Ulcerative intestine

1. ULCERATIVE LESIONS OF INTESTINES Dr.Saurav singh Guide:Dr.PM Pagaro

2. Overview Peptic Ulcer Disease Infectious Causes (Typhoid, T.B, Amoebic ulcers) Inflammatory bowel disease (Ulcerative colitis & Crohns disease)

3. PEPTIC ULCER DISEASE DEFINITION A circumscribed ulceration of the gastrointestinal mucosa occurring in areas exposed to acid and pepsin. Sites: Duodenum Stomach Oesophagus Gastro- enterostomy stoma Related to ectopic gastric mucosa (e.g. in Meckel’s diverticulum )

4. Epidemiology of PUD Prevalence about 5-10% Higher prevalence in low socioeconomic classes and with certain diseases Duodenal ulcer M/F: 3:1 Gastric ulcer equal in both sexes but increases with age Family history: 3-4 increased risk . Cigarette smoking: ulceration increased Emotional disturbances and Stress: increase gastric acid secretion

5. Etiopathogenesis H. Pylori : 70% of all cases. Other causes include NSAIDS Alcohol Gastritis Socioeconomic status Genetic factors Stress –shock, sepsis or severe trauma Burns(curling ulcer) Head trauma ( cushing ulcer)

6. Helicobacter factors in pathogenesis Some strains are more pathogenic than others. The Cag A ( cytotoxic ) antigen is one important virulence factor Human variability also plays a part (e.g. individuals who produce high levels of IL-1 b in inflammation get pan gastritis and Gastric ulcer, lower levels associated with antral gastritis and Duodenal ulcer)

7. Duodenal Ulcers duodenal sites are 4x as common as gastric sites most common in middle age peak 30-50 years Male to female ratio—4:1 Genetic link: 3x more common in 1 st degree relatives more common in patients with blood group O associated with increased serum pepsinogen H. pylori infection common up to 95% smoking is twice as common

8. Gastric Ulcers common in late middle age incidence increases with age Male to female ratio—2:1 More common in patients with blood group A Use of NSAIDs - associated with a three- to four-fold increase in risk of gastric ulcer Less related to H. pylori than duodenal ulcers – about 80% 10 - 20% of patients with a gastric ulcer have a concomitant duodenal ulcer

9. Symptoms of duodenal ulcer disease: epigastric pain 2 hours after meal or on a empty stomach or during night pyrosis good nutrition obstipation seasonal dependence (spring, autumn)

10. Symptoms of gastric ulcer disease : e pigastric pain after meal or during meal u pper dyspeptic syndrome – loss of appetite, nauzea , vomiting, flatulence v omitting brings relief r educed nutrition l oss of weight

11. Complications: Bleeding Perforation Penetration Stenosis

12. Diagnosis Stool for fecal occult blood Labs: CBC , liver function test, amylase and lipase . Upper GI Endoscopy: Any pt >50 yrs with new onset of symptoms or those with alarm markings including anemia, weight loss, or GI bleeding .

13. Helicobacter pylori detection Invasive( through endoscopy) Gastric biopsy and staining culture of Bx specimen Tests using urease enzyme in Bx specimens Bacterial DNA detection by PCR Non-invasive: Urea breath test H.pylori antibodies Stool antigen Salivary antigen

14. Staining methods of Helicobacter pylori Warthin –Starry stain- The  Warthin Starry stain (WS) is a silver nitrate based staining method Leung stain- It is a novel Alcian yellow- toluidine blue (Leung) stain for H.pylori . Methylene blue

15. Biopsy of peptic ulcer: Biopsy is necessary to distinguish between benign and malignant ulcers. Biopsy should be taken from the ulcer edge, at least from each quadrant. Upto 10-12 biopsies may be taken to exclude cancer. Repeat endoscopy may be necessary if biopsies are negative and there is high index of suspicion.

16. Morphology of peptic ulcers Clean, non-elevated edge Granulation tissue base (floor) Underlying fibrosis

17. Chronic Gastric Ulcer

18. Duodenal ulcer

19. Four histological zones are present in a peptic ulcer. Necrotic zone Nonspecific acute inflammation Granulation tissue Fibrosis

20. Microscopic features Thickening of vessels caused by subendothelial fibrous proliferation. Hypertrophy of nerve bundles. Mucosa surrounding the ulcer is pyloric type. Necrotic surface shows superimposed infection by candida albicans . In case of H. pylori infection following features are noted at the ulcer edge : loss of apical portion of cells, dropout of epithelial cells, erosion, cellular tufts.

21. Healing process- Regenerating epithelium grows over the surface. Intestinal metaplasia May contain chief and parietal cells (ulcer in the fundus area) Gastritis remains after ulcer has healed. Cellular atypia may be present.

22. Morphology of duodenal ulcer

23. Differential Diagnosis Neoplasm of the stomach Pancreatitis Pancreatic cancer Diverticulitis Nonulcer dyspepsia (also called functional dyspepsia) Cholecystitis Gastritis GERD MI—not to be missed if having chest pain

24. Natural history of PUD PUD is a chronic episodic disease with relapses and remissions. If left untreated, 30-40 % of ulcers heal within 8 weeks. Recurrence rate without treatment is 70% during first year and 90% within 2 years. Complications develop in 20% of PUD

25. Infectious causes 1. TYPHOID Acute enteric infectious disease caused by Salmonella typhi ( S.Typhi ). Clinical features : prolonged fever, Relative bradycardia , apathetic facial expressions, roseola , splenomegaly , hepatomegaly , leukopenia . Can lead to intestinal perforation, intestinal hemorrhage

26. S.Typhi. stomach Lower ileum peyer's patches & mesenteric lymph nodes thoracic duct 1st bacteremia ( Incubation stage ) 10-14d ( mononuclear phagocytes ) 2nd bacteremia liver 、 spleen 、 gall 、 BM , ect early stage (1-3W ） LN Proliferate,swell necrosis defervescence stage （ 3-4w ） Bac . In gall Bac. In feces S.Typhi eliminated convalvescence stage (4-5w) Enterorrhagia,intestinal perforation

27. Pathogenesis The amount of bacilli infection (>10 5 bacteria ) Bacteria ingested orally Stomach barrier (some Eliminated) Enters the small intestine Penetrate the mucus layer Enter mononuclear phagocytes of ileal peyer's patches and mesenteric lymph nodes Proliferate in mononuclear phagocytes spread to blood causing primary bacteremia (Incubation period ).

28. enter spleen, liver and bone marrow ( reticulo -endothelial system) further proliferation occurs A lot of bacteria enter blood again causing secondary bacteremia . Recovery

29. Proliferation of RES ( reticuloendothelial system ) Specific changes in lymphoid tissues and mesenteric lymph nodes ." typhoid nodules“ Most characteristic lesion : Ulceration of mucosa in the region of the Peyer’s patches of the small intestine PATHOLOGY

30. Peyers patches

31. Major findings in lower ileum Hyperplasia stage(1st week ): swelling lymphoid tissue and proliferation of macrophages . Necrosis stage(2nd week ): necrosis of swelling lymph nodes or solitary follicles. Ulceration stage(3rd week): Oval ulcer with its long axis parallel to the small intestine , this results from sloughing and shedding of necrotic lymphoid tissue in the peyers patches leading to intestinal hemorrhage, perforation . Stage of healing (from 4th week): healing of ulcer, no cicatrices and no contraction

32. 2. Gastrointestinal Tuberculosis Abdominal tuberculosis is usually secondary to pulmonary tuberculosis Sites: The ileocecal region is the most common area of involvement in the gastrointestinal tract due to the abundance of lymphoid tissue. The natural course of gastrointestinal tuberculosis may be Ulcerative hypertrophic or ulcer hypertrophic.

33. Clinical presentation Abdominal pain mimicking peptic ulcer disease with stomach or duodenal infection; Malabsorption with infection of the small intestine; Pain, diarrhea, or hematochezia with infection of the colon.

34. Investigations Blood routine Urine routine - to detect diabetes mellitus Plain X-ray of the abdomen Laparoscopy Laparoscopic biopsy of tubercles found in the peritoneum or other parts Barium studies

35. I ntestinal tuberculosis. 　　

36. 3. AMOEBIC ULCER The causative organism is parasitic protozoan, called Entamoeba histolytica . Site:  It usually involves caecum and ascending colon  followed by sigmoid colon, rectum, and appendix. In severe cases the entire colon is involved. The spectrum of colitis in amoebiasis ranges from mucosal thickening, to multiple cyst formation, to diffuse Inflammation / oedema, to necrosis and perforation of colonic wall.

37. Life cycle Mouth - Cyst ingested Invades gut mucosa – cyst formation Cyst Passed in stool Excyst to trophozoite Trophozoite Amoebic disease

38. Clinical presentation Gradual onset of bloody diarrhoea Abdominal pain and tenderness. Leucocytes and pus may be present in stool. Fever present in <40% of patients. Weight loss and anorexia can be present. Local inflammatory masses, amoebomas , may cause obstructive symptoms

39. Gross features: Begin as small foci of necrosis that progress to ulcers.  In the early stages the colonic ulcers have a narrow neck and thus appear as small nodules As the ulcers enlarge they always retain their undermined base but the ulcerated area of the mucosa becomes larger . The base of the ulcer is covered by grey - white exudate .  There is always undenuded mucosa between the ulcers.

40. Microscopic features : The ulcer is typically 'flask- shaped' and the broad  base is composed of fibrin and cellular debris. A sharp line divides the necrotic and viable mucosa Trophozoites are found on the surface of the ulcers, in the exudate and in the crater. They are frequently found in the submucosa , muscularis propria , serosa .

41. “ IBD is a set of chronic inflammatory conditions resulting from inappropriate and persistent activation of the mucosal immune system ,driven by the presence of normal intestinal flora.”

42. HISTORY ULCERATIVE COLITIS First officially described by Wilks and Moxon in 1875. Before this discovery , all the diarrheal diseases were believed to be caused by infectious agents and bacteria.

43. Crohn’s disease In 1913 Dr Dalziel described transmural intestinal inflammation in 13 autopsied patients. In 1930 Burril Crohn described TERMINAL ILEITIS first .

44. Epidemiology of IBD Ulcerative colitis Crohn’s disease Incidence (US) 11/100 000 7/100 000 Age of onset 15-30 & 60-80 15-30 & 60-80 Male:female ratio 1:1 1 . 1-1 . 8:1 Smoking May prevent disease May cause disease Oral contraceptive No increased risk Relative risk Appendectomy Not protective Protective Monozygotic twins 8% concordance 67% concordance

45. PATHOGENESIS GENETIC PREDISPOSITION. INFECTIOUS CAUSES. ABNORMAL HOST IMMUNOREACTIVITY.

46. GENETIC Genome wide scanning with microsatellite DNA markers has identified several genetic sites as being potentially associated with UC or CD. Significant linkages have been reported on chromosomes 1, 3, 6, 7, 12, 14, 16, and 19. One of the clearest linkages is for IBD-1, a susceptibility locus in the pericentromeric region of chromosome 16.

47. Detailed analysis has resulted in the identification of the nucleotide-binding oligomerization domain 2 (NOD2) gene and protein. NOD2 is also known as caspase activation and recruitment domain 15 (CARD15). This is a polymorphic gene, the product of which is involved in the innate immune system.

48. NOD2 PROTEIN EXPRESSED IN macrophages / monocytes FUNCTION AS AN INTRACELLULAR RECEPTOR MICROBES TRIGGER NF- kB pathway CYTOKINES AND OTHER PROTEINS INNATE IMMUNE DEFENSE MECHANISM NOD2 gene mutation DOWN REGULATION OF INNATE IMMUNITY LEADS TO INFLAMMATORY BOWEL DISEASES

49. Abnormal host immunoreactivity IBD is characterized by immunoregulatory defects in the mucosa, which appear to be associated with microbial exposure. A number of theories have been advanced concerning the pathogenesis of this process: - dysfunctional immune host response to normal luminal component - infection with a specific pathogen - defective mucosal barrier to luminal antigens.

50. It is hypothesized that exposure to commensal bacteria down-regulates the inflammatory genes and blocks activation of the NF- kB pathway, thus inhibiting the inflammatory immune response of the gut to the microbes and food antigens to which it is constantly exposed.

51. Implicated pathogens include Mycobacterium paratuberculosis Paramyxovirus Listeria monocytogenes Helicobacter hepaticus . .

52. Defective barrier function IBD is associated with increased permeability of the epithelial lining of the gut resulting in continuous stimulation of the mucosal immune system. Luminal bacteria appear to intensify the permeability defect further, establishing a self-sustaining cycle of mucosal inflammation that allows for uptake and translocation of bacteria.

53. Ulcerative colitis Is an inflammatory disease involving only the large intestine. The inner lining or mucosa of the intestine becomes inflamed and develops ulcers. Always starts in rectum and is continuous until some proximal part of the colon. Involves the mucosa and submucosa

54. sites 40-50% of patients have disease limited to the rectum and rectosigmoid 30-40% of patients have disease extending beyond the sigmoid 20% of patients have a total colitis Proximal spread occurs in continuity without areas of uninvolved mucosa

55. Ulcerative colitis – clinical presentation The major symptoms of UC are: - diarrhea - rectal bleeding - tenesmus - passage of mucus - crampy abdominal pain

56. Ulcerative colitis – macroscopic features Mucosa is : - erythematous, has a granular surface that looks like a sand paper In more severe diseases : - hemorrhagic, edematous and ulcerated In fulminant disease a toxic colitis or a toxic megacolon may develop ( wall become very thin and mucosa is severly ulcerated)

57. Acute form with marked hyperemia

58. Ulcerative colitis – microscopic features Process is limited to the mucosa and submucosa with deeper layer unaffected Two major histologic features: - the crypt architecture of the colon is distorted - some patients have basal plasma cells and multiple basal lymphoid aggregates

59. Broad based ulceration of the mucosa in distal colon or throughout its length

60. Pseudopolyps in Ulcerative colitis

61. Ulcerative colitis featuring crypt abscesses

62. Chronic ulcerative colitis in remission

63. Ulcerative colitis in an active phase .

64. Ulcerative colitis - complication s Hemorrhage Perforation Stricture Toxic megacolon (transverse colon with a diameter of more than 5 to 6 cm with loss of haustration )

65. Toxic Megacolon

66. Crohn’s disease (CD) Also referred to as granulomatous or regional enteritis, granulomatous ileitis, ileocolitis Can have non-continuous pattern-” skip lesions ”, with areas of severe inflammation with intervening normal mucosa Most frequently affects distal third of small intestine and the colon Affects all layers of the affected bowel

67. sites Can affect any part of GI tract from the mouth to the anus 30-40% of patients have small bowel disease alone 40-55% of patients have both small and large intestines disease 15-25% of patients have colitis alone In 75% of patients with small intestinal disease the terminal ileum in involved in 90%

68. Crohn’s disease – sign and symptoms Ileocolitis - right lower quadrant pain and diarhhea - palpable mass, fever and leucocytosis - pain is colickly and relieved by defecation Jejunoileitis - inflammatory disease is associated with loss of digestive and absorptive surface

69. Crohn’s disease – sign and symptoms Colitis and perianal disease - low grade fever, malaise, diarrhea, crampy abdominal pain, sometimes hematochezia - pain is caused by passage of fecal material through narrowed and inflamed segments of large bowel Gastroduodenal disease - n a usea , vomiting, epigastric pain - second portion of duodenum is more commonly involved than the bulb

70. Crohn’s disease – macroscopic features CD is a transmural process CD is segmental with skip areas in the midst of diseased intestine In one –third of patients with CD perirectal fistulas, fissures, abscesses, anal stenosis are present

71. Skip lesion of crohns disease

72. Crohn’s disease – macroscopic features mild disease is characterized by: aphtous or small superficial ulcerations In more active disease : stellate ulcerations fuse longitudinally and transversely to demarcate island of mucosa that are histologically normal Cobblestone appearance is characteristic of CD

73. SEGMENTAL INVOLVEMENT WITH TRANSMURAL SPREAD

74. TYPICAL COBBLESTONE APPEARANCE

75. M/E : Mucosal inflammation Mucosa normal and retain mucus. Well-defined focus of inflammatory cells surrounded by non inflammed and normal mucosa As the disease establish , neutrophils infiltrate isolated crypts – abscess – ultimate destruction.

76. Crohn colitis

77. Chronic mucosal damage: Architectural distortion manifested as villous blunting. Crypts exhibit irregularities and branching. Crypt destruction leads to atrophy Gastric antral type or paneth cell metaplasia occur

78. The branched crypt

79. A - Mucosal Granuloma eroding a crypt of lieberkhun and initiating crypt abscess formation. B - Crypt obliterated by Granuloma formation

80. Non Caseating Granuloma - in ½ cases , Sarcoid like, Granuloma in all tissue layers. Others: In diseased segments muscularis mucosa exhibits reduplication , thickening, irregularity's leads to strictures.

81. Crohn disease of the colon .

82. Submucosal nonnecrotizing granulomas

83. Complications of Crohn's Disease: Perianal fistulas Perianal skin ulceration Increased incidence of gall and kidney stones (due to malabsorption of fats and bile salts)

84. Extraintestinal manifestations of IBD Iritis Episcleritis Arthritis Skin involvement Pericholangitis Sclerosing cholangitis

85. Risk of Malignancy in IBD In Crohn’s disease, increased risk of cancer of the affected areas is seen In ulcerative colitis, 8-10 years after initial diagnosis, there is a steady, significant increased risk of developing cancer Prognostic factors increasing malignancy risk in UC: Duration of disease 10 yrs or more Pancolonic involvement Continuous progressive disease Severe initial onset Associated liver disease

86. Gross : Thick mucosa with finely nodular or velvety surface configuration. Lesion polypoid , elevated , nodular or villous formation.

87. M/E : Adenocarcinoma with varying degree of differentiation . Always accompanied by dysplastic changes .

88. Evaluation of Dysplasia 1 - Negative for Dysplasia. 2 - Indefinite for Dysplasia,probably Negative. 3 - Indefinite for Dysplasia, Unknown. 4 - Indefinite for Dysplasia,probably Positive. 5 - Positive for Dysplasia,Low Grade. 6 - Positive for Dysplasia,High Grade.

89. Lab Findings in IBD CBC’s: Anemia is common due to blood loss or malabsorption Leukocytosis & thrombocytosis also common ESR typically elevated; monitors disease activity Abnormal LFTs may represent pericholangitis or sclerosing cholangitis Low serum albumin (protein-losing enteropathy ) suggests extensive colitis

90. Features UC CD Clinical Rectal Bleeding Common Inconspicuous Abdominal mass Practically never 10-15% Abdominal pain Left sided Right sided Sigmoidoscopy Abnormal 95% Abnormal <50% Free perforation 12% 04% Colon CA 2 % Rare Anal complications Minor 75%, fissures, fistulas, ulceration Response to steroid 75% 25% Result of surgery Good Fair

91. Features UC CD Radiographic Sparing of rectum Exceptional 90% Involvement of ileum Rare Common Strictures Absent Present Skip areas Absent Common Internal fistula Absent May be present Longitudinal and transverse ulcers Exceptional Common Fissuring Absent Common

92. Features UC CD Morphologic Distribution of involvement Diffuse Focal Mucosal atrophy Marked Minimal Cytoplasmic Mucin Diminished Preserved Lymphoid aggregates Rare Common Edema Minimal Marked Hyperemia May be extreme Minimal Granulomas Absent Present in 60% Fissuring Absent Present Crypt abscesses Common Rare Rectal involvement Practically always 50% Ileal involvement Minimal 50%

93. REFERENCES Robbins and Cotran . Surgical Pathology – Rosai and Ackerman’s. Sternburg . Harrison’s Textbook of Internal Medicine. Internet