5th percentile.1 However, this ULN might be inherently influenced by the characteristics and conditions of the enrolled reference population. Currently, the ULN of serum ALT is usually set at 40 IU/L (range: 30–50 IU/L), although it varies slightly among BEZ235 price laboratories.4 However, several

investigators have addressed the clinical issue of lowering the ULN of serum ALT for the following reasons. First, most ULN thresholds were established in the 1980s, when ALT testing was introduced as a surrogate marker in blood donor screening for hepatitis A and hepatitis B viruses (HBV).5 Antihepatitis C virus antibody testing was not routinely performed at that time, and the concepts of non-alcoholic fatty liver disease (NAFLD) and restrictive behavioral criteria for donor selection had not been established. Because reference populations that are defined using the current threshold are likely to include many asymptomatic persons with chronic liver diseases (CLD), the ULN of serum ALT levels should be lowered. Screening using the current range of normal serum ALT values might underestimate

the prevalence of CLD. Second, considering the natural courses of NAFLD or chronic HBV/hepatitis C virus (HCV) infections, disease progress might occur in patients with persistently normal ALT levels. Such patients have shown significant degrees of necroinflammatory activity or fibrosis on liver biopsy.6–9 Adjustment of the ULN by defining borderline ALT levels as abnormal would allow more vigorous surveillance and earlier initiation of treatment. This adjustment would also result in the Ferroptosis activation provision of antiviral therapy for more patients with chronic viral hepatitis. According to current guidelines, such therapy should be initiated with evidence of viral replication in all

patients with serum ALT levels more than twice the ULN and in selected patients with serum ALT levels one to two times the ULN.8,10 Third, several population-based studies have found slightly increased ALT levels within the current normal range to be closely find more related to comorbidities and mortality.2,11,12 A prospective cohort study in Korea2 found that the serum ALT level was associated with liver-related mortality, even within the current normal range. Kang et al.11 established a range of unhealthy normal ALT values (31–40 in men, and 23–40 in women). Unhealthy normal ALT patients displayed comorbidities associated with metabolic syndrome and insulin resistance, such as dyslipidemia, obesity, alcohol consumption, and diabetes mellitus, supporting the hypothesis that the ULN of serum ALT should be lowered. Consistent with this finding, borderline ALT values were also closely associated with the incidence of NAFLD.12 From the viewpoint of general population screening, these results suggest that unhealthy normal ALT levels are early indicators of comorbidities associated with lifestyle and with liver injury due to hepatic steatosis.