Hemochromatosis refers to a group of conditions characterized by excessive iron accumulation in parenchymal tissues , leading to progressive organ damage due to iron-induced oxidative stress .
It is the most common autosomal recessive disorder in individuals of Northern European descent and a leading cause of severe iron overload .
Etiology and Classification
Hemochromatosis can be hereditary or acquired .
A. Hereditary Hemochromatosis (HH)
Characterized by increased intestinal iron absorption due to genetic mutations, leading to systemic iron overload.
| Type | Gene Involved | Inheritance | Key Features |
|---|---|---|---|
| Type 1 (Classic HH) | HFE (C282Y and H63D mutations) | Autosomal recessive | Most common form |
| Type 2A (Juvenile) | HJV (hemojuvelin) | Autosomal recessive | Presents before age 30 |
| Type 2B | HAMP (hepcidin gene) | Autosomal recessive | Severe early onset |
| Type 3 | TFR2 (transferrin receptor 2) | Autosomal recessive | Less common |
| Type 4 (Ferroportin disease) | SLC40A1 (ferroportin) | Autosomal dominant | May cause macrophage iron accumulation |
B. Acquired Iron Overload
Includes:
- Chronic transfusions (e.g., thalassemia major, sickle cell anemia)
- Sideroblastic anemia
- Chronic liver disease
- Iron-loading anemias
Pathophysiology
- Normal iron stores : ~3.5 g in men; ~2.5 g in women
- Toxicity develops when iron stores exceed ~10 g
- Iron is absorbed via the duodenum , primarily regulated by hepcidin , a liver-produced hormone
- Hepcidin suppresses ferroportin , an iron transporter; mutations in HFE , hemojuvelin , or hepcidin result in reduced hepcidin levels , increasing iron absorption
Organ Damage Mechanism:
- Excess iron catalyzes formation of free hydroxyl radicals (Fenton reaction)
- Oxidative damage to cellular components leads to:
- Liver fibrosis and cirrhosis
- Pancreatic β-cell dysfunction (diabetes mellitus)
- Cardiomyopathy
- Pituitary and gonadal failure
- Joint degeneration
Clinical Features
Most patients are asymptomatic in early stages (≈75%).
Early Non-Specific Symptoms:
- Fatigue (most common, ~74%)
- Arthralgia , especially of hands (44%)
- Impotence or decreased libido (~45%)
- "Iron Fist" : Pain in the 2nd and 3rd MCP joints (knuckles)—a specific early sign
Advanced Organ-Specific Manifestations:
| Organ | Manifestations |
|---|---|
| Liver | Hepatomegaly, elevated LFTs, fibrosis, cirrhosis, ↑HCC risk |
| Pancreas | Diabetes mellitus ("bronze diabetes") |
| Heart | Restrictive or dilated cardiomyopathy, arrhythmias |
| Skin | Hyperpigmentation (bronze or gray skin) |
| Gonads | Hypogonadotropic hypogonadism, infertility |
| Joints | Chronic arthropathy (often confused with RA) |
Diagnosis
Initial Screening:
- Transferrin saturation (TS%) : >45% is suggestive
- Serum ferritin : >300 ng/mL in men; >200 ng/mL in women
(Note: Elevated ferritin also occurs in inflammation and liver disease)
Confirmatory Testing:
- HFE gene testing for C282Y and H63D mutations
- Liver biopsy : if diagnosis is unclear or if assessing fibrosis
- MRI : to assess liver and cardiac iron concentration
Management
1. Phlebotomy (Therapeutic Venesection)
- Mainstay of treatment
- Weekly removal of 500 mL blood until ferritin <50 ng/mL
- Maintenance phlebotomy every 3–4 months thereafter
- Benefits: Prevents or slows cirrhosis, improves fatigue and skin changes
- Limitations: Does not prevent hepatocellular carcinoma (HCC)
2. Iron Chelation Therapy
- Used in patients unable to undergo phlebotomy
- Agents: Deferoxamine , Deferasirox
3. Lifestyle and Dietary Recommendations
- Avoid iron supplements , vitamin C supplements (enhance absorption)
- Moderate alcohol use—excessive alcohol potentiates liver damage
- Avoid uncooked seafood (risk of Vibrio vulnificus infection)
4. Monitoring
- Routine follow-up with serum ferritin , transferrin saturation
- Liver ultrasound or AFP screening for HCC in cirrhotic patients
High-Yield Facts
- Most specific symptom : Pain in the 2nd and 3rd MCP joints ("Iron Fist")
- Best initial test : Transferrin saturation
- Most accurate test : Genetic testing for HFE mutations
- Definitive treatment : Regular phlebotomy
- Risk of HCC : Persists even after iron depletion in cirrhotic patients
Mnemonic: “IRON FIST”
I : Increased iron
R : Restrictive cardiomyopathy
O : Organ damage (pancreas, liver, pituitary)
N : Noticed skin (bronze)
F : Fatigue
I : Impotence
S : Second and third MCP pain
T : Transferrin saturation ↑
