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Diagnostic Testing
Testing Protocol
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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 (%) |
Interpretation |
Action |
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<16%
|
Low |
Consider iron deficiency. |
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16–45% |
Normal |
Reassure patient that he/she does not have iron overload, return
to usual care.* |
|
>45% |
Elevated |
Proceed with serum ferritin tests and additional workup as
warranted. |
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(EASL, 2000; CDC Expert Panel on Hemochromatosis, 2000 and 2002) |
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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.
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/mL |
Interpretation |
Action |
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<200 for premenopausal females OR
<300 for males
|
Normal |
Recheck every 2 years and reassure patient that he/she does not
have iron overload. |
|
200-300 for post-menopausal female |
Borderline elevation |
Consider other factors in making the recommendation to treat or
observe. |
>200 for premenopausal female OR
>300 for postmenopausal female OR
>300 for male |
Elevated |
In the absence of other causes, removal of iron via phlebotomy
is indicated. Confirmation of hemochromatosis is warranted. |
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(EASL, 2000; Barton JC 2000; CDC Expert Panel on Hemochromatosis,
2000 and 2002) |
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Additional biochemical evidence of iron overload is typically required
before the hemochromatosis diagnosis is made.
Confirmation can be achieved in three ways:
A. 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.
B. 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.
C. 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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