What are the differential diagnoses and recommended initial workup for irritable bowel syndrome (IBS)?

Differential Diagnoses for Irritable Bowel Syndrome

The differential diagnosis of IBS must systematically exclude organic diseases that present with chronic abdominal pain and altered bowel habits, with the workup intensity determined by patient age and presence of alarm features. 1

Key Differential Diagnoses to Exclude

High-Priority Organic Diseases

• Inflammatory bowel disease (IBD) – Crohn's disease and ulcerative colitis can mimic IBS but require different management; approximately 20% of active Crohn's patients have normal CRP, so normal inflammatory markers don't fully exclude IBD 2
• Celiac disease – Present in a higher proportion of IBS-like presentations than previously recognized; serologic testing is mandatory in all suspected IBS cases 2, 3
• Microscopic colitis – Causes chronic diarrhea with normal-appearing mucosa on colonoscopy; requires biopsies even when mucosa looks normal 2
• Colorectal cancer – Must be excluded in patients ≥45 years or with alarm features 2, 4
• Bile acid diarrhea – Accounts for 20-30% of IBS-D cases and has specific treatment 5
• Giardiasis – Common parasitic cause of chronic diarrhea that mimics IBS 2

Additional Conditions to Consider

• Food intolerances (lactose, fructose, other FODMAPs) – Account for 30-40% of IBS-D presentations 5
• Small intestinal bacterial overgrowth (SIBO) – Contributes to 15-20% of IBS-D cases 5
• Mastocytosis/mast cell activation syndrome – Less common but can cause IBS-like symptoms 5
• Medication side effects – Particularly NSAIDs, antibiotics, and other common drugs 5
• Exocrine pancreatic insufficiency – Though testing is not routinely indicated in typical IBS 2

Alarm Features Requiring Extended Workup

Any of the following mandates further investigation beyond basic screening:

Alarm Feature	Clinical Significance	Action Required
Age ≥45 years at symptom onset	Increased risk of colorectal cancer	Colonoscopy mandatory [1,2,4]
Rectal bleeding or blood in stool	Suggests structural pathology	Endoscopic evaluation [1,2]
Unintentional weight loss	May indicate malignancy or IBD	Full diagnostic workup [1,2]
Anemia on CBC	Absolute contraindication to IBS diagnosis	Investigate for bleeding or malabsorption [1,2]
Nocturnal symptoms (pain/diarrhea awakening patient)	Excludes functional disorder	Extended evaluation [1,2]
Fever	Suggests infection or inflammation	Rule out diverticulitis, IBD [1,2]
Family history of IBD or colorectal cancer	Increases pretest probability	Lower threshold for colonoscopy [1,2]
Recent antibiotic use	Risk of post-infectious IBS or C. difficile	Stool testing [1]

Recommended Initial Workup

For ALL Patients with Suspected IBS (Regardless of Age)

Basic screening panel:

• Complete blood count (CBC) – Excludes anemia and inflammatory changes 2, 3
• C-reactive protein (CRP) or ESR – Screens for inflammation, though 20% of Crohn's patients have normal CRP 1, 2
• Celiac serology – IgA tissue transglutaminase (tTG) with total IgA level; if IgA-deficient, use IgG-based testing (IgG-deamidated gliadin peptide or IgG-tTG) 2, 3
• Fecal calprotectin – Values <50 µg/g exclude IBD with 97% specificity; >200-250 µg/g suggest IBD, particularly useful in patients <45 years with diarrhea 1, 2
• Stool testing for Giardia – High-yield test for treatable parasitic infection 2, 3
• Fecal occult blood test – Screens for occult GI bleeding 2, 3

Age-Stratified Approach

Patients <45 years WITHOUT alarm features:

• If Rome III criteria met and basic screening normal, IBS diagnosis can be made confidently without further testing 2, 4
• Colonoscopy is NOT cost-effective in this population 2, 6

Patients ≥45 years OR any patient with alarm features:

• Colonoscopy with biopsies – Take biopsies from both abnormal and normal-appearing mucosa; in diarrhea-predominant cases, biopsies are essential to detect microscopic colitis 2, 4
• Consider gastroenterology referral 4

Conditional Testing Based on Clinical Presentation

For IBS-D (diarrhea-predominant):

• Lactose breath testing – If patient consumes >0.5 pint (280 mL) milk daily, especially in high-risk ethnic groups 2
• Bile acid diarrhea testing (SeHCAT scanning or serum 7α-hydroxy-4-cholesten-3-one) – Consider if symptoms persist despite initial therapy 2
• Stool culture – If acute onset or travel history 3

For patients with positive celiac serology:

• Upper endoscopy with small bowel biopsies – Required to confirm celiac disease diagnosis 2

Tests That Are NOT Recommended

Avoid these tests in typical IBS without alarm features:

• Colonoscopy in patients <45 years without alarm features – Not cost-effective and delays appropriate care 2, 6
• Ova and parasite testing (except Giardia) – Unless travel to or immigration from high-risk areas 2
• Hydrogen breath testing for SIBO – Not recommended in typical IBS presentations 2
• Serologic tests for IBS diagnosis – Sensitivity <50%, cannot rule out IBS 2
• Abdominal ultrasound – Often detects incidental findings unrelated to symptoms 2
• Exocrine pancreatic insufficiency testing – Not indicated in typical IBS 2
• Routine CRP/ESR alone to screen for IBD – Insufficient as sole test due to false negatives 2

Diagnostic Algorithm

Step 1: Apply Rome III Criteria

• Recurrent abdominal pain or discomfort ≥3 days/month for past 3 months, with symptom onset ≥6 months prior, PLUS two or more of: 1
  • Pain relief with defecation
  • Onset associated with change in stool frequency
  • Onset associated with change in stool form

Step 2: Screen for Alarm Features

• Systematically assess all alarm features listed above 1, 2

Step 3: Perform Basic Screening Tests

• CBC, CRP/ESR, celiac serology, fecal calprotectin, Giardia testing, fecal occult blood 2, 3

Step 4: Decision Node

NO alarm features + Age <45 years + Normal screening:

• Confirm IBS diagnosis
• Initiate symptom-directed therapy
• No further testing required 2, 4, 6

Alarm features present OR Age ≥45 years:

• Proceed to colonoscopy with biopsies
• Consider gastroenterology referral
• Additional testing based on predominant symptoms 2, 4

Common Pitfalls to Avoid

• Over-testing young patients – Colonoscopy in patients <45 years with typical symptoms and no alarm features wastes resources and delays treatment 2, 6
• Assuming normal CRP excludes IBD – Up to 20% of active Crohn's disease presents with normal inflammatory markers 2
• Relying on patient-reported food intolerances without objective testing leads to unnecessary dietary restrictions 2
• Serial repetitive testing after functional diagnosis is established increases anxiety without diagnostic yield 2
• Ignoring the 6-month symptom duration requirement – Symptoms must be present ≥6 months to distinguish IBS from transient conditions like infections 1, 3
• Missing microscopic colitis – Always biopsy normal-appearing mucosa in diarrhea-predominant cases during colonoscopy 2

Clinical Features Supporting IBS Diagnosis

Positive predictive features (increase likelihood of IBS):

• Female sex, age <45 years 2
• Symptom duration >2 years 2
• Frequent consultations for non-GI symptoms 1
• Patient reports stress aggravates symptoms 1
• Pain relieved by defecation 1
• Visible abdominal distension 1
• Passage of mucus per rectum 1
• Sense of incomplete evacuation 1