Week 6 - Small Intestines, Colon & Anorectal Flashcards
Describe the aetiology of inflammatory bowel disease.
- Chronic, debilitating. Severe destruction within intestine plus extraintestinal effects. Unknown aetiology.
- Exact aetiology not known.
- Intestinal microbes, epithelial and immune dysfunction → autoimmune inflammation on gut wall → in a genetically susceptible host → IBD.
- Autoimmune uncontrolled inflammation on gut wall leading to destruction → chronic diarrhoea (in a genetically susceptible host - commonly seen within families).
Aetiology:
- Genetic susceptibility
- Environmental factor: gut flora.
- Immune dysfunction → autoimmunity (self destruction)
- 15% family history, 30-59% concordance in twins.
- HLA: DR1 (UC), DR7 (CD) - 27% (associations with HLA antigens like other autoimmune disorders).
- Hygiene hypothesis or ‘altered intestinal microbes’ has been put forward - altered intestinal microbes due to too much hygiene (less exposure to bacteria).
- 50% of stool mass and microbes are 10 times of body cells (90%) - 50% of stool mass is bacteria - more than 10x no. of bacteria in body cells (90% of us).
- Fecal microbial transplants from healthy to IBD patients - improve condition - resetting bacteria may help.
What other associations are there with IBD?
• Helminth extracts can prevent IBD development - Cairns Research.
• IBD more in western than in developing countries (more common in affluent society, western countries based on hygiene theory).
• Active smoking decreases risk and severity of UC (significantly increases risk for CD).
• Still don’t know exact cause, just risk factors.
• T cell activation - increased TNFα.
- T cell over activation has been proven in IBD - excess immune reaction.
- Important chemical marker is TNFα (marked increase).
• Mutations of the IL-10 and its receptor genes → severe, early onset IBD.
- Lack of inhibition of inflammation (IL-10) → severe IBD.
- More inflammation (TNFα) and less anti-inflammation (IL-10).
• Anti-TNF antibody (Remicade/Infliximab) - new drug of promise (Anti TNFα - new therapy).
Explain the pathogenesis of inflammatory bowel disease.
- Excess TNFα
- Decreased IL-10
- Uncontrolled inflammation.
- Exposure to antigens in the intestines.
- Normally gives rise to inflammation and IL-10 stops inflammation.
- In IBD, inflammation, lack of IL-10 → uncontrolled inflammation.
- Excess TNFα and decreased IL-10 leading to uncontrolled inflammation.
What is dietary fibre?
• Pectin, inulin etc. • Non digestible, bypass upper GI. • Fermented by probiotics in colon. • Release SCFA (butyrate, acetate, propionate). • 10% of energy for colon epithelium. • Receptors (GPR 41, 43) on - Colon epithelium. - Neurons, WBC. - T & B lymphocytes. - Lipocytes, Muscle. - Hepatocytes. • Deficiency is risk factors for IBD, obesity, DM, cancer.
Identify the types of inflammatory bowel disease.
- Marked difference in presentation and clinical features, although some common features.
- In 10% of patients - indeterminate colitis - cannot differentiate, specifically colon involvement.
Crohn's disease (CD) • Patchy, thick and narrow. • Transmural, deep. • Chronic granuloma. • Skip lesions.
Ulcerative colitis (UC) • Colon mucosa only. • Continuous, thin and dilated. • Acute inflammation. • Continuous colonic involvement beginning in rectum.
Indeterminate colitis
• Mixed pattern in 10% of cases.
Outline Crohn’s disease.
- Previously mistaken for intestinal TB (due to granulomas microscopically), named regional enteritis… Now Crohn’s (1932).
- Developed countries, whites, Jews, females.
- Increasing incidence.
- Any age, common <20-40y, minor peak in >60y.
- Smoking is a strong exogenous risk factor (not for UC).
- Any part of GIT, terminal ileum and colon - common.
- Can involve any part of GIT.
- Commonest in cecum and terminal ileum.
- Any age but young age more common.
- Smoking risk factor but not for UC.
Typical case of Crohn’s disease.
• Family history IBD
• Common location
• Constipation/diarrhoea (whenever there is obstruction - first constipation then diarrhoea).
• Irregular mass (inflammation causes marked thickening (fibrosis) and granuloma formation - forms irregular mass unlike UC).
• Extra-intestinal manifestations - arthritis (due to obstructions), aphthous ulcers of autoimmune disease.
• Crohn’s disease - extensive involvement of small intestine → may get steatorrhoea due to lack of fat absorption.
Lab:
• Leukocytosis (inflammation)
• Decreased albumin due to loss in stools.
• Increased ESR, CRP - general markers of inflammation.
• Increased ALP - cholestasis in liver.
Describe the morphology of Crohn’s disease.
Gross: • Mucosa - cobblestone. • Wall thick, fibrotic. • Creeping mesenteric fat. - Because inflammation extends to the serosal surface - fat tries to cover the area - fat covering is known as fat creeping.
Crohn’s endoscopy:
• Cobblestone, narrow deep ulcer, broad pseudopolyp. Transmural inflammation, ulcerations, fissures. Skip lesions (some areas normal, some areas not).
• Appears like narrow fissure like ulcers. Inbetween the mucosa is oedematous - cobblestone appearance.
Radiography:
• Typical case of Crohn’s disease known as string sign - narrow segments do not take up the contrast media.
Microscopy:
• Narrow deep ulcers.
• Transmural inflammation.
- Inflammation appears penetrating into the muscle layer (whole thickness inflammation).
- Inflammation is usually mixed - both lymphocytes and neutrophils,
• Lymphocytes, granuloma.
- Lymphocytes, macrophages, giant cells, no caseation.
- Granulomas - macrophages accumulating as a group.
- Giant cells feature of chronic inflammation (granulomatous inflammation).
Crypt abscess - very typical in Crohn’s disease but occurs in both CD and UC. Within the colonic glands, WBCs accumulate within the crypts - known as crypt abscesses.
What are the features and complications of Crohn’s disease?
- Spreading inflammation
- Fibrosis
- Thickening
- Narrowing
- Obstructions
- Adhesions
- Fistula/sinus
- Abscess
- Because Crohn’s disease produces granulomas and extensive fibrosis (healing) → leads to granulomatous inflammation spreading all over.
- Ulcers penetrate through - intestinal content and bacteria escape - abscess, fistula/sinuses and adhesions between the organs. Fistulas can also communicate with the skin.
- Extremely variable.
- Abdominal pain, diarrhoea, weight loss.
- Diarrhoea is often initially mild & intermediate, accompanied by a fever.
- Watery diarrhoea without blood or mucus.
- Weight loss as patients avoid food.
- Anaemia (iron/B12).
- Malabsorption sy.
- Polyarthritis.
- Erythema nodosum.
- Cholangitis (UC).
- Watering pot perineum (multiple fistulas around the anus - anorectal involvement in CD).
- Scleritis.
- Aphthous ulcers.
- Pyoderma gangrenosum.
- Budding ulcers and SCC.
- Cutaneous Crohn’s plaque
Outline ulcerative colitis.
• A lot of differences between Crohn’s and UC.
• Starts in rectum to colon - continuous (no skip lesions).
• Involves ‘colon’ only - backwash ileitis (only occasionally when there is whole colon involvement, the inflammatory mediators can enter the ileum causing backwash ileitis - but there is no ulcers in the ileum).
• Inflammation limits to mucosa - serosa normal.
• Broad shallow ulcers with oedematous intact mucosal islands (pseudopolyp).
- Broad shallow ulcers, normal epithelium. Epithelial islands appear as polyps. Not true polyps → pseudopolyps (normal epithelium hanging in between the big ulcers).
• Crypt abscess - neutrophils within glands, common but not specific. Also seen in CD.
• No thickening, fibrosis or narrowing or granulomas (no fistulas or sinuses in UC).
• Toxic damage to muscular layer may lead to toxic megacolon - dilated, stasis, gangrene. (Occassionally toxic damage to muscular layer may lead to total paralysis of the muscle with lack of peristalsis known as toxic megacolon).
Describe the morphology of ulcerative colitis.
Gross:
• Large areas of broad ulcer with pseudopolyp.
• Pseudopolyp - oedematous intact area of mucosa between broad ulcers.
• Because it starts from the rectum involving the left side of the colon → gradually spreads to the right side of colon → the active disease is in the right side (the left side goes into atrophy leading to just smooth mucosa without any folds). Atrophic side - totally inactive phase of UC - healed mucosa becomes atrophic.
Microscopy: • Acute inflammation limited to mucosa. • Crypt abscess (WBC inside glands). • Pseudopolyp (normal oedematous mucosa). • No granuloma.
- Difference between UC and CD is inflammation is limited to the mucosa - the muscle layer is usually normal.
- In the active phase - you see oedematous hanging mucosal folds.
- In the chronic phase - you see atrophic flattened mucosa.
Identify the complications of ulcerative colitis.
Intestinal:
• Perforation, haemorrhage.
• Toxic megacolon.
• Adenocarcinoma.
Extraintestinal: • Migratory polyarthritis. • Sarcoilitis, ankylosing spondylitis. • Erythema nodosum. • Pyoderma gangrenosum. • Iritis, uveitis, episcleritis • Sclerosing cholangitis (4%) • Nephrolithiasis. • Aphthous ulcers.
- Similar to Crohn’s except dilation and megacolon can occur and perforation doesn’t occur in CD.
- Colonic cancer can occur in both but more common in UC.
- Haemorrhage and bleeding → bloody stools common in UC (less common in CD).
- Uveitis, aphthous ulcers, erythema nodosum, pyoderma gangrenosum - all seen in both.
Differentiate between Crohn’s disease and ulcerative colitis.
Crohn's disease: • Whole of GIT. • Transmural, deep and narrow* • Patchy, thick and narrow lumen. • Chronic granuloma.
- Common ileocecal junction.
- Whole thickness inflammation.
- Deep and narrow ulcers.
- Multiple patchy areas - both LI and SI.
- Involved areas become narrow - give rise to obstruction - alternating constipation and diarrhoea.
- Microscopy - both acute and chronic inflammation. More chronic - lymphocytes and granulomas (granulomatous).
- Cobblestone - narrow ulcers with broad mucosal folds.
- Fat creeping - creeping of the fat on the outside of the intestine.
Ulcerative colitis:
• Rectum and colon mucosa only.
• Continuous, thin and dilated.
• Acute inflammation.
- Only rectum and colon.
- Mucosa only (not transmural).
- Continuous involvement.
- Thin and dilated walls.
- Broad ulcers.
- Active - broad ulcers with narrow pseudopolyps.
- Chronic - total smoothening of the mucosa, atrophy.
Mixed picture in 10% - indeterminate colitis.
Identify the key features of Crohn’s disease and ulcerative colitis.
Crohn's disease: • Chronic granulomatous. • Transmural - full thickness. • Ulcers deep, narrow. • Firm thick, narrow lumen. • Fibrosis - significant. • Skip lesions and fistula. • Rectum involvement ~20% • No significant perianal sores. • Malabsorption - fat (ileum). • TH2, alternate path macrophage M2.
Ulcerative colitis: • Acute inflammation - oedema. • Superficial - mucosal inflammation. • Ulcers shallow, broader. • Thin wall, dilated lumen. • Fibrosis - no/little. • Continuous, no fistula. • Rectum involvement 100%. • Perianal sores in 25-35%. • Malabsorption - no. • TH1, classic path macrophage M1.
Inflammatory bowel disease summary.
• IBD includes Crohn’s, UC and indeterminate colitis.
• Unknown etiology - genetic, environment and immune (3 factors*).
• Epithelial, bacterial flora and immune dysfunction.
• Crohn’s - any part, terminal ileum and cecum, skip lesions and non-caseating granuloma common.
• UC - rectum to colon, no skip lesions or granuloma. Only mucosa.
• Both CD and UC can have extraintestinal manifestations.
• Colonic cancer in IBD > 8-10 years (C - pancolitis)
- Colon cancer seen in both conditions, usually after 8-10 years but more common in UC with whole colon involvement (known as pancolitis).
• Anti TNFα therapy - infliximab - Remicade → remission (promising results producing long term remission in patients).
Outline polyps.
• Colon common (rare in small intestine) - commonest in the GI, specifically the colon (rare SI).
• Tumours present as polyps.
- Polyps are tumours of the intestine - both benign and malignant.
- Precursor of malignancy.
• Larger the size - high chance of malignancy.
• Inflammatory and neoplastic types.
- 2 major types - inflammatory and neoplastic.
Describe the classification of polyps.
• Classified in regards to shape - attached to wall without a stalk (sessile) and with a stalk (pedunculated).
• Non-neoplastic (90%) - low/no malignancy (DNA normal, no oncogene activation, no neoplasia, no dysplasia).
- Hyperplastic - most common - excess growth.
- Inflammatory/pseudopolyps - IBD.
- Hamartoma/congenital/juvenile - polyps.
Hamartoma rare - congenital type, embryonic disorganisation - not really tumor. Congenital/juvenile polyposis.
• Neoplastic (10%) adenoma - high malignancy (activation of an oncogene, epithelium shows abnormal DNA - uncontrolled growth, appears dysplastic).
- Tubular (90%), tubulovillous (10%), villous (1%).
- Sporadic/familial (FAP/HNPCC).
- Adenocarcinoma*
• Neoplastic benign tumors - adenoma - high chance of becoming malignant - 3 types (tubular most common, tubulovillous, villous).
Neoplastic malignant tumors - adenocarcinoma.
Can also appear as sporadic cases due to mutations or congenital (familial) - 2 major types - FAP and HNPCC.
Outline hyperplastic polyps.
- Commonest polyp in clinical setting, non neoplastic (no malignancy potential).
- Usually small <5mm, no malignancy.
- Distal/left side. Sigmoid.
- Sessile, multiple, normal colour.
- Microscopy: Increased large glands (hyperplasia, no dysplasia).
Microscopically, the glands are larger (but with normal function, no dysplasia). More common on distal/left side (sigmoid colon).
Outline sessile serrated adenoma.
- Similar appearance, not common.
- But neoplastic, right - cecum.
- Malignant potential.
- Looks similar to hyperplastic polyps but microscopically it is neoplastic and it is more common on right side (proximal colon). Have malignant potential, not common.
Outline congenital polyps - hamartomas.
- Juvenile rectum children, single to 3 - young children less then 3y - known as juvenile polyps, usually single (but up to 3 can be present), can prolapse out as a hanging polyp.
- Retention polyp adults - when present as adults - known as retention polyps - all congenital hamartomas (just a name difference).
- Juvenile polyposis syndromes: mutations in tumor suppressor genes. Not truly hamartomas. Due to mutations in tumor suppressor genes presenting as multiple polyps in young children - can present at any age but younger age more common.
• Peutz Jeghers syndrome: STK11 (tumor suppressor) - small intestine, stomach and colon, many malignancies (endocrine, thyroid, breast). Oral pigment macules.
- Due to mutation of tumor suppressor gene STK11 *EXAM HINT. When it occurs as congenital mutation - presents with many polyps within the GI tract. Dark patches around oral cavity and inside oral mucosa.
• Cowden syndrome: PTEN (tumor suppressor) - GI polyps with lipomas, neuroma etc. GI malignancy.
- Similar but different gene, associated with lipomas, neuromas.
- Peutz Jeghers and Cowden not true hamartomas - actually neoplasms because there is oncogene activation.
• All these tumors are large, irregular, stalk, have cystic glands.
Outline familial adenomatous polyposis.
- 2 important conditions clinically but not common - FAP and HNPCC.
- Plenty adenomas >100 - by definition, has to be more then 100. Starts as small sessile polyps but later on develop into larger polyps (1000s of polyps carpeting the whole intestine).
- Autosomal dominant - due to APC gene (adenomatous polyposis coli).
- 75% inherited. 25% can occur at a later age again with multiple polyps.
- 100% adenocarcinoma <50y (100% of these cases become cancer (adenocarcinoma) before the age of 50) - diagnostic feature, treatment is total colectomy.
- Systemic disorder (associated with other malignancies).
- Variant: Gardner and Turcot syndrome (2 variants of FAP).
Early age - multiple, thousands of polyps → gradually become bigger and bigger.
Outline hereditary non-polyposis colon cancer (HNPCC).
• AKA Lynch syndrome, 2-4%, GI and non GI malignancy.
Present with a malignancy, 2-4% of population may have these genes. GI and non GI - many malignancies can occur.
• MSH2 or MLH1 (DNA repair) - one mutant at birth.
DNA repair gene mutation - one mutant gene at birth, second develops after birth.
• No or <100 polyps. Differentiation from FAP - not thousands of polyps. May not be any polyps or may be a few.
• Malignancy later age than FAP (but still younger than sporadic).
Outline neoplastic adenoma - tubular/villous.
• Neoplastic polyps, larger 0.3-10cm (10% of clinical situation).
• Pedunculated (tub/villous).
• Microscopy - dysplasia (characteristically, because these are neoplastic - there will be dysplasia - cells are irregular, abnormal, pleomorphic
• Sporadic/familial (FAP/HNPCC)
- Neoplastic adenomas can occur as familial (FAP or HNPCC) or sporadic (few polyps in general population).
- 2 types of these polyps - sporadic (1 or 2 polyps in general population), familial (plenty - 1000s FAP, few HNPCC).
• All have malignant potential.
Microscopy
• Tubular - glands look like tubules.
• Villous - villi like structures.
• Both have irregular abnormal pleomorphic nuclei. Cells are irregular because have oncogene activation.
Polyps summary.
- Hyperplastic - commonest clinically. Just hyperplasia, no malignant tendency, appear like a button. Multiple or singular. More common in distal colon (sigmoid).
- Tubular - like a fruit hanging, villous - like a carpet. Both neoplastic. Together they are around 10% in clinical situation. Tubular more common. They transform to malignancy. If it is familial - present with malignancy at a very early age. Non-familial usually after 50yrs.
- Harmatoma - irregular large polyps in very young age.
Differentiate between HNPCC and FAP.
HNPCC (Lynch Syndrome) - 10% • AD, Mutation in MSH2, MLH1. • DNA mismatch repair genes MMR. • Few adenomatous polyps than FAP. • Increased Ca both GI and non GI (later than FAP).
Familial Adenomatous Polyposis - 1%
• AD, mutation in APC gene on 5q21.
• >100-2500 polyps GIT duodenum.
• 100% risk of carcinoma by 30-50 years.
- HNPCC <100 polyps. Mutation in DNA repair genes (MSH2, MLH1). Usually at a later age then FAP.
- FAP about ~1% clinically. Autosomal dominant. Mutation in APC gene on chromosome 5. Usually more then 100 but 1000s of polyps both in GIT and duodenum. 100% risk of cancer by 30-50 years.
Outline colon cancer.
• Common adenocarcinoma of colon.
• Small intestine neoplasms very rare.
• Second common in developed countries (lung cancer 1st), 1 in 20 (after age 60-80).
• Rare in the developing world - increasing (diet*) - due to adoption of Western diet.
• Ageing and males slightly more common.
• 80% sporadic in >50y, peak at 60-70y.
80% sporadic - occur in older age group, usually due to secondary risk factors although they may have genetic abnormality as well.
• 20% <50y familial, at younger age (polyposis syndrome rare).
20% familial - mutations from birth or early in age - usually produce colon cancer <50y. Don’t mistake for polyposis syndrome where there is 1000s of polyps - these syndromes very rare (around 1% clinically).
• Population screening for stool occult blood in >50y.
Most popular screening method to detect cancers early. Usually done in people over the age of 50.
• Types: right/proximal/familial and left/distal/sporadic - equal.
Describe the aetiology of colon cancer.
• 2 distinct etiologies produce the commonest colon cancers - environmental and genetic risk factors.
Environmental factors:
• Decreased dietary fibre and increased refined fat and carbohydrates.
• Increased anaerobic bacteria, high cholesterol - high risk.
- Meat, high protein and high calorie diets associated with increased anaerobic bacteria and high cholesterol in the gut → produce carcinogens → increased risk.
• Aspirin, NSAID (COX-2), calcium and folates* protective effect.
- Aspirin, NSAID (block COX-2 → colonic cancers and polyps have a very high expression of COX-2 enzyme).
- Vitamins especially calcium and folate known to be protective (although no clear laboratory evidence).
Genetic:
• APC/β-catenin - tumor suppressor - ~80% sporadic.
• MLH1 and MSH2 - DNA repair and TGF-β genes - ~20%.
- 20% have MLH1 and MSH2 - DNA repair genes effecting TGF-β gene.
- If present early in age (<50) → one of the mutations occurred at birth.
• Other genes: BAX, KRAS, TP53 etc.
• Age and risk factor related mutations of tumor suppressor and DNA repair genes is the key event.
- Sporadic (average risk) 75-80% (APC - sporadic) + DIET
- Other family history 10-15%
- HNPCC - 5%
- FAP - 1% (APC- familial)
- IBD - 1%
• Sporadic cancers due to dietary factors - commonest cause. Although do have APC mutations.
• Diet important risk factor clinically.
• Polyposis syndromes rare ~1%
