HEMOCHROMATOSIS

Wendy Graham, MD, CCFP

Academic ½ Day

November 25, 2003

Pathophysiology

Inborn error in iron metabolism Increased iron absorption from the diet Iron overload Eventual fibrosis and organ failure

Cirrhosis Cardiomyopathy Diabetes Hypogonadism

Hereditary Hemochromatosis

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

C282Y (a cysteine–to-tyrosine substitution) Also C282Y/H63D compound heterozygosity

Iron Overload

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

Influenced by 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

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

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

Homozygosity is as common as in men Symptomatic disease 10x less frequent Presentation is later in women Why?

Physiological blood loss in women and higher iron intake in men

Diagnosis

Combination of criteria 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

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

Removal of 500 ml of blood Removes 250 mg iron Do weekly until iron depletion

Hgb < 120 Ferritin < 50 Transferritin saturation < 50% 2-3 years may be required to remove >20g

Long term maintenance about once every 3 months

Genetic Testing

Gene on the short arm of chromosome 6 Point mutations C282Y and H63D 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

?population screening 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:

Chronic liver disease Signs and symptoms associated with the disease A family history of iron overload