Megaloblastic anemia in patients receiving total parenteral nutrition without folic acid or vitamin B12 supplementation Pancytopenia developed in four patients receiving postoperatively total parenteral nutrition (TPN). Symptoms and signs were related mainly to underlying bowel disease. Hematologic abnormalities, first noted from 4 to 7 weeks following institution of TPN, consisted of normocytic anemia (mean decrease in hemoglobin value, 2.2 g/dL), occasional macrocytes being noted, leukopenia (range of leukocyte counts, 1.2 to 3.6 x 109/L), some hypersegmented neutrophils being detected, and clinically significant thrombocytopenia (range of platelet counts, 25 to 52 x 109/L). In all patients the bone marrow showed megaloblastic changes, with ring sideroblasts, although pyridoxine was included in the TPN regimens. Serum vitamin B12 values were normal in one patient and at the lower limit of normal in the other two patients in whom it was measured, while serum or erythrocyte folate values, or both, were reduced in three patients. Full hematologic response was observed in the four patients after folic acid replacement therapy; leukocytosis and thrombocytosis were noted in three. Thus, folic acid and possibly vitamin B12 should be added routinely to TPN regimens to prevent deficiency of either substance. Une pancytopenie est apparue chez quatre patients recevant apr.s une op6ration une alimentation parent6rale complete (APC). Les sympt6mes et le tableau clinique refletaient surtout Ia pathologie intestinale sousjacente. Les anomalies h6matologiques, qui From the departments of pathology, medicine and surgery, St. Joseph's Hospital and McMaster University, Hamilton Reprint requests to: Dr. MAM. Au, Department of laboratory medicine, St. Joseph's Hospital, 50 Chariton Ave. E, Hamilton, Ont. L8N 1Y4

Table I-Clinical data for four patients receiving total parenteral nutrition (TPN) in whom pancytopenia developed Patient no. Variable Diagnosis

Operation Duration of TPN before pancytopenia developed (wk)

1 Recurrent intestinal fistulas following gastrojejunostomy for peptic ulcer Gastrectomy and fistula resection 7

144 CMA JOURNAL/JULY 23, 1977/VOL. 117

2 Small bowel obstruction; radiation enterocolitis

3 Crohn's disease of colon

4 Crohn's disease of terminal ileum

Iliocolic bypass

Total colectomy

Jejunocolonic bypass with resection of terminal ileum and cecum

4

6

7

Table Il-Quantities of nutrients received daily in TPN regimens Patient 2 25 12 2.5 25 6.1 3.0 250 250 2500 2.5 85 2500

1 30 14 3.0 30 6.9 3.6 300 300 3000 3.0 90 3000

Variable Protein as amino acids (g) Vitamin B1 (mg) Vitamin B2 (mg) Niacin (mg) Pantothenic acid (mg) Vitamin B6 (mg) Vitamin C (mg) Vitamin D (IV) Vitamin A(IU) Vitamin E (IV) Dextrose (g) Water (ml)

no. 3 30 14 3.0 30 6.9 3.6 300 300 3000 3.0 90 3000

4 30 14 3.0 30 6.9 3.6 300 300 3000 3.0 90 3000

Table Ill-Hematologic data* before and during TPN Patient no. Variable Hemoglobin value (g/dL) Before During Mean corpuscular volume (p3) Before During Reticulocytes (%) Before During Leukocyte count (X 10./L) Before During Platelet count (X 10./L) Before During Smear

1

2

3

4

13.0 7.8

16.0 8.1

11.8 6.1

13.2 10.5

81 87

93 89

90 81

84 92

NA 0.1

NA 0.4

1.8 0.1

NA 1.6

5.6 1.2

9.9 3.1

14.0 2.9

6.4 3.6

N 26 Nonspecific, decreased platelets

158 25 Nonspecific, decreased platelets

550 42 Decreased platelets, hypersegmented PMNs, H-J bodies

270 52 Decreased platelets, hypersegmented PMNs, oval macrocytes

Table IV-Vitamin B12 and folate concentrations 1 Concentration* 420 Serum B12 (pg/mi); N, 120-950 0.6 Serum folate (ng/mL); N, 3-16 Erythrocyte folate (ng/mL); NA N, 160-460 = normal range ± two standard deviations.

2 NA NA NA

Patient no. 3 160 0.1-1.4 85

4 150 3.2 15

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coagulation were negative for fibrin degradation products and fibrin monomers. The prothrombin, partial thromboplastin and thrombin clotting times were within the normal range in all four patients. The serum vitamin B12, serum folate and erythrocyte folate values for the four patients are given in Table IV. Serum B12 concentration was measured in three patients: it was within the normal range in one patient and at the lower limit of normal in two. Serum folate values were decreased in the three patients and erythrocyte folate values in the two patients in whom the concentrations were estimated. The bone marrow showed megaloblastic changes and ringed sideroblasts in all four patients. The response to folic acid therapy was striking. A prompt reticulocyte response occurred in all four patients between 5 and 7 days after therapy was begun. The maximum hemoglobin response, however, did not occur until 4 to 6 weeks after initiation of therapy. Rebound leukocytosis and thrombocytosis in three patients lasted for 12 weeks, then the leukocyte and platelet counts gradually returned to normal. None of the patients was given vitamin B12 therapy; however, the response to pharmacologic doses of folic acid does not completely exclude deficiency of vitamin B12. Further investigation is under way in this regard. Discussion Megaloblastic changes and pancytopenia are found most often in the postoperative period. However, the condition for which the operation was performed and its preoperative complications are of major importance in the occurrence of hematologic problems with postoperative TPN. The four patients just described had documented pre-existing gastrointestinal disorders; their cases emphasize the need for assessment of folic acid or vitamin B12 status, or both, in such patients before institution of TPN. In patients with inflammatory disease of the small and even the large intestine there is evidence for malabsorption of folic acid and vitamin B12 often early in the disease and in the absence of clinical symptoms.4'2 All the patients in this series had inflammatory bowel disease and postoperatively were treated solely by TPN with a preparation containing amino acids, electrolytes, vitamins (excluding folic acid and vitamin B12) and dextrose for 4 to 7 weeks before evidence of hematologic abnormalities appeared. The diagnosis was made by bone marrow examination following the insidious development of pancytopenia; patients were brought to the attention of

146 CMA JOURNAL/JULY 23, 1977/VOL. 117

the hematology service either because of requests for blood for transfusion or upon review of blood smears. The presence of a few oval macrocytes, hypersegmented neutrophils and pancytopenia were the main findings in the peripheral blood. The mean erythrocyte corpuscular volume did not suggest a macrocytic abnormality probably because the duration of the megaloblastic changes was too short for the changes to have been reflected in the erythrocyte indices. The response in our patients to folic acid replacement therapy - a rapid increase in reticulocyte, leukocyte and platelet counts - was consistent with predominant deficiency of folic acid, but superimposed deficiency of vitamin B12 could not be excluded in three of the four patients. The two patients with marginal vitamin B12 values might well have had borderline B12 deficiency since the radioisotope assay of serum vitamin B12 is less sensitive at the lower limit of normal concentrations. It thus seems that in patients receiving prolonged TPN one can define a subgroup that is particularly susceptible to early and severe deficiency of folic acid or vitamin B12 and potentially serious hematologic manifestations. This group includes the following patients: (a) those that may have malabsorption of folic acid or vitamin B12 prior to surgical intervention, such as those with ileal disease or inflammatory small and large bowel disease; (b) those that, prior to operation, have increased folate requirements by the tissues, such as those with malignant diseases, burns, pregnancy, chronic hemolytic anemias and other states of increased tissue turnover; (c) those with decreased hepatic stores or decreased hepatic ability to convert dietary folic acid; and (d) those with chronic alcoholism, with or without liver disease. We recommend that the status of folic acid and vitamin B1. be reviewed preoperatively in all patients undergoing complicated elective procedures for inflammatory bowel disease and that patients at high risk for folate deficiency be given a folic acid supplement prophylactically. All patients receiving TPN for more than 3 weeks should probably receive folic acid and vitamin B12 supplements routinely. References 1. DACIE JV, LEWIs SM: Practical Haema:ology, 5th ed, Edinburgh, London and New York, Churchill Livingstone, 1975, pp 21-58 2. HOFFBRAND AV, NEWCOMBE BA, MILLER DL: Method of assay of red cell folate activity and the value of the assay as a test for folate deficiency. J Clin Pathol 19: 17. 1966 3. Bsurr RP, BoLmN FG, CULL AC, et al: Simplified radioisotope assay for Bs2. Br I Haematol 16: 457, 1969 4. BALLARD HS, LINDENBAUM J: Megaloblastic anemia complicating hyperalimentation therapy. Am I Med 56: 740, 1974 5. wEIR DG, HOURIHANE DO: Coeliac disease during the teenage period: the value of serial serum folate estimations. Gut 15: 450, 1974

Megaloblastic anemia in patients receiving total parenteral nutrition without folic acid or vitamin B12 supplementation.

Megaloblastic anemia in patients receiving total parenteral nutrition without folic acid or vitamin B12 supplementation Pancytopenia developed in four...
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