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Folic acid deficiency in children with celiac disease
COMMENTS CURRENT
ON LITERATURE
Folic acid deficiency in children
ith celiac disease documented recently by Do rmandy, Waters, and Mollin* have as their purpose "to ascertain the prevalence of folic-acid deficiency in children with untreated coeliac disease by measuring the serum-folate levels and the urinary excretion of F I G L U (formiminoglutamic acid) after histidine loading, and to relate these findings to the haematological features of the anemia which may develop in this condition."* Nineteen children with celiac disease and 38 control children were included in the study reported. The children with celiac disease ranged in age from 7 months to 13 years, with 5 under the age of one year. The children serving as controls ranged in age from 2 months to 10 years, with 16 under one year of age. Except for 4 normal children, the control group of 38 consisted of patients with various conditions which were selected at random. T h e diagnosis of celiac disease was made on the basis of a history of gluten intolerance, steatorrhea, and failure to gain weight. The biochemical criteria consisted of fat absorption values of less than 90 per cent on the basis of a 5 day fat balance and of a flat curve for glucose tolerance. Jejunal biopsy was obtained in i 1 of the children, and in all of these the mucosa was flattened, showing subtotal or partial villous atrophy. Fibro-
W R I L E folic acid deficiency and megaloblastic anemia are relatively common in adults with idiopathic steatorrhea, their frequency in children with celiac disease is not well established. Overt megaloblastic anemia has not been considered common in children with this condition. In 1955 Sheldon 1 reported the complication in 7 of a group of 74 children with celiac disease. In Sheldon's series, bone marrow examinations were performed only in those patients who showed macrocytic anemia. More recent studies in children with celiac disease, however, suggest that folic acid deficiency may be more common in children with this condition than has been supposed. Girdwood -~in 1960 studied folic acid absorption in 8 children with celiac disease, and found it to be abnormal in 6 of the eight. Somewhat later Gr/isbeck, Bj6rksten, and Nyberg a stated that folic acid absorption may be faulty in celiac disease, and reported that after the administration of a histidine load, as a tolerance test, the urinary excretion of formhninoglutamic acid ( F I G L U ) , which is a precursor of glutamic acid, was abnormally high in 4 of the 5 celiac children studied. Investigations currently in progress at tile Hospital for Sick Children, Great Ormond Street, London, are of interest. These studies 344
Volume 63
Number 2
cystic disease of the pancreas was excluded by sweat test showing normal electrolytes a n d / o r normal trypsin activity in the stoo.ls. Hematologic investigations included hemoglobin estimation, microhematocrit measurement, reticulocyte count, white cell and differential' count, blood film examination and platelet count. Bone marrow from the iliae crest was examined in all except 4 of the children with celiac disease. Serum iron determinations, with total iron-binding capacity, serum vitamin ]~12 concentration, serum folate levels, and histidine-loading ( F I G L U ) tests were carried out. T h e urinary F I G L U was determined by conventional voltage eleetrophoresis on cellulose-acetate strips. ~ The histidine given by mo~th after a 4 to 6 hour fast was flavored with black currant juice. Since the excretion of an excessive amount of histidine may obscure the urinary electrophoretic pattern, the dose was adjusted to age: infants under one year of age received 3 Gila., those from one to 5 years, 5 Gm., and older children, 10 Gm. The results of these investigations are given in tabular form according to age. All the children with celiac disease had below normal serum folate levels, and in 16 of these the levels obtained were within the range found in patients with megaloblastic anemia due to folic acid deficiency (less than 4.0 mcg. per ml.). All the children showed increased amounts of urinate/ formiminoglutamic acid ( F I G L U ) after histidine administration. By comparison, the serum rotate levels and urinary F I G L U excretion were normal in all of the control children one year or older. However, in 5 of the sixteen control children under one year of age subnormal serum rotate levels were obtained, and 12 of the sixteen excreted increased amounts of F I G L U , ahhough the concentrations were less than those shown by the celiac children. These observations concerning folic acid absorption in normal infants under one year of age are explained tentatively on the basis of immaturity. Four of the children with celiac disease, who were in clinical remission at the time, were studied again after treatment with a gluten-free diet
Corr~rnents on current literature
345
for periods ranging from 2 to 9 months. Following treatment, 3 of these children showed improved folic acid absorption with normal serum folate levels and no urinary excretion of F I G L U ; the fourth child, who had been on a gluten-free diet for only 3 months, showed a low normal serum rotate level (6.0 ~g per milliliter), and still had traces of F I G L U in the urine. The hematologic findings are of interest. While 11 of the celiac children showed hemoglobin levels within the normal range, in all except 3 these leve'ls were below the normal mean. In 9 of these patients macrocytes were present in the peripheral blood film, and in 5 there was also hypochromia. Bone marrow examination was performed in 8 of these nine patients, and in all eight there was evidence of folic acid deficiency; in 6 of the patients the erythroblasts showed megaloblastic or intermediate megaloblastic change, and in 2, giant metamyelocytes only were present. In the remaining two patients considered to be nonanemic, the peripheral blood films showed hypochromia with no evidence of maeroeytosis; bone marrow examination in one of these two patients showed giant metamyelocytes. The other 8 patients with celiac disease had significant anemia, the clearest hematologic evidence being that of an iron deficiency anemia. In 3 of these children, severe hypochromia was the only abnormality of the peripheral blood film; in one, bone marrow examination showed normoblastic hemopoiesis. However, in the other 5 celiac children of the eight considered anemic, "the peripheral bloodpicture was dimorphic with macrocytosis in association with hypochromia; in 2 megaloblastic or intermediate megaloblastic change was seen in the bone-marrow, and in the other 3 giant metamyelocytes alone were found. ''4 In the authors' experience, the serum folate level seemed to be a valuable and sensitive index of folic acid deficiency. The diagnostic value of the histidine loading test ( F I G L U ) appeared to be less certain, "since factors other than folic-acid deficiency may affect the metabolism of histidine. ''4 Abnormal F I G L U excretion has been described
346
Comments
August 1963
on c u r r e n t l i t e r a t u r e
in cases of pernicious anemia, and in this instance is thought to be due to interference with folic acid metabolism on the basis of lack of vitamin B12. Deficiency of the specific liver enzyme, F I G L U transferase, is said to contribute to the abnormal F I G L U excretion which is seen in certain types of liver disease. I n the group of children studied folic acid deficiency "was a constant finding in all the coeliac children, but none h a d severe megaloblastic aenemia, and only 8 showed evidence of megaloblastic change in the bone-marrow. ''4 Four of the children with celiac disease, who were in clinical remission at the time, were re-studied after treatment with gluten-free diet. In all of these children folic acid absorption improved; the serum folate levels became normal, and the F I G L U excretion became normal in all except one child, who still excreted small amounts. T h e authors conclude that in alI probability intestinal malabsorption was the m a i n cause of folic acid deficiency in the celiac children over the age of one year, but that in celiac children under one year of age, other factors m a y h a v e contributed to the folic acid deficiency, since one third of the control children in this age group also showed serum folate levels below normal.
Suggested enzyme studies, G more particularly enzymes concerning the liver, may serve to elucidate certain problems of the celiac patient and m a y throw light on important developmental aspects of related enzyme activity in young infants. RUSSELL J. BLATTNER~ M.D.
REFERENCES
1. Sheldon, Wilfred: Coeliac disease, Lancet 9: 1097, 1955. 2. Girdwood, Ronald H. Folie acid, its analogs and antagonists, In Advances in Clinical Chemistry, Academic Press, Inc., New York, 1960, vol. 3, p. 235. 3. Gr~isbeck, R., Bjtlrksten, F., and Nyberg, W. : Formiminoglutamie acid in the urine in folie acid deficiency, Nord. Med. 66: 1343, 1961. 4. Dormandy, K. M., Waters, A. I-I., and Motlin, D. L.: Folio-acid deficiency in coeiiac disease, Lancet 1: 632, 1963. 5. Kohn, J., Mollin, D. L., and Rosenbacl L L. M.: Conventional voltage electrophoresis for formiminoglutamic-acid determination in folic deficiency, J. Clin. Path. 14: 345, 1961. 6. Waters, A. H., and Mollin, D. L.: Studies on the folio acid activity of human serum, J. Clin. Path. 14: 335, 1961; Proceedings VIII Congress of European Soc. Haematology, Vienna, 1961, Basle, 1962; Folic acid deficiency, J. Clin. Path. (in press).
ON LITERATURE
Folic acid deficiency in children
ith celiac disease documented recently by Do rmandy, Waters, and Mollin* have as their purpose "to ascertain the prevalence of folic-acid deficiency in children with untreated coeliac disease by measuring the serum-folate levels and the urinary excretion of F I G L U (formiminoglutamic acid) after histidine loading, and to relate these findings to the haematological features of the anemia which may develop in this condition."* Nineteen children with celiac disease and 38 control children were included in the study reported. The children with celiac disease ranged in age from 7 months to 13 years, with 5 under the age of one year. The children serving as controls ranged in age from 2 months to 10 years, with 16 under one year of age. Except for 4 normal children, the control group of 38 consisted of patients with various conditions which were selected at random. T h e diagnosis of celiac disease was made on the basis of a history of gluten intolerance, steatorrhea, and failure to gain weight. The biochemical criteria consisted of fat absorption values of less than 90 per cent on the basis of a 5 day fat balance and of a flat curve for glucose tolerance. Jejunal biopsy was obtained in i 1 of the children, and in all of these the mucosa was flattened, showing subtotal or partial villous atrophy. Fibro-
W R I L E folic acid deficiency and megaloblastic anemia are relatively common in adults with idiopathic steatorrhea, their frequency in children with celiac disease is not well established. Overt megaloblastic anemia has not been considered common in children with this condition. In 1955 Sheldon 1 reported the complication in 7 of a group of 74 children with celiac disease. In Sheldon's series, bone marrow examinations were performed only in those patients who showed macrocytic anemia. More recent studies in children with celiac disease, however, suggest that folic acid deficiency may be more common in children with this condition than has been supposed. Girdwood -~in 1960 studied folic acid absorption in 8 children with celiac disease, and found it to be abnormal in 6 of the eight. Somewhat later Gr/isbeck, Bj6rksten, and Nyberg a stated that folic acid absorption may be faulty in celiac disease, and reported that after the administration of a histidine load, as a tolerance test, the urinary excretion of formhninoglutamic acid ( F I G L U ) , which is a precursor of glutamic acid, was abnormally high in 4 of the 5 celiac children studied. Investigations currently in progress at tile Hospital for Sick Children, Great Ormond Street, London, are of interest. These studies 344
Volume 63
Number 2
cystic disease of the pancreas was excluded by sweat test showing normal electrolytes a n d / o r normal trypsin activity in the stoo.ls. Hematologic investigations included hemoglobin estimation, microhematocrit measurement, reticulocyte count, white cell and differential' count, blood film examination and platelet count. Bone marrow from the iliae crest was examined in all except 4 of the children with celiac disease. Serum iron determinations, with total iron-binding capacity, serum vitamin ]~12 concentration, serum folate levels, and histidine-loading ( F I G L U ) tests were carried out. T h e urinary F I G L U was determined by conventional voltage eleetrophoresis on cellulose-acetate strips. ~ The histidine given by mo~th after a 4 to 6 hour fast was flavored with black currant juice. Since the excretion of an excessive amount of histidine may obscure the urinary electrophoretic pattern, the dose was adjusted to age: infants under one year of age received 3 Gila., those from one to 5 years, 5 Gm., and older children, 10 Gm. The results of these investigations are given in tabular form according to age. All the children with celiac disease had below normal serum folate levels, and in 16 of these the levels obtained were within the range found in patients with megaloblastic anemia due to folic acid deficiency (less than 4.0 mcg. per ml.). All the children showed increased amounts of urinate/ formiminoglutamic acid ( F I G L U ) after histidine administration. By comparison, the serum rotate levels and urinary F I G L U excretion were normal in all of the control children one year or older. However, in 5 of the sixteen control children under one year of age subnormal serum rotate levels were obtained, and 12 of the sixteen excreted increased amounts of F I G L U , ahhough the concentrations were less than those shown by the celiac children. These observations concerning folic acid absorption in normal infants under one year of age are explained tentatively on the basis of immaturity. Four of the children with celiac disease, who were in clinical remission at the time, were studied again after treatment with a gluten-free diet
Corr~rnents on current literature
345
for periods ranging from 2 to 9 months. Following treatment, 3 of these children showed improved folic acid absorption with normal serum folate levels and no urinary excretion of F I G L U ; the fourth child, who had been on a gluten-free diet for only 3 months, showed a low normal serum rotate level (6.0 ~g per milliliter), and still had traces of F I G L U in the urine. The hematologic findings are of interest. While 11 of the celiac children showed hemoglobin levels within the normal range, in all except 3 these leve'ls were below the normal mean. In 9 of these patients macrocytes were present in the peripheral blood film, and in 5 there was also hypochromia. Bone marrow examination was performed in 8 of these nine patients, and in all eight there was evidence of folic acid deficiency; in 6 of the patients the erythroblasts showed megaloblastic or intermediate megaloblastic change, and in 2, giant metamyelocytes only were present. In the remaining two patients considered to be nonanemic, the peripheral blood films showed hypochromia with no evidence of maeroeytosis; bone marrow examination in one of these two patients showed giant metamyelocytes. The other 8 patients with celiac disease had significant anemia, the clearest hematologic evidence being that of an iron deficiency anemia. In 3 of these children, severe hypochromia was the only abnormality of the peripheral blood film; in one, bone marrow examination showed normoblastic hemopoiesis. However, in the other 5 celiac children of the eight considered anemic, "the peripheral bloodpicture was dimorphic with macrocytosis in association with hypochromia; in 2 megaloblastic or intermediate megaloblastic change was seen in the bone-marrow, and in the other 3 giant metamyelocytes alone were found. ''4 In the authors' experience, the serum folate level seemed to be a valuable and sensitive index of folic acid deficiency. The diagnostic value of the histidine loading test ( F I G L U ) appeared to be less certain, "since factors other than folic-acid deficiency may affect the metabolism of histidine. ''4 Abnormal F I G L U excretion has been described
346
Comments
August 1963
on c u r r e n t l i t e r a t u r e
in cases of pernicious anemia, and in this instance is thought to be due to interference with folic acid metabolism on the basis of lack of vitamin B12. Deficiency of the specific liver enzyme, F I G L U transferase, is said to contribute to the abnormal F I G L U excretion which is seen in certain types of liver disease. I n the group of children studied folic acid deficiency "was a constant finding in all the coeliac children, but none h a d severe megaloblastic aenemia, and only 8 showed evidence of megaloblastic change in the bone-marrow. ''4 Four of the children with celiac disease, who were in clinical remission at the time, were re-studied after treatment with gluten-free diet. In all of these children folic acid absorption improved; the serum folate levels became normal, and the F I G L U excretion became normal in all except one child, who still excreted small amounts. T h e authors conclude that in alI probability intestinal malabsorption was the m a i n cause of folic acid deficiency in the celiac children over the age of one year, but that in celiac children under one year of age, other factors m a y h a v e contributed to the folic acid deficiency, since one third of the control children in this age group also showed serum folate levels below normal.
Suggested enzyme studies, G more particularly enzymes concerning the liver, may serve to elucidate certain problems of the celiac patient and m a y throw light on important developmental aspects of related enzyme activity in young infants. RUSSELL J. BLATTNER~ M.D.
REFERENCES
1. Sheldon, Wilfred: Coeliac disease, Lancet 9: 1097, 1955. 2. Girdwood, Ronald H. Folie acid, its analogs and antagonists, In Advances in Clinical Chemistry, Academic Press, Inc., New York, 1960, vol. 3, p. 235. 3. Gr~isbeck, R., Bjtlrksten, F., and Nyberg, W. : Formiminoglutamie acid in the urine in folie acid deficiency, Nord. Med. 66: 1343, 1961. 4. Dormandy, K. M., Waters, A. I-I., and Motlin, D. L.: Folio-acid deficiency in coeiiac disease, Lancet 1: 632, 1963. 5. Kohn, J., Mollin, D. L., and Rosenbacl L L. M.: Conventional voltage electrophoresis for formiminoglutamic-acid determination in folic deficiency, J. Clin. Path. 14: 345, 1961. 6. Waters, A. H., and Mollin, D. L.: Studies on the folio acid activity of human serum, J. Clin. Path. 14: 335, 1961; Proceedings VIII Congress of European Soc. Haematology, Vienna, 1961, Basle, 1962; Folic acid deficiency, J. Clin. Path. (in press).