What causes elevated lactate dehydrogenase (LD) and hyperbilirubinemia?

Causes of Elevated Lactate Dehydrogenase (287 U/mL) and Total Bilirubin (22 μmol/L)

The combination of mildly elevated LDH and bilirubin most commonly indicates hemolysis, hepatocellular injury, or early cholestatic liver disease, with hemolysis being the most likely given the modest elevations. 1, 2

Immediate Diagnostic Approach

Fractionate the bilirubin immediately to determine if this represents direct (conjugated) or indirect (unconjugated) hyperbilirubinemia, as this single test will narrow your differential dramatically. 3, 1

If Indirect (Unconjugated) Bilirubin Predominates (>70% of total):

Hemolysis is the primary concern and should be evaluated first:

• Check reticulocyte count, haptoglobin, and peripheral blood smear - hemolysis causes elevated LDH, indirect hyperbilirubinemia, increased reticulocytes, and decreased haptoglobin 2, 4
• Mechanical hemolysis from cardiac devices (LVAD, mechanical valves) presents with markedly elevated LDH and bilirubin; LDH levels are particularly high in this context 4
• Hemoglobinopathies such as acquired Hemoglobin H disease can present with this pattern, especially if associated with myelodysplastic syndrome 2
• Gilbert's Syndrome affects 5-10% of the population and causes intermittent unconjugated hyperbilirubinemia with conjugated bilirubin <20-30% of total; total bilirubin rarely exceeds 68-85 μmol/L (4-5 mg/dL) 3, 1

If Direct (Conjugated) Bilirubin Predominates (>35% of total):

Hepatobiliary disease is the primary concern:

• Measure ALT, AST, and alkaline phosphatase (ALP) to distinguish hepatocellular from cholestatic patterns 1, 5

• Calculate the ALT/LD ratio - this is diagnostically powerful:

  • ALT/LD ratio >1.5 suggests viral hepatitis (mean ratio 4.65) 5
  • ALT/LD ratio <1.5 suggests ischemic hepatitis (mean ratio 0.87) or drug-induced liver injury (mean ratio 1.46) 5
  • This ratio differentiates viral hepatitis from ischemic/toxic injury with 94% sensitivity and 84% specificity 5

• Drug-induced liver injury (DILI) typically shows direct bilirubin >35% of total bilirubin 3, 1

• Cholestatic disorders (PBC, PSC) cause direct hyperbilirubinemia with elevated ALP; confirm hepatobiliary origin with GGT or ALP isoenzymes 3, 1

• Chronic liver disease/cirrhosis presents with direct hyperbilirubinemia, elevated LDH, and altered AST:ALT ratio >1.0 (normal is 0.8) 1

Critical Diagnostic Pitfall

Do not confuse direct and conjugated bilirubin - direct bilirubin includes both conjugated bilirubin AND delta bilirubin (albumin-bound with 21-day half-life), which causes persistent hyperbilirubinemia even after the underlying cause resolves. 3, 1, 6 If hyperbilirubinemia persists unexpectedly, request breakdown of direct bilirubin into conjugated and delta fractions. 3, 1, 6

Additional Causes of Elevated LDH

Tissue hypoperfusion/shock is the most common cause of isolated LDH elevation, but many non-hepatic etiologies exist including myocardial infarction, pulmonary embolism, malignancy, seizures, and trauma. 7 However, the concurrent bilirubin elevation points toward hemolysis or hepatobiliary pathology.

Next Steps Based on Pattern

• If hemolysis confirmed: Identify underlying cause (mechanical, autoimmune, hemoglobinopathy, drug-induced) 2, 4
• If hepatocellular injury: Review medications, check viral hepatitis serologies, assess for ischemia/hypoperfusion 5
• If cholestatic pattern: Obtain right upper quadrant ultrasound (98% positive predictive value for parenchymal disease, 65-95% sensitivity for biliary obstruction) 1
• Check synthetic function (albumin, PT/INR, platelets) to assess severity and prognosis 1