What lab findings suggest Hemophagocytic Lymphohistiocytosis (HLH)?

Laboratory Findings Suggestive of Hemophagocytic Lymphohistiocytosis (HLH)

Hyperferritinemia is the most characteristic laboratory finding in HLH, with levels >7000-10,000 μg/L strongly suggestive of HLH in adults, and should always prompt consideration of this diagnosis. 1

Key Diagnostic Laboratory Parameters

According to the HLH-2004 diagnostic criteria, laboratory findings that suggest HLH include:

1. Cytopenias affecting ≥2 of 3 lineages:

   • Hemoglobin <90 g/L
   • Platelets <100 × 10⁹/L
   • Neutrophils <1.0 × 10⁹/L

2. Hyperferritinemia:

   • Ferritin ≥500 μg/L (diagnostic threshold)
   • Ferritin >7000-10,000 μg/L (highly suggestive in adults)
   • Ferritin >10,000 μg/L (>90% sensitive and specific in children)

3. Coagulation abnormalities:

   • Hypertriglyceridemia (fasting triglycerides ≥3.0 mmol/L or ≥265 mg/dL)
   • Hypofibrinogenemia (fibrinogen ≤1.5 g/L)

4. Elevated soluble IL-2 receptor (sCD25):

   • ≥2400 U/mL
   • Better diagnostic marker than ferritin (AUC 0.90 vs 0.78) 1

5. Low or absent NK cell activity (according to local laboratory reference) 1

Additional Laboratory Findings

Other laboratory abnormalities that support the diagnosis include:

• Elevated liver enzymes (AST ≥30 U/L) 1
• Hypoproteinemia
• Hyponatremia
• Elevated VLDL and decreased HDL
• Elevated LDH
• Hemophagocytosis on bone marrow aspirate (neither sensitive nor specific) 1

Diagnostic Approach

To diagnose HLH, 5 of the 8 HLH-2004 criteria must be fulfilled, or a molecular diagnosis consistent with HLH must be established 1. However, it's important to note that:

1. The HLH-2004 criteria were developed for children and are not formally validated for adults 1
2. In the context of malignancy, several criteria may be present due to the underlying disease rather than HLH 1
3. Hemophagocytosis, despite the name of the syndrome, is neither sensitive nor specific for HLH 1

Monitoring Disease Activity

Certain laboratory parameters can be used to monitor disease activity and treatment response:

• Platelet count (rapidly reflects HLH activity)
• Ferritin (increases rapidly but normalizes slowly)
• Fibrinogen
• sCD25 levels
• LDH 1

Clinical Context

The likelihood of underlying malignancy increases with age:

• 60 years: 68% have lymphoma

• 30-59 years: 38% have lymphoma
• 15-29 years: 10% have lymphoma
• <14 years: 0% have lymphoma 1

Pitfalls and Caveats

1. Ferritin interpretation: While highly elevated ferritin is characteristic, it's less specific in adults than in children and can be elevated in other conditions like iron overload 1

2. Hemophagocytosis: May be absent initially and can be present in other conditions like septicemia 1

3. Cytopenias: May be due to underlying malignancy, infection, or treatment rather than HLH 1

4. Diagnostic delay: Laboratory findings may evolve over time, requiring serial testing if HLH is strongly suspected despite not meeting full criteria initially 1

5. Malignancy masking: In patients with known malignancy, distinguishing disease-related abnormalities from HLH can be challenging 1

When laboratory findings suggest possible HLH, a thorough search for underlying triggers (especially malignancy in adults) should be initiated, as prompt diagnosis and treatment are essential to prevent mortality 1.