Hereditary Hemochromatosis

Hemochromatosis 1

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 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 2^nd + 3^rd MCP, hips, knees caused by pseudogout (CPDD)
Gonads: hypogonadism -> impotence (erectile dysfunx), amenorrhea, loss of libido
Hypothyroidism
Pan hypopituitarism
Skin: hyperpigmentation (suntan, bronze-like)

Skin pigmentation

↑↑ 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

Hemochromatosis 4

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

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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