David J. Maron, MD, FACS
Assistant Professor of Surgery
Division of Colon and Rectal Surgery
University of Pennsylvania School of Medicine
Epidemiology and Etiology
Ulcerative colitis (UC) is an idiopathic chronic inflammatory disease affecting the mucosa of the rectum extending proximally to affect a variable length of the colon. In the United States and Northern Europe, the incidence varies between 2 and 10 cases per 100,000 person per year, with a prevalence of between 35 and 100 per 100,0001. The disease may affect all ages, but it predominates in young adults 20-40 years of age. Males and females are affected equally.
Inheritance may often play a role in the etiology of UC. Investigators have reported a positive family history in as high as 29% of individuals with UC2. Ulcerative colitis is not inherited in a Mendelian pattern, however genetic predisposition may be influenced by diet, smoking cessation, breast feeding, and oral contraceptive use3-5. History of appendectomy may also influence the development of UC. Compared with patients without prior appendectomy, appendectomy before diagnosis delays disease onset and gives rise to a milder disease phenotype in ulcerative colitis6. Cigarette smoking has also been shown to affect the incidence of ulcerative colitis4. While smokers tend to have a higher incidence of developing Crohn’s disease, non-smokers and former smokers appear to be at increased risk of developing UC.
The pathogenesis of ulcerative colitis remains unknown, but it has been theorized that it is triggered by an environmental stimulus7. An enormous amount of work has been dedicated to identify the antigen(s) that trigger the immune response, however, no specific pathogen has been isolated consistently. Many theories have been presented including infection, autoimmune mechanisms, and allergy to dietary components.
The most common symptoms of ulcerative colitis include diarrhea and rectal bleeding. Patients may also complain of crampy abdominal pain, fever, malaise, passage of mucus, weight loss, and symptoms related to extraintestinal manifestations. The severity of the patient’s symptoms typically correlates with the severity of the disease. Physical findings are usually nonspecific and depend on the severity of the disease. Development of abdominal distention, tachycardia, fever, and leukocytosis may signify the onset of toxic megacolon.
Ulcerative colitis begins in the rectum and progresses proximally. Macroscopic changes are generally most severe in the rectum, unless the rectum has been treated with steroid or 5-ASA enemas. With severe inflammation, the mucosa appears granular, friable, and may show areas of pronounced deep ulcerations. Pseudopolyps may be present as a result of regenerating epithelium, and represent islands of intact mucosa that become elevated secondary to ulceration of the surrounding mucosa. Progression from the rectum to the colon is variable; in study of 1116 patients, 46% had proctosigmoiditis, 17% had left-sided disease (to the splenic flexure), and 37% had pancolitis at the time of presentation1. Patients in this study presenting with pancolitis were more likely to develop refractory symptoms, toxic megacolon, malignancy, and extraintestinal manifestations.
Microscopically, the lamina propria, crypts, and surface epithelium are infiltrated by polymorphonuclear leukocytes (PMNs). Cryptitis occurs when PMNs are present within the epithelium of the crypts, and crypt abscesses form from aggregates of PMNs within the crypt lumina. Several other features may help to establish a diagnosis of UC or to evaluate the severity of the condition, including mucosal atrophy, mucin depletion, Paneth-cell metaplasia, and diffuse thickening of the muscularis mucosa. Fulminant ulcerative colitis may show deep ulcers that extend into the muscularis propria and may be associated with muscle necrosis.
Management of ulcerative colitis will vary depending on the severity of the attack, and it is therefore important to assess the extent and severity of the disease with each presentation. A system to categorize attacks as mild, moderate, or severe was proposed by Truelove and Witts8. The degree of severity is based on six clinical signs: diarrhea, presence of blood in the stool, fever, tachycardia, anemia, and elevated erythrocyte sedimentation rate. A scoring system developed at the Mayo Clinic based on stool frequency, rectal bleeding, findings of flexible proctosigmoidoscopy, and the physician’s global assessment is often used in determining the response to treatment in study groups9.
The diagnosis of ulcerative colitis is based on the combination of clinical presentation, endoscopic appearance, and biopsies of the colonic mucosa. Proctoscopy or flexible sigmoidoscopy is often sufficient in obtaining tissue for diagnosis. Colonoscopy may result in perforation during the acute attack and is therefore relatively contraindicated, however patients should undergo full evaluation by colonoscopy or barium enema once recovered from the acute presentation. Stool cultures should be obtained to rule out an infectious cause of colonic inflammation, and biopsy specimens should be analyzed by a pathologist to conform the diagnosis of UC. If the diagnosis is still in doubt, a small bowel series or CT enterography should be performed to asses the remainder of the intestine for lesions characteristic of Crohn’s disease. Approximately 15% to 20% of patients with severe ulcerative colitis have an associated “backwash ileitis”, characterized by a fixed, patulous ileocecal valve and a dilated, granular terminal ileum on double-contrast barium studies10 or colonoscopy.
The differential diagnosis of ulcerative colitis includes Crohn’s disease, infectious colitis, pseudomembranous colitis, ischemia, radiation colitis, and collagenous colitis. It is imperative to obtain a detailed medical history to achieve a correct diagnosis. It may be very difficult to differentiate between UC and Crohn’s disease, however rectal sparing and a history of perianal sepsis may help, and small bowel involvement obviously indicates Crohn’s. Infectious colitis secondary to E. coli, Campylobacter, Salmonella, or Entamoeba histolytica, is typically characterized by a sudden onset and a self-limited course. Pseudomembranous colitis secondary to C. difficile overgrowth results in yellowish, plaque-like membranes on the inflamed mucosa which may be seen on sigmoidoscopy. A history of recent antibiotic use and identification of the C. difficile toxin in the stool aid in diagnosis. Ischemic colitis is typically seen in older patients, has a sudden onset, and is often painful; rectal involvement is rare. Collagenous colitis also tends to occur in older patients, and results in watery diarrhea. The colonic mucosa in patients with collagenous colitis appears grossly normal, but histologic examination shows an eosinophilic band of subepithelial collagen and a mild chronic inflammatory infiltrate in the lamina propria.
Extraintestinal manifestations of ulcerative colitis include primary sclerosing cholangitis (PSC), erythema nodosum, pyoderma gangrenosum, arthritis, ankylosing spondylitis, and ocular complications such as episcleritis and uveitis. PSC occurs in as high as 7.5% of patients with UC, and results in fibrosis of the intra- and extrahepatic bile ducts. It is more common in men and tends to occur in patients under the age of forty. Ulcerative colitis patients with either the HLA-B8 or HLA-DR3 haplotype have been estimated to have a 10-fold increase in the relative risk of developing PSC11. Proctocolectomy has not been demonstrated to alter the course of PSC12. Erythema nodosum is a classical dermatological manifestation which presents as inflamed, red, and tender nodules, mainly in the anterior part of the lower legs. It has been reported that the prevalence of erythema nodosum in UC is between 10%-20%13. Development of pyoderma grangrenosum is related to active colonic inflammation; the lesions begin as plaques or pustules, afterwards ulcerating and becoming very painful. This is a rare condition, occurring in only 1%-2% of patients with UC. Joint involvement in enteropathic arthritis has been divided in two patterns: (1) peripheral arthritis, and (2) axial involvement, including sacroiliitis with or without spondylitis14. In one study, 3.6% of all patients with UC had more than one episode of arthritis15. Peripheral arthropathy tends to coexists with the underlying bowel disease activity and is associated with an increased incidence of erythema nodosum and uveitis. Ophthalmologic manifestations of UC are reported in 1.6% to 4.6%16. Uveitis presents as a painful eye, with blurred vision, headache and photophobia; episcleritis presents as a red, painful eye without loss of vision17. These occur in less than 10% of patients with ulcerative colitis.
Colorectal Cancer in Ulcerative Colitis
One of the most serious sequelae of ulcerative colitis is the development of colorectal carcinoma. The most important risk factors include prolonged duration of the disease, pancolonic disease, continuously active disease, and the severity of the inflammation. The cumulative risk for cancer increases with the duration of the disease, reaching 2% at 10 years, 8% at 20 years, and 18% at 30 years18. Patients with disease confined to the left side of the colon have a lower risk of developing carcinoma than those patients with disease involving the entire colon.
There is considerable debate regarding the optimal method of surveillance colonoscopy in patients with ulcerative colitis. The American Cancer Society recommends surveillance colonoscopy every one to two years beginning 8 years after the onset of pancolitis and 12 to 15 years after the onset of left-sided colitis. Several studies have recently suggested that at least 30 biopsies be obtained to rule out the presence of dysplasia.
A recent meta-analysis of twenty prospective studies was performed to determine the relative risk of developing cancer in patients with low-grade dysplasia19. When low-grade dysplasia was detected on surveillance, a nine-fold risk of developing cancer was seen, and there was a twelve-fold risk of developing an advanced lesion. Patients therefore need to be counseled about the potential for dysplasia so that they can rationally take part in their management. When high-grade dysplasia is found and has been confirmed by a second independent pathologist, proctocolectomy should be recommended. This is also true for patients who harbor a dysplasia-associated lesion or mass (DALM). If low-grade dysplasia is confirmed, strong consideration should also be given to proctocolectomy.
Medical TherapyMedications remain the primary treatment of ulcerative colitis. The goal of treatment is directed at inducing and maintaining remission of symptoms and mucosal inflammation. The approach to therapy is determined by the extent of involvement and the severity of the disease at the time of presentation. Several types of medications are useful in treating ulcerative colitis. These include aminosalicylates (sulfasalazine, olsalazine, mesalamine, balsalazide), corticosteroids (prednisone, budesonide), and immunosuppressants (6-mercaptopurine, azathioprine, cyclosporine, infliximab).
The mainstay of treatment of patients with disease limited to the rectum is 5-ASA suppositories. Mesalamine suppositories 1-1.5 g/day have been shown to be superior to oral 5-ASA therapy and to steroid enemas20. For patients who do not respond within 4 to 6 weeks, combination therapy with a topical corticosteroid (foam or enema) has been shown to be superior to either therapy alone21. For patients who are not able to tolerate topical therapy, oral mesalamine can be used as an alternative.
Mild to Moderate Distal ColitisMild to moderate involvement of the distal 30 to 40 cm of distal colonic mucosa is best treated with 5-ASA enemas or hydrocortisone enemas. Treatment is initiated with a single nightly mesalamine enema 4g/60 ml and remission rates average 70% within 4 weeks. If symptoms persist, an additional mesalamine enema or hydrocortisone enema may be added in the morning. Combination therapy with mesalamine enemas and hydrocortisone enemas has also been shown to be superior to either therapy alone22. Corticosteroid enemas include hydrocortisone foam or enemas containing budesonide, a second generation corticosteroid with a high first-pass metabolism in the liver which has fewer steroid-related side effects; both are equally effective23. For those patients who do not tolerate or refuse topical therapy, oral 5-ASA preparations are an effective alternative.
Mild to Moderate Extensive Colitis
Patients with mild to moderate extensive or pancolitis with require pharmacologic therapy with an oral 5-ASA medication. Oral sulfasalazine at dosages of 2-6 g/day will achieve remission is as high as 80% of patients, however a substantial number of patients are unable to tolerate high doses of the medication. Newer formulations of 5-ASA are better tolerated, and have been shown to be equally effective24. Topical mesalamine or topical corticosteroids may be added to control rectal symptoms. For patients with more severe colitis who do not respond to oral 5-ASA, oral corticosteroids may be added in an effort to achieve remission. In patients who do not respond to oral corticosteroids, treatment with 6-MP or azathioprine may be considered. Therapy is usually initiated with a dose of 50 mg/day, and steroids should be maintained initially because a therapeutic response may not occur for three to six months.
Severe or Fulminant ColitisPatients with fulminant colitis typically present with high fever, severe abdominal pain, tenderness, tachycardia, and leukocytosis. These patients require hospitalization with intravenous hydration, bowel rest, high-dose intravenous steroids, and broad-spectrum antibiotics. Infectious colitis should be ruled out by obtaining stool cultures and C. diff toxin. Intravenous hyperalimentation may be useful depending on the patient’s nutritional status and length of illness prior to the fulminant episode. Patients should be closely monitored with serial abdominal exams, abdominal radiographs, and leukocyte counts. Deterioration or lack of improvement within 48 to 72 hours of the initiation of medical treatment warrants an urgent procedure, as the mortality is increased four-fold in patients with colonic perforation.
Intravenous cyclosporine can also be used in the treatment of severe, steroid-refractory ulcerative colitis. It is typically given as a continuous infusion of 2-4 mg/kg/day, and has been shown to have a response rate as high as 82%25. Cyclosporine should not be administered to patients with active infection or a history of seizures.
Infliximab, a monoclonal antibody against tumor necrosis factor, has also been shown to be effective in the treatment of severe ulcerative colitis. Two large, randomized, double-blind, multicenter trials (ACT 1 and ACT 2) were conducted in which patients received placebo or infliximab (5 or 10 mg/kg) intravenously at weeks 0, 2, and 6 and then at eight week intervals26. At week 8, between 64-69% of patients receiving 5 mg/kg infliximab and 61-69% of patients receiving 10 mg/kg infliximab demonstrated a clinical response, versus 29-37% of patients who received placebo. In addition, patients treated with inflixmab were more likely to have a clinical response at week 30. Ongoing trials are evaluating the use of infliximab and other anti-TNF antibodies in maintenance therapy of ulcerative colitis.
Emergent Surgery Fulminant disease occurs as the initial presentation of UC in up to 50 percent of cases27,28, and up to twenty percent of patients will require urgent or emergent surgery for acute complications29. Potentially fatal complications of UC necessitating surgery include fulminant colitis, toxic megacolon, and massive hemorrhage. Toxic megacolon is a life-threatening variant of toxic colitis in which the dilation of the colon has progressed to the point of imminent perforation. Massive hemorrhage from UC is a less common complication, occurring in up to 4.5 percent of cases30, and approximately 10 percent of all emergency colectomies for patients with UC are performed for massive hemorrhage31.
Although the safety of a single-staged ileoanal reservoir in the acute setting has been reported32, both proctectomy and anastomosis are generally contraindicated in the acutely ill patient with an unprepared bowel. Total proctocolectomy in the urgent setting carries a prohibitively high mortality rate28,33, and the leak rate from a primary anastomosis is unacceptably high34,35. A total abdominal colectomy with ileostomy is therefore the preferred operation for these situations. This procedure can be expeditiously performed with relatively low morbidity and mortality, and it is a non-committal procedure that serves the main purpose of removing the diseased colon while leaving the rectum behind. Moreover, this is particularly important in patients in whom the diagnosis of UC is unclear (indeterminate colitis) and a subsequent ileoanal reservoir might be contraindicated.
The “blowhole” procedure was a popular procedure for the treatment of toxic megacolon prior to the availability of intensive care units and parenteral nutrition. This technique involved the creation of a loop ileostomy with an antimesenteric transverse colostomy36. This procedure limited handling of the bowel and thus the chance for fecal contamination during dissection, but was contraindicated in the presence of free perforation.
Elective Surgery Indications for elective surgery for ulcerative colitis include intractable disease, complications of medical therapy, dysplasia, carcinoma, and occasionally for attempted improvement of extraintestinal manifestations. Patients with intractable disease have persistent symptoms such as crampy abdominal pain, frequent bowel movements, and stool urgency which may result in the deterioration of patient’s social and professional lives37. Complications of long-term steroid therapy, such as diabetes mellitus, avascular necrosis of the femoral head, cataracts, psychiatric problems, osteoporosis, and weight gain are a frequent indication for surgical resection, despite the fact the patient’s UC may be under control. The finding of carcinoma is an absolute indication for surgery; patients who are found to have any dysplasia or carcinoma should be treated by colectomy38,39.
A less common indication for elective surgery in UC is for the treatment of debilitating extraintestinal manifestations of the disease. Pyoderma gangrenosum, erythema nodosum, peripheral arthritis, and uveitis should regress spontaneously postoperatively, however, sclerosing cholangitis and ankylosing spondylitis will not. Therefore, elective surgery should be considered in patients with colitis and significant extracolonic manifestations refractory to nonoperative measures40.
Elective surgical options for UC include total proctocolectomy with either an end ileostomy or continent reservoir (Kock pouch), total abdominal colectomy with an ileoproctostomy, or a restorative proctocolectomy with an ileoanal reservoir. Each procedure has its advantages and disadvantages, and selection of a specific operation must take into account the age and overall health of the patient, the presence of dysplasia and risk of carcinoma, the status of the patient’s anal continence, and the certainty of the diagnosis of UC.
Total Proctocolectomy with End IleostomyTotal proctocolectomy has the advantage of removing all possible diseased mucosa, thereby preventing further inflammation or the potential for progression to dysplasia or carcinoma. Total proctocolectomy with end ileostomy was one of the earliest operations performed for UC, and despite advances in sphincter-saving procedures continues to have a role. Elderly patients, those with poor sphincter function, and patients with carcinomas in the lower rectum may be candidates for this procedure.
Total Proctocolectomy with Continent IleostomyThe continent ileostomy was introduced by Kock in 196941 and became very popular in the 1970s as it offered patients with an ileostomy control over evacuation. Its creation involves suturing several limbs of ileum together to create a reservoir; the pouch becomes continent by intussuscepting the outflow tract to create a valve. As the pouch distends, pressure over the valve causes it close and retain stool, allowing patients to wear a simple bandage over a skin level stoma. Between two and four times per day, the patient introduces a tube through the valve to evacuate the pouch.
The major problem with the Kock pouch is the high reoperation rate, required in up to 50 percent of patients42. The most common surgical procedure required is revision of the nipple valve43, typically when one side of the valve “slips,” or loses its prolapsed position within the pouch. This leads to either the inability of the pouch to remain continent or the inability to intubate the pouch leading to spontaneous emptying of the pouch as it overflows.
Despite the high complication rate, a limited role still exists for the continent ileostomy. The most frequent current indication is conversion of a failed ileoanal reservoir in a patient who refuses a Brooke ileostomy. The Kock procedure should not be performed in obese patients, debilitated patients, or any patient with physical or mental handicap that would not allow them to safely catheterize the stoma.
Total Abdominal Colectomy with Ileorectal AnastomosisA third alternative in the surgical management of UC is total abdominal colectomy with ileorectal anastomosis. Many of the intrinsic complications of total proctocolectomy are not experienced with this procedure because there is no mobilization of the rectum. This procedure has been shown to be safe, with an anastomotic leak rate of less than 2% in several large series44,45.
Functional results after ileorectal anastomosis are variable. In one series, over ninety percent of patients had fewer bowel movements per day postoperatively than preoperatively, and forty percent had three or fewer per day46. Other authors, however, have reported increased bowel frequency with up to 6 to 10 bowel movements per day. Failure of this procedure is usually due to continued inflammation in the rectum. Another disadvantage of ileorectal anastomosis is the risk of subsequent rectal carcinoma. The risk of carcinoma varies with time and by reported series, but can reach as high as 6% at 20 years, 15% at 30 years, and 18% at 35 years47. Patients with cancer or severe dysplasia in the resected colon are therefore not candidates for total abdominal colectomy with ileorectal anastomosis.
Despite the risk of carcinoma and the potential for persistent inflammation leading to failure, ileoproctostomy may be an attractive option, especially for young male patients with UC who wish to avoid the risk of impotence involved with proctectomy. Residual inflammation in the rectum in patients undergoing this procedure may be adequately treated with topical 5-ASA or topical corticosteroids.
Total Proctocolectomy with Ileoanal ReservoirRestorative proctocolectomy with ileoanal reservoir has become the most common definitive procedure in the elective treatment of UC. The procedure involves a near-total proctocolectomy with preservation of the anal sphincter complex. The mucosa of the distal anal canal can be stripped off the internal sphincter with the aim of preventing recurrence of symptoms or the potential of the development of cancer. A pouch is then fashioned using two, three, or four loops of small bowel (S, H, J, or W configuration) and this is anastomosed to the anal canal48-51. The pouch and anastomosis were traditionally protected with a diverting loop ileostomy, however, there are some proponents of the single-stage procedure without diversion52-57. Others have cautioned against single-stage procedures58-61.
Regardless of the configuration of the pouch, functional results are similar among many reported series48-51,62. The Mayo Clinic evaluated 1193 patients with J-pouches and found that the mean number of bowel movements in a 24-hour period was five63. Similarly, Fleshman, et al.64 reported a mean of 6.2 bowel movements per day in their series of patients. Schoetz et al.65 reported 7.0 bowel movements per day during the first three months following ileostomy closure and 5.1 per day following three months. Other authors have reported similar findings that improvement in function can be expected to decrease bowel movements during the ensuing 3 to 24 months following reestablishment of continuity65,66.
Because the ileal reservoir is anastomosed directly to the anal sphincter mechanism, continence can be affected. Nocturnal incontinence is a more significant problem than daytime incontinence. In the University of Minnesota series, 91% of patients had good control of both solid and liquid stool during the day67. This number dropped to only 76% of patients during the night. Minor spotting occurred in a significant number of patients and almost two thirds wore protective pads. Pemberton, et al.68 reported that almost half of patients had nocturnal leakage at 6 months, but at one year only 20% continued to have leakage at night. Other authors have shown similar improvements in continence with time64,65.
The major complications after ileoanal reservoir are small bowel obstruction (occurring in up to 27% of patients), pelvic sepsis secondary to anastomotic and pouch suture line leaks, pouch-vaginal fistula, and pouchitis. Pouchitis, may occurs in 7% to 33% of patients68-72. It typically presents with increased frequency of stools which may be accompanied by fever, bleeding, cramps, and dehydration. The cause is unknown but may be related to bacterial overgrowth, mucosal ischemia, or other local factors73,74. Episodes will usually respond to rehydration and oral metronidazole, but the diagnosis of Crohn’s disease must also be entertained.
In some cases, the preoperative distinction between Crohn’s disease and UC can be difficult, and the pathologist may label the disease as “indeterminate” colitis. Crohn’s disease is a contraindication to ileoanal reservoir, and published series on ileoanal reservoir performed on patients with Crohn’s show very poor results75,76. Pouchitis or ileitis will affect up to 100% of these cases and pouch-vaginal fistulas occur in 33% of females; pouch failure leading to excision of the pouch occurs in more than half of these cases.
Patients with indeterminate colitis who undergo IAR who do not develop Crohn’s disease have results that are more encouraging. Yu, et al.77 reported a series of 82 patients with indeterminate colitis who underwent IAR; in comparison with patients with UC who underwent IAR, patients with the preoperative diagnosis of indeterminate colitis had significantly more episodes of pelvic sepsis, pouch fistula, and pouch failure. Fifteen percent of these patients were found to have Crohn’s disease, however, and when these patients were removed from the analysis, the rate of complications for the remaining patients with indeterminate colitis was identical to that of patients with chronic UC. Similarly, in a series at the Cleveland Clinic Florida there was no difference in the rates of complications or the functional outcome in patients with indeterminate colitis and UC who underwent double-stapled ileal pouch anal anastomosis78.
The use of laparoscopic surgery for diseases of the colon and rectum began in the early 1990s and has now become standard of care in some disease states. Although early reports noted increased morbidity79, improved techniques and equipment have produced both early and later results that are comparable to those of standard laparotomy80-86. Laparoscopy may afford the advantages of decreased intraoperative fluid loss, shorter postoperative ileus, less pain, and improved cosmesis87-89. A recent meta-analysis demonstrated that patients who underwent laparoscopic total proctocolectomy with ileoanal pouch were able to tolerate oral intake earlier and had a shorter hospital stay90. Time taken to perform the surgeries and overall complication rates were similar in both the open and laparoscopic groups.
Overall, laparoscopy can be selectively applied in patients with UC. In the hands of skilled laparoscopic surgeons, laparoscopic total proctocolectomy with ileal pouch anal anastomosis is a safe and effective procedure. In this setting, the appropriate use of laparoscopy can benefit the proper patients with improved cosmesis, shorter postoperative ileus, and quicker recovery time.
Fertility and Pregnancy
Many female patients who undergo surgical treatment for ulcerative colitis are of reproductive age, and there is therefore concern regarding the impact of pelvic surgery on both fertility and the ability to carry a fetus to term. A majority of patients will have abnormalities on hysterosalpingography following proctocolectomy91, and this may impact the ability to become pregnant92,93. A recent meta-analysis reported that the infertility rate rose from 12 percent preoperatively to 26 percent postoperatively; sexual dysfunction also rose from 8 percent preoperatively to 25 percent postoperatively94.
A majority of women who have undergone proctocolectomy will be able to carry the fetus to term and deliver vaginally. Hahnloser reported that there was no difference in birth weight, duration of labor, delivery complications, vaginal delivery rates, and unplanned cesarean sections95. Although pouch function may worsen, particularly during the third trimester, most studies show that no longer term differences persist, even after vaginal delivery94.
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