Exocrine pancreatic function after gastrectomy

GASTROENTEROLOGY

1989;97:147-53

Exocrine Pancreatic Function After Gastrectomy Specificity

of Indirect

Tests

GERHARD HEPTNER, SIGURD DOMSCHKE, and WOLFRAM

DOMSCHKE

Department of Medicine, University Federal Republic of Germany

of Erlangen-Nuremberg,

We compared intraindividually the specificity of indirect pancreatic function tests before and after total (n = 4;Roux-en-Y) or subtotal (n = 6;Billroth II) gastrectomy. Before gastrectomy only 1 patient showed a falsely pathological result with the pancreolauryl test (90% specificity), while the results of all the other tests were correctly normal (100% specificity using the usual cutoff limits). After gastrectomy the respective specificities were as follows: pancreolauryl test 10% bentiromide test 70% fecal chymotrypsin 70% and plasma ,amino acid consumption test 100%. There was no obvious difference in the reduction of specificity between subtotal and total gastrectomy. The respective preoperative to postoperative changes in the median test data were as follows: plasma amino acid consumption test +21%, bentiromide test -12%, fecal chymotrypsin -51% and pancreolauryl test -53%. It is concluded that after gastrectomy only the plasma amino acid consumption test is unaffected by postoperative anatomic alterations.

eight loss of varying degree is commonly obVV served after all types of gastrectomy (1-3). Besides malnutrition due to postprandial complaints, a number of other causal mechanisms have been discussed: lack of gastric acid and pepsin, which results in deficient protein denaturation and predigestion, loss of gastric mixing, grinding and fractional thyme delivery to the duodenum, bacterial overgrowth, insufficient endogenous pancreatic stimulation due to bypass of the duodenum, excessively rapid intestinal passage and, finally, postcibal asynchrony of the admixture of pancreatic and biliary secretions to the thyme (3-6). Peak concentrations of pancreatic enzymes and bile salts are de-

Erlangen,

creased and delayed in patients with total and Billroth II gastrectomy (7). True exocrine pancreatic function is difficult to assess after gastrectomy. Whereas a tube could be placed into the afferent loop of only a few suitable patients with Billroth II gastrojejunostomy (8), direct quantitative aspiration of pancreatic juice is impossible after subtotal or total gastrectomy with a Rouxen-Y anastomosis. On the other hand, indirect pancreatic function tests such as the bentiromide test, pancreolauryl test (PLT), and fecal chymotrypsin determination may provide falsely pathological results due to disturbed gastrointestinal anatomy and asynchronism. subsequent pancreatico-chymous Compatible with this notion, preliminary observations of a reduced specificity of these tests have been made in individual cases of operated patients by some authors (g-15) but not by others (18-19). However, the results of the indirect pancreas function tests have not yet been compared intraindividually in the same patients before and after gastrectomy. We have undertaken such a study in patients in whom preoperative imaging methods and the secretin-pancreozymin test had revealed a normal pancreas. Moreover, we employed our recently developed tubeless pancreatic function test, the amino acid consumption test (Xi), to determine whether the results reliably reflect exocrine pancreatic function in gastrectomized patients.

Abbreviations used in this paper: AACT, amino acid consumption test: BT-PABA, N-benzoyh-tyrosyl-para-aminobenzoic acid: PLT, pancreolauryl test. 0 1989 by the American Gastroenterological Association 9918.5985/89l$3.59

148 HEPTNERETAL.

GASTROENTEROLOGYVol. 97, No. 1

Materials and Methods Patients Ten patients (3 men, 7 women; aged X1-68 yr; 52100 kg in weight preoperatively and 40-90kg postoperatively) participated in the study. The patients received a clinical and laboratory check-up, had gastroduodenoscopy (n = lo), ultrasonography (n = lo), and computed tomography (n = 8). Ultrasonographically (LSC 7000; Picker International, Munich, F.R.G.), the pancreas appeared normal in each patient. Ultrasound was chosen as a suitable imaging procedure for pancreatic diseases such as a chronic pancreatitis (21). Computed tomography (Somatom DR3; Siemens, Erlangen, F.R.G.) likewise revealed no pancreatic abnormalities. The patients had no history of alcoholism or biliary disease. Upper abdominal complaints were uncharacteristic of chronic pancreatic disease, and were finally attributed to the diagnoses mentioned below. The patients were admitted to our Surgical Department for gastrectomy for the following reasons: gastric cancer (n = 7), peptic ulcer disease resistant to conservative therapy (n = 2), and gastric lymphoma (n = 1). In 6 patients a Billroth II subtotal gastrectomy with gastrojejunostomy (except for 1 patient without Braun’s enteroanastomosis) was done; in 4 patients a total gastrectomy was necessary. The duodenal loop was anastomosed in a Roux-en-Y fashion at least 40 cm distal to the esophagojejunostomy. At the proximal juncture, a small jejunal reservoir was formed (Figure 1). Postoperatively, the patients lost weight: median 9 kg, range O-17 kg (Table 1). They were advised to eat several small meals during the day. All patients with total gastrectomy regularly received intensive pancreatin supplementation (Kreon-Granulat; Kali AG, Hanover, F.R.G.). Only 2 of the 10 patients had slightly increased stool frequency (3 per day) postoperatively. Postprandial complaints were minor (sensation of fullness, bloating, cramps) early after the operation, and almost absent in the following months. Serum albumin (preoperative median 3.9 g/dl; postoperative median 4.6 g/dl) and prothrombin time (97% vs. 100%)were normal.

Pancreatic

Function

Analysis

A secretin-pancreozymin test, performed preoperatively in all patients, gave normal results without exception. Both preoperatively and several months postoperatively (median 5 mo, range 2-14 mo) pancreatic exocrine function was assessed by the amino acid consumption test (AACT), the bentiromide test, the PLT, and by fecal chymotrypsin determination. The patients gave written informed consent to the examinations. The protocol of the study had been approved beforehand by the Local Ethics Committee on March 8, 1985. Secretin-pancreozymin test. This direct function test was carried out, including volume correction, as described in detail elsewhere (22,231. The reproducibility of the test has been validated (22). Mean values and lower limits of normal have previously been established (23).

Amino acid consumption test. This indirect test has been developed in our laboratory, and its diagnostic accuracy has been compared with the “gold standard” procedure for exocrine pancreatic function, namely the secretin-pancreozymin test (20). The investigational procedure of the test has been reported elsewhere (20). In brief, blood samples for amino acid determination were drawn from an antecubital vein in fasted subjects before (twice), and at 15-min intervals after, commencing a 1-h i.v. infusion of secretin (1 CU/kg body weight . h; Secretolin, Hoechst, Frankfurt, F.R.G.) and pancreozymin (1 Ivy dog unit/kg body weight * h; Kabi-Diagnostica, Stockholm, Sweden). After centrifugation of the heparinized blood (25 IU of sodium heparin per 4 ml of blood), the plasma was removed and deproteinized with 10% sulfosalicylic acid. In the deproteinized plasma supernatant, total plasma amino acids were determined by the ninhydrin method (241. Bentiromide (N-benzoyl-r;tyrosyI-para-aminobenzoic acid) test. This test was performed between the two test days of the PLT. One gram of N-benzoyl-L-tyrosylpara-aminobenzoic acid (BT-PABA; PFT, Roche, Grenzach-Wyhlen, F.R.G.) was given together with a standard breakfast and urine recovery of split-off PABA was measured over a 6-h period. The bentiromide dose and test duration had been optimized previously (25). The PABA in the urine was measured with the Bratton-Marshall method following hydrolysis with 30% hydrochloric acid for 1 h at 100°C. The cutoff limit for normal results was 50% of the orally administered dose. Fecal chymotrypsin determination. Fecal chymotrypsin was measured photometrically (26) in three random stool samples, homogenized and suspended within a disposable device (27), using a commercially available kit (Boehringer, Mannheim, F.R.G.; 28). The normal values are 6 U/g stool and above. Pancreolauryl test. The test kit was provided by Temmler, Marburg, F.R.G. The fluorescein test procedure followed the instructions of the manufacturer: fluorescein dilaurate (349 mg) was taken orally in the middle of a standard breakfast. Urine was collected over 10 h. In an attempt to overcome extrapancreatic disturbing factors, the test was repeated 2 days later with free fluorescein (188 mg) instead of the esterified fluorescein. Urinary fluorescein was measured photometrically after heating the urine for 10 min at 70°C. The ratio of the amounts of fluorescein during the test day (T) and during the control day (C) was calculated. The more esterified fluorescein had been split by pancreatic esterases, and thus free fluorescein absorbed, the higher was the T/C index (i.e., T/C%, 29). A ratio of 30% and higher is considered to reflect normal exocrine pancreatic function. Statistics. As only patients with normal pancreatic function were assessed, the specificity [correctly normal results) of each of the indirect pancreatic function tests was calculated. The above-mentioned cutoff values were used. The individual test results were also compared preoperatively and postoperatively by Wilcoxon’s test for paired differences.

EXOCRINE PANCREATIC FUNCTION AFTER GASTRECTOMY

July 1989

Results

Fecal Chymotrypsin

Amino Acid Consumption

Test

Similarly, the specificity of the determination of fecal chymotrypsin was reduced from 100% preoperatively, to 70% after gastrectomy (Table 1). The reduced specificity was accompanied by a significant (p < 0.05) decline in fecal chymotrypsin concentration from 17.5 to 8.5 U/g (Table 1). The relative decrease in fecal chymotrypsin concentration was thus 51%.

As shown in Table 1, exocrine pancreatic function was similar preoperatively and postoperatively according to the AACT. Before surgery, plasma amino acids fell by 16.5% on average during pancreatic stimulation. After gastrectomy, the decline of plasma amino acids was more pronounced (20%). This means that the exocrine pancreatic function was not impaired postoperatively, but rather showed a tendency toward higher values [the relative change of the median test data was +2l%, a small but almost significant (p < 0.2) increase]. In no case was a pathologically low value registered. Consequently, the specificity of the AACT was 100% in our patients with a normal pancreas as shown by history, ultrasonography, and secretin-pancreozymin test.

PancreoJauryJ Test)

The bentiromide test had a 100% specificity only preoperatively (Table 1). Postoperatively, the median PABA recovery dropped from 72.5% to 63.5%. Although the relative decline was only 12%, it was statistically significant (p < 0.05). Three of 10 individual values became clearly pathological postoperatively (Table 1). In gastrectomized patients, the specificity of the bentiromide test thus reached only 70%.

1. Exocrine

Patient No. 1 2 3 4 5

6 7 a 9 10

Median

Operation TG B 11 B II B II TG TG B II TG B II B II

Pancreatic

Function

Time” (mol

Weightb (kg1

5 5 14 2 5 6 8 4 3 4

73156 72172 59159 100/90 64153 52140

5

Assessed

64158.5 100185 52144 65/63 64.5159

4.7 0 0 5.0 3.4 3.8 1.1

Dilaurate

Discussion The high specificity of the AACT, even in patients with disturbed anatomy of the upper digestive tract, as detected in the present study, had been assumed previously (20). Unlike the PLT or bentiromide test, the AACT needs no luminal stimula-

by Various Indirect

LossC (% kdmol

Test (Fluorescein

The pancreolauryl test wrongly indicated a pathological function of the exocrine pancreas in 1 patient preoperatively (90% specificity, Table 1). After gastrectomy, 9 of the 10 patients no longer showed a normal test result (10% specificity, Table 1). The reduction in specificity was independent of the type of gastrectomy performed. The gastrectomized patient (patient 10) with normal PLT results also had normal findings with the other indirect function tests.

Bentiromide (N-BenzoyJ-L-TyrosyJ-ParaAminobenzoic Acid] Test

Table

149

Tests Preoperatively BT-PABA

AACTd (%I Pre

and Postoperatively fChf (U/g)

(%I

Post

PLTs (%I

Pre

Post

Pre

Post

Pre

Post

4h 7 11

10h llh 27h llh 20h 19h

16 19 15 13 12 17

35 23 24 19 18 13

72 67 83 80 79 73

66 44h 63 56 75 70

10 19 18 18 11 17

ii 11

37 21h 70 41 42 40

3.8 5.1 0.8

18 15 28 21

21 13 17 21

95 66 72 67

35h 25h 64 86

12 17 20 22

12 7 15 10

89 38 33 62

19h 24h 13h 34

3.6

16.5

20

72.5

63.5

17.5

40.5

19h

8.5

AACT, amino acid consumption test: B II, subtotal gastrectomy of the Billroth II type: BT-PABA, N-benzoyl+tyrosyl-para-aminobenzoic acid (bentiromide) test; fCh, fecal chymotrypsin concentration; PLT, pancreolauryl test: TG, total gastrectomy. 0 Months elapsed before the patients were examined postoperatively. b Preoperative and postoperative weight. ’ Relative weight loss per month. d Maximal percent decline of plasma amino acids after pancreatic stimulation preoperatively and postoperatively (normal 212%). ’ Percentage recovery of PABA in the urine (normal 250%). 'Normal S6 U/g stool. s Data reflect the percentage of urinary fluorescein recovery (normal 230%). h Pathological test outcomes.

150 HEPTNER ET AL.

GASTROENTEROLOGY Vol. 97,No. 1

due to wncreato-blllo-chymous RT

Figure

: -!Sl

asynchrony

II

1. After gastrectomy, the amino acid consumption test (AACT) seems to mirror true glandular pancreatic function, whereas the bentiromide test (BT-PABA) reflects functional loss in proteolytic activity, and the pancreolauryl test (PLT) indicates lipolytic functional impairment. fCh, fecal chymotrypsin concentration.

tion of the pancreas by a test meal, nor the digestion of an artificial substrate in the small intestine. In the AACT, the pancreas is stimulated by exogenous secretin and pancreozymin, and the consumption of plasma amino acids as “building blocks” for pancreatic proteins (enzymes) is measured (20). The results of the AACT closely correlate with those of the duodenal secretin-pancreozymin test (2O), the gold standard of pancreatic function tests (15,301. Apparently, as shown in the present study, the AACT can also be employed in gastrectomized patients to assess the true exocrine pancreatic function, and can supplement imaging procedures in the diagnostic evaluation of the pancreas (Figure 1). The AACT shows that pancreatic function does not decrease several months after gastrectomy, but rather hints at an increasing tendency. No studies have yet compared the pancreatic secretory status before and after subtotal Billroth II and total gastrectomies, intraindividually in humans. The few postoperative studies on pancreatic secretory capacity after gastrectomies furnished conflicting results. Although some authors (31) found impaired pancreatic function several years after Billroth I gastrectomy, we were previously unable to establish a systematically reduced pancreatic exocrine function in patients with Billroth II gastrectomies, even with endogenous stimulation by a Lundh test meal (8). However, all previous studies are marred by the fact that the degree of possible function impairment due to concomitant pancreatic diseases was not known preoperatively. In rats, even pancreatic hypertrophy and hyperplasia have been reported to occur a few weeks after gastrectomy (32,33). Trophic effects of cholecystokinin and decreased plasma levels of antitrophic so-

matostatin and pancreatic polypeptide release after gastrectomy have been discussed as possible reasons (32-34). Indeed, the release of cholecystokinin is not reduced postprandially, but rather enhanced in patients with subtotal gastrectomy and Roux-en-Y anastomosis (35). The slight but almost significant postoperative increase in pancreatic function observed in our patients with the AACT would be compatible with the above considerations. The tendency toward functional pancreatic hypertrophy observed in our patients appears striking in view of the postoperative weight loss, which might be expected to impair exocrine pancreatic function. At present it remains, however, mere speculation whether a continuous hypertrophy would make the pancreas more prone to the development of adenomas and adenocarcinomas after gastrectomy (36). In contrast to the AACT, the other indirect function tests have, on average, lowered results in gastrectomized patients. The postoperative pancreaticochymous asynchronism, together with rapid intestinal transit, can be regarded as the main explanation. The similar degree of reduced specificity (70%) of the bentiromide test and fecal chymotrypsin determination is understandable, as BTPABA is an artificial substrate for chymotrypsin, and both indirect tests reflect proteolytic pancreatic activity. Whereas in unoperated patients the previously reported high specificity of the usual commercial bentiromide test and fecal chymotrypsin estimation (9,11,15,19,37,38) has been confirmed in the present study, we observed significantly deteriorated absolute test data in our group of gastrectomized patients, irrespective of the type of gastrectomy. The fecal chymotrypsin concentrations fell

July 1989

EXOCRINE PANCREATIC FUNCTION AFTER GASTRECTOMY

more than PABA recovery; dilution of chymotrypsin in more bulky stools may account for this finding. It remains to be seen whether recent modifications of the bentiromide test (serum PABA measurements; internal correction with 14C-PABA or periodic acidSchiff; 39-43) can actually improve the specificity of the test in gastrectomized patients. It is, however, doubtful, as the splitting of BT-PABA would seem to be the rate-limiting step, while free PABA is obviously easily absorbed (43,44). With the PLT, the reduction in specificity in gastrectomized patients is even more striking. Almost none of the patients continued to show a normal test result, despite a proven functionally normal pancreas. The second test day of the PLT, which employs free fluorescein alone to correct for possible concomitant malabsorptive effects, obviously does not essentially improve the specificity of the PLT. The reason for the lower specificity of the PLT as compared with the bentiromide test might be the fact that in the PLT the test procedure is similar but the substrate is different. Fluorescein dilaurate must be split by a pancreatic esterase, which is greatly dependent on intact biliary secretion (12,&j). On the whole, the PLT aims at the lipolytic activity of the pancreas, whereas the bentiromide test mirrors the proteolytic activity (Figure 1). It is well known that gastrectomy affects lipolysis more drastically than proteolysis (l-5). As in gastrectomized patients both lipase and bile salts are delivered to the small intestine too late and too diluted (7), the drastic impairment of the PLT is no surprise. Consequently, the PLT cannot be used to reliably assess pancreatic glandular function in gastrectomized patients. Only normal PLT results can be interpreted without reservation. The PLT can, however, be used to estimate functional impairment of the pancreatic-biliary-chymous interplay, especially with regard to the malassimilation of fat (Figure 1).Previously, we used the PLT as an integrative parameter for pancreatic-biliary-intestinal integrity in a study in which the influence of various brans, especially guar, on digestion was tested (46). Oral administration of guar, which binds pancreatic enzymes and bile salts (47,48), led to a more obvious reduction in the PLT results than in the bentiromide test outcome (46). A practical therapeutic consequence of the pathological PLT findings in gastrectomized patients might be that enzyme supplementation should be more generously given to these patients, especially if the patients lose weight despite adequate calorie intake. Some of these patients, if they do not respond adequately to lipase-rich pancreatic replacement, may, exceptionally, need preparations with an admixture of bile salts. Treatment failures might, of

151

course, also be due to other reasons, such as bacterial overgrowth or extremely quickened intestinal transit (l-6).

From the diagnostic standpoint it may be summarized that, in gastrectomized patients, only the AACT has a specificity high enough to reliably determine true exocrine pancreatic secretion, and that it can usefully supplement imaging procedures in the diagnostic evaluation of the pancreas (Figure 1). With the other indirect function tests, only normal results can be interpreted without reservation. Alternative indirect function tests, not dealt with in this paper, such as the oral dual-label Schilling test (49) and the cholesteryl octanoate or 13C-casein breath test (50,51), probably have the same shortcomings in gastrectomized patients, or are not helpful due to lack of sensitivity and specificity, like serum enzyme measurements (52). Finally, from the pathophysiological point of view it may be of interest that simultaneous performance of both the AACT and the PLT in gastrectomized patients would allow us to distinguish between glandular and functional pancreatic insufficiency, and to roughly estimate the impact of pancreaticbiliary-chymous asynchronism in an individual patient [Figure 1).

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EXOCRINE PANCREATIC FUNCTION AFTER GASTRECTOMY

Received October 24, 1988. Accepted January 3, 1989. Address requests for reprints to: Professor Dr. med. Sigurd Domschke, Department of Medicine, University of ErlangenNuremberg, Krankenhausstrasse 12, D-8520 Erlangen, Federal Republic of Germany. This work was supported by grants from Hoechst AG, Frankfurt: Sandoz Foundation, Nuremberg; and the Marohn Foundation, Erlangen, Federal Republic of Germany. The authors thank R.

153

Neuwirth for help with statistical analysis, A. Binder and G. Hassler for technical assistance, and U. Meyer for typing the manuscript. A preliminary report on part of this work has been published as an abstract [Domschke S, Heptner G, Domschke W. Assessment of exocrine pancreatic function after gastrectomy (abstr). Gut 1988; 29:A1457-81, and was also presented at the Annual Meeting of the British Society of Gastroenterology held in Sheffield, U.K., on September 15,1988.