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Hemochromatosis: The Neglected Diagnosis
Laboratory Medicine Hemochromatosis: The Neglected Diagnosis It seems ironic that, after so much has been written about hemochromatosis, myths and misconceptions still remain widely prevalent. Patients with this disorder need early treatment, yet hemochromatosis often is unrecognized until damage to the heart, liver, joints, pancreas, gonads, and other organs is advanced and irreversible. A recently reported analysis of 163 cases of hemochromatosis underscored the need for early diagnosis and intensive treatment of this disorder.1 Arthralgia was often an early symptom, whereas hyperglycemia and abnormal results of liver function tests were common when hepatic cirrhosis was advanced. Hepatocellular carcinoma occurred only in patients in whom cirrhosis had developed, and this complication was not prevented by vigorous phlebotomy treatment of such patients. Indeed, hepatocellular carcinoma, which occurs in about a third of the patients with advanced hemochromatosis, has not been reported in precirrhotic patients with this disease who have been successfully treated by phlebotomy. The overall duration of survival of patients with hemochromatosis was significantly reduced: the median for all 163 patients was about 20 years after the time of diagnosis, in comparison with more than 25 years for age- and sex-matched control subjects. The patients with cirrhosis, however, had decidedly shorter durations of survival (median, approximately 18 years), whereas those without cirrhosis who underwent successful iron depletion by phlebotomy within 18 months had normal life expectancies. Among the many causes of iron overloading, by far the commonest is the inborn error of iron metabolism known as hereditary (or idiopathic) hemochromatosis. Other less common causes include exogenous iron overloading from blood transfusions for chronic anemias, especially thalassemia major; various sideroblastic anemias; and, rarely, iron overloading that is associated with portal-to-systemic venous shunts. Long-term ingestion of iron medication (for an interval of Address reprint requests to Dr. V. F. Fairbanks, Department of Laboratory Medicine, Mayo Clinic, Rochester, MN 55905. Mayo Clin Proc 61:296-298, 1986
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decades) has led to iron overloading in a few reported cases. Although a few other causes of hemochromatosis have been identified, they are very rare or unknown in North America. The concept, once believed by some physicians, that ethanol abuse and alcoholic cirrhosis cause excess iron absorption and hemochromatosis has not withstood careful scrutiny. Some patients with hemochromatosis drink to excess, but the iron loading in such persons is a manifestation of hereditary hemochromatosis not of alcohol abuse. Recent studies have shown a strong linkage between the loci of the histocompatibility human leukocyte antigen (HLA) and a gene for susceptibility to hemochromatosis; both are located on chromosome 6.2~5 The frequency of occurrence of the hemochromatosis gene is about 0.05 in populations of Sweden, France, the United States, Canada, and Australia. 4 " 9 This figure implies a heterozygote frequency of about 1 person in 10 and a homozygote frequency of 2 or 3 persons per 1,000. Autopsy data in Glasgow, Scotland, 10 and at the Mayo Clinic (Ludwig J: Personal communication) are consistent with these prevalency estimates. Hereditary hemochromatosis is an autosomal recessive disorder. Thus, of the close relatives of an affected person, usually only siblings are at risk. Apparent autosomal dominant inheritance (manifested as clinical disease that has occurred in two or more successive generations) is due to marriages between homozygotes and unrelated heterozygotes—a common occurrence in view of the high prevalence of heterozygotes in the general population.4,7,11 Because of the close linkage between HLA and hemochromatosis loci, the question often arises whether HLA typing is useful as a screening or diagnostic test. About 70% of persons with hemochromatosis have the HLA-A3 antigen, in comparison with a 28% frequency of this antigen in the general population. 2,12 Twenty-eight percent of persons with alcoholic cirrhosis have HLA-A312 and thus do not differ in this regard from the general population. If a test for HLA-A3 were used to screen for hemochromatosis, a third of the cases would be missed, an unacceptable rate of false-
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negative results. Conversely, a patient with a positive test for HLA-A3 would more likely have alcoholic cirrhosis than hemochromatosis. Thus, using HLA testing as a screening procedure would also yield an unacceptably high frequency of false-positive results. HLA testing can be useful, however, for identifying siblings at risk when one member of a family has hemochromatosis. On the average, a fourth of the siblings of a patient with hemochromatosis will be HLA identical. Those sibs who are HLA identical will almost always also be homozygous for the hemochromatosis gene and therefore at high risk for the development of clinical hemochromatosis, whether they have the HLA-A3 or any other HLA antigens. Thus, HLA testing may be very useful for identifying siblings at risk. There is no other justification for HLA testing for hemochromatosis. Screening for hemochromatosis is best done by measuring the serum iron (SI) concentration and the total iron-binding capacity (TIBC). When the SI concentration exceeds 175 //g/dl and the transferrin saturation (100 x SI/TIBC) exceeds 60%, hemochromatosis must be suspected—provided other causes of increased SI have been excluded. The most common cause for elevated SI is ingestion of iron medication, often in the form of vitamin and mineral supplements, and frequently the physician is unaware of this fact because the patient forgets to acknowledge their use. An alternative screening test for hemochromatosis is measurement of serum ferritin concentration. Which of these tests should be used for screening is currently somewhat controversial, but SI and TIBC are preferred—especially in patients with arthritis, because the serum ferritin concentration is typically increased in rheumatoid arthritis in the absence of iron overloading. A sustained and otherwise unexplained increase in SI and transferrin saturation usually justifies needle biopsy of the liver to confirm or refute the tentative diagnosis of hemochromatosis. Two or 3 persons per 1,000 are at high risk for hemochromatosis. In a city of 1 million, hemochromatosis should be found in 2,000 or 3,000 persons—an epidemic. Yet most clinicians still consider it a rare disease. Thus, hemochromatosis is often not diagnosed during life. This failure of detection is because hemochromatosis mimics other common diseases. It lurks unrecognized among patients with diabetes mellitus, congestive heart failure, "idiopathic" cardiomyopathy,
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rheumatoid arthritis, alcoholic cirrhosis, or hypogonadism. The early diagnosis of hemochromatosis, at a time when it can be treated effectively, will continue to be elusive until physicians routinely request assay of SI and TIBC, or serum ferritin, as part of a general medical examination. For most ambulatory patients, these tests can be justified more easily than measurement of serum sodium or potassium concentration. Once the diagnosis has been established, examination of other family members is imperative. This approach is especially important in siblings, a fourth of whom will also have hemochromatosis. The children of patients with hemochromatosis should also be examined because about 5% of them will be homozygous for the hemochromatosis gene. Several methods are available for measuring SI and TIBC or serum ferritin concentration. Most often, SI and TIBC are performed as recommended by the International Committee for Standardization in Hematology. Serum proteins are precipitated, and the iron content of the supernatant is tested by using the intense color reaction between Fe++ and ferrozine. The method is sensitive to a few micrograms per deciliter, has approximately 100% recovery, and has a coefficient of variation of about 1%. By this method, hemolysis does not affect results unless it is marked. In many normal persons, a pronounced diurnal variation causes decidedly lower afternoon values and much lower evening values in comparison with results obtained from specimens withdrawn between 7.00 a.m. and noon. The TIBC assay necessitates, as preliminary steps, addition of iron to saturate transferrin and subsequent removal of non-transferrin-bound iron. For either measurement, plasma specimens are unacceptable because ethylenediaminetetraacetic acid chelates iron and thus yields spuriously low results. The normal ranges for adults are shown in Table 1. The serum ferritin assay is most often performed with use of an immunoradiometric method, although other techniques, such as enzymelinked immunosorbent assays (ELISA), are also frequently used. The normal ranges for serum ferritin assay vary considerably and depend on the method used; the normal ranges for one widely used ferritin assay are shown in Table 1. This sensitive procedure has a coefficient of variation of approximately 5%.
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LABORATORY MEDICINE
Table 1.—Normal Ranges for Serum Iron, Total Iron-Binding Capacity, Transferrin Saturation, and Serum Ferritin in Adults Measurement Men Women Serum iron //g/dl 75-175 65-165 //mol/L 13-31 11-29 Total iron-binding capacity /ig/dl 240-450 //mol/L 44-80 Transferrin saturation (%) 20-50 Serum ferritin Qug/L)* 20-300 20-120 *Normal ranges vary considerably and depend on method used.
Virgil F. Fairbanks, M.D. Department of Laboratory Medicine; Division of Hematology and Internal Medicine William P. Baldus, M.D. Division of Gastroenterology and Internal Medicine REFERENCES
1. Niederau C, Fischer R, Sonnenberg A, Stremmel W, Trampisch HJ, Strohmeyer G: Survival and causes of death in cirrhotic and in noncirrhotic patients with primary hemochromatosis. N Engl J Med 313:1256-1262, 1985
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2. Simon M, Alexandre J-L, Fauchet R, Genetet B, Bourel M: The genetics of hemochromatosis. Prog Med Genet 4:135168, 1980 3. Simon M, Bourel M, Fauchet R, Genetet B: Association of HLA-A3 and HLA-B14 antigens with idiopathic haemochromatosis. Gut 17:332-334, 1976 4. Dadone MM, Kushner JP, Edwards CQ, Bishop DT, Skolnick MH: Hereditary hemochromatosis: analysis of laboratory expression of the disease by genotype in 18 pedigrees. Am J Clin Pathol 78:196-207,1982 5. Edwards CQ, Skolnick MH, Kushner JP: Hereditary hemochromatosis: contributions of genetic analyses. Prog Hematol 12:43-71, 1981 6. Olsson KS, Ritter B, Rosen U, Heedman PA, Staugard F: Prevalence of iron overload in central Sweden. Acta Med Scand 213:145-150, 1983 7. Basse« ML, Doran TJ, Halliday JW, Bashir HV, Powell LW: Idiopathic hemochromatosis: demonstration of homozygous-heterozygous mating by HLA typing of families. Hum Genet 60:352-356, 1982 8. Basse« ML, Halliday JW, Ferris RA, Powell LW: Diagnosis of hemochromatosis in young subjects: predictive accuracy of biochemical screening tests. Gastroenterology 87:628-633,1984 9. Borwein ST, Ghent CN, Flanagan PR, Chamberlain MJ, Valberg LS: Genetic and phenotypic expression of hemochromatosis in Canadians. Clin Invest Med 6:171-179, 1983 10. MacSween RNM, Scott AR: Hepatic cirrhosis: a clinicopathological review of 520 cases. J Clin Pathol 26:936-942, 1973 11. Ward JH, Kushner JP, Kaplan J: Iron: metabolism and clinical disorders. Curr Hematol Oncol 3:1-50, 1984 12. LeSage GD, Baldus WP, Fairbanks VF, Baggenstoss AH, McCall JT, Moore SB, Taswell HF, Gordon H: Hemochromatosis: genetic or alcohol-induced? Gastroenterology 84:1471-1477, 1983
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decades) has led to iron overloading in a few reported cases. Although a few other causes of hemochromatosis have been identified, they are very rare or unknown in North America. The concept, once believed by some physicians, that ethanol abuse and alcoholic cirrhosis cause excess iron absorption and hemochromatosis has not withstood careful scrutiny. Some patients with hemochromatosis drink to excess, but the iron loading in such persons is a manifestation of hereditary hemochromatosis not of alcohol abuse. Recent studies have shown a strong linkage between the loci of the histocompatibility human leukocyte antigen (HLA) and a gene for susceptibility to hemochromatosis; both are located on chromosome 6.2~5 The frequency of occurrence of the hemochromatosis gene is about 0.05 in populations of Sweden, France, the United States, Canada, and Australia. 4 " 9 This figure implies a heterozygote frequency of about 1 person in 10 and a homozygote frequency of 2 or 3 persons per 1,000. Autopsy data in Glasgow, Scotland, 10 and at the Mayo Clinic (Ludwig J: Personal communication) are consistent with these prevalency estimates. Hereditary hemochromatosis is an autosomal recessive disorder. Thus, of the close relatives of an affected person, usually only siblings are at risk. Apparent autosomal dominant inheritance (manifested as clinical disease that has occurred in two or more successive generations) is due to marriages between homozygotes and unrelated heterozygotes—a common occurrence in view of the high prevalence of heterozygotes in the general population.4,7,11 Because of the close linkage between HLA and hemochromatosis loci, the question often arises whether HLA typing is useful as a screening or diagnostic test. About 70% of persons with hemochromatosis have the HLA-A3 antigen, in comparison with a 28% frequency of this antigen in the general population. 2,12 Twenty-eight percent of persons with alcoholic cirrhosis have HLA-A312 and thus do not differ in this regard from the general population. If a test for HLA-A3 were used to screen for hemochromatosis, a third of the cases would be missed, an unacceptable rate of false-
Mayo Clin Proc, April 1986, Vol 61
negative results. Conversely, a patient with a positive test for HLA-A3 would more likely have alcoholic cirrhosis than hemochromatosis. Thus, using HLA testing as a screening procedure would also yield an unacceptably high frequency of false-positive results. HLA testing can be useful, however, for identifying siblings at risk when one member of a family has hemochromatosis. On the average, a fourth of the siblings of a patient with hemochromatosis will be HLA identical. Those sibs who are HLA identical will almost always also be homozygous for the hemochromatosis gene and therefore at high risk for the development of clinical hemochromatosis, whether they have the HLA-A3 or any other HLA antigens. Thus, HLA testing may be very useful for identifying siblings at risk. There is no other justification for HLA testing for hemochromatosis. Screening for hemochromatosis is best done by measuring the serum iron (SI) concentration and the total iron-binding capacity (TIBC). When the SI concentration exceeds 175 //g/dl and the transferrin saturation (100 x SI/TIBC) exceeds 60%, hemochromatosis must be suspected—provided other causes of increased SI have been excluded. The most common cause for elevated SI is ingestion of iron medication, often in the form of vitamin and mineral supplements, and frequently the physician is unaware of this fact because the patient forgets to acknowledge their use. An alternative screening test for hemochromatosis is measurement of serum ferritin concentration. Which of these tests should be used for screening is currently somewhat controversial, but SI and TIBC are preferred—especially in patients with arthritis, because the serum ferritin concentration is typically increased in rheumatoid arthritis in the absence of iron overloading. A sustained and otherwise unexplained increase in SI and transferrin saturation usually justifies needle biopsy of the liver to confirm or refute the tentative diagnosis of hemochromatosis. Two or 3 persons per 1,000 are at high risk for hemochromatosis. In a city of 1 million, hemochromatosis should be found in 2,000 or 3,000 persons—an epidemic. Yet most clinicians still consider it a rare disease. Thus, hemochromatosis is often not diagnosed during life. This failure of detection is because hemochromatosis mimics other common diseases. It lurks unrecognized among patients with diabetes mellitus, congestive heart failure, "idiopathic" cardiomyopathy,
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rheumatoid arthritis, alcoholic cirrhosis, or hypogonadism. The early diagnosis of hemochromatosis, at a time when it can be treated effectively, will continue to be elusive until physicians routinely request assay of SI and TIBC, or serum ferritin, as part of a general medical examination. For most ambulatory patients, these tests can be justified more easily than measurement of serum sodium or potassium concentration. Once the diagnosis has been established, examination of other family members is imperative. This approach is especially important in siblings, a fourth of whom will also have hemochromatosis. The children of patients with hemochromatosis should also be examined because about 5% of them will be homozygous for the hemochromatosis gene. Several methods are available for measuring SI and TIBC or serum ferritin concentration. Most often, SI and TIBC are performed as recommended by the International Committee for Standardization in Hematology. Serum proteins are precipitated, and the iron content of the supernatant is tested by using the intense color reaction between Fe++ and ferrozine. The method is sensitive to a few micrograms per deciliter, has approximately 100% recovery, and has a coefficient of variation of about 1%. By this method, hemolysis does not affect results unless it is marked. In many normal persons, a pronounced diurnal variation causes decidedly lower afternoon values and much lower evening values in comparison with results obtained from specimens withdrawn between 7.00 a.m. and noon. The TIBC assay necessitates, as preliminary steps, addition of iron to saturate transferrin and subsequent removal of non-transferrin-bound iron. For either measurement, plasma specimens are unacceptable because ethylenediaminetetraacetic acid chelates iron and thus yields spuriously low results. The normal ranges for adults are shown in Table 1. The serum ferritin assay is most often performed with use of an immunoradiometric method, although other techniques, such as enzymelinked immunosorbent assays (ELISA), are also frequently used. The normal ranges for serum ferritin assay vary considerably and depend on the method used; the normal ranges for one widely used ferritin assay are shown in Table 1. This sensitive procedure has a coefficient of variation of approximately 5%.
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LABORATORY MEDICINE
Table 1.—Normal Ranges for Serum Iron, Total Iron-Binding Capacity, Transferrin Saturation, and Serum Ferritin in Adults Measurement Men Women Serum iron //g/dl 75-175 65-165 //mol/L 13-31 11-29 Total iron-binding capacity /ig/dl 240-450 //mol/L 44-80 Transferrin saturation (%) 20-50 Serum ferritin Qug/L)* 20-300 20-120 *Normal ranges vary considerably and depend on method used.
Virgil F. Fairbanks, M.D. Department of Laboratory Medicine; Division of Hematology and Internal Medicine William P. Baldus, M.D. Division of Gastroenterology and Internal Medicine REFERENCES
1. Niederau C, Fischer R, Sonnenberg A, Stremmel W, Trampisch HJ, Strohmeyer G: Survival and causes of death in cirrhotic and in noncirrhotic patients with primary hemochromatosis. N Engl J Med 313:1256-1262, 1985
Mayo Clin Proc, April 1986, Vol 61
2. Simon M, Alexandre J-L, Fauchet R, Genetet B, Bourel M: The genetics of hemochromatosis. Prog Med Genet 4:135168, 1980 3. Simon M, Bourel M, Fauchet R, Genetet B: Association of HLA-A3 and HLA-B14 antigens with idiopathic haemochromatosis. Gut 17:332-334, 1976 4. Dadone MM, Kushner JP, Edwards CQ, Bishop DT, Skolnick MH: Hereditary hemochromatosis: analysis of laboratory expression of the disease by genotype in 18 pedigrees. Am J Clin Pathol 78:196-207,1982 5. Edwards CQ, Skolnick MH, Kushner JP: Hereditary hemochromatosis: contributions of genetic analyses. Prog Hematol 12:43-71, 1981 6. Olsson KS, Ritter B, Rosen U, Heedman PA, Staugard F: Prevalence of iron overload in central Sweden. Acta Med Scand 213:145-150, 1983 7. Basse« ML, Doran TJ, Halliday JW, Bashir HV, Powell LW: Idiopathic hemochromatosis: demonstration of homozygous-heterozygous mating by HLA typing of families. Hum Genet 60:352-356, 1982 8. Basse« ML, Halliday JW, Ferris RA, Powell LW: Diagnosis of hemochromatosis in young subjects: predictive accuracy of biochemical screening tests. Gastroenterology 87:628-633,1984 9. Borwein ST, Ghent CN, Flanagan PR, Chamberlain MJ, Valberg LS: Genetic and phenotypic expression of hemochromatosis in Canadians. Clin Invest Med 6:171-179, 1983 10. MacSween RNM, Scott AR: Hepatic cirrhosis: a clinicopathological review of 520 cases. J Clin Pathol 26:936-942, 1973 11. Ward JH, Kushner JP, Kaplan J: Iron: metabolism and clinical disorders. Curr Hematol Oncol 3:1-50, 1984 12. LeSage GD, Baldus WP, Fairbanks VF, Baggenstoss AH, McCall JT, Moore SB, Taswell HF, Gordon H: Hemochromatosis: genetic or alcohol-induced? Gastroenterology 84:1471-1477, 1983