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Toxicity of parenteral iron dextran therapy
Kidney International, Vol. 55, Suppl. 69 (1999), S-119–S-124
RISKS AND SIDE EFFECTS OF IRON THERAPY
Toxicity of parenteral iron dextran therapy DAVID L. BURNS and JAMES J. POMPOSELLI Nutrition Support Service, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
Toxicity of parenteral iron dextran therapy. Parenteral iron dextran is efficacious and safe for iron repletion in patients with iron-deficiency anemia. The risk for developing reactions to parenteral iron infusion can be attenuated if patients are carefully selected. Patients with underlying autoimmune disease, malnutrition with indolent infection, and risk for iron overload syndromes should be carefully monitored for complications. Further, the rate of infusion and the route of administration of iron dextran play roles in the risk of adverse reactions. The purpose of this review is to identify and elucidate the mechanisms of the acute and chronic toxicities associated with parenteral iron dextran use.
Iron deficiency is the most common cause of anemia worldwide. The causes of iron deficiency include inadequate intake, chronic body loss, or a combination of both. Usually, repletion of iron stores can be simply achieved with increased oral iron intake in the form of supplements. However, some patients are intolerant to oral iron therapy or have gastrointestinal dysfunction that prohibits achieving adequate intake through dietary means. Under these circumstances, parenteral iron repletion provides a means to replete total body iron stores. Generally, parenteral iron therapy is safe and efficacious, but injudicious use can be toxic and can lead to significant morbidity and/or mortality (Table 1). Parenteral iron dextran has been used to replete iron stores in patients on chronic hemodialysis, with chronic gastrointestinal losses, and in surgical patients refusing blood transfusion. Adverse reactions included range from mild acute allergic to severe anaphylactic reactions, exacerbation of autoimmune disease, muscle disease, connective tissue malignancy, iron overload syndromes, and infection with impaired immunity. Multiple authors have documented the safety of parenteral iron therapy both in the nonuremic and hemodialysis-dependent patient population [1–5]. However, the toxicity profile and mechanisms of these reactions need to be clarified so that risks associated with parenteral iron can be reduced. Key words: anemia, malnutrition, iron deficiency, hemodialysis, blood transfusion.
1999 by the International Society of Nephrology
PARENTERAL IRON SIDE-EFFECTS Approximately 26% of all patients receiving parenteral iron therapy experience side-effects, but the majority are self-limited and mild. Three percent of patients have more severe symptoms, with 0.1% to 0.6% developing life-threatening anaphylaxis [4]. Most reactions to parenteral iron therapy occur immediately during administration of the test dose and may include dyspnea, headache, flushing, chest pain, abdominal or back pain, nausea, emesis, bronchospasm, fever, seizures, hypotension, urticaria, and anaphylaxis. Delayed reactions occurring one to three days after infusion are related to deposition of iron in tissues and include myalgia, arthralgia, phlebitis, and lymphadenopathy. In a review of 2400 patients who received parenteral iron dextran therapy, Wallerstein reported that only 1% to 2% of patients experienced significant side-effects [5]. Most of reactions were mild and transient and were similar regardless of the route of administration (intramuscular vs. intravenous). No fatalities were reported in this series. Hamstra et al studied 481 patients given intravenous iron dextran at doses ranging from 250 to 500 mg infused at a rate of approximately 100 mg per minute. Overall, 125 patients (26%) experienced side-effects, most of which were mild and self-limiting. Eight were delayed reactions characterized by arthralgia, myalgia, fever, adenopathy, thrombophlebitis, pulmonary embolism, or erythema nodosum. Three of 481 patients developed lifethreatening anaphylactoid reactions characterized by hypotension, cyanosis, syncope, bronchospasm, purpura, and respiratory arrest. Severe reactions were associated with infusion of larger iron doses (more than 500 mg). Side-effects were more prevalent in small women, especially those with pre-existing collagen vascular disease [4]. Auerbach et al studied iron dextran infusion in 87 patients with iron-deficiency anemia to determine the side-effect profile, optimal rate of infusion, the role of premedication consisting of diphenhydramine, methylprednisolone, and subcutaneous epinephrine to avoid symptoms [6]. Two patients had anaphylactoid reactions in response to the test dose. Symptoms were relieved
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Table 1. Side-effects and complications of parenteral iron dextran Short-term Anaphylaxis Hypotension Bronchospasm Fever Arthalgia Myalgia Lymphadenopathy Chest, back or abdominal pain Infection Long-term complications (both i.m. and i.v.) Iron overload syndrome Complications of intramuscular administration Chronic pain at the site of injection Skin staining Local skin atrophy Abscess Sarcoma formation
Urticaria Nausea or emesis Pruritis Seizures Headache Flushing Phlebitis Rigors
with intravenous diphenhydramine, methylprednisolone, and subcutaneous epinephrine. Delayed transient reactions of myalgia, arthralgia, and fever occurred in 37 patients and were controlled with nonsteroidal anti-inflammatory agents. The group recommended that the total dose infusion of iron dextran was safe if patients received a test dose and if the infusion rate did not exceed 6 mg per minute. Anemia in patients with end-stage renal disease on hemodialysis is common, and parenteral iron supplementation is frequently employed in this patient population. Fishbane et al reviewed 573 patients on dialysis that were treated with iron dextran. Twenty-seven (4.7%) had adverse reactions related to iron administration. Four (0.7%) patients had serious complications, one of which was a cardiac arrest, and three were hospitalized. Ten (1.7%) had anaphylactoid reactions and were treated with antihistamines, steroids, or epinephrine. In 22 (3.8%) patients, reactions led to discontinuance of the iron dextran infusion. Of all reactions, five occurred to the test dose that was 50 mg or less of iron dextran, although it is unclear whether all patients received test doses [1]. The mechanism(s) leading to iron dextran-induced symptoms remains unclear but is probably multifactorial. Novey et al studied renal dialysis patients who developed anaphylactoid reactions after parenteral iron therapy [7]. Tests performed included measurement of iron dextraninduced in vitro basophil degranulation and histamine release, formation of type I anaphylaxis specific IgE antibody, and immune complex activation by specific IgG antibody. Six patients undergoing hemodialysis who previously received iron dextran without reaction served as controls. Of the study patients, only one demonstrated positive basophil histamine release test and formed specific IgG to iron dextran. Interestingly, this patient suf-
fered from systemic lupus erythematosis, suggesting that patients with autoimmune disease may be more sensitive to iron dextran therapy. There are several reports of the safe administration of iron dextran to patients with prior episodes of allergic type reactions. Monaghan et al provide a case report of an 83-year-old man with iron-deficiency anemia secondary to chronic gastrointestinal blood loss from an unknown etiology. The patient underwent multiple endoscopic evaluations, but the source of the bleeding could not be located. After several blood transfusions, oral iron-repletion therapy was attempted but was unsuccessful because of gastrointestinal intolerance. Parenteral total dose iron therapy was planned, and the patient was given a test dose of 25 mg of iron dextran over five minutes. After one minute, the patient developed an anaphylactoid response characterized by hypotension, chest pain, and syncope, necessitating admission to the intensive care unit. Despite this dramatic reaction to parenteral iron, a desensitization protocol was attempted with iron dextran after the patient recovered. A pretreatment protocol with methylprednisolone, diphenhydramine, and ephedrine was administered prior to infusion of 1 mg of iron dextran on day 1. Escalating doses of parenteral iron dextran were safely administered over next several days after pretreatment until a total dose of 2 g was achieved. The patient tolerated the iron infusions well without further allergic reaction [8]. Porter, Blackburn and Bistrian reported on a 30-yearold man with Crohn’s disease who was hospitalized for a flare with abdominal pain and diarrhea. Laboratories demonstrated a mixed anemia of chronic disease and iron deficiency. Bowel rest and total parenteral nutrition (TPN) via a central venous catheter were initiated. The standard maintenance dose of 2 mg of iron dextran was provided daily in the TPN, and this was well tolerated. Because of low serum iron levels, parenteral iron therapy was commenced after a test dose of 25 mg of iron dextran in 100 cc D5W was given over five minutes. Within minutes of the infusion, the patient experienced severe backache, extremity pain, and headache. The test dose was discontinued, and diphenhydramine and meperidine were given, with resolution of symptoms. Subsequently, TPN containing 2 mg of iron dextran per day was administered and was well tolerated [9]. IRON AND AUTOIMMUNE DISEASE Total dose infusions of iron dextran have been reported to exacerbate symptoms of rheumatoid arthritis and collagen vascular disease and have been associated with a greater incidence of anaphylaxis in this population. In a study of 11 patients with rheumatoid arthritis given total dose infusions of iron dextran, Blake et al found that two patients had anaphylactic reactions and
Burns and Pomposelli: Toxicity of parenteral iron dextran therapy
that nine had an exacerbation of synovitis. Quantitative infrared thermal imaging demonstrated increased joint inflammation in eight of the patients imaged. The exacerbation of synovitis occurred 24 to 48 hours after the iron dextran infusion. This corresponded with increased saturation of the serum iron-binding capacity [10]. Iron dextran infusion has been reported to have induced systemic lupus erythematosis in a patient with a history of polyarthritis but no serologic evidence of lupus [11]. A 36-year-old Chinese female developed iron-deficiency anemia from menorrhagia and was treated with total dose iron therapy. Two days after receiving 2 g of iron dextran, she developed a malar rash, polyarthritis, periungual vasculitis, elevated erythrocyte sedimentation rate to 122 mm, positive antinuclear antibody (ANA) at 1:320 dilution and anti-double-stranded DNA antibody (anti-DS DNA) 25.3 mg/liter. The illness resolved rapidly after five days of prednisolone, and her disease was at baseline eight months later with ANA titer at 1:80 and undetectable anti-DS DNA. Two years later, the patient was rechallenged with 20 mg of intravenous iron dextran and again developed polyarthritis, leukopenia, lymphopenia, an ANA 1:160, and anti-DS DNA 20.9 mg/liter. The proposed mechanism(s) of the increased likelihood of adverse reactions to iron dextran in patients with collagen vascular disease includes hypersensitivity to dextran, direct toxic effects of iron on synovium by the generation of free radicals and peroxidation of lipids, and/or reticuloendothelial system blockade resulting in a secondary immune complex synovitis [10, 12, 13]. IRON-INDUCED MUSCLE DISEASE Foulkes et al reported a case of rhabdomyolysis after parenteral iron administration, a 59-year-old man with chronic malabsorption, selective IgA deficiency, and severe iron-deficient anemia. Additionally, the patient was selenium and vitamin E deficient. The patient was intolerant to oral iron therapy and received several intramuscular injections of iron dextran over a four-week period. Eighteen days later, he developed severe generalized myalgia, muscle weakness, and dark urine. Creatine kinase was 20,400 IU/liter. Urinary myoglobin was strongly positive, and muscle biopsy demonstrated regenerating myocytes. Autoimmune markers remained negative, suggesting against autoimmune polymyositis. The authors propose that deficiencies of vitamin E and selenium in conjunction with parenteral iron resulted in free radical oxidative injury to muscle membranes and rhabdomyolysis [14]. Therefore, patients receiving parenteral iron therapy should be screened for other micronutrient and macronutrient deficiencies. Although not proven, there may be an association between intramuscular iron injection and the develop-
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ment of neoplasm. Greenberg reviewed 90 cases of sarcoma of the buttock and noted that four patients had received intramuscular iron compounds [15]. The first patient was an 18-year-old man who developed a fibrosarcoma of the left buttock two years after receiving injections of Jectofer, iron sorbitol, and citric acid compound in the same buttock. Similarly, a 40-year-old woman received Jectofer for anemia of pregnancy, and four years later, she developed myxoid liposarcoma of the right buttock. Two patients developed neoplasms after intramuscular iron dextran as well. One was a 35year-old woman who was given iron dextran for anemia of pregnancy. She developed a rhabdomyosarcoma of the right buttock 13 years later. In another case, a 51year-old woman received intramuscular injections of iron dextran in the buttock for iron-deficiency anemia. Several months later, a palpable thickening occurred at the injection site. Biopsy revealed poorly differentiated chondrosarcoma [15]. Although there is no definitive evidence that intramuscular iron therapy results in neoplasm formation, we have used the intravenous route for our own patients to avoid potential complications and discomfort of intramuscular injection. IRON OVERLOAD The improper administration of iron can result in excess iron stores. The oral recommended daily allowance of iron is 15 mg/day, with healthy adults absorbing 5% to 10% of dietary iron. This is the basis for the estimated parenteral need for approximately 1 mg/day. This amount offsets obligate losses from desquamation of skin and mucosa from gut and genitourinary tract. The body’s ability to excrete parenterally administered iron is limited to these daily losses and to losses during phlebotomy or hemodialysis. Excess dietary or parenteral iron is sequestered by the reticuloendothelial system and can result in hepatosplenic siderosis. Hepatosplenic siderosis is a secondary cause of iron overload, whereas hereditary hemochromatosis (HH) represents a primary etiology. The genetic frequency of HH in the United States and Europe is 0.2% to 0.7% for homozygotes and 8% to 14% for heterozygotes [16]. Patients with homozygous or heterozygous HH are at increased risk for developing iron overload without iron supplementation, and baseline iron status should be established prior to provision of parenteral iron. Fleming et al performed five biopsies and reviewed 17 autopsy liver specimens in 22 patients receiving chronic hemodialysis for renal failure. Of these, 13 patients were treated with parenteral iron dextran. Specimens were assessed for hepatic iron content and histologic iron deposition. Five patients had mild hepatic fibrosis with iron present in hepatocytes. Two patients had high hepatic
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iron concentrations in excess of 1000 mg per 100 mg dry weight. Eight patients had elevated serum ferritin concentrations some in conjunction with fibrosis [17]. In a histologic study of spleens obtained from 40 patients on maintenance hemodialysis treated with iron dextran, Murray et al demonstrated that 24 of the specimens (60%) had massive splenic iron loading [18]. Patients routinely received 250 mg of parenteral iron dextran per month until serum ferritins became elevated, and then supplements were discontinued. The amount of splenic deposition correlated with the total amount of iron dextran administered. Ali et al studied the relationship between serum ferritin and iron deposition in the liver, spleen, and bone marrow in 36 patients with chronic renal failure. Patients had received a mean of 5450 mg of elemental iron as iron dextran. Twenty-three of 36 patients had advanced hepatosplenic siderosis with three to four plus iron deposits, which correlated with elevations in serum ferritins. However, in 10 of the iron-overloaded patients, bone marrow specimens were iron depleted [19]. These studies were limited in that patients did not receive erythropoietin therapy. Erythropoietin facilitates rapid transfer of iron sequestered in the liver and spleen to the bone marrow for developing red blood cells. The development of iron overload is facilitated by parenteral administration of iron because the intestinal regulatory mechanisms are bypassed. IRON AND INFECTION Infection and injury initiate a systemic inflammatory response (SIR), the goals of which are to limit injury, aid tissue repair, and augment immunity. Classic responses include fever, hypotension, tachycardia, hyperglycemia, increased protein catabolism, and decreased iron-transferrin saturation while increasing serum levels of copper and zinc. Elevated release of cytokines are the hallmark and include interleukin-1, tumor necrosis factor, and interleukin-6 [20]. These occur in conjunction with elevated levels of glucagon, cortisol, and epinephrine and serve to mediate the metabolic cascade of the systemic inflammatory response. Several authors have demonstrated that in vitro supplementation of iron can overcome natural immunity [21–23]. In general, doubling the saturation of the ironbinding protein in animal models yields a marked increase in the growth of various pathogens. Microorganisms require iron for growth and must acquire iron from their host. Microbes synthesize iron transport proteins or siderophores that compete with transferrin for free iron. Depressed serum iron levels, a physiological defense mechanism, have been documented during sepsis and may be mediated by interleukin-1 [22]. Proposed
mechanisms include decreased intestinal iron absorption and cytokine-mediated sequestration of iron into tissue stores, predominantly with the flux of iron into the reticuloendothelial system and the liver [21–23]. The relationship between infection and iron deficiency is unclear and remains controversial [24]. McFarlane et al studied 40 children with kwashiorkor-type malnutrition and low serum transferrin. Children were given nutritional support that included oral iron supplements. Many of the children who received iron therapy died shortly after supplements were begun, suggesting a temporal relationship [25]. The provision of iron in the setting of low serum transferrin may result in higher circulating free iron that could have contributed to the development overwhelming infection and death. Septicemia with Yersinia enterocolitica has been reported in healthy children who took overdoses of oral iron [26]. Iron-deficient Somali nomads treated with oral iron demonstrated a greater than fivefold increase in infectious complications compared with placebo, most of which represented reactivation of underlying malaria, brucellosis, or tuberculosis [27]. Seifert et al studied 39 patients with end-stage renal failure on maintenance hemodialysis that were treated with desferrioxamine. Desferrioxamine is a chelating agent used to reduce iron and/or aluminum stores in patients with overload. Twenty-three patients received desferrioxamine for aluminum-related bone disease and 16 patients due to iron overload. A control group consisted of 193 patients on maintenance dialysis who were not treated with desferrioxamine. There was no difference in the incidence of sepsis in the control group compared with patients with aluminum-related bone disease treated with desferrioxamine. The incidence of sepsis in the iron-overloaded group treated with desferrioxamine was almost three times that of the control group (0.36 vs. 0.12 sepsis episodes per patient therapy year, P , 0.001). To study the infectious risk of iron overload, patients on hemodialysis who had never received desferrioxamine were further subdivided. Patients were stratified according to serum ferritin levels: group I (ferritin 10 to 330 mg/liter, N 5 125), group II (ferritin 331 to 1000 mg/ liter, N 5 49), and group III (ferritin 1001 to 2000 mg/ liter, N 5 10). Patients with moderate-to-severe iron overload (groups II and III) had a significantly higher incidence of sepsis compared with controls (group I; 0.18 vs. 0.58 infections per patient therapy year, P , 0.01) [28]. Tielemans and Lenclud studied a similar patient population on maintenance hemodialysis never exposed to desferrioxamine [29]. The authors reviewed infectious risk according to cumulative exposure to hemodialysis expressed in patient-years. In patients with normal serum
Burns and Pomposelli: Toxicity of parenteral iron dextran therapy
ferritins representing 68 patient-years, only six infections occurred with one episode of life-threatening sepsis. Among 117 patient-years with serum ferritins greater than 500 mg/liter, there were 56 total infections, which included 33 episodes of sepsis (P , 0.00025) [25]. Several components of the immune response are iron mediated and may be depressed in the setting of deficiency. Kuvibidila et al fed mice iron-deficient diets and demonstrated atrophy of the thymus with depletion of T cells [30]. Chandra showed impaired numbers of circulating blood neutrophils and a capacity for the generation of the oxidative burst necessary to kill phagocytized bacteria in iron-deficient patients [31]. Iron overload can impair cellular immunity directly. Van Asbeck et al evaluated phagocytic function of monocytes in a patient with idiopathic hemochromatosis and Listeria monocytogenes meningitis. In this patient, initial phagocytic function was significantly diminished in monocytes and normalized completely after a series of therapeutic phlebotomies [32]. Similarly, Flament et al demonstrated decreased neutrophil phagocytosis and superoxide anion generation in patients on hemodialysis with elevated serum ferritin compared with controls [33]. Waterlot et al showed a decreased metabolic burst, myeloperoxidase activity, and phagocytic activity in neutrophils derived from patients on long-term hemodialysis that had iron overload with high serum ferritins [34]. These studies suggest that iron is a substrate for bacterial growth, and provision of iron in the setting of deficiency can promote bacterial infection or reactivation of latent infections. Further, iron overload is a risk factor for the development of infection secondary to impaired cellular immunity. CONCLUSION Parenteral iron therapy is relatively safe and very efficacious for repleting iron stores in patients with iron deficiency. The provision of parenteral iron should be limited to patients with documented iron deficiency who are unable to be repleted via the oral route. Patients need to be carefully screened for autoimmune diseases and underlying infection and need to be continuously screened for the development of iron-overload syndromes. Reprint requests to David Burns, M.D., 190 Quincy Avenue, Brockton, Massachusetts 02302–2895, USA.
REFERENCES 1. Fishbane S, Ungureanu V, Maesaka J, Kaupke C, Lim V, Wish J: The safety of intravenous iron dextran in hemodialysis patients. Am J Kidney Dis 28:529–534, 1996 2. Burns DL, Mascioli EA, Bistrian B: Parenteral iron dextran: A review. Nutrition 11:163–168, 1995
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3. Burns DL, Mascioli EA, Bistrian B: Effect of iron-supplemented total parenteral nutrition in patients with iron deficiency anemia. Nutrition 12:411–415, 1996 4. Hamstra RD, Block MH, Schocket AL: Intravenous iron dextran in clinical medicine. JAMA 243:1726–1731, 1980 5. Wallerstein RO: Intravenous iron-dextran complex. Blood 32:690–695, 1968 6. Auerbach M, Witt D, Toler W, Fierstein M, Lerner RG, Ballard H: Clinical use of the total dose intravenous infusion of iron dextran. J Lab Clin Med 111:566–570, 1988 7. Novey HS, Pahl MP, Haydik I, Vaziri ND: Immunologic studies of anaphylaxis to iron dextran in patients on renal dialysis. Ann Allergy 72:224–228, 1994 8. Monaghan MS, Glasco G, St. John G, Bradsher RW, Olsen KM: Safe administration of iron dextran to a patient who reacted to the test dose. South Med J 87:1010–1012, 1994 9. Porter KA, Blackburn GL, Bistrian B: Safety of iron dextran in total parenteral nutrition: A case study. J Am Coll Nutr 7:107– 110, 1988 10. Blake DR, Lunec J, Ahern M, Ring EF, Bradfield J, Gutteridge IM: Effect of intravenous iron dextran on rheumatoid synovitis. Ann Rheum Dis 44:183–188, 1985 11. Oh VMS: Iron dextran and systemic lupus erythematosis. BMJ 305:1000, 1992 12. Reddy PS, Lewis M: The adverse effect of intravenous iron-dextran in rheumatoid arthritis. Arthritis Rheum 12:454–457, 1969 13. Ron D: The reticuloendothelial system and rheumatoid arthritis. (letter) Lancet 2:901, 1979 14. Foulkes WD, Sewry C, Calam J, Hodgson HJF: Rhabdomyolysis after intramuscular iron-dextran in malabsorption. (abstract) Ann Rheum Dis 50:184–186, 1991 15. Greenberg G: Sarcoma after intramuscular iron injection. BMJ 3:1508–1509, 1976 16. Edwards CQ: Prevalence of hemochromatosis among 11,065 presumably healthy blood donors. N Engl J Med 318:1355–1359, 1988 17. Fleming LW, Hopwood D, Shephard AN, Stewart WK: Hepatic iron in dialysed patients given intravenous iron dextran. J Clin Pathol 43:119–124, 1990 18. Murray JA, Slater DN, Parsons MA, Fox M, Smith S, Platts MM: Splenic siderosis and parenteral iron dextran in maintenance haemodialysis patients. J Clin Pathol 37:59–64, 1984 19. Ali M, Fayemi AO, Rigolosi R, Frascino J, Marsden T, Malcolm D: Hemosiderosis in hemodialysis patients. JAMA 244:343–345, 1980 20. Casey LC, Balk RA, Bone RC: Plasma cytokine and endotoxin levels correlate with survival in patients with the sepsis syndrome. Ann Intern Med 119:771–777, 1993 21. Weinberg ED: Nutritional immunity. JAMA 231:39–41, 1975 22. Weinberg ED: Iron and infection. Microbiol Rev 42:45–66, 1978 23. Beisel WR: Trace elements in infectious processes. Med Clin N Am 60:831–849, 1976 24. Bothe A, Benotti P, Bistrian BR, Blackburn GL: Use of iron with total parenteral nutrition. (letter) N Engl J Med 239:1153, 1975 25. McFarlane H, Reddy S, Adcock KJ, Adeshina H, Cooke AR, Akene J: Immunity, transferrin and survival in kwashiorkor. BMJ 4:268–270, 1970 26. Melby K, Slordahl S, Gutteberg TJ, Nordbo SA: Septicaemia due to Yersinia enterocolitica after oral overdoses of iron. BMJ 285:467–485, 1982 27. Murray MJ, Murray AB, Murray MB, Murray CJ: The adverse effect of iron repletion on the course of certain infections. BMJ 2:1113–1115, 1978 28. Seifert A, Von Herrath D, Schaefer K: Iron overload, but not treatment with desferrioxamine favours the development of septicemia in patients on maintenance hemodialysis. Q J Med 248:1015– 1024, 1987 29. Tielemans C, Lenclud C: Respective role of haemosiderosis and desferrioxamine therapy in the risk from infection of hemodialysed patients. Q J Med 255:573–574, 1988 30. Kuvibidila S, Dardenne M, Savino W, Lepault F: Influence of
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iron-deficiency anemia on selected thymus functions in mice: Thymulin biological activity, T-cell subsets, and thymocyte population. Am J Clin Nutr 51:228–232, 1990 31. Chandra RK: Impaired immunocompetence associated with iron deficiency. J Pediatr 86:899–902, 1975 32. Van Asbeck BS, Verbrugh HA, Van Oost BA, Marx JJ, Imhof HW, Verhoff J: Listeria monocytogenes meningitis and decreased phagocytosis associated with iron overload. BMJ 284:542–544, 1982
33. Flament J, Goldman M, Waterlot Y, Dupont E, Wybran J, Vanherweghem JL: Impairment of phagocyte oxidative metabolism in hemodialyzed patients with iron overload. Clin Nephrol 25:227–230, 1986 34. Waterlot Y, Cantinieaux B, Hariga-Muller C, MaertelaereLaurent E, Vanherweghem JL, Fondu P: Impaired phagocytic activity of neutrophils in patients receiving hemodialysis: The critical role of iron overload. BMJ 291:501–504, 1985
RISKS AND SIDE EFFECTS OF IRON THERAPY
Toxicity of parenteral iron dextran therapy DAVID L. BURNS and JAMES J. POMPOSELLI Nutrition Support Service, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
Toxicity of parenteral iron dextran therapy. Parenteral iron dextran is efficacious and safe for iron repletion in patients with iron-deficiency anemia. The risk for developing reactions to parenteral iron infusion can be attenuated if patients are carefully selected. Patients with underlying autoimmune disease, malnutrition with indolent infection, and risk for iron overload syndromes should be carefully monitored for complications. Further, the rate of infusion and the route of administration of iron dextran play roles in the risk of adverse reactions. The purpose of this review is to identify and elucidate the mechanisms of the acute and chronic toxicities associated with parenteral iron dextran use.
Iron deficiency is the most common cause of anemia worldwide. The causes of iron deficiency include inadequate intake, chronic body loss, or a combination of both. Usually, repletion of iron stores can be simply achieved with increased oral iron intake in the form of supplements. However, some patients are intolerant to oral iron therapy or have gastrointestinal dysfunction that prohibits achieving adequate intake through dietary means. Under these circumstances, parenteral iron repletion provides a means to replete total body iron stores. Generally, parenteral iron therapy is safe and efficacious, but injudicious use can be toxic and can lead to significant morbidity and/or mortality (Table 1). Parenteral iron dextran has been used to replete iron stores in patients on chronic hemodialysis, with chronic gastrointestinal losses, and in surgical patients refusing blood transfusion. Adverse reactions included range from mild acute allergic to severe anaphylactic reactions, exacerbation of autoimmune disease, muscle disease, connective tissue malignancy, iron overload syndromes, and infection with impaired immunity. Multiple authors have documented the safety of parenteral iron therapy both in the nonuremic and hemodialysis-dependent patient population [1–5]. However, the toxicity profile and mechanisms of these reactions need to be clarified so that risks associated with parenteral iron can be reduced. Key words: anemia, malnutrition, iron deficiency, hemodialysis, blood transfusion.
1999 by the International Society of Nephrology
PARENTERAL IRON SIDE-EFFECTS Approximately 26% of all patients receiving parenteral iron therapy experience side-effects, but the majority are self-limited and mild. Three percent of patients have more severe symptoms, with 0.1% to 0.6% developing life-threatening anaphylaxis [4]. Most reactions to parenteral iron therapy occur immediately during administration of the test dose and may include dyspnea, headache, flushing, chest pain, abdominal or back pain, nausea, emesis, bronchospasm, fever, seizures, hypotension, urticaria, and anaphylaxis. Delayed reactions occurring one to three days after infusion are related to deposition of iron in tissues and include myalgia, arthralgia, phlebitis, and lymphadenopathy. In a review of 2400 patients who received parenteral iron dextran therapy, Wallerstein reported that only 1% to 2% of patients experienced significant side-effects [5]. Most of reactions were mild and transient and were similar regardless of the route of administration (intramuscular vs. intravenous). No fatalities were reported in this series. Hamstra et al studied 481 patients given intravenous iron dextran at doses ranging from 250 to 500 mg infused at a rate of approximately 100 mg per minute. Overall, 125 patients (26%) experienced side-effects, most of which were mild and self-limiting. Eight were delayed reactions characterized by arthralgia, myalgia, fever, adenopathy, thrombophlebitis, pulmonary embolism, or erythema nodosum. Three of 481 patients developed lifethreatening anaphylactoid reactions characterized by hypotension, cyanosis, syncope, bronchospasm, purpura, and respiratory arrest. Severe reactions were associated with infusion of larger iron doses (more than 500 mg). Side-effects were more prevalent in small women, especially those with pre-existing collagen vascular disease [4]. Auerbach et al studied iron dextran infusion in 87 patients with iron-deficiency anemia to determine the side-effect profile, optimal rate of infusion, the role of premedication consisting of diphenhydramine, methylprednisolone, and subcutaneous epinephrine to avoid symptoms [6]. Two patients had anaphylactoid reactions in response to the test dose. Symptoms were relieved
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Table 1. Side-effects and complications of parenteral iron dextran Short-term Anaphylaxis Hypotension Bronchospasm Fever Arthalgia Myalgia Lymphadenopathy Chest, back or abdominal pain Infection Long-term complications (both i.m. and i.v.) Iron overload syndrome Complications of intramuscular administration Chronic pain at the site of injection Skin staining Local skin atrophy Abscess Sarcoma formation
Urticaria Nausea or emesis Pruritis Seizures Headache Flushing Phlebitis Rigors
with intravenous diphenhydramine, methylprednisolone, and subcutaneous epinephrine. Delayed transient reactions of myalgia, arthralgia, and fever occurred in 37 patients and were controlled with nonsteroidal anti-inflammatory agents. The group recommended that the total dose infusion of iron dextran was safe if patients received a test dose and if the infusion rate did not exceed 6 mg per minute. Anemia in patients with end-stage renal disease on hemodialysis is common, and parenteral iron supplementation is frequently employed in this patient population. Fishbane et al reviewed 573 patients on dialysis that were treated with iron dextran. Twenty-seven (4.7%) had adverse reactions related to iron administration. Four (0.7%) patients had serious complications, one of which was a cardiac arrest, and three were hospitalized. Ten (1.7%) had anaphylactoid reactions and were treated with antihistamines, steroids, or epinephrine. In 22 (3.8%) patients, reactions led to discontinuance of the iron dextran infusion. Of all reactions, five occurred to the test dose that was 50 mg or less of iron dextran, although it is unclear whether all patients received test doses [1]. The mechanism(s) leading to iron dextran-induced symptoms remains unclear but is probably multifactorial. Novey et al studied renal dialysis patients who developed anaphylactoid reactions after parenteral iron therapy [7]. Tests performed included measurement of iron dextraninduced in vitro basophil degranulation and histamine release, formation of type I anaphylaxis specific IgE antibody, and immune complex activation by specific IgG antibody. Six patients undergoing hemodialysis who previously received iron dextran without reaction served as controls. Of the study patients, only one demonstrated positive basophil histamine release test and formed specific IgG to iron dextran. Interestingly, this patient suf-
fered from systemic lupus erythematosis, suggesting that patients with autoimmune disease may be more sensitive to iron dextran therapy. There are several reports of the safe administration of iron dextran to patients with prior episodes of allergic type reactions. Monaghan et al provide a case report of an 83-year-old man with iron-deficiency anemia secondary to chronic gastrointestinal blood loss from an unknown etiology. The patient underwent multiple endoscopic evaluations, but the source of the bleeding could not be located. After several blood transfusions, oral iron-repletion therapy was attempted but was unsuccessful because of gastrointestinal intolerance. Parenteral total dose iron therapy was planned, and the patient was given a test dose of 25 mg of iron dextran over five minutes. After one minute, the patient developed an anaphylactoid response characterized by hypotension, chest pain, and syncope, necessitating admission to the intensive care unit. Despite this dramatic reaction to parenteral iron, a desensitization protocol was attempted with iron dextran after the patient recovered. A pretreatment protocol with methylprednisolone, diphenhydramine, and ephedrine was administered prior to infusion of 1 mg of iron dextran on day 1. Escalating doses of parenteral iron dextran were safely administered over next several days after pretreatment until a total dose of 2 g was achieved. The patient tolerated the iron infusions well without further allergic reaction [8]. Porter, Blackburn and Bistrian reported on a 30-yearold man with Crohn’s disease who was hospitalized for a flare with abdominal pain and diarrhea. Laboratories demonstrated a mixed anemia of chronic disease and iron deficiency. Bowel rest and total parenteral nutrition (TPN) via a central venous catheter were initiated. The standard maintenance dose of 2 mg of iron dextran was provided daily in the TPN, and this was well tolerated. Because of low serum iron levels, parenteral iron therapy was commenced after a test dose of 25 mg of iron dextran in 100 cc D5W was given over five minutes. Within minutes of the infusion, the patient experienced severe backache, extremity pain, and headache. The test dose was discontinued, and diphenhydramine and meperidine were given, with resolution of symptoms. Subsequently, TPN containing 2 mg of iron dextran per day was administered and was well tolerated [9]. IRON AND AUTOIMMUNE DISEASE Total dose infusions of iron dextran have been reported to exacerbate symptoms of rheumatoid arthritis and collagen vascular disease and have been associated with a greater incidence of anaphylaxis in this population. In a study of 11 patients with rheumatoid arthritis given total dose infusions of iron dextran, Blake et al found that two patients had anaphylactic reactions and
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that nine had an exacerbation of synovitis. Quantitative infrared thermal imaging demonstrated increased joint inflammation in eight of the patients imaged. The exacerbation of synovitis occurred 24 to 48 hours after the iron dextran infusion. This corresponded with increased saturation of the serum iron-binding capacity [10]. Iron dextran infusion has been reported to have induced systemic lupus erythematosis in a patient with a history of polyarthritis but no serologic evidence of lupus [11]. A 36-year-old Chinese female developed iron-deficiency anemia from menorrhagia and was treated with total dose iron therapy. Two days after receiving 2 g of iron dextran, she developed a malar rash, polyarthritis, periungual vasculitis, elevated erythrocyte sedimentation rate to 122 mm, positive antinuclear antibody (ANA) at 1:320 dilution and anti-double-stranded DNA antibody (anti-DS DNA) 25.3 mg/liter. The illness resolved rapidly after five days of prednisolone, and her disease was at baseline eight months later with ANA titer at 1:80 and undetectable anti-DS DNA. Two years later, the patient was rechallenged with 20 mg of intravenous iron dextran and again developed polyarthritis, leukopenia, lymphopenia, an ANA 1:160, and anti-DS DNA 20.9 mg/liter. The proposed mechanism(s) of the increased likelihood of adverse reactions to iron dextran in patients with collagen vascular disease includes hypersensitivity to dextran, direct toxic effects of iron on synovium by the generation of free radicals and peroxidation of lipids, and/or reticuloendothelial system blockade resulting in a secondary immune complex synovitis [10, 12, 13]. IRON-INDUCED MUSCLE DISEASE Foulkes et al reported a case of rhabdomyolysis after parenteral iron administration, a 59-year-old man with chronic malabsorption, selective IgA deficiency, and severe iron-deficient anemia. Additionally, the patient was selenium and vitamin E deficient. The patient was intolerant to oral iron therapy and received several intramuscular injections of iron dextran over a four-week period. Eighteen days later, he developed severe generalized myalgia, muscle weakness, and dark urine. Creatine kinase was 20,400 IU/liter. Urinary myoglobin was strongly positive, and muscle biopsy demonstrated regenerating myocytes. Autoimmune markers remained negative, suggesting against autoimmune polymyositis. The authors propose that deficiencies of vitamin E and selenium in conjunction with parenteral iron resulted in free radical oxidative injury to muscle membranes and rhabdomyolysis [14]. Therefore, patients receiving parenteral iron therapy should be screened for other micronutrient and macronutrient deficiencies. Although not proven, there may be an association between intramuscular iron injection and the develop-
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ment of neoplasm. Greenberg reviewed 90 cases of sarcoma of the buttock and noted that four patients had received intramuscular iron compounds [15]. The first patient was an 18-year-old man who developed a fibrosarcoma of the left buttock two years after receiving injections of Jectofer, iron sorbitol, and citric acid compound in the same buttock. Similarly, a 40-year-old woman received Jectofer for anemia of pregnancy, and four years later, she developed myxoid liposarcoma of the right buttock. Two patients developed neoplasms after intramuscular iron dextran as well. One was a 35year-old woman who was given iron dextran for anemia of pregnancy. She developed a rhabdomyosarcoma of the right buttock 13 years later. In another case, a 51year-old woman received intramuscular injections of iron dextran in the buttock for iron-deficiency anemia. Several months later, a palpable thickening occurred at the injection site. Biopsy revealed poorly differentiated chondrosarcoma [15]. Although there is no definitive evidence that intramuscular iron therapy results in neoplasm formation, we have used the intravenous route for our own patients to avoid potential complications and discomfort of intramuscular injection. IRON OVERLOAD The improper administration of iron can result in excess iron stores. The oral recommended daily allowance of iron is 15 mg/day, with healthy adults absorbing 5% to 10% of dietary iron. This is the basis for the estimated parenteral need for approximately 1 mg/day. This amount offsets obligate losses from desquamation of skin and mucosa from gut and genitourinary tract. The body’s ability to excrete parenterally administered iron is limited to these daily losses and to losses during phlebotomy or hemodialysis. Excess dietary or parenteral iron is sequestered by the reticuloendothelial system and can result in hepatosplenic siderosis. Hepatosplenic siderosis is a secondary cause of iron overload, whereas hereditary hemochromatosis (HH) represents a primary etiology. The genetic frequency of HH in the United States and Europe is 0.2% to 0.7% for homozygotes and 8% to 14% for heterozygotes [16]. Patients with homozygous or heterozygous HH are at increased risk for developing iron overload without iron supplementation, and baseline iron status should be established prior to provision of parenteral iron. Fleming et al performed five biopsies and reviewed 17 autopsy liver specimens in 22 patients receiving chronic hemodialysis for renal failure. Of these, 13 patients were treated with parenteral iron dextran. Specimens were assessed for hepatic iron content and histologic iron deposition. Five patients had mild hepatic fibrosis with iron present in hepatocytes. Two patients had high hepatic
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iron concentrations in excess of 1000 mg per 100 mg dry weight. Eight patients had elevated serum ferritin concentrations some in conjunction with fibrosis [17]. In a histologic study of spleens obtained from 40 patients on maintenance hemodialysis treated with iron dextran, Murray et al demonstrated that 24 of the specimens (60%) had massive splenic iron loading [18]. Patients routinely received 250 mg of parenteral iron dextran per month until serum ferritins became elevated, and then supplements were discontinued. The amount of splenic deposition correlated with the total amount of iron dextran administered. Ali et al studied the relationship between serum ferritin and iron deposition in the liver, spleen, and bone marrow in 36 patients with chronic renal failure. Patients had received a mean of 5450 mg of elemental iron as iron dextran. Twenty-three of 36 patients had advanced hepatosplenic siderosis with three to four plus iron deposits, which correlated with elevations in serum ferritins. However, in 10 of the iron-overloaded patients, bone marrow specimens were iron depleted [19]. These studies were limited in that patients did not receive erythropoietin therapy. Erythropoietin facilitates rapid transfer of iron sequestered in the liver and spleen to the bone marrow for developing red blood cells. The development of iron overload is facilitated by parenteral administration of iron because the intestinal regulatory mechanisms are bypassed. IRON AND INFECTION Infection and injury initiate a systemic inflammatory response (SIR), the goals of which are to limit injury, aid tissue repair, and augment immunity. Classic responses include fever, hypotension, tachycardia, hyperglycemia, increased protein catabolism, and decreased iron-transferrin saturation while increasing serum levels of copper and zinc. Elevated release of cytokines are the hallmark and include interleukin-1, tumor necrosis factor, and interleukin-6 [20]. These occur in conjunction with elevated levels of glucagon, cortisol, and epinephrine and serve to mediate the metabolic cascade of the systemic inflammatory response. Several authors have demonstrated that in vitro supplementation of iron can overcome natural immunity [21–23]. In general, doubling the saturation of the ironbinding protein in animal models yields a marked increase in the growth of various pathogens. Microorganisms require iron for growth and must acquire iron from their host. Microbes synthesize iron transport proteins or siderophores that compete with transferrin for free iron. Depressed serum iron levels, a physiological defense mechanism, have been documented during sepsis and may be mediated by interleukin-1 [22]. Proposed
mechanisms include decreased intestinal iron absorption and cytokine-mediated sequestration of iron into tissue stores, predominantly with the flux of iron into the reticuloendothelial system and the liver [21–23]. The relationship between infection and iron deficiency is unclear and remains controversial [24]. McFarlane et al studied 40 children with kwashiorkor-type malnutrition and low serum transferrin. Children were given nutritional support that included oral iron supplements. Many of the children who received iron therapy died shortly after supplements were begun, suggesting a temporal relationship [25]. The provision of iron in the setting of low serum transferrin may result in higher circulating free iron that could have contributed to the development overwhelming infection and death. Septicemia with Yersinia enterocolitica has been reported in healthy children who took overdoses of oral iron [26]. Iron-deficient Somali nomads treated with oral iron demonstrated a greater than fivefold increase in infectious complications compared with placebo, most of which represented reactivation of underlying malaria, brucellosis, or tuberculosis [27]. Seifert et al studied 39 patients with end-stage renal failure on maintenance hemodialysis that were treated with desferrioxamine. Desferrioxamine is a chelating agent used to reduce iron and/or aluminum stores in patients with overload. Twenty-three patients received desferrioxamine for aluminum-related bone disease and 16 patients due to iron overload. A control group consisted of 193 patients on maintenance dialysis who were not treated with desferrioxamine. There was no difference in the incidence of sepsis in the control group compared with patients with aluminum-related bone disease treated with desferrioxamine. The incidence of sepsis in the iron-overloaded group treated with desferrioxamine was almost three times that of the control group (0.36 vs. 0.12 sepsis episodes per patient therapy year, P , 0.001). To study the infectious risk of iron overload, patients on hemodialysis who had never received desferrioxamine were further subdivided. Patients were stratified according to serum ferritin levels: group I (ferritin 10 to 330 mg/liter, N 5 125), group II (ferritin 331 to 1000 mg/ liter, N 5 49), and group III (ferritin 1001 to 2000 mg/ liter, N 5 10). Patients with moderate-to-severe iron overload (groups II and III) had a significantly higher incidence of sepsis compared with controls (group I; 0.18 vs. 0.58 infections per patient therapy year, P , 0.01) [28]. Tielemans and Lenclud studied a similar patient population on maintenance hemodialysis never exposed to desferrioxamine [29]. The authors reviewed infectious risk according to cumulative exposure to hemodialysis expressed in patient-years. In patients with normal serum
Burns and Pomposelli: Toxicity of parenteral iron dextran therapy
ferritins representing 68 patient-years, only six infections occurred with one episode of life-threatening sepsis. Among 117 patient-years with serum ferritins greater than 500 mg/liter, there were 56 total infections, which included 33 episodes of sepsis (P , 0.00025) [25]. Several components of the immune response are iron mediated and may be depressed in the setting of deficiency. Kuvibidila et al fed mice iron-deficient diets and demonstrated atrophy of the thymus with depletion of T cells [30]. Chandra showed impaired numbers of circulating blood neutrophils and a capacity for the generation of the oxidative burst necessary to kill phagocytized bacteria in iron-deficient patients [31]. Iron overload can impair cellular immunity directly. Van Asbeck et al evaluated phagocytic function of monocytes in a patient with idiopathic hemochromatosis and Listeria monocytogenes meningitis. In this patient, initial phagocytic function was significantly diminished in monocytes and normalized completely after a series of therapeutic phlebotomies [32]. Similarly, Flament et al demonstrated decreased neutrophil phagocytosis and superoxide anion generation in patients on hemodialysis with elevated serum ferritin compared with controls [33]. Waterlot et al showed a decreased metabolic burst, myeloperoxidase activity, and phagocytic activity in neutrophils derived from patients on long-term hemodialysis that had iron overload with high serum ferritins [34]. These studies suggest that iron is a substrate for bacterial growth, and provision of iron in the setting of deficiency can promote bacterial infection or reactivation of latent infections. Further, iron overload is a risk factor for the development of infection secondary to impaired cellular immunity. CONCLUSION Parenteral iron therapy is relatively safe and very efficacious for repleting iron stores in patients with iron deficiency. The provision of parenteral iron should be limited to patients with documented iron deficiency who are unable to be repleted via the oral route. Patients need to be carefully screened for autoimmune diseases and underlying infection and need to be continuously screened for the development of iron-overload syndromes. Reprint requests to David Burns, M.D., 190 Quincy Avenue, Brockton, Massachusetts 02302–2895, USA.
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33. Flament J, Goldman M, Waterlot Y, Dupont E, Wybran J, Vanherweghem JL: Impairment of phagocyte oxidative metabolism in hemodialyzed patients with iron overload. Clin Nephrol 25:227–230, 1986 34. Waterlot Y, Cantinieaux B, Hariga-Muller C, MaertelaereLaurent E, Vanherweghem JL, Fondu P: Impaired phagocytic activity of neutrophils in patients receiving hemodialysis: The critical role of iron overload. BMJ 291:501–504, 1985