What are the differential diagnoses for ulcerative colitis presenting with bloody diarrhea, abdominal cramping, urgency, weight loss, and anemia?

Differential Diagnosis for Ulcerative Colitis

When a patient presents with bloody diarrhea, abdominal cramping, urgency, weight loss, and anemia, the differential diagnosis must systematically exclude infectious colitis, ischemic colitis, segmental colitis associated with diverticulosis (SCAD), NSAID-induced colitis, microscopic colitis, Crohn's disease, colorectal cancer, and radiation colitis before confirming ulcerative colitis. 1

Infectious Etiologies (Must Exclude First)

Infectious colitis is the most critical differential to exclude before diagnosing UC, as treatment differs fundamentally. 1

• Bacterial pathogens including Salmonella, Shigella, Campylobacter, E. coli O157:H7, and Yersinia can all present with bloody diarrhea and abdominal pain 1, 2
• Clostridium difficile infection must be tested in every patient with suspected UC or disease flare, as it mimics UC symptoms and has been associated with higher mortality 1
• Cytomegalovirus (CMV) infection should be considered, particularly in severe or treatment-refractory cases 1
• Parasitic infections including Entamoeba histolytica require examination of fresh, warm stool samples in patients with appropriate travel history or risk factors 1
• Key distinguishing feature: Infectious colitis typically preserves crypt architecture on histology, whereas UC shows crypt distortion 1

Vascular Causes

Ischemic colitis is particularly important in elderly patients (>60 years) presenting with acute bloody diarrhea and abdominal pain. 1, 2

• Presents with sudden onset of cramping abdominal pain followed by bloody diarrhea 1
• More common in patients with cardiovascular risk factors or recent hypotensive episodes 2
• CT imaging shows segmental colonic wall thickening, often in watershed areas (splenic flexure, rectosigmoid junction) 1
• Critical distinction: Ischemic colitis typically spares the rectum, whereas UC always involves the rectum with continuous proximal extension 3, 4

Segmental Colitis Associated with Diverticulosis (SCAD)

In elderly patients with left-sided segmental colitis in the setting of diverticulosis, SCAD must be distinguished from UC and Crohn's disease. 1

• Presents with bloody diarrhea and left lower quadrant pain in patients with known diverticulosis 1
• Endoscopy shows segmental inflammation between diverticula, not the continuous pattern of UC 1
• Histology may show chronic inflammation, making distinction from IBD challenging 1

Drug-Induced Colitis

NSAID-induced colitis can mimic UC and must be excluded by careful medication history. 1

• Non-selective NSAIDs may exacerbate existing UC or cause de novo colitis 1
• Presents with bloody diarrhea, abdominal pain, and endoscopic inflammation 1
• Key management point: Discontinuation of NSAIDs should precede UC diagnosis if recent use is documented 1

Microscopic Colitis

Microscopic colitis (collagenous and lymphocytic colitis) presents with chronic watery diarrhea but typically without bloody stools, making it less likely when hematochezia is prominent. 1

• More common in elderly patients and associated with autoimmune conditions 1
• Endoscopy appears normal; diagnosis requires histologic examination 1
• Distinguishing feature: Absence of rectal bleeding and normal endoscopic appearance differentiate it from UC 1

Crohn's Disease

Crohn's disease must be differentiated from UC, as treatment strategies and prognosis differ significantly. 1, 5

• May present with bloody diarrhea, abdominal pain, and weight loss similar to UC 5, 3
• Key distinguishing features: 1, 5
  • Perianal disease (fistulae, abscesses) strongly suggests Crohn's disease
  • Skip lesions (patchy inflammation) rather than continuous inflammation
  • Ileal involvement or upper GI tract involvement
  • Transmural inflammation with granulomas on histology
  • Rectal sparing (UC always involves rectum)
• Endoscopy shows aphthous ulcers, cobblestoning, and discontinuous inflammation in Crohn's disease versus continuous mucosal inflammation starting from rectum in UC 1, 3

Colorectal Cancer

Colorectal cancer must be excluded, particularly in patients >50 years or those with alarm features, though it is rare in young adults without hereditary syndromes. 1, 5

• Presents with change in bowel habits, rectal bleeding, weight loss, and anemia 1
• Age consideration: Exceedingly rare in patients <30 years unless strong family history of early-onset colorectal cancer exists 5
• Colonoscopy with biopsy definitively distinguishes malignancy from inflammatory conditions 1

Radiation Colitis

Radiation colitis occurs in patients with history of pelvic radiation therapy (typically for prostate, cervical, or rectal cancer). 2

• Presents weeks to years after radiation exposure with bloody diarrhea and tenesmus 2
• Endoscopy shows telangiectasias and friable mucosa in the radiation field 2
• Key distinguishing feature: History of pelvic radiation and localization to previously irradiated segments 2

Diagnostic Algorithm to Establish UC Diagnosis

The diagnosis of UC requires a systematic approach combining clinical, laboratory, endoscopic, and histologic parameters—no single "gold standard" test exists. 1

Step 1: Clinical Assessment

• Document bloody diarrhea, stool frequency, urgency, tenesmus, abdominal pain, nocturnal diarrhea, and weight loss 1
• Record medication history (NSAIDs, antibiotics), recent travel, sexual behavior, smoking status, and family history of IBD or colorectal cancer 1

Step 2: Laboratory Investigations

• Complete blood count: Assess for anemia (chronic or severe disease), thrombocytosis (chronic inflammation), or leukocytosis (infectious complication) 1
• Inflammatory markers: CRP >10 mg/L correlates with clinical severity in extensive colitis (though normal in up to 15-20% of active UC) 1, 5
• Serum albumin: Hypoalbuminemia indicates severe disease 1
• Iron studies: Assess for iron deficiency anemia (ferritin <30 μg/L without inflammation, <100 μg/L with inflammation) 1
• Fecal calprotectin: Values >200-250 μg/g strongly suggest IBD and mandate endoscopy; <50 μg/g effectively excludes IBD 5

Step 3: Microbiological Exclusion

• Stool culture for Salmonella, Shigella, Campylobacter, E. coli O157:H7 1
• C. difficile toxin assay in all patients, regardless of antibiotic history 1
• Ova and parasite examination if travel history or risk factors present 1
• CMV testing in severe or treatment-refractory cases 1

Step 4: Endoscopic Evaluation

• Colonoscopy with biopsies is the gold standard for diagnosis 1, 4
• Obtain minimum of two biopsies from inflamed regions plus biopsies from uninflamed segments and every colonic segment including rectum 1
• Typical UC endoscopic findings: 3, 4
  • Continuous inflammation starting from rectum extending proximally
  • Loss of normal vascular pattern
  • Mucosal granularity, erythema, friability
  • Spontaneous bleeding and ulcerations
  • Distinct demarcation between inflamed and non-inflamed bowel
• Caution: In acute severe colitis, flexible sigmoidoscopy is preferred over full colonoscopy to avoid perforation risk 6

Step 5: Histopathologic Confirmation

• Classic UC histology: 1, 3, 7
  • Diffuse basal plasmacytosis (earliest feature, present in 38% within 2 weeks)
  • Crypt architectural distortion (cryptitis, crypt abscesses, crypt atrophy)
  • Heavy diffuse lamina propria inflammation
  • Decreased crypt density and irregular mucosal surface
  • Absence of granulomas (presence suggests Crohn's disease)
• Timing consideration: Crypt distortion appears only after 4 weeks of symptoms; early disease may show preserved architecture 1

Step 6: Imaging When Indicated

• CT abdomen/pelvis in patients with acute severe symptoms or abdominal pain to exclude complications (toxic megacolon, perforation) or alternative diagnoses (ischemic colitis, diverticulitis) 1, 3
• Mean colonic wall thickness of 8 mm suggests UC (normal is 2-3 mm) 3

Common Diagnostic Pitfalls to Avoid

• Do not diagnose UC without excluding C. difficile infection, as it can mimic or coexist with IBD and requires different treatment 1, 6
• Do not rely on normal CRP or ESR to exclude UC, as 15-20% of patients with active disease have normal inflammatory markers 1, 5
• Do not perform full colonoscopy in acute severe colitis due to perforation risk; flexible sigmoidoscopy is adequate 6
• Do not diagnose UC if rectal sparing is present; this suggests Crohn's disease or another etiology 3, 4
• Do not accept diagnosis without histologic confirmation, as endoscopic appearance alone is insufficient 1, 4
• Repeat endoscopy with histopathology after an interval may be necessary if diagnostic doubt remains, particularly in early disease where crypt architecture may be preserved 1