1. INFLAMMATORY BOWEL DISEASEBY
Dr. Nwalozie J.C.

2. Outline Introduction Classification Epidemiology Aetiopathogenesis
Pathology
Clinical presentation
-G.I. Complications
-Extraintestinal manifestations
Differential diagnoses
Investigations/Work- up
Treatment
Prognosis
Summary

3. INTRODUCTION
Inflammatory bowel disease(IBD) is a chronic idiopathic , immune- mediated gastrointestinal condition that arises from a dysregulated immune response to host intestinal microflora.
There is a genetic predisposition.
They pursue a protracted relapsing and remitting course(usually extending over years) & give rise to extraintestinal manifestations.

4. Classification
2 major types(Typical IBD): Ulcerative colitis(UC)/Colitis ulcerosa & Crohn’s disease(CD)/ Crohn syndrome/Regional enteritis.
Atypical IBD: Lymphocytic colitis
Collagenous colitis
Ischaemic colitis
Diversion colitis
Indeterminate colitis
Behcet’s disease

5. EPIDEMIOLOGY Incidence increasing:0.5-24.5/100,000 person-years(UC).
0.1-16/100,000 person-years(CD).
Overall prevalence:396/100,000 person-years
UC:80-150/100,000 person-years
CD:25-100/100,000 person-years
The incidence of IBD varies within different geographic areas
Highest incidence occurs in Europe, United Kingdom and North America.
Jewish > non-Jewish white > African American >Hispanic>Asian

6. M:F for UC is 1:1 and for CD is 1.1-1.8 :1
The peak age of onset is between 15-30yrs. A second peak occurs between the ages of 60-80yrs
M:F for UC is 1:1 and for CD is :1
More common in developed countries, colder climates, urban areas, higher socio-economic classes.
Appendectomy & cigarette smoking are protective in UC but are assoc. with increased risk for CD.
OCP use assoc. with increased risk of CD.

7. A retrospective study was done by Nwosu M
A retrospective study was done by Nwosu M.N et al between January 2007 and June 2010 at 3 teaching hospitals in Southern Nigeria.
-Diagnosis was made from clinical features, colonoscopic and histopathologic findings.
-12 patients presented with IBD: 8(66.7%) were males and 4(33.3%) were females. Age ranges from 18 to 80yrs with a median of 25.5yrs.

8. AETIOPATHOGENESIS
The aetiology of IBD is unknown.

10. Genetic susceptibility
A familial disease(5-10%)
Risk is increased(10%) among 1st degree relatives,5% if a parent has IBD & 36% if both parents have it.
Association with genetic syndromes( Turner, Hermansky-Pudlak, WAS,CGD,IPEX etc)
There is increased concordance of the disease in monozygotic twins in comparison to dizygotic twins
163 susceptibility loci(as at 2012)
Genes associated : NOD 2, ATG16LI, IRGM, JAK2, STAT 3(innate immunity & autophagy), XBP1, ORMDL3, OCTN(ER stress & metabolism), IL23R, IL12B, IL10,PTPN 2(adaptive immunity), MST1, CCR6, TNFAIP3( devt. & resolution of inflammation)

11. Others: ECM 1,IL-26(12q15),1p36.
HLA DRB0103,-0701,MICA 010,HLA B44,HLA B27 have modifying effect.
Presence of gene overlap.
Genetic influences increases the risk of 1 form while decreasing the risk for another.

12. ENVIRONMENTAL FACTORS
Nutrition- Many food and food components have been suggested to play a role in the aetiopathogenesis of IBD eg high sugar or fat intake.E3N prospective study: high animal protein
Smoking
Appendectomy
NSAIDS
Psychological factors
Hygiene

13. The Intestinal microbiota
Dysbiosis
Bacterial antigens
Specific bacterial pathogens
Defective chemical barrier/intestinal defensins
Impaired mucosal barrier function
Butyrate

14. HOST IMMUNE RESPONSE
Normally the mucosal immune system is unreactive to luminal content due to oral(mucosal) tolerance
This tolerance is induced by multiple mechanisms – deletion or anergy of antigen reactive T cells, induction of CD4 T cell type that suppress inflammation (those expressing the fox p3 transcription factor)
In IBD, this suppression is altered leading to uncontrolled inflammation

15. In IBD there is inappropriate innate immune sensing and reactivity to commensal bacteria triggering the inflammation pathway
This pathway entails activation of CD4 T cell that secrete inflammatory cytokines which recruits other inflammatory cells
These cytokines are also normally produced in response to infection but are turned off at appropriate time to limit tissue damage. But in IBD, their activity are not regulated resulting in the disease condition.

16. PATHOLOGY
Ulcerative colitis- there are macroscopic and microscopic features
Macroscopic Features
It is a mucosal disease that usually involves the rectum and extends proximally to involve all or part of the colon
There are no skip areas
The mucosa is erythematous and has fine granular surface resembling sandpaper.

17. In severe disease the mucosa is hemorrhagic, edematous and ulcerated.
In long standing disease, inflammatory polyps as a result of epithelial regeneration.
In remission mucosa may appear normal but in patients with many years of disease it appears atrophic. it can be narrowed and shortened.
Microscopic Features
Findings are limited to mucosal and submucosa
The crypt architecture of the colon is distorted. They can be bifid and reduced in number

18. There can also be cryptitis and cryptal abscess
There is plasma cells and multiple basal lymphoid aggregates
Mucosal vascular congestion with edema and focal hemorrhage
There is inflammatory cell infiltrate of plasma cells, neutrophil, lymphocytes and macrophages
If ileum is involved there is villous atrophy, neutrophil and mononuclear infiltration of lamina propria

19. Crohn’s disease
Macroscopic features
It can affect any part of the G I tract from mouth to the anus
30-40%(small bowel disease), 40-55%(terminal ileum and ascending colon), 15-25%(large bowel alone)
Affectation is segmental with skip areas in the midst of diseased intestine
It is a transmural process
In mild disease there is aphthous or superficial ulceration
Perirectal fistulas, fissures, abscess, and anal stenosis occurs in 1/3rd of patients

20. Rarely it can involve liver and pancreas.
Cobblestone appearance is characteristic of Crohn's dx and is seen on endoscopy and barium study
Microscopic features
There are aphthoid ulcerations and focal crypt abscesses with loose aggregate of macrophages which form non Caseating granulomas in all layers of the bowel.
There is submucosal or subserosal lymphoid aggregate, occurring away from areas of ulceration with gross and microscopic skip areas

21. Cobblestoning

22. CLINICAL PRESENTATION
ULCERATIVE COLITIS
Diarrhea (post prandial/nocturnal)
Rectal bleeding
Tenesmus and passage of mucus
Cramps abdominal pain
Few constitutional symptoms- fever, malaise, anorexia
On examination
Abdomen- slightly distended and tender
DRE-tender anal canal, blood on examining finger

23. Disease severity MILD MODERATE SEVERE Bowel movement < 4 per day
Blood in stool
small
moderate
severe
Fever
none
< 37.5 *C
>37.5*C
Pulse rate
normal
<90 beats/min
>90 beats/min
Anaemia
mild
> 75%
</= 75%
ESR
< 30mm1st hr
>30mm1st hr
Endoscopy
Erythema, decreased vascular pattern, fine granularity
Marked erythema, coarse granularity, absent vascular markings, contact bleed and ulcerations
Spontaneous bleed and ulcerations

24. CROHN’S DISEASE
About 15% of patients have constitutional symtoms
Site of the disease determines clinical features
ILEOCOLITIS
Right lower abdominal pain
Bloody diarrhoea
Weight loss
Right iliac fossa mass
Bowel obstruction`

25. Jejunoilieitis
Steatorrhea and malabsorption
Nutritional deficiencies
Diarrhea
Colitis and perianal disease
Constitutional symptoms
Haematochezia
Diarrhoea
Fecal incontinence, anorectal fistula and perirectal abscess
Gastro duodenal disease
Nausea, vomiting, epigastric pain, features of GOO

26. G.I.COMPLICATIONS Ulcerative colitis- Haemorrhage Toxic megacolon
Perforation
Stricture
Colonic Ca
Crohn’s disease- Adhesions
Fistula formation- enterocutaneous, colovaginal
Intra abdominal and pelvic abscess
Intestinal obstruction

27. Extra Intestinal Manifestations
Up to one-third of IBD patients have extra intestinal disease manifestation
DERMATOLOGIC
Erythema nodosum- found in 15% of CD patient and 10% of UC patient
Digital clubbing
Pyoderma gangrenosum
Pyoderma vegetans
Sweet syndrome- neutrophilic dermatosis
Psoriasis- shared immunologic basis
Perianal skin tags

28. Rheumatologic
Arthropathy
Arthralgia
Inflammatory back pain
Ankylosing spondylitis
Sacroilitis
Ocular
Occurs in 1-10% of patients
Conjunctivitis
Anterior uveitis/iritis
Episcleritis

29. Hepatobiliary
Fatty liver & cirrhosis
Cholelithiasis
Primary sclerosing cholangitis
Urologic
Calculi formation
Ureteral obstruction
Ileo-vesical fistula
Metabolic bone disease
Osteopenia
Osteonecrosis

30. Others include
Hypercoagulable states
Vasculitides
Endocarditis
Interstitial lung disease
Amyloidosis
Pancreatitis

33. Differential Diagnosis
Infectious diseases
Bacterial- Campylobacter colitis, Salmonellosis, Shigellosis, Clostridium difficile, E.coli (enterohaemorrhagic,enteroinvasive)
Viral- Cytomegalovirus, Herpes simplex
Protozoal- Isospora belli, Entamoeba histolytica
Parasitic- Trichuris Trichura, Strongyloides
Fungal- Histoplasmosis, Candidiasis

34. Non infectious
Diverticulitis
Ischaemic bowel disease
Radiation colitis
Appendicitis
Neoplasia- Ca ileum, familial polyposis
Drugs- NSAIDS, OCP, Cocaine

35. Investigations Full blood count: anaemia, leukocytosis
Acute phase reactants: ESR, CRP
Markers of intestinal inflammation- Fecal lactoferrin, Fecal calprotectin
Reduced albumin levels
Stool culture- to exclude superimposed enteric infection

36. Endoscopy
Sigmoidoscopy- used to view the rectum and sigmoid colon. Biospies can be taken for histology
Colonoscopy- shows active inflammation with ulcers and pseudopolyps. Complicating carcinoma can also be seen. Biopsies can be taken to determine disease extent. It should not be done in severe attacks for fear of perforation.
Capsule endoscopy

38. Wireless Capsule

39. Barium studies
Barium enema- it is used in colonic disease. In ulcerative colitis the colon is shortened,there are pseudopolyps and loss of haustrations. In crohn’s colitis there are strictures and ulcers with skip lesions.
Barium meal and follow through- used to detect ulcers and strictures in the upper gastrointestinal tracts

40. OTHER IMAGING:
Abdominal ultrasound and CT scan- shows thickened bowel wall and mesentery as well as intra abdominal and paraintestinal abscess
Radionuclide scan- used to localize extraintestinal abscess
Plain abdominal x-ray- shows dilated bowel and multiple air fluid level in intestinal obstruction.

42. Serological markers
Can be used 2 differentiate btw CD and UC and help in predicting the course of the disease
Perinuclear antineutrophil cytoplasmic antibodies(pANCA) – this is found in 60-70% of UC patients and 5-10% of CD patients, 5-15% of 1st degree relatives of UC patients are pANCA +ve. 2-3% of the general population are pANCA +ve. They are often associated with pancolitis, early surgery, primary sclerosing cholangitis

43. Anti Saccharomyces cerevisiae antibodies (ASCA)- found 60-70% of CD patients and 10-15% of UC patients.5% of non IBD patients are +ve.
Outer membrane porin C(OMPC)- about 55% of CD patients are +ve. Most are likely to have intestinal obstruction.
pANCA +ve with ASCA –ve results showed 57% sensitivity and 97% specificity for UC
pANCA –ve with ASCA+ve showed 49% sensitivity and 97% specificity for CD

44. Anti flagellin(anti CBir1)- identified in 55% of CD patients
Anti flagellin(anti CBir1)- identified in 55% of CD patients. It is associated with small bowel disease and is usually fibrostenosing type.

45. TREATMENT
The management of IBD involves the physician, surgeons, radiologist and dieticians.
Medical Management(Stepwise approach)
Aminosalicylates(5ASA)- sulfasalazine, melsalazine, olsalazine, balsalazide
Used in the treatment of both CD and UC.
Sulfasalazine consist of sulfapyridine linked to 5ASA via an azo bond

46. Intestinal bacteria breaks the azo bond releasing sulfapyridine which is absorbed and excreted in urine.5ASA stays in the lumen in contact with the mucosa an eventually excreted in feaces.
Mechanism of action: modulates cytokine release from the mucosa thereby regulating inflammation
Side effects: abd. discomfort attributed to salicylate effect on the GI tract, folate deficiency due to folate competition with sulfasalazine for absorption. Others include skin eruptions, bone marrow suppression.

47. Other 5ASA preparations- much of the side effects are related to the sulfa portion. So some preparations have the sulfa portion replaced.
They include:
-Olsalazine(diperitum )- consist of 2 5ASA moieties joined by an azo bond, requires bacteria degradation in the colon
-Ascol- controlled release tablet form of 5ASA encapsulated by acrylic resin that dissolves at PH higher than 6.0

48. Pentasa- controlled release formulation of 5ASA encapsulated in ethylcellulose microgranules
Balasalazide- 5ASA preperation containing azo bond. 5ASA moiety is release in the colon by cleavage of azo bond by colonic bacteria.
They induce and maintain remission in UC. They have limited role in inducing remission in CD, but no clear role in maintaining remission.

49. Glucocorticoids
Used in moderate to severe disease of UC and CD
Both oral and parenteral formulations are used
Used in those who are intolerant or unresponsive to aminosalicylates
Oral prednisolone mg dly, methylprednisolone 40-60mg daily and hydrocortisone 300mg dly
Budesonide is a controlled ileal release steroid with fewer side effects
Dosage: 9mg dly then taper
Side effects: fluid retention, fat redistribution, hypergylcaemia, osteoporosis, myopathy etc

50. Antibiotics
Those used are metronidazole and ciprofloxacin
Metronidazole is used in active inflammation, fistulous and perianal CD
Dosage is 15-20mg/kg/day in 3 divided doses
Side effects: nausea, metallic taste, disulfiram like reaction, peripheral neuropathy
Ciprofloxacin beneficial in inflammatory, perianal and fistulous CD but has been associated with achilles tendinitis and rupture.

51. Purine analogues
Azathioprine and 6 mercaptopurine
Used in the management of glucocorticoid dependent IBD and also as post operative prophylaxis of CD
They act by inhibiting immune response
Efficacy is seen by 3-4wks but can take up to 4-6wks
Dosage:Azathioprine(2-3mg/kg/day), 6MP (1-1.5mg/kg/day)
Side effects: Pancreatitis, hepatitis, nausea, fever, rash, bone marrow supression

52. Methotrexate
Inhibits dihydrofolate reductase resulting in impaired DNA synthesis
There is also anti inflammatory property by reducing IL 1 production
Can be given subcut or IM
Side effects: Leukopenia, hepatic fibrosis ,hypersensitivity pneumonitis

53. Cyclosporin
Has inhibitory effects on both cellular and humoral immunity
Given 2-4mg/kg IV in severe disease that is refractory to glucocorticoids
Side effects: renal toxicity, hypertension, tremors, parasthesias, gingival hyperplasia
Tacrolimus
It is a macrolide antibiotic with immunomodulatory properties
Used in children with refractory IBD and in adults with extensive involvement of the small bowel.

54. Biologic Therapy
They are reserved for moderate to severe ill persons who have failed with other therapies
They include:
Anti TNF therapy: eg infliximab. It is a chimeric IgG 1 antibody against TNF-alpha
It is used in patients refractory to glucorticoid, 6 MP, 5 ASA
Used in those with refractory perianal and enterocutanous fistula

55. Side effects: Malignancies like lymphoma, leukaemias, melanoma, hepatosplenic T cell lymphoma. Opportunistic infections like disseminated Histoplasmosis, coccidiodomycosis, exacerbate symptoms in patients with AF
Patients losing response to infliximab can change to adalimumab or certolizumab pegol

56. Natalizumab
It is used for patients who are refractory or intolerant to anti TNF therapy
It was approved in February 2008
There is an increased risk of progressive multifocal leukoencephalopathy in patients been treated with natalizumab
Therapies in development
Monoclonal antibodies against IL 12, 23 derived from intestinal antigen presenting cell

57. Probiotics and Prebiotics
Probiotics are live micro organisms that are used as drug therapy to help develop healthy innate immunity. Eg lactobacillus, bifidobacterium.
Prebiotics are nutrients that are utilized by the gut microflora and they support the growth of these organisms and help improve the host immune system. Eg lactulose, inulin, oligofructose.
They are currently been investigated in clinical trials as treatment for IBD.

58. IV cyclosporine &/or infliximab
Medical therapy for UC
IV cyclosporine &/or infliximab
6MP or Azathiopine
IV glucocorticoid
Oral glucocorticoid
5 ASA(oral or rectal)

59. Medical management of CD
IV cyclosporin /natalizumab
Adalimumab
Infliximab/
6MP/azathiopine/
methotrexate
IV glucocorticoid
Prednisolone/budesonide
5ASA

60. Medical management of fistulizing CD
TPN
IV cyclosporin/
natalizumab
Infliximab/adalimumab
6MP/azathiopine/methotrexate
antibiotics

61. Maintaining remission(UC)
Oral +/- topical 5ASA
Azathioprine(frequent relapses)
Maintaining remission(CD)
Oral 5ASA(limited role)
Azathiopine
Methotrexate(intolerant to azathiopine)
Infliximab

62. Nutritional therapy
Many nutritional deficiencies are associated with IBD due to malabsorption.
Iron depletion, hypoproteinemia, deficiencies in water and fat soluble vitamins, trace elements and electrolytes can be corrected using a suitable replacement regimen
Majority of the patients are advised to eat a well balanced diet and to avoid only those food which by experience are poorly tolerated.

63. Patient with small bowel strictures should avoid nuts, pulses, raw fruit and vegetable which may precipitate intestinal obstruction.
Those with proctitis and constipation will benefit from increase dietary fiber
Patient with active Crohn’s disease respond to bowel rest along with parenteral nutrition

64. Surgical Management Ulcerative colitis
Up to 60% of patients with extensive UC eventually require surgery
Surgery involves removal of the entire colon and rectum. It offers the patient cure.
Choice of surgery is either panproctocolectomy with ileostomy or proctocolectomy with ileal anal anastomosis

65. Indications for surgery(UC)
Intractable disease
Fulminant disease
Toxic megacolon
Colonic perforation
Massive colonic hemorrhage
Extra colonic disease
Colonic obstruction
Colon cancer prophylaxis
Colon dysplasia or cancer.

66. Crohn’s disease
Operation are often necessary to deal with fistulae, abscess, perianal disease and intestinal obstruction.
Up to 80% of patient eventually need some form of surgical intervention but ,unlike UC, it does not offer cure
Recurrence rate is high
Surgical intervention should therefore be conservative to minimize loss of viable intestine and to avoid short bowel syndrome.

67. Those with extensive colitis require total colectomy but ileal anal pouch formation should be avoided because of risk of disease reoccurrence within the pouch and subsequent fistulae, abscess and pouch failure
Those with perianal disease are managed conservatively by drainage of abscess and avoidance of reconstructive procedures
Indication for surgery(small bowel CD)
Stricture and obstruction
Unresponsive to medical therapy

68. Massive hemorrhage
Refractory fistula
Abscess collection
Colon and rectum CD
Intractable disease
Fulminant disease
Perianal disease unresponsive to medical therapy
Colonic obstruction
Colon dysplasia or cancer

69. IBD and Pregnancy Women with inactive IBD have normal fertility.
Those who have had surgery secondary to IBD, there fertility rate is reduced to one third of normal due to scarring or occlusion of the fallopian tube secondary to pelvic inflammation
Spontaneous abortion, stillbirths and developmental defects are increased with increase disease activity not medication
Most patients can deliver vaginally but caesarean section may be preferred in patients with anorectal, perirectal abscess and fistula to reduce the likelihood of fistula developing or extending into episiotomy scar

70. Sulfasalazine and melsalazine are safe for use during pregnancy and nursing but folate supplementation is required.
Glucocorticoids are generally safe during pregnancy and nursing and are indicated with moderate to severe disease activity
Safest antibiotics to use are ampicillin and the cephalosporins
6MP and azathiopine pose minimal or no risk during pregnancy but experience is limited

71. Little data exist on cyclosporine
Little data exist on cyclosporine. In patients treated with IV cyclosporine during pregnancy, 80% were completed.
Methotrexate is contraindicated in pregnancy and nursing.
No increased stillbirth, miscarriages or spontaneous abortion has been seen with infliximab or adalimumab.
Surgery should be performed only for emergency indication
Fetal mortality is high during surgery.

72. Cancer in IBD Ulcerative colitis
Patients with long standing UC are at increased risk for developing colonic dysplasia and carcinoma
For patient with pancolitis, the risk of cancer rises 0.5-1%/yr after 8-10 yrs
This has lead to surveillance colonoscopy with biopsies for patient with chronic UC as the standard care

73. Annual or biennial colonoscopy with multiple biopsies has been advocated for patients with >8-10 yrs pancolitis or 12-15yrs of left sided colitis
Crohn’s disease
Risk factors for developing colorectal cancer in CD are a history of colonic(or ileocolic) involvement , long disease duration, family history of colorectal Ca and presence of PSC.
Cancer risk for CD and UC are equivalent for similar extent and duration of disease.

74. Same endoscopic surveillance strategy used for UC is recommended for patients with chronic Crohn’s colitis
CD patients have a 12-fold increased risk of developing small bowel cancer but this type of carcinoma is extremely rare
Patients with CD may have an increased risk of developing non- Hodgkin’s lymphoma and squamous cell carcinoma of the skin.

75. Management
For flat high grade dysplasia, for UC treatment is colectomy and for CD is either colectomy or segmental resection.
For flat low grade dysplasia, immediate colectomy is done.
Adenoma in UC and CD patients with chronic colitis are removed endoscopically provided surrounding areas are free of dysplasia.

76. Prognosis
The chance of survival for patients with IBD is generally good
For both conditions, the overall mortality is currently less than 5%. UC is curable with proctocolectomy and ileostomy.
In CD, intestinal resection and re-anastomosis is followed by reoccurrence in about 20-25%
Extensive involvement has poor prognosis in both conditions while isolated small bowel CD and ulcerative proctitis carry good prognosis
Study done in Sweden on 709 patients with IBD, survival in the 1st year is 94% and 77% after 12yrs

77. Summary ULCERATIVE COLITIS CROHN’S DISEASE INCIDENCE (NORTH AMERICA)
:100000
:100000
MALE TO FEMALE RATIO
1:1 :1
MONOZYGOTIC TWINS
6% Concordance
58% Concordance
DIZYGOTIC TWINS
0% Concordance
4% Concordance
SMOKING
Found more in non smokers
More in smokers
OCP
No increased risk
Increased risk
APPENDECTOMY
Protective
Not protective

78. ULCERATIVE COLITIS
CROHN’S DISEASE
AREA OF INVOLVEMENT
Rectum +/- colon
Entire GI tract
TYPE OF LESION
Continuous
Skip lesions
LAYERS INVOLVED
Mucosa & submucosa
Transmural
GROSS BLOOD IN STOOL
Yes
Occasionally
MUCUS
ABDOMINAL PAIN
Frequently
ABDOMINAL MASS
Rarely
SYSTEMIC SYMPTOMS

79. ULCERATIVE COLITIS
CROHN’S DISEASE
PERIANAL DISEASE No
Frequently
FISTULAS
SMALL BOWEL OBSTRUCTION
COLONIC OBSTRUCTION
Rarely
RECTAL SPARING
COBBLESTONING
Yes
GRANULOMA ON BIOPSY
Occasionally

80. ULCERATIVE COLITIS
CROHN’S DISEASE
pANCA-POSITIVE
Frequently
Rarely
ASCA-POSITIVE
USE OF ANTIBIOTICS AND TPN No
Yes
SURGERY
Offers cure
Does not offer cure

81. Conclusion
IBD is a chronic relapsing immune-mediated GI condition with extraintestinal manifestations.
UC and CD are the major types and are ,in many respects, similar but there are contrasting features which relate to sites of involvement and other features.
Diagnosis is based on clinical, endoscopic and histopathologic features.
Management is multidisciplinary & should be individualized.

82. ThankS For listening!