What are the causes of elevated Aspartate Aminotransferase (AST) with normal Alanine Aminotransferase (ALT) in an adult patient with no significant past medical history?

Elevated AST with Normal ALT: Causes and Diagnostic Approach

Elevated AST with normal ALT should immediately prompt investigation for non-hepatic sources, particularly cardiac muscle, skeletal muscle injury, hemolysis, or macro-AST, rather than assuming primary liver disease. 1, 2

Understanding AST Specificity

AST is significantly less liver-specific than ALT because it is present in cardiac muscle, skeletal muscle, kidneys, brain, and red blood cells, making it essential to determine whether the elevation originates from hepatic or non-hepatic sources. 1, 2 In contrast, ALT is primarily concentrated in hepatocytes with minimal presence in other tissues, making its elevation highly indicative of hepatocellular damage. 2

Primary Non-Hepatic Causes to Investigate

Cardiac Muscle Injury

• Acute myocardial infarction commonly causes AST elevation without ALT elevation, as cardiac tissue contains high concentrations of AST but minimal ALT. 3, 4
• In acute coronary syndrome, 80% of patients have elevated AST, while only 47% have elevated ALT, with 43% presenting AST >3× upper limit of normal. 4
• Among patients with larger myocardial infarctions, approximately 93% present AST concentrations >3× ULN without corresponding ALT elevation. 4

Skeletal Muscle Injury

• Rhabdomyolysis, polymyositis, or recent intensive exercise can cause isolated AST elevation. 1, 5, 6
• In acute muscle injury cases, both AST and ALT are initially elevated with AST/ALT ratio >3, but this ratio approaches 1 after a few days due to faster AST decline (shorter half-life). 5
• Checking creatine kinase (CK) is essential to differentiate muscle from liver origin—markedly elevated CK with elevated AST but normal ALT confirms muscle injury. 1, 5

Hemolysis

• Red blood cell disorders and hemolysis can elevate AST without ALT elevation, as erythrocytes contain AST but minimal ALT. 1, 3
• Consider checking lactate dehydrogenase (LDH), haptoglobin, and peripheral blood smear if hemolysis is suspected. 5

Macro-AST

• Macro-AST is a benign condition where AST binds to immunoglobulins, creating high-molecular-weight complexes that persist in circulation, causing persistently elevated AST without clinical significance. 7
• This should be considered in patients with isolated AST elevation for >10 years with negative workup for liver and muscle disease. 7
• Diagnosis is confirmed by polyethylene glycol (PEG) precipitation test, which should be performed when all other causes are excluded. 7

Hepatic Causes with Disproportionate AST Elevation

Alcoholic Liver Disease

• An AST/ALT ratio ≥2 is highly suggestive of alcoholic liver disease, with ratios >3 being particularly specific for this diagnosis. 1, 2
• In alcoholic hepatitis, 70% of patients demonstrate AST/ALT ratio >2, with mean AST around 152 U/L and ALT around 70 U/L. 1
• AST/ALT ratio >1.5 is seen in >98% of histologically proven alcoholic hepatitis cases. 1
• Obtain detailed alcohol history: >40g/day for women or >50-60g/day for men for >6 months suggests alcoholic liver disease. 1

Cirrhosis from Any Cause

• In advanced cirrhosis, the AST/ALT ratio often reverses to >1 even in non-alcoholic disease, as cirrhotic liver tissue releases proportionally more AST. 1, 2
• If AST/ALT ratio >1 in non-alcoholic disease, strongly suspect cirrhosis and evaluate for complications such as varices, ascites, and synthetic dysfunction. 1

Wilson Disease

• Should be suspected in any patient <40 years with unexplained hepatocellular injury pattern, characterized by modest rises in serum aminotransferases and normal or markedly subnormal alkaline phosphatase. 2
• Check ceruloplasmin level and consider 24-hour urinary copper if Wilson disease is suspected. 1

Diagnostic Algorithm

Immediate Laboratory Testing

1. Creatine kinase (CK) to rule out muscle disorders as the primary cause. 1, 2
2. Troponin I if cardiac injury is suspected based on symptoms or risk factors. 4
3. Complete liver panel including ALT, alkaline phosphatase, GGT, total and direct bilirubin, albumin, and PT/INR to assess for hepatocellular versus cholestatic pattern. 1, 2
4. Thyroid function tests to rule out hypothyroidism, which can cause transaminase elevations. 1, 6

If CK is Markedly Elevated (>1000 U/L)

• Muscle injury is the primary cause—investigate for rhabdomyolysis, polymyositis, dermatomyositis, or recent extreme exercise. 5, 6
• Monitor for acute kidney injury and manage rhabdomyolysis complications. 5

If Cardiac Markers are Elevated

• Acute coronary syndrome is the cause—manage according to cardiology protocols. 4
• Transaminase elevations in this context are transient and typically return to baseline within 7-10 days. 8, 4

If Both CK and Cardiac Markers are Normal

• Obtain detailed alcohol consumption history to assess for alcoholic liver disease. 1, 2
• Calculate AST/ALT ratio: if ≥2, alcoholic liver disease is highly likely. 1, 2
• Perform abdominal ultrasound to assess for cirrhosis, hepatic steatosis, or structural abnormalities. 1, 2
• Check viral hepatitis serologies (HBsAg, anti-HBc IgM, anti-HCV) as chronic viral hepatitis can present with fluctuating transaminase elevations. 1

If All Testing is Negative and AST Remains Persistently Elevated

• Consider macro-AST and perform PEG precipitation test to confirm diagnosis. 7
• This is particularly relevant if AST has been elevated for months to years without other abnormalities. 7

Critical Pitfalls to Avoid

• Do not assume liver disease when AST is elevated with normal ALT—non-hepatic causes are common and must be systematically excluded. 1, 2, 3
• Do not overlook recent exercise history—intensive exercise or weight lifting can cause acute AST elevations that may be mistaken for liver injury. 1, 2
• Do not ignore cardiac symptoms—chest pain, dyspnea, or cardiac risk factors warrant immediate troponin testing, as myocardial infarction commonly elevates AST without ALT. 4
• Do not forget hemolysis—check LDH and haptoglobin if other causes are excluded, as red blood cell disorders can elevate AST. 1, 3

When to Refer

• Immediate hepatology referral if AST increases to >5× ULN with evidence of synthetic dysfunction (elevated bilirubin, prolonged PT/INR, low albumin). 1, 2
• Cardiology referral if troponin is elevated or acute coronary syndrome is suspected. 4
• Rheumatology referral if polymyositis or dermatomyositis is suspected based on elevated CK with muscle weakness. 5, 6
• Hepatology referral if AST remains elevated for ≥6 months without identified cause despite comprehensive workup. 1, 2