Inflammatory Bowel Disease
Contents (14)
- Definition: Inflammatory bowel disease (IBD) is chronic, relapsing–remitting immune-mediated inflammation of the gastrointestinal tract in a genetically susceptible host, comprising two principal phenotypes — ulcerative colitis (mucosal, continuous, colorectal) and Crohn disease (transmural, segmental, mouth-to-anus).
- Why it matters: Unlike self-limited infectious colitis, IBD causes cumulative structural bowel damage — strictures, fistulas, dysplasia — so the clinical goal has shifted from symptom relief alone to mucosal healing and prevention of disability. The American Gastroenterological Association and American College of Gastroenterology both frame management around induction, then maintenance, of steroid-free remission.
- Disease burden: Patients are typically diagnosed in the most productive decades of life and face lifelong immunosuppression, surveillance colonoscopy, surgical risk, and a measurable increase in colorectal cancer risk (greater in extensive ulcerative colitis than in Crohn disease).
Epidemiology worth recalling
- Age: Peak onset in young adulthood (20–40 years), with a smaller later-life second peak described in some cohorts.
- Sex: Roughly equal overall; Crohn disease is slightly more common in women in Western populations.
- Ancestry and geography: Highest incidence in Northern European–derived and Ashkenazi Jewish populations and in industrialized, urban, northern-latitude regions; incidence is rising rapidly in newly industrialized countries, supporting an environmental contribution.
- Prevalence: Millions of adults in the United States carry an IBD diagnosis, and prevalence is increasing as incident patients accumulate rather than die of the disease.
- Family history: The strongest single non-modifiable risk factor; concordance is higher in monozygotic twins for Crohn disease than for ulcerative colitis, indicating a stronger genetic contribution in Crohn.
On examinations, IBD is most often tested as a discrimination problem — separating ulcerative colitis from Crohn disease, and separating both from infectious, ischemic, and functional causes of chronic diarrhea.
IBD is not caused by one insult; it requires convergence of genetic susceptibility, a permissive environment, altered microbiota, and immune dysregulation.
Genetic (non-modifiable)
- NOD2/CARD15 polymorphisms: impaired intracellular sensing of bacterial muramyl dipeptide by Paneth cells and monocytes → defective bacterial clearance; associated with ileal, stricturing Crohn disease.
- Autophagy genes (ATG16L1, IRGM): defective handling of intracellular bacteria in Crohn disease.
- IL23R variants: modulate the Th17 axis; some alleles are protective, which is the biologic rationale for anti-IL-12/23 and anti-IL-23 therapy.
- HLA associations: more prominent in ulcerative colitis; family history in a first-degree relative is the strongest clinical predictor.
- Very-early-onset IBD: consider monogenic immunodeficiency (e.g., IL-10 receptor defects, chronic granulomatous disease) in an infant with severe perianal disease.
Environmental / modifiable
- Smoking: the classic split — increases risk and severity of Crohn disease, yet is protective against ulcerative colitis, where onset often follows smoking cessation. Never recommend smoking; counsel cessation in all patients.
- NSAIDs: disrupt prostaglandin-dependent mucosal defense and can precipitate flares.
- Antibiotics and enteric infection: dysbiosis after antibiotic courses or an episode of infectious gastroenteritis raises subsequent IBD risk.
- Western diet / urban living: low-fiber, high–processed-food patterns and reduced early microbial exposure (hygiene hypothesis).
- Oral contraceptives have been associated with modestly increased risk in epidemiologic studies.
Protective / negative associations
- Appendectomy before adulthood is associated with reduced ulcerative colitis risk.
- Breastfeeding is associated with reduced risk in offspring.
Stem clues to recognize: a young Ashkenazi Jewish adult, a recent ex-smoker with new bloody diarrhea (ulcerative colitis), an active smoker with perianal fistulizing disease (Crohn), or a chronic NSAID user with a flare. Note that infection — particularly Clostridioides difficile and CMV — is a precipitant, not merely a mimic.
Step 1 — Barrier failure: Defective mucin production, tight-junction leak, and (in Crohn disease) abnormal Paneth cell antimicrobial peptide secretion allow luminal commensals and their products to breach the epithelium.
Step 2 — Aberrant innate sensing: NOD2 and autophagy defects impair intracellular bacterial killing, so antigen persists in the lamina propria instead of being cleared silently. Dendritic cells present persistent commensal antigen in an inflammatory context.
Step 3 — Failure of tolerance: Regulatory T-cell restraint is overwhelmed. Effector T cells expand under IL-12 and IL-23 drive, generating TNF-α, IFN-γ, IL-17, and IL-6. Leukocytes are recruited through α4β7 integrin binding to MAdCAM-1 on gut endothelium — the target exploited by vedolizumab.
Step 4 — Tissue injury determines phenotype
- Ulcerative colitis: inflammation stays in mucosa and submucosa, begins at the rectum, and extends proximally in a continuous fashion. Neutrophils invade crypts to form crypt abscesses; goblet cell mucin is depleted; crypt architecture becomes distorted and branched. Because ulceration is superficial and confluent, the clinical output is frequent small-volume bloody diarrhea with tenesmus — an inflamed, non-compliant rectum signaling constantly.
- Crohn disease: inflammation is transmural and patchy. Focal ulcers over lymphoid aggregates enlarge into linear fissuring ulcers, and intervening edematous mucosa produces the cobblestone appearance; non-caseating granulomas may form. Transmural injury explains the complication set — fibrosis and stricture from serosal healing, sinus tracts that burrow into adjacent viscera or skin as fistulas and abscesses, and creeping mesenteric fat.
Step 5 — Systemic and malabsorptive consequences: Chronic cytokine exposure drives anemia of inflammation, thrombocytosis, hypoalbuminemia, growth failure in children, and a hypercoagulable state. Terminal ileal disease in Crohn disease removes the site of B12 and bile-acid reabsorption, causing megaloblastic anemia, bile-salt (secretory) diarrhea, steatorrhea, gallstones, and enteric hyperoxaluria with calcium oxalate stones. Shared immune drive also explains extraintestinal disease in skin, eye, joints, and biliary tree.
The typical stem: a patient in their twenties or thirties, often of Northern European or Ashkenazi Jewish ancestry, with weeks-to-months of diarrhea — too long for infection, too inflammatory for irritable bowel syndrome — plus nocturnal symptoms, weight loss, or blood.
Ulcerative colitis — mucosal, rectal-onset disease
- Bloody diarrhea with mucus: superficial confluent ulceration of a vascular mucosa.
- Tenesmus, urgency, and small-volume stools: rectal inflammation reduces compliance; proctitis may even present with constipation proximal to an irritable rectum.
- Lower abdominal cramping relieved by defecation; systemic fever, tachycardia, and anemia only when disease is severe or extensive.
Crohn disease — transmural, segmental disease
- Chronic non-bloody diarrhea with crampy right-lower-quadrant pain and a palpable mass: ileocecal inflammatory phlegmon; can mimic appendicitis in an acute presentation.
- Weight loss, low-grade fever, fatigue, growth delay in children: cytokine-driven catabolism plus malabsorption.
- Perianal disease — fistulas, fissures off the midline, indurated skin tags, abscess — is nearly pathognomonic for Crohn and should be sought on exam.
- Obstructive symptoms (postprandial bloating, vomiting, borborygmi) signal fibrostenotic stricture.
- Oral aphthous ulcers reflect true mouth-to-anus involvement.
Extraintestinal findings on exam (see associations above for the full list): conjunctival injection with pain and photophobia in uveitis, a tender erythematous shin nodule in erythema nodosum, an undermined ulcer with violaceous border in pyoderma gangrenosum, and inflammatory back pain with reduced Schober test in axial spondyloarthritis. Jaundice or pruritus with cholestatic liver tests in a colitis patient points to primary sclerosing cholangitis.
Red-flag presentation: distended, tympanitic, tender abdomen with absent bowel sounds, fever, tachycardia, and altered mentation in a patient whose diarrhea has paradoxically decreased — toxic megacolon until proven otherwise. Peritoneal signs suggest perforation.
There is no single diagnostic test; diagnosis is a composite of clinical, laboratory, endoscopic, histologic, and radiologic data, as stated by both the ACG and AGA.
Step 1 — Initial labs and exclusion of infection
- CBC, CRP/ESR, albumin, iron studies: anemia, thrombocytosis, elevated CRP, hypoalbuminemia support an inflammatory process.
- Fecal calprotectin (or lactoferrin): neutrophil-derived; distinguishes inflammatory from functional diarrhea and is used to monitor disease activity — a low value argues strongly against active mucosal inflammation.
- **Stool culture, ova and parasites, and C. difficile toxin/PCR**: mandatory before attributing symptoms to IBD and before escalating immunosuppression at every flare.
Step 2 — Confirmatory test
- Ileocolonoscopy with segmental biopsies, including the terminal ileum and rectum, is the gold standard. Ulcerative colitis: continuous, circumferential granular friable mucosa starting at the rectum with a sharp proximal demarcation; biopsy shows crypt abscesses, crypt distortion, and goblet cell mucin depletion confined to mucosa/submucosa. Crohn disease: skip lesions, aphthous and linear serpiginous ulcers, cobblestoning, rectal sparing, and non-caseating granulomas on biopsy.
- Avoid colonoscopy during suspected toxic megacolon or fulminant colitis — perforation risk.
Step 3 — Define extent and complications
- CT or MR enterography for small-bowel Crohn disease: mural hyperenhancement, the string sign of a narrowed terminal ileum, creeping fat, fistula, or abscess. MR pelvis is preferred for perianal fistula mapping.
- Plain abdominal radiograph in acute severe colitis: colonic dilation (transverse colon greater than about 6 cm) suggests toxic megacolon; free air indicates perforation. Chronic ulcerative colitis shows lead-pipe colon with loss of haustra on barium studies.
- Video capsule endoscopy for suspected isolated small-bowel Crohn — contraindicated if stricture is suspected due to capsule retention.
Named systems: Truelove and Witts criteria grade acute severe ulcerative colitis (stool frequency plus systemic toxicity — fever, tachycardia, anemia, elevated ESR); the Mayo score quantifies UC activity, the CDAI quantifies Crohn activity, and the Montreal classification categorizes extent, age, and behavior. Serologies (pANCA, ASCA) support phenotyping but lack the accuracy to make the diagnosis.
Immediate stabilization (acute severe colitis): Hospitalize; give IV fluids and electrolyte repletion, VTE prophylaxis with low-molecular-weight heparin despite rectal bleeding (IBD is prothrombotic), and test for C. difficile and CMV. Start IV corticosteroids (methylprednisolone or hydrocortisone) as induction, and obtain early surgical consultation. Withhold opioids, anticholinergics, and antidiarrheals such as loperamide — they precipitate toxic megacolon. NSAIDs should also be avoided.
Ulcerative colitis, mild–moderate (ACG 2019): 5-ASA is the backbone — rectal mesalamine for proctitis, combined oral plus rectal for left-sided or extensive disease; oral budesonide MMX or a short prednisone course if 5-ASA fails. 5-ASA is also effective for maintenance of remission; some observational data suggest a chemopreventive effect against colorectal neoplasia, but this is not an accepted stand-alone indication.
Moderate–severe disease (AGA 2020 UC guideline; ACG 2018 Crohn guideline): Move to advanced therapy rather than repeated steroid courses.
- Anti-TNF agents: infliximab, adalimumab — effective for both diseases and the treatment of choice for fistulizing Crohn disease; combination with a thiopurine reduces immunogenicity.
- Anti-integrin: vedolizumab, gut-selective α4β7 blockade, favored when infection risk is a concern.
- Anti-IL-12/23 or anti-IL-23: ustekinumab; risankizumab, which is FDA-approved for both Crohn disease and ulcerative colitis.
- JAK inhibitors: tofacitinib (ulcerative colitis) and upadacitinib (approved in both ulcerative colitis and Crohn disease) — carry boxed warnings for thrombosis, major cardiovascular events, and malignancy.
- S1P modulator: ozanimod for UC.
Steroid-refractory acute severe UC: rescue therapy with infliximab or cyclosporine after roughly three days of failed IV steroids; if no response, proceed to colectomy.
Crohn-specific points: Ileal-release budesonide for mild ileocecal disease; 5-ASA has limited efficacy in Crohn disease and should not be relied upon. Antibiotics (ciprofloxacin, metronidazole) treat septic complications such as abscess, not luminal inflammation itself. Corticosteroids must never be used as maintenance therapy.
Surgery: Total proctocolectomy with ileal pouch–anal anastomosis is curative for ulcerative colitis; surgery in Crohn disease is resection-sparing and non-curative, with recurrence typically at the anastomosis.
Before immunosuppression: screen for latent tuberculosis and hepatitis B, update vaccinations, and avoid live vaccines while on biologics; check TPMT/NUDT15 before thiopurines.
Emergencies (recognize immediately)
- Toxic megacolon: transmural inflammation paralyzes colonic smooth muscle and nitric oxide–mediated dilation follows. Fever, tachycardia, distension, and paradoxically decreasing stool frequency with colonic dilation on radiograph. Treat with bowel rest, nasogastric/colonic decompression, aggressive IV fluid and electrolyte correction (especially hypokalemia, which worsens colonic atony), broad-spectrum antibiotics covering enteric flora, IV corticosteroids, and urgent surgical consultation; opioids and antidiarrheals are the classic precipitants and must be stopped.
- Perforation and peritonitis: free air on imaging; requires emergent laparotomy.
- Massive lower GI hemorrhage: uncommon overall, but relatively more characteristic of ulcerative colitis given confluent mucosal ulceration; it also occurs in Crohn colitis.
- Intra-abdominal or perianal abscess in Crohn disease: fever and localized tenderness — drain before escalating immunosuppression, since anti-TNF therapy into an undrained abscess worsens sepsis.
Structural (mostly Crohn — transmural mechanism)
- Fibrostenotic stricture with small-bowel obstruction; enteroenteric, enterovesical (pneumaturia, recurrent polymicrobial UTI), enterocutaneous, and rectovaginal fistulas.
- Short bowel syndrome after repeated resections; bile-acid diarrhea and B12 deficiency after terminal ileal resection; gallstones and calcium oxalate nephrolithiasis from enteric hyperoxaluria.
Chronic/systemic
- Colorectal dysplasia and carcinoma: risk rises with duration, extent, and severity of inflammation and with coexisting PSC; surveillance colonoscopy with chromoendoscopy or high-definition white light is recommended by ACG/AGA. IBD-associated cancers are often flat and multifocal rather than polypoid.
- Venous thromboembolism, iron-deficiency and inflammatory anemia, osteoporosis (inflammation plus steroids), growth failure in children, and secondary amyloidosis (rare).
- Primary sclerosing cholangitis with cholangiocarcinoma risk (see associations).
Treatment-related
- Corticosteroids: hyperglycemia, osteonecrosis, adrenal suppression, infection.
- Thiopurines: myelosuppression (TPMT/NUDT15 deficiency), pancreatitis, hepatotoxicity, non-melanoma skin cancer, lymphoma — including hepatosplenic T-cell lymphoma in young men on thiopurine plus anti-TNF.
- Anti-TNF: reactivation of latent tuberculosis and hepatitis B, drug-induced lupus, demyelination, worsening of heart failure.
- Sulfasalazine: reversible oligospermia, hemolysis in G6PD deficiency, folate malabsorption; mesalamine: interstitial nephritis.
- Post-colectomy: pouchitis, treated with antibiotics such as ciprofloxacin or metronidazole.
- Smoking splits the two diseases: it worsens Crohn disease but is protective in ulcerative colitis — the stem's new-onset bloody diarrhea in a patient who just quit smoking is ulcerative colitis. Never advise smoking; this is a mechanism fact, not a recommendation.
- Best next step before escalating therapy in any flare: stool studies including C. difficile toxin. Immunosuppressing an infected patient is a favorite wrong answer.
- Suspected toxic megacolon: obtain an abdominal radiograph — do not perform colonoscopy or barium enema, and stop loperamide/opioids. Perforation risk makes this the classic "wrong test" trap.
- Perianal fistula or non-caseating granuloma = Crohn disease, regardless of how colitic the presentation sounds. Conversely, crypt abscesses are seen in ulcerative colitis but are not specific to it.
- Colectomy cures ulcerative colitis but not Crohn disease — and it does not cure associated primary sclerosing cholangitis, whose cholangiocarcinoma risk persists after surgery.
- Terminal ileal Crohn disease explains B12 deficiency, bile-salt diarrhea, gallstones, and calcium oxalate kidney stones; the string sign on enterography is the imaging buzzword.
- Check TPMT/NUDT15 before azathioprine or 6-MP and screen for latent TB and hepatitis B before anti-TNF therapy — both are commonly tested "before you prescribe" steps.
- Common distractors to avoid: pANCA/ASCA serologies do not diagnose IBD (endoscopy with biopsy does); 5-ASA is a mainstay in ulcerative colitis but has limited efficacy in Crohn disease; corticosteroids are induction-only and never maintenance; and anemia plus bloody diarrhea in a young adult is IBD, not diverticular bleeding or hemorrhoids until inflammation is excluded.
- Ulcerative colitis (UC): continuous mucosal inflammation limited to colon/rectum; bloody diarrhea; crypt abscesses
- Crohn's disease (CD): transmural, segmental inflammation of any GI tract (mouth to anus); cobblestone mucosa, fissuring ulcers, skip lesions
- Peak incidence: 20-40 years old; higher in Ashkenazi Jews and Northern Europeans
- Increased colorectal cancer risk in both (UC > CD); annual colonoscopy after 8-10 years of disease
- Diagnosis: endoscopy with biopsy (histology definitive); elevated inflammatory markers (ESR, CRP, calprotectin)
IBD results from loss of intestinal barrier function combined with dysregulated immune response to commensal flora in genetically predisposed individuals (NOD2/CARD15 mutations in CD). Th1/Th17-mediated inflammation predominates, with increased TNF-α, IL-6, and IL-23. UC inflammation is limited to mucosa/submucosa; CD is transmural with granuloma formation (non-caseating), leading to fibrosis and stricture formation.
- UC: Young adult with months of bloody diarrhea, tenesmus, urgency; left-sided or universal colonic involvement; systemic symptoms if severe
- CD: Chronic diarrhea (non-bloody), abdominal pain/cramping, weight loss; perianal disease (fistulas, skin tags); may have fever and weight loss suggesting transmural involvement
| Finding | Association |
|---|---|
| Erythema nodosum, pyoderma gangrenosum | Extraintestinal manifestations (skin) |
| Primary sclerosing cholangitis (PSC) | Associated with UC (1-4% of cases); increased cholangiocarcinoma risk |
| Aphthous ulcers, arthritis, uveitis | Extraintestinal manifestations |
| Fistulas, abscesses, obstruction | CD complications (transmural disease) |
| Toxic megacolon | Medical emergency; both UC and CD |
| ANCA+ (pANCA), ASCA+ | Serology: pANCA in UC; ASCA in CD |
- Confusing UC and CD: UC is colon-only, continuous; CD is transmural, any location with skip lesions—histology/location is definitive, not just clinical presentation
- Missing PSC screening: UC patients need liver function tests and MRCP screening for PSC; associated with increased CCA risk even after colectomy
- Inappropriately stopping 5-ASA/thiopurines: Maintenance therapy required for remission; early discontinuation causes flare (differentiate acute induction from maintenance)
Mild-Moderate Disease
- 5-ASA compounds (mesalamine): topical for distal UC; oral for pan-colonic
- Sulfasalazine (contains sulfapyridine—caution with sulfa allergy)
Moderate-Severe Disease
- Corticosteroids (prednisone): acute flare induction; taper after remission achieved
- Thiopurines (azathioprine, 6-MP): steroid-sparing maintenance
Biologic Therapy (refractory disease):
- TNF-α inhibitors: infliximab, adalimumab (especially for CD)
- Anti-IL-12/23: ustekinumab
Severe/Fulminant
- High-dose IV corticosteroids ± cyclosporine; consider colectomy for UC if medical failure
- Admit for toxic megacolon, perforation, severe dehydration