What investigations should be done in a patient with chronic diarrhea?

Investigation of Chronic Diarrhea

Begin with basic blood tests and coeliac serology, then proceed to age-stratified colonoscopy with biopsies, followed by targeted testing based on clinical features for malabsorption or specific causes. 1, 2, 3

Initial Laboratory Investigations

All patients require a standardized panel of first-line blood tests to screen for organic disease and identify common treatable causes 1, 3:

• Complete blood count to detect anemia (suggesting malabsorption, blood loss, or inflammation) 1, 2, 4
• Erythrocyte sedimentation rate or C-reactive protein (high specificity for organic disease when elevated) 1, 2
• Comprehensive metabolic panel including electrolytes, liver function tests, and albumin (low albumin suggests malabsorption or protein-losing enteropathy) 1, 2
• Iron studies, vitamin B12, and folate to assess for malabsorption 1, 4
• Thyroid function tests to exclude hyperthyroidism as a cause 1, 2
• Anti-tissue transglutaminase IgA with total IgA level for coeliac disease screening (sensitivity and specificity >90%) 1, 2, 3

Critical pitfall: Always measure total IgA alongside anti-tTG IgA, as selective IgA deficiency (occurs in 1:500) causes false-negative results 1, 4.

Stool Studies

Obtain targeted stool tests based on clinical suspicion 2, 3:

• Fecal calprotectin to distinguish inflammatory from non-inflammatory causes (elevated >900 indicates significant colonic inflammation) 2, 4
• Stool culture if infectious etiology suspected (recent travel, antibiotic exposure) 1, 2
• Clostridium difficile toxin if recent antibiotic use 1
• Giardia antigen if malabsorption features present 3, 5
• Fecal immunochemical test (FIT) for occult blood 2, 4

Avoid routine 3-day fecal fat collection as it is unreliable in clinical practice and does not discriminate between small bowel and pancreatic causes 1.

Age-Stratified Endoscopic Evaluation

Patients ≥45 Years

Full colonoscopy is mandatory due to the frequency and clinical significance of colorectal neoplasia in this age group 1, 2, 3:

• Colonoscopy with biopsies from both right and left colon even if mucosa appears normal 2, 4
• Biopsies are essential to diagnose microscopic colitis, which has entirely normal-appearing mucosa on endoscopy but characteristic histologic changes 2, 4
• Aim for >90% cecal intubation rate with terminal ileal intubation in >70% of cases when clinically indicated 3

Patients <45 Years

Flexible sigmoidoscopy with biopsies has similar diagnostic yield to colonoscopy in younger patients without alarm features 1:

• Upgrade to full colonoscopy if alarm features present (nocturnal diarrhea, weight loss, blood in stool, family history of colorectal cancer) 1, 2, 3
• Consider positive IBS diagnosis using Rome IV criteria only after completing basic screening and excluding organic disease 2, 3

Critical pitfall: Rome criteria alone have only 52-74% specificity and cannot reliably exclude microscopic colitis, IBD, or bile acid diarrhea 1, 2, 3.

Evaluation for Malabsorption

If clinical features suggest small bowel malabsorption (bulky, pale, malodorous stools; weight loss; nutritional deficiencies) 1:

• Upper endoscopy with distal duodenal biopsies if coeliac serology positive or equivocal, or if other small bowel enteropathy suspected 1, 4
• Fecal elastase as the preferred non-invasive test for pancreatic insufficiency (requires moderate impairment for adequate sensitivity) 1
• CT or MRCP if pancreatic disease suspected based on history or imaging findings 1

Critical pitfall: CT imaging alone is inadequate for detecting microscopic colitis, early IBD, or subtle mucosal abnormalities requiring endoscopy with histology 2.

Testing for Specific Treatable Causes

Bile Acid Diarrhea

Assess risk factors: terminal ileal resection, cholecystectomy, or abdominal radiotherapy 1, 3, 4:

• SeHCAT testing or serum 7α-hydroxy-4-cholesten-3-one for objective diagnosis 1, 2, 4
• Do not rely on empiric cholestyramine trial alone for diagnosis 2

Small Bowel Bacterial Overgrowth

Consider in patients with previous gastric surgery, jejunoileal bypass, or systemic sclerosis 1:

• Culture of jejunal aspirates or unwashed small bowel biopsies remains the gold standard 1
• Hydrogen breath tests (glucose or 14C-D-xylose) have only ~60% sensitivity and ~75% specificity 1

Endocrine Causes

Test for hormone-secreting tumors only in high-volume watery diarrhea when other causes excluded 1:

• Plasma vasoactive intestinal peptide, gastrin, or glucagon (extremely rare causes) 1

Special Considerations

Medication review: Up to 4% of chronic diarrhea is drug-induced (magnesium products, antihypertensives, NSAIDs, theophyllines, antibiotics, antiarrhythmics) 1

Fecal impaction with overflow diarrhea: Consider especially in elderly patients with cognitive impairment, neurological disease, or immobility 3, 4

Lactase deficiency: Consider empiric lactose-free diet trial in appropriate clinical context 1

Algorithmic Approach Summary

1. History and physical focusing on alarm features, surgical history, medications, family history 1, 3
2. Basic blood tests and coeliac serology in all patients 1, 2, 3
3. Stool studies (calprotectin, culture if indicated, FIT) 2, 3
4. Age-stratified colonoscopy with biopsies (≥45 years: full colonoscopy; <45 years: flexible sigmoidoscopy unless alarm features) 1, 2, 3
5. Upper endoscopy with duodenal biopsies if positive coeliac serology or malabsorption features 1, 4
6. Targeted testing for bile acid diarrhea, pancreatic insufficiency, or bacterial overgrowth based on clinical features 1, 2, 4

Most chronic diarrhea is due to colonic disease, so investigations should focus on the lower GI tract first in the absence of clear malabsorption features 1.