Annu. Rev. Med. 1999. 50:37-55.

INTESTINAL PSEUDO-OBSTRUCTION

Bernard Coulie, MD, PhD and Michael Camilleri, MD
Mayo Clinic and Mayo Foundation, Rochester, Minnesota 55905; e-mail: Camilleri.Michael@mayo.edu; Coulie.Bernard@mayo.edu

KEY WORDS: gastrointestinal tract, motility disorder, autonomic neuropathy, myopathy

	ABSTRACT
	INTRODUCTION
	CHRONIC INTESTINAL PSEUDO-OBSTRUCTION
	ACUTE COLONIC PSEUDO-OBSTRUCTION
	CHRONIC COLONIC PSEUDO-OBSTRUCTION
	SUMMARY AND A LOOK TO THE FUTURE
	LITERATURE CITED

Pseudo-obstruction syndromes are increasingly recognized in clinical practice. They result from impairment of intrinsic neuromuscular or extrinsic control of gut motility. Typically, pseudo-obstruction syndromes result in features suggestive of mechanical obstruction and bowel dilatation in the absence of any demonstrable obstruction or mucosal disease. The syndrome may affect any region of the gut. Less severe variants without bowel dilatation are diagnosed by measurement of gastrointestinal transit and pressure profiles. The aims of treatment are restoration of nutrition and hydration, symptom relief, normalization of intestinal propulsion with prokinetics, and suppression of bacterial overgrowth. Surgery plays a limited role, adjunctive to medical treatment, facilitating enteral nutrition and decompression by means of jejunostomy. Infrequently, resection of localized disease or intestinal transplantation are indicated. The roles of intestinal pacemakers (interstitial cells of Cajal) and genetic mutations in the etiology of pseudo-obstruction, as well as the cost-benefit ratio of transplantation for pseudo-obstruction, will be clarified in the future.

Intestinal pseudo-obstruction is an uncommon syndrome characterized by acute, recurrent, or chronic symptoms suggestive of obstruction of the small or large intestine without any radiologic, surgical, or endoscopic evidence of mechanical obstruction. Pseudo-obstruction symptoms are caused by abnormal physiology rather than abnormal gross anatomy, but they may be just as severe as in "true" obstruction. These disorders invariably result from impaired gut motility. Normal motor activity of the gastrointestinal tract requires an intact and normally functioning neuromuscular apparatus; the neural control of gastrointestinal functions involves intrinsic and extrinsic innervation (Figure 1).

View larger version (33K): [in this window] [in a new window]   Figure 1. Extrinsic and intrinsic control of gastrointestinal motility. The extrinsic sympathetic and parasympathetic supply to the gut modulates the function of the enteric brain located in ganglionated plexi along the gastrointestinal tract. Transmitters released from the enteric neurons, which are the intrinsic neural control of the gut, modulate the peristaltic reflex. The major transmitters in the peristaltic reflex are shown on the right; acetylcholine and substance P are the predominant excitatory neurotransmitters, and VIP and nitric oxide are the predominant inhibitory neurotransmitters. ACh = acetylcholine; SubP = substance P; SubK = substance K; VIP = vasoactive intestinal polypeptide; NOS = nitric oxide synthase.

The intrinsic nerves include the interstitial cells of Cajal (ICCs), which are thought to function as intestinal pacemaker cells. Any congenital or acquired abnormality affecting the neuromuscular apparatus may result in intestinal pseudo-obstruction.

The clinical presentation of intestinal pseudo-obstruction depends on the regions of the gut affected, the time course of the disease, and the presence of any extraintestinal effects. Acute pseudo-obstruction syndromes are often associated with significant extraintestinal illnesses, and the underlying pathophysiologic mechanisms are still largely unknown. On the other hand, our understanding of the physiologic and biochemical disturbances in chronic intestinal pseudo-obstruction syndromes has substantially increased during the past decade.

This chapter reviews the current status of understanding of acute pseudoobstruction and chronic small-intestinal and colonic pseudo-obstruction. Before prolonged total parenteral nutrition was feasible, patients with severe, chronic intestinal pseudo-obstruction died of malnutrition, infection, or fluid and electrolyte imbalances. With the introduction of safe parenteral nutrition and newer prokinetic agents, it became possible to improve intestinal propulsion in several patients, thereby providing symptom relief and facilitating enteral nutrition.

Etiology
A practical classification of chronic intestinal pseudo-obstruction (CIP) is based on the neuromuscular component affected by the disease process, i.e. myopathy vs neuropathy (Table 1). In clinical practice, however, diagnosis of the gut-motility disorder can be based solely on the identification of the underlying disease process, such as scleroderma or muscular dystrophy. The common underlying disease processes causing gastrointestinal myopathy are scleroderma, amyloidosis, hollow visceral myopathy, and mitochondrial myopathy; the neuropathic variant may be associated with diabetes mellitus, amyloidosis, paraneoplastic neuropathy, medication use, or no identifiable cause (idiopathic) (1, 2). Chagas' disease is clearly more common in South America (3).

Elucidation of the pathophysiologic nature of the motility disorder requires a careful clinical evaluation to identify the underlying disease process. Thus, postural dizziness, visual disturbances, and sweating abnormalities suggest the presence of an underlying autonomic neuropathy, and urinary symptoms indicate genitourinary involvement by a generalized visceral neuromyopathic disorder (4). The history should record the previous or current use of anticholinergics, phenothiazines, antihypertensives, tricyclic antidepressants, serotoninergic agents, dopaminergic drugs, opiates, and calcium-channel blockers, all of which can cause a deterioration of intestinal propulsion (2, 4). Family history can suggest that the disorder is congenital. Physical examination should encompass a careful neurological examination, including testing for orthostatism, pupillary reactions to light and accommodation, and external ocular movements to help identify conditions associated with autonomic neuropathy or external ophthalmoplegia (2, 4).

Pathophysiology
NEUROPATHIC PSEUDO-OBSTRUCTION
A neuropathic disorder affecting gut motility may be confined to the extrinsic innervation of the gut or the intrinsic or enteric nerves, or it may affect both levels of neural control. Extrinsic abnormalities include central nervous system diseases (e.g. brain tumor, Parkinson's disease, spinal cord injury) and autonomic neuropathies (e.g. diabetes mellitus, amyloidosis) (5). Specific, noninvasive tests of autonomic function (Table 2) identify the extrinsic dysregulation in the neural control of viscera (5). Structural examinations such as a CT scan or an MRI of the brain are indicated if these autonomic tests suggest a central lesion (5), for example, when the thermoregulatory sweat test is abnormal but the peripheral sympathetic tests (e.g. norepinephrine levels) are normal.

MYOPATHIC PSEUDO-OBSTRUCTION
Identification of an underlying myopathic disease process requires a thorough family history, serological tests, fat or rectal biopsy to rule out amyloidosis and infiltrative disorders such as progressive systemic sclerosis (2, 5), and measurement of muscle enzymes and lactate or pyruvate levels to search for a generalized muscle disease such as dystrophy or mitochondrial myopathy (6). The combination of cerebral, autonomic, muscular, and gastrointestinal involvement is typically associated with a mitochondrial myopathy (6, 7).

Some conditions, such as amyloidosis and scleroderma, are characterized by a bimodal evolution with an initial neuropathy, followed by a myopathic picture (8, 9).

Clinical Presentation
CIP is characterized by recurrent symptoms suggestive of intestinal obstruction (1, 2). As indicated by the prefix "pseudo," symptoms occur in the absence of any demonstrable mechanical obstruction. Notwithstanding its name, chronic intestinal pseudo-obstruction may affect any part of the gastrointestinal tract, and patients present with a whole spectrum of clinical manifestations that may vary with the natural evolution of the disease over years (2). Thus, symptoms may include dysphagia and heartburn, early satiety, nausea and vomiting, bloating, abdominal distention and discomfort, and constipation. In children there may be associated weight loss or failure to thrive, and some patients experience alterations in defecation patterns—either diarrhea (secondary to bacterial overgrowth) or constipation (which may reflect colonic involvement) (2). A considerable proportion of patients (ranging from 10% to 50%) undergoing subtotal colectomy for constipation showed evidence postoperatively of dysmotility in the esophagus, stomach, and small intestine (10, 11).

Diagnosis
A high index of clinical suspicion, with recognition of the clinical syndrome, is the first step in diagnosing CIP (4). All too often, patients undergo an unnecessary exploratory laparotomy because of suspected mechanical obstruction. It is essential to exclude mechanical obstruction and mucosal disease (e.g. Crohn's disease) by radiologic, endoscopic, and biopsy assessment. The much more prevalent functional diseases of the gastrointestinal tract (e.g. nonulcer dyspepsia, constipation-predominant irritable bowel syndrome) present similar symptoms; CIP must be differentiated by objective physiologic tests (4).

RADIOLOGIC STUDIES
The main goal of radiology in CIP is to exclude mechanical obstruction. Radiologic findings in CIP patients rarely identify the diagnosis (e.g. identifying scleroderma by the characteristic appearances of valvulae conniventes); however, radiologic features are by no means specific for a myopathic or a neuropathic disorder (2). Visceral neuropathy may be associated with disorganized muscle contractions on barium fluoroscopy (12). A myopathic process is characterized by megaduodenum or megacolon, loss of haustrations, and absent contractile activity (12). Small-bowel dilatation is a nonspecific feature of any type of CIP but is not an invariable finding, since patients in an early stage of the disease can display a normal-caliber small intestine on small-bowel X-rays (13). This stage may be referred to in the literature as chronic intestinal dysmotility. Small-bowel diverticulosis may be a manifestation of CIP. Rarely, pseudo-obstruction syndromes are associated with pneumatosis cystoides (gas in the intestinal wall) or dilatation of other smooth-muscle viscera, such as the urinary tract (renal pelvis, ureters, and urinary bladder) (13).

A chest CT may be necessary to exclude small-cell lung cancer in the appropriate clinical setting, typically middle-aged smokers with weight loss and inability to eat (5, 14).

HISTOLOGIC DIAGNOSIS
Masson's trichrome stain to identify fibrosis, as well as silver stains of longitudinal section of the myenteric plexus, have revealed several morphological abnormalities in small-bowel and colonic pseudo-obstruction syndromes. These include changes in proportion of argyrophilic neurons, plasma-cell or lymphocytic infiltrations of the myenteric plexus, neuronal intranuclear inclusions in myenteric neurons, and smooth-muscle cell degeneration with replacement fibrosis (15, 16, 17). Sprouting of cholinergic fibers outside the spastic area and lack of cholinergic neurons in the spastic zone characterize Hirschsprung's disease (18).

There is, however, little information on specific neurotransmitter disturbances. Some reports document reduced substance-P or vasoactive intestinal peptide (VIP) immunoreactivity in myenteric plexus neurons of the colon in chronic colonic pseudo-obstruction (19).

Generally, these studies require a resection of dilated segments or a full-thickness biopsy of the intestines. The introduction of laparoscopic surgery has facilitated procurement of tissue. The risk-benefit ratio of obtaining small-bowel full-thickness biopsies is unclear; laparoscopy may cause fewer adhesions than laparotomy but it is still uncertain whether biopsy results influence management more than physiological tests do.

GASTROINTESTINAL TRANSIT
In many centers, a noninvasive transit test is used to differentiate organic dysmotility from functional gastrointestinal disorders. A cost-efficient and reliable whole-gut transit test is a sensitive screening tool for the initial detection of CIP or other dysmotility disorders. This technique, which uses indium-111-labeled solid particles in a delayed-release, pH-sensitive capsule, has been evaluated in a wide variety of motility disorders including pseudo-obstruction (20, 21). Both gastric emptying and small-bowel transit of solids have been found to be prolonged in patients with CIP (22). A useful clinical approach is to obtain scans at 2, 4, 6, and 24 h after meal ingestion and compare transit profiles to those of laboratory-based healthy control values.

MOTILITY STUDIES
If transit is delayed, mechanical obstruction is excluded, and the etiology is unclear, studies of gastrointestinal pressure profiles can confirm the diagnosis and identify the pathophysiologic type of pseudo-obstruction. Normal gastric and small-bowel motility patterns during fasting and postprandially are well characterized (Figure 2).

View larger version (28K): [in this window] [in a new window]   Figure 2. Upper gastrointestinal manometric tracing in a healthy volunteer, showing an interdigestive migrating motor complex during fasting (left) and irregular high-amplitude and sustained contractile activity in the stomach, duodenum, and proximal jejunum during the postprandial period (right).

Motility abnormalities that suggest a neuropathic disorder include aberrant configuration, propagation of phase III of the interdigestive migrating motor complex, sustained uncoordinated motor activity, bursts of phasic pressure activity, and abnormal or absent conversion to a fed pattern after meal ingestion with preservation of normal-amplitude contractions (Figure 3) (13, 23).

View larger version (28K): [in this window] [in a new window]   Figure 3. Postprandial gastric and small-bowel motility recordings in a healthy control (middle), in a patient with neuropathic chronic intestinal pseudo-obstruction (left), and in a patient with a myopathic disorder (right). The neuropathy is characterized by normal-amplitude contractions but a sustained incoordinated contractile activity in the distal duodenum, as well as a lack of consistent antral response. In contrast, myopathic processes are associated with low-amplitude contractions at all levels examined.

An intestinal myopathy is characterized by decreased contraction amplitudes or the complete lack of any motor activity in the affected segment (Figure 3) (13).

Esophageal manometry is especially useful in disorders affecting smooth muscle, such as scleroderma. However, other esophageal motility abnormalities reported in CIP patients are less specific than the small-bowel motor abnormalities described above.

SEROLOGICAL MARKERS
CIP may occur as a paraneoplastic phenomenon in patients with lung cancers, particularly small-cell lung cancer (23), sometimes with other evidence of autonomic or enteric neuropathy (14, 24, 25). In studies, infiltration of the myenteric plexus with mononuclear cells was associated with serum antinuclear neuronal antibody type I (ANNA-1) (24). ANNA-1 antibodies were also accompanied by structural changes of the myenteric plexus in CIP (26). In vitro the antibody may disrupt peristalsis, probably by directly inhibiting both excitatory and inhibitory motor neurotransmission to the circular muscle (27). ANNA-1 autoantibodies are recognized in adults with a spectrum of inflammatory disorders of the central and peripheral nervous system associated with small-cell lung carcinoma (23, 28). Antinuclear neuronal antibodies have also been described in scleroderma and achalasia patients (29).

Therapy
The goals of treatment of CIP should be: (a) maintenance of adequate nutrition and hydration; (b) restoration of normal intestinal propulsion; and (c) treatment of complications such as bacterial overgrowth and intractable pain.

NUTRITIONAL SUPPORT
Chronic dysmotility will eventually result in malnutrition or vitamin deficiencies because of inadequate oral intake, vomiting, and malabsorption. Since both liquids and homogenized solids are more readily emptied from the stomach than solids are, liquid or blenderized food will be better tolerated in patients with impaired gastric emptying (2). Dietary measures also include the use of a low-lactose, low-fiber, polypeptide, or hydrolized-protein diet with multivitamins and supplementation of iron, folate, calcium, and vitamins D, K, and B₁₂ (30). Such oral regimens provide adequate nutritional support in patients with mild to moderate symptoms. If oral nutrition is not feasible, alternative means of nutrition include enteral feeding through a feeding jejunostomy. This procedure should be preceded by a trial for a few days of nasoenteric feeding with infusion rates of at least 60 ml iso-osmolar nutrient per hour (30). In diffuse myopathic disorders, total parenteral nutrition (TPN) may be the only way to deliver the necessary nutrients, maintain weight, and reverse nutritional deficiencies (31, 32). TPN is associated with considerable morbidity and mortality, and it is costly. Morbidity includes thrombosis, septicemia, immune complex glomerulonephritis, problems with venous access, pancreatitis, and alterations in hepatic biochemistry that may ultimately necessitate combined liver and intestinal transplantation (31).

BACTERIAL OVERGROWTH
In CIP, bacterial overgrowth is only reliably diagnosed by culturing small-intestine aspirates, not by using breath tests. Breath tests can produce false-negative results as a result of the delayed delivery of the substrate to be metabolized by the intestinal bacteria; altered intestinal transit could also influence the result of the breath test (33). In patients with demonstrated steatorrhea due to bacterial overgrowth, antibiotics are administered on a rotational basis for 1 week out of 2 to 4 weeks. These include doxycycline, 100 mg b.i.d.; metronidazole, 250 mg t.i.d.; co-trimoxazole, 800/160 mg b.i.d.; and ciprofloxacin, 500 mg b.i.d. (30). Treatment of bacterial overgrowth and secondary fat malabsorption with broad-spectrum antibiotics has been reported beneficial in only a small number of CIP patients (34), and effects of antibiotics on the transit profile are unclear.

MOTILITY-MODIFYING DRUGS
Metoclopramide, a central and peripheral dopamine antagonist that stimulates acetylcholine release, has been used in the treatment of familial visceral myopathy (1), idiopathic CIP (35), and scleroderma (36) but has had disappointing effects on overall symptomatology. Moreover, its long-term use is restricted by a decline in efficacy and by a troubling incidence of central nervous system side effects.

The macrolide antibiotic erythromycin is a potent gastroprokinetic, particularly in diabetic gastroparesis patients (37). It acts as an agonist at both neural and muscular motilin receptors (38, 39). Reports on the use of oral or intravenous erythromycin in selected CIP cases show contradictory results. A major drawback of erythromycin is that it loses much of its stimulatory effect after the first few weeks of treatment, possibly due to down-regulation of motilin-receptor expression (40). Macrolide prokinetics without antibiotic properties ("motilides") are currently under investigation for a number of dysmotility states.

Octreotide, a somatostatin analogue, has a potent inhibitory effect on many gastrointestinal functions, including small-bowel transit. Nevertheless, it also induces fasting-propagated migrating motor complexes in the small intestine. This paradoxical stimulation was associated with clinical improvement of symptoms in a small study of patients with scleroderma (41).

The substituted benzamide cisapride has a general stimulatory and prokinetic effect on the gastrointestinal tract. It acts via activation of a serotonin-4 receptor resulting in enhanced release of acetylcholine from nerve endings within the myenteric plexus (42). Chronic use of cisapride is not associated with undesirable hormonal and neurological side effects, and there is less tachyphylaxis during long-term treatment (43, 44) compared with metoclopramide and domperidone. Several studies showed that cisapride has a beneficial effect on gastric emptying, intestinal transit, and symptoms in pediatric and adult CIP patients. These studies also identified negative response modifiers: underlying myopathic process, absence of migrating motor complexes, and extrinsic vagal neuropathy (44, 45, 46, 47).

Anecdotal reports have documented benefits in CIP with the use of domperidone (48), leuprolide (49), naloxone (50), cholecystokinin (51), and trimebutine (52).

SURGICAL TREATMENT
Surgery has a limited role in pseudo-obstruction. Surgical bypass or resection can be beneficial only in carefully selected patients with localized disease. Perhaps the most effective form of resection is subtotal colectomy with ileorectostomy for chronic colonic pseudo-obstruction. Murr et al (53) reviewed 21 patients who underwent surgery for CIP. Of the 9 patients who underwent bypass or resection of presumably localized disease, 6 could be maintained on oral intake. For patients whose symptoms are persistently intractable and incapacitating, some have advocated radical small-bowel resection or even subtotal enterectomy combined with total parenteral nutrition (54, 55). The most common surgical procedure in CIP is placement of venting enterostomy (53). A venting enterostomy creates an effective means to relieve gaseous distention and bloating, thereby providing symptomatic relief for patients treated with parenteral nutrition (53, 56). It decreases the number of hospital admissions by a factor of 5 and also reduces the number of laparotomies performed for suspected obstruction (53, 56).

INTESTINAL TRANSPLANTATION
For those patients with intestinal failure who cannot tolerate or receive total parenteral nutrition, intestinal transplantation has become a life-saving alternative. Combined small-bowel/liver or multivisceral transplantations are options for patients who have developed liver failure on total parenteral nutrition. Close supervision of total parenteral nutrition may help avoid hepatic steatosis that contributes to the development of parenteral nutrition–related liver damage. Compared with cyclosporine, the new immunosuppressive agent tacrolimus (FK 506) has improved overall survival rates and decreased graft rejection rates (57, 58, 59). In a review of intestinal transplantation for various indications in a mixed pediatric and adult population (180 transplantations in 170 patients), one- and three-year survival rates for isolated intestinal transplantation were 83% and 47%, respectively (58). Of the recipients who were alive, 78% were able to resume oral nutrition and to stop total parenteral nutrition, which indicates that both absorptive and motor function of the denervated graft are re-established, at least partially, after transplantation. However, only 8% of the transplantations were for intestinal failure due to a motility disorder. No data are available on the outcomes of intestinal grafts in CIP patients. Intense immunosuppression with opportunistic infections, a high rate of posttransplant lymphoproliferative disease (57, 60), and complications of long-term total parenteral nutrition are significant factors in outcome of transplantation (61).

Etiology and Presentation
Acute pseudo-obstruction (also called Ogilvie's syndrome) is most frequently encountered as an isolated colonic disturbance in hospitalized patients after major surgery or in association with significant extraintestinal illnesses or medication (62). The peak age incidence for this condition is in the sixth decade and it is more common in males (63). Clinical features closely mimic acute large-bowel obstruction, including colicky abdominal pain or massive and progressive abdominal distention, constipation, nausea, and vomiting (63, 64). Fever and abdominal tenderness, when present, may indicate ischemic or perforated bowel (63, 65).

The exact pathogenesis of acute colonic pseudo-obstruction remains largely unknown and is probably multifactorial. It is likely to involve an imbalance in autonomic innervation of the colon (66) such as decreased parasympathetic (excitatory) drive to the colon and/or an increased sympathetic (inhibitory) drive (65). There are no experimental data to support this hypothesis, but the reversibility of Ogilvie's syndrome indicates that it is not associated with any permanent impairment of the control mechanisms.

Diagnosis
Unfortunately, the diagnosis of acute colonic pseudo-obstruction is often delayed, resulting in improper management and increased morbidity and mortality (63, 64, 65). Plain abdominal radiography may suggest distal colonic obstruction with dilatation of the proximal large bowel, a predominantly gas-filled colon with few if any air-fluid levels, and a normal gas and fecal pattern in the rectum (67); colonic haustral and mucosal patterns are usually preserved, distinguishing this condition from toxic megacolon or inflammatory bowel disease (62, 67). Perforation occurs most commonly in the cecum and results from progressive distention and local ischemia (63, 68). The risk of cecal perforation is low when the diameter is below 12 cm and increases with diameters of more than 14 cm (65). Contrast enemas with diluted barium or water-soluble media (e.g. Gastrografin®) confirm the diagnosis of a functional obstruction or reveal the site of a mechanical obstruction (69). Endoscopy shows dilatation and ischemic mucosal changes.

Therapy
The success of treatment depends on early recognition (63). Conservative treatment includes nasogastric decompression, minimal oral intake, correction of fluid and electrolyte abnormalities, and treatment of any associated conditions or infections (65), under monitoring of evolution by serial abdominal X-rays. If conservative management is unsuccessful, the colon should be decompressed to avoid the risk of cecal ischemia or perforation (63, 65). Perforation is an indication for an emergency laparotomy.

Decompression may be enhanced by the acetylcholine-esterase inhibitor neostigmine, with or without the ganglionic blocker guanethidine (70, 71, 72, 73). Anecdotal reports showed some benefit from the use of prokinetics such as cisapride and erythromycin (74, 75, 76).

Mortality is influenced by mode of treatment, age of the patient, diameter of the cecum at the time of intervention, delay in decompression, and concomitant illness. It can range from 15% in instances of early and appropriate management to 36–44% in the presence of a perforated or ischemic bowel (63).

Colonoscopic decompression for acute colonic pseudo-obstruction is successful in 75–90% of patients (77, 78, 79, 80, 81). Recurrence after decompression occurs in up to 15% of cases (77); repeated decompression may be necessary or a colonic decompression tube may be passed into the colon along a guidewire to reduce the need for repeated colonoscopies and to facilitate decompression by low, intermittent suction (81). Rarely, a cecostomy must be placed surgically or via a percutaneous catheter with endoscopic pull-through (65, 82).

Clinical Presentation
Chronic colonic pseudo-obstruction (CCP), also called colonic inertia or slow-transit constipation, is manifested mainly by constipation (defined as two or fewer bowel movements per week). Slow-transit constipation is when the mean colonic transit time exceeds 72 h or when >25% of ingested radio-opaque markers are retained in the colon after 5 days. This condition is associated with delayed transit through the proximal colon (83). Colonic inertia refers to failure of colonic motility to respond to physiological or pharmacological stimulation in vivo (e.g. with bisacodyl or neostigmine) (84).

The differential diagnosis of CCP includes rectal evacuation disorders, normal-transit constipation, and/or constipation-predominant irritable bowel syndrome.

Etiology and Genetics
CCP may result from extrinsic denervation (e.g. multiple sclerosis, spinal cord injury) or an intrinsic neuropathy. An enteric neuropathy is suggested by deficiencies of substance P, calcitonin gene-related peptide (CGRP), and other peptidergic neurotransmitters in the myenteric plexus of patients undergoing colectomy for colonic pseudo-obstruction (85, 86).

Hirschsprung's disease and localized or generalized megacolon are often considered in the same category as colonic pseudo-obstructions. The localized dysmotility of Hirschsprung's disease results in a spastic segment associated with proximal dilatation. In contrast, the generalized or localized megacolon syndromes are unassociated with a localized spastic segment. Hirschsprung's disease is of great interest because it demonstrates the role of an abnormal intrinsic innervation and it provides a model of chronic pseudo-obstruction with underlying genetic abnormalities.

To date, mutations at six different gene loci involving four different cell systems necessary for normal nerve-cell growth, differentiation, migration, and proliferation have been implicated in the development of Hirschsprung's disease and animal models of megacolon.

THE RET/GDNF SYSTEM
The c-ret proto-oncogene, which encodes for a tyrosine kinase receptor, is necessary for normal development of the mammalian enteric nervous system.

In both sporadic and familial cases of Hirschsprung's disease, mutations at the 10q11.2. locus containing the c-ret proto-oncogene have been identified (87, 88, 89). C-ret mutations are detected more frequently among familial (50%) than sporadic cases (15–20%) and are more closely associated with long-segment than short-segment disease (90). Glial cell line–derived neurotrophic factor (GDNF) is a ligand for the c-ret–encoded tyrosine kinase receptor (91). Murine models lacking the c-ret proto-oncogene or the GDNF-encoding gene have a similar phenotype, with renal agenesis and intestinal aganglionosis (92, 93). Mutations of GDNF-encoding gene have been described in only a few patients with Hirschsprung's disease (94, 95).

THE EDN3/EDNRB SYSTEM
Waardenburg-Shah syndrome, an autosomal recessive disorder, combines features of type 2 Waardenburg syndrome (piebaldism, bicolored irides, sensorineural deafness) and congenital megacolon. It is caused by homozygous mutations at either the EDNRB or EDN3 loci (96, 97), encoding respectively for the endothelin receptor-B and its ligand endothelin-3. These gene products serve as a signaling pathway for the correct migration and differentiation of enteric ganglions from the neural crest to the gut (98). Heterozygous, incompletely penetrant mutations of both genes have also been demonstrated in 5–10% of patients with Hirschsprung's disease (99).

SOX10
Premature termination of Sox10, a transcription factor, is responsible for absent neural-crest derivatives (precursors of the enteric nervous system) in a mutant Dom mouse (Dominant megacolon) (100). Mutations in Sox10 have been found in patients with Waardenburg-Shah syndrome; no mutations have yet been detected in Hirschsprung patients (101).

Because many patients with Hirschsprung's disease do not bear any of the mutations in known genes, it is anticipated that new susceptibility loci for Hirschsprung's disease will soon be discovered. However, the low mutation rate of susceptibility genes in sporadic Hirschsprung's disease suggests that environmental factors may also be involved in the development of the disease.

C-KIT
A fourth group of genetic disorders includes the proto-oncogene c-kit, which encodes for a tyrosine kinase receptor that is thought to be essential for proper development of interstitial cells of Cajal (ICCs) (102). ICCs are considered the pacemaker cells initiating contractile activity in the gastrointestinal tract (103). In a murine model that lacks the proto-oncogene c-kit (the W/W mutant mouse), ICCs are totally absent in the myenteric plexus of the small intestine, resulting in chaotic intestinal propulsion (104). In patients with Hirschsprung's disease and chronic idiopathic intestinal pseudo-obstruction, a relative deficiency of myenteric plexus c-kit positive cells has been reported (105, 106).

Diagnosis
Diagnosis of CCP should be primarily focused on confirming delayed or absent colonic transit, which is most effectively assessed by transit tests using radio-opaque markers or isotopes (107, 108). Simple procedures such as anorectal manometry with balloon expulsion test, defecation proctography, or rectal scintigraphic emptying test can assess evacuation disorders (109).

Therapy
Dietary fiber is rarely helpful in CCP and frequently exacerbates pain and bloating. Adequate hydration is important in order to facilitate the action of bulking agents. The mainstays of treatment are enemas, osmotic laxatives, and stimulant oral laxatives and stimulant suppositories (e.g. bisacodyl). Cisapride has proven beneficial only in CCP patients with recent-onset constipation or severe slow-transit constipation due to spinal cord injuries (110). Novel, more colon-selective prokinetics are being studied to assess their effect on symptoms and colonic transit in slow-transit constipation patients.

Surgery should be considered as a last resort in selected CCP patients. Colectomy with ileorectal anastomosis has a variable outcome, with some patients experiencing excellent results while others develop diarrhea (111). A minority of these patients will experience residual constipation.

Physicians' increased awareness of acute and chronic intestinal pseudo-obstruction syndromes has led to improved diagnosis and diagnostic criteria through manometric, scintigraphic, histological, and serological techniques. Our understanding of pathophysiology has benefitted from the identification of specific abnormalities in the neuromuscular apparatus by morphologic and immunohistochemical assessment of intrinsic neurons and their neurotransmitter content. Further advances will stimulate development of novel therapies; these studies include the elucidation of the cellular and molecular abnormalities of nerves and smooth-muscle cells from patients with these relatively rare diseases. Meanwhile, treatment should continue to focus on restoration of hydration and nutrition, decompression of bowel if required, and restoration of intestinal propulsion by means of prokinetic medication.

Annu. Rev. Med. 1999. 50:37-55
Copyright © 1999 by Annual Reviews. All rights reserved
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