Hereditary Hemochromatosis: Presentation, Diagnosis, and Management
Clinical Presentation
Hereditary hemochromatosis typically presents asymptomatically in the fourth to fifth decade of life, with most patients now identified through incidental laboratory abnormalities rather than classic end-organ damage. 1, 2
Key Presentation Patterns:
Asymptomatic presentation is now the norm—approximately 75% of identified patients have no symptoms at diagnosis and are discovered through screening or family studies 2
Classic "bronze diabetes" triad (cirrhosis, diabetes, skin hyperpigmentation) occurs in fewer than 10% of genetically susceptible individuals, making it an unreliable diagnostic marker 2
Men present earlier than women, typically in their 40s versus 50s, due to protective menstrual blood loss in premenopausal women 3
Common initial finding: Asymptomatic patient with mildly elevated liver enzymes (ALT/AST), subsequently found to have elevated ferritin and transferrin saturation 4, 3
Normal complete blood count distinguishes hemochromatosis from iron-loading anemias like thalassemia—patients have normal hemoglobin and red cell indices 2
When Symptomatic, Look For:
- Hepatic: Elevated transaminases, hepatomegaly, cirrhosis (major cause of death if untreated) 5, 4
- Endocrine: Diabetes mellitus (6-55% of symptomatic patients), hypogonadism 2
- Cardiac: Cardiomyopathy (less prominent than in thalassemia but still a major cause of death) 2, 5
- Articular: Arthropathy, particularly metacarpophalangeal joints 3
- Dermatologic: Bronze skin pigmentation 3
Diagnostic Evaluation
Screen with transferrin saturation ≥45% and elevated serum ferritin (>200 µg/mL in women, >300 ng/mL in men), then confirm with HFE genetic testing for C282Y and H63D mutations. 1, 2, 3
Step 1: Laboratory Screening
- Transferrin saturation (TS) ≥45% is the primary screening threshold 1, 2
- Serum ferritin >200 µg/mL (women) or >300 ng/mL (men) suggests iron overload 1, 3
- Both markers must be elevated to warrant genetic testing 2
Critical Pitfall: Ferritin is an acute-phase reactant—inflammatory conditions, liver disease, metabolic syndrome, and alcohol use can elevate ferritin without true iron overload 1, 6
Step 2: Genetic Testing
Order HFE genetic testing when both TS and ferritin are elevated. 1, 2
The comprehensive hemochromatosis gene panel should include: 7
- HFE gene (C282Y, H63D, S65C mutations)—accounts for 85-90% of cases 1, 7
- Non-HFE genes (HJV, HAMP, TFR2, SLC40A1)—account for remaining 10-15% 1, 7
Genotype-Phenotype Correlation: 1, 2
- C282Y homozygotes: 85-90% of hereditary hemochromatosis cases
- Incomplete penetrance: Only 58-70% of C282Y homozygotes develop iron overload; fewer than 10% progress to end-organ damage
- C282Y/H63D compound heterozygotes: Account for only 3-5% of cases
- H63D homozygotes or C282Y heterozygotes: Rarely develop clinically significant iron overload 1, 4
Step 3: Assess Disease Stage and Organ Damage
Use the European staging system to categorize patients: 1
- Stage 1: Genetic susceptibility without iron overload
- Stage 2: Phenotypic iron overload without organ damage
- Stage 3: Iron overload with tissue/organ damage
For Stage 2-3 patients, assess hepatic iron and fibrosis: 1, 2
- Liver MRI to quantify hepatic iron concentration (non-invasive preferred method) 2
- Liver biopsy if MRI unavailable or if fibrosis staging needed (historically the gold standard but now less commonly used) 1
Screen for end-organ complications in Stage 3: 5, 3
- Hepatocellular carcinoma screening (ultrasound ± AFP) if cirrhosis present
- Fasting glucose or HbA1c for diabetes
- Echocardiogram if cardiac symptoms
- Joint imaging if arthropathy symptoms
Step 4: Family Screening
Offer genetic testing to all first-degree relatives of confirmed C282Y homozygotes after age 18. 1, 3
Critical Pitfall: Population-based screening is not recommended (USPSTF Grade D)—harms outweigh benefits due to incomplete penetrance and disease labeling 2
Management
Therapeutic phlebotomy is first-line treatment: remove 500 mL blood weekly until ferritin <50 ng/mL, then maintain with phlebotomy every 2-4 months. 2, 8
Phlebotomy Protocol
- Remove 500 mL blood weekly (approximately 250 mg iron per session)
- Continue until ferritin <50 ng/mL and transferrin saturation <50%
- Typically requires 6-24 months depending on iron burden
Maintenance Phase: 2
- Phlebotomy every 2-4 months to maintain ferritin 50-100 ng/mL
- Lifelong therapy required
Monitor: 6
- Check ferritin and transferrin saturation before each phlebotomy initially
- Once stable, monitor every 3-6 months during maintenance
Alternative: Iron Chelation Therapy
Reserve chelation for patients who cannot tolerate phlebotomy due to anemia or cardiac disease. 2, 8
- Deferoxamine (parenteral), deferasirox (oral), or deferiprone (oral) 2
- Less effective and more expensive than phlebotomy for hemochromatosis 2
Dietary Modifications
Avoid iron supplements and limit vitamin C supplementation (>500 mg/day enhances iron absorption), but routine dietary iron restriction is unnecessary. 2, 3
- No need to eliminate red meat or iron-rich foods 2
- Avoid uncooked shellfish (increased Vibrio vulnificus risk in iron overload) 3
- Moderate alcohol consumption or abstain if liver disease present 3
Prognosis and Mortality Prevention
Untreated hemochromatosis causes death from cirrhosis, hepatocellular carcinoma, diabetes, and cardiomyopathy at rates 10-119 fold higher than age-matched controls. 5
Disease Progression Timeline (Untreated): 5
- Ages 0-20: Clinically insignificant iron accumulation (0-5 g)
- Ages 20-40: Iron overload without disease (10-20 g)
- Beyond age 40: Organ damage (>20 g iron) with life-threatening complications
Phlebotomy initiated before cirrhosis develops normalizes life expectancy. 3, 6
Phlebotomy benefits: 3
- Improves cardiac function
- Reduces skin pigmentation
- Lessens risk of liver complications
- Does NOT reverse cirrhosis or reduce hepatocellular carcinoma risk once established
Surveillance for Complications:
Hepatocellular carcinoma screening (ultrasound every 6 months) is mandatory for patients with cirrhosis, even after iron depletion 3
Increased cancer risk: Hepatocellular carcinoma, colorectal cancer, and breast cancer 3
Critical Pitfalls to Avoid
Do not assume all C282Y homozygotes will develop clinical disease—only 58-70% develop iron overload and <10% progress to end-organ damage 2
Do not diagnose hemochromatosis based on elevated ferritin alone—inflammatory conditions, liver disease, and metabolic syndrome commonly elevate ferritin without iron overload 1, 6
Do not screen the general asymptomatic population—genetic screening has a USPSTF Grade D recommendation due to incomplete penetrance and potential harms 2
Do not delay phlebotomy in confirmed Stage 2-3 disease—early treatment before cirrhosis normalizes life expectancy 5, 3
Do not stop hepatocellular carcinoma surveillance after iron depletion in cirrhotic patients—cancer risk remains elevated 3
Do not confuse genetic susceptibility (Stage 1) with clinical disease (Stage 3)—most C282Y homozygotes never develop symptoms 1, 2