Description

• An increase in frequency of defecation, urgency, or decrease in stool consistency (typically >3 loose stools per day) for >4 weeks (1),(2)
  • Abnormal stool form is the most important defining factor; frequent defecation with normal consistency is termed pseudodiarrhea (1).
• Etiologies fall into the following categories: osmotic, secretory, malabsorptive, inflammatory, infectious, and hypermotility (2),(3).
• Infectious causes of chronic diarrhea are uncommon in immunocompetent patients.

Epidemiology

Incidence
Difficult to estimate as definitions vary.

Prevalence
Varies by etiology. Worldwide prevalence is ~20% (2). U.S. prevalence is ~6.6% (4).

Etiology and Pathophysiology

Disturbances in luminal water and electrolyte balance cause increased water volume in the stool.

• Osmotic (fecal osmotic gap >100 mOsm/kg) (3),(5). Resolves with a fasting trial (2)
  • Carbohydrate malabsorption
    • Disaccharides (e.g., lactose), monosaccharides (e.g., fructose), and polyols (common sugar substitutes)
  • Mg, phosphate, and sulfate ingestion
• Secretory (fecal osmotic gap <50 mOsm/kg) (1),(6). Does not resolve with a fasting trial (2)
  • Alcoholism, stimulant laxative ingestion
  • Bacterial enterotoxins (i.e., cholera)
  • Postcholecystectomy/ileal resection <100 cm
    • Excessive intestinal bile salts cause choleretic diarrhea; resolves in 6 to 12 months
  • Disordered motility
    • Postvagotomy, autonomic neuropathy
    • Hyperthyroidism
  • Neuroendocrine tumors
    • VIPoma
    • Carcinoid syndrome, gastrinoma, somatostatinoma
  • Metastatic medullary thyroid cancer
  • Adrenal insufficiency
  • Noninvasive infection: giardiasis, cryptosporidiosis
  • Microscopic colitis
  • Protein-losing enteropathy
• Malabsorptive (1),(6)
  • Celiac disease, Whipple disease
  • Tropical sprue, giardiasis
  • Chronic mesenteric ischemia, lymphatic obstruction
  • Short bowel syndrome: Ileal resection of >100 cm leads to insufficient small bowel bile salts.
  • Small intestinal bacterial overgrowth (SIBO)
  • Pancreatic exocrine insufficiency
• Inflammatory (1),(6)
  • IBD—ulcerative colitis; Crohn disease
  • Microscopic colitis
  • Diverticulitis; vasculitis; radiation enterocolitis
  • Infections: Clostridium difficile, Entamoeba histolytica, cytomegalovirus, tuberculosis
  • Neoplasms: colon cancer, lymphoma
• Hypermotility (normal fecal osmotic gap; 50 to 100 mOsm/kg) (1)
  • Irritable bowel syndrome (IBS)
  • Functional diarrhea
    • Pain differentiates IBS from functional diarrhea (2),(5)
• Drugs (1),(3),(6)
  • Adverse effect of >700 drugs, most commonly: NSAIDs, PPIs, colchicine, metformin, digoxin, ACE inhibitors, β-blockers, newer gliptins, theophyllines, antibiotics, SSRIs, antineoplastic agents
    • Drug-induced diarrhea is confirmed by the resolution of symptoms with medication discontinuation (3).
  • Factitious diarrhea: excessive laxative use
• Herbal products: St. John’s wort, echinacea, garlic, saw palmetto, ginseng, etc.
• Infectious (1)
  • Bacterial: C. difficile, M. avium intracellulare
  • Viral: cytomegalovirus
  • Parasitic: Giardia lamblia, Cryptosporidium, Isospora, E. histolytica
  • Helminthic: Strongyloides
• Food allergies (1)

Genetics

• Celiac disease is associated with HLA-DQ2 and HLA-DQ8 haplotypes on major histocompatibility complex (MHC) class II (5).
• Inflammatory bowel disease (IBD) is polygenic. First-degree relative of IBD patients are at 10-fold increase of developing IBD (5).
• CF is caused by a mutation in the CF transmembrane conductance regulator (CFTR) anion channel, resulting in abnormal exocrine gland secretions of chloride.

Risk Factors

• Osmotic
  • Excess ingestion of nonabsorbable carbohydrates (i.e., artificial sweeteners)
  • Magnesium-containing antacids (3),(5)
  • Lactose intolerance, celiac disease
• Secretory (1)
  • Postsurgical: extensive small bowel resection/ileal surgery, vagotomy, bile acid malabsorption
  • History of neuroendocrine disease or stimulant laxative abuse
  • Dysmotility syndromes
  • Medications (i.e., NSAIDs, caffeine, metformin, colchicine, carbamazepine) (3),(5)
• Malabsorptive
  • CF; chronic alcohol abuse, celiac disease
  • Chronic pancreatitis/pancreatic insufficiency (fat malabsorption)
  • Medications (e.g., orlistat, acarbose)
• Inflammatory
  • IBD, NSAID use (3), radiation
  • HIV/AIDS
  • Antibiotic use (commonly clindamycin, amoxicillin, ampicillin, cephalosporins) (3)
  • Antineoplastic drugs (i.e., 5-fluorouracil, methotrexate, irinotecan) (3)
  • Immunosuppressant therapy
• Hypermotility
  • Psychosocial stress, preceding infection
  • Stimulant medications (i.e., macrolides, metoclopramide, senna) (3),(5)
• Genetic predisposition

General Prevention

Varies by etiology; treat the underlying cause.

Commonly Associated Conditions

• Extraintestinal manifestations of IBD include arthralgias, aphthous stomatitis, uveitis/episcleritis, erythema nodosum, pyoderma gangrenosum, perianal fistulas, rectal fissures, ankylosing spondylitis, and PSC.
• Celiac disease is associated with dermatitis herpetiformis, T1DM, and IgA deficiency.
• Many patients with IBS have behavioral comorbidities.
• Latex-food allergy syndrome: associated allergies to latex and banana, avocado, kiwi, and walnut (1)