ulcerative colitis (UC)

Introduction

Ulcerative colitis is an idiopathic chronic inflammatory disease of the colon & rectum characterized by exacerbations & remissions.

Etiology

• dietary linoleic acid a risk factor (HR=2.5); 30% of cases may be attributable to linoleic acid
• Mycobacterium avium paratuberculosis?

Epidemiology

• more common in Scandinavian countries, Great Britain & North America
• may develop initially after cessation of cigarette smoking

Pathology

• rectal involvement occurs in all patients
• involves all segments of bowel within the affected area
• disorder of the colonic mucosa; lesion does NOT extend transmurally (in contrast to Crohn's disease)
• up-regulation inflammatory molecules: REG4
• histopathologic remission predicts long-term outcomes

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

Clinical manifestations

• acute onset of bowel urgency, frequent watery stools, & often bloody diarrhea
  • > 6 stools/day suggests severe colitis
  • ref suggests slow onset of symptoms
• patients may remember when symptoms first started
• characterized by exacerbations (flares) & remissions
• diarrhea (inflammatory)
  • small volume, generally < 200 mL/day
  • predominant symptom is bloody diarrhea
• hematochezia (bloody stools)
  • frequent bloody stools suggests severe colitis
• abdominal pain & tenderness, abdominal distension
  • may improve after bowel movement
• fever, tachycardia, malnutrition & dehydration in severe disease
  • body temperature > 37.5 C suggests severe colitis
  • pulse > 90/minute suggests severe colitis
• proctitis, rectal pain
• tenesmus
• fecal incontinence
• extracolonic manifestations (45% of cases)
  • eyes: uveitis, iritis, episcleritis, pain or burning of eyes, blurred vision, photophobia
  • skin: erythema nodosum, pyoderma gangrenosum, most commonly on anterior aspect of lower extremities
  • joints: see enteropathic arthritis
    • arthritis, often migratory, affecting large joints
    • generally non-destructive, arthralgias
    • ankylosing spondylitis, sacroiliitis
  • liver: jaundice, hepatomegaly, splenomegaly
    • liver involvement suggest primary sclerosing cholangitis
  • extracolonic manifestations parallel colonic disease activity

Laboratory

• complete blood count (CBC)
  • anemia, leukocytosis, thrombocytosis
  • blood hemoglobin < 75% normal suggests severe colitis
• serum chemistries
  • electrolytes
  • urea nitrogen
  • serum creatinine
  • serum bicarbonate
  • liver function tests
    • abnormalities may suggest cholangitis
  • nutritional assessment
    • serum albumin, prealbumin, serum transferrin may be low
    • low serum 25-OH vitamin D common & associated with higher morbidity & disease severity
  • 25-hydroxyvitamin D in serum
    • lower levels during remission (29.5 vs 50.3 ng/mL) associated with increased with of flair
• markers of inflammation
  • erythrocyte sedimentation rate (ESR) may be elevated
    • > 30 mm/hr suggest severe colitis
  • monitor serum C-reactive protein
• stool examination:
  • fecal leukocytes,
  • fecal occult blood
  • ova & parasites
  • C difficile toxin
    • C difficile colitis may occur in patients with ulcerative colitis without recent antibiotic therapy
  • stool culture: Yersinia, Campylobacter, E. coli O157:H7
  • monitor fecal calprotectin every 3-6 months
    • rising levels warrant endoscopic evaluation
    • can be used to monitor for postoperative recurrences
    • distinguishes from irritable bowel syndrome
• blood cultures for suspected sepsis
• serum Saccharomyces cerevisiae IgG/IgA 10%; 60% in Crohn's disease
• anti-neutrophil cytoplasmic antibodies (ANCA)
  • p-ANCA 10%, 75% in ulcerative colitis
• fecal calprotectin
  • use as a surrogate for endoscopy to assess for mucosal healing when endoscopy is not feasible or available
  • may be useful for evaluating patients with non-bloody diarrhea
• see inflammatory bowel disease for therapeutic drug monitoring

Diagnostic procedures

• colonoscopy
  • delineate extent of colonic & terminal ileal disease
    • inflammation characterized by erythema, edema & friable mucosa
  • biopsy indicated
  • avoid in seriously ill patients
    • abdominal distension
  • advised within 8-10 years of IBD onset
  • high-definition colonoscopy favored over standard definition
  • routine performance of chromoendoscopy during IBD surveillance is recommended as an adjunct to high-definition colonoscopy
  • narrowband imaging is not a replacement for high-definition, white-light colonoscopy or chromoendoscopy
  • no specific recommendation on performance of random biopsies[19]
  • screening intervals of 1-3 years; 1-5 years
  • polypectomy & continued surveillance recommended for adenoma-like dysplasia-associated lesion or mass with no evidence of other flat dysplasia
    • after complete removal of endoscopically resectable polypoid or nonpolypoid dysplasia, surveillance colonoscopy is recommended rather than colectomy
  • 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
  • reduces colorectal cancer risk 35%

Radiology

• upper GI series with small bowel follow-through
  • exclude upper GI Crohn's disease
• plain abdominal radiograph - colonic distension
• avoid barium enema
  • less sensitive in mild disease
  • may precipitate toxic megacolon in patients with moderate to severe colitis

Complications

• 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
  • increased risk for cervical cancer & non-melanoma skin cancer
• osteoporosis & fractures due to malabsorption (vitamin D & calcium)
• increased risk of venous thromboembolism
  • LMW for DVT prophylaxis despite active bleeding
  • risk for DVT is highest at the time of flare
• C difficile colitis may occur in patients without recent antibiotic therapy
  • use vancomycin rather than metronidazole
• CMV colitis is a common cause of bloody diarrhea in patients with refractory ulcerative colitis (diagnose with sigmoidoscopy & biopsy)
• toxic megacolon

Differential diagnosis

• irritable bowel syndrome (IBS)
  • fecal calprotectin negative in IBS
• other forms of colitis
  • 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
  • infectious colitis
    • bacterial: Shigella, Salmonella, Yersinia, Campylobacter, E. coli O157:H7
    • parasites: Entamoeba histolytica, Giardia lamblia
  • pseudomembranous colitis
  • ischemic colitis
  • radiation colitis
  • lymphocytic colitis
• other causes of hematochezia
  • colorectal carcinoma
  • diverticulosis
• Meckel's diverticulum: generally painless rectal bleeding
• microscopic colitis: non-bloody diarrhea
• other causes of diarrhea: HIV associated diarrhea
• hepatobiliary involvement, pruritus, elevated serum alkaline phosphatase suggests primary sclerosing cholangitis

Management

• 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
  • 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
• pharmacologic agents
  • 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)
    • left-sided or pancolitis
      • 5-aminosalicylates
        • mesalamine 2-4 g once a day; prior Asacol 800 mg TID, Pentasa 1 g QID; once a day mesalamine is preferred over budesonide for mild-to-moderate disease
        • oral mesalamine + mesalamine enemas (Rowasa) 4 g helpful for inducing remission
        • sulfasalazine (Azulfidine) 1 g QID + folate 1 mg QD
      • glucocorticoids second line
        • budesonide (Uceris) 9 mg PO QD for 8 weeks
        • prednisone 40-60 mg QD
      • nicotine
    • ozanimod (Zeposia) may be effective for both induction & maintenance therapy
  • moderate to severe colitis
    • mirikizumab-mrkz (Omvoh) FDA-approved
    • glucocorticoids vs biologic agent for flare
  • 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
      • failure of glucocorticoids in the absence of systemic symptoms constitutes refractory colitis
    • ACTH 80 units IM QD
    • IV broad-spectrum antibiotics for systemic symptoms (fever, leukocytosis or peritonitis)
      • ampicillin + gentamicin + metronidazole
      • ciprofloxacin + metronidazole
      • cefoxitin (Mefoxin)
      • ticarcillin clavulanate (Timentin)
      • no mention of fecal antigen testing in association with empiric antibiotic therapy
    • surgical consult (see surgery below)
  • 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
  • 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 (effective in Crohn's disease)
  • refractory colitis
    • infliximab (TNF-alpha inhibitor) (initial 1st line biologic)
      • efficacy similar to cyclosporine
      • easier to administer than cyclosporine
      • no role in management of toxic megacolon
      • combination therapy with infliximab plus azathioprine superior to either agent alone
    • vedolizumab or tofacitinib (Xeljanz) FDA-approved May 2018
      • effective in inducing & maintaining remission in moderate-severe ulcerative colitis
      • inducing remission when anti-TNF agents have failed
      • use tofacitinib (10 mg PO BID for 8 weeks) to induce remission
    • TNF-alpha inhibitors also effective against enteropathic arthritis
    • adalimumab (Humira)
    • golimumab (Simponi)
    • discontinuation of TNF-alpha inhibitors associated with relapse more often than not
    • ustekinumab as induction & maintenance therapy
    • risankizumab (Skyrizi) may be useful for induction & maintenance
    • other immunosuppressants
      • azathioprine (Imuran) 100-150 mg QD
        • check thiopurine methyltransferase in erythrocytes prior to administration
      • 6-mercaptopurine (Purinethol) 50 mg QD
      • cyclosporine
      • 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
      • 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
  • antimotility agents
    • use with caution if at all
    • loperamide (Imodium)
    • diphenoxylate (Lomotil)
  • 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
      • 12-month response rates 50-67%
    • consider only if fistula or abscess
  • atorvastatin reduces risk of colectomy (RR=0.66)
• extraintestinal manifestations of ulcerative colitis typically resolve with treatment of the underlying inflammatory bowel disease
  • pharmaceuticals that treat both inflammatory bowel disease & enteropathic arthritis include:
    • sulfasalazine, azathioprine, methotrexate, TNF-alpha inhibitors, glucocorticoids
• diet:
  • ineffective as primary therapy for ulcerative colitis
  • parenteral nutrition & bowel rest may be needed during acute attacks
  • reduce consumption of red meat
  • reduce consumption of myristic acid (palm oil, coconut oil, dairy fat)
  • increase consumption of omega-3 fatty acids from marine fish (not from supplements)
  • vitamin D supplementation may reduce risk of flairs
• fecal microbiota transplantation
  • delivered by 6 weekly enemas for acute ulercerative colitis
    • 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
  • 40 infusions over 8 weeks achieves remission in 27% of patients vs 8% for placebo
  • pooled fecal donor specimens more successful that autologous specimens: remission at 8 weeks 32% (pooled) vs 9%
• surgery
  • total proctocolectomy is curative
  • 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
    • elective colectomy reduces mortality (33%) vs medical therapy in patients >= aged 50 years with advanced ulcerative colitis
      • colectomy on the same day patient meets criteria for advanced ulcerative colitis associated with 61% reduction in mortality
      • editor suggests medical therapy not optimum in this study
      • study not randomized, controlled trial
    • infliximab & cyclosporine do not increase postoperative complications after colectomy
• screening for cancer
  • annual screening for cervical cancer with PapSmear in women receiving immunosuppressive therapy
  • annual screening for melanoma
    • if receiving immunomodulator, screen for non-melanoma squamous cell carcinoma skin as well
  • cancer surveillance by colonoscopy after 8 years of disease & every 1-2 years thereafter
    • 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

More general terms

• inflammatory bowel disease

Additional terms

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

Patient information

ulcerative colitis patient information

Database

• OMIM: https://mirror.omim.org/entry/191390