ByJ. Mercola, D.O.
Genetic hemochromatosis is one of the most frequent inborn errorsof metabolism.[i] Hereditary hemochromatosis is the most commoninherited single-gene disorder in people of northern European descent.[ii]
Most physicians have inadequate knowledge about how to properlydiagnosis and manage hemochromatosis.[iii] The current treatmentof hereditary hemochromatosis consists of performing periodic manualwhole blood phlebotomies. There are some newer traditionally basedalternative treatments called erythroapheresis (EPH) in which irondepletion was able to reduce ferritin to below 20 µg/l.[iv]
However, these approaches are inelegant in that they require significanttime 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 ismeasuring serum iron concentration, total iron binding capacity,transferrin saturation and serum ferritin. These should be donetogether.
The transferrin saturation, as a percentage, is calculated from100 times serum iron concentration divided by total iron bindingcapacity. Transferrin saturation of greater than 50 percent detectsmost males or females with or without iron loading, whereas normallyit is 20 percent to 50 percent. It has been proposed that the screeningcutoff point should be 60 percent for males and 50 percent for females.
Other conditions may also elevate serum iron concentration andtransferrin saturation, particularly the recent ingestion of medicinaliron 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|
|Menstrual cycle ||Pre-menstrually, elevated values (SI increased by 10-30%); at menstruation, low values (SI decreased by 10-30%)|
|Pregnancy ||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) ||Alopecia ||Increased serum iron concentration |
|Fatigue ||Hyperpigmentation ||Serum transferrin saturation >60%|
|Weakness ||Tender, swollen joints ||Increased serum ALT or AST transaminase level|
|Arthralgia ||Cardiac arrhythmia ||Increased blood glucose level|
|Abdominal pain ||Cardiomegaly ||Abnormal glucose tolerance|
|Impotence ||Hepatomegaly ||Low serum testosterone level|
|Amenorrhea ||Splenomegaly ||Low serum estrogen and progesterone levels|
|Dyspnea ||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 serumferritin assay should be performed. Percent transferrin saturationhowever, is a more sensitive and specific test than is determinationof the serum ferritin level, which can be elevated for a varietyof reasons listed below.
However, since serum ferritin is an acute-phase reactant, elevatedvalues may result from chronic disease, such as inflammation (asin rheumatoid arthritis), or from malignancies. Liver injury fromhepatitis or alcohol abuse also elevates both the serum iron andthe serum ferritin concentrations. High values of serum ferritinmay be observed in Gaucher's disease and in a rare familial disorderassociated with congenital cataracts (the hyperferritinemia-cataractsyndrome), without concomitant excess iron accumulation in the liveror other organs. Therefore, elevated values of serum ferritin concentrationmust be interpreted in the context of the presence or absence ofthese other conditions.[v]
When there is marked iron overload, as in advanced hemochromatosis,the serum ferritin concentration commonly exceeds 500 mug/L andmay be >5000 mug/L. Each 1 mug/L of serum ferritin concentrationis roughly equivalent to 120 mug of iron stores/kg of body weight.A 70 kg person with a serum ferritin concentration of 3000 mug/ghas approximately 17 to 33 grams of storage iron in ferritin andhemosiderin. This contrasts with the normal iron stores of about500 to 800 mg in adult males or about 300 mg in adult women.
In some circumstances however, the relationship between plasmaferritin and body iron stores is distorted: the plasma ferritinmay greatly underestimate the extent of iron accumulation or mayeven be normal despite a considerable increase in body iron in asmall number of patients with hereditary hemochromatosis.[vi]
A serum iron and TIBC or transferrin test, with calculation ofthe transferrin saturation, along with a serum ferritin level shouldbe obtained in the fasting state. Over 50 percent of patients havetransiently elevated serum iron levels after eating, and thus ifthe blood sample is not drawn in the fasting state, the transferrinsaturation can be elevated in the absence of increased iron stores.In addition to the increased serum iron level after meals, thereis a diurnal variation in serum iron concentration as well. Forthese reasons, it is recommended that whenever one is trying toestablish the diagnosis of HHC, a fasting patient should have blooddrawn for serum iron studies in the morning.
The combination of an elevated transferrin saturation level andan elevated ferritin level in an otherwise healthy individual is93 percent sensitive for hemochromatosis. Conversely, in someoneolder than the age of 35 the combination of a normal ferritin leveland a normal transferrin saturation has a negative predictive accuracyof 97 percent, indicating that there is only a three percent chanceof missing a diagnosis of hemoochromatosis in a patient of thisage or older who has normal iron studies.[vii]
Table 3 :: Hemochromatosis Blood Values Serum Normal Hereditary Hemochromatosis Iron: (mug/dL) 60-180 180-300 (mumol/L)
11-32 32-54 Transferrin saturation (%) 20-50 55-100 Ferritin: Males (ng/mL; mug/L) 20-200
300-3000 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]
[ii]Brandhagen DJ, Fairbanks VF, Baldus W. Recognitionand management of hereditary hemochromatosis. Am Fam Physician.2002 Mar 1;65(5):853-60
[iii]Acton RT, Barton JC, Casebeer L, et. Al. Surveyof physician knowledge about hemochromatosis. Genet Med. 2002May-Jun;4(3):136-41
[iv]Muncunill J, Vaquer P, Galmes A, et al. Inhereditary hemochromatosis, red cell apheresis removes excessiron twice as fast as manual whole blood phlebotomy. J ClinApheresis. 2002;17(2):88-92.
[v]Goldman: Cecil Textbook of Medicine, 21st ed., 2000 W. B. SaundersCompany p.1133
[vi]Deugnier YM, Turlin B, Powell LW et al: Differentiationbetween heterozygotes and homozygotes in genetic hemochromatosisby means of a histological hepatic iron index: a study of 192cases. Hepatology 17:30, 1993
[vii]Feldman: Sleisenger & Fordtran's Gastrointestinal and LiverDisease, 6th ed., 1998 W. B. Saunders Company
[viii]Murtagh LJ, Whiley M, Wilson S, et al Unsaturatediron binding capacity and transferrin saturation are equally reliablein detection of HFE hemochromatosis. Am J Gastroenterol. 2002Aug;97(8):2093-9