LO 1

ON EXAM — Crohn (mouth-to-anus, transmural, skip lesions, non-caseating granulomas, cobblestone, strictures/fistulas, terminal ileum, smoking WORSENS) vs UC (rectum+continuous, mucosa/submucosa only, crypt abscesses, toxic megacolon, PSC, smoking PROTECTS)

Crohn vs UC — side-by-side

Feature	Crohn Disease	Ulcerative Colitis
Location	Mouth to anus; terminal ileum most common; rectum usually spared	Rectum always involved, extends proximally in colon only
Pattern (continuous/skip?)	Skip lesions (discontinuous)	Continuous
Depth of inflammation	Transmural (all layers)	Mucosa + submucosa only
Gross: mucosal pattern	Cobblestone mucosa, linear serpiginous ulcers, creeping fat	Diffusely erythematous with pseudopolyps; loss of haustra ("lead-pipe")
Gross: wall thickness	Thickened (string sign)	Thinned, friable
Histology buzzword	Non-caseating granulomas (~30% of biopsies); transmural lymphoid aggregates	Crypt abscesses with neutrophils; crypt distortion
Typical stool	Non-bloody diarrhea (± fat malabsorption)	Bloody diarrhea with mucus
Classic complications	Strictures, fistulas, perianal disease, abscesses, B12/fat malabsorption, oxalate stones	Toxic megacolon, PSC, colon cancer
Smoking effect	Worsens Crohn	Protective in UC
Curative surgery possible?	No — recurs at anastomosis	Yes — total colectomy is curative
Th response (Th1 vs Th2)	Th1 / Th17 driven	Th2 driven
Classic serology	ASCA positive, p-ANCA negative	p-ANCA positive, ASCA negative

Crohn gross pathology — 5 buzzword findings

Mucosal surface pattern

Cobblestoning from linear serpiginous ulcers separating edematous mucosa

Creeping fat

Mesenteric fat wraps around serosa (transmural inflammation)

String-sign (on barium study)

Severe luminal narrowing at terminal ileum from stricture/thickening

Wall thickness

Markedly thickened and rigid

Most common segment

Terminal ileum (80%); can involve anywhere mouth → anus

Crohn histology — 4 key findings

Transmural inflammation involves

All 4 layers: mucosa, submucosa, muscularis, serosa

Granulomas — type

Non-caseating epithelioid granulomas

Granuloma presence (% of biopsies)

~30% (absence does NOT rule out Crohn)

Crypt architecture distortion

Present (chronicity); Paneth cell metaplasia in colon

UC gross pathology

Starts at ______ and extends proximally

Rectum (always); continuous extension proximally in colon

Pseudopolyps (what are they?)

Islands of regenerating mucosa between ulcers — NOT true polyps

Backwash ileitis means

Mild inflammation of terminal ileum from reflux of colonic contents (pancolitis only)

Depth of ulcers

Limited to mucosa/submucosa (superficial)

UC histology

Classic finding (neutrophil aggregates in crypts)

Crypt abscesses

Chronicity marker on biopsy

Crypt distortion/branching, basal lymphoplasmacytosis, Paneth cell metaplasia

Granulomas present?

NO — absent (distinguishes from Crohn)

Extraintestinal manifestations of IBD

Eye (2)

Uveitis, episcleritis

Joint (axial + peripheral)

Ankylosing spondylitis / sacroiliitis; migratory peripheral arthritis

Skin (2)

Erythema nodosum, pyoderma gangrenosum

Liver — strongest UC association

Primary sclerosing cholangitis (PSC) — p-ANCA+, beaded ducts, ↑ cholangiocarcinoma risk

Kidney (Crohn) — stone type

Calcium oxalate stones (fat malabsorption → Ca binds fat → free oxalate absorbed)

Biliary (Crohn)

Cholesterol gallstones (terminal ileum disease → bile acid malabsorption)

🪤 TRAP: PSC is strongly associated with UC (not Crohn). Oxalate kidney stones are a Crohn issue (fat malabsorption → Ca binds fat → oxalate free to be absorbed).

LO 1

ON EXAM — toxic megacolon, severe UC complications, IBD-associated colon cancer (different from sporadic: dysplasia first, flat not polypoid, p53 early / APC late, biannual surveillance starting 8 years after diagnosis)

Severe UC complications — 4

Toxic megacolon — diameter

Transverse colon dilation > 6 cm (or cecum > 9 cm)

Toxic megacolon risk

Perforation → peritonitis → shock; high mortality

Fulminant colitis features

>10 bloody stools/day, fever, tachycardia, anemia, hypoalbuminemia, ↑ ESR/CRP

Long-term malignancy

Colorectal adenocarcinoma — risk ↑ with duration > 8 yr, pancolitis, PSC

IBD-associated colon cancer — vs sporadic

Feature	Sporadic CRC	IBD-associated CRC
Precursor lesion	Adenomatous polyp (tubular/villous)	Flat dysplasia in inflamed mucosa
Gross appearance	Polypoid / exophytic	Flat, multifocal, often missed on colonoscopy
Sequence (APC/p53 order)	APC → KRAS → p53 (APC first)	p53 first → later APC (reversed)
Multifocal?	Usually solitary	Often multifocal / synchronous
Location bias	Left colon/rectosigmoid most common	Depends on extent of colitis (often proximal)

Surveillance — IBD with long-standing colitis

Start colonoscopy _______ after diagnosis

8 years after diagnosis of pancolitis (or 12–15 yr if left-sided only)

Interval

Every 1–2 years with random biopsies (4 quadrants q10 cm)

If PSC + UC, start when?

Immediately at PSC diagnosis, then ANNUALLY (highest risk group)

Strongest risk factors (3)

Duration > 8 yr, extent (pancolitis), PSC; also family hx CRC and backwash ileitis

When would you offer colectomy?

Refractory / fulminant UC

Failed medical therapy (steroids, biologics) or severe symptoms — total proctocolectomy curative

Toxic megacolon not responding

If no improvement in 24–72 hr of IV steroids + supportive care → emergent colectomy

High-grade dysplasia or CRC

HGD on biopsy or invasive cancer → prophylactic/therapeutic colectomy

LO 2

ON EXAM — C. difficile pathogenesis (toxins A/B), risk factors (antibiotics + PPIs + hospital), pseudomembranous colitis (volcano lesions), diagnosis (PCR + EIA), treatment (oral vanco/fidaxomicin, NOT metronidazole first-line)

C. difficile microbiology

Organism (gram stain/morphology)

Gram-positive bacillus (rod)

Anaerobic or aerobic?

Obligate anaerobe

Spore-forming?

Yes — forms heat- and alcohol-resistant spores

Reason spores matter

Resist alcohol-based sanitizers → use SOAP & WATER handwashing; environmental persistence

Toxins — the real weapons

Toxin A = __________ (enterotoxin)

TcdA — binds brush border → mucosal injury, fluid secretion

Toxin B = __________ (cytotoxin, more potent)

TcdB — disrupts cytoskeleton (more virulent; key target of NAAT)

Molecular mechanism

Glucosylate/inactivate Rho GTPases → actin depolymerization → cell death

Hypervirulent strain

NAP1/BI/027 — ↑ toxin production, fluoroquinolone resistance, worse outcomes

Risk factors

Highest-risk antibiotic class 1

Clindamycin

Class 2

Fluoroquinolones (cipro, levo)

Class 3

Broad-spectrum cephalosporins (3rd/4th gen)

Class 4

Penicillins (amox-clav, pip-tazo)

Non-antibiotic med risk

PPIs / H2 blockers (loss of gastric acid barrier)

Patient risk

Hospitalization, age > 65, immunosuppression, IBD, prior C. diff

Pseudomembranous colitis

Endoscopic finding

Yellow-white plaques (pseudomembranes) on erythematous mucosa

Microscopic "volcano" lesion

Focal epithelial necrosis with plume of fibrin + neutrophils erupting from crypt

Composition of pseudomembrane

Fibrin, mucus, necrotic epithelium, neutrophils

Diagnostic testing comparison

Test	What it detects	Sens/Spec profile
Stool PCR (NAAT for tcdB)	Toxin B gene (tcdB) DNA — detects organism capable of making toxin	High sensitivity; lower specificity (detects colonization too — must have symptoms)
Stool GDH antigen	Glutamate dehydrogenase (common C. diff antigen — screening)	High sensitivity, LOW specificity (doesn't distinguish toxigenic strains)
Stool toxin EIA	Actual toxin A/B protein in stool (confirms active disease)	High specificity, lower sensitivity — best to CONFIRM true infection

Treatment

First episode, non-severe

Oral vancomycin 125 mg QID × 10 d OR oral fidaxomicin 200 mg BID × 10 d

Severe / fulminant

Oral vancomycin (high-dose) + IV metronidazole; surgical consult if toxic megacolon/perf

Recurrent (≥2nd)

Fidaxomicin or vancomycin taper; bezlotoxumab (anti-toxin B Ab) to prevent recurrence

When to give FMT

After ≥2–3 recurrences despite appropriate antibiotic therapy

⚠️ Metronidazole is NO LONGER first-line for C. diff — use oral vancomycin or fidaxomicin. Stop inciting antibiotic if possible.

LO 3

ON EXAM — false diverticulum vs true, sigmoid predilection, painless lower GI bleed (diverticulosis) vs LLQ pain + fever (diverticulitis), Hinchey classification, NO colonoscopy in acute diverticulitis

True vs false diverticulum

True diverticulum — definition

Outpouching involving ALL layers of the gut wall (mucosa, submucosa, muscularis)

True diverticulum — examples

Meckel diverticulum; cecal diverticulum

False diverticulum — definition

Only mucosa + submucosa herniate through muscularis (pseudo-diverticulum)

Colonic diverticula are _____ (true/false)

False (pseudodiverticula) — herniate through muscularis at vasa recta entry points

Pathophysiology

Weak point (why vasa recta)

Vasa recta penetrate muscularis between taeniae — natural weak points

Most common location

Sigmoid colon (90%)

Why sigmoid (LaPlace's law)

Smallest luminal radius → highest wall tension (T = P × r is reversed; P = T/r means small r → high intraluminal pressure)

Low-fiber Western diet — mechanism

Low-fiber stool → high intraluminal pressure + constipation → mucosal herniation

Diverticulosis vs diverticulitis

Feature	Diverticulosis	Diverticulitis
Symptoms	Usually asymptomatic; painless hematochezia if bleeds	LLQ pain, fever, nausea, altered bowel habits ("left-sided appendicitis")
Classic presentation	Elderly, painless bright red rectal bleeding (most common cause lower GI bleed)	Older adult, acute LLQ pain + fever; palpable mass if abscess
Lab findings	Anemia if chronic bleed; otherwise normal	Leukocytosis, ↑ CRP
Best imaging	Colonoscopy (diagnostic + therapeutic for bleed)	CT with IV/PO contrast (wall thickening, fat stranding, abscess)
Treatment	High-fiber diet; colonoscopy for bleed	Bowel rest + antibiotics (cipro/metronidazole or pip-tazo); IV if severe

Complications

Painless hematochezia source

Rupture of vasa recta at diverticulum neck → brisk lower GI bleed (right colon is most common bleed site even though left side has more diverticula)

Perforation → peritonitis

Free perforation → generalized peritonitis (Hinchey IV = feculent peritonitis)

Abscess (Hinchey)

Pericolic (Ia/Ib) or pelvic (II) walled-off collection

Fistula — most common type

Colovesical fistula (pneumaturia, fecaluria) — sigmoid to bladder, most common in men

Stricture → obstruction

Chronic inflammation → fibrosis → sigmoid stricture → large bowel obstruction

Hinchey classification

Stage	Description
I	Pericolic abscess or phlegmon (Ia = phlegmon; Ib = pericolic abscess)
II	Pelvic, intra-abdominal, or retroperitoneal abscess (distant but walled off)
III	Generalized purulent peritonitis (ruptured abscess)
IV	Generalized FECULENT peritonitis (free perforation of diverticulum)

Management

Uncomplicated (mild)

Outpatient: clear liquids + oral antibiotics (cipro + metronidazole) × 7–10 d

Complicated (abscess > 4 cm)

Admit, IV antibiotics + CT-guided percutaneous drainage

Hinchey III/IV

Emergent surgery (Hartmann procedure: sigmoid resection + end colostomy)

When to do colonoscopy

4–6 weeks AFTER resolution to exclude colorectal cancer — NEVER during acute episode (perforation risk)

🪤 TRAP: Do NOT do colonoscopy during acute diverticulitis (perforation risk). Wait 4–6 weeks after recovery to rule out cancer.

LO 4

ON EXAM — tubular vs villous adenoma (villous = worst), serrated pathway, APC→KRAS→p53 (CIN) vs MMR/MSI (Lynch), right- vs left-sided CRC, iron-deficiency anemia in older males = CRC until proven otherwise

Polyp classification by malignant potential

Polyp type	Malignant potential	Key feature
Hyperplastic polyp	None (benign)	Most common colonic polyp; serrated "saw-tooth" crypts; distal colon/rectum
Tubular adenoma	Low (but real)	Small, pedunculated, tubular glands; most common neoplastic polyp
Tubulovillous adenoma	Intermediate	Mix of tubular and villous architecture
Villous adenoma	HIGHEST (> 30% if > 4 cm)	Sessile, finger-like villi; secretory diarrhea (K+/protein loss)
Sessile serrated (SSA/P)	Moderate — precursor to MSI/MMR CRC	Right colon; BRAF mutation; CpG island methylation; MLH1 silencing
Hamartomatous (juvenile, PJ)	Low individually; syndromic forms (PJS, Juvenile Polyposis) ↑ risk	Juvenile polyp: cystic dilated glands; PJ polyp: arborizing smooth muscle core

Risk features for malignancy in adenoma

Feature 1 — size

> 1 cm (especially > 2 cm)

Feature 2 — histology

Villous architecture (more atypia)

Feature 3 — dysplasia grade

High-grade dysplasia

Villous adenoma — clinical

Classic electrolyte syndrome

McKittrick-Wheelock: secretory diarrhea → HYPOkalemia, HYPOnatremia, prerenal AKI

Typical symptom

Copious watery/mucoid diarrhea, rectal mass, tenesmus

CRC molecular pathways

Pathway	% of sporadic CRC	Mutations (in order)	Classic polyp precursor
Chromosomal instability (CIN)	~85%	APC → KRAS → p53 (+ DCC/SMAD4)	Tubular/villous adenoma
Microsatellite instability (MSI)	~15% (sporadic + Lynch)	MMR gene loss (MLH1, MSH2, MSH6, PMS2) ± BRAF V600E (sporadic)	Sessile serrated adenoma (SSA/P); right-sided

Classic adenoma-carcinoma sequence — mutations

Earliest loss (initiation)

APC (tumor suppressor) — normal mucosa → small adenoma

Then (progression)

KRAS activation → larger adenoma

Then (malignant conversion)

p53 loss → carcinoma (in situ → invasive)

Late (metastasis)

DCC / SMAD4 loss — metastatic behavior

Right-sided vs left-sided CRC

Feature	Right (ascending/cecum)	Left (descending/sigmoid)
Presentation	Iron-deficiency anemia, fatigue, occult blood in stool	Change in bowel habits, hematochezia, obstruction
Growth pattern	Bulky, exophytic ("fungating"), polypoid — wide lumen accommodates	Annular, "napkin-ring" or "apple-core" constrictive lesion
Often detected via	Workup of iron-deficiency anemia / fatigue	Hematochezia or obstructive symptoms; apple-core on barium enema/CT
Obstruction?	Late/rare (wide cecal lumen + liquid stool)	Early (narrow lumen + formed stool)

Hereditary CRC syndromes

FAP — gene / inheritance / polyp count

APC gene on 5q21; autosomal dominant; >100 adenomas; 100% CRC risk → prophylactic colectomy

Lynch (HNPCC) — gene family / pattern

MMR genes (MLH1, MSH2, MSH6, PMS2); AD; few polyps but rapid progression, right-sided, young

Lynch extracolonic cancers (top 2)

Endometrial cancer (#2, up to 60%), ovarian; also gastric, small bowel, urothelial, skin (Muir-Torre)

Peutz-Jeghers — gene / findings

STK11/LKB1; AD; mucocutaneous hyperpigmentation (lips, buccal mucosa); hamartomatous polyps; ↑ GI, breast, ovarian, pancreatic cancer

CRC screening basics

Average-risk start age (USPSTF)

Age 45 (updated from 50)

Colonoscopy interval

Every 10 years if normal (every 3–5 yr if adenomas found)

FIT test interval

Annually

Tumor marker for surveillance

CEA (carcinoembryonic antigen) — for monitoring recurrence, NOT screening

🪤 TRAP: Iron-deficiency anemia in a man > 50 = colon cancer until proven otherwise. Right-sided CRC bleeds occultly; left-sided obstructs early.

LOs 1–4

Q1: Crohn vs UC — histology

A 24-year-old man with chronic RLQ pain, diarrhea, perianal fistula, and iron deficiency undergoes colonoscopy. Terminal ileum biopsy shows transmural lymphoid aggregates and a non-caseating granuloma. Diagnosis?

A) Ulcerative colitis
B) Crohn disease
C) Intestinal TB
D) Behçet disease
E) Ischemic colitis

Correct Answer: B

Crohn disease — terminal ileum involvement, transmural inflammation, fistula, non-caseating granuloma. UC spares the terminal ileum (except backwash ileitis), is mucosa-limited, and never causes granulomas. TB causes caseating granulomas.

Q2: UC complication

A 39-year-old woman with 12-year history of UC presents with fever, severe abdominal distention, and bloody stools. AXR: transverse colon dilated to 8 cm. Which complication?

A) Fistula formation
B) Toxic megacolon
C) Terminal ileitis
D) Diverticulitis
E) Colonic volvulus

Correct Answer: B

Toxic megacolon = colonic dilation > 6 cm + systemic toxicity. Risk of perforation is high. Stop anti-motility agents, aggressive resuscitation, IV corticosteroids; colectomy if failing.

Q3: IBD extraintestinal — PSC

A 32-year-old man with long-standing UC develops pruritus and elevated ALP. MRCP: "beaded" intra- and extra-hepatic bile ducts. Diagnosis and antibody?

A) Primary biliary cholangitis; AMA
B) Primary sclerosing cholangitis; p-ANCA
C) Autoimmune hepatitis; ANA
D) Hepatocellular carcinoma; AFP
E) Cholangiocarcinoma; CA 19-9

Correct Answer: B

PSC — characteristic "onion-skin" fibrosis, beaded ducts on MRCP, strongly associated with UC, positive p-ANCA in ~70%. Increased risk of cholangiocarcinoma.

Q4: C. diff — treatment

A 65-year-old woman 5 days post-op on ceftriaxone develops 10 watery stools/day, WBC 18k, Cr stable. Stool PCR and toxin EIA positive. Best initial treatment?

A) IV metronidazole monotherapy
B) Oral vancomycin OR oral fidaxomicin
C) IV vancomycin
D) Loperamide
E) Rifaximin

Correct Answer: B

Current first-line for non-severe initial C. diff = oral vancomycin OR oral fidaxomicin. Fidaxomicin has lower recurrence. IV vanco does NOT penetrate colonic lumen. Loperamide is contraindicated.

Q5: Diverticulitis management

A 62-year-old woman presents with 3 days of LLQ pain, fever 38.5 °C, WBC 14k. CT: inflamed sigmoid diverticula with small pericolonic abscess (3 cm). Best management?

A) Emergent colectomy
B) Outpatient observation alone
C) IV antibiotics + bowel rest; CT-guided drainage if abscess enlarges
D) Colonoscopy during acute episode
E) Barium enema

Correct Answer: C

Hinchey Ib (pericolonic abscess) → IV antibiotics (cipro + metronidazole or pip-tazo) and bowel rest. Drain abscess if > 4 cm. Colonoscopy is CONTRAINDICATED in acute diverticulitis (perforation risk); do it 4–6 weeks later.

Q6: Villous adenoma

A 68-year-old man has copious watery mucoid diarrhea, K 2.8, and a 4-cm rectal mass. Biopsy: polyp composed of long finger-like projections of dysplastic epithelium. Which lesion carries the HIGHEST risk of malignant transformation?

A) Hyperplastic polyp
B) Tubular adenoma
C) Tubulovillous adenoma
D) Villous adenoma
E) Juvenile polyp

Correct Answer: D

Villous adenoma — highest malignant potential (> 30% when > 4 cm). Can cause secretory/hypokalemic diarrhea (McKittrick-Wheelock syndrome). Hyperplastic polyps have no malignant potential.

Q7: CRC — classic adenoma-carcinoma sequence

Which is the EARLIEST and most common mutation in the classic chromosomal instability pathway of sporadic CRC?

A) KRAS
B) p53
C) APC (tumor suppressor)
D) DCC / SMAD4
E) MLH1/MSH2 (MMR)

Correct Answer: C

APC loss is the earliest event (initiation → small adenoma). Sequence: APC → KRAS → p53. MMR mutations (MLH1/MSH2) define the Lynch/MSI pathway (serrated precursor or Lynch syndrome).

Q8: Right-sided CRC presentation

A 72-year-old man presents with fatigue; labs: Hgb 8.2, MCV 72, ferritin 9. No overt GI bleeding. Most likely diagnosis/location?

A) Left-sided CRC, obstructing
B) Right-sided CRC (occult GI bleed, iron-deficiency anemia)
C) Gastric ulcer
D) Hemorrhoids
E) Diverticular bleed

Correct Answer: B

Right-sided CRC typically presents with iron-deficiency anemia from chronic occult bleeding; the wide cecal lumen tolerates bulky exophytic ("fungating") growth without obstruction. Left-sided CRC tends to obstruct (napkin-ring) and present with change in bowel habits.

Q9: Lynch syndrome

A 45-year-old woman has colon cancer; her mother had endometrial cancer at 48 and her uncle had a right-sided colon cancer at 52. Germline testing shows a pathogenic MSH2 mutation. Which additional cancer is she most at risk for?

A) Osteosarcoma
B) Endometrial and ovarian cancer
C) Medullary thyroid cancer
D) Pheochromocytoma
E) Glioblastoma

Correct Answer: B

Lynch syndrome (HNPCC) — autosomal dominant MMR gene mutation (MLH1, MSH2, MSH6, PMS2). Endometrial cancer is the 2nd most common after colon cancer (lifetime risk up to 60%). Also ovarian, gastric, small bowel, urothelial.

Q10: IBD surveillance

A 35-year-old woman with 8-year history of pancolitis UC and newly diagnosed PSC asks about colon cancer screening. What is the recommended strategy?

A) FIT every year starting now
B) Colonoscopy every 10 years starting at age 50
C) Surveillance colonoscopy now and every 1–2 years thereafter
D) CT colonography every 5 years
E) No additional screening needed

Correct Answer: C

Surveillance colonoscopy every 1–2 years after 8 years of pancolitis (or 15 years of left-sided colitis). If PSC is present, start surveillance at the time of PSC diagnosis and continue annually (highest risk group).

Intestinal Path Case Review — Answer Key