Chronic Diarrhea in Diabetes Mellitus - Mayo Clinic Proceedings

Subject Review Chronic Diarrhea in Diabetes Mellitus: Mechanisms and an Approach to Diagnosis and Treatment

MIGUEL

A. VALDOVINOS, M.D.,* MICHAEL CAMILLERI, M.D., AND BRUCE R.

ZIMMERMAN, M.D.

In this study, our aim was to develop a practical strategy to facilitate the management of patients with diabetes mellitus and chronic diarrhea in a tertiary referral practice. We reviewed the pertinent English-language literature of the past 30 years that described the pathophysiologic mechanisms and treatment of patients with diabetic diarrhea and retrospectively reviewed the medical records of all patients with diabetic diarrhea examined at the Mayo Clinic during 1990. Three typical case studies are described to illustrate the diverse mechanisms that lead to chronic diarrhea in patients with diabetes. No report in the literature has systematically evaluated all the putative mechanisms of chronic diarrhea in any group of patients with diabetes. In our tertiary referral practice, diabetic diarrhea was frequently due to celiac.sprue, bacterial overgrowth in the small bowel, or fecal incontinence in conjunction with anorectal dysfunction; however, in almost 50% of the patients, these causes were excluded, and abnormal intestinal motility or secretion was postulated to be one of the likely causes ofthe diarrhea. These data suggest a practical algorithm based on three sequential assessments: first, tests of blood and stool specimens and flexible sigmoidoscopy to detect evidence of malabsorption or disease in the distal colon; second, small bowel aspirate and biopsy if the results of initial blood or stool tests are abnormal or anorectal function tests if those test results are normal; and, finally, measurement of gastrointestinal transit or therapeutic trials with opioids, clonidine hydrochloride, and, rarely, cholestyramine resin or octreotide acetate (or both methods). The mechanisms whereby abnormal neural function due to diabetes results in altered digestive, secretory, absorptive, or motor function necessitate further elucidation. The management of chronic diarrhea in patients in a tertiary referral practice, however, can be based on a practical algorithm to determine the cause and to adopt specific treatment to correct it. Gastrointestinal symptoms are common and varied in patients with diabetes mellitus who are examined in tertiary referral practices. I Diarrhea has been known to be associated with diabetes mellitus for more than 50 years,' and its overall prevalence in patients with diabetes has been reported to vary from 8 to 22%.1-3 These data may be influenced by selection (referral) bias; moreover, because no prospective epidemiologic studies are available from a random sample of From the Gastroenterology Research Unit (M.A.V., M.C.) and Diabetes Clinic (B.R.Z.), Mayo Clinic Rochester, Rochester, Minnesota. *Current address: Instituto Nacional de la Nutricion, Mexico City, Mexico. Address reprint requests to Dr. Michael Camilleri, Gastroenterology Research Unit, Mayo Clinic Rochester, 200 First Street SW, Rochester, MN 55905.

Mayo Clin Proc 1993; 68:691-702

patients with diabetes, these figures may not reflect the actual prevalence of diarrhea. The pathogenesis of chronic diarrhea in patients with diabetes is incompletely known. Several mechanisms may contribute to the development of this condition: anorectal dysfunction," abnormalities in intestinal motility' and secretion,' bacterial overgrowth in the small bowel," bile acid catharsis,' exocrine pancreatic insufficiency.v' and celiac disease." The relative frequencies of these mechanisms in unselected patients with diabetes are unclear, however. In this article, we review the literature on mechanisms of chronic diarrhea in patients with diabetes, provide examples of clinical cases, retrospectively review the causes in all patients with an indexed diagnosis of diabetes mellitus and diarrhea examined at the Mayo Clinic during 1990, and 691

© 1993 Mayo Foundation for Medical Education and Research

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CHRONIC DIARRHEA IN DIABETES MELLITUS

propose an algorithm for the diagnosis and treatment of such patients. DEFINITION AND CLINICAL FEATURES Among patients with diabetes in whom chronic diarrhea develops, one subgroup has "diabetic diarrhea"; this term was first used in 1936 by Bargen and associates- at the Mayo Clinic to describe the unexplained diarrhea associated with severe diabetes. Subsequent reports emphasized that patients with diabetic diarrhea usually have poorly controlled diabetes and evidence of a generalized neuropathy.l':" Typically, diabetic diarrhea is chronic and occurs in patients with a long-standing history of insulin-dependent diabetes mellitus; 14 generally, it begins a mean of8 years (range, from a few months to several decades) after onset of diabetes. The male-to-female preponderance is 3 to 2.J5 Peripheral neuropathy is present in most patients, and autonomic neuropathy, including abnormal pupillary responses, anhidrosis, gustatory sweating, orthostatic hypotension, impotence, retrograde ejaculation, and dysfunction of the urinary bladder, is common." Some patients have early satiety, nausea, and vomiting, factors that suggest impaired gastric emptying. 16 The diarrhea is often severe; the stools are usually brown, watery, voluminous, and, occasionally, accompanied with tenesmus.r-'? Diarrhea can occur at any time but is often nocturnal'? and may be associated with anal incontinence.'? The bouts of diarrhea are usually episodic with interposed normal bowel movements or even constipation." Diabetic diarrhea, however, is only one of the possible causes of chronic diarrhea in patients with diabetes. REPORT OF CASES The following three typical cases illustrate the various mechanisms that result in chronic diarrhea in patients with diabetes mellitus. Case I.-A 28-year-old woman with insulin-dependent diabetes mellitus of 12 years' duration and gastroparesis for the previous 6 years came to our institution because of chronic diarrhea, lack of sensation of stool in the rectum, and fecal incontinence, especially at night. The pupils reacted to accommodation but not to light; she had postural hypotension (120/80 mm Hg to 90/60 mm Hg), The anal sphincter tone was decreased. Anorectal manometry revealed mostly low resting pressures in the anal canal (proximal, 10 mm Hg [normal, 40 to 60]; middle, 38 mm Hg [normal, 50 to 80]; and distal, 50 mm Hg [normal, 30 to 50]). In contrast, maximal voluntary squeeze pressures were essentially normal (proximal, 93 mm Hg [normal, 115 to 150]; middle, 103 mm Hg [normal, 100 to 150]; and distal, 120 mm Hg [normal, 80 to 120]). The rectosphincteric reflex was elicited normally with a threshold of 15 rnl of air (normal, less than 10). A distended balloon in the rectum was

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first sensed at a volume of 30 ml (normal, less than 20). Rectal capacity and compliance as well as rectoanal angle measurements at rest, during squeeze, and during defecation were normal. A 50-rnl balloon placed into the rectum was expelled normally. In summary, the patient had autonomic neuropathy, decreased rectal sensation, and dysfunction of the internal anal sphincter that caused fecal incontinence. Case 2.-A 23-year-old woman with a 17-year history of insulin-dependent diabetes mellitus sought medical attention because of chronic diarrhea, abdominal bloating, and nocturnal fecal incontinence. In the past, she had experienced urinary tract infections, tingling in her feet, and dizziness on changing posture. Six years before the current assessment, watery, explosive diarrhea developed, which was worse postprandially. A physical examination revealed postural hypotension, distal sensory neuropathy in both lower limbs, and abdominal distention but no succussion splash or tenderness. The rectal mucosa and anal sphincter tone at rest and during squeeze were normal. The abnormal results of laboratory studies were as follows: total protein, 5.6 g/dl; albumin, 3.3 gldl; urinary protein, 564 mg/24 h (normal, 27 to 93); and stool weight, 990 g with 7 g fat/24 h. Sympathetic adrenergic, sympathetic cholinergic, and vagal dysfunction were noted on autonomic reflex tests." Gastrointestinal manometry"-" showed periodic high-amplitude bursts of phasic pressure activity alternating with quiescence during the postprandial period. By scintigraphy, gastric emptying of solids was delayed; transit of both solid and liquid markers through the small bowel was rapid. In summary, this patient's diarrhea was due to abnormal motility of the small bowel in association with peripheral and autonomic neuropathy. Case 3.-A 27-year-old woman with a 6-month history of chronic intermittent diarrhea came to our institution. She had had insulin-dependent diabetes mellitus since the age of 6 years; retinopathy, autonomic and peripheral neuropathy, and nephropathy were diagnosed when she was 19 years old. She would have two to three bouts of profuse watery diarrhea associated with abdominal cramps and distention for I day and then no stools for 2 to 3 days. On physical examination, the patient's pupils did not react to light, but the accommodation response was normal. Patellar and ankle jerk responses were decreased. The abdomen was distended and tympanitic. Results of an anorectal examination and of proctoscopy were normal. The abnormal results of laboratory studies were as follows: mean corpuscular volume, 77.3 fl; albumin, 2.9 g/dl; and fecal fat, 39,2 g/24 h. No pancreatic calcification was noted on roentgenography; a barium examination showed a hypotonic, moderately dilated small intestine and coarsening of the mucosa. A biopsy specimen of the small bowel revealed subtotal villous atrophy and mononuclear cell infiltration of the lamina propria, findings


compatible with celiac sprue. Small bowel aspirates were negative for Giardia and bacteria. Thus, this patient's chronic diarrhea was attributable to celiac sprue. MECHANISMS OF CHRONIC DIARRHEA IN PATIENTS WITH DIABETES Patients with diabetes in whom chronic diarrhea develops may have incidental diseases that occur in the general population. Several mechanisms (Table 1) that result in chronic diarrhea, however, are induced either by the autonomic dysfunction attributed to diabetes or by a disease more prevalent in patients with diabetes than in nondiabetic persons.

Mechanisms Associated With Autonomic Neuropathy. Motility Disorders of the Small Bowel-Intestinal motility is the end result of an intricately balanced series of control mechanisms: the electrical properties of the smooth muscle cell, the intrinsic nervous system, the extrinsic neural pathways (sympathetic and parasympathetic), the peptidergic transmitters, and the hormonal mediators. 19 Although the digestive tract can function fairly normally without extrinsic nerves, they modulate intrinsic neural reflexes and integrate activity in various regions. Thus, derangements of the extrinsic nerves at any level may result in abnormal gastro' intestinal motility.P-" Certain evidence supports a role of visceral autonomic neuropathy in diabetic diarrhea. First, diarrhea is commonly associated with symptoms of autonomic dysfunction in patients with diabetes.l-" and it occurs in other conditions and situations that affect autonomic nervous function, such as vagotomy, sympathectomy, administration of ganglionic blocking agents, amyloidosis, and primary visceral neuropathies. 1&,21 Second, the density of unmyelinated axons is severely decreased, and the surviving axons in the abdominal vagus nerves of patients with diabetes are of small caliber." Similarly, in patients with diabetic diarrhea, the sympathetic nervous system demonstrates two types of lesions: a hydropic neural change that produces giant neurons and dendritic swelling of postganglionic neurons in prevertebral and paravertebral gangliav-" and decreased fiber density in the splanchnic nerves.P-" Third, although histologic studies of the myenteric plexus in the esophagus and stomach of humans with diabetes demonstrated no abnormalities.v-" streptozotocin-treated rats have decreased sympathetic fibers in the myenteric plexus." Patients with diabetic diarrhea have abnormal motility of the small bowel during fasting and postprandially; migrating motor complexes develop prematurely during the postprandial period." In their study of 12 patients with non-insulindependent diabetes, autonomic neuropathy, and diarrhea, Dooley and associates" found that the duration or propagation velocity of the interdigestive migrating motor complexes was abnormal.


693

Table I.-Mechanisms of Chronic Diarrhea in Patients With Diabetes Causes associated with autonomic neuropathy

Abnormal motility of the smallbowel Bacterial overgrowth in the smallbowel Abnormal colonic motility Anorectal dysfunction Exocrine pancreatic insufficiency Intestinal secretion

Factors associated with diabetes mellitus

Celiacsprue Bile acid catharsis Dietetic foods

Incidental causes

Small intestinal transit in patients with diabetes has been studied by several groups; the results have been conflicting. One group of investigators" found no significant difference in orocecal transit between control subjects and 25 unselected male patients with insulin-dependent diabetes. A third of these patients, however, had abnormal intestinal transit of the liquid test meal (four had rapid and four had delayed transit); one patient with diarrhea had rapid intestinal transit. Other investigators" measured duodenocecal transit in 19 patients with chronic diabetes: those without gastrointestinal, symptoms had prolonged transit times in comparison with patients who had diabetes and constipation or diarrhea and healthy control subjects. Another group of investigators" found no significant overall difference in orocecal transit between 43 patients with insulin-dependent diabetes and gastrointestinal symptoms and 30 normal control subjects. The proportion of subjects with prolonged transit was substantially higher, however, in the group with diabetes. In another study, 12 patients with non-insulindependent diabetes and diarrhea had prolonged orocecal transit time in comparison with control subjects." Overall, no convincing evidence supports abnormal transit in studies in which orocecal transit time was used. Nevertheless, two types of abnormal intestinal transit among patients with diabetes and altered bowel habits are conceivable-slow intestinal transit in some and rapid transit in others. Whether diarrhea develops in patients with slow small bowel transit because of bacterial overgrowth or another mechanism, such as intestinal secretion, is unclear. Systematic studies are needed; the availability of novel, separate scintigraphic measurement of gastric emptying and small bowel transit (see subsequent discussion) may provide further insights into this issue. Bacterial Overgrowth in the Small Bowel-In conditions such as systemic sclerosis, the absence of interdigestive migrating motor complexes and delayed intestinal transit are associated with bacterial overgrowth in the small boweP5.36

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that results in deconjugation of bile salts, fat malabsorption, and diarrhea. Increased concentrations of colonic bile acids induce colonic secretion. This sequence of events may pertain to patients with diabetes whose diarrhea frequently responds to broad-spectrum antibiotics.V:" This sequence, however, has rarely been proved, and steatorrhea and bacterial overgrowth have been reported infrequently in previous studies. Whalen and colleagues'? found evidence of bacterial overgrowth in the upper part of the digestive tract in 1 of 13 patients with diabetes and diarrhea; however, it was verified only in the stomach of this patient, and a decrease in bacterial counts after 10 days of tetracycline therapy was not associated with diminished diarrhea. Goldstein and coworkers" analyzed aerobic cultures of small bowel aspirates in seven patients with diabetic diarrhea; only two had more than lOS colony-forming units/mI. Dooley and associates" reported bacterial overgrowth in 3 of 12 patients (25%) with diabetes and diarrhea. Abnormal Colonic Motility.-Colonic motility has not been measured in patients with diabetes and diarrhea, but colonic dilatation- has been reported in patients with nocturnal diarrhea associated with diabetes mellitus." Some patients with diabetes mellitus have myoelectrical and motor abnormalities in the colon. Battle and colleagues" demonstrated that the colonic motor response to eating is absent or extremely delayed in patients with diabetes and constipation in comparison with normal subjects. More systematic studies of colonic motility are awaited, however, to evaluate the role of colonic dysmotility in the pathogenesis of diarrhea in patients with diabetes. Anorectal Dysfunction-Anorectal dysfunction is relatively common in patients with diabetes assessed at tertiary referral centers. Fecal incontinence is experienced by approximately 20% of patients with chronic diabetes mellitus.' Patients with fecal incontinence frequently complain of "diarrhea," even though stool volume or consistency may be unaltered. In an outpatient survey conducted in a Veterans Administration and university medical center, 1 almost half the patients with diabetes and diarrhea had incontinence; 10% of these patients had episodes of fecal incontinence without chronic diarrhea. Factors that maintain fecal continence are the high-pressure zone in the anal canal (internal and external sphincters); angulation at the junction between the rectum and the anal canal; anorectal sensory and reflex mechanisms; distensibility, tone, and capacity of the rectum; rectal motility and evacuation; and stool volume and consistency. Wald and Tunuguntla? compared anorectal sensation in 14 patients with diabetes and incontinence with three patient control groups: patients with diabetes and continence, nondiabetic patients, and nondiabetic patients with incontinence. They demonstrated that patients with diabetes and incontinence

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had a higher threshold for rectal perception of balloon distention, an outcome that suggests sensory dysfunction. The mean resting anal sphincter pressure was also significantly decreased in 16 patients with diabetes and incontinence in comparison with that of both healthy persons and patients with diabetes and continence;" however, the squeeze pressure was similar among these three groups. Because the internal anal sphincter contributes up to 85% of resting basal pressure and the squeeze pressure is generated by contraction of the external anal sphincter, these results suggest that patients with diabetes and fecal incontinence have dysfunction of the internal anal sphincter. Sympathetic dysfunction contributes to this abnormality. Exocrine Pancreatic Dysfunction-Impaired exocrine pancreatic function is manifest by the decreased output of pancreatic enzymes and bicarbonate or by the decreased volume of stimulated secretion8,9,44-46 due to pancreatic atrophy," disruption of cholinergic enteropancreatic reflexes,48,49 or increased serum levels of peptides, such as glucagon, 50 somatostatin," and pancreatic polypeptide," which diminish pancreatic secretion. Exocrine pancreatic function was significantly impaired in 10 patients with non-insulin-dependent diabetes, neuropathy, and diarrhea." Although most of these patients had some degree of impaired pancreatic function, only 20% had steatorrhea. Thus, most patients have sufficient pancreatic reserve to maintain normal digestion. Intestinal Secretion-Alterations in transport of water and electrolytes by the intestinal epithelium have also been implicated in diarrhea in patients with diabetes. Intestinal perfusion studies showed absence of a basal secretory state but increased fluid secretion in the ileum in response to a "meal" of D-xylose in water.v Chang and colleagues' demonstrated that impaired adrenergic regulation of mucosal transport of ions resulted in a decreased rate of absorption of fluid and electrolytes in the ileum and colon of diabetic rats. The ~ -adrenergic agonist clonidine hydrochloride was useful in treating three patients with diabetes and unexplained diarrhea after other therapies had failed. 53 A clinical response to clonidine might suggest that diarrhea in these patients is due to intestinal secretion. ~-Adrenergic agonists, however, also affect gastrointestinal motor function. Intrathecal and systemic stimulation of ~-adrenergic receptors in dogs" abolishes normal postprandial motility of the stomach and small bowel and may substantially prolong intestinal transit; thereby, normal absorption can occur. Experimental models of diarrhea induced by intragastric infusion of fluids in healthy volunteers have shown that clonidine increased the total gut volume and decreased the volume of rectal effluent; hence, its antidiarrheal effect apparently is exerted by altering the motility of the gut." Impaired motor function and secretion may coexist and act synergistically to cause diarrhea.


Another potential mechanism that results in intestinal secretion in diabetes is increased intestinal permeability as reported by Cooper and coworkers.f This observation, obtained by using mannitol and lactulose, has not been confirmed by other investigators or with other probe molecules, such as polyethylene glycol 400. The precise role of altered permeability necessitates further elucidation. Factors Associated With Diabetes Mellitus. Celiac Sprue.-The association of celiac disease with diabetes mellitus in children'" and adults lO•58 is well known. The incidence of celiac disease in adults with diabetes mellitus has been estimated at 1 in 1,700 among those who attended a diabetic clinic in Birmingham, England.'? Whether this rate applies to all racial groups is unclear. A genetic predisposition to both diseases has been suggested; the prevalence of the histocompatibility antigens HLA-B8 and HLA-DR3 is significantly higher in patients with celiac disease or insulindependent diabetes mellitus than in control populations.Y" Bile Acid Catharsis.-Molloy and Tomkin? found that patients with diabetes and diarrhea had significantly smaller bile-salt pools and increased fecal excretion of total bile salts than those without diarrhea, findings that suggest that bile acid malabsorption is important in the pathogenesis of diarrhea. Other investigators, however, did not find increased fecal excretion of bile acids, and they reported that cholestyramine resin was an ineffective treatment." Therefore, the precise role of this entity in chronic diarrhea in patients with diabetes is unclear. Moreover, impaired ileal reabsorption of bile acids is conceivably at least partly due to accelerated small bowel transit or bacterial deconjugation. Dietetic Foods.-Another factor that may be responsible for diarrhea in patients with diabetes is the excessive consumption of dietetic foods that contain sorbitol as the sweetener. Ingestion of sorbitol, in amounts as little as 10 g, may produce diarrhea in healthy persons." A similar prevalence of sorbitol intolerance was detected in persons with or without diabetes." Many persons who consume sorbitol are unaware of its presence in the diet; diarrhea may be significantly more prevalent among patients with diabetes who consume sorbitol than among those who do not."

ANIMAL STUDIES-FURTHER CLUES TO UNDERSTANDING THE MECHANISM OF DIARRHEA IN DIABETES Motility and Transit.-Gastrointestinal motility is disordered in diabetic animals because of a disruption in the integrity of the nerves that regulate gastrointestinal motor function. Megacolon" and delayed small bowel transit" were described in rats with streptozotocin-induced diabetes. Spontaneously diabetic Chinese hamsters had impaired gastric emptying, atony of the stomach and intestines, and decreased intestinal peristaltic activity." Some investigators


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reported abnormalities in myoelectrical activity of the rat small intestine within 2 weeks after diabetes mellitus was induced/" Changes in myoelectrical activity promoted overgrowth of bacteria. These abnormalities became more apparent after a prolonged diabetic state/" Enteric Nerves.-Histologic evidence of visceral nerve destruction and biochemical evidence of cholinergic and adrenergic denervation have been found in rats with streptozotocin-induced diabetes." Selective degeneration of adrenergic nerves of the myenteric plexus of the rat ileum has been demonstrated." Vasoactive intestinal peptide (immunoreactivity and concentration) is increased in the myenteric plexus and smooth muscle layers in both the ileum and the proximal colon from diabetic rats." Decreased concentrations of neuropeptide Y, serotonin, substance P, and calcitonin gene-related peptide in submucosal neurons suggest that visceral sensation and peptidergic control of the mucosal transport of fluids and the peristaltic reflex may also be altered in diabetic rats. 69,70 Impaired adrenergic regulation of the transport of ileal and colonic fluids and electrolytes has been suggested as the pathophysiologic basis for diabetic diarrhea in rats.' This disorder is associated with decreased mucosal norepinephrine stores, which are a measure of adrenergic tone." In vitro, exogenous I-epinephrine induced substantial transmural short-circuit currents in the diabetic rat ileum, an outcome that suggests denervation hypersensitivity due to increased numbers of postsynaptic ~-adrener gic receptors. Clonidine, an ~-adrenergic agonist, corrected impaired absorption of fluids in these rats." Smooth Muscle.- The structural and functional characteristics of smooth muscle from the small intestine of diabetic rodents have been described. A net increase in the weight and surface area of the small intestine is associated with increased mucosal and intestinal smooth muscle mass." Insulin treatment or pancreatic transplantation" partially reversed the increase in total mucosal and intestinal mass. Despite these morphologic changes, however, diabetic intestinal muscle retains its tensile properties and sensitivity to cholinergic stimulation. The relationship between the morphologic changes and the mechanisms of altered motility previously described is unclear. Pancreatic Function.-Pancreatic function is altered in animal models of diabetes. Cerulein-stimulated secretion is decreased," and this decrease is accompanied with a parallel change in amylase messenger RNA,75 outcomes that suggest impaired enzyme synthesis. Other studies have shown altered secretory responses to specific secretagogues.":" In vitro studies support defects both in the synthesis and in the secretory response to cholecystokinin and cholinergic agonists." In contrast, in vivo studies have shown that cholecystokinin-8 stimulates greater increases in output of protein and rate of juice flow from diabetic rat pancreas in compari-

696



son with normal animals." These apparently conflicting data may be reconciled by recent observations in the isolated perfused pancreas from diabetic rats that have a decreased sensitivity to cholecystokinin and an increased sensitivity to carbachol." The sensitivity of the pancreas to vagal stimulation may be increased in order to compensate for the decreased sensitivity to other secretagogues, such as secretin and cholecystokinin. In summary, studies in animal models of diabetes confirm abnormalities of transit, secretion, and pancreatic function. They provide useful models for studies of the mechanisms that lead to these altered functions; however, much work is needed for a clearer understanding and an improvement in the management of patients with diabetes and diarrhea.

CAUSES OF CHRONIC DIARRHEA IN PATIENTS WITH DIABETES IN A TERTIARY PRACTICE A practical algorithm for the management of patients with diabetic diarrhea depends on the relative prevalence of the various causes. Thus, we retrospectively reviewed the case records of 85 patients in whom a diagnostic computerized listing at the Mayo Clinic identified the two codes-"diabetes mellitus" and "diarrhea"-during 1990. We excluded

patients with a primary diagnosis of exocrine pancreatic insufficiency. In approximately two-thirds of patients identified by the computerized listing, the diarrhea was acute, persisted less than 3 weeks, or was associated with an infectious cause or another specific gastrointestinal disorder, such as inflammatory bowel disease or cancer of the colon; the medical records of these patients were excluded from subsequent analysis. Of the 85 patients, 33 fulfilled diagnostic criteria of chronic diarrhea-that is, increased frequency or liquidity of bowel movements of more than 3 weeks' duration, unassociated with a demonstrable acute infection or specific diagnosis. The 22 female and 11 male patients ranged in age from 2 to 82 years (mean, 55). All except five patients had insulin-dependent diabetes mellitus of 2 to 45 years' duration (mean, 17.3) at the time of the current assessment. The diagnostic criteria used to classify the various mechanisms of diabetic diarrhea as definite, probable, or possible are listed in Table 2. Thus, a definite diagnosis was based on the demonstration of the mechanism and clinical or histologic response to treatment of that specific disturbance. A possibility of the diagnosis was usually based on a clinical response. In the current study, the only time the category of "probable" diagnosis was encountered was in a patient in

Table 2.-Criteria for Classification of the Various Mechanisms of Diabetic Diarrhea* Mechanism

Criterion

Definite

Diagnosis Probable

Possible

Bacterial overgrowth in the smallbowel

> 105 cfu/ml of bacteriain smallbowelaspirate Response to antibiotics Flat biopsyof the smallbowel Improved biopsyfindings afterGFD Clinical response to GFD i stoolbile acids Response to cholestyramine J, resting pressure or abnormal rectalsensation on anorectal manometry Fecalincontinence Abnormal results on GI manometry or transit study Response to opioidsor clonidine Abnormal resultsof lactosehydrogen breathtest Response to lactose-free diet Intakeof medication known to causediarrhea Response to withdrawal

+

+

-orNA

+ + +

+

+ NA NA

+ +

+ NA

+

NA

Celiacsprue

Bile acid catharsis Anorectal dysfunction

Intestinal motility or secretory disorder Lactose intolerance Iatrogenic

+ + + + + +

+ + +

+ +

+

+ +

+

+

+

+ +

*cfu =colony-forming units; GFD =gluten-free diet; GI =gastrointestinal; NA = not available; + =present; - =absent. Each subjectwas classified on the basis of at least two criteriafor each mechanism.

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whom a flat biopsy of the small bowel was obtained and who clinically responded to a gluten-free diet; no follow-up biopsy was done. The most common causes of definite diagnoses, celiac sprue and bacterial overgrowth (Table 3), were determined on the basis of mucosal biopsy specimens or aspirates of the small bowel. Among mechanisms in the "possible" categories, anorectal dysfunction, intestinal motility or secretory disorders, and bacterial overgrowth were the most frequent. In this retrospective study, investigations were limited, and many diagnoses were based on "empiric" trials. Future studies are necessary to confirm these findings prospectively. These data, however, provide the basis for initiating a strategy to investigate patients with diabetes and chronic diarrhea. DIAGNOSTIC ALGORITHM A practical algorithm is proposed for the diagnosis of the cause of chronic diarrhea among patients with diabetes mellitus (Fig. 1). The elicitation of the history is the first step in this assessment; the features that suggest malabsorption or fecal incontinence must be carefully evaluated. A detailed history eliminates sorbitol-containing dietetic foods as a cause of osmotic diarrhea. Laxatives and prokinefic agents should also be excluded among drugs that may cause diarrhea. The neurologic examination should be thoroughly performed; in particular, signs of autonomic neuropathy (such as orthostatic hypotension, absence of sweating, and pulse and blood pressure responses to the Valsalva maneuver) should be carefully sought. An anorectal examination provides information on resting and squeeze sphincter tone, sensation, and response of voluntary sphincter contraction.

Absence of the cutaneous anal "wink" reflex is indicative of pudendal neuropathy. The second step in the diagnosis of diabetic diarrhea (Fig. 1) should include routine hematologic and biochemical screening; analysis of stool specimens for blood, leukocytes, ova, and parasites; and flexible sigmoidoscopy. This evaluation allows the exclusion of a specific cause of diarrhea, such as parasitic infection, carcinoma or polyps in the colon, and inflammatory bowel disease. Quantification of stool fat during 48 or 72 hours would be ideal, particularly in a tertiary referral practice; however, recent data" suggest that fecal fat levels of up to 14 g/day may result from altered small bowel motor or secretory function. Hence, fat levels of up to 14 g/day in stool specimens may not distinguish conditions associated with nutrient malabsorption from the effects of altered small bowel motor or secretory function, a factor that may be important in patients with diabetes and diarrhea. If these two initial steps do not reveal the cause of diarrhea, the next approach is to review the history for indicators of anorectal dysfunction and to perform anorectal tests. Fecal incontinence should be considered in patients who complain of chronic diarrhea because many such patients consider both frequent bowel movements and loose stools as synonymous with diarrhea. If a history of fecal incontinence is found, an objective evaluation of anorectal function should be done. Anorectal manometry evaluates the length and symmetry of the anal canal, resting and squeeze sphincter pressures, rectal sensation, compliance and capacitance, and rectoanal inhibitory reflex." Typically, patients with incontinence and diabetes have weakness of the internal anal sphincter" and decreased rectal sensation." Other methods such as scintigraphic assessment of the anorectal angle,"

Table 3.-Causes of Diarrhea in 33 Patients With Diabetes Assessed at a Tertiary Referral Practice Cause Associated with autonomic neuropathy Bacterial overgrowth in the small bowel Anorectal dysfunction Intestinal motility or secretory disorder Associated with diabetes mellitus Celiac sprue Bile acid malabsorption Incidental Lactose intolerance Iatrogenic* Unknown

697

Definite

3 1

3

2

Diagnosis Probable

Possible

Total

5 6

8 7

7

7 4 1 1 2 3

*The condition of two patients treated with cisapride and lovastatin improved after therapy was discontinued.

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History and physical examination Hematology, chemistry, P'I', carotene, thyroxine Stool for excess fat, blood, leucocytes, parasites Flexible sigmoidoscopy POsmVE - Investigate for associated disease: - Celiac sprue - Pancreatic exocrine insufficiency - Bacterial overgrowth -Consider unassociated disease: - Giardiasis - Inflammatory boweldisease

A

NEGATIVE History: Rectal sensation defecation, incontinence

ABNORMAL

A

- Anorectal manometry - Rectal sensation - Rectal balloon expulsion - Defecography

NORMAL -Consider: Bile acid malabsorption - Trial of cholestyramine - Gut dysmotility - Measurement of transit - Trial of: I~ramide

clonidine

antibiotics octreotide

Fig. I. Algorithm for management of patients with diabetes and chronic diarrhea. PT = prothrombin time.

electromyography" nerve stimulation tests," and defecating proctography'" reveal additional information about the anatomy of the rectum and anal canal, electrical activity of the puborectal muscle and external anal sphincter, nerve conduction, and efficiency of evacuation, respectively. If abnormalities such as anemia, macrocytosis, or excessive fat in the stool, which suggest a malabsorptive disorder, are found on the initial tests, specific studies are indicated to diagnose the cause of malabsorption. In patients with diabetes mellitus, the important associated causes of malabsorption are bacterial overgrowth in the small bowel," celiac disease,'? and pancreatic insufficiency." Bacterial overgrowth in the small intestine is usually diagnosed by quantitative culture of jejunal aspirates. A concentration of more than 105 organisms/ml of either aerobic or anaerobic bacteria in intestinal fluid is diagnostic and should lead to a therapeutic trial with antibiotics." Breath tests based on bacterial metabolism and absorption of substrate such as glucose or 14C-o-xylose have also been used to detect bacterial overgrowth. 85 The association of celiac disease with diabetes mellitus should especially be considered if the diabetes is of short duration and if clinical and biochemical studies show evidence of anemia and low folate or albumin levels, findings suggestive of malabsorption.'? A jejunal biopsy is necessary.

Exocrine pancreatic insufficiency due to diabetes can be determined by direct pancreatic function testing with' secretin-cholecystokinin stimulation. Chronic pancreatitis should be suspected if the patient has no family history of diabetes, is not obese, and has a history of heavy consumption of alcohol, recurrent abdominal pain, and severe steatorrhea. In the absence of fecal incontinence or indicators of malabsorption, bile acid malabsorption, abnormal gastrointestinal motility, or altered intestinal secretion is considered. Diagnosing bile acid malabsorption is difficult:" chemical measurement of fecal bile acids" and quantification of the fecal loss of a 14C-bile acid" necessitate collection of stool specimens for 3 days and subsequent expensive and timeconsuming manipulations of the sample. Breath tests, such as the 14C-glycocholate test, have also been used to detect bile acid malabsorption if the breath measurements are accompanied with direct assays of radioactivity in the stools." The "Se-homocholic acid taurine 5Se-HCAT) retention test is a simple method to determine bile acid absorption." The gamma-emitting isotope 75Se can be easily measured either by whole-body counting or by counting of unprocessed sealed samples of stool specimens, and results with this method have correlated well with direct measurements of fecal excretion of bile acids." Patients with diarrhea of small

e


bowel origin, however, may show an abnormal retention of the isotope, possibly because of impaired bile acid reabsorption resulting from altered contact time of luminal content with ileal mucosa. If the 75Se-HCAT test is unavailable, the response to a therapeutic trial with cholestyramine, 4 g administered four times a day, can also be used as an indirect test to diagnose bile acid malabsorption, but falsepositive results can be a problem." Gut dysmotility may be demonstrated by various techniques, including manometty." mouth-to-cecum transit time," and radioisotopic methods." Small bowel manometry is a useful technique for identifying abnormal contractile profiles associated with visceral autonomic neuropathy;" however, these patterns do not differ in patients with slow transit (for example, gastroparesis) or in those with diarrhea and presumed rapid transit. Orocecal transit time is usually measured by the sustained excretion of hydrogen after bacterial metabolism of a nonabsorbable carbohydrate." The sustained increase in breath hydrogen is assumed to reflect substrate arriving in the cecum. Although such breath tests are simple and relatively inexpensive, the results can be influenced by abnormal gastric emptying, a high number of hydrogen-forming bacteria in the small bowel (attributed to bacterial overgrowth), or a low number of bacteria in the colon. Recently, we developed a more accurate, noninvasive radioisotopic technique to measure gastric emptying and small bowel and colonic transit simultaneously;" strategies are available to minimize costs and maintain accuracy." We believe that accurate measurement of small and large intestinal transit time 98,99 may be useful to select patients for treatment with prokinetic agents (that is, diarrhea with delayed intestinal transit and secondary bacterial overgrowth) or with opioids (that is, diarrhea with rapid intestinal transit). Intestinal perfusion studies to detect abnormalities in intestinal absorption or secretion are available at only a few medical centers.l'" A clinical response to clonidine may suggest an underlying secretory disorder.

TREATMENT The initial management of patients with diabetes and chronic diarrhea should be directed toward the correction of the imbalance of water and electrolytes, control of diabetes, and restoration of nutrition, if necessary, with intravenously administered hyperalimentation. We suggest that treatment should be directed at the identified cause of diarrhea rather than sequential empiric trials. For bacterial overgrowth in the small bowel, broad-spectrum orally administered antibiotics, such as tetracycline, cephalosporins, quinolones, and metronidazole, are effective. Antibiotics are prescribed for 10 to 14 days each month on a rotating basis to avoid development of bacterial resistance. A gluten-free diet is


699

prescribed for celiac disease, and pancreatic enzymes are administered to patients with pancreatic insufficiency. Biofeedback techniques seem efficacious in the treatment of fecal incontinence.? Bile acid malabsorption is usually treated with cholestyramine (4 to 12 g/day) or aluminum hydroxide. For patients in whom the pathogenesis of diarrhea is unclear, antidiarrheal agents, such as loperamide hydrochloride and diphenoxylate hydrochloride, can decrease the number of stools, particularly if diarrhea is associated with rapid intestinal transit. Controlled studies are indispensable for accurately establishing the benefit of these agents in the management of diabetic diarrhea. Retardation of motility may actually promote stasis and thereby potentially aggravate bacterial overgrowth. Clonidine, at dosages of 0.1 to 0.6 mg twice a day, decreased the number and volume of stools in a few patients with diabetic diarrhea. 53 Orally administered clonidine may be associated with substantial adverse effects, such as orthostatic hypotension or worsening of gastric emptying, which may limit its use. Topically applied clonidine may control diarrhea without causing hypotension. 101 Its efficacy in diabetic diarrhea warrants further study. The long-acting somatostatin analogue octreotide acetate was proposed as an alternative treatment of chronic diarrhea in patients with diabetes mellitus. 102 Somatostatin inhibits stimulated water secretion in animals and humans.P'-'?' increases gut absorptive capacity,'?' and suppresses gastrointestinal hormones that are potentially diarrheogenic.'?" Octreotide is administered subcutaneously by injecting 50 to 75 ug twice a day and may be given with insulin. 102 Of note, octreotide may inhibit exocrine pancreatic secretion and aggravate nutrient malabsorption.

CONCLUSION AND A LOOK TO THE FUTURE The clinical syndrome of chronic diarrhea in patients with diabetes mellitus has been recognized for almost 6 decades; some aspects of its pathogenesis are understood, but much still needs to be learned about the relative frequency of each putative mechanism of chronic diarrhea in a cohort of unselected patients with diabetes mellitus. Further systematic studies are needed to evaluate some of these potential mechanisms, such as altered motility of the small intestine and intestinal secretion. The published literature presents either conflicting results or limited experience. Among the commonly suspected causes of diarrhea, bacterial overgrowth is demonstrable in a relatively small proportion of patients with diabetic diarrhea, and the reports are only anecdotal rather than series that evaluate the efficacy of empiric antibiotic treatment. The proposed algorithm will allow a systematic study for elucidating the cause of diabetic diarrhea and for selecting more specific treatments for patients with this disorder. Finally, the experimental animal

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models of diabetes should be pursued further to bridge the gap between our understanding of alterations in neurotransmitters in the enteric nerves or extrinsic control and the increasingly recognized gastrointestinal symptoms of patients with diabetes mellitus. ACKNOWLEDGMENT We thank Cynthia L. Stanislav for preparing the submitted manuscript. REFERENCES I. Feldman M, Schiller LR. Disorders of gastrointestinal motility associated with diabetes mellitus. Ann Intern Med 1983; 98:378-384 2. Bargen JA, Bollman JL, Kepler EJ. The "diarrhea of diabetes" and steatorrhea of pancreatic insufficiency. Mayo Clin Proc 1936; 11:737-742 3. Dandona P, Fonseca V, Mier A, Beckett AG. Diarrhea and metformin in a diabetic clinic. Diabetes Care 1983; 6:472474 4. Schiller LR, Santa Ana CA, Schmulen AC, Hendler RS, Harford WV, Fordtran JS. Pathogenesis of fecal incontinence in diabetes mellitus: evidence for internal-analsphincter dysfunction. N EnglJ Med 1982; 307: 1666-1671 5. Chang EB, Bergenstal RM, Field M. Diarrhea in streptozocin-treated rats: loss of adrenergic regulation of intestinal fluid and electrolyte transport. J Clin Invest 1985; 75:1666-1670 6. Goldstein F, Wirts CW, Kowlessar OD. Diabetic diarrhea and steatorrhea: microbiologic and clinical observations. Ann Intern Med 1970; 72:215-218 7. Molloy AM, Tomkin GH. Altered bile in diabetic diarrhoea. BMJ 1978; 2:1462-1463 8. Vacca JB, Henke WJ, Knight WA Jr. The exocrine pancreas in diabetes mellitus. Ann Intern Med 1964; 61:242247 9. Frier BM, Saunders JHB, Worms ley KG, Bouchier lAD. Exocrine pancreatic function in juvenile-onset diabetes mellitus. Gut 1976; 17:685-691 10. Walsh CH, Cooper BT, Wright AD, Malins JM, Cooke WT. Diabetes mellitus and coeliac disease: a clinical study. Q J Med 1978; 47:89-100 11. Rundles RW. Diabetic neuropathy: general review with report of 125 cases. Medicine 1945; 24:111-160 12. Sheridan EP, Bailey Cc. Diabetic nocturnal diarrhea. JAMA 1946; 130:632-634 13. Berge KG, Wollaeger EE, Scholz DA, Rooke ED, Sprague RG. Steatorrhea complicating diabetes mellitus with neuropathy: report of cases without apparent external pancreatic insufficiency. Diabetes 1956; 5:25-31 14. Katz LA, Spiro HM. Gastrointestinal manifestations of diabetes. N Engl J Med 1966; 275:1350-1361 15. Miller LJ. Small intestinal manifestations of diabetes mellitus. Yale J Bioi Med 1983; 56:189-193 16. Yang R, Arem R, Chan L. Gastrointestinal tract complications of diabetes mellitus: pathophysiology and management. Arch InternMed 1984; 144:1251-1256 17. Goyal RK, Spiro HM. Gastrointestinal manifestations of diabetes mellitus. Med Clin North Am 1971 Jul; 55:10311044


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