Title 3. INFLAMMATORY BOWEL DISEASE.pdf ✅

PHARMD GURU Page 1 INFLAMMATORY BOWEL DISEASE INTRODUCTION:  Inflammatory bowel disease (IBD) is an idiopathic disease caused by a dysregulated immune response to host intestinal microflora.  Inflammatory bowel disease (IBD) comprises two distinct diseases: Crohn’s disease (CD) and ulcerative colitis (UC).  Ulcerative colitis: This condition causes long-lasting inflammation and sores (ulcers) in the innermost lining of large intestine (colon) and rectum. Classically, ulcerative colitis begins in the rectum, and in continuity extends upwards into the sigmoid colon, descending colon, transverse colon, and sometimes may involve the entire colon. The colonic contents may rarely back flow in the terminal ileum in continuity, causing ‘back wash ileitis’ in about 10% of cases.  Crohn's disease: Crohn’s disease may involve any portion of the gastrointestinal tract but affect most commonly 15-25 cm of the terminal ileum which may extend into the caecum and sometimes into the ascending colon. Both ulcerative colitis and Crohn's disease usually involve severe diarrhoea, abdominal pain, and fatigue and weight loss. EPIDEMIOLOGY:  Inflammatory bowel disease (IBD) is most prevalent in Western countries and in areas of northern latitude. GASTROINTESTINAL SYSTEM INFLAMMATORY BOWEL DISEASE CROHN'S DISEASE ULCERATIVE COLITIS
PHARMD GURU Page 2  The reported rates of IBD are highest in Scandinavia, Great Britain, and North America. Crohn’s disease (CD) has an incidence of 3.6 to 8.8 per 100,000 persons in the United States and a prevalence of 20 to 40 per 100,000 people.  The incidence of CD varies considerably among studies, but has clearly increased dramatically over the last 3 or 4 decades. Ulcerative colitis (UC) incidence ranges from 3 to 15 cases per 100,000 persons per year among the white population with a prevalence of 80 to 120 per 100,000.  The incidence of UC has remained relatively constant over many years. Although most epidemiologic studies combine ulcerative proctitis with UC, 17% to 49% of cases are classified as proctitis.  Both sexes are affected equally with IBD, although some studies show slightly greater numbers of women with CD and males with UC. UC and CD have bimodal distributions in age of initial presentation. The peak incidence occurs in the second or third decades of life, with a second peak occurring between 60 and 80 years of age.  A high incidence of UC (4 to 5 times normal) occurs in Ashkenazi Jews, while blacks and Asians have a relatively low incidence of occurrence. ETIOLOGY: 1. IMMUNOLOGICAL FACTORS: The exact cause of IBD is unknown, but IBD is the result of a defective immune system. A properly functioning immune system attacks foreign organisms, such as viruses and bacteria, to protect the body. In IBD, the immune system responds incorrectly to environmental triggers, which causes inflammation of the gastrointestinal tract. 2. GENETIC FACTORS:  There is about 3 to 20 time higher incidence of occurrence of IBD in first degree relatives. This is due to genetic defect causing diminished epithelia barrier function.  There is approximately 50% chance of development of IBD (Crohn’s disease about 60%, ulcerative colitis about 6%) in monozygotic twins. However there is no clear link between the abnormal genes and IBD.
PHARMD GURU Page 3 3. EXOGENOUS FACTORS: 1) Microbial factors: Microbial factors (bacteria, viruses, protozoa and fungi) have been suspect but without definite evidence. 2) Psychosocial factors: It has been observed that individuals who are unduly sensitive, dependent on others and unable to express themselves, or some major life events such as illness or death in the family, divorce, interpersonal conflicts etc. suffer from irritable colon or have exacerbation of symptoms. 3) Smoking: Role of smoking in causation of Crohn’s disease has been reported. 4) Oral contraceptives: An increased risk to develop Crohn’s disease with long term use of oral contraceptive has been found in some studies but there is no such increased risk of ulcerative colitis. PATHOPHYSIOLOGY:
PHARMD GURU Page 4  The location and appearance of inflammatory lesions differs between the two forms.  In Crohn’s disease, inflammatory lesions extend through the bowel wall and develop simultaneously in separate areas.  Granuloma formation occurs first, followed by ulceration and abscess formation, fistula may form between the affected areas and the bladder, vagina or rectum. With repeated episodes, the gut wall assumes a cobblestone appearance, with permanent scarring and constriction.  The characteristic lesion of UC is the crypt abscess, pus filled, necrotic lesion that starts at the bases of any of the tubular glands of the intestinal mucous membrane. These lesions ulcerate and bleed during flares, then heal with scarring and constriction.  In a normal individual, there is lack of immune responsiveness to dietary antigens and commersal flora in the intestinal lumen. The mechanism responsible for this is by activation of CD4+T cell secreting cytokines inhibitory to inflammation (IL-10, TGF- β) which suppress inflammation in the gut wall.  In IBD, this immune mechanism of suppression of inflammation is defective and thus results in uncontrolled inflammation. In both types of IBD, activated CD4+T cells are present in the lamina propria and in the peripheral blood. These cells either activate other inflammatory cells macrophages and B cells. There are two main types of CD4+T cells in IBD.  TH1 cells secrete proinflammatory y-cytokines IFN-γ and TNF which induce transmural granulomatous inflammation seen in Crohn’s disease. IL-12 initiates TH1 cytokine pathway.  TH2 cells secrete IL-4, IL-5 and IL-13 which induce superficial mucosal inflammation characteristically seen in ulcerative colitis.  Crohn’s disease begins with crypt inflammation and abscesses, which progress to tiny focal aphthoid ulcers.  These mucosal lesions may develop into deep longitudinal and transverse ulcers with intervening mucosal edema, creating a characteristic cobblestoned appearance to the bowel.