HEMOCHROMATOSIS Wendy Graham MD CCFP Academic Day November

HEMOCHROMATOSIS Wendy Graham, MD, CCFP Academic ½ Day November 25, 2003

Pathophysiology n n Inborn error in iron metabolism Increased iron absorption from the diet Iron overload Eventual fibrosis and organ failure q q Cirrhosis Cardiomyopathy Diabetes Hypogonadism

Hereditary Hemochromatosis n n n n Autosomal recessive disorder Hemochromatosis gene (HFE) Most common single gene disorder 1/250 – 1/300 white persons is homozygous for the gene mutation 1/10 carrier for mutation 60 -93% with disorder homozygous for the mutation C 282 Y (a cysteine–to-tyrosine substitution) Also C 282 Y/H 63 D compound heterozygosity

Iron Overload n n n Net absorption of 3 -4 mg/day Accumulation of 500 to 1000 mg iron/yr Clinical manifestations often occur after age 40 OR when stores are 15 -40 g

Clinical Manifestations n Influenced by q q q n n Age Sex Dietary iron Alcohol Blood loss in menstruation and pregnancy Unknown factors Alcohol abuse and Hepatitis C accelerate Classic description: cutaneous hyperpigmentation and diabetes in a patient with cirrhosis

Reversible Manifestations n n Heart: cardiomyopathy, conduction disturbances Liver: abdominal pain, elevated LFTs, hepatomegaly (95%) Skin: bronzing (melanin deposition), gray pigmentation (iron deposition) Infection (Vibrio vulnificus, Listeria monocytogenes, Pasteurella pseudotuberculosis)

Irreversible Manisfestations n n n Liver: cirrhosis, hepatocellular carcinoma (most common cause of death) Pituitary gland: gonadotropin insufficiency leading to secondary hypogonadism Pancreas: diabetes mellitus (30 -60%) Thyroid: hypothyroidism Genitalia: primary hypogonadism Joints: arthropathy in MCPs (20 -70%), pseudogout

Women & Hemochromatosis n n Homozygosity is as common as in men Symptomatic disease 10 x less frequent Presentation is later in women Why? q Physiological blood loss in women and higher iron intake in men

Diagnosis n Combination of criteria q q q n n n Clinical Laboratory Pathologic Elevated serum transferrin saturation >45%(earliest abnormality) and an elevated serum ferritin Caution serum ferritin = acute phase reactant Confirmation = ‘gold standard” = liver biopsy (also defines extent of disease)

Treatment n n n Reserved for evidence of iron overload/complications Desferrioxamine (DFO) ineffective Avoid iron supplements, red meat Avoid alcohol and tobacco Avoid handling of raw seafood Trestment = phlebotomy

Phlebotomy n n n Removal of 500 ml of blood Removes 250 mg iron Do weekly until iron depletion q q n Hgb < 120 Ferritin < 50 Transferritin saturation < 50% 2 -3 years may be required to remove >20 g Long term maintenance about once every 3 months

Genetic Testing n n n n Gene on the short arm of chromosome 6 Point mutations C 282 Y and H 63 D HFE gene test in adult family members of an identified case Should replace HLA typing Pretest counselling (insurance, employment…) Gene testing not recommended < 18 years Done on whole bloold sample $200 U. S.

Screening n ? population screening q q n n Looking @ WHO criteria likely cost effective Not yet endorsed because need more information on disease burden and expression of disease Ongoing study in Canada and U. S of 100 000 Currently screen in patients who have: q q q Chronic liver disease Signs and symptoms associated with the disease A family history of iron overload