What are the symptoms and causes of elevated Alanine Aminotransferase (ALT) levels?

Elevated Alanine Aminotransferase (ALT): Symptoms and Causes

Symptoms of Elevated ALT

Most patients with elevated ALT are completely asymptomatic, with approximately 25% having no symptoms at diagnosis, including some with advanced cirrhosis. 1

When symptoms do occur, they include:

• Fatigue and general malaise - the most common presenting symptom, sometimes dating back years 1
• Anorexia and weight loss - frequently reported in chronic liver disease 1
• Nausea - often a prominent symptom 1
• Right upper quadrant abdominal pain - particularly in cholestatic conditions 1
• Jaundice - occurs in approximately 40% of acute presentations and 30% of patients with cirrhosis at presentation 1
• Pruritus (itching) - associated with cholestatic liver disease 1
• Joint pains - reported in 30-60% of autoimmune hepatitis patients, though joint swelling is uncommon 1
• Amenorrhea - common in women with chronic liver disease 1
• Fever and rash - rare presentations 1

Critical caveat: The absence of symptoms does not exclude significant liver disease. Many patients with cirrhosis remain asymptomatic until decompensation occurs with ascites or variceal bleeding. 1

Causes of Elevated ALT

Most Common Causes (Account for >80% of cases)

Nonalcoholic fatty liver disease (NAFLD/MASLD) is the leading cause of elevated ALT in developed countries, affecting over 30% of the general population. 1, 2

• Metabolic syndrome components strongly predict NAFLD: obesity (particularly central adiposity), type 2 diabetes, hypertension, and dyslipidemia 1, 3
• AST:ALT ratio typically <1 in NAFLD, distinguishing it from alcoholic liver disease 3
• ALT elevations are usually mild (<5× upper limit of normal), though can be higher in active steatohepatitis 1, 3

Alcoholic liver disease is the second most common cause 4, 2

• AST:ALT ratio ≥2:1 is highly suggestive of alcoholic liver disease 3, 5
• Even moderate alcohol consumption (defined differently by various guidelines) can cause persistent ALT elevation 3
• Complete abstinence is required for biochemical improvement 3

Common Causes Requiring Systematic Exclusion

Drug-induced liver injury (DILI) accounts for 11% of notably elevated ALT cases 6

• Prescription medications, over-the-counter drugs, and herbal supplements can all cause hepatotoxicity 3
• Common culprits include: minocycline, nitrofurantoin, infliximab, ezetimibe, and various herbal medicines 1
• Atypically, many patients have been taking the offending drug for months to years before ALT elevation 1
• Discontinuation of suspected hepatotoxic medications is essential when DILI is suspected 3

Viral hepatitis 6, 2

• Hepatitis B and C should be tested in all patients with elevated ALT using HBsAg and HCV antibody 3
• Acute viral hepatitis (hepatitis A, E, cytomegalovirus, Epstein-Barr virus) can precipitate liver injury 1
• Viral hepatitis accounts for 11% of notably elevated ALT cases in prospective studies 6

Uncommon but Important Causes

Autoimmune hepatitis 1

• Affects women 3-4 times more frequently than men 1
• Can present at any age, though may be more common in older patients in some populations 1
• Characterized by: hyperglobulinemia, positive autoantibodies (ANA, SMA), and interface hepatitis on biopsy 1
• Approximately 40% present as "acute hepatitis" with jaundice and markedly elevated transaminases 1
• Can present as acute liver failure in some cases 1

Hereditary hemochromatosis 2

• Should be evaluated with serum iron, total iron-binding capacity, and ferritin 3
• More common in populations of Northern European descent

Biliary obstruction 6

• Choledocholithiasis accounts for 34% of notably elevated ALT (>500 U/L) cases 6
• Typically presents with elevated GGT and alkaline phosphatase in addition to ALT 1, 3
• Abdominal ultrasound is the first-line imaging modality to detect biliary dilation 3

Rare Causes

• Wilson disease - consider in patients <40 years with unexplained liver disease 2
• Alpha-1 antitrypsin deficiency 4, 2
• Ischemic hepatitis - accounts for 18% of notably elevated ALT cases, with 35% liver-related mortality 6
• Primary sclerosing cholangitis - strongly associated with inflammatory bowel disease 1

Extrahepatic Causes

Important pitfall: AST can be elevated from non-hepatic sources, making ALT the more specific marker for liver injury 3, 7

• Muscle disorders - check creatine kinase to rule out rhabdomyolysis or myopathy 3
• Thyroid disorders - thyroid function tests should be performed 3
• Hemolysis - can elevate AST more than ALT 2
• Cardiac injury - myocardial infarction can cause transient AST elevation 7

Clinical Context and Severity

ALT reference ranges differ by sex: 29-33 IU/L for males and 19-25 IU/L for females, with lower thresholds (>33 U/L in males, >25 U/L in females) now proposed for defining abnormal values. 1, 3

Severity classification: 3

• Mild elevation: <5× upper limit of normal (ULN)
• Moderate elevation: 5-10× ULN
• Severe elevation: >10× ULN

ALT >5× ULN is rare in NAFLD alone and should prompt urgent evaluation for viral hepatitis, autoimmune hepatitis, ischemic hepatitis, drug-induced injury, or acute biliary obstruction. 3

Normal synthetic function (normal albumin, bilirubin, and INR) despite elevated ALT indicates preserved liver function and suggests earlier-stage disease rather than cirrhosis. 3