared with 50 consecutive subjects with NAFLD and elevated ALT. The major indications for liver biopsy in those with normal ALT were unexplained hepatomegaly (n = 21) and evaluation as a potential donor for living donor liver transplantation (n = 16). The 2 groups were comparable with respect to age, gender distribution, and ethnicity. Approximately 80% of cases in both groups had at least 1 feature of the metabolic syndrome, the major risk factor for NAFLD. The 2 groups were also comparable with respect to the grade of the individual histologic parameters of NAFLD. A total of 12 subjects with normal ALT levels had bridging fibrosis, whereas 6 had cirrhosis. Diabetes was the only factor independently associated with an increased risk of advanced fibrosis (bridging fibrosis or cirrhosis) by multivariate analysis (relative risk: 2.3, P < .01). The mean steatosis (1.6 vs. 2.16, P < .04) and perisinusoidal fibrosis scores (0.35 vs. 0.9, P < .049) were lower in those with low normal (<30 IU/L) ALT versus high normal ALT. However, the prevalence of advanced fibrosis was similar (5 of 15 vs. 13 of 36, respectively). In conclusion, (1) the entire histologic spectrum of NAFLD can be seen in
individuals with normal ALT values, (2) the histologic spectrum in these individuals is not significantly different from those with elevated ALT levels, and (3) a low normal ALT value does not guarantee freedom from underlying steatohepatitis with advanced fibrosis.
It is interesting to note the relatively high prevalence of bridging fibrosis or cirrhosis in those with NAFLD and normal ALTs. This may be at least partly due to the bias inherent in a retrospective analysis. The differences in the rates of advanced fibrosis among those undergoing biopsy for hepatomegaly versus asymptomatic and apparently healthy individuals being evaluated as transplant donors indeed support this possibility. On the other hand, the data from the transplant donor group also indicate that the absence of any obvious symptoms, signs, or ALT values suggestive of liver disease does not guarantee the absence of clinically significant liver disease, i.e., advanced stage chronic liver disease. In this respect, these data corroborate and extend the existing literature regarding other chronic liver diseases, e.g., hepatitis C and normal ALT values.
An important question is the following: How does one identify subjects with clinically significant NAFLD in the absence of symptoms, signs, or abnormal ALT values? It is clearly both unreasonable and impractical to perform routine liver biopsies for this purpose. Although much more work needs to be done to determine who should be screened for NAFLD and how such individuals should be evaluated, the current studies suggest that those with hepatomegaly, especially in the presence of diabetes, are more likely to have clinically significant underlying pathology.
In summary, patients with NAFLD and normal ALT values may have steatohepatitis and advanced fibrosis. Diabetes is an independent predictor of advanced fibrosis. Although further work remains to be done to answer the clinical questions raised by these data, this study is an initial step toward the identification, characterization, and management of NAFLD in patients with normal ALTs.
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