Crohn Disease

Genetic Factors

Genome-wide Association Studies (GWAS)

• Over 71 genetic susceptibility loci have been identified, with significant associations involving the CARD15/NOD2 gene, the IBD5 locus, ATG16L1 (autophagy-related), and IL23R (interleukin-23 receptor).
• CARD15/NOD2 polymorphisms are particularly associated with ileal disease and earlier-onset CD.
• Additional loci, including STAT3, JAK2, PTPN22, and ITLN1, have been implicated in immune signaling and intestinal microbial recognition.

Autophagy Pathway Genes

• Variants in ATG16L1 and IRGM suggest defective bacterial clearance mechanisms, emphasising the importance of autophagy in pathogenesis.

Genetic Contribution

• Identified genetic factors explain less than 20% of heritable risk, underscoring the importance of environmental triggers.

Environmental Factors

Diet and Lifestyle

• Diets low in fruits, vegetables, and fiber but high in refined sugars and ultra-processed foods have been linked to increased CD risk.
• Smoking is strongly associated with disease onset and progression, doubling the risk of developing CD.

Medications and Exposures

• Use of oral contraceptives, NSAIDs, and antibiotics has been implicated in disease initiation or exacerbation.

Other Factors

• Lack of breastfeeding during infancy and a sedentary lifestyle may contribute to susceptibility.
• Deficiencies in vitamin D and zinc are often observed but their causative roles are uncertain.

Microbial and Infectious Influences

Pathogenic Microorganisms

• Species like Mycobacterium avium paratuberculosis, Campylobacter, and Pseudomonas have been linked to disease onset or exacerbation.
• Whether these microbes play a causative role or are secondary to existing inflammation remains debated.

Dysbiosis

• An imbalance in gut microbiota composition is frequently observed, potentially driving inappropriate immune activation.

Immunologic and Cytokine Pathways

Immune Dysregulation

• CD is marked by an exaggerated Th1 and Th17 immune response, with elevated levels of IL-12, IL-23, and TNF-α promoting chronic inflammation.

TNF-α Role

• TNF-α is a key proinflammatory mediator, with its overexpression linked to mucosal damage and systemic inflammation.

Psychosocial and Miscellaneous Factors

Stress and Psychosocial Stressors

• Though not directly causal, stress is a recognised exacerbating factor in disease flares.

Surgical History

• Unlike in ulcerative colitis, appendectomy does not provide a protective effect in CD.

Immune Dysregulation

• Dysregulated Th1 and Th17 immune responses drive chronic inflammation, mediated by cytokines such as IL-12, IL-23, and TNF-α.
• Deficiencies in epithelial barrier integrity and innate immune recognition exacerbate mucosal inflammation and tissue injury.

Inflammatory Cascade

• Pro-inflammatory mediators released by immune cells include:
  • Arachidonic acid metabolites.
  • Platelet-activating factors.
  • Proteases and free radicals, leading to epithelial damage and tissue destruction.

Histological Features

Initial Lesion

• Focal inflammatory infiltrates around intestinal crypts progress to superficial ulcerations and non-caseating granulomas.
• Granulomas involve all layers of the intestinal wall but may not always be present.

Chronic Changes

• Neutrophilic infiltration forms crypt abscesses and destroys crypts, causing mucosal atrophy and villous blunting.
• Alternating areas of inflamed and normal mucosa result in characteristic "skip lesions."

Macroscopic and Endoscopic Findings

Early Changes

• Hyperemia and edema of mucosa, visible on endoscopy.

Advanced Findings

• Deep, serpiginous ulcers and a cobblestone appearance due to intervening healthy mucosa.
• Thickened bowel walls with luminal narrowing, leading to obstruction and strictures.

Complications

• Penetrating disease manifests as fistulae (enteroenteral, enterovesical, enterocutaneous).
• Chronic transmural inflammation predisposes to abscess formation and adhesions.

Nutritional and Systemic Implications

Nutritional Impact

• Terminal ileum involvement disrupts bile acid reabsorption, leading to:
  • Steatorrhea and malabsorption.
  • Fat-soluble vitamin deficiencies (A, D, E, K).
  • Gallstone and oxalate kidney stone formation.

Extraintestinal Manifestations

• Skin: Erythema nodosum, pyoderma gangrenosum.
• Joints: Peripheral arthritis, ankylosing spondylitis.
• Eyes: Uveitis, episcleritis.
• Liver: Primary sclerosing cholangitis, gallstones.

Disease Progression

• Acute inflammation causes reversible symptoms like edema and spasm.
• Chronic disease leads to fibrosis, strictures, fistulae, and adhesions.
• "Creeping fat" (mesenteric fat wrapping around inflamed bowel) contributes to local inflammation.

Vienna Classification of Crohn Disease

Age at Diagnosis

• A1: ≤40 years.
• A2: >40 years.

Disease Location

• L1: Terminal ileum (± cecum involvement).
• L2: Colon (excluding small bowel involvement).
• L3: Ileocolon (both small and large bowel involvement).
• L4: Upper gastrointestinal (proximal to terminal ileum, excluding mouth).

Disease Behavior

• B1: Non-stricturing, non-penetrating.
• B2: Stricturing (luminal narrowing with pre-stenotic dilation).
• B3: Penetrating (fistulae, abscesses, or other perforating complications).

Montreal Classification of Crohn’s Disease

Age at Diagnosis

• A1: ≤16 years.
• A2: 17–40 years.
• A3: >40 years.

Disease Location

• L1: Terminal ileum (± cecum involvement).
• L2: Colon (excluding small bowel involvement).
• L3: Ileocolon (both small and large bowel involvement).
• L4: Upper gastrointestinal (proximal to terminal ileum, excluding mouth).
• L4a: Oesophagus, stomach, duodenum.
• L4b: Jejunum and proximal ileum.

Disease Behavior

• B1: Non-stricturing, non-penetrating.
• B2: Stricturing (luminal narrowing with pre-stenotic dilation).
• B3: Penetrating (fistulae, abscesses, or other perforating complications).
• p: Perianal disease modifier (applies to any B classification if perianal disease is present).

Global and Regional Prevalence and Incidence

North America and Europe

• Incidence rates:
  • 20.2 per 100,000 person-years in North America.
  • 12.7 per 100,000 person-years in Europe.
• Prevalence rates:
  • 319 per 100,000 in Canada.
  • 322 per 100,000 in Germany.

Asia and Developing Regions

• Incidence rates in Asia range from 0.5 to 4.2 per 100,000 persons, with Japan reporting a prevalence of 27 per 100,000 individuals.
• Newly industrialising regions in Asia, South America, and Africa are experiencing rising incidence.

Urban vs. Rural Distribution

• Higher prevalence in urban areas than in rural regions, possibly due to environmental exposures and healthcare access disparities.

Age and Gender Distribution

Bimodal Age Distribution

• First peak: Ages 15–30 years (young adulthood).
• Second peak: Ages 50–70 years (more pronounced in women).

Gender Differences

• Slight female predominance in adults, with rates 1.1–1.8 times higher in women.
• Pediatric Crohn disease has a higher incidence in males (male-to-female ratio ~1.6:1).

Ethnic and Genetic Factors

Ethnic Variability

• Higher prevalence in white populations and individuals of Ashkenazi Jewish descent, with the latter group exhibiting a 2- to 4-fold increased risk.
• Lower prevalence in Asians, Africans, and South Americans.

Familial and Genetic Risk

• 10–25% of patients report a first-degree relative with Crohn's disease.

Time Trends

• Epidemiologic studies show statistically significant increases in incidence globally, particularly in newly industrialised countries.
• Time-trend analyses reveal stabilisation or slight declines in incidence in highly industrialised regions.

Environmental Influences

• Urbanisation and adoption of Western diets have been linked to increased disease prevalence.
• Smoking is a known risk factor, doubling the likelihood of disease development.

Key Historical Factors

Risk Factors

Ethnicity and Genetics

• White ethnicity and Ashkenazi Jewish ancestry are associated with higher prevalence.
• Family history is significant, with 10–25% of patients reporting an affected first-degree relative.

Age of Onset

• Bimodal distribution, peaking between 15–40 years and 50–60 years.

Environmental Exposures

• Smoking increases the risk and severity of Crohn's disease (CD).
• Diets high in refined sugars, low in fiber, or rich in ultra-processed foods may be contributory.

Symptoms

Abdominal Pain

• Frequently localised to the right lower quadrant or periumbilical region.
• Often crampy and relieved by defecation.
• May mimic acute appendicitis or present as diffuse pain in colitis.

Diarrhoea

• Intermittent, chronic, and non-bloody, although bloody diarrhoea may occur, especially in colonic disease.
• Diarrhoea may worsen at night and often fluctuates over long periods.

Weight Loss

• Commonly results from reduced oral intake due to pain or fear of eating.
• Malabsorption and nutrient deficiencies contribute to progressive weight loss.

Fatigue

• A prominent feature caused by systemic inflammation, malnutrition, and chronic disease burden.

Fever

• Low-grade fever is typical; higher-grade fever may indicate abscess formation or perforation.

Bowel Obstruction

• Recurrent postprandial bloating, cramping, and loud bowel sounds.
• Chronic inflammation and fibrosis can lead to progressive strictures, presenting as obstipation or vomiting.

Perianal Disease

• History of perianal pain, drainage, or discomfort.
• May present with recurrent infections, fistulae, or abscesses.

Systemic and Extraintestinal Symptoms

Malabsorption

• Symptoms of nutrient deficiencies, including fatigue, weakness, and steatorrhoea, may arise from bile salt malabsorption or intestinal damage.

Extraintestinal Manifestations:

• Symptoms of arthritis, eye irritation (uveitis, episcleritis), or skin changes (erythema nodosum, pyoderma gangrenosum).

Duration and Intermittency

• Symptoms may precede diagnosis by years, with periods of remission and recurrence.

Importance of Historical Details

Growth Failure in Children

• Growth delays or failure to thrive may be the earliest sign in paediatric populations.

Triggers and Aggravating Factors

• Emotional or physical stress often correlates with symptom flares.
• Prior surgical history, especially involving the gastrointestinal tract, may indicate previous disease progression or complications.

General Observations

Malnutrition and Vital Signs

• Signs of malnutrition, including pallor, low body mass index, and muscle wasting.
• Fever, tachycardia, or hypotension may indicate active inflammation, dehydration, or complications like sepsis.

Abdominal Examination

 Inspection

• Visible abdominal scars from prior surgeries or enterocutaneous fistulae in advanced cases.
• Abdominal distension may suggest bowel obstruction or significant inflammatory changes.

Auscultation

• Hyperactive bowel sounds may indicate obstruction or active inflammation.
• Absent or reduced bowel sounds could signify ileus or severe inflammation.

Palpation

• Localised Tenderness:
  • Commonly in the right lower quadrant, correlating with terminal ileal involvement.
• Mass Formation:
  • A palpable inflammatory mass may represent thickened bowel loops or abscess formation.
• Guarding and Rebound Tenderness:
  • May indicate peritonitis due to perforation or intra-abdominal abscess.

Percussion

• Tympany may indicate dilated bowel loops or obstruction.

Perianal and Rectal Examination

 Perianal Findings

• Present in ~25–30% of patients.
• Findings include skin tags, fissures, fistulae, abscesses, or scarring.

Rectal Examination

• May reveal gross or occult blood, reduced sphincter tone, or rectal masses.
• Perianal pain and purulent discharge are common with active fistulae or abscesses.

Extraintestinal Manifestations

 Skin

• Erythema Nodosum:
  • Painful, red nodules typically found on the anterior lower legs.
• Pyoderma Gangrenosum:
  • Deep, necrotic ulcers with violaceous borders, often on the extremities.

Eyes

• Signs of episcleritis (redness and irritation) or uveitis (pain, photophobia, blurred vision).
• A slit-lamp examination may be necessary to confirm uveitis.

Oral Cavity

• Aphthous ulcers, mucosal inflammation, and discomfort are common findings.

Joints

• Peripheral arthritis (large joints such as knees, ankles).
• Axial involvement, such as sacroiliitis or ankylosing spondylitis.

Liver and Biliary System

• Right upper quadrant tenderness may indicate primary sclerosing cholangitis or gallstones.

Renal and Pelvic Exam

• Flank tenderness could suggest nephrolithiasis.
• Examination of the genital area may reveal fistulae or associated skin changes.

Paediatric-Specific Examination

 Growth Parameters

• Monitoring height, weight, and growth velocity is critical to detect growth delays.
• Decreased growth velocity is often the earliest sign of Crohn's disease in children.

Pubertal Development

• Delayed puberty may be evident in adolescents, requiring Tanner staging.

Laboratory Investigations

 Blood Tests

 Complete Blood Count (CBC)

• Anaemia (chronic inflammation, iron deficiency, B12/folate malabsorption).
• Leukocytosis (inflammation, infection, steroid use).
• Thrombocytosis (marker of active inflammation).

Inflammatory Markers

• C-reactive protein (CRP) and Erythrocyte Sedimentation Rate (ESR) correlate with disease activity.

Nutritional Markers

• Serum albumin, iron studies, vitamin D, vitamin B12, and folate levels to evaluate malnutrition or malabsorption.

Electrolytes

• May reveal hypokalemia, hypocalcemia, or hypoalbuminemia in cases of chronic diarrhoea.

Stool Tests

 Pathogen Screening

• Stool cultures, ova and parasite tests, and Clostridioides difficile toxin assays to exclude infectious causes.

Fecal Calprotectin or Lactoferrin

• Non-invasive markers of intestinal inflammation, useful in distinguishing inflammatory bowel disease (IBD) from irritable bowel syndrome (IBS).

Endoscopic Evaluation

 Ileocolonoscopy

• Gold standard for diagnosis.
• Endoscopic findings include:
  • Skip lesions: Segmental inflammation interspersed with normal mucosa.
  • Cobblestone appearance: Ulcers and nodularity.
  • Pseudopolyps: Hypertrophied mucosa.
  • Rectal sparing.
• Biopsies are essential for histologic confirmation:
  • Granulomas (present in 30–50% of cases) strongly support CD diagnosis but are not mandatory.

Upper Endoscopy (Oesophagogastroduodenoscopy)

• Indicated in cases with upper gastrointestinal symptoms (e.g., nausea, dyspepsia, or early satiety).
• Findings may include gastric/duodenal ulcerations or inflammation.

Video Capsule Endoscopy (VCE)

• Visualises small bowel lesions not accessible by conventional endoscopy.
• Contraindicated in suspected strictures due to capsule retention risks.

Imaging Studies

 Small Bowel Imaging

 CT Enterography (CTE) and MRI Enterography (MRE)

• Identify small bowel involvement, strictures, and penetrating complications (e.g., fistulae or abscesses).
• Preferred for assessing disease distribution and transmural involvement:
  • Segmental wall thickening (>2 mm).
  • "Comb sign" (engorged mesenteric vessels).
  • Creeping fat and bowel strictures with upstream dilation.
• MRE is favored for younger patients or those requiring repeated imaging due to its lack of radiation exposure.

Pelvic MRI

• Evaluates perianal disease, defining fistulae and abscess tracts.

Ultrasound

• Useful for detecting bowel wall thickening, abscesses, and hyperemia.
• Highly operator-dependent and limited in obese patients.

Plain Radiography

• May reveal complications such as bowel obstruction, perforation, or toxic megacolon.

Advanced Diagnostics

 Histology

• Biopsies from endoscopic evaluations reveal:
  • Non-caseating granulomas.
  • Cryptitis or crypt abscesses.
  • Transmural lymphoid aggregates.

Serologic Testing

 Anti-Saccharomyces cerevisiae antibodies (ASCA)

• More prevalent in CD than ulcerative colitis.

p-ANCA (perinuclear antineutrophil cytoplasmic antibody)

• More common in ulcerative colitis but may be positive in some CD cases.

Emerging and Specialised Tools

 Fecal Biomarkers

• Serial measurements of fecal calprotectin are increasingly used to monitor disease activity and predict relapses.

Cross-sectional Imaging with PET/CT

• Experimental use in assessing inflammation and complications such as abscesses or fistulae.

Inflammatory Bowel Diseases

Ulcerative Colitis (UC)

•  Distinguishing features:
  • Continuous colonic involvement starting at the rectum.
  • No small bowel or perianal disease.
• Investigations:
  • Colonoscopy: Rectal involvement, no skip lesions.
  • Biopsy: Diffuse mucosal inflammation without granulomas.
  • Laboratory: Anti-glycan antibodies more common in CD.

Indeterminate Colitis

• Used when features of both CD and UC are present, making differentiation impossible.
• Evolution into definitive CD or UC may occur with time.

Infectious Causes

Infectious Colitis

•  Pathogens: Shigella, Salmonella, Campylobacter, Escherichia coli O157:H7, Yersinia, Clostridioides difficile, parasites (Entamoeba histolytica).
• Features:
  • Acute diarrhoea, abdominal pain, and fever.
  • History of travel or foodborne illness.
• Investigations:
  • Stool culture, ova and parasite examination, and pathogen-specific tests.

Cytomegalovirus (CMV) Colitis

• Mimics CD in immunocompromised patients.
• Investigations:
  • Biopsy with histological findings of cytomegalic cells and inclusion bodies.

Intestinal Tuberculosis

•  Features:
  • Terminal ileitis, weight loss, and fever.
  • Endemic regions or immunosuppression increase suspicion.
• Investigations:
  • Biopsy: Caseating granulomas, acid-fast bacilli staining, TB PCR or culture.

Amoebiasis

• Mimics CD with diarrhea and ileocecal inflammation.
• Investigations:
  • Stool testing for Entamoeba histolytica.

Malabsorption Syndromes

Coeliac Disease

•  Features:
  • Diarrhoea, weight loss, and abdominal pain, resembling CD.
• Investigations:
  • Serology: Tissue transglutaminase-IgA antibody.
  • Biopsy: Villous atrophy and crypt hyperplasia.

Lactose Intolerance

•  Features:
  • Diarrhoea, bloating, and flatulence after dairy ingestion.
• Investigations:
  • Hydrogen breath test.

Functional Disorders

Irritable Bowel Syndrome (IBS)

•  Features:
  • Abdominal pain, diarrhea, and bloating without systemic symptoms or inflammation.
• Investigations:
  • Normal fecal calprotectin, CRP, and ileocolonoscopy findings.

Ischemic and Structural Conditions

Ischemic Colitis

•  Features:
  • Left-sided abdominal pain with bloody diarrhea.
• Risk factors: Atherosclerosis, hypoperfusion states.
• Investigations:
  • Colonoscopy: Mucosal friability, segmental ischemia.

Diverticular Colitis

• Inflammation restricted to interdiverticular mucosa.
• Investigations:
  • Colonoscopy: Inflammation sparing diverticular orifices.

Appendicitis

• Mimics CD with right lower quadrant pain and fever.
• Investigations:
  • Imaging: CT or ultrasound confirms inflammation limited to the appendix.

Neoplasms and Other Rare Conditions

Colorectal Cancer

• Mimics CD with weight loss, obstruction, or altered bowel habits.
• Investigations:
  • Colonoscopy with biopsy.
  • Imaging: CT or MRI for staging.

Common Variable Immunodeficiency (CVID)

•  Features:
  • Chronic diarrhoea, abdominal pain, and weight loss.
• Investigations:
  • Serum immunoglobulin levels.

Endometriosis

•  Features:
• Cyclical abdominal pain in women of reproductive age.
• Investigations:
  • Laparoscopy.

Radiation Colitis

• History of pelvic radiation.
• Investigations:
  • Colonoscopy: Ulcerations and mucosal friability.

Providing Information and Support

Tailored information

• Provide age-appropriate, culturally sensitive, and literacy-level-suitable advice.
• Resources should address:
  • Nature and prognosis of CD.
  • Impact on growth and puberty in children.
  • Implications for fertility and sexual health.
  • Importance of smoking cessation to reduce disease activity.

Comprehensive support

• Explain treatment options, monitoring requirements, and potential side effects.
• Discuss body image concerns, especially for patients undergoing surgery or living with chronic disease.
• Address concerns about school or workplace accommodations, transitions between paediatric and adult services, and social interactions.

Multidisciplinary input

• Engage the patient, family members, and multidisciplinary teams (gastroenterologists, dietitians, surgeons) in care planning.

Inducing Remission

Monotherapy

Conventional glucocorticosteroids

• First-line therapy for initial presentations or single exacerbations.
• Effective for controlling inflammation and achieving remission.

Budesonide

• Considered for mild ileal or right-sided colonic disease.
• Provides lower systemic side effects compared to conventional steroids but is less effective.

Aminosalicylates

• May be used for mild disease if glucocorticosteroids are contraindicated.
• Less effective than steroids but with fewer adverse effects.

Enteral nutrition

• Especially beneficial for children and adolescents to promote growth and reduce systemic side effects.
• Exclusive enteral nutrition is an option for remission induction.

Add-On Therapy

Azathioprine/Mercaptopurine

• Add to glucocorticosteroids for patients experiencing frequent exacerbations (>2/year) or those unable to taper steroid doses.
• TPMT activity testing is essential to reduce the risk of myelosuppression.

Methotrexate

• Alternative for patients intolerant to thiopurines or with TPMT deficiency.
• Effective for steroid-sparing and remission induction but requires careful monitoring due to hepatotoxicity and teratogenicity.

Biological Therapies

Infliximab and adalimumab

• Indicated for severe, refractory disease or fistulising CD.
• Patients must be monitored for infection risks, including tuberculosis and hepatitis reactivation.

Combination therapy

• Combining biologics with immunosuppressants (e.g. infliximab + azathioprine) is more effective for inducing remission.
• Increases the risk of immunosuppression-related complications.

Maintaining Remission

Thiopurines

• Effective for corticosteroid-dependent remission maintenance.
• Azathioprine or mercaptopurine is preferred for maintaining remission achieved with steroids.

Methotrexate

• Reserved for patients intolerant to thiopurines or those requiring corticosteroid-sparing agents.
• Administer intramuscularly or subcutaneously, with careful monitoring of liver and bone marrow function.

Biologics

• Continue the same agent used for induction if effective.
• Alternatives like ustekinumab or vedolizumab are considered for patients unresponsive to TNF-alpha inhibitors.

Surgical remission maintenance

• Postoperative maintenance with azathioprine ± metronidazole is effective for preventing recurrence in ileocolonic CD.

Post-Surgical Maintenance

Medication

• Azathioprine alone or in combination with metronidazole for 3 months postoperatively to maintain remission.
• Biologics are not routinely recommended unless started preoperatively.

Monitoring

• Regular endoscopic evaluation to detect early recurrence.
• Nutritional optimisation and surveillance for complications like short bowel syndrome are critical.

Surgical Interventions

Indications for surgery

• Early surgery is an option for patients with refractory ileal disease or growth failure.
• Address complications like strictures, fistulas, or obstruction.

Stricture management

• Balloon dilation for short, simple strictures accessible via colonoscopy.
• Surgical resection for more complex or refractory strictures.

Monitoring and Risk Assessment

Bone health

• Monitor bone density in children with risk factors such as low BMI or chronic steroid use.

Infection screening

• Screen for tuberculosis, hepatitis B/C, and opportunistic infections in patients starting immunosuppressive or biological therapy.

Side effect monitoring

• Regular laboratory tests for neutropenia, hepatotoxicity, and thiopurine metabolite levels to ensure safety.

Special Populations

Paediatrics

• Emphasise growth monitoring, nutritional support, and age-appropriate interventions.
• Address pubertal delays and psychosocial concerns.

Pregnancy

• Optimise disease control before conception.
• Discuss the safety of biologics and thiopurines during pregnancy and lactation.

Elderly

• Carefully evaluate the risks of immunosuppression and comorbidities in older adults.

Emerging Treatments and Research

Future directions

• Investigate novel agents like JAK inhibitors and S1P modulators for refractory CD.
• Explore the role of microbiome-based therapies, including faecal microbiota transplantation and probiotics.
• Evaluate cost-effectiveness and long-term safety of biosimilars in real-world settings.

Natural History

Relapse and remission

• Most patients experience periodic exacerbations interspersed with remission.
• Approximately 10–20% of individuals achieve prolonged remission following their initial presentation.
• The relapse rate within the first year after diagnosis is approximately 50%, with about 10% developing a chronic relapsing course.

Surgical intervention

• Surgical management is common, particularly for complications like strictures, fistulas, or abscesses.
• Up to 90% of patients with ileocolonic disease may require surgery within 10 years of diagnosis, though 50% may not need additional surgical interventions.
• Gastroduodenal CD often necessitates gastrojejunostomy bypass in about one-third of cases with obstruction.

Complications and disease progression

• Early indicators of severe disease include young age at diagnosis (<40 years), perianal disease, and initial corticosteroid requirement.
• Proximal small bowel involvement correlates with higher mortality rates compared to ileal or ileocecal disease.

Mortality

General observations

• CD is associated with a slight decrease in life expectancy, particularly with disease duration, socioeconomic factors, and post-surgical complications.
• Population studies indicate a 1.4 to 1.5-fold increased mortality compared to the general population.

Causes of death

• Gastrointestinal malignancies, including colorectal cancer, are leading causes of disease-related mortality.
• Other causes include non-Hodgkin's lymphoma, sepsis, pulmonary embolism, and complications of gastrointestinal disease.

Impact of surgery

• The risk of mortality increases in the immediate postoperative period, especially within 30 days of gastrointestinal surgery.
• Post-surgical recurrence is common, with an endoscopic recurrence rate of approximately 90% at the anastomosis site.

Corticosteroid impact

• Current corticosteroid use is associated with higher mortality, highlighting the importance of tapering and minimising long-term dependence.

Prognostic Factors

High-risk characteristics

• Age <30 years at diagnosis.
• Active or recent tobacco use.
• Elevated inflammatory markers (CRP or faecal calprotectin).
• Extensive bowel involvement or long-segment disease.
• Deep colonic ulcers visualised on colonoscopy.
• Presence of perianal disease or extraintestinal manifestations (e.g. arthritis, uveitis).
• History of bowel resections or short intervals between surgeries.

Genetic markers

• Variants in the CARD15 gene have been linked to specific disease patterns, including ileal disease, stricture formation, and early-onset CD.
• Ongoing research may enhance prognostication and targeted treatment approaches.

Surveillance and Long-Term Management

Endoscopic monitoring

• Surveillance endoscopy is recommended within 6–12 months post-surgery and every 1–3 years subsequently if no endoscopic recurrence is observed.

Post-surgical recurrence

• Risk factors for early recurrence include smoking, short duration from diagnosis to surgery, penetrating disease, and multiple resections.
• Preventive strategies, including smoking cessation and biologic therapy, may mitigate recurrence risk.

Emerging trends

• Improved therapies have reduced the risk of gastrointestinal cancer in CD.
• Ongoing advancements offer better disease control and outcomes.

Intestinal Complications

Strictures and obstruction

• Aetiology: Repeated inflammation leads to bowel wall thickening and fibrosis, causing luminal narrowing.
• Clinical features: Symptoms include abdominal pain, nausea, vomiting, and bowel obstruction.
• Management:
  • Acute cases: Bowel rest, nasogastric suction, corticosteroids.
  • Chronic strictures:
    • Endoscopic balloon dilation for strictures ≤4 cm.
    • Surgical options include strictureplasty (for segments <10 cm) or resection for longer or complex strictures.
    • Colonic strictures often require segmental resections or subtotal colectomy.
• Cancer risk: Strictureplasty sites may harbour carcinoma.

Fistulas and abscesses

• Fistulas: Abnormal tracts connecting bowel loops or other organs. Types include enteroenteric, enterovesical, and enterocutaneous.
• Abscesses: Localised collections presenting with fever, pain, and abdominal tenderness.
• Management:
  • Antibiotics and drainage for abscesses.
  • Surgical intervention for complex fistulas or recurrent infections.

Toxic megacolon

• Definition: Non-obstructive colonic dilatation with systemic toxicity due to severe colitis.
• Management:
  • Intensive medical therapy: Corticosteroids, antibiotics, or immunosuppressants.
  • Surgical colectomy in refractory cases.

Malignancy

• Increased risk: Patients with longstanding colonic CD have a heightened risk of colorectal cancer, anal squamous cell carcinoma, and small bowel adenocarcinoma.
• Surveillance: Regular endoscopic monitoring for dysplasia.

Short bowel syndrome

• Aetiology: Extensive surgical resections leave insufficient bowel for nutrient absorption.
• Management: Parenteral nutrition, hydration, and electrolyte supplementation.

Extraintestinal Complications

Musculoskeletal

• Osteoporosis and fractures:
  • Causes: Corticosteroid use, malabsorption, inflammation.
  • Prevention: Calcium and vitamin D supplementation, bisphosphonates, smoking cessation.
• Arthropathy:
  • Types: Peripheral arthritis, axial arthritis (e.g., ankylosing spondylitis).
  • Treatment: NSAIDs, corticosteroids, or biologics (e.g., infliximab).

Hepatobiliary

• Cholelithiasis:
  • Causes: Bile salt malabsorption and fat malabsorption.
  • Incidence: Affects up to one-third of patients with ileitis or ileal resections.
• Primary sclerosing cholangitis (PSC):
  • Rare but severe liver involvement.
  • Ursodeoxycholic acid is occasionally used.
• Fatty liver and liver abscess:
  • Caused by malnutrition, corticosteroids, or portal pyaemia.

Renal

• Nephrolithiasis:
  • Pathophysiology: Hyperoxaluria due to fat malabsorption, acidosis, and dehydration.
  • Types: Calcium oxalate and uric acid stones.
  • Prevention: Adequate hydration and dietary modifications.

Dermatologic

• Erythema nodosum: Tender red nodules, often linked to disease flares.
• Pyoderma gangrenosum: Ulcerative lesions requiring corticosteroids or biologics.

Ophthalmologic

• Manifestations: Episcleritis, uveitis, iritis.
• Management: Topical or systemic corticosteroids and ophthalmologic referral.

Haematologic

Anaemia

• Causes: Chronic inflammation, iron deficiency, vitamin B12 or folate deficiency.
• Management: Treat underlying cause, nutritional supplementation.

Thrombosis

• CD is associated with a hypercoagulable state.
• Preventive measures include anticoagulation in high-risk patients.

Treatment-Related Complications

Immunomodulators

• Adverse effects:
  • Azathioprine: Risk of sepsis and lymphoma.
  • Methotrexate: Myelosuppression, hepatotoxicity, pulmonary fibrosis.
• Monitoring:
  • Regular blood counts and liver function tests.
  • Avoid live vaccinations and assess prior exposure to infections (e.g., varicella, hepatitis B).

Biologics

• Tumour necrosis factor (TNF)-alpha inhibitors:
  • Risks: Tuberculosis reactivation, opportunistic infections.
  • Pre-treatment: Screening for latent tuberculosis, hepatitis B and C.
  • Long-term: Slightly increased risk of malignancies (e.g., lymphoma).

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