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Accurate assessment of body iron burden is necessary, not only to diagnose iron overload but also to effectively manage therapy. In addition, given the late onset of clinical symptoms after substantial organ damage has already occurred, it is important that an accurate, non-invasive, readily available screening test for iron overload available.

A variety of tests are available to assess iron burden and its functional effects. Laboratory tests such as serum ferritin can be used for both screening and monitoring, especially when performed repeatedly over a period of time. Imaging studies such as magnetic resonance imaging (MRI) can detect hepatic and cardiac iron deposition, and may be useful in the assessment of hepatic iron burden. For patients with diagnosed or strongly suspected iron overload, liver biopsy remains the most quantitatively accurate, sensitive, and specific test for liver iron concentration. The use of two or more tests will usually be required to define the patient's iron burden and distribution in tissues (1).

Diagnosing iron overload in HH

The diagnosis of iron overload secondary to hereditary hemochromatosis (HH), can be made using several modalities:

• Laboratory tests: Serum ferritin >200 mcg/L in premenopausal women and 300 mcg/L in men and postmenopausal women combined with serum transferrin saturation (fasting value >50% in women and >60% in men) is a sensitive marker for excess iron (2,3). In confirmed HH serum ferritin >1000 mcg/L is an accurate predictor of the degree of hepatic fibrosis (cirrhosis) (4).
• Imaging studies: MRI may detect hepatic iron stores (5).
• Biopsy:Liver biopsy was at one time the gold standard for assessment of iron overload. However, among patients with hereditary iron overload it now mainly serves in the evaluation of cirrhosis.

Diagnosing transfusional iron overload

Because transfusions may lead to rapid iron accumulation, monitoring a patient's number of transfused blood units, serum ferritin levels, and/or liver iron concentrations can play an essential role in the management of iron overload (6,7).

Overview of iron overload tests

Method	Advantages	Disadvantages
Serum ferritin	Non-invasive Can be performed frequently, allowing regular monitoring Inexpensive (commercial kits available) Positive correlation with morbidity and mortality Allows longitudinal follow-up	Indirect measurement of iron burden Levels are influenced by many factors, including nutrition, infection, and inflammation Serial measurement and/or combination with other indicators is required
Liver biopsy	Validated reference standard Direct measurement that provides accurate information Allows non-heme storage iron to be measured Allows accurate assessment of disease progression Positive correlation with morbidity and mortality	Invasive, painful, potentially serious complications Requires skilled professional personnel and standardized laboratory procedures Small biopsy may not be representative of tissue iron distribution Spurious measurements may occur as a result of certain hepatic diseases Poorly correlated with cardiac iron Difficult follow-up
MRI	Non-invasive Able to analyze whole organ Pathologic status of the liver can be assessed in parallel Allows longitudinal follow-up of patients	Requires imager with a dedicated imaging method Indirect measurement of LIC
SQUID	Non-invasive Measurement may be repeated frequently Linear correlation with LIC assessed by biopsy	Limited availability High cost Indirect measurement of LIC Complex procedure requiring trained personnel Underestimates LIC versus biopsy

Serum ferritin

The most commonly used test for iron overload is serum ferritin. Inexpensive, noninvasive, and widely available, it provides reliable estimates of iron burden when performed on a serial basis. Serum ferritin levels consistently >1000 mcg/L are suggestive of iron overload (6,8), and in the absence of appropriate therapy are associated with adverse clinical outcomes in both transfusional iron overload(9,10) and hereditary hemochromatosis (11).

More about serum ferritin testing for iron overload

Liver biopsy

Liver biopsy provides direct information about the structure, function, and extent of iron deposition within the liver, and may also have prognostic value.

More about liver biopsy testing for iron overload

Magnetic resonance imaging

MRI provides a non-invasive alternative to liver biopsy, and may be more accurate than biopsy in patients with heterogeneous liver iron deposition (such as those with cirrhosis) since it measures iron in the whole organ.

More about MRI testing for iron overload

Cardiac biopsy

A cardiac biopsy enables the histologic assessment of heart tissue changes and iron loading in patients with iron overload. However, like the liver, the distribution of stored iron in the heart is not homogeneous, so the test may not provide a true estimate of iron content, particularly in the early stages of disease (12). In addition, the invasive approach can result in serious complications (13), meaning that the use of cardiac biopsy is primarily restricted to the research rather than the clinical setting. Other methods available for assessing cardiac iron levels include MRI and the determination of cardiac function — using echocardiography and multiple-gated acquisition scanning for example.

Quantitative phlebotomy

Although not feasible for transfusion-dependent patients, quantitative phlebotomy is the reference method for assessing iron storage in patients with hereditary hemochromatosis (14). It cannot be used in anemic patients, however, and its cost, inconvenience, and side effects limit its use.

LVEF imaging studies

Accurate assessments of left ventricular ejection fraction (LVEF) can be provided noninvasively by resting or stress echocardiography (15,16) or radionuclide ventriculography (17,18). These studies may be useful in the diagnosis of early iron-induced cardiac disease, since diastolic dysfunction has been shown to be of prognostic value in the development of symptomatic iron-induced cardiac disease (19).