Gastroenterology Book

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HemochromatosisAka: Bronze diabetes

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  1. Epidemiology: Hereditary Hemochromatosis
    1. Clinically important hereditary hemochromatosis is rare
      1. Only a small subset of homozygotes manifest disease
      2. Cirrhosis develops in 1-2% of C282Y homozygotes
      3. Twice as common in men
    2. Homozygous C282Y Incidence varies across ethnicity
      1. White: 4.4 per 1000
      2. Hispanic: 0.27 per 1000
      3. Black: 0.14 per 1000
      4. Asian American: <0.001 per 1000
    3. References
      1. Whitlock (2006) Ann Intern Med 145:209
  2. Etiologies
    1. Hereditary hemochromatosis
      1. General
        1. Autosomal recessive disease (HFE Gene)
        2. Homozygous HFE Incidence: 1 in 250-300 caucasians
      2. Chromosome 6 mutations responsible
        1. C282Y Mutation (90% of cases)
          1. Tyrosine for cysteine at 282
        2. H63D Mutation (10% of cases)
    2. Secondary iron overload
      1. Chronic Anemia (e.g. Thalassemia major)
      2. Chronic Liver Disease (e.g. Viral Hepatitis)
      3. Iron Supplementation (rare with oral iron)
        1. Multiple transfusions
        2. Parenteral iron dextran
  3. Pathophysiology: Hereditary Hemochromatosis
    1. Inappropriately high intestinal iron absorption
      1. Only a few extra iron milligrams absorbed each day
      2. Iron slowly accumulates over decades
    2. Results in excess body iron stores
      1. Normal body iron stores: 4 grams
        1. Exceeded by age 10 in hereditary hemochromatosis
      2. Tissue injury occurs when body iron 25 grams (age 30)
      3. Cirrhosis when body iron 30-40 grams (age 40)
    3. Factors that provoke expression of disease
      1. Male sex (women may be protected due to Menses)
      2. Alcohol Abuse
      3. Hepatitis C
  4. Classic Presentation: Bronze Diabetes (late stage, rare)
    1. Hyperpigmented skin
    2. Diabetes Mellitus
    3. Cirrhosis
  5. Symptoms (asymptomatic in most cases)
    1. Common symptoms
      1. Fatigue, Lassitude, or weakness
      2. Arthralgias
      3. Impotence
    2. Other symptoms
      1. Weight loss
      2. Abdominal Pain
      3. Hyperpigmented skin
  6. Signs
    1. Brown skin pigmentation
    2. Hepatomegaly
    3. Loss of body hair
    4. Edema
    5. Ascites
    6. Peripheral neuritis
    7. Testicular atrophy
  7. Complications
    1. Cirrhosis
      1. Associated 200 fold risk of Hepatocellular Carcinoma
    2. Diabetes Mellitus
    3. Arthritis (MCP joints) or Pseudogout
    4. Hypogonadism
    5. Hypothyroidism
    6. Cardiomyopathy
    7. Skin Hyperpigmentation (bronze or gray color)
    8. Infection
      1. Vibrio vulnificus
      2. Listeria monocytogenes
      3. Pasteurella pseudotuberculosis
  8. Labs: Screening
    1. Indications for screening
      1. Generalized weakness
      2. Arthralgias (especially involving hand joints)
      3. Hepatomegaly
      4. Aspartate Aminotransferase (AST) elevation
      5. Hypogonadism (Impotence or Infertility)
      6. Skin Hyperpigmentation
      7. Cardiomyopathy or cardiac arrhythmia
      8. Diabetes Mellitus
      9. Family History of hemochromatosis
        1. Risk if sibling with hemochromatosis: 25%
        2. Risk if parent with hemochromatosis: 5%
    2. Iron Saturation (Serum Transferrin Saturation)
      1. Earliest lab change in hereditary hemochromatosis
      2. Confirm elevated value as fasting early morning test
      3. Test Sensitivity approaches 94% in C282Y homozygote
      4. Most accurate when patient is fasting
      5. Abnormal levels suggesting hemochromatosis
        1. Men >50%
        2. Women > 45%
    3. Serum Ferritin
      1. Sensitive but not specific
      2. False positives as an acute phase reactant
      3. Abnormal levels suggesting hemochromatosis
        1. Men >300 ng/ml
        2. Women > 200 ng/ml
  9. Labs: Genetic Testing
    1. Test for C282Y
    2. Indications for testing
      1. First degree relative of C282Y homozygote
      2. Abnormal Serum Ferritin
      3. Abnormal Transferrin Saturation
  10. Diagnosis: Liver biopsy
    1. Indications
      1. Non-hereditary hemochromatosis
      2. Late presentation
        1. Aspartate Aminotransferase (AST) >40 U/L
        2. Ferritin >1000 ng/ml
    2. Findings
      1. Hepatic tissue iron index>2 (tissue iron umoles/age)
      2. Excessive Hemosiderin deposits
      3. Site of iron deposition varies per cause
        1. Hereditary Hemochromatosis: Hepatocytes
        2. Secondary iron overload: Kupffer cells
  11. Evaluation: if hemochromatosis screening positive
    1. Rule-out secondary cause of iron overload (see above)
      1. Alcoholic Liver Disease
      2. Hepatitis C and other Viral Hepatitis
      3. Exogenous iron intake
      4. Thalassemia major and other chronic Anemias
    2. Obtain HFE gene test (consider via consultation)
      1. Homozygous for HFE C282Y mutation
        1. Phlebotomy if liver biopsy indications not met
        2. Liver biopsy indications
          1. Increased Aspartate Aminotransferase (AST)
          2. Serum Ferritin >1000 ng/ml
          3. Hepatomegaly
      2. Findings not consistent with hereditary form
        1. Obtain Liver biopsy (see above)
        2. Phlebotomy for hemochromatosis liver findings
  12. Management
    1. Test ALL first degree relatives
    2. Phlebotomy
      1. Remove 500 ml blood weekly
      2. Endpoint: Iron depletion (reached in 6 to 24 months)
        1. Hemoglobin <13 g/dl (check before each phlebotomy)
        2. Serum Ferritin <50 ng/ml
        3. Transferrin Saturation <50%
      3. Removes excess iron
      4. Prevents progression and complications
    3. Dietary recommendations
      1. Avoid Hepatotoxins including Alcohol
      2. Avoid exogenous iron sources
        1. Avoid iron supplements
        2. Avoid multivitamins with iron
        3. Limit red meat intake
      3. Avoid exposure to Vibrio vulnificus
        1. Avoid raw seafood intake
        2. Do not handle raw seafood
  13. Resources
    1. Iron Disorders Institute
      1. http://www.irondisorders.org
    2. Iron Overload Diseases Association
      1. http://www.ironoverload.org
  14. References
    1. Brandhagen (2002) Am Fam Physician 65(5):853
    2. Felitti (1999) Am J Med Sci 318(4):257
    3. Harrison (2002) Can Fam Physician 48:1326
    4. Powell (1998) Ann Intern Med 129(11):925

Hemochromatosis (C0018995)

Definition (AIR)WHAT: Hemochromatosis: Hemochromatosis: a disorder of iron metabolism characterized by excess deposition of iron in the tissues, especially the liver. It is characterized by pigmentation of the skin, hepatic cirrhosis, decreased carbohydrate tolerance, cardiomyopathy and endocrinopathy (especially hypogonadism). Mainly seen in men over the age of 40 years. It has an associated arthropathy distinguished by involvement of the metacarpophalangeal joints (particularly the second and third), wrists, knees, shoulders, and hips. There is often an associated chondrocalcinosis. WHY: Hemochromatosis is an autosomal recessive disease that produces an arthritis similar to osteoarthritis or pseudogout. HOW: Hemochromatosis is diagnosed by the typical physical and radiographic findings supported by elevated serum iron concentrations and high transferrin saturations. Serum ferritin is also markedly elevated. Confirmation of the diagnosis can be done by demonstrating hepatic iron deposition on liver biopsy.
Definition (MSH)A disorder due to the deposition of hemosiderin in the parenchymal cells, causing tissue damage and dysfunction of the liver, pancreas, heart, and pituitary. Full development of the disease in women is restricted by menstruation, pregnancy, and lower dietary intake of iron. Acquired hemochromatosis may be the result of blood transfusions, excessive dietary iron, or secondary to other disease. Idiopathic or genetic hemochromatosis is an autosomal recessive disorder of metabolism associated with a gene tightly linked to the A locus of the HLA complex on chromosome 6. (From Dorland, 27th ed)
Definition (CSP)condition in which there is a deviation or interruption in the storage of iron in the body.
ConceptsDisease or Syndrome (T047)
ICD9275.0
EnglishBronze diabetes, Bronzed diabetes, diabetes bronze, Haemochromatosis, Hemochromatoses, Hemochromatosis, iron accumulation disorders, Iron storage disease, iron storage disorder
Spanishdiabetes bronceada, hemocromatosis
CreditsDerived from the NIH UMLS (Unified Medical Language System)



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