Causes of Transaminitis
Most Common Causes
Non-alcoholic fatty liver disease (NAFLD) is the most common cause of mild transaminitis in developed countries, followed by alcoholic liver disease, drug-induced liver injury, and viral hepatitis. 1, 2, 3
Primary Etiologies (in order of prevalence):
NAFLD/NASH: The leading cause of asymptomatic transaminase elevation, strongly associated with metabolic syndrome components including obesity, type 2 diabetes, hypertension, and hypercholesterolemia 4, 1, 3
Alcoholic liver disease: Second most common cause; requires detailed quantification of alcohol consumption including duration and amount 1, 2
Drug-induced liver injury (DILI): Common hepatotoxic medications include methotrexate, NSAIDs, statins, anticonvulsants, antiarrhythmics, tamoxifen, nitrofurantoin, minocycline, and infliximab 4, 1, 5
Viral hepatitis: Hepatitis B and C are frequent causes requiring screening with hepatitis B surface antigen and hepatitis C antibody 1, 3
Uncommon but Important Causes
Autoimmune hepatitis: Presents with persistently elevated transaminases, hyperglobulinemia, and positive autoantibodies (ANA, anti-smooth muscle antibody); affects women 3-4 times more than men 4, 1
Hereditary hemochromatosis: Identified through iron studies (elevated ferritin and transferrin saturation) 1, 3
Celiac disease: Associated with transaminase elevations that improve or normalize with gluten-free diet in 75-100% of cases 4
Rare Causes
Wilson disease: Copper metabolism disorder requiring ceruloplasmin testing 2, 3
Alpha-1 antitrypsin deficiency: Hereditary condition causing liver disease 2, 3
Context-Specific Causes
In Cancer Patients:
- Immune checkpoint inhibitor-induced liver injury (ILICI): Immune-mediated hepatotoxicity from ICIs, distinct from traditional DILI 4
- Primary liver tumors or hepatic metastases 4
- Biliary obstruction (intra- or extrahepatic) 4
- Systemic infection or sepsis 4
In HIV-Infected Patients:
- Coinfection with hepatitis B or C viruses 6
- Antiretroviral therapy hepatotoxicity 6
- HIV itself causing direct liver damage 6
- NAFLD from metabolic comorbidities 6
In Rheumatoid Arthritis Patients on Methotrexate:
- NASH-like pattern is the most prevalent histological finding in patients with persistent transaminitis during low-dose MTX treatment 5
- Risk factors mirror those of NAFLD: obesity (OR 3.23), type 2 diabetes (OR 3.52), hypercholesterolemia (OR 2.56), and hyperuricemia (OR 3.52) 5
Extrahepatic Causes
Important pitfall: Not all transaminase elevations originate from the liver. 3
- Muscle disorders: Particularly affect AST levels (myopathies, rhabdomyolysis, vigorous exercise) 4, 3
- Hemolysis: Releases AST from red blood cells 2, 3
- Thyroid disorders: Both hypo- and hyperthyroidism can elevate transaminases 3
- Celiac disease: Causes transaminitis independent of liver pathology 4, 3
- Cardiac conditions: Congestive heart failure causes hepatic congestion 4
Critical Clinical Pearls
Mild elevations (>1x to <3x ULN) without bilirubin elevation are often non-specific and may be related to NAFLD, dietary changes, or vigorous exercise rather than clinically significant liver injury 4
Statin-induced transaminitis (>3x ULN) is infrequent, often resolves with dose reduction or alternative statins, and statins are not contraindicated in chronic stable liver disease like NAFLD 4
Acute presentations: Approximately 40% of autoimmune hepatitis cases present as acute hepatitis with jaundice and markedly elevated transaminases (several thousand), and 30% have cirrhosis at presentation 4
Medication discrepancies: Over 50% of patients with liver disease have discrepancies between reported and documented medications, particularly those taking more than five medications 1