Toxicopathology of

gastrointestinal tract

Submitted with respect to:Submitted with respect to:Dr. D. J. GhodasaraDr. D. J. GhodasaraAssociate ProfessorAssociate ProfessorDepartment of Veterinary Pathology

Submitted by:Mukesh kumarMukesh kumarM.V.Sc (2M.V.Sc (2ndnd Semester) Semester)

Normal structure of GIT

• Mouth cavity

• Pharynx

• Oesophagus

• Stomach– Ruminant

– Non ruminant

• Small intestine– Duodenum

– Jejunum

– Ileum

• Large intestine– Caecum

– Colon

– Rectum

Normal structure of Small Intestine

Normal structure of Rectum

Drug associated with esophageal injury

• Antibiotics(doxycycline,tetrecycline,clindamycin)

• NSAIDs

• Emprolium bromide

• Ferrous sulfate

• Potassium chloride(slow release)

• Quinidine

Drug associated with gastric lesions

• NSAIDs

• Antibiotics

• Iron

• Corticosteroids

• Colchicines

• Proton pump inhibitors(omperazole)

Drug associated with small intestinal lesions

• NSAIDs- mefenamic acid, indomethacine, ibuprofen, diclofenac potassium chloride

• Cytotoxic agents- colchicine, methotrexate,5-FU, vincristine

• Antibiotics- neomycin, penicillins, cyclosporins

• Progestional steroids

• Clofazimine (granulomatous enteritis)

Drug associated with large intestinal lesions

• Melanosis coli-Antraquinone laxatives- colitis(inflammation) presence of neutrophiles

• Penicillamine, methyldopa,indomethcin suppostories,(colitis)

• Gold salts, methyl dopa, & NSAIDs(colitic lesions)

• Cyclosporins

• Rantidine

• Antibiotics (clindamycin and lincomycin, cephalosporins, ampicillins)

• Pseudomembranous colitis(antibiotics chlorpropamide)

• Anticoagulants- haemorrhage

• Oral contraceptives, estrogen- arterial or venous thrombosis with ischaemia

Main alteration due to drug toxicity

• Epithelial hyperplasia

• Erosions/ulcers

• Villous atrophy/stunting• Tumours of GIT

• Caecal enlargement• Lymphangiectasis • Accumulation enteropathies

• Miscellaneous changes in intestine

Epithelial hyperplasiaEpithelial hyperplasia

• Generally found in stomach

• Occurs in response to irritant drugs

• It is a protective mechanism against loss of surface structure.

• Failure in hyperplasia results in erosions and ulcers.

• It some time also occur due to accumulation of a drugs in epithilium.

Hexenal toxicity in rat(fore stomach)(A) Control: no significant lesions(B) 10 mg/kg of hexenal: minimal mucosal hyperplasia. (C) 30 mg/kg of hexenal: mild mucosal hyperplasia with hyperkeratosis. (D) 100 mg/kg of hexenal: severe diffuse mucosal hyperplasia with hyperkeratosis.

(A) Control: no significant lesions. (B) 50 mg/kg of hexenal: no significant lesions. (C) 200 mg/kg of hexenal: necrosis with loss of the epithelium and vesicle formation. (D) 500 mg/kg of hexenal: diffuse coagulative necrosis of the epithelium.

Erosions/ulcersErosions/ulcers

• Common in stomach due to low PH condition

• These are seen generally due to NSAID toxicity.

• Mechanism-

• Alters blood flow inhibit cyclooxygenase reduce synthesis of prostaglandins loss of barrier function cell damage neutophils influx bacterial invasion erosion inflammation ulcer

Iodomethacine induced ulcer in GIT

Histology of small bowel biopsy showing oedematous lamina propria containing patchy mixed inflammatory cell infiltrate with focal erosion of the surface epithelium. Mucosal and submucosal

granulomata are also seen

Microscopically, the ulcer here is sharply demarcated, with normal gastric mucosa on the left falling away into a deep ulcer whose base contains infamed, necrotic debris. An arterial branch at the ulcer base is eroded and bleeding.

Villous atrophy/stunting Villous atrophy/stunting

• Reduction in size and height of villi.

• Increased loss, degeneration and apoptosis of enterocytes occur.

• Inhibition of mitosis of crypt cells results in reduced and arrested replacements in crypts.

• This may also leads to chronic inflammatory condition.

Duodenal biopsy showing mild and moderate villous atrophy. A mild grade of villous atrophy (red arrow) is adjacent to an area of

moderate villous atrophy (black arrow).

Tumours of GIT• Intestinal carcinogens

– di methyl hydrazine, iron containing compounds are colon carcinogens.

– Carrageenans produce colonic polyps and adenocarcinomas.

– Synthetic steroids produce duodenal invasive carcinomas.

– Folpet produce carcinomas and hyperplastic changes

sequential changes occurs during origin of tumours:-

Goblet cell hyperplasia mucosal hyperplasia atypical mucosal hyperplasia adenomas adenocarcinomas

Villous atrophy (arrows) along with hyperplasia of the crypts (arrow heads), producing an appearance with features of ileal and colonic mucosa.

A) Tubular adenoma with high-grade dysplasia. (B) Tubular adenoma with high-grade dysplasia. (C) Tubular adenoma with adjacent colonic metaplasia (D)

Nuclear staining in the dysplastic ileal epithelium

Squamous cell papilloma (top panel) and squamous cell carcinoma in rats with invasion into submucosa and muscularis mucosa(bottom

panel)

Malignant neuroendocrine tumor

Sections of stomach from mice (A and B) The mucosa was severely hyperplastic demonstrating branching tortuous glands, (C and D) inflammatory foci associated with

dysplasia. (E, white arrow) Numerous mitotic and apoptotic profiles (E, black arrow) were observed. (F) A proportion of the blood vessels contained thrombotic clots. (G) Numerous

epithelial cells demonstrate nuclear atypia as well as significant nuclear stratification.

Cecal carcinoma observed in the o-nitrotoluene carcinogenicity study in mice .

Large intestinal adenoma (top panel) and adenocarcinoma (bottom panel) observed in the bromo dichloromethane carcinogenicity study in rats.

Caecal enlargement

• It seen in alcohol, sugar, and antibiotics toxicity

• It is due to disturbance in microflora.

• Results in damage and distention by opportunistic pathogens.

Lymphangiectasis

• Dilated lacteals/lymphatic found in lamina propria can extend up to the lymphatic sinuses of mesenteric lymph node.

• Generally occurs in toxicity which are related with protein loses.

The large white areas within the intestinal microvillus shown.

Duodenal lymphangiectasia, Dilated lymphatic vessels in the apical part of duodenal villi

Accumulation enteropathies

• Ingested products are accumulated within enterocytes, lamina propria, or within macrophages.

• Such accumulation results in foreign body reaction.

• E.g. puromycin, ethionine, tetracyclins, cholesterol rich/fatty diets, detergents, pigmented dyes, plant extracts etc.

Aggregation of macrophage-containing pigment in the lamina propia of the colon.

Section of rectum showing macrophages after feeding cholesterol rich diet

Miscellaneous changes in intestine

• Intussusceptions- seen due to increased peristalsis. E.g. alpha adrenergic agents

• Vacuolation of brunner’s gland- beta blocker, atenolol toxicity

• Degeneration of brunner’s gland-VEGF’s

• Hypertrophy & dilation of brunner’s gland-GLP-1 antagonist

• No. of goblet cell increase- prolactin inhibitors

Photomicrograph of Brunner's gland hyperplasia shows lobular proliferation of Brunner's glands, some of which are cystically

dilated. The overlying mucosa exhibits duodenitis.