Hemochromatosis¶
Chapter 426 | Part 12: Endocrinology and Metabolism
KEY CLINICAL POINTS¶
- Hemochromatosis is an inherited iron-storage disorder caused primarily by HFE gene mutations (C282Y homozygosity, C282Y/H63D compound heterozygosity), leading to excessive iron absorption and organ damage.
- Key clinical features include hepatomegaly, diabetes mellitus, arthropathy, hypogonadism, and cirrhosis. Iron overload is most common in northern European populations (1 in 10 heterozygotes, 0.3–0.5% homozygotes).
- Diagnosis requires assessing transferrin saturation (>45%) and serum ferritin (>300 µg/L), with genetic testing for C282Y/H63D mutations. Liver biopsy confirms iron overload and fibrosis.
- Treatment involves phlebotomy to remove excess iron (500 mL weekly) and management of complications (e.g., cardiac failure, diabetes). Early intervention prevents cirrhosis and hepatocellular carcinoma.
- Family screening is critical for asymptomatic carriers, as 70% of untreated patients develop symptoms between ages 40–60. Liver transplantation may be required for end-stage disease.
1. DEFINITION & OVERVIEW¶
Hemochromatosis is a genetic iron-storage disorder characterized by excessive iron absorption, leading to parenchymal iron deposition and organ damage. It is most common in northern European populations, with HFE gene mutations accounting for 80–90% of cases. Non-HFE forms include juvenile hemochromatosis (TFR2/SLC40A1 mutations) and rare genetic variants. Secondary iron overload occurs in anemias (e.g., thalassemia) and chronic liver disease.
Table 426-1 Classification of Iron Overload States¶
| Category | Types | Examples |
|---|---|---|
| Hereditary Hemochromatosis | HFE-related (Type 1) | C282Y homozygosity, C282Y/H63D compound heterozygosity |
| Non-HFE-related | Juvenile hemochromatosis (Type 2A/B), TFR2 mutation (Type 3), SLC40A1 mutation (Type 4) | |
| Acquired Iron Overload | Iron-loading anemias | Thalassemia major, Sideroblastic anemia, Chronic hemolytic anemias |
| Transfusional/parenteral iron overload, Dietary iron overload, Chronic liver disease, Hepatitis C, Alcoholic cirrhosis, Porphyria cutanea tarda, Dysmetabolic iron overload syndrome |
1.1 Genetic Basis¶
The HFE gene (chromosome 6p) encodes a protein structurally related to MHC class I. C282Y homozygosity (G>A transition at codon 282) is the most common mutation, found in 85–90% of northern European patients. H63D (A>G at codon 63) is less common and typically asymptomatic. Compound heterozygotes (C282Y/H63D) have mild iron overload.
1.2 Pathophysiology¶
Hepcidin deficiency is central to pathogenesis. Hepcidin regulates iron export via ferroportin; mutations in HFE, TFR2, HJV, or hepcidin itself disrupt this pathway, leading to uncontrolled iron absorption. Excess iron deposits in liver, pancreas, heart, and endocrine glands, causing fibrosis, cirrhosis, and organ failure.
2. EPIDEMIOLOGY¶
HFE-associated hemochromatosis is most common in northern European populations (1 in 10 heterozygotes, 0.3–0.5% homozygotes). Prevalence is higher in Celtic populations (e.g., Ireland, Brittany). ~40% of homozygous men develop iron overload complications; 6% develop cirrhosis. Women show ~10% complication rates. Disease onset typically occurs between ages 40–60, though asymptomatic carriers may be identified via screening.
2.1 Risk Factors¶
Alcohol consumption, dietary iron intake, menstrual blood loss, pregnancy, and blood donation modify disease expression. Secondary iron overload occurs in anemias (e.g., thalassema) and chronic liver disease.
3. ETIOLOGY & PATHOPHYSIOLOGY¶
Primary hemochromatosis is caused by HFE mutations (C282Y, H63D) or other genes (TFR2, HJV, SLC40A1). Secondary iron overload occurs in anemias (e.g., thalassemia) and chronic liver disease. Hepcidin deficiency leads to uncontrolled iron absorption, with iron deposition in parenchymal cells causing fibrosis, cirrhosis, and organ failure. Iron overload in the liver, pancreas, and heart is most clinically significant.
3.1 Hepcidin Role¶
Hepcidin represses ferroportin-mediated iron export. Mutations in HFE, TFR2, HJV, or hepcidin itself disrupt this pathway, leading to increased iron absorption. Excess iron deposits in liver, pancreas, and heart, causing fibrosis and organ failure.
4. CLINICAL FEATURES¶
Early symptoms include fatigue, arthralgia, and skin pigmentation (bronzing). Advanced disease presents with hepatomegaly, diabetes mellitus, cirrhosis, arthropathy, hypogonadism, and cardiac failure. Iron overload is associated with increased risk of hepatocellular carcinoma (30% of cirrhotic patients) and metabolic dysfunction–associated steatohepatitis (MASH).
4.1 Arthropathy¶
25–50% of symptomatic patients develop arthropathy, often involving hands (metacarpophalangeal joints). Features distinguish hemochromatosis from idiopathic arthritis (e.g., chondrocalcinosis).
4.2 Cardiac Involvement¶
Congestive heart failure occurs in ~10% of young adults. Cardiac arrhythmias (e.g., atrial fibrillation) and diffuse myocardial enlargement may occur. Early diagnosis and phlebotomy can reverse cardiac damage.
5. DIFFERENTIAL DIAGNOSIS¶
Differentiate from secondary iron overload (e.g., thalassemia, chronic liver disease), other iron overload syndromes (e.g., aceruloplasminemia), and metabolic disorders (e.g., porphyria cutanea tarda). Assess for alcohol use, blood transfusions, and dietary iron intake.
6. INVESTIGATIONS & DIAGNOSIS¶
Diagnosis requires assessing transferrin saturation (>45%) and serum ferritin (>300 µg/L). Genetic testing for C282Y/H63D mutations is critical. Liver biopsy confirms iron overload and fibrosis. MRI quantifies hepatic iron stores. Exclude secondary causes (e.g., anemias, alcohol use).
Table 426-2 Iron Values in Normal Subjects vs. Hemochromatosis¶
| Parameter | Normal | Symptomatic H emochromatosi s | Asymptomatic Hemochromato sis | Heterozygotes | Alcoholic Liver Disease |
|---|---|---|---|---|---|
| Plasma iron (mmol/L) | 9–27 (50–150) | 32–54 (180–300) | Usually elevated | Elevated or normal | Often elevated |
| Total iron-binding capacity (mmol/L) | 45–66 (250–370) | 36–54 (200–300) | 36–54 (200–300) | Normal | Normal |
| Transferrin saturation (%) | 22–45 | 50–100 | 50–100 | Normal or elevated | 27–60 |
| Serum ferritin (mg/L) | 100–500 | 1000–6000 | 200–500 | Usually <500 | 10–500 |
| Liver iron (mg/g dry wt) | 300–1400 | 6000–18,000 | 2000–4000 | 300–3000 | 300–2000 |
6.1 Laboratory Tests¶
Serum iron, total iron-binding capacity (TIBC), transferrin saturation, and ferritin levels are key. Liver function tests (LFTs) assess hepatic damage. MRI quantifies hepatic iron concentration.
7. MANAGEMENT & TREATMENT¶
Phlebotomy (500 mL weekly) is the primary treatment to remove excess iron. Maintain serum ferritin ≤ 100 µg/L. Chelating agents (deferoxamine, deferasirox, deferiprone) are used in severe anemia/hypoproteinemia. Lifestyle modifications include alcohol abstinence and avoiding iron/vitamin C supplements. Liver transplantation may be required for end-stage disease.
7.1 Phlebotomy Protocol¶
Weekly phlebotomy (500 mL) for 1–2 years until ferritin ≤ 100 µg/L. Maintain intervals based on ferritin levels. One 500 mL unit removes 200–250 mg iron. Avoid overtreatment to prevent iron deficiency.
7.2 Chelation Therapy¶
Deferoxamine (parenteral) removes 10–20 mg iron/day. Deferasirox and deferiprone are oral alternatives but costly and carry side effects. Used when phlebotomy is contraindicated.
8. PROGNOSIS & COMPLICATIONS¶
Early diagnosis and phlebotomy improve survival (5-year survival 89% vs. 33%). Cirrhosis and hepatocellular carcinoma (30% of cirrhotic patients) are major risks. Untreated, 50% of homozygotes develop complications by age 60. Liver transplantation reverses metabolic abnormalities but may not prevent hepatocellular carcinoma if cirrhosis is present at diagnosis.
8.1 Complications¶
Hepatocellular carcinoma, cirrhosis, cardiac failure, diabetes, and hypogonadism are leading causes of mortality. Iron overload in the liver, pancreas, and heart is most clinically significant.
9. SPECIAL CONSIDERATIONS¶
Pregnancy and heavy alcohol use increase vascular risks. Genetic screening is critical for family members (C282Y/H63D testing). Children need not be tested before age 18 unless a parent is affected. Avoid iron/vitamin C supplements. Monitor for hepatocellular carcinoma in cirrhotic patients.
9.1 Family Screening¶
All first-degree relatives of patients should be tested for C282Y/H63D mutations. Asymptomatic carriers with iron overload require phlebotomy. Early detection prevents organ damage and improves outcomes.
10. KEY POINTS & CLINICAL PEARLS¶
- Hemochromatosis is an inherited iron overload disorder caused by HFE mutations (C282Y, H63D) or other genes. 2. Diagnosis requires transferrin saturation (>45%) and serum ferritin (>300 µg/L) with genetic testing. 3. Phlebotomy is the primary treatment to remove excess iron. 4. Early intervention prevents cirrhosis and hepatocellular carcinoma. 5. Family screening is critical for asymptomatic carriers. 6. Avoid alcohol and iron supplements to reduce complications.