Diseases of the Large Bowel.

Ulcerative Colitis.

• Ulcerative colitis (UC) is one of the 2 major

types of inflammatory bowel disease

(IBD), along with Crohn disease.

• Unlike Crohn disease, which can affect

any part of the gastrointestinal (GI) tract,

UC characteristically involves only the large bowel

• Signs and symptoms

Patients with UC predominantly complain of the following:

• Rectal bleeding

• Frequent stools

• Mucous discharge from the rectum

• Tenesmus (occasionally)

• Insidious onset

• Lower abdominal pain and severe dehydration from purulent rectal discharge (in severe cases, especially in the elderly)

In some cases, UC has a fulminant course

marked by the following:

• Severe diarrhea and cramps

• Fever

• Leukocytosis

• Abdominal distention

UC is associated with various extracolonic manifestations, as follows:

• Uveitis

• Pyoderma gangrenosum

• Pleuritis

• Erythema nodosum

• Ankylosing spondylitis

• Spondyloarthropathies

Other conditions associated with UC include

the following:

• Primary sclerosing cholangitis (PSC)

• Recurrent subcutaneous abscesses

unrelated to pyoderma gangrenosum

• Multiple sclerosis

• Immunobullous disease of the skin

Physical findings are typically normal in mild

disease, except for mild tenderness in the

lower left abdominal quadrant. In severe

disease, the following may be observed:

• Fever

• Tachycardia

• Significant abdominal tenderness

• Weight loss

The severity of UC can be graded as follows:

• Mild: Bleeding per rectum, fewer than 4 bowel motions per day

• Moderate: Bleeding per rectum, more than 4 bowel motions per day

• Severe: Bleeding per rectum, more than 4 bowel motions per day, and a systemic illness with hypoalbuminemia (< 30 g/L)

Diagnosis

Laboratory studies are useful principally in excluding other diagnoses and assessing the patient’s nutritional status. They may include the following:

• Serologic markers (eg, antineutrophil cytoplasmic antibodies [ANCA], anti– Saccharomyces cerevisiaeantibodies [ASCA])

• Complete blood count (CBC)

• Comprehensive metabolic panel

• Inflammation markers (eg, erythrocyte sedimentation rate [ESR], C-reactive protein [CRP])

• Stool assays

Diagnosis is best made with endoscopy and biopsy, on which the following are characteristic:

• Abnormal erythematous mucosa, with or without ulceration, extending from the rectum to a part or all of the colon

• Uniform inflammation, without intervening areas of normal mucosa (skip lesions tend to characterize Crohn disease)

• Contact bleeding may also be observed, with mucus identified in the lumen of the bowel

The extent of disease is defined by the following findings on endoscopy:

• Extensive disease: Evidence of UC proximal to the splenic flexure

• Left-side disease: UC present in the descending colon up to, but not proximal to, the splenic flexure

• Proctosigmoiditis: Disease limited to the rectum with or without sigmoid involvement

Management

Medical treatment of mild UC includes the following:

• Mild disease confined to the rectum: Topical mesalazine via suppository (preferred) or budesonide rectal foam

• Left-side colonic disease: Mesalazine suppository and oral aminosalicylate (oral mesalazine is preferred to oral sulfasalazine)

• Systemic steroids, when disease does not quickly respond to aminosalicylates

• Oral budesonide

• After remission, long-term maintenance therapy (eg, once-daily mesalazine)

Medical treatment of acute, severe UC may

include the following:

• Hospitalization

• Intravenous high-dose corticosteroids

• Alternative induction medications:

Cyclosporine, tacrolimus, infliximab,

adalimumab, golimumab

Indications for urgent surgery include the

following:

• Toxic megacolon refractory to medical

management

• Fulminant attack refractory to medical

management

• Uncontrolled colonic bleeding

Indications for elective surgery include the

following:

• Long-term steroid dependence

• Dysplasia or adenocarcinoma found on

screening biopsy

• Disease present 7-10 years

Surgical options include the following:

• Total colectomy (panproctocolectomy) and ileostomy

• Total colectomy

• Ileoanal pouch reconstruction or ileorectal anastomosis

• In an emergency, subtotal colectomy with end-ileostomy

Anatomy

• Ulcerative colitis extends proximally from the anal verge in an uninterrupted pattern to involve part or the entire colon.

• The rectum is involved in more than 95% of cases.

• Ulcerative colitis occasionally involves the terminal ileum, as a result of an incompetent ileocecal valve. In these cases, which may constitute as many as 10% of patients, the reflux of noxious inflammatory mediators from the colon results in superficial mucosal inflammation of the terminal ileum, called backwash ileitis .

Etiology

• The exact etiology of ulcerative colitis is unknown.

• Etiologic factors potentially contributing to ulcerative colitis include genetic factors, immune system reactions, environmental factors, nonsteroidal anti-inflammatory drug (NSAID) use, low levels of antioxidants, psychological stress factors, a smoking history, and consumption of milk products.

Genetics

The current hypothesis is that genetically susceptible individuals have abnormalities of humoral and cell-mediated immunity and/or generalized enhanced reactivity against commensal intestinal bacteria and that this dysregulated mucosal immune response predisposes to colonic inflammation.

• A family history of ulcerative colitis is

associated with a higher risk for developing the disease.

• Disease concordance has been

documented in monozygotic twins.

Immune reactions

• Immune reactions that compromise the integrity of the intestinal epithelial barrier may contribute to ulcerative colitis.

• Serum and mucosal autoantibodies against intestinal epithelial cells may be involved.

• The presence of antineutrophil cytoplasmic antibodies (ANCA) and anti– Saccharomyces cerevisiae antibodies (ASCA) is a well-known feature of inflammatory bowel disease

NSAID use

• Nonsteroidal anti-inflammatory drug

(NSAID) use is higher in patients with

ulcerative colitis than in control subjects.

• One third of patients with an exacerbation

of ulcerative colitis report recent NSAID use.

Other etiologic factors

• Vitamins A and E, both considered antioxidants, are found in low levels in as many as 16% of children with ulcerative colitis exacerbation.

• Psychological and psychosocial stress factors can play a role in the presentation of ulcerative colitis and can precipitate exacerbations.

• Smoking is negatively associated with ulcerative colitis.

• Milk consumption may exacerbate the disease.

Epidemiology

• The annual incidence is 10.4-12 cases per 100,000 people.

• The prevalence rate is 35-100 cases per 100,000 people.

• The incidence of ulcerative colitis is reported to be 2-4 times higher in Ashkenazi Jews.

• Ulcerative colitis is slightly more common in women than in men.

• Age of onset follows a bimodal pattern, with a peak at 15-25 years and a smaller one at 55-65 years.

International statistics

• Ulcerative colitis is more common in the

Western and Northern hemispheres; the incidence is low in Asia and the Far East.

Prognosis

• Overall mortality is not increased in patients with ulcerative colitis.

• Chronic and severe cases can be associated with areas of precancerous changes, such as carcinoma in situ or dysplasia.

• 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.

• 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.

History

• Patients with ulcerative colitis predominantly complain of rectal bleeding, with frequent stools and mucous discharge from the rectum.

• Some patients also describe tenesmus.

• In severe cases, purulent rectal discharge causes lower abdominal pain and severe dehydration.

Fulminant disease

• In some cases, ulcerative colitis has a

fulminant course marked by severe

diarrhea and cramps, fever, leukocytosis,

and abdominal distention.

• An estimated 15% of patients present with

an attack severe enough to require

hospitalization and steroid therapy.

Extracolonic manifestations

• Include uveitis, pyoderma gangrenosum,

pleuritis, erythema nodosum, ankylosing

spondylitis, and spondyloarthropathies.

• Uveitis with an incidence of 3.8%.

• Primary sclerosing cholangitis 3%.

• Ankylosing spondylitis 2.7%.

• Erythema nodosum 1.9%.

• Pyoderma gangrenosum 1.2%.

Uveitis

Primary sclerosisn cholangitis

Ankylosing spondylitis

Erythema nodosum

Pyoderma gangrenosum

Primary sclerosing cholangitis

• Primary sclerosing cholangitis (PSC) is a potentially severe associated condition, often resulting in cholestatic jaundice and liver failure that requires transplantation.

• Of patients with PSC, 75% have inflammatory bowel disease.

• Of patients with ulcerative colitis, 5% have cholestatic liver disease, and 40% of those have PSC.

Physical Examination

• Physical findings are typically normal in

patients with mild disease.

• Patients with severe disease can have :

– Fever

– Tachycardia

– Significant abdominal tenderness

– Weight loss

Grading

• Mild - Bleeding per rectum and fewer than

4 bowel motions per day.

• Moderate - Bleeding per rectum with more

than 4 bowel motions per day.

• Severe - Bleeding per rectum, more than 4

bowel motions per day, and a systemic illness with hypoalbuminemia (< 30 g/L).

Diagnostic Considerations

• Differentiation between ulcerative colitis

and Crohn disease is critical to developing a treatment plan.

• Other problems to be considered include

collagenous colitis and lymphocytic colitis

infectious colitis, ischemic colitis in elderly patients, and radiation colitis.

• Chronic schistosomiasis

• Amebiasis

• Intestinal tuberculosis

• Ischemic colitis

• Radiation colitis

Approach Considerations

• The diagnosis of ulcerative colitis is best made with endoscopy.

• Endoscopically, ulcerative colitis is characterized by abnormal erythematous mucosa, with or without ulceration, extending from the rectum to part or all of the colon.

• Biopsy of the mucosa is recommended to identify the extent of the disease with respect to the thickness of the bowel wall.

Ulcerative colitis

Ulcerative colitis

Radiographic imaging

• Plain abdominal radiographs: the images

may show colonic dilatation, suggesting

toxic megacolon; evidence of perforation;

obstruction; or ileus.

• Double-contrast barium enema

examination is a valuable technique for diagnosing ulcerative colitis.

Toxic megacolon

Toxic megacolon

Serologic Markers

• ANCA (Antineutrophil cytoplasmic antibodies) is most commonly associated with ulcerative colitis.

• Specifically, perinuclear ANCA (pANCA).

• ANCA assay results are positive in 60-80% of patients with ulcerative colitis.

• The presence of pANCA is associated with an earlier need for surgery.

• ASCA (anti– Saccharomyces cerevisiae

antibodies) is more highly associated with

Crohn disease.

• ASCA is present in only 12% of patients

with ulcerative colitis.

• ANCA and ASCA titers are not correlated with disease activity.

Complete Blood Count

• Findings on CBC count may include the following:

– Anemia (ie, hemoglobin < 14 g/dL in males

and < 12 g/dL in females)

– Thrombocytosis (ie, platelet count

>350,000/µL)

Comprehensive Metabolic Panel

• Findings on the comprehensive metabolic panel may include the following:

– Hypoalbuminemia (ie, albumin < 3.5 g/dL)

– Hypokalemia (ie, potassium < 3.5 mEq/L)

– Hypomagnesemia (ie, magnesium < 1.5 mg/dL)

– Elevated alkaline phosphatase: More than 125 U/L

suggests primary sclerosing cholangitis (usually >3

times the upper limit of the reference range).

Inflammation Markers

• Elevation of the

• erythrocyte sedimentation rate and

• C-reactive protein level (ie, >100 mg/L) correlates with disease activity.

Stool Assays

• Stool studies are used to exclude other

causes.

• These include evaluation of fecal

leukocytes, ova and parasite studies,

culture for bacterial pathogens, and Clostridium difficile titer.

Endoscopy and Biopsy

• Once ulcerative colitis is suspected, endoscopy must be performed.

• Multiple biopsy samples should be

obtained from both inflamed and normal-appearing mucosa.

The extent of disease is defined by the following:

• Extensive disease - Evidence of ulcerative colitis

proximal to the splenic flexure

• Left-sided disease - Ulcerative colitis present in

the descending colon up to, but not proximal to,

the splenic flexure

• Proctosigmoiditis - Disease limited to the rectum

with or without sigmoid involvement

Histologic Findings

• Most of the pathology is limited to the mucosa and submucosa.

• Pathologic features that are typically seen include intense infiltration of the mucosa and submucosa with neutrophils and crypt abscesses, lamina propria with lymphoid aggregates, plasma cells, mast cells and eosinophils, and shortening and branching of the crypts.

Ulcerative colitis

Radiological Assessment of Ulcerative Colitis

• Plain abdominal radiographs are a useful adjunct to imaging in cases of ulcerative colitis of acute onset.

• Double-contrast barium enema examination also is a valuable technique for diagnosing ulcerative colitis.

• US, MRI, CT scanning.

• Radionuclide studies are useful in cases of acute fulminant colitis when colonoscopy or barium enema examination is contraindicated.

Treatment of Mild Disease

• In mild disease confined to the rectum, topical mesalazine given by suppository is the preferred therapy.

• Left-sided colonic disease is best treated with a combination of mesalazine suppository and an oral aminosalicylate.

• After remission, long-term maintenance therapy is encouraged.

• Systemic steroids are indicated when disease fails to quickly respond to aminosalicylates.

• Budesonide is indicated for the induction of remission in adults with active mild-to-moderate distal ulcerative colitis extending up to 40 cm from the anal verge.

Treatment of Acute, Severe Disease

• Acute, severe ulcerative colitis requires hospitalization and treatment with intravenous high-dose corticosteroids (hydrocortisone 400 mg/d or methylprednisolone 60 mg/d).

• Cyclosporine,tacrolimus, infliximab, adalimumab, and golimumab are often effective in bringing steroid-resistant disease under control.

• Infliximab

• Adalimumab

• Golimumab

• Vedolizumab

Indications for Surgery

• Failure of medical management is the most common indication for surgery.

• Indications for urgent surgery in patients with

ulcerative colitis include

– (1) toxic megacolon refractory to medical

management,

– (2) fulminant attack refractory to medical

management, and

– (3) uncontrolled colonic bleeding.

• Indications for elective surgery in

ulcerative colitis include

– (1) long-term steroid dependence,

– (2) dysplasia or adenocarcinoma found on

screening biopsy,

– (3) and disease present 7-10 years.

Maintenance Therapy

• Maintenance therapy is recommended for all patients to prevent relapse.

• Oral aminosalicylates are indicated for disease that responded to ASA or steroids.

• Azathioprine and 6-mercaptopurine are alternatives.

• For patients who were induced with infliximab, maintenance therapy should continue with infliximab or azathioprine.

• If golimumab is used for induction with good response, monthly maintenance therapy should continue with golimumab.

• Probiotics also appear to be effective at

maintaining remission:

– Escherichia coli strain Nissle 1917

Complications

• Pouchitis

– 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.

Toxic megacolon

• 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.

• Patients may eventually require a total colectomy.

Carcinoma

• The cancer tends to be multicentric, atypical in its appearance, and rapidly metastasizing.

• The risk of colorectal cancer increases by 0.5-1% per year.

• After 8-10 years of colitis, patients with ulcerative colitis should undergo annual or biannual surveillance colonoscopy with multiple biopsies at regular intervals.

• The finding of high-grade dysplasia in flat mucosa, is an indication for colectomy; the finding of low-grade dysplasia in flat mucosa may also be an indication for colectomy to prevent progression to a higher grade of neoplasia.

Medication

5-aminosalicylic Acid Derivative

• These agents have anti-inflammatory effects. They are used to maintain remission and to induce remission of mild flares of disease.

• Sulfasalazine

• Balsalazide

• Mesalamine

Tumor Necrosis Factor Inhibitor

• These agents prevent the endogenous cytokine from binding to cell surface receptor and exerting biological activity. These agents adversely affect normal immune responses and allow development of superinfections; reactivation of latent TB has been reported in patients with previous exposure to TB.

• Infliximab (Remicade)

• Adalimumab (Humira)

• Golimumab (Simponi)

Immunosuppressant Agent

• These agents regulate key factors of the immune system.

• Azathioprine (Imuran)

• Cyclosporine (Neoral, Sandimmune)

• 6-Mercaptopurine (Purinethol)

• Tacrolimus (Prograf)

Corticosteroids

• Corticosteroids decrease inflammation by suppressing migration of polymorphonuclear leukocytes and reversing increased capillary permeability. They are used for induction of remission in moderate-to-severe active ulcerative colitis.They have no benefit in maintaining remission; long-term use can cause adverse effects.

• Methylprednisolone (Solu-Medrol, Depo-Medrol, Medrol)

• Prednisone

• Hydrocortisone (Cortef, Solu-Cortef, A-Hydrocort)

• Budesonide

Alpha 4 Integrin Inhibitors

• Integrin inhibitors are emerging as options for

moderate-to-severe active IBD in patients who

have had an inadequate response with, lost

response to, or were intolerant to a TNF blocker

or immunomodulator; or had an inadequate

response with, were intolerant to, or demonstrated dependence on corticosteroids.

• Vedolizumab (Entyvio)

Antimicrobials

• They are usually administered on an

empiric basis in patients with severe colitis

in whom they may help with averting a life-threatening infection.

• Ciprofloxacin

• Metronidazole

Antidiarrheal

• These agents are nonabsorbable synthetic

opioids that provide symptomatic relief in the

treatment of ulcerative colitis. They prolong GI

transit time and decrease secretion via peripheral mu-opioid receptors.

• Diphenoxylate hydrochloride 2.5 mg with

atropine sulfate 0.025 mg

• Loperamide (Imodium)