Hereditary Hemochromatosis: When Your Body Absorbs Too Much Iron
The HFE gene, iron overload, and why early detection could save your liver
By GenomeInsight Science Team
Key Takeaways
- Hereditary hemochromatosis (C282Y homozygous) affects ~1 in 200 Northern Europeans — it's the most common genetic disorder in this population
- Iron accumulates silently over decades — symptoms like fatigue and joint pain are often attributed to other causes
- Organ damage (liver cirrhosis, diabetes, cardiomyopathy) is largely preventable if caught before symptoms develop
- Treatment is simple and effective: regular phlebotomy (blood removal) to keep ferritin below 50-100 ng/mL
- If your genotype is C282Y/C282Y, get serum ferritin and transferrin saturation checked as soon as possible
- Screen first-degree relatives — siblings have a 25% chance of carrying the same genotype
What Is Hereditary Hemochromatosis?
Hereditary hemochromatosis (HH) is the most common genetic disorder in people of Northern European descent. It causes your body to absorb too much iron from the food you eat. Since the human body has no active mechanism to excrete excess iron, it accumulates over decades in organs — primarily the liver, heart, pancreas, and joints — causing progressive damage.
The most common form (Type 1, or HFE-related hemochromatosis) is caused by variants in the HFE gene on chromosome 6. HFE protein normally helps regulate iron absorption by interacting with the transferrin receptor and the hormone hepcidin — the master regulator of iron homeostasis.
When HFE is dysfunctional, hepcidin production is reduced. Hepcidin normally acts as a brake on iron absorption: low hepcidin means the brake is released, and iron floods in through the intestinal lining unchecked.
The two key variants:
- •C282Y (rs1800562): A missense mutation (cysteine → tyrosine at position 282) that severely disrupts HFE protein folding. This is the "major" hemochromatosis variant.
- •H63D (rs1799945): A milder variant (histidine → aspartic acid at position 63) that modestly reduces HFE function. Much less likely to cause clinical iron overload on its own.
Genotypes, Prevalence, and Risk
Hereditary hemochromatosis follows autosomal recessive inheritance — you need two copies of pathogenic variants to be at significant risk. However, the clinical expression (penetrance) is highly variable.
| Genotype | Frequency (Northern European) | Iron Overload Risk | Clinical Disease Risk |
|---|---|---|---|
| C282Y/C282Y (homozygous) | 1 in 200 (~0.5%) | ~60-80% develop elevated ferritin | ~25-30% develop clinical disease |
| C282Y/H63D (compound heterozygous) | ~2% (1 in 50) | ~5-10% develop mild iron elevation | <5% develop clinical disease |
| H63D/H63D (homozygous) | ~2% (1 in 50) | ~1-2% mild iron elevation | Very rarely causes clinical disease |
| C282Y/WT (carrier) | ~10% (1 in 10) | Generally normal iron | Not at risk for HH |
| H63D/WT (carrier) | ~20% (1 in 5) | Normal iron | Not at risk for HH |
Key point: C282Y homozygosity is the primary concern. It's remarkably common — roughly 1 in 200 people of Northern European descent are C282Y homozygous. This makes hemochromatosis arguably the most common genetic disorder in this population, yet it remains widely underdiagnosed.
Sex differences: Men develop clinical disease 5-10× more frequently than women. Menstruation, pregnancy, and lactation all remove iron from the body, providing natural protection. Women typically present later (post-menopause) and with milder disease.
Variable penetrance: Not all C282Y homozygotes develop clinical disease. Penetrance estimates range from 25-60% depending on the study and the definition of "clinical disease." Modifying factors include sex, diet, alcohol use, blood donation history, and likely other genetic modifiers.
Symptoms: The Silent Accumulation
Hemochromatosis is often called the "silent killer" because iron accumulates gradually over 20-40 years before symptoms appear. Early symptoms are maddeningly nonspecific — often attributed to aging, stress, or other conditions:
Early symptoms (iron overload beginning):
- •Chronic fatigue and weakness — the most common complaint, present in >80% of symptomatic patients
- •Joint pain — especially the second and third metacarpophalangeal joints (knuckle joints), causing a characteristic handshake pain
- •Abdominal pain — vague right upper quadrant discomfort from liver enlargement
- •Loss of libido / erectile dysfunction — from iron deposition in the pituitary gland
Advanced symptoms (organ damage):
- •Liver disease — elevated liver enzymes → fibrosis → cirrhosis (25-30% of untreated symptomatic patients). Cirrhotic patients have ~200× increased risk of hepatocellular carcinoma
- •Bronze diabetes — iron deposits damage pancreatic beta cells, causing diabetes (present in ~50% of advanced cases). The combination of diabetes + skin bronzing gave hemochromatosis its classic name "bronze diabetes"
- •Cardiomyopathy — iron-loaded heart muscle leads to heart failure and arrhythmias, the leading cause of death in younger patients with severe hemochromatosis
- •Skin bronzing — a grayish-bronze skin discoloration from iron deposition in the skin
- •Hypothyroidism — iron deposition in the thyroid gland
- •Hypogonadism — testicular atrophy and infertility from pituitary iron deposition
The critical insight: Most organ damage is reversible if caught early (before cirrhosis and diabetes develop). Joint pain, unfortunately, often persists even after iron normalization. This makes early detection — ideally before any symptoms — the most important factor in outcomes.
Treatment: Surprisingly Simple
The treatment for hereditary hemochromatosis is elegantly straightforward and has been used for centuries: phlebotomy — therapeutic blood removal. It's the same as donating blood, but done more frequently and prescribed by your doctor.
Treatment protocol:
Phase 1: Iron Depletion (weekly phlebotomy)
- •Remove 1 unit of blood (500 mL, containing ~250 mg iron) every 1-2 weeks
- •Continue until serum ferritin reaches 50-100 ng/mL (target <50 ng/mL preferred by many specialists)
- •Duration depends on iron burden: typically 6-18 months for moderately loaded patients, potentially 1-2+ years for severely loaded patients
- •Each session removes about the same amount of iron your body would absorb over 1-2 months on a normal diet
Phase 2: Maintenance (periodic phlebotomy)
- •Once target ferritin is achieved, continue phlebotomy every 2-4 months lifelong
- •Monitor ferritin every 3-6 months to maintain <50-100 ng/mL
- •Many patients can donate blood through standard blood banks (your blood is perfectly safe for transfusion)
Dietary considerations:
- •Avoid iron supplements and iron-fortified cereals
- •Limit red meat consumption (heme iron is most readily absorbed)
- •Vitamin C increases iron absorption — avoid large-dose supplements with meals (but dietary vitamin C in food is fine)
- •Alcohol accelerates liver damage in iron-overloaded individuals — limit or avoid
- •Tea and coffee with meals reduce iron absorption (can be mildly helpful)
- •Cooking in cast iron cookware can add significant dietary iron — consider alternatives
When phlebotomy isn't possible: For patients who can't tolerate phlebotomy (anemia, severe heart disease), iron chelation therapy (deferoxamine, deferasirox) can be used to remove iron through the kidneys, though this is much less common for HFE hemochromatosis.
When to Get Your Ferritin Checked
If your GenomeInsight report shows C282Y homozygosity or compound heterozygosity (C282Y/H63D), the single most important next step is a simple blood test:
Essential initial blood tests:
- •Serum ferritin — measures iron stored in your body. Normal: 12-300 ng/mL (men), 12-150 ng/mL (women). In hemochromatosis: can reach 1,000-10,000+ ng/mL
- •Transferrin saturation (TSAT) — the percentage of transferrin (iron transport protein) that's loaded with iron. Normal: 20-45%. In hemochromatosis: often >45%, frequently >60%
When to test:
✅ Immediately if you're C282Y homozygous — regardless of symptoms. Early detection prevents all organ damage.
✅ Immediately if you're C282Y/H63D compound heterozygous — lower risk but still worth screening.
✅ If you have unexplained fatigue, joint pain (especially knuckles), elevated liver enzymes, or erectile dysfunction — even with lower-risk genotypes.
✅ Male C282Y homozygotes should begin monitoring by age 20-25. Iron overload typically begins developing in the 20s-30s in men.
✅ Female C282Y homozygotes should begin monitoring by age 30-35, or earlier if not menstruating regularly. Post-menopausal women should be especially vigilant.
Monitoring schedule (if genetically at risk):
- •If initial ferritin and TSAT are normal: recheck annually
- •If ferritin is 200-500 ng/mL: check every 3-6 months, consider referral to hematologist or hepatologist
- •If ferritin >500 ng/mL or TSAT >60%: referral to specialist, begin treatment, consider liver imaging/biopsy
Family screening: If you're C282Y homozygous, all first-degree relatives (siblings, parents, children) should be tested for HFE variants. Siblings have a 25% chance of being homozygous. Early identification in family members prevents all disease complications.
Medical Disclaimer: This article is for educational purposes only and does not constitute medical advice. Genetic information should be interpreted in the context of your full medical history by a qualified healthcare provider. Never change medications without consulting your doctor.
References
- [1]Bacon BR et al. (2011). Diagnosis and management of hemochromatosis: 2011 practice guideline by AASLD. Hepatology. 54(1):328-43.PubMed
- [2]Allen KJ et al. (2008). Iron-overload-related disease in HFE hereditary hemochromatosis. N Engl J Med. 358(3):221-30.PubMed
- [3]Feder JN et al. (1996). A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nat Genet. 13(4):399-408.PubMed
- [4]Powell LW et al. (2016). Haemochromatosis. Lancet. 388(10045):706-16.PubMed
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