Arya B. Mohabbat and Matthew A. Ciorba
GENERAL PRINCIPLES
· Ulcerative colitis (UC) and Crohn disease (CD) are chronic inflammatory disorders of the gastrointestinal (GI) tract categorized under the spectrum of inflammatory bowel disease (IBD). Though the underlying etiology of IBD is not precisely known, genetic, environmental, and immune factors all play a role.
· Clinical history and physical examination in combination with objective findings from laboratory studies, radiology, endoscopy, and pathology are used to diagnose IBD.1–3
· IBD occurs at a high enough prevalence that most primary care physicians care for one or more IBD patients in their own practice. Therefore, understanding the nomenclature, clinical features, and basic management strategies of IBD is important.
· Key principles for the primary care clinician include 1) recognizing the clinical disease presentation, the cyclical nature of disease activity, and common extraintestinal disease manifestations; 2) understanding general treatment strategies including limiting the frequency and duration of corticosteroid use and smoking cessation for CD; 3) assisting in managing disease comorbidities including osteoporosis and anxiety/depression.
· UC is defined by mucosal inflammation limited to the colon. Inflammation most typically involves the distal rectum and extends proximally in a circumferential and contiguous distribution. The nomenclature for UC describes the extent of inflammation and is important in determining medical therapy (Table 31-1).
o Bloody diarrhea with associated rectal urgency and tenesmus (sense of incomplete defecation) is the hallmark presentation of active UC.
o Disease severity is characterized by patient symptoms.
§ Mild disease: <4 stools per day and no signs of systemic toxicity.
§ Moderate disease: 4–6 stools per day and minimal signs of systemic toxicity.
§ Severe disease: >6 stools per day with signs of systemic toxicity (fever, tachycardia, anemia, and increased erythrocyte sedimentation rate).
§ Fulminant disease: >10 stools per day, continuous bleeding, abdominal tenderness or distention, and dilation on radiographic imaging.
§ Clinical manifestations of UC are compared with those of CD in Table 31-2.
o Patients with UC can develop toxic megacolon (which can also be caused by infectious or toxin-mediated colitis). Precipitating factors include electrolyte abnormalities, opiates, and other antimotility agents. Life-threatening complications of toxic megacolon include perforation, hemorrhage, and sepsis.
· CD is characterized by transmural intestinal inflammation that can involve any part of the GI tract from the oropharynx to the anus.
o Inflammatory changes are usually asymmetric and discontinuous with skip areas (normal tissue separating diseased intestinal segments).
o CD is described by location (ileal, colonic, and ileocolonic) and behavior (penetrating [fistulae, abscesses], stricturing, inflammatory, or perianal disease).
o The manifestations of CD vary with the degree and segment of intestinal involvement.
§ Upper GI tract involvement may present as oral ulcers, gum pain, odynophagia, dysphagia, or gastric outlet obstruction.
§ Small bowel and colonic symptoms include diarrhea, abdominal pain, weight loss, obstructive symptoms, and fever.
§ Gross rectal bleeding occurs less commonly than in UC. Many CD patients do not have diarrhea and, in fact, may trend toward constipation early in an obstructive process.
o Disease severity assessment is more difficult than with UC and is sometimes complicated by concurrent irritable bowel syndrome. With that caveat noted, classification system for CD includes the following.
§ Mild-moderate disease: Outpatients able to tolerate oral intake without signs of dehydration, abdominal pain, systemic toxicity, or weight loss of >10%.
§ Moderate-severe disease: Patients who have failed therapy for mild-moderate disease or have abdominal pain, nausea/vomiting, and signs of systemic toxicity such as fevers, dehydration, anemia, or weight loss of >10%.
§ Severe-fulminant disease: Persistent symptoms despite corticosteroid use or patients with high fevers, cachexia, persistent vomiting, intestinal obstruction, surgical abdomen, or abscess formation.
§ Remission: Asymptomatic patients or those who have responded to medical or surgical intervention without evidence of residual/recurrent disease (not on steroids).
o Patients with CD can also develop toxic megacolon.
TABLE 31-1 Classifying Disease Extent in Ulcerative Colitis
TABLE 31-2 Comparison of Crohn Disease and Ulcerative Colitis
Modified from Iskandar H, Ciorba MA. Inflammatory bowel disease. In: Gyawali CP, ed. The Washington Manual Gastroenterology Subspecialty Consult, 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2012:169–179.
Epidemiology
· IBD can develop at any age; peak incidence rates occur between 15 and 30 years of age.
· Though all races are affected, the incidence rates are higher in white Northern Europeans and North Americans.
· The prevalence of IBD in the United States is4
o CD: 58 to 241/100,000
o UC: 34 to 263/100,000
Risk Factors
· Patients with a first-degree relative with IBD have an increased risk of having IBD themselves.
· Current smokers have a lower risk of developing UC. Former smokers, however, have a 1.7-fold increased risk for UC over lifetime nonsmokers.
· Smoking is associated with an increased risk of CD, increased chance of disease recurrence, and reduced therapeutic efficacy.
· Though no single microbe causes IBD, concomitant infections (intestinal and extraintestinal) as well as antibiotic use can exacerbate IBD.
Associated Conditions
· IBD can be associated with extraintestinal manifestations (EIMs), which often correlate to colonic IBD activity.5 EIMs occur more frequently in UC than CD.
· Musculoskeletal
o Central arthropathies (ankylosing spondylitis and sacroiliitis) associated with IBD are progressive conditions and tend to correlate poorly with IBD activity.
o Pauciarticular peripheral arthritis correlates well with colonic inflammation. Asymmetric large joint (knees, hips, ankles, wrists, and elbows) involvement is typical.
o Polyarticular peripheral arthritis is symmetric, involves smaller joints (fingers and toes), and may occur independent of IBD activity.
o Osteoporosis risk is increased in IBD patients presumably due to cumulative steroid use, malabsorption, low body weight, and relative hypogonadism related to disease activity. Guidelines suggest using dual-energy x-ray absorptiometry (DEXA) testing to screen for osteoporosis in all postmenopausal women with IBD and those individuals who have received prolonged or frequent courses of corticosteroids. All patients with disease severe enough to require steroids at least once should take supplemental vitamin D (800 IU) daily along with 1,000 to 1,500 mg calcium supplementation.
· Dermatologic
o Erythema nodosum (EN) is a painful, poorly demarcated, nodular lesion that tends to be bilateral but asymmetric. It is closely related to IBD activity, and treatment of the underlying disease resolves EN lesions.
o Pyoderma gangrenosum (PG) is a debilitating skin disease characterized by irregular, blue-red ulcers with purulent necrotic bases. Lesions are usually found on the lower extremities, buttocks, abdomen, and face. PG can develop independent of IBD activity. A high index of suspicion for PG should exist for patients with poorly healing skin lesions.
o Aphthous ulcers in the oropharynx occur in 10% to 30% of patients with IBD.
· Ocular
o Episcleritis is a painless inflammation of the eye’s surface. Visual acuity is not affected, and episodes tend to coincide with IBD flares.
o Uveitis is an inflammation of the eye that can be painful and associated with decreased visual acuity. It does not always coincide with disease activity. Uncontrolled uveitis can cause permanent ocular damage.
o Prompt referral to an eye specialist is necessary for all new changes in vision or eye complaints in the setting of IBD.
· Hepatobiliary
o Gallstones may develop in patients with CD due to malabsorption of bile salts in the ileum.
o Primary sclerosing cholangitis (PSC) is more commonly associated with UC than CD and is a chronic inflammatory disease of the bile ducts (refer to Chapter 30). Endoscopic retrograde cholangiopancreatography (ERCP) or magnetic resonance cholangiopancreatography (MRCP) reveals strictures of intrahepatic and extrahepatic ducts. Patients with PSC have an increased risk of developing cholangiocarcinoma and colitis-associated cancer.
· Vascular: The risk of venous and arterial thrombosis is increased in patients with IBD and can be a major source of mortality.
· Renal: Nephrolithiasis (calcium oxalate stones) can occur with CD. Hyperoxaluria is common and related to fat malabsorption, which increases the amount of dietary oxalate available for absorption in the colon.
DIAGNOSIS
Clinical Presentation
History
· A thorough history is the first step in diagnosing IBD and defining disease severity.
· Questions should be aimed at abdominal symptoms, systemic signs of toxicity, family history of IBD, medication history, smoking history, and the presence of EIMs.
· UC primarily presents with bloody diarrhea, urgency, tenesmus, and abdominal pain.
· CD patients primarily present with abdominal pain, weight loss, fatigue, and sometimes fever. Diarrhea and rectal bleeding are less common than in UC, but can be significant.
Physical Examination
· Fever, hypotension, and tachycardia are signs of systemic toxicity.
· High-pitched or absent bowel sounds may suggest obstruction.
· Peritoneal signs (rebound, guarding, and rigidity) suggest intestinal perforation.
· A right lower quadrant mass is often palpable in patients with active ileal CD.
· A careful rectal and perianal examination is important. Skin tags, fistulae, and anal fissures suggest perianal CD.
· With toxic megacolon, the colon rapidly dilates to >5 to 6 cm and the abdomen is distended and painful. As the name implies, patients appear quite toxic (e.g., fever, hypotension, and tachycardia). Steroids may mask some of these signs.
· Ocular, skin, and musculoskeletal exams identify EIMs of IBD.
Differential Diagnosis
The differential diagnosis of IBD is extensive, including infection, neoplasia, ischemia, and other inflammatory conditions (Table 31-3).
TABLE 31-3 Differential Diagnosis for Irritable Bowel Disease
HIV, human immunodeficiency virus; IBD, inflammatory bowel disease; NSAID, nonsteroidal anti-inflammatory drug.
Modified from Iskandar H, Ciorba MA. Inflammatory bowel disease. In: Gyawali CP, ed. The Washington Manual Gastroenterology Subspecialty Consult, 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2012:169–179.
Diagnostic Testing
Laboratories
· No specific laboratory test confirms IBD; however, several autoantibodies have been detected in IBD patients, including perinuclear antineutrophil cytoplasmic antibody (P-ANCA) and anti–Saccharomyces cerevisiaeantibodies (ASCA).
· Initial evaluation should include complete blood cell count (evaluate for anemia and leukocytosis); comprehensive metabolic panel (evaluate for metabolic derangements); erythrocyte sedimentation rate; and C-reactive protein (measure of active inflammation), calcium, vitamin D, vitamin B12, iron studies.
· Antibody panels (ASCA/pANCA) sometimes aid in clinical decision making.
· Stool studies (Clostridium difficile toxin, culture, ova, and parasites) are important to look for infectious etiologies that may mimic IBD.
Imaging
· Urgent CT scans are used for patients presenting with systemic toxicity and significant abdominal complaints to examine for signs of obstruction, perforation, or megacolon.
· Elective small bowel follow-through computerized tomography enterography (CTE) or magnetic resonance enterography (MRE) are frequently ordered to look for strictures, abscesses, and fistulae and to assess disease activity.
Diagnostic Procedures
· Endoscopy is used to differentiate between CD and UC, while also allowing for determination of disease location, extent, and severity.
· Histology in UC shows inflammation confined to the mucosa and superficial submucosa. The crypt architecture is distorted (branching), and basal lymphoid aggregations and plasma cells are often present.
· Inflammation in CD is transmural with crypt abscesses and noncaseating granulomas. Microscopic skip areas also occur.
TREATMENT
Medications
· The goals of medical management of CD and UC are to induce and maintain remission.4,5
· Disease location and the nature of extraintestinal complaints influence choice of therapy. The goal is to maximize benefit while minimizing the chances of drug toxicity.
· Prior to initiating immunosuppressive/immunomodulator therapy, concurrent infection (hepatitis B, C. difficile, and TB) should be ruled out. Also, ensure influenza, hepatitis B, and pneumococcal immunizations are up to date. Tobacco screening/cessation counseling should be a part of this discussion as well.
· Treatment of toxic megacolon consists of complete bowel rest, correction of dehydration and electrolyte abnormalities, discontinuation of all drugs that can reduce motility, and high-dose steroids. Surgery may be necessary for those unresponsive to medical management or for those with perforation or severe hemorrhage.
Antibiotics
· Ciprofloxacin and metronidazole are often used to treat perianal, fistulizing, and mildly active CD of the colon.
· Peripheral neuropathy is an important toxicity of prolonged metronidazole use. Tendon rupture has been reported with ciprofloxacin use.
Aminosalicylates
· 5-Aminosalicylates (5-ASA) drugs are often the first-line therapies to treat patients with mild-to-moderate UC.
· Various formulations of 5-ASA compounds are available and are generally well tolerated. Mesalamine and balsalazide are the formulations available in the United States.
· Mesalamine as a suppository or enema is effective treatment for proctitis and left-sided colitis.
· A small percentage of patients are intolerant of 5-ASA, which results in a paradoxical increase in diarrhea.
· Sulfasalazine (a 5-ASA prodrug) is a less expensive alternative medication and has demonstrated efficacy for colonic disease and IBD-associated peripheral arthropathy. Its use is dose limited by the sulfa moiety.
Corticosteroids
· While undesirable in both side effect profile and the inability to maintain remission, steroids are commonly used to induce remission in moderate-to-severe IBD.
· The need to initiate steroids portends a poor prognosis. An increase in frequency of usage or prolonged usage generally signals the need for an immunomodulatory drug to be initiated (see below).
· Steroid dependency (i.e., symptoms flare with decreased doses) or steroid resistance (i.e., symptoms persist despite increasing doses of steroids) occurs in 50% of patients.
· Locally delivered/released steroids reduce systemic side effects. Enteric-coated budesonide is used in ileal/ileocolonic CD due to terminal ileum and right colon delivery. Suppositories and enemas are useful in proctitis and left colon disease.
· Steroids are ineffective as maintenance therapy and lead to significant side effects including metabolic, psychiatric, ocular, GI, and osseous side effects.
· Steroids are usually started at a dose of 1 mg/kg and continued until remission of symptoms. A slow taper (over 2 to 3 months) is then initiated; more rapid taper typically leads to recurrence of symptoms.
Immunomodulators
· Immunomodulators such as 6-mercaptopurine (6-MP) and its prodrug azathioprine (AZA) are widely used in the management of IBD to maintain steroid-free disease remission. Therapeutic effect may take 3 to 5 months of continued use.
· Immunomodulators are typically initiated in patients unable to wean from steroids and in those requiring >1 course of steroids per year.
· Bone marrow suppression can occur; thus the need for routine CBCs.
· Checking a thiopurine methyltransferase (TPMT) activity level is standard of care prior to immunomodulator initiation to identify patients at risk for severe bone marrow suppression.
· Thiopurine metabolite (6-TGN/6-MMP) levels provide information on medication adherence, adequacy of therapeutic levels (6-TGN), and risk for hepatotoxicity (6-MMP).
· Idiosyncratic pancreatitis occurs in approximately 1% to 3% of patients. If pancreatitis develops, the drug should be immediately discontinued. Repeat challenge with either 6-MP or AZA is contraindicated.
· Other immunosuppressant drugs, including methotrexate (for CD) and cyclosporine (in UC), have been used successfully to manage moderate-to-severe IBD.
· Use of these drugs during pregnancy remains controversial. It is generally considered that the risk-to-benefit ratio favors continuation of AZA/6-MP over possible recurrence of disease activity during pregnancy. Methotrexate and cyclosporine are contraindicated during pregnancy.
Tumor Necrosis Factor Alpha Antagonists
· Tumor necrosis factor alpha antagonists (anti–TNF-α) are indicated for moderate-to-severe or steroid-dependent disease.
· Infliximab, adalimumab, and certolizumab pegol are FDA-approved anti–TNF-α therapies for CD. Infliximab and adalimumab are approved for the therapy of UC.
· If a patient responds to induction dosing regimen by 8 to 12 weeks, long-term maintenance dosing is recommended.
· Prior to starting treatment, latent tuberculosis and occult hepatitis B must be ruled out.
· Adverse effects include acute and delayed infusion reactions, injection site reactions, infection, an increased risk of lymphoma, and perhaps nonmelanoma skin cancer.
Surgical Management
· Indications for surgery include severe GI hemorrhage, toxic megacolon, perforation, medically refractory disease, recurrent/persistent obstructions, significant fistulizing disease, and abscess.
· Total colectomy is curative for UC. Surgery for CD involves resection limited to diseased segments.
· UC patients with colonic carcinoma, high-grade dysplasia, or multifocal low-grade dysplasia found during surveillance colonoscopy should also be referred for total colectomy.
· Postcolectomy, many patients opt to have an ileal pouch created in lieu of a permanent ileostomy. Pouchitis occurs in up to 50% of patients—typical symptoms include increased stool frequency, abdominal cramping, rectal urgency, rectal bleeding, incontinence, and fever.
o Antibiotics (ciprofloxacin or metronidazole) are effective therapy for pouchitis.
o Recurrent or refractory pouchitis may represent misdiagnosed CD. Pouch excision is required in approximately 5% of patients.
o Cuffitis is inflammation due to a short “cuff” of retained rectal mucosa and is treated with topical steroid or 5-ASA suppositories.
· Postoperative recurrence of CD is common. Smoking has been associated with an accelerated time to disease recurrence postoperatively in CD patients.
SPECIAL CONSIDERATIONS
Treatment of Extraintestinal Manifestations of IBD
· Treatments for ankylosing spondylitis and sacroiliitis include analgesics, exercise, sulfasalazine, methotrexate, or anti-TNF therapy (Chapter 33).
· Treatment of the underlying colitis tends to improve pauciarticular peripheral arthritis. The course of polyarticular peripheral arthritis is more protracted, often requiring immunosuppressants for treatment.
· Low bone density and vitamin D deficiency are common in patients with IBD, particularly CD. Steroid therapy intensifies these complications. Adequate vitamin D and calcium supplementation is suggested for all IBD patients.
· Treatment of the underlying disease results in improvement of EN lesions. PG calls for aggressive local wound care, and systemic steroids are often required. Aphthous ulcers tend to resolve with disease remission.
· Treatment of episcleritis consists of controlling the underlying disease flare as well as topical steroids. Topical steroids are the primary treatment for uveitis.
· Treatment of PSC includes endoscopic dilation of symptomatic strictures. Patients with severe disease may ultimately require liver transplantation (refer to Chapter 30).
· Inpatients should be given thromboembolism prophylaxis with heparin products (unless severe bleeding is present) and avoid immobilization and prolonged indwelling catheters.
Cancer Surveillance
· Patients with IBD have an increased risk of developing colorectal cancer.
· A family history of colon cancer and concurrent PSC elevates the risk even further.
· Cancer risk is related to IBD disease duration (after 8 to 10 years), extent, and severity.
· The current recommendation is to begin colorectal cancer screening after 8 to 10 years of disease. Surveillance colonoscopies should be performed every 1 to 2 years.
· Patients with PSC should begin surveillance colonoscopies at the time of diagnosis.
· Patients with high-grade dysplasia or multifocal low-grade dysplasia seen on colon biopsies should be referred to a colorectal surgeon.
REFERENCES
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3.Kornbluth A, Sachar DB. Ulcerative colitis practice guidelines in adults: American College of Gastroenterology, Practice Parameters Committee. Am J Gastroenterol 2010;105:501–523.
4.Kappelman MD, Rifas-Shiman SL, Kleinman K, et al. The prevalence and geographic distribution of Crohn’s disease and ulcerative colitis in the United States. Clin Gastroenterol Hepatol 2007;5:1424–1429.
5.Rothfuss KS, Stange EF, Herrlinger KR. Extraintestinal manifestations and complications in inflammatory bowel diseases. World J Gastroenterol 2006;12:4819–4831.