Digestive Diseases and Sciences, Vol. 37, No. I1 (November 1992), pp. 1685-1690

Postprandial Gallbladder Motility and Plasma Cholecystokinin at Regular Time Intervals After Injection of Octreotide in Acromegalics on Long-Term Treatment W.P.M. HOPMAN, MD, PhD, P.A. VAN LIESSUM, MD, PhD, G.F.F.M. PIETERS, MD, PhD, J.B.M.J. JANSEN, MD, PhD, C.B.H.W. LAMERS, MD, PhD, A.G.H. SMALS, MD, PhD, G. ROSENBUSCH, MD, PhD, and P.W.C. KLOPPENBORG, MD, PhD

The increased risk o f gallstone formation in acromegalics treated with the somatostatin analog octreotide has been related to an impaired gallbladder emptying. To determine the duration o f these inhibitory effects, meal-stimulated gallbladder motility, plasma cholecystokinin (CCK), and pancreatic polypeptide (PP) were measured in five acromegalics treated for 6-32 months with 200--300 ttg octreotide daily. Meal tests were performed 45 min, 8 hr and two weeks after the last lO0-tzg subcutaneous dose. Results were compared with those in normal subjects. Integrated postprandial gallbladder contraction (-125 +_ 194 cm3/120 min) and integrated PP secretion ( - 0 . I +_ 0.2 nmol/liter/120 min) were completely suppressed in the 45-min study, but significantly improved (P < 0.05) when measured 8 hr (1376 +--322 crn~/120 rain and 3.0 +- 1.0 nmol/liter/120 min) and two weeks (1437 +- 263 cm3/120 min and 10.6 +- 1.6 nmol/liter/120 rain) after the last dose o f octreotide. The integrated gallbladder contraction in acromegalics at 8 hr was comparable to that at two weeks and to that in normal subjects, but the integrated PP response at 8 hr was significantly smaller (P < 0.05 vs two weeks and vs normals). Integratedplasma CCK secretion at 45 min (0.13 +- 0.06 nmol/liter/120 min) was not statistically significantly different from the response at 8 hr (0.15 +- 0.02 nmol/liter/120 rain) and from that in normal subjects, but it was significantly increased at two weeks after cessation o f octreotide (P < 0.05 vs 45 min and 8 hr). In conclusion, during long-term octreotide treatment in acromegalics, initial abolishment o f postprandial gallbladder emptying is completely reverted to normal values 8 hr after the last subcutaneous dose. No major differences in postprandial plasma CCK at 45 min and at 8 hr were observed when compared with normal subjects, whereas plasma PP responses were diminished. KEY WORDS: acromegaly; octreotide; somatostatin; gallbladder motility; cholecystokinin; pancreatic polypeptide.

Manuscript received December 30, 1991; revised manuscript received April 15, 1992; accepted April 16, 1992. From the Department of Internal Medicine, Division of Gastroenterology and Endocrinology, University Hospital Nijmegen; Department of Gastroenterology, University Hospital Leiden; and Department of Radiology, University Hospital Nijmegen, Nijmegen, The Netherlands. Address for reprint requests: Dr. W.P.M. Hopman, Department of Internal Medicine, Division of Gastroenterology, University Hospital Nijmegen, 6500 HB Nijmegen, The Netherlands.

Octreotide is a long-acting octapeptide analog of somatostatin (1). Several studies have demonstrated its beneficial effect in the management of patients with VIPoma, carcinoid syndrome, insulinoma, dumping syndrome, and acromegaly (2-4). Although octreotide has a potent inhibitory action on the secretion of several regulatory peptides, side

Digestive Diseases and Sciences, Vol. 37, No. 1l (November 1992)

0163-2116/92/1100-1685506.50/09 1992PlenumPublishingCorporation

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HOPMAN ET AL effects in patients on long-term treatment are minimal and in general tolerance is good (2). H o w e v e r , recent studies strongly suggest that patients on chronic octreotide treatment are at an increased risk for the formation of gallstones (5-8). Development of gallstones in patients on octreotide treatment is probably related to complete suppression of postprandial gallbladder motility at least for the first 2 hr after subcutaneous injection (9, 10). Data on the duration of this inhibitory effect may have important implications for the appropriate timing of meals in patients who are treated intermittently with octreotide. The aim of this study was therefore to determine postprandial gallbladder motility at several intervals after the last subcutaneous injection in acromegalics on chronic octreotide treatment. Plasma cholecystokinin (CCK) and plasma pancreatic polypeptide (PP) were simultaneously studied. C C K is a major hormonal stimulant of gallbladder contraction in response to meal ingestion (11-14), whereas PP is a regulatory peptide that has been suggested to exert inhibitory actions on gallbladder motility opposite to that of CCK (15, 16). MATERIALS AND METHODS Five patients with active acromegaly (two men and three women; 26-40 years) were studied on three occasions. They had been treated by subcutaneous injections of octreotide, 100 ~g two to three times daily, for 6-32 months. After an overnight fast, the patients ingested a standard breakfast during a 15-min period. The breakfast consisted of one slice of white bread, 5 g of margarine, 50 g of cheese, 200 g of yogurt with 50 g dextrose, one soft-boiled egg, and 150 ml tea (30 g fat, 30 g protein, and 70 g carbohydrate). Meal tests were performed 45 min, 8 hr, and two weeks after the last 100-~g subcutaneous octreotide dose. In addition the meal test was performed in eight healthy volunteers (four men, four women; 19-25 years) without octreotide pretreatment. All subjects gave informed consent before entering the study. The study was approved by the ethics committee of Nijmegen University Hospital. Blood was drawn for CCK and PP measurement before and at 15-min intervals until 120 min after start of the meal. Each time a blood sample was drawn, two longitudinal and two transverse images of the gallbladder were obtained by real-time ultrasonography. Gallbladder volume was calculated by the sum of cylinders method using a computer system as described before (17). The variation of volume measurements ranged from 6.0 to 22.4%. Plasma CCK levels were measured by a sensitive and specific radioimmunoas say using antibody T204 (18). This antibody binds to all biologically active carboxy-terminal CCK peptides containing the sulfated tyrosine region. The detection limit of the assay was between 0.5 and 1.0

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pmol/liter plasma. The intraassay variation ranged from 4.6 to 11.5% and the interassay variation from 11.3 to 26.1%. Plasma PP was measured by radioimmunoassay as previously described (19). The intraassay variation was 4.4-7.2%, and the interassay variation 6.8-12.1%. Plasma CCK levels, plasma PP levels, and gallbladder volumes were measured in duplicate. The mean of two measurements was used for further analysis of results. Results were expressed as means -+ 1 SEM. Decrease in gallbladder volume in each subject was expressed in maximum percent decrease of gallbladder volume relative to basal volume. Integrated plasma CCK, integrated plasma PP, and integrated gallbladder contraction were determined by calculating the area under the timeresponse curve after subtraction of basal value. Statistical analysis was done by ANOVA. If a statistically significant effect was obtained, the means were compared with the least significant difference method. All testings were performed at a probability level of 0.05 (two-tailed). RESULTS Basal gallbladder volumes in acromegalics were larger when measured 45 min after the last dose of octreotide (32.3 - 3.2 cm 3) than 8 hr after the last dose of octreotide (25.9 --. 4.0 cm 3) and two weeks after octreotide (21.6 --- 3.6 cm3). H o w e v e r , these differences were not statistically different. In the acromegalics, meal ingestion 45 min after subcutaneous octreotide injection did not induce any significant change in gallbladder volume during the meal-stimulation period of 120 min. On the other hand, 8 hr after the last injection, mean gallbladder volume significantly decreased by 68 --- 9% (P < 0.05; Figure 1). Similarly, after an interval of two weeks without octreotide, gallbladder volume significantly decreased by 81 --- 8% (P < 0.05; Figure 1). Integrated postprandial gallbladder contraction significantly improved at 8 hr and at two weeks when compared to the integrated response at 45 min after octreotide injection (P < 0.05; Figure 2). In acromegalics, integrated gallbladder contraction in the 8-hr and two-week study was comparable to that in healthy subjects (NS; Figure 2), whereas integrated contraction in the 45 min study was significantly lower than that in normal subjects (P < 0.05; Figure 2). Basal plasma C C K levels in acromegalics (1.6 --0.2, 2.0 --- 0.3, and 2.0 --- 0.2 pmol/liter, respectively, 45 min, 8 hr, and two weeks after the last subcutaneous octreotide injection) were virtually identical to those in normal subjects (2.0 - 0.1 pmol/liter; NS). In the acromegalics meal ingestion induced a statistically significant increase in plasma CCK in the 45-min study (P < 0.05; Figure 3), in the Digestive Diseases and Sciences, Vol. 37, No. 11 (November 1992)

GALLBLADDER MOTILITY, CCK AND OCTREOTIDE Gallbladder volume (cm 3 }

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Time (min)

Fig 1. Gallbladder volume in response to meal ingestion in five acromegalics on long-term octreotide treatment and in eight normal subjects. Meal tests in acromegalics were performed 45 min, 8 hr, and two weeks after the last subcutaneous injection of 100 p~g octreotide. Postprandial gallbladder volumes in the 45min study were significantly larger (P < 0.05) than those in the other three studies at 15-120 min.

8-hr study (P < 0.05; Figure 3), and in the two-week study (P < 0.05; Figure 3). In the 45-min and 8-hr study, a gradual increase of plasma CCK was observed without reaching a peak level. Although postprandial plasma CCK in the 8-hr study tended to increase earlier and was somewhat higher, no statistically significant differences between the 8-hr and 45-min study were observed in acromegalics. On the other hand, postprandial plasma CCK levels in acromegalics without octreotide for two weeks were significantly higher than those in the 45-min and 8-hr study at 15, 30, 45, and 75 min (P < 0.05; Figure 3). Integrated plasma CCK 45 min after octreotide was comparable to that at 8 hr (NS), but it was significantly increased at two weeks after the last dose (P < 0.05 vs 45 min and vs 8 hr; Figure 4). When postprandial plasma CCK levels in the three studies in acromegalics were compared with those in normal subjects, no statistically significant differDigestive Diseases and Sciences, Vol. 37, No. 11 (November 1992)

ences were observed, except at 15 min when octreotide was injected 45 min before the meal (P < 0.05; Figure 3). However, integrated plasma CCK in the two-week study was significantly higher than that in normal subjects (P < 0.05 vs two-week study, NS vs 8-hr and 45-min study; Figure 4). Integrated plasma PP was -0.1 -+ 0.2 nmol/liter/ 120 min at 45 min after octreotide. It significantly improved at 8 hr after octreotide (P < 0.05 vs 45-min study) and at two weeks after the last octreotide injection (P < 0.05 vs 45-min study and P < 0.05 vs 8 hr study; Figure 5). When compared to normal subjects, integrated plasma PP in acromegalics was significantly lower at 45 min and at 8 hr (P < 0.05; Figure 5) but not at two weeks after the last octreotide injection (NS; Figure 5). DISCUSSION Recent observations indicate that patients on long-term octreotide treatment are at an increased risk for development of cholelithiasis (5-8). Since native somatostatin and the somatostatin analog octreotide have been demonstrated to exert potent inhibitory actions on gallbladder motility in acute

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HOPMAN ET AL integrated ptasma CCK (nmol/t .120m[n ) 0.4

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and short-term studies (10, 20), it has been suggested that stasis of bile is a major factor contributing to the formation of gallstones in these patients. However, it has to be noted that the inhibitory actions of octreotide may differ in patients on long-term treatment since an escape of several gastrointestinal functions from the inhibitory effects of octreotide occurs (21, 22). The present study in acromegalics pretreated with subcutaneous octreotide for 6-32 months demonstrates that initial abolishment of postprandial gallbladder motility is almost completely restored to normal values 8 hr after the last subcutaneous injection. This finding may have important clinical implications for the prevention of gallstones. To prevent stasis of bile, patients on long-term octreotide should take at least one of their daily meals about 8 hr after the last injection. This meal should contain a sufficient amount of fats and proteins to guarantee an adequate stimulus for plasma cholecystokinin release and gallbladder contraction (23).

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acromegatics normal Z,5rain 8h 2wk subjects (n=5) (n=8) Fig 4. Integrated plasma cholecystokinin (CCK) in response to meal ingestion in five acromegalics on long-term octreotide treatment and in eight normal subjects. Meal tests in acromegalics were performed 45 miD, 8 hr, and two weeks after the last subcutaneous injection of 100 ~g octreotide. The asterisk denotes a significant difference (P < 0.05) from the other three experiments.

However, it has to be noted that a change in gallbladder motility is not the only factor involved in the formation of gallstones (7, 14, 24-26). It remains possible that octreotide induces an increased biliary lipid concentration as a result of changes in the composition of bile acids, although this suggestion is controversial (27, 28). In addition, theoretically it could be possible that nucleation of supersaturated bile is affected by an effect of octreotide on promotors and inhibitors of crystallization of supersaturated bile (7). In short-term studies, the inhibitory action of native somatostatin and octreotide on gallbladder motility has been attributed to suppression of meal stimulated release of cholecystokinin from the intestine (10, 20). Octreotide almost completely suppressed meal-stimulated plasma CCK release in healthy volunteers after six days of pretreatment with 25 I~g twice daily (10). On the other hand, the presen t study reveals that integrated postprandial plasma CCK responses are not diminished in acromegalics pretreated for 6-32 months with the higher dose of 100 Ixg two to three times daily. The reason for this discrepancy in CCK responsiveness between long- and short-term studies is not Digestive Diseases and Sciences, VoL 37, No. 11 (November 1992)

GALLBLADDER MOTILITY, CCK AND OCTREOTIDE integrated plasma PP (nmol/I .120min) 12

~4-

normal acromegalic s z,5 rain 8h 2wk subjects (n=5) (n=8)

Fig 5. Integrated plasma pancreatic polypeptide (PP) in response to meal ingestion in five acromegalics on long-term octreotide treatment and in eight normal subjects. Meal tests in acromegalics were performed 45 min, 8 hr, and two weeks after the last subcutaneous injection of 100 p.g octreotide. The asterisk denotes a significant difference (P < 0.05) from the meal test at 45 min and the dagger denotes a significant difference (P < 0.05) from the meal test at 8 hr after the last injection.

known, but it suggests an escape of the CCKproducing cells from the suppressing action of the somatostatin analog. During chronic treatment such a mechanism of adaptation has been suggested in healthy subjects (20, 21) and in patients with gastrointestinal hormone-producing tumors (29, 30). However, the tendency of a more sluggish increase of plasma CCK 45 min and 8 hr after octreotide without reaching a peak level might indicate that some delay of CCK release occurs, suggesting that the escape of the CCK-producing cells from the suppressive action of octreotide is not complete. Nevertheless, a direct effect of the somatostatin analog at the gallbladder level independent of CCK release seems more likely to explain the findings of the present study. Apart from direct effects, octreotide may indirectly change the gallbladder response to an appropriate CCK stimulus by interfering with the release of inhibitory peptides of gallbladder motility. However, the present study demonstrates that the release of pancreatic polypeptide, a putative physiologic inhibitor of gallbladder motility (15, 16), is completely abolished during the first 3 hr after injection and that its release is only partially restored 8 hr later. The reason for the Digestive Diseases and Sciences, Vol. 37, No. I1 (November 1992)

increased release of CCK in acromegalics two weeks after cessation of octreotide when compared to normal volunteers is not known. Several explanations may account for this observation. It may be possible that the increased CCK release is related to a rebound phenomenon after cessation of octreotide. Furthermore, high levels of growth hormone may induce an increased number of CCK-producing cells in the mucosa of the upper small intestine of acromegalics. Another possibility is that an increased digestive capacity due to pancreatic enzymes, as suggested previously, results in a more efficient digestion of fatty nutrients and proteins, and subsequently in a better availability of stimulating substances to the CCK-producing cells in acromegalics (31-33). In conclusion, during long-term octreotide treatment in acromegalics, initial abolishment of postprandial gallbladder emptying 45 min after the last subcutaneous injection is completely reverted to normal values over 8 hr. It is suggested that CCK and PP are of minor importance in mediating this effect, since postprandial plasma CCK responses at 45 min and at 8 hr were comparable to those in normal subjects, while plasma PP responses were diminished. To warrant sufficient gallbladder emptying, thereby eliminating an important factor in the development of gallstones, patients on long-term treatment with octreotide should take at least one meal containing a sufficient amount of proteins and fats about 8 hr after the last subcutaneous injection. REFERENCES 1. Bauer W, Briner U, Doepfner W, Hailer R, Huguenin R, Marbach P, Petcher TJ, Pless J: SMS 201-995: A very potent and selective octapeptide analogue of somatostatin with prolonged action. Life Sci 31:1133-1140, 1982 2. Gordon P, Comi RJ, Maton PN, Go VLW: Somatostatin and somatostatin analogue (SMS 201-995) in treatment of hormone-secreting tumours of the pituitary and gastrointestinal tract and non-neoplastic diseases of the gut. Ann Intern Med 110:35-50, 1989 3. Pieters GFFM, Van Liessum PA, Smals AGH, Van Gennep JA, Benraad T J, Kloppenborg PWC: Long-term treatment of acromegaly with Sandostatin (SMS 201-995). Normalization of most anomalous growth hormone responses. Acta Endocrinol (Copenh) 116(suppl 286):9-18, 1987 4. Hopman WPM, Wolberink RGJ, Lamers CBHW, Van Tongeren JHM: Treatment of the dumping syndrome with the somatostatin analogue SMS 201-995. Ann Surg 207:155159, 1988 5. Ho KY, Weissberger AJ, Marbach P, Lazarus L: Therapeutic efficacy of the somatostatin analog SMS 201-995 (octreotide) in acromegaly. Ann Intern Med 36:108-124, 1990 6. McKnight JA, McCance DR, Crothers JG, Atkinson AB:

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