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REF: ACP-PIER 2008 |  hemochromatosis2006   |  
  • Serum iron (transferrin) saturation >45-50%, or ferritin >200-250 ug/ml in female or >300-350 ug/ml in male

  • Liver biopsy

  • Genetic testing: C282Y/C282Y homozygous or C282Y/H63D compound heterozygous HFE genotypes to be diagnostic of hemochromatosis


  • Phlebotomies

  • Consider deferoxamine (parenteral iron chelator)

  • EXJADE® (deferasirox), an iron chelating agent indicated for the treatment of chronic iron overload due to blood transfusions (transfusional hemosiderosis) in patients 2 years of age and older.    
    EXJADE is available as 125-mg, 250-mg, and 500-mg tablets for oral suspension.           9-2006

Hereditary hemochromatosis is a genetic disorder of iron metabolism (HFE gene C282Y mutation genetic screening) resulting in excessive iron overload and is associated with clinically significant morbid and fatal complications related to tissue iron deposition.  The morbid complications of hereditary hemochromatosis are the result of tissue deposition, and they develop late in its course. They include arthritis, diabetes mellitus, congestive heart failure, cirrhosis, and hepatocellular carcinoma.  Liver iron deposition with cirrhosis is associated with reduced survival.

The estimated prevalence of hereditary hemochromatosis is 1 in 200 persons to 1 in 250 persons in the general population (The prevalence of hemochromatosis is much lower in nonwhite populations), making hereditary hemochromatosis one of the most common genetic disorders.  Using strict criteria, we found that the prevalence of hereditary hemochromatosis within a primary care setting was 0.18% to 0.59% (1 in 169 patients screened to 1 in 556 patients screened).

In a prospective study of biochemical screening for hemochromatosis, random transferrin saturation >62% represented a false-positive value 81% of the time when compared to fasting transferrin saturation levels.

Recognize elements of the medical history that suggest manifestations of hemochromatosis.

Ask about:

  • Fatigue
  • Arthralgias
  • Abdominal pain
  • Impotence
  • Symptoms of chronic liver disease
  • Cardiac arrhythmia, Congestive heart failure
  • Diabetes mellitus
  • History of previous phlebotomy


  • Sibling with hemochromatosis
    Autosomal recessive disorder
  • Multi-organ involvement with liver disease, cardiac disease, diabetes, hypothyroidism, arthritis
    Ask about fatigue, abdominal pain, palpitations, dyspnea, polyuria, arthralgias
  • >4 g iron removed by quantitative phlebotomy
    Each unit of blood contains approximately 250 mg iron


Physical Exam:
  • Skin hyperpigmentation  - Usually a late finding ; Skin stigmata of chronic liver disease, e.g., spider nevi, palmar erythema, jaundice (in cirrhosis)
  • Signs of liver cirrhosis - Ascites, splenomegaly, asterixis
  • Signs of cardiac arrhythmia or congestive heart failure - Irregular heart beat, cardiac gallops, jugular venous distension, pulmonary rales
  • Testicular atrophy - Typically secondary hypogonadism from iron deposition in pituitary
  • Degenerative joint changes, especially of the metacarpophalangeal joints; Other joints involved may include hips, knees, feet, and shoulders

Laboratory Tests:
  • Transferrin saturation >45-50% (specificity 94%, specificity 94%) and ferritin >200 ng/mL in women and >300 ug/L in men - sensitivity 50%, specificity 87%)
    * Ferritin can be falsely elevated as an acute phase reactant.
  • Liver function tests, blood glucose and HgbA1c, TSH, Testosterone, EKG
  • C282Y/C282Y homozygous genotype if transferrin saturation >

Obtain genetic testing for hemochromatosis in patients with elevated fasting serum transferrin saturation.

  • Test for HFE genotype in patients with a fasting serum transferrin saturation greater than 45%.
  • In patients with elevated serum transferrin saturation and ferritin, consider C282Y/C282Y homozygous or C282Y/H63D compound heterozygous HFE genotypes to be diagnostic of hemochromatosis.
  • Recognize that a nondiagnostic genotype does not rule out a diagnosis of hemochromatosis.
  • Consider a liver biopsy for patients with elevated serum transferrin saturation and ferritin who lack a diagnostic HFE genotype.
  • Note that C282Y/C282Y homozygous and C282Y/H63D compound heterozygous genotypes do not necessarily imply phenotypic hemochromatosis and must be interpreted in the context of serum iron studies, hepatic iron quantitation, or both.


Exclude causes of secondary iron overload in the evaluation of a patient with suspected hemochromatosis.

In patients being evaluated for iron overload:

  • Ask about history of blood transfusions
  • Ask about parenteral or oral iron supplementation
  • Ask about a personal or family history of hematologic abnormalities
  • Ask about alcohol intake
  • Check a CBC with peripheral smear
  • Check hepatitis B surface antigen and hepatitis C antibody in patients with elevated serum aminotransferases or risk factors for viral hepatitis
  • Assess risk factors for nonalcoholic steatohepatitis, such as diabetes mellitus, hypertriglyceridemia, and obesity

Management of Hemachomatosis

Non-drug Therapy

  • Begin a course of phlebotomy treatment  - weekly or biweekly “induction phlebotomy” of one unit whole blood to deplete iron stores in patients with hemochromatosis.
  • Check hemoglobin or spun hematocrit before each phlebotomy session.
  • When the equivalent of hemoglobin <13 g/dL in men or <11.5 g/dL in women is reached, stop phlebotomy and check serum ferritin; the target serum ferritin is <50 ng/mL.
  • After induction of iron depletion, check serum ferritin approximately every 3 months, with phlebotomy as needed to maintain serum ferritin <50 ng/mL for life (“maintenance phlebotomy”).
  • Recognize that there is no clinical utility for ongoing measurements of serum transferrin saturation in patients undergoing phlebotomy for hemochromatosis.

Drug Therapy - Deferoxamine 20 -50 mg/kg.d subc or IV  only in patients who cannot tolerate phlebotomy therapy, such as those with significant anemia.

  • Consider deferoxamine, a parenteral iron chelator, to lower body iron levels in selected patients with hemochromatosis.
  • Not as effective as phlebotomy in removing iron. Use only in patients who cannot tolerate phlebotomy.
  • In patients with life-threatening complications such as severe heart failure or arrhythmias, consider a combination of deferoxamine and phlebotomy to maximize the rate of iron reduction.


Differential Diagnosis of Hemochromatosis (Secondary Causes of Iron Overload)
  1. Secondary iron overload
    Parenteral or transfusional iron loading
  2. Ineffective erythropoiesis, increased red cell turnover, or both
    Thalassemia major, sideroblastic anemia, hereditary spherocytosis
    Patients may have excessive intestinal iron absorption as well as a history of frequent blood transfusions
  3. Chronic viral hepatitis - Chronic hepatitis B or C
    Chronic viral hepatitis is often associated with mild to moderate iron overload
  4. Steatohepatitis
    Alcoholic liver disease and nonalcoholic steatohepatitis
    Steatohepatitis is often associated with mild to moderate iron overload
  5. Previous Portal Caval Shunting


Screening Primary Care Patients for Hereditary Hemochromatosis with Transferrin Saturation and Serum Ferritin Level
4 October 2005 | Volume 143 Issue 7 | Pages 522-536