Small Intestinal Absorptive Function in Regional Enteritis

GASTROENTEROLOGY® Official Publication of the American Gastroenterological Association @ COPVRIGIrT 1973 THE WILLIAMS

VOLUME

64

&

WILKINS Co.

May 1973

Number 5

SMALL INTESTINAL ABSORPTIVE FUNCTION IN REGIONAL ENTERITIS CHARLES D. GERSON, M.D., NATHANIEL COHEN, M.D., AND HENRY D. JANOWITZ, M.D.

Division of Gastroenterology, Department of Medicine, Mount Sinai School of Medicine of the City University of New York, New York, New York

Small bowel absorptive function was investigated in 65 patients with regional enteritis in an effort to relate this to extent of disease or resection. Twenty-six patients had no surgery, 7 had been operated upon without recurrence, 22 had significant recurrence after resection, and 10 were suffering from a markedly shortened bowel. There was a close correlation between length of resected or diseased ileum and vitamin B12 and fat malabsorption. When the length of ileal dysfunction exceeded 90 cm, Schilling test was abnormal in 13 of 13 patients and steatorrhea became more marked. Patients with resection and postoperative recurrence had significantly lower fat and B12 absorption than those with disease and no surgery, reflecting the greater length of ileal dysfunction in the surgically treated group. Jejunal function as measured by n-xylose absorption was preserved in most patients. The usual locale of regional enteritis in the distal ileum allows study of the effect of ileal disease or ileal resection on intestinal absorption. While it has been demonReceived August 11, 1972. Accepted November 24, 1972. Address requests for reprints to: Dr. Charles D. Gerson, Division of Gastroenterology, The Mount Sinai Hospital, Fifth Avenue and 100th Street, New York, New York 10029. Supported by the National Foundation for Ileitis and Colitis, Inc., and Grant G5-5468 to the Clinical Research Center, The Mount Sinai Hospital. The authors are grateful to Dr. J. H. Katz for the vitamin B12 absorption determinations, to Dr. P. Gelfand for reviewing the gastrointestinal X-rays, to Mrs. Eva Fabry for valuable technical assistance, and to the nurses of the Clinical Research Center for their help in these studies. 907

strated that malabsorption of B 12,1-4 bile salts,5-10 and faV- 4, 6-10 may occur in this disease, detailed studies of a significant number of patients has not been available. Although there is some evidence for correlation between length of ileal resection and degree of steatorrhea, 10, 11 a recent study 12 was unable to confirm this for fat or for B12 absorption. We have therefore carefully examined the quantitative aspects of the relationship between ileal disease and intestinal absorption and report our findings.

Experimental Procedures Subjects. The diagnosis of regional enteritis was based on characteristic pathological findings in patients with intestinal resection, including 7 patients operated upon after study.

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Primary disease and recurrences were diagnosed radiographically. The length of resection was measured by the surgeon or in the fresh state by a pathologist. On the basis of comparison of measurement by these several methods in the same patients, the measurements obtained are felt to be reasonably accurate except in the group with massive resection where length was estimated partly on the basis of the radiological length of the remaining shortened bowel. Length of inflamed bowel seen on X-ray was estimated by the same radiologist in all patients, without any clinical information. Almost all patients were studied in the hospital: 15 of them on a metabolic research unit and the rest hospitalized for problems related to their disease, although acutely ill patients were not studied. The patients were divided into four clinical groups, those who had never had resection (no surgery or NS), those who had surgery with no recurrence (SNR), those who had surgery with recurrence (SR), and those who had extensive resection and were left with a short bowel (SB). All in the last group had less than 200 cm remaining small bowel and most had less than 150 cm. Although all tests were not performed in all patients, there were 65 patients in all. The total number of patients in each group were 26 NS, 7 SNR, 22 SR, and 10 SE. Two patients in the NS group had granulomatous colitis alone with no evidence at present of ileitis. There were 40 males and 25 females with more males in every group. Age ranged from 15 to 69 years witli a similar mean age for the first three groups, 35.2, 34.9, and 35.5, and a mean age of 44.5 years in the SB group. Mean duration of illness increased from 5.8 years in NS to 11.9 and 10.9 in SNR and SR, and finally to 16.0 years in SB, so that mean age of onset of disease for all patients was 27.0 years. Steroid, salicylazosulfapyridine, and other more nonspecific medications were administered with the same frequency in all groups except SNR and were not a determining factor in the results. Methods. Twenty-four hour Schilling testl 3 was modified 14 so that 0.5 f.Lg of free B 12 labeled with Coso was given simultaneously with 0.5 f.Lg of B12 bound to intrinsic factor and labeled with CoS?, yielding results for B12 absorption with and without intrinsic factor. Greater than 6% excretion is normal. Seventy-two hour fecal fat was measured 15 while patients were on a 100-g fat diet. Less than 6 g per 24 hr is normal. n-xylose was measured 1s in a 5-hr urine and a 2-hr blood sample after oral ingestion of 25 g.

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Less than 200 ml of urine was considered inadequate and the test repeated. Greater than 5.0 excretion is normal. Measurements of hemoglobin, serum cholesterol, calcium, carotene, prothrombin time, and iron were made by standard methods. Serum folate l7 and B 12 18 were measured by microbiological assay and serum albumin by serum protein electrophoresis.

Results Schilling test. Vitamin B12 absorption was measured in 39 patients, 18 NS, 5 SNR, 12 SR, and 4 SB. In only 1 patient was there a marked difference between free- and intrinsic factor-bound B12 absorption, with 3.9% and 9.36% excretion respectively indicating some intrinsic factor deficiency. In the rest, there was little variation in excretion of the two differently labeled vitamin B12 compounds. There was progressive decrease in mean percentage of excretion of B12 from one group to the next (fig. 1) with a significant difference between the NS and SR groups (T = 2.38, P <0.05). Although the mean percentage in NS was normal, 8 of 18 had a subnormal Schilling test, in the absence of resected bowel. There was a significant correlation between B12 absorption and length of disease and/or resection (fig. 2) (r = ~0.55, P < 0.001). When patients had both resection and recurrence, the lengths for each were summed. All 13 patients with 100 cm or greater length involved had abnormal results. Two patients with greater than 75 cm involved had normal results, although 1 had resection of proximal ileum with preservation of a normal terminal ileum, and the other had inflammation but had never been resected. The longest resection associated with a normal Schilling test was 60 cm. When the 4 SB patients were removed from the calculation, correlation remained significant (r = -0.57). Fecal fat. This was determined in 50 patients, 20 NS, 3 SNR, 18 SR, and 9 SB. There was a progressive increase in mean fat excretion from one group to the next (fig. 1) with a significant difference between NS and SR (T = 3.32, P <0.01),

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INTESTINAL ABSORPTIVE FUNCTION

May 1973

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FIG. 1. B 12 , fat, and xylose absorption for all four clinical groups. The mean value ( - ) , standard error (J_, T) and normal level (- - -) is indicated for each group. NS, no surgery; SNR, surgery with no recurrence; SR, surgery with recurrence; SB, short bowel.

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fat with length of disease and/or resection = +0.75, P < 0.001) (fig. 3). Of those with 100 cm or more involved, 17 of 19 patients had increased fecal fat while steatorrhea was present in only 5 of 31 with 90 cm or less involved. When patients in the SB group were excluded, a positive correlation still existed (r = +0.61, P < 0.001) so that the amount of fat in the stool clearly was related to ileal dysfunction. The reduction in fat and B12 absorbed from one group to the next is consistent with an increase in mean total length of diseased and/or resected bowel. When the groups are compared, the mean values are 44.7 cm for NS, 62.9 cm for SNR, 97.1 cm for SR, and 260 cm for SB. - D-Xylose. Xylose excretion was meas. ured in 50 patients, 18 NS, 6 SNR, 18 SR, and 8 SB. Two-hour serum levels correlated with urinary levels (r = +0.54, P < 0.001). Xylose absorption did not vary much among NS, SNR, and SR groups with mean value above normal in all three (fig. 1). Although the mean SB level was subnormal and 6 of 8 patients had low (r

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FIG. 2. Results of Schilling tests related to length of ileum resected and/or diseased.

and between SR and SB (T = 4.62, P < 0.001). Only 3 of 20 patients in NS had steatorrhea and those 3 had 60,75, and 110 cm of inflamed ileum. All 9 patients in the SB group had steatorrhea, usually of marked degree. Four of the 9 had evidence of recurrent disease but the abnormalities in absorption in this group were so gross that results in those with and without recurrence did not differ. There was a strong correlation of fecal

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GERSON ET AL.

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FIG. 4. Xylose excretion related to length of ileum resected and/or diseased.

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FIG. 3. Fecal fat excretion related to length of ileum resected and/or diseased.

absorption, there was no significant difference between SR and SB (T = 0.80, P> 0.1) just as there was none between NS and SR (T = 1.02, P>O.l). Only 3 patients in the NS group had low xyloses and the 1 markedly reduced value was in 1 of the sickest patients in this group, with an intraabdominal abscess. The correlation between length of disease and/or resection was much less impressive for xylose than for B12 or fat (fig. 4), especially when the SB group was excluded (r = -0.34, P < 0.05). Schilling, fat, and xylose. A number of patients had two or all three of the above tests performed. In the SB group, there was high association between abnormal results in all three parameters. Among the other three groups, there were 10 patients with steatorrhea who had Schilling tests performed and 8 had low B12 absorption. There were 6 patients with low Schillings who had normal fecal fat. In contrast, of 11 patients with steatorrhea who had a Dxylose test, only 3 were abnormal. Even in the SB group, there were 2 patients with steatorrhea who had normal xylose absorption (fig. 5). Colitis. Granulomatous colitis was present in 21 patients, and 8 additional patients had prior subtotal or total colectomy. The presence of colitis or colectomy did not correlate with any abnormal absorption parameters.

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Blood tests. Serum albumin was low in most patients in NS, SR, and SB groups with little difference among them. Only 1 of 6 SNR patients had a low albumin and the mean level in this group was significantly higher than NS (T = 3.73, P < 0.005) and SR (T = 4.23, P 0.001) (table 1). Carotene, iron, and cholesterol levels were low or low normal in most patients.

Discussion We have found a strong correlation between the length of ileum resected or inflamed and impaired absorption of vitamin B 12 and fat, while jejunal function appeared normal in most patients with ileitis. Since Booth and Mollin's report 1 that B12 is absorbed in the ileum, it has not been clear how much ileum must be removed or diseased to produce B12 malab-

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INTESTINAL ABSORPTIVE FUNCTION

May 1973

TABLE

1. Various blood test measurements"

NS

Test

Hemoglobin .. . . . . . . . . . . . . . . .. .. .. . Folate ... ... . . ....... . .. . .. ... .... Vitamin B12 .... . . . . . . .... . . .. .. . . . . .. . Iron. ..... .. . . .. . . .. . ..... .. Albumin . . . . . . . . .. ..... .. .. . .... Cholesterol .. ... . . .. . . . . ' " ... . . . . .. . .. . . .. ...... .... . Calcium .. . . . . . . . . . . . . . .. . . .... . Carotene . , ' . ......... Prothrombin time .. "

"

'

SNR

11.8 (15/26)b

9.8 (3/19) 433 (1/19) 54.8 (7/13) 3.00 (16/20) 189 (3/26) 9.1 (4/26) 52.9 (13/15) 1.6 (9/21)

I I

14.2 (0/7) 9.1 (0/15) 523 (1/6) 114 (0/1) 3.98 (1/6) 166 (2/9) 9.8 (0/7) 51.9 (7/7) 1.3 (2/7)

SR 12.5 (8/21) 8.2 (3/12) 275 (2/13) 42.4 (4/7) 2.87 (12/19) 164 (7/20) 9.0 (4/20) 42.9 (16/17) 1.5 (4/18)

SB 11.8 (5/9) 10.3 (2/8) 356 (2/8) 41 (4/5) 2.98 (6/8) 161 (5/9) 8.3 (3/10) 19.4 (8/8) 3.4 (5/9)

"NS, no surgery; SNR, surgery with no recurrence; SR, surgery with recurrence; SB, short bowel. b Mean (no. abnormal/total).

sorption. It now appears that the critical length is from 60 to 90 cm as every patient with more than 60 cm resected or with more than 90-cm resection plus inflammatory disease had a low Schilling test. Some patients with inflammatory disease alone, involving relatively short ~engths of terminal ileum, also had subnormal Schilling tests so inflammation per se can reduce B12 absorption. From this series, it appears that intrinsic factor deficiency rarely contributes to impaired BJ2 absorption in Crohn's disease. Serum BI2 levels were normal in most patients despite the results of the Schilling tests. This is probably attributable to the common administration of p.a renteral B12 to this patient population. It is also possible that not enough time had passed for BI2 deficiency to have become manifest. Meynall et al. 19 found a much higher incidence of low serum BI2 in patients with ileitis presenting to the hospital in England. Fat absorption was normal in most patients having lost less than 90 cm of ileum by resection or disease. This is in contrast to the group with 100 cm or more where steatorrhea occurred in 17 of 19 patients. These data fit very well with two prior reports. Hofmann and Poley II described a series of patients with ileal resection, and steatorrhea was common only when more than 100 cm had been removed . Woodbury and Kern 10 also divided their patients into those with less than and more than 100 cm resected and measured rate of fecal bile salt loss. Bile salt loss was only 1 to 2 times control in the first group with absent or

mild steatorrhea, while 2 to 8 times normal in the second. They found a correlation between length of resection and rate of bile salt loss as well as fecal water mass for all patients . This may be reflected in our finding that there was a correlation between length and fecal fat even for patients with absent or mild steatorrhea. The concept that ileal rather than jejunal dysfunction is responsible for steatorrhea in these patients is supported by our finding that 8 of 11 patients with steatorrhea (excluding SB) had normal xylose absorption. The division of the patients into four clinical subgroups proved useful in illustrating which type of patient is more likely to have malabsorption. The increased frequency and degree of abnormality in the SR group is consistent with the mean length of dysfunction of97.1 cm compared with 44.7 cm in the NS group. Among the various serum parameters, the finding of normal albumin in patients postresection with no evidence of recurrence was of most interest. This is consistent with the report by Beeken et al,l2 of a correlation between protein leak and length of inflammatory disease in ileitis. REFERENCES 1. Booth CC, Mollin DL: The site of absorption of vitamin B12 in man. Lancet 1:18-21, 1959 2. Dotevall G, Kock NG: Absorption studies in regional enterocolitis. Scand J Gastroenterol 3:293-298, 1968 3. Hertzberg IN, Myren J, Semb LS: Regional

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enterocolitis (Crohn's disease). Absorption studies after surgical treatment. Scand J Gastroenterol 4:569-573, 1969 Krone CL, Theodor E, Sleisinger MH, et al: Studies on the pathogenesis of malabsorption. Medicine 47:89-106, 1968 Austad WI, Lack L, Tyor MP: Importance of bile acids and of an intact distal small intestine for fat absorption. Gastroenterology 52:638-646, 1967 Hardison WGM, Rosenberg IH: Bile-salt deficiency in the steatorrhea following resection of the ileum and proximal colon. N Engl J Med 277:337-342, 1967 Meihoff WE, Kern F Jr: Bile salt malabsorption in regional ileitis, ileal resection, and mannitolinduced diarrhea. J Clin Invest 47:261-267,1968 Stanley MM, Nemchausky B: Fecal C"-bile acids excretion in normal subjects and patients with steroid-wasting syndromes secondary to ileal dysfunction. J Lab Clin Med 70:627-639, 1967 Van Deest BW, Fordtran JS, Morawski SG, et al: Bile salt and micellar fat concentration in proximal small bowel contents of ileectomy patients. J Clin Invest 47:1314-1324, 1968 Woodbury JF, Kern F Jr: Fecal excretion of bile acids: a new technique for studying bile acid kinetics in patients with ileal resection. J Clin Invest 50:2531-2540, 1971 Hofmann AF, Poley Jr: Cholestyramine treat-

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ment of diarrhea associated with ileal resection. N Engl J Med 281:398-402, 1969 Beeken WL, Busch HJ, Sylwester DL: Intestinal protein loss in Crohn's disease. Gastroenterology 62:207-215, 1972 Schilling RF: Intrinsic factor studies. II. The effect of gastric juice on the urinary excretion of radioactivity after the oral administration of radioactive vitamin B ... J Lab Clin Med 42:860-866, 1953 Katz JH, DiMase J, Donaldson RM Jr: Simultaneous administration of gastric juice-bound and free radioactive cyanocobalamin: rapid procedure for differentiation between intrinsic factor and other causes of vitamin B .. malabsorption. J Lab Clin Med 61:266-271, 1963 Van de Kamer JR, Bokkel-Huinink HT, Weyers HA: Rapid method for the determination offat in feces. J Bioi Chern 177:347-355,1949 Roe JH, Rice EW: Photometric method for determination of free pentoses in animal tissues. J Bioi Chern 173:507-512, 1948 Herbert V: Aseptic addition method for lactobacillus casei assay of folate activity in human serum. J Clin Pathol 10:16-21, 1966 Spray GH: An improved method for the rapid estimation of vitamin B12 in serum. Clin Sci 14:661-667, 1955 Meynall MJ, Cooke WT, Cox EV, et al: Serumcyanocobalamin level in chronic intestinal disorders. Lancet 1:901-904, 1957