How should I evaluate and manage a female patient with fatigue, easy bruising, and elevated serum vitamin B12 and ferritin?

Evaluation and Management of Fatigue and Easy Bruising with Elevated B12 and Ferritin

This presentation requires urgent hematology referral to exclude myelodysplastic syndrome (MDS), myeloproliferative disorders, or reactive macrophage activation syndrome, as the combination of constitutional symptoms with elevated B12 and ferritin suggests serious underlying hematologic pathology rather than simple nutritional excess.

Critical Initial Assessment

The constellation of fatigue, easy bruising, and paradoxically elevated B12 and ferritin is a red flag pattern that demands immediate comprehensive hematologic evaluation 1.

Mandatory Initial Laboratory Workup

• Complete blood count with differential and peripheral blood smear review to assess for dysplasia, cytopenias (particularly thrombocytopenia explaining bruising), and blast cells 1
• Reticulocyte count to evaluate bone marrow response 2
• Comprehensive metabolic panel including liver function tests, as hepatic dysfunction can elevate both B12 and ferritin 1
• Inflammatory markers (ESR, CRP) since ferritin is an acute phase reactant and can be elevated in inflammatory conditions 1
• Coagulation studies (PT, PTT, platelet function) if easy bruising is prominent 1

Key Diagnostic Considerations by Pattern

If cytopenias are present (particularly multi-lineage):

• Bone marrow aspiration and biopsy with cytogenetics is mandatory to evaluate for MDS, as this disorder commonly presents with fatigue, cytopenias, and paradoxically elevated ferritin 1
• Screen for paroxysmal nocturnal hemoglobinuria (PNH) clone via flow cytometry 1
• Consider HIV screening if clinically indicated 1

If hyperferritinemia is marked (>1000 ng/mL):

• Calculate glycosylated ferritin fraction if available, as levels <20% with extreme hyperferritinemia (often >4000 ng/mL) suggest Adult-onset Still's disease (AOSD), particularly when combined with elevated B12 1, 3
• AOSD can present with fatigue, easy bruising from thrombocytopenia, fever, rash, and sore throat 1, 3
• Elevated B12 (mean ~1900 pg/mL) combined with hyperferritinemia has 100% sensitivity and 75% specificity for reactive macrophage activation syndrome complicating AOSD 3

If B12 is markedly elevated (>1000 pg/mL):

• Paradoxically elevated B12 occurs in myeloproliferative disorders, liver disease, and reactive macrophage activation syndrome—not from dietary excess 3
• This pattern warrants bone marrow evaluation if other cytopenias exist 1

Common Pitfalls to Avoid

• Do not assume elevated B12 and ferritin represent supplementation or dietary excess—these elevations in the context of constitutional symptoms suggest serious pathology 1, 3
• Do not overlook the easy bruising—this requires specific evaluation with CBC, platelet count, and coagulation studies even before other workup 1
• Do not delay hematology referral if peripheral smear shows dysplasia or if multi-lineage cytopenias are present, as MDS requires prompt diagnosis 1, 2
• Ferritin >500 ng/mL in the presence of inflammation may mask true iron status—obtain transferrin saturation and consider other markers if iron deficiency is suspected despite elevated ferritin 1

Algorithmic Approach

1. Obtain CBC with differential, peripheral smear, reticulocyte count, comprehensive metabolic panel, inflammatory markers, and coagulation studies immediately 1, 2

2. If any cytopenias or dysplasia present: Refer to hematology urgently for bone marrow evaluation 1, 2

3. If ferritin >1000 ng/mL with elevated B12: Consider AOSD with possible reactive macrophage activation syndrome; obtain glycosylated ferritin if available and assess for fever, rash, arthritis, hepatosplenomegaly 1, 3

4. If inflammatory markers elevated: Investigate underlying inflammatory/rheumatologic conditions that could explain hyperferritinemia 1

5. If initial workup unrevealing but symptoms persist: Hematology consultation remains warranted given the atypical biochemical pattern 1

Specific Management Considerations

• Before any surgical procedure, complete hematologic evaluation including platelet function studies if easy bruising is present 1
• Do not initiate empiric iron or B12 supplementation until underlying cause is identified, as this may obscure diagnosis 1
• Monitor for progression with serial CBCs if initial workup is negative, as MDS can evolve over time 1