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MILAN, Italy, Sept. 9 -- Patients with nonalcoholic fatty liver disease but normal alanine aminotransferase (ALT) levels are still at risk of severe hepatic disease, researchers found.

More than half of such patients had advanced fibrosis, as well as altered glucose metabolism and insulin resistance, Silvia Fargion, M.D., of the University of Milan, and colleagues reported in the September issue of Hepatology.

Nonalcoholic fatty liver disease is now considered the hepatic expression of metabolic syndrome -- obesity, type 2 diabetes, and dyslipidemia account for the risk of advanced liver disease, in addition to the well-established cardiovascular risk, the researchers wrote.

However, the most common criterion for referral to a liver unit is the presence of elevated liver enzymes, and only individuals with increased ALT levels have been enrolled in most nonalcoholic fatty liver disease studies.

So, the researchers said, it is uncertain whether patients with normal ALT have a milder disease and whether they should undergo liver biopsy.

To shed some light on the subject, the researchers reviewed the histological data of 458 patients with nonalcoholic fatty liver disease who underwent liver biopsy from January 2003 through June 2006.

Of these, 395 (86%) had altered liver enzymes; 63 with persistently elevated ferritin or long-lasting severe steatosis had normal ALT levels.

Factors associated with nonalcoholic steatohepatitis (NASH) and fibrosis( ≥2) were identified by multivariate analysis. Patients with normal ALT were significantly older, had lower body mass index, fasting triglycerides, insulin resistance, ALT, and gamma-glutamyltransferase, but a higher prevalence of hypertension.

Nonalcoholic steatohepatitis was diagnosed in 59% of patients with normal ALT and in 74% of those with increased ALT (P=0.01).

In the overall series of patients, nonalcoholic fatty liver was independently predicted by ALT (odds 1.11, 95% confidence interval 1.04 to 1.19 per 10-IU/mL increase) and diabetes (OR 1.5, 95% CI 1.1 to 2.0).

The same variables were selected in patients with increased ALT, whereas in those with normal ALT, homeostasis model assessment (HOMA-IR), and ALT were independent predictors.

Severe fibrosis was independently predicted by serum ferritin (OR 1.04, 95% CI 1.001 to 1.08 per 50-ng/mL increase), ALT (OR 1.07, 95% CI 1.02 to 1.14), and diabetes (OR 1.8, 95% CI 1.4 to 2.3) in the overall series; serum ferritin and diabetes in those with increased ALT.

However, only homeostasis model assessment (HOMA-IR) predicted more severe fibrosis in patients with normal ALT (OR 1.97, 95% CI 1.2 to 3.7).

The evidence suggests that liver biopsy might be mandatory in most cases unless sensitive and specific noninvasive tests currently unavailable prove their efficacy. However, the investigators said, this raises the question of the feasibility and cost-effectiveness of liver biopsy in an extremely large at-risk population.

At present, biopsy is rarely indicated for patients with normal ALT. For this reason there were only 63 cases with normal ALT for this study, a definite limitation, the researchers noted.

A recently proposed scoring system (NASH score) to identify patients with advanced fibrosis potentially rendering liver biopsy unnecessary in 75% of cases, found a positive predictive value of 100% and a negative predictive value of 89.6% for identifying patients with and without advanced fibrosis, respectively.

The findings from the present study suggest that the score could also be used in the general population, including in persons with normal ALT.

Diabetes and insulin resistance were factors most closely associated with severe liver disease in that population.

In addition, hypertension, a key feature of the metabolic syndrome, was surprisingly more prevalent in patients with normal ALT.

This underlines the fact that the metabolic alterations related to steatosis and to adipose tissue-related endocrine dysfunction occur independently of overt liver damage.

Study limitations included the small number of patients with a normal ALT, and the variability of liver biopsy in the sample. The large number of patients referred to the liver units for hyperferritinemia means that this patient population was not truly representative, the researchers said.

These data indicate that more than half of nonalcoholic liver disease patients with normal ALT levels have a potentially progressive liver disease, they said.

In the absence of biopsy or of an adequate score to identify those at risk, these patients could miss careful follow-up and might not be motivated to adopt lifestyle changes that might cure their liver disease and the extrahepatic manifestations of the metabolic syndrome.

Clinicians should be aware of the importance of a complete clinical evaluation for early diagnosis and treatment of liver disease, as well as the different manifestations of the metabolic syndrome, they concluded.

The study was supported by grants from FIRST 2005-2006, Ricerca Corrente IRCCS 2004-2006, and Centro Universitario per lo Studio delle Malattie Metaboliche del Fegato. No conflicts of interest were reported.

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