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Management of Hemochromatosis
- James C. Barton, MD;
- Sharon M. McDonnell, MD, MPH;
- Paul C. Adams, MD;
- Pierre Brissot, MD;
- Lawrie W. Powell, MD;
- Corwin Q. Edwards, MD;
- James D. Cook, MD;
- Kris V. Kowdley, MD; and
- The Hemochromatosis Management Working Group*
- From Southern Iron Overload Disorders Center, Birmingham, Alabama; Centers for Disease Control and Prevention, Atlanta, Georgia; London Health Sciences Centre, London, Ontario, Canada; Hopital Universitaire Pontchaillou, Rennes, France; University of Queensland, Brisbane, Australia; University of Utah College of Medicine and LDS Hospital, Salt Lake City, Utah; University of Kansas Medical Center, Kansas City, Kansas; and University of Washington, Seattle, Washington. *The Hemochromatosis Management Working Group also includes Linda Cocchiarella, MD, MSc; James S. Dooley, MD; Vincent Fellitti, MD; David Brandhagen, MD; Victor Herbert, MD, JD; and Margit A. Krikker, MD. Acknowledgments: The authors thank Dr. Anne C. Looker of the National Center for Health Statistics for reviews of data on age, sex, and serum iron variables from the National Health and Nutrition Examination Survey. Grant Support: In part by Maternal and Child Health Branch, Division of Nutrition, Centers for Disease Control and Prevention (Atlanta, Georgia) and Southern Iron Disorders Center (Birmingham, Alabama). Requests for Reprints: James C. Barton, MD, Southern Iron Disorders Center, Suite G-105, 2022 Brookwood Medical Center Drive, Birmingham, AL 35209; e-mail, ironmd{at}mem.po.com. Current Author Addresses: Dr. Barton: Southern Iron Overload Disorders Center, suite G-105, 2022 Brookwood Medical Center Drive, Birmingham, AL 35209. Dr. McDonnell: Centers for Disease Control and Prevention, Division of Nutrition and Physical Activity, 4770 Buford Highway Mailstop K-25, Atlanta, GA 30341-3724. Dr. Adams: Department of Medicine, London Health Sciences Centre, University Campus, 339 Windermere Road, PO Box 5339, London, Ontario N6A 5A5, Canada. Dr. Brissot: Clinique des Maladies du Foie, Unite INSERM U49, Hopital Universitaire Pontchaillou, 35033 Rennes, France. Dr. Powell: The University of Queensland, Queensland Institute of Medical Research, The Bancroft Center, 300 Herston Road, Brisbane 4029 QLD, Australia. Dr. Edwards: Department of Medicine, University of Utah College of Medicine and LDS Hospital, Outpatient Clinic, 325 8th Avenue, Salt Lake City, UT 84143. Dr. Cook: Division of Hematology, University of Kansas Medical Center, 39th and Rainbow, Kansas City, KS 66103. Dr. Kowdley: Division of Gastroenterology and Hepatology, RG-24, University of Washington, Seattle, WA 98195. Note: This article is one of a series of articles comprising an Annals of Internal Medicine supplement entitled “Iron Overload, Public Health, and Genetics.” To view a complete list of the articles included in this supplement, please view its Table of Contents.
Abstract
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.
Diagnosis and Initial Evaluation
Diagnosis of Hemochromatosis
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].
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
Described in 1952, therapeutic phlebotomy was the first successful treatment for iron overload due to hemochromatosis [15] and is still the preferred treatment for this condition today [1, 2]. The removal of 1 unit of blood (450 to 500 mL) results in the loss of 200 to 250 mg of iron. Although iron chelation and erythrocytapheresis have also been used [16, 17], therapeutic phlebotomy is safer, more efficient, and more economical [1, 2].
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].
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].
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
Hepatic Disorders
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 α-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 α-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
Iron Intake and Absorption
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).
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
Physicians can expect to diagnose and treat increasing numbers of persons with hemochromatosis because awareness of the frequency and diagnostic criteria of hemochromatosis and the multisystem disease caused by iron overload is increasing. Early diagnosis and therapeutic phlebotomy to maintain low normal body iron stores can prevent all known complications of hemochromatosis. Most patients with hemochromatosis who have developed iron overload before diagnosis also benefit from therapeutic phlebotomy. Many will need additional evaluation and treatment of complications of iron overload, including hepatic disorders, joint disease, diabetes mellitus and other endocrinopathic conditions, and cardiac dysfunction. Proper dietary management can decrease the rate of iron reaccumulation and can reduce or avoid complications of hepatic disease, diabetes mellitus, and Vibrio infection in patients with hemochromatosis. This comprehensive approach to the management of hemochromatosis can decrease the frequency and severity of iron overload, improve quality of life, and increase longevity.
- Copyright ©2004 by the American College of Physicians
References
- 1.↵
- 2.↵
- 3.↵
- 4.↵
- 5.↵
- 6.↵
- 7.↵
- 8.↵
- 9.↵
- 10.↵
- 11.↵
- 12.↵
- 13.↵
- 14.↵
- 15.↵
- 16.↵
- 17.↵
- 18.↵
- 19.↵
- 20.↵
- 21.↵
- 22.↵
- 23.↵
- 24.↵
- 25.↵
- 26.↵
- 27.↵
- 28.↵
- 29.↵
- 30.↵
- 31.↵
- 32.↵
- 33.↵
- 34.↵
- 35.↵
- 36.↵
- 37.↵
- 38.↵
- 39.↵
- 40.↵
- 41.↵
- 42.↵
- 43.↵
- 44.↵
- 45.↵
- 46.↵
- 47.↵
- 48.↵
- 49.↵
- 50.↵
- 51.↵
- 52.↵
- 53.↵
- 54.↵
- 55.↵
- 56.↵
- 57.↵
- 58.↵
- 59.↵
- 60.↵
- 61.↵
- 62.↵
- 63.↵
- 64.↵
- 65.↵
- 66.↵
- 67.↵
- 68.↵
- 69.↵
- 70.↵
- 71.↵
- 72.↵
- 73.↵
- 74.↵
- 75.↵
- 76.↵
- 77.↵
- 78.↵
- 79.↵
- 80.↵
- 81.↵
- 82.↵
- 83.↵
- 84.↵
- 85.↵
- 86.↵
