What is the initial workup and differential diagnosis for a patient presenting with diarrhea?

Differential Diagnosis and Workup for Diarrhea

Initial Clinical Stratification

The first critical step is determining whether diarrhea is acute (<4 weeks) or chronic (≥4 weeks), as this fundamentally changes the differential diagnosis and workup approach. 1, 2

Acute Diarrhea (<4 weeks)

For acute diarrhea, testing should be reserved for patients with fever, bloody or mucoid stools, severe abdominal cramping, signs of sepsis, severe dehydration, or immunocompromised status. 1, 3 Most acute diarrhea is viral gastroenteritis and self-limited, requiring no workup. 4

Acute Diarrhea Workup (when indicated):

Stool testing:

• Culture for Salmonella, Shigella, Campylobacter, Yersinia 1
• STEC O157 by culture on sorbitol-MacConkey agar; non-O157 STEC by Shiga toxin or genomic assays 1
• C. difficile testing if recent antibiotic use (within 8-12 weeks) or hospitalization ≥3 days prior to onset 1, 3
• Vibrio species if exposure to brackish water, raw shellfish, or travel to cholera-endemic regions 1

Blood work (when testing indicated):

• Complete blood count with differential 3
• Electrolytes and renal function 3
• Blood cultures for infants <3 months, signs of septicemia, suspected enteric fever, or immunocompromised patients 1

Critical pitfall: Do not give empiric antibiotics to immunocompetent patients with bloody diarrhea while awaiting results, except for infants <3 months, bacillary dysentery, or international travelers with temperature ≥38.5°C or sepsis. 3

Chronic Diarrhea (≥4 weeks)

For chronic diarrhea, the workup must systematically exclude organic disease before attributing symptoms to functional disorders. 1, 2

Alarm Features Requiring Urgent Investigation:

• Nocturnal diarrhea 2, 5
• Unintentional weight loss 2, 5
• Blood in stool 2, 5
• Persistent fever 2
• Age >45 years with new-onset symptoms 5
• Recent onset (<3 months duration) 1

First-Line Laboratory Tests (Primary Care):

Blood tests:

• Complete blood count 1, 2, 5
• Erythrocyte sedimentation rate and C-reactive protein 1, 2
• Comprehensive metabolic panel (electrolytes, renal function) 2, 5
• Liver function tests 1, 2, 5
• Calcium 1
• Iron studies, vitamin B12, folate 1, 2, 5
• Thyroid function tests 1, 2, 5
• Anti-tissue transglutaminase IgA with total IgA (celiac disease screening—most common small bowel enteropathy in Western populations) 1, 2, 5

Stool studies:

• Fecal calprotectin (to exclude inflammatory causes) 2, 5
• Stool culture and microscopy (though uncommon in immunocompetent patients with chronic symptoms) 1
• Laxative screen (factitious diarrhea increasingly common in specialist practice; test for anthraquinones, bisacodyl, phenolphthalein in urine; magnesium and phosphate in stool) 1

Endoscopic Evaluation:

Age-stratified approach:

• Patients ≥45 years: Full colonoscopy with biopsies to exclude colorectal neoplasia 2, 5. Studies show 27% prevalence of colonic neoplasms in patients with change in bowel habit, with approximately 50% proximal to splenic flexure. 1
• Patients <45 years without alarm features and normal fecal calprotectin: Flexible sigmoidoscopy may suffice, as 99.7% of diagnoses (microscopic colitis, Crohn's disease, ulcerative colitis) can be made from distal colon biopsies. 1, 2 Consider positive diagnosis of IBS using Rome IV criteria after basic screening. 5
• Patients <40 years without alarm features and normal fecal calprotectin: Avoid immediate colonoscopy. 2, 5

Critical pitfall: Microscopic colitis cannot be diagnosed without colonoscopy and biopsies from both right and left colon. 5

Differential Diagnosis by Category

Watery Diarrhea:

• Secretory: Bile acid malabsorption, microscopic colitis, endocrine disorders (hyperthyroidism, VIPoma), post-cholecystectomy 6
• Osmotic: Lactose intolerance, carbohydrate malabsorption, laxative abuse 6
• Functional: Irritable bowel syndrome, functional diarrhea 6

Fatty Diarrhea (Steatorrhea):

• Malabsorption: Celiac disease, giardiasis, small intestinal bacterial overgrowth 6
• Maldigestion: Pancreatic exocrine insufficiency, bile acid deficiency 6

Inflammatory Diarrhea:

• Inflammatory bowel disease (Crohn's disease, ulcerative colitis) 6
• C. difficile colitis 6
• Colorectal cancer 6
• Microscopic colitis 1

Infectious (Persistent ≥14 days):

• Parasitic: Giardia, Cryptosporidium, Cyclospora, Cystoisospora 1, 7
• Bacterial: Enteroaggregative E. coli, Shigella 7
• Consider in travelers or immunocompromised patients 1, 7

Special Populations

Immunocompromised patients:

• Broader differential including Cryptosporidium, Cyclospora, Cystoisospora, microsporidia, Mycobacterium avium complex, CMV 1
• Lower threshold for testing; include blood cultures and coagulation tests 3
• Stool culture, viral studies, and parasite examination 1

Travelers with persistent diarrhea (≥14 days):

• Evaluate for intestinal parasitic infections 1
• Test for C. difficile if antimicrobial treatment within preceding 8-12 weeks 1
• Consider post-infectious IBS or inflammatory bowel disease 1

Common Pitfalls to Avoid

• Premature IBS diagnosis: Do not diagnose IBS based on Rome criteria alone without completing basic blood and stool screening first. 5
• Missing celiac disease: Always perform celiac serology (anti-tissue transglutaminase IgA with total IgA). 1, 5
• Missing microscopic colitis: Requires colonoscopy with biopsies; cannot be diagnosed clinically. 5
• Inadequate colonoscopy in older patients: Full colonoscopy mandatory in patients ≥45 years to exclude colorectal cancer. 5
• Overlooking factitious diarrhea: Screen for laxative abuse early, especially in specialist referral practice. 1
• Missing bile acid diarrhea: Requires objective testing (SeHCAT or serum 7α-hydroxy-4-cholesten-3-one), not empiric trial. 5

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