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Step 1: Transferrin Saturation Test

The transferrin saturation test (TS) is a sensitive and relatively inexpensive biochemical measure of iron overloading.

Transferrin is a blood protein that picks up iron absorbed by the intestines and transports it from one location to another. When iron absorption is abnormally high, transferrin proteins become more saturated with iron. An elevated TS value therefore reflects an increase in iron absorption.

The first step in working up a patient with suspected iron overload is the TS measurement in a fasting blood draw.


Interpreting the results of a fasting transferrin saturation (TS) test:

Transferrin saturation (%)InterpretationAction
<16%LowConsider iron deficiency.
16–45%NormalReassure patient that he/she does not have iron overload, return to usual care.*
>45%ElevatedProceed with serum ferritin tests and additional workup as warranted.
(EASL, 2000; CDC Expert Panel on Hemochromatosis, 2000 and 2002)


When interpreting the results of a fasting transferrin saturation (TS) test, keep in mind that:

  • Several factors can falsely elevate TS values, including the use of vitamin C, dietary supplements containing iron, medicinal iron, and estrogen preparations. Patients should be advised to avoid these products for 24 hours prior to the fasting blood draw. The placebos contained in some oral contraceptive packages may contain iron. These iron containing placebos should be avoided for 24 hours prior to the fasting blood draw.
  • Colds, inflammation, liver disease, and malignancies can falsely lower TS values.
  • Pathologic blood loss or a history of frequent blood donations should be considered reasons for normal iron status in patients who have symptoms consistent with hemochromatosis.

*Note: Patients with nonalcoholic steatohepatitis can exhibit normal TS but may exhibit elevated SF.

Step 2: Serum Ferritin Test

Patients with elevated TS values should proceed with serum ferritin testing and additional workup as warranted.

Ferritin is a protein that stores iron. The body increases serum ferritin production when excess iron is absorbed. Serum ferritin levels therefore reflect the body's iron stores.

Note: Because serum ferritin is also an acute phase reactant affected by cancer and inflammatory or infectious processes, SF values may increase if these underlying conditions are present.


Interpreting serum ferritin test results in patients with elevated fasting TS:

SF levels ng/mLInterpretationAction
<200 for premenopausal females OR

<300 for males
NormalRecheck every 2 years and reassure patient that he/she does not have iron overload.
200-300 for post-menopausal femaleBorderline elevationConsider other factors in making the recommendation to treat or observe.
>200 for premenopausal female OR

>300 for postmenopausal female OR

>300 for male
ElevatedIn the absence of other causes, removal of iron via phlebotomy is indicated. Confirmation of hemochromatosis is warranted.
(EASL, 2000; Barton JC 2000; CDC Expert Panel on Hemochromatosis, 2000 and 2002)

Step 3: Confirming the Hemochromatosis Diagnosis

Additional biochemical evidence of iron overload is typically required before the hemochromatosis diagnosis is made.

Confirmation can be achieved in three ways:

  1. Indirectly by quantitative phlebotomy.

    Most health care providers consider quantitative phlebotomy the confirmatory test of choice.

    The amount of mobilizable iron removed from the body by weekly or biweekly phlebotomy is an accepted criterion for measuring the degree of iron overload and confirming a hemochromatosis diagnosis (EASL, 2000).

    Removal of 3 g or more of mobilizable iron stores before the development of iron-limited erythropoiesis confirms the presence of primary iron overload due to hemochromatosis.

    This typically requires approximately 15 phlebotomies, each removing 500 mL of blood. Each 500 mL of blood extracted removes approximately 200 mg of iron. The goal is to reduce the ferritin level to ~20 ng/mL.
  2. HFE genotyping.

    Genotyping for HFE mutations can provide additional confirmatory evidence that a patient has hereditary hemochromatosis.

    However, this information should be combined with clinical history, examination, and laboratory assessment.

    Identification of any HFE mutation is, by itself, insufficient for diagnosing hereditary hemochromatosis (EASL, 2000). Other heritable forms of hemochromatosis may not be part of the standard genetic screen because some HFE mutations are not yet identified. Other genes involved in iron metabolism may be responsible for iron overloading (EASL, 2000; Pietrangelo A, 1999).

    Therefore, if a patient is negative for an HFE mutation yet has disease symptoms and iron overload, phlebotomy treatment and proper management of the patient’s iron overload are still important.
  3. Directly by liver biopsy.

    Liver biopsy directly assesses the amount of iron per gram of liver tissue.

    Many authorities once considered liver biopsy an essential diagnostic test when hemochromatosis was suspected because of clinical or biochemical abnormalities.

    Today, liver biopsy is used more often as a prognostic, rather than a diagnostic, test (Whittington CA, 2002; Barton JC, 1998).
    • A recent study by Morrison ED et al. (2003) concluded patients with hemochromatosis and serum ferritin levels less than 1000 ng/mL are unlikely to have cirrhosis.
      • Liver biopsy may be unnecessary to determine fibrosis or cirrhosis in patients with serum ferritin level less than 1000 ng/mL, normal serum AST and ALT levels, and without excess alcohol intake or risk factors for other liver disease.
      • Conversely, the authors suggest liver biopsy be considered for patients with serum ferritin levels greater than 1000 ng/mL because of significantly increased risk for advanced fibrosis.

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