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Normal ALT levels may mask advanced fibrosis in liver disease patients

Liver biopsy still the best way to assess disease severity


Patients with nonalcoholic fatty liver disease (NAFLD) may have normal alanine aminotransferase (ALT) levels in spite of having advanced fibrosis, according to a new study in the September issue of Hepatology, a journal published by John Wiley & Sons on behalf of the American Association for the Study of Liver Diseases (AASLD). The article is available online at Wiley Interscience (

NAFLD is the hepatic expression of the metabolic syndrome and it can progress to cirrhosis, portal hypertension and even liver cancer. Most studies of NAFLD only include patients with elevated ALT levels, since that is a reason for referral to liver units. However, studies have not shown a systematic association between elevated ALT and severe NAFLD, leading to the question of whether NAFLD patients with normal ALT levels should also undergo liver biopsy and be examined for other manifestations of the metabolic syndrome.

Researchers, led by Anna Ludovica Fracanzani of the University of Milan, aimed to compare NAFLD patients with and without increased ALT to determine whether ALT is a valuable criterion to exclude patients from liver biopsy. They examined data from 458 consecutive patients who underwent liver biopsy between January 2003 and June 2006. Of these, 395 had abnormal liver function tests, while 63 had normal ALT.

The researchers found no difference in the prevalence and number of the components of the metabolic syndrome and in the prevalence of severe fibrosis between the two groups of patients. However, those with normal ALT had significantly milder inflammation and milder steatosis.

Nonalcoholic steatohepatitis (NASH) was diagnosed in 59 percent of patients with normal ALT and in 75 percent of patients with elevated ALT. For the latter group, serum ferritin and diabetes were independent predictors of more severe fibrosis. Only HOMA-IR independently predicted it in patients with normal ALT.

"The present study confirms that also NAFLD patients with normal ALT are at risk of progressive and severe hepatic disease, as well as of extrahepatic manifestations," the authors report. Doctors might consider liver biopsy for these patients, because a less-invasive way to assess liver disease is not yet available. However, the cost/effectiveness of this policy, given the extremely large at-risk population, would be a concern.

The recently proposed NASH score, which is a non-invasive assessment of severity developed by Angulo et. al., identified patients in the current study with advanced fibrosis with a negative predictive value of nearly 90 percent and a positive predictive value of 100 percent. "Our data support the hypothesis that this score could also be used in the general population, including subjects with normal ALT," the authors report.

This study was limited by the small number of NAFLD subjects with normal ALT, the sample variability of liver biopsy, and the high number of subjects referred to the liver units for hyperferritinemia.

Still, the authors conclude: "Our data indicate that more than half of NAFLD patients with persistently normal ALT have a potentially progressive liver disease. In the absence of biopsy or of an adequate score able to identify subjects at risk, these patients could miss careful follow-up."


Article: "Risk of severe liver disease in nonalcoholic fatty liver disease with normal aminotransferase levels: A role for insulin resistance and diabetes." Fracanzani, Anna Ludovica; Valenti, Luca; Bugianesi, Elisabetta; Andreoletti, Marco; Colli, Agostino; Vanni, Ester; Bertelli, Cristina; Fatta, Erika; Bignamini, Daniela; Marchesini, Giulio; Fargion, Silvia. Hepatology ; September 2008; 10.1002/hep.22429.

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