What are the causes of transaminitis (elevated liver enzymes)?

Causes of Transaminitis (Elevated Liver Enzymes)

Nonalcoholic fatty liver disease (NAFLD) is the leading cause of transaminitis in developed countries, affecting up to 70% of obese patients and 90% of diabetics, followed by medication-induced liver injury (8-11% of cases), alcohol-related liver disease, and viral hepatitis. 1, 2, 3

Most Common Causes

Nonalcoholic Fatty Liver Disease (NAFLD)

• NAFLD is strongly associated with metabolic syndrome components including obesity, type 2 diabetes, hypertension, and hypercholesterolemia 3
• Typically presents with AST:ALT ratio <1 and mild to moderate transaminase elevations 1, 3
• Ultrasound has 84.8% sensitivity and 93.6% specificity for detecting moderate to severe hepatic steatosis (>30% fat content), though it misses mild steatosis when <20-30% of hepatocytes are affected 1, 3

Medication-Induced Liver Injury (DILI)

• Accounts for 8-11% of cases with mildly elevated liver enzymes 1, 2
• Common hepatotoxic medications include methotrexate, NSAIDs, statins, anticonvulsants, antiarrhythmics, tamoxifen, nitrofurantoin, minocycline, and infliximab 2
• Herbal supplements and over-the-counter products are frequently overlooked causes 1, 2
• Cholestatic drug-induced injury comprises up to 61% of cases in patients ≥60 years 3

Alcohol-Related Liver Disease

• Typically presents with AST:ALT ratio >2 (often >3), with mean AST around 152 U/L and ALT around 70 U/L 2
• Defined as ≥14-21 drinks/week in men or ≥7-14 drinks/week in women 3
• In alcoholic hepatitis, 70% of patients demonstrate AST:ALT ratio >2, and >98% have ratio >1.5 in histologically proven cases 2

Viral Hepatitis

• Chronic hepatitis B and C commonly present with fluctuating transaminase elevations over months 2
• Acute viral hepatitis typically shows higher elevations (>400 IU/mL for hepatitis A, B, C, D, or E) 2
• Chronic hepatitis B reactivation presents with elevated, often fluctuating ALT levels and moderate fluctuating HBV DNA levels >2000 IU/mL 2

Less Common but Important Causes

Autoimmune Hepatitis

• Presents with persistently elevated transaminases, hyperglobulinemia, and positive autoantibodies (ANA, ASMA, anti-LKM1) 2, 3
• Affects women 3-4 times more than men 2
• Approximately 30% of cases have cirrhosis at presentation 2
• Can present acutely with jaundice and markedly elevated transaminases 2

Hereditary Hemochromatosis

• Requires screening with fasting transferrin saturation and ferritin 1, 2
• Iron overload can cause persistent transaminitis even without other clinical manifestations 2

Celiac Disease

• Associated with transaminase elevations that improve or normalize with a gluten-free diet in 75-100% of cases 2

Alpha-1 Antitrypsin Deficiency

• Can present with chronic hepatitis, cirrhosis, or asymptomatic enzyme elevation 2
• Requires alpha-1 antitrypsin phenotyping (not just serum levels) for definitive diagnosis 2

Wilson Disease

• Must be excluded in patients under 40 years old with unexplained liver enzyme elevation 2
• Can present with isolated transaminitis 2
• Requires ceruloplasmin level and 24-hour urine copper collection if ceruloplasmin is low-normal 2

Non-Hepatic Causes to Exclude

Muscle Disorders

• Recent strenuous exercise, rhabdomyolysis, or polymyositis can elevate AST more than ALT 3
• Check creatine kinase (CK) to exclude muscle origin, as AST is present in cardiac muscle, skeletal muscle, kidneys, brain, and red blood cells 1, 2

Thyroid Disease

• Both hypothyroidism and hyperthyroidism can affect liver enzymes 3
• Screen with TSH in all patients with unexplained transaminitis 3

Cardiac Conditions

• Congestive heart failure can cause hepatic congestion and transaminitis 2
• Ischemic hepatitis presents with extremely elevated transaminases 4

HIV-Related Causes

• HIV-infected patients have multiple risk factors including coinfection with hepatitis B and C viruses, alcohol abuse, ART hepatotoxicity, HIV itself, and metabolic comorbidities leading to NAFLD 5

Context-Specific Causes

In Cancer Patients

• Immune checkpoint inhibitor-induced liver injury (ILICI) is a distinct cause 2
• Primary liver tumors or hepatic metastases, biliary obstruction, systemic infection, or sepsis 2

Statin-Induced Transaminitis

• Elevated hepatic transaminases occur in 0.5% to 2.0% of cases and are dose-dependent 6
• Progression to liver failure specifically due to statins is exceedingly rare if it ever occurs 6
• Reversal of transaminase elevation is frequently noted with dose reduction 6
• Statins are not contraindicated in chronic stable liver disease like NAFLD 2

Critical Clinical Pearls

ALT is more liver-specific than AST because it is primarily concentrated in liver tissue with minimal presence in cardiac muscle, skeletal muscle, or red blood cells. 1, 2, 3

• Normal ALT ranges are sex-specific: 29-33 IU/L for men and 19-25 IU/L for women, significantly lower than commercial laboratory cutoffs 1, 2
• Mild elevations (>1x to <3x ULN) without bilirubin elevation are often non-specific and may be related to NAFLD, dietary changes, or vigorous exercise 2
• Normal ALT does not exclude significant liver disease; up to 10% of patients with advanced fibrosis have normal ALT using conventional thresholds 1
• Approximately 50% of HCV-infected patients have normal transaminases 2
• Discrepancies between patient-reported and documented medications exist in >50% of patients with liver disease, particularly those taking more than five medications 2