Ulcerative colitis

Ulcerative colitis (UC) is an inflammatory bowel disease (IBD) characterized by chronic mucosal inflammation of the rectum, colon, and cecum. Common symptoms include bloody diarrhea, abdominal pain, and fever. Laboratory findings typically show elevated inflammatory markers and the presence of autoantibodies (pANCA). Definitive diagnosis requires biopsies showing abnormal colonic mucosa and characteristic histopathology. Aminosalicylic acid derivatives are the mainstay of treatment, although severe episodes typically require corticosteroids and immunosuppressants to achieve remission. In the case of distal colitis, some drugs may be administered topically (e.g., via enema), whereas more proximal inflammation requires systemic treatment. Proctocolectomy is curative and indicated for complicated UC or dysplasia. Individuals with UC are predisposed to colorectal cancer and should thus undergo regular surveillance colonoscopy.

• Prevalence
  • Approx. 600,000 adults in the U.S. are affected by UC ^[1]
  • Ethnicity
    • Higher in the white than in the black, Hispanic, or Asian populations
    • Highest among individuals of Ashkenazi Jewish descent.
  • Slightly higher in men than women ^[2]
• Peak incidence
  • 15–35 years ^[3]
  • Another smaller peak may be observed in individuals > 55 years ^[4]

References: ^[4][5][2]

Epidemiological data refers to the US, unless otherwise specified.

Pathogenesis

The exact mechanism is unknown but studies suggest that ulcerative colitis is the result of abnormal interactions between host immune cells and commensal bacteria. ^[8][2]

• Dysregulation of intestinal epithelium: increased permeability for luminal bacteria → activation of macrophages and dendritic cells → antigen presentation to macrophages and naive CD4+ cells leads to
  • Secretion of pro-inflammatory cytokines (IL-6, IL-12, TNF-α) and chemokines (CXCL1, CXCL3, and CXCL8) → recruitment of other immune cells (e.g., neutrophils) to the site
  • Differentiation of naive CD4+ cells to Th2 effector cells
  • Recruitment of NK cells
• Dysregulation of the immune system: upregulation of lymphatic cell activity in bowel walls (T cells, B cells, plasma cells) → enhanced immune reaction and cytotoxic effect on colonic epithelium → inflammation with local tissue damage (ulcerations, erosions, necrosis) in the submucosa and mucosa
  • Autoantibodies (pANCA) against cells of the intestinal epithelium
  • Th2 cell-mediated response
• Pattern of involvement
  • Ascending inflammation beginning in the rectum and spreading continuously proximally throughout the colon
  • Inflammation is limited to the mucosa and submucosa.

The rectum is always involved in UC!

Risk factors ^[8][2][4]

• Genetic predisposition (e.g., HLA-B27 association)
• Ethnicity (white populations, individuals of Ashkenazi Jewish descent)
• Family history of inflammatory bowel disease
• Episodes of previous intestinal infection
• Increased fat intake (esp. saturated fat and animal fat)
• Oral contraceptive intake
• NSAIDs may exacerbate UC

Protective factors ^[8][2]

• Appendectomy
• Smoking has a protective effect

Intestinal symptoms

• Bloody diarrhea with mucus
• Fecal urgency
• Abdominal pain and cramps
• Tenesmus

Extraintestinal symptoms

• Skeletal: (most common extraintestinal manifestation of ulcerative colitis): osteoarthritis, ankylosing spondylitis, sacroiliitis ^[9][10]
• Ocular: uveitis; , episcleritis, iritis
• Biliary: primary sclerosing cholangitis (PSC)
  • Rare for patients with UC to develop PSC, but up to 90% of all patients affected by PSC will also be affected by UC.
• Cutaneous: erythema nodosum, pyoderma gangrenosum, aphthous stomatitis, pyostomatitis vegetans (multiple aphthae and pustules of the oral mucosa)
• General: fatigue, fever
• In children/adolescents: growth retardation and delayed puberty

Primary sclerosing cholangitis (PSC) is often associated with inflammatory bowel disease, especially UC. However, only around 4% of people with inflammatory bowel disease develop PSC!

For the characteristics of ulcerative colitis, think “ULCCCERS”: Ulcers, Large intestine, Continuous/Colon cancer/Crypt abscesses, Extends proximally, Red diarrhea, Sclerosing cholangitis.

Course of the disease

• Chronic intermittent
  • Most common course
  • Exacerbation is followed by complete remission.
• Chronic continuous
  • Complete remission does not occur.
  • Severity of the disease varies.
• Acute fulminant
  • Sudden onset
  • Severe diarrhea, dehydration, shock

Laboratory tests

• Blood
  • ↑ ESR, ↑ CRP, leukocytosis
  • Anemia
  • Thrombocytosis in some cases
  • ↑ Perinuclear ANCA (pANCA)
    • Medium sensitivity but high specificity ^[12][13]
    • No correlation between titer and disease activity
    • Serologic testing is not recommended for definitive diagnosis or exclusion of UC but can support the diagnosis. ^[3]
  • In case of concurrent PSC: elevated gamma-glutamyl transferase
• Stool analysis
  • Test for bacteria to rule out infectious causes. ^[3]
  • Calprotectin and lactoferrin are indicators of mucosal inflammation.

Endoscopy

Endoscopy (e.g., colonoscopy) with histological examination is considered the best test to definitively diagnose UC.

• Typical findings: : See “Gross pathology” below.
• Pattern of disease involvement ^[3]
  • Proctosigmoiditis: limited to the rectum, with possible sigmoid involvement
  • Left-sided colitis: extends distally to the splenic flexure
  • Extensive colitis: extends beyond the splenic flexure
• Recommendations ^[3]
  • Evaluate the ileum to rule out Crohn disease
  • Stepwise biopsy (for findings, see "Pathology" below)
  • Colonoscopy is contraindicated in patients with acute flare because of the high risk of perforation but should be performed once symptoms improve.
    • Sigmoidoscopy may be considered as an alternative.

Observe caution in taking biopsies from patients with severe disease, as the risk of perforation is high.

Imaging ^[14][3]

Imaging studies may serve as useful adjunct diagnostic procedures for UC, particularly when it comes to detecting complications.

• Radiography
  • Plain radiography
    • Typically normal in mild to moderate disease
    • Findings
      • Loss of colonic haustra (lead pipe appearance) may be seen in severe cases
      • Massive distention in cases of toxic megacolon
      • Pneumoperitoneum in cases of perforation
  • Barium enema radiography
    • Able to detect very early changes
    • Findings
      • Granular appearance of the mucosa
      • Deep ulcerations
      • Loss of haustra
      • Pseudopolyps that appear as filling defects
• CT: Detection of bowel wall thickening is possible in severe disease.
• MRI: can be helpful in assessing disease severity and extent of bowel wall involvement
• Ultrasound: can detect bowel wall thickening (manifests with absent hyperechoic reflection from the lumen)

References:^[12][13][15]

Gross pathology

• Early stages
  • Inflamed, erythematous, edematous mucosa
  • Friable mucosa with bleeding on contact with endoscope
  • Fibrin-covered ulcers
  • Small mucosal ulcerations
  • Loss of superficial vascular pattern
• Chronic disease
  • Loss of mucosal folds
  • Loss of haustra
  • Strictures
  • Deep ulcerations
  • Pseudopolyps
    • Raised areas of normal mucosal tissue that result from repeated cycles of ulceration and healing
    • Ulceration → formation of granulation tissue → deposition of granulation tissue → epithelization
    • Morphologically resemble polyps but do not undergo neoplastic transformation
    • Found in advanced disease

In ulcerative colitis, the extent of intestinal inflammation is limited to the mucosa and submucosa. In contrast, Crohn disease shows a transmural pattern of intestinal involvement.

Histological findings

• Early stages
  • Granulocyte (neutrophil) infiltration: limited to mucosa and submucosa
  • Crypt abscesses: an infiltration of neutrophils into the lumen of intestinal crypts due to a breakdown of the crypt epithelium
• Chronic disease
  • Lymphocyte infiltration
  • Mucosal atrophy
  • Altered crypt architecture
    • Branching of crypts
    • Irregularities in size and shape
  • Epithelial dysplasia

Noncaseating granulomas are seen in Crohn disease but are not a feature of ulcerative colitis!

Differential diagnosis considerations

• Crohn disease (see “Differential diagnostic considerations: Crohn disease and ulcerative colitis”)
• Exudative-inflammatory diarrhea
• Diverticular disease
• Appendicitis
• Ischemic colitis
• Infectious colitis
  • C. difficile colitis
  • Shigella dysenteriae
  • Salmonella enterocolitis
  • Escherichia coli colitis
  • Campylobacter enterocolitis
  • Yersiniosis
  • Tuberculosis
  • CMV colitis
• Radiation colitis
• Celiac disease
• Inflammatory diarrhea

Microscopic colitis

• Definition: An idiopathic form of colitis that is characterized by a normal macroscopic appearance of bowel on colonoscopy and collagenous or lymphocytic infiltrates on microscopy.
• Forms: collagenous colitis and lymphocytic colitis
• Etiology: unknown
• Clinical findings
  • Chronic, nonbloody, watery diarrhea for > 4 weeks
  • Weight loss
  • Abdominal pain
• Pathological findings
  • Gross pathology: normal appearance
  • Histology
    • Collagenous colitis: proliferation of collagenous connective tissue
    • Lymphocytic colitis: mainly lymphocytic infiltrates with little/no proliferation of connective tissue
• Treatment
  • Cease nonsteroidal anti‑inflammatory drugs (NSAIDs may be a trigger for disease)
  • Symptomatic therapy (e.g., loperamide for mild diarrhea)
  • Corticosteroids

The differential diagnoses listed here are not exhaustive.

Initially, UC is treated conservatively with drugs to induce and maintain disease remission. Curative proctocolectomy is generally indicated if medical therapy fails or complications arise.

General management

• Rehydration
• Supplementation of nutritional deficiencies (e.g., iron)
• Supplementation of nutrition: severe cases may warrant consideration of a feeding tube or parenteral nutrition.

Medical therapy ^[3]

Supportive care

• Antidiarrheal agents (e.g., loperamide): can only be used in the absence of a flare
• Anticholinergic medication (e.g., propantheline, dicyclomine): relieves abdominal cramping
• NSAIDs, opioids, and anticholinergics should be avoided in severe disease.

Mild disease

• 5-aminosalicylic acid derivatives (5-ASAs)
  • Drugs
    • Mesalamine
    • Sulfasalazine
    • Olsalazine (compound of two 5-ASA molecules)
  • Mechanism of action
    • 5-ASA alone (mesalamine) or bound to sulfapyridine as a carrier (sulfasalazine)
    • Sulfasalazine is activated by colon bacteria
      • 5-ASA: antiinflammatory, immunosuppressive
      • Sulfapyridine: antibacterial
  • Indications
    • Ulcerative colitis
    • Colitis component of Crohn disease
  • Side effects
    • Mesalamine
      • GI irritation: nausea, diarrhea
      • In rare cases: peripheral neuropathy, myocarditis or pericarditis, myelosuppression
    • Sulfasalazine
      • Most of the side effects are caused by the sulfapyridine component of sulfasalazine.
      • GI irritation: nausea, diarrhea
      • Headache, fatigue; , malaise, depression
      • Megaloblastic anemia and folate deficiency due to interference with dihydropteroate synthase
      • Immune thrombocytopenia ^[16]
      • Transient oligospermia
      • Sulfa drug: allergic reactions, sulfonamide toxicity
  • Drug interactions: coadministration of nephrotoxic drugs (e.g. NSAIDs, aminoglycosides, lithium) → ↑ risk of renal impairment
  • Additional information
    • Can be administered orally, as suppositories; , or as enemas
    • Sulfapyridine has proven to have beneficial effects in patients with rheumatic disease.
• If no improvement or 5-ASA agents are not tolerated
  • Topical corticosteroids (e.g., budesonide)
  • Oral systemic corticosteroids

Moderate disease

• Oral and topical 5-ASAs
• Topical corticosteroids (e.g., budesonide) → systemic corticosteroids only if no response
• Anti-TNF therapy; (adalimumab, golimumab, or infliximab)
• Vedolizumab (integrin receptor antagonist)
• Tofacitinib (JAK3 inhibitor)

Severe or refractory disease

• High‑dose oral and topical 5-ASAs
• Systemic corticosteroids
• Anti-TNF therapy; (e.g., adalimumab, golimumab, or infliximab)
• Calcineurin antagonists (e.g., cyclosporine, tacrolimus)
• Thiopurines (6-mercaptopurine, azathioprine) may be considered but are no longer recommended as monotherapy due to lack of efficacy ^[3]
• Vedolizumab (integrin receptor antagonist)
• Tofacitinib (JAK3 inhibitor)
• Referral for surgical proctocolectomy (see below)

Systemic corticosteroids should only be used for the treatment of an active flare and are not recommended as a maintenance medication for ulcerative colitis.

Surgical intervention

• Goal
  • Curative approach with full recovery
  • Reduce risk of colorectal cancer
• Indications
  • Emergent: Acute complications despite adequate conservative management (e.g., toxic megacolon, perforation, sepsis, uncontrolled bleeding, etc.)
  • Elective: epithelial dysplasia, severe relapses, long-term dependence on steroids, impairment of the patient's general condition
• Procedure: proctocolectomy with an ileal pouch-anal anastomosis (IPAA or J pouch)
  • Resection of the entire colon and rectal mucosa while sparing the anal sphincters.
  • Loops of small intestine (serving as the pouch) are used to create an artificial rectum (reservoir for feces) and thus a continence-conserving connection between the ileum and anus.
• Complications
  • Anastomotic leak
  • Pouchitis (↑ stool frequency, malaise, and possibly incontinence caused by bacterial overgrowth)

In contrast to Crohn disease, ulcerative colitis can be cured surgically (proctocolectomy).

• Gastrointestinal bleeding (both acute and chronic)
• Toxic megacolon
• Perforation → peritonitis (see “Gastrointestinal perforation”)
• Fulminant colitis; : severe bowel inflammation that typically causes > 10 stools per day, lower gastrointestinal bleeding, abdominal pain, and abdominal distention
• ↑ Risk of cancer (see ”Colorectal carcinoma”)
  • Risk increases with increased duration and/or extent of disease (e.g., pancolitis).
  • Risk is not significantly increased in patients with mild UC
  • Prevention: Screening colonoscopy with biopsies every 1–3 years starting 8 years after the initial diagnosis to screen for colorectal cancer ^[3]
• Colonic stricture
• Amyloidosis

References:^[14][17]

We list the most important complications. The selection is not exhaustive.