What is the diagnosis and treatment for a 56-year-old male with leukocytosis, macrocytic anemia, thrombocytosis, hypercalcemia, hyperkalemia, hypothyroidism, hypertriglyceridemia, and dyslipidemia?

Diagnosis and Treatment Approach

This patient most likely has a myeloproliferative neoplasm (MPN), specifically chronic myeloid leukemia (CML) or essential thrombocythemia (ET), and requires immediate hematology referral with bone marrow biopsy, peripheral blood smear, and molecular testing including BCR-ABL and JAK2 mutation analysis. 1, 2

Primary Diagnostic Considerations

Hematologic Malignancy Workup

The constellation of leukocytosis (WBC 14.6), absolute lymphocytosis (8.3), and thrombocytosis (464) strongly suggests a myeloproliferative neoplasm rather than reactive causes 1, 2:

• Immediate peripheral blood smear examination is essential to identify immature granulocytes (metamyelocytes, myelocytes, promyelocytes), basophilia, or abnormal lymphocytes that would indicate CML versus other MPNs 1, 3
• Bone marrow aspiration and biopsy must be performed to assess cellularity, blast percentage, and dysplastic features to differentiate between CML, ET, polycythemia vera, primary myelofibrosis, or myelodysplastic syndrome 1, 3
• Cytogenetic analysis is mandatory to detect t(9;22)(q34;q11) Philadelphia chromosome characteristic of CML 1, 3
• Molecular testing should include BCR-ABL transcripts by RT-PCR for CML and JAK2, CALR, and MPL mutations for essential thrombocythemia 1, 3, 2
• Flow cytometry of peripheral blood and bone marrow is crucial to determine lineage involvement and confirm clonality 3

Essential Thrombocythemia Considerations

If thrombocytosis (464) is the predominant finding with leukocytosis 2:

• Approximately 90% of ET patients have JAK2 (64%), CALR (23%), or MPL (4%) mutations that upregulate JAK-STAT signaling 2
• Differential diagnosis must exclude reactive thrombocytosis from inflammatory conditions (rheumatoid arthritis, lupus), infections, iron deficiency anemia, or solid tumors 2
• Thrombosis risk assessment is critical: age >60 years, prior thrombosis, JAK2 variant, and cardiovascular risk factors (hypertension, diabetes, hyperlipidemia) increase risk 2

Myelodysplastic Syndrome Evaluation

The macrocytic anemia (MCV 100) with cytopenias raises concern for MDS 1:

• Cytomorphology should evaluate for dysplastic features in ≥10% of marrow cells in erythroid, granulocytic, or megakaryocytic lineages 1
• Bone marrow trephine biopsy is strongly recommended to exclude other causes of cytopenia and provide prognostic information 1
• Next-generation sequencing to demonstrate clonality is indicated when morphological changes are nonspecific 1
• MDS classification should follow WHO criteria with prognosis established by IPSS-R scoring system 1

Secondary Metabolic Abnormalities

Hypothyroidism Management

The elevated TSH (5.840) with macrocytic anemia requires thyroid hormone replacement 4, 5:

• Hypothyroidism causes macrocytosis in up to 55% of patients through direct effects of thyroid hormone deficiency on erythropoiesis, independent of nutritional deficits 6, 7
• Macrocytic anemia in hypothyroidism is characterized by reticulopenia, hypoplasia of erythroid lineage, and decreased erythropoietin levels 6
• However, the concurrent leukocytosis and thrombocytosis cannot be explained by hypothyroidism alone and mandate hematologic malignancy workup 4

Dyslipidemia Treatment

The severe hypertriglyceridemia (340 mg/dL) with low HDL (38 mg/dL) requires intervention 5:

• Hypothyroidism must be treated first as it is a contributory disease to hyperlipidemia and should be adequately addressed before initiating lipid-lowering therapy 5
• Once thyroid function is optimized, fenofibrate 54-160 mg daily with meals is indicated for severe hypertriglyceridemia, with dosage individualized based on response at 4-8 week intervals 5
• Caution with fenofibrate: the elevated potassium (5.7) suggests possible renal impairment, and fenofibrate should be initiated at 54 mg daily in patients with mild-to-moderate renal dysfunction 5
• Lipid-lowering diet, weight management, and alcohol reduction should be implemented before and during pharmacotherapy 5

Electrolyte Abnormalities

The hyperkalemia (5.7) and hypercalcemia (10.5) require evaluation:

• Renal function assessment with creatinine and estimated GFR is essential before initiating any therapy, particularly fenofibrate which is contraindicated in severe renal impairment 5
• Hypercalcemia may be related to underlying hematologic malignancy and warrants further investigation 1

Critical Next Steps Algorithm

1. Immediate hematology referral for suspected myeloproliferative neoplasm 4, 3
2. Peripheral blood smear with manual differential counting ≥200 cells to identify immature forms, basophilia, or dysplasia 1, 3
3. Bone marrow aspiration and biopsy with cytogenetics, molecular testing (BCR-ABL, JAK2, CALR, MPL), and flow cytometry 1, 3, 2
4. Renal function testing (creatinine, eGFR) before initiating any pharmacotherapy 5
5. Thyroid hormone replacement for hypothyroidism once hematologic workup is underway 4
6. Thrombosis risk stratification if essential thrombocythemia is confirmed: consider aspirin 81-100 mg daily for most patients, with hydroxyurea cytoreduction for high-risk patients (age >60 or prior thrombosis) 2

Common Pitfalls

• Do not attribute all findings to hypothyroidism: while hypothyroidism causes macrocytic anemia, it does not explain leukocytosis or thrombocytosis 4, 6
• Do not delay hematology referral: the combination of leukocytosis, thrombocytosis, and macrocytosis warrants urgent evaluation for myeloproliferative neoplasm or myelodysplastic syndrome 4, 3
• Do not start fenofibrate without assessing renal function: the elevated potassium suggests possible renal impairment, and fenofibrate requires dose adjustment or avoidance in renal dysfunction 5
• Do not overlook thrombosis risk: if essential thrombocythemia is confirmed, failure to initiate aspirin or cytoreductive therapy in high-risk patients significantly increases thrombotic complications 2