What is the appropriate management for a patient with erythrocytosis, significantly elevated ferritin levels, and normal EPO levels, without a JAK mutation?

Management of Erythrocytosis with Elevated Ferritin and Low-Normal EPO

This patient requires immediate evaluation for polycythemia vera (PV) despite the low-normal EPO level, as JAK2-negative PV can still occur and the markedly elevated ferritin (901.7 μg/L) with erythrocytosis suggests either primary polycythemia or a secondary cause with iron overload that demands urgent investigation.

Diagnostic Approach

Confirm the Diagnosis of Erythrocytosis

• RBC 6.12 × 10¹²/L with Hgb 17.7 g/dL and Hct 54.4% confirms true erythrocytosis requiring further workup to distinguish primary from secondary causes 1
• The low-normal EPO level (9.6 mIU/mL) is atypical but does not exclude PV, as some PV patients can present with normal or even elevated EPO levels 2

Critical Laboratory Tests to Order Immediately

• Repeat JAK2 V617F mutation testing if not already done with high-sensitivity assays, as this mutation is present in >95% of PV cases 1
• Test for JAK2 exon 12 mutations in JAK2 V617F-negative patients with suspected PV, as these account for most remaining PV cases 1
• Fasting transferrin saturation (TS) to distinguish true iron overload from inflammatory causes of elevated ferritin 3
• Complete metabolic panel including ALT, AST to assess for liver disease given the markedly elevated ferritin 3
• Inflammatory markers (CRP, ESR) to evaluate whether ferritin elevation is secondary to inflammation 3

Evaluate for Secondary Causes of Erythrocytosis

• Arterial oxygen saturation and carboxyhemoglobin levels to exclude hypoxic causes 1
• Renal ultrasound to evaluate for renal masses or cysts that could produce EPO 1
• Sleep study consideration if clinical suspicion for sleep apnea exists 1

Risk Stratification Based on Ferritin Level

Ferritin >1000 μg/L Threshold Not Met But Close

• At ferritin 901.7 μg/L, you are approaching the critical threshold of 1000 μg/L where liver biopsy should be considered to assess for cirrhosis, especially if liver enzymes are elevated 3
• If ALT/AST are elevated or platelet count <200,000/μL, strongly consider liver biopsy to stage liver disease 3
• If liver enzymes are normal and patient is <40 years old with no hepatomegaly, liver biopsy may be deferred 3

Assess for Organ Damage

• Obtain ECG and consider echocardiography if severe iron overload is suspected, as cardiac evaluation is recommended when assessing for organ damage 3
• Evaluate for hepatomegaly and splenomegaly on physical examination, as these suggest advanced disease 1

Management Algorithm

If Primary Polycythemia (PV) is Confirmed

Therapeutic phlebotomy is the cornerstone of treatment with the following protocol 3:

• Remove 500 mL blood weekly or biweekly as tolerated 3
• Check hemoglobin/hematocrit before each phlebotomy 3
• Allow hemoglobin to fall no more than 20% from baseline 3
• Target hematocrit <45% to minimize thrombotic risk 1
• Check ferritin every 10-12 phlebotomies 3
• Target ferritin 50-100 μg/L for the induction phase endpoint 3

Critical management considerations:

• Avoid vitamin C supplementation during phlebotomy therapy, as it accelerates iron mobilization and increases oxidative stress 3
• Avoid iron supplements entirely 3
• Avoid raw shellfish due to risk of Vibrio vulnificus infection in iron-overloaded patients 3
• Consider low-dose aspirin for thrombotic risk reduction in high-risk patients 2

If Secondary Polycythemia is Identified

• Treat the underlying condition rather than focusing on the elevated ferritin alone 3
• Phlebotomy may still be indicated if hematocrit remains dangerously elevated despite treating the underlying cause 4

Special Consideration: Functional Iron Deficiency

• Despite the elevated ferritin, assess transferrin saturation to determine if functional iron deficiency exists 5
• In dialysis patients with ferritin 500-1200 ng/mL but TS <25%, intravenous iron may still be beneficial if receiving erythropoietin therapy 3
• However, this patient's erythrocytosis makes iron supplementation contraindicated 3

Common Pitfalls to Avoid

Do Not Assume Low EPO Excludes PV

• EPO levels can be normal or even elevated in some PV patients, making it an imperfect discriminator 2
• JAK2 mutation testing is essential and should not be skipped based on EPO level alone 2, 1

Do Not Use Ferritin Alone to Diagnose Iron Overload

• Always measure transferrin saturation alongside ferritin to distinguish true iron overload from inflammatory causes 3
• Ferritin is an acute phase reactant and can be elevated in inflammatory conditions, liver disease, and malignancy 3

Do Not Delay Specialist Referral

• Refer to hematology immediately for evaluation of possible PV given the erythrocytosis and negative JAK2 V617F 3
• Consider gastroenterology referral if ferritin remains >1000 μg/L or if liver enzymes are elevated 3

Expected Outcomes with Treatment

Therapeutic phlebotomy prevents hepatic cirrhosis, primary liver cancer, diabetes mellitus, hypogonadism, arthropathy, and cardiomyopathy when initiated before severe iron overload develops 3

Phlebotomy does not reverse established cirrhosis but prevents progression 3

The goal of therapy in PV is to normalize blood counts to minimize the risk of thrombotic events, which are the major cause of morbidity and mortality 1