What is the most likely cause of the abnormal liver function tests in a 28‑year‑old man with ischemic heart disease post‑left anterior descending artery stent, recent MDMA and alcohol use, indirect bilirubin 9 mg/dL, direct bilirubin 4 mg/dL, total bilirubin 13 mg/dL, lactate dehydrogenase 1600 U/L, normal aspartate aminotransferase, alanine aminotransferase, creatine phosphokinase, mildly elevated gamma‑glutamyl transferase, and normal hemoglobin electrophoresis?

Most Likely Cause of Deranged LFTs: Hemolysis

The most likely cause of this patient's abnormal liver function tests is hemolysis, evidenced by the markedly elevated indirect bilirubin (9 mg/dL), very high LDH (1600 U/L), normal transaminases, and normal CPK—a pattern that points away from primary hepatocellular or muscle injury.

Understanding the Laboratory Pattern

Bilirubin Fractionation Analysis

• Indirect (unconjugated) bilirubin of 9 mg/dL with direct bilirubin of 4 mg/dL indicates a predominantly unconjugated hyperbilirubinemia (69% unconjugated), which is characteristic of prehepatic causes, particularly hemolysis 1
• Isolated unconjugated hyperbilirubinemia is seen in hemolysis, where excessive bilirubin reaching the liver overwhelms the conjugation process 1
• The presence of some conjugated bilirubin (4 mg/dL) suggests the liver is attempting to process the excessive bilirubin load but cannot keep pace with production 1

LDH Elevation as a Key Diagnostic Marker

• LDH of 1600 U/L is markedly elevated and strongly supports hemolysis as the primary process 2
• LDH is released from red blood cells during hemolysis and rises proportionally to the degree of red cell destruction 2
• The combination of high LDH with elevated indirect bilirubin and normal transaminases is pathognomonic for hemolysis rather than hepatocellular injury 3, 4

Normal Transaminases Exclude Primary Liver Injury

• Normal SGOT (AST) and SGPT (ALT) effectively rule out significant hepatocellular damage as the primary cause of hyperbilirubinemia 1
• If alcohol-induced liver disease or MDMA hepatotoxicity were responsible, ALT would be elevated (typically >3× upper limit of normal) 1
• Normal CPK excludes rhabdomyolysis or muscle injury as a source of enzyme elevation 5

Mildly Elevated GGT (90 U/L)

• The mildly elevated GGT suggests some degree of alcohol exposure but is insufficient to explain the marked hyperbilirubinemia 6
• GGT elevation occurs in approximately 75% of habitual drinkers but does not cause isolated indirect hyperbilirubinemia 7, 6
• In alcohol-related liver disease, you would expect AST/ALT elevation with AST > ALT ratio, which is absent here 7

Potential Hemolytic Mechanisms in This Patient

MDMA-Induced Hemolysis

• MDMA can cause hemolytic anemia through multiple mechanisms, including oxidative stress and direct red cell membrane damage 2
• Drug-induced hemolysis typically presents with elevated indirect bilirubin, elevated LDH, and normal liver enzymes—matching this patient's profile 1, 2

Alcohol-Related Hemolysis

• Chronic alcohol consumption causes structural and metabolic abnormalities of the erythrocyte membrane leading to hemolytic anemia 2
• Alcohol-induced hemolysis can range from very mild to potentially lethal and is associated with lipid bilayer expansion and membrane shape changes 2
• The combination of MDMA and alcohol may have synergistic effects on red cell membrane integrity 2

Cardiac Stress and Hemolysis

• Post-LAD angioplasty patients can develop mechanical hemolysis from shear stress, particularly if there are residual flow abnormalities 2
• Ischemic heart disease itself can contribute to hemolysis through increased shear stress and altered red cell deformability 2

Diagnostic Algorithm to Confirm Hemolysis

Immediate Laboratory Tests (Within 24 Hours)

1. Complete blood count with reticulocyte count to assess for anemia and reticulocytosis (elevated reticulocytes confirm active hemolysis) 7, 3
2. Peripheral blood smear to identify schistocytes, spherocytes, or other morphologic changes suggesting hemolysis 2
3. Haptoglobin level (will be low or undetectable in hemolysis) 3, 4
4. Direct Coombs test to exclude autoimmune hemolytic anemia 3

Secondary Evaluation (If Hemolysis Confirmed)

• Glucose-6-phosphate dehydrogenase (G6PD) level to exclude enzyme deficiency, particularly relevant given MDMA exposure 1
• Hemoglobin electrophoresis was already performed and is normal, excluding hemoglobinopathies 1
• Review medication list for other potential hemolytic agents beyond MDMA 1

Management Priorities

Immediate Actions

• Discontinue MDMA immediately and counsel complete abstinence from recreational drugs 1
• Recommend complete alcohol cessation, as alcohol can exacerbate hemolysis and impair liver function 7, 2
• Monitor hemoglobin levels closely to assess severity of hemolysis and need for transfusion 3

Short-Term Monitoring (2-4 Weeks)

• Repeat bilirubin, LDH, and reticulocyte count in 2-4 weeks after substance cessation to confirm resolution 5, 4
• If hemolysis resolves with abstinence, this confirms substance-induced etiology 7, 2
• If hemolysis persists despite abstinence, investigate for underlying hemolytic disorders or cardiac mechanical causes 3, 2

Hepatology Referral Criteria

• Persistent hyperbilirubinemia >6 months without improvement warrants hepatology referral 5
• Development of transaminase elevation >5× ULN requires urgent hepatology evaluation 5
• Evidence of synthetic dysfunction (low albumin, elevated INR) necessitates specialist assessment 1, 3

Critical Pitfalls to Avoid

• Do not assume Gilbert syndrome without first excluding hemolysis; Gilbert syndrome does not cause LDH elevation or require treatment, but hemolysis does 1
• Do not attribute findings solely to alcohol when normal transaminases argue against primary hepatocellular injury 7, 8
• Do not overlook cardiac causes of hemolysis in a patient with recent coronary intervention 2
• Do not delay haptoglobin and reticulocyte testing, as these simple tests rapidly confirm or exclude hemolysis 3, 4