Skip to main content
SpringerLink
Log in

Somatostatin analogs and gallstones: A retrospective survey on a large series of acromegalic patients

  • Original Articles
  • Published:
Journal of Endocrinological Investigation Aims and scope Submit manuscript

Abstract

Context: Development of gallstones (GS) is reported during the use of somatostatin analogs (SA) that are at present the mainstay for the medical treatment of acromegaly. Objective: To review the prevalence and clinical and biochemical correlates of GS in acromegalic patients. Design and seting: Retrospective survey on hospital records in acromegalic patients followed up in the last 20 yr in tertiary referral centers. Patients: Four hundred and fifty-nine patients (272 females). Main outcome measures: According to SA use and GS occurrence, patients were divided in 4 groups: 1) treated with SA without GS (SA+GS−), 2) GS developed while on SA (SA+GS+), 3) GS without SA use (SA−GS+), 4) neither GS nor SA (SA−GS−). Results: Patients were unevenly distributed in the 4 groups: 232, 125, 38, 64, respectively, pointing to a prevalence of GS in acromegaly of 8.3% at diagnosis with an additional 35% developing GS during SA. GS occurred after 3 months-18 yr (median 3 yr) of SA treatment, were diagnosed after symptoms in 17.6%, were associated to steatosis, ultrasound biliary dilation, and biochemical cholestasis, in 25.6%, 12.8%, and 4% of patients, respectively. Ursodehoxicolic acid was administered after GS occurrence, causing their dissolution in 39% of patients after 3–48 months (median 12). Cholecystectomy was performed in 16.8% of patients in group 2. At multivariate analysis obesity, dyslipidemia, and SA treatment were independent predictors of GS onset, whereas gender and age were not. Conclusions: GS are a frequent occurrence in acromegalic patients treated with SA, may occur at any time, but are seldom symptomatic or prompt acute surgery. Obesity and dyslipidemia appear to play a major role in the occurrence of GS in acromegalic patients on SA treatment.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Melmed S. Acromegaly. N EnglJ Med 2006, 355: 2558–73.

    Article  CAS  Google Scholar 

  2. Wright AD, Hill DM, Lowy C, Fraser TR. Mortality in acromegaly. Q J Med 1970, 39: 1–16.

    CAS  PubMed  Google Scholar 

  3. Colao A, Ferone D, Marzullo P, Lombardi G. Systemic complications of acromegaly: epidemiology, pathogenesis and management. Endocr Rev 2004, 25: 102–52.

    Article  CAS  PubMed  Google Scholar 

  4. Giustina A, Barkan A, Casanueva FF, et al. Criteria for cure of acromegaly: a consensus statement. J Clin Endocrinol Metab 2000, 85: 526–9.

    CAS  PubMed  Google Scholar 

  5. Bates AS, Van’t Hoff W, Jones JM, Clayton RN. An audit of outcome of treatment in acromegaly. Q J Med 1993, 86: 293–9.

    CAS  PubMed  Google Scholar 

  6. Rajasoorya C, Holdaway IM, Wrightson P, Scott DJ, Ibbertson HK. Determinants of clinical outcome and survival in acromegaly. Clin Endocrinol (Oxf) 1994, 41: 95–102.

    Article  CAS  Google Scholar 

  7. Swearingen B, Barker FG 2nd, Katznelson L, et al. Long-term mortality after transsphenoidal surgery and adjunctive therapy for acromegaly. J Clin Endocrinol Metab 1998, 83: 3419–26.

    CAS  PubMed  Google Scholar 

  8. Biermasz NR, Dekker FW, Pereira AM, et al. Determinants of survival in treated acromegaly in a single center: predictive value of serial insulin-like growth factor I measurements. J Clin Endocrinol Metab 2004, 89: 2789–96.

    Article  CAS  PubMed  Google Scholar 

  9. Holdaway IM, Rajasoorya RC, Gamble GD. Factors influencing mortality in acromegaly. J Clin Endocrinol Metab 2004, 89: 667–74.

    Article  CAS  PubMed  Google Scholar 

  10. Kauppinen-Mäkelin R, Sane T, Reunanen A, et al. A nationwide survey of mortality in acromegaly. J Clin Endocrinol Metab 2005, 90: 4081–6.

    Article  PubMed  CAS  Google Scholar 

  11. Freda PU, Katznelson L, van der Lely AJ, Reyes CM, Zhao S, Rabinowitz D. Long-acting somatostatin analog therapy of acromegaly: a meta-analysis. J Clin Endocrinol Metab 2005, 90: 4465–73.

    Article  CAS  PubMed  Google Scholar 

  12. Cozzi R, Attanasio R. Octreotide for acromegaly. Expert Rev Endocrinol Metab 2007, 2: 129–45.

    Article  CAS  Google Scholar 

  13. Redfern JS, Fortuner WJ 2nd. Octreotide-associated biliary tract dysfunction and gallstone formation: pathophysiology and management. Am J Gastroenterol 1995, 90: 1042–52.

    CAS  PubMed  Google Scholar 

  14. Peng WK, Sheikh Z, Paterson-Brown S, Nixon SJ. Role of liver function tests in predicting common bile duct stones in acute calculous cholecystitis. Br J Surg 2005, 92: 1241–7.

    Article  CAS  PubMed  Google Scholar 

  15. Acalovschi M. Cholesterol gallstones: from epidemiology to prevention. Postgrad Med J 2001, 77: 221–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. Mittal B, Mittal RD. Genetics of gallstone disease. J Postgrad Med 2002, 48: 149–52.

    CAS  PubMed  Google Scholar 

  17. Tseng M, Everhart JE, Sandler RS. Dietary intake and gallbladder disease: a review. Public Health Nutrition 1999, 2: 161–72.

    Article  CAS  PubMed  Google Scholar 

  18. Dowling RH. Review: pathogenesis of gallstones. Aliment Pharmacol Ther 2000, 14 (Suppl 2): 39–47.

    Article  PubMed  Google Scholar 

  19. Cuevas A, Miquel JF, Reyes MS, Zanlungo S, Nervi F. Diet as a risk factor for cholesterol gallstone disease. J Amer Coll Nutr 2004, 23: 187–96.

    Article  Google Scholar 

  20. Hofmann AF. Increased deoxycholic acid absorption and gall stones in acromegalic patients treated with octreotide: more evidence for a connection between slow transit constipation and gall stones. Gut 2005, 54: 575–8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  21. Marcus SN, Heaton KW. Deoxycholic acid and the pathogenesis of gallstones. Gut 1988, 29: 522–33.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Marcus SN, Heaton KW. Intestinal transit, deoxycholic acid, and the cholesterol saturation of bile: three inter-related factors. Gut 1986, 27: 550–8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Veysey MJ, Thomas LA, Mallet AI, et al. Prolonged large bowel transit increases serum deoxycholic acid: a risk factor for octreotide induced gallstones. Gut 1999, 44: 675–81.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  24. Lembcke B, Creutzfeldt W, Schleser S, Ebert R, Shaw C, Koop I. Effect of somatostatin analogue sandostatin (SMS 201–995) on gastro-intestinal, pancreatic, and biliary function, and hormone release in normal men. Digestion 1987, 36: 108–24.

    Article  CAS  PubMed  Google Scholar 

  25. Fisher RS, Rock E, Levin G, Malmud L. Effect of somatostatin on gallbladder emptying. Gastroenterology 1987, 92: 885–90.

    CAS  PubMed  Google Scholar 

  26. Moschetta A, Stolk MF, Rehfeld JF, et al. Severe impairment of postprandial cholecystokinin release and gall-bladder emptying and high risk of gallstone formation in acromegalic patients during Sandostatin LAR. Aliment Pharmacol Ther 2001, 15: 181–5.

    Article  CAS  PubMed  Google Scholar 

  27. John KD, Ballantyne GH, Modlin IM. Octreotide acetate inhibits motility in the rabbit distal colon. Eur Surg Res 1997, 29: 311–8.

    Article  CAS  PubMed  Google Scholar 

  28. Stacpoole PW, Kasselberg AG, Berelowitz M, Chey WY. Somatostatinoma syndrome: does a clinical entity exist? Acta Endocrinol 1983, 102: 80–7.

    CAS  PubMed  Google Scholar 

  29. McKnight JA, McCance DR, Crothers JG, Atkinson AB. Changes in glucose tolerance and development of gall stones during high dose treatment with octreotide for acromegaly. BMJ 1989, 299: 604–5.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  30. Dowling RH, Hussaini SH, Murphy GM, Besser GM, Wass JA. Gallstones during octreotide therapy. Metabolism 1992, 41 (Suppl 2): 22–33.

    Article  CAS  PubMed  Google Scholar 

  31. Hussaini SH, Murphy GM, Kennedy C, Besser GM, Wass JA, Dowling RH. The role of bile composition and physical chemistry in the pathogenesis of octreotide-associated gallbladder stones. Gastroenterology 1994, 107: 1503–13.

    Article  CAS  PubMed  Google Scholar 

  32. Plöckinger U, Dienemann D, Quabbe HJ. Gastrointestinal side-effects of octreotide during long-term treatment with acromegaly. J Clin Endocrinol Metab 1990, 71: 1658–62.

    Article  PubMed  Google Scholar 

  33. Catnach SM, Anderson JV, Fairclough PD, et al. Effect of octreotide on gallstone prevalence and gallbladder motility in acromegaly. Gut 1993, 34: 270–3.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Montini M, Gianola D, Pagani MD, et al. Cholelithiasis and acromegaly: therapeutic strategies. Clin Endocrinol 1994, 40: 401–6.

    Article  CAS  Google Scholar 

  35. Thomas LA, Veysey MJ, Murphy GM, et al. Octreotide induced prolongation of colonic transit increases faecal anaerobic bacteria, bile acid metabolising enzymes, and serum deoxycholic acid in patients with acromegaly. Gut 2005, 54: 630–5.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  36. Erlinger S, Chanson P, Dumont M, et al. Effects of octreotide on biliary lipid composition and occurrence of cholesterol crystals in patients with acromegaly. A prospective study. Dig Dis Sci 1994, 39: 2384–8.

    Article  CAS  PubMed  Google Scholar 

  37. Olivecrona H, Ericsson S, Angelin B. Growth hormone treatment does not alter biliary lipid metabolism in healthy adult man. J Clin Endocrinol Metab 1995, 80: 1113–7.

    CAS  PubMed  Google Scholar 

  38. Heubi JE, Burstein S, Sperling MA, Gregg D, Subbiah MT, Matthews DE. The role of human growth hormone in the regulation of cholesterol and bile acid metabolism. J Clin Endocrinol Metab 1983, 57: 885–91.

    Article  CAS  PubMed  Google Scholar 

  39. Turner HE, Lindsell DRM, Vadivale A, Thillainayagam AV, Wass JAH. Differing effects on gallbladder motility of lanreotide SR and octreotide LAR for treatment of acromegaly. Eur J Endocrinol 1999, 141: 590–4.

    Article  CAS  PubMed  Google Scholar 

  40. Hussaini SH, Pereira SP, Veysey MJ, et al. Roles of gall bladder emptying and intestinal transit in the pathogenesis of octreotide-induced gall bladder stones. Gut 1996, 38: 775–83.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  41. Thomas LA, Veysey MJ, Bathgate T, et al. Mechanism for the transit-induced increase in colonic deoxycholic acid formation in cholesterol cholelithiasis. Gastroenterology 2000, 119: 806–15.

    Article  CAS  PubMed  Google Scholar 

  42. Lewis SJ, Heaton KW. Increasing butyrate concentration in the distal colon by accelerating intestinal transit. Gut 1997, 41: 245–51.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  43. Hussaini SH, Pereira SP, Murphy GM, Dowling RH. Deoxycholic acid influences cholesterol solubilization and microcrystal nucleation time in gallbladder bile. Hepatology 1995, 22: 1735–44.

    CAS  PubMed  Google Scholar 

  44. Lamberts SWJ, van der Lely AJ, de Herder WW, Hofland LJ. Octreotide. N Engl J Med 1996, 334: 246–54.

    Article  CAS  PubMed  Google Scholar 

  45. Stolk%MFJ, van Erpecum KJ, Koppeschaar HPF, et al. Postprandial gall bladder motility and hormone release during intermittent and continuous octreotide therapy in acromegaly. Gut 1993, 34: 808–13.

    Article  Google Scholar 

  46. Tauber JP, Poncet MF, Harris AG, et al. The impact of continuous subcutaneous infusion of octreotide on gallstone formation in acromegalic patients. J Clin Endocrinol Metab 1995, 80: 3262–6.

    CAS  PubMed  Google Scholar 

  47. Chanson P, Leselbaum A, Blumberg J, Schaison G. Efficacy and tolerability of the long-acting somatostatin analog lanreotide in acromegaly. A 12-month multicenter study of 58 acromegalic patients. French Multicenter Study Group on Lanreotide in Acromegaly. Pituitary 2000, 2: 269–76.

    Article  CAS  PubMed  Google Scholar 

  48. Lancranjan I, Atkinson AB. Results of a European multicentre study with Sandostatin LAR in acromegaly patients. Sandostatin LAR Group. Pituitary 1999, 1: 105–14.

    Article  CAS  PubMed  Google Scholar 

  49. Avila NA, Shawker TH, Roach P, Bradford MH, Skarulis MC, Eastman R. Sonography of gallbladder abnormalities in acromegaly patients following octreotide and ursodiol therapy: incidence and time course. J Clin Ultrasound 1998, 26: 289–94.

    Article  CAS  PubMed  Google Scholar 

  50. Shi YF, Zhu XF, Harris AG, Zhang JX, Deng JY. Restoration of gallbladder contractility after withdrawal of long-term octreotide therapy in acromegalic patients. Acta Endocrinol (Copenh) 1993, 129: 207–12.

    CAS  Google Scholar 

  51. Sadoul JL, Benchimol D, Thyss A, Freychet P. Acute pancreatitis following octreotide withdrawal. Am J Med 1991, 90: 763–4.

    Article  CAS  PubMed  Google Scholar 

  52. Rhodes M, James RA, Bird M, Clayton B, Kendall-Taylor P, Lennard TW. Gallbladder function in acromegalic patients taking long-term octreotide: evidence of rebound hypermotility on cessation of treatment. Scand J Gastroenterol 1992, 27: 115–8.

    Article  CAS  PubMed  Google Scholar 

  53. Paisley AN, Roberts ME, Trainer PJ. Withdrawal of somatostatin analogue therapy in patients with acromegaly is associated with an increased risk of acute biliary problems. Clin Endocrinol 2007, 66: 723–6.

    Article  CAS  Google Scholar 

  54. Attili AF, De Santis A, Capri R, Repice AM, Maselli S. The natural history of gallstones: the GREPCO experience. The GREPCO Group. Hepatology 1995, 21: 655–60.

    Article  CAS  PubMed  Google Scholar 

  55. Fromm H, Malavolti M. Bile acid dissolution therapy of gallbladder stones. Baillieres Clin Gastroenterol 1992, 6: 689–95.

    Article  CAS  PubMed  Google Scholar 

  56. Petroni ML, Jazrawi RP, Pazzi P, et al. Ursodeoxycholic acid alone or with chenodeoxycholic acid for dissolution of cholesterol gallstones: a randomized multicentre trial. The British-Italian Gallstone Study group. Aliment Pharmacol Ther 2001, 15: 123–8.

    Article  CAS  PubMed  Google Scholar 

  57. Hussaini SH, Pereira SP, Murphy GM, et al. Composition of gall bladder stones associated octreotide: response to oral ursodeoxycholic acid. Gut 1995, 36: 126–32.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  58. Paumgartner G, Sauerbruch T. Gallstones: pathogenesis. Lancet 1991, 338: 1117–21.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Endocrinology, Ospedali Riuniti, Bergamo

    R. Attanasio MD, M. Montini, L. Cortesi, M. Albizzi, R. M. Testa & G. Pagani

  2. Pituitary Unit, Istituto Ortopedico Galeazzi IRCCS, Milan

    R. Attanasio MD

  3. Endocrinology and Metabolism, University of Turin, Turin

    A. Mainolfi, S. Grottoli, D. De Giorgio & E. Ghigo

  4. Endocrinology and Metabolism, Azienda Ospedaliero-Universitaria “S. Maria della Misericordia”, Udine

    F. Grimaldi

  5. Endocrinology, Ospedale Niguarda, Italy

    R. Cozzi & P. Loli

  6. Endocrinology, Ospedale S. Luca Istituto Auxologico Italiano IRCCS, Milan

    C. Carzaniga, L. Fatti & F. Cavagnini

  7. Endocrinology, University of Padua, Padua, Italy

    R. M. Testa & C. Scaroni

Authors
  1. R. Attanasio MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A. Mainolfi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. F. Grimaldi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. R. Cozzi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M. Montini
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. C. Carzaniga
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. S. Grottoli
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. L. Cortesi
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. M. Albizzi
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. R. M. Testa
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. L. Fatti
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. D. De Giorgio
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. C. Scaroni
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. F. Cavagnini
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. P. Loli
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. G. Pagani
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. E. Ghigo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to R. Attanasio MD.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Attanasio, R., Mainolfi, A., Grimaldi, F. et al. Somatostatin analogs and gallstones: A retrospective survey on a large series of acromegalic patients. J Endocrinol Invest 31, 704–710 (2008). https://doi.org/10.1007/BF03346419

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF03346419

Key-words

Search

Navigation