Ulcerative colitis

Ulcerative colitis is a type of chronic inflammatory bowel disease (IBD) characterized by mucosal inflammation of the colon that typically starts in the rectum and may extend proximally affecting the distal colon or the entire colon up to the cecum. The most common clinical feature is bloody diarrhea, often accompanied by abdominal pain, fecal urgency, and tenesmus. Extraintestinal manifestations such as arthritis, uveitis, erythema nodosum, and primary sclerosing cholangitis can also occur. Diagnosis is confirmed by ileocolonoscopy with biopsy, while laboratory (e.g., ESR, CRP) and stool studies (e.g., fecal calprotectin) help assess disease severity. Treatment depends on disease severity, ranging from 5-ASA preparations for mild disease to systemic immunomodulatory medications for severe disease. Major complications include toxic megacolon, perforation, and an increased risk of colorectal cancer, which necessitates regular endoscopic screening. A restorative proctocolectomy is a curative surgical option for patients with refractory disease or complications.

• Prevalence
  • Approx. 1.2 million adults in the US are affected by ulcerative colitis.^[1]
  • Ethnicity
    • Higher in White populations than in Black, Hispanic, or Asian populations
    • Highest among individuals of Ashkenazi Jewish descent
• Incidence
  • Peak incidence: 20–30 years of age ^[1]
  • Another smaller peak may be observed in individuals > 55 years of age. ^[2]
  • Childhood onset occurs in > 10% of patients; see “IBD in children.” ^[3]
  • ♂=♀ ^[4]

Epidemiological data refers to the US, unless otherwise specified.

Risk factors ^[2][5][6]

• Genetic predisposition (e.g., HLA-B27 association)
• Ethnicity (White populations, individuals of Ashkenazi Jewish descent)
• Family history of inflammatory bowel disease
• History of intestinal infections
• Increased fat intake (especially saturated fat and animal fat)
• Oral contraceptive use
• NSAIDs may exacerbate ulcerative colitis.

Protective factors ^[5][6]

• Appendectomy
• Smoking

Classification of ulcerative colitis by disease extent ^[1]

The extent of disease is classified based on endoscopic findings.

Classification of ulcerative colitis by severity ^[1]

There are several classification systems that can be used to assess disease severity. There is significant overlap among the criteria used. Criteria include:

• Endoscopic findings
  • Ulcerative colitis endoscopic index of severity (UCEIS)
  • Mayo endoscopic score (MES)
• Clinical presentation
  • Simple clinical colitis activity index (SCCAI)
  • Truelove and Witts severity index for ulcerative colitis
• A combination of both endoscopic findings and clinical presentation
  • Mayo score for ulcerative colitis activity
  • American College of Gastroenterology (ACG) ulcerative colitis activity index
• Other: response to medication, disease course, patient's quality of life
• Remission (ACG ulcerative colitis activity index): all of the following ^[1]
  • Absence of diarrhea, blood in stools, and fecal urgency
  • Fecal calprotectin < 150–200 mcg/g; normal Hb, ESR and CRP ^[1]
  • Normal endoscopy

Treatment recommendations by the ACG are based on their ulcerative colitis activity index, while recommendations by the American Gastroenterological Association (AGA) are based on the Truelove and Witts severity index and the Mayo score for ulcerative colitis activity.

The exact mechanism is unknown but studies suggest that ulcerative colitis is caused by abnormal interactions between host immune cells and commensal bacteria. ^[5][6]

• 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 proinflammatory 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 natural killer cells
• Dysregulation of the immune system: upregulation of lymphatic cell activity (T cells, B cells, plasma cells) in bowel walls → 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 that begins in the rectum and spreads continuously proximally throughout the colon
  • Inflammation is limited to the mucosa and submucosa.

The rectum is always involved in ulcerative colitis.

Intestinal features

• Bloody diarrhea with mucus (hematochezia)
• Fecal urgency
• Increased stool frequency
• Abdominal pain and cramps
• Tenesmus

Extraintestinal features of ulcerative colitis

• General: fatigue, fever
• Skeletal: (most common extraintestinal feature of ulcerative colitis): arthritis, ankylosing spondylitis, sacroiliitis ^[9][10]
• Ocular: uveitis, episcleritis, iritis
• Biliary: primary sclerosing cholangitis (it is rare for patients with ulcerative colitis to develop PSC, but up to 90% of all patients with PSC will also have ulcerative colitis)
• Cutaneous
  • Erythema nodosum
  • Pyoderma gangrenosum
  • Aphthous stomatitis
  • Pyostomatitis vegetans
    • A very rare condition that is associated with other cutaneous diseases and inflammatory bowel disease, particularly ulcerative colitis
    • Manifests with multiple aphthae and pustules of the oral mucosa

PSC is often associated with inflammatory bowel disease, especially ulcerative colitis. However, only approximately 4% of patients with inflammatory bowel disease develop PSC.

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

Disease course

• Chronic intermittent
  • Most common course
  • Exacerbation is followed by complete remission.
• Chronic continuous
  • Complete remission does not occur.
  • Disease severity varies.
• Acute fulminant (i.e., acute severe ulcerative colitis)
  • Sudden onset
  • Severe diarrhea, dehydration, shock

Backwash ileitis

• Definition: inflammation of the terminal ileum in the context of ulcerative colitis
• Epidemiology: affects approximately 10–20% of all patients diagnosed with ulcerative colitis
• Localization: typically affects an area a few centimeters proximal to the ileocecal valve
• Pathophysiology: The pathological mechanism is not fully understood.
• Differential diagnosis: Clinically, backwash ileitis is hardly relevant but its presence makes it harder to differentiate between ulcerative colitis and Crohn disease.

Approach ^[1]

The diagnosis is based on clinical features, endoscopic and pathology findings. ^[1]

• Suspect ulcerative colitis in patients with hematochezia, increased stool frequency, and fecal urgency.
• Assess for extraintestinal features of ulcerative colitis.
• Order laboratory studies to:
  • Rule out infectious gastroenteritis
  • Assess disease severity (e.g., baseline levels of CRP, fecal calprotectin) ^[11]
• Consult gastroenterology for an ileocolonoscopy with biopsy to:
  • Confirm the diagnosis of ulcerative colitis
  • Determine the extent of disease in ulcerative colitis and severity of ulcerative colitis
• Assess disease severity
  • See "Classification of ulcerative colitis by severity."
  • Identify patients with acute severe ulcerative colitis (ASUC).
• Consider CT or MRI abdomen if endoscopy is contraindicated.

Laboratory studies ^[1]

Stool testing for infectious gastroenteritis is indicated in all patients. Blood tests are not required for diagnosis, but help assess disease activity and severity.

• Blood tests
  • CBC: anemia, leukocytosis, thrombocytosis ^[4]
  • ESR, CRP: Elevated levels may indicate active ulcerative colitis and often correlate with disease severity.
  • Hypoalbuminemia: associated with a poor prognosis and more severe disease
  • ALP, GGT: elevated in patients with concurrent PSC
  • pANCA
    • Not recommended to establish diagnosis, monitor disease activity, or determine prognosis ^[1]
    • Elevated in up to 70% of patients with ulcerative colitis ^[1]
• Stool diagnostic studies ^[1][11]
  • Stool test for Clostridioides difficile infection ^[1][11]
  • Fecal calprotectin: to monitor disease activity and response to therapy ^[1][11]
  • GI PCR panel: Consider based on clinical features and risk factors for diarrhea. ^[11]
  • Stool culture and microscopy: to assess for bacteria, ova, and parasites if a GI PCR panel is not available

CRP, ESR, or hemoglobin levels are not required for the diagnosis of ulcerative colitis; they help determine disease severity.

Hypoalbuminemia and ↑ CRP are significant poor prognostic factors. Other factors include age < 40 years at diagnosis, extensive ulcerative colitis, and severe disease on endoscopic evaluation scores. ^[1]

Endoscopy ^[1]

• Ileocolonoscopy
  • Recommended method for diagnosis and disease monitoring ^[1]
  • Severe disease is a relative contraindication. ^[1]
  • See "Histopathology findings" in "Pathology".

• Sigmoidoscopy ^[1]
  • Indications
    • Initially used as an alternative to ileocolonoscopy, e.g., in ASUC
    • Monitoring treatment response
  • Findings are similar to ileocolonoscopy findings.
• EGD: recommended for patients with upper GI symptoms to rule out Crohn disease ^[1]

There is a high risk for colonic perforation in severe ulcerative colitis; caution should be used when performing biopsies.

Imaging studies ^[1]

• Not routinely recommended for diagnosis
• Adjunct to endoscopy, particularly for the detection of complications; , or if endoscopy is not possible. ^[1]

Abdominal x-rays ^[1]

• Indication: initial and serial evaluation of suspected ASUC
• Findings
  • Typically normal in mild-to-moderate disease
  • Severe disease
    • Loss of colonic haustra (lead pipe appearance)
    • Increased bowel wall thickness
  • May show signs of complications, e.g.:
    • Toxic megacolon: massive distention
    • Ulceration: segmental dilation with irregular edges outlined by gas ^[12]
    • Perforation: pneumoperitoneum ^[13]

CT or MRI abdomen ^[1][13]

• Indications
  • Abdominal symptoms unexplained by endoscopic findings ^[1]
  • Evaluation of proximal disease involvement when endoscopy is not feasible
  • Suspected complications (e.g., bowel perforation)
  • Differentiation from other conditions, e.g., Crohn disease ^[1]
• Findings
  • Loss of haustra
  • Increased bowel wall thickness
  • Mural hyperenhancement
  • Signs of complications (similar to abdominal x-ray findings)

Barium enema radiography ^[12]

The role of barium enema is limited, as it is less sensitive than other imaging modalities and is contraindicated in patients with obstruction or perforation.

• Indication: : assessment of the proximal colon when colonoscopy is contraindicated (e.g., obstruction, perforation)
• Findings
  • Granular appearance of the mucosa
  • Deep ulcerations
  • Loss of haustra
  • Pseudopolyps that appear as filling defects

Abdominal ultrasound ^[1]

• Indication: monitoring disease activity and treatment response
• Findings: increased bowel wall thickness

Gross pathology

See “Endoscopic findings in ulcerative colitis” in “Diagnostics.”

Histopathology 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

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.

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
• Microscopic colitis
• Radiation colitis
• Celiac disease
• Inflammatory diarrhea

The differential diagnoses listed here are not exhaustive.

General principles ^[1]

The goal of treatment is clinical and endoscopic remission.

• Consult gastroenterology before starting management.
• Provide supportive care measures for all patients.
• Choice of pharmacological therapy is based on the classification of ulcerative colitis by severity and patient-specific prognostic factors.
• Surgical management should be considered if medical therapy is unsuccessful or complications occur.
• Long-term management includes:
  • Monitoring for complications related to the disease and its treatment.
  • Screening for colorectal cancer and other common comorbidities (e.g., depression and anxiety).

While most cases of ulcerative colitis can be managed in an outpatient setting, patients with ASUC should be admitted for management.

Supportive care ^[1]

• Pain management
  • Nonpharmacological measures, e.g., heating pads
  • Consider acetaminophen, anxiolytics, and sedatives.
  • Avoid opioids and NSAIDs.
• Nutritional support
  • Assess for and manage malnutrition.
  • Avoid parenteral nutrition unless required to improve nutritional status prior to colectomy.
• Probiotics: There is insufficient evidence to support their use.

Surgical management ^[1]

Surgical treatment is curative for ulcerative colitis and reduces the risk of colorectal cancer. ^[1]

• Indications
  • Complications of ASUC
    • Toxic megacolon
    • Bowel perforation
    • Severe hematochezia
    • Multiorgan failure
  • Refractory ulcerative colitis (; i.e., no response after; 3– 5 days of medical management; and/or glucocorticoid dependence) ^[1]
  • Dysplasia or carcinoma
• Procedure: restorative proctocolectomy with an ileal pouch-anal anastomosis (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, resulting in a continence-conserving connection between the ileum and anus.
• Complications of surgery
  • Early (≤ 30 days): anastomotic leak, pelvic sepsis
  • Late: bowel stricture, bowel obstruction, fertility issues, sexual dysfunction ^[4]
  • Most common late postoperative issue: pouchitis (increased stool frequency, malaise, and possibly incontinence caused by bacterial overgrowth)

Nutritional status should be optimized before colectomy to improve patient outcomes.

Long-term management of ulcerative colitis

• Disease monitoring
  • Flexible sigmoidoscopy: 3–6 months after starting a new treatment ^[4]
  • Clinical assessment: every 3 months until remission, then every 6–12 months ^[4]
  • Follow-up after symptomatic remission
    • Symptom assessment
    • Inflammation biomarkers (i.e., fecal calprotectin, fecal lactoferrin, and/or serum CRP) ^[1][11]
• Colorectal cancer screening ^[14][15]
  • Start screening 8–10 years after the initial diagnosis or at the time of diagnosis of primary sclerosing cholangitis.
    • Modality: ileocolonoscopy with biopsies
    • Interval: every 1–3 years
• Additional measures ^[16][17]
  • Annual LFTs to monitor for primary sclerosing cholangitis ^[16][18]
  • See also “Preventive care in IBD”.

Definition

The presence of both of the following indicates acute severe ulcerative colitis (ASUC): ^[1]

• ≥ 6 bowel movements daily
• ≥ 1 sign of systemic toxicity (e.g., tachycardia, fever, hemoglobin < 10.5 g/dL, ESR > 30 mm/hour) ^[1]

Management of ASUC ^[1]

• Consult gastroenterology for urgent flexible sigmoidoscopy (ideally within 24 hours).
• Obtain a stool test for CDI.
• Obtain cross-sectional imaging (e.g., CT scan) if there is concern for extraluminal complications or perforation.
• Initiate treatment with IV glucocorticoids (e.g., methylprednisolone, hydrocortisone)
• Provide supportive care with IV fluid resuscitation and electrolyte repletion as needed.
• Consider empiric antibiotics only in patients with signs of sepsis and/or concern for extraluminal complications.
• Closely monitor for:
  • Complications: Order serial abdominal examinations and abdominal x-rays.
  • Treatment response: based on clinical features (i.e., rectal bleeding and stool frequency), vital signs, physical examination findings, and serial CRP
• Assess for concomitant CMV colitis in patients with ASUC who do not improve with glucocorticoid therapy; see “Antiviral therapy for CMV.” ^[1]
• Consult surgery if:
  • Complications arise (e.g., toxic megacolon, bowel perforation, hemorrhage, sepsis)
  • There is no improvement after 3 days of medical management

Avoid NSAIDs, opioids, and anticholinergic medications in patients with ASUC.

Neither total parenteral nutrition nor empiric antibiotics are routinely indicated in ASUC.

General principles ^[1]

• The goal of pharmacological therapy is to induce and maintain disease remission.
  • 5-ASA monotherapy are first-line in mild-to-moderate ulcerative colitis.
  • Oral glucocorticoids are indicated for induction of remission of ulcerative colitis resistant to 5-ASA monotherapy.
  • Systemic immunomodulators (e.g., anti-TNF agents) should be considered for: ^[1][19]
    • Patients with moderate-to-severe ulcerative colitis
    • Patients with poor prognosis factors:
      • Age < 40 years at diagnosis
      • ↑ CRP, hypoalbuminemia
      • Extensive colitis, severe disease on endoscopy
      • Hospitalization for colitis

Glucocorticoids should only be used for induction of remission and then gradually tapered. Glucocorticoid-sparing agents are preferred for maintenance of remission. ^[1]

Induction of remission ^[1]

For induction of remission, azathioprine may be considered in combination with anti-TNF agents, not as monotherapy. ^[14]

Maintenance of remission

• The same agents used for induction should be continued for maintenance of remission, except for glucocorticoids.
• Thiopurine (e.g., azathioprine) monotherapy may be considered if remission was achieved with glucocorticoids alone.^[19]

Overview of 5-ASA and 5-ASA derivatives ^[14][20]

• ↑ Risk of cancer (see ”Long-term management of ulcerative colitis” for screening protocol)
  • Risk increases with duration and/or extent of disease (e.g., pancolitis).
  • Colorectal carcinoma risk is not significantly increased in patients with mild ulcerative colitis.
• Toxic megacolon
• Fulminant colitis: severe bowel inflammation that typically causes > 10 stools per day, lower gastrointestinal bleeding, abdominal pain, and abdominal distention
• Gastrointestinal bleeding (both acute and chronic)
• Perforation → peritonitis (see “Gastrointestinal perforation”)
• Colonic stricture
• Amyloidosis

References:^[23]

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

Inflammatory bowel disease in children ^[3][24][25]

Epidemiology

• The incidence of IBD in children is rising, especially very early onset IBD (before 6 years of age). ^[3][26]
• Prevalence: 77 per 100,000 ^[3]

Clinical features ^[3][25]

The clinical features of IBD are similar in adults and children. Additionally, in children, IBD is characterized by: ^[3]

• Delayed onset of puberty
• Growth stunting (more commonly associated with Crohn disease) ^[16]
• Increased risk of extraintestinal symptoms ^[24][25]
  • Extraintestinal symptoms may precede gastrointestinal symptoms by months or years.
  • Approx. 25% of children have extraintestinal symptoms at diagnosis. ^[24]
  • See “Extraintestinal symptoms of Crohn disease” and “Extraintestinal symptoms of ulcerative colitis.”
• Increased risk of severe disease and complications

Red flags for IBD in children ^[3]

Any of the following features in a child with chronic (≥ 4 weeks) abdominal pain and/or diarrhea should prompt evaluation for IBD.

• Major red flags for IBD in children
  • Rectal bleeding
  • Perianal findings (e.g., perianal fistula, perianal abscess, perianal ulcers)
• Minor red flags for IBD in children
  • First-degree relative with IBD
  • Unplanned weight loss
  • Extraintestinal symptoms of ulcerative colitis or extraintestinal symptoms of Crohn disease

Diagnosis of IBD in children ^{[3][24][25][27]}

• Assess for red flags for IBD in children.
• Obtain CBC, inflammatory markers (CRP, ESR), liver chemistries, and stool studies. ^[28]
  • Normal laboratory findings do not rule out IBD.
  • See “Laboratory studies” in “Diagnostics for ulcerative colitis” or “Diagnostics for Crohn disease” for details.
• Refer for ileocolonoscopy and EGD as indicated. ^[25][29]
  • Major red flags for IBD in children: Refer for endoscopy.
  • Minor red flags for IBD in children: Consider a risk-stratified approach based on fecal calprotectin levels to determine the need for endoscopy. ^[3]
    • Fecal calprotectin > 250 mcg/g: Refer for endoscopy.
    • Fecal calprotectin 50–250 mcg/g: Consider endoscopy based on shared decision-making.
    • Fecal calprotectin < 50 mcg/g: IBD is excluded; consider other causes of abdominal pain in children.
• Imaging is indicated as an adjunctive diagnostic modality to determine the extent and severity of bowel involvement. ^[24][25][29]
  • Small bowel imaging is recommended for all patients (unless endoscopic and histology findings are characteristic of ulcerative colitis). ^[25]
  • MR enterography is the preferred imaging modality. ^[25][27][30]
  • Wireless capsule endoscopy may be considered if conventional endoscopy or imaging is not feasible. ^[25][30]

Fecal calprotectin < 50 mcg/g excludes IBD. ^[3]

Management^[3][24]

Multidisciplinary management (including a pediatric gastroenterologist, nutritionist, primary care physician, and psychologist) is recommended. ^[3]

• Treatment of ulcerative colitis is similar in children and adults, except thiopurines are not recommended for induction of remission in children. ^{[3][16][31][32]}
• Treatment of Crohn disease is similar in children and adults, with the following exceptions for children: ^[3][27]
  • Early initiation of anti-TNF therapy may be considered if prognostic indicators are poor.
  • Exclusive enteral nutrition for 6–8 weeks (instead of glucocorticoids) may be considered to induce remission in selected patients.
• Long-term management of IBD is similar for children and adults.
  • See “Long-term management of ulcerative colitis” and “Long-term management of Crohn disease” for details.
  • In children, also monitor for growth faltering and delayed onset of puberty. ^[16]
  • See also “Preventive care in IBD” for details on vaccination and screening for other complications.

The transition from a pediatric to an adult care team must be well coordinated to avoid disease complications and/or relapse. ^[3]

Inflammatory bowel disease in pregnancy ^[33][34]

Fertility and preconception counseling

• Fertility is not affected in women with IBD in remission and no history of abdominal surgery.
• Women with active disease have decreased fertility rates.
• Pharmacological therapy for IBD does not impact fertility.
• Active disease at conception increases the risk of persistently active disease during gestation.
• Active disease is associated with an increased risk of preterm birth and low birth weight.
• Patients who wish to conceive should be on appropriate pharmacological therapy to maintain disease remission.
• With the exception of methotrexate, all other treatments can be continued at conception.

Disease management during pregnancy

• Most medications used in the treatment of IBD are considered safe during pregnancy.
• Glucocorticoids; are indicated for disease flares but should be avoided as maintenance therapy because of the increased risk of gestational diabetes, preterm birth, and low birth weight.
• 5-ASA, 5-ASA derivatives, immunomodulators, and biopharmaceuticals can be used during pregnancy.
• Monotherapy is preferred for maintenance treatment to reduce the risk of adverse effects.

• On average, the life expectancy of patients with ulcerative colitis is normal.
• Poor prognosis factors include: ^[1]
  • Laboratory studies: hypoalbuminemia and ↑ CRP
  • Age < 40 years at diagnosis
  • Extensive ulcerative colitis
  • Severe disease on endoscopic evaluation scores