In a 56‑year‑old diabetic woman with fever, leukocytosis, severe thrombocytopenia, anemia and ferritin >2000 µg/L, does a normal fibrinogen level of 400 mg/dL and triglyceride level of 170 mg/dL exclude hemophagocytic lymphohistiocytosis (HLH)?

Normal Fibrinogen and Triglycerides Do NOT Exclude HLH

A fibrinogen of 400 mg/dL and triglycerides of 170 mg/dL do not exclude hemophagocytic lymphohistiocytosis (HLH) in this patient, and you should proceed urgently with further diagnostic workup and strongly consider initiating HLH-directed therapy given the constellation of fever, severe thrombocytopenia, anemia, leukocytosis, and markedly elevated ferritin >2000 µg/L. 1

Why These "Normal" Values Don't Rule Out HLH

The HLH-2004 diagnostic criteria require 5 of 8 criteria to be met, and the hypertriglyceridemia/hypofibrinogenemia criterion is satisfied if either triglycerides ≥265 mg/dL or fibrinogen ≤1.5 g/L (150 mg/dL) is present. 1 Your patient's values (triglycerides 170 mg/dL, fibrinogen 400 mg/dL) do not meet this specific criterion, but this is only one of eight possible criteria. 1

Critical point: HLH can be diagnosed and treatment initiated even when fewer than 5 criteria are fulfilled if clinical suspicion is sufficiently high. 1 The guidelines explicitly state that "HLH may be strongly considered, and HLH-directed therapy may be initiated, even though 5 criteria are not fulfilled." 1

Your Patient Likely Already Meets Multiple HLH Criteria

Let's count what you have:

1. Fever – present 1
2. Cytopenias affecting ≥2 lineages – severe thrombocytopenia (platelets <100 × 10⁹/L) and anemia (hemoglobin <90 g/L) = 2 criteria met 1
3. Ferritin ≥500 mg/L – your patient has >2000 µg/L = criterion met 1, 2

You already have at least 4 criteria, and potentially 5 if leukocytosis represents neutrophilia masking underlying lymphopenia or if splenomegaly is present on imaging. 1

Essential Next Steps

Immediately Obtain These Tests:

• Soluble CD25 (sCD25/soluble IL-2 receptor) – this is the single best diagnostic test for adult HLH with AUC 0.90 versus ferritin's 0.78; a level ≥2400 U/mL meets diagnostic criteria 2
• NK cell activity – low or absent activity is a diagnostic criterion 1, 2
• Bone marrow aspirate – look for hemophagocytosis, though its absence does NOT exclude HLH; serial aspirates or examination of other tissues (liver, lymph nodes, spleen) may be needed 1, 3
• Imaging – assess for splenomegaly and hepatomegaly 1

Search for Underlying Triggers:

In a 56-year-old diabetic woman, you must aggressively pursue: 1

• Malignancy screening (especially T-cell/NK-cell lymphomas, B-cell lymphomas) – malignancy-associated HLH occurs in up to 68% of adults and is the leading cause in this age group 1, 2
• Viral infections – EBV, CMV, other herpes viruses 4, 5
• Autoimmune triggers – macrophage activation syndrome in rheumatic diseases 5

Important Caveats About Fibrinogen and Triglycerides in HLH

Fibrinogen can be falsely "normal" or even elevated in HLH because it is an acute-phase reactant. 4, 5 In the setting of severe inflammation, fibrinogen may rise despite ongoing consumption, masking the expected hypofibrinogenemia. A level of 400 mg/dL in a critically ill patient with suspected HLH should be interpreted cautiously—it may actually represent relative hypofibrinogenemia for the degree of inflammation present. 4

Triglycerides at 170 mg/dL are below the HLH threshold (≥265 mg/dL), but lipid abnormalities can evolve over time and may not be present at initial presentation. 1, 5 Serial measurements are warranted. 1

Case reports document HLH with normal ferritin, triglycerides, or fibrinogen, particularly in atypical presentations or early disease. 6 One pediatric case series showed that even familial HLH can present with normal ferritin. 6

Treatment Should Not Be Delayed

Do not wait for all diagnostic criteria to be met before initiating therapy. 1, 2 HLH is a life-threatening hyperinflammatory syndrome with 50% mortality across all etiologies. 4 The HLH-2004 treatment protocol (dexamethasone, etoposide, cyclosporine A) should be started urgently when clinical suspicion is high, even if only 4 criteria are met. 1, 7

Multidisciplinary involvement including intensive care is essential given the risk of multi-organ failure. 4

Alternative Diagnostic Tool: HScore

Consider calculating the HScore, which was developed specifically for adults with suspected secondary HLH and may be more applicable than pediatric-derived HLH-2004 criteria. 1, 3 The HScore incorporates:

• Known immunosuppression (diabetes may contribute) 1
• Temperature 1
• Organomegaly 1
• Number of cytopenias (your patient has ≥2) 1
• Ferritin level (>2000 scores points) 1
• Triglyceride and fibrinogen levels 1
• AST elevation 1
• Hemophagocytosis on bone marrow 1

A high HScore (typically >169) supports HLH diagnosis even when classic criteria are not fully met. 1, 3

Bottom Line

Your patient's clinical picture—fever, severe cytopenias, markedly elevated ferritin >2000 µg/L in a diabetic woman—is highly concerning for HLH regardless of normal fibrinogen and triglycerides. 1, 2 Proceed immediately with sCD25, NK cell activity, bone marrow examination, and malignancy/infection workup while preparing to initiate HLH-directed therapy. 1, 2 Delay in treatment significantly worsens mortality. 4, 5