Hemochromatosis

Hemochromatosis

 

Hemochromatosis (HH) is a hereditary iron overload disorder caused by excessive absorption and storage of dietary iron.

Epidemiology

  • Incidence – 1/200-400
  • Age – symptoms occur between the ages of 40-60 years
  • Sex –  M>F, 2:1
  • Ethnicity – Caucasian

Inheritance

  • HFE gene mutations are responsible for the most common form of hereditary hemochromatosis and are autosomal recessive
    • Common HFE gene mutations
      • C282Y (severe)
      • H63D (mild)
      • S65C (unknown effect)
    • Allele carrier frequency in Caucasians
      • C282Y (11%)
      • H63D (25%)
      • S65C (1%)
    • Prevalence of HFE HH mutations
      • C282Y homozygosity in 60-90% of cases
      • C282Y/H63D compound heterozygosity in 3-8% of cases
      • H63D homozygosity in 1% of cases
    • Heterozygosity for C282Y, H63D or S65C does not cause HH
    • Penetrance for C282Y homozygosity is high for biochemical abnormalities but may be as low as 2% for characteristic clinical endpoints

Pathophysiology

  • Iron is absorbed by enterocytes in the duodenum and jejunum at a rate of 1-2 mg/d
    • Stored as ferritin with limited excretion  
  • Excess iron causes tissue damage
  • First biochemical manifestation in hemochromatosis is an increase in transferrin saturation due to:
    • Uncontrolled influx of iron from enterocytes and macrophages
    • Inadequate synthesis of hepcidin (the hepatic iron-regulating hormone)

Clinical Presentation

  • Prior to clinical diagnosis – subtle, nonspecific symptoms
    • Fatigue
    • Skin bronzing
    • Loss of libido
    • Arthralgias
  • Hepatic disease
    • Liver function abnormalities (>95% of patients)
    • Hepatomegaly
    • Cirrhosis
    • Hepatocellular carcinoma (200-fold increase compared to cirrhotic patients with chronic viral hepatitis)
  • Cardiac disease
    • Cardiomyopathy (dilated, restrictive or mixed)
    • Arrhythmias (atrial tachycardias most common)
  • Endocrine disease
    • Diabetes – deposition in pancreas (iron impairs insulin sensitivity)
    • Thyroid dysfunction – iron deposition with fibrosis
    • Hypogonadism, infertility – iron deposition in the pituitary; relatively rare  
  • Skeletal disease
    • Arthritis – metacarpophalangeal joint (2nd and 3rd)
  • Dermatologic disease
    • Melanoderma
      • Bronzing, gray or brown discoloration (increased melanin production and iron deposition in skin)
      • Not usually truncal in distribution
      • Relatively rare

Diagnosis

  • Laboratory testing
    • Elevated fasting transferrin saturation
      • Saturation levels >60% in men or >50% in women on 2 or more repeated tests identifies 80% of affecteds
      • Using a saturation cutoff of 45% is more sensitive but also identifies heterozygotes not at risk for developing clinical findings
    • Elevated serum ferritin
      • Increases progressively over time in individuals with untreated HFE-caused HH; an elevated serum ferritin concentration alone is not specific for iron overload as it is an acute phase reactant and may be caused by inflammatory or neoplastic disorders
    • C282Y and H63D genotyping
      • C282Y homozygosity or C282Y/H63D compound heterozygosity
    • Quantitative phlebotomy
      • Can be used to determine the quantity of iron that can be mobilized, thus confirming the diagnosis of HFE-HHC in an individual with iron overload who does not have the diagnostic genotype and is unwilling to undergo liver biopsy; affected persons can mobilize at least 4 grams of iron
  • Liver biopsy
    • Useful to confirm hepatic iron overload, particularly in individuals with hemochromatosis lacking the common HFE mutations; testing should include measurement of hepatic iron concentration, calculation of hepatic iron index and stains to assess pattern and severity of iron overload, as well as stains to determine the presence or absence of hepatitis and fibrosis

Differential diagnosis of iron overload

  • Other inherited forms of  hemochromatosis (non HFE)
    • Ferroprotein disease (SLC4OA1 gene)
    • Transferrin receptor 2 mutation (TFR2)
    • Juvenile hemochromatosis (HJV, HAMP variants)
    • Neonatal hemochromatosis
  • Miscellaneous
    • Iron loading anemias (eg, thalassemia)
    • Transfusion iron overload
    • Aceruloplasminemia
    • Alcoholic siderosis
    • Porphyria cutanea tarda
    • Portocaval shunt
    • African iron overload

Treatment

  • Clearly indicated only when clinical symptoms are present
  • Therapeutic phlebotomy until hematocrit is 75% of baseline
  • Reduce serum ferritin to approximately 50 μg/L as goal

See Also