ALT

**Biochemistry** - Reaction: alanine + α-ketoglutarate ⇌ pyruvate + glutamate (a transamination reaction). - Cofactor: pyridoxal phosphate (PLP, active vitamin B6). Deficiency (e.g., isoniazid therapy) can lower aminotransferase activity. - Links amino acid and carbohydrate metabolism. It is part of the glucose-alanine (Cahill) cycle: muscle sends alanine to the liver, where ALT converts it to pyruvate for gluconeogenesis.

**Localization** - Found mainly in the cytosol of hepatocytes. It is much more liver-specific than AST, which is also in cardiac muscle, skeletal muscle, kidney, and RBCs, and is present in both cytosol and mitochondria. - ALT is released with hepatocyte injury or membrane damage. It is a marker of hepatocellular injury, not of liver function. Synthetic function is assessed by PT/INR, albumin, and bilirubin.

**Reference range** - About 7–56 U/L, varying by lab and sex. Half-life is about 47 hours (AST is about 17 hours).

**Patterns of elevation** - **Marked elevation (>1000 U/L):** acute viral hepatitis (A, B, E), ischemic hepatitis ("shock liver"), acetaminophen toxicity, and toxin-induced injury (e.g., Amanita mushrooms). Acute biliary obstruction, such as a passed stone, can also cause transient spikes. - **Moderate elevation (about 100–500 U/L):** chronic viral hepatitis (HBV, HCV), autoimmune hepatitis, drug-induced liver injury, Wilson disease, and hemochromatosis. - **Mild elevation:** MASLD/NAFLD (the most common cause of mildly elevated ALT in the US), alcohol-related liver disease, and medications (statins, others). - **ALT > AST:** typical of viral hepatitis and NAFLD, though AST may exceed ALT once cirrhosis develops. - **AST:ALT > 2:1:** alcoholic hepatitis. Possible reasons are alcohol-induced pyridoxine deficiency (ALT depends more on PLP) and mitochondrial injury releasing mitochondrial AST. AST and ALT are usually below about 300 U/L in alcoholic hepatitis. - **Extrahepatic AST > ALT:** myocardial infarction, rhabdomyolysis, hemolysis.

**Hepatocellular vs. cholestatic pattern** - Hepatocellular injury: ALT/AST rise disproportionately more than ALP. - Cholestatic/obstructive injury: ALP and GGT (and often bilirubin) rise disproportionately more than ALT/AST. - R ratio = (ALT/ULN) ÷ (ALP/ULN). R > 5 suggests hepatocellular injury, R < 2 suggests cholestatic injury, and 2–5 suggests a mixed pattern.

**Clinical pearls** - Acetaminophen toxicity: AST and ALT are often in the thousands. Treat with N-acetylcysteine, which replenishes glutathione. - Ischemic hepatitis: very high ALT/AST with a rapid decline over days, often with elevated LDH. - Wilson disease: the ALT elevation can be modest relative to the degree of liver disease, and ALP/bilirubin ratio is often low. - Normal ALT does not exclude significant liver disease, including advanced fibrosis or cirrhosis, because the enzyme level reflects ongoing hepatocyte injury rather than total liver reserve. - A persistently elevated ALT of unclear cause warrants a workup: viral hepatitis serologies, iron studies, autoimmune markers, ceruloplasmin, and imaging.