How do beta thalassemia and hereditary hemochromatosis differ in pathophysiology, clinical presentation, and management of iron overload?

Beta Thalassemia vs Hereditary Hemochromatosis: Key Differences

Beta thalassemia and hereditary hemochromatosis are fundamentally different disorders—thalassemia is an inherited hemoglobin synthesis defect causing anemia with secondary iron overload from ineffective erythropoiesis, while hemochromatosis is a primary iron absorption disorder caused by HFE gene mutations (predominantly C282Y) leading to progressive iron accumulation without anemia. 1

Pathophysiology

Hereditary Hemochromatosis

• Primary defect in iron regulation: The C282Y mutation in the HFE gene (found in >90% of cases) causes inappropriately low hepcidin levels, leading to excessive dietary iron absorption from the intestine 1
• Genetic pattern: Autosomal recessive inheritance requiring C282Y homozygosity (C282Y/C282Y) for full disease expression, with compound heterozygosity (C282Y/H63D) accounting for only 3-5% of cases 1, 2
• Incomplete penetrance: Only 58-70% of C282Y homozygotes develop progressive tissue iron overload, and fewer than 10% develop end-organ damage (cirrhosis, diabetes, cardiomyopathy) 1, 3
• Iron accumulation mechanism: Increased absorption of dietary iron through intact intestinal mucosa due to hepcidin deficiency 4

Beta Thalassemia

• Primary defect in hemoglobin synthesis: Reduced or absent beta-globin chain production causes chronic hemolytic anemia and ineffective erythropoiesis 1
• Secondary iron overload mechanism: Inappropriately low hepcidin levels result from the suppressive effect of ineffective erythropoiesis on hepcidin expression, combined with transfusional iron loading in thalassemia major 4
• Dual iron loading: Both increased intestinal iron absorption (from low hepcidin) and parenteral iron from chronic red blood cell transfusions contribute to iron overload 1

Clinical Presentation

Hereditary Hemochromatosis

• Typically asymptomatic early: Most C282Y homozygotes identified through screening or family studies have no symptoms 1
• Age of presentation: Clinical manifestations typically appear in the 4th-5th decade if untreated, with men affected earlier than women 1
• Classic triad (late manifestations): Cirrhosis, diabetes mellitus, and skin hyperpigmentation ("bronze diabetes") occur in <10% of genetic homozygotes 3
• Cardiovascular complications: Heart disease from iron deposition, though less prominent than in thalassemia 1
• No anemia: Normal hemoglobin and red blood cell indices distinguish this from thalassemia 1

Beta Thalassemia Major

• Severe anemia from birth/early childhood: Transfusion-dependent anemia is the primary clinical feature 1
• Cardiovascular adaptation to chronic anemia: Resting tachycardia, low blood pressure, enlarged end-diastolic volume, high ejection fraction, and high cardiac output are baseline findings 1
• Cardiac iron overload is the leading cause of death: Heart failure from myocardial siderosis is the most common cause of mortality in thalassemia major 1
• Background dyspnea from anemia: Chronic anemia causes dyspnea that can mask early heart failure symptoms 1
• Earlier and more severe cardiac complications: Cardiac iron deposition occurs earlier and more aggressively than in hemochromatosis 1

Beta Thalassemia Trait (Minor)

• Mild microcytic anemia: Typically asymptomatic with mild anemia and microcytosis 5, 6
• Generally no iron overload alone: Heterozygous carriers do not develop iron overload from thalassemia trait alone 5, 7
• Exception—coinheritance with HFE mutations: Severe iron overload can develop when thalassemia trait is combined with C282Y homozygosity or even H63D heterozygosity 5, 6, 7

Diagnostic Approach

Hereditary Hemochromatosis

• Screening tests: Transferrin saturation ≥45% and elevated serum ferritin are primary screening markers 1, 3
• Genetic testing: HFE testing for C282Y and H63D mutations when both transferrin saturation and ferritin are elevated 1, 8
• Comprehensive gene panel: Include HFE, HJV, HAMP, TFR2, and SLC40A1 for non-HFE hemochromatosis (10-15% of cases) 8
• Liver assessment: Liver biopsy or MRI for hepatic iron concentration and fibrosis staging in advanced cases 1
• Normal CBC: Absence of anemia or microcytosis helps distinguish from thalassemia 1

Beta Thalassemia

• CBC findings: Microcytic anemia with low MCV, elevated red blood cell count, and normal or low reticulocyte count 6
• Hemoglobin electrophoresis: Elevated HbA2 (>3.5%) confirms beta thalassemia trait; absent or reduced HbA in thalassemia major 6
• Cardiac T2 MRI:* Essential for detecting cardiac iron overload—T2* <10 ms is the most important predictor of heart failure development 1
• Serial cardiac function monitoring: Trends in ejection fraction and other parameters are more valuable than single measurements due to abnormal baseline hemodynamics from chronic anemia 1
• Serum ferritin and liver iron are inadequate surrogates: These do not reliably predict cardiac iron burden in thalassemia 1

Management of Iron Overload

Hereditary Hemochromatosis

• Phlebotomy is first-line therapy: Weekly removal of 500 mL blood (250 mg iron) until ferritin <50 ng/mL, then maintenance phlebotomy every 2-4 months 1
• Excellent prognosis with early treatment: Survival is normal in patients treated before development of cirrhosis or diabetes 2
• Chelation therapy is second-line: Reserved for patients who cannot tolerate phlebotomy (anemia, cardiac disease) 1
• Dietary modification has minimal role: Avoiding iron supplements and excessive vitamin C, but dietary iron restriction is not necessary 1

Beta Thalassemia Major

• Continuous transfusion support: Maintain hemoglobin 9-10.5 g/dL to suppress ineffective erythropoiesis 1
• Iron chelation is mandatory: Deferoxamine, deferasirox, or deferiprone to prevent transfusional iron overload 1
• Acute heart failure requires urgent intensive chelation: Continuous intravenous deferoxamine infusion at high doses is the first principle of management for acute decompensated heart failure 1
• Cardiac T2 monitoring guides chelation intensity:* Target T2* >20 ms for cardiac protection 1
• Phlebotomy is contraindicated: Would worsen anemia in transfusion-dependent patients 9

Beta Thalassemia Trait with Hemochromatosis

• Critical diagnostic challenge: When thalassemia trait coexists with HFE mutations, particularly C282Y homozygosity, severe iron overload can develop 5, 7
• Thalassemia trait aggravates hemochromatosis: Higher rates of iron accumulation and more severe complications occur in C282Y homozygotes who also have thalassemia trait 7
• Management dilemma: Phlebotomy may worsen the mild anemia from thalassemia trait, while chelation is less effective than phlebotomy for hemochromatosis 9
• Practical approach: Gentle phlebotomy with hemoglobin monitoring, or chelation therapy if anemia worsens, with hepatology consultation recommended 9

Critical Pitfalls to Avoid

• Do not assume microcytic anemia excludes hemochromatosis: Check for coexisting thalassemia trait in patients with iron overload and microcytosis 5, 7
• Do not use serum ferritin alone to assess cardiac iron in thalassemia: Cardiac T2* MRI is essential as liver iron and ferritin do not predict cardiac iron burden 1
• Do not screen asymptomatic general population for HFE mutations: USPSTF gives this a grade D recommendation as harms outweigh benefits 3
• Do not assume all C282Y homozygotes will develop clinical disease: Only 58-70% develop iron overload, and <10% develop end-organ damage 1, 3
• Do not delay intensive chelation in thalassemia patients with acute heart failure: This is a medical emergency requiring immediate continuous IV deferoxamine 1
• Do not attribute iron overload in thalassemia trait to the trait alone: Investigate for coexisting HFE mutations or other causes of secondary iron overload 5, 6, 7