Crohn's Disease

Crohn's disease is a chronic, relapsing transmural granulomatous inflammatory disorder that can affect any part of the gastrointestinal tract from mouth to anus, most commonly the terminal ileum and colon, characterized by skip lesions and a tendency to form fistulas, strictures, and abscesses.

II. Epidemiology

East Asian IBD (including Hong Kong) differs from Western IBD ^[1]:

Feature	East Asia	West
*Gender in CD*	*M > F*	F > M
*Family clustering*	*Less*	More prominent
*Surgery rates*	*Lower (5-8%)*	Higher (~30-50% at 10 years)
*Extraintestinal manifestations*	*Fewer*	More common
*Primary sclerosing cholangitis with UC*	*Less*	More common
*Penetrating and perianal disease in CD*	*Higher rates*	Lower
CD location	*More ileocolonic CD*	More ileal-predominant

High Yield

For HKU exams: remember that Hong Kong CD patients tend to be male, have more perianal/penetrating disease, less family history, and fewer extraintestinal manifestations compared to Western populations. This is a commonly tested distinction.

Established Risk Factors for Crohn's Disease

Smoking — Smoking is a risk factor for Crohn's disease (but NOT ulcerative colitis — in fact, smoking is PROTECTIVE for UC) ^[2]
- Why? Smoking impairs Th1/Th17 immune regulation, reduces mucosal blood flow, and alters the gut microbiome. CD is predominantly a Th1/Th17-mediated disease, and smoking amplifies this pathway. UC is predominantly Th2-mediated, and nicotine appears to enhance mucus production and colonic mucosal blood flow, which are protective in UC.
- Smoking doubles the risk of CD, increases the risk of relapse, the need for surgery, and post-operative recurrence
Prior appendicectomy — Prior appendicectomy is a risk factor for Crohn's disease (conversely, protective for UC) ^[2]
- The mechanism is debated: appendicectomy may alter the gut immune landscape, removing an immune regulatory organ (the appendix contains significant lymphoid tissue)
Family history — Family history of IBD ^[2]
- First-degree relative with CD increases risk 5-20×
- Concordance rate in monozygotic twins ~50% for CD (vs. ~15% for UC), indicating a stronger genetic component in CD
- Less family clustering in East Asia compared to West ^[1]
Infectious gastroenteritis — Infectious gastroenteritis in the prior 1 year is a risk factor ^[2]
- Likely through disruption of the mucosal barrier and alteration of the gut microbiome, triggering an abnormal immune response in genetically susceptible individuals
Drug history
- NSAIDs can trigger flares (they inhibit protective prostaglandin synthesis in the gut, disrupt the mucosal barrier, and may increase intestinal permeability) ^[3]
- Oral contraceptives — modest increased risk, possibly through microvascular thrombosis
- Isotretinoin — previously suggested but now considered controversial
Diet
- High refined sugar, low fibre, high fat, high processed food diets are associated with increased risk
- Western diet in Asia may explain the rising incidence
Genetic factors
- NOD2/CARD15 gene mutation (chromosome 16) — the most well-established genetic association with CD (particularly ileal disease and stricturing phenotype)
  - NOD2 is an intracellular receptor for bacterial muramyl dipeptide. Mutation → defective innate immune response to gut bacteria → paradoxical chronic inflammation
- ATG16L1 and IRGM genes — involved in autophagy (cellular "self-eating" of damaged organelles/bacteria). Mutations impair bacterial clearance
- IL23R gene — involved in Th17 differentiation
- 200 susceptibility loci identified by GWAS

Smoking and IBD — The Classic Exam Question

Students frequently confuse this: Smoking is BAD for Crohn's, GOOD for UC. The mnemonic: "Crohn's = Cigarettes Cause it; UC = cigarettes are Useful (protective)." However, obviously you would never recommend smoking for UC patients!

IV. Anatomy and Function (Relevant to CD)

Understanding the anatomy is critical because CD's transmural, skip-lesion pattern directly determines its clinical manifestations and complications.

Layer	CD Involvement	Clinical Consequence
Mucosa	Ulceration, aphthous ulcers	Bleeding, malabsorption
Submucosa	Oedema, fibrosis	Stricture formation
Muscularis propria	Inflammation, fibrosis	Dysmotility, strictures, obstruction
Serosa	Inflammation reaches surface	Fistulae (track to adjacent structures), abscesses (walled-off perforation), adhesions

This is why fistula formation and abscess formation are features of CD but NOT UC ^[1]^[2]. In UC, inflammation is limited to mucosa/submucosa and never penetrates deeply enough to form fistulae.

V. Etiology and Pathophysiology

The pathogenesis of Crohn's disease involves a complex interplay of four key elements. Think of it as a "perfect storm":

VI. Classification

This is the standard classification system for CD, classifying by Age at diagnosis, Location, and Behaviour:

Category	Code	Description	*Frequency*
Age at onset	A1	*< 16 years old*
	A2	*17-40 years old*	Most common
	A3	*> 40 years old*
Disease Location	L1	*Ileal*	*24.5%*
	L2	*Colonic*	*32.3%*
	L3	*Ileocolonic*	*43.1% (most common)*
	L4	*Isolated upper GI disease*	Can be added to L1-L3
Disease Behaviour	B1	*Non-stricturing, non-penetrating (inflammatory)*	*65.2%*
	B2	*Stricturing*	*25.1%*
	B3	*Penetrating*	*16.1%*
	P	*Perianal fistula or abscess*	*24.5% (modifier, added to B1-B3)*

Montreal Classification — What It Means Clinically

B1 (Inflammatory) → predominantly mucosal inflammation → responds best to medical therapy
B2 (Stricturing) → chronic inflammation → fibrosis → luminal narrowing → bowel obstruction. "Stricture" = "strictus" (Latin: drawn tight). Fibrostenotic strictures do NOT respond to anti-inflammatory drugs and need endoscopic dilatation or surgery
B3 (Penetrating) → transmural inflammation breaches the serosa → fistulae and abscesses. "Penetrating" = the disease penetrates through the full wall
P (Perianal) → added as a modifier to any B classification, e.g., B3P = penetrating disease with perianal involvement

Behaviour of disease determines management strategy ^[4]:

Inflammatory disease (30%): medical treatment, surgical resection if refractory
Fibrostenotic disease (50%): endoscopic dilatation, surgical (stricturoplasty or resection for small bowel, resection for large bowel)
Fistulising disease (20%): drainage, medical (combined anti-TNF + azathioprine), surgical resection

Subtype	Frequency	Key Features
*Ileal disease*	*24.5%*	B12/bile salt malabsorption, RIF pain, obstruction
*Ileocaecal disease*	*43.1%*	Most common; mimics appendicitis
*Colonic disease*	*32.3%*	More like UC; bloody diarrhoea
*Perianal disease*	*8.4%* (isolated) / *up to 40%* (any CD)	Fistulae, abscesses, skin tags
Others	Rare	CD confined to mouth, stomach, duodenum, or rectum

	*Mild*	*Moderate*	*Severe*
*CDAI*	*150-220*	*220-450*	*> 450*
General	Ambulatory, eating and drinking	Intermittent vomiting	Cachexia with *BMI < 18*
Weight loss	*< 10%*	*> 10%*
CRP	Usually > ULN	*> ULN*	Increased
Examination		*Tender mass, no overt obstruction*	*Abscess formation, obstruction*
Treatment response		*Ineffective for mild disease treatment*	*Persistent symptoms despite intensive treatment*

VII. Clinical Features

The clinical features of CD are directly determined by the disease location, behaviour, and severity. The transmural nature of inflammation is the root cause of most unique CD features.

A. Symptoms

a) Chronic Diarrhoea (most common presenting symptom)

Mechanism: Multifactorial:
- Mucosal inflammation → impaired water/electrolyte absorption → osmotic and secretory diarrhoea
- Bile salt malabsorption (terminal ileal disease) → bile salts reach colon → stimulate colonic secretion (secretory diarrhoea)
- Bacterial overgrowth in strictured/stagnant loops → deconjugation of bile salts → fat malabsorption → steatorrhoea
- Fistulae bypassing absorptive surface → reduced transit time
CD diarrhoea is typically non-bloody (unless colonic involvement) — this contrasts with UC where bloody diarrhoea is the hallmark
When the colon is involved, there may be fresh blood in stool and urgency ^[5]

b) Abdominal Pain

Typically right lower quadrant (RLQ) pain — because the terminal ileum/ileocaecal region is the most commonly affected ^[2]^[6]
Mechanism: Transmural inflammation → serosal irritation → localised peritoneal pain in the RLQ
Pain may be colicky (crampy, intermittent) — especially with stricturing disease → partial small bowel obstruction (SBO) → waves of peristalsis against obstruction
Post-prandial pain — eating stimulates peristalsis → bowel contracts against a stricture → pain → patient stops eating → weight loss (this is "food fear")
The RLQ mass from ileocaecal CD is a classic exam finding

c) Nausea and Vomiting

More common in CD than UC because CD can affect the upper GI tract
In moderate-severe disease: intermittent vomiting ^[2]
In stricturing disease: vomiting due to small bowel obstruction

d) Perianal Symptoms

Perianal disease in up to 40% of CD patients ^[1]
Perianal pain, discharge (purulent or faecal), swelling
Symptoms include: perianal abscess (throbbing pain, swelling, fever), fistula-in-ano (persistent discharge), anal fissure (sharp pain on defecation), skin tags (painless but characteristic — "sentinel tags")
Mechanism: Transmural inflammation extends through the rectal wall into the perianal tissues → tracks through tissue planes → abscess → fistula

e) Oral Symptoms

Oral aphthous ulcers — small, painful ulcers on the buccal mucosa, gums, or tongue
Mechanism: CD can affect any part of the GI tract including the oral mucosa; aphthous ulcers represent mucosal inflammation
Present in ~10% of CD patients; may be the first manifestation

f) Dysphagia / Odynophagia

Rare; occurs with oesophageal or gastric CD
Upper GI CD with stricturing may cause dysphagia

Extraintestinal manifestations are fewer in East Asian CD compared to Western CD ^[1], but they still occur and are high-yield for exams.

EIMs can be classified by whether they correlate with disease activity or are independent of disease activity:

EIMs that Correlate with Disease Activity (flare when gut disease flares):

EIM	Features	Mechanism
Erythema nodosum	Painful, red, raised nodules on the shins (anterior tibiae)	Immune complex deposition in subcutaneous fat (panniculitis); Type III hypersensitivity
Oral aphthous ulcers	Painful oral ulcers	Direct mucosal inflammation (same disease process)
Peripheral arthropathy (Type 1 — large joint, pauciarticular)	Acute, asymmetric, affects large joints (knees, ankles, wrists); non-destructive	Circulating immune complexes deposit in synovium; molecular mimicry between gut bacterial antigens and joint antigens
Episcleritis	Red, uncomfortable eye without visual loss	Immune complex-mediated inflammation of the episcleral tissue

EIMs Independent of Disease Activity (persist even when gut disease is quiescent):

EIM	Features	Mechanism
Pyoderma gangrenosum	Deep, necrotic ulcer with violaceous undermined border, often on legs; pathergy	Neutrophilic dermatosis; aberrant neutrophil chemotaxis
Axial arthropathy (sacroiliitis, ankylosing spondylitis)	Low back pain/stiffness, worse in morning, improves with activity; HLA-B27 associated	Molecular mimicry + genetic predisposition; shared antigens between gut and sacroiliac joint
Primary sclerosing cholangitis (PSC)	Progressive fibrosis of intra- and extrahepatic bile ducts → cholestasis → cirrhosis	Autoimmune; aberrant gut-homing lymphocytes colonise the liver; *less common with UC in East Asia* ^[1]
Uveitis (anterior)	Painful red eye, photophobia, visual loss	Autoimmune inflammation of the uveal tract
Peripheral arthropathy (Type 2 — small joint, polyarticular)	Symmetric, affects small joints of hands; may be persistent	Immune-mediated

Remembering EIMs

Mnemonic for IBD extraintestinal manifestations: "A PIE SuCKS" — Aphthous ulcers, Pyoderma gangrenosum, Iritis/uveitis, Erythema nodosum, Sclerosing cholangitis, Cholelithiasis (CD), Kidney stones (CD), Sacroiliitis/ankylosing spondylitis

EIMs Specific to CD (due to terminal ileal disease/malabsorption):

EIM	Mechanism
Cholelithiasis (gallstones)	Terminal ileal bile salt malabsorption → depleted bile salt pool → cholesterol supersaturation of bile → cholesterol gallstones ^[2]
Nephrolithiasis (oxalate kidney stones)	Normally, calcium binds oxalate in the gut lumen → excreted in stool. With bile salt malabsorption, free fatty acids bind calcium instead → free oxalate is absorbed → hyperoxaluria → calcium oxalate renal stones
B12 deficiency	Terminal ileum is the sole site of B12 absorption → megaloblastic anaemia, neuropathy

B. Signs

Deficiency	Sign	Why?
Iron	Koilonychia, angular stomatitis, glossitis	Chronic blood loss + malabsorption in duodenal/proximal jejunal CD
B12	Glossitis, peripheral neuropathy, subacute combined degeneration	Terminal ileal disease/resection → B12 not absorbed
Folate	Megaloblastic anaemia	Proximal small bowel malabsorption or methotrexate use
Vitamin D	Bone tenderness, proximal myopathy	Fat malabsorption (bile salt deficiency) → fat-soluble vitamin malabsorption
Zinc	Acrodermatitis, poor wound healing	Small bowel inflammation → impaired absorption
Protein	Oedema (hypoalbuminaemia), muscle wasting	Protein-losing enteropathy + malabsorption + catabolism

Feature	*Crohn's Disease*	*Ulcerative Colitis*
*Distribution*	*GI tract, rectal sparing, skip lesions*	*Colon & rectum, continuous*
*Depth*	*Full thickness (transmural)*	*Mucosal/submucosal*
*Fistula*	*Common (intestinal/perianal)*	*Never*
*Benign stricture*	*Common*	*Rare*
*Perianal disease*	*Up to 40%*	*Rare*
Histology pattern	*Focal patchy*	*Diffuse continuous*
*Granuloma*	*✓ (MUST exclude TB)*	✗
Goblet cells	*Preserved (✓)*	*Depleted (✗)*
Distorted crypt architecture	✓	✓
Cryptitis and crypt abscess	✓	✓
Endoscopic: skip lesions	✓	✗
Endoscopic: ulcers	*Solitary, deep and focal* (rose-thorn, longitudinal, serpiginous)	*Shallow*
*Fistula formation*	✓	✗
*Abscess formation*	✓	✗
Pseudopolyps	Less common	✓
Smoking	Risk factor	Protective
Appendicectomy	Risk factor	Protective

The Cobblestone Mucosa

In CD, deep longitudinal and transverse ulcers criss-cross across the mucosa, with oedematous islands of surviving mucosa in between. This gives the "cobblestone" appearance on endoscopy — literally looks like a cobblestone street. This does NOT occur in UC because UC ulcers are shallow and continuous.

IX. Specific Pathological Features Explained

Deep, narrow, penetrating ulcers that project into the bowel wall on barium studies
Named because they look like thorns on a rose stem
Reflect the transmural nature of CD ulceration

High Yield Summary

Definition: CD = chronic relapsing-remitting IBD with patchy, transmural inflammation affecting any part of the GI tract (mouth to anus); most commonly affects the terminal ileum

Epidemiology: Peak onset 3rd decade; globally F > M but M > F in East Asia; rising incidence in HK; urban > rural, higher socioeconomic status

East Asia differences: More male, less family clustering, lower surgery rates, fewer EIMs, less PSC with UC, higher penetrating/perianal disease

Risk Factors: Smoking (CD risk, UC protective), prior appendicectomy (CD risk, UC protective), family history, prior GI infection, NSAIDs, NOD2/CARD15 mutations

Montreal Classification: Age (A1/A2/A3) + Location (L1 ileal / L2 colonic / L3 ileocolonic (43.1%, most common) / L4 upper GI) + Behaviour (B1 inflammatory 65.2% / B2 stricturing 25.1% / B3 penetrating 16.1% / P perianal 24.5%)

Key Clinical Features: Chronic non-bloody diarrhoea, RLQ pain, weight loss/cachexia, perianal disease (up to 40%), oral aphthous ulcers; EIMs (erythema nodosum, pyoderma gangrenosum, uveitis, sacroiliitis, PSC); nutritional deficiencies (B12, iron, vitamin D)

Key Signs: RLQ tenderness/mass, perianal skin tags/fistulae/abscesses, cachexia, clubbing, anaemia

Pathology: Non-caseating granulomas (must exclude TB), skip lesions, deep focal ulcers, cobblestone mucosa, transmural inflammation, creeping fat, fistulae and abscesses (never in UC)

Behaviour determines management: Inflammatory (30%) → medical; Fibrostenotic (50%) → endoscopic/surgical; Fistulising (20%) → drainage + biologics + surgery

Active Recall - Crohn's Disease: Definition to Clinical Features

Differential Diagnosis of Crohn's Disease

When a patient presents with features suggestive of Crohn's disease — chronic diarrhoea, abdominal pain (especially RLQ), weight loss, perianal disease, or extraintestinal manifestations — you need a systematic approach to the differential. The key question is: "What else could cause chronic intestinal inflammation, RLQ pain, or bloody diarrhoea?"

The differentials can be organised anatomically and by mechanism. Think about what CD looks like clinically and what other conditions mimic those features.

Differential Diagnoses — Detailed Breakdown

This is the most important differential because both are IBD and share many features ^[2].

Feature	Crohn's Disease	Ulcerative Colitis
Distribution	GI tract, rectal sparing, skip lesions	Colon & rectum, continuous ^[1]
Depth	Full thickness (transmural)	Mucosal/submucosal ^[1]
Fistula	Common (intestinal/perianal)	Never ^[1]
Benign stricture	Common	Rare ^[1]
Perianal disease	Up to 40%	Rare ^[1]
Hematochezia	Rare	Common
Passage of mucus/pus	Rare	Common
Abdominal mass	Sometimes	Rare
Small bowel involvement	✓	✗ (except backwash ileitis)
Histology	Focal patchy, transmural, non-caseating granulomas	Diffuse continuous, mucosal/submucosal, no granulomas
Endoscopy	Solitary, deep, focal ulcers; cobblestone; skip lesions	Shallow ulcers; pseudopolyps; continuous
Serological markers	ASCA positive	pANCA positive ^[3]
Smoking	Risk factor	Protective
Appendicectomy	Risk factor	Protective

Why is this distinction important?

Surgical approach differs fundamentally: UC is curable by total proctocolectomy (remove colon + rectum → disease is gone). CD is NOT curable by surgery — disease can recur anywhere in the GI tract, so the surgical principle is preservation of bowel length ^[4]. If you misdiagnose UC as CD, you might under-operate; if you misdiagnose CD as UC and create an ileal pouch-anal anastomosis (IPAA), Crohn's recurrence in the pouch is devastating.
Indeterminate colitis (10%) — when you genuinely cannot distinguish: treat surgically as UC ^[1]^[2]

ASCA vs pANCA

A helpful mnemonic: ASCA = Affects CD ("A" for "Another bowel disease, not UC"). pANCA = prototypical of UC. Neither is diagnostic alone, but the combination ASCA+/pANCA− strongly suggests CD, while ASCA−/pANCA+ suggests UC.

This is the critical differential in Hong Kong where TB is endemic ^[5]^[2].

Feature	Crohn's Disease	Intestinal TB
Site	Terminal ileum (most common)	Terminal ileum / ileocaecal (also most common)
Granulomas	Non-caseating, small, scattered	Caseating, large, confluent
Ulcers	Longitudinal (along mesenteric border)	Transverse/circumferential (perpendicular to long axis — because TB spreads via lymphatics which run transversely)
Strictures	Common	Common
Fistulae	Common	Less common
Systemic features	Possible low-grade fever	Fever, night sweats, weight loss (more prominent)
CXR	Usually normal	May show pulmonary TB (but can be negative)
AFB stain/culture	Negative	May be positive (low sensitivity ~30%)
TB PCR	Negative	Higher sensitivity
Histology	Non-caseating, < 5 granulomas per section	Caseating, > 5 granulomas per section, larger granulomas
Response to anti-TB therapy	No improvement	Improves within 2-3 months

Why does intestinal TB mimic CD?

Both cause granulomatous inflammation of the terminal ileum with strictures and mass formation. The ileocaecal region is the site of highest lymphoid tissue concentration — TB bacilli are ingested, survive in macrophages, and preferentially settle where lymphoid tissue is abundant (Peyer's patches), just like the immune-mediated process of CD.

Key approach in Hong Kong:

MUST do AFB smear and culture with sensitivity testing on all biopsies to rule out enteric TB ^[2]^[3]
If histology is equivocal, a therapeutic trial of anti-TB therapy (2 months) is sometimes given before committing to CD diagnosis and immunosuppressive therapy (which would be disastrous in TB)
Tissue TB PCR (GeneXpert) has improved sensitivity
IGRA (QuantiFERON) and Mantoux test assess exposure but cannot distinguish latent from active TB

TB Before Biologics

Before starting any biologic therapy (anti-TNF, etc.) for CD, you MUST screen for latent TB (CXR + IGRA/Mantoux). TNF-α is critical for granuloma maintenance in TB — anti-TNF therapy can reactivate latent TB with devastating consequences (disseminated TB). This is especially important in Hong Kong.

Infections including E. coli, Salmonella, Shigella, Campylobacter, Yersinia and amebiasis should be excluded with stool studies ^[2].

Organism	Key Features	Why It Mimics CD
Yersinia enterocolitica	Acute ileitis, RLQ pain, mesenteric lymphadenitis; may be misdiagnosed as acute appendicitis ^[5]	Affects terminal ileum; can cause granulomatous inflammation; presents identically to acute CD flare
Campylobacter	Bloody diarrhoea, fever, abdominal cramps	Colonic inflammation on endoscopy can look like IBD
Salmonella	Enteritis with watery → bloody diarrhoea, fever	Ileocaecal involvement
Shigella	Dysentery (bloody mucoid diarrhoea), tenesmus	Rectal/colonic inflammation mimics UC or colonic CD
E. coli O157:H7	Bloody diarrhoea, may cause HUS	Colonic inflammation and ulceration
Entamoeba histolytica	Amoebic dysentery, flask-shaped ulcers in colon	Chronic colitis, may form amoeboma (inflammatory mass)
Cytomegalovirus (CMV)	Immunosuppressed patients; deep colonic ulcers	Can superinfect existing IBD; deep ulcers mimic CD

Why must you exclude infection before diagnosing CD?

Starting immunosuppressive therapy (steroids, biologics) in a patient with undiagnosed infection is dangerous — you would worsen the infection
Infective colitis is self-limiting (days to weeks) while CD is chronic and relapsing
A single episode of bloody diarrhoea with positive stool cultures = infection, not IBD
However, note that infectious gastroenteritis in the prior 1 year is actually a risk factor for triggering CD onset in genetically susceptible individuals ^[2]

Key discriminating factors:

Acute onset (days) vs. chronic/relapsing course (weeks-months) in CD
Travel history (TOCC — travel, occupation, contacts, clusters)
Stool cultures, microscopy for ova/parasites, C. difficile toxin PCR ^[3]

Presents with chronic abdominal pain and altered bowel habits in the absence of an organic cause ^[2].

Feature	Crohn's Disease	IBS
Inflammatory markers	Elevated (CRP, ESR, faecal calprotectin)	Normal
Nocturnal symptoms	Common (wakes patient from sleep)	Rare (functional disorders spare sleep)
Weight loss	Common	Absent
Rectal bleeding	Possible (colonic disease)	Absent
Fever	Possible	Absent
Endoscopy/histology	Abnormal	Normal
Faecal calprotectin	Elevated	Normal (< 50 μg/g)

Why is this differential important?

IBS is extremely common (10-15% of the population) while CD is rare (~0.1%). Many patients initially diagnosed with IBS actually have early or mild CD. The key is that IBS has no objective evidence of inflammation — if inflammatory markers are elevated, you must investigate further.
Faecal calprotectin is the most sensitive marker of intestinal inflammation in IBD ^[3] and is the best screening test to differentiate IBD from IBS. A normal faecal calprotectin essentially excludes active IBD.

Differential	Key Distinguishing Feature from CD
UC	Continuous colonic inflammation, no skip lesions, no fistulae, rectal always involved, pANCA+, shallow ulcers
Intestinal TB	Caseating granulomas, transverse ulcers, AFB+/PCR+, responds to anti-TB Rx; must exclude in HK
Infective colitis	Acute onset, positive stool cultures, self-limiting, TOCC history
C. difficile	Recent antibiotics, pseudomembranes, toxin PCR positive
IBS	No inflammation (normal CRP, calprotectin, endoscopy)
Lactose intolerance	Symptoms only with dairy, no inflammation
CRC	Progressive, older age, mass/stricture on imaging, biopsy shows adenocarcinoma
Ischaemic colitis	Acute onset, elderly, CVS risk factors, watershed zones
Appendicitis	Acute single episode, migratory pain, no chronic diarrhoea
Diverticular disease	Acute episodic, diverticula on CT, older age, right-sided in Asia
Radiation colitis	History of pelvic radiotherapy, distribution matches radiation field
NSAID enteropathy	History of NSAID use, resolves on cessation

This will be covered in detail in the Diagnosis section, but the key tests used to differentiate CD from its mimics include:

Investigation	Purpose
Faecal calprotectin	Differentiates inflammatory (IBD) from non-inflammatory (IBS) causes — most sensitive marker of intestinal inflammation in IBD ^[3]
Stool cultures, ova/parasites, C. difficile toxin PCR	Excludes infectious causes ^[2]^[3]
ASCA / pANCA	ASCA common in CD; pANCA common in UC ^[3]
Colonoscopy + biopsy	Gold standard — tissue diagnosis; MUST do AFB smear and culture ^[2]
CXR, IGRA, Mantoux	Excludes pulmonary/latent TB
CT/MR enterography	Evaluates small bowel disease (strictures, fistulae, abscesses) — helps distinguish CD from lymphoma, TB
MRI anal canal	Evaluates perianal CD ^[3]
Anti-tTG antibodies	Excludes coeliac disease

High Yield Summary — Differential Diagnosis of Crohn's Disease

Intestinal TB — AFB smear/culture/PCR on all biopsies; CXR; IGRA
Infection — stool cultures, ova/parasites, C. difficile toxin
Malignancy — colonoscopy with biopsy (CRC); cross-sectional imaging (lymphoma)

Only after excluding these can you confidently diagnose CD and start immunosuppression.

Active Recall - Crohn's Disease: Differential Diagnosis

References

^[1] Lecture slides: Inflammatory bowel disease.pdf (p2, p6, p9) ^[2] Senior notes: felixlai.md (Inflammatory bowel disease — Crohn's disease, differential diagnosis and diagnosis sections) ^[3] Lecture slides: Inflammatory bowel disease.pdf (p10, p11, p12) ^[4] Senior notes: maxim.md (Inflammatory bowel disease — surgical principles) ^[5] Lecture slides: GC 195. Lower and diffuse abdominal pain RLQ problems; pelvic inflammatory disease; peritonitis and abdominal emergencies.pdf (p20 — Ileitis) ^[6] Lecture slides: GC 186. Lower and diffuse abdominal painfresh blood in stool.pdf (p8 — Causes of PR bleeding) ^[7] Senior notes: maxim.md (Colorectal cancer — risk factors) ^[8] Senior notes: maxim.md (Ischaemic bowel — clinical features and pathogenesis) ^[9] Senior notes: maxim.md (Acute appendicitis — differential diagnosis) ^[10] Senior notes: maxim.md (Diverticular disease — clinical features)

Diagnostic Criteria, Algorithm, and Investigations for Crohn's Disease

While there is no single set of universally accepted "diagnostic criteria" like the Jones criteria for rheumatic fever, the diagnosis of CD rests on demonstrating a characteristic constellation of findings:

Domain	Characteristic CD Finding	Why This Matters
Clinical	Chronic (> 6 weeks) diarrhoea, abdominal pain, weight loss, perianal disease	Acute diarrhoea (< 2 weeks) = likely infectious, not IBD
Endoscopic	Skip lesions, deep focal ulcers, cobblestone mucosa, aphthous ulcers, strictures, fistulae ^[2]	These patterns reflect the patchy transmural nature of CD
Histological	Focal patchy transmural inflammation, non-caseating granulomas (must exclude TB), preserved goblet cells, crypt architectural distortion ^[2]	Granulomas found in ~30-50% of biopsies; their absence does NOT exclude CD
Radiological	Small bowel wall thickening, strictures, fistulae, creeping fat, mesenteric lymphadenopathy on CTE/MRE	Demonstrates transmural and extraluminal disease invisible to endoscopy
Biochemical	Elevated inflammatory markers (CRP, ESR), elevated faecal calprotectin, ASCA positivity	Supports inflammatory aetiology; helps differentiate from IBS

No Granuloma ≠ No Crohn's

A very common student mistake: expecting granulomas on every CD biopsy. Non-caseating granulomas are found in only ~30-50% of mucosal biopsies. Their presence strongly supports the diagnosis, but their absence does NOT exclude CD. The overall pattern of focal patchy chronic inflammation with architectural distortion is more important than the granuloma alone.

Investigation Modalities — Detailed Breakdown

II. Laboratory Tests

Blood tests: CBP, CRP, ESR, albumin, ferritin ^[3]

Test	Expected Finding in CD	Pathophysiological Basis	Clinical Utility
CBP (Complete Blood Picture)	Anaemia (microcytic or macrocytic), leucocytosis, thrombocytosis	Microcytic: iron deficiency from chronic GI blood loss or impaired duodenal iron absorption. Macrocytic: B12 deficiency from terminal ileal disease. Leucocytosis: active inflammation or infection/abscess. Thrombocytosis: reactive — platelets are acute phase reactants (IL-6 stimulates thrombopoiesis)	Detects anaemia type and guides supplementation; leucocytosis may suggest complication ^[2]
CRP (C-reactive protein)	Elevated (typically higher in CD than UC) ^[2]	CRP is synthesised by hepatocytes in response to IL-6 (released from activated macrophages in the inflamed bowel wall). CD's transmural inflammation generates more IL-6 than UC's superficial inflammation → higher CRP	CRP monitoring under therapy is useful to document efficacy of anti-inflammatory treatment ^[2]. Rapidly responsive (half-life ~19 hours) — good for acute monitoring
ESR (Erythrocyte Sedimentation Rate)	Elevated	Fibrinogen (acute phase protein) coats RBCs → increased rouleaux formation → faster sedimentation. Less specific than CRP, slower to change	Trends over time; less useful for acute monitoring
Albumin	Hypoalbuminaemia	Malabsorption and protein-losing enteropathy ^[2] — inflamed mucosa leaks albumin into the gut lumen; reduced hepatic synthesis (negative acute phase reactant); reduced oral intake	Marker of nutritional status and disease severity. Low albumin = poor prognosis
Ferritin	Low (iron deficiency) or normal/high (acute phase reactant in active inflammation)	Ferritin stores iron but is also an acute phase reactant. In active CD, ferritin may be falsely "normal" despite true iron deficiency because inflammation elevates it	Check transferrin saturation alongside ferritin to assess true iron stores
Serum iron and vitamin B12	Iron ↓, B12 ↓	Iron: malabsorption (duodenal/proximal jejunal disease) + chronic blood loss. Vitamin B12 deficiency: terminal ileum is the SOLE site of B12 absorption → ileal disease or resection → deficiency ^[2]	Guides supplementation; B12 deficiency suggests ileal involvement

Additional blood tests:

LFT: Elevated ALP/GGT may suggest primary sclerosing cholangitis (PSC); assess liver function before starting hepatotoxic drugs (methotrexate, azathioprine)
RFT: Baseline renal function; oxalate nephropathy in terminal ileal disease
Hepatitis serology, HIV, TB testing ^[3] — mandatory before starting immunosuppression/biologics
- Hepatitis B reactivation can occur with anti-TNF therapy → screen HBsAg, anti-HBc, anti-HBs
- HIV affects treatment decisions and differential diagnosis
- TB screening (CXR + IGRA) is essential before anti-TNF therapy because TNF-α is critical for granuloma maintenance in TB

Marker	Association	Sensitivity/Specificity	Interpretation
Anti-Saccharomyces cerevisiae antibodies (ASCA)	Common in Crohn's disease (CD) ^[2]^[3]	Sensitivity ~50-60% for CD; Specificity ~90%	ASCA = antibodies against the yeast Saccharomyces cerevisiae. Present in ~60% of CD. Suggests abnormal immune response to gut microbes
Perinuclear antineutrophil cytoplasmic antibodies (pANCA)	Common in ulcerative colitis (UC) ^[2]^[3]	Sensitivity ~60-70% for UC	pANCA targets perinuclear antigens in neutrophils. Present in ~65% of UC, ~10-15% of CD
Anti-OmpC antibody	Potential serological marker for IBD ^[2]	Less well-established	Antibody against outer membrane porin C of E. coli

How to use serology in practice:

ASCA+/pANCA− → strongly suggests CD
ASCA−/pANCA+ → strongly suggests UC
Neither is diagnostic alone — they are adjuncts, not definitive tests
Most useful in indeterminate colitis to help lean towards CD or UC

Stool examination: culture, Cl. difficile toxin, calprotectin ^[3]

Test	What It Detects	Why It's Important
Faecal calprotectin	Neutrophil-derived protein, 60% of neutrophil cytosol ^[3]	Most sensitive marker of intestinal inflammation in IBD ^[3]. Well correlated with endoscopic disease activity ^[3]. Predicts disease relapse, post-op relapse ^[3]. A normal result (< 50 μg/g) essentially excludes active IBD — brilliant for differentiating IBD from IBS without invasive endoscopy
Stool culture	E. coli O157:H7, Salmonella, Shigella, Yersinia, Campylobacter ^[2]	Must exclude infectious colitis before diagnosing CD
Microscopy	Ova, parasites ^[2]	Excludes parasitic infection (amoebiasis, giardiasis)
Antigen detection	E. coli O157:H7, Entamoeba, Cryptosporidium, Giardia ^[2]	More sensitive than microscopy for protozoa
C. difficile toxin PCR	Clostridium difficile toxin A (enterotoxin) and B (cytotoxin) ^[2]^[3]	Must be considered in patients treated with antibiotics ^[2]. Can superinfect IBD patients on immunosuppression — always check before escalating therapy for a "flare"

Faecal Calprotectin — The Gatekeeper Test

Think of faecal calprotectin as the gatekeeper to endoscopy. In a young patient with chronic diarrhoea:

Calprotectin < 50 μg/g → IBD is very unlikely → think IBS, lactose intolerance → avoid invasive endoscopy
Calprotectin > 50 μg/g (especially > 250) → significant intestinal inflammation → proceed to endoscopy

It's also invaluable for monitoring: rising calprotectin in a patient in clinical remission predicts relapse before symptoms appear, allowing pre-emptive treatment escalation.

III. Endoscopy

Endoscopy is the cornerstone of CD diagnosis because it allows direct visualisation of the mucosa AND tissue sampling for histology.

Colonoscopy is the primary endoscopic investigation for both UC and CD ^[3].

Technique and requirements:

Ileocolonoscopy — the scope must be passed through the ileocaecal valve to intubate the terminal ileum, as this is the most commonly affected site in CD. A colonoscopy that does not examine the terminal ileum is incomplete for IBD evaluation.
Biopsy should be taken from the left and right colon and rectum even if normal in appearance to assess for microscopic inflammation ^[2]
Multiple biopsies from at least 5 sites (terminal ileum, ascending colon, transverse colon, descending colon, rectum) — this is essential because CD can have microscopic inflammation even where the mucosa looks macroscopically normal
MUST do AFB smear and culture with sensitivity testing to rule out enteric TB ^[2] — this is mandatory in Hong Kong

Endoscopic findings in CD ^[2]:

Finding	Description	Pathophysiological Basis
Skip lesions	Skip areas of involvement with segments of normal-appearing bowel interrupted by large areas of disease ^[2]	CD starts at discrete Peyer's patches → doesn't spread continuously
Aphthous ulcers	Small, shallow, round ulcers with erythematous halo; earliest endoscopic lesion	Focal inflammation at lymphoid follicles; earliest visible mucosal damage overlying Peyer's patches
Solitary, deep and focal ulceration ^[2]	Deep, linear or serpiginous ulcers	Transmural inflammation erodes deeply (unlike shallow UC ulcers which are limited to mucosa)
Cobblestone appearance	Polypoid mucosal changes; deep linear ulcers = "cracks"; inflamed tissues = "stones" ^[2]	Deep longitudinal and transverse ulcers criss-cross → oedematous surviving mucosa islands resemble cobblestones
Fistulae	Openings visible on mucosal surface	Transmural inflammation breaches serosa → tracks to adjacent structures
Strictures	Luminal narrowing — scope may not be able to pass	Chronic transmural inflammation → fibrosis → stricture
Abscesses	May see purulent material or localised swelling	Walled-off transmural perforation
Rectal sparing	Rectum appears normal	CD typically spares the rectum (unlike UC which always starts there)

Contrast with UC endoscopic findings:

Feature	CD	UC
Pattern	Skip lesions	Uniform and continuous lesions
Mucosa	Cobblestone, deep ulcers	Hyperemic mucosa, diffuse granularity, touch friability, petechiae ^[2]
Ulcers	Deep, focal	Shallow ^[2]
Other	Fistulae, abscesses, strictures	Pseudopolyps (hypertrophied masses of mucous membrane resembling polyps) ^[2]

Biopsy specimens from colonoscopy undergo H&E staining. The key histological findings in CD:

Finding	Description	Diagnostic Significance
Focal patchy involvement	Inflammation is not continuous; some crypts involved, adjacent crypts normal	Distinguishes from UC (diffuse continuous)
Transmural inflammation	Inflammatory infiltrate extends through all bowel wall layers	Only seen in full-thickness surgical specimens, not mucosal biopsies; on mucosal biopsy, submucosal inflammation may be hinted at
Non-caseating granulomas	Organised collections of epithelioid macrophages ± multinucleated giant cells without central necrosis	Found in ~30-50%; highly suggestive of CD when present. MUST exclude TB — TB granulomas are caseating ^[2]
Goblet cells preserved (not depleted) ^[2]	Goblet cells (mucus-secreting) are maintained	In UC, goblet cells are depleted due to diffuse mucosal damage
Distortion of crypt architecture	Crypt branching, shortening, disarray	Indicates chronic inflammation (not just acute) — distinguishes IBD from self-limiting infectious colitis
Crypt abscess and atrophy	Neutrophils accumulate within crypt lumina	Active inflammation; seen in both CD and UC (not specific)
Crypt branching, shortening and disarray ^[2]	Chronic architectural change	Chronicity marker; absent in acute infections

Additional stains and tests on biopsy:

AFB smear and culture — mandatory to exclude TB ^[2]
TB PCR (GeneXpert) — higher sensitivity than AFB stain
CMV immunohistochemistry — if deep ulcers in immunosuppressed patient (CMV superinfection)

V. Cross-Sectional Imaging

Endoscopy only sees the mucosal surface. CD is transmural — you need cross-sectional imaging to see the full bowel wall, extraluminal complications (abscesses, fistulae), and mesenteric involvement.

MRE is the preferred imaging modality for small bowel CD assessment ^[3].

Feature	Details
Principle	MRI with oral contrast (to distend the small bowel lumen) + IV gadolinium (to enhance the inflamed bowel wall)
Advantages	No ionising radiation (crucial for young CD patients who need repeated imaging over a lifetime); excellent soft tissue contrast; superior for detecting fistulae and perianal disease
Key findings	Wall thickening (> 3mm), mural enhancement (indicating active inflammation), restricted diffusion (active inflammation), strictures, fistulae, abscesses, creeping fat, mesenteric lymphadenopathy, "comb sign" (engorged vasa recta in the mesentery = increased blood flow to inflamed segment)
Active vs fibrostenotic	MRE can distinguish active inflammatory strictures (wall enhancement, oedema, restricted diffusion) from fibrostenotic strictures (no enhancement, dark on T2) — this distinction guides therapy (anti-inflammatory drugs vs. surgery/dilatation)

CTE is an alternative to MRE ^[3].

Feature	Details
Principle	CT with oral contrast + IV contrast
Advantages	Faster, more widely available, better for detecting abscesses and evaluating for complications in acute settings
Disadvantages	Ionising radiation — cumulative dose is a concern in young patients with chronic disease; less sensitive for perianal disease
Key findings	Same as MRE: wall thickening, enhancement, strictures, fistulae, abscesses, "fat stranding" (haziness of mesenteric fat = inflammation)
When to use over MRE	Acute presentations (faster), claustrophobic patients, when MRI is unavailable, evaluation of extra-intestinal complications

Test	Indication	Key Findings
CXR	Indicated in patients presenting with fever or if perforation is suspected ^[2]; also for TB screening ^[3]	Pneumoperitoneum (free air under diaphragm = perforation); pulmonary TB (upper lobe infiltrates, cavitation)
AXR	Indicated to evaluate for colonic calibre ^[2]	Toxic megacolon: total or segmental non-obstructive dilatation of colon ≥ 6 cm or caecum > 9 cm with systemic toxicity ^[2]; small bowel obstruction (dilated loops, air-fluid levels); thumb-printing (mucosal oedema)

Study	Findings	Current Role
Barium enema	Detects aphthous ulcers, strictures, perforations with fistula tracts ^[2]	Largely replaced by colonoscopy and CTE/MRE
Small bowel follow-through (SBFT)	Nodularity, strictures and ulceration; "cobblestone" appearance; "string sign" due to luminal narrowing ^[2]	Largely replaced by MRE/CTE and capsule endoscopy; still useful if cross-sectional imaging is unavailable

VI. Disease Activity Assessment

Once the diagnosis is established, quantifying disease activity guides treatment decisions.

Severity	CDAI Score	Features
Remission	< 150	Asymptomatic
Mild	150-220	Ambulatory, eating and drinking, weight loss < 10%, CRP usually > ULN
Moderate	220-450	Intermittent vomiting, weight loss > 10%, CRP > ULN, tender mass, no overt obstruction, ineffective treatment for mild disease
Severe	> 450	Cachexia with BMI < 18, abscess formation, obstruction, persistent symptoms despite intensive treatment

The CDAI incorporates 8 variables over 7 days: number of liquid stools, abdominal pain rating, general well-being, extraintestinal features, anti-diarrhoeal use, abdominal mass, haematocrit, and body weight. It's primarily a research tool — in clinical practice, a combination of symptoms, CRP, calprotectin, and endoscopic findings guides management.

After completing the diagnostic workup, the patient is classified using the Montreal classification ^[1]:

Category	Code	Description	Frequency
Age	A1	< 16 years
	A2	17-40 years	Most common
	A3	> 40 years
Location	L1	Ileal	24.5%
	L2	Colonic	32.3%
	L3	Ileocolonic	43.1%
	L4	Isolated upper GI	Modifier
Behaviour	B1	Inflammatory (non-stricturing, non-penetrating)	65.2%
	B2	Stricturing	25.1%
	B3	Penetrating	16.1%
	P	Perianal	24.5%

The Montreal classification is established using the combination of endoscopy (location, fistulae), imaging (strictures, fistulae, abscesses), and clinical assessment (perianal disease). It is dynamic — a patient initially classified as B1 may progress to B2 or B3 over time, requiring reclassification and treatment adjustment.

Before initiating therapy (especially immunosuppression/biologics), the following must be completed:

Screening	Purpose
Hepatitis serology (HBsAg, anti-HBc, anti-HBs) ^[3]	HBV reactivation risk with immunosuppression
HIV testing ^[3]	Affects treatment and differential
TB testing (CXR, IGRA/Mantoux) ^[3]	Latent TB reactivation with anti-TNF agents
Varicella zoster immunity	Risk of severe varicella on immunosuppression
Immunization status ^[3]	Live vaccines contraindicated on biologics — complete before starting
Baseline TPMT/NUDT15	Before azathioprine/6-MP — genetic polymorphisms cause fatal myelosuppression
Baseline LFT, RFT, CBP	Hepatotoxicity (methotrexate, azathioprine), myelosuppression monitoring

Mandatory TB Screening Before Biologics

In Hong Kong, where TB is endemic, EVERY patient must have TB screening (CXR + IGRA) before starting anti-TNF therapy. Failure to do so can lead to reactivation of latent TB with potentially fatal disseminated disease. TNF-α is essential for forming and maintaining granulomas that contain TB bacilli — blocking TNF-α releases the contained bacteria.

High Yield Summary — Diagnosis of Crohn's Disease

No single diagnostic test exists — diagnosis requires integration of clinical, endoscopic, histological, radiological, and biochemical findings.

Key investigations:

Blood tests: CBP, CRP, ESR, albumin, ferritin, B12, iron ^[3]
Stool: culture, C. difficile toxin, calprotectin ^[3] — calprotectin is the gatekeeper (most sensitive marker, correlates with activity, predicts relapse)
Serology: ASCA (CD), pANCA (UC) ^[3]
Ileocolonoscopy + biopsies from all segments + AFB smear/culture ^[2] — gold standard
MRE or CTE for small bowel evaluation ^[3]; MRI anal canal for perianal disease ^[3]
Pre-treatment: Hepatitis serology, HIV, TB testing, immunisation status ^[3]

Endoscopic hallmarks: Skip lesions, deep focal ulcers, cobblestone mucosa, aphthous ulcers, strictures, fistulae

Histological hallmarks: Focal patchy transmural inflammation, non-caseating granulomas (30-50%, must exclude TB), preserved goblet cells, crypt architectural distortion

Disease activity: CDAI (mild 150-220, moderate 220-450, severe > 450) or HBI; CRP and calprotectin for monitoring

Montreal classification at diagnosis: A (age) + L (location) + B (behaviour) + P (perianal modifier)

Active Recall - Crohn's Disease: Diagnosis

References

^[1] Lecture slides: Inflammatory bowel disease.pdf (p2, p8) ^[2] Senior notes: felixlai.md (Inflammatory bowel disease — Crohn's disease, diagnosis section) ^[3] Lecture slides: Inflammatory bowel disease.pdf (p10, p11, p12) ^[4] Senior notes: maxim.md (Inflammatory bowel disease — surgical principles) ^[11] Lecture slides: Inflammatory bowel disease.pdf (p45 — Perianal CD) ^[12] Lecture slides: Inflammatory bowel disease.pdf (p27 — Indications for surgery, HBI)

Management of Crohn's Disease

I. Medical Treatment

The medical management of CD uses drugs with distinct roles: induction (getting the inflammation under control quickly) vs maintenance (keeping it under control long-term). Understanding which drug does what — and why — is fundamental.

Antibiotics ^[2]:

Feature	Details
Indications	Active luminal disease (for primary or adjunctive therapy for colonic CD but NOT isolated small intestine disease); Perianal diseases such as fistula; Septic complications of IBD such as abscess and wound infections ^[2]
Mechanism of action	Efficacy may be due to treatment of an undetected pathogen, bacterial overgrowth or an unsuspected microperforation ^[2] — they reduce the bacterial antigenic load driving the immune response
Examples	Ciprofloxacin / Metronidazole ^[2]
Clinical role	Adjunctive — not primary therapy for most CD. Most useful in perianal disease and septic complications

Why ciprofloxacin and metronidazole specifically?

Metronidazole ("metro" = relating to the uterus historically, but it's actually a nitroimidazole) — effective against anaerobic bacteria and some protozoa. The gut, especially the colon, is an anaerobic environment, so metronidazole targets the predominant colonic flora. Also has immunomodulatory properties.
Ciprofloxacin — a fluoroquinolone effective against gram-negative aerobes. The combination covers a broad spectrum of gut bacteria.

Limitations: Metronidazole causes peripheral neuropathy with prolonged use (damages nerve axons — metallic taste and tingling are early warning signs). Ciprofloxacin can cause tendinopathy.

5-aminosalicylates (5-ASA) ^[2]:

Feature	Details
Role	Initial therapy in patients with mild to moderate Crohn's disease who do not have systemic symptoms based on its relative safety to other drugs ^[2]
Mechanism	Anti-inflammatory effect — 5-ASA acts locally on the intestinal mucosa. It inhibits the lipoxygenase and cyclooxygenase pathways (reduces leukotriene B4 and prostaglandin synthesis), scavenges reactive oxygen species, inhibits NF-κB, and reduces TNF-α production. Think of it as a "topical mucosal anti-inflammatory."
Clinical role	Induction agent only — NO consistent evidence that 5-ASA is effective in maintenance of remission ^[2]. Mesalamine can be used as maintenance after surgical intervention but NOT after medically induced remission ^[2]
Dosage	Mesalamine = 2-4 g/day; Sulfasalazine = 3-6 g/day ^[2]

Key drug distinctions:

Drug	Formulation	Site of Action	Notes
Mesalamine (Pentasa/Asacol)	Oral (various release mechanisms), enema, suppository	Both ileitis and colitis	More commonly used; NOT useful in active diseases (i.e., limited efficacy in moderate-severe CD) ^[2]; Nephrotoxicity is the key adverse effect
Sulfasalazine	Oral	Colitis only	Colonic bacteria must cleave the drug to release the 5-ASA moiety (sulfapyridine is the carrier linked to 5-ASA by an azo bond — colonic bacteria break this bond) ^[2]. Cannot work in the small bowel because the bacteria needed for cleavage are in the colon

Why sulfasalazine only works in the colon — explained from first principles: Sulfasalazine = sulfapyridine + 5-ASA linked by an azo bond. This bond is resistant to gastric acid and small bowel enzymes. Only colonic bacteria (which produce azoreductases) can cleave the bond → 5-ASA is released locally in the colon. For ileal disease, you need mesalamine formulations that release 5-ASA in the small bowel (e.g., Pentasa uses ethylcellulose-coated microgranules that release 5-ASA throughout the GI tract).

Adverse effects:

Mesalamine: Nephrotoxicity ^[2] — interstitial nephritis (monitor renal function)
Sulfasalazine: Nausea, headache, fever, agranulocytosis, pancreatitis, SJS ^[2]. Also associated with "sulfa" allergy and pregnancy complications including kernicterus (crosses placenta) and neural tube defects (inhibits absorption and metabolism of folic acid) ^[2] — always co-prescribe folic acid 5mg daily if using sulfasalazine in women of childbearing age

5-ASA in CD vs UC — An Important Distinction

5-ASA is much more effective in UC than in CD. In UC, 5-ASA is both an induction AND maintenance agent and is the backbone of mild-moderate UC treatment. In CD, 5-ASA has a limited role — only for mild disease, only for induction, and it's NOT effective for maintenance after medical remission. Many students incorrectly apply UC 5-ASA principles to CD. Don't make this mistake.

Glucocorticoids ^[2]:

Feature	Details
Indication	Indicated in patients who do not respond to 5-ASA and antibiotics ^[2] — the workhorse for inducing remission in moderate-severe CD
Clinical role	Induction agent only — Ineffective in maintenance of remission and NOT used for long-term ^[2]
Mechanism	Glucocorticoids suppress the immune system at multiple levels: inhibit NF-κB transcription → reduce pro-inflammatory cytokine production (TNF-α, IL-1, IL-6); reduce leukocyte migration to inflamed tissue; induce apoptosis of T lymphocytes; stabilise lysosomal membranes. They are the most potent non-biologic anti-inflammatory available.

Key drug distinctions:

Drug	Route	Dosage	Special Features
Prednisolone	Oral	40 mg/day reducing by 5 mg/day at weekly intervals; or 20 mg/day for 4 weeks reducing by 5 mg/day at weekly intervals ^[2]	More commonly used ^[2]; systemic effects (Cushingoid, osteoporosis, hyperglycaemia, adrenal suppression)
Budesonide	Oral (modified release)	9 mg/day ^[2]	Indicated for terminal ileum or ileocaecal disease ^[2]; extensive first-pass effect in liver → less systemic side effects but also less effective ^[2]. ~90% hepatic first-pass metabolism → minimal systemic bioavailability
Hydrocortisone	IV	100 mg QDS	Used in acute severe disease (hospital setting)
Methylprednisolone	IV	60 mg/day	Alternative IV steroid

Why budesonide for ileocaecal disease specifically? Budesonide modified-release formulations (e.g., Entocort) are designed to release the drug in the ileum and right colon — exactly where ileocaecal CD occurs. Because of the extensive first-pass hepatic metabolism (~90% is inactivated on first pass through the liver), systemic steroid side effects are minimised. However, this also means it's less potent than prednisolone for widespread or severe disease.

Critical rules about steroids in CD:

Calcium and vitamin D supplements required for osteoprotective effect if prescribed for more than 12 weeks ^[2]
Never use steroids for maintenance — they don't prevent relapse and cause cumulative toxicity (osteoporosis, cataracts, diabetes, adrenal suppression, avascular necrosis)
Steroid-dependent = patient relapses when steroids are tapered or within 3 months of stopping → needs immunomodulator or biologic
Steroid-refractory = no response despite adequate dose → needs escalation to biologic

D. Immunomodulators

Immunomodulators ^[2]:

These are the bridge between steroids (short-term induction) and long-term maintenance. Their onset of action is slow (2-3 months), so they cannot be used alone for acute flares.

Feature	Details
Mechanism	AZA is a prodrug → converted to 6-MP → converted to 6-thioguanine nucleotides (6-TGN) which incorporate into DNA of rapidly dividing immune cells (T lymphocytes) → inhibits purine synthesis → reduces T cell proliferation and clonal expansion. "Azathio-" (sulfur-containing) + "-prine" (purine analogue) — the name tells you it's a purine antimetabolite
Clinical role	Maintenance agent — used to maintain steroid-induced remission and allow steroid withdrawal ("steroid-sparing agent")
Onset	Slow — 2-3 months to reach full effect (because it takes time for the active metabolites to accumulate and for the pool of existing T cells to turn over)
Key screening	TPMT / NUDT15 genotyping BEFORE starting — thiopurine methyltransferase (TPMT) and NUDT15 are enzymes that metabolise thiopurines. Genetic polymorphisms cause deficiency → toxic accumulation of 6-TGN → fatal bone marrow suppression. NUDT15 polymorphisms are particularly common in East Asian populations (including Hong Kong) — up to 2% are homozygous deficient
Adverse effects	Myelosuppression (dose-related and idiosyncratic), hepatotoxicity, pancreatitis (idiosyncratic — occurs in ~3%, usually within first month, contraindication to re-challenge), nausea, increased infection risk, lymphoma risk (especially hepatosplenic T-cell lymphoma in young males on combination AZA + anti-TNF)
Monitoring	Regular CBP (every 1-2 weeks initially, then every 3 months) to detect myelosuppression; LFT

Feature	Details
Mechanism	Folate antagonist — inhibits dihydrofolate reductase (DHFR) → blocks purine and thymidylate synthesis → inhibits rapidly dividing cells. At low doses used in autoimmune disease, the immunosuppressive effect is more complex — it promotes adenosine release (anti-inflammatory) and inhibits pro-inflammatory cytokines
Indication	Indicated in active or relapsing disease refractory to or intolerant of AZA or 6-MP ^[2] — second-line immunomodulator
Clinical role	Both induction and maintenance
Route	SC or IM (oral bioavailability is variable)
Adverse effects	Hepatotoxicity (monitor LFT), pneumonitis, myelosuppression, teratogenicity (ABSOLUTE contraindication in pregnancy — must ensure effective contraception)
Co-prescription	Folic acid 5 mg weekly (on a different day from MTX) to reduce side effects
Note	Methotrexate is NOT effective in UC unlike in Crohn's disease ^[2] — this is an important distinction

E. Biologic Therapies

This is the most important and rapidly evolving area of CD management. Biologics are monoclonal antibodies that target specific components of the inflammatory cascade.

Biologic therapies (Anti-TNFα) ^[2]:

Feature	Details
Indication	Indicated in patients with refractory disease or patients with extra-intestinal manifestations and fistulas ^[2]
Clinical role	Induction agent AND Maintenance agent ^[2] — unlike steroids which are induction-only
Mechanism	TNF-α ("tumour necrosis factor alpha") is the master pro-inflammatory cytokine in CD, driving macrophage activation, granuloma formation, tissue destruction, and fistula formation. Anti-TNF monoclonal antibodies bind and neutralise TNF-α → rapidly suppress inflammation. They also induce apoptosis of TNF-expressing inflammatory cells and promote mucosal healing.

Pre-treatment screening — MANDATORY ^[2]:

MUST screen for TB with CXR / QuantiFERON-TB Gold + HBV infection with HBsAg ^[2]:

Requires TB prophylaxis with isoniazid or rifampicin ^[2] — if latent TB is detected, treat with isoniazid 9 months (or rifampicin 4 months) BEFORE or concurrently with anti-TNF
Requires HBV prophylaxis with entecavir ^[2] — if HBsAg positive or anti-HBc positive, start antiviral prophylaxis to prevent reactivation

Key drugs:

Drug	Structure	Route	Induction	Maintenance	Notes
Infliximab (Remicade)	Chimeric (mouse-human) anti-TNF antibody	IV	5 mg/kg at 0, 2, 6 weeks ^[2]	5 mg/kg Q8 weeks ^[2]	1st line biologic; response quicker and better ^[2]; "chimeric" = part mouse, part human → higher immunogenicity → anti-drug antibody formation
Adalimumab (Humira)	Humanised anti-TNF antibody	SC	160 mg at 0 week, 80 mg at 2 weeks ^[2]	40 mg Q2 weeks ^[2]	Response slower and less effective ^[2]; "humanised" = fully human → lower immunogenicity; convenient SC self-administration

Stopping rules:

Do not stop anti-TNF easily unless there is deep remission of at least 18 months with normal blood and endoscopic parameters ^[2]
Deep remission = clinical remission + biochemical remission (normal CRP, calprotectin) + endoscopic remission (mucosal healing)

Contraindications ^[2]:

Contraindication	Why
Latent untreated or active TB	TNF-α is essential for granuloma formation that contains TB bacilli → anti-TNF → granuloma breakdown → disseminated TB
Lymphoma	Anti-TNF may promote lymphoma progression (TNF-α has some anti-tumour activity)
Heart failure NYHA Class III-IV	TNF-α supports cardiac function in failing hearts paradoxically; anti-TNF worsens outcomes in severe HF
Demyelinating disease (Multiple sclerosis)	Anti-TNF can trigger or worsen demyelination (TNF-α has complex roles in myelin maintenance)
Optic neuritis	Related to demyelinating risk

Adverse effects ^[2]:

Reactivation of infection (e.g. TB/HBV)
Lymphoma (especially hepatosplenic T-cell lymphoma — rare but often fatal, particularly in young males on combination AZA + anti-TNF)
Non-melanoma skin cancer
Infusion reactions (infliximab — acute anaphylactoid reactions; delayed serum sickness-like reactions)
Anti-drug antibodies → loss of response (more common with infliximab due to chimeric structure; co-administration with AZA reduces antibody formation — this is the rationale for combination therapy)

Combination Therapy: Anti-TNF + Immunomodulator

The landmark SONIC trial showed that combination of infliximab + azathioprine was superior to either agent alone for inducing steroid-free remission and mucosal healing in moderate-severe CD. Why? AZA reduces the formation of anti-drug antibodies against infliximab → maintains higher drug levels → better efficacy. This is now standard practice for moderate-severe CD, particularly with infliximab.

For patients who fail or are intolerant of anti-TNF agents:

Drug	Target	Mechanism	Key Indications	Route
Vedolizumab (Entyvio)	α4β7 integrin	Blocks gut-homing of T lymphocytes — α4β7 integrin on T cells binds MAdCAM-1 on gut endothelial cells → T cell migration into gut mucosa. Vedolizumab blocks this → "gut-selective" immunosuppression without systemic immunosuppression	Moderate-severe CD failing anti-TNF; gut-selective → safer profile (less systemic infections)	IV Q8 weeks
Ustekinumab (Stelara)	IL-12/23 (p40 subunit)	IL-12 drives Th1 differentiation; IL-23 drives Th17 differentiation. Both pathways are central to CD pathogenesis. Ustekinumab blocks both → reduces Th1/Th17 inflammation	Moderate-severe CD failing anti-TNF; also effective for extraintestinal manifestations (psoriasis, psoriatic arthritis)	IV loading then SC Q8-12 weeks
Risankizumab (Skyrizi)	IL-23 (p19 subunit)	Selectively blocks IL-23 only (not IL-12) → more targeted than ustekinumab	Moderate-severe CD; increasingly used as first-line biologic in some guidelines	IV loading then SC
Upadacitinib (Rinvoq)	JAK inhibitor (JAK1)	Janus kinase (JAK) inhibitors block intracellular signalling downstream of multiple cytokine receptors. JAK1 inhibition reduces signalling from IL-6, IFN-γ, IL-12, IL-23	Moderate-severe CD; oral administration (advantage)	Oral

The Evolving Biologics Landscape

The field is moving rapidly. In 2025-2026, risankizumab (anti-IL-23) and upadacitinib (JAK1 inhibitor) have emerged as important options. The traditional hierarchy of "try anti-TNF first, then vedolizumab/ustekinumab" is being challenged by head-to-head trials showing comparable or superior efficacy of newer agents. For exams, know anti-TNF agents in detail (they remain the most commonly tested) and be aware of the newer options.

Drug	Class	Mechanism	Notes
Tofacitinib	JAK inhibitor (pan-JAK, primarily JAK1/3)	Blocks multiple cytokine signalling pathways	Approved for UC; NOT approved for CD (failed in CD trials — interesting because it highlights that CD and UC have distinct immunological drivers)
Upadacitinib	Selective JAK1 inhibitor	More selective than tofacitinib	Approved for CD; oral — avoids injections/infusions
Ozanimod	S1P receptor modulator	Traps lymphocytes in lymph nodes → reduces lymphocyte trafficking to the gut	Approved for UC; trials ongoing in CD

II. Surgical Treatment

Surgical treatment is NOT curative in Crohn's disease and is mainly used to treat complications only ^[2].

This is the most important principle. Unlike UC where total proctocolectomy removes ALL diseased tissue (because UC only affects the colon/rectum), CD can recur anywhere in the GI tract after resection. Therefore:

Surgical principles ^[4]:

Preservation of bowel length (should document residual SB length) ^[4] — repeated resections can lead to short bowel syndrome (< 200 cm of remaining small bowel → malabsorption, dependence on TPN)
Conservative and minimal resection as possible ^[2]
Extended resection does not decrease recurrence ^[2] — you don't need wide margins. Even a 2cm margin is sufficient because recurrence is driven by systemic immune factors, not "missed" disease at the resection margin
Bypass is NOT recommended since there is risk of malignant transformation in the bypassed segment ^[2]

Surgical Procedures by Location and Behaviour

Procedure	Indication
Right hemicolectomy	MOST commonly performed ^[2] — because ileocaecal disease is the most common CD location
Total colectomy with ileorectal anastomosis (IRA)	If rectum is spared (functional rectum preserved)
Total proctocolectomy with IPAA	In patients with limited perianal disease
Total proctocolectomy with end ileostomy	If rectum is affected / severely diseased perianal disease

Management strategy for small bowel strictures ^[15]:

If inflammatory → Medical therapy ^[15]
If fibrostenotic → Stricturoplasty preferred; Resection if suspect malignancy or isolated stricture ^[15]

Procedure	Indication	Details
Heineke-Mikulicz stricturoplasty	Short stricture < 10 cm ^[2]	Incision along the length of the stricture → closure perpendicular to the bowel axis (same principle as pyloroplasty) → widens the lumen without removing bowel
Finney stricturoplasty	Long stricture 10-20 cm ^[2]	Bowel is folded into U-shape → side-to-side anastomosis created
Endoscopic balloon dilatation	Distal ileal strictures are sometimes amenable to balloon dilatation ^[2]; also for anastomotic strictures	Less invasive; can be repeated; limited to short strictures (< 4-5 cm) without acute inflammation or fistula
Resection	Suspicion of malignancy; failed dilatation/stricturoplasty	Remove the segment entirely

Why stricturoplasty over resection when possible? Because it preserves bowel length. CD patients may need multiple operations over their lifetime — if you resect every time, you'll eventually cause short bowel syndrome. Stricturoplasty widens the narrowed segment without sacrificing bowel.

Important exception: NO role for stricturoplasty in Crohn's colitis since there is a 7% risk of malignancy over 20 years ^[2] — large bowel strictures in CD should be resected, not stricturoplastied, because of the CRC risk.

Non-operative treatment for partial obstruction applies in several situations including Crohn's disease ^[16] — if the patient has partial SBO from a known CD stricture, initial conservative management (bowel rest, IV fluids, nasogastric decompression) may resolve the episode without surgery.

Enterocutaneous fistula: abnormal communications between 2 epithelialised surfaces ^[4].

Causes: FRIEND ^[4] — Foreign body, Radiation, Inflammation/infection, Epithelialization, Neoplasm, Distal obstruction.

SNAP management principle ^[2]:

Step	Details
S — Sepsis control	Antibiotics + Percutaneous abscess drainage (CT-guided) ^[2]
N — Nutrition support	TPN aids closure of fistula ^[2] — bowel rest reduces fistula output; nutrition prevents catabolism
A — Anatomical location	Imaging to locate fistula: Fistulogram / CT or MR enteroclysis ^[2]
P — Procedure	Medical treatment by Infliximab OR Surgical treatment by en-bloc resection of bowel involving fistula with primary anastomosis and diverting stoma ^[2]

Enterocutaneous fistula specific management ^[4]:

Delineate anatomy of fistula: CT abdomen
Replace fluid and electrolytes, chart fistula output
Wound care, e.g. negative pressure wound therapy (NPWT)
Bowel rest → drugs (loperamide, octreotide) → endoscopic/surgical closure ^[4]

Nutrition is a critical and often underappreciated pillar of CD management:

Modality	Indication	Details
Exclusive Enteral Nutrition (EEN)	First-line induction therapy in paediatric CD (equivalent to steroids); adjunctive in adults	Polymeric formula exclusively for 6-8 weeks → induces remission by altering the gut microbiome and reducing antigenic exposure. Avoids steroid side effects in growing children.
Supplemental nutrition	All CD patients with malnutrition	Iron supplementation (IV preferred if oral intolerant), B12 injections (if terminal ileal disease/resection), vitamin D, calcium, folate
TPN	Fistula management, pre-operative optimisation, short bowel syndrome	Provides bowel rest; aids fistula closure; corrects malnutrition before surgery

Since CD recurs after surgery (endoscopic recurrence at the neo-terminal ileum in ~70-80% at 1 year without prophylaxis), post-operative prophylaxis is essential:

Risk Stratification	Prophylaxis
Low risk (first resection, short stricture, non-smoker)	Mesalamine or surveillance alone
High risk (smoker, penetrating disease, second resection, extensive disease)	Thiopurine (AZA/6-MP) or anti-TNF
Very high risk	Anti-TNF (infliximab/adalimumab)

Colonoscopy at 6-12 months post-surgery to assess for recurrence (Rutgeerts score)
Faecal calprotectin predicts post-op relapse ^[3] — rising calprotectin before symptoms appear allows early intervention

Drug Class	Induction	Maintenance	Key CD Indication	Must-Know Point
Antibiotics	Adjunct	No	Perianal, septic complications, colonic CD	NOT for isolated SB disease
5-ASA	Yes (mild only)	No (unlike UC)	Mild CD without systemic symptoms	Sulfasalazine = colon only
Corticosteroids	Yes	No (never)	Moderate-severe CD	Budesonide for ileocaecal; never long-term
Thiopurines (AZA/6-MP)	No (too slow)	Yes	Steroid-sparing maintenance	Screen TPMT/NUDT15; pancreatitis risk
Methotrexate	Yes	Yes	AZA-intolerant/refractory	Teratogenic; NOT effective in UC
Anti-TNF	Yes	Yes	Moderate-severe, fistulising, EIMs	Screen TB/HBV; contraindicated in HF, MS
Vedolizumab	Yes	Yes	Anti-TNF failure; gut-selective	Slow onset; less effective in fistulising CD
Ustekinumab	Yes	Yes	Anti-TNF failure; also treats skin EIMs	Targets IL-12/23
Surgery	N/A	N/A	Complications, refractory disease	NOT curative; preserve bowel length

High Yield Summary — Management of Crohn's Disease

Principles: Induce and maintain remission; treat-to-target (mucosal healing); smoking cessation; early escalation in high-risk patients.

Medical therapy by role:

Induction only: Corticosteroids (prednisolone, budesonide)
Maintenance only: Thiopurines (AZA/6-MP)
Both: Anti-TNF (infliximab 1st line, adalimumab), vedolizumab, ustekinumab, methotrexate
5-ASA: Induction in mild CD only; NOT effective for maintenance (unlike UC)

Anti-TNF key points: Screen TB (CXR + IGRA) and HBV; prophylaxis if positive. Contraindications: active TB, lymphoma, severe HF, MS. Infliximab = chimeric, IV; Adalimumab = humanised, SC. Don't stop unless deep remission ≥ 18 months.

Surgery: NOT curative; preserve bowel length. Indications: complications (stricture, abscess, fistula, perforation, bleeding), refractory disease (CDAI > 450, HBI > 15), malignancy. 80% ileocaecal CD require surgery — laparoscopic ileocaecal resection is a valid early alternative.

Strictures: Inflammatory → medical; Fibrostenotic → stricturoplasty (SB) or resection (LB). No stricturoplasty in colon (malignancy risk).

Fistulae: SNAP (Sepsis, Nutrition, Anatomy, Procedure). Anti-TNF ± AZA. Enterocutaneous: bowel rest → loperamide/octreotide → surgical closure.

Perianal CD: Drain abscess first → antibiotics + AZA → EUA + seton → infliximab → if partial: adalimumab → if failed: defunctioning stoma ± proctectomy.

Active Recall - Crohn's Disease: Management

References

^[2] Senior notes: felixlai.md (Inflammatory bowel disease — Crohn's disease, treatment section) ^[3] Lecture slides: Inflammatory bowel disease.pdf (p11 — faecal calprotectin) ^[4] Senior notes: maxim.md (Inflammatory bowel disease — surgical management; Surgical procedures for CD) ^[11] Lecture slides: Inflammatory bowel disease.pdf (p45 — Perianal CD) ^[12] Lecture slides: Inflammatory bowel disease.pdf (p27 — Indications for surgery) ^[13] Lecture slides: Inflammatory bowel disease.pdf (p41 — Ileocaecal CD) ^[14] Lecture slides: Inflammatory bowel disease.pdf (p43 — Stevens et al. LIR!C trial data) ^[15] Lecture slides: Inflammatory bowel disease.pdf (p28 — Small bowel stricture) ^[16] Lecture slides: GC 194. Intestinal obstruction colorectal cancer.pdf (p27 — Non-operative treatment) ^[17] Lecture slides: Inflammatory bowel disease.pdf (p49 — Perianal CD algorithm) ^[18] Lecture slides: Inflammatory bowel disease.pdf (p52 — IBD-associated CRC risk factors) ^[19] Lecture slides: Inflammatory bowel disease.pdf (p55 — Management of dysplasia)

Complications of Crohn's Disease

Understanding the complications of CD flows directly from understanding the pathology: transmural inflammation of a chronic, relapsing disease that can affect any part of the GI tract. Almost every complication can be traced back to one of these three features. Let's work through them systematically.

The complications can be organised into:

Luminal/structural complications (direct consequences of transmural inflammation)
Perianal complications
Metabolic/nutritional complications (consequences of malabsorption)
Malignant complications
Extraintestinal manifestations (immune-mediated complications beyond the gut)
Treatment-related complications
Post-surgical complications

I. Luminal / Structural Complications

These are the hallmarks of CD that distinguish it from UC. They all stem from the transmural (full-thickness) nature of CD inflammation.

Fistulas are communication that connect two epithelial-lined organs ^[2].

Pathophysiology — explained from first principles ^[2]:

Transmural inflammation leads to development of sinus tract — the inflammation erodes through the mucosa → submucosa → muscularis → serosa
Sinus tract that penetrates the serosa gives rise to fistulas — once the inflammation breaches the outer wall of the bowel, it can track to any adjacent structure
The sinus tract becomes epithelialised over time (lined by epithelium), which is why fistulae don't heal spontaneously — you can't easily close a tube that has its own lining

Types of fistula and their clinical presentations ^[2]:

Fistula Type	Structures Connected	Clinical Presentation	Why These Symptoms?
Enteroenteric	Bowel loop → bowel loop	Palpable mass; diarrhoea (bypass of absorptive surface)	Inflammatory mass from adherent loops; short-circuiting of intestinal contents
Enterovesical	Bowel → bladder	Urinary symptoms due to UTI; pneumaturia (air in urine); faecaluria (faeces in urine)	Bowel contents (gas, bacteria, faecal material) enter the bladder → recurrent polymicrobial UTIs, air bubbles in urine
Enterovaginal	Bowel → vagina	Passage of gas or faeces through vagina	Bowel contents exit via vagina; extremely distressing for patients
Enterocutaneous	Bowel → skin surface	Drainage of bowel contents to surface of skin	Visible fistula opening on abdominal wall with faeculent/bilious output
Retroperitoneal	Bowel → retroperitoneum	Psoas abscess or ureteral obstruction with hydronephrosis	Inflammatory/infectious material tracks into retroperitoneal space → can compress the ureter or form abscess in the psoas muscle

Enterocutaneous fistula ^[4]^[20]:

Causes: FRIEND ^[4] — Foreign body, Radiation, Inflammation/infection, Epithelialization, Neoplasm, Distal obstruction.

Management follows the SNAP principle ^[2]^[20]:

S — Sepsis control: Abscess drainage, antibiotics ^[20]
N — Nutrition support: High vs low output; Nutritional assessment and support ^[20]
A — Anatomy: CTE or MRE to delineate ^[20]
P — Procedure: Medication adjustment; Closure with biological agents; En-bloc resection of involved bowel and fistula ^[20]

High vs Low Output Fistula

A high-output fistula ( > 500 mL/day) is more likely to be proximal (jejunal) and causes severe dehydration, electrolyte disturbances (hypokalaemia, hyponatraemia, metabolic acidosis), and malnutrition. A low-output fistula ( < 200 mL/day) is more likely to be distal (ileal/colonic) and is more likely to close spontaneously. Output guides the intensity of fluid/electrolyte replacement and nutritional support.

Strictures are common in CD ^[1] — they are listed as a key surgical complication ^[12].

Pathophysiology: Chronic transmural inflammation → fibrosis (replacement of normal tissue with collagen) → progressive luminal narrowing → intestinal obstruction. This is the natural progression of untreated or under-treated CD.

Two types of strictures — this distinction is CRITICAL for management:

Type	Mechanism	MRE Findings	Management
Inflammatory stricture	Active inflammation causing oedema and narrowing	Wall enhancement, T2 hyperintensity (oedema), restricted diffusion	Medical therapy ^[15] — anti-inflammatory drugs can reverse the oedema
Fibrostenotic stricture	Chronic fibrosis causing fixed narrowing	No enhancement, T2 hypointensity (fibrosis, no oedema)	Stricturoplasty preferred; Resection if suspect malignancy or isolated stricture ^[15] — fibrosis does NOT respond to medical therapy

Clinical features of obstruction:

Colicky abdominal pain (waves of peristalsis against the obstruction)
Abdominal distension
Vomiting (bilious if distal to ampulla; faeculent if distal SBO)
Obstipation (complete obstruction) or reduced stool/flatus (partial)
High-pitched/tinkling bowel sounds → later absent bowel sounds

Important points:

NO role for stricturoplasty in Crohn's colitis since there is a 7% risk of malignancy over 20 years ^[2]
Bypass is NOT recommended since there is risk of malignant transformation in the bypassed segment ^[2]
In CD, colonic strictures should be considered malignant until proven otherwise (biopsy essential)

Perianal diseases are common in CD, occurring in up to 40% of patients ^[1]. 24.5% of patients with Crohn's disease have perianal disease and 83% required surgery ^[11].

Perianal Complication	Description	Pathophysiology
Perianal abscess	Acute, tender, fluctuant, erythematous swelling adjacent to the anus	Transmural inflammation of the rectum → tracks through the anorectal spaces → bacterial infection → pus collection
Perianal fistula	More complicated courses of fistula tract ^[11]; persistent purulent or faeculent discharge from an external opening near the anus	An abscess that drains spontaneously or is surgically drained → the track persists and epithelialises → chronic fistula
Anal fissure	Painful linear tear in the anal canal; classically lateral in CD (vs posterior midline in idiopathic)	Transmural inflammation of the anoderm; NOT from mechanical tearing
Skin tags	Large, oedematous, "elephant ear" perianal skin tags	Chronic lymphoedema from obstructed lymphatic drainage in inflamed perianal tissue; virtually pathognomonic of CD
Anorectal stricture	Narrowing of the anal canal/rectum causing difficulty with defecation	Chronic perianal inflammation → fibrosis → stricture

MRI and EAUS are necessary to document before the definitive treatment ^[11] — because the anatomy of perianal fistulae is complex (relationship to sphincter muscles) and determines the surgical approach.

Management: Anti-TNF ± AZA and/or seton drainage ^[11] (see Management section for full algorithm).

III. Metabolic and Nutritional Complications

These arise primarily from terminal ileal disease or resection and chronic inflammation-driven malabsorption.

Complication	Pathophysiology	Clinical Features
Vitamin B12 deficiency	Terminal ileum is the sole site of B12 absorption → ileal disease or resection → no B12 uptake	Megaloblastic anaemia, peripheral neuropathy, subacute combined degeneration of the spinal cord ^[2]; glossitis
Iron deficiency anaemia	Chronic GI blood loss + impaired iron absorption (duodenal/jejunal disease)	Microcytic hypochromic anaemia; fatigue, pallor, koilonychia, angular stomatitis
Anaemia of chronic disease	Chronic inflammation → hepcidin production by liver → hepcidin blocks ferroportin on enterocytes and macrophages → iron sequestration → reduced iron availability for erythropoiesis	Normocytic normochromic anaemia (or microcytic); low serum iron, normal/high ferritin
Fat-soluble vitamin deficiency (A, D, E, K)	Bile salt malabsorption (terminal ileal disease) → impaired fat absorption → fat-soluble vitamins not absorbed	Vitamin D: osteomalacia, osteoporosis; Vitamin K: coagulopathy (prolonged PT/INR); Vitamin A: night blindness; Vitamin E: neuropathy
Steatorrhoea	Bile acid malabsorption due to inflamed or resected terminal ileum; bacterial overgrowth from small bowel strictures and enterocolonic fistula ^[2]	Pale, greasy, smelly and bulky stool that floats on water and difficult to flush ^[2]

IV. Malignant Complications

CRC in IBD patients is preceded by dysplasia. Incidence of CRC in IBD: 18% after 30 years of colitis ^[22].

Pathophysiology: The dysplasia-carcinoma sequence in IBD differs from the sporadic adenoma-carcinoma sequence:

Sporadic CRC: Normal mucosa → adenoma → carcinoma (discrete polyp)
IBD-CRC: Chronic inflammation → flat dysplasia (not a polyp) → carcinoma. The chronic inflammatory milieu generates reactive oxygen species, DNA damage, and promotes clonal expansion of dysplastic cells across a wide field ("field cancerisation")

Risk factors for IBD-associated colorectal neoplasia ^[18]:

Category	Risk Factors
Patient-specific	Primary sclerosing cholangitis; History of colorectal neoplasia; Family history of CRC in first-degree relative; Smoking; Early age of disease onset; Male sex ^[18]
Disease-specific	Disease duration; Disease extent; Cumulative inflammatory burden; Active inflammation endoscopically or histologically ^[18]
Endoscopic features	Stricture (UC, longer disease duration, proximal location, symptoms); Shortened tubular colon; Pseudopolyps ^[18]

CRC Surveillance ^[23]:

AGA guideline 2010 ^[23]:

Started at a maximum 8 years after UC or Crohn's colitis
Optimal surveillance interval not clearly defined
Left-sided or extensive colitis: within 1-2 years after initial screening colonoscopy
After two negative examinations, every 1 to 3 years
Individualised (i.e. presence of other risk factors)
Primary sclerosing cholangitis: yearly
Ulcerative proctitis: not considered at increased risk
Ideally, surveillance colonoscopy should be performed when the disease is in remission

Surveillance methods ^[2]:

Chromoendoscopy — highest yield for dysplasia detection; involves topical application of methylene blue or indigo carmine to enhance mucosal irregularities
High-definition white light colonoscopy — alternative when chromoendoscopy yield is decreased
Narrow band imaging (NBI) — does NOT enhance dysplasia detection ^[2]

These are immune-mediated manifestations occurring outside the GI tract. They were discussed in detail in the Clinical Features section but are also true complications of CD.

Extraintestinal manifestations ^[2]^[1]:

System	Complications	Key Notes
Vascular	Arterial and venous thromboembolism (portal and mesenteric thrombosis / DVT) ^[2]	IBD patients have a 2-3× increased risk of VTE. Mechanism: chronic inflammation → endothelial activation, upregulation of tissue factor, platelet activation, hyperfibrinogenaemia. VTE can occur during flares AND in remission. Prophylactic anticoagulation should be considered during hospital admissions.
Hepatobiliary	Primary sclerosing cholangitis (PSC); Fatty liver; Autoimmune liver disease ^[2]	PSC is more associated with UC but can occur in CD colitis. PSC independently increases CRC risk and is an indication for annual surveillance.
Gastrointestinal	Colorectal cancer ^[2]	See above
Ocular	Uveitis; Episcleritis; Scleritis; Iritis; Conjunctivitis ^[2]	Episcleritis correlates with disease activity; anterior uveitis may be independent. All patients with eye symptoms need urgent ophthalmology review.
Urogenital	Renal stones ^[2]	Calcium oxalate stones (mechanism above); also uric acid stones (from dehydration/diarrhoea → concentrated urine)
Haematology	Autoimmune haemolytic anaemia ^[2]	Rare; warm autoantibodies against RBCs; may be drug-related (sulfasalazine)
Endocrine	Vitamin B12 deficiency ^[2]	Terminal ileal disease/resection (mechanism above)
Dermatological	Erythema nodosum (more common); Pyoderma gangrenosum ^[2]	EN correlates with disease activity; PG is independent. PG can also occur at stoma sites (peristomal pyoderma gangrenosum).
Musculoskeletal	Arthritis; Ankylosing spondylitis; Osteoporosis; Osteomalacia ^[2]	Peripheral arthropathy (Type 1 large joint, correlates with activity; Type 2 small joint, independent). AS is HLA-B27 associated and independent of activity. Osteoporosis from malabsorption + steroids.

VTE in IBD — Often Forgotten

Students often forget that IBD patients have a significantly increased risk of venous thromboembolism (DVT, PE, portal vein thrombosis). This is one of the most dangerous complications. All hospitalised IBD patients should receive VTE prophylaxis (LMWH) unless actively bleeding. IBD is an independent risk factor for VTE even in young patients.

The therapies we use for CD carry their own complications — an unavoidable trade-off:

Treatment	Key Complications	Mechanism
Corticosteroids (long-term)	Osteoporosis, diabetes, cataracts, adrenal suppression, avascular necrosis, Cushing's, growth retardation (paediatric)	Steroids suppress osteoblasts, promote insulin resistance, cause posterior subcapsular cataracts, suppress the HPA axis
Thiopurines (AZA/6-MP)	Myelosuppression, pancreatitis, hepatotoxicity, lymphoma (especially hepatosplenic T-cell lymphoma), increased infections	Myelosuppression from 6-TGN accumulation; pancreatitis is idiosyncratic; lymphoma from chronic immunosuppression
Methotrexate	Hepatotoxicity, pneumonitis, myelosuppression, teratogenicity	Folate antagonism; cumulative hepatotoxicity → fibrosis
Anti-TNF agents	TB reactivation, HBV reactivation, lymphoma, non-melanoma skin cancer, infusion reactions, demyelination, heart failure exacerbation	TNF-α blockade removes TB containment, removes anti-tumour surveillance, triggers autoimmune demyelination in susceptible individuals
Vedolizumab	PML (theoretical, extremely rare — unlike natalizumab which targets α4 integrin non-selectively)	Vedolizumab is gut-selective (α4β7) so PML risk is essentially nil, unlike natalizumab (α4β1 in brain)
Thiopurine + Anti-TNF combination	Hepatosplenic T-cell lymphoma (HSTCL) — rare but almost always fatal, particularly in young males	Dual immunosuppression → profound T-cell suppression → γδ T-cell lymphoproliferation

VII. Post-Surgical Complications

If a stoma is created (ileostomy or colostomy), potential complications include:

Timing	Complication	Notes
Early	Ischaemia/necrosis, retraction, peristomal abscess, high output (ileostomy)	High output → dehydration, electrolyte disturbances
Intermediate	Dermatitis (effluent irritation), granuloma, stenosis, fistula	Fistula: usually ileostomy, especially Crohn's disease ^[21] — CD can recur at the stoma site
Late	Parastomal hernia, prolapse	Parastomal hernia is the most common late complication

Pulling it all together according to the Montreal classification ^[1]:

Behaviour	Complications	Why
B1 (Inflammatory, 65.2%)	Malnutrition, anaemia, EIMs; may progress to B2 or B3 over time	Active inflammation causes systemic effects; ~50% of B1 patients will develop B2 or B3 within 20 years
B2 (Stricturing, 25.1%)	Intestinal obstruction, bacterial overgrowth proximal to stricture, short bowel syndrome (if multiple resections)	Fibrosis narrows the lumen; stagnant bowel proximal to stricture allows bacterial overgrowth
B3 (Penetrating, 16.1%)	Fistulae, abscesses, perforation	Transmural inflammation breaches the serosa
P (Perianal, 24.5%)	Perianal abscess, fistula, stricture, incontinence	Transmural rectal inflammation extends into perianal tissues

Disease Behaviour Progresses Over Time

CD does not stay in one category. A patient initially classified as B1 (inflammatory) may progress to B2 (stricturing) or B3 (penetrating) over time as chronic inflammation leads to fibrosis or transmural damage. This is the rationale for the "top-down" or early aggressive treatment approach — by achieving deep remission early, you may prevent the irreversible structural complications (strictures, fistulae) from developing in the first place.

High Yield Summary — Complications of Crohn's Disease

Luminal complications (all from transmural inflammation):

Fistulae: Enteroenteric (mass), enterovesical (pneumaturia, UTI), enterovaginal (faecal vaginal discharge), enterocutaneous (skin drainage), retroperitoneal (psoas abscess). SNAP management.
Abscesses: Intra-abdominal, retroperitoneal, perianal. CT-guided drainage + antibiotics. Must drain BEFORE biologics.
Strictures: Inflammatory (medical Rx) vs fibrostenotic (stricturoplasty/resection). No stricturoplasty in colon (7% malignancy risk). No bypass (malignant transformation risk).
Perforation: Free → peritonitis → emergency surgery. Contained → abscess.
Toxic megacolon: Colon ≥ 6 cm + systemic toxicity. Diagnosed by AXR. Medical → if fails → emergency colectomy.

Perianal: Up to 40%; 83% need surgery. MRI essential. Anti-TNF ± AZA ± seton.

Metabolic/nutritional: B12 deficiency (terminal ileal), iron deficiency, fat-soluble vitamins, gallstones (bile salt malabsorption → cholesterol supersaturation), kidney stones (hyperoxaluria), metabolic bone disease (vitamin D + steroids), short bowel syndrome.

Malignancy: CRC (18% at 30 years of colitis; preceded by dysplasia; surveillance from 8 years). Risk factors: PSC, disease duration/extent, active inflammation, family history.

EIMs: VTE (2-3× risk — prophylaxis in hospital), PSC, uveitis, erythema nodosum, pyoderma gangrenosum, arthritis/AS, autoimmune haemolytic anaemia.

Treatment-related: Steroid toxicity (osteoporosis, diabetes); thiopurine (myelosuppression, HSTCL); anti-TNF (TB/HBV reactivation, lymphoma).

Post-surgical: Recurrence (70-80% at 1 year without prophylaxis), short bowel syndrome, anastomotic leak/stricture, adhesive SBO, stoma complications.

Active Recall - Crohn's Disease: Complications

References

^[1] Lecture slides: Inflammatory bowel disease.pdf (p6, p8, p9) ^[2] Senior notes: felixlai.md (Inflammatory bowel disease — Crohn's disease, complications and signs/symptoms of complications sections) ^[4] Senior notes: maxim.md (Inflammatory bowel disease — surgical management; Surgical procedures for CD) ^[11] Lecture slides: Inflammatory bowel disease.pdf (p45 — Perianal CD) ^[12] Lecture slides: Inflammatory bowel disease.pdf (p26, p27 — Surgery for CD) ^[13] Lecture slides: Inflammatory bowel disease.pdf (p41 — Ileocaecal CD) ^[15] Lecture slides: Inflammatory bowel disease.pdf (p28 — Small bowel stricture) ^[18] Lecture slides: Inflammatory bowel disease.pdf (p52 — IBD-associated CRC risk factors) ^[20] Lecture slides: Inflammatory bowel disease.pdf (p34 — Enterocutaneous fistula) ^[21] Senior notes: felixlai.md (Short bowel syndrome complications; CRC screening section) ^[22] Lecture slides: Inflammatory bowel disease.pdf (p51 — IBD-associated CRC) ^[23] Lecture slides: Inflammatory bowel disease.pdf (p56 — AGA guideline 2010)