How to Diagnose Iron Overload

By J. Mercola, D.O.

Genetic hemochromatosis is one of the most frequent inborn errors of metabolism.[i] Hereditary hemochromatosis is the most common inherited single-gene disorder in people of northern European descent.[ii]

Most physicians have inadequate knowledge about how to properly diagnosis and manage hemochromatosis.[iii] The current treatment of hereditary hemochromatosis consists of performing periodic manual whole blood phlebotomies. There are some newer traditionally based alternative treatments called erythroapheresis (EPH) in which iron depletion was able to reduce ferritin to below 20 µg/l.[iv]

However, these approaches are inelegant in that they require significant time to be therapeutically effective and are also quite inconvenient. The use of naturally derived iron-based chelators like phytic acid (discussed below) is more rapidly implemented, inexpensive and non-toxic. Diagnosis of Iron Overload

The most useful laboratory test to ascertain hemochromatosis is measuring serum iron concentration, total iron binding capacity, transferrin saturation and serum ferritin. These should be done together.

The transferrin saturation, as a percentage, is calculated from 100 times serum iron concentration divided by total iron binding capacity. Transferrin saturation of greater than 50 percent detects most males or females with or without iron loading, whereas normally it is 20 percent to 50 percent. It has been proposed that the screening cutoff point should be 60 percent for males and 50 percent for females.

Other conditions may also elevate serum iron concentration and transferrin saturation, particularly the recent ingestion of medicinal iron or iron-fortified vitamin preparations, or oral contraceptives (Table 1). Therefore, if the transferrin saturation is elevated, the test should be repeated after eliminating such confounding variables.

Table 1 :: Phenomena Known To Affect Percent Transferrin Saturation
Phenomenon Effect
Menstrual cycle
Pre-menstrually, elevated values (SI increased by 10-30%); at menstruation, low values (SI decreased by 10-30%)
May elevate SI through increased progesterone; may lower SI through Fe deficiency
Ingestion of iron (including iron-fortified vitamins)
High values (SI may rise by 300+ mug/dL and transferrin saturation to 75%)
Iron contamination of tube (Vacutainer) or other glassware (phenomenon may be rare, sporadic, very difficult to prove)
High values (SI 200-300 mug/dL, transferrin saturation of 75-100%)
Iron dextran injection
Very high values (SI may be >500 mug/dL, transferrin saturation 100%, probably from circulating iron dextran; effect may persist for several weeks)
Hepatitis (including steatohepatitis)
Very high values (SI may exceed 1000 mug/dL through hyperferritinemia from hepatocyte injury)
Acute inflammation (respiratory infection), abscess, immunization, myocardial infarction
Low or normal SI; normal or low Tsat
Chronic inflammation or malignancy Low or normal SI; normal or low Tsat
Iron deficiency
Low or normal SI; increased TIBC; low or normal Tsat
Iron overload (hemochromatosis) High SI, high Tsat
SI = Serum Iron;TIBC = Total Iron-Binding Capacity; Tsat = Transferrin Saturation (Percentage).


Table 2 :: Clinical And Laboratory Manifestations Of Hemochromatosis
Symptoms Signs Abnormal Laboratory Findings
None (common)
Increased serum iron concentration
Serum transferrin saturation >60%
Tender, swollen joints
Increased serum ALT or AST transaminase level
Cardiac arrhythmia
Increased blood glucose level
Abdominal pain
Abnormal glucose tolerance
Low serum testosterone level
Low serum estrogen and progesterone levels
Pleural effusion
Low FSH and LH levels
Abdominal swelling Ascites Low serum T4 , high TSH level
Weight loss "Spider" telangiectases, Signs of hypothyroidism, Testicular atrophy
Azoospermia, Thrombocytopenia, Macrocytosis, Electrocardiographic abnormalities, Echocardiographic abnormalities,
Roentgenographic and imaging abnormalities
ALT = Alanine Aminotransferase; AST = Aspartate Aminotransferase. FSH = Follicle-Stimulating Hormone; LH = Luteinizing Hormone; T4 = Thyroxine; TSH = Thyrotropin

If the percent transferrin saturation is still elevated, a serum ferritin assay should be performed. Percent transferrin saturation however, is a more sensitive and specific test than is determination of the serum ferritin level, which can be elevated for a variety of reasons listed below.

However, since serum ferritin is an acute-phase reactant, elevated values may result from chronic disease, such as inflammation (as in rheumatoid arthritis), or from malignancies. Liver injury from hepatitis or alcohol abuse also elevates both the serum iron and the serum ferritin concentrations. High values of serum ferritin may be observed in Gaucher's disease and in a rare familial disorder associated with congenital cataracts (the hyperferritinemia-cataract syndrome), without concomitant excess iron accumulation in the liver or other organs. Therefore, elevated values of serum ferritin concentration must be interpreted in the context of the presence or absence of these other conditions.[v]

When there is marked iron overload, as in advanced hemochromatosis, the serum ferritin concentration commonly exceeds 500 mug/L and may be >5000 mug/L. Each 1 mug/L of serum ferritin concentration is roughly equivalent to 120 mug of iron stores/kg of body weight. A 70 kg person with a serum ferritin concentration of 3000 mug/g has approximately 17 to 33 grams of storage iron in ferritin and hemosiderin. This contrasts with the normal iron stores of about 500 to 800 mg in adult males or about 300 mg in adult women.

In some circumstances however, the relationship between plasma ferritin and body iron stores is distorted: the plasma ferritin may greatly underestimate the extent of iron accumulation or may even be normal despite a considerable increase in body iron in a small number of patients with hereditary hemochromatosis.[vi]

A serum iron and TIBC or transferrin test, with calculation of the transferrin saturation, along with a serum ferritin level should be obtained in the fasting state. Over 50 percent of patients have transiently elevated serum iron levels after eating, and thus if the blood sample is not drawn in the fasting state, the transferrin saturation can be elevated in the absence of increased iron stores. In addition to the increased serum iron level after meals, there is a diurnal variation in serum iron concentration as well. For these reasons, it is recommended that whenever one is trying to establish the diagnosis of HHC, a fasting patient should have blood drawn for serum iron studies in the morning.

The combination of an elevated transferrin saturation level and an elevated ferritin level in an otherwise healthy individual is 93 percent sensitive for hemochromatosis. Conversely, in someone older than the age of 35 the combination of a normal ferritin level and a normal transferrin saturation has a negative predictive accuracy of 97 percent, indicating that there is only a three percent chance of missing a diagnosis of hemoochromatosis in a patient of this age or older who has normal iron studies.[vii]

Table 3 :: Hemochromatosis Blood Values
Serum Normal Hereditary Hemochromatosis
   (mug/dL) 60-180 180-300
11-32 32-54
Transferrin saturation (%) 20-50 55-100
   Males (ng/mL; mug/L) 20-200
   Females (ng/mL; mug/L) 15-150 250-3000

Unsaturated iron binding capacity is an inexpensive alternative to percent transferrin saturation for the detection of hereditary hemochromatosis. The optimum threshold for detection is 143 microg/dL (25.6 micromol/L), giving a sensitivity of 0.91 and specificity of 0.95. [viii]



[i] Niederau C, Strohmeyer G. Strategies for early diagnosis of haemochromatosis. Eur J Gastroenterol Hepatol. 2002 Mar;14(3):217-21

[ii] Brandhagen DJ, Fairbanks VF, Baldus W. Recognition and management of hereditary hemochromatosis. Am Fam Physician. 2002 Mar 1;65(5):853-60

[iii] Acton RT, Barton JC, Casebeer L, et. Al. Survey of physician knowledge about hemochromatosis. Genet Med. 2002 May-Jun;4(3):136-41

[iv] Muncunill J, Vaquer P, Galmes A, et al. In hereditary hemochromatosis, red cell apheresis removes excess iron twice as fast as manual whole blood phlebotomy. J Clin Apheresis. 2002;17(2):88-92.

[v] Goldman: Cecil Textbook of Medicine, 21st ed., 2000 W. B. Saunders Company p.1133

[vi] Deugnier YM, Turlin B, Powell LW et al: Differentiation between heterozygotes and homozygotes in genetic hemochromatosis by means of a histological hepatic iron index: a study of 192 cases. Hepatology 17:30, 1993

[vii] Feldman: Sleisenger & Fordtran's Gastrointestinal and Liver Disease, 6th ed., 1998 W. B. Saunders Company

[viii] Murtagh LJ, Whiley M, Wilson S, et al Unsaturated iron binding capacity and transferrin saturation are equally reliable in detection of HFE hemochromatosis. Am J Gastroenterol. 2002 Aug;97(8):2093-9

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