Review Article
DIABETIC GASTROPARESIS : AN UNDERDIAGNOSED ENTITY J JAIN*, V JAIN**, OP GUPTA***,
Introduction : Gastroparesis, also called delayed gastric emptying, is a disorder in which the stomach takes too long to empty its contents in absence of obstruction.(1) Gastroparesis is most often caused by diabetes mellitus and known as diabetic gastroparesis, or gastroparesis diabeticorum (GD). Gastroparesis as a specific complication of diabetes does not appear to increase mortality rate, but it can represent a major challenge in patient's management. It should also be stressed that the spectrum of gastric motor abnormalities among diabetics extends to include both accelerated and delayed emptying. Until recently, gastroparesis was thought to be an infrequent complication of diabetes, occurring only in patients with longstanding diabetes who had severe microvascular complications. We now know that this is not the case.
The majority of patients with GD are middle age females (82% with a mean age of 34 years in a series). (1) Sign and symptoms The symptoms of GD are nonspecific, mild to severe and differ in frequency. Prominent symptoms include nausea, postprandial abdominal distress, early satiety, vomiting, constipation, diarrhea, fecal incontinence, and dysphagia. Nocturnal symptoms are common and interfere with the normal sleeping pattern. (3) Exacerbation of symptoms occurs with high-fiber diet, fatty foods and carbonated drinks. Some patients may present with heartburn, lack of appetite and weight loss, which may occur due to poor intake and absorption of nutrients. Although many diabetics have abnormal gastric emptying, few develop overt clinical symptoms. A simple severity grading scale has been proposed for stratification of symptoms. (Table-1)
Epidemiology Prevalence rates for manifestations of GD have varied widely, depending on patient population studied and methodology employed. Although there are no true population-based studies of gastric emptying in diabetic patients, cross-sectional studies using radioisotopic methods have established that gastric emptying is delayed in about 50-58% of patients with long-standing type diabetes. (2)
Pathophysiology Several motor abnormalities like abnormal intragastric distribution of food, a reduced incidence of the antral component of the MMC, antral dilatation and fasting and postprandial hypomotility, and electrical dysrrhythmias have been documented in symptomatic GD. Fundic tone is reduced and the accommodation response impaired. (4)
*Prof., **Assistant Prof., ***Prof., Deptt. of Medicine, Address for Corresponsdence : J JAIN, Department of Medicine, MGIMS, Sevagram, Phone: 91-07152-284341 Ext 327, Fax : 07152-284967, Email :
[email protected]
Gastric emptying reflects the integration of tonic contractions of the fundus, phasic 1 5 J MGIMS, September 2011, Vol 16, No (ii), 15-19
Diabetic Gastroparesis : An Underdiagnosed entity
Table 1: Classification for severity of diabetic gastroparesis(1) Grade 1:Mild gastroparesis
Grade 2:Compensated gastroparesis
Grade 3:Severe gastroparesis
Symptoms relatively easily controlled. Able to maintain weight and nutrition on a regular diet or minor dietary modifications.
Moderate symptoms with partial control with drugs. Able to maintain nutrition with dietary and lifestyle adjustments. Rare hospital admissions.
Refractory symptoms despite medical therapy. Inability to maintain nutrition via oral route. Frequent emergency room visits or hospitalization.
contractions of the antrum and the inhibitory forces of pyloric and duodenal contractions. These contractions require a complex interaction between gastric smooth muscle, the enteric nervous system and specialized pacemaker cells, the interstitial cells of Cajal (ICC). Motor dysfunction of the stomach may result from autonomic neuropathy, enteric neuropathy, abnormalities of ICCs, fluctuations in blood glucose and psychosomatic factors. (1)
contractions, and provoke gastric electrical dysrrhythmias. It is important to emphasize that relatively minor elevations in blood sugar level, even within the physiologic range, can delay emptying in both normal volunteers and diabetics. (6) However, the magnitude of the delay is small and of questionable clinical significance. Fasting hyperglycemia, induced by raising blood glucose to a level that mimics that of physiologic postprandial hyperglycemia, can induce fullness, impair antral contractility, blunt the pyloric response to intraduodenal lipid infusion, and modify sensory responses.
A variety of neurotransmitters including noradrenalin, acetylcholine, 5-hydroxy tryptamine and nitric oxide are involved in initiating, maintaining and regulating gastric contractility. High plasma levels of the gut peptide motilin are reported in these patients. Gastric emptying is slower during experimentally induced acute hyperglycemia and accelerated during hypoglycemia in diabetic patients as well as in normal volunteers.
Differential diagnosis Other causes of gastroparesis are postviral syndromes, anorexia nervosa, surgery on the stomach or vagus nerve, medications (anticholinergics and narcotics), gastroesophageal reflux disease, amyloidosis scleroderma, Parkinson's disease, and hypothyroidism.
The exact pathophysiology of these motor disturbances is unclear. (5) Thus, disordered gastrointestinal motility is likely to be multifactorial in origin. Several recently developed lines of evidence, as well as prior clinical observations, indicate that a number of other factors may be relevant to the pathophysiologic mechanisms of GI symptoms in the diabetic. First, hyperglycemia per se can modulate a variety of GI functions. Hyperglycemia can delay gastric emptying, induce antral hypomotility, promote isolated pyloric
Complications of diabetic gastroparesis Gastroparesis can lead to bacterial overgrowth, gastric bezoars, worsening of diabetes, electrolyte imbalances, dehydration, and malnutrition. Hyperglycemia impairs gastric emptying and may accelerate the onset of diabetic ketoacidosis, particularly when it is associated with persistent vomiting. 16 J MGIMS, September 2011, Vol 16, No (ii), 15-19
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Diagnosis The diagnosis of GD should be strongly suspected from the history. History of drug intake like anticholinergics, tricyclic antidepressants, and benzodiazepines should be asked. Physical examination may reveal gastric dilation with a succussion splash. A saline load test is not a sensitive test in GD, because liquid emptying is frequently normal. The diagnosis is made by directed evaluation to exclude organic diseases.
Scintigraphic methods are much more sensitive than radiographic methods using liquid barium sulfate. It is contraindicated in healthy children and pregnant women, due to radiation exposure.(7) Antropyloroduodenal manometry - This test measures electrical and muscular activity in the stomach. Antroduodenal manometry is available mainly at tertiary referral centers, and the test is invasive and time consuming and requires skilled technical support. (7) Breath test - These tests constitute a promising method to evaluate gastric emptying noninvasively and without radiation hazard. After ingestion of a meal containing a isotope, breath samples are taken to measure the presence of the isotope in carbon dioxide, which is expelled. Pitfalls of these tests include potential loss of accuracy in patients with other diseases involving the intestinal mucosa, pancreas, liver, and respiratory system. (7)
Esophagogastroduodenoscopy - The usual method for diagnosis is exclusion of structural lesions in stomach. Ultrasound - Routine method to rule out gallbladder disease and pancreatitis. The advantages of ultrasonography is good interobserver agreement for the gastric emptying of a liquid meal. Pitfalls include assessment of gastric emptying of liquids, which may be preserved even in advanced cases of gastroparesis.(7)
Real time MRI - It is a reliable tool for assessment of gastric motion. Due to the non-invasive character of MRI, this imaging modality may be an attractive alternative to conventional invasive diagnostic tools for gastric motility disorders and therapeutic monitoring. (8) Pitfalls of MRI that it can only be performed in the supine position, which is a drawback since gravity is an important driving force in gastric emptying, especially of liquids.(7)
Standard barium x ray - Normally, the stomach will be empty of all food after 12 hours of fasting. Gastroparesis is likely if the x ray shows food in the stomach after 12 hours. Gastric emptying scintigraphy - Radiolabeled scintigraphy is the preferred and the most widely used test to confirm the diagnosis and to quantify the response to therapy. This scan measures the rate of gastric emptying at 1, 2, 3, and 4 hours, after eating a bland meal, which contains radioisotope. Presence of more than 10 % at 4 hours or more than half of the meal in the stomach after 2 hours, confirms the diagnosis.
Wireless pH and Motility Capsules (Capsule endoscopy) - The advantages of this procedure are ease of conduct of the study anywhere, reasonable discrimination between normal and delayed gastric emptying, lack of radioactivity, and ability to determine small bowel, colon, and whole gut transit times, as well as gastric 1 7 J MGIMS, September 2011, Vol 16, No (ii), 15-19
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Antibiotics - Erythromycin a motilin agonist, clear bacterial infection, has been found to be effective in accelerating gastric emptying. A recent meta-analysis suggests that the beneficial effects of oral erythromycin on gastric emptying and on symptoms are superior to those seen with either metaclopramide, domperidine, or cisapride. Unfortunately, tachyphylaxis to the effects of erythromycin remains a significant problem. (1)
contractility . It is contraindicated in patients of gastric bezoar, dysphagia, suspected strictures, GI surgery within the last 3 months, Crohn's disease, known small bowel or complicated colonic diverticulosis, and subjects who use implanted or portable electromechanical medical devices such as cardiac pacemaker or infusion pump. (7) Treatment - In GD, the objectives are to restore hydration and nutrition, enhance gastric emptying, relieve symptoms, and improve glycemic control. The management of GD is complex and depends on the severity of symptoms. In most cases, treatment does not cure the disease. (9)
III. Surgical management It is indicated only when GD is severe, not managed by medical therapy or the tube is necessary to stabilize blood glucose levels with diabetes. Surgical procedures, such as gastrectomy, antrectomy and jejunostomy, are the last option of treatment since they involve the removal of part or all of the stomach.. In patients with severe GD but normal small intestinal motility, jejunostomy tube feeding may be applied. (10)
I . Non pharmacological measures Dietary Changes in the form of small frequent meals. Avoidance of high-fat and high-fiber foods. Improvement in the control of blood glucose levels may accelerate emptying. II. Pharmacological measures : Several medications that are used to treat GD are
IV. Other management Parenteral Nutrition-can be an alternative to surgery and is usually a temporary method to get through a difficult period with GD.
Antiemetics and Prokinetics - Antiemetics drugs are not usually effective. Indeed, they may have serious anticholinergic side effects. Prokinetic agents like metoclopramide, domperidone, are frequently used to treat GD. These drugs increase gastric tone and accelerate gastric emptying, coordinating pyloric relaxation and duodenal peristalsis and help with nausea and vomiting. The beneficial effects of these agents may diminish after 4 to 6 weeks, although patients may continue to be symptom free. (2)
Gastric Electrical Stimulation - A gastric neurostimulator is a surgically implanted device that releases mild electrical pulses to help control nausea and vomiting. This is indicated in patients in whom nausea and vomiting do not improve with medications. (3) Botulinum Toxin - Botulinum injection of the pylorus at endoscopy has been associated 18 J MGIMS, September 2011, Vol 16, No (ii), 15-19
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2. Qiu WC, Wang ZG, Wang WG, Yan J, Zheng Q. Gastric motor effects of ghrelin and growth hormone releasing peptide 6 in diabetic mice with gastroparesis. World J Gastroenterol. 2008 Mar 7;14(9):1419-24.
with improvement in symptoms of gastroparesis in some patients; however was ineffective in the two controlled trials. Further research is needed on this therapy. (9)
3. Lin Z, Forster J, Sarosiek I, McCallum RW. Treatment of diabetic gastroparesis by highfrequency gastric electrical stimulation. Diabetes Care. 2004 May;27(5):1071-6.
Will strict blood sugar level control prevent or reverse these GI problems ? Few studies have addressed this issue. Holzapfel et al studied gastric emptying in a group of type 2 diabetics before and after readjustment of diabetic control and documented no relationship between blood glucose concentration and gastric emptying rate, despite improving control.
4. James AN, Ryan JP, Crowell MD, Parkman HP. Regional gastric contractility alterations in a diabetic gastroparesis mouse model: effects of cholinergic and serotoninergic stimulation. Am J Physiol Gastrointest Liver Physiol. 2004 Sep; 287(3): G612-9. 5. Vinik AI, Maser RE, Mitchell BD, Freeman R. Diabetic autonomic neuropathy. Diabetes Care. 2003 May;26(5):1553-79.
Conclsion - Diabetic gastroparesis is clinically important because it may be associated with gastrointestinal symptoms, alterations in glycemic control, and changes in oral drug absorption. Prospective studies of gastric emptying in patients with long-standing diabetes mellitus have demonstrated that among symptomatic patients, this disease frequently runs a fluctuating course of episodes of pronounced symptoms interspersed with relatively symptom-free intervals.
6. Zhao J, Frokjaer JB, Drewes AM, Ejskjaer N. Upper gastrointestinal sensory-motor dysfunction in diabetes mellitus. World J Gastroenterol. 2006 May 14;12(18):2846-57. 7.
8. Ajaj W, Goehde SC, Papanikolaou N, Holtmann G, Ruehm SG, Debatin JF, et al. Real time high resolution magnetic resonance imaging for the assessment of gastric motility disorders. Gut. 2004 Sep;53(9):1256-61.
Other evidence suggests the direct involvement of the enteric nervous system in diabetes. This includes reports of pathologic abnormalities in both the myenteric and submucosal plexus in diabetic patients.
9. Szarka LA, Camilleri M. Stomach dysfunction in diabetes mellitus: emerging technology and pharmacology. J Diabetes Sci Technol. 4(1):180-9. 10. Song GQ, Chen JD. Synchronized gastric electrical stimulation improves delayed gastric emptying in nonobese mice with diabetic gastroparesis. J Appl Physiol. 2007 Nov; 103(5): 1560-4.
References : 1.
Szarka LA, Camilleri M. Methods for measurement of gastric motility. Am J Physiol Gastrointest Liver Physiol. 2009 Mar;296(3):G461-75.
Waseem S, Moshiree B, Draganov PV. Gastroparesis: current diagnostic challenges and management considerations. World J Gastroenterol. 2009 Jan 7;15(1):25-37.
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