Chronic intestinal pseudoobstruction

0016-5085/78/7405-0922$02.00/O GA~~ROENTEROLWY ‘74922-931, 1978 Copyright 0 1978 by the American Gastroenterological Association

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Vol. 74,No. 5,Part I Prmted in U.S.A.

AND TOPICS

CHRONIC INTESTINAL PSEUDOOBSTRUCTION DAVID

L.

FAULK,

M.D.,

Division of Gastroenterology,

SINN

ANURAS,

Department

oflnternal

M.D.,

AND JAMES

Medicine,

CHRISTENSEN,

M.D.

University ofIowa Hospitals, Iowa City,

Iowa

Intestinal pseudoobstruction is a term that is used for a syndrome in which there are symptoms and signs of intestinal obstruction without concrete evidence for an actual lesion obstructing the intestinal lumen.’ The term is often modified to describe special cases, as in acute or transient intestinal pseudoobstruction and chronic or recurrent intestinal pseudoobstruction. This review will be limited mostly to the latter syndrome, chronic or recurrent intestinal pseudoobstruction. The acute syndrome seems to have been described mainly in the old and chronically i11,2-”in contrast to the chronic syndrome. In many cases, of course, the chronic or recurrent syndrome is also associated with other more familiar disease entities, and so the chronic syndrome may be considered to be a manifestation of some more generalized process. In other cases, though, the chronic syndrome occurs without such associations. Thus, the syndrome of chronic or recurrent intestinal pseudoobstruction may be thought of as primary or secondary. Because so little is known of the pathogenesis of the syndrome, it is, in either case, properly called idiopathic. Primary Intestinal Pseudoobstruction: Features

Clinical

This term is intended to specify cases in which the syndrome occurs free of association with other disease entities. It occurs in patients of all ages and both sexes.7-2xThe patients have recurrent attacks of highly variable frequency, intensity, and duration that are characterized by nausea, vomiting, cramping abdominal pain, and abdominal distention. Unlike the syndrome of organic intestinal obstruction, this symptom complex does not include constipation or the absence of flatus as a major feature. Although constipation may occur 21the episodes are characterized usually by some degree of diarrhea. After months or years, recurrent discrete attacks are replaced often by a state in which Received August 4, 1977. Accepted October 20, 1977. Address requests for reprints to: David L. Faulk, M.D., Division of Gastroenterology, Department of Internal Medicine, University of Iowa Hospitals and Clinics, Iowa City, Iowa 52242. This study was supported in part by Research Grant AM08901 from the National Institute of Arthritis, Metabolism and Digestive Diseases and in part by Grant RR-59 from the General Research Centers Program, Division of Research Resources, National Institutes of Health.

the syndrome never fully abates, but fluctuates in intensity. Laboratory assessment commonly reveals steatorrhea or other evidence for intestinal malabsorption quite early in the course of the illness. The steatorrhea is generally thought to be attributable to the proliferation of colonic bacteria in the small intestine, an overgrowth that is allowed by the impaired capacity of the small intestinal contractions to clear the intestinal lumen.16*l7 The malabsorption becomes so severe as to be an important contributor to the mortality of the disease. Malnutrition may also be attributable to anorexia. Radiographic studies often reveal lesions in other viscera in addition to the small intestine: the esophagus, stomach, and colon may all exhibit dilatation or abnormal transit.11, 14, 16, 22, 26 Also, relatives of patients have been found to have radiographic evidence of abnormal motility of the gastrointestinal tract, or impaired motor function of the urinary bladder.‘“, 21 The response of the sweat glands to autonomic stimulation was impaired in 3 patients.‘” Rather few manometric studies of gastrointestinal motor functions have been reported. The esophagus has been most often examined, probably because it is so much more accessible to study than are the other segments of the gut. In some cases, esophageal manometry has revealed abnormal or absent peristalsis in the distal part of the esophageal body; the lower esophageal sphincter pressure has been found to be normal, low, or even high, and the sphincter may not relax or only partly relax during swallowing.“, 15,Iti,I77p2,24,26,27 It is notable, however, that dysphagia is not a common complaint. This is not surprising, for in other motor disorders of the esophagus it is a matter of common experience that the degree of dysphagia is poorly correlated with the severity of the abnormality. Schuffler and Popez3have shown that many relatives of patients with the syndrome have abnormal esophageal motility demonstrated by manometry, and those authors suggested that an autosomal dominant mode of inheritance prevails. Pathophysiology. From the clinical features of the syndrome, it is clear that the disorder is not confined to the small intestine, but usually involves other regions of the tubular gut as well. Also, it is generally agreed that the abnormality is one of motility. The nature of the abnormality is unknown. The control of intestinal transit is still incompletely

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understood.‘*31 The flow of the luminal contents along the gastrointestinal tract is a consequence of the movements or contractions of the muscular walls of the gut. The patterns of these contractions are influenced, in part, by certain properties of the smooth muscle itself and, in part, by the autonomic nervous system: there are recent suggestions that some gastrointestinal hormones may also have some role in the normal regulation of gastrointestinal transit. From these considerations, it follows that the abnormalities in the syndrome of primary intestinal pseudoobstruction could lie in the smooth muscle itself, in the autonomic nervous system or, more remotely, in the sphere of gastrointestinal endocrinology. That is, the abnormalities could exist in the myogenic, neurogenic, or endocrine controls of gastrointestinal movements. The myogenic controls, those influences on wall movements that arise from special properties of the muscle itself, are complex.2S34In the distal stomach, intestine, and colon, the smooth muscle is specialized in such a way that brief contractions recur at quite regular intervals. This pattern of movement is dictated by the presence of pacemaking electrical signals in the muscle of those regions. 32,33These signals, called electrical slow waves, pacesetter potentials or the electrical control activity, are generated by the smooth muscle cells themselves. These signals are not action potentials, for they recur continuously, whether or not contractions are occurring. When a part of the muscular wall responds to an electrical slow wave with a contraction, that slow wave is accompanied by another electromyographic feature called the spike burst. This is a sequence of much briefer and more rapid electrical transients occurring with a phase relationship to the pacesetter potential that is constant. The spike burst is an action potential, for it always marks the initiation of a contraction. Because the electrical slow waves impose a restriction upon the time and location of occurrence of the spike bursts (and the same restriction upon the contractions which follow the spike bursts), the electrical slow waves are logically called pacesetter potentials. In any given region of those organs where such pacesetter potentials occur, they are not simultaneous at all points: rather, they always appear to spread away from some source. Thus, they dictate the timing, velocity, and direction of migration of contractions. According to current views, the autonomic nerves act mainly to induce or suppress contractile responses to electrical slow waves in those areas where such potentials occur. The nerves which are responsible lie in the intramural plexuses, and these plexuses are connected, through the extrinsic nerves of the gut, to the autonomic centers in the central nervous system. The great technical difficulties that exist in studying the morphology or function of the intramural nerves have severely limited study of their role in the governance of motility. It is even more difficult to ascribe to the gastrointestinal hormones any responsibility for the control of normal intestinal motility. In pharmacological doses, cholecystokinin and gastrin excite contractions in intestinal muscle, whereas secretin and glucagon inhibit them.35*36Species and organ differences in responses of

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gastrointestinal muscle to these and other polypeptide hormones remain to be explored. Because of the variety of controls that may exist to regulate or modify gastrointestinal motility, it seems reasonable to suppose that the syndrome of primary intestinal pseudoobstruction may arise from a variety of causes. The few studies directed toward the pathogenesis do, indeed, suggest that the causes are heterogeneous. In many cases, the small intestine seems to be free from pathological changes, but, in other cases, hypertrophy of one or both muscle layers has been described.8, lo In other cases, there is atrophy, in which the smooth muscle is replaced by collagen in one or both muscle layers. 7,*’In many cases, the myenteric plexus is apparently normal on histological examination, but in other cases both ganglia and nerve bundles in the plexus have been found to be reduced in number, and the remaining neuronal structures have been seen to be morphologically abnormal. ’’3I*, I4 Flattening of mucosal villi in the small intestine was reported in one case.” Physiological studies also suggest that the causes are heterogeneous. It has been suggested that the abnormality can arise from a selective disorder of the aRerent elements of the autonomic innervation,24*27a conclusion based in part on the finding that responses of the muscle to cholinergic agents, anticholinesterases, and gastrointestinal hormones are intact. In addition, some patients have been found to have aperistalsis of the esophagus with incomplete relaxation of the lower esophageal sphincter after swallowing or balloon distention, and no increase in duodenal contractile activity after intestinal distention. This suggests impaired physiological neural responses in these patients.** In another recent report, in contrast, responses to cholinergic agents, anticholine&erases, and adrenergic antagonists were absent,‘?, *O but cerulein (a close structural analogue of cholecystokinin) was found to be an effective stimulant of contractions in the small intestine.20 In another report, the serum levels of prostaglandin E were found to be elevated, and indomethacin was found to alleviate the syndrome. *j Management. It is characteristic of the syndrome that it is episodic, neither exacerbations nor remissions being at all predictable. This m&es the assessment of response to therapy very difficult. Thus, the recent suggestions that cerulein20 and indomethacin2”may be therapeutically beneficial must be accepted as tentative. Cholinergic agents have not been found to be effective, in general, Is,“9 *Onor has metoclopromide. ** Prednisone has not been observed to affect either the abnormal intestinal motility or the steatorrhea.8’lo, I3 The steatorrhea has, in some cases, responded to antibiotic therapyI but not in others. lo, G I7Operations to remove or bypass dilated segments of the small intestine have, in some cases, relieved symptoms,YvI4but it is generally believed that operations are to be avoided insofar as possible. Indeed, when these patients are once operated upon, only to return with recurrent obstructive symptoms, the temptation to repeat operations looking for adhesions is very great. Of course, adhesions may be found, and so a long sequence of repeated laparotomies may result. Although parenteral

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small intestine. But in another study of 19 patients,“!’10 were found to have colonic dilatation, and, in another study of 8 patients40 one-half were found to have evidence of abnormal colonic motility. Abnormal findings on radiographic examination of the gut may be Secondary Intestinal Pseudoobstruction The syndromes of acute or chronic recurrent intes- present in as many as 40% of patients who are lacking tinal pseudoobstruction have occurred in association symptoms of gastrointestinal dysfunction.:j7.4’.42 Chronic or intermittent constipation is common,40.43 with a large number of disease entities and drug abuses. and alternating constipation and diarrhea occur. SympIn many cases, sufficient understanding of the pathotoms may simulate acute abdominal obstruction. Severe physiology of these associated disorders has given atony may predispose to intestinal ulceration, and fatal strong support to particular theories of the pathogenesis of the associated pseudoobstruction. Table 1 constitutes perforation has occurred.“‘, 4’,Q It is remarkable that a classification of the associations of the secondary the symptoms of gastrointestinal dysfunction may be the first manifestation of scleroderma, preceding by pseudoobstruction syndrome. many months the more usual signs and symptoms of Scleroderma. The occurrence of abnormal gastrointestinal motility in patients with scleroderma has been arthritis, Raynaud’s phenomenon and sclerodactyly. In well recognized. 17,374sIn a review of 364 cases of scle- most of Poirier and Rankin’s cases,37 gastrointestinal roderma,3744% of the men and 51% of the women were symptoms developed in the 12 months preceding the found to have symptoms of gastrointestinal disease. Of diagnosis of progressive systemic sclerosis. Treaty et al. these patients, 36 had radiographic examinations of the described a patient who developed obstructive sympesophagus, stomach, and small intestine, and 15 (or toms 14 months before Raynaud’s phenomenon and 41.7%) of them showed such abnormalities as duodenal other skin changes occurred.:jHRodnan and FennelPA dilatation and delayed intestinal transit. Forty-five of described 4 patients who developed progressive and the patients had radiographic examination of the colon, fatal gastrointestinal involvement with no manifestabut megacolon was not demonstrated. Two of those tions of scleroderma except for minimal skin involvecases reportedly died of the consequences of intestinal ment. Because the natural history of scleroderma is not atony. Another review of 306 cases of scleroderma38 fully known, it may be that some patients previously reported only 15 with abnormal motor function in the considered to have primary intestinal pseudoobstruction may actually have had scleroderma without skin and joint manifestations sufficient to be noticed. TABLE 1. Chronic intestinalpseudoobstruction: secondary causes Dilatation of the gastrointestinal tract in scleroderma I. Diseases involving the intestinal smooth muscle may occur in any region from the smooth muscle segA. Collagen vascular disease ment of the esophagus to the rectum. Common radio1. Scleroderma graphic features are megaesophagus, delayed gastric 2. Dermatomyositis/polymyositis emptying with gastric dilatation, hypomotile duodenal 3. Systemic lupus erythematosus segments with dilatation, particularly in the second B. Amyloidosis C. Primary muscle disease and third parts, and variable jejunal and ileal dilata1. Myotonic dystrophy tion.3c’*4o The colon may show dilatation with loss of 2. Progressive muscular dystrophy haustrations, spiculation, and wide mouth diverticD. Ceroidosis ula 3Y. 40 E. Nontropical sprue The pathological finding which is usually used to II. Endocrine disorders explain the clinical motility disturbance in scleroderma A. Myxedema is focal atrophy of both the circular and longitudinal B. Diabetes mellitus layers of smooth muscle: there is replacement of the C. Hypoparathyroidism submucosa, muscularis, and serosa by a densely hyalinD. Pheochromocytoma ized fibrous connective tissue. 3c’41. , 45,46A variable deIII. Neurological diseases A. Parkinson’s disease gree of lymphocytic infiltration into the muscle layers B. Hirschsprung’s disease is also present. The submucosal and myenteric plexuses C. Chagas’ disease are normal. Ceroid deposits have been described,4’but D. Familial autonomic dysfunction their significance is not clear. The overgrowth of colonic IV. Pharmacological causes bacteria in the small intestine is a common occurrence A. Phenothiazines in intestinal scleroderma, but its contribution to the B. Tricyclic antidepressants syndrome of chronic intestinal pseudoobstruction is not C. Antiparkinsonian medications fully clarified. D. Ganglionic blockers There are no specific treatments for the intestinal E. Clonidine motility disturbances associated with scleroderma. F. Amanita (mushroom) poisoning Broad spectrum antibiotics can be used to treat steatorV. Miscellaneous A. Jejunoileal bypass rhea and malabsorption caused by overgrowth of intesB. Diverticulosis (jejunal) tinal flora. Operations that are intended to relieve the C Psychosis apparent obstruction or to bypass involved segments D. Cathartic colon may help, but they may also contribute to the high nutrition does nothing to treat the underlying disease, central venous nutrition is often used to provide necessary support while obstructive symptoms are present.

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morbidity and mortality of the disease. Frequently patients may be subjected to multiple surgical procedines.45347,‘48and postoperative deaths from pneumonia or progressive gastrointestinal atony are not infrequent. 44, 45, 46 Dermatomyositis. Chronic constipation, abdominal distention, and diminished intestinal motility are decidedly less frequent in dermatomyositis than they are in the other collagen diseases. Malkinson and Rothman described 2 patients who had dermatomyositis with associated symptoms of intestinal obstruction, a dilated duodenum, and microscopic fibrosis in intestinal muscle at autopsy. In separate reports, KlecknelSO and Feldman and Marshaksl reported patients with dysphagia, Raynaud’s phenomenon, and dermatomyositis in whom X-ray studies demonstrated esophageal dilatation, megaduodenum, delayed intestinal transit, and colonic dilatation. In the latter cases, the gastrointestinal symptoms preceded the other manifestations of the disease by years. Swenson et a1.52 reported a patient with dermatomyositis who had dilatation limited to the colon: he was treated by total colectomy. The mechanisms of pseudoobstruction in dermatomyositis are obscure. Feldman and Marshak5’ suggested that this syndrome has similarities to scleroderma in that thickening and edema of the submucosa and atrophy of the muscular coats with subsequent fibrosis lead to altered transit. Wainger and Levels3 suggested a vascular cause, having noted fibrinous narrowing of arterioles and mucosal ulcerations. Polymyositis. Patterson and Rios54had a 26-year-old patient with vomiting, muscle weakness, Raynaud’s phenomenon, and electromyographic evidence of polymyositis. Multiple radiographic studies demonstrated gastric atony and retention, and duodenal dilatation. At autopsy, atrophic changes were found in both striated and smooth muscle, and intestinal smooth muscle was replaced by fibrous tissue. The exact diagnosis was not clear in this isolated case, so that the evidence for intestinal pseudoobstruction associated with polymyositis is not strong at present. Lupus erythematosus. In a review of 87 patients with systemic lupus erythematosus, Brown et a1.55reported 5 patients with intestinal pseudoobstruction. Abdominal distention and vomiting were present in all; constipation was not described. Radiographic findings included dilatation of the stomach and of the second and third parts of the duodenum, and delayed intestinal transit. Three of these patients responded to antacids and other elements of a treatment regimen for gastric ulcer, although such ulcers had not been demonstrated in these cases. A 4th patient, who had jejunal dilatation, was treated successfully by jejunostomy. An autopsy was done in only 1 case; focal submucosal hemorrhages were found in the small intestine. In a thorough review of 138 cases of systemic lupus erythematosus, Harvey et a1.56described a patient with alternating bloody diarrhea and constipation. A radiographic examination of the upper gastrointestinal tract revealed a dilated small intestine, and an autopsy demonstrated arteritis in intestinal vessels. It is possible that the syndrome of

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intestinal pseudoobstruction seen in lupus is a consequence of vasculitis, with ischemia producing the abnormal motility. Amyloidosis. Gastrointestinal involvement with amyloid has been reviewed before.57j5RLegge et a1.57 reported 8 cases and reviewed 7 others with intestinal pseudoobstruction. They suggested that the infiltration of smooth muscle by amyloid interferes with motor function. However, because some of their patients had hypercalcemia or uremia, or were taking Alkeran for multiple myeloma, the pathogenesis of the motility disturbances in those cases cannot be firmly attributed to the infiltration. Gilat and Spiro58reported a 70-yearold male with the syndrome of recurrent intestinal pseudoobstruction, multiple myeloma, and amyloidosis. Radiographic studies showed a dilated stomach with delayed emptying and dilatation of the transverse colon; reduced motility was found by esophageal and colonic manometry. In another patient who was asymptomatic, manometry demonstrated low amplitude nonpropulsive waves in the esophagus, and X-rays showed delayed gastric emptying. These authors proposed that amyloid deposition in the bowel wall, neuropathy from damage to major nerve trunks, and vascular insufficiency resulting from amyloid deposits in blood vessels all could contribute to the syndrome. Myotonic dystrophy and progressive muscular dystrophy. Harvey et a1.5greported 16 patients with myotonic

dystrophy, 1 of whom presented with the syndrome of intestinal obstruction; 6 others complained of constipation and diarrhea. In 11, abnormal motility was demonstrated on esophageal manometry. Goldberg and SheftGoand Kohn et a1.61described patients with intermittent constipation for months or years before the diagnosis of myotonic dystrophy was made. They emphasized that smooth muscle involvement may be an outstanding feature early in the course of this disease. Radiographic abnormalities include dilatation of the esophagus, stomach, small intestine, and co1on.6os 61In autopsy material from patients with myotonic dystrophy with no gastrointestinal symptoms, Pruzanski and Huvo@* found fatty infiltration of the intestinal walls: fat-containing vacuoles separated the muscle bundles and cells. Myofibers were atrophic and hypereosinophilic. Muscle nuclei were swollen and vacuolated. The nerve plexuses were intact. In progressive muscular dystrophy, the smooth muscle of the gastrointestinal tract may be involved to cause motility disturbances.63~ 64Pathological findings, described all the way from esophagus to rectum, consist of edema causing separation of muscle fibers, and atrophy of the myofibers, with very little fibrous tissue replacement, Fatty infiltration of the myenteric plexus has also been described.w Ceroidosis. Boller et a1.65reported a patient with chronic abdominal distention of la-year duration in whom laparotomies revealed a dilated brown intestine; microscopically there was ceroid pigment in the muscularis propria. The authors proposed that the ceroid deposits affected the function of intestinal smooth muscle, resulting in hypomotility and dilatation. Ceroid

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pigment is a lipofuscin pigment that, according to one hypothesis, is caused by vitamin E deficiency. It is found in other diseases associated with the syndrome of intestinal pseudoobstruction. Braunstei# observed ceroid pigmentation in the smooth muscle of 22 of 36 patients with chronic pancreatitis, a disease more commonly associated with acute ileus than with chronic pseudoobstruction. Hoskins et a1.41found ceroid deposits in their extensive pathological evaluation of a patient with scleroderma. Ceroid deposition is associated with nontropical sprue,65 and it has been described in those patients with sprue who also have the syndrome of intestinal pseudoobstruction. It is possible that these patients had primary pseudoobstruction with ceroidosis resulting from the consequent vitamin E malabsorption. The role of ceroid pigment in intestinal pseudoobstruction needs further study. Nontropical sprue. In his description of nontropical sprue, Ingelfingel-67 described 1 patient with chronic abdominal distention and vomiting whose symptoms were not relieved by three operations. Naish et al.* described 3 other patients with abdominal distention, recurrent obstruction, and sprue who were noted to have increased but “ineffective” peristalsis. In his study of intestinal pressures in disease states, Fink6’ noted decreased phasic activity in the small intestine in patients with sprue. Because the small intestinal mucosa may be flat in bacterial overgrowth syndromes,‘ls 6s these patients could have had primary pseudoobstruction and a flattened mucosa resulting from bacterial overgrowth. Myxedema. Intestinal atony in hypothyroidism is less commonly seen than it was formerly because improved diagnostic methods now lead to earlier diagnosis; myxedema remains an important consideration in the work-up of intestinal pseudoobstruction, however, because the intestinal symptoms may precede or dominate the symptoms of hypothyroidism70, ‘l and because of the high degree of morbidity of the condition.70* 72-74Bastenie’O found 19 patients with intestinal signs, including constipation and abdominal distention, in 29 cases of myxedema. The chronicity of these symptoms may be striking, with constipation for 3 years or more before the diagnosis of hypothyroidism is made.72, 75Vomiting is not common, but it has been reported.74 Radiographic findings may include dilatation of the stomach,70 small intestine,74* 76 or colon, but the distention is usually most prominent in the colon.7o Surgical and autopsy specimens demonstrate hypotonic, hypertrophied bowel without evidence of an obstructive lesion. Microscopically, there is a mucopolysaccharide infiltration of the stroma, atrophy of the mucosa, and diffuse infiltration of the submucosa with lymphocytes and plasma cells.70*77 The most frequently proposed mechanism for chronic pseudoobstruction in myxedema is altered impulse transmission at myoneural junctions caused by the myxedematous infiltrate imposed between the muscular fibers and the plexuses.70s 71,76*77 Wells et a1.78 found abnormal axons in the myenteric plexus without muco-

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polysaccharide deposition in 1 patient with myxedema, and he suggested that autonomic neuropathy had caused the ileus. Paralytic ileus could also result from intestinal ischemia secondary to the low output cardiac failure of myxedema,74 or it could reflect altered calcium metabolism.71 Many authors emphasize the hazards of surgical operations in this condition.7oT 73*74 This is because the rate of postoperative complications is high with this underlying metabolic abnormality. Also, multiple operations are sometimes done in cases of cryptic myxedema before the diagnosis is made and proper therapy started.73* 74 Diabetes mellitus. Diarrhea, with or without steatorrhea, is common in diabetes.7s* 8o Several reviews, however,7ss R1 cite constipation as the most frequent gastrointestinal complaint of diabetic patients. Katz and Spiro7s reported a patient with diabetes who required hospitalization for constipation. Radiographic studies showed colonic dilatation, but no tissue specimens were examined. It is not clear whether their patient had the pseudoobstruction syndrome or, instead, chronic constipation with consequent colonic dilatation. Paley et alx2 described a diabetic patient who developed extensive intestinal dilatation after many years of severe diarrhea. Autopsy failed to show abnormalities in the muscular layers or nervous plexuses, and demonstrated only ulcerations in the colon. These were not attributable to the colonic dilatation that had developed terminally. The mechanism of the altered gastrointestinal motility in diabetes is not known, but it has been attributed to autonomic neuropathy.7g* 81 Pathological swelling and disruption of parasympathetic fibers and lymphocytic infiltration in the ganglia have been demonstrated in esophageal tissue from patients with diabetes mellitus, even in those without dysphagia or signs of peripheral neuropathy.*3 Hypoparathyroidism. Taybi and’ Keelen reported 2 sisters with hypoparathyroidism, 1 of whom had persistent vomiting and abdominal distention with radiographic evidence of jejunal dilatation and delayed transit. The patient did not respond to calcium replacement or to multiple operations. Pathological findings were not specific, constituting a lymphocytic infiltration of the submucosa that was interpreted as being compatible with celiac disease. Because of the complexity of this single isolated case, the role of hypoparathyroidism in causing the syndrome of intestinal pseudoobstruction is not clear. Pheochromocytoma. Duffy et al.“” described a 30year-old male with constipation in whom megacolon and bilateral adrenal tumors were found at laparotomy. Rectal histology revealed increased numbers of nerve fibers and ganglion cells. The authors postulated that altered gastrointestinal motility resulted from sympathetic-parasympathetic imbalance producing excessive sympathetic activity, or possibly that there had been abnormal migration of neural crest cells. Parkinson’s disease. Chronic intestinal pseudoobstruction has been reported in Parkinson’s disease. 86.87 All patients, however, were taking anticholinergic med-

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ications at some time during their course, a fact which of 556 autopsies in Brazil. An additional 8 cases were makes the actual cause of the intestinal motility dis- mentioned in whom 5 had megagastrium, 2 had megaturbance difficult to ascertain. duodenum, and 1 had megajejunum. Decreased numHirschsprung’s disease. The incidence of Hirsch- bers of ganglion cells or destruction of ganglion cells sprung’s disease is 0.2 per 1000 live births.HH, HgThe were attributed to the infection with Trypanosoma diagnosis is strongly suggested when a child has persist- cruzi. Pathological examination of tissue specimens also ent constipation and a history of abnormal bowel activ- demonstrated smooth muscle hypertrophy. Atias et a1.s4 ity in the neonatal period. There is usually no perianal reported similar findings from Chile in 88 patients, and soiling, as occurs in simple constipation, and paradoxi- they emphasized the greater frequency of colonic incal diarrhea may occur. Rectal examination character- volvement in Chagas’disease as compared with esophistically discloses an empty narrow rectum with a ageal involvement. palpable fecal mass in the upper rectum. Barium studFamilial autonomic dysfunction. Grossman et a1.s5 ies demonstrate an abnormally distended colon (the reported a 3-year-old male who, from the age of 3 ganglionic segment) proximal to a segment that has a months, had megacolon and bowel dysfunction that normal caliber (the aganglionic segment) rectum, or a were attributed to familial autonomic dysfunction. Inrectum and colon with a cone-shaped transition zone. testinal pseudoobstruction has not been described in Kottmeier and ClatworthpO emphasized the need for adults with this disease. rectal biopsy in these patients: they had 7 cases who Drug-induced chronic intestinal pseudoobstrucwere subjected to “unnecessary surgery” because subse- tion. Davis and Nusbaums6reported a patient who was quent pathological specimens contained normal gan- found to have generalized colonic atony at laparotomy. glia. On the other hand, they reported patients treated This was attributed to the parasympatholytic activity without operation for as long as 12 years with the of chlorpromazine, although the drug was reinstituted mistaken diagnosis of functional megacolon before a postoperatively without further development of obstrucbiopsy was done and the absence of ganglia was discov- tive symptoms. Other authorss74scite similar examples ered. of patients developing apparent intestinal obstruction In patients with Hirschsprung’s disease, there is an while taking other phenothiazines, including trifluoperabsence of ganglion cells in both the submucosal and azines7 and thioridazine. s8 Milneps emphasized that intramuscular plexuses in the distal segment.8g The alcohol may worsen the obstructive symptoms, pointing aganglionic segment always extends to the anus, and in out the potentiation of alcohol-induced inhibition of 85% of cases it involves the entire length of the rectum; gastrointestinal activity by antidepressant drugs. involvement of the entire colon and terminal ileum Milner et al. loo*lulreported 6 patients who developed occurs in 5% of cases.88 Hypertrophied nerve bundles rather acute obstructive symptoms while on imipraare variably present in the aganglionic segment.8g mine, amitriptyline, and nortriptyline. 0therss8*lo23lo3 Corker-y8 found that 35% of his cases were diagnosed reported similar findings, but the multiplicity of mediin the first 28 days of life and the rest by 6 years of age. cations and the absence of reported histological findings However, Fair-grieves1described 7 patients between the make it difficult to blame specific drugs for the obstrucages of 17 and 36 in whom the diagnosis of Hirschs- tive symptoms. These medications are important to prung’s disease was made by the absence of ganglion remember in the evaluation of patients with intestinal cells on rectal biopsy. All of them were males who had pseudoobstruction, because of the morbidity of operaa history of constipation since birth or early infancy, tion in this syndromelo and because of the hypomotility but the intermittancy of the constipation, and even the itself 98, 100, 102 occurrence of diarrhea at times, delayed serious considUntreated Parkinson’s disease has been associated eration of the diagnosis at an earlier age. X-rays showed with intestinal pseudoobstruction.86*x7 But such antivariable degrees of dilatation of the rectum and colon, parkinsonian drugs as benztropine and trihexyphenibut aganglionosis was limited to the rectal segment. dyl, have been associated with severe and even morbid In most instances, Hirschsprung’s disease is not con- constipation when used for other medical illnesses.s7ss8 fused with intestinal pseudoobstruction, often termed It seems possible that these drugs antagonize parasymidiopathic megacolon, when dilatation is limited to the pathetic influences on the bowel to reduce motility. colon. Lane and Todds2point out that, in addition to the Although ganglionic antagonists are no longer comdifferences on barium enema and rectal biopsy dis- monly used clinically, patients taking hexamethonium cussed previously, the internal rectal sphincter in pa- or pentolinium for hypertension frequently have constitients with Hirschsprung’s disease fails to relax in pation requiring cathartics, laxatives, or neostigmine response to rectal distention in contrast to patients with for relief. lo4*lo5 Occasionally, however, symptoms are idiopathic megacolon whose sphincters transiently re- severe, suggesting intestinal obstruction.los,lo7 Dilatalax, with an accompanying transient increase in intra- tion is usually limited to the small intestinelo6plox but rectal pressure. gastric dilatation may occur as we11.1°7 Chaga,s’ disease. The association of the syndrome of There have been 2 recent case reports with intestinal intestinal pseudoobstruction with Chagas’ disease is pseudoobstruction developing in patients who were takwell established. Ferreira-Santoss3 found 62 cases of ing the antihypertensive agent, clonidine.losj Ilo In both megaesophagus and 69 cases of megacolon in a review cases, dilatation appeared to be limited to the colon,

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and symptoms resolved when the medication was withdrawn. Amanita poisoning. Hanelin and Moss”’ reported 4 patients who complained of nausea, vomiting, and diarrhea, and who had, on radiographic examinations, a distended, atonic small bowel and colon. All had histories of recent ingestion of mushrooms of the genus Amanita. All but one responded to conservative therapy. The authors suggested that some constituent of the mushrooms exerted a toxic effect on the muscle, or that it had anticholinergic properties, although ileus caused by an electrolyte imbalance could not be ruled out. Jejunoileal bypass. Fikri and Cassella112 recently saw 3 of 52 patients who had had jejunoileal bypass for obesity develop megacolon 2 years after operation. Laboratory evaluation was normal, and no explanation for the phenomenon was offered. Subsequently, Barry and his associatesn3*114reported an additional 13 cases with distention of the colon 18 to 19 months after jejunoileal bypass. Using quantitative bacterial cultures taken from the lumen in the region of bypassed bowel, they showed that antibiotics effective against obligate anaerobes relieved the symptoms of pseudoobstruction, with a disappearance of the anaerobes. They also noted that dilatation was localized to that part of the colon which was distal to the site of anastomosis in those patients with an end-to-end bypass, whereas in those cases with an end-to-side bypass the dilatation affected the whole length of the colon. This observation suggests that the contents of the blind loop, draining into the colon or terminal ileum, may be involved in the pathogenesis of this complication. Drenick et a1.115monitored 28 patients after jejunoileal bypass from 8 months to 8 years. Sixteen of them complained of acute or chronic abdominal distention and, in 16 of the 24 who had radiographic examinations, gas-fluid levels were observed in the small intestine. No organic obstruction was found in 4 who had laparotomy for apparent intestinal obstruction, Microscopic examination of specimens of the intestinal wall revealed only nonspecific changes with blunting of villi and an infiltration of mononuclear cells in the mucosa and in the lamina propria. These authors proposed that bacterial overgrowth contributes to the altered motility; large numbers of bacterial organisms were cultured in the proximal part of the bypassed jejunum in 5 patients who had jejunal aspirations, and there was an excellent clinical response to treatment with broad spectrum antibiotics. Jejunal diverticulosis. In 62 patients with jejunal diverticulosis, Altemeier et a1.116found 16 with symptoms of obstruction. No mechanical obstruction was found on radiographic examinations and, in the 3 patients who eventually went to operation, duodenal dilatation without an obstructing lesion was noted. The authors proposed that the diverticula interfered with normal peristalsis, although intermittent volvulus or kinking could not be ruled out. Phillips117suggested that the primary problem is local bowel dyskinesia with pulsion diverticula resulting from the segmental irregular peristalsis. Psychosis. Kraft and his co-workers”” reported 16

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psychotic patients, most of whom had coexisting neurological disorders, with abdominal distention and meteorism, a relaxed anal sphincter with fecal incontinence, and a distended sigmoid colon that was filled with feces. Histological examination of the mucosa revealed mucosal atrophy, hemorrhage, and hypertrophy of the muscularis. Because these patients had chronic bowel enlargement confined to the rectosigmoid, it seemed to differ from the generalized megacolon that is commonly seen in patients in psychiatric hospitals. Watkins and Oliverns described 6 mentally defective patients with chronic constipation and dilatation of the entire colon who were treated by colectomy. After the operation, the authors noted a dilatation of the distal ileum, although no evidence of mechanical obstruction was apparent. It is unclear whether these patients represented part of the spectrum of pseudoobstruction. Inasmuch as no mention was made of concomitant administration of drugs in either report, the findings could represent undesirable effects of antipsychotic drugs. Cathartic colon. The abuse of laxatives, especially those containing anthraquinones, may lead habitues to develop constipation, abdominal pain, and vomiting and colonic dilatation is common.120~ 121Usually these patients are females with associated psychiatric disorders. Characteristically, radiographic studies show a dilated, distensible, and featureless colon with loss of haustrations. The presence of melanosis on gross or microscopic rectal biopsy specimen is virtually diagnostic. Smith122has demonstrated neuronal damage and loss in the myenteric plexus in patients abusing laxatives that act by virtue of their content of anthraquinones. Comment Even though intestinal pseudoobstruction has been described in association with a number of disease entities, a thorough understanding of the mechanisms involved and of the precise relationship of the syndrome to the associated disease is lacking. Incomplete evaluation, without full laboratory investigation, manometry, and histological examinations may have led to incorrect classifications in the past. This is further complicated by the fact that abnormal gastrointestinal motility simulating obstruction may precede other manifestations of the primary disease by months or years, or may overshadow them, as clearly demonstrated in cases of scleroderma,37,38* 44 myxedema,?O*I1 and myotonic dystrophy. 60,61A better understanding of the normal controls of intestinal motility should alter the classification and management of the victims of the syndrome of chronic intestinal pseudoobstruction. Clinical studies should be initiated to define and to clarify the differential diagnosis of this syndrome. REFERENCES

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78. Wells I, Smith B, Hinton M: Acute ileus in myxoedema. Br Med J 1:211-212, 1977 79. Katz LA, Spiro HM: Gastrointestinal manifestations of diabetes. N Engl J Med 275:1350-1361, 1966 80. Whalen GE, Soergel KH, Geenen JE: Diabetic diarrhea: a clinical and pathophysiological study. Gastroenterology 56:1021-1032, 1969 81. Rundles RW: Diabetic neuropathy: general review with report 54. Patterson M, Rios G: Disturbed gastrointestinal motility-an unusual manifestation of a systemic muscular disorder: polyof 125 cases. Medicine (Baltimore) 24:111-160, 1945 82. Paley RG, Mitchell W, Watkinson G: Terminal colonic dilation myositis or progressive muscular dystrophy. Gastroenterology 36:261-268, 1959 following intractable diarrhea in a diabetic. Gastroenterology 41:401-407, 1961 55. Brown CH, Shirey EK, Haserick JR: Gastrointestinal manifes83. Smith B: Neuropathology of the oesophagus in diabetes mellitations of systemic lupus erythematosus. Gastroenterology 31:649-666, 1956 tus. 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