Hirschsprung's Enterocolitis, Prostaglandins, and Response to Cholestyramine By John D. Lloyd-Still and Laurence M. Demers • An infant with Hirschsprung's enterocolitis developed a fulminant secretory diarrhea unresponsive to all conventional therapy until cholestyramine was administered, A 12-fold decrease in prostaglandin E (PGE) levels in the colostomy fluid was documented in response to cholestyramine therapy. It is postul ated that increased PG E activity, errterotoxin, and bile acid malabsorption may be involved in the errterocolitis of Hirschsprung's disease. INDEX WORDS: Bile acids; cholestyramine; enterocolitis; Hirschsprung's disease; prostaglandin E; protracted diarrhea.
T
HE ETIOLOGY of the enterocolitis of Hirschsprung's disease remains unknown, although infections, toxins, and an allergic vascular Schwartzman-type reaction have all been postulated. I Recently, a trial of cholestyramine has been recommended for infants with intractable diarrhea." Prostaglandins are known to be involved in certain secretory diarrhea syndromes." In man, prostaglandin E, (PGE) causes appreciable secretion of water and electrolytes from the jejunum." We are reporting an infant in whom fulminant enterocolitis secondary to Hirschsprung's disease responded to cholestyramine therapy. The PGE activity in the stools as determined by radioimmunoassay" decreased 12-fold after cholestyramine therapy. CASE REPORT
This male infant weighed 3.0 kg at birth. Abdominal distention was noted at 36 hr and Hirschsprung's disease was confirmed by rectal biopsy. Three episodes of gastroenteritis occurred, and a transverse colostomy was performed at9 wk of age. At 5 mo, he was readmitted with enterocolitis (weight, 4.95 kg); apart from 5% dehydration, examination was unremarkable. Investigation showed hematocrit 26%, WBC 8900/cu mm, BUN 34 mg/d]. His subsequent progress is shown in Fig. I. After 5 days of failure to respond to i.v, fluids, i.v, peripheral nutrition was instituted and continued for the next 30 days. Despite no oral fluids for 24 days, the colostomy drained up to 790 ml/24 hr with an electrolyte content isotonic with plasma (Fig. I). The fluid and electrolyte abnormalities were corrected, but his nutritional status deteriorated. The prothrombin time was 25 sec (control 12 sec), total protein 5.2 gm/dl, albumin 3.0 gm/dl, alkaline phosphatase 655 units, SOOT rose from 75 to 690 units (normal, 5-40, and lactic dehydrogenase was (LDH) 699 units (normal, 50-180). A duodenal biopsy was performed on the 15th day and showed grade II villus at-
Journal of Pediatric Surgery, Vol. 13, No.4 (August), 1978
rophy on histology. Disaccharidase activity of hydrolyzed substrate in Itmoles/g protein/min at 37"C showed lactase 6.3 (normal, 30.5 ± 16.6), sucrase 25.4 (normal, 62.8 ± 26.7), maltase 89.8 (normal, 203.6 ± 75.2), and palatinase 0 (normal, 15.7 ± 5.1). The duodenal aspirate grew over 55,000 coloniea/cu mm of Pseudomonas aeruginosa. Methicillin 100 mg/kg/24 hr, gentamicin 6 mg/kg/24 hr, and bydrocortisone lO/mg/kg/24 hr were administered intravenously for 10 days. An upper gastrointestinal series, barium enema, intravenous pyelogram, and vanilmandelic acid excretion were all normal and no obstruction to the colostomy stoma could be demonstrated at any time. A colon biopsy performed on the 18th day was normal. No clinical improvement was noted. On the 21st day, oral cholestyramine I g q6h was begun. An effect on the volume and constituency of the colostomy fluid was noted within 12 hr. On the 14th day, the patient was started on dilute Pregestimils orally and all biochemical abnormalities had returned to normal. The duodenal aspirate on the 28th day was sterile. A Soave pull-through operation was performed uneventfully at I yr.
DISCUSSION
The colostomy output in this infant resembled the secretory diarrhea described in association with certain tumors. Pharmacologically active agents produced by tumor cells include 5-hydroxy tryptamine, kallikrein, prostaglandins, and histamine." Samples of colostomy fluid from our infant were examined for PGE concentration. The data in Fig. I demonstrates that the administration of cholestyramine reduced the fecal volume and correlates with the reduction in total PGE concentration in the fecal fluid. Although the mode of action of the ionexchange resin cholestyramine in our patient remains unknown, cholestyramine binds bile acids, thus rendering them ineffective in stimulating diarrhea." Other hypotheses include binding of enterotoxin from the Pseudomonas cultured from the upper intestine.?" Lastly,
From the Division of Gastroenterology, The Children's Memorial Hospital. Chicago, III. and the Departments of Pathology and Pediatrics, The Milton S. Hershey Medical Center, The Pennsylvania State University, Hershey, Pa. Address reprint requests to 10!", D. Lloyd-Still, M.D., The Children's Memorial Hospital, 2300 Children's Plaza, Chicago, 1/1.60614. @ 1978 by Grone & Stratton.Lnc.
417
LLOYD-STILL AND DEMERS
418
200
Coioitomy
D
No
• K
electrolytes 100
o 1-.=::=:::::::::::=::::::::=-------
6 WI
Kg
.5
CHOLESTYRAMINE
I C~om y
J
I.v.
1000
Input
::
hrs
o
::
::: ::: ::: :::: = :: =- : : ~
m1l2 " 500 .5 DAYS
25
10
PGE Tolol 50 ng/do y
0 '--_ _
cholesty r a m in e may combine with prostaglandins .
REFERENCES 1. Berry CL, Fraser GC: Expe rimental production of colitis in the rabbit. J Pediatr S urg 3:36-42, 196& 2. T a m e r MA, Santora TR, Sandberg DH: Cholestyramine therapy for int rac ta ble d iarrhea. Pediatrics 53:217-220,1974 3. Jaffe BM, Condom S : Prost agla nd ins E a nd F in end ocrine d ia rrhcag cnic syndrom es. Ann Surg 1&4 :5 16-523, 1976
Fig . 1. Cl inical course of patient with Hirschsp rung's enterocolitis. Note secretory diarrhea , electrolyte composition of colostomy output, fecal PG E concentration, and response to cholestyramine therapy.
4. Matucha nski C, M ar y J Y, Bernier JJ : Effec t of prostag la ndin E, upon tr ansit time, net and indir ec tional movements of wa ter and elect rolytes in the hu man jej u num. BioI Ga st roentero I 5:175-1 79,1972 5. Demers LM , Yosh inaga K . G reep RO: P rost aglandin F levels in ut erine fluid. Prost agland ins 5:513··517, 1974 6. Hofm ann AF, Poley JR: C holesty ra mine treatment of dia rrh ea associated with ileal resect ion. N Engl J Med 2& I:397- 402, 1969 7. Kubot a Y, Liu PV: An enterotoxin of Pseudomonas aeruglnos a. J Infect Dis 123:97-98 , 1971 8. Lloyd-St ill J D, Sh wachm an H: Duodenal micro flora. A prospect ive study in pediatric gast rointestina l disorders. Am J Dig Dis 20:70&- 7 15, 1975
T
HE ETIOLOGY of the enterocolitis of Hirschsprung's disease remains unknown, although infections, toxins, and an allergic vascular Schwartzman-type reaction have all been postulated. I Recently, a trial of cholestyramine has been recommended for infants with intractable diarrhea." Prostaglandins are known to be involved in certain secretory diarrhea syndromes." In man, prostaglandin E, (PGE) causes appreciable secretion of water and electrolytes from the jejunum." We are reporting an infant in whom fulminant enterocolitis secondary to Hirschsprung's disease responded to cholestyramine therapy. The PGE activity in the stools as determined by radioimmunoassay" decreased 12-fold after cholestyramine therapy. CASE REPORT
This male infant weighed 3.0 kg at birth. Abdominal distention was noted at 36 hr and Hirschsprung's disease was confirmed by rectal biopsy. Three episodes of gastroenteritis occurred, and a transverse colostomy was performed at9 wk of age. At 5 mo, he was readmitted with enterocolitis (weight, 4.95 kg); apart from 5% dehydration, examination was unremarkable. Investigation showed hematocrit 26%, WBC 8900/cu mm, BUN 34 mg/d]. His subsequent progress is shown in Fig. I. After 5 days of failure to respond to i.v, fluids, i.v, peripheral nutrition was instituted and continued for the next 30 days. Despite no oral fluids for 24 days, the colostomy drained up to 790 ml/24 hr with an electrolyte content isotonic with plasma (Fig. I). The fluid and electrolyte abnormalities were corrected, but his nutritional status deteriorated. The prothrombin time was 25 sec (control 12 sec), total protein 5.2 gm/dl, albumin 3.0 gm/dl, alkaline phosphatase 655 units, SOOT rose from 75 to 690 units (normal, 5-40, and lactic dehydrogenase was (LDH) 699 units (normal, 50-180). A duodenal biopsy was performed on the 15th day and showed grade II villus at-
Journal of Pediatric Surgery, Vol. 13, No.4 (August), 1978
rophy on histology. Disaccharidase activity of hydrolyzed substrate in Itmoles/g protein/min at 37"C showed lactase 6.3 (normal, 30.5 ± 16.6), sucrase 25.4 (normal, 62.8 ± 26.7), maltase 89.8 (normal, 203.6 ± 75.2), and palatinase 0 (normal, 15.7 ± 5.1). The duodenal aspirate grew over 55,000 coloniea/cu mm of Pseudomonas aeruginosa. Methicillin 100 mg/kg/24 hr, gentamicin 6 mg/kg/24 hr, and bydrocortisone lO/mg/kg/24 hr were administered intravenously for 10 days. An upper gastrointestinal series, barium enema, intravenous pyelogram, and vanilmandelic acid excretion were all normal and no obstruction to the colostomy stoma could be demonstrated at any time. A colon biopsy performed on the 18th day was normal. No clinical improvement was noted. On the 21st day, oral cholestyramine I g q6h was begun. An effect on the volume and constituency of the colostomy fluid was noted within 12 hr. On the 14th day, the patient was started on dilute Pregestimils orally and all biochemical abnormalities had returned to normal. The duodenal aspirate on the 28th day was sterile. A Soave pull-through operation was performed uneventfully at I yr.
DISCUSSION
The colostomy output in this infant resembled the secretory diarrhea described in association with certain tumors. Pharmacologically active agents produced by tumor cells include 5-hydroxy tryptamine, kallikrein, prostaglandins, and histamine." Samples of colostomy fluid from our infant were examined for PGE concentration. The data in Fig. I demonstrates that the administration of cholestyramine reduced the fecal volume and correlates with the reduction in total PGE concentration in the fecal fluid. Although the mode of action of the ionexchange resin cholestyramine in our patient remains unknown, cholestyramine binds bile acids, thus rendering them ineffective in stimulating diarrhea." Other hypotheses include binding of enterotoxin from the Pseudomonas cultured from the upper intestine.?" Lastly,
From the Division of Gastroenterology, The Children's Memorial Hospital. Chicago, III. and the Departments of Pathology and Pediatrics, The Milton S. Hershey Medical Center, The Pennsylvania State University, Hershey, Pa. Address reprint requests to 10!", D. Lloyd-Still, M.D., The Children's Memorial Hospital, 2300 Children's Plaza, Chicago, 1/1.60614. @ 1978 by Grone & Stratton.Lnc.
417
LLOYD-STILL AND DEMERS
418
200
Coioitomy
D
No
• K
electrolytes 100
o 1-.=::=:::::::::::=::::::::=-------
6 WI
Kg
.5
CHOLESTYRAMINE
I C~om y
J
I.v.
1000
Input
::
hrs
o
::
::: ::: ::: :::: = :: =- : : ~
m1l2 " 500 .5 DAYS
25
10
PGE Tolol 50 ng/do y
0 '--_ _
cholesty r a m in e may combine with prostaglandins .
REFERENCES 1. Berry CL, Fraser GC: Expe rimental production of colitis in the rabbit. J Pediatr S urg 3:36-42, 196& 2. T a m e r MA, Santora TR, Sandberg DH: Cholestyramine therapy for int rac ta ble d iarrhea. Pediatrics 53:217-220,1974 3. Jaffe BM, Condom S : Prost agla nd ins E a nd F in end ocrine d ia rrhcag cnic syndrom es. Ann Surg 1&4 :5 16-523, 1976
Fig . 1. Cl inical course of patient with Hirschsp rung's enterocolitis. Note secretory diarrhea , electrolyte composition of colostomy output, fecal PG E concentration, and response to cholestyramine therapy.
4. Matucha nski C, M ar y J Y, Bernier JJ : Effec t of prostag la ndin E, upon tr ansit time, net and indir ec tional movements of wa ter and elect rolytes in the hu man jej u num. BioI Ga st roentero I 5:175-1 79,1972 5. Demers LM , Yosh inaga K . G reep RO: P rost aglandin F levels in ut erine fluid. Prost agland ins 5:513··517, 1974 6. Hofm ann AF, Poley JR: C holesty ra mine treatment of dia rrh ea associated with ileal resect ion. N Engl J Med 2& I:397- 402, 1969 7. Kubot a Y, Liu PV: An enterotoxin of Pseudomonas aeruglnos a. J Infect Dis 123:97-98 , 1971 8. Lloyd-St ill J D, Sh wachm an H: Duodenal micro flora. A prospect ive study in pediatric gast rointestina l disorders. Am J Dig Dis 20:70&- 7 15, 1975
