Hemochromatosis
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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.

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Hemochromatosis

HEMOCHROMATOSIS

Wendy Graham, MD, CCFP

Academic ½ Day

November 25, 2003


Pathophysiology

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

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

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

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

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

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

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

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

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

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

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

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


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