Hemochromatosis

Diagnostic Algorithm

Clinical Background

Hemochromatosis is an iron overload disorder caused by excess iron in the body. Hereditary hemochromatosis (HH) is an inherited disorder caused by excessive absorption and storage of dietary iron leading to progressive iron accumulation in tissues resulting in organ damage.

Epidemiology

  • Incidence – 1/300 in individuals of Northern European descent; unknown in other ethnic groups
  • Age – peaks in 40s-50s
  • Sex –  M>F, 2:1
  • Ethnicity – Caucasian

Inheritance

  • Autosomal recessive mutations of the HFE gene are responsible for the most common form of HH (HFE-HH)
    • Common HFE mutations
      • C282Y (severe)
      • H63D (mild)
      • S65C (unknown effect)
    • Allele carrier frequency in Caucasians
      • C282Y (11%)
      • H63D (25%)
      • S65C (1%)
    • Prevalence of HFE mutations
      • C282Y homozygosity in 85% of cases
      • C282Y/H63D compound heterozygosity in 5% 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/dL
    • Stored as ferritin with limited excretion  
  • Excess iron generates oxyradicals that cause tissue damage
  • First biochemical manifestation in hemochromatosis is an increase in transferrin saturation due to the following
    • Uncontrolled influx of iron from enterocytes and macrophages
    • Inadequate synthesis of hepcidin (the hepatic iron-regulating hormone)

Clinical Presentation

  • Classic HH – severe disease rarely occurs in people <35 years
  • Prior to clinical diagnosis – subtle, nonspecific symptoms
    • Fatigue, weakness
    • Progressive increase in skin pigmentation
    • Loss of libido
    • Arthralgias
  • Hepatic disease
  • Cardiovascular disease
    • Cardiomyopathy (dilated, restrictive or mixed)
    • Arrhythmias (atrial tachycardias most common)
  • Endocrine disease
  • Skeletal disease
    • Arthritis – metacarpophalangeal joint (second and third)
  • Dermatologic disease
    • Melanoderma
      • Bronzing, gray or brown discoloration (increased melanin production and iron deposition in skin)
      • Not usually truncal in distribution
      • Relatively rare

Treatment

  • Phlebotomy (first and preferred method of ferritin control)
    • 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
  • Iron chelation therapy
    • Useful for patients who cannot have phlebotomy

Diagnosis

Indications for Testing

Laboratory Testing

  •  Fasting transferrin saturation (calculated from serum iron and iron binding capacity)
    • Elevated fasting transferrin saturation
      • Saturation levels >60% in men and >50% in women on 2 or more repeated tests identifies 80% of those affected
      • 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
        • Serum ferritin is an acute phase reactant and elevated concentration alone is not specific for iron overload because increased levels may also be caused by inflammatory or neoplastic disorders
    • C282Y and H63D genotyping
      • C282Y homozygosity or C282Y/H63D or C282/S65C heterozygosity – hemochromatosis confirmed
      • C282Y/wt or H63D homozygosity or H63D/S65C  heterozygosity – monitor STS; consider liver biopsy
    • Quantitative phlebotomy
      • Can be used to determine the quantity of iron that can be mobilized, thus confirming the diagnosis of HFE-HH in an individual with iron overload with no diagnostic genotype and who is unwilling to undergo liver biopsy
        • Affected persons can mobilize at least 4 grams of iron

Histology

  • Liver biopsy – useful to confirm hepatic iron overload, particularly in individuals with hemochromatosis and no 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
        • Index >1.9 suggests hemochromatosis
      • Stains to determine the presence or absence of hepatitis and fibrosis

Imaging Studies

  • Quantitative MRI – may be used as an alternative to liver biopsy
    • Requires expertise with validation

Differential Diagnosis

  • Other inherited forms of  hemochromatosis (non-HFE)
    • Type 2B – juvenile hemochromatosis (HJV, HAMP variants)
    • Type 3 – transferrin receptor 2 mutation (TFR2)
    • Type 4 – ferroportin disease (SLC4OA1)
    • Neonatal hemochromatosis
  • Secondary iron overload
    • Iron loading anemias (eg, thalassemia)
    • Transfusion iron overload
  • Chronic liver disease 
    • Alcoholic siderosis
    • Porphyria cutanea tarda
    • Portocaval shunt
    • Alcoholic liver disease
    • Hepatitis
  • Other
    • Aceruloplasminemia
    • Sub-Saharan African iron overload

Screening

  • U.S. Preventative Services Task Force does not recommend widespread screening
  • American College of Physicians (ACP) recommendation – offer testing to
    • Adult men >25 years of North European ancestry
    • First-degree relatives of patients with disease
  • Screen with fasting transferrin saturation (calculated from serum iron and iron binding capacity) and serum ferritin

Monitoring

  • Depletion phase – hemoglobin/hematocrit, mean corpuscular volume (MCV), serum ferritin until ferritin <50 μg/L
    • If hematocrit drops more than 20% of initial level, next phlebotomy should be postponed
  • Maintenance phase – check ferritin every 6 months to maintain <50 μg/L
  • Do not base frequency of phlebotomy on transferrin levels

Indications for Laboratory Testing

  • Tests generally appear in the order most useful for common clinical situations
  • Click on number for test-specific information in the ARUP Laboratory Test Directory
Test Name and Number Recommended Use Limitations Follow Up
Iron & Iron Binding Capacity 0020420
Method: Spectrophotometry/Calculation

First-line screening for hemochromatosis

Note: Serum transferrin saturation is calculated as part of this test: transferrin saturation (%) = (100 x serum iron)/total iron binding capacity (TIBC)

    
Ferritin 0070065
Method: Chemiluminescent Immunoassay

First-line screening for hemochromatosis

Monitor treatment for hemochromatosis

    
Aspartate Aminotransferase, Serum or Plasma 0020007
Method: Enzymatic

Monitor treatment of hemochromatosis

    
Hemochromatosis (HFE) 3 Mutations 0055656
Method: Polymerase Chain Reaction/Fluorescence Monitoring

Determine the presence of HFE gene mutations C282Y, H63D and S65C in patients with iron overload or a family history of HH

If mutations are present, repeat serum transferrin saturation and ferritin testing

Only the 3 targeted HFE gene mutations will be detected

Rare diagnostic errors may occur due to primer site mutations

Not recommended for asymptomatic patients <18

  
Iron, Liver 0028250
Method: Inductively Coupled Plasma/Mass Spectrometry
 Quantify iron excess in the liver

Hepatic iron distribution may be heterogenous; verification of biopsy quality or testing multiple biopsy cores is preferred

  
Additional Tests Available
 
 
Click the plus sign to expand the table of additional tests.
Test Name and NumberComments
Iron, Plasma or Serum 0020037
Method: Spectrophotometry

Can be used to estimate serum transferrin saturation

Order with serum transferrin
Transferrin, Serum 0050570
Method: Immunoturbidimetric

Can be used to estimate serum transferrin saturation

Order with iron (plasma or serum)

To determine serum transferrin saturation when ordering both serum transferrin and plasma or serum iron tests, the following equation is necessary for interpreting test results:

  • Transferrin saturation (%) = (100 x serum iron)/(1.43 x transferrin)