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Malabsorption of iron in children with iron deficiency
May 1976 The Journal o f P E D I A T R I C S
795
Malabso rp tio n o f iron in children with iron
deficiency Inability to absorb oral iron is believed to be an extremely rare cause of therapeutic failure in the treatment of iron deficiency anemia. Six patients who had failed to respond to oral iron therapy were studied by a simple oral absorption test and contrasted with 25 patients with untreated iron deficiency anemia and 10 normal subjects. All six of the patients who were therapeutic failures demonstrated impaired iron absorption in the absence of other clinical evidence o f gastrointestinal disease. In the 25 newly diagnosed patients with iron deficiency, 24 demonstrated elevated iron absorptions while 10 ironreplete normal subjects had minimal elevations in their serum iron values following the administration of the test dose of 1 mg of elemental iron per kilogram. When the therapeutic failures were treated with parenteral iron, all had a therapeutic response, In addition, after treatment the impaired absorption of iron improved transiently. All children who absorbed iron readily responded to oral iron therapy.
Steven J. Gross,* Marie J. Stuart, Phillip T. Swender, and Frank A. Oski, S y r a c u s e , N. Y.
AN ASSOCIATION between iron deficiency anemia and abnormalities in gastrointestinal structure and function has been noted by several investigators. Gastric achlorhydria,1, 2 impaired absorption of xylose and vitamin A, 3 duodenal mucosal changes, 34 and occult blood loss ~. ~ have all been previously documented in children. Despite the abnormalities in gastrointestinal absorption, most studies of Children? " and adults 9-1~ with iron deficiency anemia have demonstrated increased iron absorption, and it is generally believed that failure to absorb inorganic iron by iron-deficient children is rare. Since we have seen children with iron deficiency anemia who have not responded to 0ral iron therapy, a study was designed to determine the absorption of inorganic iron in normal and iron-deficient children.
MATERIALS AND METHODS Patients follows:
and
control subjects
were
grouped
as
Group I consisted of ten control subjects (5 adults and 5
From the Department of Pediatrics, State University of New York, Upstate Medical Center. *Reprint address: Department of Pediatrics, State University Hospital, 750 E. Adams St., Syracuse, N. Y. 13210.
children) with normal hemoglobin and iron saturation values > 20%. Group H cons!sted of 25 newly diagnosed children with iron deficiency anemia who had not received prior iron therapy ("de novo group"). Group I I I had six children with iron deficiency anemia who had received therapeutic doses of oral iron under close medical supervision for 2 to 42 months without improvement in their hemoglobin concentrations ("nonresponders"). Children in this group had discontinued oral iron supplementation for greater than 72 hours prior to study.
See related article, p. 909. The diagnosis of iron deficiency anemia was established in all cases by a serum transferrin saturation level of < 16% and a hemoglobin concentration of < 11 gm/dl in the presence of hypochromic, microcytic red cell indices. In Group III ("nonresponders") other causes of microcytosis were excluded by blood lead determinations and hemoglobin electrophoreses; concommitant folate deficiency was also excluded in this group. Any patient wi~h acute or chronic infection, fever, or evidence of malabsorptive disease was also excluded" from the study.
VoL 88, No. 5, pp. 795-799
796
Gross et al.
The Journal of Pediatrics May 1976
400
400 350
350
a
~d +1
.
300
300
(.9
GROUP TT (24/25)
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o
250
250
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----- 150 :::3 n,.-
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I
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2
3
4
TIME
IN H O U R S
Fig. 1. Flat oral iron absorption curve; data from 10 ironsufficient control subjects (Group I). None of the "nonresponders" had a history of diarrhea, impaired xylose absorption, or evidence of occult gastrointestinal bleeding. Each patient had negative stool guaiac tests on at least three occasions. All had serum albumin concentrations in excess of 3.0 gm/dk After an eight-hour overnight fast, an early morning oral iron absorption test was performed by a modification of the method of Crawley?3 Following the collection of blood for a fasting serum iron and iron binding capacity, a test dose of 1 mg of elemental iron per kilogram of body weight was administered by mouth to all subjects. Serum iron levels were obtained at i, 2, and 4 hours following the oral iron test dose; the resulting absorption curves were described as being "elevated" or "flat" depending on whether the maximum rise over baseline values in the serum iron concentrations at either 1, 2, or 4 hours was greater or less than 100 ffg/dl, respectivelyP Those iron-deficient children who had elevated iron absorption curves were treated with oral ferrous sulfate, 9 mg/kg/day of elemental iron; follow-up hemoglobin determinations were obtained within one to six weeks after the initiation of iron therapy. Those iron-deficient children who had flat absorption curves were given
I
I I
GROUP ]I (I/25)
I
I 2 3 TIME IN HOURS
I
4
Fig. 2. Oral iron absorption curves in de novo iron-deficient children (Group II) and in iron-deficient nonresponders (Group III). An elevated absorption curve was present in 24 of 25 Group II patients. A fiat absorption curve was present in 1 of 25 Group II and 6 of 6 Group III patients.
parenteral iron at doses calculated to correct anemia and replenish iron stores. TM Follow-up determinations of hemoglobin and serum iron values, and of iron binding capacity, and oral iron absorption studies were performed whenever possible. No dietary modifications were made between study periods. All blood was obtained by venipuncture. Hemoglobin and red blood cell counts were calculated on the Coulter Electronic Counter, Model S) 5 Serum iron and unsaturated iron binding capacity were determined by the method of Jung and Parekh2 6 Hemoglobin fractionation was performed by cellulose acetate electrophoresis. 17 Blood lead TM and folate TM were determined by previously described methods. RESULTS The results of the oral iron absorption tests in the 10 normal control subjects (Group I) are depicted in Fig. 1. These control subjects demonstrated "flat" absorption curves with an average maximum rise in serum iron over the fasting level of only 42 ffg/dl. The results observed in both groups of iron-deficient children are shown in Fig. 2. Of the 25 children in the "de novo" group (Group II), 24
Volume 88 Number 5
Malabsorption of iron
25O -
/
o~ 2 0 0
\
P re I9.3gms % d.S. 6 % s o t
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.~n/7.Zoms ~
10.ggms~
797
sat
~L z 150
g D r~ bJ r.f)
~ 6 WEEKS P O S T I,M, IRON
'
~
----- I 0 0
50
PRE I.M. IRON
I
0
I
I 2
I
.3
I 4
TIIV[E IN H O U R S
Fig. 3. Mean oral iron absorption curves before and after intramuscular (IM) administration of iron in two nonresponders (Group III). had "elevated" iron absorption curves with an average maxiinum rise in serum iron over the fasting level o f 274 /~g/dl. In contrast, all six of the children who were "nonresponders" (Group III) plus one child belonging to Group II had "flat" iron absorption curves with an average maximum rise in serum iron of only 42 /~g/dl. The maximum rise in serum iron in all three groups occurred at two hours after administration of oral iron. Differences in the serum iron levels following the test dose between the "fiat" and "elevated" absorbers were significantly different (p < 0.001). The "flat" versus "elevated" absorbers were further compared in several respects. There were no significant differences in age, height, and weight percentiles, or degree of anemia as reflected by initial hemoglobin, fasting serum iron, or iron saturation. They had comparable intakes of whole milk. Mean birth weights in both groups were identical. In the 24 of 25 children in Group II with "elevated" iron absorptions, correction of anemia occurred promptly with oral iron therapy. The mean hemoglobin rise per day was 0.31 gm, 0.15 gm, and 0.10 gm with observation periods of 7 to 10 days, 14 to 21 days, and 24 to 42 days, respectively. All seven of the children who had "flat" iron absorptions (6 of the children in G~'oup III plus one of the 25 children in the de novo group) were given iron* intramuscularly; they had substantial rises in their hemoglobin *Imferon, LakesideLaboratories,Milwaukee,Wis.
values. In four of these seven patients, repeat oral iron absorption tests were carried out. It is noteworthy that at the time of the repeat absorption studies these children were in varying stages of iron repletion as reflected by their serum iron values and percentage of transferrin saturation. Two of these four children had repeat absorption tests at five to six weeks after parenteral iron. Fig. 3 demonstrates their mean absorption curves before and after parenteral iron. Initially, the curves were flat; when repeated they were elevated. At the time of the second absorption studies, these children may still have been iron deficient. In Patient S. D., the hemoglobin had risen from 7.2 to only 10.9 gm/dl. (Unfortunately, a percentage of saturation is not available for the second study). In Patient J. S., the repeat iron saturation was just 16%. The fourth case is shown graphically in Fig. 4. Three absorption tests were performed on Patient A. H. Following an initial flat curve (A), intramuscular iron was given. Nine weeks later, when the patient was still iron deficient with an iron saturation of only 13%, a repeat absorption test was somewhat elevated (Curve B). Without further iron therapy the oral absorption test was repeated 20 weeks after therapy with Inferon. The patient is now iron sufficient with an iron saturation of 19%; the absorption curve is again flat (Curve C). DISCUSSION Using an oral test dose of 1 mg/kg of elemental iron, we have demonstrated that iron-replete adults and children
798
Gross et al.
250 -
f" /
The Journal of Pediatrics, May 1976
A
B
C
Pre
9 Weeks Po s t
20Weeks Po st
d
o o
A'H'/10.9 gms% L I0 ~ sat
200
11.6 gmsO/o 13Olosat
12.0 gms~ 19% sat
::L z _
150
g
B
13s
100
LU
5(
03
A w
0
9
9
f
I
I
I
1
2
3
4
TIME
IN HOURS
Fig. 4. Oral iron absorption curves before (curve A) and after (curves B and C) administration of iron in one nonresponder (Group III). (See text.)
have flat iron absorption curves when studied serially for four hours following ingestion of the test dose of inorganic iron. Most children with iron deficiency anemia have elevated iron absorption curves and their anemia is responsiv e to therapeutic doses of oral iron. There are some iron-deficient children, however, who have flat oral iron absorption curves, their anemia being refractory to oral iron therapy. In this latter group, during parenteral correction of their iron deficient state, an elevated absorption curve is observed, followed by a return to a flat curve when iron sufficiency is complete. The amount of inorganic iron used as the test dose is an important variable as was observed by Crawley. '3 In adults, using a test dose of 2 mg/kg of elemental iron, they obtained findings similar to those reported here--flat absorption curves in iron-replete control subjects and in iron-deficient patients refractory to oral iron therapy. Adults comparable to our "de novo" Group II irondeficient patients responded to this test dose with increased absorption rates similar to the responses in our Group II children. However, using 4 m g / k g o f elemental iron, Crawley and associates demonstrated elevated absorption rates in their control population and even greater elevations in serum iron in their de novo irondeficient group. Following this larger test dose, their refractory group of patients with iron deficiency continued to exhibit flat absorption curves and were treated with parenteral iron. In their study, no repeat iron
absorption tests were performed in these latter patients following parenteral iron replacement. Most other studies relating to the absorption of either a radioiron salt 7 (ferrous sulfate) or food iron s in children with iron deficiency anemia have demonstrated a 2- to 3fold increase in absorption over iron-sufficient control subjects. However, Kimber and associates12 using ~gFelabeled hemoglobin, measured intestinal absorption in iron-deficient children and demonstrated a marked impairment (28.5% absorption) when compared to ironreplete control subjects (41.8% absorption). In the irondeficient children, after correction of the anemia, the absorption of hemoglobin iron improved in all but one of the children tested. Interestingly, only six of the eight iron-deficient children responded to oral ferrous sulfate. The other two children were given intramuscular iron, after which there was prompt hematologic improvement. Organic and inorganic iron are absorbed by different mechanisms so that the findings in our patients are not directly comparable to those of Kimber and co-workers. It seems unlikely that our refractory (Group Ill) patients demonstrated impaired iron absorptions on the basis of allergy to fresh cow milk that has been found concommitantly with iron deficiency anemia in many infants. None of these patients had occult gastrointestinal blood loss as has been observed in patients with cow milk-induced gastrointestinal bleeding. The structural and functional abnormalities noted by previous authors 1-4 and the impaired absorption of hemoglobin iron noted by Kimber and colleagues, 12 were reversed with iron repletion. Similarly, in our irondeficient children with flat inorganic iron absorption curves, we found elevated absorption several weeks after parenteral iron replacement. The reversal of abnormalities following iron therapy indicates that the abnormalities noted are effects rather than causes of the iron deficiency. Since iron balance is almost exclusively controlled by intestinal absorption, it is understandable that if iron absorption is minimal in normal control subjects, it would also be minimal in iron-deficient children after iron repletion is complete. The precise mechanism by which iron deficiency results in gastrointestinal abnormalities is unclear. It is now recognized that a reduction in cellular enzymes which require iron for their chemical structure or functional activity may accompany iron deficiency. Cytochrome oxidase is the most widely studied of these iron-dependent enzymes and has been shown to be diminished in buccal ..... and intestinal= mucosa of iron-deficient patients. The cytochrome enzymes play an essential role in the
Volume 88 Number 5
production o f cellular oxidative energy. Since m a n y secretory a n d absorptive functions are energy d e p e n d e n t , it is possible t h a t abnormalities in intestinal function m a y be related to a deficiency of these h e m e proteins. We h a v e d e m o n s t r a t e d that most children with iron deficiency a n e m i a h a v e elevated oral inorganic iron absorptions a n d their a n e m i a is responsive to t h e r a p e u t i c dosages o f oral iron. T h e r e are s o m e iron-deficient children, however, w h o d e m o n s t r a t e i n a p p r o p r i a t e l y flat absorptions, their a n e m i a b e i n g refractory to oral iron therapy. This clinical entity of m a l a b s o r p t i o n o f oral iron in iron-deficient children not responsive to oral i r o n m u s t be considered, a n d can be easily d o c u m e n t e d by the p e r f o r m a n c e o f a n oral iron a b s o r p t i o n test. We wish to express our appreciation to Ms. Marjorie Gillette for her secretarial assistance and to Ms. Thelma Schneider for her valuable aid in conducting our clinical investigations. In addition, we wish to acknowledge our gratitude to the house officers whose cooperation made this study possible. REFERENCES
1. Hawksley JC, Lightwood R, and Bailey UM: Iron deficiency anemia in children: its association with gastrointestinal disease, achlorhydria and hemorrhage, Arch Dis Child 9:359, 1934. 2. Ghosh S, Daga S, Kasthuri D, Misra RC, and Chuttani HK: Gastrointestinal function in iron deficiency states in children, Am J Dis Child 123:14, 1972. 3. Naiman JL, Oski FA, Diamond LK, Vawter GF, and Shwachman H: The gastrointestinal effects of iron deficiency anemia, Pediatrics 33:83, 1964. 4. Guha DK, Walia NS, Tandon BN, Deo ME, and Ghai OP: Small bowel changes in iron deficiency anemia of childhood, Arch Dis Child 43:239, 1968. 5. Hoag M, Wallerstein R, and Pollycove M: Occult blood loss in iron deficiency anemia of infancy, Pediatrics 27:199, 1961. 6. Wilson JE, Heiner DC, and Lahey ME: Studies on iron metabolism. I. Evidence of gastrointestinal dysfunction in infants with iron deficiency anemia: a preliminary report, J PEDIATR 60:787, 1962.
Malabsorption o f iron
7.
8.
9.
10.
11.
12. 13.
14.
15. 16.
17.
18. 19. 20. 21.
22.
799
Schulz J, and Smith N J: Quantitative study of absorption of iron salts in infants and children, Am J Dis Child 95:I20, 1958. Schulz J, and Smith NJ: A quantitative study of the absorption of food iron in infants and children, Am J Dis Child 95:109, 1958. Moore CV: The importance of nutritional factors in the pathogenesis of iron-deficiency anemia, Am J Clin Nutr 3:3, 1955.. Chodos RB, et al: The absorption of radio-iron labelled foods in normal and iron deficient subjects and in idiopathic hemochromatosis, J Clin Invest 36:314, 1957. Pirzio-Biroli G, Bothwell TH, and Finch CA: Iron absorption. II. The absorption of radio-iron administered with a standard meal in man, J Lab Clin Med 51:37, 1958. Kimber C, and Weintraub L: Malabsorption of iron secondary to iron deficiency, N Engl J Med 279:453, 1968. Crawley J: Iron absorption tests in anemia: the use of intravenous iron preparations, Edinburgh Med J 59:478, 1952. Mauer AM: Pediatric hematology: iron deficiency anemia, New York, 1969, McGraw-Hill Book Company, Inc, p 209. Brittin GM, Brecher G, and Johnson CA: Evaluation of the Coulter Counter Modet S, Am J Clin Pathoi 52:679, 1969. Jung DH, and Parekh AC: A semi-micromethod of the determination of serum iron and iron-binding capacity without deproteinization, Am J Clin Pathol 54:813, 1970. Briere RO, Golias T, and Batsakis JW: Rapid qualitative and quantitative hemoglobin fractionation, cellular acetate electrophoresis, Am J Clin Pathol 44:695, 1965. Mitchell DG, Aldous KM, and Ryan FJ: Mass screening for lead poisoning, NY State J Med 74:1599, 1974. Folate: Folic Acid Assay Kit, Diagnostic Products Corporation, Culver City, Calif. 90230. Jacobs A: Iron containing enzymes in the buccal epithelium, Lancet 2:1331, 1961. Dagg JH, Jackson JM, Curry B, and Goldberg A: Cytochrome oxidase in latent iron deficiency (sideropenia), Br J Haematol 12:331, 1966. Dallman PR, Sunshine P, and Leonard Y: Intestinal cytochrome response with repair of iron deficiency, Pediatrics 6:863, 1967.
795
Malabso rp tio n o f iron in children with iron
deficiency Inability to absorb oral iron is believed to be an extremely rare cause of therapeutic failure in the treatment of iron deficiency anemia. Six patients who had failed to respond to oral iron therapy were studied by a simple oral absorption test and contrasted with 25 patients with untreated iron deficiency anemia and 10 normal subjects. All six of the patients who were therapeutic failures demonstrated impaired iron absorption in the absence of other clinical evidence o f gastrointestinal disease. In the 25 newly diagnosed patients with iron deficiency, 24 demonstrated elevated iron absorptions while 10 ironreplete normal subjects had minimal elevations in their serum iron values following the administration of the test dose of 1 mg of elemental iron per kilogram. When the therapeutic failures were treated with parenteral iron, all had a therapeutic response, In addition, after treatment the impaired absorption of iron improved transiently. All children who absorbed iron readily responded to oral iron therapy.
Steven J. Gross,* Marie J. Stuart, Phillip T. Swender, and Frank A. Oski, S y r a c u s e , N. Y.
AN ASSOCIATION between iron deficiency anemia and abnormalities in gastrointestinal structure and function has been noted by several investigators. Gastric achlorhydria,1, 2 impaired absorption of xylose and vitamin A, 3 duodenal mucosal changes, 34 and occult blood loss ~. ~ have all been previously documented in children. Despite the abnormalities in gastrointestinal absorption, most studies of Children? " and adults 9-1~ with iron deficiency anemia have demonstrated increased iron absorption, and it is generally believed that failure to absorb inorganic iron by iron-deficient children is rare. Since we have seen children with iron deficiency anemia who have not responded to 0ral iron therapy, a study was designed to determine the absorption of inorganic iron in normal and iron-deficient children.
MATERIALS AND METHODS Patients follows:
and
control subjects
were
grouped
as
Group I consisted of ten control subjects (5 adults and 5
From the Department of Pediatrics, State University of New York, Upstate Medical Center. *Reprint address: Department of Pediatrics, State University Hospital, 750 E. Adams St., Syracuse, N. Y. 13210.
children) with normal hemoglobin and iron saturation values > 20%. Group H cons!sted of 25 newly diagnosed children with iron deficiency anemia who had not received prior iron therapy ("de novo group"). Group I I I had six children with iron deficiency anemia who had received therapeutic doses of oral iron under close medical supervision for 2 to 42 months without improvement in their hemoglobin concentrations ("nonresponders"). Children in this group had discontinued oral iron supplementation for greater than 72 hours prior to study.
See related article, p. 909. The diagnosis of iron deficiency anemia was established in all cases by a serum transferrin saturation level of < 16% and a hemoglobin concentration of < 11 gm/dl in the presence of hypochromic, microcytic red cell indices. In Group III ("nonresponders") other causes of microcytosis were excluded by blood lead determinations and hemoglobin electrophoreses; concommitant folate deficiency was also excluded in this group. Any patient wi~h acute or chronic infection, fever, or evidence of malabsorptive disease was also excluded" from the study.
VoL 88, No. 5, pp. 795-799
796
Gross et al.
The Journal of Pediatrics May 1976
400
400 350
350
a
~d +1
.
300
300
(.9
GROUP TT (24/25)
..J
o o
o
250
250
0
=L ~L 200
z
z 200 0 n~
z 0
----- 150 :::3 n,.-
150
uJ co I 0 0
r uJ 03
,oJJ/5-
100
i
50
0
0
I
I
I
I
I
2
3
4
TIME
IN H O U R S
Fig. 1. Flat oral iron absorption curve; data from 10 ironsufficient control subjects (Group I). None of the "nonresponders" had a history of diarrhea, impaired xylose absorption, or evidence of occult gastrointestinal bleeding. Each patient had negative stool guaiac tests on at least three occasions. All had serum albumin concentrations in excess of 3.0 gm/dk After an eight-hour overnight fast, an early morning oral iron absorption test was performed by a modification of the method of Crawley?3 Following the collection of blood for a fasting serum iron and iron binding capacity, a test dose of 1 mg of elemental iron per kilogram of body weight was administered by mouth to all subjects. Serum iron levels were obtained at i, 2, and 4 hours following the oral iron test dose; the resulting absorption curves were described as being "elevated" or "flat" depending on whether the maximum rise over baseline values in the serum iron concentrations at either 1, 2, or 4 hours was greater or less than 100 ffg/dl, respectivelyP Those iron-deficient children who had elevated iron absorption curves were treated with oral ferrous sulfate, 9 mg/kg/day of elemental iron; follow-up hemoglobin determinations were obtained within one to six weeks after the initiation of iron therapy. Those iron-deficient children who had flat absorption curves were given
I
I I
GROUP ]I (I/25)
I
I 2 3 TIME IN HOURS
I
4
Fig. 2. Oral iron absorption curves in de novo iron-deficient children (Group II) and in iron-deficient nonresponders (Group III). An elevated absorption curve was present in 24 of 25 Group II patients. A fiat absorption curve was present in 1 of 25 Group II and 6 of 6 Group III patients.
parenteral iron at doses calculated to correct anemia and replenish iron stores. TM Follow-up determinations of hemoglobin and serum iron values, and of iron binding capacity, and oral iron absorption studies were performed whenever possible. No dietary modifications were made between study periods. All blood was obtained by venipuncture. Hemoglobin and red blood cell counts were calculated on the Coulter Electronic Counter, Model S) 5 Serum iron and unsaturated iron binding capacity were determined by the method of Jung and Parekh2 6 Hemoglobin fractionation was performed by cellulose acetate electrophoresis. 17 Blood lead TM and folate TM were determined by previously described methods. RESULTS The results of the oral iron absorption tests in the 10 normal control subjects (Group I) are depicted in Fig. 1. These control subjects demonstrated "flat" absorption curves with an average maximum rise in serum iron over the fasting level of only 42 ffg/dl. The results observed in both groups of iron-deficient children are shown in Fig. 2. Of the 25 children in the "de novo" group (Group II), 24
Volume 88 Number 5
Malabsorption of iron
25O -
/
o~ 2 0 0
\
P re I9.3gms % d.S. 6 % s o t
Post 12.3gms% 16%sat
.~n/7.Zoms ~
10.ggms~
797
sat
~L z 150
g D r~ bJ r.f)
~ 6 WEEKS P O S T I,M, IRON
'
~
----- I 0 0
50
PRE I.M. IRON
I
0
I
I 2
I
.3
I 4
TIIV[E IN H O U R S
Fig. 3. Mean oral iron absorption curves before and after intramuscular (IM) administration of iron in two nonresponders (Group III). had "elevated" iron absorption curves with an average maxiinum rise in serum iron over the fasting level o f 274 /~g/dl. In contrast, all six of the children who were "nonresponders" (Group III) plus one child belonging to Group II had "flat" iron absorption curves with an average maximum rise in serum iron of only 42 /~g/dl. The maximum rise in serum iron in all three groups occurred at two hours after administration of oral iron. Differences in the serum iron levels following the test dose between the "fiat" and "elevated" absorbers were significantly different (p < 0.001). The "flat" versus "elevated" absorbers were further compared in several respects. There were no significant differences in age, height, and weight percentiles, or degree of anemia as reflected by initial hemoglobin, fasting serum iron, or iron saturation. They had comparable intakes of whole milk. Mean birth weights in both groups were identical. In the 24 of 25 children in Group II with "elevated" iron absorptions, correction of anemia occurred promptly with oral iron therapy. The mean hemoglobin rise per day was 0.31 gm, 0.15 gm, and 0.10 gm with observation periods of 7 to 10 days, 14 to 21 days, and 24 to 42 days, respectively. All seven of the children who had "flat" iron absorptions (6 of the children in G~'oup III plus one of the 25 children in the de novo group) were given iron* intramuscularly; they had substantial rises in their hemoglobin *Imferon, LakesideLaboratories,Milwaukee,Wis.
values. In four of these seven patients, repeat oral iron absorption tests were carried out. It is noteworthy that at the time of the repeat absorption studies these children were in varying stages of iron repletion as reflected by their serum iron values and percentage of transferrin saturation. Two of these four children had repeat absorption tests at five to six weeks after parenteral iron. Fig. 3 demonstrates their mean absorption curves before and after parenteral iron. Initially, the curves were flat; when repeated they were elevated. At the time of the second absorption studies, these children may still have been iron deficient. In Patient S. D., the hemoglobin had risen from 7.2 to only 10.9 gm/dl. (Unfortunately, a percentage of saturation is not available for the second study). In Patient J. S., the repeat iron saturation was just 16%. The fourth case is shown graphically in Fig. 4. Three absorption tests were performed on Patient A. H. Following an initial flat curve (A), intramuscular iron was given. Nine weeks later, when the patient was still iron deficient with an iron saturation of only 13%, a repeat absorption test was somewhat elevated (Curve B). Without further iron therapy the oral absorption test was repeated 20 weeks after therapy with Inferon. The patient is now iron sufficient with an iron saturation of 19%; the absorption curve is again flat (Curve C). DISCUSSION Using an oral test dose of 1 mg/kg of elemental iron, we have demonstrated that iron-replete adults and children
798
Gross et al.
250 -
f" /
The Journal of Pediatrics, May 1976
A
B
C
Pre
9 Weeks Po s t
20Weeks Po st
d
o o
A'H'/10.9 gms% L I0 ~ sat
200
11.6 gmsO/o 13Olosat
12.0 gms~ 19% sat
::L z _
150
g
B
13s
100
LU
5(
03
A w
0
9
9
f
I
I
I
1
2
3
4
TIME
IN HOURS
Fig. 4. Oral iron absorption curves before (curve A) and after (curves B and C) administration of iron in one nonresponder (Group III). (See text.)
have flat iron absorption curves when studied serially for four hours following ingestion of the test dose of inorganic iron. Most children with iron deficiency anemia have elevated iron absorption curves and their anemia is responsiv e to therapeutic doses of oral iron. There are some iron-deficient children, however, who have flat oral iron absorption curves, their anemia being refractory to oral iron therapy. In this latter group, during parenteral correction of their iron deficient state, an elevated absorption curve is observed, followed by a return to a flat curve when iron sufficiency is complete. The amount of inorganic iron used as the test dose is an important variable as was observed by Crawley. '3 In adults, using a test dose of 2 mg/kg of elemental iron, they obtained findings similar to those reported here--flat absorption curves in iron-replete control subjects and in iron-deficient patients refractory to oral iron therapy. Adults comparable to our "de novo" Group II irondeficient patients responded to this test dose with increased absorption rates similar to the responses in our Group II children. However, using 4 m g / k g o f elemental iron, Crawley and associates demonstrated elevated absorption rates in their control population and even greater elevations in serum iron in their de novo irondeficient group. Following this larger test dose, their refractory group of patients with iron deficiency continued to exhibit flat absorption curves and were treated with parenteral iron. In their study, no repeat iron
absorption tests were performed in these latter patients following parenteral iron replacement. Most other studies relating to the absorption of either a radioiron salt 7 (ferrous sulfate) or food iron s in children with iron deficiency anemia have demonstrated a 2- to 3fold increase in absorption over iron-sufficient control subjects. However, Kimber and associates12 using ~gFelabeled hemoglobin, measured intestinal absorption in iron-deficient children and demonstrated a marked impairment (28.5% absorption) when compared to ironreplete control subjects (41.8% absorption). In the irondeficient children, after correction of the anemia, the absorption of hemoglobin iron improved in all but one of the children tested. Interestingly, only six of the eight iron-deficient children responded to oral ferrous sulfate. The other two children were given intramuscular iron, after which there was prompt hematologic improvement. Organic and inorganic iron are absorbed by different mechanisms so that the findings in our patients are not directly comparable to those of Kimber and co-workers. It seems unlikely that our refractory (Group Ill) patients demonstrated impaired iron absorptions on the basis of allergy to fresh cow milk that has been found concommitantly with iron deficiency anemia in many infants. None of these patients had occult gastrointestinal blood loss as has been observed in patients with cow milk-induced gastrointestinal bleeding. The structural and functional abnormalities noted by previous authors 1-4 and the impaired absorption of hemoglobin iron noted by Kimber and colleagues, 12 were reversed with iron repletion. Similarly, in our irondeficient children with flat inorganic iron absorption curves, we found elevated absorption several weeks after parenteral iron replacement. The reversal of abnormalities following iron therapy indicates that the abnormalities noted are effects rather than causes of the iron deficiency. Since iron balance is almost exclusively controlled by intestinal absorption, it is understandable that if iron absorption is minimal in normal control subjects, it would also be minimal in iron-deficient children after iron repletion is complete. The precise mechanism by which iron deficiency results in gastrointestinal abnormalities is unclear. It is now recognized that a reduction in cellular enzymes which require iron for their chemical structure or functional activity may accompany iron deficiency. Cytochrome oxidase is the most widely studied of these iron-dependent enzymes and has been shown to be diminished in buccal ..... and intestinal= mucosa of iron-deficient patients. The cytochrome enzymes play an essential role in the
Volume 88 Number 5
production o f cellular oxidative energy. Since m a n y secretory a n d absorptive functions are energy d e p e n d e n t , it is possible t h a t abnormalities in intestinal function m a y be related to a deficiency of these h e m e proteins. We h a v e d e m o n s t r a t e d that most children with iron deficiency a n e m i a h a v e elevated oral inorganic iron absorptions a n d their a n e m i a is responsive to t h e r a p e u t i c dosages o f oral iron. T h e r e are s o m e iron-deficient children, however, w h o d e m o n s t r a t e i n a p p r o p r i a t e l y flat absorptions, their a n e m i a b e i n g refractory to oral iron therapy. This clinical entity of m a l a b s o r p t i o n o f oral iron in iron-deficient children not responsive to oral i r o n m u s t be considered, a n d can be easily d o c u m e n t e d by the p e r f o r m a n c e o f a n oral iron a b s o r p t i o n test. We wish to express our appreciation to Ms. Marjorie Gillette for her secretarial assistance and to Ms. Thelma Schneider for her valuable aid in conducting our clinical investigations. In addition, we wish to acknowledge our gratitude to the house officers whose cooperation made this study possible. REFERENCES
1. Hawksley JC, Lightwood R, and Bailey UM: Iron deficiency anemia in children: its association with gastrointestinal disease, achlorhydria and hemorrhage, Arch Dis Child 9:359, 1934. 2. Ghosh S, Daga S, Kasthuri D, Misra RC, and Chuttani HK: Gastrointestinal function in iron deficiency states in children, Am J Dis Child 123:14, 1972. 3. Naiman JL, Oski FA, Diamond LK, Vawter GF, and Shwachman H: The gastrointestinal effects of iron deficiency anemia, Pediatrics 33:83, 1964. 4. Guha DK, Walia NS, Tandon BN, Deo ME, and Ghai OP: Small bowel changes in iron deficiency anemia of childhood, Arch Dis Child 43:239, 1968. 5. Hoag M, Wallerstein R, and Pollycove M: Occult blood loss in iron deficiency anemia of infancy, Pediatrics 27:199, 1961. 6. Wilson JE, Heiner DC, and Lahey ME: Studies on iron metabolism. I. Evidence of gastrointestinal dysfunction in infants with iron deficiency anemia: a preliminary report, J PEDIATR 60:787, 1962.
Malabsorption o f iron
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