Coexistence of diabetes mellitus and celiac disease

Volume 85 Number 4

Brief cl&ical and laboratory observations

has n o t b e e n associated with decreased plasma fibrinogen levels.8 Several clinical and chemical findings are shared by anorexia n e r v o s a a n d h y p o t h y r o i d i s m , although the conditions are unlikely to be confused. The low ESR values in anorexia n e r v o s a form an additional dist i n g u i s h i n g characteristic, since elevated ESRs are usually found in hypothyroidism.9 REFERENCES 1. Forbes GB: Relation of lean body mass to height in children and adolescents, Pediatr Res 6:32, 1972. 2. Pincherle G, and Shanks J: Value of the erythrocyte sedimentation rate as a screening test, Br J Prev Soc Med 21:133, 1967. 3. Mant MJ, and Faragher BS: The haematology of anorexia nervosa, Br J Haematol 23:737, 1972.

Coex&tence of diabetes mellitus and celiac disease M. E. Thain, M.D., J. R. Hamilton, M.D., and R. M. Ehrlich, M.D., Toronto, Ont., Canada

IN 1951 THOMPSON noted an increased incidence of diabetes mellitus in relatives of patients with celiac disease. 1 At that time techniques for peroral biopsy of intestinal mucosa were unavailable and the diagnosis of celiac disease could not be made with the specificity possible today. Since then coexisting diabetes mellitus and celiac disease, proved by biopsy, have been reported in individual children 2, 3 and adults. 4 We suspect that these two diseases occur together more frequently than generally recognized. CLINICAL MATERIALS

AND METHODS

We s t u d i e d six c h i l d r e n , all hospitalized b e t w e e n 1965 and 1973 in T h e Hospital for Sick C h i l d r e n , Toronto, for the diagnosis and early care of diabetes mellitus or for the diagnosis and early care of celiac disease (gluten-induced enteropathy, celiac sprue). Continuing ambulatory care was supervised in a special outpatient clinic. Celiac disease had been diagnosed by finding a typical lesion in the duodenal mucosa and by demonstrating a favourable response to the withdrawal of wheat and rye gluten from the diet. 5 Other causes of chronic malabsorption including cystic fibrosis were excluded.

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4. Lamy M, Frezal J, Polonovski J, Druez G, and Rey J: Congenital absence of beta-lipoproteins. Pediatrics, 31:277, 1963. 5. Gracey M, Wilson RG, and Petersen M: Transient acanthocytosis and hypobetalipoproteinaemia, Aust NZ J Med 2:397, 1972. 6. Gray SJ, and Mitchell EB: Effect of purified protein fractions on sedimentation rate of erythrocytes, Proc Soc Exp Biol Med 51:403, 1942. 7. Ham TH, and Curtis FC: Plasma fibrinogen response in man, Medicine 17:413, 1938. 8. Moxley RT, Brakman P, and Astrup T: Resting levels of fibrinolysis in blood in inactive and exercising men, J Appl Physiol 28:549, 1970. 9. Larsson SO: On serum proteins and erythrocyte sedimentation rate in hypothyroidism, Acta Med Scand 172:545, 1962.

Fat was measured in stools collected for at least four days, and excretion expressed as a percentage of the calculated intake. Routine laboratory techniques were used to measure concentrations of serum electrolytes, cholesterol, triglycerides, lipoproteins, h e m o g l o b i n , white blood cell count, and differential, serum iron and total iron-binding capacity, serum proteins, calcium, a n d phosphorus. T h y r o i d f u n c t i o n was assessed by measuring serum thyroxine, and the T 3 resin uptake. In selected cases, thyroid-stimulating hormone and thyroid autoantibodies (tanned red blood cell agglutinins a n d t h y r o g l o b u l i n c o m p l e m e n t fixation antibodies) were measured. RESULTS The clinical data are summarized in Table I. Five of six children were known to have diabetes before celiac disease was diagnosed, but in retrospect they all had subtle intestinal symptoms dating back at least to the onset of diabetes. The diagnosis of celiac disease was sometimes delayed because of preoccupation with the problems of diabetes. The clinical manifestations of active celiac disease were typical in all six children: foul, bulky stools, episodic diarrhea, abdominal distention, anorexia, and poor or no weight gain. Malabsorption had been suggested in the children with diabetes by problems of control, particularly diminishing insulin requirements, and frequent hypoglycemic reactions. The child who developed diabetes mellitus after celiac disease had symptoms of hyperglycemia. All children had normal concentrations of serum cholesterol, triglycerides, and lipoproteins. Five o f the six patients had

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Table

Brief clinical and laboratory observations

The Journal of Pediatrics October 1974

I. Corn ~arisons before and after gluten restricted diet

Age at diagnosis

Case 1

2 3 4 5 6

Fecal fat (% of intake)

Weight percentile

Diabetes mellitus

Celiac disease

Before

After

15 yr 4 yr 10 yr 10 mo 13 mo 6 yr

16 yr 7 yr 11 yr 2 yr 20 mo 3 yr

20 5 5 25 5 25

70 10 45 60

Before 8

10 10 19 28 54

Insulin requirement (Units~day)

After

Before

After

-

20 14 10 16 1 *

40 26 24 16 9 *

2.5 2 3

*Developed celiac disease first.

steatorrhea with fat excretions of 10-54% of dietary intake. One 15-year-old boy excreted only 8% of dietary fat. Biopsy of the intestinal mucosa and clinical response to dietary therapy were typical of celiac disease. One p a t i e n t was h y p o a l b u m i n e m i c and three had decreased serum iron concentrations expressed as a percentage of the total iron-binding capacity. One patient had definite biochemical evidence of hypothyroidism without thyroid antibodies; another had measurable t a n n e d red blood cell a n t i b o d i e s with n o r m a l thyroid function. After t r e a t m e n t with a g l u t e n - f r e e diet i n t e s t i n a l s y m p t o m s i m p r o v e d rapidly and all children gained weight. Fat absorption returned to normal in the three children in whom it was reassessed. Control of the diabetes improved and the n u m b e r and severity of hypoglycemic episodes declined. Insulin requirement increased significantly in four of the five children as absorptive function improved in response to diet. DISCUSSION The coexistence of diabetes mellitus and celiac disease apparently is commoner than would be expected by chance alone. During the 8-year-period of our study, 112 new cases of celiac disease and approximately 400 new cases of diabetes mellitus were seen at our institution. The occurrence of diabetes in approximately 6% of children with celiac disease, and celiac disease in approximately 1.5% of diabetic children is much more frequent than the reported figures for the prevalence of these diseases in the general population.6,7 Genetic factors are important in the etiology of both diabetes mellitus8 and celiac disease, 7 but neither the exact n a t u r e nor the basic m e c h a n i s m s u n d e r l y i n g these two conditions is known. No clear-cut patterns of i n h e r i t a n c e are k n o w n , b u t b o t h celiac disease and diabetes occur more frequently in relatives of patients

with each of these diseases than in the general population. The increased frequency of the histocompatibility antigens HLA-8 and HLA-1 in patients with celiac disease and their families also supports a genetic predisposition .7 We speculate that the two conditions may be linked by some c o m m o n etiologic factor. The finding of autoantibodies to various tissues, an increased incidence of autoimmune disease, as well as the lymphocytic infiltration of the pancreas observed in early diabetes suggest some alteration in i m m u n e surveillance.9 I m m u n e factors have been implicated indirectly in the pathogenesis of celiac diseasO ~ b u t other observers favor deficiency of a mucosal dipeptidasO 1as the primary defect. Whether further studies will identify a common etiology remains to be seen. Meanwhile the physician caring for a young diabetic should be aware of the increased likelihood that the child may also have celiac disease. REFERENCES

1. Thompson MW: Heredity, maternal age and birth order in the etiology of celiac disease, Am J Hum Genet 3:159, 1951. 2. Walker-Smith JA, and Grigor W: Coeliac disease in a diabetic child, Lancet 1:1021, 1969. 3. Visakorpi JK: Diabetes and coeliac disease, Lancet 2:1192, 1969. 4. Green PA, Wollaeger EE, Sprague RG, and Brown AL: Diabetes mellitus associated with nontropical sprue, Report of four cases, Diabetes 11:388, 1962. 5. Hamilton JR, Lynch MJ, and Reilly BJ: Active coeliac disease in childhood. Clinical and laboratory findings of forty-two cases, Q J Med 38:135, 1969. 6. White P: The child with diabetes, Med Clin North Am 49:1069, 1965. 7. StokesPL, Asquith P, and Cooke WT: Genetics of coeliac disease; Clin Gastrol 2:547, 1973. 8. Rimoin DL: Inheritance in diabetes mellitus, Med Clin North Am 55:807, 1971.

Volume 85 Number 4

9. Nissley SP, Drash AL, Blizzard RM, Sperling M, and Childs B: Comparison of juvenile diabetics with positive and negative organ specific antibody titers, Diabetes 22:63, 1973. 10. Shiner M, and Ballard J: Antigen-antibody reactions in je-

Congenital hypoplastic anemia associated with hypogammaglobulOwmia Ernest G. Brookfield, M.D.,* and Promilla Singh, M.D., Toledo, Ohio

THE ASSOCIATION of pure red cell anemia and hyp o g a m m a g l o b u l i n e m i a has been reported in adults with t h y m o m a : Patients with h y p o g a m m a g l o b u l i n e m i a also d e v e l o p o t h e r h e m a t o l o g i c a b n o r m a l i t i e s s u c h as neutropenia, lymphopenia, eosinopenia, hemolytic anemia, and pernicious anemia. 2 Congenital hypoplastic a n e m i a in children as originally described by D i a m o n d and Blackfan 3 is now a well-established entity with o v e r 100 reported cases that include siblings 4 as well as a child with hypocalcemia and a chromosome abnormality) This report involves a child that we h a v e followed for four years in w h o m cortiocosteroid-responsive pure red cell a n e m i a has b e e n a s s o c i a t e d w i t h p e r s i s t e n t hypogammaglobulinemia, a relationship that has not been reported previously. CASE HISTORY J. B., a 4-year-old Caucasian girl, the first child of unrelated parents, was first seen at the age of 3 months with gastroenteritis and marked anemia. Physical examination revealed a markedly pale infant with wide-set eyes, a snub nose, and a thick upper lip. The liver was slightly enlarged, and the spleen tip was palpable. The hemoglobin was 3.7 gm/100 ml; hematocrit, 14%; platelets, 444,000/mm3; white blood cell count, 10,800/ mm 3, with a normal differential. The peripheral smear was characteristic of a normochromic, normocytic anemia. Hemoglobin electrophoresis showed type AA, with 16% hemoglobin F, In tibial bone marrow the red cell precursors were decreased, resulting in an increased myeloid-erythroid ratio. The cells of both the myeloid and erythroid series were normal in structure, and there was an adequate number of megakaryocytes and 0.6% From the Departments of Pediatrics, Mercy Hospital and the Medical College o f Ohio at Toledo. *Reprintaddress:1544S. Byrne Rd., Toledo, Ohio43614.

B r i e f clinical and laboratory observations

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junal mucosa in childhood coeliac disease after gluten challenge, Lancet 1:120, 1972. 11. Cornell H J, and Townley RRW: Investigation of a possible intestinal peptidase deficiency in coeliac disease, Clin Chim Acta 43:113, 1973.

plasmacytes. She was treated with transfusions and folic acid; three transfusions were required during the first year to maintain a hemoglobin level of 7-10 gm/100 ml (Fig. 1). At 19 months of age she was rehospitalized because of a right middle lobe pneumonitis and history of frequent respiratory infections. There was no history of severe skin rashes, chronic adenopathy, intractable diarrhea, or failure to thrive. At this time she was pale, short in stature, and her previously described facial appearance was even more notable. There were dullness to percussion and fine inspiratory r~les over the right middle lung. The liver and spleen were not enlarged. The hemoglobin was 7.9 gm/100 ml; the hematocrit, 25%; reticulocytes, 2.1%; leukocyte count, 21,0001rnm 3, with 39% neutrophils, 3% band cells, 1% eosinophils, 2% monocytes, and 55% lymphocytes. The platelet count was 215,000/mm 3. A second bone marrow specimen showed a decrease in the number of red cell precursors and 0.2% plasmacytes. Serum protein values as determined by electrophoresis were albumin, 4.5 gm/100ml; alpha-1 globulin, 0.2 gm/100 ml; alpha-2 globulin, 0.6 gm/100 ml; gamma globulin, 0.2 gm/100 ml. By immunodiffusion the IgG was 115 mg/100 ml; IgA, 62'mg/100 ml; IgM, 45 mg/100 ml (Figs. 2 to 4). The patient had another episode of pneumonitis at 22 months of age; gamma globulin replacement therapy was started at that time. After 12 months the gamma globulin injections were discontinued and no serious infections have developed subsequently, although her immunoglobulin values have remained low. Her anemia remained moderate until 32 months of age, when her hemoglobin fell to 5.9 gm/100 ml. At this time a daily dose of 20 mg of prednisone was started; the hemoglobin promptly rose to 13 gin/100 ml. A reasonable hemoglobin level has been maintained during gradual reduction of the prednisone dose to 5 mg. every other day. All three immunoglobulins have remained below normal values; they have not been affected by the use of prednisone therapy (Figs. 2 to 4). DISCUSSION T h e e t i o l o g y o f B l a c k f a n - D i a m o n d c o n g e n i t a l hypoplastic anemia is uncertain. Suggested causes have included genetic factors, metabolic abnormalities, i m m u n e m e c h a n i s m s , deficiency of erythropoietin, and a decrease in the differentiation and transition of s t e m cells to the erythrocyte.6The two abnormalities in our patient could represent partial expression of a basic anomaly in the m e s e n c h y m a l cells as suggested by G o o d and colleagues. 7 A c o m m o n humoral factor could also produce