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12. Esler MD, Goulston KJ. Levels of anxiety in colonic disorders. N Engl J Med 1973; 288: 16-20. 13. Snape WJ, Carlson GJ, Matarazzo SA, Cohen S. Evidence that abnormal myoelectrical activity produces colonic motor dysfunction in the irritable bowel syndrome. Gastroenterology 1977; 72: 383-87. 14. Latimer P, Sarna S, Campbell D, et al. Colonic motor and myoelectrical activity: a comparative study of normal subjects, psychoneurotic patients and patients with irritable bowel syndrome. Gastroenterology

1981; 80: 893-901. Snape WJ, Matarazzo SA, Cohen S. Effect of eating and gastrointestinal hormones on human colonic myoelectrical and motor activity. Gastroenterology 1978; 75: 373-79. 16. Trotman IF, Misiewicz JJ. Sigmoid motility in diverticular disease and the irritable bowel syndrome. Gut 1988; 29: 218-22. 17. Thompson WG. The irritable gut: functional disorders of the alimentary canal. Baltimore: University Park Press, 1979. 18. Manning AP, Thompson WG, Heaton KW, Morns AF. Towards positive diagnosis of the irritable bowel. BMJ 1978; 2: 653-54. 19. Kruis W, Thieme CH, Weinzerl M, et al. A diagnostic score for the irritable bowel syndrome: its value in the exclusion of organic disease. Gastroenterology 1984; 87: 1-7. 20. Whitehead WE, Bosmajian L, Zonderman AB, Costa BJ, Schuster MM. 15.

Symptoms

of

psychologic distress associated with irritable bowel syndrome: comparison of community and medical clinic samples. Gastroenterology 1988; 95: 709-14. 21. Thompson WG, Dotevall G, Drossman DA, Heaton KW. Irritable bowel syndrome: guidelines for the diagnosis. Gastroenterol Int 1989; 2: 92-95. 22. Kumar D, Pfeffer J, Wingate DL. Role of psychological factors in the irritable bowel syndrome. Digestion 1990; 45: 80-87. 23. Kellow JE, Langeluddecke PM, Eckersley GM, Jones MP, Tennant CC. Effects of acute psychological stress on small-intestinal motility in health and the irritable bowel syndrome. Scand J Gastroenterol 1992; 27: 53-58.

Talley NJ, Phillips SF, Bruce B, Twomey CK, Zinsmeister AR, Melton LJ. Relation among personality and symptoms in nonulcer dyspepsia and the irritable bowel syndrome. Gastroenterology 1990; 99: 327-33. 25. Smith RC, Greenbaum DS, Vancouver JB, et al. Psychosocial factors are associated with health care seeking rather than diagnosis in irritable bowel syndrome. Gastroenterology 1990; 98: 293-301. 26. Kumar D, Wingate DL. The irritable bowel syndrome: a paroxysmal motor disorder. Lancet 1985; ii: 973-77. 27. Trotman IF, Price CC. Bloated irritable bowel defined by dynamic 99Tc brain scan. Lancet 1986; ii: 364-66. 28. Kellow JE, Gill RC, Wingate DL. Prolonged ambulant recordings of small bowel motility demonstrate abnormalities in the irritable bowel syndrome. Gastroenterology 1990; 98: 1208-18. 29. Ritchie J. Pain from distension of the pelvic colon by inflating a balloon in the irritable bowel syndrome. Gut 1983; 14: 125-32. 30. Kendall GPN, Thompson DG, Day SJ, Lennard-Jones JE. Inter and intraindividual variation in pressure-volume relations of the rectum in normal subjects and patients with the irritable bowel syndrome. Gut 1990; 31: 1062-68. 31. Whitehead WE, Holtkotter B, Enck P, et al. Tolerance for rectosigmoid distension in irritable bowel syndrome. Gastroenterology 1990; 98: 24.

1187-92. 32. McAllister C, McGrath

F, Fielding JF. Altered skin temperature and electromyographic activity in the irritable bowel syndrome. Biomed

Pharmacother 1990; 44: 399-401. 33. Dinan TG, Barry S, Alchion S, Chua A, Keeling PWN. Assessment of central noradrenergic functioning in irritable bowel syndrome using a neuroendocrine challenge test. J Psychosomatic Res 1990; 34: 575-80. 34. Talley NJ, Zinsmeister AR, Van Dyke C, Melton LJ. Epidemiology of colonic symptoms and the irritable bowel syndrome. Gastroenterology 1991; 101: 927-34. 35. Jones R, Lydeard S. Irritable bowel syndrome in the general population. BMJ 1992; 304: 87-90.

Clinical approaches to irritable bowel syndrome

Irritable bowel syndrome (IBS) is among the most of gastrointestinal disorders, affecting 15-20% of the population in western countries1 and accounting for 25-50% of referrals to gastroenterologists.2 Its morbidity is responsible for considerable absenteeism from work (second only to the common cold), and repeated visits to physicians lead to patient anxiety, substantial costs to the health-care system, and occasionally to unnecessary abdominal

done during subsequent visits. Therapeutic trials can prove helpful in confirming a provisional diagnosis of IBS, thereby avoiding costly and unnecessary further testing. Confident and clear explanation of the chronic nature of IBS and its implications will help allay patient misconceptions and fears and will provide reassurance during future exacerbations of symptoms.

surgery.33

Symptom criteria A positive diagnosis is critical to successful management

common

Diagnostic strategy After

preliminary diagnosis of IBS has been made, investigations are necessary only to convince both the patient and the physician that other disorders are not being missed. Early performance of a limited number of tests can prevent the erosion of patient confidence and the suspicion of diagnostic uncertainty that may arise if investigations are a

and relies on symptom patterns rather than exhaustive exclusion of other disorders. The criteria of Manning and colleagues-relief of abdominal pain with defaecation, looser or more frequent bowel movements with pain onset, distension, passage of mucus, and sensation of incomplete evacuation4-have been validated and are specific although not highly sensitive.5 An international working panel has further defined the symptom criteria for IBS (table 1).6

History Effective history taking is the key to the diagnosis of IBS. Symptoms typically have a gradual onset in late adolescence or early adulthood and often follow a consistent pattern throughout the patient’s life. Abrupt onset of symptoms late on in life, or a change in a previously characteristic symptom pattern suggests a disorder other than IBS. Upper ADDRESS: Department of Medicine, University of Virginia, Health Sciences Center, Charlottesville, Virginia 22908, USA (F. H. Weber, MD, Prof R W. McCallum, MD). Correspondence to Prof R. W. McCallum.

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abdominal symptoms, though frequently described, are not diagnostically helpful and the emerging notions of "irritable oesophagus", non-ulcer dyspepsia, and functional biliary pain have narrowed the sites of classic IBS symptoms to the small intestine and colon. Extraintestinal symptoms suggestive of vasomotor instability, mood or behavioural disturbances, urinary frequency, dysmenorrhea, and dyspareunia7 are frequently present but are not helpful diagnostically. Fever, gastrointestinal bleeding, nocturnal symptoms, faecal incontinence, weight loss, or a progressively deteriorating course are suggestive of other

diagnoses. dietary history together with a food diary will secondary to ingestion of lactose, fructose, sorbitol, caffeine, alcohol, or gas-producing foods. Psychosocial factors and stressors, though not of value in the diagnostic processinfluence the decision to seek health care and can be important in planning therapy. Past physical and sexual abuse has been strongly associated with functional bowel disease in women,9 although the role of such events in symptom expression remains unclear. A detailed

uncover bowel disturbance

Abdominal Pain- The abdominal pain of IBS is variable in location and intensity but its character is usually consistent in each patient. It is typically intermittent but can be continuous with superimposed crampy symptoms.7 Pain may develop anywhere in the abdomen, even in the epigastrium, but it is usually in the right or left lower quadrants. Trigger areas may exist from oesophagus to colon and balloon distension at one trigger point can result in pain in several locations. Pain often gets worse 60-90 min after meals, and has been temporally correlated with characteristic ileal10 and sigmoid" contraction patterns. Rectal or colonic balloon distension reproduces the abdominal pain in 75 % of patients. Patients with IBS have a lower pain threshold to gastrointestinal tract distension than controls, but this does not necessarily represent a generalised decrease in pain tolerance since their tolerance to other painful stimuli is at least equal to that of healthy controls. Disturbed defaecation-IBS characteristically involves a disturbance in stool frequency, form (hard or loose/watery), or passage (straining, urgency, feeling of incomplete evacuation). Patients may note a predominance of diarrhoea, constipation, or alternating diarrhoea and constipation. Constipation-predominant IBS often dates to adolescence and the typical narrow hard stools may relate to excessive colonic segmental contractions12 leading to stool dehydration. Loose stools in IBS are frequently small volume and frequent but of normal 24 h volume. Early morning, postprandial, or stress-related urgency is commonly encountered and is followed by feelings of incomplete evacuation requiring more attempts to pass bowel movements. A defaecatory discharge of mucus is reported by up to 50% of IBS patients; its pathogenesis remains obscure. Abdominal distension-Complaints of abdominal distension are common in IBS; it tends to worsen during the day and improve after sleeping. Measurements of the quantity and distribution of abdominal gas reveal no differences between patients and controls, but objective increases in abdominal girth suggest alterations in bowel wall tone.13 Reflux of gas from distal to proximal small bowel is more common in IBS patients than in controls and may partly explain complaints of excessive belching.

Physical examination Examination is generally unremarkable but is essential to exclude other diagnoses and provides the foundation for reassurance. Signs of anxiety, a palpable sigmoid colon, and a tender bowel loop3 are commonly encountered but are non-specific. A thorough gynaecological examination in the female patient is necessary to exclude pelvic disease such as endometriosis. Insufflation of air during sigmoidoscopywill reproduce abdominal pain in 75 % of patients. Any signs of nutritional deficiency or structural abnormality are incompatible with IBS and demand further evaluation. Initial investigations Since IBS is a common yet benign disorder that should be diagnosed positively by history taking, care is necessary to avoid costly and potentially harmful investigations. However, a few initial studies are needed to exclude infectious, metabolic, and structural disorders of the gastrointestinal tract that mimic IBS. Further colonic evaluation may be indicated in those over 40 years of age, those with a family history of colorectal neoplasia, and those with a recent onset of symptoms. Myoelectrical activity has not been helpful to date in distinguishing patients with IBS from normal subjects. Once other disorders have been excluded, reassurance should be provided through explanation of the nature of IBSS and emphasis on the importance of the normal physical initial examination and investigations. Further will investigations vary according to the patient’s predominant symptoms, adjustment to illness, and response to initial dietary and therapeutic intervention.

Diagnostic and therapeutic subgroups IBS is a frustrating disorder to treat. The heterogeneity of symptoms, the lack of a reliable pathophysiological marker of improvement, and placebo response rates ranging from 20 to 70% have made the assessment of drug efficacy difficult. Klein, in a detailed critique of controlled studies from 1966 through 1988, concluded that no single study offered convincing evidence for any drug regimen in IBS." Specific difficulties with these clinical trials included vague entry criteria, unreliable measures of efficacy, short study lengths, poorly designed crossover formats, poor statistical methods, and inadequate sample sizes. However, the lack of a universally accepted therapeutic agent does not preclude individualised therapy for selected symptoms. Indeed, clinically and therapeutically disparate subgroups of IBS patients are emerging from subgroup analyses of past clinical trials. A rational approach to IBS management begins with education and reassurance about its functional and benign nature, identifies psychosocial factors that led the patient to seek advice, and directs therapy to the predominant symptom complex. Drug treatment should be given only for symptoms that prove refractory to counselling and dietary manipulations. A schematic approach to IBS focusing on symptomatic subgroups is shown in the figure.

Diarrhoea-predominant IBS Since luminal factors (carbohydrates, bile acids, shortchain fatty acids, food allergens) may have a role in the symptomatology of some patients with diarrhoeapredominant IBS, a detailed history is necessary to uncover dietary influences that contribute to symptoms. A one-to-

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Therapy for irritable bowel syndrome. The failure of reassurance, education, dietary changes, and behavioural intervention should lead to a therapeutic trial directed at the main symptom. The treatments listed have theoretical appeal or have shown promise in preliminary studies.

week dietary and symptom diary is often helpful. Particular attention should be paid to lactose, fructose, sorbitol, and caffeine intake. Since lactose intolerance is common, a lactose-tolerance test, a lactose-hydrogen breath test, or a therapeutic trial of a lactose-free diet should be initiated. Elimination diets may identify food sensitivity but remain controversial. 15 Patients who have previously

two

exclusion diets should be re-challenged with the excluded foods and symptoms must be monitored for

adopted

recurrence.

If specific dietary or behavioural factors are not found, effective symptom control may be achieved with loperamide or diphenoxylate. Several studies have found loperamide superior to placebo in this subgroup of IBS patients with regard to improvement in stool frequency, consistency, and/or urgency.16 Since loperamide does not cross the blood-brain barrier, it is preferable to diphenoxylate or other opioids. A trial of cholestyramine may be worthwhile since this drug has proven efficacy in some patients with idiopathic bile acid malabsorption. 17 Soluble dietary fibre may improve diarrhoea through stool water absorption or induction of more normal colonic contractility patterns. Exclusion of endocrinopathy, parasitic infection, malabsorption, laxative misuse, bacterial overgrowth, and structural small intestinal disease may be necessary in patients with intractable symptoms (table II). Accelerated small bowel transit can be identified by a lactulose breath hydrogen tests and accelerated colonic transit may be confirmed by radioscintigraphic methods.19 Radio-opaque markers have not proven reliable for measurement of accelerated colonic transit. Because a lack of clinical response to cholestyramine does not rule out bile acid malabsorption, the 75Se-HCAT test may help to confirm this diagnosis. Antidepressants are reported to improve diarrhoeapredominant IBS, perhaps because of their anticholinergic relax activity.2O Although calcium antagonists smooth there are no results from muscle, gastrointestinal controlled trials to support their use in patients with IBS. Verapamil is the most suitable agent to try, with its specific

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delay of colonic transit in normal volunteers, favourable effects on absorption and secretion, and reports of clinical efficacy. 21,22 A role for disodium cromoglycate has been proposed in view of the high prevalence of allergic manifestations in this subgroup of IBS patients. A preliminary and uncontrolled trial revealed

a

67% overall response rate in those with 27 complete responders had positive

positive skin tests; 24 of skin tests.23

P-blockers have been reported to relieve diarrhoea but placebo-controlled trials in unselected IBS patients have not suggested benefit.24 5-HT3 receptor antagonists have a potent anti-emetic effect and also slow colonic transit in normal subjects. In diarrhoea-predominant IBS, a preliminary study showed relief of loose stools and a slowed colonic transit.25 The lack of an available oral formulation of these agents remains a limitation to their use. Octreotide, through its ability to normalise a disturbed rectal distension threshold in these patients26 and its inhibition of bowel secretion, offers a unique therapeutic approach but placebocontrolled trials are required; high costs and the need for injection will remain limitations to chronic use.

Constipation-predominant IBS Although existing studies suggest that supplemental dietary insoluble or soluble fibre is no better than placebo for global IBS symptoms, patients with a predominance of constipation do benefit from an intensive fibre regimen.27 An initial estimate of total dietary fibre from a brief food diary enables the addition of supplemental fibre up to 30 g total fibre per day. Bloating and flatulence may result if this supplementation is not gradual. A regular uninterrupted daily time set aside for defaecation is encouraged and tap water enemas may be used as an adjunct to fibre supplementation. Osmotic laxatives or stool softeners may be added if fibre alone is insufficient, but stimulant laxatives are discouraged. In patients with intractable symptoms, further investigation must focus on confirming abnormal transit and then on distinguishing pelvic-floor dysfunction from colonic inertia. Delayed transit may be explored by a radio-opaque or radionuclide marker study. Pelvic-floor retraining may be indicated for those with outlet dysfunction; patients with colonic inertia will require prokinetic agents, stimulant laxatives, or total colectomy with ileorectal anastomosis. For other patients with intractable symptoms and without evidence for outlet obstruction or inertia, several newer approaches are evolving. Although prokinetic agents such as metoclopramide and domperidone do not show distal gut activity, cisapride does increase small bowel and colonic transit in normal volunteers as well as those with impaired colonic transit. Passaretti et al reported that in patients with constipation-predominant IBS, the increase in stool frequency with cisapride correlated with an acceleration of whole gut transit.211 Another study found that cisapride was

significantly superior to placebo in improving constipation, relieving abdominal pain, and reducing abdominal distension.29 Cisapride’s mechanism of action is through acetylcholine release at the myenteric plexus level and agonism of 5-HT4 receptor subtypes. Calcium channel blockers may also be beneficial in

patients with constipation-predominant IBS because of their inhibition of excessive postprandial non-propulsive contractions. To prevent systemic side-effects, gut-selective

agents have been developed-eg, pinaverium bromide. Preliminary studies suggest that this drug inhibits sigmoid contractions and accelerates colonic transit,3O and trials are underway to evaluate clinical efficacy. Anticholinergic agents also inhibit the postprandial colonic motor response in patients with IBS. Though inhibition of propulsive contractions in normal subjects may lead to constipation, inhibition of excessive non-propulsive postprandial contractions could theoretically prove beneficial in constipated IB S patients. Indeed, a preliminary study found that cimetropium bromide significantly shortened whole gut transit and improved global symptoms in patients with delayed intestinal transit but had no effect on those with shortened transit. 31 Those with constipation due to impairment of propulsive contractions would not be expected to benefit. Abdominal pain/distension/gas-predominant IBS Once bowel obstruction has been excluded, luminal factors (lactose, fructose, sorbitol) should be investigated. A food diary may be helpful and a dietary trial avoiding gas-producing foods, such as milk, vegetables, fruits, and some carbohydrates, is indicated. For patients with postprandial episodic abdominal pain, a trial of an anticholinergic agent or mebeverine is worthwhile despite the lack of correlation between pain and gut motility. Peppermint oil has smooth muscle relaxant properties but the largest and best designed study to date did not show pain relief.32 Despite theoretical appeal, convincing evidence for clinical efficacy has not been shown for benzodiazepines, simethicone, or activated charcoal in IBS patients. Intestinal pseudo-obstruction should be excluded by barium contrast examination. Occasionally, intestinal manometric studies help to support diagnoses of myopathic or neuropathic pseudo-obstruction or to identify the clustered jejunoileal contractions of IBS. Balloon distension studies and abdominal imaging procedures have reassurance value. Referral to a multidisciplinary pain centre is indicated for disabling symptoms. Antidepressant agents may be helpful through their central analgesic effect, anticholinergic effect, or relief of a coexisting clinical depression; methodological difficulties have plagued existing clinical trials, however.l4 Centrally acting opioids must be avoided, but trimebutine, a peripherally acting agent, improved duration and frequency of abdominal pain when compared with mebeverine in patients with IBS.33 The female predominance among patients with IBS and evidence suggesting exacerbation of IBS symptoms during menses34 have led some workers to manipulate the hormonal environment in those with functional bowel disease. Leuprolide acetate, a gonadotropin-releasing hormone agonist that down-regulates gonadotropin production, improved symptoms in a small study of patients with intractable chronic abdominal pain, nausea, vomiting, and an altered stool habit.35 Drug withdrawal or progesterone challenge resulted in prompt symptomatic recurrence.

Inhibition of postprandial peptide release has theoretical appeal for patients with a predominance of postprandial abdominal pain or bloating. A single case report described a patient with long-standing pain-predominant IBS who became nearly pain free after institution of somatostatin for acromegaly.36 Controlled trials of octreotide in IBS are awaited.

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Serotonin receptors (5-HT3 and/or 5HT4 receptor are involved in the release of substance P, an afferent mediator of the pain reflex in the enteric nervous system. 5-HT3 antagonists, through suppression of visceral afferent function, may offer a novel approach to visceral pain control. Although a preliminary study of ondansetron in

subtypes)

diarrhoea-predominant IBS suggested improvement in the frequency of loose stools and transit time, relief of abdominal pain was variable.25 Exploration of compounds affecting 5-HT receptor physiology remains an area of active research.

Behavioural techniques and psychotherapy The influence of psychosocial factors on IBS symptoms and the limited efficacy of conventional medical therapies for this disorder has led to investigation of the role of behavioural and psychotherapeutic techniques in moderateto-severe IBS. Maintaining a schedule of brief regular appointments in those with a poor adjustment to illness helps to demonstrate care and commitment on the part of the primary care physician. Specific behavioural and psychotherapeutic techniques will often be limited by availability and cost. Relaxation-training, meditation, stress-management procedures, and hypnosis produce sustained in somatic reductions symptoms.37,38 Psychotherapy may be helpful for motivated patients, especially if bowel symptoms are of short duration, abdominal pain is not constant, and there are overt signs of

anxiety or depression.39 Conclusion IBS is a chronic relapsing functional bowel disorder of unknown cause. It can be diagnosed positively from symptoms, and these diagnoses generally remain stable over time. Management is complicated by its high prevalence, heterogeneous nature, lack of a uniformly effective therapy, and association of psychological disturbance in those who seek health care. A rational clinical approach balances the exclusion of organic disorders with the avoidance of exhaustive negative investigations. Advances in our knowledge of IBS pathophysiology during the past decade now allow identification of clinical subgroups and form a practical basis for directing therapy as well as designing further clinical trials. For many patients, a confident diagnosis combined with education, reassurance, dietary modifications, and a compassionate physician prove effective. In some cases, drug treatment directed at the predominant symptoms will be necessary. Intractable symptoms may warrant further investigations and therapeutic trials. Well-designed clinical studies, based on emerging pathophysiological ideas, are needed to aid physicians to help patients cope with this challenging chronic disorder. REFERENCES 1.

Thompson WG, Heaton KW. Functional bowel disorders in apparently healthy people. Gastroenterology 1980; 79: 283-88. 2. Harvey RF, Salih SY, Read AE. Organic and functional disorders in 2000 gastroenterology outpatients. Lancet 1983; i: 632-34. 3. Keeling PWN, Fielding JF. The irritable bowel syndrome: a review of 50 consecutive cases. J Irish Coil Surg Physicians 1975; 4: 91-94. 4. Manning AP, Thompson WG, Heaton KW, Morris AF. Towards positive diagnosis of the irritable bowel. BMJ 1978; ii: 653-54. 5. Talley NJ, Phillips SF, Melton LJ, Zinsmeister AR. Diagnostic value of the Manning criteria in irritable bowel syndrome. Gut 1990; 31: 77-81. 6. Thompson WG, Dotevall G, Drossman DA, Heaton KW, Kruis W. Irritable bowel syndrome: guidelines for the diagnosis. Gastroenterol Int 1989; 2: 92-95.

7.

Chaudhary NA, Truelove SC. The irritable colon syndrome: a study of the clinical features, predisposing causes and prognosis in 130 cases. QJ

Med 1962; 31: 307-23. 8. Smith RC, Greenbaum DS, Vancouver JB, et al. Psychosocial factors are associated with health care seeking rather than diagnosis in irritable bowel syndrome. Gastroennterology 1990; 98: 293-301. 9. Drossman DA, Leserman J, Nachman G, et al. Sexual and physical abuse in women with functional or organic gastrointestinal disorders. Ann Intern Med 1990; 113: 828-33. 10. Kellow JE, Phillips SF. Altered small bowel motility in irritable bowel syndrome is correlated with symptoms. Gastroenterology 1987; 92: 1885-93. 11. Ritsema GH, Thijn CJP. Painful irritable bowel syndrome and sigmoid

contractions. Clin Radiology 1991; 43: 113-16. 12. Sasaki D, Kido A, Yoshida Y. An endoscopic method to study the relationship between bowel habit and motility of the ascending and sigmoid colon. Gastrointest Endoscopy 1986; 32: 185-89. 13. Maxton DG, Martin DF, Whorwell PJ, Godfrey M. Abdominal distension in female patients with irritable bowel syndrome: exploration of possible mechanisms. Gut 1991; 32: 662-64. 14. Klein K. Controlled treatment trials in the irritable bowel syndrome: a critique. Gastroenterology 1988; 95: 232-41. 15. Nanda R, James R, Smith H, Dudley CR, Jewell DP. Food intolerance and the irritable bowel syndrome. Gut 1989; 30: 1099-104. 16. Lavo B, Stenstam M, Neilson A-L. Loperamide in treatment of irritable bowel syndrome—a double-blind placebo controlled study. Scand J Gastroenterol 1987; 22 (suppl 130): 77-80. 17. Sciarretta G, Fagioli G, Farno A, et al. 75Se HCAT test in the detection of bile acid malabsorption in functional diarrhoea and its correlation with small bowel transit. Gut 1987; 28: 970-75. 18. Camilleri M, Colemont LJ, Phillips SF, et al. Human gastric emptying and colonic filling of solids characterized by a new method. Am J Physiol 1989; 257: G284-90. 19. Stubbs JB, Valenzuela GA, Stubbs CC, et al. A noninvasive scintigraphic assessment of the colonic transit of nondigestible solids in man. J Nucl Med 1991; 32: 1375-81. 20. Greenbaum DS, Mayle JE, Vanegeren LE, et al. Effects of desipramine on irritable bowel syndrome compared with atropine and placebo. Dig Dis Sci 1987; 32: 257-66. 21. Krevsky B, Maurer AM, Niewiarowski T, Cohen S. Effect of verapamil as human intestinal transit. Dig Dis Sci 1992; 37: 919-24. 22. Byrne S. Verapamil in the treatment of the irritable bowel syndrome. J Clin Psychiatry 1987; 48: 388. 23. Stafanini GF, Prati E, Albini C, et al. Oral disodium cromoglycate treatment on irritable bowel syndrome: an open study on 101 subjects with diarrheic type. Am J Gastroenterol 1992; 87: 55-57. 24. Fielding JF. Timolol treatment in the irritable bowel syndrome. Digestion 1981; 22: 155-58. 25. Steadman CJ, Talley NJ, Phillips SF, Mulvihill C. Trial of a selective serotonin type 3 (5-HT3) receptor antagonist ondansetron (GR 38032F) in diarrhea predominant irritable bowel syndrome (IBS). Gastroenterology 1990; 98: A394. 26. Hasler W, Soudah H, Owyang C. Somatostatin analog inhibits sensory afferent response to rectal distension in irritable bowel patients with rectal urgency. Gastroenterology 1992; 102: A457. 27. Prior A, Whorwell PJ. Double-blind study of ispaghula in irritable bowel syndrome. Gut 1987; 28: 1510-13. 28. Passaretti S, Tittobello A, Capozzi C, Verlinden M. Cisapride accelerates total intestinal transit in patients with irritable bowel syndromeassociated constipation. Progr Med 1987; 43 (suppl 1): 121-29. 29. Van Outryve M, Milo R, Toussaint J, Van Eeghem P. "Prokinetic" treatment of constipation-predominant irritable bowel syndrome: a placebo-controlled study of cisapride. J Clin Gastroenterol 1991; 13: 49-57. 30. Froguel E, Chaussade S, Roche H, Fallet M, Couturie D, Guerre J. Effects of an intestinal smooth muscle calcium channel blocker (pinaverium bromide) on colonic transit time in humans. J Gastrointest Mot 1990; 2: 176-79. 31. Passaretti S, Guslandi M, Imbimbo BP, Daniotti S, Tittobello A. Effects of cimetropium bromide on gastrointestinal transit time in patients with irritable bowel syndrome. Aliment Pharmacol Ther 1989; 3: 267-76. 32. Walsh P, Gould SR, Barnardo DE. Peppermint oil does not relieve the pain of irritable bowel syndrome. Br J Clin Pract 1986; 40: 292-93. 33. Schaffstein W, Panijel M, Luttecke K. Comparative safety and efficacy of trimebutine versus mebeverine in the treatment of irritable bowel syndrome. Curr Ther Res 1990; 47: 136-45. 34. Whitehead WE, Cheskin LJ, Heller BR, et al. Evidence for exacerbation of irritable bowel syndrome during menses. Gastroenterology 1990; 98: 1485-89. 35. Mathias J, Ferguson KL, Clench MH. Debilitating "functional" bowel disease controlled by leuprolide acetate, gonadotropin-releasing hormone (GnRH) analog. Dig Dis Sci 1989; 34: 761-66.

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36.

Turner I, Middleton WRJ. Somatostatin and symptomatic relief of irritable bowel syndrome. Lancet 1987; ii: 1144. 37. Whorwell PJ, Prior A, Colgan SM. Hypnotherapy in severe irritable bowel syndrome: further experience. Gut 1987; 28: 423-25. 38. Drossman DA, Thompson WG. The irritable bowel syndrome: review of

Talley NJ,

graduated multi-component treatment approach. Ann Intern Med 1992; 116: 1001-16. 39. Guthrie E, Creed F, Dawson D, Tomenson B. A controlled trial of a

psychological treatment for the irritable bowel syndrome. Gastroenterology 1991; 100: 450-57.

HYPOTHESIS Insulin resistance: an adaptation for weight maintenance

Insulin resistance can be physiological, but most often is associated with metabolic disorders such as obesity and non-insulin dependent diabetes mellitus. The reduction in insulin action seen in insulin-resistant states affects metabolic fuel partitioning in a way that would prevent additional weight gain. Despite the potential adverse effects of cardiovascular risk factors that accompany insulin resistance, reductions in insulin action may well be necessary to prevent additional weight gain in those in whom excessive food intake is coupled with

inactivity. Lancet 1992; 340: 1452-53.

Insulin resistance is not only commonplace in metabolic disorders, but also is often a physiological state during pregnancy,1 puberty, and starvation.3 It is partly genetically determined,4and can also be severe in individuals of normal weight.5 Severe forms of insulin resistance arise in rare diseases such as leprechaunism6 and lipoatrophic diabetes7 obesity, non-insulin dependent diabetes mellitus (NIDDM); hypertension, dyslipidaemia and glucocorticoid excess are also associated with variable degrees of resistance to insulin action.8 In obesity, insulin resistance seems to result from alterations in both the number of insulin receptors and 9 post-receptor activity.9 The origin of post-receptor alteration is suggested by a return to normal numbers of insulin receptor when hyperinsulinaemia is corrected in the absence of weight reduction.10 When insulin action is

diminished, hyperinsulinaemia presumably develops

to

sustain the tissue-specific effects of insulin. The primary sites of insulin action are skeletal muscle, adipose tissue, and liver. In skeletal muscle, insulin increases glucose transport,

glucose oxidation, glycogen synthesis, and protein synthesis, but inhibits proteolysis and lipoprotein lipase (LPL). In adipose tissue, insulin increases glucose transport, glucose oxygenation and LPL, but inhibits lipolysis. In the liver, insulin inhibits glycogenolysis, gluconeogenesis, and very-low-density lipoprotein (VLDL) secretion. Despite hyperinsulinaemia, however, alterations in insulin action may to a variable extent be present in obesity. This variability could predict whether weight will stabilise or further increase. Support for the notion that insulin resistance may be an adaptation for weight maintenance comes from several lines of evidence. When insulin resistance is present, increases in adipose tissue lipolysis and circulating free fatty acids (FFA) produce or are associated with increases in fatty acid versus

glucose oxidation in skeletal muscle." In addition, overproduction of VLDL triglycerides12 and tissue-specific alterations in LPL result. Lipoprotein lipase (LPL) is the rate-limiting enzyme for the hydrolysis and uptake of triglyceride fatty acids from circulating triglyceride-rich lipoproteins, chylomicrons, and VLDL. 13 Usually, LPL is increased by insulin in adipose tissue, but reduced by insulin in skeletal muscle.14 In obesity, however, the dose-response curve for adipose tissue LPL stimulation by insulin is shifted to the right. Moreover, in the vastus lateralis muscle of obese women, lipase is increased by insulin. When the effect of insulin on muscle LPL was compared in obese (n = 13) and normal weight women (n = 6), an increase (mean +1-7 [SEM 04] nmol FFA/g per min) rather than a decrease (-0-8 [0’3] nmol FFA/g per min) was noted (p=00001, Eckel RH, et al, unpublished data). All these changes are consistent with a metabolic environment in which partitioning of lipid fuels is away from storage in adipose tissue to immediate or delayed oxidation in skeletal muscle. After weight reduction, a metabolic setting exists that allows weight gain. Insulin resistance is in part diminished with increases in insulin-mediated glucose metabolism,12 antilipolysis15 and return to near-normal values of lipoprotein metabolism.12 Moreover, the maintenance of raised concentrations of fasting adipose tissue LPL,15 the enhanced responsiveness of the adipose tissue lipase to insulin, and the failure of corn oil ingestion to inhibit the insulin-stimulated adipose tissue LPL response all support accelerated uptake and storage of lipid fuels. In reality, resumption of the obese state typically occurs, with fewer than 5 % of subjects remaining lean for more than four

years. 16 Studies at the Phoenix epidemiology and clinical research branch of the National Institute of Diabetes and Digestive and Kidney Diseases provide evidence that a reduced basal metabolic rate, 17 increased respiratory quotient,18 and increased insulin sensitivity19 predict weight gain in Pima Indians. In addition, after weight gain, increases in metabolic rate, reductions in respiratory quotient, and insulin resistance occur. Pima Indians also have a high incidence and prevalence of NIDDM wherein insulin resistance is more severe. It is noteworthy that body weight is often stabilised, and may even fall, before the diagnosis of NIDDM .20 When NIDDM is treated with sulfonylureas or insulin, insulin resistance may be reduced, but body weight frequently increases.21 ADDRESS: Department of Medicine, Division of Endocrinology, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA (Prof R. H. Eckel, MD).

Clinical approaches to irritable bowel syndrome.

1447 12. Esler MD, Goulston KJ. Levels of anxiety in colonic disorders. N Engl J Med 1973; 288: 16-20. 13. Snape WJ, Carlson GJ, Matarazzo SA, Cohen...
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