Pathophysiology:
- Autosomal recessive
- Clinical manifestations usually appear after age 30-40, earlier in men than women
- Hereditary: mutation is the HFE (C282y or H63D) gene on chromosome 6
- Secondary iron overload: ineffective erythropoiesis: thalassemia or sideroblastic anemia
- Risk factors: male and alcohol -> ↓ phenotypic expression if homozygous C282yY)
- Overtime, excess iron -> hydroxyl free radicals -> fibrosis in the involved organs
- Organs affected: Liver, pancreas, heart, joints, skin, thyroid, gonads, hypothalamus
Clinical presentation:
Clinical triad: skin pigmentation, cirrhosis, and diabetes
- Most: initially asx
- Fatigue, weakness, wt loss
- Liver: cirrhosis (MCC of death) (higher risk of HCC), hepatoma
- Heart: restrictive cardiomyopathy, CHF, arrhythmias
- Pancreas: DM “bronze-diabetes” -> due to iron deposition in pancreas
- Joints: arthritis in 2nd + 3rd MCP, hips, knees caused by pseudogout (CPDD)
- Gonads: hypogonadism -> impotence (erectile dysfunx), amenorrhea, loss of libido
- Hypothyroidism
- Pan hypopituitarism
- Skin: hyperpigmentation (suntan, bronze-like)
Investigations:
- ↑↑ serum iron + serum ferritin (>300 mg\L)
- ↑ transferrin saturation (>45%)
- ↓ total iron-binding capacity (TIBC)
- Gold standard: liver biopsy: determines hepatic iron conc (>71 mmol\g is highly suggestive)
- MRI of the liver + HFe (C282y) gene testing -> spares liver biopsy
- ECG: conduction defects
- Echo: dilated or restrictive cardiomyopathy
Treatment:
- Treatment of choice: repeated phlebotomies (improves survival if started early):
- Induction phase: weekly venesection of 1 unit of blood = 500 mL = 250 mg of iron until serum ferritin = 50 mg\L (may take 2 yrs)
- Maintenance phase: followed by maintenance phlebotomy less frequently (every 1-4 mo) as needed to keep ferritin levels < 50 mg\L
- If phlebotomy is inappropriate (anemia or hypoproteinemia) -> chelating therapy: deferoxamine (removes 10-20 mg of iron\d)
- Treat complications (CHF, DM. hypothyroidism, arthritis)
Liver transplant if advanced\cirrhosis
- Screen very 6 mo for HCC by US
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Types of hereditary hemochromatosis:
- HFE related hemochromatosis (type 1) [AR]: C282Y, H63D, other HFE mutations
- Non-HFE related hemochromatosis:
- Juvenile hemochromatosis (type 2) [AR]: presents early in life (10-30 yr), more rapid and severe course
- Type 2A: hemojuvelin mutations
- Type 2B: hepcidin mutations
- Transferrin receptor 2 hemochromatosis (type 3) [AR]
- Ferroprotien diseases (type 4) [AD]: loss of FPN activity -> accumulation of iron in macrophages -> ↑ serum ferritin, mild anemia (low avalabilty of iron) -> don’t tolerate phlebotomy
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References:
- The Johns Hopkins Internal Medicine Board Review
- Davidson’s Principles and Practice of Medicine
- Step up to medicine
- Master the boards