CLINICAL DIABETES

VOL. 18 NO. 4 Fall 2000

PRACTICAL POINTERS

Diabetes and the Gastrointestinal Tract

James D. Wolosin, MD, FACP, and Steven V. Edelman, MD

Gastrointestinal (GI) disorders are common among all people, including those
affected by diabetes. At some point in any patient's life, the chances that he or she will develop a GI tract problem, be it peptic ulcer disease, gallstones, irritable bowel syndrome, food poisoning, or some other malady, are extremely high. As many as 75% of patients visiting diabetes clinics will report significant GI symptoms. The entire GI tract can be affected by diabetes from the oral cavity and esophagus to the large bowel and anorectal region. Thus, the symptom complex that may be experienced can vary widely. Common complaints may include dysphagia, early satiety, reflux, constipation, abdominal pain, nausea, vomiting, and diarrhea. Many patients go undiagnosed and under-treated because the GI tract has not been traditionally associated with diabetes and its complications. Both acute and chronic hyperglycemia can lead to specific GI complications. Diabetes is a systemic disease that may affect many organ systems, and the GI tract is no exception. As with other complications of diabetes, the duration of the disorder and poor glycemic control seem to be associated with more severe GI problems. Patients with a history of retinopathy, nephropathy, or neuropathy should be presumed to have GI abnormalities until proven otherwise, and this is best determined by asking a few simple questions. (See "Patient Information".) Many GI complications of diabetes seem to be related to dysfunction of the neurons supplying the enteric nervous system. Just as the nerves in the feet may be affected in peripheral neuropathy, involvement of the intestinal nerves may lead to enteric neuropathy. This is a type of autonomic or "involuntary" neuropathy and may lead to abnormalities in intestinal motility, sensation, secretion, and absorption. Different nerve fibers can either stimulate or inhibit intestinal motility and function, and damage to these nerves can lead to a slowing or acceleration of intestinal function, giving rise to a variable symptom complex. This article will highlight the most

common GI disorders seen in people with diabetes. The Esophagus and Stomach in Diabetes Gastroparesis Diabetic gastroparesis is a condition in which emptying of food from the stomach is delayed, leading to retention of stomach contents. This may cause bloating, early satiety, distention, abdominal pain, nausea, or vomiting. Gastric stasis may lead to worsening gastroesophageal reflux along with symptoms of heartburn and mechanical regurgitation of gastric contents. In addition, fatty foods and very fibrous foods normally exit the stomach slowly and may be poorly tolerated. The diagnosis of gastroparesis is often suspected on the basis of symptoms alone. Upper GI endoscopy is helpful to rule out anatomic obstruction of the stomach or duodenum but does not provide an accurate physiological assessment of gastric emptying. Upper GI barium studies may confirm delayed gastric emptying with a dilated atonic/aperistaltic stomach with retained gastric contents. However, the upper GI series is more commonly nondiagnostic because liquids may empty normally from the stomach in spite of severe abnormalities in the ability to empty solid materials from the stomach into the duodenum. The nuclear medicine gastric emptying test is the best confirmatory test for evaluation of gastroparesis. A test solid-food meal containing a technetium isotopic tracer is ingested, and scintography is used to quantitatively measure the rate of gastric emptying. This test is highly sensitive and specific, although false positives and negatives may occur in response to medications that accelerate or slow the rate of gastric emptying. When performing initial diagnostic testing, it is best to measure gastric emptying rates when patients are off of medications that may affect the rate of gastric emptying. Several different treatments may provide benefit in the management of diabetic gastroparesis. Consumption of frequent small meals may provide some symptomatic relief. Avoidance of high-fat and high-fiber foods may be beneficial as well. It is common to recommend a liquid diet during an exacerbation of gastroparesis. As symptoms worsen, parenteral hydration and alimentation may be required. Nasogastric tube suction may also be used during severe episodes. Numerous medications have been shown to provide some benefit in the treatment of gastroparesis. Metclopropamide (Reglan) is a dopaminergic antagonist that enhances gastric emptying and has primary antiemetic properties. Unfortunately, it crosses the blood-brain barrier and causes frequent neurological side effects, such as sedation, tremor, confusion, dystonia, and, at times, tardive dyskinesia, which may or may not reverse after the drug is stopped. Cisapride (Propulsid) is a prokinetic agent that is very effective at facilitating gastric emptying. Pharmacological tolerance, a problem common with metclopropamide, does not seem to occur with cisapride, and patient acceptability is excellent. The Food and Drug Administration (FDA) has recently placed severe restrictions on the use of cisapride because of the potential for cardiac dysrhythmias due to

prolongation of the QT interval. This is of particular concern when the medication is taken with agents that delay the metabolism of cisapride, such as erythromycin, clarithromycin, fluconazole, idinavir, and other agents that inhibit the cytochrome P34A system. The medication is contraindicated in any individual with a prolonged QT interval, and an electrocardiogram should be checked in all individuals in whom therapy with cisapride is being considered. Concomitant administration of agents that can prolong the QT interval are to be avoided. Clinically, this problem occurs infrequently, especially when the prescribing guidelines are followed. At this time, cisapride is available only through the FDA directly and only for patients who have failed other therapies and meet strict criteria for use of the drug. Domperidone (Motilium) is another dopaminergic antagonist similar to metclopropamide that accelerates gastric emptying but does not cross the bloodbrain barrier and has very few side effects. It is not yet available in the United States but is available in Mexico and elsewhere. Erythromycin has unique properties that stimulate gastric motility and may be beneficial in selected individuals. It functions as an agonist of motilin and enhances gastric emptying. Unfortunately, erythromycin has many potential side effects including nausea and may not be well tolerated. Nonspecific antiemetic agents including prochlorperazine (Compazine) and promethazine (Phenergan) often can provide symptomatic relief of nausea and vomiting. There appears to be no substantial benefit for the preferential use of the more expensive 5HT3 receptor antagonists such as ondansetron (Zofran) or dolastetron (Anzemet). Recently, a novel approach to refractory gastroparesis has been to use an implantable gastric pacemaker. It has long been recognized that many patients with gastroparesis have abnormal electrical gastric rhythms that may or may not correlate with delayed gastric emptying. Surgical placement of a gastric pacemaker has been shown to accelerate gastric emptying and provide symptomatic relief in a small number of patients in preliminary uncontrolled clinical trials. Smoking cessation, light postprandial exercise (such as walking), and dietary manipulation (such as eating multiple smaller meals and avoiding high-fiber and fatty foods) can also improve gastric emptying. Most importantly, careful attention to blood glucose control is essential and can have a tremendous impact on gastroparesis. Ulcer disease Ulcer disease is a common problem in patients with or without diabetes and affects up to 10% of the population at some time during their lives. Acid irritation of the stomach or esophagus leads to heartburn, indigestion, and a burning sensation in the upper abdomen, or dyspepsia. Helicobacter pylori, the bacteria responsible for most duodenal ulcers and many gastric ulcers, is no more common in patients with diabetes than in the general population. In fact, diabetes itself does not increase one's risk of developing ulcers.

Individuals with ulcers and ulcer-like symptoms are treated in the same fashion regardless of whether or not they have diabetes. Treatment is geared toward suppression of gastric acid secretion with antisecretory medications (i.e., H2 receptor antagonists or proton pump inhibitors). If H. pylori is present, it will usually be treated with a specific antibiotic regimen along with antisecretory agents. Common antibiotic regimens include a 2-week course of amoxacillin (Amoxil)/clarithromycin (Biaxin), metronidazole (Flagyl)/clarithromycin, metronidazole/tetracycline, or metronidazole/amoxacillin. In individuals with gastro-esophageal reflux, eradication of H. pylori may result in worsening symptoms because acid secretion increases after this bacteria-related gastritis resolves. Many individuals with reflux will require therapy with proton pump inhibitors to control symptoms. These provide effective relief of symptoms in >80% of affected individuals as opposed to the H2 receptor antagonists, which provide symptomatic relief in ~50% of individuals with reflux disease. Candida infections Patients with diabetes may develop yeast infections in the GI tract, especially when glycemic control has been poor. Yeast infection in the mouth (thrush) is characterized by a thick white coating of the tongue and throat along with pain and burning. If the infection extends further, candida esophagitis results, which may cause intestinal bleeding, heartburn, and difficulty swallowing. Oral candida can readily be diagnosed by physical examination, but candida esophagitis will usually require endoscopy for accurate diagnosis. Treatment is highly effective and is focused on the eradication of the yeast infection with antifungal medications such as nystatin (Mycostatin), ketocanazole (Nizoral), or flucanazole (Diflucan). The Small Intestine in Diabetes In some cases of longstanding diabetes, the enteric nerves supplying the small intestine may be affected, leading to abnormal motility, secretion, or absorption. This leads to symptoms such as central abdominal pain, bloating, and diarrhea. Delayed emptying and stagnation of fluids in the small intestine may lead to bacterial overgrowth syndromes, resulting in diarrhea and abdominal pain. Metclopropamide and cisapride may help to accelerate the passage of fluids through the small intestine, whereas broad-spectrum antibiotics will decrease bacterial levels. Diagnosis can be quite difficult and may require small-bowel intubation for quantitative small-bowel bacterial cultures. Breath hydrogen testing and the [14C]-Dxylose test may be helpful in diagnosing bacterial overgrowth as well. All of these tests are somewhat cumbersome, and an empiric trial of antibiotics is often the most efficient means of diagnosing and treating this condition. Numerous antibiotic regimens have been shown to be effective, including 5- to 10day courses of tetracycline, ciprofloxin, amoxacillin, or tetracycline. A short course

may provide prolonged relief, but typically, additional courses of antibiotics are required when symptoms recur in several weeks or months. At times, enteric neuropathy may lead to a chronic abdominal pain syndrome similar to the pain of peripheral neuropathy in the feet. This condition may be very difficult to treat but will sometimes respond to pain medications and tricyclic antidepressant medications, such as amitryptilline (Elavil). Unfortunately, narcotic addiction may be common in patients with chronic painful enteric neuropathy. Individuals with diabetes also have an increased risk of celiac sprue. In this condition, an allergy to wheat gluten develops, leading to inflammation and thinning of the mucosa of the small intestine. Why this association occurs is not clear. However, sprue may lead to diarrhea, weight loss, and malabsorption of food. This condition responds well to a gluten-free diet, but patients may have difficulty adhering to such a diet. Diagnosis can be made with endoscopic biopsy of the small intestine or with serological evaluation for anti-endomysial and anti-gliadin antibodies. The Colon in Diabetes Limited information is available regarding the effects of diabetes on the large intestine. We do know that enteric neuropathy may affect the nerves innervating the colon, leading to a decrease in colon motility and constipation. Anatomic abnormalities of the colon, such as structure, tumor, or diverticulitis, should be excluded with a barium enema or colonoscopy. Fiber supplementation with bran or psyllium products, as well as a high-fiber diet, increases the water content of the bowel movement and may relieve constipation. Mild laxatives and stool softeners will often help as well. In addition, cisapride accelerates colonic movement and may increase the frequency of bowel movements. Diabetic Diarrhea Patients with a longstanding history of diabetes may experience frequent diarrhea, and this has been reported to occur in up to 22% of patients. This may be related to problems in the small bowel or colon. Abnormally rapid transit of fluids may occur in the colon, leading to increased stool frequency and urgency. In addition, abnormalities in the absorption and secretion of colonic fluid may develop, leading to increased stool volume, frequency, and water content. Diabetic diarrhea is a syndrome of unexplained persistent diarrhea in individuals with a longstanding history of diabetes. This may be due to autonomic neuropathy leading to abnormal motility and secretion of fluid in the colon. There are also a multitude of intestinal problems that are not unique to people with diabetes but that can cause diarrhea. The most common is the irritable bowel syndrome. The workup and treatment of diarrhea is similar in patients with or without diabetes. If the basic medical evaluation of diarrhea is nondiagnostic, which it frequently is, then treatment is tailored toward providing symptomatic care with antidiarrheal agents such as diphenoxylate (Lomotil) or loperamide (Immodium). Fiber

supplementation with bran, Citrucel, Metamucil, or high-fiber foods may also thicken the consistency of the bowel movement and decrease watery diarrhea. In addition, antispasmodic medicines such as hyosymine (Levsin), dicyclomine (Bentyl), and chordiazepoxide (Librax)/clindinium (Clindex) may decrease stool frequency. Sometimes an empiric trial of antibiotics and/or pancreatic enzymes is warranted because pancreatic exocrine insufficiency and bacterial overgrowth may be the etiology. More recently, the 5HT3 receptor antagonist alosetron (Lotronex) has been used effectively for the treatment of diarrhea-predominant irritable bowel syndrome. Tincture of opium and paregoric have also been used to improve the quality of daily life in some cases. Finally, in severe cases, injections of octreotide (Sandostatin), a somatostatin-like hormone, have been shown to significantly decrease the frequency of diabetic diarrhea. Obviously, in these severe cases, referral to a gastroenterologist is indicated. The Pancreas in Diabetes Pancreatic exocrine dysfunction occurs in up to 80% of individuals with type 1 diabetes but is rarely significant enough to lead to any clinical problems with digestion. The pancreas has a tremendous reserve, and a modest reduction in pancreatic enzyme secretion rarely leads to difficulty in digesting or absorbing carbohydrate, fat, or protein. The exocrine pancreas may also be affected in some patients with type 2 diabetes but to a lesser extent. Individuals who have secondary diabetes because of severe pancreatitis or surgical removal of the pancreas usually have more severe symptoms of pancreatic exocrine insufficiency. Treatment with pancreatic enzyme replacement therapy is usually effective. A trial of oral enzyme replacement therapy can be done safely for diagnostic and therapeutic purposes. The Liver in Diabetes Although liver function tests are commonly abnormal in patients with diabetes, it is unclear whether this is a reflection of the underlying obesity that is so common in patients with type 2 diabetes or whether it is an effect of poorly controlled diabetes. Fatty infiltration of the liver (nonalcoholic steatohepatitis) is common in obese individuals (up to 90%) as well as in type 2 diabetic individuals (up to 75%). People with type 1 diabetes in very poor control may also develop this syndrome, although it is much less common. Fatty infiltration of the liver may lead to tender hepatomegally, elevated liver enzyme tests, and abdominal pain syndromes. Occasionally, this may progress to fibrosis and cirrhosis of the liver. The diagnosis is usually suspected on the basis of the clinical presentation but can be confirmed with abdominal ultrasonography and, if needed, percutaneous liver biopsy. Metabolic abnormalities such as hemochromatosis and infectious etiologies such as viral hepatitis need to be excluded as part of the evaluation. Therapy is geared toward improving glycemic control and instituting a low-calorie,

low-fat diet. Caloric restriction will lead to weight loss, better glycemic control, lower serum triglycerides and cholesterol, and improvement in the fatty infiltration of the liver. Ursodiol (Actigal) may provide some benefit in the treatment of hepatic steatosis. Diabetic patients seem to have an increased incidence of gallstones and gall bladder problems, but these, much like fatty infiltration of the liver, are primarily related to the obesity associated with type 2 diabetes and not to the diabetes itself. Obesity leads to secretion of bile by the liver that is supersaturated with cholesterol, leading to crystallization and stone formation. Typical symptoms of biliary colic include intermittent right upper abdominal pain, jaundice, or pancreatitis. In the past, patients with diabetes have been instructed to have surgery for asymptotic gallstones because of a concern for an increased risk of complications from gallstones, such as infection, pancreatitis, or rupture of the gall bladder. However, more recent experience with modern medical and surgical care indicates that this is no longer the case. Thus, patients with diabetes and gallstones should be managed in a fashion similar to nondiabetic patients. Surgery is generally recommended only for those individuals whose gallstones are causing symptoms. Conclusions GI problems in diabetes are common but not commonly recognized in clinical practice. The duration of diabetes and the degree of glycemic control are major determinants in the incidence and severity of GI problems. The entire GI tract can be affected, including the mouth, esophagus, stomach, small intestine, colon, liver, and pancreas, leading to a variable symptom complex. The workup starts with a thorough patient history and appropriate laboratory, radiographic, and GI testing. In addition to pharmacological therapy, glycemic control and dietary manipulation play an important role in managing GI disorders in people with diabetes.

James D. Wolosin, MD, FACP, is a gastroenterologist in clinical practice in Jackson, Tenn. He serves as a clinical instructor at the University of Tennessee Medical School Family Practice Residency Program in Jackson. Steven V. Edelman, MD, is an associate professor of medicine in the Division of Endocrinology and Metabolism at the University of California, San Diego, and the Division of Endocrinology and Metabolism at the San Diego VA Health Care Systems. He is an associate editor ofClinical Diabetes.

Note of Disclosure: Dr. Wolosin has received honoraria for speaking engagements from the TAP, Janssen, Wyeth, Glaxo, and Astra-Zeneco Pharmaceutical companies, all of which manufacture products related to the treatment of GI disorders.

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