InternalMed_Harrison

InternalMed_Harrison. The majority of patients with moderate to severe UC benefit from oral or parenteral glucocorticoids. Prednisone is usually started at doses of 40–60 mg/d for active UC that is unresponsive to 5-ASA therapy. Parenteral glucocorticoids may be administered as hydro-cortisone, 300 mg/d, or methylprednisolone, 40–60 mg/d. A new glucocorticoid for UC, budesonide (Uceris), is released entirely in the colon and has minimal to no glucocorticoid side effects. The dose is 9 mg/d for 8 weeks, and no taper is required. Topically applied glucocorticoids are also beneficial for distal colitis and may serve as an adjunct in those who have rectal involvement plus more proximal disease. Hydrocortisone enemas or foam may control active disease, although they have no proven role as maintenance therapy. These glucocorticoids are significantly absorbed from the rectum and can lead to adrenal suppression with prolonged administration. Topical 5-ASA therapy is more effective than topical steroid therapy in


InternalMed_Harrison

InternalMed_Harrison. glucocorticoids are significantly absorbed from the rectum and can lead to adrenal suppression with prolonged administration. Topical 5-ASA therapy is more effective than topical steroid therapy in the treatment of distal UC.


InternalMed_Harrison

InternalMed_Harrison. Glucocorticoids are also effective for treatment of moderate to severe CD and induce a 60–70% remission rate compared to a 30% placebo response. The systemic effects of standard glucocorticoid formulations have led to the development of more potent formulations that are less well-absorbed and have increased first-pass metabolism. Controlled ileal-release budesonide has been nearly equal to prednisone for ileocolonic CD with fewer glucocorticoid side effects. Budesonide is used for 2–3 months at a dose of 9 mg/d, and then tapered. Budesonide 6 mg/d is effective in reducing relapse rates at 3–6 months but not at 12 months in CD patients with a medically induced remission.


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InternalMed_Harrison. Glucocorticoids play no role in maintenance therapy in either UC or CD. Once clinical remission has been induced, they should be tapered according to the clinical activity, normally at a rate of no more than 5 mg/week. They can usually be tapered to 20 mg/d within 4–5 weeks but often take several months to be discontinued altogether. The side effects are numerous, including fluid retention, abdominal striae, fat redistribution, hyperglycemia, subcapsular cataracts, osteonecrosis, osteoporosis, myopathy, emotional disturbances, and withdrawal symptoms. Most of these side effects, aside from osteonecrosis, are related to the dose and duration of therapy. Antibiotics have no role in the treatment of active or quiescent UC. However, pouchitis, which occurs in about a third of UC patients after colectomy and IPAA, usually responds to treatment with metronidazole and/or ciprofloxacin.


InternalMed_Harrison

InternalMed_Harrison. Metronidazole is effective in active inflammatory, fistulous, and perianal CD and may prevent recurrence after ileal resection. The most effective dose is 15–20 mg/kg per day in three divided doses; it is usually continued for several months. Common side effects include nausea, metallic taste, and disulfiram-like reaction. Peripheral neuropathy can occur with prolonged administration (several months) and on rare occasions is permanent despite discontinuation. Ciprofloxacin (500 mg bid) is also beneficial for inflammatory, perianal, and fistulous CD but has been associated with Achilles tendinitis and rupture. Both ciprofloxacin and metronidazole antibiotics can be used as first-line drugs for short periods of time in active inflammatory, fistulizing, and perianal CD.


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InternalMed_Harrison. Azathioprine and 6-mercaptopurine (6-MP) are purine analogues commonly employed in the management of glucocorticoid-dependent IBD. Azathioprine is rapidly absorbed and converted to 6-MP, which is then metabolized to the active end product, thioinosinic acid, an inhibitor of purine ribonucleotide synthesis and cell proliferation. These agents also inhibit the immune response. Efficacy can be seen as early as 3–4 weeks but can take up to 4–6 months. Adherence can be monitored by measuring the levels of 6-thioguanine and 6-methylmercaptopurine, end products of 6-MP metabolism. Azathioprine (2–3 mg/kg per day) and 6-MP (1–1.5 mg/kg per day) have been used successfully as glucocorticoid-sparing agents in up to two-thirds of UC and CD patients previously unable to be weaned from glucocorticoids. They are also used as maintenance therapy in UC and CD and for treating active perianal disease and fistulas in CD. In addition, 6-MP or azathioprine is effective for postoperative prophylaxis of


InternalMed_Harrison

InternalMed_Harrison. They are also used as maintenance therapy in UC and CD and for treating active perianal disease and fistulas in CD. In addition, 6-MP or azathioprine is effective for postoperative prophylaxis of CD.


InternalMed_Harrison

InternalMed_Harrison. Although azathioprine and 6-MP are usually well tolerated, pancreatitis occurs in 3–4% of patients, typically presents within the first few weeks of therapy, and is completely reversible when the drug is stopped. Other side effects include nausea, fever, rash, and hepatitis. Bone marrow suppression (particularly leukopenia) is dose-related and often delayed, necessitating regular monitoring of the complete blood cell count (CBC). Additionally, 1 in 300 individuals lacks thiopurine methyltransferase, the enzyme responsible for drug metabolism to inactive end-products (6-methylmercaptopurine); an additional 11% of the population are heterozygotes with intermediate enzyme activity. Both are at increased risk of toxicity because of increased accumulation of active 6-thioguanine metabolites. Although 6-thioguanine and 6-methylmercaptopurine levels can be followed to determine correct drug dosing and reduce toxicity, weight-based dosing is an acceptable alternative. CBCs and liver function


InternalMed_Harrison

InternalMed_Harrison. 6-thioguanine and 6-methylmercaptopurine levels can be followed to determine correct drug dosing and reduce toxicity, weight-based dosing is an acceptable alternative. CBCs and liver function tests should be monitored frequently regardless of dosing strategy. IBD patients treated with azathioprine/6-MP are at approximately a fourfold increased risk of developing a lymphoma. This increased risk could be a result of the medications, the underlying disease, or both.


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InternalMed_Harrison. Methotrexate (MTX) inhibits dihydrofolate reductase, resulting in impaired DNA synthesis. Additional anti-inflammatory properties may be related to decreased IL-1 production. Intramuscular (IM) or subcutaneous (SC) MTX (25 mg/week) is effective in inducing remission and reducing glucocorticoid dosage; 15 mg/week is effective in maintaining remission in active CD. Potential toxicities include leukopenia and hepatic fibrosis, necessitating periodic evaluation of CBCs and liver enzymes. The role of liver biopsy in patients on long-term MTX is uncertain but is probably limited to those with increased liver enzymes. Hypersensitivity pneumonitis is a rare but serious complication of therapy.


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InternalMed_Harrison. Cyclosporine (CSA) is a lipophilic peptide with inhibitory effects on both the cellular and humoral immune systems. CSA blocks the production of IL-2 by T helper lymphocytes. CSA binds to cyclophilin, and this complex inhibits calcineurin, a cytoplasmic phosphatase enzyme involved in the activation of T cells. CSA also indirectly inhibits B cell function by blocking helper T cells. CSA has a more rapid onset of action than 6-MP and azathioprine. CSA is most effective when given at 2–4 mg/kg per day IV in severe UC that is refractory to IV glucocorticoids, with 82% of patients responding. CSA can be an alternative to colectomy. The long-term success of oral CSA is not as dramatic, but if patients are started on 6-MP or azathioprine at the time of hospital discharge, remission can be maintained. For the 2 mg/kg dose, levels as measured by monoclonal radioimmunoassay or by the high-performance liquid chromatography assay should be maintained between 150 and 350 ng/mL.


InternalMed_Harrison

InternalMed_Harrison. CSA may cause significant toxicity; renal function should be monitored frequently. Hypertension, gingival hyperplasia, hypertrichosis, paresthesias, tremors, headaches, and electrolyte abnormalities are common side effects. Creatinine elevation calls for dose reduction or discontinuation. Seizures may also complicate therapy, especially if the patient is hypomagnesemic or if serum cholesterol levels are <3.1 mmol/L (<120 mg/dL). Opportunistic infections, most notably Pneumocystis carinii pneumonia, may occur with combination immunosuppressive treatment; prophylaxis should be given. Major adverse events occurred in 15% of patients in one large study, including nephrotoxicity not responding to dose adjustment, serious infections, seizures, anaphylaxis, and death of two patients. This high incidence suggests that vigorous monitoring by experienced clinicians at tertiary care centers may be required. To compare IV cyclosporine versus infliximab, a large trial was conducted in Europe by


InternalMed_Harrison

InternalMed_Harrison. incidence suggests that vigorous monitoring by experienced clinicians at tertiary care centers may be required. To compare IV cyclosporine versus infliximab, a large trial was conducted in Europe by the GETAID group. The results indicated identical 7-day response rates between cyclosporine 2 mg/kg (with doses adjusted for levels of 150–250 ng/mL) and infliximab 5 mg/kg, with both groups achieving response rates of 85%. Serious infections occurred in 5 of 55 cyclosporine patients and 4 of 56 infliximab patients. Response rates were similar in the two groups at day 98 among patients treated with oral cyclosporine versus infliximab at the usual induction dose and maintenance dose regimen (40% and 46%, respectively). In light of data showing equal efficacy of CSA and infliximab in severe UC, more physicians are relying on infliximab rather than CSA in these patients.


InternalMed_Harrison

InternalMed_Harrison. Tacrolimus is a macrolide antibiotic with immunomodulatory properties similar to CSA. It is 100 times as potent as CSA and is not dependent on bile or mucosal integrity for absorption. These pharmacologic properties enable tacrolimus to have good oral absorption despite proximal small bowel Crohn’s involvement. It has shown efficacy in children with refractory IBD and in adults with extensive involvement of the small bowel. It is also effective in adults with glucocorticoid-dependent or refractory UC and CD as well as refractory fistulizing CD.


InternalMed_Harrison

InternalMed_Harrison. Biologic therapy was traditionally reserved for moderately to severely ill patients with CD who had failed other therapies. However, it is now commonly given as an initial therapy for patients with moderate to severe CD in order to prevent future disease complications. Patients who respond to biologic therapies enjoy an improvement in clinical symptoms; a better quality of life; less disability, fatigue, and depression; and fewer surgeries and hospitalizations.


InternalMed_Harrison

InternalMed_Harrison. Anti-TNF Therapies The first biologic therapy approved for CD was infliximab, a chimeric IgG1 antibody against TNF-α, which is now also approved for treatment of moderately to severely active UC. Of active CD patients refractory to glucocorticoids, 6-MP, or 5-ASA, 65% will respond to IV infliximab (5 mg/kg); one-third will enter complete remission. The ACCENT I (A Crohn’s Disease Clinical Trial Evaluating Infliximab in a New Long-Term Treatment Regimen) study showed that of the patients who experience an initial response, 40% will maintain remission for at least 1 year with repeated infusions of infliximab every 8 weeks. Infliximab is also effective in CD patients with refractory perianal and enterocutaneous fistulas, with the ACCENT II trial showing a 68% response rate (50% reduction in fistula drainage) and a 50% complete remission rate. Reinfusion, typically every 8 weeks, is necessary to continue therapeutic benefits in many patients.


InternalMed_Harrison

InternalMed_Harrison. The SONIC (Study of Biologic and Immunomodulator-Naive Patients with Crohn’s Disease) trial compared infliximab plus azathioprine, infliximab alone, and azathioprine alone in immunomodulatorand biologic-naive patients with moderate to severe CD. At 1 year, the infliximab plus azathioprine group had a glucocorticoid-free remission rate of 46% compared with 35% for infliximab alone and 1961 24% for azathioprine alone. There was also complete mucosal healing at week 26 with the combined approach relative to either infliximab or azathioprine alone (44% vs 30% vs 17%). The adverse events were equal between groups.


InternalMed_Harrison

InternalMed_Harrison. Two large trials of infliximab in moderate to severe UC also showed efficacy with a response rate of 37–49%, with about one-fifth of patients maintaining remission after 54 weeks. Dosing for UC and CD are identical, with induction dosing at 0, 2, and 6 weeks and every 8 weeks thereafter. There is a similar study to SONIC in patients with moderate to severe UC. After 16 weeks of therapy, UC patients taking azathioprine plus infliximab had a glucocorticoidfree remission rate of 40% compared to 24% (article now published) and 22% of those on azathioprine and infliximab alone, respectively. This is even further evidence for “top-down” or more aggressive therapy for both moderate to severe CD and UC.


InternalMed_Harrison

InternalMed_Harrison. Adalimumab is a recombinant human monoclonal IgG1 antibody containing only human peptide sequences and is injected subcu taneously. Adalimumab binds TNF and neutralizes its function by blocking the interaction between TNF and its cell-surface receptor. Therefore, it seems to have a similar mechanism of action to infliximab but with less immunogenicity. Adalimumab has been approved for treatment of moderate to severe CD. CHARM (Crohn’s Trial of the Fully Human Adalimumab for Remission Maintenance) is an adalimumab maintenance study in patients who responded to adalimumab induction therapy. About 50% of the patients in this trial were previously treated with infliximab. Remission rates ranged from 42–48% of infliximab-naïve patients at 1 year compared with remission rates of 31–34% in patients who had previously received infliximab. Another trial showed a remission rate of 21% at 4 weeks in patients who had initially responded to and then failed infliximab. In clinical practice, the


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InternalMed_Harrison. who had previously received infliximab. Another trial showed a remission rate of 21% at 4 weeks in patients who had initially responded to and then failed infliximab. In clinical practice, the remission rate in patients taking adalimumab increases with a dose increase to 40 mg weekly instead of every other week. Adalimumab is now also approved for the treatment of moderately to severely active UC.


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InternalMed_Harrison. Certolizumab pegol is a pegylated form of an anti-TNF Fab portion of an antibody administered SC once monthly. SC certolizumab pegol was effective for induction of clinical response in patients with active inflammatory CD. In the PRECISE II (Pegylated Antibody Fragment Evaluation in Crohn’s Disease) trial of maintenance therapy with certolizumab in patients who responded to certolizumab induction, the results were similar to the CHARM trial. At week 26, the subgroup of patients who were infliximab naïve had a response of 69% as compared to 44% in patients who had previously received infliximab. Golimumab is another fully human IgG1 antibody against TNF-α and is currently approved for the treatment of moderately to severely active UC. All of the patients in the golimumab trial were infliximab-naive. Like adalimumab and certolizumab, golimumab is injected SC.


InternalMed_Harrison

InternalMed_Harrison. Side Effects of Anti-TNF Therapies • Development of antiboDies The development of antibodies to infliximab (ATIs) is associated with an increased risk of infusion reactions and a decreased response to treatment. Current practice does not include giving on-demand or episodic infusions in contrast to periodic (every 8 week) infusions because patients are most likely to develop ATIs. ATIs are generally present when the quality of response or the response duration to infliximab infusion decreases. Decreasing the dosing intervals or increasing the dosage to 10 mg/kg may restore the efficacy. There are commercial assays for both infliximab and adalimumab antibodies and trough levels to determine optimal dosing. If a patient has high ATIs and a low trough level of infliximab, it is best to switch to another anti-TNF therapy. Most acute infusion reactions and serum sickness can be managed with glucocorticoids and antihistamines. Some reactions can be serious and would necessitate a change in


InternalMed_Harrison

InternalMed_Harrison. to another anti-TNF therapy. Most acute infusion reactions and serum sickness can be managed with glucocorticoids and antihistamines. Some reactions can be serious and would necessitate a change in therapy, especially if a patient has ATIs.


InternalMed_Harrison

InternalMed_Harrison. non-HoDGkin’s lympHoma (nHl) The baseline risk of NHL in CD patients is 2:10,000, which is slightly higher than in the general population. 1962 Azathioprine and/or 6-MP therapy increases the risk to about 4:10,000. The highest risk for thiopurine-associated NHL is in patients over 65 years old, with a moderate risk in those between the ages of 50 and 65. Anti-TNF therapy increases the risk to approximately 6:10,000.


InternalMed_Harrison

InternalMed_Harrison. Hepatosplenic t cell lympHoma (Hstcl) HSTCL is a nearly universally fatal lymphoma in patients with or without CD. In patients with CD, events reported to the Food and Drug Administration Adverse Event Reporting System (FDA AERS) and search of PubMed and Embase published case reports demonstrate a total of 37 unique cases. Eighty-six percent of the patients were male, with a median age of 26 years. Patients had CD for a mean of 10 years before the diagnosis of HSTCL. Thirty-six cases had used either 6-MP or azathioprine, and 28 cases had used infliximab. Of these 28 cases, 27 had also used 6-MP or azathioprine. The other case had a history of both infliximab and adalimumab exposure.


InternalMed_Harrison

InternalMed_Harrison. skin lesions New-onset psoriasiform skin lesions develop in nearly 5% of IBD patients treated with anti-TNF therapy. Most often, these can be treated topically, and rarely, anti-TNF therapy must be decreased, switched, or stopped. The risk of melanoma is increased almost twofold with anti-TNF and not thiopurine use. The risk of nonmelanoma skin cancer is increased with thiopurines and biologics, especially with 1 year of follow-up or greater. Patients on these medications should have a skin check at least once a year.


InternalMed_Harrison

InternalMed_Harrison. infections All of the anti-TNF drugs are associated with an increased risk of infections, particularly reactivation of latent tuberculosis and opportunistic fungal infections including disseminated histoplasmosis and coccidioidomycosis. It is recommended that patients have a purified protein derivative (PPD) or a QuantiFERON-TB gold test as well as a chest x-ray before initiation of anti-TNF therapy. Patients over 65 have a higher rate of infections and death on infliximab or adalimumab than those younger than 65 years of age.


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InternalMed_Harrison. otHer Acute liver injury due to reactivation of hepatitis B virus and to autoimmune effects and cholestasis has been reported. Rarely, infliximab and the other anti-TNF drugs have been associated with optic neuritis, seizures, new onset or exacerbation of clinical symptoms, and radiographic evidence of central nervous system demyelinating disorders, including multiple sclerosis. They may exacerbate symptoms in patients with New York Heart Association functional class III/IV heart failure. anti-inteGrins Integrins are expressed on the cell surface of leukocytes and serve as mediators of leukocyte adhesion to vascular endothelium. α4-Integrin along with its β1 or β7 subunit interact with endothelial ligands termed adhesion molecules. Interaction between α4β7 and mucosal addressin cellular adhesion molecule (MAdCAM-1) is important in lymphocyte trafficking to gut mucosa.


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InternalMed_Harrison. Natalizumab is a recombinant humanized IgG4 antibody against α4-integrin that has been shown to be effective in induction and maintenance of patients with CD. It has been approved since February 2008 for the treatment of patients with CD refractory or intolerant to anti-TNF therapy. The rates of response and remission at 3 months are about 60% and 40%, respectively, with a sustained remission rate of about 40% at 36 weeks.


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InternalMed_Harrison. One case of progressive multifocal leukoencephalopathy (PML) after eight infusions of natalizumab was observed among 1043 patients in the clinical trials for CD, and two patients developed PML in the multiple sclerosis (MS) trials after a median of 120 weeks. There were 410 postmarketing cases of PML, 408 in MS and 2 in CD. The most important risk factor for development of PML is exposure to the John Cunningham (JC) polyomavirus, seen in 50–55% of the adult population. The other two risk factors for development of PML are longer duration of treatment, especially beyond 2 years, and prior treatment with an immunosuppressant medication. Patients with all three risk factors have an estimated risk of 11:1000.


InternalMed_Harrison

InternalMed_Harrison. The FDA approved a commercial enzyme-linked immunosorbent assay (ELISA) kit to assay anti-JC viral antibodies (Stratify JCV Antibody ELISA; Focus Diagnostics, Cypress, CA) in early 2012. The test is 99% accurate in stratifying risk of PML. It is recommended that all patients be tested prior to initiating natalizumab therapy. JC virus serologies are then measured every 6 months because 1–2% of patients will seroconvert yearly. All patients taking natalizumab and their providers must be enrolled in the TOUCH (Tysabri Outreach Unified Commitment for Health) pharmacovigilance program. Natalizumab is administered IV, 300 mg every 4 weeks. Labeling requirements mandate that it not be used in combination with any immunosuppressant medications.


InternalMed_Harrison

InternalMed_Harrison. Vedolizumab, another leukocyte trafficking inhibitor, is indicated for patients who have had an inadequate response or lost response to, or were intolerant of a TNF blocker or immunomodulator; or had an inadequate response or were intolerant to, or demonstrated dependence on glucocorticoids. It is an option for patients who are JC antibody positive since it does not cross the blood-brain barrier. Vedolizumab is a monoclonal antibody directed against α4β7 integrin specifically and has the ability to convey gut-selective immunosuppression. Ustekinumab, a fully human IgG1 monoclonal antibody, blocks the biologic activity of IL-12 and IL-23 through their common p40 subunit by inhibiting the interaction of these cytokines with their receptors on T cells, natural killer cells, and antigen presenting cells. It shows efficacy in moderate to severe CD in clinical trials.


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InternalMed_Harrison. Tofacitinib is an oral inhibitor of Janus kinases 1, 3, and, to a lesser extent, 2. It is expected to block signaling involving common gamma chain–containing cytokines including IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. These cytokines are integral to lymphocyte activation, function, and proliferation. It is effective in moderate to severe UC in clinical trials.


InternalMed_Harrison

InternalMed_Harrison. Dietary antigens may stimulate the mucosal immune response. Patients with active CD respond to bowel rest, along with TPN. Bowel rest and TPN are as effective as glucocorticoids at inducing remission of active CD but are not effective as maintenance therapy. Enteral nutrition in the form of elemental or peptide-based preparations is also as effective as glucocorticoids or TPN, but these diets are not palatable. Enteral diets may provide the small intestine with nutrients vital to cell growth and do not have the complications of TPN. In contrast to CD, dietary intervention does not reduce inflammation in UC. Standard medical management of UC and CD is shown in Fig. 351-12.


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InternalMed_Harrison. SURGICAL THERAPY Ulcerative Colitis Nearly one-half of patients with extensive chronic UC undergo surgery within the first 10 years of their illness. The indications for surgery are listed in Table 351-8. Morbidity is about 20% for elective, 30% for urgent, and 40% for emergency proctocolectomy. The risks are primarily hemorrhage, contamination and sepsis, and neural injury. The operation of choice is an ileoanal J pouch anastomosis (IPAA).


InternalMed_Harrison

InternalMed_Harrison. Because UC is a mucosal disease, the rectal mucosa can be dissected and removed down to the dentate line of the anus or about 2 cm proximal to this landmark. The ileum is fashioned into a pouch that serves as a neorectum. This ileal pouch is then sutured circumferentially to the anus in an end-to-end fashion. If performed carefully, this operation preserves the anal sphincter and maintains continence. The overall operative morbidity is 10%, with the major complication being bowel obstruction. Pouch failure necessitating conversion to permanent ileostomy occurs in 5–10% of patients. Some inflamed rectal mucosa is usually left behind, and thus endoscopic surveillance is necessary. Primary dysplasia of the ileal mucosa of the pouch has occurred rarely.


InternalMed_Harrison

InternalMed_Harrison. Patients with IPAA usually have about 6–10 bowel movements a day. On validated quality-of-life indices, they report better performance in sports and sexual activities than ileostomy patients. The most frequent complication of IPAA is pouchitis in about 30–50% FIGURE 351-12 Medical management of inflammatory bowel disease. 5-ASA, 5-aminosalicylic acid; CD, Crohn’s disease; UC, ulcerative colitis.


InternalMed_Harrison

InternalMed_Harrison. FIGURE 351-12 Medical management of inflammatory bowel disease. 5-ASA, 5-aminosalicylic acid; CD, Crohn’s disease; UC, ulcerative colitis. of patients with UC. This syndrome consists of increased stool frequency, watery stools, cramping, urgency, nocturnal leakage of stool, arthralgias, malaise, and fever. Pouch biopsies may distinguish true pouchitis from underlying CD. Although pouchitis usually responds to antibiotics, 3–5% of patients remain refractory and may require glucocorticoids, immunomodulators, anti-TNF therapy, or even pouch removal. A highly concentrated probiotic preparation with four strains of Lactobacillus, three strains of Bifidobacterium, and one strain of Streptococcus salivarius can prevent the recurrence of pouchitis when taken daily.


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InternalMed_Harrison. Intractable disease Small Intestine Fulminant disease Stricture and obstruction Toxic megacolon unresponsive to medical therapy Colonic perforation Massive hemorrhage Massive colonic hemorrhage Refractory fistula Extracolonic disease Abscess Colonic obstruction Colon and rectum Colon cancer prophylaxis Intractable disease Colon dysplasia or cancer Fulminant disease Perianal disease unresponsive to medical therapy Refractory fistula Colonic obstruction Cancer prophylaxis Colon dysplasia or cancer Crohn’s Disease Most patients with CD require at least one operation in their lifetime. The need for surgery is related to duration of disease and the site of involvement. Patients with small-bowel disease have an 80% chance of requiring surgery. Those with colitis alone have a 50% chance. Surgery is an option only when medical treatment has failed or complications dictate its necessity. The indications for surgery are shown in Table 351-8.


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InternalMed_Harrison. small intestinal Disease Because CD is chronic and recurrent, with no clear surgical cure, as little intestine as possible is resected. Current surgical alternatives for treatment of obstructing CD include resection of the diseased segment and strictureplasty. Surgical resection of the diseased segment is the most frequently performed operation, and in most cases, primary anastomosis can be done to restore continuity. If much of the small bowel has already been resected and the strictures are short, with intervening areas of normal mucosa, strictureplasties should be done to avoid a functionally insufficient length of bowel. The strictured area of intestine is incised longitudinally and the incision sutured transversely, thus widening the narrowed area. Complications of strictureplasty include prolonged ileus, hemorrhage, fistula, abscess, leak, and restricture.


InternalMed_Harrison

InternalMed_Harrison. There is evidence that mesalamine, nitroimidazole antibiotics, 6-MP/azathioprine, infliximab, and adalimumab are all superior to placebo for the prevention of postoperative recurrence of CD. Mesalamine is the least effective, and the side effects of the nitroimidazole antibiotics limit their use. Risk factors for early recurrence of disease include cigarette smoking, penetrating disease (internal fistulas, abscesses, or other evidence of penetration through the wall of the bowel), early recurrence since a previous surgery, multiple surgeries, and a young age at the time of the first surgery. Aggressive postoperative treatment with 6-MP/ 1964 azathioprine, infliximab, or adalimumab should be considered for this group of patients. It is also recommended to evaluate for endoscopic recurrence of CD via a colonoscopy, if possible, 6 months after surgery.


InternalMed_Harrison

InternalMed_Harrison. colorectal Disease A greater percentage of patients with Crohn’s colitis require surgery for intractability, fulminant disease, and anorectal disease. Several alternatives are available, ranging from the use of a temporary loop ileostomy to resection of segments of diseased colon or even the entire colon and rectum. For patients with segmental involvement, segmental colon resection with primary anastomosis can be performed. In 20–25% of patients with extensive colitis, the rectum is spared sufficiently to consider rectal preservation. Most surgeons believe that an IPAA is contraindicated in CD due to the high incidence of pouch failure. A diverting colostomy may help heal severe perianal disease or rectovaginal fistulas, but disease almost always recurs with reanastomosis. These patients often require a total proctocolectomy and ileostomy.


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InternalMed_Harrison. Patients with quiescent UC and CD have normal fertility rates; the fallopian tubes can be scarred by the inflammatory process of CD, especially on the right side because of the proximity of the terminal ileum. In addition, perirectal, perineal, and rectovaginal abscesses and fistulae can result in dyspareunia. Infertility in men can be caused by sulfasalazine but reverses when treatment is stopped. In women who have an ileoanal J pouch anastomosis, most studies show that the fertility rate is reduced to about 50–80% of normal. This is due to scarring or occlusion of the fallopian tubes secondary to pelvic inflammation.


InternalMed_Harrison

InternalMed_Harrison. In mild or quiescent UC and CD, fetal outcome is nearly normal. Spontaneous abortions, stillbirths, and developmental defects are increased with increased disease activity, not medications. The courses of CD and UC during pregnancy mostly correlate with disease activity at the time of conception. Patients should be in remission for 6 months before conceiving. Most CD patients can deliver vaginally, but cesarean delivery may be the preferred route of delivery for patients with anorectal and perirectal abscesses and fistulas to reduce the likelihood of fistulas developing or extending into the episiotomy scar. Unless they desire multiple children, UC patients with an IPAA should consider a cesarean delivery due to an increased risk of future fecal incontinence.


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InternalMed_Harrison. Sulfasalazine, Lialda, Apriso, Delzicol, and balsalazide are safe for use in pregnancy and nursing with the caveat that additional folate supplementation must be given with sulfasalazine. Asacol HD and olsalazine are considered by the FDA to be class C agents in pregnancy and thus not recommended. Topical 5-ASA agents are also safe during pregnancy and nursing. Glucocorticoids are generally safe for use during pregnancy and are indicated for patients with moderate to severe disease activity. The amount of glucocorticoids received by the nursing infant is minimal. The safest antibiotics to use for CD in pregnancy for short periods of time (weeks, not months) are ampicillin and cephalosporins. Metronidazole can be used in the second or third trimester. Ciprofloxacin causes cartilage lesions in immature animals and should be avoided because of the absence of data on its effects on growth and development in humans.


InternalMed_Harrison

InternalMed_Harrison. 6-MP and azathioprine pose minimal or no risk during pregnancy, but experience is limited. If the patient cannot be weaned from the drug or has an exacerbation that requires 6-MP/azathioprine during pregnancy, she should continue the drug with informed consent. Breast milk has been shown to contain negligible levels of 6-MP/azathioprine when measured in a limited number of patients. Little data exist on CSA in pregnancy. In a small number of patients with severe IBD treated with IV CSA during pregnancy, 80% of pregnancies were successfully completed without development of renal toxicity or congenital malformations. However, because of the lack of data, CSA should probably be avoided unless the patient would otherwise require surgery.


InternalMed_Harrison

InternalMed_Harrison. MTX is contraindicated in pregnancy and nursing. In a large prospective study, no increased risk of stillbirths, miscarriages, or spontaneous abortions was seen with infliximab, adalimumab, or certolizumab, which are all class B drugs. Infliximab and adalimumab are IgG1 antibodies and are actively transported across the placenta in the late second and third trimester. Infants can have serum levels of both infliximab and adalimumab up to 7 months of age, and live vaccines should be avoided during this time. Certolizumab crosses the placenta by passive diffusion, and infant serum and cord blood levels are minimal. The anti-TNF drugs are relatively safe in nursing. Miniscule levels of both infliximab and adalimumab, but not certolizumab, have been reported in breast milk. These levels are of no clinical significance. It is recommended that drugs not be switched during pregnancy unless necessitated by the medical condition of the IBD. Natalizumab is considered as a class C drug because


InternalMed_Harrison

InternalMed_Harrison. of no clinical significance. It is recommended that drugs not be switched during pregnancy unless necessitated by the medical condition of the IBD. Natalizumab is considered as a class C drug because there is limited data in pregnancy.


InternalMed_Harrison

InternalMed_Harrison. Surgery in UC should be performed only for emergency indications, including severe hemorrhage, perforation, and megacolon refractory to medical therapy. Total colectomy and ileostomy carry a 50% risk of postoperative spontaneous abortion. Fetal mortality is also high in CD requiring surgery. Patients with IPAAs have increased nighttime stool frequency during pregnancy that resolves postpartum. Transient small-bowel obstruction or ileus has been noted in up to 8% of patients with ileostomies. Patients with long-standing UC are at increased risk for developing colonic epithelial dysplasia and carcinoma (Fig. 351-13).


InternalMed_Harrison

InternalMed_Harrison. Patients with long-standing UC are at increased risk for developing colonic epithelial dysplasia and carcinoma (Fig. 351-13). The risk of neoplasia in chronic UC increases with duration and extent of disease. From one large meta-analysis, the risk of cancer in patients with UC is estimated at 2% after 10 years, 8% after 20 years, and 18% after 30 years of disease. Data from a 30-year surveillance program in the United Kingdom calculated the risk of colorectal cancer to be 7.7% at 20 years and 15.8% at 30 years of disease. The rates of colon cancer are higher than in the general population, and colonoscopic surveillance is the standard of care.


InternalMed_Harrison

InternalMed_Harrison. Annual or biennial colonoscopy with multiple biopsies is recommended for patients with >8–10 years of extensive colitis (greater than one-third of the colon involved) or 12–15 years of proctosigmoiditis (less than one-third but more than just the rectum) and has been widely used to screen and survey for subsequent dysplasia and carcinoma. Risk factors for cancer in UC include long-duration disease, extensive disease, family history of colon cancer, PSC, a colon stricture, and the presence of postinflammatory pseudopolyps on colonoscopy.


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InternalMed_Harrison. Risk factors for developing cancer in Crohn’s colitis are long-duration and extensive disease, bypassed colon segments, colon strictures, PSC, and family history of colon cancer. The cancer risks in CD and UC are probably equivalent for similar extent and duration of disease. In the CESAME study, a prospective observational cohort of IBD patients in France, the standardized incidence ratios of colorectal cancer were 2.2 for all IBD patients (95% confidence interval [CI], 1.5–3.0; p < .001) and 7.0 for patients with long-standing extensive colitis (both Crohn’s and UC) (95% CI, 4.4–10.5; p < .001). Thus, the same endoscopic surveillance strategy used for UC is recommended for patients with chronic Crohn’s colitis. A pediatric colonoscope can be used to pass narrow strictures in CD patients, but surgery should be considered in symptomatic patients with impassable strictures.


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InternalMed_Harrison. FIGURE 351-13 Medium-power view of low-grade dysplasia in a patient with chronic ulcerative colitis. Low-grade dysplastic crypts are interspersed among regenerating crypts. (Courtesy of Dr. R. Odze, Division of Gastrointestinal Pathology, Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts; with permission.) Dysplasia can be flat or polypoid. If flat high-grade dysplasia is encountered on colonoscopic surveillance, the usual treatment is colectomy for UC and either colectomy or segmental resection for CD. If flat low-grade dysplasia is found (Fig. 351-13), most investigators recommend immediate colectomy. Adenomas may occur coincidently in UC and CD patients with chronic colitis and can be removed endoscopically provided that biopsies of the surrounding mucosa are free of dysplasia. High-definition and high-magnification colonoscopes and dye sprays have increased the rate of dysplasia detection.


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InternalMed_Harrison. IBD patients are also at greater risk for other malignancies. Patients with CD may have an increased risk of non-Hodgkin’s lymphoma, leukemia, and myelodysplastic syndromes. Severe, chronic, complicated perianal disease in CD patients may be associated with an increased risk of cancer in the lower rectum and anal canal (squamous cell cancers). Although the absolute risk of small-bowel adenocarcinoma in CD is low (2.2% at 25 years in one study), patients with long-standing, extensive, small-bowel disease should consider screening.


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InternalMed_Harrison. Irritable bowel syndrome (IBS) is a functional bowel disorder characterized by abdominal pain or discomfort and altered bowel habits in the absence of detectable structural abnormalities. No clear diagnostic markers exist for IBS; thus the diagnosis of the disorder is based on clinical presentation. In 2006, the Rome II criteria for the diagnosis of IBS were revised (Table 352-1). Throughout the world, about 10–20% of adults and adolescents have symptoms consistent with IBS, and most studies show a female predominance. IBS symptoms tend to come and go over time and often overlap with other functional disorders such as fibromyalgia, headache, backache, and genitourinary symptoms. Severity of symptoms varies and can significantly impair quality of life, resulting in high health care costs. Advances in basic, mechanistic, and clinical investigations have improved our understanding of this disorder and its physiologic and psychosocial determinants. Altered


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InternalMed_Harrison. Recurrent abdominal pain or discomfortb at least 3 days per month in the last 3 months associated with two or more of the following: 1. Improvement with defecation 2. Onset associated with a change in frequency of stool 3. Onset associated with a change in form (appearance) of stool aCriteria fulfilled for the last 3 months with symptom onset at least 6 months prior to diagnosis. bDiscomfort means an uncomfortable sensation not described as pain. In pathophysiology research and clinical trials, a pain/discomfort frequency of at least 2 days a week during screening evaluation is required for subject eligibility. Source: Adapted from GF Longstreth et al: Gastroenterology 130:1480, 2006.


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InternalMed_Harrison. Source: Adapted from GF Longstreth et al: Gastroenterology 130:1480, 2006. gastrointestinal (GI) motility, visceral hyperalgesia, disturbance of 1965 brain-gut interaction, abnormal central processing, autonomic and hormonal events, genetic and environmental factors, and psychosocial disturbances are variably involved, depending on the individual. This progress may result in improved methods of treatment.


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InternalMed_Harrison. IBS is a disorder that affects all ages, although most patients have their first symptoms before age 45. Older individuals have a lower reporting frequency. Women are diagnosed with IBS two to three times as often as men and make up 80% of the population with severe IBS. As indicated in Table 352-1, pain or abdominal discomfort is a key symptom for the diagnosis of IBS. These symptoms should be improved with defecation and/or have their onset associated with a change in frequency or form of stool. Painless diarrhea or constipation does not fulfill the diagnostic criteria to be classified as IBS. Supportive symptoms that are not part of the diagnostic criteria include defecation straining, urgency or a feeling of incomplete bowel movement, passing mucus, and bloating.


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InternalMed_Harrison. Abdominal Pain According to the current IBS diagnostic criteria, abdominal pain or discomfort is a prerequisite clinical feature of IBS. Abdominal pain in IBS is highly variable in intensity and location. It is frequently episodic and crampy, but it may be superimposed on a background of constant ache. Pain may be mild enough to be ignored or it may interfere with daily activities. Despite this, malnutrition due to inadequate caloric intake is exceedingly rare with IBS. Sleep deprivation is also unusual because abdominal pain is almost uniformly present only during waking hours. However, patients with severe IBS frequently wake repeatedly during the night; thus, nocturnal pain is a poor discriminating factor between organic and functional bowel disease. Pain is often exacerbated by eating or emotional stress and improved by passage of flatus or stools. In addition, female patients with IBS commonly report worsening symptoms during the premenstrual and menstrual phases.


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InternalMed_Harrison. Altered Bowel Habits Alteration in bowel habits is the most consistent clinical feature in IBS. The most common pattern is constipation alternating with diarrhea, usually with one of these symptoms predominating. At first, constipation may be episodic, but eventually it becomes continuous and increasingly intractable to treatment with laxatives. Stools are usually hard with narrowed caliber, possibly reflecting excessive dehydration caused by prolonged colonic retention and spasm. Most patients also experience a sense of incomplete evacuation, thus leading to repeated attempts at defecation in a short time span. Patients whose predominant symptom is constipation may have weeks or months of constipation interrupted with brief periods of diarrhea. In other patients, diarrhea may be the predominant symptom. Diarrhea resulting from IBS usually consists of small volumes of loose stools. Most patients have stool volumes of <200 mL. Nocturnal diarrhea does not occur in IBS. Diarrhea may be


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InternalMed_Harrison. symptom. Diarrhea resulting from IBS usually consists of small volumes of loose stools. Most patients have stool volumes of <200 mL. Nocturnal diarrhea does not occur in IBS. Diarrhea may be aggravated by emotional stress or eating. Stool may be accompanied by passage of large amounts of mucus. Bleeding is not a feature of IBS unless hemorrhoids are present, and malabsorption or weight loss does not occur.


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InternalMed_Harrison. Bowel pattern subtypes are highly unstable. In a patient population with ~33% prevalence rates of IBS-diarrhea predominant (IBSD), IBS-constipation predominant (IBS-C), and IBS-mixed (IBS-M) forms, 75% of patients change subtypes and 29% switch between IBS-C and IBS-D over 1 year. The heterogeneity and variable natural history of bowel habits in IBS increase the difficulty of conducting pathophysiology studies and clinical trials.


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InternalMed_Harrison. Gas and Flatulence Patients with IBS frequently complain of abdominal distention and increased belching or flatulence, all of which they attribute to increased gas. Although some patients with these symptoms actually may have a larger amount of gas, quantitative measurements reveal that most patients who complain of increased gas generate no more than a normal amount of intestinal gas. Most IBS patients have impaired transit and tolerance of intestinal gas loads. In addition, patients with IBS tend to reflux gas from the distal to the more proximal intestine, which may explain the belching.


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InternalMed_Harrison. 1966 Some patients with bloating may also experience visible distention with increase in abdominal girth. Both symptoms are more common among female patients and in those with higher overall Somatic Symptom Checklist scores. IBS patients who experienced bloating alone have been shown to have lower thresholds for pain and desire to defecate compared to those with concomitant distention irrespective of bowel habit. When patients were grouped according to sensory threshold, hyposensitive individuals had distention significantly more than those with hypersensitivity and this was observed more in the constipation subgroup. This suggests that the pathogenesis of bloating and distention may not be the same.


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InternalMed_Harrison. Upper Gastrointestinal Symptoms Between 25 and 50% of patients with IBS complain of dyspepsia, heartburn, nausea, and vomiting. This suggests that other areas of the gut apart from the colon may be involved. Prolonged ambulant recordings of small-bowel motility in patients with IBS show a high incidence of abnormalities in the small bowel during the diurnal (waking) period; nocturnal motor patterns are not different from those of healthy controls. The overlap between dyspepsia and IBS is great. The prevalence of IBS is higher among patients with dyspepsia (31.7%) than among those who reported no symptoms of dyspepsia (7.9%). Conversely, among patients with IBS, 55.6% reported symptoms of dyspepsia. In addition, the functional abdominal symptoms can change over time. Those with predominant dyspepsia or IBS can flux between the two. Although the prevalence of functional gastrointestinal disorders is stable over time, the turnover in symptom status is high. Many episodes of symptom


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InternalMed_Harrison. dyspepsia or IBS can flux between the two. Although the prevalence of functional gastrointestinal disorders is stable over time, the turnover in symptom status is high. Many episodes of symptom disappearance are due to subjects changing symptoms rather than total symptom resolution. Thus it is conceivable that functional dyspepsia and IBS are two manifestations of a single, more extensive digestive system disorder. Furthermore, IBS symptoms are prevalent in noncardiac chest pain patients, suggesting overlap with other functional gut disorders.


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InternalMed_Harrison. The pathogenesis of IBS is poorly understood, although roles of abnormal gut motor and sensory activity, central neural dysfunction, psychological disturbances, mucosal inflammation, stress, and luminal factors have been proposed.


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InternalMed_Harrison. Gastrointestinal Motor Abnormalities Studies of colonic myoelectrical and motor activity under unstimulated conditions have not shown consistent abnormalities in IBS. In contrast, colonic motor abnormalities are more prominent under stimulated conditions in IBS. IBS patients may exhibit increased rectosigmoid motor activity for up to 3 h after eating. Similarly, inflation of rectal balloons both in IBS-D and IBS-C patients leads to marked and prolonged distention-evoked contractile activity. Recordings from the transverse, descending, and sigmoid colon showed that the motility index and peak amplitude of high-amplitude propagating contractions (HAPCs) in diarrhea-prone IBS patients were greatly increased compared to those in healthy subjects and were associated with rapid colonic transit and accompanied by abdominal pain.


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InternalMed_Harrison. Visceral Hypersensitivity As with studies of motor activity, IBS patients frequently exhibit exaggerated sensory responses to visceral stimulation. The frequency of perceptions of food intolerance is at least twofold more common than in the general population. Postprandial pain has been temporally related to entry of the food bolus into the cecum in 74% of patients. On the other hand, prolonged fasting in IBS patients is often associated with significant improvement in symptoms. Rectal balloon inflation produces nonpainful and painful sensations at lower volumes in IBS patients than in healthy controls without altering rectal tension, suggestive of visceral afferent dysfunction in IBS. Similar studies show gastric and esophageal hypersensitivity in patients with nonulcer dyspepsia and noncardiac chest pain, raising the possibility that these conditions have a similar pathophysiologic basis. Lipids lower the thresholds for the first sensation of gas, discomfort, and pain in IBS


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InternalMed_Harrison. and noncardiac chest pain, raising the possibility that these conditions have a similar pathophysiologic basis. Lipids lower the thresholds for the first sensation of gas, discomfort, and pain in IBS patients. Hence, postprandial symptoms in IBS patients may be explained in part by a nutrient-dependent exaggerated sensory component of the gastrocolonic response. In contrast to enhanced gut sensitivity, IBS patients do not exhibit heightened sensitivity


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InternalMed_Harrison. Abbreviation: CNS, central nervous system. elsewhere in the body. Thus, the afferent pathway disturbances in IBS appear to be selective for visceral innervation with sparing of somatic pathways. The mechanisms responsible for visceral hypersensitivity are still under investigation. It has been proposed that these exaggerated responses may be due to (1) increased end-organ sensitivity with recruitment of “silent” nociceptors; (2) spinal hyperexcitability with activation of nitric oxide and possibly other neurotransmitters; (3) endogenous (cortical and brainstem) modulation of caudad nociceptive transmission; and (4) over time, the possible development of longterm hyperalgesia due to development of neuroplasticity, resulting in permanent or semipermanent changes in neural responses to chronic or recurrent visceral stimulation (Table 352-2).


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InternalMed_Harrison. Central Neural Dysregulation The role of central nervous system (CNS) factors in the pathogenesis of IBS is strongly suggested by the clinical association of emotional disorders and stress with symptom exacerbation and the therapeutic response to therapies that act on cerebral cortical sites. Functional brain imaging studies such as magnetic resonance imaging (MRI) have shown that in response to distal colonic stimulation, the mid-cingulate cortex—a brain region concerned with attention processes and response selection—shows greater activation in IBS patients. Modulation of this region is associated with changes in the subjective unpleasantness of pain. In addition, IBS patients also show preferential activation of the prefrontal lobe, which contains a vigilance network within the brain that increases alertness. These may represent a form of cerebral dysfunction leading to the increased perception of visceral pain.


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InternalMed_Harrison. Abnormal Psychological Features Abnormal psychiatric features are recorded in up to 80% of IBS patients, especially in referral centers; however, no single psychiatric diagnosis predominates. Most of these patients demonstrated exaggerated symptoms in response to visceral distention, and this abnormality persists even after exclusion of psychological factors. Psychological factors influence pain thresholds in IBS patients, as stress alters sensory thresholds. An association between prior sexual or physical abuse and development of IBS has been reported. Abuse is associated with greater pain reporting, psychological distress, and poor health outcome. Brain functional MRI studies show greater activation of the posterior and middle dorsal cingulate cortex, which is implicated in affect processing in IBS patients with a past history of sexual abuse.


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InternalMed_Harrison. Thus, patients with IBS frequently demonstrate increased motor reactivity of the colon and small bowel to a variety of stimuli and altered visceral sensation associated with lowered sensation thresholds. These may result from CNS–enteric nervous system dysregulation (Fig. 352-1).


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InternalMed_Harrison. Postinfectious IBS IBS may be induced by GI infection. In an investigation of 544 patients with confirmed bacterial gastroenteritis, one-quarter developed IBS subsequently. Conversely, about a third of IBS patients experienced an acute “gastroenteritis-like” illness at the onset of their chronic IBS symptomatology. This group of “postinfective” IBS occurs more commonly in females and affects younger rather than older patients. Risk factors for developing postinfectious IBS include, in order of importance, prolonged duration of initial illness, toxicity of infecting bacterial strain, smoking, mucosal markers of inflammation, female gender, depression, hypochondriasis, and adverse life events in the preceding 3 months. Age older than 60 years might protect against postinfectious IBS, whereas treatment with antibiotics has been CNS Antidepressants, Psychological Cognitive


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InternalMed_Harrison. CNS Antidepressants, Psychological Cognitive Psychotherapy, behavioral therapy, hypnotherapy, Somatization-disorder management Antispasmodics, Antidiarrheals, Dietary modification, Fiber supplements, Newer gut serotonin modulators Heightened sensorimotor activity FIGURE 352-1 Therapeutic targets for irritable bowel syndrome. Patients with mild to moderate symptoms usually have intermittent symptoms that correlate with altered gut physiology. Treatments include gut-acting pharmacologic agents such as antispasmodics, antidiarrheals, fiber supplements, and gut serotonin modulators. Patients who have severe symptoms usually have constant pain and psychosocial difficulties. This group of patients is best managed with antidepressants and other psychosocial treatments. CNS, central nervous system; ENS, enteric nervous system.


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InternalMed_Harrison. associated with increased risk. The microbes involved in the initial infection are Campylobacter, Salmonella, and Shigella. Those patients with Campylobacter infection who are toxin-positive are more likely to develop postinfective IBS. Increased rectal mucosal enteroendocrine cells, T lymphocytes, and increased gut permeability are acute changes following Campylobacter enteritis that could persist for more than a year and may contribute to postinfective IBS.


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InternalMed_Harrison. Immune Activation and Mucosal Inflammation Some patients with IBS display persistent signs of low-grade mucosal inflammation with activated lymphocytes, mast cells, and enhanced expression of proinflammatory cytokines. These abnormalities may contribute to abnormal epithelial secretion and visceral hypersensitivity. There is increasing evidence that some members of the superfamily of transient receptor potential (TRP) cation channels such as TRPV1 (vanilloid) channels are central to the initiation and persistence of visceral hypersensitivity. Mucosal inflammation can lead to increased expression of TRPV1 in the enteric nervous system. Enhanced expression of TRPV1 channels in the sensory neurons of the gut has been observed in IBS, and such expression appears to correlate with visceral hypersensitivity and abdominal pain. Interestingly, clinical studies have also shown increased intestinal permeability in patients with IBS-D. Psychological stress and anxiety can increase the release of


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InternalMed_Harrison. and abdominal pain. Interestingly, clinical studies have also shown increased intestinal permeability in patients with IBS-D. Psychological stress and anxiety can increase the release of proinflammatory cytokine, and this in turn may alter intestinal permeability. This provides a functional link between psychological stress, immune activation, and symptom generation in patients with IBS.


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InternalMed_Harrison. Altered Gut Flora A high prevalence of small intestinal bacterial overgrowth in IBS patients has been noted based on positive lactulose hydrogen breath test. This finding, however, has been challenged by a number of other studies that found no increased incidence of bacterial overgrowth based on jejunal aspirate culture. Abnormal H2 breath test can occur because of small-bowel rapid transit and may lead to 1967 erroneous interpretation. Hence, the role of testing for small intestinal bacterial overgrowth in IBS patients remains unclear.


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InternalMed_Harrison. Studies using culture-independent approaches such as 16S rRNA gene-based analysis found significant differences between the molecular profile of the fecal microbiota of IBS patients and that of healthy subjects. IBS patients had decreased proportions of the genera Bifidobacterium and Lactobacillus and increased ratios of Firmicutes:Bacteroidetes. It has been speculated that these changes may be related to stress and diet. A temporary reduction in lactobacilli has been reported in animal models of early-life stress. On the other hand, Firmicutes is the dominant phylum in adults consuming a diet high in animal fat and protein. However, it is still unclear whether such changes in fecal microbiota are causal, consequential, or merely the result of constipation and diarrhea. In addition, the stability of the change in the microbiota needs to be determined.


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InternalMed_Harrison. Abnormal Serotonin Pathways The serotonin (5-HT)-containing enterochromaffin cells in the colon are increased in a subset of IBS-D patients compared to healthy individuals or patients with ulcerative colitis. Furthermore, postprandial plasma 5-HT levels were significantly higher in this group of patients compared to healthy controls. Because serotonin plays an important role in the regulation of GI motility and visceral perception, the increased release of serotonin may contribute to the postprandial symptoms of these patients and provides a rationale for the use of serotonin antagonists in the treatment of this disorder. APPROACH TO THE PATIENT:


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InternalMed_Harrison. Because IBS is a disorder for which no pathognomonic abnormalities have been identified, its diagnosis relies on recognition of positive clinical features and elimination of other organic diseases. Symptom-based criteria have been developed for the purpose of differentiating patients with IBS from those with organic diseases. These include the Manning, Rome I, Rome II, and Rome III criteria (Table 352-1). The diagnostic values of these criteria are shown in Table 352-3. In a validation study, Rome III performed less well than either the Rome I and II criteria and all criteria studied to date showed positive predictive values of <50%, which underscores the need for developing diagnostic strategies for IBS that are more cost-effective than the current approaches. A careful history and physical examination are frequently helpful in establishing the diagnosis. Clinical features suggestive of IBS include the following: recurrence of lower abdominal pain with altered bowel habits over a


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InternalMed_Harrison. examination are frequently helpful in establishing the diagnosis. Clinical features suggestive of IBS include the following: recurrence of lower abdominal pain with altered bowel habits over a period of time without progressive deterioration, onset of symptoms during periods of stress or emotional upset, absence of other systemic symptoms such as fever and weight loss, and small-volume stool without any evidence of blood.


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InternalMed_Harrison. On the other hand, the appearance of the disorder for the first time in old age, progressive course from time of onset, persistent diarrhea after a 48-h fast, and presence of nocturnal diarrhea or steatorrheal stools argue against the diagnosis of IBS. SEnSiTiViTy, SPECifiCiTy, PoSiTiVE AnD nEGATiVE PREDiCTiVE VAluES, AnD PoSiTiVE AnD nEGATiVE likEliHooD RATioS foR THE RomE AnD mAnninG CRiTERiA foR iRRiTABlE BoWEl SynDRomEa


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InternalMed_Harrison. Because the major symptoms of IBS—abdominal pain, abdominal bloating, and alteration in bowel habits—are common complaints of many GI organic disorders, the list of differential diagnoses is a long one. The quality, location, and timing of pain may be helpful to suggest specific disorders. Pain due to IBS that occurs in the epigastric or periumbilical area must be differentiated from biliary tract disease, peptic ulcer disorders, intestinal ischemia, and carcinoma of the stomach and pancreas. If pain occurs mainly in the lower abdomen, the possibility of diverticular disease of the colon, inflammatory bowel disease (including ulcerative colitis and Crohn’s disease), and carcinoma of the colon must be considered. Postprandial pain accompanied by bloating, nausea, and vomiting suggests gastroparesis or partial intestinal obstruction. Intestinal infestation with Giardia lamblia or other parasites may cause similar symptoms. When diarrhea is the major complaint, the possibility of lactase


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InternalMed_Harrison. or partial intestinal obstruction. Intestinal infestation with Giardia lamblia or other parasites may cause similar symptoms. When diarrhea is the major complaint, the possibility of lactase deficiency, laxative abuse, malabsorption, celiac sprue, hyperthyroidism, inflammatory bowel disease, and infectious diarrhea must be ruled out. On the other hand, constipation may be a side effect of many different drugs, such as anticholinergic, antihypertensive, and antidepressant medications. Endocrinopathies such as hypothyroidism and hypoparathyroidism must also be considered in the differential diagnosis of constipation, particularly if other systemic signs or symptoms of these endocrinopathies are present. In addition, acute intermittent porphyria and lead poisoning may present in a fashion similar to IBS, with painful constipation as the major complaint. These possibilities are suspected on the basis of their clinical presentations and are confirmed by appropriate serum and urine tests.


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InternalMed_Harrison. Few tests are required for patients who have typical IBS symptoms and no alarm features. Unnecessary investigations may be costly and even harmful. The American Gastroenterological Association has delineated factors to be considered when determining the aggressiveness of the diagnostic evaluation. These include the duration of symptoms, the change in symptoms over time, the age and sex of the patient, the referral status of the patient, prior diagnostic studies, a family history of colorectal malignancy, and the degree of psychosocial dysfunction. Thus, a younger individual with mild symptoms requires a minimal diagnostic evaluation, while an older person or an individual with rapidly progressive symptoms should undergo a more thorough exclusion of organic disease. Most patients should have a complete blood count and sigmoidoscopic examination; in addition, stool specimens should be examined for ova and parasites in those who have diarrhea. In patients with persistent diarrhea not


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InternalMed_Harrison. have a complete blood count and sigmoidoscopic examination; in addition, stool specimens should be examined for ova and parasites in those who have diarrhea. In patients with persistent diarrhea not responding to simple antidiarrheal agents, a sigmoid colon biopsy should be performed to rule out microscopic colitis. In those age >40 years, an air-contrast barium enema or colonoscopy should also be performed. If the main symptoms are diarrhea and increased gas, the possibility of lactase deficiency should be ruled out with a hydrogen breath test or with evaluation after a 3-week lactose-free diet. Some patients with IBS-D may have undiagnosed celiac sprue. Because the symptoms of celiac sprue respond to a gluten-free diet, testing for celiac sprue in IBS may prevent years of morbidity and attendant expense. Decision-analysis studies show that serology testing for celiac sprue in patients with IBS-D has an acceptable cost when the prevalence of celiac sprue is >1% and is the dominant


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InternalMed_Harrison. attendant expense. Decision-analysis studies show that serology testing for celiac sprue in patients with IBS-D has an acceptable cost when the prevalence of celiac sprue is >1% and is the dominant strategy when the prevalence is >8%. In patients with concurrent symptoms of dyspepsia, upper GI radiographs or esophagogastroduodenoscopy may be advisable. In patients with postprandial right upper quadrant pain, an ultrasonogram of the gallbladder should be obtained. Laboratory features that argue against IBS include evidence of anemia, elevated sedimentation rate, presence of leukocytes or blood in stool, and stool volume >200–300 mL/d. These findings would necessitate other diagnostic considerations.


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InternalMed_Harrison. Reassurance and careful explanation of the functional nature of the disorder and of how to avoid obvious food precipitants are important first steps in patient counseling and dietary change. Occasionally, a meticulous dietary history may reveal substances (such as coffee, disaccharides, legumes, and cabbage) that aggravate symptoms. Excessive fructose and artificial sweeteners, such as sorbitol or mannitol, may cause diarrhea, bloating, cramping, or flatulence. As a therapeutic trial, patients should be encouraged to eliminate any foodstuffs that appear to produce symptoms. However patients should avoid nutritionally depleted diets. A diet low in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs) (Table 352-4) has been shown to be helpful in IBS patients. FODMAPs are poorly absorbed by the small intestine and fermented by bacteria in the colon to produce gas and osmotically active carbohydrates. Clinical studies demonstrate that in IBS patients,


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InternalMed_Harrison. FODMAPs are poorly absorbed by the small intestine and fermented by bacteria in the colon to produce gas and osmotically active carbohydrates. Clinical studies demonstrate that in IBS patients, ingestion of FODMAPs such as lactose, fructose, or sorbitol, alone or in combination, produce gut symptoms such as gas and diarrhea. On the other hand, a randomized controlled study showed that a diet low in FODMAPs reduced symptoms in IBS patients. This


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InternalMed_Harrison. Inulin, FOS Sorbitol, mannitol, maltitol, xylitol, isomalt Abbreviations: FODMAPs, fermentable oligosaccharides, disaccharides, monosaccharides, and polyols; FOS, fructo-oligosaccharides Source: Adapted from PR Gibson et al: Am J Gastroenterol 107:657, 2012. approach may be used in diarrhea-predominant IBS patients with severe gas and bloating. Durable adherence can be expected in up to 75% of patients.


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InternalMed_Harrison. Stool-Bulking Agents High-fiber diets and bulking agents, such as bran or hydrophilic colloid, are frequently used in treating IBS. The water-holding action of fibers may contribute to increased stool bulk because of the ability of fiber to increase fecal output of bacteria. Fiber also speeds up colonic transit in most persons. In diarrhea-prone patients, whole-colonic transit is faster than average; however, dietary fiber can delay transit. Furthermore, because of their hydrophilic properties, stool-bulking agents bind water and thus prevent both excessive hydration and dehydration of stool. The latter observation may explain the clinical experience that a high-fiber diet relieves diarrhea in some IBS patients. Fiber supplementation with psyllium has been shown to reduce perception of rectal distention, indicating that fiber may have a positive effect on visceral afferent function.


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InternalMed_Harrison. The beneficial effects of dietary fiber on colonic physiology suggest that dietary fiber should be an effective treatment for IBS patients, but controlled trials of dietary fiber have produced variable results. This is not surprising since IBS is a heterogeneous disorder, with some patients being constipated and other having predominant diarrhea. Most investigations report increases in stool weight, decreases in colonic transit times, and improvement in constipation. Others have noted benefits in patients with alternating diarrhea and constipation, pain, and bloating. However, most studies observe no responses in patients with diarrheaor pain-predominant IBS. It is possible that different fiber preparations may have dissimilar effects on selected symptoms in IBS. A cross-over comparison of different fiber preparations found that psyllium produced greater improvements in stool pattern and abdominal pain than bran. Furthermore, psyllium preparations tend to produce less bloating and


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InternalMed_Harrison. of different fiber preparations found that psyllium produced greater improvements in stool pattern and abdominal pain than bran. Furthermore, psyllium preparations tend to produce less bloating and distention. Despite the equivocal data regarding efficacy, most gastroenterologists consider stool-bulking agents worth trying in patients with IBS-C. Fiber should be started at a nominal dose and slowly titrated up as tolerated over the course of several weeks to a targeted dose of 20–30 g of total dietary and supplementary fiber per day. Even when used judiciously, fiber can exacerbate bloating, flatulence, constipation, and diarrhea.


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InternalMed_Harrison. Antispasmodics Clinicians have observed that anticholinergic drugs may provide temporary relief for symptoms such as painful cramps related to intestinal spasm. Although controlled clinical trials have produced mixed results, evidence generally supports beneficial effects of anticholinergic drugs for pain. A meta-analysis of 26 double-blind clinical trials of antispasmodic agents in IBS reported better global improvement (62%) and abdominal pain reductions (64%) compared to placebo (35% and 45%, respectively), suggesting efficacy in some patients. The drugs are most effective when prescribed in anticipation of predictable pain. Physiologic studies demonstrate that anticholinergic drugs inhibit the gastrocolic reflex; hence, postprandial pain is best managed by giving antispasmodics 30 min before meals so that effective blood levels are achieved shortly before the anticipated onset of pain. Most anticholinergics contain natural belladonna alkaloids, which may cause xerostomia, urinary


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InternalMed_Harrison. before meals so that effective blood levels are achieved shortly before the anticipated onset of pain. Most anticholinergics contain natural belladonna alkaloids, which may cause xerostomia, urinary hesitancy and retention, blurred vision, and drowsiness. They should be used in the elderly with caution. Some physicians prefer to use synthetic anticholinergics such as dicyclomine that have less effect on mucous membrane secretions and produce fewer undesirable side effects.


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InternalMed_Harrison. Antidiarrheal Agents Peripherally acting opiate-based agents are the initial therapy of choice for IBS-D. Physiologic studies demonstrate increases in segmenting colonic contractions, delays in fecal transit, increases in anal pressures, and reductions in rectal perception with these drugs. When diarrhea is severe, especially in the painless diarrhea variant of IBS, small doses of loperamide, 2–4 mg every 4–6 h up to a maximum of 12 g/d, can be prescribed. These agents are less addictive than paregoric, codeine, or tincture of opium. In general, the intestines do not become tolerant of the antidiarrheal effect of opiates, and increasing doses are not required to maintain antidiarrheal potency. These agents are most useful if taken before anticipated 1969 stressful events that are known to cause diarrhea. However, not infrequently, a high dose of loperamide may cause cramping because of increases in segmenting colonic contractions. Another antidiarrheal agent that may be used in IBS


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InternalMed_Harrison. to cause diarrhea. However, not infrequently, a high dose of loperamide may cause cramping because of increases in segmenting colonic contractions. Another antidiarrheal agent that may be used in IBS patients is the bile acid binder cholestyramine resin.


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InternalMed_Harrison. Antidepressant Drugs In addition to their mood-elevating effects, antidepressant medications have several physiologic effects that suggest they may be beneficial in IBS. In IBS-D patients, the tricyclic antidepressant imipramine slows jejunal migrating motor complex transit propagation and delays orocecal and whole-gut transit, indicative of a motor inhibitory effect. Some studies also suggest that tricyclic agents may alter visceral afferent neural function. A number of studies indicate that tricyclic antidepressants may be effective in some IBS patients. In a 2-month study of desipramine, abdominal pain improved in 86% of patients compared to 59% given placebo. Another study of desipramine in 28 IBS patients showed improvement in stool frequency, diarrhea, pain, and depression.


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InternalMed_Harrison. When stratified according to the predominant symptoms, improvements were observed in IBS-D patients, with no improvement being noted in IBS-C patients. The beneficial effects of the tricyclic compounds in the treatment of IBS appear to be independent of their effects on depression. The therapeutic benefits for the bowel symptoms occur faster and at a lower dosage. The efficacy of antidepressant agents in other chemical classes in the management of IBS is less well evaluated. In contrast to tricyclic agents, the selective serotonin reuptake inhibitor (SSRI) paroxetine accelerates orocecal transit, raising the possibility that this drug class may be useful in IBS-C patients. The SSRI citalopram blunts perception of rectal distention and reduces the magnitude of the gastrocolonic response in healthy volunteers. A small placebo-controlled study of citalopram in IBS patients reported reductions in pain. However, these findings could not be confirmed in another randomized controlled trial


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InternalMed_Harrison. healthy volunteers. A small placebo-controlled study of citalopram in IBS patients reported reductions in pain. However, these findings could not be confirmed in another randomized controlled trial that showed that citalopram at 20 mg/d for 4 weeks was not superior to placebo in treating nondepressed IBS patients. Hence, the efficacy of SSRIs in the treatment of IBS needs further confirmation.


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InternalMed_Harrison. Antiflatulence Therapy The management of excessive gas is seldom satisfactory, except when there is obvious aerophagia or disaccharidase deficiency. Patients should be advised to eat slowly and not chew gum or drink carbonated beverages. Bloating may decrease if an associated gut syndrome such as IBS or constipation is improved. If bloating is accompanied by diarrhea and worsens after ingesting dairy products, fresh fruits, vegetables, or juices, further investigation or a dietary exclusion trial may be worthwhile. Avoiding flatogenic foods, exercising, losing excess weight, and taking activated charcoal are safe but unproven remedies. Data regarding the use of surfactants such as simethicone are conflicting. Antibiotics may help in a subgroup of IBS patients with predominant symptoms of bloating. Beano, an over-the-counter oral β-glycosidase solution, may reduce rectal passage of gas without decreasing bloating and pain. Pancreatic enzymes reduce bloating, gas, and fullness during


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InternalMed_Harrison. bloating. Beano, an over-the-counter oral β-glycosidase solution, may reduce rectal passage of gas without decreasing bloating and pain. Pancreatic enzymes reduce bloating, gas, and fullness during and after high-calorie, high-fat meal ingestion.


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InternalMed_Harrison. Modulation of Gut Flora Antibiotic treatment benefits a subset of IBS patients. In a double-blind, randomized, placebo-controlled study, neomycin dosed at 500 mg twice daily for 10 days was more effective than placebo at improving symptom scores among IBS patients. The nonabsorbed oral antibiotic rifaximin is the most thoroughly studied antibiotic for the treatment of IBS. In a double-blind, placebo-controlled study, patients receiving rifaximin at a dose of 550 mg two times daily for 2 weeks experienced substantial improvement of global IBS symptoms over placebo. Rifaximin is the only antibiotic with demonstrated sustained benefit beyond therapy cessation in IBS patients. The drug has a favorable safety and tolerability profile compared with systemic antibiotics. A systematic review and meta-analysis of five studies of IBS patients found that rifaximin is more effective than placebo for global symptoms and bloating (odds ratio 1.57) with a number needed to treat (NNT) of 1970 10.2.


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InternalMed_Harrison. meta-analysis of five studies of IBS patients found that rifaximin is more effective than placebo for global symptoms and bloating (odds ratio 1.57) with a number needed to treat (NNT) of 1970 10.2. The modest therapeutic gain was similar to that yielded by other current available therapies for IBS. However, currently there are still insufficient data to recommend routine use of this antibiotic in the treatment of IBS. Because altered colonic flora may contribute to the pathogenesis of IBS, this has led to great interest in using probiotics to naturally alter the flora. A meta-analysis of 10 probiotic studies in IBS patients found significant relief of pain and bloating with the use of Bifidobacterium breve, B. longum, and Lactobacillus acidophilus species compared to placebo. However, there was no change in stool frequency or consistency. Large-scale studies of well-phenotyped IBS patients are needed to establish the efficacy of these probiotics.


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InternalMed_Harrison. Serotonin Receptor Agonist and Antagonists Serotonin receptor antagonists have been evaluated as therapies for IBS-D. Serotonin acting on 5-HT3 receptors enhances the sensitivity of afferent neurons projecting from the gut. In humans, a 5-HT3 receptor antagonist such as alosetron reduces perception of painful visceral stimulation in IBS. It also induces rectal relaxation, increases rectal compliance, and delays colonic transit. Meta-analysis of 14 randomized controlled trials of alosetron or cilansetron showed that these antagonists are more effective than placebo in achieving global improvement in IBS symptoms and relief of abdominal pain and discomfort. These agents are more likely to cause constipation in IBS patients with diarrhea alternating with constipation. Also, 0.2% of patients using 5-HT3 antagonists developed ischemic colitis versus none in the control group. In postrelease surveillance, 84 cases of ischemic colitis were observed, including 44 cases that required surgery


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InternalMed_Harrison. using 5-HT3 antagonists developed ischemic colitis versus none in the control group. In postrelease surveillance, 84 cases of ischemic colitis were observed, including 44 cases that required surgery and 4 deaths. As a consequence, the medication was voluntarily withdrawn by the manufacturer in 2000. Alosetron has been reintroduced under a new risk-management program where patients have to sign a patient-physician agreement. This has significantly limited its usage.


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InternalMed_Harrison. Novel 5-HT4 receptor agonists such as tegaserod exhibit prokinetic activity by stimulating peristalsis. In IBS patients with constipation, tegaserod accelerated intestinal and ascending colon transit. Clinical trials involving >4000 IBS-C patients reported reductions in discomfort and improvements in constipation and bloating, compared to placebo. Diarrhea is the major side effect. However, tegaserod has been withdrawn from the market; a meta-analysis revealed an increase in serious cardiovascular events.


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InternalMed_Harrison. Chloride Channel Activators Lubiprostone is a bicyclic fatty acid that stimulates chloride channels in the apical membrane of intestinal epithelial cells. Chloride secretion induces passive movement of sodium and water into the bowel lumen and improves bowel function. Oral lubiprostone was effective in the treatment of patients with constipation-predominant IBS in large phase II and phase III randomized, double-blinded, placebo-controlled multicenter trials. Responses were significantly greater in patients receiving lubiprostone 8 μg twice daily for 3 months than in those receiving placebo. In general, the drug was quite well tolerated. The major side effects are nausea and diarrhea. Lubiprostone is a new class of compounds for treatment of chronic constipation with or without IBS.


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InternalMed_Harrison. Guanylate Cyclase-C Agonist Linaclotide is a minimally absorbed 14-amino-acid peptide guanylate cyclase-C (GC-C) agonist that binds to and activates GC-C on the luminal surface of intestinal epithelium. Activation of GC-C results in generation of cyclic guanosine monophosphate (cGMP), which triggers secretion of fluid, sodium, and bicarbonate. In animal models, linaclotide accelerates GI transit and reduces visceral nociception. The analgesic action of linaclotide appears to be mediated by cGMP acting on afferent pain fibers innervating the GI tract. A phase III, double-blind, controlled trial showed that linaclotide, 290 μg given once daily, significantly improved abdominal pain, bloating, and spontaneous bowel movement. The only significant side effect was diarrhea, which occurred in 4.5% of the patients. The drug has been approved for treatment of constipation in IBS-C patients. Correlations with gut physiology +++ ++ +


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InternalMed_Harrison. The treatment strategy of IBS depends on the severity of the disorder (Table 352-5). Most IBS patients have mild symptoms. They are usually cared for in primary care practices, have little or no psychosocial difficulties, and do not seek health care often. Treatment usually involves education, reassurance, and dietary/lifestyle changes. A smaller portion have moderate symptoms that are usually intermittent and correlate with altered gut physiology, e.g., worsened with eating or stress and relieved by defecation. For IBS-D patients, treatments include gut-acting pharmacologic agents such as antispasmodics, antidiarrheals, bile acid binders, and the newer gut serotonin modulators (Table 352-6). In IBS-C patients, increased fiber intake and the use of osmotic agents such as polyethylene glycol may achieve satisfactory results. For patients with more severe constipation, a chloride channel opener (lubiprostone) or GC-C agonist (linaclotide) may be considered. For IBS patients with


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InternalMed_Harrison. glycol may achieve satisfactory results. For patients with more severe constipation, a chloride channel opener (lubiprostone) or GC-C agonist (linaclotide) may be considered. For IBS patients with predominant gas and bloating, a low-FODMAP diet may provide significant relief. Some patients may benefit from probiotics and rifaximin treatment. A small proportion of IBS patients have severe and refractory symptoms, are usually seen in referral centers, and frequently have constant pain and psychosocial difficulties (Fig. 352-1). This group of patients is best managed with antidepressants and other psychological treatments (Table 352-6).


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InternalMed_Harrison. aAvailable only in the United States. Abbreviation: FODMAP, fermentable oligosaccharides, disaccharides, monosaccharides, and polyols. Source: Adapted from GF Longstreth et al: Gastroenterology 130:1480, 2006. Diverticular Disease and Common Anorectal Disorders Rizwan Ahmed, Susan L. Gearhart DIVERTICULAR DISEASE Incidence and Epidemiology In the United States, diverticulo-353 sis affects 70% of the population above the age of 80.


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InternalMed_Harrison. Fortunately, only 20% of patients with diverticulosis develop symptomatic disease, 1–2% require hospitalization, and <1% will require surgery. Diverticular disease has become the fifth most costly gastrointestinal disorder in the United States. Previously overlooked, the majority of patients with diverticular disease report a lower health-related quality of life and more depression as compared to matched controls, thus adding to health care costs. Formerly, diverticular disease was confined to developed countries; however, with the adoption of westernized diets in underdeveloped countries, diverticulosis is on the rise across the globe. Immigrants to the United States develop diverticular disease at the same rate as U.S. natives. Although the prevalence among females and males is similar, males tend to present at a younger age. The mean age at presentation of the disease is 59 years and is now shifting to affect younger populations.


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InternalMed_Harrison. Anatomy and Pathophysiology Two types of diverticula occur in the intestine: true and false (or pseudo diverticula). A true diverticulum is a saclike herniation of the entire bowel wall, whereas a pseudo diverticulum involves only a protrusion of the mucosa and submucosa through the muscularis propria of the colon (Fig. 353-1). The type of diverticulum affecting the colon is the pseudodiverticulum. Diverticula commonly affect the left and sigmoid colon; the rectum is always spared. However, in Asian populations, 70% of diverticula are seen in the right colon and cecum as well. Diverticulitis is inflammation of a diverticulum. Previous understanding of the pathogenesis of diverticulosis attributed a low-fiber diet as the sole culprit, and onset of diverticulitis would occur acutely when these diverticula become obstructed. However, evidence now suggests that the pathogenesis is more complex and multifactorial. The diverticula occur at the point where the nutrient artery, or vasa recti,


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InternalMed_Harrison. diverticula become obstructed. However, evidence now suggests that the pathogenesis is more complex and multifactorial. The diverticula occur at the point where the nutrient artery, or vasa recti, penetrates through the muscularis propria, resulting in a break in the integrity of the colonic wall. This anatomic restriction may be a result of the relative high-pressure zone within the muscular sigmoid colon. Thus, higher-amplitude contractions combined with constipated, high-fat-content stool within the sigmoid lumen in an area of weakness in the colonic wall results in the creation of these diverticula. Consequently, the vasa recti is either compressed or eroded, leading to either perforation or bleeding. Chronic low-grade inflammation is thought to play a key role. Furthermore, better understanding of the gut microbiota suggests that dysbiosis is an important aspect of disease.


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InternalMed_Harrison. Presentation, Evaluation, and Management of Diverticular Bleeding Hemorrhage from a colonic diverticulum is the most common cause of hematochezia in patients >60 years, yet only 20% of patients with diverticulosis will have gastrointestinal bleeding. Patients at increased risk for bleeding tend to be hypertensive, have atherosclerosis, and regularly use aspirin and nonsteroidal anti-inflammatory agents. Most bleeds are self-limited and stop spontaneously with bowel rest. The lifetime risk of rebleeding is 25%.


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InternalMed_Harrison. Initial localization of diverticular bleeding may include colonoscopy, multiplanar computed tomography (CT) angiogram, or nuclear medicine tagged red cell scan. If the patient is stable, ongoing bleeding is best managed by angiography. If mesenteric angiography can localize the bleeding site, the vessel can be occluded successfully with a coil in 80% of cases. The patient can then be followed closely with repetitive colonoscopy, if necessary, looking for evidence of colonic ischemia. Alternatively, a segmental resection of the colon can be undertaken to eliminate the risk of further bleeding. This may be advantageous in patients on chronic anticoagulation. However, with highly selective coil embolization, the rate of colonic ischemia is <10% and the risk of FIGURE 353-1 Gross and microscopic view of sigmoid diverticular disease. Arrows mark an inflamed diverticulum with the diverticular wall made up only of mucosa.


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InternalMed_Harrison. FIGURE 353-1 Gross and microscopic view of sigmoid diverticular disease. Arrows mark an inflamed diverticulum with the diverticular wall made up only of mucosa. acute rebleeding is <25%. Long-term results (40 months) indicate that more than 50% of patients with acute diverticular bleeds treated with highly selective angiography have had definitive treatment. As another alternative, a selective infusion of vasopressin can be given to stop the hemorrhage, although this has been associated with significant complications, including myocardial infarction and intestinal ischemia. Furthermore, bleeding recurs in 50% of patients once the infusion is stopped.


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InternalMed_Harrison. If the patient is unstable or has had a 6-unit bleed within 24 h, current recommendations are that surgery should be performed. If the bleeding has been localized, a segmental resection can be performed. If the site of bleeding has not been definitively identified, a subtotal colectomy may be required. In patients without severe comorbidities, surgical resection can be performed with a primary anastomosis. A higher anastomotic leak rate has been reported in patients who received >10 units of blood.


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InternalMed_Harrison. Presentation, Evaluation, and Staging of Diverticulitis Acute uncomplicated diverticulitis characteristically presents with fever, anorexia, left lower quadrant abdominal pain, and obstipation (Table 353-1). In <25% of cases, patients may present with generalized peritonitis indicating the presence of a diverticular perforation. If a pericolonic abscess has formed, the patient may have abdominal distention and signs of localized peritonitis. Laboratory investigations will demonstrate a leukocytosis. Rarely, a patient may present with an air-fluid level in the left lower quadrant on plain abdominal film. This is a giant diverticulum of the sigmoid colon and is managed with resection to avoid impending perforation.


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InternalMed_Harrison. The diagnosis of diverticulitis is best made on CT with the following findings: sigmoid diverticula, thickened colonic wall >4 mm, and inflammation within the periodic fat ± the collection of contrast material or fluid. In 16% of patients, an abdominal abscess may be present. Symptoms of irritable bowel syndrome (Chap. 352) may mimic those of diverticulitis. Therefore, suspected diverticulitis that does not meet CT criteria or is not associated with a leukocytosis or fever is not diverticular disease. Other conditions that can mimic diverticular disease include an ovarian cyst, endometriosis, acute appendicitis, and pelvic inflammatory disease.


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InternalMed_Harrison. Although the benefit of colonoscopy in the evaluation of patients with diverticular disease has been called into question, its use is still considered important in the exclusion of colorectal cancer. The parallel epidemiology of colorectal cancer and diverticular disease provides enough concern for an endoscopic evaluation before operative management. Therefore, a colonoscopy should be performed ~6 weeks after an attack of diverticular disease.


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InternalMed_Harrison. Complicated diverticular disease is defined as diverticular disease associated with an abscess or perforation and less commonly with a fistula (Table 353-1). Perforated diverticular disease is staged using the Hinchey classification system (Fig. 353-2). This staging system was developed to predict outcomes following the surgical management of complicated diverticular disease. In complicated diverticular disease with fistula formation, common locations include cutaneous, vaginal, or vesicle fistulas. These conditions present with either passage of stool through the skin or vagina or the presence of air in the urinary stream (pneumaturia). Colovaginal fistulas are more common in women who have undergone a hysterectomy.


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InternalMed_Harrison. Asymptomatic diverticular disease discovered on imaging studies or at the time of colonoscopy is best managed by diet alterations. Patients should be instructed to eat a fiber-enriched diet that includes 30 g of fiber each day. Supplementary fiber products such as Metamucil, Fibercon, or Citrucel are useful. The incidence of complicated diverticular disease appears to be increased in patients who smoke. Therefore, patients should be encouraged to refrain from smoking. The historical recommendation to avoid eating nuts is not based on more than anecdotal data.


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InternalMed_Harrison. Symptomatic uncomplicated diverticular disease with confirmation of inflammation and infection within the colon should be treated initially with antibiotics and bowel rest. Nearly 75% of patients hospitalized for acute diverticulitis will respond to nonoperative treatment with a suitable antimicrobial regimen. The current recommended antimicrobial coverage is trimethoprim/ sulfamethoxazole or ciprofloxacin and metronidazole targeting aerobic gram-negative rods and anaerobic bacteria. Unfortunately, these agents do not cover enterococci, and the addition of ampicillin


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InternalMed_Harrison. FIGURE 353-2 Hinchey classification of diverticulitis. Stage I: Perforated diverticulitis with a confined paracolic abscess. Stage II: Perforated diverticulitis that has closed spontaneously with distant abscess formation. Stage III: Noncommunicating perforated diverticulitis with fecal peritonitis (the diverticular neck is closed off, and therefore, contrast will not freely expel on radiographic images). Stage IV: Perforation and free communication with the peritoneum, resulting in fecal peritonitis. to this regimen for nonresponders is recommended. Alternatively, single-agent therapy with a third-generation penicillin such as IV piperacillin or oral penicillin/clavulanic acid may be effective. The usual course of antibiotics is 7–10 days, although this length of time is being investigated. Patients should remain on a limited diet until their pain resolves.


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InternalMed_Harrison. Once the acute attack has resolved, the mainstay medical management of diverticular disease to prevent symptoms has evolved. Newer directions are targeted at colonic inflammation and dysbiosis. Diverticular disease is now considered a functional bowel disorder associated with low-grade inflammation. Therefore, the use of anti-inflammatory medications such as mesalazine has become popular. Patients treated with mesalazine have a decreased recurrence of symptomatic disease. Randomized trials of anti-inflammatory medications are ongoing.


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InternalMed_Harrison. Treatment strategies targeting dysbiosis in diverticular disease are also beneficial. Use of the polymerase chain reaction (PCR) on stool specimens from consumers of a high-fiber diet has shown different bacterial content than stool of consumers of a low-fiber, high-fat diet. Probiotics are being increasingly used by gastroenterologists for multiple bowel disorders and have been shown to prevent recurrence of diverticulitis. Specifically probiotics containing Lactobacillus acidophilus and Bifidobacterium strains have been shown to be beneficial. Furthermore, rifaximin (a poorly absorbed broad-spectrum antibiotic), when compared to fiber alone, is associated with 30% less frequent recurrent symptoms from uncomplicated diverticular disease.