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The disappearing enzymes
The A STUDY
Disappearing
OF PANCREATIC BILLROTH
Enzymes*
ENZYMES IN NORMAL PATIENTS I AND II GASTRIC RESECTIONS
AND AFTER
THOMAS TAYLOR WHITE, M.D., RONALD G. ELMSLIE, M.n.t AND DONAL F. MAGEE, Seattle,
From tbe Departments of Surgery and Pharmacology, University of Wasbington, School of Medicine, Seattle, Wasbington. Supported by U.S.P.H.S. Grant A-3637 and U.S.P.H.S. Clinical Research Program O.G.-13.
Comfort and Osterberg [IO], ButIer [II] and Lawrence et a1. [12].) ButIer [II] performed fat baIances on eightysix BI and 208 BII patients three months and three years after operation. At three months postoperative onIy one BI patient (I per cent) and ninety-three BII patients (44.7 per cent) had steatorrhea, whiIe at three years seven BI patients (8. I per cent) and 121 BII patients (54.2 per cent) had steatorrhea. (Figs. I and 2.) Isotopic fat studies by ShingIeton and associates [5,13] indicated that the absorption defect foIIowing gastrectomy is simiIar to that found in patients with pancreatic insuffrciency. Norma1 excretion of 1131 IabeIIed triolein was 0.6 per cent, whereas 4.5 per cent appeared in the stoo1 of BI patients and 14 per cent in BII patients. Further support to the theory that the negative fat and nitrogen baIances are due to impaired pancreatic secretion has been offered by Lundh [14], ButIer [rr,15] GoIdstein, Wirts and Kramer [16] and Wirts and Goldstein [r7]. Both Lundh and Butler have shown that there is a depression in pancreatic response to a test mea1 which is greater in a BII than a BI patient. Their studies are slightly different in severa detaiIs. Lundh’s standard ora test mea1 incIudes a poIyethyIene gIyco1 (PEG) marker to measure changes in diIution, radioactive serum aIbumen (RISA) to measure protein absorption and fat. He monitors the disappearance of RISA at various IeveIs of the intestine by aspirating through a poIyviny1 tube whiIe measuring volume, PEG and trypsin concentration and fat loss. The trypsin curve for
N
THE PRESENT study, we have attempted to evaIuate the pancreatic response to secretin in a series of ten patients who had BilIroth II (BII) gastric resection, eight BiIIroth I (BI) gastric resection, and twelve normaI patients. We wished to investigate the relative sensitivity of the pancreas to secretin in BI, BII and norma patients. It has been cIearIy estabIished that a Iarge proportion of gastric resection patients Iose weight. This has been attributed to intestina1 hurry, inadequate absorptive capacity of the intestine, inadequate pancreatic secretion, improper mixing, or destruction of pancreatic enzymes. In a coIIected series of 864 patients with BII resections, Ivy, Grossman and Bachrach [I], found that 47 per cent had Iost weight, whiIe 80 per cent of Rauch’s [2] 699 BI patients Iost weight. Harkins and Nyhus [3] found that onIy 42 per cent of their 529 patients Iost weight as opposed to 74 per cent of 135 BII patients. In the same series 46 per cent of BI patients and 24 per cent of BII patients gained weight. Borg [4] presents similar figures: 20 per cent of 698 BII patients gained weight, whiIe 78 per cent of 171 BI patients gained weight. EarIy evidence as to the cause of the weight Ioss has been the negative fat and nitrogen baIances found in approximateIy haIf of the BII patients. (ShingeIton et aI. [5], EIIison [6,7], Babb et al. [8], Everson [9], WoIIaeger,
I
M.D.,
Washington
* Presented at the annual meeting of the Pacific Coast Surgical Association, PaIm Springs, California, 1963. t In receipt of a Wekome TraveI Grant.
307
American
Journai of Surgery,
V&me
February
3-6,
106, August
1963
White, FAECAL (Three
FAT
Months (After
EImsIie
and
Magee FAECAL
EXCRETION
Post
(Three
Gostrectomy)
Bil lroth
EXCRETION
Post
(After
Butler)
(86
FAT
Yeors
Gastrectomy)
Butler)
Bil Iroth
I
,I
potients)
B ‘;;
8il lroth 11 (208 potients)
60
: 50 2 40
Billroth
II
2 30
5 IO 15 18 25 30 35 40 Faecol Fot / 3 days (grams fatty
45 acid)
c
50 IO
Fed 210 grams fat.
Foecal
FIG. I. Data from ButIer [I r] indicating one of eightysix BilIroth I and ninety-three of 208 BiIIroth II patients with steatorrhea three months postoperative to their gastric surgery.
Fot
25
I518
/ 3 doys Fed
210
30
35
(grams grams
40 fatty
45
:3
acid)
fat.
FIG. 2. Data from ButIer [II] on fat baIances on the same gastric resection patients. Seven of eighty-six BiIIroth I patients and 121 of 208 Billroth II patients had steatorrhea. (Done three years later.)
his thirty-two BI patients was beIow that of normaI aIthough higher than that in his twentynine BII patients. Not onIy were the average IeveIs Iowest in the BII patients, but no trypsin was present in six of the twenty-nine patients. AI1 of the patients with the BI procedure had some trypsin in their aspirates. Butler was interested in the difference between the effect of jejuna1 feeding of a test mea1 on duodena1 secretion as opposed to duodena1 feeding. JejunaI feeding after a BI resection produced 25 per cent Iess duodena1 secretion than before resection in the same patient. The duodena1 secretion foIIowing a duodena1 meal in the same was patients both pre- and postoperative roughIy double that foIIowing a jejuna1 mea1, even taking into account factors of diIution. These findings fit in with experimenta work indicating decreasing reIease of secretin as the stimulus descends the intestine. WhiIe Lundh observed that trypsin was sometimes absent in the efferent Ioop of the BiIIroth II patient, ButIer, Wirts and GoIdstein have cannuIated the proxima1 Ioop of the BiIIroth II patients with and without steatorrhea to study the enzymes found therein.
WhiIe seven of I 38 determinations on forty-six BII patients without steatorrhea had no Iipase in the proxima1 Ioop in Butler’s series, fortyseven of 138 determinations on forty-six patients with steatorrhea had no Iipase in the proximal Ioop. The proportion of patients without protease (trypsin) were somewhat Iower in these studies. AI1 patients had amyIase in the proxima1 Ioop. SimiIarIy GoIdstein and Wirts found a marked depression of Iipase without depression of amyIase, particuIarIy in the steatorrhea group. WhiIe these authors agree that pancreatic Iipase in fasting duodena1 juice is depressed in postgastrectomy steatorrhea (BII) patients, they did not determine whether this was due to decreased pancreatic function or inactivation of the enzyme within the proxima1 Ioop. In this investigation we have obviated the d&uIty inherent in the use of a test meal stimulus which may not remain Iong enough in contact with the duodenum as in the BI patients, or which is diverted from the duodenum as in the BII patients. This has been done by 308
Disappearing
12
NORMAL
8
Enzymes
BILLROTH
I
IO BILLROTH
It
FIG. 3. Position of tubes. Position of the Matzner tube in the norma subjects and the BiIlroth I and II patients.
giving al1 norma subjects, BI and BII patients a standard intravenous dose of secretin, then measuring the voIume and enzyme activities of the drainage obtained from the first few cm. of intestine beyond the stomach, and in the case of the BII patients from the proximal Ioop as weI1. METHOD
Thirty subjects were intubated with a Matzner duodenal tube using an x-ray image intensifier. In tweIve normal persons and eight patients six or more months postoperative to a BI gastric resection, the tube was passed into the duodenum opposite the ampuIIa of Vater. In ten BII patients, it was passed so that the bucket Iay 5 to 7 cm. beyond the gastrojejunostomy. (Fig. 3.) DuodenaI or jejunal materia1 was aIIowed to siphon into an ice bucket in two, fifteen minute coIIections. An average of these two coIIections was used as a contro1. One unit of secretin* per kiIogram was given intravenousIy and four more fifteen minute coIIections taken. VoIume, amyIase (as maItose reIeased in three minutes using Sumner’s dinitrosaIicyIic acid method) protease as 0.05N NaOH using a specific substrateBAEE) and Iipase (as 0.05N NaOH in five minutes using oIive oi1 as a substrate) were determined. A Radiometer, pH stat apparatus was used in the determinations of protease and Iipase. Fat baIance studies using an 80 gm. fat diet for five days and coIIection for the * AvaiIabIe from Apoteksvarucentralen Box I 2 I 70, StockhoIm, Sweden.
Vitrum,
final seventy-two hours were performed BI and seven BII patients.
on six
RESULTS Volume. The resting voIume per 15 minutes was Iess in the BI patients (17.5 ml. &- 10.7) than in the norma persons (31.1 m1 f 12.9). The resting volume was even Iower in the BII patients (6.9 m1. + 6.3), significantly Iower than the norma persons (p = .OOI) and onIy sIightIy Iess significantIy Iower than the BI patients (p = .006). The difference between the BI patients and the normal subjects was not significant. The voIume in one hour after secretin in BI patients (145 m1. f 50.1) was significantIy Iess (p = .02) than in the normaIs (227.3 ml. + 47.4). StimuIated voIume in the BII patients (57.7 m1. _t 83.2) was significantIy Iower than in the BI patient (p = .003). The difference between the BII patients and the norma subjects was significant (p = .OOI). The variation in voIume was great in a11 three groups, but was greatest in the BII group. (TabIe I.) The configuration of the secretory pattern was the same, although Iower, in the BI patients than in the norma subjects while there was a Iow deIayed peak in the BII patients. (Fig. 4.) Amylase. Resting rate of secretion of amyIase was 941 mg. + 657 for the normaI subjects, 913 mg + 669 for the Br patients and 393 mg + 578 for the BII patients. The difference between the BI patients and the normal subjects was not significant, whiIe the difference between the BII and the BI was significant
309
White, EImsIie and Magee VOLUME
AFTER
SECRETIN
m I. 80I
706050-
I
1
Norma I
403020IO0
_ Control
1 I 30
I 15
I Secretin f W/kg
1 45
r 60
Minutes
FIG. 4. The voIume secretory pattern before and after I unit secretin per Kg. in normal subjects, BiIIroth I and II patients. Notice that the BiIIroth I secretion, aIthough depressed from normal subjects, foIIows the same pattern; the BiIIroth II secretion reaches a Iate rather than an earIy peak. The stimuIated differences are particuIarIy sign&ant. TABLE TOTAL RESTING
I
FIFTEEN MINUTES AND ONE HOUR SECRETION AFTER ONE UNIT PER Kg. SECRETIN IN NORMAL,
BILLROTH
I AND BILLROTH
Mean
VoIume ml. contro1. . One hour after Secretin. Protease controI*. One hour after Secretin. Lipase controI*. . One hour after Secretin. AmyIase contro1 t. One hour after Secretin,
31. I 227.3 ‘5.3 :x 53.9 941 ,304
Standard Deviation
fr2.g
k47.4 19.7 k86 kg.1 *so.7 +657 + 4050
BII Patients
BI Patients
Norma1 Subjects Data
II PATIENTS
Range
Mean
259.5 148-324 4.3-35.4 ;12. I-252.t I-24.4 2-252 2-2246 Io82-16648
17.5 145 9.9 52.1 6.4 45.3 9’3 igor
Standard Deviation
+10.7 k50. I f7.8 +32.1 +2.26 k3g.r f 669 * 4920
Range
Mean
Standard Deviation
Range
rt6.3 o-22.7 1-30 6.9 +83.2 o-274 26.5-252 ‘Z +2.6 o-4.2 ,925.E k34.8 0-80.2 9.4-94.5 24.2 f2.520-7 .5-15.6 I.3 k41.4 O-105 g.6-121.4 28.6 45o-2160 393 ,578 o-2335 rgg5-167222618 &-4200 o-15809
* Protease and Iipase as ml. .05N NAOH in five minutes. t AmyIase as mg. mahose reIeased in three minutes. Enzymes are aI expressed as tota amount secreted in the period described,
the BI patients and 2618 mg. + 4200 for the BII patients. The difference between the BI and the BII patients, the BI and the normal subjects and the BII patients and the norma subjects were equaIIy significant (p = .OOI).
(p = .OOI), as was that between the BII and the normaI subjects (p = .oI). (Fig. 5.) The amount of amyIase secreted in one hour after secretin stimuIation was 9304 mg. * 4050 for the norma group, 6901 mg. _+ 4920 for
3’0
Disappearing AMYLASE
Enzymes
AFTER
SECRETIN
3000-
0
Control
I
Secretin ! 1Wkg.
I
15
I
30 Minutes
I
I
45
60
-
FIG. 3. The amyIase secreted per fifteen minutes in the three groups is iktrated here. WhiIe there is no significant difference between the BiIIroth I and norma secretion, the BII is significantIy lower. There is a significant difference between the BiIIroth 11, BiIlroth I and normaI secretin. AmyIase secretion folIows the voIume.
PROTEASE
2
AFTER
SECRETI
N
25-
‘.2 F Q 20-
Norma I
i! $
l5-
% BI
? rc, 0 IO-
I
?l
Or
Control
I
Secreti nf lU/kg
I
I5
I
30
I
45
I
60
Minutes
FIG. 6. The pattern of protease secretion before and after secretin is significant particuIarIy in the difference between the BII patients and norma subjects.
3”
White,
EImsIie
and
Magee
LI PASE
2
IO--
8
_--a_--a_-a--mm
.3 4
I
oC0ntr0
I
I
I
I
i
I5
Secretin
I
I
1
30
45
60
Minutes
1Wkg FIG. 7. The Iipase pattern in the three groups shows no significant differences between the three groups. The amyIase secretory pattern folIowed and the volume, BI was Iower than normal, and BII was even Iower with a deIayed peak. Protease. Resting protease secretion was 19.3 f g,7 for the norma subjects, 9.9 & 7.8 for the BI patients, and 1.8 ) 2.6 for the BII patients. There was no significant difference between the Br and the normal persons, while the BII patients were significantIy lower than the norma group (p = .OOI) and significantIy Iess than the BI patients (p = .oI). The amount of protease secreted in one hour after secretin was 95.2 _+ 86 for the normais, 52.1 f 32.~ for the BI patients and 24.2 &- 34.8 for the BIG patients. There was no significant difference between the BI and the normaI subjects, whiIe the BII patients were signif;cantIy Iower than the norma subjects (p = .03) and were Iess than the BI patients (p = .07). The protease pattern was reduced in a manner simiIar to amyIase and voIume although it was ffatter. (Fig. 6.) Lipase. Control Ievels of Iipase folIowed the same pattern as protease and amyIase: Norma1 : 11.6 + 9.1; BI: 6.4 f 2.3; BII: 1.3 + 2.5. One hour stimulated IeveIs were: Normal. 53.9 ) 50.7; Br: 45.3 4 39.1, and BII: 28.6 -t_ 41.4.
There is no significant difference between the values in the various groups. (Fig. 7.) The trend towards reduced enzymes in the patients who were operated on is obvious. (TabIe I.) Fat Balances. When the voIumes, enzymes and the fat baIances were compared in severa BI and BII patients, it was obvious that the volumes and enzyme levels were very much Iower in the BII than in the Br patients and the average coeficient of absorption in the BII patients (88.3 per cent + 7.4) was less than in the BI patients (94.8 per cent -/- 2.2). (TabIe II.) Norma1 range is 94 to IOO per cent. COMMENTS It is clear from the foregoing studies that the sensitivity of the pancreas to secretin is significantIy reduced in both the BiIIroth I and BilIroth II patients. The reduction is greater in the BII patients. AmyIase production is simiIarIy reduced, StimuIated protease production is significantIy reduced only in the BII patients as compared to norma patients. The variability in protease and Iipase, even in the norma group, was so great that, in the thirty patients studied, it is impossibte to draw further conclusions from this study. 312
Disappearing
Enzymes TABLE II CORRELATIONOF FAT BALANCES WITH PANCREATIC SECRETION (ONE HOUR COLLECTIONAFTER SECRETIN)
In the BI patients, a definite depression of volume and amyIase response to secretin occurred, with approximately the same pattern as in the normaI group. On the other hand protease and Iipase production in response to secretin was slight in the Br patients without the early peak seen in the norma persons. In a11 but one of the fat studies the coefficient of absorption feI1 within the norma range. In general, this fitted the degree of enzyme depression found in the individua1 patient. Using test meaIs, ButIer and Lundh found a simiIar depression of Iipase, protease and amyIase concentration. Whether or not intestina1 hurry prevented proper contact of the mea1 with the intestine with consequent inadequate reIease of secretin and pancreazymin was not cIear. Vitrum secretin aIone was used in these studies because this preparation was avaiIabIe in quantities when the investigation was started. The secretin manufactured by EIi LiIIy was discontinued in 1960. Pancreozymin and secretin produced by the Boots Pure Drug Company and Cecekin@ (ChoIecystokinin, possibIy synonymous with pancreozymin) Vitrum have been avaiIabIe to us recentIy. The volume response to the Vitrum secretin is considerabIy higher in the norma than it was to secretin made by EIi Lilly in our hands. If we were to repeat this study now we wouId use a mixture of secretin and pancreazymin rather than secretin aIone. These studies do show, however, that pancreatic sensitivity to secretin is greatly reduced in the BI patient. Thus, the Iow voiume and enzyme response observed in BI patients by Lundh and ButIer may be due to decreased sensitivity of the pancreas as much as to intestina1 hurry. The significantIy greater depression of voIume and enzymes in the BII patients as opposed to the BI patients compared with norma subjects both in resting coIIections and in response to secretin suggests that some other process is invoIved than that in the BI patients. It seems unIikeIy that the pancreatic sensitivity to secretin wouId be significantIy different after a gastrojejunostomy from that after a gastroduodenostomy with remova of a simiIar amount of stomach. ButIer has shown that a jejuna1 mea1 fed to a postoperative BI patient produces Iess pancreatic response than a duodena1 mea1. Lundh has shown that trypsin is reduced or absent in the jejunum after a test meal fed to BII patients, a finding that we
-
Fat Balance Absorbed (Per cent)
Data
VOI.
W.1
97.5 95
S. M. B.
78
J. 0. J. J. W. H.
85 97 88.4 __
.
38.5 9 9 26.5* 2 61* 0.75 43 69.5’ 56* -_
w. L. W. K.
94 92.3
B. S. J. L.
98.2
_-
94
.s 14.8 -
+ 2.2
3.579 5,280 4,090
2
I 0,782
3 05 2 * :;.5* I 71 I 55
6,752 1995 6,500 I 6,722 4,683 7,024 8,81 I
26.5
--
t -
zi
0
0 0
0 0 0 0
0
28.6 _.
65.9 57.4
-.
* iiT*
94.5
Protease .05N NaOH
2,028 0 1,966 2,220 19: 7 15,809 1,152 0
.E18.3 f 7.4 t _--
Patients with BI operation L. H.
Average........
13* 0
85
M. 0. A. R.
Average.
AmyIase (mg. maltose) _=
a=
Patients with BII operation A. M.
-
-
0
31 .o
_.
9.4 93.5 74.4 29.7 55.8 74.2
..
. -
* Duplicate experiments t + standard deviation Normal absorption of fat is over 94 per cent on an 80 gm. diet.
have confirmed usingsecretin rather than a mea1. Both authors beheved that the reduced pancreatic response was due to reduced secretin release foIIowing jejunal rather than duodena1 feeding. A reduced pancreatic output wouId inevitabIy foIIow reduced secretin reIease. In this study, the same reIative dose on a weight basis was given to normaIs, BI and BII patients. The response to secretin shouId be the same in a BII as in a BI patient. We believe that the actual reduction in secretions found at the gastrojejunostomy is due to absorption or destruction by bacteria or to autodigestion of the enzymes on the route from the duodenum 313
White,
EImsIie
Magee
7. ELLISON, E. H. Nutritiona probIems foIlowing gastrectomy. Surg. Clin. N. Amer., 35: 1683,
to the gastrojejunostomy. We suspect from preIiminary catheterization studies of the proxima1 loop that absorption is the most Iikely cause. Further studies now under way with catheterization of the upper proxima1 Ioop wiI1 teI1 us, we hope, whether or not the duodenal response to secretin and test meaIs is in fact comparabIe to that of BII patients. In addition, we hope to find out what happens to Auid and enzymes in the proxima1 Ioop.
1955.
8. BABB, L. I., CHINN, A. B., STITT, R. M., LAVIK, P. S., LEVEY, S., KRIEGER, H. and ABBOTT, W. E. EvaIuation of nrotein and fat metabolism in postgastrectomy patients. Arch. Surg., 67: 462, 1953. g. EVERSON, T. C. Experimenta comparison of protein and fat metaboIism in postgastrectomy patients. Surgery, 36: 525, 1954. IO. WOLLAEGER, E. E., COMFORT, M. W. and OSTERBERG, A. E. Disturbances in gastrointestina1 function foIIowing partia1 gastrectomy. Postgrad. Med., 8: 251, 1950. I I. BUTLER, T. J. The effect of gastrectomy on the externa1 secretion of the pancreas. M.D. Thesis. Univ. of BristoI, 1959. 12. LAWRENCE, W. JR., VANAMEE, P., PETERSON,A. S., MCNEER, G., LEWIS, S. and RANDALL, H. T. AIterations in fat and nitrogen metabolism after tota and subtotal gastrectomy. Surg. Gynec. &+ Oh., I IO: 601, 1960. 13. SHINCLETON,W. w., BAYLIN, G. J., ISLEY, J. K., SANDERS. A. P. and RUFFIN. J. M. A study of fat absorption after gastric surgery using II131 Iabeled fat. Tr. Am. Surg. Assoc., 74: 145, 1956. 14. LUNDH, G. IntestinaI digestion and absorption after gastrectomy. Acta cbir. scandinav. SuppIement 231, 1958. 15. BUTLER, T. J. A study of the pancreatic response to food after gastrectomy in man. Gut, I: 55, 1960. 16. GOLDSTEIN, F., WIRTS, A. V. and KRAMER, S. ReIationship of afferent limb stasis and bacteria1 Aora to the production of postgastrectomy steatorrhea. Gastroenterology, 40: 47, 195 I. 17. WIRTS, C. W. and GOLDSTEIN, F. Studies of the mechanism of postgastrectomy steatorrhea. Presented at the annua1 session of the American CoIIege of Physicians, April 9, 1962.
CONCLUSIONS I. There is a significant decrease in pancreatic response to secretin in the BI patient. 2. The decrease in pancreatic secretion is more significant in the BII than in the BI patient. 3. The decrease in enzymes, foIIowing gastric resection, may be due to decreased sensitivity of the pancreas to stimuIation by secretin and simiIar substances. 4. A BI type of resection or a short Ioop retrocolic BII shouId be the most satisfactory type of arrangement from a digestive point of view in the average patient. Acknowledgment: We wish to thank Miss Joan F. RisIey, B.S., M.A., for her technica assistance in preparing data for the paper. Secretin and Ceceki@ Acknowledgment: (ChoIecystokinin) Vitrum are avaiIabIe from ApoteksvarucentraIen, Vitrum, Box 12 I 70, StockhoIm 12, Sweden. Secretin and Pancreozymin are also avaiIabIe from the Boots Pure Drug Company, Nottingham, England.
Additional
References
HAYAMA, T., MAGEE, D. F. and WHITE, T. T. The inffuence of autonomic nerves on the daiIy secretion of pancreatic juice in dogs. Ann. Surg. In press. SUMNER, J. B. The estimation of sugar using dinitrosaIicyIic acid. J. Biol. Cbem., 62: 287, 1925.
REFERENCES I. IVY, A. C., GROSSMAN, M. I. and BACHRACH,W. H. Peptic UIcer. PhiIadeIphia, 1950. BIakiston Co. 2. RAUCH, R. F. An evaIuation of gastric resection for peptic uIcer. Review of 893 cases. Surgery,
DISCUSSION
32: 638, 1952. 3. HARKINS. H. N. and NYHUS. L. M. A comoarison I
of the BiIIroth I and Billroth II procedures: cIinica1 and experimenta studies. Bull. Sot. Znternat. Cbir., 15 : I I I, 1956.
rl. BORG, I. Cited bv Lundh in Reference 14. 5. SHIN&ETON, W.“W., ISLEY, J. K., FLO&, R. D.,
SANDERS, A. P., BAYLIN, G. J., POSTLETHWAIT, R. W. and RUFFIN, J. M. Studies on postgastrectomy steatorrhea using radioactive triolein and
oIeic acid. Surgery, 42:-12, 1957. syndromes in the postgastrectomy patient. Am. J. Digest. Dis., 2:
6. ELLISON, E. H. MaIabsorption 6%
and
1957.
314
JAMES S. CLARKE (Los AngeIes, CaIif.): In this exceIlent paper Doctors White, ElmsIie and Magee have presented resuIts which heIp us to understand better the nutritiona probIems which occur in some patients after BilIroth II gastrectomy. They found that the volume and enzyme content of the pancreatic juice which mixes with a mea1 are Iess than norma after the BiIIroth I procedure and much Iess than norma after the BiIIroth II. It is Iogical to assume that the defect in the normal digestive process which they have demonstrated contributes to weight loss and steatorrhea which
Disappearing often foIIow gastrectomy. This inference would be strengthened if weight loss and steatorrhea after Billroth II gastrectomy could be prevented by feeding the patients pancreatic enzymes. I wouId like to ask the authors if they have found this to be the case. There are two features of these experiments which shouId be noted in interpreting their significance. First the stimuIus was parenteraIIy administered secretin rather than the usua1 physioIogic stimuIi which foIIow ingestion of food. Second the coIIections were made from the second portion of the duodenum in the norma and BiIIroth I patients and from the efferent jejuna1 Limb dista1 to the gastrojejunostomy in the Billroth II patients. The authors chose the stimulus of parenteral secretin to avoid the use of a test mea1 with its inevitable bypassing of the duodenum in the BiIIroth II patients. NaturaIIy, there wouId be a greater endogenous secretin release from the duodenum after a meal if the gastric content emptied into the duodenum than if it entered directIy into the jejunum, and the pancreatic exocrine response wouId be greater. The present study has been designed to rule out this source of confusion. It is of great interest that the fasting and stimulated response from the pancreas was consistentIy Iess after a BiIIroth I resection than in norma persons. Perhaps Dr. White wouId tell us his theories as to why this is so. The finding of markedIy reduced voIume and enzyme content in BiIIroth II patients, both whiIe fasting and in response to parentera secretin, is subject to at least two interpretations. The volume and enzyme output of the pancreas itself at the papiIla of Vater could be reduced; or alternativejy they could be normal, but absorption of Auid and destruction of enzymes could occur en route between the second portion of the duodenum and the tip of the collecting tube in the efferent limb of the gastrojejunostomy. Lundh and others have shown that the concentration of pancreatic enzymes decreases as one passes distally from the duodenum, and in the present experiments the sampIes of the BiIIroth II group are drawn from a point far dista1 to the point of entrance of pancreatic juice into the duodenum. Further experiments using Billroth II patients and sampling pancreatic secretion by a tube pIaced opposite the papiIIa of Vater wouId aIIow a firm answer as to which of these two interpretations is correct. The factors which Iead to nutritiona deficiencies after gastric operations are undoubtedIy multipIe. Beside the “disappearing enzyme,” we should mention inadequate intake of food as an important one. The problem has been beautifulIy reviewed by Horace G. Moore, Jr., in the new book on Surgery of the Stomach and Duodenum edited by Harkins and Nyhus.
315
Enzymes Lest the gastrectomists present take offense at this paper and discussion which are concerned with one of the disturbing features of abIation of the stomach, I aIso believe that similar studies on patients who have had vagotomy and a drainage procedure would be of great interest, allowing a comparison of avaiIabIe operations for duodena1 ulcer in this regard. It is generaIIy beIieved that nutritionat diffrcuIties are Iess after vagotomy and drainage than after a gastric resection. This paper by Doctors White, EImsIie and Magee is an important contribution to our knowledge of the physioIogic aberrations we produce by certain operations on the stomach. It does not pretend to answer the question of which operation is best for ulcers. It outIines one criterion that we can test, the volume and enzyme content of pancreatic juice recoverabIe from the site where food Ieaves the stomach. There are many other important criteria, among them operative mortaIity, morbidity, frequency of recurrent uIceration, dumping, weight Ioss, steatorrhea, aIteration of bowel habits, and so on. These must a11 be considered and, as Dr. Weinberg suggested, they must be considered in approaching a conclusion, for they are vastIy different in their importance to the weIl-being of the patient. DAVID B. HINSHAW (Los AngeIes, CaIif.): I had the priviIege of reading Dr. White’s stimulating paper and I want to congratuIate him on his lucid presentation. It wouId seem heIpfu1 if the concentration and volume of enzymes couId be measured at comparabIe distances down the jejunum from the ampulla of Vater in both the BiIIroth I and BiIIroth II situations. AIso, enzyme determinations made in the duodenum just below the ampuha of Vater would be of interest. This type of study should prove to be important in the delineation of some of the probIems associated with these operations. THOMAS T. WHITE (closing): I realize that this is a compIicated discussion for most of you and it is aIso complicated for me to mention a11 these different figures. As far as the questions asked by Dr. Clarke, feeding enzymes in some instances does control symptoms which the BII patients have. However, the onIy BiIIroth II patients which we have studied have been patients who have been in extremely poor condition as far as nutrition was concerned. These patients have been much benefited. We did not have a Iarge series, but in the few which we have studied this has occurred. We are not far enough advanced to answer Dr. CIarke’s other question; however, I shaI1 explain our procedure. A triple Iumen tube was inserted through a gastrostomy and into the proximal loop at time of operation. It was fastened by a single NyIon@ suture which could be puIIed out Iater
White,
EImsIie and Magee
through the skin. SampIes were coIIected from duodenum, just above the gastrojejunostomy, and between both after test meaIs and after secretin administration. I beIieve that we wiI1 be abIe to show that there is actua1 reabsorption of both ffuid and enzymes in the proxima1 Ioop of BiIIroth II patients. I did not mention it when I started the discussion, but the amount of materia1 which we can collect from right opposite the ampuIIa of Vater in the BiIIroth II patient is aImost exactIy the amount which we can coIIect from a BiIIroth I patient, so that if the same stimuIus is given to a BiIIroth II patient, one wiI1 get just as much secretion from the upper part of the duodenum as in a BiIIroth I patient. There
3’6
is something about this proxima1 Ioop which aIters the materia1 which is being secreted before it gets in the gastroenterostomy. The only other question which I wiI1 attempt to answer right now is: Why is there Iess secretion in the BiIIroth I type resection than in the norma patient? It has been suggested that perhaps there is a certain amount of acid Auid running into the duodenum a11 the time in the norma person. In the Billroth I patient the Auid is reduced. I wouId have thought that the amount of enzyme secretion wouId be onIy a IittIe bit Iess in the BiIIroth I patient than in the norma patient, but I reaIIy do not have a good answer other than that perhaps nervous stimuIation is absent in the situation.
Disappearing
OF PANCREATIC BILLROTH
Enzymes*
ENZYMES IN NORMAL PATIENTS I AND II GASTRIC RESECTIONS
AND AFTER
THOMAS TAYLOR WHITE, M.D., RONALD G. ELMSLIE, M.n.t AND DONAL F. MAGEE, Seattle,
From tbe Departments of Surgery and Pharmacology, University of Wasbington, School of Medicine, Seattle, Wasbington. Supported by U.S.P.H.S. Grant A-3637 and U.S.P.H.S. Clinical Research Program O.G.-13.
Comfort and Osterberg [IO], ButIer [II] and Lawrence et a1. [12].) ButIer [II] performed fat baIances on eightysix BI and 208 BII patients three months and three years after operation. At three months postoperative onIy one BI patient (I per cent) and ninety-three BII patients (44.7 per cent) had steatorrhea, whiIe at three years seven BI patients (8. I per cent) and 121 BII patients (54.2 per cent) had steatorrhea. (Figs. I and 2.) Isotopic fat studies by ShingIeton and associates [5,13] indicated that the absorption defect foIIowing gastrectomy is simiIar to that found in patients with pancreatic insuffrciency. Norma1 excretion of 1131 IabeIIed triolein was 0.6 per cent, whereas 4.5 per cent appeared in the stoo1 of BI patients and 14 per cent in BII patients. Further support to the theory that the negative fat and nitrogen baIances are due to impaired pancreatic secretion has been offered by Lundh [14], ButIer [rr,15] GoIdstein, Wirts and Kramer [16] and Wirts and Goldstein [r7]. Both Lundh and Butler have shown that there is a depression in pancreatic response to a test mea1 which is greater in a BII than a BI patient. Their studies are slightly different in severa detaiIs. Lundh’s standard ora test mea1 incIudes a poIyethyIene gIyco1 (PEG) marker to measure changes in diIution, radioactive serum aIbumen (RISA) to measure protein absorption and fat. He monitors the disappearance of RISA at various IeveIs of the intestine by aspirating through a poIyviny1 tube whiIe measuring volume, PEG and trypsin concentration and fat loss. The trypsin curve for
N
THE PRESENT study, we have attempted to evaIuate the pancreatic response to secretin in a series of ten patients who had BilIroth II (BII) gastric resection, eight BiIIroth I (BI) gastric resection, and twelve normaI patients. We wished to investigate the relative sensitivity of the pancreas to secretin in BI, BII and norma patients. It has been cIearIy estabIished that a Iarge proportion of gastric resection patients Iose weight. This has been attributed to intestina1 hurry, inadequate absorptive capacity of the intestine, inadequate pancreatic secretion, improper mixing, or destruction of pancreatic enzymes. In a coIIected series of 864 patients with BII resections, Ivy, Grossman and Bachrach [I], found that 47 per cent had Iost weight, whiIe 80 per cent of Rauch’s [2] 699 BI patients Iost weight. Harkins and Nyhus [3] found that onIy 42 per cent of their 529 patients Iost weight as opposed to 74 per cent of 135 BII patients. In the same series 46 per cent of BI patients and 24 per cent of BII patients gained weight. Borg [4] presents similar figures: 20 per cent of 698 BII patients gained weight, whiIe 78 per cent of 171 BI patients gained weight. EarIy evidence as to the cause of the weight Ioss has been the negative fat and nitrogen baIances found in approximateIy haIf of the BII patients. (ShingeIton et aI. [5], EIIison [6,7], Babb et al. [8], Everson [9], WoIIaeger,
I
M.D.,
Washington
* Presented at the annual meeting of the Pacific Coast Surgical Association, PaIm Springs, California, 1963. t In receipt of a Wekome TraveI Grant.
307
American
Journai of Surgery,
V&me
February
3-6,
106, August
1963
White, FAECAL (Three
FAT
Months (After
EImsIie
and
Magee FAECAL
EXCRETION
Post
(Three
Gostrectomy)
Bil lroth
EXCRETION
Post
(After
Butler)
(86
FAT
Yeors
Gastrectomy)
Butler)
Bil Iroth
I
,I
potients)
B ‘;;
8il lroth 11 (208 potients)
60
: 50 2 40
Billroth
II
2 30
5 IO 15 18 25 30 35 40 Faecol Fot / 3 days (grams fatty
45 acid)
c
50 IO
Fed 210 grams fat.
Foecal
FIG. I. Data from ButIer [I r] indicating one of eightysix BilIroth I and ninety-three of 208 BiIIroth II patients with steatorrhea three months postoperative to their gastric surgery.
Fot
25
I518
/ 3 doys Fed
210
30
35
(grams grams
40 fatty
45
:3
acid)
fat.
FIG. 2. Data from ButIer [II] on fat baIances on the same gastric resection patients. Seven of eighty-six BiIIroth I patients and 121 of 208 Billroth II patients had steatorrhea. (Done three years later.)
his thirty-two BI patients was beIow that of normaI aIthough higher than that in his twentynine BII patients. Not onIy were the average IeveIs Iowest in the BII patients, but no trypsin was present in six of the twenty-nine patients. AI1 of the patients with the BI procedure had some trypsin in their aspirates. Butler was interested in the difference between the effect of jejuna1 feeding of a test mea1 on duodena1 secretion as opposed to duodena1 feeding. JejunaI feeding after a BI resection produced 25 per cent Iess duodena1 secretion than before resection in the same patient. The duodena1 secretion foIIowing a duodena1 meal in the same was patients both pre- and postoperative roughIy double that foIIowing a jejuna1 mea1, even taking into account factors of diIution. These findings fit in with experimenta work indicating decreasing reIease of secretin as the stimulus descends the intestine. WhiIe Lundh observed that trypsin was sometimes absent in the efferent Ioop of the BiIIroth II patient, ButIer, Wirts and GoIdstein have cannuIated the proxima1 Ioop of the BiIIroth II patients with and without steatorrhea to study the enzymes found therein.
WhiIe seven of I 38 determinations on forty-six BII patients without steatorrhea had no Iipase in the proxima1 Ioop in Butler’s series, fortyseven of 138 determinations on forty-six patients with steatorrhea had no Iipase in the proximal Ioop. The proportion of patients without protease (trypsin) were somewhat Iower in these studies. AI1 patients had amyIase in the proxima1 Ioop. SimiIarIy GoIdstein and Wirts found a marked depression of Iipase without depression of amyIase, particuIarIy in the steatorrhea group. WhiIe these authors agree that pancreatic Iipase in fasting duodena1 juice is depressed in postgastrectomy steatorrhea (BII) patients, they did not determine whether this was due to decreased pancreatic function or inactivation of the enzyme within the proxima1 Ioop. In this investigation we have obviated the d&uIty inherent in the use of a test meal stimulus which may not remain Iong enough in contact with the duodenum as in the BI patients, or which is diverted from the duodenum as in the BII patients. This has been done by 308
Disappearing
12
NORMAL
8
Enzymes
BILLROTH
I
IO BILLROTH
It
FIG. 3. Position of tubes. Position of the Matzner tube in the norma subjects and the BiIlroth I and II patients.
giving al1 norma subjects, BI and BII patients a standard intravenous dose of secretin, then measuring the voIume and enzyme activities of the drainage obtained from the first few cm. of intestine beyond the stomach, and in the case of the BII patients from the proximal Ioop as weI1. METHOD
Thirty subjects were intubated with a Matzner duodenal tube using an x-ray image intensifier. In tweIve normal persons and eight patients six or more months postoperative to a BI gastric resection, the tube was passed into the duodenum opposite the ampuIIa of Vater. In ten BII patients, it was passed so that the bucket Iay 5 to 7 cm. beyond the gastrojejunostomy. (Fig. 3.) DuodenaI or jejunal materia1 was aIIowed to siphon into an ice bucket in two, fifteen minute coIIections. An average of these two coIIections was used as a contro1. One unit of secretin* per kiIogram was given intravenousIy and four more fifteen minute coIIections taken. VoIume, amyIase (as maItose reIeased in three minutes using Sumner’s dinitrosaIicyIic acid method) protease as 0.05N NaOH using a specific substrateBAEE) and Iipase (as 0.05N NaOH in five minutes using oIive oi1 as a substrate) were determined. A Radiometer, pH stat apparatus was used in the determinations of protease and Iipase. Fat baIance studies using an 80 gm. fat diet for five days and coIIection for the * AvaiIabIe from Apoteksvarucentralen Box I 2 I 70, StockhoIm, Sweden.
Vitrum,
final seventy-two hours were performed BI and seven BII patients.
on six
RESULTS Volume. The resting voIume per 15 minutes was Iess in the BI patients (17.5 ml. &- 10.7) than in the norma persons (31.1 m1 f 12.9). The resting volume was even Iower in the BII patients (6.9 m1. + 6.3), significantly Iower than the norma persons (p = .OOI) and onIy sIightIy Iess significantIy Iower than the BI patients (p = .006). The difference between the BI patients and the normal subjects was not significant. The voIume in one hour after secretin in BI patients (145 m1. f 50.1) was significantIy Iess (p = .02) than in the normaIs (227.3 ml. + 47.4). StimuIated voIume in the BII patients (57.7 m1. _t 83.2) was significantIy Iower than in the BI patient (p = .003). The difference between the BII patients and the norma subjects was significant (p = .OOI). The variation in voIume was great in a11 three groups, but was greatest in the BII group. (TabIe I.) The configuration of the secretory pattern was the same, although Iower, in the BI patients than in the norma subjects while there was a Iow deIayed peak in the BII patients. (Fig. 4.) Amylase. Resting rate of secretion of amyIase was 941 mg. + 657 for the normaI subjects, 913 mg + 669 for the Br patients and 393 mg + 578 for the BII patients. The difference between the BI patients and the normal subjects was not significant, whiIe the difference between the BII and the BI was significant
309
White, EImsIie and Magee VOLUME
AFTER
SECRETIN
m I. 80I
706050-
I
1
Norma I
403020IO0
_ Control
1 I 30
I 15
I Secretin f W/kg
1 45
r 60
Minutes
FIG. 4. The voIume secretory pattern before and after I unit secretin per Kg. in normal subjects, BiIIroth I and II patients. Notice that the BiIIroth I secretion, aIthough depressed from normal subjects, foIIows the same pattern; the BiIIroth II secretion reaches a Iate rather than an earIy peak. The stimuIated differences are particuIarIy sign&ant. TABLE TOTAL RESTING
I
FIFTEEN MINUTES AND ONE HOUR SECRETION AFTER ONE UNIT PER Kg. SECRETIN IN NORMAL,
BILLROTH
I AND BILLROTH
Mean
VoIume ml. contro1. . One hour after Secretin. Protease controI*. One hour after Secretin. Lipase controI*. . One hour after Secretin. AmyIase contro1 t. One hour after Secretin,
31. I 227.3 ‘5.3 :x 53.9 941 ,304
Standard Deviation
fr2.g
k47.4 19.7 k86 kg.1 *so.7 +657 + 4050
BII Patients
BI Patients
Norma1 Subjects Data
II PATIENTS
Range
Mean
259.5 148-324 4.3-35.4 ;12. I-252.t I-24.4 2-252 2-2246 Io82-16648
17.5 145 9.9 52.1 6.4 45.3 9’3 igor
Standard Deviation
+10.7 k50. I f7.8 +32.1 +2.26 k3g.r f 669 * 4920
Range
Mean
Standard Deviation
Range
rt6.3 o-22.7 1-30 6.9 +83.2 o-274 26.5-252 ‘Z +2.6 o-4.2 ,925.E k34.8 0-80.2 9.4-94.5 24.2 f2.520-7 .5-15.6 I.3 k41.4 O-105 g.6-121.4 28.6 45o-2160 393 ,578 o-2335 rgg5-167222618 &-4200 o-15809
* Protease and Iipase as ml. .05N NAOH in five minutes. t AmyIase as mg. mahose reIeased in three minutes. Enzymes are aI expressed as tota amount secreted in the period described,
the BI patients and 2618 mg. + 4200 for the BII patients. The difference between the BI and the BII patients, the BI and the normal subjects and the BII patients and the norma subjects were equaIIy significant (p = .OOI).
(p = .OOI), as was that between the BII and the normaI subjects (p = .oI). (Fig. 5.) The amount of amyIase secreted in one hour after secretin stimuIation was 9304 mg. * 4050 for the norma group, 6901 mg. _+ 4920 for
3’0
Disappearing AMYLASE
Enzymes
AFTER
SECRETIN
3000-
0
Control
I
Secretin ! 1Wkg.
I
15
I
30 Minutes
I
I
45
60
-
FIG. 3. The amyIase secreted per fifteen minutes in the three groups is iktrated here. WhiIe there is no significant difference between the BiIIroth I and norma secretion, the BII is significantIy lower. There is a significant difference between the BiIIroth 11, BiIlroth I and normaI secretin. AmyIase secretion folIows the voIume.
PROTEASE
2
AFTER
SECRETI
N
25-
‘.2 F Q 20-
Norma I
i! $
l5-
% BI
? rc, 0 IO-
I
?l
Or
Control
I
Secreti nf lU/kg
I
I5
I
30
I
45
I
60
Minutes
FIG. 6. The pattern of protease secretion before and after secretin is significant particuIarIy in the difference between the BII patients and norma subjects.
3”
White,
EImsIie
and
Magee
LI PASE
2
IO--
8
_--a_--a_-a--mm
.3 4
I
oC0ntr0
I
I
I
I
i
I5
Secretin
I
I
1
30
45
60
Minutes
1Wkg FIG. 7. The Iipase pattern in the three groups shows no significant differences between the three groups. The amyIase secretory pattern folIowed and the volume, BI was Iower than normal, and BII was even Iower with a deIayed peak. Protease. Resting protease secretion was 19.3 f g,7 for the norma subjects, 9.9 & 7.8 for the BI patients, and 1.8 ) 2.6 for the BII patients. There was no significant difference between the Br and the normal persons, while the BII patients were significantIy lower than the norma group (p = .OOI) and significantIy Iess than the BI patients (p = .oI). The amount of protease secreted in one hour after secretin was 95.2 _+ 86 for the normais, 52.1 f 32.~ for the BI patients and 24.2 &- 34.8 for the BIG patients. There was no significant difference between the BI and the normaI subjects, whiIe the BII patients were signif;cantIy Iower than the norma subjects (p = .03) and were Iess than the BI patients (p = .07). The protease pattern was reduced in a manner simiIar to amyIase and voIume although it was ffatter. (Fig. 6.) Lipase. Control Ievels of Iipase folIowed the same pattern as protease and amyIase: Norma1 : 11.6 + 9.1; BI: 6.4 f 2.3; BII: 1.3 + 2.5. One hour stimulated IeveIs were: Normal. 53.9 ) 50.7; Br: 45.3 4 39.1, and BII: 28.6 -t_ 41.4.
There is no significant difference between the values in the various groups. (Fig. 7.) The trend towards reduced enzymes in the patients who were operated on is obvious. (TabIe I.) Fat Balances. When the voIumes, enzymes and the fat baIances were compared in severa BI and BII patients, it was obvious that the volumes and enzyme levels were very much Iower in the BII than in the Br patients and the average coeficient of absorption in the BII patients (88.3 per cent + 7.4) was less than in the BI patients (94.8 per cent -/- 2.2). (TabIe II.) Norma1 range is 94 to IOO per cent. COMMENTS It is clear from the foregoing studies that the sensitivity of the pancreas to secretin is significantIy reduced in both the BiIIroth I and BilIroth II patients. The reduction is greater in the BII patients. AmyIase production is simiIarIy reduced, StimuIated protease production is significantIy reduced only in the BII patients as compared to norma patients. The variability in protease and Iipase, even in the norma group, was so great that, in the thirty patients studied, it is impossibte to draw further conclusions from this study. 312
Disappearing
Enzymes TABLE II CORRELATIONOF FAT BALANCES WITH PANCREATIC SECRETION (ONE HOUR COLLECTIONAFTER SECRETIN)
In the BI patients, a definite depression of volume and amyIase response to secretin occurred, with approximately the same pattern as in the normaI group. On the other hand protease and Iipase production in response to secretin was slight in the Br patients without the early peak seen in the norma persons. In a11 but one of the fat studies the coefficient of absorption feI1 within the norma range. In general, this fitted the degree of enzyme depression found in the individua1 patient. Using test meaIs, ButIer and Lundh found a simiIar depression of Iipase, protease and amyIase concentration. Whether or not intestina1 hurry prevented proper contact of the mea1 with the intestine with consequent inadequate reIease of secretin and pancreazymin was not cIear. Vitrum secretin aIone was used in these studies because this preparation was avaiIabIe in quantities when the investigation was started. The secretin manufactured by EIi LiIIy was discontinued in 1960. Pancreozymin and secretin produced by the Boots Pure Drug Company and Cecekin@ (ChoIecystokinin, possibIy synonymous with pancreozymin) Vitrum have been avaiIabIe to us recentIy. The volume response to the Vitrum secretin is considerabIy higher in the norma than it was to secretin made by EIi Lilly in our hands. If we were to repeat this study now we wouId use a mixture of secretin and pancreazymin rather than secretin aIone. These studies do show, however, that pancreatic sensitivity to secretin is greatly reduced in the BI patient. Thus, the Iow voiume and enzyme response observed in BI patients by Lundh and ButIer may be due to decreased sensitivity of the pancreas as much as to intestina1 hurry. The significantIy greater depression of voIume and enzymes in the BII patients as opposed to the BI patients compared with norma subjects both in resting coIIections and in response to secretin suggests that some other process is invoIved than that in the BI patients. It seems unIikeIy that the pancreatic sensitivity to secretin wouId be significantIy different after a gastrojejunostomy from that after a gastroduodenostomy with remova of a simiIar amount of stomach. ButIer has shown that a jejuna1 mea1 fed to a postoperative BI patient produces Iess pancreatic response than a duodena1 mea1. Lundh has shown that trypsin is reduced or absent in the jejunum after a test meal fed to BII patients, a finding that we
-
Fat Balance Absorbed (Per cent)
Data
VOI.
W.1
97.5 95
S. M. B.
78
J. 0. J. J. W. H.
85 97 88.4 __
.
38.5 9 9 26.5* 2 61* 0.75 43 69.5’ 56* -_
w. L. W. K.
94 92.3
B. S. J. L.
98.2
_-
94
.s 14.8 -
+ 2.2
3.579 5,280 4,090
2
I 0,782
3 05 2 * :;.5* I 71 I 55
6,752 1995 6,500 I 6,722 4,683 7,024 8,81 I
26.5
--
t -
zi
0
0 0
0 0 0 0
0
28.6 _.
65.9 57.4
-.
* iiT*
94.5
Protease .05N NaOH
2,028 0 1,966 2,220 19: 7 15,809 1,152 0
.E18.3 f 7.4 t _--
Patients with BI operation L. H.
Average........
13* 0
85
M. 0. A. R.
Average.
AmyIase (mg. maltose) _=
a=
Patients with BII operation A. M.
-
-
0
31 .o
_.
9.4 93.5 74.4 29.7 55.8 74.2
..
. -
* Duplicate experiments t + standard deviation Normal absorption of fat is over 94 per cent on an 80 gm. diet.
have confirmed usingsecretin rather than a mea1. Both authors beheved that the reduced pancreatic response was due to reduced secretin release foIIowing jejunal rather than duodena1 feeding. A reduced pancreatic output wouId inevitabIy foIIow reduced secretin reIease. In this study, the same reIative dose on a weight basis was given to normaIs, BI and BII patients. The response to secretin shouId be the same in a BII as in a BI patient. We believe that the actual reduction in secretions found at the gastrojejunostomy is due to absorption or destruction by bacteria or to autodigestion of the enzymes on the route from the duodenum 313
White,
EImsIie
Magee
7. ELLISON, E. H. Nutritiona probIems foIlowing gastrectomy. Surg. Clin. N. Amer., 35: 1683,
to the gastrojejunostomy. We suspect from preIiminary catheterization studies of the proxima1 loop that absorption is the most Iikely cause. Further studies now under way with catheterization of the upper proxima1 Ioop wiI1 teI1 us, we hope, whether or not the duodenal response to secretin and test meaIs is in fact comparabIe to that of BII patients. In addition, we hope to find out what happens to Auid and enzymes in the proxima1 Ioop.
1955.
8. BABB, L. I., CHINN, A. B., STITT, R. M., LAVIK, P. S., LEVEY, S., KRIEGER, H. and ABBOTT, W. E. EvaIuation of nrotein and fat metabolism in postgastrectomy patients. Arch. Surg., 67: 462, 1953. g. EVERSON, T. C. Experimenta comparison of protein and fat metaboIism in postgastrectomy patients. Surgery, 36: 525, 1954. IO. WOLLAEGER, E. E., COMFORT, M. W. and OSTERBERG, A. E. Disturbances in gastrointestina1 function foIIowing partia1 gastrectomy. Postgrad. Med., 8: 251, 1950. I I. BUTLER, T. J. The effect of gastrectomy on the externa1 secretion of the pancreas. M.D. Thesis. Univ. of BristoI, 1959. 12. LAWRENCE, W. JR., VANAMEE, P., PETERSON,A. S., MCNEER, G., LEWIS, S. and RANDALL, H. T. AIterations in fat and nitrogen metabolism after tota and subtotal gastrectomy. Surg. Gynec. &+ Oh., I IO: 601, 1960. 13. SHINCLETON,W. w., BAYLIN, G. J., ISLEY, J. K., SANDERS. A. P. and RUFFIN. J. M. A study of fat absorption after gastric surgery using II131 Iabeled fat. Tr. Am. Surg. Assoc., 74: 145, 1956. 14. LUNDH, G. IntestinaI digestion and absorption after gastrectomy. Acta cbir. scandinav. SuppIement 231, 1958. 15. BUTLER, T. J. A study of the pancreatic response to food after gastrectomy in man. Gut, I: 55, 1960. 16. GOLDSTEIN, F., WIRTS, A. V. and KRAMER, S. ReIationship of afferent limb stasis and bacteria1 Aora to the production of postgastrectomy steatorrhea. Gastroenterology, 40: 47, 195 I. 17. WIRTS, C. W. and GOLDSTEIN, F. Studies of the mechanism of postgastrectomy steatorrhea. Presented at the annua1 session of the American CoIIege of Physicians, April 9, 1962.
CONCLUSIONS I. There is a significant decrease in pancreatic response to secretin in the BI patient. 2. The decrease in pancreatic secretion is more significant in the BII than in the BI patient. 3. The decrease in enzymes, foIIowing gastric resection, may be due to decreased sensitivity of the pancreas to stimuIation by secretin and simiIar substances. 4. A BI type of resection or a short Ioop retrocolic BII shouId be the most satisfactory type of arrangement from a digestive point of view in the average patient. Acknowledgment: We wish to thank Miss Joan F. RisIey, B.S., M.A., for her technica assistance in preparing data for the paper. Secretin and Ceceki@ Acknowledgment: (ChoIecystokinin) Vitrum are avaiIabIe from ApoteksvarucentraIen, Vitrum, Box 12 I 70, StockhoIm 12, Sweden. Secretin and Pancreozymin are also avaiIabIe from the Boots Pure Drug Company, Nottingham, England.
Additional
References
HAYAMA, T., MAGEE, D. F. and WHITE, T. T. The inffuence of autonomic nerves on the daiIy secretion of pancreatic juice in dogs. Ann. Surg. In press. SUMNER, J. B. The estimation of sugar using dinitrosaIicyIic acid. J. Biol. Cbem., 62: 287, 1925.
REFERENCES I. IVY, A. C., GROSSMAN, M. I. and BACHRACH,W. H. Peptic UIcer. PhiIadeIphia, 1950. BIakiston Co. 2. RAUCH, R. F. An evaIuation of gastric resection for peptic uIcer. Review of 893 cases. Surgery,
DISCUSSION
32: 638, 1952. 3. HARKINS. H. N. and NYHUS. L. M. A comoarison I
of the BiIIroth I and Billroth II procedures: cIinica1 and experimenta studies. Bull. Sot. Znternat. Cbir., 15 : I I I, 1956.
rl. BORG, I. Cited bv Lundh in Reference 14. 5. SHIN&ETON, W.“W., ISLEY, J. K., FLO&, R. D.,
SANDERS, A. P., BAYLIN, G. J., POSTLETHWAIT, R. W. and RUFFIN, J. M. Studies on postgastrectomy steatorrhea using radioactive triolein and
oIeic acid. Surgery, 42:-12, 1957. syndromes in the postgastrectomy patient. Am. J. Digest. Dis., 2:
6. ELLISON, E. H. MaIabsorption 6%
and
1957.
314
JAMES S. CLARKE (Los AngeIes, CaIif.): In this exceIlent paper Doctors White, ElmsIie and Magee have presented resuIts which heIp us to understand better the nutritiona probIems which occur in some patients after BilIroth II gastrectomy. They found that the volume and enzyme content of the pancreatic juice which mixes with a mea1 are Iess than norma after the BiIIroth I procedure and much Iess than norma after the BiIIroth II. It is Iogical to assume that the defect in the normal digestive process which they have demonstrated contributes to weight loss and steatorrhea which
Disappearing often foIIow gastrectomy. This inference would be strengthened if weight loss and steatorrhea after Billroth II gastrectomy could be prevented by feeding the patients pancreatic enzymes. I wouId like to ask the authors if they have found this to be the case. There are two features of these experiments which shouId be noted in interpreting their significance. First the stimuIus was parenteraIIy administered secretin rather than the usua1 physioIogic stimuIi which foIIow ingestion of food. Second the coIIections were made from the second portion of the duodenum in the norma and BiIIroth I patients and from the efferent jejuna1 Limb dista1 to the gastrojejunostomy in the Billroth II patients. The authors chose the stimulus of parenteral secretin to avoid the use of a test mea1 with its inevitable bypassing of the duodenum in the BiIIroth II patients. NaturaIIy, there wouId be a greater endogenous secretin release from the duodenum after a meal if the gastric content emptied into the duodenum than if it entered directIy into the jejunum, and the pancreatic exocrine response wouId be greater. The present study has been designed to rule out this source of confusion. It is of great interest that the fasting and stimulated response from the pancreas was consistentIy Iess after a BiIIroth I resection than in norma persons. Perhaps Dr. White wouId tell us his theories as to why this is so. The finding of markedIy reduced voIume and enzyme content in BiIIroth II patients, both whiIe fasting and in response to parentera secretin, is subject to at least two interpretations. The volume and enzyme output of the pancreas itself at the papiIla of Vater could be reduced; or alternativejy they could be normal, but absorption of Auid and destruction of enzymes could occur en route between the second portion of the duodenum and the tip of the collecting tube in the efferent limb of the gastrojejunostomy. Lundh and others have shown that the concentration of pancreatic enzymes decreases as one passes distally from the duodenum, and in the present experiments the sampIes of the BiIIroth II group are drawn from a point far dista1 to the point of entrance of pancreatic juice into the duodenum. Further experiments using Billroth II patients and sampling pancreatic secretion by a tube pIaced opposite the papiIIa of Vater wouId aIIow a firm answer as to which of these two interpretations is correct. The factors which Iead to nutritiona deficiencies after gastric operations are undoubtedIy multipIe. Beside the “disappearing enzyme,” we should mention inadequate intake of food as an important one. The problem has been beautifulIy reviewed by Horace G. Moore, Jr., in the new book on Surgery of the Stomach and Duodenum edited by Harkins and Nyhus.
315
Enzymes Lest the gastrectomists present take offense at this paper and discussion which are concerned with one of the disturbing features of abIation of the stomach, I aIso believe that similar studies on patients who have had vagotomy and a drainage procedure would be of great interest, allowing a comparison of avaiIabIe operations for duodena1 ulcer in this regard. It is generaIIy beIieved that nutritionat diffrcuIties are Iess after vagotomy and drainage than after a gastric resection. This paper by Doctors White, EImsIie and Magee is an important contribution to our knowledge of the physioIogic aberrations we produce by certain operations on the stomach. It does not pretend to answer the question of which operation is best for ulcers. It outIines one criterion that we can test, the volume and enzyme content of pancreatic juice recoverabIe from the site where food Ieaves the stomach. There are many other important criteria, among them operative mortaIity, morbidity, frequency of recurrent uIceration, dumping, weight Ioss, steatorrhea, aIteration of bowel habits, and so on. These must a11 be considered and, as Dr. Weinberg suggested, they must be considered in approaching a conclusion, for they are vastIy different in their importance to the weIl-being of the patient. DAVID B. HINSHAW (Los AngeIes, CaIif.): I had the priviIege of reading Dr. White’s stimulating paper and I want to congratuIate him on his lucid presentation. It wouId seem heIpfu1 if the concentration and volume of enzymes couId be measured at comparabIe distances down the jejunum from the ampulla of Vater in both the BiIIroth I and BiIIroth II situations. AIso, enzyme determinations made in the duodenum just below the ampuha of Vater would be of interest. This type of study should prove to be important in the delineation of some of the probIems associated with these operations. THOMAS T. WHITE (closing): I realize that this is a compIicated discussion for most of you and it is aIso complicated for me to mention a11 these different figures. As far as the questions asked by Dr. Clarke, feeding enzymes in some instances does control symptoms which the BII patients have. However, the onIy BiIIroth II patients which we have studied have been patients who have been in extremely poor condition as far as nutrition was concerned. These patients have been much benefited. We did not have a Iarge series, but in the few which we have studied this has occurred. We are not far enough advanced to answer Dr. CIarke’s other question; however, I shaI1 explain our procedure. A triple Iumen tube was inserted through a gastrostomy and into the proximal loop at time of operation. It was fastened by a single NyIon@ suture which could be puIIed out Iater
White,
EImsIie and Magee
through the skin. SampIes were coIIected from duodenum, just above the gastrojejunostomy, and between both after test meaIs and after secretin administration. I beIieve that we wiI1 be abIe to show that there is actua1 reabsorption of both ffuid and enzymes in the proxima1 Ioop of BiIIroth II patients. I did not mention it when I started the discussion, but the amount of materia1 which we can collect from right opposite the ampuIIa of Vater in the BiIIroth II patient is aImost exactIy the amount which we can coIIect from a BiIIroth I patient, so that if the same stimuIus is given to a BiIIroth II patient, one wiI1 get just as much secretion from the upper part of the duodenum as in a BiIIroth I patient. There
3’6
is something about this proxima1 Ioop which aIters the materia1 which is being secreted before it gets in the gastroenterostomy. The only other question which I wiI1 attempt to answer right now is: Why is there Iess secretion in the BiIIroth I type resection than in the norma patient? It has been suggested that perhaps there is a certain amount of acid Auid running into the duodenum a11 the time in the norma person. In the Billroth I patient the Auid is reduced. I wouId have thought that the amount of enzyme secretion wouId be onIy a IittIe bit Iess in the BiIIroth I patient than in the norma patient, but I reaIIy do not have a good answer other than that perhaps nervous stimuIation is absent in the situation.