Date Published: April 11, 2019
Publisher: Public Library of Science
Author(s): Hemda Schmilovitz-Weiss, Rachel Gingold-Belfer, Alon Grossman, Nidal Issa, Doron Boltin, Yichayaou Beloosesky, Nira Morag Koren, Joseph Meyerovitch, Avraham Weiss, Mark W. Sonderup.
This study sought to determine the prevalence of significant liver disease in those subjects with serum alanine aminotransferase levels in the range between the current and the newly suggested upper limit of normal (termed the delta range). The files of the previous study subjects (who underwent at least one alanine aminotransferase measurement in 2002 and followed to 2012) were reviewed for a diagnosis of chronic liver disease; aspartate aminotransferase/platelet ratio index, FIB-4 and alanine aminotransferase/aspartate aminotransferase ratio were used to evaluate liver fibrosis. The prevalence of significant liver disease, by diagnoses and fibrosis scores was compared between subjects with alanine aminotransferase levels in the delta range (men, 42–45 IU/L; women, 26–34 IU/L) and in the newly suggested normal range (men, 15–42 IU/L; women, 10–26 IU/L). The cohort included 49,634 subjects (41% male, mean age 83±6 years) of whom 2022 were diagnosed with chronic liver disease including 366 with cirrhosis. Compared to subjects with alanine aminotransferase levels in the newly suggested normal range, subjects with alanine aminotransferase levels in the delta range had a significantly higher rate of chronic liver disease (men, 15.3% vs. 4.9%; women, 7.8% vs. 3.3%) and of cirrhosis specifically (men, 4.2% vs. 0.9%; women, 1.5% vs. 0.4%) and also had higher mean fibrosis scores (P <0.001 for all). Lowering the current upper limit of normal of serum alanine aminotransferase may help to identify elderly patients at risk of significant liver disease.
Higher levels of serum hepatocellular enzymes, alanine aminotransferase (ALT) and aspartate aminotransferase (AST), with or without higher levels of canalicular enzymes (alkaline phosphatase and gamma glutamyl transferase) and bilirubin, are a sign of significant liver disease. However, even an isolated mild elevation of serum ALT level above the normal range, may serve as a marker of liver injury [1,2] due to nonalcoholic fatty liver disease (NAFLD) and chronic hepatitis C infection (HCV) [3–6]. Furthermore, many studies have reported an association of elevated serum ALT level with increased liver-related morbidity and mortality [7,8] and all-cause mortality . Recently, clinical guidelines have suggested lowering the upper limit of normal (ULN) of serum ALT for men and women [10–12]. This was supported by our previous study  showing that in elderly subjects, levels at the currently accepted ULN for ALT in Israel, were associated with significantly high mortality rates.
Clalit Health Services (CHS) is the largest of the four health management organizations in Israel. Its member base numbers more than 4 million and 1.4 million in the Dan-Petach Tikva District Branch (in central Israel) alone. The comprehensive electronic data warehouse of CHS, aggregates continuous real-time medical input from hospital and community physicians and health service providers for each of its members.
The study included 49,634 subjects, 41% male, median age 83±6 years (range: 65–115 years).
Our earlier study suggested that the accepted ULN for serum ALT level should be lowered in the elderly population, to 10–26 IU/L for women and 15–42 IU/L for men . In the present study, we tested the value of lowering the ULN for ALT for the detection of liver disease. Using the same large health management organization registry of community dwelling elderly subjects, we found, on the basis of the clinical diagnoses and the estimated fibrosis scores, that significant liver disease was more prevalent in individuals with ALT levels in the delta range between the current and suggested ULN than in individuals with levels below the newly suggested ULN. This finding indicates that elderly individuals who meet the currently accepted normal range of ALT may in fact harbor clinically significant liver disease.
Lowering the ULN of serum ALT in the elderly may help to identify patients with significant liver disease. A global standardization of this simple, low cost, and highly available laboratory test is needed and may upgrade the standard of care for these individuals worldwide.