Liver Enzymes (ALT, AST)

Multiple studies have associated an elevated ALT with increased liver-related mortality. ^[1] According to the ACG guideline, a true healthy normal ALT ranges from 29 to 33 IU/l in males and from 19 to 25 IU/l in females, and levels above this should be assessed. ^[1] Evaluation of hepatocellular injury includes testing for viral hepatitis A, B and C, assessment for fatty liver disease and alcohol-related liver disease, screening for hereditary hemochromatosis, autoimmune hepatitis, Wilson's disease and alpha-1 antitrypsin deficiency, and a review of prescribed and over-the-counter medicines. ^[1] A common initial presentation of hereditary hemochromatosis is an asymptomatic patient with mildly elevated liver enzymes who is then found to have elevated serum ferritin and transferrin saturation. ^[13] Abnormal liver enzymes are one of the triggers for case-finding of MASLD with liver fibrosis using non-invasive tests, particularly in people with type 2 diabetes or obesity with additional metabolic risk factors. ^{[10] [11]} GGT is associated with the metabolic syndrome, is often elevated in NAFLD, and elevated GGT is associated with cardiovascular mortality, atrial fibrillation and exacerbation of congestive heart failure. ^[4] Serum GGT is associated with the risk of coronary heart disease, type 2 diabetes and stroke, and people with high GGT have higher mortality, partly through its association with other risk factors and partly because GGT is an independent predictor of risk. ^[6]

When drug-induced liver injury develops, the culprit drug should be discontinued, especially when transaminases are at or above 5 times the upper limit of normal and/or jaundice is present. ^[14] Drug discontinuation should lead to an improvement in liver biochemistries in most patients with idiosyncratic drug-induced liver injury. ^[15] In clinical trials, any serum ALT elevation above 3 times the upper limit of normal accompanied by a serum bilirubin above 2 times the upper limit of normal, or any serum ALT elevation above 8-10 times the upper limit of normal, is a signal of liver toxicity. ^[5] The American Thoracic Society recommends ALT monitoring during treatment of latent tuberculosis for people who chronically consume alcohol, take other hepatotoxic drugs, have viral hepatitis or other preexisting liver disease, or have an abnormal baseline ALT. ^[16] In MASLD, the EASL-EASD-EASO guideline advises lifestyle modification (weight loss, dietary changes, physical exercise and discouraging alcohol) and optimal management of comorbidities, including incretin-based therapies for type 2 diabetes or obesity when indicated. ^{[10] [11]} In a meta-analysis of RCTs in MASLD or MASH, the Mediterranean diet reduced ALT by a weighted mean difference of 3.96 IU/L versus control and resistance exercise reduced it by 15.40 IU/L. ^[17] A meta-analysis of randomized controlled trials involving 2600 patients with MASLD or MASH who used GLP-1 receptor agonist-based therapies, including semaglutide and tirzepatide, found significant decreases in serum ALT, AST and GGT compared with control. ^[18]