Iron deficiency anemia in patients receiving home total parenteral nutrition

Khaodhiar, Lalita

ABSTRACT. Background: Certain patients receiving home total parenteral nutrition (HPN) are likely to develop irondeficiency anemia because of inadequate absorption or chronic iron loss from gastrointestinal lesions. The objective of this study was to examine the incidence and prevalence of iron deficiency anemia in patients on long-term HPN (>6 months) and to investigate both the efficacy of and rate of adverse reactions to parenteral iron dextran therapy. Methods: The records of 55 patients treated with HPN for >6 months between January 1, 1994 and December 31, 1999 were examined. Results: Thirty patients (55%) had evidence of iron-deficiency anemia. Ten patients were diagnosed at the initiation of HPN, and in 20 patients, iron deficiency devel

oped after receiving HPN. The time between initiation of HPN and development of anemia ranged from 2 to 97 months (mean 28.8 +/- 26.2 months). Mild iron loss from the gastrointestinal tract seemed to be the predominant reason for iron deficiency. Regular treatment with small amounts of iron in HPN appeared to be safe and efficacious, with no reported side effects. Total dose infusion of iron was associated with adverse reactions in as many as 25% of these patients, although all reactions were mild and self-limited. Conclusions: Iron-deficiency anemia is common in patients receiving chronic HPN. Regular small doses of iron in HPN formula, rather than total dose infusion, is the preferred treatment. (Journal of Parenteral and Enteral Nutrition 26:114-119, 2002)

Iron deficiency is the most common form of nutritional deficiency worldwide. Its prevalence is highest among young children and women of childbearing age, particularly pregnant women.1 It is, however, uncommon among adult men and postmenopausal women in the United States. Chronic gastrointestinal (GI) blood loss is the major cause of iron deficiency in adults. In a study of 100 adults with iron deficiency, 62% were found to have a GI lesion that accounted for the chronic blood loss.2 In patients with intestinal failure requiring home total parenteral nutrition (HPN), there would seem to be many potential causes for iron deficiency. These patients are prone to blood loss from the GI tract related, in part, to underlying disease. They may also require multiple surgeries with associated blood loss or excessive blood withdrawal. In addition, patients with short bowel syndrome (SBS) may have iron malabsorption as a result of reduced absorptive area, even though the duodenum, which is intact in all HPN patients, is the primary site for iron absorption. Generally, iron is not routinely provided as a supplement in parenteral nutrition solutions, and it is not a component of commercially available trace element preparations. To date, there are little available data on prevalence, incidence, clinical course, or treatment of this nutritional deficiency in this unique group of patients. Furthermore, the treatment, when indicated, is often complicated by the patients’ inability to tolerate oral iron preparations. The administration of IV iron has been used in several groups of patients in the past, including pregnant women and women who have recently given birth,3,4 patients undergoing surgery,5 patients under going hemodialysis,6,7 and predialysis patients with chronic renal disease.8,9 IV iron administration is also a convenient means to treat and prevent deficiency in patients receiving HPN. However, there are some limitations and concerns. The compatibility of iron with parenteral nutrition solutions has not been clearly established.10 One study has shown compatibility of iron dextran, 100 mg in 1 L of amino acid-dextrose formula, after 18 hours at room temperature, but the compatibility over 24 hours has not been tested.11 In contrast, iron dextran added to a total nutrient admixture containing amino acids, dextrose, and lipids can cause breakdown of the admixture, coalescence of lipid droplets, and cracking and creaming of the lipid component.12-14 Thus, iron is not added to lipid emulsions or total nutrient admixtures (3 in 1 solutions). In addition, iron overload has been reported in children receiving prolonged iron supplementation in HPN14 and in adult hemodialysis patients receiving long-term parenteral iron therapy.15 There is also concern that parenteral iron administration may impair immune function and stimulate bacteria growth during active infection.16-18 Finally, adverse drug reactions associated with parenteral iron therapy are common, although the majority are mild and self-limited.19,20

In the present study, we examined the incidence and prevalence of iron deficiency anemia in patients requiring prolonged HPN. In addition, we also investigated the efficacy and morbidity of IV iron therapy in this group of patients.


Iron-deficiency anemia is common in patients beginning HPN and also develops during long-term HPN, emphasizing the need to screen these patients for iron deficiency. Furthermore, the routine provision of iron, as is done with other essential nutrients, can lead to iron overload, making this an unacceptable option. Iron-deficiency anemia can have a substantial impact on quality of life and may be a factor in increased risk for infection. Previous studies have shown decreased physical performance, diminished worker productivity, altered mental functioning, poor pregnancy outcome, and delayed growth and mental development in children as a consequence of iron deficiency. This study shows that once iron deficiency is identified, it can be treated with low doses of iron in HPN. This treatment is safe and efficacious and has no serious adverse effects.


The records of 207 HPN patients seen between January 1, 1994 and December 31, 1999 at Beth Israel Deaconess Medical Center Home Nutrition Support Service (NSS) were reviewed. Exclusion criteria were a diagnosis of acquired immunodeficiency syndrome or the use of HPN for

All patients received supplemental hypertonic dextrose and crystalline amino acid solutions to meet total energy needs, which were estimated to be 25 to 30 kcal/kg with appropriate electrolytes, multivitamins, and trace minerals. Lipid was supplied as a component of a total nutrient admixture in most cases and comprised up to 25% of total calories. Essentially, all patients who received HPN ingested substantial amounts of food despite malabsorption, and parenteral energy was adjusted to maintain a stable, normal weight. All patients received anticoagulant therapy. Minidose warfarin, 1 to 2 mg, was used to limit thrombosis risk,21 and some patients who had previous intravascular thrombosis received full anticoagulation with warfarin. The following laboratory data were abstracted: complete blood count with red blood cell indices, serum iron, total iron binding capacity (TIBC), ferritin, and reticulocyte counts. Iron-deficiency anemia was identified in patients whose hemoglobin (Hb) level was 350 )mu)g/dL, iron to TIBC ratio (or transferrin saturation, % sat) 16% or less, or ferritin

To determine the causes of iron deficiency, any documented active blood losses were noted. These included bleeding from the GI tract or genitourinary tract or as the result of a surgical procedure that required blood transfusion or hospitalization. Medications such as proton pump inhibitors to counter hypersecretion in SBS patients, and the use of aspirin, nonsteroidal anti-inflammatory drugs, or corticosteroids, which increase risk of GI bleeding, were noted. In addition, the charts of patients receiving IV iron therapy (InFed, Schein Pharmaceutical, Inc, Florham Park, NJ) were reviewed to assess the efficacy and the presence of any adverse events possibly related to this medication. A subset of 9 patients who had no evidence of active bleeding, who did not receive blood transfusions, and who received the prescribed iron dosage were analyzed. Hematologic data at 3 months before iron therapy, at the time of iron therapy (baseline), and at 1, 3, and 6 months after iron therapy were compared. Doses and regimens of iron administration were noted.

Results were analyzed by means of the paired Student t-test (STATVIEW; SAS Institute Inc, Cary, NC). All data are presented as the mean +/- SD with a p value


Prevalence, Incidence, and Causes of Iron-Deficiency Anemia

Evidence of iron-deficiency anemia was present in 30 of 55 HPN patients (54.5%; Table I). There were 22 women and 8 men ranging in age from 20 to 86 years (48.8 +/- 17.6 years). Patients had received HPN support from 0.5 to 20.5 years (6.0 +/- 5.9 years). Most of the patients had SBS as a result of Crohn’s disease, vascular thrombosis, or radiation enteritis. Ten patients whose primary diagnoses were Crohn’s disease (3), cancer (2), diabetes mellitus (1), intestinal volvulus (1), polymyositis (1), amyloidosis (1), and chronic intestinal pseudo-obstruction (1) were diagnosed with iron deficiency at the initiation of HPN or at the time of transfer to the NSS. Iron-deficiency anemia developed in 20 patients while they were receiving HPN; the time between initiation of HPN and development of iron– deficiency anemia ranged from 2 to 97 months (mean 28.8 +/- 26.2 months). Of these 30 total patients, 13 had episodes of acute blood loss (bleeding from the GI tract, genitourinary tract, or intraoperative bleeding documented in the charts) that caused acute iron-deficiency anemia. However, in most patients (24), including those with episodes of acute blood loss, slowly progressive iron deficiency also developed during subsequent periods without evidence of acute blood loss. Interestingly, nearly all patients (27/30) were taking either a histamine HZ receptor antagonist or a proton pump inhibitor during the time that anemia developed. None of our patients were taking nonsteroidal anti-inflammatory drugs on a regular basis. Two patients with a history of vascular disease were taking 81 mg of aspirin daily, and 3 patients with active Crohn’s disease required corticosteroid therapy.

Iron Replacement Regimen and Side Effects of Iron Therapy

After 1991, when routine administration of IV iron (2 mg daily) as a part of HPN solution was discontinued in our institution, 20 patients continued to receive IV iron as a treatment for iron-deficiency anemia (others received blood transfusion or an oral iron supplement). Of these 20 patients, 8 received total dose infusion (TDI) or multiple IV infusions with doses ranging from 100 to 500 mg; 7 patients received small doses of iron in HPN (10 to 75 mg/d); and 5 patients received both TDI and lower dose iron in HPN solution. Patients were prescribed between 500 and 1200 mg of iron therapy depending on their initial hemoglobin level and body weight. The duration of treatment ranged from a few hours (in patients receiving TDI) to 6 months (in patients receiving small doses of iron in HPN). Of the 13 patients who received TDI, 4 had adverse reactions: 2 patients had a rash, 1 patient had urticaria and shortness of breath, and 1 patient had shortness of breath and chest tightness that required prompt discontinuation of the infusion. Central venous catheter infection developed in 1 patient who had radiation enteritis 2 days after TDI of 500 mg. In contrast, none of the patients receiving iron in HPN experienced any side effects. Interestingly, 1 patient with a history of allergic reaction to TDI (shortness of breath and chest tightness) has been re-challenged repeatedly with daily iron of 10 mg in HPN with no adverse reactions.

Effects of TV Iron Replacement

A subset of 9 patients with iron deficiency and no active bleeding were treated with IV iron therapy. There were 2 men, 3 postmenopausal women, and 4 premenopausal women; patients ranged in age from 24 to 68 years. Of these 9 patients, 4 required multiple courses of iron treatment for a total of 18 courses of treatment among all patients. At the time of treatment, mean levels of Hb were 10.4 +/- 0.7 g/dL and iron study results were hematocrit 31.3 +/- 2.3%, serum iron 32 +/- 20 (mu)g/dL, TIBC 394 +/- 73 (mu)g/dL, % sat 7.8 +/- 3.8, and serum ferritin 12 +/- 11 ng/mL (Table II). Compared with values 3 months prior, Hb declined by 1.3 g/dL (p = .0002), hematocrit declined by 3.1% (p = .009), serum iron declined by 23 (mu)g/dL (p = .065), serum ferritin declined by 20 ng/mL (p = .055), and % sat declined by 7.4% (p = .018). At the same time, TIBC increased by 42 (mu)g/dL (p = .002), suggesting the progressive development of iron-deficiency anemia. One month after receiving iron therapy of 500 to 1200 mg (854 +/- 211 mg), there were significant increases in hemoglobin and hematocrit from baseline levels. Hemoglobin level increased by 1.9 g/dL (p = .0001) and hematocrit increased by 5.2% (p = .0004). At 3 months after therapy, hemoglobin level and hematocrit were still significantly increased from baseline, but there was a small decline from the first month, with hemoglobin level increasing 1.4 g/dL (p = .009) from baseline, and hematocrit increasing 3.6% (p = .001) from baseline. In contrast, the increases in serum iron and ferritin were not statistically different from baseline (iron 13 (mu)g/dL, p = .117; ferritin 3 ng/mL, p = .2). Serum TIBC was significantly decreased by 75 (mu)g/dL (p = .03), causing % sat to increase by 6.77% (p = .036).

During months 3 and 6, 3 of these 9 patients demonstrated recurrent evidence of iron-deficiency anemia and required another course of iron infusion. One premenopausal woman required 500 to 1200 mg iron therapy every 3 to 6 months. She denied metromenorrhagia or active GI bleeding. Although she has a history of occult blood in her stool, her GI work-ups have been negative. Of those who did not receive additional iron infusions, hemoglobin level was still significantly increased from baseline (1.7, p = .017) at 6 months, but other indices were not statistically different from baseline.


Total body iron averages approximately 3.8 g in men and 2.3 g in women.1 Iron balance is mainly regulated through intestinal absorption. In a typical Western diet, the usual iron intake is about 15 to 30 mg/d, of which an average 6% of dietary iron is absorbed for men and 13% for nonpregnant women of childbearing age.22 In iron deficiency, a greater fraction can be absorbed. In general, adult men lose approximately 1 mg of iron daily through the feces and in desquamated mucosal and skin cells.23 Premenopausal women have an additional loss of 0.4 to 0.5 mg of iron/d during the menstrual cycle, which makes a total average loss of 1.3 mg/d. In normal individuals, minute amounts of blood are lost in the GI tract daily. Many of the conditions requiring HPN are characterized by increased opportunities for excessive blood loss. Because blood contains 0.5 mg of iron per 1 mL, even minor chronic blood loss can be clinically important. In addition, patients receiving HPN, particularly those with SBS or enteritis, may have a reduced ability to absorb dietary iron. Our patients receiving HPN generally consume 1000 kcal or more per day orally and up to their full caloric requirement, even though absorption of macronutrients and micronutrients is substantially diminished. To date, there are no data on the efficacy of absorption of iron in home TPN patients. However, only approximately one-half of our patients on HPN require iron supplementation, and this seems unrelated to the length of remaining small bowel. This suggests that iron loss rather than iron malabsorption is the primary factor in the development of iron deficiency. Another factor that should be considered is that, although the loss of small bowel may decrease absorptive percentage, it may also diminish intestinal control of iron absorption. Because IV iron bypasses this intestinal control of iron absorption, routine parenteral iron replacement could eventually cause iron overload. This was the principal reason for the discontinuation of routine iron replacement in our patients on HPN in 1991.

Iron-deficiency anemia is not uncommon in patients receiving HPN. A previous cross-sectional study of 49 patients actively receiving HPN for from 1 to 175 months showed 14 (31%) patients with evidence of iron-deficiency anemia.24 Anemia developed from 0 to 8 years after TPN started. Six patients had identifiable events, including active Crohn’s disease (3), upper GI bleeding (3), and menorrhagia (1). After supplemental iron therapy, anemia resolved in all patients except 1 who had persistent blood loss.

Adverse reactions to iron dextran are of 2 types. Type 1 IgE-mediated anaphylactic reaction seen exclusively with iron dextran is caused by preformed dextran antibodies.25 This type of reaction is uncommon, with a reported incidence of 500 mg). Fishbane et al20 reviewed the records from 4 dialysis centers comprising 573 patients treated with IV iron dextran. They found a 4.7% incidence of adverse reactions, with 0.7% of these classified as serious. Doses in this study were lower, averaging 100 mg per treatment. Recently, Barton et al28 treated 135 iron– deficient adults with normal renal function using 500-mg doses of iron dextran after premeditation with diphenhydramine, cimetidine, and dexamethasone. Of the 135 patients, 117 (86.7%) had no adverse reaction, and 18 (13.3%) had mild reactions, especially arthralgia and myalgia. No patient experienced an anaphylaxis-like reaction. Although these premedications seem to be safe and effective in preventing adverse reactions from iron dextran therapy, whether they are appropriate for patients on HPN who have chronic indwelling venous catheters remains unclear. TDI is more likely to be poorly tolerated than the more frequent administration of lesser amounts of iron and therefore, the chronic provision of iron in amounts predicted to equal that lost would seem to be the preferred treatment. Furthermore, we have documented that patients who have an allergic reaction to parenteral iron may well tolerate smaller doses.29 Patients who might be considered candidates for such therapy are those in whom iron deficiency has been shown to develop repeatedly or in whom iron deficiency is developing to a worsening degree. Once clinically assured of the cause, the amount of iron to be replaced can be roughly estimated by determining the iron equivalent of rate of hematocrit or hemoglobin drop over time by means of the following equation: iron (mg) = 0.3 x weight (lbs) x [100 – (actual Hb (g/dL) x 100)/desired Hb].30 For the group of patients described in the present study, the rate of iron loss was estimated to be about 10 mg/d, which could easily be provided parenterally on a long-term basis.

Additional evidence suggesting iron loss as the primary cause of iron-deficiency anemia can be found in the 9 patients who received iron dextran therapy. At 1 month after therapy, an increase in hemoglobin level and hematocrit was seen, as expected. At 3 months, however, most patients showed a slight drop in hemoglobin level and hematocrit from the first month, with iron indices compatible with the redevelopment of mild iron deficiency. Between 3 and 6 months, 3 of 9 patients had evidence of iron-deficiency anemia and required an additional course of iron treatment.

There are some limitations to our study. The retrospective nature of the study may result in the exaggeration of the true incidence of iron deficiency. However, the rates of adverse reactions should be reasonable approximations. Our reported incidence of side effects is in fact similar to the incidence reported in a previous large, prospective study.20 In any case, further prospective studies will be required to refine recommendations regarding which patients should receive iron, when it should be provided, and how much should be provided in HPN.

In summary, iron-deficiency anemia occurred in approximately one-half of our patients on long-term HPN and appeared to be caused primarily by chronic blood loss. We suggest the routine monitoring of iron studies in these patients. For the first year after initiation of TPN, iron studies should be done every 3 months. If no problem is found during that examination, yearly assessment is sufficient. If iron deficiency is found, treatment should be proposed and monitored every 3 months until a stable iron regimen is defined, and then monitored every 6 months thereafter. Parenteral iron therapy can be used safely in patients who have evidence of iron deficiency after appropriate clinical investigation. Small amounts of iron in TPN (10 to 15 mg(d) are compatible with amino acid-dextrose solution (2 in 1 solution) and appear to be safe and effective repletion therapy.


1. Centers for Disease Control and Prevention: Recommendations to prevent and control iron deficiency in the United States. MMWR 47:1-29, 1998

2. Rockey D, Cello J: Evaluation of the gastrointestinal tract in patients with iron-deficiency anemia. N Engl J Med 329:16911695, 1993

3. Bonnar J: Anaemia in obstetrics: An evaluation of treatment by iron dextran infusion. BMJ 2:1030-1033, 1965

4. Mays T, Mays T: Intravenous iron-dextran therapy in the treatment of anemia occurring in surgical, gynecologic and obstetric patients. Surg Gynecol Obstet 143:381-384, 1976

5. Ashby EC: Total dose iron-dextran infusions in general surgery. Lancet 2:807-809, 1967

6. Bailie GR, Johnson CA, Mason NA: Parenteral iron use in the management of anemia in end-stage renal disease patients. Am J Kidney Dis 35:1-12, 2000

7. Auerbach M, Winchester J, Wahab A, et al: A randomized trial of three iron dextran infusion methods for anemia in EPO-treated dialysis patients. Am J Kidney Dis 31:81-86, 1998

8. Dahdah K, Patrie JT, Bolton WK: Intravenous iron dextran treatment in predialysis patients with chronic renal failure. Am J Kidney Dis 36:775-782, 2000

9. Bhowmik D, Modi G, Ray D, et al: Total dose iron infusion: Safety and efficacy in predialysis patients. Ren Fail 22:39-43, 2000

10. Kumpf V: Parenteral iron supplementation. Nutri Clin Pract 11:139-146, 1976

11. Wan KK, Tsallas G: Dilute iron dextran formulation for addition to parenteral nutrient solutions. Am J Hosp Pharm 37:206-210, 1980

12. Lavoie JC, Chessex P: Bound iron admixture prevents the spontaneous generation of peroxides in TPN solutions. J Pediatr Gastroenterol Nutr 25:307-311, 1997

13. Vaughan LM, Small C, Plunkett V: Incompatibility of iron dextran and a total nutrient admixture. Am J Hosp Pharm 47:17451746, 1990

14. Ben Hariz M, Goulet 0, De Potter S, et al: Iron overload in children receiving prolonged parenteral nutrition. J Pediatr 123: 238-241, 1993

15. Fleming LW, Hopwood D, Shephard AN, et al: Hepatic iron in dialysed patients given intravenous iron dextran. J Clin Pathol 43:59-64, 1990

16. Patruta SI, Horl WH: Iron and infection. Kidney Int 55:125-130, 1999

17. Bullen JJ: The significance of iron in infection. Rev Infect Dis 3:1127-1138, 1981

18. Weinberg ED: Iron and infection. Microbiol Rev 42:45-66, 1978 19. Burns DL, Pomposelli J: Toxicity of parenteral iron dextran therapy. Kidney Int 55:119-124, 1999

20. Fishbane S, Ungureanu VD, Maesaka JK, et al: The safety of intravenous iron dextran in hemodialysis patients. Am J Kidney Dis 28:529-534, 1996

21. Bern MM, Bothe A Jr, Bistrian BR, et al: Prophylaxis against central vein thrombosis with low dose warfarin. Surgery 99:216221, 1986

22. Duffy T: Microcytic and hypochromic anemias. IN Cecil Textbook of Medicine, Goldman L, Bennett J (eds). WB Saunders, Philadelphia, 2000, p 855

23. Yip R, Dallman PR: Iron. IN Present Knowledge in Nutrition. Ziegler E, Filer L (eds). ILSI Press, Washington, DC, 1996, p 277 24. Forbes GM. Forbes A: Micronutrient status in patients receiving home parenteral nutrition. Nutrition 13:941-944, 1997 25. Macdougall I: Strategies for iron supplementation: Oral versus intravenous. Kidney Int 55:561-566, 1999

26. Zanen AL, Adriaansen HJ, van Bommel EFH, et al: Oversaturation of transferrin after intravenous ferric gluconate (Ferrlecit) in haemodialysis patients. Nephrol Dial Transplant 11:820824, 1996

27. Hamstra RD, Bloack MH, Schoket AL: Intravenous iron dextran in clinical medicine. JAMA 243:1726-1731, 1980

28. Barton JC, Barton EH, Bertoli LF, et al: Intravenous iron dex

tran therapy in patients with iron deficiency and normal renal function who failed to respond to or did not tolerate oral iron supplementation. Am J Med 109:27-32, 2000

29. Porter KA, Blackburn GL, Bistrian BR: Safety of iron dextran in TPN: A case report. J Am Coll Nutr 7:107-110, 1998

30. Burns DL, Mascioli EA, Bistrian BR: Parenteral iron dextran therapy: A review. Nutrition 11:163-168, 1995

Lalita Khaodhiar, MD*; Mary Keane-Ellison, RN*; Nicholas E. Tawa, MD, PhD*; Ann Thibault, RN*; Peter A. Burke, MD^; and Bruce R. Bistrian, MD, PhD*

From the Nutrition Support Service, *Departments of Medicine and Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, and ^Department of Surgery, Boston University Medical Center, Boston, Massachusetts

Received for publication, March 31, 2001.

Accepted for publication, October 18, 2001.

Correspondence: Bruce R. Bistrian, MD, PhD Beth Israel Deaconess Medical Center, One Deaconess Road, Boston, MA 02215. Electronic mail may be sent to

Copyright American Society for Parenteral and Enteral Nutrition Mar/Apr 2002

Provided by ProQuest Information and Learning Company. All rights Reserved

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