Question

• Describe the chronic relapsing inflammatory bowel diseases (ulcerative colitis and Crohn disease), and summarize the pathophysiology, clinical manifestations, evaluation, and treatment recommendations for each.

Answer 1

Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, is characterized by chronic relapsing intestinal inflammation. ... It is thought that IBDresults from an aberrant and continuing immune response to the microbes in the gut, catalyzed by the genetic susceptibility of the individual.

In Crohn's disease, there are healthy parts of the intestine mixed in between inflamed areas. Ulcerative colitis, on the other hand, is continuous inflammation of the colon. Ulcerative colitis only affects the inner most lining of the colon while Crohn's disease can occur in all the layers of the bowel walls.

Crohn's disease and ulcerative colitis are idiopathic, chronic, relapsing, inflammatory conditions that are immunologically mediated. Although their exact etiologies remain uncertain, results from research in animal models, human genetics, basic science and clinical trials have provided important new insights into the pathogenesis of chronic, immune-mediated, intestinal inflammation. These studies indicate that Crohn's disease and ulcerative colitis are heterogeneous diseases characterized by various genetic abnormalities that lead to overly aggressive T-cell responses to a subset of commensal enteric bacteria. The onset and reactivation of disease are triggered by environmental factors that transiently break the mucosal barrier, stimulate immune responses or alter the balance between beneficial and pathogenic enteric bacteria. Different genetic abnormalities can lead to similar disease phenotypes; these genetic changes can be broadly characterized as causing defects in mucosal barrier function, immunoregulation or bacterial clearance.

While much of the exact nature of its pathophysiology is unknown, several key risk factors for IBD have been identified:

• Genetic susceptibility: As of 2015, 163 IBD-associated gene variants had been discovered. The risk for developing IBD has a positive correlation with gene number; however, gene presence alone accounts for approximately 25% of IBD cases, suggesting that the manifestation of IBD is influenced by the interaction of these genes with each other or with environmental factors.7
• Ethnicity: White Northern European and North American populations have the highest IBD prevalence. The lowest prevalence is found in the populations of continental Asia.8
• Infection: Gastrointestinal infections confer an increased risk for IBD development, particularly acute gastroenteritis caused by Salmonella, Campylobacter, and Shigella.9,10 Although the risk is highest in the year following infection, a 2009 cohort study showed that exposed subjects had an elevated risk throughout the 15-year study period.10
• Environment: A variety of environmental factors have been linked to IBD, particularly those that correspond to a Westernized environment and lifestyle. Of these, smoking, gut microbiota, diet (high-fat, high-sugar), and medications (early and frequent antibiotic exposure in the first years of life) have the strongest supporting evidence for links to IBD.7,8

Crohn Disease

CD causes full-thickness, transmural inflammation of the intestinal wall. Although CD can affect any portion of the gastrointestinal tract, from the mouth to the anus, approximately 70% percent of patients will have some degree of terminal ileal disease. In approximately 55% of CD patients, inflammation involves both the colon and terminal ileum. Isolated terminal ileal disease and isolated colon disease each account for approximately 15% of those with CD.11

Although the most common CD manifestations are chronic diarrhea, abdominal pain, and weight loss, due to the heterogeneity in disease phenotype, the presentation of a CD flare can vary significantly.8 Active small-bowel inflammation typically presents as an obstruction or ileus, with colicky abdominal pain, distension, nausea, or loose bowel movements.7 Hematochezia is often a sign that the colon is involved and is usually associated with diarrhea and muco-purulent discharge. Patients with perianal disease will present with perianal drainage and pain with sitting and defecating.12 The transmural nature of CD leads to the progression of penetrating disease and the formation of strictures, fistulas, and abscesses,13 complications that have the potential to become surgical emergencies. Additionally, small-bowel disease leads to malabsorption and vitamin deficiencies.

Fevers.Fevers are seen in 40% of patients with IBD at the time of presentation. Fevers can be high spiking on occasion but are usually low grade and chronic and may be unrecognized.

Weight loss.Weight loss may be a feature of IBD in both adults and children. In children, weight loss or a failure to maintain a normal growth velocity is the commonest systemic feature of IBD and is observed more frequently with CD than with UC.

Delayed growth and sexual maturation in children.Growth failure (defined as either reduced growth velocity, in centimeters per year, for age or a fall in height percentile from the child’s previous level) and delayed sexual maturation occasionally may be the initial presentation of CD in children (45). Patients also may have a concomitant delay in skeletal maturation, which is evaluated by radiologic determination of the nondominant hand. Delayed growth is more common in CD (60 to 88%) than in UC (6 to 12%), with the greatest frequency found in prepubertal children. Growth delay also can occur as a consequence of chronic corticosteroid use.

TREATMENT

Medical Management of Ulcerative Colitis

Mild disease.Oral sulfasalazine alone or in combination with topical medications is used in the treatment of mild disease. Newer 5-aminosalicylic acid medications (mesalamine, olsalazine, and balsalazide) are useful in patients unable to tolerate sulfasalazine due to side effects. Topical preparations including mesalamine and steroid enemas, mesalamine suppositories, and corticosteroid foam also may reduce symptoms in patients with limited distal colonic disease.

Moderate to severe disease.Patients with significant abdominal cramping, bloody diarrhea, abdominal tenderness, anemia, and hypoalbuminemia need to be hospitalized for close clinical observation and intravenous medications (corticosteroids), fluids, and nutrition. Antispasmodic agents should be avoided because they predispose patients to the development of toxic megacolon. Blood counts and chemistries are closely monitored. Intravenous steroid treatment is continued until abdominal cramping and hematochezia subside. Dietary restrictions, which initially include avoidance of high-fiber, high-residue, and spicy foods, are liberalized as disease activity responds to medical intervention. Concomitant treatment with sulfasalazine/5-aminosalicylic acid preparations is initiated once acute symptoms subside to maintain remission.

Immunosuppressive therapy.Azathioprine and 6-mercaptopurine are used due to their steroid-sparing effects, since approximately 50% of patients experience adverse effects from corticosteroids. Due to delayed onset of action, these agents are not used to treat acute colitis. Cyclosporine and tacrolimus have been used to treat acute steroid-refractory UC when surgery seemed inevitable. Clinical improvement is seen within 7 to 10 days in patients who achieve remission (15). However, the majority of patients relapse when these agents are withdrawn. Remission can be prolonged by starting azathioprine or 6-mercaptopurine treatment at least 4 weeks prior to discontinuing cyclosporine treatment (92).

  

Medical Management of Crohn’s DiseaseThe medical treatment approach for CD is individualized based on the severity of symptoms and degree and site of intestinal involvement.

Corticosteroids.Corticosteroids (I mg/kg/day) are effective in decreasing disease activity and inducing remission in most patients. However, due to undesirable side effects (cosmetic effects, suppression of linear growth in children, and osteopenia), long-term use of corticosteroids is not recommended. Furthermore, corticosteroids have not proved effective for the maintenance of remission. Budesonide, a potent steroid that undergoes extensive first-pass hepatic metabolism, is useful, but approximately one-third of patients experience adverse effects related to budesonide use.

Sulfasalazine and mesalamine.Sulfasalazine and mesalamine are used to treat mild to moderate disease and to maintain remission induced by corticosteroids. Sulfasalazine is useful for ileocolonic and colonic disease. About 30% of patients are unable to tolerate sulfasalazine due to side effects, mainly headaches, which can sometimes be averted by starting at a lower dose and gradually increasing the dose as tolerated. Other side effects include hemolytic anemia and pruritic dermatitis. The newer mesalamine preparation, pentasa, has been used for small bowel CD to facilitate steroid withdrawal and to reduce relapse rates following steroid withdrawal (74).

Antibiotics: metronidazole and ciprofloxacin.Metronidazole and ciprofloxacin are useful in the treatment of mild to moderate disease, particularly in patients with perianal disease and infectious complications. Sensory neuropathy, which may be seen with long-term metronidazole use, usually resolves completely or improves after discontinuation of the drug.

Immunosuppressive therapy.6-Mercaptopurine and azathioprine are indicated in patients with steroid dependency, extensive small bowel disease, history of previous resections, gastroduodenal disease, and perianal disease especially with refractory fistulae. In a recent study of 95 children with CD, azathioprine/6-mercaptopurine was well tolerated in 82% of patients and led to a steroid reduction in 87% of patients (47). Discontinuation of azathioprine or 6-mercaptopurine was required in 18% of patients due to hypersensitivity reactions (pancreatitis or high fever) or infectious complications. Other side effects such as elevated aminotransferase levels, leukopenia, and gastrointestinal intolerance either respond to dose reduction or resolve spontaneously. Methotrexate has been used to maintain long-term remission in adult patients with CD. Cyclosporine has been used for patients with severe CD with active fistulae.

Biological therapies.Increased production of inflammatory cytokines, especially tumor necrosis factor alpha (TNF-α), has been described both in histologically normal mucosa and in the inflamed mucosa in CD. Targan et al. showed that a single infusion of 5 mg of a chimeric monoclonal antibody against TNF-α (infliximab) per kg induced a clinical response in 81% and clinical remission in 48% of CD patients compared with 17 and 4%, respectively, in the placebo group (119). Infliximab infusions have since been successfully used to maintain remission as well for the treatment of fistulae in patients with CD (90, 101).

Thalidomide, originally used for its sedative and antiemetic properties, has recently been shown to inhibit TNF-α production by monocytes and other cells. Thalidomide was found to be efficacious in two recent studies of patients with chronically active, steroid-dependent CD. Side effects were mild and dose dependent, with the most common being drowsiness, peripheral neuropathy, edema, and dermatitis (18, 131).

Nutritional intervention.Nutritional intervention is often used to control disease activity, provide restitution of deficiencies, and provide adequate calories to reverse growth failure in children. Continuous nasogastric infusion or gastrostomy feedings of an elemental or semielemental formula at night may be beneficial. Patients with IBD are given a daily multivitamin and calcium supplementation if their milk intake is suboptimal and oral iron preparations if they have iron deficiency anemia