II. Epidemiology: Hereditary Hemochromatosis

  1. Clinically important hereditary Hemochromatosis is rare
    1. Only 10% of C282Y Homozygotes manifest disease (remainder are asymptomatic)
    2. Cirrhosis develops in 1-2% of C282Y Homozygotes
    3. Manifestations are twice as common and more severe in men
  2. Homozygous C282Y Prevalence 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 145:209-23 [PubMed]

III. Etiologies

  1. Hereditary Hemochromatosis
    1. General
      1. Autosomal Recessive disease (HFE Gene)
      2. Homozygous HFE Incidence: 1 in 250-300 caucasians
      3. Disrupted iron regulation results in toxic iron accumulation and tissue iron deposition
    2. HFE protein regulates hepcidin (iron regulatory protein)
      1. Hepatocytes secrete hepcidin in response to excess iron
      2. Hepcidin decreases intestinal iron absorption and Macrophage iron release
      3. Hepcidin expression is decreased in hereditary Hemochromatosis, resulting in excess iron levels
    3. Chromosome 6 mutations responsible
      1. C282Y Mutation (90% of cases)
        1. Homozygous in 0.64% of white patients (Heterozygous in 10%)
        2. Missense mutation with Tyrosine for cysteine at 282 on Chromosome 6
      2. H63D Mutation (10% of cases)
        1. Combination of C282Y/H63D occurs in 2% of white patients
      3. S65C Mutation
  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

IV. 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 gender (women may be protected due to Menses)
    2. Hepatitis C
    3. Alcohol Abuse
      1. Cirrhosis risk increases 9 fold for daily Alcohol intake of more than 60g or 4 drinks
  4. Manifestations
    1. Organ iron deposition
      1. Iron deposits in heart, liver and Pancreas, bones and joints
      2. Results in Cardiomyopathy, Cirrhosis, Diabetes Mellitus and Arthritis
    2. Increased oxidative DNA and free radical activity
      1. Hepatocellular Carcinoma risk (20 fold increase risk when Cirrhosis present)
      2. Breast Cancer risk (variable evidence)

V. Findings: Presentations

  1. Classic Presentation - Bronze diabetes (late stage, rare)
    1. Hyperpigmented skin
    2. Diabetes Mellitus
    3. Cirrhosis
  2. Typical presentations
    1. Weakness, lethargy and Arthralgias
    2. Erectile Dysfunction
    3. Liver Function Test abnormalities

VI. 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

VII. Signs

  1. Brown skin pigmentation
  2. Hepatomegaly
  3. Loss of body hair
  4. Edema
  5. Ascites
  6. Peripheral neuritis
  7. Testicular atrophy
  8. Synovitis at second and third metacarpophalangeal joints

VIII. Complications

  1. Cirrhosis
    1. Associated 20 fold increased lifetime risk of Hepatocellular Carcinoma (4% annual Incidence)
  2. Diabetes Mellitus
  3. Arthritis (MCP joints) or Pseudogout
  4. Hypogonadism
  5. Hypothyroidism
  6. Restrictive Cardiomyopathy (reversible if treated before Heart Failure develops)
    1. Diastolic Dysfunction
    2. Atrioventricular Block
    3. Dysrhythmias
  7. Skin Hyperpigmentation (bronze or gray color)
  8. Infection
    1. Vibrio vulnificus
    2. Listeria monocytogenes
    3. Pasteurella pseudotuberculosis

IX. Labs: Screening

  1. Indications for screening
    1. Generalized weakness
    2. Arthralgias (especially involving hand joints, MCP joints 2 and 3)
    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. Previously guidelines recommended Fasting iron tests (or confirmation with Fasting test)
      1. Fasting is no longer required as non-Fasting values are accurate
      2. Serum Iron was thought to be impacted by oral intake and presumed most accurate when Fasting
    3. Test Sensitivity approaches 94% in C282Y Homozygote
    4. Abnormal levels suggesting Hemochromatosis
      1. Men >45-50%
      2. Women >45%
  3. Serum Ferritin
    1. Obtain with Iron Saturation
      1. High Test Sensitivity but poor Specificity
      2. False positives as an acute phase reactant
      3. Positive Predictive Value is <18%
    2. Offers prognostic value
      1. Cirrhosis is unlikely when Ferritin <1000 ng/ml
    3. Abnormal levels suggesting Hemochromatosis
      1. Men >250-300 ng/ml
      2. Women > 200 ng/ml

X. Labs: Genetic Testing

  1. Test for C282Y Mutation (Homozygous)
  2. Indications for testing
    1. First degree relative of C282Y Homozygote
    2. Abnormal Serum Ferritin
    3. Abnormal Transferrin Saturation

XI. 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

XII. 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) or abdominal MRI
      2. Phlebotomy for Hemochromatosis liver findings

XIII. Management

  1. Test ALL first degree relatives
  2. Phlebotomy
    1. May be performed at some blood donation centers (requires waiver)
    2. Remove 500 ml blood weekly (one unit of blood or 200-250 ml pRBC)
      1. Removes 200-250 mg iron
      2. Reduces Serum Ferritin by 30 ng/ml
    3. Goals: Iron depletion (reached in 6 to 24 months)
      1. Hemoglobin: 12.5 to 13 g/dl (check before each phlebotomy)
      2. Serum Ferritin: 50 to 150 ng/ml
      3. Transferrin Saturation <50%
    4. Expected effects of phlebotomy
      1. Removes excess iron and normalizes tissue iron stores
      2. Prevents progression and complications
      3. Fatigue and lethargy resolve
      4. Skin bronzing improves
      5. Cardiac function and Restrictive Cardiomyopathy improve
      6. Hepatomegaly and Liver Function Test abnormalities improve (hepatic fibrosis improves in 30% of cases)
      7. However, Diabetes Mellitus control may be unaffected
    5. Complications
      1. Iron avidity
        1. Results from overcorrection of iron overload
        2. Presents with iron craving and normal Serum Ferritin with increased Iron Saturation
  3. Dietary recommendations
    1. Avoid Hepatotoxins including Alcohol
    2. Avoid exogenous iron sources
      1. Avoid iron supplements
      2. Avoid Multivitamins with iron
      3. Avoid Vitamin C Supplementation
      4. Limit red meat intake
        1. However unlikely to have significant impact at typically <4 mg Dietary Iron per day
    3. Avoid exposure to Vibrio vulnificus
      1. Avoid raw seafood intake
      2. Do not handle raw seafood

XIV. Management: Cirrhosis

  1. Predictors of Cirrhosis development (each factor increases risk in succession up to risk >80%)
    1. Increased Serum Ferritin over 1000 ng/ml
    2. Increased hepatic transaminases (ALT or AST)
    3. Decreased Platelet Count <200k
    4. Excessive alchol use (>60 grams per day or 4 drinks per day)
  2. Refer to gastroenterology for signs of Cirrhosis
    1. Surveillance for Hepatocellular Carcinoma
    2. Consideration for liver transplantation
  3. Surveillance for Hepatocellular Carcinoma
    1. Obtain RUQ Ultrasound
    2. No Liver Lesion
      1. RUQ Ultrasound every 6-12 months
    3. Liver Lesion <1 cm
      1. RUQ Ultrasound every 3-6 months
      2. Gastroenterology consult
    4. Liver Lesion >1 cm
      1. Evaluate for Hepatocellular Carcinoma
      2. Gastroenterology consult

XV. Prognosis: Conditions increasing mortality

XVI. Resources

  1. Iron Disorders Institute
    1. http://www.irondisorders.org
  2. Iron Overload Diseases Association
    1. http://www.ironoverload.org

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Ontology: Hemochromatosis (C0018995)

Definition (MEDLINEPLUS)

Hemochromatosis is an inherited disease in which too much iron builds up in your body. It is one of the most common genetic diseases in the United States.

Iron is a mineral found in many foods. Your body normally absorbs about 10 percent of the iron in the food you eat. If you have hemochromatosis, you absorb more iron than you need. Your body has no natural way to get rid of the extra iron. It stores it in body tissues, especially the liver, heart and pancreas. The extra iron can damage your organs. Without treatment, it can cause your organs to fail.

The most common treatment is to remove some blood, just like when you donate blood. This is called therapeutic phlebotomy. Medicines may also help remove the extra iron. Your doctor might suggest some changes in your diet.

NIH: National Heart, Lung, and Blood Institute

Definition (MSH) A disorder of iron metabolism characterized by a triad of HEMOSIDEROSIS; LIVER CIRRHOSIS; and DIABETES MELLITUS. It is caused by massive iron deposits in parenchymal cells that may develop after a prolonged increase of iron absorption. (Jablonski's Dictionary of Syndromes & Eponymic Diseases, 2d ed)
Definition (NCI_NCI-GLOSS) A condition in which the body takes up and stores more iron than it needs. The extra iron is stored in the liver, heart, and pancreas, which may cause liver disease, heart problems, organ failure, and cancer. It may also cause bronze skin, diabetes, pain in the joints and abdomen, tiredness, and impotence. Hemochromatosis may be inherited, or it may be caused by blood transfusions.
Definition (NCI) An inherited metabolic disorder characterized by iron accumulation in the tissues.
Definition (CSP) condition in which there is a deviation or interruption in the storage of iron in the body.
Concepts Disease or Syndrome (T047)
MSH D006432
ICD10 E83.11 , E83.110, E83.119
SnomedCT 86781004, 154751003, 267504005, 399187006, 399144008
English Diabetes, Bronze, Hemochromatosis, HAEMOCHROMATOSIS, HEMOCHROMATOSIS, iron storage disorder, diabetes bronze, iron accumulation disorders, hemochromatosis (diagnosis), hemochromatosis, Hemochromatosis [Disease/Finding], Hemochromatosis NOS, iron storage disease, bronze diabetes, bronzed diabetes, disorders iron storage, hemochromatoses, bronze diabetes (diagnosis), Hemochromatosis, unspecified, Iron overload disease, Iron Overload Disease, Pigmentary Cirrhosis, Haemochromatoses, Disorders, Iron Storage, Disease, Von Recklenhausen-Applebaum, Hemochromatoses, Iron Storage Disorder, Bronze Diabetes, Recklenhausen-Applebaum Disease, Von, Troisier Hanot Chauffard Syndrome, Von Recklenhausen Applebaum Disease, Troisier-Hanot-Chauffard Syndromes, Storage Disorder, Iron, Cirrhoses, Bronzed, Diseases, Von Recklenhausen-Applebaum, Iron Storage Disorders, Pigmentary Cirrhoses, Syndrome, Troisier-Hanot-Chauffard, Hemochromatose, Troisier-Hanot-Chauffard Syndrome, Haemochromatosis, Von Recklenhausen-Applebaum Diseases, Von Recklenhausen-Applebaum Disease, Bronzed Cirrhoses, Cirrhosis, Pigmentary, Recklenhausen-Applebaum Diseases, Von, Disorder, Iron Storage, Cirrhosis, Bronzed, Storage Disorders, Iron, Bronzed Cirrhosis, Cirrhoses, Pigmentary, Syndromes, Troisier-Hanot-Chauffard, von Recklinghausen-Appelbaum disease, Hematochromatosis, Iron storage disease, Bronzed diabetes, Bronze diabetes (disorder), Bronze diabetes, Hemochromatosis (disorder), Hanot-Chauffard, bronzed; diabetes, diabetes; bronzed, iron; storage disorder, Hemochromatosis, NOS, Iron storage disease, NOS, haemochromatosis
Portuguese HEMOCROMATOSE, Diabetes bronzeada, Hemocromatose, Diabetes Bronzeada
Spanish HEMOCROMATOSIS, Diabetes bronceada, diabetes bronceada (trastorno), diabetes bronceada, hemocromatosis (trastorno), hemocromatosis, Hemocromatosis, Diabetes Bronceada
German HAEMOCHROMATOSE, Haemochromatose, Bronzediabetes, Diabetes, Bronze-, Siderophilie, Hämochromatose
Dutch bronsdiabetes, bronzé; diabetes, diabetes; bronzé, ijzer; stapelingsstoornis, hemochromatose, Bronze diabetes, Chromatose, hemo-, Cirrose, pigment-, Hemochromatose, Pigment-cirrose
Japanese 青銅糖尿病, セイドウトウニョウビョウ, ヘモクロマトーシス, ヘモクロマトーシス, 血色症, ブロンズ糖尿病, 血色素沈着症, 血色素症, 青銅色糖尿病, 糖尿病-青銅色
Swedish Bronsdiabetes
Czech hemochromatóza, Bronzový diabetes, Hemochromatóza, bronzový diabetes
Finnish Hemokromatoosi
Italian Diabete bronzino, Emocromatosi
Russian GEMOKHROMATOZ, DIABET BRONZOVYI, TSIRROZ PIGMENTNYI, SIDEROFILIIA, GEMOMELANOZ, ГЕМОМЕЛАНОЗ, ГЕМОХРОМАТОЗ, ДИАБЕТ БРОНЗОВЫЙ, СИДЕРОФИЛИЯ, ЦИРРОЗ ПИГМЕНТНЫЙ
French HEMOCHROMATOSE, Diabète bronzé, Hémochromatose
Croatian HEMOKROMATOZA
Polish Hemochromatoza, Cukrzyca brązowa
Hungarian Haemochromatosis, Bronzdiabetes
Norwegian Bronsediabetes, Hemokromatose, Haemochromatosis