The Pathogenesis of Iron Deficiency Anemia Following Partial Gastrectomy

A
Carlien

Study

of Iron Balance

Kimber, MD, James F. Patterson, MD, and Lewis R. Weintraub, MD

Methods The following determinations were made using standard techniques for every patient: hemoglobin level10; hematocrit reading11; whole blood smear, white blood cell count and platelet count12; serum iron level and total serum iron binding capacity10; serum vitamin Bi- level14; and 72-hour fecal fat excretion.13 All the patients were receiving a hospital diet containing between 80 and 100 gm of fat during the period of fecal collections. In addition, aspirates of bone marrow were examined to determine mor phology, and marrow stores of iron were assessed by the Prussian blue stain for hemosiderin.16 In seven patients, acid secretion by the gastric remnant was measured after stimulation with betazole hydro chloride (Histalog) administered subcutaneously in a standard dose of 2 mg/kg of body weight.17 Be cause of the recognized difficulties in measuring gastric acid output after partial gastrectomy, the tip of the aspiration tube was always placed in the gastric stump under fluoroscopic control. Samples were aspirated by hand, and those containing bile were noted. Often, volumes were checked with a nonabsorbable marker substance. Iron Absorption.Radioactive hemoglobin was prepared by the injection of 500/j.c of ferrous citrate Fe 59 into a rabbit which weighed 2 kg. Ten days after the injection, blood was withdrawn by cardiac puncture, washed three times with normal saline solution, and the cells were lysed with distilled wa ter. The radioactivity and the hemoglobin level of this blood were determined, and it was then diluted with "cold" hemoglobin to give a concentration of O.ljuc 59Fe per 0.5 mg of hemoglobin iron per milliliter. One milliliter of the solution was placed on each of nine slices of bread, and the patients ate one with each meal (three times a day) for three days. The total amount of radioactivity administered in the nine doses was 0.9/ic. Stools were collected for 14 days, and each daily specimen was counted in toto in a small-animal whole-body liquid scintilla tion counter. The activity in the stools was compared with the activity of a standard dose diluted in 500 ml of distilled water, and the proportion of the ad-

Eight patients who had iron deficiency anemia after partial gastrectomy were tested to determine the role of blood loss and impaired absorption of iron in the individual case. Significant intermittent blood loss was documented in seven patients, while decreased iron absorption was found in only five. In four patients, both these factors were additive in causing iron deficiency. In the single patient with decreased absorption of the test dose of iron without evidence of bleeding, the anemia responded rapidly to therapeutic doses of orally administered iron. These data stress the relative importance of blood loss as a causal factor in iron deficiency after gastric surgery.

Iron deficiency proximately patients subjected gastrectomy.14 Impaired absorption

one

with anemia has been found in ap third of the to subtotal of food iron or limitation of food intake due to per sistent gastrointestinal symptoms have been con sidered the major factors contributing to the defi ciency.57 Continued intestinal bleeding has been mentioned by Witts8 as a possible etiologic factor, but this aspect has been minimized by other investi gators who have found positive stool tests for occult blood in only a small percentage of cases.3,9 During the past year, we have seen eight patients who had iron deficiency anemia following subtotal gastrectomy. In these patients, various aspects of body iron balance were carefully studied. The amount of iron ingested was assessed from the dietary history. In addition, blood loss in the stools was measured during a three-week period, and ab sorption of food iron was tested using hemoglobin labeled with iron 59. Thus, the relative importance of occult intestinal bleeding and impaired iron ab sorption were determined. The results in these studies are documented in order to stress the im portance of blood loss as a significant factor con tributing to the development of iron deficiency after

partial gastrectomy.
From the

New

traub).

departments of hematology and gastroenterology, England Medical Center Hospitals, and the Department of Medicine, Tufts University School of Medicine, Boston. Reprint requests to 171 Harrison Ave, Boston, 02111 (Dr. Wein-

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ministered dose not recovered was presumed to have been absorbed. Absorption in the 8 patients who form the basis of this study was compared with that in 12 volunteers with replete iron stores and 12 pa tients with intact stomachs who were iron deficient due to bleeding. In the latter two groups, iron ab sorption was determined by whole-body counting or fecal collections or both. There was no significant difference between the results of these techniques when performed in the same individual. Fecal Blood Loss.Intestinal blood loss was quantitated by the measurement of red blood cells tagged with sodium chromate Cr 51 in the stools.18 Follow ing the injection of autologous red blood cells labeled with sodium chromate Cr 51, 5 ml of the patient's blood was withdrawn daily, and the radioactivity present was compared with the total radioactivity found in the daily output of stool. Guaiac tests were made on each stool specimen. Samples of blood di luted to a volume of 500 ml and the whole stool were counted in the liquid scintillation counter using pulse-height analysis to differentiate between 59Fe and 31Cr. In eight control subjects, daily blood loss never exceeded 2 ml. Menstrual Loss.Menstrual blood loss from three patients was also measured. In our study, the tam pons and napkins were counted in toto in the smallanimal whole-body counter, and the total blood loss calculated as above by reference to the 51Cr activity in an aliquot of the circulating blood. Results
The clinical and laboratory features of the eight patients are recorded in Tables 1 and 2. All patients had a Billroth type II partial gastrectomy. Six of the eight patients (1, 2, 3, 5, 6, 8) bled overtly from the gastrointestinal tract prior to surgery, and in four of them (2, 3, 5, 6), the degree of blood loss had necessitated replacement transfusion. Three pa tients (2, 5, 6) had received therapeutic doses of orally administered iron in the months immediately following surgery, and by the third postoperative month, all the patients had hemoglobin levels in ex cess of 12 gm/100 ml. None of the patients had recent ulcer symptoms, and only one (patient 3) had overt alimentary bleeding following surgery. At the time of this study, all the patients had a
Table 1.Clinical and

deficiency anemia characterized by hypochromic microcytic red cells, low serum iron levels, and absent stainable bone marrow iron. The serum level of vitamin B]2 was normal in each patient. Chromium 51 Red Cell Loss.Six of the eight pa tients were discovered to have increased gastro intestinal blood loss during the time that the stools were monitored for 51Cr (Table 2). In these six, the mean daily blood loss was 3.9 ml, with a range be tween 3.2 and 6.5 ml per day (normal 0 to 2 ml per day). In the remaining two patients (3, 4), bleeding from the bowel was never detected, although patient 3 gave a history of overt bleeding in the recent past. Usually, leaking from the gastrointestinal tract was small and constant in amount, but in patient 8, there was insignificant bleeding at first, followed by one week of heavier bleeding, during which the daily loss of blood reached 28 ml. In general, there was a close correlation between a positive guaiac test for occult blood in the stools and excessive loss of 51Cr-labeled red cells. However, occasional whole stool specimens containing 3 to 4 ml of blood gave a negative or weakly positive guaiac test on a smear of feces. Two of the three premenopausal women (patients 1 and 7) lost approximately 50 ml of blood during men struation while patient 6 lost 40 ml during a single cycle, which she reported to be subjectively less se vere than normal. Hemoglobin Iron Absorption (59Fe).Five of the patients (1, 4, 6, 7, 8) absorbed less than 17% of the dose of iron, which value is the lower range in our normal control group with either the whole-body liquid scintillation counter or the fecal collection method (Figure). However, absorption was mark edly reduced only in patient 4, who had mild steatorrhea (Table 1). Absorption was increased in three patients (2, 3, 5). There was no correlation between the level of absorption of the test dose of iron and the presence of bleeding during the study period. Two of the three patients (2, 5) with increased iron absorption were bleeding excessively from the gut. However, in four others (1, 6, 7, 8), blood loss con tinued during the study without a compensatory in crease in iron absorption. Secretory and Roentgenologic Examinations. There was no absolute relationship found between the ability of the patient to secrete gastric acid and the ability to absorb radio active iron. Patient 5, who
pure iron
was
Fecal

Laboratory Findings in Eight Patients With Postgastrectomy Iron Deficiency Anemia

Hemo

Sex 52 F

Age,

Preoperative History of Bleeding

+ + +

globin (gm/100 ml)

6.3 7.8 7.8
10.8

Serum Iron

(Ag/ 100 ml)

26 32 22
31

Serum Vitamin B1:

Oi/ig/ml)
210 270
300

24 hr)

(gm/
3.6 4.0 4.0
7.5 4.5 3.9 3.7
4.2

Fat

GastroStudies-

X-ray

Findings
Normal Normal Normal Normal Gastritis

scopy

63 F 39 M

Negative Negative
Rapid
transit

ed an increased amount of the test dose, and patient 8, who produced an ade quate amount of acid after stimulation, absorbed iron made to exclude a site of blood loss in the bowel but roentgenologic examina tion demonstrated no bleeding lesion in any

achlorhydric, absorb

40 F 36 M 36 F
47 F 8

180 150 250 250

Rapid

transit

poorly (Table 2). A particular search was

8.5 6.1 10.8

18 17 40
48
enema.

Negative Negative Rapid

transit

57 M

+
tract

7.2

Negative

" Upper gastrointestinal

follow-through and

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Gastroscopy was also performed in five pa tients. In patient 8, the gastric mucosa was hyperemic with occasional small ulcrations. In the others, the gastric mucosa appeared normal (Table
case.

100
u tf>

9080

Treatment.In all patients an at tempt was made to reduce gastric irritation and bleeding with careful regulation of the diet and with antacids taken between meals and at bedtime. Four of the patients (1, 3, 6, 8) were treated initially with dextriferron (Astrafer) containing 20 mg of ferric iron per cubic centimeter. Three hundred milligrams, in divided doses, were given intravenously followed by orally administered ferrous sulfate. Four patients (2, 4, 5, 7) were treated with orally administered iron alone (ferrous sulfate, 300 mg three times daily). All patients had a prompt hmatologie re sponse, with return to normal hemoglobin concen trations after three months. Patients 4 and 7 re sponded rapidly to therapeutic amounts of orally administered iron, despite reduced absorption of the test dose of radioactive iron.

1).

O
V)

Responses

to

i-

o
Iz
Q.

70

60-

te o
<

5040

0)
m
i

z m

-i

30H
20

Comment Maintenance of the body stores of iron and the normal hemoglobin mass is dependent on the balance between the amount of iron absorbed from the diet and the loss of iron which occurs both by insensible loss from the skin and intestine, and by bleeding from any site. Thus, postgastrectomy iron deficiency may develop from a variety of causes differing from patient to patient. Preoperative depletion of iron stores by gastrointestinal bleeding, blood loss at surgery, postoperative blood loss from gastritis or from recurrent ulcer, limitation of food intake due to persistent abdominal pain, and impaired absorp tion of iron may all be present in the patient with subtotal gastrectomy and often interact to cause clinical iron deficiency. Severe or recurrent bleeding was the indication for partial gastrectomy in five of the eight patients. Al though the hemoglobin value had been restored to normal before surgery, the body stores of iron were probably markedly depleted. Such a condition of iron deficiency with normal values for hemoglobin has been confirmed by the work of Conrad and Crosby.1" In such subjects with depleted stores of

10-

IRON

CONTR0L

DEFICIENCY WITNOUT

QASTRECT0MY

POST 0ASTRECTOMY IRON DEFICIENCY

absorption studies in three groups of subjects. iron, anemia would be expected to develop rapidly should bleeding occur and absorption of food iron be
Iron
even

Patient No. 1

After surgery, loss of iron was commonly increased in our patients due to continuous oozing from the gastrointestinal tract, and in patient 3 due to overt melena. The intermittent nature of the bleeding which was documented in patient 8 highlights the importance of continued testing of the stools for blood in any patient in whom intestinal bleeding is suspected. There is a limitation of the guaiac exami nation done on a small sample of stool, that is, up to 4 ml of 51Cr-tagged blood may be present in the whole stool specimen before the guaiac test be Table 2.Red Blood Cell Loss and Iron Absorption Studies in Eight Patients With comes positive. Postgastrectomy Iron Deficiency Anemia The frequency of recur rent, major hemorrhage in 5'Cr-Labeled Red Blood Cell 5Fe-Labeled patients who have had Stool Loss Approximate Hemoglobin
Hemoglobin Age, Sex (gm/100 ml)
52
63 F M

slightly impaired.

Intake of Iron

Mean in
4

6.3

(mg/Day)
6 8 15 9-11 10

(Range)

ml/Day

Absorption (% Test Dose)

16

(1-7)

Maximal Acid Output''

39 40 36 36 47 57 "Acid

7.8 7.8

_?JL<0:ZL
1.2 (0-2)

47
35

F
M

0 3.2 17
0.1

partial gastrectomy to treat bleeding peptic ulcer

a

has

10.8 8.5

F M

6.1
10.8

0.8 (0-1.5) 6 (4-9)

3.2 (2-4) 3.5 (2-6)

10 12

63 16 16

ofl.!" These authors found

that

recently been stressed by Serebo and Mendelapproximately

one

2.7t
5.9

7.2

6.5 (2-28)

in hour following administration of betazole tCalculated from one-half hour collection.

mEq of HCL

hydrochloride, 2mg/kg body weight.

third of the surgically treated patient bled again. It is indicated by the

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present study that occult blood loss is even more common. In their larger series, bleeding was often
attributable to recurrent ulcration or gastritis, al though no lesion was found in one third of the cases. Radiological examination of the stomach and intes tine to determine the site of bleeding and often even gastroscopy were noncontributory in our cases. Gas tritis due to the ingestion of aspirin or other gastric irritants could be incriminated in only one instance

These studies were supported in part by US Army contract DA49-193-MD-2815, and Public Health Service grant AM 5424-03
from the National Institute of Arthritis and Metabolic Disease. Dr. Weintraub is a recipient of Public Health Service career award AM 31243.

References
1.

The measured mean blood loss from the gut in our series was of the order of 3.2 to 6.5 ml of blood per day. This rate of bleeding in the patients at a time when their hemoglobin concentrations were in excess of 12 gm/100 ml would result in a daily iron loss of 2 to 4 mg per day. To this one must add 1 to 2 mg of iron lost from the desquamation of epithelial cells from the gut and skin.21 "2 Thus the total daily loss of iron is in the range of 3 to 6 mg. This slightly ex ceeds the ability of the gastrointestinal tract to re tain iron from a normal diet.23 Any impairment in the ability of the small intestine to absorb iron would compound the situation, and hasten the develop ment of iron deficiency anemia. Iron absorption, as tested in our laboratory, was less than normal in five patients. In one (patient 4), impaired absorption of food iron was especially se vere and was associated with malabsorption of fats. In this case, failure to absorb dietary iron appeared to be the major cause of iron deficiency in that there was no history of bleeding, and stool loss of 51Crtagged red cells was never excessive. However, this patient responded very quickly to orally admin istered iron, and it is possible that undetected blood loss had also occurred. Impaired absorption of iron following subtotal gastrectomy is probably due to operative bypass of the duodenum, and to rapid intestinal transit in the first portion of the jejunum, which is the major site of iron absorption. Achlorhydria, a common conse quence of subtotal gastrectomy, has been incrimi nated as the causal factor in iron deficiency by decreasing iron absorption.24 25 We were unable to confirm this association in our study, as impaired absorption was found in both those who were achlorhydric and those who secreted normal amounts of gastric acid. In addition, there were two patients with achlorhydria (4 and 5) in whom the anemia was corrected by orally administered iron. Iron absorption was found to be increased in three of the iron deficient subjects, who thus appeared to be capable of absorbing sufficient iron from the diet to maintain body iron balance under normal condi tions. It is likely that in these subjects, blood loss of an intermittent nature was responsible for con tinued negative iron balance. Several factors interact to cause postgastrectomy iron deficiency: inadequate dietary intake, contin ued bleeding, and impaired absorption. These studies suggest that oozing of blood from the gastrointestinal tract is the most important single cause of continu ing negative iron balance.

(case 8).

1955. 3. Hobbs, J.R.: Iron Deficiency After Partial Gastrectomy, Gut 2:141-149 (June) 1961. 4. Deller, D.J., and Witts, L.J.: Changes in the Blood After Partial Gastrectomy With Special Reference to Vitamin B12: I. Serum Vitamin B12, Hemoglobin, Serum Iron and Bone Marrow, Quart J Med 31:71-88 (Jan) 1962. 5. Baird, I.M., and Wilson, G.M.: The Pathogenesis of Anaemia After Partial Gastrectomy, Quart J Med 28:35-41 (Jan) 1959. 6. Stevens, A.R., et al: Iron Metabolism in Patients After Partial Gastrectomy, Ann Surg 149:534-438 (April) 1959. 7. Turnberg, L.A.: The Absorption of Iron After Partial Gastrectomy, Quart J Med 35:107-118 (Jan) 1966. 8. Witts, L.J.: Sydney Watson Smith Lecture, read before the Royal College of Physicians, Edinburgh, Dec 15, 1955. 9. Baird, I.M.; Blackburn, E.K.; and Wilson, G.M.: The Pathogenesis of Anaemia After Partial Gastrectomy: I. Development of Anaemia in Relation to Time After Operation, Blood Loss and Diet, Quart J Med 28:21-34 (Jan) 1959. 10. Crosby, W.H.; Munn, J.L.; and Furth, F.W.: Standardizing a Method for Clinical Hemoglobinometry, U S Armed Forces Med J 5:693-703 (May) 1954. 11. Houchin, D.N.; Lamanna, A.L.; and Lambert, M.: Improved Technique for Capillary Hematocrit Determination, Med Tech Bull 6:171-173 (May) 1955. 12. Cartwright, G.E.: Diagnostic Laboratory Hematology New York: Grune & Stratton, Inc., 1958. 13. Ramsay, W.N.H.: "Plasma Iron," in Sobotka, H., and Stewart, C.P. (eds.): Advances in Clinical Chemistry, New York: Academic Press, Inc., 1958. 14. Kam-Sengl, L., et al: Measurement of Serum Vitamin B12 Level Using Radioisotope Dilution and Coated Charcoal, Blood
26:202

Ulcer, Acta Med Scand, suppl 247, pp 131-132 (Dec) 1950. 2. Wallensten, S.: The Relation Between Sideropenia and Anemia and the Occurrence of Post-Cibal Symptoms Following Partial Gastrectomy for Peptic Ulcer, Surgery 38:289-297 (Aug)

Lyngar, E.:

Blood

Changes After Partial Gastrectomy for

(Aug) 1965. 15. Van de Kamer, J.H., et al: Rapid Method for the Determination of Fat in Feces, J Biol Chem 177:347-351 (April) 1949. 16. Dacie, J.V.: Practical Haematology, ed 2, New York: Chemical Publishing Co., 1956. 17. Kirsner, J.B., and Ford, H.: The Gastric Secretory Response to Histalog, J Lab Clin Med 46:307-311 (Aug) 1955. 18. Owen, C.A.; Bollman, J.L.; and Grindlay, J.H.: Radio\x=req-\ Chromium-Labeled Erythrocytes for the Detection of Gastrointestinal Hemorrhage, J Lab Clin Med 44:238-245 (Aug) 1954. 19. Conrad, M.E., and Crosby, W.H.: The Natural History of Iron Deficiency Induced by Phlebotomy, Blood 20:173-185 (Aug) 1962. 20. Serebo, H.O., and Mendeloff, A.I.: Late Results of Medical and Surgical Treatment of Bleeding Peptic Ulcer, Lancet 2:505\x=req-\ 508, (Sept 3) 1966. 21. Conrad, M.E.; Weintraub, L.R.; and Crosby, W.H.: The Role of the Intestine in Iron Kinetics, J Clin Invest 43:963-974, (May) 1964. 22. Weintraub, L.R., et al: Iron Excretion by the Skin: Selective Localization of Iron59 in Epithelial Cells, Amer J Path 46:121-127 (Jan) 1965. 23. Crosby, W.H.; Conrad, M.E.; and Wheby, M.S.: The Rate of Iron Accumulation in Iron Storage Disease, Blood 22:429-440 (Aug) 1963. 24. Goldberg, A.; Lochhead, A.C.; and Dagg, J.H.: Histamine\x=req-\ Fast Achlorhydria and Iron Absorption, Lancet 1:848-850 (April 20) 1963. 25. Jacobs, A., et al: Gastric Acidity in Iron Absorption, Brit J Haemat 12:728-736 (Nov) 1966.

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