Are You Sure the Patient Has a Gastrointestinal Complication of Diabetes?
Diabetes is associated with a range of complications involving the gastrointestinal tract, biliary tree, pancreas, and liver (see Table I). Up to 75% of patients with longstanding diabetes report chronic or intermittent GI complaints resulting from abnormal sensory or motor function of the gut. Patient with diabetes may have altered function of multiple organs as evidenced in studies using methods to assess transit or motor function in several gut regions (i.e. whole gut scintigraphy or wireless motility capsules).
Definition: Diabetic gastropathy is a term used to collectively describe all disorders that occur as a result of autonomic neuropathy affecting the stomach. The most severe disorder is gastroparesis which is defined by delayed gastric emptying in the absence of mechanical obstruction. Approximately 40% of patients with type 1 diabetes and 10-20% of patients with type 2 diabetes will develop gastroparesis.
An expert consensus group has proposed the following grading system for gastroparesis:
Grade 1–symptoms controlled with maintenance of weight and nutrition on a standard diet
Grade 2–moderate symptoms with partial control on prokinetic and antiemetic medications and ability to maintain nutrition with dietary modifications
Grade 3–refractory, uncontrolled symptoms requiring frequent emergency department and clinic visits or hospitalizations and/or inability to maintain nutrition orally
Symptoms and Signs: Patients with diabetic gastropathy may present with nausea and vomiting (45%), abdominal pain or discomfort (20%), bloating (7%), early satiety, and postprandial fullness. Vomiting typically occurs 30-60 minutes after eating but may occur up to 8 hours after oral intake. Patients with frequent or refractory vomiting may have loss of dental enamel, GI bleeding from tearing of the gastroesophageal junction (Mallory-Weiss tear) or hemorrhagic gastropathy. Abdominal pain is typically postprandial and described as vague burning, crampy, sharp, or pressure-like. Symptoms in diabetic gastroparesis are chronic in >50% of patients but may also occur in a cyclical nature in up to 10%. The Gastroparesis Cardinal Symptom Index (GCSI) is a validated symptom survey composed of nine symptoms and often used in clinical investigation and patient care (Table II). There are no pathognomonic signs in patients with diabetic gastroparesis but in severe cases may include a succussion splash on auscultation.
Small Intestinal Bacterial Overgrowth
Definition: Small intestinal bacterial overgrowth (SIBO) is a condition that develops as a consequence of excessive bacteria colonized in the small intestine. Bacterial metabolism of food residue delivered into the small intestine promotes generation of gases (hydrogen, methane) and other by-products that cause symptoms. Patients with GI motility disorders (e.g., gastroparesis, small bowel dysmotility), such as those seen in patients with longstanding diabetes due to injury of the enteric nervous system, are at higher risk for developing SIBO.
Symptoms and Signs: Symptoms of SIBO include bloating, distention, flatulence, eructation, abdominal discomfort, diarrhea, or weight loss. The predominant symptoms depends on the microbial flora present in the individual patients. Patients with bacteria that metabolize carbohydrates to short-chain fatty acids and gaseous by-products primarily report bloating symptoms. On the other hand, bacteria that metabolize bile salts to insoluble compounds cause diarrhea or other symptoms of fat malabsorption. The physical exam in most patients with SIBO is nonfocal, although some individuals may exhibit visible abdominal distention on inspection or tympany on percussion.
Definition: Diabetic constipation is characterized by decreased stool frequency, straining with defecation, lumpy or hard stools, sensation of incomplete evacuation, or need for manual maneuvers for defecation. Constipation is reported in approximately two-thirds of patients with diabetes. One possible cause of diabetic constipation is neuropathy leading to decreased colonic motility and impaired gastrocolic reflex.
Symptoms and Signs: Patients with diabetic constipation report a range of bowel disturbances including infrequent passage of hard stools with significant straining. Additional symptoms as a consequence of constipation may include bloating, distention, abdominal pain, discomfort, and fullness. Physical examination may be nonfocal. In severe cases digital anorectal examination may reveal hard, firm stool in the rectal vault.
Definition: Diabetic diarrhea refers to the passage of frequent or loose stools occurring as a consequence of longstanding diabetes. The pathogenesis of this condition is multifactorial (Table III). Diets with significant amounts of poorly absorbed carbohydrates (e.g., sorbitol that is commonly used in sugar free foods) can cause an osmotic diarrhea. Patients with SIBO may have mucosal injury, malabsorption, or maldigestion. Increased delivery of unconjugated bile acids to the colon stimulates fluid and electrolyte secretion. Type 1 diabetes is associated with other autoimmune disorders (e.g., celiac disease, Addison’s disease) which commonly cause diarrhea. Finally, a subset of diabetics with diarrhea exhibit a true secretory diarrhea due to an imbalance between cholinergic intestinal secretion and impaired adrenergic absorption.
Symptoms and Signs: Diabetics with diarrhea report passage of loose and/or frequent stools. Nocturnal symptoms may occur depending on the underlying etiology for the patient’s diarrhea. If there is associated malabsorption due to associated SIBO, celiac disease, or pancreatic insufficiency, patients may also experience bloating, distention, flatulence, weight loss, or steatorrhea. Many patients with high volume liquid stool output will experience fecal incontinence.
Definition: Fecal incontinence refers to inadvertent expulsion of feces. In diabetic patients, this complication is due to a neuropathy that may affect both the internal and external anal sphincters. Symptoms may be further exacerbated by the presence of loose or liquid stools.
Symptoms and Signs: Diabetics with fecal incontinence may have varying degrees of symptoms, ranging from minor soiling to expulsion of large amounts of stool that requires the use of adult incontinence undergarments. In patients with associated rectal sensory neuropathy, the presence of stool in the rectum may be unrecognized prior to its uncontrolled passage. Episodes of fecal incontinence may occur during sleep. Digital rectal examination of the diabetic with fecal incontinence may show evidence of anal neuropathy including decreased anal tone, weak squeeze pressure, and a loss of the anal wink reflex.
Miscellaneous GI Complications of Diabetes
Abdominal Pain: Some diabetics present with upper abdominal pain due to neuropathy or radiculopathy of nerves exiting from the thoracic spinal cord. Physical examination in this setting may show cutaneous sensory deficits.
Esophageal: Many diabetics exhibit evidence of reduced lower esophageal sphincter tone or impaired esophageal acid clearance. Abnormalities on esophageal manometry studies may include reduced contractile amplitudes and velocities, double peaked waves, or simultaneous aperistaltic contractions in the esophageal body and reduced upper esophageal sphincter pressures. Symptoms are predominantly typically to uncontrolled acid reflux, including heartburn and regurgitation. Higher incidence of Candida and pill-induced esophagitis have been reported in patients with diabetes.
Intestinal: Chronic intestinal pseudo-obstruction is a neuropathic or myopathic condition with delayed intestinal transit often with luminal dilation. This is a less common complication of diabetes than gastroparesis or constipation.
Biliary: Neuropathic dysfunction as a consequence of longstanding diabetes may lead to impaired gallbladder contractility or loss of coordinated emptying. Patients with diabetes have a two- to three-fold increase incidence of cholelithiasis though patients with diabetes often have additional confounding risk factors (e.g., obesity, dyslipidemia). Diabetics may have a sensory neuropathy of the gallbladder causing patients to present with atypical symptoms or late in the course of disease.
Pancreatic: Due to vagal neuropathy, patients with longstanding diabetes may exhibit uncoordinated pancreatic exocrine secretion of digestive enzymes. Poorly controlled glucose levels may trigger activation of inflammatory cytokine pathway, leading to increased rates of pancreatitis and pancreatic adenocarcinoma.
Hepatic: Nonalcoholic fatty liver disease, or hepatic steatosis, is a recognized complication of poorly controlled diabetes. Patients are typically asymptomatic and identified based on laboratory testing for other conditions (e.g., abnormal transaminase levels). Some patients may exhibit right upper quadrant abdominal pain if steatosis has led to hepatomegaly, due to stretching of the hepatic capsule, though this is uncommon. Hepatic steatosis can progress to more severe forms of liver disease including steatohepatitis and ultimately cirrhosis. Physical examination may reveal hepatomegaly with tenderness or typical signs of cirrhosis if the disease has progressed to that stage.
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 endocrine disorders.
Patients with evidence of gastroparesis require screening for additional disorders including gastric outlet obstruction, thyroid dysfunction, neurologic disease, autoimmune disorders, prior gastric or bariatric surgery, and recent viral illness. In a tertiary care setting, the majority of gastroparesis cases are idiopathic (36%), diabetic (29%), or postsurgical (29%).
As the name implies, idiopathic gastroparesis are those cases without a primary underlying etiology. Postsurgical gastroparesis is a consequence of intentional vagotomy or inadvertent vagus nerve injury. Other iatrogenic causes of gastroparesis are due to medications with anticholinergic properties, 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 medications used for the treatment of diabetes (e.g., metformin, exenatide, liraglutide, pramlintide).
Less common causes of gastroparesis include connective tissue disorders (e.g., lupus or scleroderma), Parkinson’s disease, amyloidosis, muscular dystrophy, paraneoplastic disease (e.g., small cell lung cancer), or endocrine disorders (e.g., hypothyroidism, hyperparathyroidism, hypoadrenalism). Pregnancy should always be considered in women of child-bearing age who report nausea and vomiting. Other GI-related disorders that may cause symptoms similar to diabetic gastroparesis include acid-related esophagitis, fungal esophagitis, peptic ulcer disease, gastritis, duodenitis, gastric outlet obstruction, gastric cancer, gallstone disease, and pancreaticobiliary neoplasia.
Delayed gastric emptying may be seen in patients with rumination syndrome or eating disorders, such as anorexia nervosa and bulimia. Rumination syndrome is characterized by regurgitation of gastric contents into the mouth within 15 minutes of eating that is typically effortless and characteristically different from vomiting; furthermore, these patients typically do not report associated nausea. Other disorders that may present with symptoms similar to gastroparesis include cyclic vomiting syndrome, chronic cannabinoid use, and functional disorders.
Small Intestinal Bacterial Overgrowth
Due to the nonspecific symptom presentation of SIBO in diabetics, diagnosis may be difficult to differentiate from irritable bowel syndrome, functional dyspepsia, or functional diarrhea. All causes of malabsorption should be considered in the differential, including celiac disease, inflammatory bowel disease, and pancreatic insufficiency. Dietary factors commonly produce symptoms similar to those of SIBO including lactose or fructose intolerance, gluten intolerance, and consumption of high FODMAP (fermentable oligosaccharides, disaccharides, monosaccharides, and polyols) foods (Table IV). Diabetic patients may substitute sugar with artificial sweeteners i.e. sorbitol which may lead to maldigestion.
Constipation due to diabetes presents in the same manner as constipation due to innumerable other causes. Impaired colon transit also occurs with connective tissue diseases (e.g., scleroderma), infiltrative processes (e.g., amyloid), smooth muscle diseases (e.g., muscular dystrophy), endocrine disorders (e.g., hypothyroidism, hyperparathyroidism), and other autoimmune conditions. Colorectal neoplasia should be ruled out in all patients with new onset constipation or unintentional weight loss. Other obstructive etiologies include inflammatory bowel disease with strictures, rectoceles, or endometriosis. Dyssynergic defection may also present with chronic constipation.
Other conditions that cause diarrhea include 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, dietary factors should also be considered.
Fecal incontinence related to diabetes is typically related to anal sphincter neuropathy that may be exacerbated by diarrhea. Other causes for anal sphincter dysfunction include local anal trauma or disruption, prior damage during forceful childbirth or inadequately repaired episiotomies, and sacral spinal nerve disease. Fistulas, such as those seen in inflammatory bowel disease, may be mistaken as fecal incontinence.
Miscellaneous GI Complications of Diabetes
Esophageal: Esophageal manifestations of diabetes may be mimicked by severe gastroesophageal reflux disease, infectious esophagitis, or esophageal dysmotility disorders.
Intestinal: Intestinal pseudo-obstruction may be caused connective tissue diseases (e.g., lupus, scleroderma, dermatomyositis), infiltrative diseases (e.g., amyloid), paraneoplastic disease, or endocrine disorders. Symptoms of pseudo-obstruction are similar to those of small intestinal mechanical obstruction due to adhesions, strictures, or tumors.
Biliary: Additional risk factors for cholecystitis or other biliary complications include pregnancy, female sex, obesity, older age, prior biliary infection, and medications (e.g., octreotide).
Pancreatic: Other causes of pancreatic insufficiency include alcohol use, idiopathic disease, cystic fibrosis, hypercalcemia, dyslipidemia, autoimmune disorders, and mechanical factors causing ductal obstruction (e.g., neoplasm, strictures).
Hepatic: Hepatic steatosis is associated with diabetes, dyslipidemia, and obesity. Other causes of hepatic steatosis include starvation, parenteral nutrition, hepatitis C genotype 3, Wilson’s disease, abetalipoproteinemia, inborn errors of metabolism (e.g., LCAT deficiency, cholesterol ester storage disease, Wolman disease), acute fatty liver of pregnancy, HELLP syndrome, and medications (e.g., valproic acid, anti-retroviral medications, amiodarone, methotrexate, tamoxifen, corticosteroids).
Key Laboratory and Imaging Tests
Diagnosis of gastroparesis requires objective evidence of delayed gastric emptying. Patients should be evaluated for complications of vomiting and alternative causes of delayed gastric emptying, such as mechanical obstruction.
Laboratory Studies: A basic metabolic panel is needed to identify electrolyte abnormalities and evidence of dehydration, particularly hypokalemia, contraction alkalosis and elevated blood urea nitrogen or creatinine levels. Complete blood count and thyroid-stimulating hormone are typically checked to rule out alternative etiologies.
Structural Evaluation: Upper endoscopy is needed to rule out gastric outlet obstruction secondary to stricture, ulcer disease, or neoplasm. Retained food or bezoars may be found on endoscopic evaluation. A plain upright abdominal radiograph, upper gastrointestinal contrast radiography, or computed tomography (CT) can be obtained if more distal obstruction is suspected. If abdominal pain is a prominent symptom or liver chemistries are abnormal, then abdominal ultrasound may be considered to exclude a hepatobiliary cause such as symptomatic gallstone disease.
Functional Evaluation: Delayed gastric emptying is diagnosed with scintigraphy, typically measuring gastric retention after the patient consumes a 99mTc-labeled egg-substitute meal. Gastroparesis is defined as >60% gastric retention at 2 hours or >10% retention at 4 hours. An important part of diagnostic testing requires holding medications (i.e. opioids and anticholingeric medications) that may affect gastric emptying time for 48 hours prior to the test.
Breath tests can determine gastric emptying after consuming nonradioactive 13C-labeled meals. Wireless motility capsules can detect gastric emptying by measuring the pH increase as the capsule passes from the antrum to the duodenum. Both breath testing and wireless motility capsule studies have been correlated with scintigraphy but require further validation before widespread use clinically.
Small Intestinal Bacterial Overgrowth
Laboratory tests are most useful for assessing nutritional and metabolic consequences but cannot diagnose SIBO.
Laboratory Studies: Patient with diarrhea due to SIBO may have vitamin deficiencies secondary to maldigestion or malabsorption if mucosal damage has occurred. Labs suggestive of this process include hypoalbuminemia and fat soluble vitamin (A, D, E, K) deficiencies, vitamin B12, or iron. Elevated folate levels may be seen due to the production by bacteria in the small bowel. Workup should also evaluation for concomitant celiac disease.
Options to Define SIBO: The gold standard for diagnosing SIBO is fluid aspiration from the small bowel and sent for culture and bacterial count. The threshold for diagnosis is >103 CFU/mL. Potential limitations with this method include the need for invasive testing (endoscopy), false negative results due to sample obtained from the proximal rather than mid-distal small bowel, false positive results from contamination with oral and esophageal flora, and limited availability of microbiology labs to perform bacterial quantitation.
Normal intestinal gas contains primarily hydrogen, carbon dioxide, methane. Patient with SIBO have excessive production of hydrogen and/or methane due to the microbial fermentation of carbohydrates. Therefore, an alternate, less invasive method for diagnosing SIBO is the use of breath tests. Breath samples are obtained after ingestion of a carbohydrate substrate (e.g., lactulose or glucose). SIBO is diagnosed if there is a rise ( 10 or 20 parts per million in methane or hydrogen levels, respectively, above the baseline. False negative results may be seen in patients with SIBO due to a non-hydrogen or methane producing bacteria or delayed gastric emptying with metabolism of the substrate prior to reaching the small bowel. False positive results may be seen in patients with carbohydrate malabsorption due to other causes, such as celiac disease or chronic pancreatitis, nonadherence to prep prior to testing, or rapid transit with metabolism of substrate and gas production in the colon.
The third management option is empiric treatment with oral antibiotics instead of diagnostic testing. With this approach, symptom reduction after antibiotic therapy is considered to be evidence of SIBO.
Diagnostic testing may not be necessary in patients with diabetic constipation unless presentation suggests the need to exclude other potential causes of symptoms.
Laboratory Studies: In the absence of additional localizing symptoms, laboratory workup may not be necessary but consideration may be given to check a basic metabolic panel rule out electrolytes disturbance (e.g., hypercalcemia), complete blood count to rule out anemia, and thyroid stimulating hormone to screen for hypothyroidism.
Structural Evaluation: Colonoscopic evaluation should be considered in patients patients with alarm symptoms (e.g., bleeding, weight loss, fever, abrupt onset of symptoms), anemia, or family histories of colorectal neoplasia or inflammatory bowel disease. Additionally, all patients should be screened appropriately for colorectal neoplasia per guidelines.
Laboratory Studies: Routine laboratory tests include a basic metabolic panel to exclude disturbances that may suggestive of dehydration (e.g., hypokalemia, contraction alkalosis, elevated blood urea nitrogen). Though not diagnostic, erythrocyte sedimentation rate or C-reactive protein may be an indication to consider inflammatory bowel disease. Tissue transglutaminase antibody is checked to rule out concomitant celiac disease. If clinically suspected with additional symptoms, hyperthyroidism and adrenal insufficiency should be ruled out. Stool studies are obtained in patients with exposure to well water, recent contact with sick individuals, or travel history. Fecal fat determination may indicate pancreatic insufficiency, SIBO, celiac disease, or even rapid small bowel transit.
Structural and Functional Evaluation: If the noninvasive studies do not reveal an underlying cause of diarrhea, colonoscopy with biopsies from the colon and ileum are obtained to exclude inflammatory bowel disease and microscopic colitis. Upper endoscopy with duodenal biopsies and small bowel aspirate for culture may also be considered.
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 anal tone, anorectal squeeze pressure, and rectal sensation. In some cases, electromyographic testing of pudendal nerve latencies is included to exclude damage to this nerve.
Miscellaneous GI Complications of Diabetes
Esophageal: Upper endoscopy is indicated for persistent esophageal reflux symptoms to assess for esophagitis and associated complications. If the patient complains of dysphagia, a barium swallow can screen for mechanical causes and may also detect evidence of dysmotility, though this can be better characterized with an esophageal manometry study. Acid reflux can be 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 tissue transglutaminase IgA level. Negative HLA DQ2 and DQ8 levels are nearly 100% specific to rule out celiac disease, but these tests are not part of routine laboratory workup. Upper endoscopy with duodenal biopsies may be obtained to diagnose or determine severity of celiac disease.
Small intestinal pseudoobstruction is supported by abdominal CT scanning (which may show luminal dilation) and small bowel barium radiography (which can indicate dilation and/or delayed intestinal transit). Testing for SIBO should be considered in any patient with suspected intestinal dysmotility given the high prevalence of bacterial overgrowth.
Biliary: Ultrasound should be obtained to evaluate the gallbladder and biliary tree in any patients with abnormal liver chemistries or symptoms raising suspicion of such conditions. If biliary dilation is seen, further evaluation (MRCP, EUS, ERCP) may be needed for diagnosis or treatment.
Pancreatic: Despite the association between longstanding diabetes and pancreatic disorders, current guidelines do not suggest widespread screening programs. Workup for pancreatic involvement is considered in patients with steatorrhea, malnutrition, or cholestatic liver chemistries. Pancreatic enzymes (amylase, lipase) may be elevated in diabetics in the setting of ketoacidosis or frequent vomiting. Imaging modalities for the pancreas include CT, MRI, or EUS. Ultrasound may be able to visualize the pancreas, but the images are often inadequate due to the presence of intestinal gas. Fecal elastase levels may be used to screen for pancreatic insufficiency.
Hepatic: Most patients with non-alcoholic fatty liver disease are asymptomatic until the end stages of the disease. NAFLD occurs at higher rates in diabetic patients, particularly those with longstanding diabetes and/or patients who are insulin dependent. If elevated liver chemistries are found, additional work up to rule out other causes of chronic liver diseases include viral hepatitis, autoimmune hepatitis, metabolic storage disorders. Ultrasound commonly shows heterogeneous echotexture with steatosis.
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.
Antroduodenal manometry uses a catheter to record phasic contractions in the antrum and proximal small bowel. Normal recordings show normal migrating motor complex activity, an organized pattern that clears the upper gut of undigested debris, and a contractile response to meals or motor stimulating medications. Abnormalities that may be detected include pylorospasm (increases in tone and phasic contractions in the pylorus), visceral neuropathy (chaotic, intense uncoordinated small bowel contractions), visceral myopathy (low amplitude contractions with otherwise normal morphology and propagation patterns), and rumination (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 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 that increase in amplitude with eating. Patients with gastroparesis may have cycling that is too fast (tachygastria) or too slow (bradygastria) or waveforms that do not increase in amplitude after a meal.
Small Intestinal Bacterial Overgrowth
Small bowel barium radiography may be performed to exclude conditions promoting refractory SIBO including small intestinal strictures, diverticula, fistulae, or profound dilation or transit delay suggestive of pseudo-obstruction. In resistance cases, an upper endoscopy with quantitative culture of duodenal fluid can be performed to obtain antibiotic sensitivity on a positive culture.
Patients with diabetic constipation unresponsive to appropriate dietary and medication therapies may benefit from additional testing. Dyssynergic defecation, diagnosed with anorectal manometry, is an important entity to rule out since it presents as constipation. MRI defecography may detect structural abnormalities (e.g., rectoceles, rectal intussusception) that are not identified on static cross-sectional images.
Stool electrolytes are obtained to calculate the stool osmolality which delineates between osmotic (>125 mOsm/kg) and secretory (<50 mOsm/kg) diarrhea. Stool studies are also performed to look for evidence of inflammation (e.g., lactoferrin, calprotectin), fat malabsorption (e.g., elastase, qualitative and/or quantitative fat), or infection.
Normal stool volumes are <250 mL per day. Patient with secretory diarrhea often have daily stool volume exceeding 1 liter. Rarer causes of secretory diarrhea include hormonal disturbances (e.g., carcinoid, VIPoma, gastrinoma) and surreptitious laxative intake which can be evaluated by specific stool or urine tests.
Miscellaneous GI Complications of Diabetes
Intestinal: Antroduodenal manometry may be used to diagnose small intestinal pseudo-obstruction. If amyloidosis is a suspected cause for small intestinal motility disorders, subcutaneous fat pad or deep rectal biopsy with Congo red staining is obtained.
Hepatic: Liver biopsy is not required in all cases of hepatic steatosis, but should be considered if there is suspicion for more than one etiology of patient’s liver disease. Additionally, when advanced fibrosis is suspected, a liver biopsy or transient elastography may be performed.
Management and Treatment of the Disease
Management of gastroparesis requires optimization of glycemic control both acute and chronically. Blood glucose levels >270 mg/dL prolongs gastric emptying time.
Dietary Recommendations: Vitamin and mineral deficiencies may be seen in patient with gastroparesis due to food intolerance. Diet modifications are needed to compensate for impaired gastric motor and sensory function. The gastroparesis diet requires 4-6 small, low fat, low fiber meals each day (an inclusive list of suggested foods for patients can be found at https://uvahealth.com/services/digestive-health/images-and-docs/gastroparesis-diet.pdf). Patients may be dependent on high calorie liquids to meet their caloric and nutritional needs during flares when they are unable to tolerate solid food. Carbonated beverages and alcohol should be avoided. In severe cases, patients may need a jejunal feeding tube to bypass the stomach.
Medication Therapy: Medications used for diabetic gastroparesis include prokinetic drugs that stimulate gastric emptying and symptomatic treatment with antiemetic agents, and neuromodulators that blunt gastric nerve hypersensitivity.
(i) Prokinetic Therapy
The first-line prokinetic agent and only FDA approved medication for long-term treatment of gastroparesis is metoclopramide. As a maintenance medication, it should be used at the lowest effective dose, typically 5 mg three times daily titrated up to a total daily dose of 40 mg orally (oral tablet, oral dissolution tablet, or liquid solution). It is also available to be given intravenously, intramuscularly, or subcutaneously in patients with gastroparesis flares who are unable to tolerate the oral formulation. Possible side effects include neurolopsychiatric symptoms (i.e. dystonia, sleep disturbances, depression, anxiety, tremors), hyperprolactinemia (gynecomastia, lactation), and QT prolongation. An FDA black box warning has been issued for tardive dyskinesia which may be irreversible in some patients. All prescribers should review these potential side effects with patients and follow them closely.
Domperidone is a peripheral dopamine antagonist that does not cross the blood brain barrier; thus neurologic side effects are rare compared to metoclopramide. The starting dose is 10 mg three times daily before meals with a maximum dose of 20 mg four times daily. The most notable side effect is prolongation of QTc interval. EKGs must be obtained prior to starting and during therapy. Hyperprolactinemia and drug-drug interactions may be seen due to alteration of CYP2D6 function. Domperidone is only available in the United States under an Investigational New Drug approval program by the FDA.
Erythromycin is a motilin agonist that is most effective when used intravenously at 3 mg/kg every 8 hours. While it may be given in oral formulation, studies have shown that long term use (greater than 4 weeks) leads to downregulation of the motilin receptor, and as a result, the medication becomes ineffective. Drug interactions with CYP3A4 activity and QT prolongation may occur.
(ii) Symptomatic Management
Additional medications used for symptomatic treatment of nausea and vomiting include dopamine antagonists (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 or to show superiority of one of these medication classes.
Neuromodulator therapy may be used, but data supporting their efficacy are provided only by case series or case reports. Tricyclic antidepressants (e.g., nortriptyline) and selective serotonin reuptake inhibitors (e.g., mirtazapine) have been found to reduce symptoms of nausea, vomiting, and abdominal pain. Additional medications that may provide relief particularly in patients persistent pain include tramadol, gabapentin, pregabalin, and tapentadol.
Options Other Than Oral Medications: Pylorospasm refers to the intermittently increased pyloric tone and contractions that has been observed in some patients with diabetic gastroparesis. Endoscopic injection of botulinum toxin (100-200 units) into the pylorus has been studied with conflicting results and is not recommended in current guidelines. Gastric electrical stimulators continually deliver high frequency, low energy electrical pulses to the greater curvature of the stomach and is approved by the FDA for compassionate treatment in patients with refractory symptoms. Open-label trials have shown improvement in symptoms with variable improvement in gastric emptying time.
Jejunostomy tubes permit nutrient delivery distal to the stomach, while venting gastrostomies allow periodic release of retained gastric fluid and gas to reduce symptoms. Enteral feedings should be considered in patients with repeated hospitalizations for refractory symptoms or patients with greater than 10% weight loss in 3-6 months. Surgeries (e.g., gastrojejunostomy, subtotal or complete gastrectomy, pyloromyotomy) have been reported to improve symptoms in those with refractory gastroparesis, but further studies are needed.
Small Intestinal Bacterial Overgrowth
Management of SIBO includes antibiotic therapy to eliminate the excess small bowel bacterial load, nutritional support if needed, and treatment of underlying risks for recurrence. In patients with diabetes, strict glucose control and management of the associated motility disorders is important to prevent recurrent episodes of SIBO.
Dietary Recommendations: Patients with SIBO may experience intolerance of poorly absorbed carbohydrates, especially when bacterial colonization of the upper gut is incompletely treated. Supplementation with B12 and fat-soluble vitamins may be needed. If mucosal damage has occurred, patients typically may need to avoid lactose and fructose due to the lack of the necessary enzymes for degradation.
Medication Therapy: If small bowel sampling was obtained, antibiotic therapy can be targeted to sensitivity testing. In cases where the diagnosis is made based on breath testing or in patients who are being treated empirically, the preferred medication is rifaximin, a non-absorbable antibiotic with minimal adverse effects at a dose of 550 mg 2-3 times daily for 10-14 days. If rifaximin is not tolerated, ineffective, or not covered by insurance, alternatives include tetracycline derivatives, fluoroquinolones, amoxicillin with or without clavulanic acid, cephalosporins, trimethoprim-sulfamethoxazole, metronidazole, and neomycin. However, these antibiotics have higher rates of adverse events compared to rifaximin. It is not uncommon to observe recurrences after effective SIBO treatment, particularly in patients whose risk factors have not been resolved. Patients may cycle antibiotics at 10 to 14 day intervals.
Management of constipation in diabetic patients is similar to the general population. (Table VI).
Dietary and Lifestyle Recommendations: High fiber diets may be recommended but caution should be advised as sudden increase in fiber intake with inadequate hydration may worsen constipation initially. For patients who complain of bloating and distention, avoidance of gas forming carbohydrates (e.g., low FODMAP diets) may be recommended.
Medication Therapy: Fiber supplements are often used but may cause worsening of bloating. Most patients will respond to polyetyhlence glycol (Miralax) 17g 1-3 times daily but should be advised that effects are not seen immediately. Additional alternative include over-the-counter stimulants such as senna, bisacodyl, or magnesium hydroxide (if renal function is normal). Nonabsorbable carbohydrate laxatives such as lactulose and sorbitol often cause significant bloating, distention, and flatulence. In patients with no response to above therapies, secretory stimulants (e.g., lubiprostone and linaclotide) may be considered.
Nonmedication Options: Patient with dyssynergic defecation benefit from physical therapy for biofeedback and sensory retraining. Surgery may be indicated for repair of large rectoceles or intussusceptions. In severe, refractory cases of slow transit constipation, patients may consider subtotal colectomy.
Given the varied underlying causes of diabetic diarrhea, management and therapy should be targeted to the particular etiology (Table VII).
Dietary Recommendations: Dietary management of diabetic diarrhea aims to reduce consumption of poorly absorbed carbohydrates. Avoidance of dairy products should be advised as patients may have a relative lactase deficiency. In general, patients should minimize intake of high FODMAP foods, especially those with high fructose or sorbitol content. This includes foods that are advertised with “no sugar added” labels as most of these products contain sorbitol, which is poorly absorbed.
Medication Therapy: Underlying conditions that have specific medical therapies should be appropriately managed. (Table VII). Medications that prolong intestinal transit and increase intestinal absorption include loperamide, diphenoxylate-atropine, codeine-containing preparations, tincture of opium. Bile acid binders (e.g., cholestyramine, colestipol, colesevelam) may be beneficial as patient may have an unrecognized bile acid diarrhea. However, strong opiate agents and bile acid binders may significantly exacerbate symptoms in patient with concomitant gastroparesis. Antisecretory medications (e.g., clonidine, octreotide) can be offered for high output diabetic diarrhea, but have notable side effects that must be monitored closely.
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.
Management of fecal incontinence associated with diabetes relies on controlling the associated diarrhea as well as measures specifically designed to improve anorectal function.
Dietary Recommendations: Fiber supplementation may be cautiously recommended for this indication to provide stool bulking.
Medication Therapy: If the diabetic with fecal incontinence has associated diarrhea, the medication recommendations for diabetic diarrhea listed above are appropriate.
Nonmedication Options: Patients with evidence of abnormal anorectal function should be referred to physical therapy for biofeedback and sensory training. In rare cases, surgery to augment sphincter function is offered; however these procedures have high complication rates. Patients with persistent symptoms may consider an ostomy to limit infectious consequences of uncontrolled fecal soiling.
Miscellaneous GI Complications of Diabetes
Esophageal: Severe esophagitis secondary to esophageal dysmotility is most often managed with acid suppressive agents such as proton pump inhibitors. Candida esophagitis is treated with antifungals such as fluconazole. Esophageal strictures may be endoscopically dilated.
Intestinal: Celiac disease is managed by initiating a gluten free diet. Restriction of dairy products is also suggested during the initial phase of gluten exclusion due to lactase deficiency that occurs as a consequence of the villous atrophy in celiac disease. Intestinal pseudo-obstruction is a challenging condition with limited therapeutic options. Prokinetic agents (pyridostigmine, octreotide, and erythromycin) may have some benefit in small motility disorders. Most diabetics with pseudo-obstruction have associated SIBO which may be treated with oral antibiotics. Diet recommendations in this condition include avoidance of high residue and high fat foods as well as poorly absorbable carbohydrates. Enteral feedings with elemental formulas may be used in refractory cases to optimize tolerability given the associated small intestinal dysmotility. 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: Choledocholithiasis requires endoscopic retrograde cholangiopancreatography with sphincterotomy and stone extraction. Cholecystectomy should be considered in any patient with an episode of choledocholithiasis or cholecystitis.
Pancreatic: Pancreatic enzyme supplementation is given with meals and snacks in patients with evidence of fat malabsorption.
Hepatic: There are currently no medications to specifically treat hepatic steatosis. The cornerstone of management includes optimizing glycemic and lipid control, diet, exercise, and weight loss. Patients with progression to cirrhosis may ultimately need liver transplantation.
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- Are You Sure the Patient Has a Gastrointestinal Complication of Diabetes?
- What Else Could the Patient Have?
- Key Laboratory and Imaging Tests
- Other Tests That May Prove Helpful Diagnostically
- Management and Treatment of the Disease