MUHAMMAD ADIB THAQIF BIN MAZLAN 11-2012-211 UNIVERSITAS KRISTEN KRIDA WACANA

ULCERATIVE COLITIS Definitions:- A relapsing and remitting inflammatory disorder of the colonic mucosa. It may affect just the rectum (~50%) or extend proximally to involve part of the colon (~30%) or entire colon (~20%). It never spreads proximal to the ileocaecal valve.1,2,3 Prevalence:- 100 to 200/100,000 with female to male ratio >1:1. Most preset aged 15-30 years. 3-fold as common in non-smoker symptoms may relapse on stopping smoking. Ulcerative colitis is more common in the Western and Northern hemispheres; the incidence is low in Asia and the Far East.1,2 Incidence:10-20/100,000/yr1 Cause:Unknown. Etiologic factors contributing to UC include: Genetics Genetically susceptible individuals have abnormalities of humoral and cell-mediated immunity and/or generalized enhanced reactivity against commensal intestinal bacteria which becomes a predisposition to colonic inflammation. Family history has a higher risk for developing the disease.2 Immune reactions Compromises the integrity of the intestinal epithelial barrier may contribute to UC. Serum and mucosal autoantibodies against intestinal epithelial cells may be involved. Presence of antineutrophil cytoplasmic antibodies and anti-Saaccharomyces cerevisiae antibodies is a well-known feature of inflammatory bowel disease.2 Environmental factors Sulphate reducing bacteria, which produce sulfides, are found in large numbers in patients with UC, and sulfide production is higher in patients with UC than in other people. Sulfide production is even higher in patiens with active UC than in patients in remission.2 NSAID NSAID use is higher in patients with UC than in control subjects, and one third of patients with an exacerbation of UC report recent NSAID use. This finding leads some to recommend avoidance of NSAID use in patients with UC2 Other factors o Low vitamins A and E (antioxidants) o Psychological and psychological stress factors can precipitate exacerbations o Smoking is negatively associated with UC. This relationship is reversed in Crohn disease o Milk consumption may exacerbate the disease Pathology:- Subsets of T cells accumulate in the lamina propria of the diseased colonic segment. In patients with ulcerative colitis, these T cells are cytotoxic to colonic epithelium. This change is accompanied by an increase in the

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population of B cells and plasma cells, with increased production of IgG and IgE.2 Hyperaemic/ Haemorrhagic granular colonic mucosa with or without pseudopolyps formed by inflammation. Punctate ulcers may extend deep into the lamina propria inflammation is normally not transmural. Mucosal disease differentiates it from Crohns disease.2 Microscopically, acute and chronic inflammatory infiltrate of the lamina propria, crypt branching, and villous atrophy are present in ulcerative colitis. Microscopic changes also include inflammation of the crypts of Lieberkhn and abscesses accompanied by a discharge of mucus from the goblet cells. The undermining of mucosa and an excess of granulation tissue lead to the formation of polypoidal mucosal excrescences, which are known as inflammatory polyps or pseudopolyps.2 Gradual onset of diarrhoea ( blood and mucous). Crampy abdominal discomfort is common; bowel frequency is related to severity of disease. Systemic symptoms are common during attacks (fever, malaise, anorexia, weight loss). Urgency and tenesmus occurs with rectal disease.1 May be none. In acute, severe ulcerative collitis there may be fever, tachycardiaa and a tender, distended abdomen. Extraterrestrial signs include clubbing, aphthous oral ulcers, erythema, nodosum, pyoderma gangrenosum, conjungtivitis, episcleritis, iritis, large joint arthritis, sacroillitis, ankylosing spondylitis, fatty liver, cholangiosarcoma, nutritional deficits, amyloidosis.1 Full Blood Count (Leukocytosis), Erythrocyte Sendimentation Rate, CReactive Protein, Urea and Electrolyte, Liver Function Test and Blood Cultures. Stool Microscopic, culture and sensitivity to exclude infections. Abdominal roentgent will show no fecal shadows, mucosal thickening/islands, colonic dilatation. Erect chest roentgent shows perforation. Sigmoidoscopy shows inflamed, friable mucosa. Rectal biopsy will show inflammatory infiltrate, goblet cell depletion, glandular distortion, mucosal ulcers, crypt abscesses. Colonoscopy shows disease extent and allows biopsy.1

Assessing Severity in Ulcerative Colitis: The Truelove and Witts Criteria Mild Moderate Severe Parameter <4 4-6 >6 Motions/day Small Moderate Large Rectal Bleeding o o Apyrexial 37.1 C-37.8 C >37.8oC Temperature at 6am <70 70-90 >90 Pulse rate >11g/dL 10.5g/dL 11g/dL <10.5g/dL Haemoglobin <30mm/h >30mm/h ESR

Complications:-Perforation and bleeding are 2 serious dangers, also Toxic dilatation of colon (mucosal islands, colonic diameter >6cm) Venous thrombosis: Give prophylaxis to all inpatients Colonic cancer with risk = 15% with pancolitis for 20 years; surveilance colonoscopy may be used but proving this saves lives has been difficult Inducing Remissions Mild UC:If <4 motions/day and the patient is well, give prednisolone (2040mg/day per oral) and mesalazine (00m tabs; up to 1g/6hours). For mild distal disease use twice daily steroid foams per rectal (hydrocortisone or prednisolone 20mg retention enemas. If symptoms improve, lessen the steroids gradually. If no improvement after 2 weeks, treat as moderate UC1,3 Moderate UC:If 4-6 motions/day but otherwise well, give oral prednisolone 40mg/day for 1 week, then 30mg/day for 1 week, then 20mg/day for 4 weeks with a 5-aminosalycilic acid and twice daily steroid enemas. If improving, lessen the steroids gradually. If no improvement after 2 weeks, treat as a severe UC1,3 Severe UC:If Systematically unwell and passing >6 motions/day, admit for Nil by mouth and IV maintenance hydration (1L of Saline 0.9% + 2L dextrose saline per 24 hours with 20mmol Potassium/L) Hydrocortisone 100mg/6h IV Rectal steroids, eg hydrocortisone 100mg in 100ml 0.9% saline/12 hours per rectal Monitor temperature, pulse and blood pressure and record stool frequency/characters on a stool chart Twice daily exam; document distension, bowel sounds and tenderness Daily full blood count, Erythrocyte sendientation rate, C-reactive protein, ureum and electrolyte, abdominal roentgen Consider the need for blood transfusion. Parenteral nutrition is only very rarely required If improving in 5 days, transfer to prednisolone per oral (40mg/24hours) with a 5 aminosalycilic acid to maintain remission If on day 3 c-reactive protein or stool frequency >6, consider ciclosporin/infliximab/surgery1,3 FDA approved a new indication for golimumab for the treatment of adults with moderate-to-severe UC that is resistant to prior treatment or requires continuous steroid therapy. The dosing regimen consist of 200 mg subcutaneously injected at 0 weeks, followed by 100 mg at week 2 and then by 100 mg every 4 weeks thereafter.2 Increased risk for serious infections, invasive fungal infections, reactivated hepatitis B virus infection, lymphoma, heart failure, nervous system disorders and allergic reactions.2

Topical therapies Proctitis may responds to suppositories (prednisolone 5mg or mesalazine 250mg/8hours) topical 5 aminosalycilic acid work better than topical steroids. Proctosigmoiditis may responds to foams per rectal; disposable applicators aid accurate delivery. Rentention enemas may be needed in left sided colitis.1 Surgery Around 20% require surgery at some stage. Indications of surgery is: Perforation Massive haemorrhage Toxic dilatation Failure to respond to medical therapy Proctocolectomy and terminal ileostomy to retain the ileocecal valve, and hence reduce liquid loss. Colectomy with later ileo-anal pouch. Mortality is around 2-7%: can increase to 50% if perforation. Pouchitis can be treated with antibiotics and immunosuppresants.1 Novel Therapies A short course of ciclosporin (2mg/kg IV per day) may help obtain remission quickly in patients with steroid refractory UC, although it is markedly nephrotoxic and not suitable for long courses. Short-term response to ciclosporin is generally good (>75%) but long term remission is disappointing. Infliximab may be effective as rescue therapy in UC, though evidence is scarce.1 Maintaining Remission All 5-Aminosalycilic acid reduces relapse rate from 80% to 20% at 1 years- examples are sulfasalazine,mesalazine, and olsalazine. Maintenance continues for life. Sulfasalazine (500mg/6hours per oral) is the first line drug. Newer drugs (mesalazine 400mg-800mg/8hours per oral or olsalazine 500mg/12hours per oral) are just as effective at maintaining remission, have fewer side effects (headaches, nausea, anorexia, malaise) but are more expensive. They are indicated in sulfasalazine intolerance and young men whose fertility is a concern. Azathioprine (2.0-2.5 mg/kg/day per oral after eating) is indicated as a steroid sparing drug in those with steroid side effects or those who relapse quickly if steroids are reduced. Treat for several months, and monitor full blood count every 4 to 6 weeks.1 Prognosis Ulcerative colitis may result in disease-related mortality. However, overall mortality is not increased in patients with ulcerative colitis, as compared with the general population. An increase in mortality may be observed among elderly patients with the disease. Mortality is also increased in patients who develop complications (shock, malnutrition, anemia). Evidence suggests that mortality is increased in patients with ulcerative colitis who undergo any form of medical or surgical intervention.2 Involvement of the muscularis propria in the most severe cases can lead to damage to the nerve plexus, resulting in colonic dysmotility, dilation, and eventual infarction and gangrene, a condition termed toxic megacolon. This condition is characterized by a thin-walled, large, dilated colon that may eventually become perforated. Chronic disease is associated with pseudopolyp formation in about 15-20% of cases. Chronic

and severe cases can be associated with areas of precancerous changes, such as carcinoma in situ or dysplasia.2 The most common cause of death of patients with ulcerative colitis is toxic megacolon. Colonic adenocarcinoma develops in 3-5% of patients with ulcerative colitis, and the risk increases as the duration of disease increases. The risk of colonic malignancy is higher in cases of pancolitis and in cases in which onset of the disease occurs before the age of 15 years. Benign structure rarely causes intestinal obstruction.2 Complications Reported after ileal pouch-anal anastomosis procedures. The anastomotic leak rate is 7-9%. Pelvic abscess, which frequently accompanies an anastomotic leak, occurs in about 5% of the case. If the abscess is managed with diversion and drainage, the pouch may be spared. Stool frequency is less than 5 per day in as many as 74%. Difficulty with evacuation occurs in 20%. Complete incontinence is reported in only 2%. Sexual dysfunction, manifest by retrograde ejaculation or impotence, occurs in 3% of males.2 Pouchitis is defined as a clinical syndrome in which the patient has increased stool frequency, malaise, fever, or incontinence. This syndrome usually responds to antibiotic therapy. The most frequently used antibiotics are ciprofloxacin or metronidazole. The incidence is reported to be 40-60%. Pouch dilatation and pouchanal anastomotic stricture may lead to fecal stasis and predispose the patient to pouchitis.2 Toxic megacolon occurs in less than 2% of cases and can be induced by hypokalemia, opiates, anticholinergics, and barium enemas. Conservative treatment can be tried for 24-48 hours with IV fluids, IV steroids, antibiotics, and IV cyclosporine.2 Carcinoma is a known complication of ulcerative colitis in the small group of patients who have had the disease for approximately 10 years. The residual colonic mucosa is at risk for dysplasia and neoplastic transformation. Guidelines from the American College of Gastroenterology recommend that after 8-10 years of colitis, patients with ulcerative colitis should undergo annual or biannual surveillance colonoscopy with multiple biopsies at regular intervals.2 Reference 1. Murray Longmore, Wilkinson I.B., Davidson E.H, Alexander Foulkes, Mafi A.R. Ulcerative Colitis. Oxford handbook of clinical medicine 8th edition, United States. Oxford University Press: 2010; 272-273 2. Basson M.D, Julian Katz. Ulcerative Colitis. Diunduh di http://emedicine.medscape.com/article/183084-overview pada 21 Juli 2013. Update artikel pada tanggal 27 May 2013. 3. Kenneth R.M. Gastrointestinal bleeding. Dalam Papadakis M.A, McPhee S.J. Current medical diagnosis and treatment 49th edition, United States: McGraw-Hill; 2013. Lange638-640