Crohn Disease

Etiology and Risk Factors

Crohn disease arises from interactions among genetic susceptibility, epithelial barrier function, gut microbiota, environmental exposures, and an inadequately regulated mucosal immune response. Risk-associated pathways include microbial sensing and autophagy; NOD2-associated susceptibility is informative but neither necessary nor sufficient for diagnosis. Th1/Th17-related signaling, including TNF-alpha, IL-12, and IL-23, helps sustain leukocyte recruitment and tissue injury. Smoking worsens Crohn disease and increases risk of relapse and complications (Bhat, 2026; Mills & Ciorba, 2019).

Epidemiology and Clinical Context

Population context: Crohn disease often begins during adolescence or early adulthood, although onset is possible throughout life. Pediatric disease deserves explicit assessment of linear growth, pubertal development, bone health, and nutrition; smoking is a modifiable exposure associated with more difficult Crohn outcomes (Brumbaugh et al., 2025; Mills & Ciorba, 2019).

Pathophysiology

Stepwise pathogenesis: from ulcer to obstruction and fistula

• An impaired host-microbiome interface promotes chronic activation of innate and adaptive immunity within susceptible segments.
• Focal mucosal inflammation produces aphthous lesions that can extend into deep linear ulcers, separated by normal-appearing mucosa (skip lesions). Edema and intersecting ulcers create a cobblestone appearance.
• Inflammation reaches deeper bowel layers, resulting in tissue damage, wall thickening, creeping mesenteric fat, and sometimes noncaseating granulomas. Granulomas support the diagnosis but are not required.
• Repeated injury and repair drive fibrosis and fixed luminal narrowing (fibrostenotic phenotype). Deep penetrating injury creates sinus tracts, fistulas, abscesses, or perforation (penetrating phenotype).

Key distinction: An inflammatory stricture may partly respond to anti-inflammatory treatment, but established fibrosis generally will not reverse with corticosteroids or biologics. A fistula or abscess represents penetrating disease, not merely “a worse flare” (Mills & Ciorba, 2019; Norris, 2020).

Clinical Manifestations

Children and extraintestinal disease: findings that may precede diarrhea

Children may present with slowed height velocity, delayed puberty, weight loss, reduced bone mineralization, anemia, or fatigue before an obvious GI diagnosis. Assess serial height/weight percentiles, pubertal progression, dietary intake, iron, vitamin B12, zinc, vitamin D, and growth-limiting steroid exposure as appropriate. Very-early-onset or unusually severe disease raises consideration of monogenic or immune-deficiency-associated IBD (Brumbaugh et al., 2025).

Inflammation may extend beyond the bowel: peripheral or axial arthritis, uveitis, oral aphthae, erythema nodosum, pyoderma gangrenosum, and hepatobiliary involvement are relevant clues. Painful red eye with photophobia needs prompt ophthalmologic evaluation; painful skin ulcers or new joint symptoms should not be dismissed because bowel symptoms are quiet. Screen for thromboembolic risk and assess psychosocial, educational, and nutritional effects across age groups (Brumbaugh et al., 2025; Mills & Ciorba, 2019).

Diagnostic Evaluation

• History: chronic diarrhea, pain pattern, bleeding, oral ulcers, perianal symptoms, fever, unintended weight loss, smoking, family history, medication/NSAID exposure, extraintestinal symptoms, and prior bowel surgeries.
• Testing: CBC, CRP, albumin, iron indices, vitamin B12 and other nutritional tests as indicated; fecal calprotectin for intestinal inflammation. A normal CRP does not exclude active disease. With new or worsening diarrhea, assess for Clostridioides difficile infection, particularly in colonic Crohn disease or during immunomodulation. When CDI is suspected in IBD, the 2026 AGA update advises a multistep toxin-based diagnostic assay rather than treating an isolated positive nucleic acid result as proof of symptomatic toxin-mediated infection. When CDI is confirmed, AGA prefers fidaxomicin for an initial episode, with oral vancomycin when fidaxomicin is inaccessible; metronidazole should not be used for initial CDI in IBD (Khanna et al., 2026).
• Ileocolonoscopy with segmental biopsies is central to confirming distribution and chronic inflammatory change. MR enterography, CT enterography, or intestinal ultrasound evaluates small-bowel involvement and extraluminal complications; pelvic MRI is useful for complex perianal fistulas.

Expected Findings

Location predicts findings and nutritional complications

Anatomy / phenotype	Clinical consequences	Interpretive priority
Terminal ileum	Right lower quadrant pain, bile acid malabsorption, vitamin B12 deficiency, diarrhea, enteric hyperoxaluria.	Assess B12, iron/nutrition, prior ileal resection, and obstructive symptoms.
Colonic disease	Diarrhea and, at times, hematochezia, urgency, anemia.	Distinguish Crohn colitis from continuous ulcerative colitis and infectious colitis.
Upper GI / extensive small bowel	Early satiety, pain, poor intake, malabsorption and weight loss.	Evaluate extent and nutrition; consider alternative causes of upper GI symptoms.
Perianal / penetrating disease	Painful drainage, fissures, fistulae, recurrent abscess, systemic infection.	Examine perianal region and image suspected deep sepsis.
Fibrostenotic disease	Crampy postprandial pain, distension, vomiting, decreased stool/flatus, obstruction.	Evaluate urgently when obstructed; distinguish active edema from fixed fibrosis.

Differential Diagnosis

• Endoscopic or histologic features require clinical correlation. Skip areas, deep ulcers, or granulomas support Crohn disease; infection (including intestinal tuberculosis), ischemia, medication injury, and neoplasia can mimic aspects of its presentation.

Diagnostic Limitations and Reassessment

A normal CRP does not exclude active disease (Lichtenstein et al., 2025).

Treatment and Management

Goals are steroid-free remission, mucosal healing where assessable, prevention of structural damage, restoration of nutrition, and avoidance of hospitalization and surgery when feasible. Symptom relief alone is inadequate: clinical outcomes are interpreted with fecal calprotectin/CRP trends, endoscopic or imaging evidence, and complications (Bhat, 2026).

• For active inflammation, options include short-term corticosteroid induction in selected presentations and steroid-sparing targeted treatment for moderate-to-severe or high-risk disease. Anti-TNF, anti-integrin, anti-interleukin, and selected small-molecule classes act at different inflammatory nodes. Selection depends on phenotype, prior exposure, comorbidities, and treatment safety.
• The 2025 ACG guideline recommends against oral mesalamine for induction or maintenance of mild-to-moderate Crohn disease. Sulfasalazine may have a limited symptomatic role in selected mild colonic disease but is not an adequate strategy for achieving mucosal healing. Controlled ileal-release budesonide can induce symptomatic remission in selected mild-to-moderate ileocecal disease, not maintain remission. Systemic corticosteroids are not maintenance therapy, and routine antibiotics do not treat uncomplicated luminal inflammation (Lichtenstein et al., 2025).
• Manage fistulas, abscesses, and obstructive disease with multidisciplinary input; drainage or surgery is sometimes necessary. Surgical resection can control complications but does not cure Crohn disease, and recurrence may occur elsewhere or near the anastomosis.
• Before advanced immunosuppression, evaluate infection risk (including tuberculosis and hepatitis B when indicated), vaccinations, malignancy history, pregnancy intentions, and drug-specific precautions. Monitor anemia, nutrition, thrombosis risk, adverse effects, and objective response.

For moderate-to-severe or high-risk Crohn disease, the 2025 ACG guideline supports timely advanced therapy without requiring sequential failure of thiopurines or methotrexate. Select the agent based on activity, location, penetrating or stricturing behavior, prior therapies, comorbidity, pregnancy considerations and infection screening. Reassess objective inflammation rather than interpreting transient steroid response as durable control (Lichtenstein et al., 2025).

Phenotype determines the intervention and the treatment target

Assess the dominant disease behavior separately from lesion location: predominantly inflammatory luminal disease, fixed fibrostenotic narrowing, and penetrating disease with fistula or abscess need different plans. Objective inflammation in a narrowed segment may justify effective anti-inflammatory treatment, but a fixed fibrotic stricture with upstream obstruction may require endoscopic dilation or surgery. An intra-abdominal abscess calls for sepsis assessment, antimicrobials and source control when indicated; immunosuppressive escalation without infection control is unsafe. Perianal complex fistulas require anatomic definition, commonly pelvic MRI, and combined medical-surgical management (Bhat, 2026; Mills & Ciorba, 2019).

For longitudinal care, distinguish patient-reported improvement from demonstrable control of inflammation. Track stool symptoms, weight, iron/B12 and other deficiencies, CRP or fecal calprotectin where informative, and endoscopic or cross-sectional healing when indicated. Discordance between persistent pain and quiescent inflammation should prompt evaluation for strictures, bile-acid diarrhea, postsurgical problems or disorders of gut-brain interaction rather than automatic biologic escalation.

Complications and Red Flags

Complications that change the immediate decision

Presentation	Mechanism / concern	Immediate implication
Distension, bilious emesis, obstipation	Inflammatory edema or fibrotic stricture causing obstruction.	Urgent imaging, fluids, electrolyte correction, surgical assessment when indicated.
Fever, localized severe pain, tender mass	Transmural penetration and localized abscess.	Cross-sectional imaging and source-control evaluation; do not assume uncomplicated flare.
Perianal drainage / recurrent infection	Fistulizing disease with possible deep tract or abscess.	Examine, consider pelvic MRI and colorectal evaluation.
Chronic weight loss, anemia, neuropathy	Insufficient intake, mucosal malabsorption, or ileal B12 loss.	Targeted nutrient replacement and treatment of intestinal inflammation.
New leg swelling, dyspnea, pleuritic pain	Inflammation-associated venous thromboembolism risk.	Assess thrombotic complications rather than attributing symptoms to fatigue.

Medication harm is a separate differential, not proof of a flare

New epigastric pain and vomiting after starting a therapy can represent acute pancreatitis, biliary disease, obstruction, or another process. Review the timeline and exposures; obtain lipase and appropriate abdominal/biliary evaluation rather than assigning causation from chronology alone. Rare pancreatitis has been associated with 5-ASA drugs, while thiopurines may cause pancreatitis, cytopenias, hepatotoxicity, and infection susceptibility (Bhat, 2026; Brumbaugh et al., 2025).

Fever with new leukopenia or lymphopenia in an immunomodulated patient requires urgent evaluation for infection and medication-associated marrow suppression. Review the precise agent, recent blood counts, liver tests, co-prescribed drugs and baseline monitoring; evaluate fever and organ injury on their own merits. Temporarily holding an implicated immunomodulator and urgent specialty input may be appropriate, but a viral explanation or drug toxicity should not be presumed without assessment. Thiopurine-specific enzyme or metabolite testing and monitoring depend on the selected medication (Bhat, 2026).

Clinical Reasoning Priorities

A young adult with intermittent diarrhea develops colicky abdominal pain, vomiting, and CT-demonstrated terminal ileal thickening with upstream small-bowel dilation. The differential includes active inflammatory narrowing, established Crohn stricture, infection, and neoplasm. Stabilize possible obstruction first; then investigate the nature of the stricture and determine whether medical therapy, endoscopic intervention, or surgery is warranted. The presence of narrowing means this is not merely an “IBD diarrhea” presentation.

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References

Bhat, S. (2026). Inflammatory bowel disease. In M. A. Chisholm-Burns, J. M. Kolesar, P. M. Malone, K. C. Lee, P. B. Bookstaver, & K. R. Matthias (Eds.), Pharmacotherapy principles & practice (7th ed., Chapter 20). McGraw Hill.

Brumbaugh, D., Furuta, G. T., Hoffenberg, E. J., Kobak, G. E., Kramer, R. E., Nguyen, N., Septer, S., Shull, M., Soden, J., & Walker, T. (2025). Gastrointestinal tract. In M. Bunik, M. J. Levin, M. J. Abzug, & T. L. Schreiner (Eds.), Current diagnosis & treatment: Pediatrics (27th ed., Chapter 21). McGraw Hill.

Khanna, S., Allegretti, J. R., Hashash, J. G., & Feuerstadt, P. (2026). AGA clinical practice update on management of Clostridioides difficile infection in inflammatory bowel disease: Expert review. Gastroenterology, 171(1), 184–192. https://doi.org/10.1053/j.gastro.2026.03.008

Lichtenstein, G. R., Loftus, E. V., Afzali, A., Long, M. D., Barnes, E. L., Isaacs, K. L., & Ha, C. Y. (2025). ACG clinical guideline: Management of Crohn’s disease in adults. American Journal of Gastroenterology, 120(6), 1225–1264. https://doi.org/10.14309/ajg.0000000000003465

Mills, J. C., & Ciorba, M. A. (2019). Gastrointestinal disease. In G. D. Hammer & S. J. McPhee (Eds.), Pathophysiology of disease: An introduction to clinical medicine (8th ed., Chapter 13). McGraw-Hill Education.

Norris, T. L. (2020). Porth’s essentials of pathophysiology (5th ed.). Wolters Kluwer.