Hemochromatosis

Epidemiology
Hereditary Hemochromatosis

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
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
References
1. Whitlock (2006) Ann Intern Med 145:209-23 [PubMed]

Etiologies

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
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

Pathophysiology
Hereditary Hemochromatosis

Inappropriately high intestinal iron absorption
1. Only a few extra iron milligrams absorbed each day
2. Iron slowly accumulates over decades
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)
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
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)

Findings
Presentations

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

Symptoms (asymptomatic in most cases)

Common symptoms
1. Fatigue, Lassitude, or weakness
2. Arthralgias
3. Impotence
Other symptoms
1. Weight loss
2. Abdominal Pain
3. Hyperpigmented skin

Signs

Brown skin pigmentation
Hepatomegaly
Loss of body hair
Edema
Ascites
Peripheral neuritis
Testicular atrophy
Synovitis at second and third metacarpophalangeal joints

Complications

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

Labs
Screening

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%
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%
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

Labs
Genetic Testing

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

Diagnosis
Liver biopsy

Indications
1. Non-hereditary Hemochromatosis
2. Late presentation
  1. Aspartate Aminotransferase (AST) >40 U/L
  2. Ferritin >1000 ng/ml
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

Evaluation (If Hemochromatosis screening positive)

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
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

Management

Test ALL first degree relatives
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
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

Management
Cirrhosis

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)
Refer to gastroenterology for signs of Cirrhosis
1. Surveillance for Hepatocellular Carcinoma
2. Consideration for liver transplantation
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

Prognosis
Conditions increasing mortality

Cirrhosis (5 year survival reduced 50%)
Diabetes Mellitus
Restrictive Cardiomyopathy with Heart Failure

Resources

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

References