What are the potential causes of elevated Lactate Dehydrogenase (LDH) levels in a patient with a history of hyponatremia and currently taking quetiapine (quetiapine is an atypical antipsychotic medication)?

Elevated LDH: Causes and Clinical Approach

Primary Causes of Elevated LDH

Elevated LDH is a nonspecific marker of tissue damage or increased cellular turnover that requires systematic evaluation across multiple organ systems, with particular attention to hematologic malignancies, hemolysis, solid tumors, liver disease, and cardiac/muscle injury. 1

Hematologic Malignancies

• Hematologic malignancies are among the most common causes of marked LDH elevation, particularly in patients with high proliferative rates such as Burkitt's lymphoma, B-cell acute lymphoblastic leukemia (ALL), other B-cell non-Hodgkin's lymphomas, and T-cell ALL. 1, 2
• Elevated LDH may be the only early sign of occult malignant lymphoma in asymptomatic patients, appearing months before clinical manifestations. 3
• In plasma cell leukemia, elevated LDH reflects high tumor burden and aggressive clinical presentation. 2

Hemolysis and Thrombotic Microangiopathy (TMA)

• Hemolysis causes LDH elevation in combination with decreased haptoglobin and elevated indirect bilirubin. 1
• The combination of thrombocytopenia, elevated LDH, and decreased haptoglobin is specific for hemolysis according to the European Hematology Association. 4
• In patients with thrombocytopenia, immediately check LDH, haptoglobin, and indirect bilirubin to determine if microangiopathic hemolysis is present. 4
• Elevated LDH levels at presentation predict worse outcomes and mortality in TMA. 4

Solid Tumors

• Testicular germ cell tumors frequently elevate LDH, which serves as a tumor marker for diagnosis, prognosis, and treatment monitoring. 1, 2
• In osteosarcoma, elevated serum LDH correlates with metastatic disease and worse prognosis (5-year disease-free survival of 39.5% versus 60% for normal values). 2
• Bulky small cell lung cancer and metastatic germ cell carcinoma are high-risk solid tumors for marked LDH elevation. 2

Tissue Damage

• Myocardial infarction releases LDH from damaged cardiac tissue. 1
• Liver disease of various etiologies elevates LDH, though this is nonspecific. 5, 1
• Muscle damage from strenuous exercise or rhabdomyolysis temporarily elevates LDH. 1, 2
• Kidney disease contributes to elevated LDH levels in patients with renal impairment. 1

Infection and Critical Illness

• Sepsis and septic shock can elevate lactate levels, which may be accompanied by LDH elevation in critically ill patients. 1
• Various infections can cause LDH elevation. 1, 2

Pleural and Peritoneal Fluid Disorders

• Exudative pleural effusions show pleural fluid LDH >2/3 the upper limit of normal serum LDH (>67% of upper limit normal) or pleural fluid LDH/serum LDH ratio >0.6 by Light's criteria. 1, 2
• Secondary peritonitis from perforated viscus shows ascitic LDH levels higher than serum LDH levels. 1, 2

Pregnancy-Related

• Preeclampsia causes LDH elevation and requires evaluation for underlying pathological processes in pregnant women. 1, 2

Iatrogenic and Device-Related

• Mechanical circulatory support devices cause baseline hemolysis with LDH elevation; levels >2.5 times upper limit of normal require evaluation for pump thrombosis. 1, 2
• Tumor lysis syndrome occurs spontaneously or after treatment with corticosteroids, monoclonal antibodies, or chemotherapeutic agents, particularly in high tumor burden malignancies. 1, 2
• Drug-induced liver injury is an uncommon cause of mild aminotransferase and LDH elevation. 1, 2

Specific Context: Quetiapine and Hyponatremia

Quetiapine-Related Considerations

• Atypical antipsychotics including quetiapine may produce elevations in hepatic transaminase levels, which are often transient and generally resolve with cessation of the drug. 5
• Quetiapine has been associated with hematological abnormalities including one unpublished report of a precipitous drop in absolute neutrophil count (ANC) and platelets in a 12-year-old boy. 5
• Neuroleptic malignant syndrome (NMS) is a rare but potentially fatal complication of quetiapine that includes elevated creatinine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. 6

Hyponatremia and Antipsychotics

• Antipsychotic use may be associated with hyponatraemia, with an adjusted reporting odds ratio of 1.58 (95% CI 1.46,1.70) for the association between antipsychotic use and hyponatraemia. 7
• Syndrome of inappropriate antidiuretic hormone secretion (SIADH) has been described with quetiapine and almost all psychotropic drugs. 8
• Hyponatremia is an independent risk factor for development of hepatic encephalopathy in patients with cirrhosis, and the response rate to lactulose therapy decreases with decreasing serum sodium concentrations. 5
• Monitor serum sodium during the first 2-4 weeks of pharmacotherapy in patients at increased risk (older age, comorbid somatic disorders, polypharmacy). 8

Diagnostic Algorithm by Degree of Elevation

Mild Elevation (<5× Upper Limit Normal)

• Most commonly associated with benign causes including liver disease, hemolysis, myocardial infarction, kidney disease, muscle damage, and infections. 1, 2, 9
• Review medication history as drug-induced liver injury is an uncommon cause of mild aminotransferase elevation. 2

Moderate to Severe Elevation (5-10× Upper Limit Normal)

• Requires systematic evaluation for malignancy, hemolysis, and organ damage. 9
• No significant difference exists between average LDH values of benign (2708 UI/L) versus malignant (2842 UI/L) etiologies. 9

Extreme Elevation (>10× Upper Limit Normal)

• Carries a poor prognosis with hospitalization in intensive care in 73% of cases and mortality rate of 53%, regardless of benign or malignant etiology. 1, 9
• Benign causes still account for the majority (11 of 15 cases) even at this extreme elevation. 9

Critical Diagnostic Pitfalls

• Clinical context is essential: LDH must be interpreted alongside other clinical and laboratory findings. 1, 2
• Laboratory artifact: Hemolysis of blood samples can falsely elevate LDH levels. 1, 2
• The degree of LDH elevation alone does not reliably differentiate benign from malignant diseases. 9
• In patients with no apparent cause for elevated serum LDH levels, a thorough work-up including abdominal CT scan may be warranted to exclude occult malignancy. 3