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ulcerative colitis (UC)

Ulcerative colitis is an idiopathic chronic inflammatory disease of the colon & rectum characterized by exacerbations & remissions [2]. Etiology: - dietary linoleic acid a risk factor (HR=2.5); 30% of cases may be attributable to linoleic acid [8] - Mycobacterium avium paratuberculosis? Epidemiology: 1) more common in Scandinavian countries, Great Britain & North America 2) may develop initially after cessation of cigarette smoking Pathology: 1) rectal involvement occurs in all patients 2) involves all segments of bowel within the affected area 3) disorder of the colonic mucosa; lesion does NOT extend transmurally (in contrast to Crohn's disease) 4) up-regulation inflammatory molecules: REG4 5) histopathologic remission predicts long-term outcomes [41] Genetics: - familial tendency, increased concordance in twins, more common in Jewish & Caucasians - presence of the single nucleotide variation HLA-DRB1*01:03 is associated with severe ulcerative colitis [48] Clinical manifestations: 1) acute onset of bowel urgency, frequent watery stools, & often bloody diarrhea [3] - > 6 stools/day suggests severe colitis [3] - ref [3] suggests slow onset of symptoms 2) patients may remember when symptoms first started [3] 3) characterized by exacerbations (flares) & remissions 4) diarrhea (inflammatory) a) small volume, generally < 200 mL/day b) predominant symptom is bloody diarrhea 5) hematochezia (bloody stools) - frequent bloody stools suggests severe colitis 6) abdominal pain & tenderness, abdominal distension - may improve after bowel movement [45] 7) fever, tachycardia, malnutrition & dehydration in severe disease - body temperature > 37.5 C suggests severe colitis - pulse > 90/minute suggests severe colitis [3] 8) proctitis, rectal pain 9) tenesmus 10) fecal incontinence [3] 11) extracolonic manifestations (45% of cases) a) eyes: uveitis, iritis, episcleritis, pain or burning of eyes, blurred vision, photophobia b) skin: erythema nodosum, pyoderma gangrenosum, most commonly on anterior aspect of lower extremities c) joints: see enteropathic arthritis - arthritis, often migratory, affecting large joints - generally non-destructive, arthralgias - ankylosing spondylitis, sacroiliitis d) liver: jaundice, hepatomegaly, splenomegaly - liver involvement suggest primary sclerosing cholangitis e) extracolonic manifestations parallel colonic disease activity [45,46] Laboratory: 1) complete blood count (CBC) - anemia, leukocytosis, thrombocytosis - blood hemoglobin < 75% normal suggests severe colitis 2) serum chemistries a) electrolytes b) urea nitrogen c) serum creatinine d) serum bicarbonate e) liver function tests - abnormalities may suggest cholangitis f) nutritional assessment - serum albumin, prealbumin, serum transferrin may be low - low serum 25-OH vitamin D common & associated with higher morbidity & disease severity [23] g) 25-hydroxyvitamin D in serum - lower levels during remission (29.5 vs 50.3 ng/mL) associated with increased with of flair [24] 3) markers of inflammation - erythrocyte sedimentation rate (ESR) may be elevated - > 30 mm/hr suggest severe colitis - monitor serum C-reactive protein [28] 4) stool examination: a) fecal leukocytes, b) fecal occult blood c) ova & parasites d) C difficile toxin - C difficile colitis may occur in patients with ulcerative colitis without recent antibiotic therapy [3] e) stool culture: Yersinia, Campylobacter, E. coli O157:H7 f) monitor fecal calprotectin every 3-6 months [28] - rising levels warrant endoscopic evaluation - can be used to monitor for postoperative recurrences - distinguishes from irritable bowel syndrome 5) blood cultures for suspected sepsis 6) serum Saccharomyces cerevisiae IgG/IgA 10%; 60% in Crohn's disease 7) anti-neutrophil cytoplasmic antibodies (ANCA) - p-ANCA 10%, 75% in ulcerative colitis 8) fecal calprotectin - use as a surrogate for endoscopy to assess for mucosal healing when endoscopy is not feasible or available [36] - may be useful for evaluating patients with non-bloody diarrhea [45] 9) see inflammatory bowel disease for therapeutic drug monitoring Special laboratory: - colonoscopy a) delineate extent of colonic & terminal ileal disease - inflammation characterized by erythema, edema & friable mucosa b) biopsy indicated c) avoid in seriously ill patients - abdominal distension d) advised within 8-10 years of IBD onset e) high-definition colonoscopy favored over standard definition [19] f) routine performance of chromoendoscopy during IBD surveillance is recommended as an adjunct to high-definition colonoscopy [19] g) narrowband imaging is not a replacement for high-definition, white-light colonoscopy or chromoendoscopy [10] h) no specific recommendation on performance of random biopsies[19] i) screening intervals of 1-3 years [3,36]; 1-5 years [44] j) polypectomy & continued surveillance recommended for adenoma-like dysplasia-associated lesion or mass with no evidence of other flat dysplasia [9] - after complete removal of endoscopically resectable polypoid or nonpolypoid dysplasia, surveillance colonoscopy is recommended rather than colectomy [19] k) for patients with endoscopically invisible dysplasia (confirmed by a GI pathologist), referral is suggested to an endoscopist with expertise in IBD surveillance using chromoendoscopy with high-definition colonoscopy [19] l) reduces colorectal cancer risk 35% [18] Radiology: 1) upper GI series with small bowel follow-through - exclude upper GI Crohn's disease 2) plain abdominal radiograph - colonic distension 3) avoid barium enema a) less sensitive in mild disease b) may precipitate toxic megacolon in patients with moderate to severe colitis Differential diagnosis: 1) irritable bowel syndrome (IBS) - fecal calprotectin negative in IBS 2) other forms of colitis a) Crohn's disease - involvement of patchy areas in Crohn's diseas vs contiguous involvement for ulcerative (UC) - rectal involvement in UC, rare in Crohn's - fistulas, abscesses & strictures rare in UC - perianal disease (rare in UC) - granulomas in 30% of Crohn's, unlikely in UC - rectal bleeding common in UC, less common in Crohn's - tobacco protective for UC, exacerbated in Crohn's b) infectious colitis - bacterial: Shigella, Salmonella, Yersinia, Campylobacter, E. coli O157:H7 - parasites: Entamoeba histolytica, Giardia lamblia c) pseudomembranous colitis d) ischemic colitis e) radiation colitis f) lymphocytic colitis 3) other causes of hematochezia a) colorectal carcinoma b) diverticulosis 4) Meckel's diverticulum: generally painless rectal bleeding 5) microscopic colitis: non-bloody diarrhea 6) other causes of diarrhea: HIV associated diarrhea 7) hepatobiliary involvement, pruritus, elevated serum alkaline phosphatase suggests primary sclerosing cholangitis [3] Complications: 1) increased risk for cancer - increased risk of colon carcinoma - 10% risk at 10-20 years - increase of 10% for each decade thereafter - additional risk factors - disease duration - extensive disease - primary sclerosing cholangitis - family history of colorectal cancer [9] - increased risk for cervical cancer & non-melanoma skin cancer [3] 2) osteoporosis & fractures due to malabsorption (vitamin D & calcium) 3) increased risk of venous thromboembolism [3] - LMW for DVT prophylaxis despite active bleeding [3] - risk for DVT is highest at the time of flare [3] 4) C difficile colitis may occur in patients without recent antibiotic therapy [3,17] - use vancomycin rather than metronidazole [36] 5) CMV colitis is a common cause of bloody diarrhea in patients with refractory ulcerative colitis [17] (diagnose with sigmoidoscopy & biopsy) [45] 6) toxic megacolon [3] Management: 1) general - treat to target - resolution of rectal bleeding & diarrhea - endoscopic remission - treat to target could overtreat patients with low risk of disease progression - used personalized approach [28] - vaccines - pneumococcal vaccine prior to immunosuppressive therapy if possible - seasonal influenza vaccine - avoid live virus vaccines with immunosuppressive therapy - delay live virus vaccination 1-6 months after discontinuation of immunosuppressive therapy - Shingrix vaccine recommended 2) pharmacologic agents a) mild to moderate colitis - proctitis - mesalamine suppositories (Rowasa) 500 mg 1st line - rectal glucocorticoid if intolerant of mesalamine - effective for induction but not maintenance of remission - hydrocortisone suppositories (Anusol-HC) 25 mg - hydrocortisone foam (Cortifoam) - budesonide MMX (Entocort EC, Uceris, Cortiment) - left-sided colitis - oral mesalamine + mesalamine enemas (Rowasa) 4 g - hydrocortisone enemas (Cortenema) 100 mg - QHS or BID (once a day mesalamine 2-4 g) [34] - left-sided or pancolitis - 5-aminosalicylates - mesalamine 2-4 g once a day [34]; prior Asacol 800 mg TID, Pentasa 1 g QID; once a day mesalamine is preferred over budesonide for mild-to-moderate disease [34] - oral mesalamine + mesalamine enemas (Rowasa) 4 g helpful for inducing remission [3] - sulfasalazine (Azulfidine) 1 g QID + folate 1 mg QD - glucocorticoids second line [34] - budesonide (Uceris) 9 mg PO QD for 8 weeks [12] - prednisone 40-60 mg QD - nicotine [3] - ozanimod (Zeposia) may be effective for both induction & maintenance therapy b) moderate to severe colitis - mirikizumab-mrkz (Omvoh) FDA-approved - glucocorticoids vs biologic agent for flare [45,46] c) severe colitis or toxic megacolon - methylprednisilone (Solumedrol) 20-30 mg IV TID followed by 5-aminosalicylate - either infliximab or cyclosporine is suggested if refractory to methylprednisilone [39] - failure of glucocorticoids in the absence of systemic symptoms constitutes refractory colitis [3] - ACTH 80 units IM QD - IV broad-spectrum antibiotics for systemic symptoms (fever, leukocytosis or peritonitis) [3] - ampicillin + gentamicin + metronidazole - ciprofloxacin + metronidazole - cefoxitin (Mefoxin) - ticarcillin clavulanate (Timentin) - no mention of fecal antigen testing in association with empiric antibiotic therapy [3] - surgical consult (see surgery below) [25] d) assessment of severity - stools: < 4/day mild; > 6/day severe - bloody stools: intermittent mild; frequent severe - body temperature: normal mild; > 37.5 C severe - pulse: normal mild; > 90/min severe - blood hemoglobin: normal mild; < 75% normal severe - ESR < 30 mm/hr mild; > 30 mm/hr severe - colonoscopy [45,46] e) maintenance therapy - glucocorticoids are ineffective as maintenance therapy - proctitis - mesalamine suppositories (Rowasa) 500 mg at least frequent interval maintaining remission - left-sided colitis - mesalamine enemas (Rowasa) 4 g - hydrocortisone enemas (Cortenema) 100 mg - at least frequent interval maintaining remission - left-sided or pancolitis - 5-aminosalicylates - sulfasalazine (Azulfidine) 1-2 g BID + folate 1 mg QD - mesalamine (Asacol) 800-1200 mg BID - olsalazine (Dipentum) 500 mg BID - ozanimod (Zeposia) may be effective for both induction & maintenance therapy - methotrexate is ineffective for long-term maintenance [31] (effective in Crohn's disease) f) refractory colitis - infliximab (TNF-alpha inhibitor) [7] (initial 1st line biologic [39]) - efficacy similar to cyclosporine - easier to administer than cyclosporine [11] - no role in management of toxic megacolon [25] - combination therapy with infliximab plus azathioprine superior to either agent alone [15] - vedolizumab or tofacitinib (Xeljanz) [30,38] FDA-approved May 2018 - effective in inducing & maintaining remission in moderate-severe ulcerative colitis [39] - inducing remission when anti-TNF agents have failed [39] - use tofacitinib (10 mg PO BID for 8 weeks) to induce remission [36] - TNF-alpha inhibitors also effective against enteropathic arthritis - adalimumab (Humira) [10,38] - golimumab (Simponi) [13] - discontinuation of TNF-alpha inhibitors associated with relapse more often than not [28] - ustekinumab as induction & maintenance therapy [37] - risankizumab (Skyrizi) may be useful for induction & maintenance [47] - other immunosuppressants - azathioprine (Imuran) 100-150 mg QD - check thiopurine methyltransferase in erythrocytes prior to administration [3] - 6-mercaptopurine (Purinethol) 50 mg QD - cyclosporine [3] - indicated as steroid-sparing agents - complications: pancreatitis (generally within 1st month), leukopenia, allergic reactions, hepatitis - monitor: CBC monthly, liver function tests quarterly - American Gastrenterologic Association (AGA) 2020 guidelines - use infliximab, adalimumab, golimumab, vedolizumab, tofacitinib or ustekinumab rather than no treatment [39] - infliximab or vedolizumab over adalimumab for inducing remission in 1st time biologic users - ustekinumab or tofacitinib may be preferable to vedolizumab or adalimumab for inducing remission in patients who fail infliximab g) antimotility agents - use with caution if at all - loperamide (Imodium) - diphenoxylate (Lomotil) h) antibiotic therapy - combination therapy with amoxicillin 500 mg, tetracycline 500 mg, & metronidazole 250 mg TID for 2 weeks to induce & maintain remission in patients refractory to or dependent on glucocorticoids [16] - 12-month response rates 50-67% - consider only if fistula or abscess [45] i) atorvastatin reduces risk of colectomy (RR=0.66) [42] 3) extraintestinal manifestations of ulcerative colitis typically resolve with treatment of the underlying inflammatory bowel disease [3] - pharmaceuticals that treat both inflammatory bowel disease & enteropathic arthritis include: - sulfasalazine, azathioprine, methotrexate, TNF-alpha inhibitors, glucocorticoids [3,46] 4) diet: a) ineffective as primary therapy for ulcerative colitis b) parenteral nutrition & bowel rest may be needed during acute attacks c) reduce consumption of red meat [40] d) reduce consumption of myristic acid (palm oil, coconut oil, dairy fat) [40] e) increase consumption of omega-3 fatty acids from marine fish (not from supplements) [40] f) vitamin D supplementation may reduce risk of flairs [24] 5) fecal microbiota transplantation [20,35] a) delivered by 6 weekly enemas for acute ulercerative colitis [20] - remission in 24% of patients vs 5% for placebo - 7 of 9 patients with remission with same donor - at 12 months, 8 of 9 patients still in remission [20] b) 40 infusions over 8 weeks achieves remission in 27% of patients vs 8% for placebo [29] c) pooled fecal donor specimens more successful that autologous specimens: remission at 8 weeks 32% (pooled) vs 9% [35] 6) surgery a) total proctocolectomy is curative b) indications - colon perforation or obstruction - toxic megacolon - severe disease unresponsive to 3-7 days of intensive medical therapy - confirmed dysplasia - flat, high-grade dysplasia is associated with high risk of undetected carcinoma - colectomy is advised for patients with non-adenoma-like dysplasia-associated lesion or mass [9] - elective colectomy reduces mortality (33%) vs medical therapy in patients >= aged 50 years with advanced ulcerative colitis [21] - colectomy on the same day patient meets criteria for advanced ulcerative colitis associated with 61% reduction in mortality [21] - editor suggests medical therapy not optimum in this study [21] - study not randomized, controlled trial [21] - infliximab & cyclosporine do not increase postoperative complications after colectomy [36] 7) screening for cancer a) annual screening for cervical cancer with PapSmear in women receiving immunosuppressive therapy [3] b) annual screening for melanoma - if receiving immunomodulator, screen for non-melanoma squamous cell carcinoma skin as well [3] c) cancer surveillance by colonoscopy after 8 years of disease & every 1-2 years thereafter [3] - perform during a time of disease remission - evaluation for dysplasia is difficult in the presence of inflammation - hemoccult cards are not useful - flexible sigmoidoscopy is not useful

Interactions

disease interactions

Related

distinguishing features of ulcerative colitis vs Crohn's disease inflammatory bowel disease in pregnancy risk factors for colon cancer in patients with ulcerative colitis

General

inflammatory bowel disease

Database Correlations

OMIM 191390

References

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