Actu Pzdiutr Scand 68: 275-276, 1979 SHORT COMMUNICATION
EXOCRINE PANCREATIC INSUFFICIENCY, SMALL INTESTINAL DYSFUNCTION AND PROTEIN INTOLERANCE A Chance Occurrence or a Connection?
The coexistence of cystic fibrosis (CF) and coeliac disease (CD) is reported in eight children (for ref. see 4,5), the odds against this occurring in the same child being 1 : 2 million to 1 :5.9 million (4). In Sweden, it would be around 1 : 3 million (incidence of C F 1 : 3 000 (6) and of CD 1 : 1000 ( 2 ) ) . The coexistence of these two diseases is thought to be chance (9, although C F might predispose to the development of CD (4). In a I0-year period (with 33 405 live births), we observed three children with exocrine pancreatic insufficiency and small intestinal dysfunction. Patient I . CF and CD. Boy, only child of Jewish unrelated parents. At age I month, he had bronchopneumonia with atelectasis; at 5 , 7, and 8 months, bronchitis. Glutencontaining diet from age 4 months. From 6 months, diarrhoea, failure to thrive, and weight loss. At 8 months, two pilocarpine iontophoresis gave a sweat sodium of 123, and 106 mmol/l. Duodenal juice had no trypsin and no amylase activities. No Giardia lumbliu. Xylose and lactose tolerance tests abnormal. Intestinal biopsy showed a morphology in agreement with coeliac disease; intestinal disaccharidases (cf. 3) very low (Table 1). He gained weight and dramatically improved on pancreatic extract and vitamins, physiotherapy, antibiotics, and a gluten-free diet. At 13 months, intestinal biopsy showed marked morphological improvement (Table 1). Intestinal dipeptidase activities (cf. 3) against val-glu and ala-pro were extremely low (Table I ) . Xylose test normal. Gluten challenge at 15 months gave diarrhoea and decreased xylose absorption. Two further gluten challenges at 4 and 5 years resulted in diarrhoea. Now at age 6.5 years he has normal weight and height. Patient 2 . CF and disacchuriduse deficiency. Girl, second child of unrelated parents and with a healthy brother. Recurrent respiratory infections from age 9 months, diarrhoea, and no weight gain. Two pilocarpin iontophoresis at 21 months showed a sweat sodium of 100 and 92 mmol/l. No trypsin activity detected in duodenal juice. Xylose tolerance test normal; lactose tolerance test abnormal. Intestinal biopsy showed: villous mucosa with inspissated mucous secretion in the crypts; normal intestinal dipeptidases; low disaccharidase activities (especially lactase
activity) (Table 1). N o symptoms of disaccharide intolerance. Died at age 5.5 years. Patient 3. Shwwchman syndrome, food intolerunce, decreased intestinul lactase, ala-pro and val-gli~dipeptiduse actii,ities. Boy, only child of unrelated parents. Admitted at age 2 months for infantile colic and eczema. He got diarrhoea and failed to thrive; had neutropenia and slight thrombocytopenia. On three occasions, low or zero values of trypsin, amylase, and lipase in duodenal juice. Pilocarpin iontophoresis x3 gave a sweat sodium of 17, 19, and 34 mmol/l. Xylose and lactose tolerance tests normal at age 4 months. Intestinal biopsy at 6 months showed a slightly damaged mucosa, low val-glu and ala-pro dipeptidase activities, and low lactase activity (Table I ) . At 9 and 18 months, urticaria after an egg and skin rash repeatedly after drinking milk. At 3 years, he tolerated egg; at 6 years milk. Height now at age 9 years 115 cm ( = - 3 S.D.).
The small intestinal dysfunction reported in C F includes, besides CD, specific lactase deficiency (1, 8), reduced lactase activities (7, S), and reduced uptake of phenylalanine and cycloleucine (8). In Shwachman syndrome (lo), the morphology of the intestinal mucosa was reported normal (7, 10) or slightly changed (9, 10). Intestinal disaccharidases (7,9) and enterokinase (7) normal. Besides eczema, observed in Shwachman syndrome (9, lo), our patient had allergic skin reactions after egg and milk; also low intestinal lactase, ala-pro and val-glu dipeptidase activities. These two dipeptidase activities were also proportionally further decreased in the second biopsy from the boy with CF+CD. A.bbreviationst CF=cystic fibrosis; CD=coeliac disease; Gly-leu=glycyl-L-leucine; Ala-glu=L-alanyl-L-glutamic acid; val-glu=L-valine-L-glutamic acid; glu-val=L-glutamyl-L-valine; ala-pro= L-alanyl-L-proline; ala-phe= L-alanyl-L-phenylalanine. Grants from Swedish Medical Research Council (project no. 5143 and 5364) supported this work. Actcr Pordicitr Srcmd 68
216
N . 0 .Berg et a l .
Table 1. Morphology, intestinal dipeptidases and disaccharidases in small intestinal biopsies (duodeno-jejunalflexure)f r o m the three patients I: C F + C D
Morphology Dissecting microscopy Histology
On gluten
Without gluten
Mosaic-convoluted Cuboidal and irregular epithelial cells. Elongation of crypts. Infiltration of plasma cells and leucocytes
Leaves+ ridges Normal epithelial cells. Elongation of crypts, inspissated mucous secretion. Infiltration of plasma cells
Intestinal dipeptidases (ulmg N . ) Gly-leu (98-350)a Ala-glu (2040) Val-glu (7.2-27) Glu-val(7.241) Ala-pro (5.1-19) -
71 17 ~ 0 . 5
2.7 0.8
Intestinal disaccharidases (ulg protein) Maltase (91-600)" 16 Isomaltase (20-126) 7.8 Sucrase (23-166) 4.8 Trehalase (8.3-50) 0.5 Lactase (6.6-73) 0.8 Controls, range (n=49) (3).
3: Shwachman syndrome
Finger+leaves Normal epithelial cells. Slight elongation of crypts, inspissated mucous secretion. Slight infiltration of plasma cells and leucocytes
Leaves Normal epithelial cells. Slight elongation of crypts, slight infiltration of plasma cells and leucocytes
223 60 36 17 13
119, 2266 21, 4.8, 6.4 8.2, 8.7 1.0. 1.9
24 9.5 10.5 2.2
160 54.4 44.4 5.3
1.1
5.8
Two biopsies from the same biopsy occasion.
To conclude: we found morphological and enzymatical abnormalities in intestinal mucosa in both CF and Shwachman syndrome, favouring the hypothesis that exocrine pancreatic insufficiency predisposes to the development of small intestinal dysfunction in phenotypically high-risk individuals. N . 0 .Berg
2: CF
A . Dahlqvist
Tor Lindberg
Departments of Pathology and Nutrition, University of Lund and Departments of Paediatrics and Experimental Research, Malmo General Hospital, University of Lund, Sweden.
REFERENCES 1. Antonowicz, I . , Reddy, V . , Khaw, K.-T. & Shwach-
man, H.: Lactase deficiency in patients with cystic fibrosis. Pediatrics, 42: 492, 1968. 2. Berg, N . 0. & Lindberg, T.: Incidence of coeliac disease and of transient gluten intolerance in a Swedish urban community. Acta Paediatr Scand, 68, 1979. In press. 3. Dahlqvist, A . , Lindberg, T., Meeuwisse, G. & Aker-
man, M.: Intestinal dipeptidases and disaccharidases in children with malabsorption. Acta Paediatr Scand, 59:621, 1970. 4. Goodchild, M. C., Nelson, R. & Anderson, Ch. M.: Cystic fibrosis and coeliac disease: coexistence in two children. Arch Dis Child. 48: 684. 1973. 5 . Katz, A . J., Falchuk, M. Z . & Shwachman, H.: The coexistence of cystic fibrosis and coeliac disease. Pediatrics, 57: 715, 1976. 6. Kollberg, H.: Cystic fibrosis in Sweden. Thesis. Acta Universitatis Upsaliensis, 192, 1974. 7. Lebenthal, E., Antonowicz, I . & Shwachman, H.: Enterokinase and trypsin activities in pancreatic insufficiency and diseases of the small intestine. Gastroenterology, 70: 508, 1976. 8. Morin, C. L., Roy, C. C . , Lasalle, R. & Bonin, A . : Small bowel dysfunction in patients with cystic fibrosis. J Prdiut, 88: 213, 1976. 9. Shmerling, D. H., Prader, A , , Hitzig, W. H., Giedion, A,, Hadorn, B. & Kiihni, M.: The syndrome of exocrine pancreatic insufficiency, neutropenia, metaphyseal dysostosis and dwarfism. Heiv Paediatr Acta, 24: 547, 1969. 10. Shwachman, H., Diamond, L. K., Oski, F. A. & Khaw, K.-T.: The syndrome of pancreatic insufficiency, and bone marrow dysfunction. J Pediat, 65: 645, 1964.
EXOCRINE PANCREATIC INSUFFICIENCY, SMALL INTESTINAL DYSFUNCTION AND PROTEIN INTOLERANCE A Chance Occurrence or a Connection?
The coexistence of cystic fibrosis (CF) and coeliac disease (CD) is reported in eight children (for ref. see 4,5), the odds against this occurring in the same child being 1 : 2 million to 1 :5.9 million (4). In Sweden, it would be around 1 : 3 million (incidence of C F 1 : 3 000 (6) and of CD 1 : 1000 ( 2 ) ) . The coexistence of these two diseases is thought to be chance (9, although C F might predispose to the development of CD (4). In a I0-year period (with 33 405 live births), we observed three children with exocrine pancreatic insufficiency and small intestinal dysfunction. Patient I . CF and CD. Boy, only child of Jewish unrelated parents. At age I month, he had bronchopneumonia with atelectasis; at 5 , 7, and 8 months, bronchitis. Glutencontaining diet from age 4 months. From 6 months, diarrhoea, failure to thrive, and weight loss. At 8 months, two pilocarpine iontophoresis gave a sweat sodium of 123, and 106 mmol/l. Duodenal juice had no trypsin and no amylase activities. No Giardia lumbliu. Xylose and lactose tolerance tests abnormal. Intestinal biopsy showed a morphology in agreement with coeliac disease; intestinal disaccharidases (cf. 3) very low (Table 1). He gained weight and dramatically improved on pancreatic extract and vitamins, physiotherapy, antibiotics, and a gluten-free diet. At 13 months, intestinal biopsy showed marked morphological improvement (Table 1). Intestinal dipeptidase activities (cf. 3) against val-glu and ala-pro were extremely low (Table I ) . Xylose test normal. Gluten challenge at 15 months gave diarrhoea and decreased xylose absorption. Two further gluten challenges at 4 and 5 years resulted in diarrhoea. Now at age 6.5 years he has normal weight and height. Patient 2 . CF and disacchuriduse deficiency. Girl, second child of unrelated parents and with a healthy brother. Recurrent respiratory infections from age 9 months, diarrhoea, and no weight gain. Two pilocarpin iontophoresis at 21 months showed a sweat sodium of 100 and 92 mmol/l. No trypsin activity detected in duodenal juice. Xylose tolerance test normal; lactose tolerance test abnormal. Intestinal biopsy showed: villous mucosa with inspissated mucous secretion in the crypts; normal intestinal dipeptidases; low disaccharidase activities (especially lactase
activity) (Table 1). N o symptoms of disaccharide intolerance. Died at age 5.5 years. Patient 3. Shwwchman syndrome, food intolerunce, decreased intestinul lactase, ala-pro and val-gli~dipeptiduse actii,ities. Boy, only child of unrelated parents. Admitted at age 2 months for infantile colic and eczema. He got diarrhoea and failed to thrive; had neutropenia and slight thrombocytopenia. On three occasions, low or zero values of trypsin, amylase, and lipase in duodenal juice. Pilocarpin iontophoresis x3 gave a sweat sodium of 17, 19, and 34 mmol/l. Xylose and lactose tolerance tests normal at age 4 months. Intestinal biopsy at 6 months showed a slightly damaged mucosa, low val-glu and ala-pro dipeptidase activities, and low lactase activity (Table I ) . At 9 and 18 months, urticaria after an egg and skin rash repeatedly after drinking milk. At 3 years, he tolerated egg; at 6 years milk. Height now at age 9 years 115 cm ( = - 3 S.D.).
The small intestinal dysfunction reported in C F includes, besides CD, specific lactase deficiency (1, 8), reduced lactase activities (7, S), and reduced uptake of phenylalanine and cycloleucine (8). In Shwachman syndrome (lo), the morphology of the intestinal mucosa was reported normal (7, 10) or slightly changed (9, 10). Intestinal disaccharidases (7,9) and enterokinase (7) normal. Besides eczema, observed in Shwachman syndrome (9, lo), our patient had allergic skin reactions after egg and milk; also low intestinal lactase, ala-pro and val-glu dipeptidase activities. These two dipeptidase activities were also proportionally further decreased in the second biopsy from the boy with CF+CD. A.bbreviationst CF=cystic fibrosis; CD=coeliac disease; Gly-leu=glycyl-L-leucine; Ala-glu=L-alanyl-L-glutamic acid; val-glu=L-valine-L-glutamic acid; glu-val=L-glutamyl-L-valine; ala-pro= L-alanyl-L-proline; ala-phe= L-alanyl-L-phenylalanine. Grants from Swedish Medical Research Council (project no. 5143 and 5364) supported this work. Actcr Pordicitr Srcmd 68
216
N . 0 .Berg et a l .
Table 1. Morphology, intestinal dipeptidases and disaccharidases in small intestinal biopsies (duodeno-jejunalflexure)f r o m the three patients I: C F + C D
Morphology Dissecting microscopy Histology
On gluten
Without gluten
Mosaic-convoluted Cuboidal and irregular epithelial cells. Elongation of crypts. Infiltration of plasma cells and leucocytes
Leaves+ ridges Normal epithelial cells. Elongation of crypts, inspissated mucous secretion. Infiltration of plasma cells
Intestinal dipeptidases (ulmg N . ) Gly-leu (98-350)a Ala-glu (2040) Val-glu (7.2-27) Glu-val(7.241) Ala-pro (5.1-19) -
71 17 ~ 0 . 5
2.7 0.8
Intestinal disaccharidases (ulg protein) Maltase (91-600)" 16 Isomaltase (20-126) 7.8 Sucrase (23-166) 4.8 Trehalase (8.3-50) 0.5 Lactase (6.6-73) 0.8 Controls, range (n=49) (3).
3: Shwachman syndrome
Finger+leaves Normal epithelial cells. Slight elongation of crypts, inspissated mucous secretion. Slight infiltration of plasma cells and leucocytes
Leaves Normal epithelial cells. Slight elongation of crypts, slight infiltration of plasma cells and leucocytes
223 60 36 17 13
119, 2266 21, 4.8, 6.4 8.2, 8.7 1.0. 1.9
24 9.5 10.5 2.2
160 54.4 44.4 5.3
1.1
5.8
Two biopsies from the same biopsy occasion.
To conclude: we found morphological and enzymatical abnormalities in intestinal mucosa in both CF and Shwachman syndrome, favouring the hypothesis that exocrine pancreatic insufficiency predisposes to the development of small intestinal dysfunction in phenotypically high-risk individuals. N . 0 .Berg
2: CF
A . Dahlqvist
Tor Lindberg
Departments of Pathology and Nutrition, University of Lund and Departments of Paediatrics and Experimental Research, Malmo General Hospital, University of Lund, Sweden.
REFERENCES 1. Antonowicz, I . , Reddy, V . , Khaw, K.-T. & Shwach-
man, H.: Lactase deficiency in patients with cystic fibrosis. Pediatrics, 42: 492, 1968. 2. Berg, N . 0. & Lindberg, T.: Incidence of coeliac disease and of transient gluten intolerance in a Swedish urban community. Acta Paediatr Scand, 68, 1979. In press. 3. Dahlqvist, A . , Lindberg, T., Meeuwisse, G. & Aker-
man, M.: Intestinal dipeptidases and disaccharidases in children with malabsorption. Acta Paediatr Scand, 59:621, 1970. 4. Goodchild, M. C., Nelson, R. & Anderson, Ch. M.: Cystic fibrosis and coeliac disease: coexistence in two children. Arch Dis Child. 48: 684. 1973. 5 . Katz, A . J., Falchuk, M. Z . & Shwachman, H.: The coexistence of cystic fibrosis and coeliac disease. Pediatrics, 57: 715, 1976. 6. Kollberg, H.: Cystic fibrosis in Sweden. Thesis. Acta Universitatis Upsaliensis, 192, 1974. 7. Lebenthal, E., Antonowicz, I . & Shwachman, H.: Enterokinase and trypsin activities in pancreatic insufficiency and diseases of the small intestine. Gastroenterology, 70: 508, 1976. 8. Morin, C. L., Roy, C. C . , Lasalle, R. & Bonin, A . : Small bowel dysfunction in patients with cystic fibrosis. J Prdiut, 88: 213, 1976. 9. Shmerling, D. H., Prader, A , , Hitzig, W. H., Giedion, A,, Hadorn, B. & Kiihni, M.: The syndrome of exocrine pancreatic insufficiency, neutropenia, metaphyseal dysostosis and dwarfism. Heiv Paediatr Acta, 24: 547, 1969. 10. Shwachman, H., Diamond, L. K., Oski, F. A. & Khaw, K.-T.: The syndrome of pancreatic insufficiency, and bone marrow dysfunction. J Pediat, 65: 645, 1964.
