BASICSLakshmi Devi Nelson Lattimer, MD • Matthew Chandler, MD • Marie L. Borum, MD, EdD, MPH
BASICS
DESCRIPTION
• An increase in frequency of defecation or decrease in stool consistency (typically >3 loose stools per day) for >4 weeks (1,2):
– Etiologies include osmotic, secretory, malabsorptive, inflammatory, infectious and hypermotility.
– Bacterial infectious etiologies are less common in chronic diarrhea, parasitic infectious are more common.
• System(s) affected: gastrointestinal (GI)
EPIDEMIOLOGY
Prevalence
Variable depending on etiology, but overall ~3–5% of the U.S. population is affected (2)
ETIOLOGY AND PATHOPHYSIOLOGY
In most cases, chronic diarrhea is the result of disturbances in the intestinal luminal water and electrolyte balance. This varies depending on etiology.
• Osmotic (fecal osmotic gap >125 mOsm/kg) (2)
– Carbohydrate malabsorption
Disaccharides including lactose
Monosaccharides including fructose
Polyols including sorbitol, xylitol, sucralose, and saccharin (common sugar substitutes)
These substances cannot be metabolized and create an osmotic gradient.
– Magnesium, phosphate, and sulfate overload
• Secretory (fecal osmotic gap <50 mOsm/kg) (2)
– Stimulant laxative ingestion
– Postcholecystectomy
Excessive bile salts in intestinal lumen cause cholerheic diarrhea; often resolves in 6 to 12 months
– Ileal bile acid malabsorption
– Ileal resection of <100 cm leads to cholerheic diarrhea due to excessive colonic bile salts.
– Disordered motility
Postvagotomy
Diabetic autonomic neuropathy
Hyperthyroidism
– Neuroendocrine tumors
VIPoma
Gastrinoma
Somatostatinoma
Carcinoid syndrome
– Metastatic medullary carcinoma of the thyroid
– Systemic mastocytosis
– Protein-losing enteropathy
• Malabsorption (2)
– Celiac disease
– Whipple disease
– Giardiasis
– Short bowel syndrome
Ileal resection of >100 cm leads to insufficient bile salt concentrations in the duodenum for optimal fat absorption, leading to fat and fat-soluble vitamin malabsorption.
– Small intestinal bacterial overgrowth
– Pancreatic exocrine insufficiency (CF, chronic pancreatitis)
– Inadequate bile acid production/secretion
• Inflammatory (2)
– Ulcerative colitis
– Crohn disease
– Microscopic colitis (lymphocytic or collagenous)
– Vasculitis
– Radiation enterocolitis
– Eosinophilic enterocolitis
• Hypermotility (normal fecal osmotic gap) (1,2)
– Irritable bowel syndrome (IBS)
– Functional diarrhea
• Drugs: NSAIDs, PPIs, colchicine, metformin, digoxin, SSRIs
• Herbal products: St. John’s wort, echinacea, garlic, saw palmetto, ginseng, cranberry extract, aloe vera
• Infectious (2)
– Bacterial: Clostridium difficile, Mycobacterium avium intracellulare
– Viral: cytomegalovirus
– Parasitic: Giardia lamblia, Cryptosporidium, Isospora, Entamoeba histolytica
– Helminthic: Strongyloides
Genetics
• Celiac disease is associated with HLA-DQ2 and HLA-DQ8 haplotypes on major histocompatibility complex (MHC) class II antigen-presenting cells (3).
• IBD is polygenic (4).
• Cystic fibrosis (CF) is caused by a mutation in the CF transmembrane conductance regulator (CFTR), resulting in abnormal exocrine gland secretions.
RISK FACTORS
• Osmotic
– Excessive ingestion of nonabsorbable carbohydrates
– Lactose intolerance
– Celiac disease
• Secretory
– Extensive small bowel resection/ileal surgery
– History of neuroendocrine disease
– History of stimulant laxative abuse
– Dysmotility syndromes
• Malabsorptive
– CF
– Chronic alcohol abuse
– Chronic pancreatitis/pancreatic insufficiency
– Celiac disease
– Medications (e.g., orlistat, acarbose)
• Inflammatory
– Inflammatory bowel disease (IBD)
– NSAID use
– Thoracoabdominal radiation
– HIV/AIDS
– Antibiotic use
– Immunosuppressant therapy
• Hypermotility
– Psychosocial stress
– Preceding infection
• Genetic predisposition
ALERT
Diabetes mellitus and/or prior cholecystectomy both cause secretory and osmotic diarrhea.
GENERAL PREVENTION
• Variable depending on etiology of the diarrhea
• Treat the underlying disorder.
COMMONLY ASSOCIATED CONDITIONS
• Extraintestinal manifestations of IBD include arthralgias, aphthous stomatitis, uveitis/episcleritis, erythema nodosum, pyoderma gangrenosum, perianal fistulas, rectal fissures, ankylosing spondylitis, and primary sclerosing cholangitis.
• Celiac disease is associated with dermatitis herpetiformis, type 1 diabetes, other autoimmune disorders and IgA deficiency.
• Many patients with IBS have psychiatric comorbidities.
DIAGNOSIS
HISTORY
• Detailed history of symptoms, including (1,2):
– Onset, pattern, and frequency
– Stool volume and quality (including presence of blood or mucus)
– Presence of nocturnal symptoms
– Travel history
– Antibiotic exposure
– Dietary habits
– Current medications
– Family history
• Determine aggravating or alleviating factors, including changes with oral intake or improvement with selective food avoidance (e.g., dairy products).
• Evaluate unintentional weight loss.
• Complete review of systems, including rashes, arthritis, ocular problems, heat intolerance, polyuria/polydipsia, headache, fever, flushing, alcohol intake
• IBS or functional diarrhea by Rome III criteria:
– IBS: recurrent abdominal pain or discomfort at least 3 days/month for past 3 months; ≥2 of:
Improvement with defecation
Onset associated with change in frequency of stool
Onset associated with change in form of stool
– Functional diarrhea: ≥75% loose or watery stools without pain for >3 months (symptoms >6 months)
PHYSICAL EXAM
• General: Assess for volume depletion, nutritional status, recent weight loss (2).
• Skin: flushing (carcinoid), erythema nodosum (IBD), pyoderma gangrenosum (IBD), ecchymoses (vitamin K deficiency), dermatitis herpetiformis (celiac disease) (1,2)
• HEENT: iritis/uveitis (IBD)
• Neck: goiter (hyperthyroid), lymphadenopathy (Whipple disease)
• Cardiovascular: tachycardia (hyperthyroid)
• Pulmonary: wheezing (carcinoid)
• Abdomen: hyperactive bowel sounds (IBD), abdominal distention (IBD/IBS), diffuse tenderness (IBD/IBS)
• Anorectal: anorectal fistulas (IBD), anal fissures (IBD)
• Extremities: arthritis (IBD)
• Neurologic: tremor (hyperthyroid)
See “Etiology and Pathophysiology” and “Commonly Associated Conditions.”
DIAGNOSTIC TESTS & INTERPRETATION
Initial Tests (lab, imaging)
• Blood: CBC with differential, electrolytes (Mg, P, Ca), total protein, albumin, thyroid-stimulating hormone (TSH), free T4, erythrocyte sedimentation rate, iron studies (2)
• Stool: WBCs, culture, ova and parasites, Giardia stool antigen, C. difficile toxin, stool electrolytes (fecal osmotic gap), fecal occult blood, qualitative fecal fat (Sudan stain) (2)
• Plain film of the abdomen to evaluate for obstruction, toxic megacolon, bowel ischemia (1)
• CT to rule out chronic pancreatitis if abnormal pancreatic enzymes or evidence of malabsorption (1,2)
Follow-Up Tests & Special Considerations
• Celiac disease: antiendomysial antibody IgA, antitissue transglutaminase (TTG) IgA, antigliadin (AGA) IgA, serum IgA (10% of celiac patients have IgA deficiency that may result in false-negative results) (3)[A]
• Chronic pancreatic insufficiency: fecal elastase (2)[A]
• Protein-losing enteropathy: fecal α1 antitrypsin (2)[A]
• Carbohydrate malabsorption: fecal pH
• Small bowel overgrowth: hydrogen breath test
• Prior history of hospitalization or antibiotics: C. difficile toxin
• Neuroendocrine tumor
– Serum: chromogranin A, VIP, gastrin (1)
– Urine: 5-HIAA, histamine (1)
Diagnostic Procedures/Other
• Ileocolonoscopy with biopsies: to diagnose IBD, microscopic colitis, CMV colitis, and colorectal neoplasia (5)[A]
• Flexible sigmoidoscopy: especially if pregnant, with comorbidities, or if left-sided symptoms predominate (tenesmus and urgency) (5)[A]
• Esophagogastroduodenoscopy (EGD) with small bowel biopsies if malabsorption is suspected:
– Celiac, Giardia infection, Crohn disease, eosinophilic gastroenteropathy, Whipple disease, intestinal amyloid, pancreatic insufficiency (5)[A]
• Capsule endoscopy if further evaluation of small bowel is needed (5)[C]
• Upper GI series with small bowel follow-through
• CT or magnetic resonance (MR) enterography (1,2)
Test Interpretation
• Celiac disease: Marsh classification:
– Intraepithelial lymphocytosis, crypt hyperplasia, villous atrophy (3)
• Crohn disease: cobblestoning, linear ulcerations, skip lesions, noncaseating granulomas
• Ulcerative colitis: crypt abscesses, superficial inflammation (5)
• Lymphocytic colitis: increased intraepithelial infiltration of lymphocytes, increased inflammatory cells within the lamina propria, normal mucosal architecture (5)
• Melanosis coli suggests laxative abuse (2).
TREATMENT
GENERAL MEASURES
• If stable, treatment is generally outpatient.
MEDICATION
First Line
• Based on underlying cause:
– Lactose intolerance: lactose-free diet
– Cholecystectomy or ileal resection: cholestyramine or colestipol 2 to 16 g/day PO divided BID.
– Diabetes: aggressive diabetes management and glucose control
– Hyperthyroidism: methimazole 5 to 20 mg/day PO, propylthiouracil (PTU) 100 to 150 mg/day PO divided; thyroid ablation
– C. difficile: vancomycin 125 mg PO q6h or metronidazole (Flagyl) 500 mg PO q8h or fidaxomicin 200 mg PO BID
– G. lamblia: metronidazole 250 mg PO q8h, nitazoxanide 500 mg PO q12h (2)[A]
– Whipple disease: ceftriaxone 2 g IV for 14 days then Bactrim DS 160/800 mg PO BID for 1 to 2 years
– Small intestinal bacterial overgrowth: rifaximin 550 mg PO BID, fluoroquinolones 250 to 750 mg PO BID, metronidazole 500 mg PO q6–8h, penicillins
– Pancreatic insufficiency: pancreatic enzyme replacement (1)[A]
– HIV/AIDS: antiretroviral therapy
– Microscopic colitis: budesonide 9 mg/day PO, mesalamine 800 mg PO TID, Pepto-Bismol 786 mg PO TID
– IBD: 5-aminosalicylic acid (5-ASA), corticosteroids (short-term only), antibiotics (short-term only), immunomodulators (6-mercaptopurine [6-MP], azathioprine, methotrexate), anti-TNF therapy (infliximab, adalimumab, certolizumab) (4)[A]
– Neuroendocrine tumor: octreotide 100 to 600 g/day SC (2)[A]
– Celiac disease: gluten-free diet (wheat/barley/rye avoidance) (3)[A]
– IBS diarrhea predominant: rifaximin 550 mg PO BID, alosetron 0.5 to 1 mg PO BID, peppermint oil
• Symptom relief:
– Loperamide 4 to 8 mg/day PO divided
– Diphenoxylate-atropine 1 to 2 tabs PO BID–QID (2)[A]
SURGERY/OTHER PROCEDURES
• Resection of neuroendocrine tumors
• Intestinal resection for medically refractory IBD
• Fecal transplant for recurrent C. difficile infection
COMPLEMENTARY & ALTERNATIVE MEDICINE
Many homeopathic and naturopathic formulations are available; most have not been evaluated by the FDA.
ONGOING CARE
DIET
Abstain from gluten-containing foods, nonabsorbable carbohydrates, lactose-containing products, and food allergens depending of etiology of diarrhea.
PATIENT EDUCATION
• Reassure patient of wide variation in what is accepted as “normal” bowel habits.
• Restrict colon stimulants.
• Specific education and dietary changes based on underlying etiology.
PROGNOSIS
Depends on etiology
COMPLICATIONS
• Fluid and electrolyte abnormalities (1)
• Malnutrition (1); anemia (1)
• Malignancy (colon cancer in IBD, small bowel cancer in celiac disease and Crohn disease, lymphoma with IBD therapies) (4)
• Infection with immunomodulator, biologic, and corticosteroid therapies for IBD (4)
REFERENCES
1. Schiller LR. Definitions, pathophysiology, and evaluation of chronic diarrhoea. Best Pract Res Clin Gastroenterol. 2012;26(5):551–562.
2. Fine KD, Schiller LR. AGA technical review on the evaluation and management of chronic diarrhea. Gastroenterology. 1999;116(6):1464–1486.
3. Rubio-Tapia A, Hill ID, Kelly CP, et al. ACG clinical guidelines: diagnosis and management of celiac disease. Am J Gastroenterol. 2013;108(5):656–676.
4. Talley NJ, Abreu MT, Achkar JP, et al. An evidence-based systematic review on medical therapies for inflammatory bowel disease. Am J Gastroenterol. 2011;106(Suppl 1):S2–S25.
5. Shen B, Khan K, Ikenberry SO, et al. The role of endoscopy in the management of patients with diarrhea. Gastrointest Endosc. 2010;71(6):887–892.
ADDITIONAL READING
van Nood E, Vrieze A, Nieuwdorp M, et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med. 2013;368(5):407–415.
SEE ALSO
Algorithm: Diarrhea, Chronic
CODES
ICD10
K52.9 Noninfective gastroenteritis and colitis, unspecified
CLINICAL PEARLS
• Consider IBS, IBD, malabsorption syndromes (such as lactose intolerance), celiac disease, over-the-counter medications, and herbal products and chronic infections (particularly in patients who are immunocompromised).
• A comprehensive medical history guides the appropriate workup and avoids unnecessary testing.