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Short Small Intestine Associated with Malrotation: A Newly Described Congenital Cause of Intestinal Malabsorption
Vol. 56, No.1 Printed in U.S.A.
GASTROENTEROLOGY
Copyright © 1969 hy The Williams & Wilkins Co.
SHORT SMALL INTESTINE ASSOCIATED WITH MALROTATION: A NEWLY DESCRIBED CONGENITAL CAUSE OF INTESTINAL MALABSORPTION J. R. HAMILTON, M.D., F.R.C.P. (CANAD.), B. J. REILLY, M.D., CH.B., AND R. MORECKI, M.D .
Departments of Pediatrics and Radiology, University of Toronto, and the Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada
A new and rare cause of intestinal malabsorption is described in a 6-year-old girl. The diagnosis was established at laparotomy, but it might have been made by careful radiological examination of the small bowel. Steatorrhea beginning in early childhood associated with intestinal malrotation but without obstruction should alert the clinician to the possible diagnosis of a congenital short small intestine. Spontaneous improvement of symptoms and absorptive function was observed when the child was followed over a 6-year-period. Defective fat absorption probably resulted from inadequate small intestinal absorptive surface. The anomaly may have arisen because of failure of the primitive gut to enter the intraumbilical coelom during early embryonic life. During early fetal life many aberrations may complicate the complex process of maturation of the alimentary tract. I In this report we describe a child with a congenital anomaly that has not been recorded previously, short small intestine. Studies undertaken first when the patient was 4 months old and at intervals over nearly 7 years have permitted us to document intestinal function and structure in this disorder, a new cause of intestinal malabsorption. Received May 13, 1968. Accepted June 28, 1968. Address requests for reprints to: Dr. J. R. Hamilton, The Hospital for Sick Children, 555 University Avenue, Toronto 2, Ontario, Canada. This work was supported by a grant from the Medical Research Council of Canada. Dr. Morecki's present address is: Montefiore Hospital and Medical Center, III East 210th Street, Bronx, New York 10467. The technical assistance of Mr. Bill Wilson and Mrs. Mary Kelly, and the advice of Dr. M. C. Johnston are gratefully acknowledged. The nutritionists and nurses of the Clinical Investigation Unit, The Hospital for Sick Children, Toronto, also contributed greatly to the studies reported.
Case Report History
The child, a girl, was admitted to hospital first at the age of 4 months in April 1962 for investigation of chronic diarrhea and failure to thrive. Born at term, she weighed 5 lb 12 oz. Pregnancy, labor, and delivery were uneventful. The mother did not receive drug therapy during the first trimester. The patient remained well until 4 days of age when loose, watery diarrhea began. Although she received an adequate quantity of an evaporated milk formula beginning at 36 hr of age, her gain and growth were slow. When examined at the age of 4 months, the child was below the third percentile for height and weight. Apart from small stature there were no physical signs of undernutrition. Her abdomen was flat and soft with normal musculature. Transit time of a carmine red marker from mouth to anus was 12 hr. Barium enema demonstrated the cecum in the left upper quadrant, indicating partial malrotation of the gut. There was no clinical or radiological evidence of intestinal obstruction. Because of continuing symptoms and after excluding the usual causes of chronic diarrhea by investigations, laparotomy was undertaken 124
January 1969
when the child was 7 months of age. The cecum, with a normal appendix, was on the left. Unexpectedly, the small intestine was only 40 cm in length. Otherwise, both small and large bowel and the intestinal vessels and lymphatics were normal. The intestine was not obstructed. Bands adherent to the duodenum were freed and the abdomen closed. There was no anomaly of any other organ apart from a minor irregularity of the fifth middle phalanx of one hand. Hepatic and renal function were normal. Chromosomal pattern was normal (46/xx). Intelligence quotients (Stanford-Binet) measured at the ages of 3 and 6 years were 58 and 68, respectively. The child has grown and gained slowly, but consistently, over the past 6 years (fig. 1). Her severe diarrhea persisted until she reached 5 years of age when spontaneous improvement occurred . Now, at the age of 7 with no medication, she has two semi formed stools per day. Apart from small stature, she has none of the clinical features of intestinal malabsorption (fig. 2). The patient's parents are French-Canadian and are not related. There have been five live births, all females, and no abortions. One sibling died at the age of 1 month. No post mortem was done but at laparotomy, 1 week prior to death, a short small intestine, 30 cm long, was found. The cecum with an appendix was located in the left upper quadrant. Three 110 100
90 30 WEIGHT (kg.)
HEIGHT 80 (em.) 70
10
.......--r--.-.,-,,......,..-.-~.....-+O
o
125
CASE REPORTS
2
4 6 8 AGE IN YEARS
10
FIG. 1. Patient's body weight and height compared with standard percentile curves. Solid lines represent 50th percentile; broken lines represent the 3rd and 97th. (Normal percentile curves from chart prepared by J . M. Tanner and R. H. Whitehouse, University of London, Institute of Child Health, for The Hospital for Sick Children, Great Ormond Street, London, W.C.l, England.)
siblings are healthy. Their intestinal function and structure have not been studied. No additional cases of intestinal anomaly were found in a search of the medical histories of three generations of maternal and paternal relations.
Methods The patient was studied in a Clinical Investigation Unit where conditions permitted close control of dietary intake and precisely timed collection of urine and stools. Fecal fat was assayed 2 on pooled collections of 5 days duration and results expressed as a percentage of dietary intake. Urinary 0xylose, 3 blood sugar,' serum vitamin A,5 plasma iron,6 and serum vitamin B!27 were measured by methods described previously. Urinary excretion of formiminoglutamic acid was measured after oral administration of histidine.8 Intestinal absorption of vitamin BI2 was assessed by measuring 24-hr urinary excretion of 57 Co after oral administration of the labeled vitamin and a "flushing" parenteral dose. 9 Intrinsic factor was administered with the vitamin. Tryptic activity was measured in fasting duodenal juice. \0 Trypsin and chymotrypsin was measured on fecal specimens pooled over 72 hr.ll Colloidal barium was used for radiological assessment of the small intestine. The barium column was observed at frequent intervals by fluroscopy as it progressed throughout the length of the bowel. The Crosby-Kugler intestinal biopsy capsule was used to obtain specimens of mucosa. 12 The position of the capsule was identified by fluoroscopy. Tissues were taken at a level corresponding to the distal duodenum and divided into fragments, for the assay of disaccharidase activity, for light microscopy, and for electron microscopy. Lactase, maltase, invertase, and isomaltase activities were measured on whole mucosal homogenate by the method of Dahlqvist. I. After examination under a dissecting microscope, a fragment was fixed in 10% formalin and embedded in paraffin for light microscopy. For alkaline phosphatase staining!' a portion of the tissue was fixed in chilled acetone. For electron microscopy, tissue was fixed in a 1 % solution of osmium tetroxide!5 for 1 hr at 4 C and then embedded in Epon l6 following rapid dehydration in increasing concentrations of ethanol. Sections 1 Jl thick were stained with toluidine blue l7 and examined by light microscopy. The blocks were oriented
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CASE REPORTS
r -t-----
I0
50
FIG. 2. The patient, age 6 years, showing small stature and good nutritional status.
in such a way that a specific zone could be chosen for thin sectioning. Thin sections were stained with lead hydroxide l 8 and examined in a Phillips 200 electron microscope.
Results Intestinal Function Certain parameters of intestinal absorptive function, measured at stages during the course of the patient's disease, are summarized in table 1. The most marked abnormality was that of fat absorption. Fecal fat excretion was 40% of dietary intake when first measured at age 20 months. Initially, oral glucose tolerance and o-xylose excretion were abnormal also. Serum protein concentrations were normal at all times. Over the 6 years during which the child has been followed,
spontaneous improvement of fat absorption, xylose excretion, and oral glucose tolerance has been observed. Concentration of trypsin in fasting duodenal juice and the activities of both trypsin and chymotrypsin in feces were normal. Examination of fecal smears by light microscopy revealed the presence of fatty acid but few meat fibers and little neutral fat. Response of fat excretion to the administration of a medium chain triglyceride formula (product 701O-H, Mead Johnson Company, Ltd.) and to dephenoxylate HCI (Lomotil) were measured when the patient was 31J2 years old. After a 12-day baseline period, medium chain triglyceride formula was substituted for the normal diet keeping the fat intake con-
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January 1969 TABLE
1. Laboratory data related to alimentary tract function Patient's age Normal range - - - - - - , - - - - ; - - -- - - -- , - - -- 4-7 months 20 months 3~2 years Hi years 6~ years
Fat excretion (% of dietary intake) . <10% Vitamin A tolerance (max . rise: ILg/ml) .. >50 Prothrombin time (sec). . . .. . . ...... . 14 Oral glucose tolerance (max. rise: 1 hr, mg/100 ml). . . . . . . .......... . . >40 D-xylose excretion (% of dose) ....... .. . >15% Serum proteins albumin (g/100 ml) . . ... 3.3-5.8 a 1 .... . ........................... . .. . 0 . 1-0 .3 a 2. . . . .... . . . . . . . . . . . . ... .. .. . ..... . . . 0.4-1.0 {3. . . . . . . ... .. . . . . . . .. . . . . . . . . . . . . . . . .0.3-1.2 .. 7 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · 0.4-1.4 Trypsin in fasting duodenal juice (units/ ml). ... ... . .. . ...... . ..... . Fecal trypsin. . . . . . . . . ...... ... . Fecal chymotrypsin (1000 units/72 hr) .. . . Sweat chloride (mEq/liter) ... . ..... .. . <60
TABLE
45 46
26
40
16
20 140 15
154
12.5 26 4.1 0.2 0.7 0 .5 0 .3
23 38 4.7 0.2 0.7 0.7 0.6
12 8
9
4.6 0.3 0.7 0.4 0.5
45 24
400 23 . 6
32.0
27 23
I.
I
2. Electrolyte dala Patient's age
1\ ormal range
4-7 months
Plasma Na (mEq/liter). ... . . . . . .... . .. K (mEq/liter) .. . . . . .... .. .. .. . . Cl (mEq/liter) . .. . . . . . . . . . . . .. . pH ....... ... . . . . . .... . CO 2 content (mM/li ter) . . . . ... .. Mg (mEq/liter). .. . . .. . . . .. .. . .. Serum Ca (mg/lOO ml) .. ... . ...... Phosphate (mg/lOO ml) . Alkaline phosphatase (K-A units) . .. . . ...... .. .
135-145 4.(}-5.0 98-108 7.35-7.45 2(}-28 1.5-1 .8
139.0 4.1 102 .0 7.42 19.9
I
20 months
years
139.0 4.5 99.5 7.32 17 .8 2.02
9.5-11.5 3 .8-5.8
10.3 3.8
8-20
18.1
stant (35 g per day) . Over a lO-day period, fat excretion fell from a mean of 37 to 12 )0 of the dietary intake. When the baseline diet was resumed and medium chain triglyceride formula discontinued, fat excretion rose again to 40% over a lO-day period. Dephenoxylate Hel administered for 6 days in a dosage of 5 mg per day had no beneficial effect on fat excretion, although fecal volume decreased from a mean of 420 ml to 150 ml per day. Serum and plasma electrolyte data are summarized in table 2. Even when she
3~2
9.3 5.5
I
20.6
Hi years
6l. years
144 4.4 104 7.39 23.1
142 4.6 102 7.36 24.2 1.86
I I
I
was an infant with severe watery diarrhea, the patient's electrolyte balance was never seriously impaired. Serum calcium, phosphate, and magnesium concentrations remained normal. Hematological indices, summarized in table 3, were normal. No abnormalities were detected in folic acid nutrition (as reflected by the measurement of form iminoglutamic acid excretion), serum concentration of vitamin B 12 , or intestinal absorption ofthe same vitamin. Disaccharidase activity was measured
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3. Hematological findings Patient's age
Normal range 20 months
. ..... . . . . ... . . , . . 11.0--13 .5" Hb (g/l00 ml) . ... White blood cells (1000 cells/mm 3 ) . . . . . .. . 7-11" Platel ets/ lOOO . ......... . ... . .... . . .. . . .. . . . . . . .. 150--350 Bone marrow. ............... . . .. . . .. . . . .. .. . . . . . >50 Serum F e ("g/lOO ml) .. ... . .. . ... .. . . . . . . . . . ... . 44 - 212b Serum vitamin BI2 ("l'g/lOO m!) . . Urina ry formiminoglutami c acid (5-hr urine, mM/ hr) .. . . . ........ . . . . . . .... .. . . .. . .. . . ... <10.3 Schilling test (S7CO) (24-hr urine , % of dose). . . . . >10% With intrinsic factor . . , . ... .. . .... '
.
.
a b
_ _
10.8 16.0 276,000 Normal 92 220
3~2
years
11.4 12.5
148
0.72
6H, years
12.0 6.8 190,000 Normal , 120 210 1.82 11%
.. I
Range encompasses minimum, maximum for ages 6 months to 7 years. R ange for normal adults .
in duodenal mucosa obtained when the child was 6V2 years of age. Lactase (19), maltase (215), invertase (69), and isomaltase (93) activites were normal. (Disaccharidase activity in units per gram tissue protein; 1 unit = 1 ~mole substrate hydrolyzed per min. 13 ) Stools were consistently alkaline from the age of 7 months. Roentgenological Investigation Barium enema. This was repeated when the child was 3V2 years old (fig. 3). The configuration of the colon was normal as far retrograde as the hepatic flexure, but proximal to this point, the ascending colon and cecum were rotated through 90 degrees and lay parallel to the transverse colon. The cecum lay below and medial to the splenic flexure in the left upper quadrant of the abdomen. The ileocecal valve was situated on the inferior margin of the malrotated, ascending colon. Barium meal. Representative films from the study done when the child was 6 1/2 years of age are reproduced in figures 4 and 5. The esophagus, stomach, and duodenum were normal. Precise measurement of the length of the small bowel was not practical. A continuous column of barium outlining the entire small bowel as far as the ileocecal valve showed that the small bowel was indeed short when compared with that of a normal child (fig. 6). The mucosal pattern was slightly
FIG. 3. Large bowel examined when patient was 3 \/2 years old by barium enema showing cecum in left upper quadrant.
coarser than normal Jejunum, but was otherwise unremarkable. However, instead of jejunum continuing on to ileum, the small bowel ended abruptly at the abnormally placed ileocecal valve. Mucosal Morphology Proximal intestinal mucosa was obtained at 3 V2 years of age. Examined by
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FIG. 4. Barium meal showing a single column of barium filling the entire small bowel at 50 min. Lower end has reached the cecum.
dissecting microscopy, the villi were ridgelike rather than paddle-shaped as they are usually in a normal child's duodenum. However, light microscopic studies showed no specific abnormalities (fig. 7). Normal Paneth cell granulation was observed at
the crypt bases. The surface epithelium was regular, columnar, and stained densely for alkaline phosphatase (fig. 8). Studied by electron microscopy, the absorptive epithelium had a normal brush border with normal cytoplasmic organelles (fig. 9).
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FIG. 5. At 70 min barium is seen in large bowel. The entire small bowel is outlined by barium.
Discussion Proof of the diagnosis of short small intestine in our patient rests on observations made at laparotomy when she was 7 months of age and on subsequent radiological assessments of her bowel. Although absolute measurements of in-
testinal length are notoriously inaccurate, there can be little doubt that the measured length of 40 cm was significantly short compared with estimates of approximately 250 cm for a normal, full term human newborn. 19 In the premature child, the length may vary from 160 to
January 1969
CASE REPORTS
131
FIG. 6. Barium meal in a child age 7 years with small intestine of normal length.
240 cm. 20 Abnormalities of rotation and probable that the child's malabsorptive fixation of the intestinal tract occur rela- state dates from early infancy. The most tively frequently, but to our knowledge noteworthy absorptive defect was that of an associated congenital shortening of the fat. Decreased absorptive surface in the small intestine has not been described small intestine, due to its abbreviated previously.21 . 22 length, probably was responsible for the Because of her clinical history it is patient's steatorrhea . Pancreatic function
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FIG. 7. Proximal intestinal mucosa obtained approximately 10 cm distal to pylorus. Villous structure is intact (hematoxylin and eosin, X 150).
tests were normal, although the techniques used were relatively crude. Clinical assessment and liver function studies did not indicate defective synthesis or excretion of bile. Bile salts are reabsorbed normally in the ileum and defective function or absence of the ileum may lead to steatorrhea.23 That the serum concentrations of magnesium and vitamin BI2 were normal and intestinal absorption of the vitamin as measured by a Schilling test was normal also indicates that some aspects of ileal function probably were intact. 24. 25 The possibility of a defect in the function of the intestinal mucosal epithelium was unlikely, apart from that due to obvious decrease in over-all cell mass. Cellular structure was normal and mature as studied by light and electron microscopy. Indirect evidence to support the functional integrity of the mucosal epithelium and, in particular, the brush border region was obtained from mucosal
disaccharidase assays26 and from histochemical staining of mucosal phosphatase. 27 Mucosal capacity for the incorporation and metabolism of fat was not measured, but an isolated defect of this type would not explain the abnormalities in glucose tolerance and xylose excretion. Failure to improve on diphenoxylate HCI, an inhibitor of peristalsis, suggests that rapid transit was not the only factor producing steatorrhea. Some improvement in the child's intestinal absorptive function occurred between the age of 20 months and the age of 6 years. This spontaneous improvement may have occurred because of increasing intestinal length since recent intestinal X-rays of the small intestine suggested a length in excess of 40 cm. Adaptation within the villi comparable to that occurring after resection of the intestine 28 • 29 may have occurred. The observed improvement raises the possibility that some
January 1969
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133
FIG. 8. Higher power view of the tissue shown in figure 7. Surface epithelium is columnar and regular. Alkaline phosphatase stain shows dense band in the brush border region (X 690).
of the parameters of intestinal function and structure that were normal in later childhood may not have been so at birth. The embryological basis for the child's intestinal defect cannot be defined but
some speculation is in order. The initial phase of rotation of both the duodenojejunal loop and the cecocolic loop of the primitive gut did occur in this patient. Normally these events, the 90 degree
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FIG. 9. Electron micrograph of absorptive cells. MV, microvilli; ec, extracutaneous coat; TW, terminal web; tb, terminal bar; d, desmosomes; M, mitochondria; Ly, lysosome; and mvb, multivesicular body. Approximately X 15,000.
Janumy 1969
CASE REPORTS
rotation of the upper loop and the ascent of the cecum to the left upper quadrant, are complete in the lO-mm embryo (5 weeks).3o,31 With elongation of the middle portion of the gut beginning at the 5th week, a ventrally directed loop extends out into the umbilical coelom. At about 7 weeks the cranial portion of that loop, most of the small intestine, begins to elongate and coil. The caudal portion, on which the cecal swelling appears at this time, grows more slowly. Its growth is accommodated not by coiling, but by dextral rotation bringing the cecum to the right side. Subsequently, the intestine returns to the abdominal cavity by the time the embryo reaches the 40-mm stage (10 weeks). It is clear that in our patient the normal process of elongation of the cranial portion and probably the caudal portion of the digestive tube was interrupted. The time of the event can be placed at between 7- and 10-weeks gestation. Perhaps the defect was caused by a circumscribed occurrence in the embryo at that stage. The intestinal tract alone was involved and, in fact, certain aspects of intestinal maturation, villous structure and function, and development of the cecum and appendix were not involved. If some vascular insult or trauma within the digestive tube had occurred, a more devastating and generalized effect on intestinal structure might have been observed. In our patient, perhaps the primitive digestive tube could not be accommodated in the intraumbilical coelom and remained in the abdominal cavity throughout embryonic life. The reason for such an event occurring in two siblings defies speculation! REFERENCES 1. Bremer, J . L. 1957. Congenital anomalies of the viscera. Harvard University Press, Cambridge. 2. van de Kamer, J. H., H . H . Ten Bokkel, and H. A. Weijers. 1949. A rapid method for the determination of fat in feces. J. Bioi. Chem. 177: 347-355. 3. Benson, J. A., Jr., P. J. Culver, S. Ragland, C. M. Jones, G. D. Drummery, and E. Bougas. 1957. The D-xylose absorption test in mal-
4.
5.
6. 7.
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absorption syndromes. New Eng. J. Med. 256: 335-339. Hoffman, W. S. 1937. A rapid photoelectric method for the determination of glucose in blood and urine. J . Bioi. Chem. 120: 51-55. Bessey, O. A., O. H. Lowry, M. H. Brock, and J. A. Lopez. 1946. The determination of vitamin A and carotene in small quantities of blood serum . J. BioI. Chem. 166: 177-188. Ramsey, W. N. M. 1958. Plasma iron. Advances Clin. Chem. 1: 1-39. Crosowicz, N., D. Sulitzianu, and D. Merzbach. 1962. Isotopic determination of vitamin B12 binding capacity and concentratjon. Proc. Soc.
Exp. Bioi. Med. 109: 604-608.
8. Dormandy, K. M., R. H . Walter, and D. L. Mollen. 1963. Folic acid deficiency in coeliac disease. Lancet 1: 632-635. 9. Schilling, R. F. 1953. The effect of gastric juice on the urinary excretion of radioactivity after the oral administration of radioactive vitamin B12. J. Lab. Clin. Med . 42: 860-866. 10. Andersen, D. H., and M . J . Early. 1942. Method of assaying trypsin suitable for routine use in diagnosis of congenital pancreatic deficiency. Amer. J. Dis. Child : 63: 891-893. 11. Dyck, W. P . 1967. Titrimetric measurements of fecal trypsin and chymotrypsin in cystic fibrosis with pancreatic exocrine insufficiency. Amer. J. Dig. Dis. 12: 310-317. 12. Crobsy, W. H ., and H. W. Kugler. 1957. Intraluminal biopsy of the small intestine. Amer. J. Dig. Dis. 2: 236-241. 13. Dahlqvist, A. 1964. Method for assay of intestinal disaccharidases. Analyt. Biochem. 7: 1825. 14. Gomori, G. 1939. Microtechnical demonstration of alkaline phosphatase in tissue sections. Proc. Soc. Exp. BioI. Med. 42: 23-26. 15. Millonig, G. 1962. Further observations on phosphate buffer for osmium solutions in fixation. In S. S. Breese [ed.I, International congress on electron microscopy, 5th Proceedings, Vol. 2, Section P-8. Academic Press, New York. 16. Luft, J . R. 1961. Improvements in epoxy resin embedding methods. J. Biophys. Biochem. Cytol. 9: 409-414. 17. Trump, B. F. , E. A. Smuckler, and E. P. Benditt. 1961. A method for staining epoxy sections for electron microscopy. J. Ultrastruct . Res. 5: 343-348. 18. Karnovsky, M. J . 1961. Simple methods for staining with lead at high pH in electron microscopy. J . Biophys. Biochem. Cytol. 11: 729-732. 19. Benson, C. D. 1955. Resection and primary anastomosis of the jejunum and ileum in the newborn. Ann. Surg. 142: 478.
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20. Benson, C. D., J. R Lloyd, and J . D. Smith. 1960. Resection and primary anastomosis in the management of stenosis and atresia of the jejunum and ileum. Pediatrics 26: 265-280. 21. Soderlund, S. 1962. Anomalies of mid-gut rotation and fixation. Acta Paediat. 51: supp. 135, 225-238. 22 . Schultz, L. R, E. P. Lasher, and A. H. Bill, Jr. 1961. Abnormalities of rotation of bowel. Amer. J. Surg. 101: 128-133. 23. Hofmann, A. F., and D. M . Small. 1967. Detergent properties of bile salts: correlation with physiological function. Ann. Rev. Med. 18: 333-376. 24. Booth, C. C. , and D. L . Mollins. 1959. The site of absorption of vitamin BI2 in man . Lancet 1: 18-21. 25. Booth, C. C. , I. Macintyre, and D. L. Mollin. 1964. Nutritional problems associated with extensive lesions of the distal small intestine in man. Quart. J. Med. 33: 401-420.
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26. Dahlqvist, A. 1967. Localization of the small intestinal disaccharidases. Amer. J. Clin. Nutr. 20: 81-88. 27. Rhodes, J. B. , A. Eichholz, and R K. Crane. 1967. Studies on the organization of the brush border in intestinal epithelial cells. Biochim . Biophys. Acta 135: 959-965. 28. Porus, R L. 1964. Epithelial hyperplasia with massive bowel resection in man. J. Clin. Invest. 43: 1295. 29. Dowling, R H., and C. C. Booth. 1966. Functional compensation after small bowel resection in man. Lancet 2: 146-147. 30. Snyder, W. H., Jr., and L. Chaffin. 1954. Embryology and pathology of the intestinal tract: presentation of 40 cases of malrotation. Ann. Surg. 140: 368-380. 31. Johnson, F. P. 1913. The development of the mucous membrane of the large intestine and veriform process in the human embryo. Amer. J. Anat. 14: 187-226.
GASTROENTEROLOGY
Copyright © 1969 hy The Williams & Wilkins Co.
SHORT SMALL INTESTINE ASSOCIATED WITH MALROTATION: A NEWLY DESCRIBED CONGENITAL CAUSE OF INTESTINAL MALABSORPTION J. R. HAMILTON, M.D., F.R.C.P. (CANAD.), B. J. REILLY, M.D., CH.B., AND R. MORECKI, M.D .
Departments of Pediatrics and Radiology, University of Toronto, and the Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada
A new and rare cause of intestinal malabsorption is described in a 6-year-old girl. The diagnosis was established at laparotomy, but it might have been made by careful radiological examination of the small bowel. Steatorrhea beginning in early childhood associated with intestinal malrotation but without obstruction should alert the clinician to the possible diagnosis of a congenital short small intestine. Spontaneous improvement of symptoms and absorptive function was observed when the child was followed over a 6-year-period. Defective fat absorption probably resulted from inadequate small intestinal absorptive surface. The anomaly may have arisen because of failure of the primitive gut to enter the intraumbilical coelom during early embryonic life. During early fetal life many aberrations may complicate the complex process of maturation of the alimentary tract. I In this report we describe a child with a congenital anomaly that has not been recorded previously, short small intestine. Studies undertaken first when the patient was 4 months old and at intervals over nearly 7 years have permitted us to document intestinal function and structure in this disorder, a new cause of intestinal malabsorption. Received May 13, 1968. Accepted June 28, 1968. Address requests for reprints to: Dr. J. R. Hamilton, The Hospital for Sick Children, 555 University Avenue, Toronto 2, Ontario, Canada. This work was supported by a grant from the Medical Research Council of Canada. Dr. Morecki's present address is: Montefiore Hospital and Medical Center, III East 210th Street, Bronx, New York 10467. The technical assistance of Mr. Bill Wilson and Mrs. Mary Kelly, and the advice of Dr. M. C. Johnston are gratefully acknowledged. The nutritionists and nurses of the Clinical Investigation Unit, The Hospital for Sick Children, Toronto, also contributed greatly to the studies reported.
Case Report History
The child, a girl, was admitted to hospital first at the age of 4 months in April 1962 for investigation of chronic diarrhea and failure to thrive. Born at term, she weighed 5 lb 12 oz. Pregnancy, labor, and delivery were uneventful. The mother did not receive drug therapy during the first trimester. The patient remained well until 4 days of age when loose, watery diarrhea began. Although she received an adequate quantity of an evaporated milk formula beginning at 36 hr of age, her gain and growth were slow. When examined at the age of 4 months, the child was below the third percentile for height and weight. Apart from small stature there were no physical signs of undernutrition. Her abdomen was flat and soft with normal musculature. Transit time of a carmine red marker from mouth to anus was 12 hr. Barium enema demonstrated the cecum in the left upper quadrant, indicating partial malrotation of the gut. There was no clinical or radiological evidence of intestinal obstruction. Because of continuing symptoms and after excluding the usual causes of chronic diarrhea by investigations, laparotomy was undertaken 124
January 1969
when the child was 7 months of age. The cecum, with a normal appendix, was on the left. Unexpectedly, the small intestine was only 40 cm in length. Otherwise, both small and large bowel and the intestinal vessels and lymphatics were normal. The intestine was not obstructed. Bands adherent to the duodenum were freed and the abdomen closed. There was no anomaly of any other organ apart from a minor irregularity of the fifth middle phalanx of one hand. Hepatic and renal function were normal. Chromosomal pattern was normal (46/xx). Intelligence quotients (Stanford-Binet) measured at the ages of 3 and 6 years were 58 and 68, respectively. The child has grown and gained slowly, but consistently, over the past 6 years (fig. 1). Her severe diarrhea persisted until she reached 5 years of age when spontaneous improvement occurred . Now, at the age of 7 with no medication, she has two semi formed stools per day. Apart from small stature, she has none of the clinical features of intestinal malabsorption (fig. 2). The patient's parents are French-Canadian and are not related. There have been five live births, all females, and no abortions. One sibling died at the age of 1 month. No post mortem was done but at laparotomy, 1 week prior to death, a short small intestine, 30 cm long, was found. The cecum with an appendix was located in the left upper quadrant. Three 110 100
90 30 WEIGHT (kg.)
HEIGHT 80 (em.) 70
10
.......--r--.-.,-,,......,..-.-~.....-+O
o
125
CASE REPORTS
2
4 6 8 AGE IN YEARS
10
FIG. 1. Patient's body weight and height compared with standard percentile curves. Solid lines represent 50th percentile; broken lines represent the 3rd and 97th. (Normal percentile curves from chart prepared by J . M. Tanner and R. H. Whitehouse, University of London, Institute of Child Health, for The Hospital for Sick Children, Great Ormond Street, London, W.C.l, England.)
siblings are healthy. Their intestinal function and structure have not been studied. No additional cases of intestinal anomaly were found in a search of the medical histories of three generations of maternal and paternal relations.
Methods The patient was studied in a Clinical Investigation Unit where conditions permitted close control of dietary intake and precisely timed collection of urine and stools. Fecal fat was assayed 2 on pooled collections of 5 days duration and results expressed as a percentage of dietary intake. Urinary 0xylose, 3 blood sugar,' serum vitamin A,5 plasma iron,6 and serum vitamin B!27 were measured by methods described previously. Urinary excretion of formiminoglutamic acid was measured after oral administration of histidine.8 Intestinal absorption of vitamin BI2 was assessed by measuring 24-hr urinary excretion of 57 Co after oral administration of the labeled vitamin and a "flushing" parenteral dose. 9 Intrinsic factor was administered with the vitamin. Tryptic activity was measured in fasting duodenal juice. \0 Trypsin and chymotrypsin was measured on fecal specimens pooled over 72 hr.ll Colloidal barium was used for radiological assessment of the small intestine. The barium column was observed at frequent intervals by fluroscopy as it progressed throughout the length of the bowel. The Crosby-Kugler intestinal biopsy capsule was used to obtain specimens of mucosa. 12 The position of the capsule was identified by fluoroscopy. Tissues were taken at a level corresponding to the distal duodenum and divided into fragments, for the assay of disaccharidase activity, for light microscopy, and for electron microscopy. Lactase, maltase, invertase, and isomaltase activities were measured on whole mucosal homogenate by the method of Dahlqvist. I. After examination under a dissecting microscope, a fragment was fixed in 10% formalin and embedded in paraffin for light microscopy. For alkaline phosphatase staining!' a portion of the tissue was fixed in chilled acetone. For electron microscopy, tissue was fixed in a 1 % solution of osmium tetroxide!5 for 1 hr at 4 C and then embedded in Epon l6 following rapid dehydration in increasing concentrations of ethanol. Sections 1 Jl thick were stained with toluidine blue l7 and examined by light microscopy. The blocks were oriented
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r -t-----
I0
50
FIG. 2. The patient, age 6 years, showing small stature and good nutritional status.
in such a way that a specific zone could be chosen for thin sectioning. Thin sections were stained with lead hydroxide l 8 and examined in a Phillips 200 electron microscope.
Results Intestinal Function Certain parameters of intestinal absorptive function, measured at stages during the course of the patient's disease, are summarized in table 1. The most marked abnormality was that of fat absorption. Fecal fat excretion was 40% of dietary intake when first measured at age 20 months. Initially, oral glucose tolerance and o-xylose excretion were abnormal also. Serum protein concentrations were normal at all times. Over the 6 years during which the child has been followed,
spontaneous improvement of fat absorption, xylose excretion, and oral glucose tolerance has been observed. Concentration of trypsin in fasting duodenal juice and the activities of both trypsin and chymotrypsin in feces were normal. Examination of fecal smears by light microscopy revealed the presence of fatty acid but few meat fibers and little neutral fat. Response of fat excretion to the administration of a medium chain triglyceride formula (product 701O-H, Mead Johnson Company, Ltd.) and to dephenoxylate HCI (Lomotil) were measured when the patient was 31J2 years old. After a 12-day baseline period, medium chain triglyceride formula was substituted for the normal diet keeping the fat intake con-
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January 1969 TABLE
1. Laboratory data related to alimentary tract function Patient's age Normal range - - - - - - , - - - - ; - - -- - - -- , - - -- 4-7 months 20 months 3~2 years Hi years 6~ years
Fat excretion (% of dietary intake) . <10% Vitamin A tolerance (max . rise: ILg/ml) .. >50 Prothrombin time (sec). . . .. . . ...... . 14 Oral glucose tolerance (max. rise: 1 hr, mg/100 ml). . . . . . . .......... . . >40 D-xylose excretion (% of dose) ....... .. . >15% Serum proteins albumin (g/100 ml) . . ... 3.3-5.8 a 1 .... . ........................... . .. . 0 . 1-0 .3 a 2. . . . .... . . . . . . . . . . . . ... .. .. . ..... . . . 0.4-1.0 {3. . . . . . . ... .. . . . . . . .. . . . . . . . . . . . . . . . .0.3-1.2 .. 7 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · 0.4-1.4 Trypsin in fasting duodenal juice (units/ ml). ... ... . .. . ...... . ..... . Fecal trypsin. . . . . . . . . ...... ... . Fecal chymotrypsin (1000 units/72 hr) .. . . Sweat chloride (mEq/liter) ... . ..... .. . <60
TABLE
45 46
26
40
16
20 140 15
154
12.5 26 4.1 0.2 0.7 0 .5 0 .3
23 38 4.7 0.2 0.7 0.7 0.6
12 8
9
4.6 0.3 0.7 0.4 0.5
45 24
400 23 . 6
32.0
27 23
I.
I
2. Electrolyte dala Patient's age
1\ ormal range
4-7 months
Plasma Na (mEq/liter). ... . . . . . .... . .. K (mEq/liter) .. . . . . .... .. .. .. . . Cl (mEq/liter) . .. . . . . . . . . . . . .. . pH ....... ... . . . . . .... . CO 2 content (mM/li ter) . . . . ... .. Mg (mEq/liter). .. . . .. . . . .. .. . .. Serum Ca (mg/lOO ml) .. ... . ...... Phosphate (mg/lOO ml) . Alkaline phosphatase (K-A units) . .. . . ...... .. .
135-145 4.(}-5.0 98-108 7.35-7.45 2(}-28 1.5-1 .8
139.0 4.1 102 .0 7.42 19.9
I
20 months
years
139.0 4.5 99.5 7.32 17 .8 2.02
9.5-11.5 3 .8-5.8
10.3 3.8
8-20
18.1
stant (35 g per day) . Over a lO-day period, fat excretion fell from a mean of 37 to 12 )0 of the dietary intake. When the baseline diet was resumed and medium chain triglyceride formula discontinued, fat excretion rose again to 40% over a lO-day period. Dephenoxylate Hel administered for 6 days in a dosage of 5 mg per day had no beneficial effect on fat excretion, although fecal volume decreased from a mean of 420 ml to 150 ml per day. Serum and plasma electrolyte data are summarized in table 2. Even when she
3~2
9.3 5.5
I
20.6
Hi years
6l. years
144 4.4 104 7.39 23.1
142 4.6 102 7.36 24.2 1.86
I I
I
was an infant with severe watery diarrhea, the patient's electrolyte balance was never seriously impaired. Serum calcium, phosphate, and magnesium concentrations remained normal. Hematological indices, summarized in table 3, were normal. No abnormalities were detected in folic acid nutrition (as reflected by the measurement of form iminoglutamic acid excretion), serum concentration of vitamin B 12 , or intestinal absorption ofthe same vitamin. Disaccharidase activity was measured
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3. Hematological findings Patient's age
Normal range 20 months
. ..... . . . . ... . . , . . 11.0--13 .5" Hb (g/l00 ml) . ... White blood cells (1000 cells/mm 3 ) . . . . . .. . 7-11" Platel ets/ lOOO . ......... . ... . .... . . .. . . .. . . . . . . .. 150--350 Bone marrow. ............... . . .. . . .. . . . .. .. . . . . . >50 Serum F e ("g/lOO ml) .. ... . .. . ... .. . . . . . . . . . ... . 44 - 212b Serum vitamin BI2 ("l'g/lOO m!) . . Urina ry formiminoglutami c acid (5-hr urine, mM/ hr) .. . . . ........ . . . . . . .... .. . . .. . .. . . ... <10.3 Schilling test (S7CO) (24-hr urine , % of dose). . . . . >10% With intrinsic factor . . , . ... .. . .... '
.
.
a b
_ _
10.8 16.0 276,000 Normal 92 220
3~2
years
11.4 12.5
148
0.72
6H, years
12.0 6.8 190,000 Normal , 120 210 1.82 11%
.. I
Range encompasses minimum, maximum for ages 6 months to 7 years. R ange for normal adults .
in duodenal mucosa obtained when the child was 6V2 years of age. Lactase (19), maltase (215), invertase (69), and isomaltase (93) activites were normal. (Disaccharidase activity in units per gram tissue protein; 1 unit = 1 ~mole substrate hydrolyzed per min. 13 ) Stools were consistently alkaline from the age of 7 months. Roentgenological Investigation Barium enema. This was repeated when the child was 3V2 years old (fig. 3). The configuration of the colon was normal as far retrograde as the hepatic flexure, but proximal to this point, the ascending colon and cecum were rotated through 90 degrees and lay parallel to the transverse colon. The cecum lay below and medial to the splenic flexure in the left upper quadrant of the abdomen. The ileocecal valve was situated on the inferior margin of the malrotated, ascending colon. Barium meal. Representative films from the study done when the child was 6 1/2 years of age are reproduced in figures 4 and 5. The esophagus, stomach, and duodenum were normal. Precise measurement of the length of the small bowel was not practical. A continuous column of barium outlining the entire small bowel as far as the ileocecal valve showed that the small bowel was indeed short when compared with that of a normal child (fig. 6). The mucosal pattern was slightly
FIG. 3. Large bowel examined when patient was 3 \/2 years old by barium enema showing cecum in left upper quadrant.
coarser than normal Jejunum, but was otherwise unremarkable. However, instead of jejunum continuing on to ileum, the small bowel ended abruptly at the abnormally placed ileocecal valve. Mucosal Morphology Proximal intestinal mucosa was obtained at 3 V2 years of age. Examined by
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FIG. 4. Barium meal showing a single column of barium filling the entire small bowel at 50 min. Lower end has reached the cecum.
dissecting microscopy, the villi were ridgelike rather than paddle-shaped as they are usually in a normal child's duodenum. However, light microscopic studies showed no specific abnormalities (fig. 7). Normal Paneth cell granulation was observed at
the crypt bases. The surface epithelium was regular, columnar, and stained densely for alkaline phosphatase (fig. 8). Studied by electron microscopy, the absorptive epithelium had a normal brush border with normal cytoplasmic organelles (fig. 9).
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FIG. 5. At 70 min barium is seen in large bowel. The entire small bowel is outlined by barium.
Discussion Proof of the diagnosis of short small intestine in our patient rests on observations made at laparotomy when she was 7 months of age and on subsequent radiological assessments of her bowel. Although absolute measurements of in-
testinal length are notoriously inaccurate, there can be little doubt that the measured length of 40 cm was significantly short compared with estimates of approximately 250 cm for a normal, full term human newborn. 19 In the premature child, the length may vary from 160 to
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FIG. 6. Barium meal in a child age 7 years with small intestine of normal length.
240 cm. 20 Abnormalities of rotation and probable that the child's malabsorptive fixation of the intestinal tract occur rela- state dates from early infancy. The most tively frequently, but to our knowledge noteworthy absorptive defect was that of an associated congenital shortening of the fat. Decreased absorptive surface in the small intestine has not been described small intestine, due to its abbreviated previously.21 . 22 length, probably was responsible for the Because of her clinical history it is patient's steatorrhea . Pancreatic function
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FIG. 7. Proximal intestinal mucosa obtained approximately 10 cm distal to pylorus. Villous structure is intact (hematoxylin and eosin, X 150).
tests were normal, although the techniques used were relatively crude. Clinical assessment and liver function studies did not indicate defective synthesis or excretion of bile. Bile salts are reabsorbed normally in the ileum and defective function or absence of the ileum may lead to steatorrhea.23 That the serum concentrations of magnesium and vitamin BI2 were normal and intestinal absorption of the vitamin as measured by a Schilling test was normal also indicates that some aspects of ileal function probably were intact. 24. 25 The possibility of a defect in the function of the intestinal mucosal epithelium was unlikely, apart from that due to obvious decrease in over-all cell mass. Cellular structure was normal and mature as studied by light and electron microscopy. Indirect evidence to support the functional integrity of the mucosal epithelium and, in particular, the brush border region was obtained from mucosal
disaccharidase assays26 and from histochemical staining of mucosal phosphatase. 27 Mucosal capacity for the incorporation and metabolism of fat was not measured, but an isolated defect of this type would not explain the abnormalities in glucose tolerance and xylose excretion. Failure to improve on diphenoxylate HCI, an inhibitor of peristalsis, suggests that rapid transit was not the only factor producing steatorrhea. Some improvement in the child's intestinal absorptive function occurred between the age of 20 months and the age of 6 years. This spontaneous improvement may have occurred because of increasing intestinal length since recent intestinal X-rays of the small intestine suggested a length in excess of 40 cm. Adaptation within the villi comparable to that occurring after resection of the intestine 28 • 29 may have occurred. The observed improvement raises the possibility that some
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FIG. 8. Higher power view of the tissue shown in figure 7. Surface epithelium is columnar and regular. Alkaline phosphatase stain shows dense band in the brush border region (X 690).
of the parameters of intestinal function and structure that were normal in later childhood may not have been so at birth. The embryological basis for the child's intestinal defect cannot be defined but
some speculation is in order. The initial phase of rotation of both the duodenojejunal loop and the cecocolic loop of the primitive gut did occur in this patient. Normally these events, the 90 degree
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FIG. 9. Electron micrograph of absorptive cells. MV, microvilli; ec, extracutaneous coat; TW, terminal web; tb, terminal bar; d, desmosomes; M, mitochondria; Ly, lysosome; and mvb, multivesicular body. Approximately X 15,000.
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CASE REPORTS
rotation of the upper loop and the ascent of the cecum to the left upper quadrant, are complete in the lO-mm embryo (5 weeks).3o,31 With elongation of the middle portion of the gut beginning at the 5th week, a ventrally directed loop extends out into the umbilical coelom. At about 7 weeks the cranial portion of that loop, most of the small intestine, begins to elongate and coil. The caudal portion, on which the cecal swelling appears at this time, grows more slowly. Its growth is accommodated not by coiling, but by dextral rotation bringing the cecum to the right side. Subsequently, the intestine returns to the abdominal cavity by the time the embryo reaches the 40-mm stage (10 weeks). It is clear that in our patient the normal process of elongation of the cranial portion and probably the caudal portion of the digestive tube was interrupted. The time of the event can be placed at between 7- and 10-weeks gestation. Perhaps the defect was caused by a circumscribed occurrence in the embryo at that stage. The intestinal tract alone was involved and, in fact, certain aspects of intestinal maturation, villous structure and function, and development of the cecum and appendix were not involved. If some vascular insult or trauma within the digestive tube had occurred, a more devastating and generalized effect on intestinal structure might have been observed. In our patient, perhaps the primitive digestive tube could not be accommodated in the intraumbilical coelom and remained in the abdominal cavity throughout embryonic life. The reason for such an event occurring in two siblings defies speculation! REFERENCES 1. Bremer, J . L. 1957. Congenital anomalies of the viscera. Harvard University Press, Cambridge. 2. van de Kamer, J. H., H . H . Ten Bokkel, and H. A. Weijers. 1949. A rapid method for the determination of fat in feces. J. Bioi. Chem. 177: 347-355. 3. Benson, J. A., Jr., P. J. Culver, S. Ragland, C. M. Jones, G. D. Drummery, and E. Bougas. 1957. The D-xylose absorption test in mal-
4.
5.
6. 7.
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absorption syndromes. New Eng. J. Med. 256: 335-339. Hoffman, W. S. 1937. A rapid photoelectric method for the determination of glucose in blood and urine. J . Bioi. Chem. 120: 51-55. Bessey, O. A., O. H. Lowry, M. H. Brock, and J. A. Lopez. 1946. The determination of vitamin A and carotene in small quantities of blood serum . J. BioI. Chem. 166: 177-188. Ramsey, W. N. M. 1958. Plasma iron. Advances Clin. Chem. 1: 1-39. Crosowicz, N., D. Sulitzianu, and D. Merzbach. 1962. Isotopic determination of vitamin B12 binding capacity and concentratjon. Proc. Soc.
Exp. Bioi. Med. 109: 604-608.
8. Dormandy, K. M., R. H . Walter, and D. L. Mollen. 1963. Folic acid deficiency in coeliac disease. Lancet 1: 632-635. 9. Schilling, R. F. 1953. The effect of gastric juice on the urinary excretion of radioactivity after the oral administration of radioactive vitamin B12. J. Lab. Clin. Med . 42: 860-866. 10. Andersen, D. H., and M . J . Early. 1942. Method of assaying trypsin suitable for routine use in diagnosis of congenital pancreatic deficiency. Amer. J. Dis. Child : 63: 891-893. 11. Dyck, W. P . 1967. Titrimetric measurements of fecal trypsin and chymotrypsin in cystic fibrosis with pancreatic exocrine insufficiency. Amer. J. Dig. Dis. 12: 310-317. 12. Crobsy, W. H ., and H. W. Kugler. 1957. Intraluminal biopsy of the small intestine. Amer. J. Dig. Dis. 2: 236-241. 13. Dahlqvist, A. 1964. Method for assay of intestinal disaccharidases. Analyt. Biochem. 7: 1825. 14. Gomori, G. 1939. Microtechnical demonstration of alkaline phosphatase in tissue sections. Proc. Soc. Exp. BioI. Med. 42: 23-26. 15. Millonig, G. 1962. Further observations on phosphate buffer for osmium solutions in fixation. In S. S. Breese [ed.I, International congress on electron microscopy, 5th Proceedings, Vol. 2, Section P-8. Academic Press, New York. 16. Luft, J . R. 1961. Improvements in epoxy resin embedding methods. J. Biophys. Biochem. Cytol. 9: 409-414. 17. Trump, B. F. , E. A. Smuckler, and E. P. Benditt. 1961. A method for staining epoxy sections for electron microscopy. J. Ultrastruct . Res. 5: 343-348. 18. Karnovsky, M. J . 1961. Simple methods for staining with lead at high pH in electron microscopy. J . Biophys. Biochem. Cytol. 11: 729-732. 19. Benson, C. D. 1955. Resection and primary anastomosis of the jejunum and ileum in the newborn. Ann. Surg. 142: 478.
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20. Benson, C. D., J. R Lloyd, and J . D. Smith. 1960. Resection and primary anastomosis in the management of stenosis and atresia of the jejunum and ileum. Pediatrics 26: 265-280. 21. Soderlund, S. 1962. Anomalies of mid-gut rotation and fixation. Acta Paediat. 51: supp. 135, 225-238. 22 . Schultz, L. R, E. P. Lasher, and A. H. Bill, Jr. 1961. Abnormalities of rotation of bowel. Amer. J. Surg. 101: 128-133. 23. Hofmann, A. F., and D. M . Small. 1967. Detergent properties of bile salts: correlation with physiological function. Ann. Rev. Med. 18: 333-376. 24. Booth, C. C. , and D. L . Mollins. 1959. The site of absorption of vitamin BI2 in man . Lancet 1: 18-21. 25. Booth, C. C. , I. Macintyre, and D. L. Mollin. 1964. Nutritional problems associated with extensive lesions of the distal small intestine in man. Quart. J. Med. 33: 401-420.
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26. Dahlqvist, A. 1967. Localization of the small intestinal disaccharidases. Amer. J. Clin. Nutr. 20: 81-88. 27. Rhodes, J. B. , A. Eichholz, and R K. Crane. 1967. Studies on the organization of the brush border in intestinal epithelial cells. Biochim . Biophys. Acta 135: 959-965. 28. Porus, R L. 1964. Epithelial hyperplasia with massive bowel resection in man. J. Clin. Invest. 43: 1295. 29. Dowling, R H., and C. C. Booth. 1966. Functional compensation after small bowel resection in man. Lancet 2: 146-147. 30. Snyder, W. H., Jr., and L. Chaffin. 1954. Embryology and pathology of the intestinal tract: presentation of 40 cases of malrotation. Ann. Surg. 140: 368-380. 31. Johnson, F. P. 1913. The development of the mucous membrane of the large intestine and veriform process in the human embryo. Amer. J. Anat. 14: 187-226.