James C. Barton

Management of Hemochromatosis

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]. Table 1. Evaluation of Patients with Hemochromatosis and Iron Overload 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]. Table 2. Criteria for initiating Therapeutic Phlebotomy in Homozygotes or Heterozygotes for Hemochromatosis Gene or Genes and Other Persons with a Hemochromatosis Phenotype, Regardless of Genotype* 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 physicians office but can be done in a medical laboratory, a blood bank, or a patients home. However, comprehensive management of hemochromatosis is usually accomplished best in a physicians 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 g/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 a

A survey of 2,851 patients with hemochromatosis:: Symptoms and response to treatment

PURPOSE Hemochromatosis is a genetic disorder of iron absorption that affects 5 per 1,000 persons and is associated with reduced health and quality of life. We sought to determine the type and frequency of symptoms that patients experienced before the diagnosis and the treatments that they received. METHODS We mailed a questionnaire to 3,562 patients with hemochromatosis who were located using patient advocacy groups, physicians, blood centers, newsletters, and the Internet. RESULTS Of the 2,851 respondents, 99% were white and 62% were men. Circumstances that led to diagnosis of hemochromatosis included symptoms (35%), an abnormal laboratory test (45%), and diagnosis of a family member with hemochromatosis (20%). The mean (+/- SD) age of symptom onset was 41 +/- 14 years. Symptoms had been present for an average of 10 +/- 10 years before the diagnosis was made. Among the 58% of patients with symptoms, 65% had physician-diagnosed arthritis and 52% had liver disease. The most common and troublesome symptoms were extreme fatigue (46%), arthralgia (44%), and loss of libido (26%). Physician instructions to patients included treatment with phlebotomy (90%), testing family members (75%), and avoiding iron supplements (65%). CONCLUSIONS The diagnosis of hemochromatosis in most patients was delayed. Physician education is needed to increase the detection of patients with the disease and to improve its management.

Prophylactic Dosing of Anti Inhibitor Coagulant Complex (FEIBA) Reduces Bleeding Frequency In Hemophilia A Patients with Inhibitors Results of the Pro FEIBA Study

Hemochromatosis is a common genetic disorder in which iron may progressively accumulate in the liver, heart, and other organs. The primary goal of therapy is iron depletion to normalize body iron stores and to prevent or decrease organ dysfunction. The primary therapy to normalize iron stores is phlebotomy. In this opinion article, we discuss the indications for and monitoring of phlebotomy therapy to achieve iron depletion, maintenance therapy, dietary and pharmacologic maneuvers that could reduce iron absorption, and the role of voluntary blood donation.

Ferroportin 1 (SCL40A1) variant associated with iron overload in African-Americans.

We find that in the Black American population average ferritin levels are higher than those in Whites, both among men and women. African-Americans have an increased prevalence of iron storage disease characterized by prominent iron deposition in macrophages of the liver and other organs. The iron distribution in patients with mutations of the ferroportin gene is similar. A c.744 G-->T (Gln 248 His) mutation was detected among African-Americans at polymorphic frequencies. This variant is associated with increased ferritin levels in African-Americans and may play a role in their propensity to develop iron overload.

Iron overload in African Americans

PURPOSE Iron overload unexplained by dietary or medicinal iron excess, transfusion, or sideroblastic anemia has been described infrequently in Americans of African descent. The purpose of this study was to characterize iron overload attributable to excessive iron absorption in African Americans. PATIENTS AND METHODS In a community hematology and medical oncology practice during the interval 1990 to 1993, we identified and evaluated a series of cases comprised of 6 men and 1 woman, with a mean age of 55 +/- 14 (SD) years (range 33 to 69). Data on clinical features, serum iron parameters, liver and body iron stores, evaluations of anemia, human leukocyte antigen (HLA) typing, and family studies were analyzed. RESULTS Among our patients, the serum iron parameters were: iron concentration 26 +/- 13 mumol/L, transferrin saturation 59 +/- 21%, and ferritin concentration 1,588 +/- 1,053 micrograms/L. Clinical abnormalities observed included weakness and fatigue, decreased libido and impotence, hepatopathy, arthropathy, diabetes mellitus, hypogonadotrophic hypogonadism, and hyperpigmentation. Hepatic parenchymal cell iron deposits were increased in each of the 6 patients studied, and Kupffer cell iron deposits were prominent in 4. The occurrence of iron overload was verified by liver iron quantification and therapeutic phlebotomy. Four subjects had alpha-thalassemia minor; 2 others had hemoglobin S and C traits. No proband had HLA-A3 positivity. Four probands had other family members with iron overload. CONCLUSIONS In comparison with Caucasians with hemochromatosis, our patients have slightly lower mean values of serum iron concentration and transferrin saturation, more Kupffer cell iron deposits, a higher incidence of thalassemia and hemoglobinopathy, and infrequent positivity for HLA-A3. Iron overload in African Americans appears to be more similar to that in certain sub-Saharan African natives than to hemochromatosis.

Hemochromatosis and Iron Overload Screening (HEIRS) study design for an evaluation of 100,000 primary care-based adults.

BackgroundThe HEIRS Study will evaluate the prevalence, genetic and environmental determinants, and potential clinical, personal, and societal impact of hemochromatosis and iron overload in a multiethnic, primary care-based sample of 100,000 adults over a 5-year period. Participants are recruited from 5 Field Centers. Laboratory testing and data management and analysis are performed in a Central Laboratory and Coordinating Center, respectively. MethodsParticipants undergo testing for serum iron measures and common mutations of the hemochromatosis gene (HFE) on chromosome 6p and answer questions on demographics, health, and genetic testing attitudes. Participants with elevated values of transferrin saturation and serum ferritin and/or C282Y homozygosity are invited to undergo a comprehensive clinical examination (CCE), as are frequency-matched control subjects. These examinations provide data on personal and family medical history, lifestyle characteristics, physical examination, genetic counseling, and assessment of ethical, legal, and social implications. Primary and secondary causes of iron overload will be distinguished by clinical criteria. Iron overload will be confirmed by quantification of iron stores. Recruiting family members of cases will permit DNA analysis for additional genetic factors that affect iron overload. ResultsOf the first 50,520 screened, 51% are white, 24% are African American, 11% are Asian, 11% are Hispanic, and 3% are of other, mixed, or unidentified race; 63% are female and 37% are male. ConclusionsInformation from the HEIRS Study will inform policy regarding the feasibility, optimal approach, and potential individual and public health benefits and risks of primary care-based screening for iron overload and hemochromatosis.

Calcium Inhibition of Inorganic Iron Absorption in Rats

Calcium significantly diminishes the absorption of ferrous and ferric iron in a dose-related manner, whether the test doses of calcium and radioiron are administered orally or introduced into isolated intestinal segments; the effect is maximal in the duodenum and jejunum. Electron microscopic observations and quantitative studies of the mucosal uptake and transfer of iron show that calcium decreases the entry of iron into the microvilli of intestinal epithelial cells. Animals fed a high-calcium, iron-replete diet developed iron depletion; animals consuming high-calcium food of marginal iron content developed mild iron deficiency anemia. Further, more radioiron was absorbed from human milk than either bovine milk or human milk supplemented with calcium. These data suggest that individuals consuming a high-calcium diet contain marginal amounts of iron could develop iron deficiency anemia and may explain why infants who are fed cows milk have a greater incidence of iron deficiency anemia than those fed human milk.

Ultrastructural localization of transferrin, transferrin receptor, and iron‐binding sites on human placental and duodenal microvilli

Ultrastructural methods were used to determine the subcellular location of the transferrin receptor, transferrin and iron‐binding sites on human term placenta and human duodenum microvillus surfaces. The transferrin receptor and transferrin were localized by immunocytochemical methods employing either OKT9, a human transferrin receptor monoclonal antibody, or mouse anti‐human transferrin (ATfn), both followed by a horseradish peroxidase (HRP)‐conjugated goat anti‐mouse IgG (GAM‐HRP) and diaminobenzidine (DAB) sequence. Iron‐binding sites were localized by acid ferrocyanide (AF) staining after saturation of tissue specimens with iron, accomplished with iron nitrilotriacetate (FeNTA), a known transferrin iron donor. Placental microvillus surfaces demonstrated staining for the OKT9‐GAM‐HRP‐DAB‐reactive transferrin receptor, ATfn‐GAM‐HRP‐DAB‐reactive transferrin, and FeNTA‐AF‐reactive iron acceptor, whereas enterocyte microvillus surfaces lacked significant staining with each of these methods. FeNTA‐AF stained iron‐binding substance in placental and enterocyte microvilli and cytoplasmic matrix. Thus using the same ultrastructural immunostaining and cytochemical methods transferrin receptor, transferrin, and nitrilotriacetate iron acceptor sites can be demonstrated on the microvillus surface of human placenta but not on the microvillus surface of human duodena.

Beneficial effects of hepatitis in patients with acute myelogenous leukemia.

Of 50 consecutive patients admitted with acute myelogenous leukemia, 30 developed complete remissions on antileukemic therapy. Nineteen of the 30 repeatedly had elevated serum glutamic oxalacetic transaminase (SGOT) concentrations 3 to 14 weeks after the start of therapy. Patients with SGOT elevations had a significantly greater chance of remission and a longer survival (76 +/- 11 weeks) than those with normal SGOT levels (39 +/- 5 weeks), suggesting that hepatitis may have a beneficial effect in acute myelogenous leukemia. The hepatitis was mild in all patients. Review of patients at this institution alive 2 years after the diagnosis of acute myelogenous leukemia showed that they repeatedly had elevated SGOT levels. We believe that most had non-A, non-B post-transfusion hepatitis, which may have a beneficial effect on the leukemia or serve as an indicator of patients who have greater immunocompetence and thus a better prognosis.

Intravenous iron dextran therapy in patients with iron deficiency and normal renal function who failed to respond to or did not tolerate oral iron supplementation.

PURPOSE To evaluate the safety and effectiveness of using 500-mg doses of iron as intravenous iron dextran after premedication with diphenhydramine, cimetidine, and dexamethasone. SUBJECTS AND METHODS We treated 135 iron-deficient adults (26 men, 109 women) with normal renal function (serum creatinine level </=1.5 mg/dL or blood urea nitrogen level </=26 mg/dL) who could not be treated adequately with oral iron supplements due to gastrointestinal symptoms (59%), inadequate hematologic response (39%), severe anemia (19%), or noncompliance (4%). Some patients had more than one reason for treatment. Resolution of iron deficiency was defined as the restoration of transferrin saturation, serum ferritin level, anemia, and abnormal erythrocyte indexes to normal or baseline values. RESULTS Before treatment with iron dextran, patients had a mean (+/- SD) transferrin saturation of 8% +/- 5%, a median serum ferritin level of 11 ng/mL, and a mean hemoglobin level of 10 +/- 2 g/dL. Ninety-two percent were anemic; 60% had unrecognized or untreated causes of anemia other than iron deficiency. We administered 285 iron dextran infusions (median 2, mean 2 infusions per patient; range 1 to 7). Eighty-seven percent of patients had no adverse reaction; 13% had mild reactions, especially arthralgias and myalgias. No patient had an anaphylaxis-like reaction. Fifty-four (40%) patients had resolution of iron deficiency, 34 (25%) continue to receive therapy, 36 (27%) returned to the care of their primary physician, and 11 (8%) died before iron repletion could be achieved. CONCLUSIONS Iron-deficient adults with normal renal function who cannot be treated adequately with oral iron supplements can be treated effectively and safely with this intravenous iron dextran regimen.