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1 December 1998 | Volume 129 Issue 11 Part 2 | Pages 932-939
The complications of iron overload in hemochromatosis can be avoided by early diagnosis and appropriate management.Therapeutic phlebotomy is used to remove excess iron and maintain low normal body iron stores, and it should be initiated in men with serum ferritin levels of 300 µg/L or more and in women with serum ferritin levels of 200 µg/L or more, regardless of the presence or absence of symptoms. Typically, therapeutic phlebotomy consists of 1) removal of 1 unit [450 to 500 mL] of blood weekly until the serum ferritin level is 10 to 20 µg/L and 2) maintenance of the serum ferritin level at 50 µg/L or less thereafter by periodic removal of blood. Hyperferritinemia attributable to iron overload is resolved by therapeutic phlebotomy. When applied before iron overload becomes severe, this treatment also prevents complications of iron overload, including hepatic cirrhosis, primary liver cancer, diabetes mellitus, hypogonadotrophic hypogonadism, joint disease, and cardiomyopathy. In patients with established iron overload disease, weakness, fatigue, increased hepatic enzyme concentrations, right upper quadrant pain, and hyperpigmentation are often substantially alleviated by therapeutic phlebotomy. Patients with liver disease, joint disease, diabetes mellitus and other endocrinopathic abnormalities, and cardiac abnormalities often require additional, specific management. Dietary management of hemochromatosis includes avoidance of medicinal iron, mineral supplements, excess vitamin C, and uncooked sea-foods. This can reduce the rate of iron reaccumulation; reduce retention of nonferrous metals; and help reduce complications of liver disease, diabetes mellitus, and Vibrio infection. This comprehensive approach to the management of hemochromatosis can decrease the frequency and severity of iron overload, improve quality of life, and increase longevity.
Persons with hemochromatosis have an inherited propensity to absorb excess iron; most persons are of European origin and are homozygotes or compound heterozygotes for a mutant gene or genes on chromosome 6p [1, 2]. Hyperferremia and increased iron saturation of transferrin are essential attributes of hemochromatosis. A transferrin saturation of 60% or more for men and 50% or more for women on at least two occasions in the absence of other known causes of elevated transferrin saturation suggests the diagnosis of hemochromatosis [1, 2] and permits affected persons to be identified before iron overload develops. Normal or subnormal serum transferrin saturation values occur in unusual circumstances [3]. Many persons who have hemochromatosis without iron overload are children, young adults, and premenopausal women. Although iron overload often develops in patients with hemochromatosis, the demonstration of hepatic or systemic iron overload and associated complications is not needed to confirm the diagnosis (Table 1) [1, 2, 4]. DIAGNOSIS AND MANAGEMENT
Management of Hemochromatosis
Diagnosis and Initial Evaluation
Diagnosis of Hemochromatosis
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Evaluation of Iron Overload
Iron overload develops primarily because mechanisms to eliminate excess iron are limited. Many persons, particularly men, eventually develop severe iron overload. Women are at lower risk, partly because of iron losses during menstruation, childbirth, and lactation [1, 2]. The severity of iron overload is most often determined by measuring the serum ferritin level, although inflammation or cancer can elevate this level in the absence of iron overload. Approximately 90% of excess iron is retained in the liver. Therefore, many patients benefit from analysis of liver biopsy specimens to identify liver disease and to determine the presence or absence of cirrhosis, which directly affects prognosis. Biopsy specimens should be evaluated for iron by histochemical methods (Perls staining) and quantitative techniques (atomic absorption spectrometry) [4-7]. The quantity of iron removed by therapeutic phlebotomy is a valuable retrospective indicator of the severity of iron overload [8]. Radiologic imaging techniques are too insensitive for the evaluation of most young, asymptomatic persons with little or no excess hepatic iron [1, 2]. The hepatic iron index is useful in distinguishing persons who are homozygous for hemochromatosis from heterozygotes and persons with other hepatic disorders [5, 9]. Some patients have coincidental conditions that augment iron absorption and thus increase iron overload (for example, excessive dietary iron supplementation, excess ethanol ingestion, porphyria cutanea tarda, or hemolytic anemia) [1, 2, 10, 11]. Because serum iron variables in patients with viral hepatitis can mimic those in patients with hemochromatosis and because some patients have both disorders, persons with hemochromatosis must often be evaluated for hepatitis [12-14].
Medical Evaluation before Treatment
From each patient, physicians should collect information that includes a review of current and past symptoms and health problems, especially those related to liver, joint, and heart disease; diabetes mellitus and other endocrinopathic conditions; sexual function; and skin pigmentation [1, 2]. A dietary history should focus on general dietary habits and food choices, use of dietary supplements, and ingestion of ethanol. Any history of blood donation, receipt of blood transfusion, and illness associated with blood loss should be documented. The details of menstruation, childbirth, lactation, menopause, and hysterectomy are important (women taking oral contraceptives may have decreased menstrual blood loss or may absorb less dietary iron). The history should include inquiries about family members, especially first-degree relatives. The physical examination must include assessment of the liver, joints, heart, endocrine status, and skin coloration. Certain sequelae of iron overload may require additional specific evaluations to assess management needs (Table 1).
Therapeutic Phlebotomy
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Selection of Patients for Treatment
Most persons with hemochromatosis benefit from therapeutic phlebotomy (Table 2). Rarely, children and adolescents have severe iron overload (often associated with cardiac and anterior pituitary failure) and need aggressive therapeutic phlebotomy for removal of 1.5 to 2.0 units weekly, if possible [18-20]. Withholding therapeutic phlebotomy from older patients on the basis of age alone is not justifiable. In asymptomatic persons with iron overload (Table 2), therapy must not be delayed until symptoms develop. However, some patients are not candidates for treatment because they are intolerant toward phlebotomy or have limited life expectancy. Patients with severe, refractory anemia require iron chelation therapy [21].
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Approximately 8% of white persons of western European descent inherit one detectable hemochromatosis gene and thus are heterozygotes [22]. Of the 1% to 3% of heterozygotes who develop iron overload [23], many have a coincidental disorder that increases iron absorption or alters iron metabolism [1, 2, 14]; others may have an additional hemochromatosis mutation or mutations undetectable by current testing methods [24]. Many persons with porphyria cutanea tarda have skin lesions that are alleviated with therapeutic phlebotomy, and many are heterozygous for HFE mutations [2, 25-27]. No study has shown the benefits of therapeutic phlebotomy in other persons with iron overload who are heterozygotes or compound heterozygotes for the hemochromatosis gene or genes. However, we recommend that all persons with iron overload who have a clinical phenotype consistent with hemochromatosis, regardless of genotype, receive therapeutic phlebotomy and management similar to that recommended for homozygotes for "classic" hemochromatosis (Table 2).
Performance of Therapeutic Phlebotomy
Therapeutic phlebotomy should be done by experienced persons and should be supervised by a physician. It is usually performed in a physician's office but can be done in a medical laboratory, a blood bank, or a patient's home. However, comprehensive management of hemochromatosis is usually accomplished best in a physician's office. For many patients, compliance with treatment is proportional to the skill of the phlebotomist and the confidence of the patient in the treatment staff and environment. Adequate hydration and avoidance of vigorous physical activity for 24 hours after treatment minimize the effects of hypovolemia caused by therapeutic phlebotomy. Persons with a hemoglobin concentration less than 110 g/L or a hematocrit less than 0.33 before treatment are more likely to have symptoms of hypovolemia and anemia, and phlebotomy is less efficient in removing iron in these patients. However, many patients with chronic hemolytic anemia and iron overload tolerate phlebotomy well. The hemoglobin concentration or hematocrit and volume (or weight) of blood removed with each phlebotomy session should be documented.
Frequency and Duration of Therapeutic Phlebotomy
Depletion of iron stores typically involves the removal of 1 unit of blood weekly until mild hypoferritinemia occurs [1, 2]. Some men and persons with large body mass can sustain removal of 1.5 to 2.0 units of blood weekly. Some women; persons with small body mass; elderly persons; and patients with anemia, cardiac problems, or pulmonary problems can sustain removal of only 0.5 units of blood weekly. After a few weeks of therapeutic phlebotomy, erythroid hyperplasia permits more blood to be removed more often in many patients. Although recombinant human erythropoietin therapy also enhances erythrocyte production, this therapy should be reserved for patients who also have renal dysfunction or anemia of chronic disease [28]. Life expectancy may be substantially decreased in patients in whom iron depletion by phlebotomy cannot be completed within 1 year [29].
Serum ferritin and hepatic iron levels permit a relative estimation of the amount of therapeutic phlebotomy required for iron depletion [2]. On average, men require twice as many units of therapeutic phlebotomy as women do [24, 30, 31]. Older persons typically have more severe iron overload, as do persons who are homozygous for HFE mutation C282Y [2, 24, 32]. Hormonal factors, diet, abnormalities that alter iron absorption, and blood loss also influence the severity of iron overload [33]. Persons who have been regular blood donors often have less severe iron overload than do nondonors [1, 34].
The serum ferritin level is the most reliable, readily available, and inexpensive way to monitor therapeutic phlebotomy; the serum iron level and the transferrin saturation are less suitable [1, 2]. In general, patients who have higher serum ferritin levels have more severe iron overload and need more phlebotomy. Among patients who have serum ferritin levels greater than 1000 µg/L before treatment, it is sufficient to quantify the serum ferritin level every 4 to 8 weeks during the initial months of treatment. The serum ferritin level should be measured more often in patients who have received many phlebotomy treatments and in those who have mild or moderate iron overload at diagnosis. In all patients, serum ferritin levels should be quantified after each additional one or two treatments once the value is 100 µg/L or less. Progress of treatment is also monitored by assessing hemoglobin concentration and hematocrit, their recovery rates, and mean corpuscular volume. Iron depletion is complete when the serum ferritin level is 10 to 20 µg/L or when the hemoglobin concentration is less than 110 g/L or the hematocrit is less than 0.33 for more than 3 weeks (in patients without chronic anemia). These values indicate that mild iron deficiency has been induced and that potentially pathogenic iron deposits have been removed. Sustaining overt iron deficiency by phlebotomy is not justifiable. After iron depletion, the hemoglobin concentration and hematocrit are allowed to return to and remain within the normal range. Phlebotomy should be done throughout the patient's life to keep the serum ferritin level at 50 µg/L or less. This requires the annual removal of 3 or 4 units of blood in men and 1 or 2 units of blood in women, on average [8]. Some persons, especially elderly persons, may require no maintenance phlebotomy, but their serum ferritin levels should be monitored annually.
Complications Often Improved by Therapeutic Phlebotomy
Malaise, weakness, and ease of fatigue affect approximately 80% of patients with iron overload but are often not attributable to specific organ dysfunction. Iron depletion usually alleviates these symptoms, often early in the course of treatment (Table 3) [1, 2]. Liver-associated abnormalities (other than cirrhosis) usually resolve (Table 3) [1, 2], and benefit may also be seen with respect to manifestations of viral hepatitis [35, 36]. Diabetes mellitus sometimes improves, if temporarily, although it rarely disappears [37]. Cardiomyopathy (dilated or restrictive) and refractory arrhythmia caused by myocardial siderosis (with or without congestive heart failure) are usually alleviated or cured by the aggressive removal of stored iron [38-40]. The hyperpigmentation associated with iron overload gradually fades in most patients. Hyperferremia due to iron overload invariably resolves after iron depletion. Normal life expectancy has been noted among patients with hemochromatosis who do not have hepatic cirrhosis, diabetes mellitus, or cardiomyopathy and who undergo and maintain iron depletion by phlebotomy [29, 41-43]. Among patients who have these serious complications, therapeutic phlebotomy often improves quality of life and may increase longevity [29, 41-43].
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Complications Usually Not Improved by Phlebotomy
Hepatic cirrhosis due to iron overload rarely resolves with therapeutic phlebotomy (Table 3) [44-46]. A change from a micronodular to a macronodular pattern of hepatic scarring is the likely explanation for the "disappearance" of cirrhosis seen in a few patients [46]. Cirrhosis is associated with an increased risk for primary liver cancer, and the risk is not diminished by therapeutic phlebotomy (Table 3) [1, 2, 29, 47]. Significant improvement in joint function and alleviation of deformity after iron depletion are uncommon, and joint disease may progress despite therapy (Table 3) [1, 2, 48]. Some patients have exacerbation of joint pain during phlebotomy that resolves with depletion of iron stores. Hypogonadotrophic hypogonadism is usually not alleviated, but therapeutic phlebotomy has been associated with the restoration of normal pituitary and gonadal function if these complications are of recent onset [37, 49-52]. Thyroid disorders rarely respond to phlebotomy treatment [54]. When therapeutic phlebotomy is monitored properly by using the serum ferritin level, serum iron levels and transferrin saturation values usually remain elevated (Table 3) [3, 54].
Management of Complications of Iron Overload without Phlebotomy
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The estimated longevity of persons with hepatic cirrhosis due to hemochromatosis is reduced. Because hepatic biopsy is the most reliable means by which to diagnose hepatic cirrhosis [2, 41], this biopsy is important, especially in patients with hemochromatosis who have elevated serum concentrations of hepatic enzymes or a serum ferritin level greater than 750 µg/L. An additional biopsy specimen should be obtained if the first is unsatisfactory for interpretation, particularly if there is uncertainty about the presence of cirrhosis [1, 2]. However, routine hepatic biopsy after iron depletion is unnecessary. Some persons with clinical evidence of advanced hepatic cirrhosis and portal hypertension cannot undergo biopsy safely [14]. When a biopsy specimen is not available, prognosis and estimation of risks for primary liver cancer must be based on available data. Coincidental hepatic disorders occur in approximately 5% of patients with hemochromatosis, and persons with hepatic abnormalities atypical of hemochromatosis need further evaluation (Table 1) [14]. Patients with cirrhosis and other important hepatic disease (such as ethanol-associated hepatic injury or active viral hepatitis) may have persistently elevated serum concentrations of hepatic enzymes or more rapid deterioration of hepatic function than would be expected from iron overload alone. Hepatic failure and hemorrhage from esophagogastric varices cause substantial illness and require routine medical and surgical management [1, 2].
Primary Liver Cancer
Primary liver cancer causes 10% to 30% of hemochromatosis-related deaths, and it is the leading cause of death in patients with hepatic cirrhosis [29, 55, 56]. With few exceptions, only patients with cirrhosis develop primary liver cancer. The risk is increased approximately 200-fold in patients with cirrhosis, particularly those older than 55 years of age, those seropositive for hepatitis B surface antigen, and those who drink excess ethanol [56-58]. Serum concentrations of 
-fetoprotein are elevated in one third of patients [1, 2], and occult cancers are sometimes visualized with hepatic ultrasonography. We recommend that patients with hepatic cirrhosis have measurement of -fetoprotein levels and hepatic ultrasonography every 6 months, although the efficacy and cost-effectiveness of this testing are not clearly established. Any patient with cirrhosis who develops hepatic pain, increasing liver size, unexplained fever, or weight loss should be evaluated for primary liver cancer. Treatment methods for primary liver cancer in hemochromatosis, including liver transplantation, are reviewed elsewhere [59-64].
Joint Disease
Hemochromatosis-related joint disease often progresses despite therapeutic phlebotomy [48, 65]. Many patients need joint rest, treatment with salicylates or nonsteroidal anti-inflammatory drugs, or physical therapy. Surgical replacement, usually of the hip or the knee, is necessary in some patients. Other hereditary or acquired joint disorders can also cause progressive discomfort and disability in patients with hemochromatosis after therapeutic phlebotomy is complete, and these disorders should be evaluated and managed independently (Table 1).
Endocrinopathic Disease
Diabetes mellitus in patients with hemochromatosis should be treated as it is in other patients. In men with hypogonadotrophic hypogonadism, sexual potency and renewed vigor often return with monthly testosterone replacement. Severe iron overload in women of reproductive age is frequently associated with hypogonadotrophic hypogonadism. After iron depletion, menstruation and successful pregnancy can occur with appropriate gonadotrophin and other hormone therapy [52]. In older women, estrogen and progesterone replacement therapy should be considered. Thyroid disorders are more frequent among men with hemochromatosis than among men in the general population [53]. The management of thyroid dysfunction is the same for patients with and patients without hemochromatosis (Table 1) [53].
Cardiac Disorders
Severe cardiomyopathy and arrhythmias are typical of the massive iron overload that sometimes occurs in teenagers or young adults. Medical therapy to control congestive heart failure and minimize serious arrhythmias must be applied until vigorous therapeutic phlebotomy (possibly combined with iron chelation therapy) relieves the myocardial siderosis. In middle-aged or elderly persons, cardiac dysfunction is occasionally due to iron overload, but atherosclerosis of coronary arteries or other forms of heart disease are more common (Table 1) [14, 66].
Dietary Recommendations
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Patients should consume in moderation foods that contain large concentrations of bioavailable iron, such as red meats and organ meats [67, 68], and they should not use iron supplements, including multivitamins with iron (Table 4). Dietary changes intended to minimize or eliminate iron ingestion are usually unnecessary and are often not feasible. Furthermore, the 0.5 to 1.0 mg of iron absorbed daily in excess of normal in most persons with hemochromatosis is small in comparison with the 200 to 250 mg of iron per unit of blood removed weekly by therapeutic phlebotomy. Substances in foods and drinks, including tannates, phytates, oxalates, calcium, and phosphates, can bind iron and inhibit its absorption [67, 68]. The consumption of large quantities of tea, which contains tannates, can decrease iron absorption [69]. However, altering a patient's diet in an attempt to inhibit iron absorption is unnecessary unless the patient cannot tolerate therapeutic phlebotomy (persons with severe thalassemia, for example, cannot tolerate this therapy).
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Ethanol
Ethanol sometimes increases iron absorption [70, 71], and certain alcoholic drinks, especially red wines, also contain relatively high concentrations of iron [70, 71]. Ingestion of 30 g or more of ethanol daily can potentiate hepatic injury due to iron overload [57, 72] and increases the relative risk for primary liver cancer in persons with cirrhosis [57]. Patients with evidence of hepatic injury should consume little or no ethanol. Others should consume ethanol in moderation (Table 4).
Vitamin and Mineral Supplements
Vitamin C (ascorbic acid) increases the intestinal absorption of inorganic iron [73]. However, vitamin C deficiency sometimes occurs in untreated patients with hemochromatosis but resolves after iron depletion [74]. Rarely, ingestion of large quantities of vitamin C has been associated with fatal cardiac arrhythmias in persons with iron overload, presumably as a result of oxidative injury caused by mobilization of stored iron [75]. There is no rationale for discouraging patients with hemochromatosis from consuming fresh fruits and vegetables containing vitamin C, but it seems prudent to advise them to limit ingestion of vitamin C in supplements to 500 mg/d (Table 4).
In patients with hemochromatosis, absorption of inorganic forms of some nonferrous metals, including cobalt, manganese, zinc, and lead, is increased [76-82]. Excess inorganic cobalt is rapidly excreted [79]. Manganese and zinc, however, are deposited in the liver and other tissues [80, 82]. Lead, which is toxic in small amounts, is retained for prolonged periods [77]. The role of these metals in the pathogenesis of symptoms and tissue injury associated with hemochromatosis has not been elucidated, but we suggest that persons with hemochromatosis use dietary supplements containing these metals only if a specific nutritional deficiency has been shown (Table 4) [83]. Because blood concentrations of zinc, manganese, and lead are low, therapeutic phlebotomy is not effective in reducing retention of these metals [76, 77].
Shellfish
Vibrio vulnificus occurs naturally in many warm coastal waters, including those along the U.S. shore in the Gulf of Mexico, and it sometimes contaminates shellfish harvested from these areas. This spiral organism can cause infection when ingested in raw or improperly cooked contaminated shellfish or when introduced into the open wounds of persons who handle contaminated seafood or bathe in contaminated waters [84-86]. Bacteremia due to V. vulnificus in patients with hemochromatosis may be related to the availability of iron for microbial metabolism or to the presence of hepatic cirrhosis [85], and it is often fatal [84-86]. Persons with hemochromatosis should consume seafood from potentially contaminated waters only if it is thoroughly cooked, and they should take other indicated measures to prevent infection (Table 4). Therapeutic phlebotomy probably does not reduce susceptibility to infections with Vibrio species.
Comprehensive Dietary Management
Many patients appreciate being given a list of dietary recommendations that includes the amounts of iron in servings of common foods and beverages. Some patients rigidly (and unnecessarily) avoid certain dietary items, usually on the basis of iron content. Many patients have iron overload-associated or coincidental medical conditions (such as diabetes mellitus, hepatic dysfunction, anemia, hyperlipidemia, hypertension, or obesity) that also require changes in diet. In patients with complex dietary requirements, a dietitian who understands hemochromatosis can help formulate an effective diet that is acceptable to the patient. Diets do not enhance iron excretion, and patients must understand that there is no substitute for iron depletion therapy.
Conclusions
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Author and Article Information
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 Top Author & Article Info References |
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References
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TopAuthor & Article InfoReferences |
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1. Powell LW, Jazwinska E, Halliday JW. Primary iron overload. In: Brock JH, Halliday JW, Pippard MJ, Powell LW, eds. Iron Metabolism in Health and Disease. Philadelphia: WB Saunders; 1994:227-70.
2. Witte DL, Crosby WH, Edwards CQ, Fairbanks VF, Mitros FA. Practice guideline development task force of the College of American Pathologists. Hereditary hemochromatosis Clin Chim Acta. 1996;245:139-200.
3. Barton JC, Bertoli LF, Janich MR, Arthur MW, Alford TJ. Normal transferrin saturation in hemochromatosis Hosp Pract (Off Ed). 1991;26(Suppl 3):46-8.
4. Scheuer PJ, Williams R, Muir AR. Hepatic pathology in relatives of patients with haemochromatosis Journal of Pathology and Bacteriology. 1962;84:53-64.
5. Bassett ML, Halliday JW, Powell LW. Value of hepatic iron measurements in early hemochromatosis and determination of the critical iron level associated with fibrosis Hepatology. 1986;6:24-9.
6. Brissot P, Bourel M, Herry D, Verger JP, Messner M, Beaumont C, et al. Assessment of liver iron content in 271 patients: a reevaluation of direct and indirect methods Gastroenterology. 1981;80:557-65.
7. Searle J, Kerr JF, Halliday JW, Powell LW. Iron storage disease. In: McSween RN, Anthony PP, Scheuer PJ, Burt AD, Portmann BC, eds. Pathology of the Liver. 3d ed. New York: Churchill Livingstone; 1993:219-41.
8. Barton JC, Harmon L, Rivers C, Acton RT. Hemochromatosis: association of severity of iron overload with genetic markers Blood Cells Mol Dis. 1996;22:195-204.
9. Bonkovsky HL, Slaker DP, Bills EB, Wolf DC. Usefulness and limitations of laboratory and hepatic imaging studies in iron-storage disease Gastroenterology. 1990;99:1079-91.
10. Roberts AG, Whatley SD, Morgan RR, Worwood M, Elder GH. Increased frequency of the haemochromatosis Cys282Tyr mutation in sporadic porphyria cutanea tarda Lancet. 1997;349:321-3.
11. Mohler DN, Wheby MS. Hemochromatosis heterozygotes may have significant iron overload when they also have hereditary spherocytosis Am J Med Sci. 1986;292:320-4.
12. Edwards CQ, Griffen LM, Kushner JP. Coincidental hemochromatosis and viral hepatitis Am J Med Sci. 1991;301:50-4.
13. Di Bisceglie AM, Axiotis CA, Hoofnagle JH, Bacon BR. Measurements of iron status in patients with chronic hepatitis Gastroenterology. 1992;102:2108-13.
14. Barton JC, Barton NH, Alford TJ. Diagnosis of hemochromatosis probands in a community hospital Am J Med. 1997;103:498-503.
15. Davis WD, Arrowsmith WR. The effect of repeated phlebotomies in hemochromatosis: report of three cases J Lab Clin Med. 1952;39:526-32.
16. Wohler F. The treatment of haemochromatosis with desferrioxamine Acta Haematol. 1963;30:65-87.
17. Kellner H, Zoller WG. Repeated isovolemic large-volume erythrocytapheresis in the treatment of idiopathic hemochromatosis Z Gastroenterol. 1992;30:779-83.
18. Haddy TB, Castro OL, Rana SR. Hereditary hemochromatosis in children, adolescents, and young adults Am J Pediatr Hematol Oncol. 1988;10:23-34.
19. Kaltwasser JP, Schalk KP, Werner E. Juvenile hemochromatosis. in: Weintraub LR, Edwards CQ, Krikker M, eds. Hemochromatosis. Proceedings of the First International Conference Ann NY Acad Sci. 1988;526:339-41.
20. Kaikov Y, Wadsworth LD, Hassall E, Dimmick JE, Rogers PC. Primary hemochromatosis in children: report of three newly diagnosed cases and review of the pediatric literature. Pediatrics. 1992; 90(1 pt 1):37-42.
21. Pippard MJ, Rajagopalan B, Callender ST, Weatherall DJ. Iron loading, chronic anaemia, and erythroid hyperplasia as determinants of the clinical features of ß-thalassaemia intermedia. In: Weatherall DJ, Fiorelli G, Gorini S, eds. Advances in Red Blood Cell Biology. New York: Raven Pr; 1982:103-13.
22. McLaren CE, Gordeuk VR, Looker AC, Hasselblad V, Edwards CQ, Griffen LM, et al. Prevalence of heterozygotes for hemochromatosis in the white population of the United States Blood. 1995;86:2021-7.
23. Bulaj ZJ, Griffen LM, Jorde LB, Edwards CQ, Kushner JP. Clinical and biochemical abnormalities in people heterozygous for hemochromatosis N Engl J Med. 1996;335:1799-805.
24. Barton JC, Shih WW, Sawada-Hirai R, Acton RT, Harmon L, Rivers C, et al. Genetic and clinical description of hemochromatosis probands and heterozygotes: evidence that multiple genes linked to the major histocompatibility complex are responsible for hemochromatosis Blood Cells Mol Dis. 1997;23:135-45.
25. Lundvall O. Phlebotomy treatment of porphyria cutanea tarda Acta Derm Venereol Suppl (Stockh). 1982;100:107-18.
26. Roberts AG, Whatley SD, Morgan RR, Worwood M, Elder GH. Increased frequency of the haemochromatosis Cys282Tyr mutation in sporadic porphyria cutanea tarda Lancet. 1997;349:321-3.
27. Sampietro M, Piperno A, Lupica L, Arosio C, Vergani A, Corbetta N, et al. High prevalence of the His63Asp HFE mutation in Italian patients with porphyria cutanea tarda Hepatology. 1998;27:181-4.
28. Bilgrami S, Bartolomeo A, Synnott V, Rickles FR. Management of hemosiderosis complicated by coexistent anemia with recombinant human erythropoietin and phlebotomy Acta Haematol. 1993;89:141-3.
29. 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. 1985;313:1256-62.
30. Edwards CQ, Dadone MM, Skoinick MH, Kushner JP. Hereditary hemochromatosis Clin Haematol. 1982;11:411-35.
31. Moirand R, Adams PC, Bicheler V, Brissot P, Deugnier Y. Clinical features of genetic hemochromatosis in women compared with men Ann Intern Med. 1997;127:105-10.
32. Sham RL, Ou CY, Cappuccio J, Braggins C, Dunnigan K, Phatak PD. Correlation between genotype and phenotype in hereditary hemochromatosis: analysis of 61 cases Blood Cell Mol Dis. 1997;23:314-20.
33. Skikne B, Baynes RD. Iron absorption. In: Brock JH, Halliday JW, Pippard MJ, Powell LW, eds. Iron Metabolism in Health and Disease. Philadelphia: WB Saunders; 1994:151-88.
34. Edwards CQ, Griffen LM, Goldgar D, Drummond C, Skolnick MH, Kushner JP. Prevalence of hemochromatosis among 11,065 presumably healthy blood donors N Engl J Med. 1988;318:1355-62.
35. Hayashi H, Takikawa T, Nishimura N, Yano M, Isomura T, Sakamoto N. Improvement of serum aminotransferase levels after phlebotomy in patients with chronic active hepatitis C and excess hepatic iron Am J Gastroenterol. 1994;89:986-8.
36. Piperno A, Sampietro M, D'Alba R, Roffi L, Fargion S, Parma S, et al. Iron stores, response to -interferon therapy, and effects of iron depletion in chronic hepatitis C Liver. 1996;16:248-54.
37. Stremmel W, Niederau C, Berger M, Kley HK, Kruskemper HL, Strohmeyer G. Abnormalities in estrogen, androgen, and insulin metabolism in idiopathic hemochromatosis. in: Weintraub LR, Edwards CQ, Krikker M, eds. Hemochromatosis. Proceedings of the First International Conference Ann N Y Acad Sci. 1988;526:209-23.
38. Cutler DJ, Isner JM, Bracey AW, Hufnagel CA, Conrad PW, Roberts WC, et al. Hemochromatosis heart disease: an unemphasized cause of potentially reversible restrictive cardiomyopathy Am J Med. 1980;69:923-8.
39. Candell-Riera J, Lu L, Seres L, Gonzalez JB, Batlle J, Permanyer-Miralda G, et al. Cardiac hemochromatosis: beneficial effects of iron removal therapy. An echocardiographic study Am J Cardiol. 1983;52:824-9.
40. Rivers J, Garrahy P, Robinson W, Murphy A. Reversible cardiac dysfunction in hemochromatosis Am Heart J. 1987;113:216-7.
41. Powell LW. Hemochromatosis: precirrhotic therapy restores normal life expectancy Hepatology. 1986;6:1423-5.
42. Adams PC, Speechley M, Kertesz AE. Long-term survival in hereditary hemochromatosis Gastroenterology. 1991;101:368-72.
43. Niederau C, Fischer R, Purschel A, Stremmel W, Haussinger D, Strohmeyer G. Long-term survival in patients with hereditary hemochromatosis Gastroenterology. 1996;110:1107-19.
44. Knauer CM, Gamble CN, Monroe LS. The reversal of hemochromatotic cirrhosis by phlebotomies. Report of a case Gastroenterology. 1965;49:667-71.
45. Weintraub LR, Conrad ME, Crosby WH. The treatment of hemochromatosis by phlebotomy Med Clin North Am. 1966;50:1579-90.
46. Powell LW, Kerr JF. Reversal of "cirrhosis" in idiopathic haemochromatosis following long-term intensive venesection therapy Australas Ann Med. 1970;19:54-7.
47. Blumberg RS, Chopra S, Ibrahim R, Crawford J, Farraye FA, Zeldis JB, et al. Primary hepatocellular carcinoma in idiopathic hemochromatosis after reversal of cirrhosis Gastroenterology. 1988;95:1399-402.
48. Schumacher HR, Straka PC, Krikker MA, Dudley AT. The arthropathy of hemochromatosis. Recent studies. in: Weintraub LR, Edwards CQ, Krikker M, eds. Hemochromatosis. Proceedings of the First International Conference Ann N Y Acad Sci. 1988;526:224-33.
49. Kelly TM, Edwards CQ, Meikle AW, Kushner JP. Hypogonadism in hemochromatosis: reversal with iron depletion Ann Intern Med. 1984;101:629-32.
50. Lufkin EG, Baldus WP, Bergstralh EJ, Kao PC. Influence of phlebotomy treatment on abnormal hypothalamic-pituitary function in genetic hemochromatosis Mayo Clin Proc. 1987;62:473-9.
51. Siminoski K, D'Costa M, Walfish PG. Hypogonadotrophic hypogonadism in idiopathic hemochromatosis: evidence for combined hypothalamic and pituitary involvement J Endocrinol Invest. 1990;13:849-53.
52. Farina G, Pedrotti C, Cerani P, Rovati A, Strada E, Bergamaschi G, et al. Successful pregnancy following gonadotropin therapy in a young female with juvenile idiopathic hemochromatosis and secondary hypogonadotrophic hypogonadism Haematologica. 1995;80:335-7.
53. Edwards CQ, Kelly TM, Ellwein G, Kushner JP. Thyroid disease in hemochromatosis. Increased incidence in homozygous men Arch Intern Med. 1983;143:1890-3.
54. Edwards CQ, Griffen LM, Kaplan J, Kushner JP. Twenty-four hour variation of transferrin saturation in treated and untreated haemochromatosis homozygotes J Intern Med. 1989;226:373-9.
55. Bradbear RA, Bain C, Siskind V, Schofield FD, Webb S, Axelsen EM, et al. Cohort study of internal malignancy in genetic hemochromatosis and other chronic nonalcoholic liver diseases J Natl Cancer Inst. 1985;75:81-4.
56. Colombo M, de Franchis R, Del Ninno E, Sangiovanni A, De Fazio C, Tommasini M, et al. Hepatocellular carcinoma in Italian patients with cirrhosis N Engl J Med. 1991;325:675-80.
57. Deugnier YM, Guyader D, Crantock L, Lopez JM, Turlin B, Yaouanq J, et al. Primary liver cancer in genetic hemochromatosis: a clinical, pathological, and pathogenetic study of 54 cases Gastroenterology. 1993;104:228-34.
58. Fargion S, Fracanzani AL, Piperno A, Braga M, D'Alba R, Ronchi G, et al. Prognostic factors for hepatocellular carcinoma in genetic hemochromatosis Hepatology. 1994;20:1426-31.
59. Nonami T, Harada A, Kurokawa T, Nakao A, Takagi H. Hepatic resection for hepatocellular carcinoma Am J Surg. 1997;173:288-91.
60. Liu CL, Fan ST. Nonresectional therapies for hepatocellular carcinoma Am J Surg. 1997;173:358-65.
61. Powell LW. Does transplantation of the liver cure genetic hemochromatosis? J Hepatol. 1992;16:259-61.
62. Farrell FJ, Nguyen M, Woodley S, Imperial JC, Garcia-Kennedy R, Man K, et al. Outcome of liver transplantation in patients with hemochromatosis Hepatology. 1994;20:404-10.
63. Poulos JE, Bacon BR. Liver transplantation for hereditary hemochromatosis Dig Dis. 1996;14:316-22.
64. Kowdley KV, Hassanein T, Kaur S, Farrell FJ, Van Thiel DH, Keeffe EB, et al. Primary liver cancer and survival in patients undergoing liver transplantation for hemochromatosis Liver Transpl Surg. 1995;1:237-41.
65. Askari AD, Muir WA, Rosner IA, Moskowitz RM, McLaren GD, Braun WE. Arthritis of hemochromatosis. Clinical spectrum, relation to histocompatibility antigens, and effectiveness of early phlebotomy Am J Med. 1983;75:957-65.
66. Edwards CQ, Cartwright GE, Skolnick MH, Amos DB. Homozygosity for hemochromatosis: clinical manifestations Ann Intern Med. 1980;93:519-25.
67. Bothwell TH, Charlton RW, Cook JD, Finch CA. Iron absorption. In: Iron Metabolism in Man. Oxford: Blackwell Scientific; 1979:256-83.
68. Conrad ME, Barton JC. Factors affecting iron balance Am J Hematol. 1981;10:199-205.
69. de Alarcon PA, Donovan ME, Forbes GB, Landaw S, Stockman JA. 3d. Iron absorption in the thalassemia syndromes and its inhibition by tea N Engl J Med. 1979;300:5-8.
70. Celada A, Rudolf H, Donath A. Effect of experimental chronic alcohol ingestion and folic acid deficiency on iron absorption Blood. 1979;54:906-15.
71. Conrad ME, Barton JC. Anemia and iron kinetics in alcoholism Semin Hematol. 1980;17:149-63.
72. LeSage GD, Baldus WP, Fairbanks VF, Baggenstoss AH, McCall JT, Moore SB, et al. Hemochromatosis: genetic or alcohol-induced? Gastroenterology. 1983;84:1471-7.
73. Nienhuis AW. Vitamin C and iron [Editorial] N Engl J Med. 1981;304:170-1.
74. Brissot P, Deugnier Y, Le Treut A, Regnouard F, Simon M, Bourel M. Ascorbic acid status in idiopathic hemochromatosis Digestion. 1978;17:469-87.
75. McLaren CJ, Bett JH, Nye JA, Halliday JW. Congestive cardiomyopathy and haemochromatosis-rapid progression possibly accelerated by excessive ingestion of ascorbic acid Aust N Z J Med. 1982;12:187-8.
76. Brissot P, Le Treut A, Dien G, Cottencin M, Simon M, Bourel M. Hypovitaminemia A in idiopathic hemochromatosis and hepatic cirrhosis. Role of retinol-binding protein and zinc Digestion. 1978;17:469-78.
77. Barton JC, Patton MA, Edwards CQ, Griffen LM, Kushner JP, Meeks RG, et al. Blood lead concentrations in hereditary hemochromatosis J Lab Clin Med. 1994;124:193-8.
78. Butt EM, Nusbaum RE, Gilmour TC, DiDio SL. Trace metal patterns in disease states. Hemochromatosis, Bantu siderosis and iron storage in Laennec's cirrhosis and alcoholism. In: Seven MJ, Johnson LA, eds. Metal-Binding in Medicine: Proceedings of a Symposium. Philadelphia: JB Lippincott; 1960:43-9.
79. Olatunbosun D, Corbett WE, Ludwig J, Valberg LS. Alteration of cobalt absorption in portal cirrhosis and idiopathic hemochromatosis J Lab Clin Med. 1977;75:754-62.
80. Altstatt LB, Pollack S, Feldman MH, Reba RC, Crosby WH. Liver manganese in hemochromatosis Proc Soc Exp Biol Med. 1967;124:353-5.
81. Spencer H, Sontag SJ, Derler J, Osis D. Intestinal absorption of iron in patients with hemochromatosis Ann N Y Acad Sci. 1988;526:336-8.
82. Adams PC, Bradley C, Frei JV. Hepatic zinc in hemochromatosis Clin Invest Med. 1991;14:16-20.
83. Barton JC, Bertoli LF. Zinc gluconate lozenges for treating the common cold [Letter] Ann Intern Med. 1997;126:738-9.
84. Muench KH. Hemochromatosis and infection: alcohol and iron, oysters and sepsis Am J Med. 1989;87:40N-3N.
85. Bullen JJ, Spalding PB, Ward CG, Gutteridge JM. Hemochromatosis, iron and septicemia caused by Vibrio vulnificus Arch Intern Med. 1991;151:1606-9.
86. Hlady WG, Klontz KC. The epidemiology of Vibrio infections in Florida, 1981-1993 J Infect Dis. 1996;173:1176-83.
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