What is the appropriate management for a 60-year-old female patient with macrocytosis, neutropenia, and hyperferritinemia?

Management of Macrocytosis, Neutropenia, and Hyperferritinemia in a 60-Year-Old Female

This patient requires urgent evaluation for hemophagocytic lymphohistiocytosis (HLH) and underlying malignancy, particularly lymphoma, given the combination of neutropenia (1.6 × 10⁹/L), macrocytosis (MCV 100 fL), and moderately elevated ferritin (337 ng/mL).

Immediate Diagnostic Workup

Rule Out HLH/Macrophage Activation Syndrome

• Assess HLH-2004 diagnostic criteria immediately, as this patient already meets 2 of 8 criteria: neutropenia (<1.0 × 10⁹/L) and ferritin ≥500 ng/mL threshold is not met, but clinical suspicion warrants evaluation 1.
• Obtain additional HLH criteria: fever documentation, splenomegaly assessment, triglycerides (≥3.0 mmol/L), fibrinogen (≤1.5 g/L), soluble CD25/IL-2 receptor (≥2400 U/mL), and NK cell activity 1.
• Ferritin >9,083 µg/L has 92.5% sensitivity and 91.9% specificity for HLH in critically ill patients, though this patient's ferritin of 337 ng/mL is below typical HLH range (usually >7,000-10,000 ng/mL) 1, 2.
• Consider calculating the HScore as a screening tool, particularly if ferritin rises above 6,000 µg/L, which significantly correlates with HLH diagnosis 3.

Evaluate for Underlying Malignancy

• Perform comprehensive malignancy workup immediately, as lymphomas (T-cell, NK-cell, and B-cell) account for 67% of malignancy-associated HLH in adults, with mean age at onset of 49 years 1.
• Obtain peripheral blood smear, lactate dehydrogenase, comprehensive metabolic panel, and consider bone marrow biopsy to evaluate for hemophagocytosis and exclude myelodysplastic syndrome or leukemia 1.
• CT chest/abdomen/pelvis to assess for lymphadenopathy and splenomegaly 1.

Differential Diagnosis Based on Laboratory Pattern

Macrocytosis (MCV 100 fL) Evaluation

• Check vitamin B12 and folate levels immediately, as macrocytosis with normal hemoglobin suggests nutritional deficiency or medication effect 1.
• Review medication list for thiopurines (azathioprine, 6-mercaptopurine), which commonly cause macrocytosis 1.
• Assess thyroid function (TSH) and consider reticulocyte count to differentiate between impaired production versus hemolysis 1.

Neutropenia (1.6 × 10⁹/L) Assessment

• Obtain complete differential white blood cell count and review for atypical lymphocytes or blasts 1.
• Consider autoimmune workup if no malignancy identified: ANA, anti-neutrophil antibodies 1.
• Evaluate for infectious triggers: EBV, CMV, HIV, hepatitis panel, as infections are the most prevalent HLH triggers 1.

Hyperferritinemia (337 ng/mL) Interpretation

• This ferritin level is elevated but not extreme; in the context of inflammation, ferritin up to 500 ng/mL may reflect acute-phase reaction rather than iron overload 1, 4.
• Obtain transferrin saturation (TSAT) and C-reactive protein to distinguish iron overload from inflammatory hyperferritinemia 1, 5.
• Ferritin >500 ng/mL with TSAT <25% strongly suggests inflammation rather than iron excess 5.
• Check glycosylated ferritin if available: <20% glycosylation is characteristic of Adult-Onset Still's Disease (AOSD), though this patient lacks typical AOSD features 1.

Specific Disease Considerations

Adult-Onset Still's Disease (AOSD)

• Assess for AOSD clinical features: high spiking fevers, salmon-pink rash, arthralgia, sore throat 1.
• AOSD typically presents with ferritin >4,000-30,000 ng/mL with glycosylated fraction <20% 1.
• This patient's ferritin of 337 ng/mL makes AOSD unlikely unless very early presentation 1.

Inflammatory Bowel Disease

• If gastrointestinal symptoms present, ferritin <100 µg/L with inflammation may still indicate iron deficiency 1.
• This patient's ferritin of 337 ng/mL with normal hemoglobin argues against iron deficiency anemia 1.

Monitoring and Follow-Up

Serial Laboratory Assessment

• Repeat complete blood count, ferritin, and inflammatory markers (CRP, ESR) within 1-2 weeks 1, 4.
• If ferritin rises above 2,000 ng/mL, urgently reassess for HLH/MAS and malignancy 4, 3.
• Monitor for development of additional cytopenias (hemoglobin <90 g/L, platelets <100 × 10⁹/L), which would increase HLH probability 1.

Red Flags Requiring Urgent Intervention

• Development of fever, progressive cytopenias, or rising ferritin >6,000 µg/L warrants immediate HLH protocol initiation 3, 2.
• Mortality rate is significantly increased in HLH patients, necessitating prompt immunosuppressive therapy if diagnosed 3.
• Rapidly rising ferritin with cytopenia progression suggests hemophagocytic syndrome requiring urgent treatment 1.

Treatment Considerations

Avoid Empiric Iron Supplementation

• Do not administer iron therapy without confirming true iron deficiency (ferritin <30 µg/L without inflammation or <100 µg/L with inflammation) 1.
• This patient's ferritin of 337 ng/mL with normal hemoglobin does not indicate iron deficiency 1.

If HLH Confirmed

• Initiate HLH-directed therapy immediately: corticosteroids, tocilizumab (anti-IL-6), and consider anakinra for refractory cases 1.
• Treat underlying trigger (infection, malignancy) concurrently with immunosuppression 1.