Endocrinology Metabolism

Diabetes and GI Diseases

Are You Sure the Patient Has A Gastrointestinal Complication of Diabetes?

Diabetes is associated with a range of complications involving the GI tract, biliary tree, pancreas, and liver (see Table I). As many as three quarters of patients with longstanding diabetes report chronic or intermittent GI complaints potentially referable to abnormal sensory or motor function of the gut. Although these conditions are described separately here, recent studies using methods to assess transit or motor function in several gut regions in single tests (such as whole gut scintigraphy or wireless motility capsules) observed evidence of abnormal function in multiple gut regions, emphasizing that many diabetics show generalized gut dysfunction.

Table I.

Diabetes and GI Diseases

Diabetic Gastroparesis/Gastropathy

Definition: Diabetic gastroparesis is a disorder characterized by symptoms of gastric retention occurring in diabetics with objective evidence of delayed gastric emptying of food. Diabetic gastropathy (also referred to as diabetic dyspepsia and gastroparesis-like syndrome) is a condition with similar symptoms but with no evidence of delayed emptying on gastric function testing. Approximately 40% of diabetics with symptoms of gastroparesis will exhibit delayed gastric emptying on diagnostic testing, whereas the remainder will show normal or even accelerated emptying in some cases. The prevalence of delayed gastric emptying in longstanding diabetes irrespective of symptoms has been estimated at 27% to 58%.

Symptoms and Signs: Both diabetic gastroparesis and gastropathy present with a range of symptoms including nausea, vomiting, early satiety, postprandial fullness, bloating, and upper abdominal pain or discomfort. In gastroparesis, nausea and vomiting are the predominant symptoms in approximately 45% of cases, while pain or discomfort are predominant in 20%, emphasizing that gastroparesis is in the differential diagnosis of unexplained abdominal pain. Bloating is reported by 75% of diabetics with gastroparesis and is the predominant symptom in about 7%. Vomiting in the patient with diabetic gastroparesis most often occurs 30-60 minutes after eating. Vomiting of old food ingested more than 8 hours previously is often reported but is not necessary for diagnosis. Complications of vomiting with gastroparesis and gastropathy include loss of dental enamel, GI bleeding from tearing of the gastroesophageal junction (Mallory-Weiss tear) or hemorrhagic gastropathy, and poor glycemic control, which may be manifested as increased risk of both hyperglycemia and hypoglycemia. The pain of gastroparesis commonly is postprandial but may be reported nocturnally in up to 80% of cases. Gastroparesis pain occurs daily in up to 40% of affected diabetics and is described as burning, vague, crampy, sharp, or pressure-like. Symptoms in diabetic gastroparesis are chronic in >50%, but up to 10% will have cyclical symptoms mimicking cyclic vomiting syndrome. Despite these symptoms, weight loss is less common and most diabetics with gastroparesis or gastropathy are overweight or obese. The Gastroparesis Cardinal Symptom Index (GCSI), a validated symptom survey, is composed of nine symptoms in three domains (nausea/vomiting, postprandial fullness/early satiety, and bloating/distention) and is increasingly used in clinical investigation and patient care (Table II). Physical findings on examination of the patient with diabetic gastroparesis or gastropathy usually are normal or nonspecifically abnormal, including epigastric tenderness or evidence of distention with tympany to percussion. In rare cases where there is significant gastric retention of liquids, a succussion splash may be detected on auscultation upon rocking the patient back and forth.

Table II.

Gastroparesis Cardinal Symptom Index (From Revicki et al., Aliment Pharmacol Ther 2003)

Small Intestinal Bacterial Overgrowth

Definition: Small intestinal bacterial overgrowth (SIBO) refers to the syndrome developing as a consequence of an excessive number of bacteria in the small intestine. In this condition, bacterial metabolism of triturated food residue delivered into the small intestine promotes generation of gases (hydrogen, methane) and other byproducts that lead to symptoms and other clinical manifestations of the disorder. In an older study, approximately 40% of long-term diabetics exhibited this syndrome. More recently, 60% of patients with gastroparesis (not all diabetic) exhibited evidence of SIBO with increases in production of hydrogen (63%), methane (27%), or both (10%).

Symptoms and Signs: Symptoms of SIBO overlap substantially with those of gastroparesis as well as those of irritable bowel syndrome (IBS) and other lower functional and motor disorders in nondiabetics and diabetics (including diabetic constipation and diabetic diarrhea discussed below). Unlike gastroparesis and IBS, no symptom scores specifically referable to SIBO have been devised. Symptoms potentially attributable to SIBO include bloating, distention, flatulence, eructation, abdominal discomfort or pain, constipation (especially in patients who produce a predominance of methane gas on diagnostic testing), diarrhea (especially in those who generate predominantly hydrogen gas on testing), steatorrheic manifestations (passage of greasy, oily, or floating stools), or weight loss. It has not been defined if SIBO exacerbates nausea, vomiting, or other symptoms relating to impaired food ingestion in diabetic gastroparesis or gastropathy. The physical exam in most diabetic patients with SIBO is normal, although some individuals exhibit visible abdominal distention on inspection or tympany on percussion.

Diabetic Constipation

Definition: Diabetic constipation is characterized by infrequent or difficult defecation occurring as a consequence of longstanding diabetes. The prevalence of this diabetic complication is uncertain. Older studies report that up to 60% of patients with diabetes of more than 10 years' duration will report constipation, while more recent investigations note much smaller percentages. Some large population surveys report similar rates of constipation in nondiabetics and diabetics; however, these investigations likely include large cohorts with short-duration diabetes or individuals with good glycemic control. Studies using radiopaque marker techniques and whole gut scintigraphy observe prominent delays in colon transit in diabetics with constipation.

Symptoms and Signs: Patients with diabetic constipation report a range of bowel disturbances including infrequent passage of hard stools with significant straining. Diabetics with constipation commonly report other symptoms that occur as a consequence of an inability to evacuate their stools including bloating, distention, abdominal pain, discomfort, and fullness. It is unproved that diabetic constipation worsens other symptoms of gastroparesis; however, delays in colon transit are prevalent in diabetic gastroparesis and physiologic studies involving distention of the rectum retard gastric emptying. Patients with diabetic constipation may exhibit visible distention with variable tympany and/or tenderness or palpable stool-filled bowel loops, usually in the left lower quadrant. Digital anorectal examination may detect hard firm stool in the rectal vault.

Diabetic Diarrhea

Definition: Diabetic diarrhea refers to the passage of frequent or loose stools occurring as a consequence of diabetes usually over a many-year period. The prevalence of diabetic diarrhea has been incompletely characterized. The pathogenesis of this condition is multifactorial (Table III). Many individuals exhibit evidence of SIBO on diagnostic testing and respond to courses of oral antibiotics. One consequence of SIBO is bacterial deconjugation of intestinal bile acids. This can promote development of bile acid diarrhea due to stimulation of colonic fluid and electrolyte secretion by unconjugated bile acids that are not reabsorbed in the distal ileum. Type 1 diabetes is associated with celiac disease; this condition should be excluded in type 1 diabetics especially if there are associated findings to suggest sprue, including anemia or bone demineralization. Type 1 diabetes also is associated with Addison's disease; this disorder is a consideration if there is associated diarrhea, weight loss, and orthostasis unrelated to diabetic dysautonomia. Some patients with relatively recent onset diabetes may exhibit rapid rather than delayed gastric emptying. This suggests that this subset may possess a variant of dumping syndrome, although this has not been verified in clinical studies. Some longstanding diabetics show reductions in pancreatic enzyme secretion secondary to vagal neuropathy and may benefit from enzyme supplementation. Rare cases of diabetic diarrhea may be complications of diabetic constipation with overflow passage of liquid stool around a firm impacted stool bolus in the distal colon. Finally, a subset of diabetics with diarrhea exhibit a true secretory diarrhea occurring as a neuropathic consequence of an imbalance between preserved cholinergic intestinal secretion and impaired adrenergic absorption.

Table III.

Factors Contributing to Diabetic Diarrhea

Symptoms and Signs: Diabetics with diarrhea commonly report passage of loose and/or frequent stools. A commonly noted characteristic of diabetic diarrhea is nocturnal symptoms. If there is associated malabsorption due to associated SIBO, celiac disease (or possibly pancreatic insufficiency), patients may also experience bloating, distention, flatulence, weight loss, or passage of greasy, oily, or floating stools due to steatorrhea. Many patients with high stool volumes will experience associated fecal incontinence because of associated anal neuropathy. Individuals with secretory diarrhea may experience presyncopal events or true syncope due to voluminous fluid loss unrelated to autonomic dysfunction. Physical findings in diabetic diarrhea depend in part on the underlying pathophysiology in a given patient. Examinations may be normal or show evidence of reduced anal tone and squeeze pressures, liquid stool in the rectal vault, distention with or without tympany or tenderness, orthostatic findings on pulse and blood pressure measurement, pallor due to anemia (if associated with celiac disease), or muscle wasting secondary to malnutrition.

Fecal Incontinence

Definition: Fecal incontinence in diabetic patients refers to inadvertent expulsion of feces occurring as a consequence of diabetes. This complication most often is a consequence of anal neuropathy but commonly is exacerbated by associated diabetic diarrhea that overwhelms the ability of the affected patient to voluntarily withhold the stool until it can be evacuated in controlled fashion. Physiologic studies using anorectal manometry suggest that changes consistent with anal neuropathy are as prevalent as delays in gastric emptying in diabetic gastroparesis. Abnormalities demonstrable on testing include reduced resting anal tone (a function of the internal anal sphincter), variably preserved squeeze pressure (a function of the external anal sphincter and levator ani complex), and reduced sensation of rectal stimulation.

Symptoms and Signs: Diabetics with fecal incontinence may report inadvertent stool loss to varying degrees ranging from minor soiling to expulsion of large amounts of stool necessitating wearing of disposable absorptive adult incontinence undergarments. Because of the associated rectal sensory neuropathy, many patients are unable to sense the presence of stool in the rectum prior to its uncontrolled passage. As with diabetic diarrhea, many episodes of fecal incontinence in diabetics occur nocturnally during sleep. Digital examination of the diabetic with fecal incontinence will commonly show evidence of anal neuropathy including marked reductions in anal tone, variable impairments in the ability to maximally squeeze the anus against the examiner's inserted finger, and a loss of the anal wink reflex to perianal stimulation. Patients with associated diabetic diarrhea may have liquid stool in the rectal vault, while those with voluminous stool loss may show signs of perianal irritation due to prolonged contact with expelled feces.

Miscellaneous GI Complications of Diabetes

Abdominal Pain: Some diabetics present with upper abdominal pain occurring as a consequence of neuropathy or radiculopathy of nerves exiting from the thoracic spinal cord. Physical examination in this setting may show cutaneous sensory deficits.

Esophageal: May diabetics exhibit evidence of reduced lower esophageal sphincter tone on manometry or impaired esophageal acid clearance with increased recording time with pH < 4 on ambulatory testing presumably due to altered propulsive clearance in the distal esophagus. Other manometric abnormalities seen in diabetics include reduced contractile amplitudes and velocities, double peaked waves, or simultaneous aperistaltic contractions in the esophageal body and reduced upper esophageal sphincter pressures. Symptoms attributable to these abnormalities are predominantly related to uncontrolled acid reflux and include heartburn and regurgitation. Increases in Candida and pill-induced esophagitis also have been reported with diabetes. Dysphagia due to dysmotility is rare but may occur secondary to stricturing as a complication of acid reflux.

Intestinal: As stated, celiac disease is associated with type 1 diabetes. In this diabetic subtype, celiac disease is detectable in 1.3% to 6.2% of adult patients and 1% to 16% of children. Affected patients most often present with diarrhea, bloating, distention, flatulence, eructation, and weight loss. If the disease is severe, patients may exhibit pallor or emaciation. Chronic intestinal pseudo-obstruction, a neuropathic or myopathic condition with delayed intestinal transit often with luminal dilation, had been reported but is a much less common complication of diabetes than gastroparesis or constipation.

Bilary: The gallbladder can develop profound neuropathic dysfunction as a consequence of longstanding diabetes including impaired stimulated contractility. The main clinical correlate of this dysfunction is an approximate doubling of the risk of developing gallstones and gallstone complications including cholecystitis, gangrene, and sepsis. These complications are especially relevant to type 2 diabetics, many of whom are obese—an independent risk factor for gallstone disease. There often is impaired sensation of biliary complications presumably due to sensory neuropathy involving the gallbladder. Thus, diabetics with cholecystitis may report atypical symptoms or present late in the course of disease.

Pancreatic: Due to vagal neuropathy, patients with longstanding diabetes can exhibit impairments in pancreatic exocrine secretion of digestive enzymes. The clinical consequences of these physiologic impairments have not been well defined, but it has been postulated that reductions in enzyme release can contribute to diarrhea, steatorrhea, bloating, distention, and weight loss. Diabetes also has been associated with increased risks of developing acute pancreatitis and pancreatic adenocarcinoma.

Hepatic: Hepatic steatosis is a recognized complication of poorly controlled diabetes. This condition is more often observed in type 2 patients with associated obesity—an independent risk factor for fatty deposition in the liver. Commonly, this diabetic complication is asymptomatic and is detected on laboratory testing for other conditions. Some patients may exhibit right upper quadrant abdominal pain due to stretching of the hepatic capsule. Physical examinations may be normal or show hepatomegaly with tenderness. Jaundice in uncomplicated cases is unusual. However, hepatic steatosis in diabetics can progress to more severe forms of liver disease including steatohepatitis and end-stage cirrhosis in rare cases, manifest by the typical symptoms and signs of liver failure.

What Else Could the Patient Have?

The differential diagnosis of GI complications of diabetes is very broad and includes other functional, motor, inflammatory, neoplastic, and endocrinologic disorders.

Diabetic Gastroparesis/Gastropathy

There are several other causes of delayed gastric emptying. Idiopathic gastroparesis is the most prevalent form of this condition and, in large series, significantly outnumbers those with diabetic disease. This condition would be considered in diabetics with short duration or very well controlled diabetes who have no other causes of symptoms. Approximately 10% of cases of gastroparesis are postsurgical, occurring after operations for peptic ulcer, after fundoplication for acid reflux, or after bariatric surgery for morbid obesity.

Many such cases occur as a consequence of intended or inadvertent vagotomy. Rarer causes of gastroparesis include connective tissue disorders (e.g., lupus or scleroderma), amyloid, muscular dystrophy, paraneoplastic (e.g., with small cell lung cancer), or endocrinologic (e.g., hypothyroidism, hyperparathyroidism, hypoadrenalism). Pregnancy is a consideration in women of child-bearing potential who report recent onset of nausea and vomiting. Particularly in young women, many of the functional gastroduodenal disorders, defined by the Rome Committee, can mimic gastroparesis, including functional vomiting, chronic idiopathic nausea, and functional dyspepsia.

The Rome Committee also has defined a condition, rumination syndrome, commonly misinterpreted as causing refractory nausea and vomiting. From a clinical standpoint, rumination syndrome is characterized by regurgitation of gastric contents into the mouth within minutes of eating rather than true vomiting, usually without associated nausea. Medications commonly taken by diabetics also can produce symptoms similar to gastroparesis and include calcium channel antagonists taken for cardiac disease or hypertension, opiates for chronic pain (e.g., for diabetic neuropathy), antidepressants in several classes (e.g., venlafaxine, desvenlafaxine, duloxetine), smoking cessation medications (e.g., varenicline), and several antidiabetic medications (e.g., metformin, exenatide, liraglutide, pramlintide).

Other organic diseases producing symptoms similar to diabetic gastroparesis and gastropathy include inflammatory and neoplastic diseases of the upper GI tract (e.g., acid-related esophagitis, fungal esophagitis, peptic ulcer disease, gastritis, duodenitis, gastric outlet obstruction, gastric cancer, gallstone disease, pancreaticobiliary neoplasia).

Small Intestinal Bacterial Overgrowth

As described, symptomatic manifestations of SIBO in diabetics substantially overlap with those of diabetic gastroparesis/gastropathy, diabetic constipation, and diabetic diarrhea. Other functional disorders producing symptoms similar to SIBO include IBS, functional dyspepsia, chronic constipation, functional diarrhea, and other rarer functional disorders such as functional bloating. Celiac disease and other malabsorptive and maldigestive conditions (e.g., chronic giardiasis, pancreatic insufficiency, some cases of Crohn's disease) can mimic SIBO. Dietary factors that commonly produce symptoms similar to those of SIBO include lactose intolerance, nonceliac gluten intolerance, and consumption of high FODMAP (fermentable oligosaccharides, disaccharides, monosaccharides, and polyols) foods, including selected vegetables and fruits and foods and gums artificially sweetened with sorbitol (including many supplements and snacks specifically marketed to diabetics) (Table IV).

Table IV.

FODMAP (Fermentable, Oligosaccharide, Disaccharide, Monosaccharide, and Polyol) Diet (from Eswaran et al., Gastroenterol Clin North Am 2011)

Diabetic Constipation

Diabetic constipation may be mimicked by a number of conditions that impair fecal evacuation of normal consistency stools. The infrequent bowel movements, difficult defecation, and other associated symptoms of this condition are similar to those of selected functional bowel disorders such as IBS or chronic functional constipation. Impaired colon transit also is observed with connective tissue diseases (e.g., scleroderma), infiltrative processes (e.g., amyloid), smooth muscle disease (e.g., muscular dystrophy), endocrinologic disorders (e.g., hypothyroidism, hyperparathyroidism), and autoimmune conditions similar to gastroparesis. In older patients (>50 years), colorectal neoplasia is a consideration. Other obstructive etiologies including inflammatory bowel disease or endometriosis are rarer. Finally, constipation may result from anatomic and functional abnormalities at the anorectal outlet rather than from the colon itself. Large rectoceles or rectal intussusception can present with prolonged straining and incomplete fecal evacuation. Rectosphincteric dyssynergia presents with similar symptoms; affected patients also may repeatedly use digital maneuvers to facilitate stool passage.

Diabetic Diarrhea

As described, diabetic diarrhea may result from a range of pathophysiologic abnormalities. Other conditions may produce diarrhea mimicking diabetic diarrhea including inflammatory bowel disease, microscopic colitis, chronic intestinal infection with Giardia lamblia, rarer infections (e.g., cytomegalovirus, Whipple's), other endocrinopathies (e.g., hyperthyroidism), and intentional or unknowing ingestion of laxatives. As with SIBO, unsuspected dietary factors primarily including high FODMAP foods are considered as potential causes of diarrhea mimicking diabetic diarrhea.

Fecal Incontinence

Incontinence mimicking that reported by diabetics most often results from either local anal trauma or disruption or from significant diarrhea that overwhelms the protective capabilities of the anus. In women, anal damage during forceful childbirth or after inadequately repaired episiotomies is common. Local anal disease including hemorrhoids, fissures, and fistulas (either isolated or secondary to inflammatory bowel disease) can produce similar symptoms. Anal neuropathies also may be reported with sacral spinal nerve disease.

Miscellaneous GI Complications of Diabetes

Abdominal Pain: The differential diagnosis of abdominal pain in a diabetic patient is broad and includes inflammatory causes (pancreatitis, gallstone disease) as well as frequently unrecognized abdominal wall strain secondary to violent emesis. Exacerbation of abdominal tenderness with performance of a Valsalva maneuver or straight leg lift is consistent with abdominal wall strain.

Esophageal: Esophageal manifestations of diabetes may be mimicked by severe gastroesophageal reflux disease or infectious esophagitis unrelated to diabetes or by other selected esophageal dysmotility syndromes (e.g., with scleroderma).

Intestinal: Celiac disease may be mimicked by SIBO, other malabsorptive or maldigestive disorders, or dietary factors as described for SIBO earlier. Intestinal pseudo-obstruction may be caused by a range of other conditions including idiopathic disease, connective tissue diseases (e.g., lupus, scleroderma, dermatomyositis), amyloid, paraneoplastic disease, or endocrinologic conditions. Symptoms of pseudoobstruction also are similar to those of small intestinal mechanical obstruction occurring with adhesions, stricturing from inflammatory bowel disease or medications, or tumors.

Biliary: Several other factors contribute to development of cholecystitis or other biliary complications of diabetes including pregnancy, female sex, obesity, older age, prior biliary infection, and selected medications (e.g., octreotide).

Pancreatic: Other causes of pancreatic insufficiency mimicking that associated with diabetes include alcohol-related, idiopathic disease, cystic fibrosis, hypercalcemia, selected hyperlipidemias, autoimmunity, and mechanical factors causing ductal obstruction (e.g., neoplasm, strictures).

Hepatic: Hepatic steatosis similar to that observed with diabetes may result from obesity, excessive alcohol intake, hyperlipidemia, thyroid disease, and a range of medications.

Key Laboratory and Imaging Tests

The important diagnostic tests needed for evaluation of each of the GI complications of diabetes is distinct as detailed next:

Diabetic Gastroparesis/Gastropathy

Key studies for diagnosis of diabetic gastroparesis include (i) laboratory tests to assess complications of vomiting and to evaluate for other endocrine causes of symptoms, (ii) structural studies to exclude mechanical causes of symptoms, and (iii) tests of gastric function to discriminate diabetic gastroparesis from gastropathy.

Laboratory Studies: A basic electrolyte panel should be obtained to evaluate for hypokalemia and contraction alkalosis. Blood urea nitrogen and creatinine levels should be assessed to screen for evidence of dehydration vs. renal insufficiency. Complete blood count testing can evaluate for anemia (suggesting a mucosal injury process), leukocytosis (suggesting inflammation), or leukopenia (raising the possibility of viral gastroenteritis). A thyroid-stimulating hormone level can test for hypothyroidism.

Structural Evaluation: Exclusion of mechanical obstruction is mandatory in evaluating the patients with suspected gastroparesis. Upper endoscopy can rule out gastric outlet obstruction secondary to stricture, ulcer disease, or neoplasm and can detect retained food or bezoars that can complicate gastroparesis. A plain upright abdominal radiograph can be obtained if more distal obstruction is suspected. This can be further characterized by upper gastrointestinal contrast radiography or computed tomography (CT) methods. If pain is prominent or if liver chemistries are abnormal, abdominal ultrasound may be considered to exclude symptomatic gallstone disease.

Functional Evaluation: Delayed gastric emptying most commonly is documented using scintigraphy. Current consensus recommendation advocate measuring gastric retention after consuming a 99mTc-labeled egg-substitute meal. Gastroparesis is documented when gastric retention at 2 hours is >60% and/or at 4 hours is >10%. Breath tests that measure gastric emptying after consuming nonradioactive 13C-labeled meals are in wide use internationally but are not yet approved in the United States. Wireless motility capsules that measure pH and contractions can detect gastric emptying by measuring the pH increase as the capsule passes from the antrum to the duodenum. Such capsules are approved and available in the United States and have the added capability of quantifying small bowel and colon transit.

Small Intestinal Bacterial Overgrowth

Laboratory tests are most useful for assessing nutritional and metabolic consequences of SIBO but cannot facilitate diagnosis.

Laboratory Studies: A complete blood count can assess for anemia, while basic chemistries can detect hypokalemia or contraction alkalosis if there is associated diarrhea. Celiac disease serologies may be obtained to exclude this condition from the differential diagnosis.

Options to Define SIBO: A recent systematic review concluded there is no one test that can definitively diagnose SIBO. Three alternative methods are commonly used. Fluid aspirated from the duodenum or jejunum at the time of upper endoscopy can be quantitatively cultured; >105 colony forming units/mL is considered diagnostic of SIBO. Concerns are raised about this method because of the need to perform invasive testing, the potential for contamination of the sample from oral flora carried into the intestine during the procedure, and the reluctance of many microbiology labs to perform bacterial quantitation. Consequently, breath testing after consuming a carbohydrate substrate has become the mainstay of diagnosis of SIBO. With this method, a sugar such as glucose or lactulose is swallowed and emptied into the intestine. If there are bacteria in the small bowel, the sugar is metabolized with liberation of hydrogen or methane gas. These gases diffuse across the intestinal mucosa and are carried to the lungs where they diffuse into the alveola and are exhaled.

SIBO is diagnosed when one of these gases exceeds a diagnostic threshold (e.g. >12 parts per million over basal levels). Glucose breath tests may be falsely negative due to rapid absorption of the sugar before it can be metabolized by intestinal bacteria. Conversely, breath tests using the non-absorbable sugar lactulose may be falsely positive because rapid transit of this sugar quickly propels it into the colon where colonic bacterial metabolism produces hydrogen or methane gas that may be indistinguishable from that produced in the small intestine. The accuracy of breath test methods is estimated to be approximately 70% for diagnosing SIBO. The third option is empiric administration of oral antibiotics without diagnostic testing. With this approach, symptom reduction after antibiotics is considered to be evidence of SIBO. However as with many treatments for unexplained GI symptoms, significant placebo responses may be observed. As a result, most clinicians do pursue either intestinal culture or breath test methods to avoid giving multiple antibiotic courses to patients without SIBO.

Diabetic Constipation

Key diagnostic testing needs are minimal in patients with diabetic constipation and serve to exclude other potential causes of symptoms.

Laboratory Studies: A thyroid stimulating hormone commonly is obtained to screen for hypothyroidism, while a calcium level is measured to assess for possible hyperparathyroidism.

Structural Evaluation: Most younger patients without alarm symptoms (e.g. bleeding, weight loss, fever, abrupt onset), signs/abnormal laboratory findings (e.g occult fecal blood, anemia), or family histories of colorectal neoplasia or inflammatory bowel disease do not need endoscopic or radiographic evaluation of the colon. In contrast, individuals with one or more alarm features and all patients over age 50 years should undergo colonoscopy to rule out polyps or colon cancer.

Diabetic Diarrhea

The key diagnostic tests for the patient with diabetic diarrhea are performed to assess underlying causes of diarrhea as well as complications of fluid loss. In most instances, diagnosis of secretory diarrhea occurring in diabetics as a consequence of altered intestinal absorptive/secretory function is made after other potential etiologies are excluded.

Laboratory Studies: Routine laboratory tests should be performed including a basic chemistry panel to exclude hypokalemia, contraction alkalosis, and elevated blood urea nitrogen suggestive of dehydration. Sedimentation rates or C-reactive proteins may be obtained to screen for underlying inflammatory disease, although these levels may be elevated in obese diabetics. Celiac serologies or genetic tests are considered if celiac disease has not been considered. If clinically suspected, TSH levels may be quantified to rule out hyperthyroidism and fasting morning cortisol values can screen for Addison's disease. Patients with exposure to well water or other potentially impure sources should undergo stool testing (either ova and parasites or Giardia antigen) to screen for parasitic etiologies. Qualitative fecal fat determinations can be made to screen for steatorrhea with parncreatic insufficiency, however this may be nonspecifically elevated with SIBO, celiac disease, or even rapid small bowel transit.

Structural and Functional Evaluation: If the noninvasive studies do not reveal an underlying cause of significant diarrhea in the affected diabetic patient, colonoscopy with ileal intubation and performance of random colonic mucosal biopsies is indicated to exclude inflammatory bowel disease and microscopic colitis (which may occur as an independent finding or in association with celiac disease). Upper endoscopy with performance of duodenal biopsies is indicated for positive celiac disease serologies, negative celiac disease serologies with IgA deficiency, positive celiac disease genetics, and in many cases of microscopic colitis. Evaluation for SIBO should be undertaken as described above either with duodenal fluid culture, breath testing, or empiric antibiotic trial. There are no routinely performed tests for bile acid diarrhea, although bile acid breath tests have been employed in some settings.

Fecal Incontinence

Diagnostic evaluation of the diabetic with fecal incontinence parallels that of diabetic diarrhea if there is a diarrhea component to this complaint. Otherwise, testing focuses on characterizing functional anorectal deficits underlying this problem.

Functional Evaluation: Impaired motor and sensory function can be characterized by anorectal manometry. This test quantifies basal anal tone and maximal squeeze pressure. Rectal sensation is assessed by querying the patient about perception of progressive distention of a balloon affixed to the end of the manometry catheter. In some cases, electromyographic testing of pudendal nerve latencies is included to exclude damage to this nerve.

Miscellaneous GI Complications of Diabetes

Abdominal Pain: The evaluation of unexplained abdominal pain may include laboratory tests to evaluate for hepatobiliary or pancreatic abnormalities, ultrasound or cross-sectional imaging tests, and luminal evaluation with endoscopy or barium testing. As pain is reported by the majority of diabetics with gastroparesis, additional functional testing may be indicated especially if there is associated nausea or vomiting.

Esophageal: Upper endoscopy is indicated for the diabetic with persistent esophageal reflux symptoms to assess for esophagitis and associated complications (e.g. strictures) and exclude Candidal infection or Barrett's metaplasia as a risk factor for adenocarcinoma. If the patient complains of dysphagia, a barium swallow can screen for mechanical causes and may also detect evidence of dysmotility. Esophageal manometry can, in rare cases, characterize abnormal motor patterns. Acid reflux can be further quantified using catheter- or capsule-based ambulatory pH monitoring methods. Addition of catheter-based impedance techniques can assess for non-acid reflux.

Intestinal: Screening tests for celiac disease include serologies (e.g. tissue transglutaminase antibodies) with associated quantification of IgA levels to exclude IgA deficiency. In some cases, celiac genetic tests are ordered; negative tests for HLA DQ2 and DQ8 have a hign negative predictive value for celiac disease. Upper endoscopy with performance of duodenal biopsies is indicated for positive celiac serologies or genetic tests or if other clinical factors strongly suggest this condition (e.g. associated microscopic colitis, unexplained iron deficiency anemia or bone loss). Screening tests for intestinal pseudoobstruction include abdominal CT scanning (which may show luminal dilation) and small bowel barium radiography (which can indicate dilation and/or delayed intestinal transit). Most diabetics with pseudoobstruction also should undergo testing for SIBO given the high prevalence of bacterial overgrowth with intestinal dysmotility.

Biliary: Asymptomatic diabetics do not need evaluation for gallstone disease. If there are typical or atypical symptoms raising suspicion of such conditions, ultrasound can detect gallstones within the gallbladder and may find dilated bile ducts if there is choledocholithiasis. Ultrasonography also should be performed if liver chemistries are elevated. Biliary dilation may also be defined using CT or magnetic resonance imaging (MRI) techniques. The presence of stones within the common bile duct or more proximal hepatic ducts mandates performance of magnetic resonance cholangiopancreatography (MRCP) or endoscopic ultrasound (EUS).

Pancreatic: Pancreatic evaluations rarely are performed in diabetics unless unexplained steatorrhea is found or if there is a suspicion for pancreatic adenocarcinoma. Pancreatic enzymes (amylase, lipase) are occasionally elevated in diabetics, often during periods of ketoacidosis. Visualization of pancreatic anatomy can be accomplished using pancreatic protocol CT, MRCP, or EUS protocols. Adequacy of pancreatic enzyme release can be estimated from fecal levels of elastase.

Hepatic: Liver chemistries should be obtained if there is unexplained right upper quadrant discomfort or tenderness. If elevated liver chemistries are found, additional blood work should be considered including viral testing for hepatitis B and C, autoimmune serologies to screen for autoimmune causes, iron saturation and ferritin levels to screen for hemochromatosis, and (in selected cases) additional blood work to assess for other hereditary conditions such as Wilson's disease and alpha-1-antitrypsin deficiency. Ultrasound commonly shows heterogeneous echotexture with steatosis. In most cases, no additional testing is required.

Other Tests That May Prove Helpful Diagnostically

The previous section detailed the diagnostic evaluations that typically may be performed to assess each of the potential GI complications of diabetes. The following text discusses additional testing that may be considered for patients unresponsive to appropriate therapy or for whom alternate rare diagnoses are possibilities.

Diabetic Gastroparesis/Gastropathy

Additional testing of the diabetic patient with presumed gastroparesis sometimes is warranted to exclude alternate causes of delayed gastric emptying or symptoms or to confirm the presence of more generalized gut motor dysfunction. If suspected clinically, inflammatory etiologies, connective tissue diseases, hormonal conditions, infiltrative disorders, and paraneoplastic syndromes can be screened by obtaining blood samples for sedimentation rate, C-reactive protein, antinuclear antibody, scleroderma-70 antibody, fasting morning cortisol, serum protein electrophoresis (with spot urine testing for Bence-Jones protein), and paraneoplastic autoantibody testing. Associated small bowel dysmotility can be screened by initially ordering dedicated small bowel barium radiography which can exclude any areas of narrowing as well as assess for luminal dilation and slow intestinal transit.

In some cases, additional testing involves performance of antroduodenal manometry. With this test, a catheter with capabilities of recording phasic contractions is positioned either fluoroscopically or endoscopically such that several pressure ports are located in the antrum and several are in the duodenum (and possibly proximal jejunum). Fasting recording is obtained to determine the presence of normal migrating motor complex activity, an organized pattern that serves to clear the upper gut of undigested debris, and a normal contractile response to meals (and sometimes motor stimulating medications). Antroduodenal recordings are examined for specific abnormal patterns including pylorospasm (characterized by increases in tone and phasic contractions in the pylorus), visceral neuropathy (characterized by chaotic, intense uncoordinated small bowel contractions), visceral myopathy (characterized by low amplitude contractions with otherwise normal morphology and propagation patterns), and rumination (characterized by intense simultaneous contractions occurring in all pressure sites within minutes of eating that correspond to contractions of the thoracic and abdominal walls rather than the stomach or intestine). Electrogastrography (EGG) is rarely performed to assess for abnormal cycling of the gastric electrical pacemaker that controls normal propagation of contractions in the distal stomach.

This involves placing electrodes similar to those used for electrocardiogrphy on the skin overlying the stomach and recording activity during fasting and after a meal. Normal EGG tracings show uniform electrical oscillations with a frequency of 3 cycles per minute (cpm; one wave every 20 seconds) that increase in amplitude with eating. Abnormalities associated with some cases of both diabetic gastroparesis and gastropathy include cycling that is too fast (tachygastria) or too slow (bradygastria) or waveforms that do not increase in amplitude after a meal. The clinical utility of EGG has been questioned because of a paucity of treatments designed to correct any pacemaker abnormalities found during testing.

Small Intestinal Bacterial Overgrowth

If SIBO is confirmed and the patient either does not respond to antibiotics or develops a prompt symptom recurrence after antibiotic treatment, small bowel barium radiography sometimes is performed to exclude conditions promoting refractory SIBO including small intestinal strictures, diverticula, fistulae, or profound dilation or transit delay suggestive of pseudoobstruction. If SIBO is diagnosed by breath testing and there is no improvement on antibiotics, an upper endoscopy with quantitative culture of duodenal fluid can be performed to rule out the possibility of a falsely positive breath test vs. confirming an antibiotic-resistant form of enteric infection.

Diabetic Constipation

Patients with diabetic constipation unresponsive to appropriate dietary and medication therapies may benefit from additional diagnostic testing. Some of the disorders for which other laboratory tests described for diabetic gastroparesis are ordered also can cause constipation. Thus, similar blood work sometimes is obtained. Testing of coloanal function can provide insight into other anatomic and motor abnormalities that can lead to constipation. Voiding defecography can be obtained to exclude large rectoceles or rectal intussusception. With this technique, a thickened barium paste is infused into the rectum. The patient then attempts to expel the paste while cinefluoroscopy is performed. Silhouetted imaging can visualize abnormal rectal outlines in both conditions. MRI defecography is performed in some academic centers and offers superior definition of muscular structures, however this method has been criticized as unphysiologic as expulsion of the rectal paste must be performed while supine under the scanner. Anorectal manometry can test for rectosphincteric dyssynergia. To test for this condition, a balloon on the tip of the manometry catheter is inflated in the rectum and the patient is asked to perform a simulated defecation maneuver to expel the balloon. Under normal circumstances, the balloon is expelled within 1 minute and manometry records an increase in rectal pressure and a decrease in anal pressure to facilitate balloon passage. With dyssynergia, there is failure of the anus to relax sometimes in association with impaired rectal contractility. Of note, dyssynergia has been reported in diabetics with constipation.

Diabetic Diarrhea

Additional testing of the patient with diabetic diarrhea primarily focuses on confirming the presence of a secretory or malabsorptive process and subsequently excluding causes other than diabetes. Stool electrolytes can be obtained to suggest the presence of colonic secretion. If the fecal or serum osmolarity exceeds two time the sum of the fecal sodium and potassium concentrations by more than 50 mOsm, this suggests an osmotic process while a difference less than this value is consistent with possible secretory diarrhea. In addition, 72 hour fecal collections on a 100 gram of fat per day diet can be obtained for total volume and fecal fat determinations.

Normal stool volumes are <250 mL per day. A daily stool volume exceeding 1 liter is consistent with active secretion. In rare cases, other causes of secretory diarrhea are considered including hormonal causes (e.g. carcinoid, VIPoma, gastrinoma) which can be screened by appropriate blood and urine collections and surreptitious laxative intake which can be evaluated by specific stool or urine tests. Normal daily fecal fat excretion is <7 grams. Values exceeding this amount are abnormal and indicate further investigation for causes of steatorrhea.

Miscellaneous GI Complications of Diabetes

Intestinal: Intestinal pseudoobstruction can be further characterized by antroduodenal manometry findings as described above. In rare cases where amyloidosis is suspected as a cause of pseudo-obstruction, a subcutaneous fat pad or deep rectal biopsy with Congo red staining can confirm the diagnosis. A full thickness small intestinal biopsy sometimes is obtained surgically to define the histopathologic process underlying manometrically documented visceral neuropathy or myopathy.

Hepatic: In cases where liver disease more severe than steatosis is suspected, a percutaneous liver biopsy may be performed to demonstrate progression to steatohepatitis or cirrhosis.

Management and Treatment of the Disease

Specific dietary, medication, and nonmedication therapies can be offered for each of the GI complications of diabetes as detailed below: As many of the GI complications of diabetes are exacerbated by inadequate glycemic control, additional measures to regulate blood sugar levels may be indicated.

Diabetic Gastroparesis/Gastropathy

An expert consensus group has proposed stratifying gastroparesis as follows: Grade 1--symptoms relatively easily controlled with maintenance of weight and nutrition on a standard diet; Grade 2--moderate symptoms with partial control on daily medications but with ability to maintain nutrition with dietary modification; and Grade 3--refractory, uncontrolled symptoms requiring frequent emergency department and outpatient clinic visits or hospitalizations and/or inability to maintain nutrition orally. Grade 1 gastroparetics usually are managed just with dietary recommendations; Grade 2 patients require prescription medications with a range of effects; and Grade 3 patients are considered for non-medication options in addition to nonpharmaceutical treatments (Table V). For all cases, optimization of glycemic control is recommended as pronounced hyperglycemia (>270 mg/dL) can worsen gastric emptying delays. Changes in timing of periprandial insulin injections may be needed for severe delays in gastric emptying. Preprandial injections may increase the risk of hypoglycemia after eating due to slow nutrient delivery into the intestine. Such risks may be minimized by insulin administration after rather than before eating.

Table V.

Therapies of Diabetic Gastroparesis/Gastropathy

Dietary Recommendations: A recent study determined that diabetics with gastroparesis consume an average of 1200 kcal per day and show frequent deficient intake of several essential vitamins and minerals. Modifications of meal for diabetic gastroparesis/gastropathy are designed to compensate for impaired gastric motor and sensory function. Ingestion of 4-6 small meals each day is advocated to minimize gastric distention from larger meals. Low fat (avoid red meat, fried food, thick sauces), low residue (avoid raw fruit, raw vegetables, nuts, popcorn), and low fiber diets are recommended as fat, indigestible residue, and fiber contribute to sensations of fullness and discomfort. For more severe cases, consuming a low fat liquid diet may be necessary.

Medication Therapy: Medications used to treat diabetic gastroparesis fall into three categories: prokinetic drugs that stimulate gastric emptying, antiemetic agents, and neuromodulators that blunt gastric nerve hypersensitivity. The appropriateness of prokinetics in those with normal gastric emptying is less clear; such individuals typically are managed with antiemetics or neuromodulators.

(i) The first-line prokinetic is metoclopramide which is adminstered orally or sublingually at a dose of 5-10 mg 30-60 minutes before meals and at bedtime (to facilitate clearance of undigested meal residue during sleep). This agent also may be given intravenously to inpatients with gastroparesis flares. Although frequently effective, metoclopramide elicits unacceptable side effects in 25-40% of patients including neurologic (sleep disturbances, depression, anxiety, tremors, dystonias) and hyperprolactinemic (gynecomastia, lactation) consequences. An FDA black box warning has been issued for the irreversible side effect of tardive dyskinesia with metoclopramide, thus patients on this therapy should be closely followed for neurologic symptoms. A backup agent, erythromycin can stimulate gastric emptying and reduce gastroparesis symptoms when given as a liquid suspension at 125-250 mg 30-60 minutes before meals and at bedtime. Intravenous erythromycin commonly is used for inpatients with gastroparesis exacerbations. Comparable effects are seen with similar doses of azithromycin and clarithromycin. Drawbacks of erythromycin therapy include worsening of nausea, vomiting, and abdominal pain at higher doses and development of tolerance when taken for more a few weeks. Thus, some propose using erythromycin for acute rather than chronic management. Domperidone is a peripheral dopamine antagonist that does not cross into the brain, thus neurologic side effects are rare. This agent is taken orally at 10-20 mg 30-60 minutes before meals and at bedtime. Side effects are minimal and include hyperprolactinemic effects. This agent as well as erythromycin prolong the QTc interval on EKG testing and thus increase the risk of dangerous cardiac arrhythmias including torsades de pointes, thus EKG surveillance is indicated when using these drugs. Domperidone is not approved in the United States, but can be legally obtained at centers that have been approved by the FDA to dispense this agent under an Investigational New Drug approval process. Other avenues not encouraged by the FDA include obtaining the drug from compounding pharmacies or international pharmacies.

(ii) Antiemetic medications are used as adjuncts to prokinetics in diabetic gastroparesis and represent primary therapies for gastropathy. Drug classes commonly prescribed include antidopaminergics (e.g. prochlorperazine), serotonin antagonists (e.g. ondansetron), antihistamines (e.g. promethazine), anticholinergics (e.g. transdermal scopolamine), and more rarely neurokinin antagonists (e.g. aprepitant) or cannabinoids (e.g. dronabinol). There are no controlled trials documenting antiemetic benefits in diabetic gastroparesis/gastropathy. Indeed, benefits of these drugs are suggested only by a few case reports.

(iii) Neuromodulators in selected antidepressant classes have been proposed, but data supporting their efficacy are provided only by uncontrolled case series or case reports. Tricyclic agents (e.g. nortriptyline) reduce symptoms in diabetics with nausea and vomiting, including those with both delayed and normal gastric emptying in an open label series. Related agents such as mirtazapine decrease nausea and vomiting in single case reports of diabetic patients. Benzodiazepines often are used to treat vomiting in diabetics. However, these agents likely do not have true antiemetic effects and have benefits by virtue of their sedating and anxiolytic actions. Neuromodulators most often are only considered when therapy with prokinetics and/or antiemetics produce inadequate symptom control. Some have additional proposed using these agents selectively in those patients with severe pain or discomfort given their antinociceptive actions in some models.

Options Other Than Oral Medications: Therapies other than oral medications are considered for refractory cases. Endoscopic injection of botulinum toxin (100-200 units) into the pylorus has reported symptom benefits in gastroparesis in uncontrolled trials that have not been confirmed in the few published, small controlled trials. Endoscopic lavage of bezoars may reduce symptoms in some individuals. An implantable gastric electrical stimulator that continually delivers low energy electrical pulses to the greater curvature of the stomach also has shown symptom benefits in uncontrolled case series followed out to 10 years or more. However, small sham-stimulation controlled trials show no benefit of active stimulation in diabetic gastroparesis. Other surgical options sometimes are considered as heroic measures. Surgical placement of jejunostomy tubes permit nutrient delivery distal to the stomach, while venting gastrostomies can allow periodic release of retained gastric fluid and gas to reduce symptoms. Gastric resections have rarely been performed, but are frought with high complication rates. Pancreatic transplantation has no clear benefit in reducing gastroparesis symptoms in poorly controlled diabetics.

Small Intestinal Bacterial Overgrowth

The main therapy of SIBO in diabetes is administration of oral antibiotics for a self-limited period. Several different antibiotic classes show benefit in reducing symptoms and decreasing hydrogen production on breath testing, however it is not uncommon to observe recurrences within the first year of treatment that can mandate additional antibiotic courses. In more refractory cases, continual antibiotic administration with cycling of two or more antibiotics at 10- to 14-day intervals is sometimes needed. Some investigators have proposed limiting use of proton pump inhibitors in patients with SIBO because some but not all studies have reported increases in intestinal bacterial counts and clinical manifestations of SIBO while on chronic proton pump inhibitor therapy.

Dietary Recommendations: Patients with SIBO may experience intolerance of poorly absorbed carbohydrates, especially when bacterial colonization of the upper gut is incompletely treated. Such individuals may benefit from avoidance of dairy products as well as some high FODMAP foods.

Medication Therapy: There is little in the way of controlled investigation comparing different antibiotic regimens to treat SIBO. Current regimens have focused most commonly on rifaximin as this agent is non-absorbable and, thus, may have a safety advantage over other agents. Rifaximin exhibited superiority over chlortetracycline in one trial and showed higher response rates in a second retrospective analysis. The main drawback of this agent is its significantly greater cost over older, generic antibiotics. When given as a first line agent, rifaximin is given at a dose of 550 mg 2-3 times daily for 10-14 days. Alternatives to rifaximin if this agent is not covered by insurance, if it is ineffective, or if there are multiple SIBO recurrences include tetracycline derivatives, fluoroquinolones, amoxicillin with or without clavulinate, cephalosporins, trimethoprim-sulfamethoxazole, metronidazole, and neomycin.

Diabetic Constipation

Management of diabetic constipation primarily relies on laxatives that increase fecal fluid content to promote propulsion and may also include dietary measures designed to reduce bacterial fermentation to limit gaseous symptoms that may worsen discomfort in this condition (Table VI). Rarely, referral for physical therapy or surgery is considered for refractory cases.

Table VI.

Therapies of Diabetic Constipation

Dietary and Lifestyle Recommendations: For diabetic constipation patients who complain of bloating and distention, avoidance of gas forming carbohydrates may be indicated. Low FODMAP recommendations may be offered, although these have not specifically been studied in diabetics. Likewise, limitation of rather than increases in fiber intake may have symptom benefits. Adequate fluid intake will prevent fecal dessication, however excessive fluid intake will not promote laxation. Some clinicians advocate mild physical exertion prior to defecation to provide a minor stimulus to colonic propulsion.

Medication Therapy: Any specific underlying diseases responsible for constipation such as hypothyroidsm or hyperparathyroidism should be managed as indicated. For cases without specific therapies, the goal of laxative therapy in diabetic constipation is to enhance fecal water content without inducing intense spasticity. A reasonable first line agent would be PEG 3350 given at a dose of 17 grams in water 1-3 times daily. Fiber supplements can be considered if there is no associated gaseous symptomatology or gastroparesis. Other alternatives would include over-thecounter stimulants including senna, bisacodyl, or magnesium hydroxide (if renal function is normal). Older nonabsorbable carbohydrate laxatives such as lactulose and sorbitol may elicit adequate laxative responses; however, these agents may produce unacceptable degrees of bloating, distention, and flatulence particularly in patients with associated gastroparesis or SIBO. Recent introduction of secretory stimulants including lubiprostone and linaclotide offer additional options, although there are little data for these agents in diabetic constipation. Older colonic prokinetics potentially beneficial in this condition have been pulled from the market; however, a recent report suggests that the acetylcholinesterase inhibitor pyridostigmine may improve bowel function in diabetics with constipation.

Nonmedication Options: Options other than laxatives are considered in selected refractory cases. If dyssynergia is found on anorectal manometry, physical therapy consultation for initiation of biofeedback training to improve anal relaxation and enhance rectal sensation may be indicated. Surgical repair of large rectoceles or intussusceptions found on defecography may rarely be performed. Subtotal colectomy with ileosigmoid anastomosis has been performed in patient subsets with profound slow transit constipation, however there are no reports touting this therapy in diabetic constipation.

Diabetic Diarrhea

Given the varied underlying causes of diabetic diarrhea, several dietary and medication options are available (Table VII).

Table VII.

Therapies of Diabetic Diarrhea

Dietary Recommendations: Dietary managment of diabetic diarrhea aims to reduce consumption of poorly absorbed carbohydrates. Type 1 diabetics with associated celiac disease should be treated with dietary gluten exclusion. Such individuals should also be told to avoid dairy products during the initial phases of gluten restriction due to the associated lactase deficiency that is present prior to resolution of intestinal villous atrophy. Likewise, SIBO patients may experience transient intolerance of dairy products prior to adequate antibiotic eradication of small bowel bacterial flora. In general, diabetic diarrhea patients should minimize intake of high FODMAP foods, especially those with high fructose or sorbitol content. This will include many "no sugar added" foods specifically marketed to diabetics as well as chewing gums or sugarless candies containing sorbitol. Fiber supplementation rarely is beneficial and may exacerbate bloating and fullness in patients with associated gastroparesis or SIBO.

Medication Therapy: Underlying conditions that have specific medical therapies should be appropriately managed. For example, SIBO should be treated with oral antibiotics as described above, Addison's disease should be treated with hydrocortisone replacement, Giardiasis is treated with oral metronidazole, and hyperthyoidism should be managed as directed by the endocrine consultant. Some patients with steatorrhea may respond to oral pancreatic enzyme supplements taken at the time of meals and snacks. Most patients with diabetic diarrhea not responding to dietary measures or specific medication programs described above are offered opiate-based agents designed to retard intestinal transit and increase intestinal absorption and include over the counter options such as loperamide to prescription strength drugs like diphenoxylate-atropine or codeine-containing preparations. More potent medications such as tincture of opium or paregoric are reserved for refractory cases. Bile acid binders such as cholestyramine, colestipol, and colesevelam can be offered if associated bile acid diarrhea is suspected. These strong opiate agents and bile acid binders may significantly exacerbate gastroparesis symptoms, thus dosing of these medications may need to be cautiously increased as tolerated. Antisecretory medications can be offered for high output diabetic diarrhea. Clonidine is a centrally acting adrenergic agent that is reported to reduce intestinal secretion in this condition, however its use may be complicated by worsening hypotension which may be problematic particularly in diabetics with associated dysautonomia. This may lead to significant dose restrictions of this medication. The somatostatin analog octreotide also has antisecretory actions in diabetic diarrhea, however this drug can alter glycemic control and can cause gallstone formation. Consequently, its use must be accompanied by appropriate side effect surveillance.

Nonmedication Options: Intravenous fluids with supplemental electrolyte solutions administered through an indwelling central venous catheter sometimes are needed for refractory high output secretory diabetic diarrhea.

Fecal Incontinence

Management of fecal incontinence associated with diabetes relies on controlling any associated diarrhea as well as measures specifically designed to improve impaired anorectal function. As with recommendations for gastroparesis, optimizing glycemic control has been advocated as high blood sugars can inhibit anal function and reduce rectal compliance.

Dietary Recommendations: If the diabetic with fecal incontinence has associated diarrhea, the dietary recommendations for diabetic diarrhea are appropriate. Fiber supplementation may be cautiously recommended for this indication to provide added stool bulking. This should be escalated very slowly if there is associated gastroparesis or SIBO.

Medication Therapy: If the diabetic with fecal incontinence has associated diarrhea, the medication recommendations for diabetic diarrhea listed above are appropriate.

Nonmedication Options: Diabetics with fecal incontinence not responsive to dietary and medication regimens are offered biofeedback training by physical therapists. These measures are designed to enhance external anal sphincter function to compensate for impaired internal anal sphincter tone and to improve rectal sensation so that any stool within the rectal vault is sensed so that it can be evacuated into the toilet prior to its uncontrolled expulsion into the undergarments. This form of therapy reportedly is effective in approximately 70% of cases. In rare cases, surgery to augment sphinctter function is offered, however these procedures have high complication rates. Others undergo surgical ostomy construction to limit infectious consequences of uncontrolled fecal soiling. Future adoption of sacral nerve stimulators may provide an additional surgical option for this diabetic complication.

Miscellaneous GI Complications of Diabetes

Abdominal Pain: Management of abdominal pain due to gastroparesis, neuropathy, or radiculopathy in diabetics with an associated dysmotility can be challenging. The goal is to avoid high dose opiates which may exacerbate transit delays and elicit nausea, vomiting, or constipation. Agents such as tramadol or pain modulators such as gabapentin, pregabalin, or tricyclic agents can be considered.

Esophageal: Severe esophagitis secondary to esophageal dysmotility is most often managed with acid suppressive agents such as proton pump inhibitors. High doses (e.g., two to four doses daily) may be needed for endoscopic healing and symptom control. Some patients with associated Candida esophagitis should be treated with antifungals such as fluconazole or mycostatin. Esophageal strictures may be endoscopically dilated. Surgical antireflux options considered for non-diabetics such as such as fundoplication are relatively contraindicated for diabetics with gastroparesis due to very high risks of gas-bloat symptoms and profound gastroparesis exacerbations.

Intestinal: Celiac disease in type 1 diabetics is managed by initiating a gluten free diet. Restriction of dairy products is also suggested during the initial phase of gluten exclusion due to associated secondary lactase deficiency with the villous atrophy of celiac disease. Intestinal pseudoobstruction is a challenging condition with limited therapeutic options. Small intestinal specific prokinetics such as pyridostigmine or octreotide, sometimes given in concert with erythromycin, may offer benefits to some patients. Most diabetics with pseudoobstruction have associated SIBO; oral antibiotics may provide some measure of symptom control. Diet recommendations in this condition include avoidance of high residue and high fat foods as well as poorly absorbable carbohydrates. Enteral feedings through a jejunostomy tube may be needed in rare cases, however often must be elemental in nature to optimize tolerability given the associated small intestinal dymotility. Total parenteral nutrition is provided for those cases refractory to oral or enteral supplementation, however this option may have significant complications relating to glycemic control and systemic infection.

Biliary: Cholecystitis is managed with surgical cholecystectomy. Choledocholithiasis most often is treated by endoscopic retrograde cholangiopancreatography with sphinterotomy and subsequent stone extraction.

Pancreatic: Pancreatic enzyme supplementation is offered for symptomatic steatorrhea and some cases of diabetic diarrhea. Enzymes are taken with each meal and snack.

Hepatic: No medication therapy is proved to be reliably beneficial for hepatic steatosis. Management of this consequence of diabetes included supervised weight reduction as well as optimizing glycemic control with periodic surveillance of liver chemistry values. More advanced forms of liver disease will mandate involvement of a hepatologist consultant. Severe cases of end-stage liver disease may ultimately need hepatic transplantation.

What’s the Evidence?/References

Overall Review Articles

Gatopoulou, A, Papanas, N, Maltezos, E. "Diabetic gastrointestinal autonomic neuropathy: current status and new achievements for everyday clinical practice". Eur J Int Med. vol. 23. 2012. pp. 499-505.

(This is an excellent recent overall review of GI complications of diabetes.)

Vinik, AI, Maser, RE, Mitchell, BD, Freeman, R. " Diabetic autonomic neuropathy". Diabetes Care. vol. 26. 2003. pp. 1553-1579.

(An older but very comprehensive overall review of GI complications of diabetes.)

Bytzer, P, Talley, NJ, Hammer, J, Young, LJ, Jones, MP. "GI symptoms in diabetes are associated with both poor glycemic control and diabetic complications". Am J Gastroenterol. vol. 97. 2002. pp. 604-11.

(This study presents data from a large questionnaire study relating GI symptoms to diabetic complications and A1c values.)

Diabetic Gastroparesis/Gastropathy

Hasler, WL. " Gastroparesis: pathogenesis, diagnosis, and management". Nat Rev Gastroenterol Hepatol. vol. 8. 2011. pp. 438-53.

(This is a comprehensive review of all aspects relating to gastroparesis, both diabetic and non-diabetic.)

Camilleri, M. "Clinical practice: diabetic gastroparesis". N Engl J Med. vol. 356. 2007. pp. 820-9.

(This is a well-written case-based discussion of the approach to the diabetic patient with presumed gastroparesis.)

Small Intestinal Bacterial Overgrowth

Virally-Monod, M, Tielmans, D, Kevorkian, JP, Bouhnik, Y, Flourie, B. "Chronic diarrhoea and diabetes mellitus: prevalence of small intestinal bacterial overgrowth". Diabetes Metab. vol. 24. 1988. pp. 530-6.

(This is an older paper that presents a quantitative evaluation of the prevalence of SIBO in diabetes.)

Khoshini, R, Dai, SC, Lezcano, S, Pimentel, M. "A systematic review of diagnostic tests for small intestinal bacterial overgrowth". Dig Dis Sci. vol. 53. 2008. pp. 1443-54.

(This paper presents an assessment of the relative merit of the different tests of SIBO.)

Diabetic Constipation

Lida, M, Ikeda, M, Kishimoto, M, Tsujino, T, Kaneto, H. "Evaluation of gut motility in type II diabetes by the radiopaque marker method". J Gastroenterol Hepatol. vol. 15. 2000. pp. 381-5.

(This paper quantifies colon transit in diabetics in relation to bowel complaints of constipation.)

Diabetic Diarrhea

Saslow, SB, Camilleri, M. "Diabetic diarrhea". Semin Gastrointest Dis. vol. 6. 1995. pp. 187-93.

(This is an older but still relevant review of the breadth of abnormalities that can contribute to diarrhea in diabetics.)

Fecal Incontinence

Wald, A, Tunuguntla, AK. " Anorectal sensorimotor dysfunction in fecal incontinence and diabetes mellitus. Modification with biofeedback therapy". N Engl J Med. vol. 310. 1984. pp. 1282-7.

(This is an early but excellent paper describing manometric abnormalities in diabetics with fecal incontinence and the benefits of biofeedback training for this condition.)

Miscellaneous GI Complications of Diabetes

Annese, V, Bassotti, G, Caruso, N, De Cosmo, S, Gabbrielli, A. " Gastrointestinal motor dysfunction, symptoms, and neuropathy in noninsulin-dependent (type 2) diabetes mellitus". J Clin Gastroenterol. vol. 29. 1999. pp. 171-7.

(This is a careful physiologic study of esophageal motor abnormalities in type 2 diabetics.)

Holmes, GK. "Coeliac disease and type 1 diabetes mellitus--the case for screening". Diabet Med. vol. 18. 2001. pp. 169-77.

(This paper presents a quantitative assessment of the rate of coexistent celiac disease with type 1 diabetes.)

Dooley, CP, el Newihi, HM, Zeidler, A, Valenzuela, JE. "Abnormalities of the migrating motor complex in diabetics with autonomic neuropathy and diarrhea". Scand J Gastroenterol. vol. 23. 1988. pp. 217-23.

(This paper describes the small intestinal motor abnormalities that are present in some diabetics. More severe variants of these abnormalities may lead to development of pseudoobstruction in rare patients.)

Cho, JY, Han, HS, Yoon, YS, Ahn, KS. "Risk factors for acute cholecystitis and a complicated clinical course in patients with symptomatic cholelithiasis". Arch Surg. vol. 145. 2010. pp. 329-33.

(This is a recent review of those factors, most prominently diabetes, that lead to complicated gallstone disease.)

Creutzfeldt, W, Gleichmann, D, Otto, J, Stockmann, F, Maisonneuve, P. " Follow-up of exocrine pancreatic function in type-1 diabetes mellitus". Digestion. vol. 72. 2005. pp. 71-5.

(This recent study reports on the relatively mild pancreatic abnormalities of enzyme secretion in type 1 diabetics.)

Williams, KH, Shackel, NA, Gorrell, MD, McLennan, SV, Twigg, SM. "Diabetes and nonalcoholic fatty liver disease: a pathogenic duo". Endocr Rev. vol. 34. 2013. pp. 84-129.

(This represents a very comprehensive recent review of the fatty liver complications associated with diabetes.)

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