What is the best course of action for a patient with erythrocytosis, macrocytosis, and high iron levels, who also has a history of smoking, Irritable Bowel Syndrome (IBS), and daily alcohol use?

Diagnostic Workup and Management

Immediate Priority: Rule Out Hereditary Hemochromatosis

This patient requires urgent genetic testing for HFE mutations (C282Y and H63D) and measurement of transferrin saturation and ferritin to evaluate for hereditary hemochromatosis, as the combination of high iron, macrocytosis, and daily alcohol use creates a dangerous synergy that accelerates liver fibrosis, cirrhosis, and hepatocellular carcinoma. 1

Critical Alcohol-Iron Interaction

• Alcohol consumption must be immediately reduced or eliminated because chronic alcohol intake downregulates hepcidin transcription, abrogating protective mechanisms against iron accumulation and creating synergistic oxidative stress with iron overload 1
• Daily alcohol consumption is an independent cause of elevated transferrin saturation and can mask or exacerbate underlying hemochromatosis 1
• The combination of alcohol and iron overload dramatically increases risk of cirrhosis and hepatocellular carcinoma, with effects beginning at doses as low as 10 g/day of ethanol 1

Essential Laboratory Evaluation

Iron Studies

• Measure fasting transferrin saturation and serum ferritin as initial screening 1
• If ferritin >1,000 μg/L or transaminases are elevated, assess for liver fibrosis (non-invasive methods preferred) 1
• Check complete blood count with peripheral smear to evaluate macrocytosis pattern 2

Macrocytosis Workup

• Obtain reticulocyte count to differentiate regenerative from non-regenerative causes 2
• Measure serum vitamin B12 level (deficiency <150 pmol/L); if borderline, add methylmalonic acid (>271 nmol/L confirms deficiency) 2
• Check serum and RBC folate levels (deficiency: serum folate <10 nmol/L or RBC folate <305 nmol/L) 2
• Alcohol is a direct cause of macrocytosis independent of vitamin deficiencies and impairs B12 absorption 2, 3
• Evaluate red cell distribution width (RDW), as an elevated RDW may indicate coexisting iron deficiency despite macrocytosis 2

Erythrocytosis Evaluation

• Measure serum erythropoietin level to distinguish primary from secondary causes 4
• For smokers, secondary erythrocytosis from chronic hypoxemia is the most likely etiology 1
• If erythropoietin is suppressed, test for JAK2 V617F mutation, MPL gene, JAK2 exon 12 mutations, and CALR gene to exclude polycythemia vera 5, 4
• Consider bone marrow biopsy only if molecular testing suggests clonal disorder 5

Genetic Testing Strategy

• HFE gene testing for C282Y and H63D mutations is mandatory given the constellation of high iron and macrocytosis 1, 4
• Even H63D heterozygotes can rarely develop clinically significant iron overload, particularly with concurrent alcohol use 4
• C282Y homozygosity with elevated transferrin saturation and hyperferritinemia confirms hereditary hemochromatosis diagnosis 1

Risk Stratification for Liver Disease

• If serum ferritin <1,000 μg/L without hepatomegaly, thrombocytopenia, or abnormal transaminases, the negative predictive value for advanced fibrosis is 94% 1
• If ferritin ≥1,000 μg/L or transaminases elevated, perform liver MRI R2 quantification* to assess hepatic iron content and guide management 1
• MRI can quantify iron in liver, spleen, pancreas, and heart, and predicts number of phlebotomies required 1

Treatment Algorithm

If Hereditary Hemochromatosis Confirmed

• Initiate therapeutic phlebotomy (removing 400-500 mL weekly) with isovolumic saline replacement until ferritin reaches 50-100 μg/L and transferrin saturation <50% 1
• Absolute alcohol abstinence or reduction to occasional, very small amounts given the synergistic hepatotoxicity 1
• Monitor ferritin every 3 months during maintenance phase 1

If Vitamin Deficiencies Present

• Treat vitamin B12 deficiency BEFORE initiating folate supplementation to prevent precipitating subacute combined degeneration of the spinal cord 2
• For B12 deficiency: administer 1 mg intramuscularly three times weekly for 2 weeks, then 1 mg every 2-3 months for life 2
• For folate deficiency (after excluding B12 deficiency): oral folic acid 5 mg daily for minimum 4 months 2

If Secondary Erythrocytosis from Smoking

• Smoking cessation is the definitive treatment for hypoxemia-driven erythrocytosis 1
• Avoid routine phlebotomy unless hemoglobin >20 g/dL and hematocrit >65% with hyperviscosity symptoms (headache, poor concentration) in the absence of dehydration 1
• Repeated routine phlebotomies risk iron depletion, microcytosis, and increased stroke risk 1

If Polycythemia Vera Diagnosed

• Maintain hematocrit <45% with phlebotomy 5
• Add low-dose aspirin (81 mg once or twice daily) unless contraindicated 5
• Consider hydroxyurea as first-line cytoreductive therapy if high-risk (age >60 or thrombosis history) 5

Critical Pitfalls to Avoid

• Never perform therapeutic phlebotomy without first checking iron studies and ferritin - iron deficiency with erythrocytosis dramatically increases stroke risk through microcytosis and reduced red cell deformability 1, 6
• Do not assume elevated hemoglobin excludes iron deficiency - patients with erythrocytosis can have concurrent iron deficiency that requires careful assessment with ferritin and transferrin saturation 6
• Ferritin may be falsely elevated in inflammatory conditions (including IBS with inflammation), potentially masking iron deficiency; check transferrin saturation and RDW 2
• Macrocytosis from alcohol can mask concurrent microcytosis from iron deficiency, resulting in normal MCV with elevated RDW 2

Monitoring Strategy

• Repeat complete blood count every 4 weeks during initial treatment phase 2
• Hemoglobin increase ≥2 g/dL within 4 weeks indicates adequate response to vitamin supplementation 2
• Serial ferritin monitoring every 3-6 months if hemochromatosis confirmed 1
• Annual liver ultrasound for hepatocellular carcinoma surveillance if cirrhosis develops 1