What is the differential diagnosis and management approach for a patient with chronic diarrhea?

Chronic Diarrhea: Differential Diagnosis and Management

The differential diagnosis for chronic diarrhea (≥3 loose stools/day for >4 weeks) should be systematically categorized into watery (secretory, osmotic, functional), fatty (malabsorptive), and inflammatory types, with initial assessment focusing on excluding colonic neoplasia, inflammatory bowel disease, celiac disease, and microscopic colitis before considering functional disorders. 1, 2

Initial Clinical Assessment

Key Historical Features to Elicit

Alarm features requiring urgent evaluation include: 1

• Diarrhea duration <3 months (suggests organic disease)
• Nocturnal or continuous (vs. intermittent) diarrhea
• Unintentional weight loss
• Persistent blood in stool
• Fever with systemic symptoms

Specific risk factors to identify: 1

• Family history: Neoplastic disease, inflammatory bowel disease, celiac disease
• Previous surgery: Ileal resection (bile acid diarrhea), gastric surgery (bacterial overgrowth), jejunoileal bypass
• Medications: Recent antibiotics within 8-12 weeks (C. difficile risk), laxatives, NSAIDs, PPIs
• Systemic disease: Thyrotoxicosis, diabetes mellitus, systemic sclerosis
• Alcohol abuse: Direct epithelial toxicity, rapid transit, pancreatic dysfunction
• Travel history: Parasitic infections if diarrhea >14 days post-travel

Stool Characteristics Guide Differential

Malabsorptive (fatty) diarrhea: Bulky, pale, malodorous, greasy stools with steatorrhea 1

Inflammatory/colonic diarrhea: Liquid loose stools with blood or mucus 1, 3

Watery diarrhea: Large volume, no blood, may be secretory or osmotic 2, 4

First-Line Investigations (Primary Care)

Mandatory initial blood tests: 1

• Complete blood count and inflammatory markers (ESR/CRP)
• Electrolytes, liver function tests
• Anti-tissue transglutaminase IgA with total IgA (celiac disease screening—most common small bowel enteropathy)
• Thyroid function tests
• Iron studies, vitamin B12, folate

Stool testing when infectious etiology suspected: 1

• Test for Salmonella, Shigella, Campylobacter, Yersinia, C. difficile, and STEC if fever, bloody/mucoid stools, or severe cramping present
• C. difficile testing mandatory if any antibiotic exposure in past 8-12 weeks
• Parasitic evaluation (ova and parasites) if diarrhea persists >14 days, especially post-travel

Categorization by Diarrhea Type

Watery Diarrhea

Functional disorders (most common): 2, 4, 5

• Irritable bowel syndrome: Pain peaks before defecation, relieved by defecation, associated with stool form/frequency changes (Rome IV criteria)
• Functional diarrhea: Watery stools without pain

Secretory causes: 1, 2, 4

• Bile acid malabsorption: Occurs after meals, responds to fasting and bile acid sequestrants; common after terminal ileal resection
• Microscopic colitis: Secretory diarrhea in older adults; requires colonic biopsies for diagnosis
• Endocrine disorders: Hyperthyroidism, VIPoma, carcinoid syndrome

Osmotic causes: 2, 4

• Carbohydrate malabsorption (lactose intolerance, fructose)
• Laxative abuse (magnesium, sorbitol)
• High FODMAP food sensitivities

Fatty (Malabsorptive) Diarrhea

Small bowel causes: 1

• Celiac disease: Diagnosed by positive anti-tissue transglutaminase IgA; confirm with endoscopic distal duodenal biopsies
• Giardiasis: Classic infectious malabsorption with excess gas and weight loss
• Small bowel bacterial overgrowth: Culture of jejunal aspirates is gold standard; hydrogen breath tests have only ~60% sensitivity

Pancreatic causes: 1

• Pancreatic exocrine insufficiency: Diagnosed by fecal elastase (preferred over fecal fat); requires moderate impairment for adequate sensitivity
• Previous pancreatic disease or surgery

Inflammatory Diarrhea

Requires urgent evaluation: 1, 3

• Inflammatory bowel disease (ulcerative colitis, Crohn's disease): Mucoid diarrhea with rectal bleeding, urgency, abdominal pain; elevated fecal calprotectin
• Microscopic colitis: Requires colonic biopsies despite normal endoscopic appearance
• C. difficile colitis: Recent antibiotic exposure; toxin testing indicated
• Colorectal cancer: Age-stratified risk assessment required

Age-Stratified Colonic Investigation

Patients ≥45 years old: 1

• Full colonoscopy preferred due to increased neoplasia risk
• Higher risk with first-degree relatives with colorectal cancer or male gender

Patients <45 years old: 1

• Flexible sigmoidoscopy with biopsies has similar diagnostic yield to colonoscopy in this age group
• Upgrade to colonoscopy if alarm features present

Biopsies mandatory even if mucosa appears normal: 1

• Microscopic colitis requires histological diagnosis
• Random colonic biopsies increase diagnostic yield

Special Population Considerations

Immunocompromised Patients

Broad differential diagnosis required: 1

• Stool evaluation by culture, viral studies, and parasitic examination
• AIDS patients with persistent diarrhea: Test for Cryptosporidium, Cyclospora, Cystoisospora, Microsporidia, Mycobacterium avium complex, and cytomegalovirus

Post-Travel Diarrhea

Evaluation strategy: 1

• Diagnostic testing not recommended for uncomplicated traveler's diarrhea
• Diarrhea ≥14 days post-travel: Evaluate for intestinal parasitic infections
• Test for C. difficile if antibiotics used within 8-12 weeks
• Consider post-infectious IBS and inflammatory bowel disease

Diagnostic Algorithm When Initial Tests Normal

If celiac serology negative but malabsorption suspected: 1

• Proceed to endoscopic distal duodenal biopsies to exclude other enteropathies
• This strategy has replaced older small bowel function tests

For suspected pancreatic insufficiency: 1

• Fecal elastase preferred over fecal fat (easier, more specific)
• Three-day fecal fat no longer recommended due to unreliability

For suspected bile acid malabsorption: 1

• Empirical trial of bile acid sequestrants often employed
• Responds to fasting; symptoms worse after meals

For suspected small bowel bacterial overgrowth: 1

• Culture of jejunal aspirates or unwashed small bowel biopsies is gold standard
• Hydrogen breath tests have limited sensitivity (60%) and specificity (75%)

Empirical Therapy Considerations

When diagnosis remains unclear after appropriate testing: 1

• Approximately two-thirds of cases can be diagnosed with systematic approach
• Remaining patients often have watery, functional, or undiagnosed factitious diarrhea
• Empirical trial of therapy justified when specific diagnosis strongly suspected and follow-up available
• Symptomatic treatment with antidiarrheals appropriate when prognosis appears benign

Critical Pitfalls to Avoid

Do not miss treatable conditions: 1, 6

• Celiac disease, microscopic colitis, and bile acid diarrhea are common and have specific therapies
• These conditions can overlap with functional bowel disorders

Infectious causes in chronic diarrhea: 1

• Persistent parasitic infections (Giardia, Cryptosporidium, Cyclospora, Entamoeba histolytica)
• C. difficile in patients with recent antibiotic exposure
• Small bowel bacterial overgrowth post-surgery

Molecular multiplex testing interpretation: 1

• These assays detect DNA, not necessarily viable organisms
• Clinical context essential for interpretation
• Positive results may require culture for public health reporting and antimicrobial susceptibility testing

Colorectal neoplasia exclusion: 1

• Age-appropriate colonic imaging mandatory given prevalence and serious consequences
• Cannot be excluded on clinical grounds alone