What is the likely cause of hepatomegaly in a patient with chronically elevated platelet (thrombocytosis) counts and neurologic symptoms?

Hepatomegaly with Chronic Thrombocytosis and Neurologic Symptoms: Diagnostic Approach

This clinical presentation strongly suggests essential thrombocythemia (ET), a myeloproliferative neoplasm that commonly presents with hepatomegaly, chronically elevated platelets with giant forms, and the specific constellation of neurologic symptoms described. 1

Primary Diagnostic Consideration: Essential Thrombocythemia

Key Clinical Features Supporting ET

• Chronic thrombocytosis (447-589 × 10⁹/L for 7 years) with giant platelet forms is characteristic of ET, a clonal myeloproliferative disorder primarily involving the megakaryocytic lineage 1

• Neurologic symptoms are the most common manifestation of ET, occurring in 67% of patients and including:

  • Headaches (present in 39% of ET patients) 2
  • Peripheral neuropathy/paresthesias (present in 30% of patients) 2
  • Visual disturbances and tinnitus (related to microcirculatory disturbances) 3
  • Brain fog and fatigue (related to cerebral microvascular occlusion) 1
  • Facial twitches (movement disorders associated with ET) 2

• Hepatomegaly occurs frequently in ET as part of the myeloproliferative process, with organomegaly being a recognized feature 1

• Past menorrhagia is consistent with ET, as hemorrhagic complications occur in approximately 30% of patients due to platelet dysfunction 3

Critical Diagnostic Point

Thrombotic and hemorrhagic complications in ET commonly occur at platelet counts below 600 × 10⁹/L, with 50% of symptomatic patients experiencing manifestations at counts below 500 × 10⁹/L, and 22% at counts below 400 × 10⁹/L 4. This patient's platelet range (447-589) falls squarely within the symptomatic range.

Essential Diagnostic Workup

Immediate Laboratory Testing Required

• Peripheral blood smear examination to identify giant platelets and evaluate for other myeloproliferative features 1

• JAK2 V617F mutation testing, as mutations in genes regulating thrombopoiesis (particularly JAK2) are diagnostic of ET 5, 1

• Bone marrow biopsy with cytogenetics to confirm megakaryocytic proliferation and exclude other myeloproliferative neoplasms (polycythemia vera, primary myelofibrosis) 1

• BCR-ABL testing to exclude chronic myeloid leukemia 1

Additional Testing to Exclude Secondary Causes

• Serum ferritin and iron studies to exclude iron deficiency as a cause of reactive thrombocytosis 5

• Comprehensive metabolic panel including liver function tests to assess hepatic involvement and exclude other causes of hepatomegaly 1

• Serum ceruloplasmin and 24-hour urine copper to exclude Wilson disease, which can present with hepatomegaly, neurologic symptoms (including migraines, movement disorders, peripheral neuropathy), and menstrual irregularities in young adults 1

• Slit-lamp ophthalmologic examination to evaluate for Kayser-Fleischer rings if Wilson disease is suspected 1

Alternative Diagnoses to Consider

Wilson Disease

• Should be strongly considered in any patient under 40 years with unexplained hepatomegaly and neurologic symptoms 1

• Can present with hepatomegaly, movement disorders (facial twitches), migraines, peripheral neuropathy, and menstrual irregularities 1

• The upper age limit for Wilson disease diagnosis extends beyond 40 years when neurologic symptoms are present 1

• Low ceruloplasmin (<20 mg/dL) and elevated 24-hour urine copper (>100 μg) would be diagnostic 1

Polycythemia Vera or Primary Myelofibrosis

• Both can present with thrombocytosis, hepatosplenomegaly, and neurologic symptoms related to thrombosis 1

• Primary myelofibrosis specifically presents with hepatosplenomegaly, constitutional symptoms (fatigue), and cytopenias or cytoses 1

• Bone marrow biopsy would show characteristic fibrosis in myelofibrosis or erythroid hyperplasia in polycythemia vera 1

Management Algorithm Based on Diagnosis

If Essential Thrombocythemia is Confirmed

This patient qualifies as high-risk ET (symptomatic with neurologic manifestations) and requires cytoreductive therapy 1:

• First-line treatment: Hydroxyurea to reduce platelet count well into the lower normal range (target <400 × 10⁹/L given symptomatic presentation) 1, 4

• Aspirin 81-100 mg daily for microvascular symptoms (headaches, paresthesias, tinnitus) unless contraindicated by bleeding history 1

• If hydroxyurea is not tolerated or ineffective: Consider anagrelide or interferon-alpha as second-line agents 1

• Avoid alkylating agents and ³²P in young patients due to leukemogenic risk 1, 3

If Wilson Disease is Confirmed

• Initiate chelation therapy with D-penicillamine or trientine 1

• Zinc acetate as maintenance therapy or in presymptomatic patients 1

• Neurologic symptoms may initially worsen with chelation before improving 1

Critical Clinical Pitfalls

• Do not dismiss thrombotic symptoms because platelet count is "only moderately elevated" - severe complications occur at counts as low as 300-350 × 10⁹/L in ET 4

• Do not attribute all symptoms to a single diagnosis - this patient could have both ET and another condition (e.g., Wilson disease) given the young age and specific symptom constellation 1

• Normal inflammatory markers do not exclude myeloproliferative neoplasms - ET typically does not cause elevated inflammatory markers 1

• Giant platelet forms are a key diagnostic clue pointing toward a primary bone marrow disorder rather than reactive thrombocytosis 3