What are the possible causes of transaminitis (elevated liver enzymes) in a patient with epigastric subacute pain and normal Computed Tomography (CT) scan results?

Differential Diagnosis of Transaminitis with Epigastric Subacute Pain and Normal CT

In a patient with epigastric subacute pain, transaminitis, and a normal CT scan, the most likely causes are drug-induced liver injury (particularly statins), nonalcoholic fatty liver disease, alcoholic liver disease, viral hepatitis, and less commonly, chronic cholecystitis or autoimmune hepatitis.

Most Common Causes

Drug-Induced Liver Injury

• Statins are a frequent cause of transaminitis, with persistent elevations (>3x ULN) occurring in 0.7% of patients, though severe transaminitis (>10x ULN) is rare at 0.1% 1.
• Statin-related severe transaminitis is often associated with drug interactions and resolves upon discontinuation 2.
• Other medications including norethindrone can cause transaminitis, with resolution occurring within 1-12 months after discontinuation 3.
• Review all current medications, particularly statins, hormonal therapies, and any recent additions or dose changes 1.

Nonalcoholic Fatty Liver Disease (NAFLD)

• NAFLD is one of the two most common causes of elevated transaminases in primary care, affecting approximately 10% of the U.S. population 4.
• The American Academy of Family Physicians recommends assessing for metabolic syndrome components: waist circumference, blood pressure, fasting lipid levels, and fasting glucose or A1C 4.
• NAFLD typically presents with mild elevations (<5x ULN) but can occasionally cause higher elevations 4.

Alcoholic Liver Disease

• Alcoholic liver disease is the other most common cause of transaminitis alongside NAFLD 4.
• Obtain detailed alcohol consumption history, as patients may underreport intake 4.

Hepatobiliary Causes Despite Normal CT

Chronic Cholecystitis

• Chronic cholecystitis can present with acute severe transaminitis, despite being an uncommon presentation 5.
• While acute cholecystitis commonly causes elevated liver enzymes, chronic cholecystitis presenting with severe transaminitis represents a diverse phenotype that expands the differential 5.
• CT may miss subtle gallbladder pathology; ultrasound is the initial imaging modality of choice for hepatobiliary evaluation 6.

Viral Hepatitis

• Hepatitis B and C are uncommon but important causes of transaminitis 4.
• Initial evaluation should include hepatitis C antibody and hepatitis B surface antigen testing 4.

Less Common but Important Causes

Autoimmune Hepatitis

• Autoimmune hepatitis can present with severe transaminitis and epigastric pain 7.
• Consider in patients with other autoimmune conditions or when common causes are excluded 7.

Hereditary Hemochromatosis

• Hereditary hemochromatosis is an uncommon cause that should be evaluated with serum iron, total iron-binding capacity, and ferritin 4.

Rare Causes

• Alpha-1 antitrypsin deficiency and Wilson disease are rare causes requiring specific testing when common etiologies are excluded 4.

Extrahepatic Sources

Systemic Conditions

• Thyroid disorders, celiac disease, hemolysis, and muscle disorders can cause mildly elevated transaminases 4.
• Complete blood count with platelets and serum albumin help evaluate for these conditions 4.

Critical Diagnostic Pitfalls

Limitations of CT Imaging

• CT has a relatively low negative predictive value (64%) for upper abdominal pathology, with commonly missed diseases including pancreaticobiliary inflammatory processes, gastritis, and duodenitis 8.
• Normal CT does not exclude significant hepatobiliary disease, particularly chronic cholecystitis or early autoimmune hepatitis 5, 7.

Inadequate Initial Workup

• Failing to obtain comprehensive metabolic panel including liver function tests can delay diagnosis 9.
• The American Academy of Family Physicians recommends complete blood count, comprehensive metabolic panel, hepatitis serologies, iron studies, and assessment for metabolic syndrome 9, 4.

Recommended Diagnostic Algorithm

Initial Laboratory Evaluation

• Complete blood count with differential and platelets 9, 4
• Comprehensive metabolic panel with liver function tests 9, 4
• Hepatitis B surface antigen and hepatitis C antibody 4
• Serum iron, total iron-binding capacity, and ferritin 4
• Fasting lipid panel and glucose or A1C 4
• Serum albumin 4

Imaging Considerations

• If hepatobiliary pathology suspected, obtain right upper quadrant ultrasound as CT may miss gallbladder disease 6, 5.
• Ultrasound is superior to CT for evaluating acute cholecystitis and hepatobiliary pathologies 6.

Management Based on Findings

• If drug-induced liver injury suspected, discontinue offending medication and monitor for resolution 1, 2.
• If consistent with NAFLD and other testing unremarkable, trial of lifestyle modification is appropriate 4.
• If elevation persists after addressing common causes, consider hepatic ultrasonography and testing for uncommon causes including autoimmune hepatitis, hemochromatosis, alpha-1 antitrypsin deficiency, and Wilson disease 4, 7.