Differential Diagnoses for Chronic Daily Diarrhea
The most important initial step is distinguishing between functional disorders (like irritable bowel syndrome) and organic pathology by identifying alarm features and performing targeted first-line investigations. 1, 2
Key Alarm Features Requiring Urgent Investigation
These features mandate immediate gastroenterology referral and suggest organic disease rather than functional disorders 1, 2:
- Nocturnal diarrhea (waking from sleep to defecate) 1, 2
- Unintentional weight loss 1, 2
- Persistent blood in stool 1, 2
- Fever 1, 2
- Age >45 years with new-onset symptoms 2
- Recent onset (<3 months duration) 1
- Family history of colorectal cancer or inflammatory bowel disease 1
Primary Differential Diagnoses by Category
Functional Disorders (Most Common in Absence of Alarm Features)
- Irritable bowel syndrome with diarrhea (IBS-D): Diagnosed using Rome IV criteria (abdominal pain that peaks before defecation, is relieved by defecation, and is associated with changes in stool form or frequency), but only after excluding organic disease with basic screening 1, 2, 3
- Functional diarrhea: Similar presentation but without the pain component 4
Critical pitfall: Rome criteria alone have only 52-74% specificity for functional disorders and do not reliably exclude inflammatory bowel disease, microscopic colitis, or bile acid diarrhea 1, 2
Inflammatory/Immune-Mediated Disorders
- Inflammatory bowel disease (Crohn's disease, ulcerative colitis): Suggested by elevated fecal calprotectin, blood in stool, weight loss, and elevated inflammatory markers 1, 2
- Microscopic colitis: Cannot be diagnosed without colonoscopy with biopsies from right and left colon; often missed if biopsies not performed 1, 2
- Celiac disease: Prevalence 0.5-1% in general population; requires anti-tissue transglutaminase IgA with total IgA testing 1, 2, 4
Malabsorptive Disorders
- Bile acid diarrhea: Requires objective testing with SeHCAT or serum 7α-hydroxy-4-cholesten-3-one; empiric trials are inadequate for diagnosis 1, 2
- Pancreatic exocrine insufficiency: Consider in patients with history of pancreatic disease, alcohol abuse, or steatorrhea 1, 4
- Small intestinal bacterial overgrowth: Particularly after gastric or intestinal surgery, or in systemic sclerosis 1
- Lactose intolerance and other carbohydrate malabsorption: Consider dietary triggers including FODMAPs 1, 4
Infectious Causes (Less Common in Chronic Diarrhea >4 Weeks)
- Clostridioides difficile: Test if recent antibiotic use within 8-12 weeks 1
- Parasitic infections (Giardia, Cryptosporidium, Entamoeba histolytica): Particularly in travelers or immunocompromised patients 1, 4
- Chronic bacterial infections: Rare but consider in immunocompromised hosts 1
Endocrine/Metabolic Disorders
- Hyperthyroidism: Check thyroid-stimulating hormone; suppressed TSH is best predictor 1, 4
- Diabetes mellitus with autonomic neuropathy 1
- Addison's disease 1
Medication-Induced Diarrhea
Up to 4% of chronic diarrhea cases are medication-related 1:
- Magnesium supplements 1
- ACE inhibitors and other antihypertensives 1
- NSAIDs 1
- DPP-4 inhibitors (gliptins) 1
- Antibiotics 1
- Chemotherapy agents (fluorouracil, irinotecan) 1
- Targeted cancer therapies (tyrosine kinase inhibitors, checkpoint inhibitors) 1
Neoplastic Causes
- Colorectal cancer: Mandatory consideration in patients ≥45 years; requires colonoscopy 1, 2
- Neuroendocrine tumors 4
Post-Surgical/Anatomic Causes
- Short bowel syndrome: After extensive small bowel resection 1, 5
- Terminal ileum resection: Leads to bile acid diarrhea 1
- Post-cholecystectomy diarrhea: Related to bile acid malabsorption 1
- Gastric surgery: Can cause dumping syndrome or bacterial overgrowth 1
Radiation-Induced
- Radiation enteritis/colitis: After abdominal or pelvic radiation therapy 1
Essential First-Line Investigations
All patients require these baseline tests before diagnosis 1, 2, 4:
Blood Tests
- Complete blood count (iron deficiency suggests small bowel enteropathy, particularly celiac disease) 1, 2
- C-reactive protein and erythrocyte sedimentation rate 1, 2
- Comprehensive metabolic panel (electrolytes, renal function, calcium) 2, 4
- Liver function tests 1, 2
- Iron studies, vitamin B12, folate 1, 2
- Thyroid-stimulating hormone 1, 2
- Anti-tissue transglutaminase IgA with total IgA 1, 2, 4
Stool Studies
- Fecal calprotectin: Helps differentiate inflammatory from functional disorders 1, 2
- Fecal immunochemical test (FIT): For occult blood 1, 2
- Stool culture and C. difficile testing: If infectious etiology suspected or recent antibiotic use 1, 2
- Stool ova and parasites: If travel history or persistent symptoms 1
Age-Based Endoscopic Approach
Patients ≥45 Years
Full colonoscopy with biopsies is mandatory to exclude colorectal cancer, even without alarm features 1, 2
Patients <40 Years Without Alarm Features
- Avoid immediate colonoscopy if fecal calprotectin is normal 1, 2
- Consider positive diagnosis of IBS using Rome IV criteria after completing basic screening 1, 2
- However, colonoscopy with biopsies is still needed if symptoms persist despite treatment, as microscopic colitis cannot be excluded without histology 1, 2
Common Diagnostic Pitfalls to Avoid
Premature IBS diagnosis: Never diagnose IBS based on Rome criteria alone without completing blood tests (including celiac serology) and fecal calprotectin 1, 2
Missing microscopic colitis: This requires colonoscopy with biopsies from both right and left colon; normal-appearing mucosa does not exclude it 1, 2
Missing bile acid diarrhea: Requires objective testing (SeHCAT or serum 7α-hydroxy-4-cholesten-3-one); do not rely on empiric cholestyramine trial for diagnosis 1, 2
Inadequate cancer screening: Patients ≥45 years require full colonoscopy regardless of normal FIT or lack of alarm features 1, 2
Forgetting celiac serology: This is a common, treatable cause that must be excluded in all patients with chronic diarrhea 1, 2
Overlooking medication causes: Systematically review all medications, supplements, and over-the-counter products 1