Somatostatin analogues and their clinical applicationLaparoscopic cholecystectom

Abrahamson, M. J.

Dunn, J. P.

Terblanche, J.

English

AJOL - African Journals Online

SAMJ VOL 78 15 SEPT 1990 295Van die Redaksie/EditorialSomatostatin analogues and theirclinical applicationSomatostatin was detected accidentally in 1968 byKrulich during investigations into the distribution ofgrowth hormone-releasing factors in rat hypothalami. lConcurrently, Hellman and Lemmark2 discovered asubstance in extracts of pigeon pancreatic islets thatinhibited insulin release. These separate observationsproved to be related several years later, with the chemicalidentification of this potent inhibitor of hormone release.3Somatostatin, so called because of its original descriptionas a somatotrophin release-inhibiting factor (SRIF), issynthesised in many tissues, including the central nervoussystem, hypothalamus, peripheral nervous system, pan-creatic islet cells (D cells) and epithelial, glandular andneuronal cells of the gastro-intestinal tract. In thesetissues a single gene encodes a large peptide, pre-pro-somatostatin, which is cleaved to form the large precursorprosomatostatin, which in turn is subsequently processedto two much smaller biologically active forms, somato-statin-14 and somatostatin-28. When secreted, somato-statin enters the circulation and acts at a distant site inan endocrine fashion, or it may act locally, exhibitingparacrine and autocrine functions. Infusion of the peptidein man causes numerous effects, including inhibition ofendocrine secretions (growth hormone, thyroid-stimu-lating hormone, insulin, glucagon and all the gut hor-mones, e.g. gastrin, vaso-active intestinal polypeptideand cholecystokinin) and exocrine secretions (gastricacid, pancreatic enzymes and pancreatic bicarbonate).The hormone has also been shown to reduce splanchnicblood flow, intestinal absorption, gastric emptying andgallbladder contraction.4,5The native peptide's obvious pharmacological potentialhas been restricted by a number of factors, including (Dits multiple simultaneous effects on different physiologi-cal functions, especially the inhibitory effect on insulinsecretion; (il) its short duration of action due to rapidclearance of the hormone from plasma; (iil) the need toadminister the peptide intravenously; and (iv). therebound hypersecretion of hormones (tumorous andnon'-tumorous) that occurs after infusion of SRIF.6A major advance in overcoming these obstacles wasachieved with the development of a cyclic 8 amino-acidanalogue (SMS 201-99:;), now marketed as octreotide(Sandostatin).7 This analogue is 45 times more active inits growth hormone release-inhibitory effects, 11 timesmore active in its glucagon release-inhibitory effects andonly 1,3 times more active than the natural peptide in itsinsulin release-inhibitory effects. In addition, it has along circulatory half-life of 90 - 115 minutes, causing aprolonged inhibitory effect in target organs, it can beadministered subcutaneously (even orally with higherdoses), and it does not cause rebound hypersecretion ofhormones following administration.The analogue has now been used in the treatment of anumber of endocrine and gastro-enterological disorders.In acromegaly octreotide causes persistent reduction ofgrowth hormone concentration by more than 50% in86% of patients, with normalisation of somatomedin-Cconcentration in 36%.8 In addition, excessive sweating,headache, paraesthesiae and tiredness markedly decreasewithin the first weeks of therapy, while longer periods oftreatment lead to reduced soft-tissue swelling andimprovement of facial coarsening. Improved glycaemicand blood pressure control has been reported in somepatients with insulin-resistant diabetes and severe hyper-tension.9 Slight shrinkage of tumours has also beendocumented in up to 50% of patients treated.8Octreotide has been used with variable success totreat patients with neuro-endocrine tumours of the gut.In the carcinoid syndrome, up to 90% of patients reportedsignificant improvement of symptoms (flushing anddiarrhoea) during therapy.lo The analogue effectivelycontrols the diarrhoea and severe metabolic abnormalitiesassociated with tumours secreting vaso-active intestinalpolypeptide (VIPomas) in over 80% of cases.11 Clinicaland!or biochemical responses to therapy have also beenreported in some patients with glucagonomas, insulino-mas, and gastrinomas. 12 In persistent hyperinsulinaemichypoglycaemia of infancy (nesidioblastosis), octreotideeffectively controls hypoglycaemia without the need forparenteral glucose in up to 90% of cases reported. 13Octreotide has been used to treat a variety of non-malignant gastro-intestinal disorders. Up to 80% ofpatients with small-bowel fistula respond to therapy,with reduction in output and closure of the fistulawithin 1 - 2 weeks. 14,15 Similarly, reduced.'Outpnt fromand subsequent closure of pancreatic fistula have beenreported in 85 - 100% of patients within 6 days oftherapy.16 Preliminary reports of successful treatment ofpancreatic ascites and pancreatic pseudocysts are alsoencouraging. I?Somatostatin's effects on splanchnic blood flow haveled to its use in peptic ulcer and variceal haemorrhage,with small studies reporting initial control of bleeding inapproximately 80% of cases. I? Treatment with the drugin other conditions, including biliary fistula 18 anddumping syndrome,19 has been investigated, but its useis not justified at this stage, except where failure torespond to conventional therapy has been documentedor as part of a clinical trial.296 SAMJ VOL 78 15 SEPT 1990Despite its wide-ranging physiological effects, treat-ment with oetreotide causes relatively few side-effects.The abdominal discomfort, loose stools and symptomsof malabsorption sometimes reported during the initialfew weeks of therapy are usually transient. Long-termtherapy has been associated with the development ofgallstones in 10 - 25% of cases. Glucose intolerance hasalso been reported.20 Resistance to treatment has beendocumented in a number of patients with metastaticneuro-endocrine tumours of the gut,2t but no tachyphy-laxis has been observed in acromegalies treated for morethan 3 years.22Thus the clinical introduction of this new long-actingSRIF analogue adds a new dimension to the medicaltherapy of a variety of conditions. While short-termtreatment of a number of the non-malignant gastro-intestinal disorders, e.g. fistula, is relatively cheap andcost-effective, long-term therapy for conditions such asacromegaly is expensive - the estimated cost of treat-ment with 300 J-Lg daily is R45000 per annum. In anattempt to avoid unnecessary and unjustified use of thisdrug, the Society for Endocrinology, Metabolism andDiabetes of Southern Africa (SEMDSA) and the SouthAfrican Gastroenterological Society (SAGES) have esta-blished somatostatin subcommittees whose function isto approve and monitor long-term use of these SRIFanalogues. Each subcommittee comprises representativesfrom the major teaching hospitals in South Africa.Guidelines for the use of SRIF analogues, together withdosage protocols, have been drawn up by these commit-tees and are published in this issue of the SAMJ (p.379). Used appropriately, oetreotide should benefit manypatients suffering from a wide range of mostly rare oruncommon conditions.M. J. AbrahamsonJ. P. DunnI. Krulich I. Dhariwal APS, McCann SM. Stimulatory and inhibitory effectS- of purified hypothalamic extracts on growth hormone release from ratpituitary in viero. Endocrinology 1968; 83: 783-790.2. Hcllman B, Lernmark A. Inhibition of the in viero secretion of insulin by anextract of pancreatic alpha-l cells. Endocrinology 1969; 84: 1484-1487.3. Brazeau P, Vale W, Burgus R et al. Hypothalamic peptide that inhibits thesecretion of immunoreactive pituitary growth hormone. Science 1973; 179:77-79.4. Reichlin S. Somatostatin: I. N EnglJ Med 1983; 309: 1495-1501.5. Reichlin S. Somatostatin: 11. N EnglJ Med 1983; 309: 1556-1563.6. Besset GM, Morrimer CH, McNeilly AS et al. Long-term infusion ofgrowth hormone release inhibiting hormone in acromegaly: effects on pitui-tary and pancreatic hormones. Br MedJ .1974; 4: 622-627.7. Bauer W, Briner U, Doepfner W et al. SMS 201-995: a very potent andselective octapeptide analogue of somatostatin with prolonged action. LifeSciences 1982; 31: 1133-1140.8. Harris AG, Prestele H, Herold K, Boerlin V. Longterm efficacy of Sando-Statin (SMS 201-995, octreotide) in 178 acromegalic patients: results fromthe International Multicentre Acromegaly Study Group. In: Lambens SWJ,ed. Sandostatin in the Treatment of Acromegaly. New York: Springer-Veriag,1988: 117-125.9. Abrahamson MJ. Death from diabetic ketoacidosis following cessation oftreatment with octreotide in acromegaly (Leners). Lancet 1990; 336: 318-319.10. Kvols LK, Moenel CG, O'Connell MJ, Schun AJ, Rubin J, Hahn RG.Treatment of the malignant carcinoid syndrome: evaluation of a long-actingsomatostatin analogue. N EnglJ Med 1986; 315: 663-666.11. Krejs GJ. VIPoma syndrome. AmJ Med 1987; 82 (suppl 5B): 37-48.12. Anderson JV, Bloom SR. Neuroendocrine tumours of the gut: long termtherapy with the somatostatin analogue SMS 201-995. SeandJ Gastroenterol1986; 21 (suppl119): 115-128.13. Glaser B, Landau H, Smilovici A, Nesher R. Persistent hyperinsulinaemichypoglycaemia of infancy: 10ngterm treatment with the somatostatin analogue,Sandostatin. Clin Endocrinol 1989; 31: 71-80.14. Nubiola-Calonje P, Badia JM, Sancho J, Gil MJ, Segura M, Sitges-Serra A.Blind evaluation of the effect of octreotide (SMS 201-995), a somatostatinanalogue, on small-bowel fistula output. Lancet 1987; 2: 672-674.15. Ntlbiola P, Badia JM, Martinez-Rodemas F et al. Treatment of 27 POSt-operative enterocutaneous fistulas with the long half-life somatostatinanalogue SMS 201-995. Ann Surg 1989; 210: 56-58.16. Pederzoli P, Bussi C, Falconi M et al. Conservative treatment of externalpancreatic fistulas with parenteral nutrition alone or in combination withcontinuous intravenous infusion of somatostatin, glucagon or calcitonin.Surg Gyneeol Obuet 1986; 163: 428-432. -17. Mulvihill S, Pappas TN, Passaro E, Debas HT. The use.of somatostatin andits analogues in the treatment of surgical disorders. Surgery 1986; 100:467-475.18. Desport J-C, Sardin B, Bertrand H, Peze P, Ferre F. Fistules biliares:possible interet de la somarostatine. Presre Medieale 1986; 15: 2257.19. Tulassy Z, Tulassy T, Gupta R, Ciemy G. Long-acting somatostatinanalogue in dumping syndrome. Brj Surg 1989; 76: 1294-1295.20. Batrershill PE, Clissold SP. Ocrreotide: a review of its pharmacodynamicand pharmacokinetic properties, and therapeutic potential in conditionsassociated with excessive peptide secretion. Drugs 1989; 38: 658-702.21. LambertS SWJ, Pieters GFFM, Metselaar HJ, Ong GL, Tan HS, ReubiJe. Development of resistance to a long-acting somatostatin analogue duringtreatment of 2 patients with metastatic endocrine pancreatic tumours. ActaEndocrinol 1988; 119: 561-566.22. Lamberts SWJ. The role of somatostatin in the regulation of anteriorpituitary hormone secretion and the use of its analogs in the treatment ofhuman pituitary tumors. Endocr Rev 1988; 9: 417-436.Laparoscopic cholecystectomyThe 'gold standard' for treating patients with stones inthe gallbladder is standard operative cholecystectomy.Only patients with symptomatic gallstones should beconsidered for cholecystectomy. Neither patients with'silent' gallstones nor patients with so-called 'biliarydyspepsia', who happen to have stones in the gallbladder,should be subjected to cholecystectomy. Some wouldargue that young patients with small gallstones, or youngotherwise fit diabetic patients, should be considered forcholecystectomy in the presence of 'silent' stones. l I donot subscribe to this view.Laparoscopic cholecystectomy is a newly describedprocedure whereby the gallbladder can be removedwithout open laparotomy using a modem operatinglaparoscope with newly designed instruments insertedthrough portals in the abdominal wall. The operationwas first performed in France in 1987. The patient isanaesthetised and has a pneumoperitoneum inducedwith carbon dioxide, and is then placed in the foot-down position to facilitate exposure. Laparoscopiccholecystectomy has captured the imagination of generalsurgeons and the lay public world-wide because of thereported advantages of removing the gallbladder with.outthe necessity for an open operation. This could put.pressure on surgeons to perform the procedure withoutadequate training or without the requisite instrumenta-tion, which could have disastrous consequences andthreaten a valuable operative procedure, particularly ifmorbidity - including damage to the common bile duct- or mortality were to occur.The possibility of performing major surgery via alaparoscope is appealing. Gynaecologists have used thelaparoscope for pelvic surgery for some years. Generalsurgeons have been slow to follow. It is interesting thata cholecystectomy performed through a laparoscope isassociated with less metabolic response to trauma, pro-bably because the trauma of laparotomy access isabolished, and it is usually not associated with thetransient ileus that frequently accompanies standardoperative cholecystectomy. As a result, the hospital stayis shortened to I or 2 days, which reduces the overallcosts. In addition, most patients can return to work afterI week rather than the usual 6 weeks. The procedurealso has the advantage of avoiding a laparotomy scar.On the other hand, laparoscopic cholecystectomy is afull operative procedure with all the attendant dangersand takes longer to perform than standard operativecholecystectomy. The general contraindications are thesame as for open cholecystectomy or other majoroperative procedures. Specific contraindications includemarked intra-abdominal adhesions or a thickened in-flamed gallbladder wall, since these increase the hazardsto the patient. It is also contraindicated in portal hyper-tension. All patients undergoing laparoscopic chole-cystectomy should give consent for full operative chole-cystectomy in case this becomes necessary. Estimatesare that between 5% and 20% of patients are unsuitablefor laparoscopic cholecystectomy. The procedure is bestperformed using modem television camera attachmentsfor the laparoscope so that the surgeon and operatingteam are able to see the procedure on a television screen.This has the disadvantage of a two-dimensional pictureof a three:-dimensional operative procedure, which canbe hazardous until expertise has been achieved. This,together with the limited access, increases the danger ofdamaging the common bile duct and of initiating majorhaemorrhage.The problems and ethical dilemmas surroundinglaparoscopic cholecystectomy were the subject of a majorSAMJ VOL. 78 15 SEPT 1990 297symposium at the combined Second World Congress ofEndoscopic Surgery and the Annual Meeting of theSociety of American Gastrointestinal EndoscopicSurgeons held in Atlanta, Georgia, USA, in March1990. The full proceedings of this symposium have beenpublished.2 Questions of particular importance raised atthe symposium were: (i) who should undertake laparo-scopic cholecystectomy; and (ii) what training wasrequired? The conclusion was that only fully trainedgeneral surgeons with expertise in biliary surgery shouldperform the procedure. Such surgeons require laparo-scopic training, if they have not had this previously, andalso need to learn to use instruments working from atelevision screen. At overseas institutions there arecourses with workshops and seminars to assist generalsurgeons with biliary surgery training to acquire thenecessary skills for laparoscopic work using the newinstrumentation, including training in the animallabora-tory. Similar training facilities will be essential in thiscountry if we are to avoid the danger to patients in whatis otherwise likely to be an important milestone in thedevelopment of abdominal surgery. It is totally inappro-priate for anyone other than a fully trained surgeon withexpertise in biliary surgery, who also has laparoscopictraining, to undertake laparoscopic cholecystectomy.Laparoscopic training alone is inadequate, and if personswith laparoscopic expertise, but without training in biliarysurgery, undertake laparoscopic cholecystectomy, theywill jeopardise the procedure and render themselvesliable to justifiable litigation.J. Terblanchel. Gibney EJ. Asymptomatic gallstones. Br J Surg 1990; 77: 368-372.2. Terblanche J, Cusehieri A, Berei G, Reddiek E, Perissat J. Gallstones in thegallbladder, in or out and how? A panel presentation. Surg Endosc 1990; 4:(in press).

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