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Hemochromatosis

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Hemochromatosis, Bronze Diabetes, Hereditary Hemochromatosis, HFE-Associated Hereditary Hemochromatosis, Secondary Hemochromatosis, Hemosiderosis, Bronze Cirrhosis

  • Epidemiology
  • Hereditary Hemochromatosis
  1. Hereditary Hemochromatosis is the most common inherited condition in those of northern european descent
    1. Highest Prevalence is in Irish and Scandinavian descendents
    2. Prevalence 1 per 200-400 in U.S., Europe, Australia
  2. Clinically important Hereditary Hemochromatosis is rare
    1. Only 10% of C282Y Homozygotes manifest disease with end organ damage (remainder are asymptomatic)
    2. Cirrhosis develops in 1-2% of C282Y Homozygotes
    3. Manifestations are twice as common and more severe in men
  3. Homozygous C282Y Prevalence varies across ethnicity (rare in non-white patients)
    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
  4. Age
    1. Typical manifestations of iron overload occur in ages >40 to 50 years
    2. Women present at a later age than men (due to menstrual blood loss up to Menopause)
  5. References
    1. Whitlock (2006) Ann Intern Med 145:209-23 [PubMed]
  • Causes
  • 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. Types: Chromosome 6 mutations responsible
    1. Type 1A: Hereditary Hemochromatosis (90-95% of cases)
      1. HFE Gene C282Y Mutation (Autosomal Recessive)
      2. Missense mutation with Tyrosine for cysteine at 282 on Chromosome 6
      3. Homozygous in 0.64% of white patients (Heterozygous in 10%)
      4. Associated with Arthropathy, Hyperpigmentation, Diabetes Mellitus, Cardiomyopathy, Hypogonadism
      5. In addition to risk of hepatoceullar carcinoma, also increases risk of Colorectal Cancer and Breast Cancer
    2. Type 1B: Compound Hemochromatosis (10% of cases)
      1. HFE Gene H63D Mutation (Autosomal Recessive)
      2. Associated with Arthropathy, Hyperpigmentation, Diabetes Mellitus, Cardiomyopathy, Hypogonadism
      3. Combination of C282Y/H63D occurs in 2% of white patients
    3. Type 1C
      1. HFE Gene S65C Mutation (Autosomal Recessive)
      2. Serum Iron and Ferritin may be increased, but no evidence of iron deposition in tissue
    4. Type 2: Juvenile Hereditary Hemochromatosis (rare)
      1. HJV and HAMP Gene Mutation (Autosomal Recessive)
      2. Onset age <30 years, Hypogonadism, Cardiomyopathy
    5. Type 3
      1. TFR2 Gene Mutation (Autosomal Recessive)
      2. Associated with Arthropathy, Hyperpigmentation, Diabetes Mellitus, Cardiomyopathy, Hypogonadism
      3. Rare (seen in Japan, Brazil)
    6. Type 4
      1. SLC40A1 Gene Mutation (Autosomal Dominant, rare)
      2. Associated with Arthropathy, Anemia, Fatigue and Spleen iron deposition
  • Causes
  • 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 IronDextran
  • Pathophysiology
  • Hereditary Hemochromatosis
  1. Hepcidin is an iron regulatory protein that is deficient in Hemochromatosis
  2. Inappropriately high intestinal iron absorption
    1. Only a few extra iron milligrams absorbed each day
    2. Iron slowly accumulates over decades
    3. Other than menstruation, there are no physiologic mechanisms for iron excretion
  3. 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)
  4. 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
  5. Manifestations
    1. Organ iron deposition
      1. Iron deposits in heart, liver and Pancreas, bones, joints, skin and Pituitary Gland
      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)
  • 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 (esp. increased liver transaminases)
  • Symptoms (asymptomatic in most cases)
  1. Common symptoms
    1. Fatigue or lassitude
    2. Malaise
    3. Generalized weakness
    4. Arthralgias
  2. Endocrine
    1. Erectile Dysfunction
    2. Amenorrhea
    3. Decreased libido
  3. Gastrointestinal
    1. Weight loss
    2. Abdominal Pain (esp. right upper quadrant)
  4. Skin
    1. Hyperpigmented skin
  • Signs
  1. Gastrointestinal and Genitourinary
    1. Ascites
    2. Hepatomegaly
    3. Testicular atrophy
  2. Musculoskeletal
    1. Synovitis at second and third metacarpophalangeal joints
  3. Neurologic
    1. Peripheral Neuropathy
  4. Skin
    1. Brown skin Hyperpigmentation (bronze)
    2. Spider angiomas
    3. Edema
    4. Loss of body hair
  • Complications
  1. Liver Disease
    1. Cirrhosis
    2. Hepatocellular Carcinoma
      1. Associated 20 fold increased lifetime risk of Hepatocellular Carcinoma (4% annual Incidence)
  2. Endocrinopathy
    1. Diabetes Mellitus
    2. Hypogonadism
    3. Hypothyroidism
  3. Arthritis or Pseudogout
    1. MCP Joints (2nd and 3rd)
    2. Synovitis (boggy, tender joints)
    3. Decreased grip strength
  4. Restrictive Cardiomyopathy (reversible if treated before Heart Failure develops)
    1. Diastolic Dysfunction
    2. Atrioventricular Block
    3. Dysrhythmias
  5. Skin Hyperpigmentation (bronze or gray color)
  6. Infection
    1. Vibrio vulnificus
    2. Listeria monocytogenes
    3. Pasteurella pseudotuberculosis
  • 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
      1. Asymptomatic increase in liver transaminases are among the most common presentations
    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. Efficacy
      1. Test Sensitivity approaches 94-98% in C282Y Homozygote
      2. Test Specificity: 99%
    4. Abnormal levels suggesting Hemochromatosis
      1. Men >45-50%
      2. Women >45%
  3. Serum Ferritin
    1. Efficacy
      1. Obtain with Iron Saturation (due to lower Ferritin sensitivity and Specificity)
      2. Test Sensitivity: 66%
      3. Test Specificity: 85%
        1. False Positives as an acute phase reactant
        2. Positive Predictive Value is <18%
    2. Offers prognostic value
      1. Cirrhosis is unlikely when Ferritin <1000 ng/ml
    3. Abnormal Serum Ferritin levels suggesting Hemochromatosis
      1. Men >300 ng/ml
      2. Women > 200 ng/ml
  1. Test for C282Y Mutation (Homozygous)
  2. Indications for testing
    1. First degree relative of C282Y Homozygote
      1. May delay testing until over age 18 years
    2. Increased Serum Ferritin
    3. Increased Transferrin Saturation
      1. Repeat with Serum Ferritin yearly if the Serum Ferritin is normal
  • Imaging
  1. Low T2 Weighted Magnetic Resonance Imaging (MRI)
    1. Hepatic tissue iron index>=2 (tissue iron umoles/age)
      1. Test Sensitivity: 93%
      2. Test Specificity: 100%
  2. Transient Elastography
    1. Noninvasive evaluation for Cirrhosis
  1. Indications
    1. Non-Hereditary Hemochromatosis
    2. Hepatic Fibrosis Staging
    3. Late presentation
      1. Aspartate Aminotransferase (AST) >40 U/L
      2. Ferritin >1000 ng/ml
  2. Findings
    1. Excessive Hemosiderin deposits
    2. Site of iron deposition varies per cause
      1. Hereditary Hemochromatosis: Hepatocytes
      2. Secondary iron overload: Kupffer cells
  • 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
  • Staging
  1. Stage 0: Genetic Predisposition (100% of patients)
  2. Stage 1: Biochemical Findings (75% of patients)
    1. Increased Transferrin Saturation with normal Serum Ferritin
  3. Stage 2: Biochemical Findings (50% of patients)
    1. Increased Transferrin Saturation and increased Serum Ferritin
  4. Stage 3: Clinical Findings (25% of patients)
    1. Arthralgias
    2. Skin Discoloration
    3. Malaise
    4. Fatigue
  5. Stage 4: Clinical Findings (<10% of patients)
    1. Hepatocellular Carcinoma
    2. Cardiomyopathy
    3. Diabetes Mellitus
    4. Hepatic Fibrosis
    5. Cirrhosis
    6. Hypogonadism
  • Management
  • General
  1. Early diagnosis and treatment before end-organ damage results in best outcomes
    1. Test ALL first degree relatives
  2. Dietary recommendations
    1. Avoid Hepatotoxins including Alcohol
    2. Maintain healthy body weight (decrease concurret Fatty Liver)
    3. Encourage regular Physical Activity
    4. Avoid exogenous iron sources
      1. Avoid iron supplements
      2. Avoid Multivitamins with iron
      3. Avoid Vitamin C Supplementation
        1. Limit Vitamin C to 500 mg/day
      4. Limit red meat intake
        1. However unlikely to have significant impact at typically <4 mg Dietary Iron per day
    5. Avoid exposure to Vibrio vulnificus
      1. Avoid raw seafood intake
      2. Do not handle raw seafood
  3. Other measures
    1. Hepatitis A Vaccine
    2. Hepatitis B Vaccine
    3. Consider Proton Pump Inhibitors
      1. Decrease iron absorption
      2. Dirweesh (2020) Eur J Gastroenterol Hepatol +PMID:32769410 [PubMed]
  • Management
  • Phlebotomy
  1. May be performed at some blood donation centers (requires waiver)
  2. Indications
    1. Serum Ferritin >300 ng/ml in men, >200 ng/ml in women
    2. Transferrin Saturation >45%
  3. Initial Protocol
    1. 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
    2. 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 (monitor monthly Serum Ferritin levels)
      3. Transferrin Saturation <50%
  4. Maintenance Protocol (after initial targets are met)
    1. Remove 500 ml blood 3-4 times yearly (one unit of blood or 200-250 ml pRBC)
    2. Monitor Serum Ferritin every 6 months
      1. Target Serum Ferritin 50 ng/ml
  5. 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. Unlikely to effect pre-existing end-organ damage
      1. Diabetes Mellitus
      2. Arthralgias
      3. Cirrhosis
      4. Hypogonadism
  6. Adverse Effects with initial weekly phlebotomy (37-50%)
    1. Phlebitis
    2. Malaise or Fatigue
    3. Hematoma
    4. Delayed Bleeding
    5. Infection
    6. Neurovascular injury
    7. Iron avidity
      1. Results from overcorrection of iron overload
      2. Presents with iron craving and normal Serum Ferritin with increased Iron Saturation
  7. Alternatives
    1. Erythrocytapheresis
      1. Red Blood Cell apheresis that removes Red Blood Cells and returns other cells and blood components
      2. Expensive, limited availability and unclear benefit over standard phlebotomy
    2. Iron Chelation
      1. Indicated only if phlebotomy is contraindicated or refractory
      2. Significant adverse effects
        1. Neurotoxicity
        2. Agranulocytosis including Neutropenia
        3. Acute Kidney Injury
        4. Increased Liver Function Tests
  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
      1. May normalize hepcidin secretion and prevent further liver iron deposition
      2. Bardou-Jacquet Hepatology (2014) 59(3): 839-47 [PubMed]
  1. Obtain RUQ Ultrasound
    1. No Liver Lesion
      1. RUQ Ultrasound every 6-12 months
    2. Liver Lesion <1 cm
      1. RUQ Ultrasound every 3-6 months
      2. Gastroenterology consult
    3. Liver Lesion >1 cm
      1. Evaluate for Hepatocellular Carcinoma
      2. Gastroenterology consult
  2. Other monitoring to consider
    1. Alpha fetoprotein
  • Prognosis
  • Conditions Increasing Mortality
  1. Serum Ferritin >2000 ng/ml at diagnosis
  2. Cirrhosis (5 year survival reduced 50%)
  3. Diabetes Mellitus
    1. Mortality increases 2-6 fold if increased Transferrin Saturation or HFE Genotype (Types 1A, 1B or 1C)
  4. Restrictive Cardiomyopathy with Heart Failure
  5. Hepatocellular Carcinoma
    1. Hereditary Hemochromatosis increases risk 20-200 fold
    2. HIghest risk in Stage 3 liver fibrosis and Cirrhosis (Hepatocellular Carcinoma risk as high as 20%)
    3. Accounts for 45% of Hereditary Hemochromatosis deaths
  6. Other factors that increase mortality
    1. Advanced age
    2. Alcohol consumption
  • Resources
  1. Iron Disorders Institute
    1. http://www.irondisorders.org
  2. Iron Overload Diseases Association
    1. http://www.ironoverload.org