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IRON OVERLOAD LABORATORY TESTS

Laboratory tests are the least expensive, most widely available methods for assessing iron overload. Nevertheless, isolated single measurements cannot reliably diagnose iron overload since they only provide a rough estimate and can be influenced by various factors. In order to achieve statistically significant results serial measurements must be carried out. Laboratory tests can, however, provide information that may be used to guide the use of biopsies and monitor therapy.

SERUM FERRITIN

The most commonly used test for estimating iron burden is the measurement of serum ferritin levels, which has a ‘polar’ predictive value:

•  Low serum ferritin levels indicate normal pathology; <300 ng/mL is within the limit of normal for a male, while <150 ng/mL is the normal limit for a menstruating female.

•  High serum ferritin levels indicate high body iron burden and are therefore associated with an increased risk of disease. Mild–moderate iron overload is indicated by serum ferritin levels 300–2500 ng/mL and levels >2500 ng/mL have been correlated with substantially worsened cardiac prognosis when maintained over a long period of time [11].

Measured over time, the observed trends in serum ferritin provide a reliable marker of body iron burden. Serial measurements of this marker are therefore recommended.

The limitation of serum ferritin is that its interpretation may be complicated by a number of factors, including inflammation [12, 13], ascorbate deficiency [14], hepatic damage, hemolysis and ineffective erythropoiesis, all of which are common in severe chronic anemia. In addition, the predictive value of serum ferritin for major complications of iron overload varies according to the type and severity of underlying anemia and the mechanism of iron loading.

EXPLORATORY TESTS

Various laboratory tests have been developed to address the limitations of some markers of iron overload, although these tests are not as widely used in clinical practice as the ones already discussed:

• Serum ferritin iron has been introduced to address some of the limitations of serum ferritin. It has been hypothesized that it may be less susceptible to confounding factors such as inflammation [15], but thus far its clinical value is limited.

• Serum transferrin saturation measures the proportion of transferrin saturated with iron, and might therefore be expected to correlate with iron burden. Its diagnostic predictive value is greater than that of serum ferritin in patients with hereditary iron overload; for these patients, serum transferrin saturation of 16–60% is suggestive of iron overload [16]. However, the test has not proven useful in iron estimation for patients with transfusional iron overload [17].

• Serum transferrin receptor concentration has been used to detect both iron deficiency and excess iron. In the presence of iron overload, cells downregulate transferrin receptor expression, and therefore serum transferrin receptor concentration would be expected to be decreased [18].

• Labile plasma iron (LPI) quantifies the oxidative activity of plasma iron. One approach to measuring this is to compare the reactive radicals generated in the subject's serum by ascorbate with those generated after the addition of a chelating agent that blocks the oxidative activity of LPI [19]. LPI is commonly used in research but its clinical application remains undefined.

• Directly chelatable iron is the pool of plasma iron that best reflects the level of non-transferrin-bound iron.

QUANTITATIVE PHLEBOTOMY

Although not feasible for transfusion-dependent patients, quantitative phlebotomy is the reference method for assessing iron storage in patients with hereditary hemochromatosis [20]. It is a safe, easy, effective and inexpensive technique but is not usually a treatment option for patients with transfusional hemosiderosis.

Therapeutic phlebotomy is indicated in individuals less than 18 years of age. Although the number of phlebotomies required to obtain adequate iron depletion will vary between individuals, men generally require more sessions than women. It is estimated that each unit of blood removed will lead to a decrease in serum ferritin of around 30 ng/mL. In order to maintain iron levels once a suitable level has been achieved, phlebotomy may still be required 3 to 4 times each year [21].

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