What is the differential diagnosis and treatment approach for a patient presenting with diarrhea?

Differential Diagnosis for Diarrhea

The differential diagnosis for diarrhea must be systematically approached by first determining the duration (acute <14 days, persistent 14-29 days, or chronic ≥30 days), then assessing for alarm features, and finally categorizing by mechanism and epidemiologic clues. 1

Duration-Based Classification

Acute Diarrhea (0-13 days)

• Infectious causes (most common): Viral (norovirus, rotavirus), bacterial (Salmonella, Shigella, Campylobacter, E. coli including STEC, Yersinia, Vibrio, C. difficile), and parasitic (Giardia, Cryptosporidium, Entamoeba) 1, 2
• Medication-induced: Antibiotics, antacids, metformin, NSAIDs 1
• Food-related: Food poisoning from preformed toxins (Staphylococcus aureus, Bacillus cereus) 1

Persistent Diarrhea (14-29 days)

• Post-infectious syndromes: Lactose intolerance, small intestinal bacterial overgrowth (SIBO) 1
• Parasitic infections: Giardia, Cryptosporidium, Cyclospora 1
• Medication effects: Ongoing antibiotic use, proton pump inhibitors 1

Chronic Diarrhea (≥30 days)

• Inflammatory bowel disease (IBD): Crohn's disease, ulcerative colitis 1
• Malabsorption syndromes: Celiac disease, chronic pancreatitis, bile acid malabsorption 1, 3
• Functional disorders: Irritable bowel syndrome with diarrhea (IBS-D) 1
• Endocrine causes: Hyperthyroidism, diabetes mellitus, adrenal insufficiency 1
• Neoplastic: Colorectal cancer, neuroendocrine tumors (VIPoma, carcinoid) 1
• Microscopic colitis: Collagenous or lymphocytic colitis 1

Mechanism-Based Classification

Secretory Diarrhea

• Bacterial toxins: Cholera, enterotoxigenic E. coli (ETEC) 4
• Hormonal: VIPoma, carcinoid syndrome, gastrinoma 4
• Bile acid malabsorption: Post-ileal resection, idiopathic 3, 4
• Medications: Laxatives, prostaglandins 4

Inflammatory/Invasive Diarrhea

• Bacterial: Shigella, Salmonella, Campylobacter, STEC, Yersinia, C. difficile 1
• IBD: Active Crohn's disease or ulcerative colitis 1
• Ischemic colitis 1

Osmotic Diarrhea

• Carbohydrate malabsorption: Lactose intolerance, fructose malabsorption 1
• Magnesium-containing antacids or laxatives 1

Malabsorptive Diarrhea

• Celiac disease 1
• Chronic pancreatitis with exocrine insufficiency 1
• Small bowel bacterial overgrowth 1
• Post-surgical: Short bowel syndrome, post-gastrectomy 1

Critical Epidemiologic and Exposure History

Obtain detailed exposure history in all patients, as this narrows the differential significantly: 1

• Travel history: Recent travel to developing countries suggests traveler's diarrhea (ETEC, Campylobacter, Shigella, Giardia); travel to cholera-endemic regions with rice-water stools suggests Vibrio cholerae 1
• Food exposures: Raw/undercooked meat (Salmonella, Campylobacter, STEC), unpasteurized dairy (Salmonella, Campylobacter, STEC), raw shellfish (Vibrio, norovirus, hepatitis A), raw eggs (Salmonella) 1
• Water exposures: Untreated surface water from lakes/streams (Giardia, Cryptosporidium); swimming in pools/lakes (cryptosporidiosis, giardiasis) 1
• Animal contacts: Petting zoos, farms, or reptile exposure (Salmonella, Campylobacter, STEC); pets with diarrhea 1
• Occupational/institutional: Daycare workers/attendees, healthcare workers, food handlers, long-term care facility residents (Salmonella, Shigella, norovirus, C. difficile) 1
• Antibiotic use: Recent or current antibiotics strongly suggest C. difficile infection 1
• Sexual history: Receptive anal intercourse or oral-anal contact (Shigella, Salmonella, Campylobacter, Entamoeba histolytica, sexually transmitted proctitis) 1
• Immunocompromised status: HIV/AIDS, immunosuppressive medications, chemotherapy (broader differential including opportunistic infections like Cryptosporidium, Microsporidium, CMV, Mycobacterium avium complex) 1

Alarm Features Requiring Urgent Evaluation

The presence of any of these features mandates immediate assessment and often hospitalization: 1, 5

• Severe dehydration: Orthostatic hypotension, tachycardia, decreased skin turgor, altered mental status, decreased urine output 1
• Bloody or mucoid stools (dysentery) 1, 5
• High fever (>38.5°C or 101.3°F) 1
• Severe abdominal pain or tenderness 1
• Signs of sepsis: Hypotension, altered mental status, organ dysfunction 1
• Age extremes: Infants <3 months or elderly patients 1
• Unintentional weight loss 1, 5
• Nocturnal diarrhea (suggests organic disease) 1
• Duration >3 months without diagnosis 1

Age-Specific Considerations

Pediatric Patients

• Infants <2 years: Contraindication to loperamide due to respiratory depression and cardiac risks 6
• School-aged children with right lower quadrant pain: Consider Yersinia enterocolitica causing mesenteric adenitis mimicking appendicitis 1
• Daycare attendees: Higher risk for Shigella, Giardia, Cryptosporidium, rotavirus 1

Elderly Patients

• Fecal impaction: Can present as paradoxical diarrhea (overflow incontinence) 3
• Medication review critical: Polypharmacy increases risk of drug-induced diarrhea 3
• Higher risk for dehydration complications and electrolyte abnormalities 1
• Ischemic colitis: More common in elderly with vascular disease 1

Initial Diagnostic Approach

When to Test Stool

Stool testing should be performed selectively, not routinely: 1

• Bloody diarrhea (test for Salmonella, Shigella, Campylobacter, STEC, Yersinia) 1
• Fever with moderate-to-severe diarrhea 1
• Severe or persistent symptoms (>7 days) 1
• Recent antibiotic use (test for C. difficile) 1
• Immunocompromised patients 1
• Inflammatory diarrhea (fecal leukocytes or lactoferrin positive) 1
• Outbreak or public health concern (food handlers, healthcare workers, daycare) 1

Specific Pathogen Testing

• STEC: When bloody diarrhea or hemolytic uremic syndrome suspected, test for Shiga toxin (or genes) and distinguish E. coli O157:H7 from non-O157 STEC 1
• Yersinia: Test when persistent abdominal pain in children or exposure to undercooked pork 1
• Vibrio: Test when large-volume rice-water stools, exposure to brackish water, raw shellfish consumption, or travel to cholera-endemic areas 1

Blood Cultures

Obtain blood cultures in: 1

• Infants <3 months of age
• Signs of septicemia or bacteremia
• Suspected enteric fever (Salmonella Typhi or Paratyphi)
• Immunocompromised patients
• High-risk conditions (hemolytic anemia, prosthetic devices)

Chronic Diarrhea Workup

For chronic diarrhea (≥30 days), initial testing should include: 1

• Blood tests: Complete blood count, comprehensive metabolic panel, thyroid function, celiac serology (tissue transglutaminase IgA with total IgA)
• Stool studies: Fecal calprotectin or lactoferrin (inflammatory vs. non-inflammatory), stool culture if infectious etiology suspected, C. difficile testing if recent antibiotics, ova and parasites if travel history
• Colonoscopy with biopsies: If alarm features present, age >45 with new-onset diarrhea, or inflammatory markers elevated 1

Treatment Approach

Rehydration (First Priority)

Oral rehydration solution (ORS) is the cornerstone of treatment for mild-to-moderate dehydration and is superior to IV fluids when tolerated: 1

• ORS composition: Sodium 90 mM, potassium 20 mM, chloride 80 mM, bicarbonate 30 mM, glucose 111 mM 1
• Commercial preparations: Pedialyte, Ceralyte, or generic equivalents 1
• Administer ORS until clinical dehydration corrected, then maintain with ongoing losses 1

IV fluids indicated for: 1

• Severe dehydration with shock
• Altered mental status
• Inability to tolerate oral intake
• Ileus
• Failure of ORS therapy

Antimotility Agents

Loperamide is first-line for uncomplicated acute watery diarrhea in adults: 3, 6

• Dosing: Initial 4 mg, then 2 mg after each unformed stool, maximum 16 mg/day 3, 6
• Contraindications: Age <18 years, bloody diarrhea, high fever, suspected inflammatory or invasive diarrhea (risk of toxic megacolon), suspected STEC infection 1, 6
• Cardiac warnings: Avoid in patients taking QT-prolonging drugs (Class IA/III antiarrhythmics, antipsychotics, certain antibiotics), congenital long QT syndrome, or doses exceeding recommendations 6
• Drug interactions: CYP3A4 inhibitors (itraconazole), CYP2C8 inhibitors (gemfibrozil), and P-glycoprotein inhibitors (quinidine, ritonavir) significantly increase loperamide levels 6

Antibiotic Therapy

Empiric antibiotics are indicated only in specific situations: 1

• Severe traveler's diarrhea: Fluoroquinolone or azithromycin
• Febrile dysentery: Fluoroquinolone or azithromycin pending culture
• Suspected cholera: Doxycycline or azithromycin
• Immunocompromised patients with moderate-to-severe symptoms
• Avoid antibiotics in suspected STEC (may increase hemolytic uremic syndrome risk) 1

Cause-Specific Treatments

• Bile acid malabsorption: Bile acid sequestrants (colesevelam, cholestyramine) 3
• Celiac disease: Strict gluten-free diet 1
• Lactose intolerance: Lactose-free diet 3
• Chronic pancreatitis: Pancreatic enzyme replacement 1
• Microscopic colitis: Budesonide 1

Common Pitfalls to Avoid

• Don't confuse fecal incontinence with true diarrhea—clarify stool consistency and frequency with patients 3
• Never use loperamide in children <18 years due to serious cardiac and respiratory risks 1, 6
• Avoid antimotility agents in bloody diarrhea, high fever, or suspected inflammatory colitis (risk of toxic megacolon) 1, 3, 6
• Don't overlook medication-induced diarrhea—review all medications including over-the-counter products, supplements, and recent antibiotics 1, 3
• Don't miss fecal impaction in elderly patients—it presents as paradoxical diarrhea with alternating constipation 3
• Avoid empiric antibiotics in suspected STEC infection—may precipitate hemolytic uremic syndrome 1
• Don't forget to assess hydration status in all patients—dehydration is the primary cause of morbidity and mortality, especially in young children and elderly 1
• Don't ignore public health implications—report cases in food handlers, healthcare workers, and daycare settings per jurisdictional requirements 1