What are the causes of elevated Lactate Dehydrogenase (LDH), alkaline phosphatase, and protein levels?

Causes of Elevated LDH, Alkaline Phosphatase, and Protein

The simultaneous elevation of LDH, alkaline phosphatase, and protein most strongly suggests malignancy—particularly metastatic disease with hepatic involvement, hematologic malignancies, or plasma cell disorders—and warrants urgent investigation for these life-threatening conditions.

Malignant Causes (Highest Priority)

Metastatic Disease

• Metastatic cancer to liver and/or bone is the most common cause of combined LDH and alkaline phosphatase elevation, accounting for 57% of isolated elevated alkaline phosphatase cases in one cohort, with infiltrative intrahepatic malignancy being particularly common 1
• Very high isolated LDH (≥800 IU/L) is a distinguishing biomarker for cancer (27% vs 4% in controls), liver metastases (14% vs 3%), and is an independent predictor of mortality 2
• Extremely high alkaline phosphatase levels (>1000 U/L) are most frequently associated with malignant biliary obstruction and diffuse liver metastases 3
• Elevated LDH is seen in 40-60% of patients with germ cell tumors and indicates high tumor burden 4

Hematologic Malignancies

• Plasma cell leukemia presents with elevated LDH, elevated protein (monoclonal), and often elevated alkaline phosphatase, characterized by aggressive clinical presentation with high tumor burden, leukocytosis, and extramedullary involvement 4
• Primary plasma cell leukemia shows high LDH levels reflecting aggressive disease with rapid clinical course and high proliferative index 4
• Lymphoma and multiple myeloma can cause elevated LDH and protein with bone involvement elevating alkaline phosphatase 4
• Very high isolated LDH is associated with hematologic malignancies (5% vs 0% in controls) 2

Bone Malignancies

• Osteosarcoma commonly presents with elevated serum LDH and alkaline phosphatase, with elevated LDH associated with worse prognosis and metastatic disease 4
• Bone metastases from various primary cancers elevate alkaline phosphatase and LDH simultaneously 1

Infectious Causes

Sepsis and Systemic Infections

• Sepsis is a major cause of extremely high alkaline phosphatase (>1000 U/L), accounting for 10 of 31 patients in one series, and can occur with normal bilirubin 3
• Very high isolated LDH is strongly associated with infection (57% vs 28% in controls) 2
• Gram-negative organisms, gram-positive organisms, and fungal sepsis can all cause marked alkaline phosphatase elevation 3
• Mycobacterium avium intracellulare and cytomegalovirus infections, particularly in AIDS patients, cause elevated alkaline phosphatase 3

Hepatobiliary Causes

Cholestatic Liver Disease

• Primary biliary cholangitis, primary sclerosing cholangitis, and drug-induced cholestasis are major causes of chronic alkaline phosphatase elevation 5
• Malignant biliary obstruction (7 of 8 patients with biliary obstruction in one series) causes extremely high alkaline phosphatase 3
• Choledocholithiasis and biliary strictures cause alkaline phosphatase elevation through cholestasis 5

Infiltrative Liver Disease

• Amyloidosis and hepatic metastases cause chronic alkaline phosphatase elevation 5
• Sarcoid hepatitis can cause extremely high alkaline phosphatase levels 3
• Cirrhosis, chronic hepatitis, and congestive heart failure are associated with alkaline phosphatase elevation 5

Bone Disorders (Non-Malignant)

• Paget's disease causes marked alkaline phosphatase elevation from increased bone turnover 5, 6
• Fractures and high bone turnover states elevate alkaline phosphatase 5
• Bone disease accounts for 29% of isolated elevated alkaline phosphatase cases 1

Protein-Specific Causes

Monoclonal Gammopathies

• Plasma cell disorders (multiple myeloma, plasma cell leukemia) cause elevated monoclonal protein with LDH elevation indicating high tumor burden 4
• Light-chain disease (Bence Jones protein) is common in plasma cell leukemia (26-44% of cases) 4

Polyclonal Protein Elevation

• Chronic inflammation and infection can cause polyclonal hypergammaglobulinemia
• Liver disease with impaired protein metabolism may alter protein levels

Diagnostic Approach Algorithm

Step 1: Determine Alkaline Phosphatase Source

• Measure GGT concurrently: elevated GGT confirms hepatobiliary origin; normal GGT suggests bone origin 5, 6
• Consider ALP isoenzyme fractionation if GGT is equivocal 5

Step 2: Assess Severity and Urgency

• Very high LDH (≥800 IU/L) warrants urgent investigation for metastatic cancer, hematologic malignancies, and severe infection 2
• Extremely high alkaline phosphatase (>1000 U/L) requires expedited workup for malignant obstruction, sepsis, or infiltrative disease 3
• Combined elevation with elevated protein strongly suggests plasma cell disorder or metastatic disease 4

Step 3: Initial Workup Based on Source

If Hepatobiliary Origin (elevated GGT):

• Abdominal ultrasound as first-line imaging to assess for dilated ducts, masses, or infiltrative lesions 5, 6
• If ultrasound negative but alkaline phosphatase remains elevated, proceed to MRI with MRCP 5, 6
• Review medications for drug-induced cholestasis, particularly in patients ≥60 years (61% of cholestatic drug-induced liver injury) 5

If Bone Origin (normal GGT):

• Bone scan indicated for localized bone pain or suspected metastases 5
• Patients under 40 with suspected bone pathology require urgent referral to bone sarcoma center 5

If Protein Elevated:

• Serum protein electrophoresis with immunofixation to identify monoclonal protein 4
• Peripheral blood smear to assess for circulating plasma cells (>20% suggests plasma cell leukemia) 4
• Bone marrow examination if plasma cell disorder suspected 4

Step 4: Additional Testing Based on Clinical Context

• Complete blood count to assess for anemia, thrombocytopenia, leukocytosis 4
• Comprehensive metabolic panel including calcium, phosphorus, creatinine (monitor for tumor lysis syndrome) 4
• Blood cultures if sepsis suspected 3
• β2-microglobulin if hematologic malignancy suspected 4

Critical Pitfalls to Avoid

• Do not assume all alkaline phosphatase elevations are liver-related—always confirm source with GGT 6
• Do not overlook malignancy: 47% of patients with isolated elevated alkaline phosphatase of unclear etiology died within average of 58 months 1
• Do not delay workup for very high LDH: it is an independent predictor of mortality (26.6% vs 4.3% in controls) and associated with major in-hospital complications 2
• Do not miss plasma cell leukemia: the combination of elevated LDH, protein, and rapid clinical deterioration requires urgent bone marrow examination 4
• In patients with inflammatory bowel disease and elevated alkaline phosphatase, do not miss primary sclerosing cholangitis—obtain high-quality MRC 5

Prognostic Implications

• Very high isolated LDH is associated with significantly more admission days (9.3 vs 4.1 days), major in-hospital complications, and high mortality rate 2
• Elevated LDH in osteosarcoma correlates with metastatic disease and worse 5-year disease-free survival (39.5% vs 60% for normal LDH) 4
• Plasma cell leukemia with elevated LDH indicates aggressive disease with rapid progression (weeks) and poor prognosis 4