The epidemiology of inflammatory bowel disease: are we learning anything new?
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Biomedical subjects
Publications and source records attributed to B A Lashner.
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Colorectal cancer screening in ulcerative colitis patients is a commonly accepted practice whose parameters are based on convention and not necessarily on the epidemiology of disease. This review summarizes previously published data from a single university-based surveillance program to estimate important screening parameters. The hazard rate (annual risk) of developing cancer was found to rise exponentially with disease duration and to be approximately 2% at 20 yr of disease and nearly 8% at 30 yr of disease. Older age at symptom onset was a significant risk factor for neoplasia. The lead time between the development of low-grade dysplasia and high-grade dysplasia or cancer was approximately 3 yr. Efficient scheduling of tests (maximum benefit for a given cost) implied that the screening test interval should be inversely proportional to the square root of the hazard rate. As the hazard rate increased with duration of disease, the screening interval should shorten accordingly. An historical cohort study demonstrated that the parameters used in our program were not associated with the anticipated result of reduced colorectal cancer mortality. A surveillance program should be tested that uses a more sensitive criterion for a positive test.
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Epidemiologic studies have documented an association between nonsmoking and ulcerative colitis and case reports have demonstrated that symptoms improve with smoking and worsen with removal of a nicotine source. A double-blind randomized crossover trial for individual ulcerative colitis patients (single-patient trial, or N of 1 clinical trial) was designed to study the safety, patient acceptance, and the effectiveness of nicotine gum in improving patient symptoms and proctoscopic appearance of involved colon. Seven nonsmoking patients chewed up to 10 squares/day (20 mg) of nicotine gum or placebo gum for two weeks. Therapy was crossed-over every two weeks over the eight-week trial. Effectiveness was judged from comparisons between nicotine-gum and placebo-gum periods of patient self-reported symptoms at the conclusion of each two-week period using visual analog scales and proctoscopic appearance using ordered categorical scales. Three of seven patients, all three of whom were former smokers, demonstrated sufficient improvement without adverse effects to warrant institution of nicotine gum into their drug treatment regimens. Three patients demonstrated an uncertain response, despite tolerating the drug, and have not had nicotine gum added to their regimens. One patient could not tolerate the medication and was withdrawn from the study. No serious side effects were noted. We conclude that a randomized trial for an individual patient is a useful method for evaluating treatment regimens for ulcerative colitis and that nicotine gum may be effective therapy for individual patients with ulcerative colitis who demonstrate an objective response with few adverse effects.
Previous studies have found a widely variable prevalence of dysplasia and cancer in colonic strictures in patients with ulcerative colitis. Consequently, therapeutic recommendations are conflicting. To better assess the prevalence, we reviewed the clinical and pathological findings in all 27 patients with ulcerative colitis complicated by stricture who were entered into our Inflammatory Bowel Disease Registry. A true stricture was defined as a persistent localized narrowing of the colon found on air-contrast barium enema or on colonoscopy. Upon careful review, 12 of 27 patients were found to have transient colonic spasm, not a stricture, and were excluded. The remaining 15 patients with true strictures represented 3.2% of all ulcerative colitis patients in the registry. Strictures were identified at 13.3 +/- 9.9 years following the diagnosis of ulcerative colitis. Eleven patients had multiple strictures that were principally located in the left colon. Of the 15 patients, 11 had dysplasia and two had cancer found on colonoscopic biopsy. Ultimately, six patients had carcinoma found at colonoscopy or colectomy (three modified Dukes' stage A, one stage B, and two stage D). All cancers were at the site of a stricture. These findings indicate that a true colonic stricture in ulcerative colitis is frequently associated with dysplasia and cancer, which can be diagnosed with colonoscopic biopsy. A stricture should be considered a strong risk factor for cancer, requiring intensive colonoscopic surveillance. If dysplasia is discovered, or if the stricture cannot be adequately biopsied, consideration should be given to total colectomy.
Previous epidemiological studies suggesting an association between oral contraceptive use and ulcerative colitis incidence have been weak and conflicting. To measure a possible association, 46 incident cases of ulcerative colitis patients, women aged 18-50 years, were compared with peer-nominated age-matched and sex-matched controls. There were no differences between case and control patients in demographic characteristics. There was no association between oral contraceptive use and ulcerative colitis (current use: odds ratio 0.70, 95% confidence interval 0.27-1.83; former use: odds ratio 1.14, confidence interval 0.41-3.15; current or former use: odds ratio 0.86, confidence interval 0.40-1.85). Stratifying by disease location (pancolitis or left-sided disease) also failed to identify an association. Controlling for possible confounding effects of cigarette smoking did not alter the lack of association between oral contraceptive use and ulcerative colitis. Similarly, testing for interaction failed to demonstrate any effect modification. Analyzing for duration of current oral contraceptive use or time interval since last use failed to demonstrate a "dose-response" effect. The study was of sufficient size to detect statistical significance for oral contraceptive use for odds ratios of 2.8 and higher. In this matched case-control study of incident cases and community controls, there was no association between oral contraceptive use and ulcerative colitis incidence. To date, there is no evidence suggesting that women predisposed to the development of ulcerative colitis should be advised to avoid oral contraceptive use.
Colonic lavage with enemas or with Golytely are standard preparation methods for colonoscopy. Previous studies have demonstrated that Golytely has a statistically significant advantage in both adequacy of preparation and patient tolerance. To determine if these effects are present in the elderly, we performed a randomized clinical trial on 124 consecutive patients scheduled for colonoscopy who were greater than or equal to 75 years of age. Sixty-three patients were randomized to receive Golytely; 17 were inpatients, 33 were outpatients, and colonoscopy was canceled in 13. Sixty-one patients were randomized to receive the enema preparation; 17 were inpatients, 30 were outpatients, and colonoscopy was canceled in 14. For adequacy of the preparation, no differences were statistically significant, but the enema preparation was superior in outpatients while Golytely was superior in inpatients. Patients tolerated the enema preparation better, a finding present in both outpatients and inpatients. Contrary to previous reports of a significant advantage with Golytely, patients greater than or equal to 75 years old did not enjoy this advantage, but seemed to tolerate enemas better than Golytely with little difference in adequacy of the preparation.
Colorectal cancer is the second most common malignancy in the United States, and its incidence rates have sharply increased recently, especially in males. Industrial exposures, both occupational and environmental, are important colorectal cancer risk factors that are generally unrecognized by clinicians. Migration studies have documented that colorectal cancer is strongly associated with environmental risk factors. The causal role of occupational exposures is evidenced by a substantial literature associating specific work practices with increased colorectal cancer risks. Industrially related environmental exposures, including polluted drinking water and ionizing radiation, have also been associated with excess risks. Currently, there is a tendency to attribute colorectal cancer, largely or exclusively, to dietary and other lifestyle factors, thus neglecting these industrially related effects. Concerted efforts are needed to recognize the causal role of industrial risk factors and to encourage government and industry to reduce carcinogenic exposures. Furthermore, cost-effective screening programs for high-risk population groups are critically needed to further reduce deaths from colorectal cancer.
We performed a decision analysis to evaluate cost per cancer detected, cost per neoplasm detected, and cost per treatable lesion of two common diagnostic strategies, barium enema-proctoscopy or colonoscopy as the first diagnostic test, for patients with fecal occult blood loss. The prevalence of polyps, cancer, and angiodysplasia, and the colonoscopy success rate were obtained from consecutive colonoscopy records. Costs were estimated from hospital charges; sensitivity and specificity of barium enema and colonoscopy were obtained from the literature. For treatable lesions (cancer, polyps, and angiodysplasia), the colonoscopy first strategy had a higher sensitivity (80% vs. 57%) and a higher specificity (95% vs. 80%) than the barium enema first strategy. Cost effectiveness measures were similar for the two strategies. Colonoscopy as the first diagnostic test had a lower cost per treatable lesion ($2,319 vs. $2,895) and a lower cost per neoplasm detected ($2,694 vs. $2,896), whereas the barium enema first strategy had a lower cost per cancer detected ($10,050 vs. $10,297). The lower cost per treatable lesion of the colonoscopy first strategy was not affected by changes in the prevalence of lesions, test characteristics, costs of tests, or colonoscopy success rate over clinically relevant ranges. The higher cost of colonoscopy was offset by its greater sensitivity and its capacity for biopsy and therapy. Therefore, since the cost per treatable lesion is lower and the sensitivity, specificity, and predictive value is superior, colonoscopy is recommended as the preferred initial test in evaluating a patient with fecal occult blood loss.
Screening for dysplasia in ulcerative colitis is expected to improve cancer-related survival by advancing the diagnosis of cancer to a more favorable pathologic stage or by identifying patients for prophylactic colectomy who are at at high risk of developing cancer. To evaluate the effectiveness of a surveillance program of annual colonoscopy and mucosal sampling, 91 screened and 95 control ulcerative colitis patients with extensive disease for at least 8 yr were compared for differences in survival, cancer detection, and colectomy rates. The two groups were of similar age at symptom onset, duration of disease, and sex. In the surveillance group, there were eight fewer deaths (p less than 0.05 by survival-curve analysis), but two more cancer deaths (not significant). Colectomy was less common (p less than 0.05) and was performed 4 yr later in the surveillance group. The effect of surveillance was not confounded by age at symptom onset, sex, or duration of disease. In our program, screening for cancer in ulcerative colitis was associated with improved survival and delayed colectomy. However, improvement was not related to the anticipated benefits of improved cancer-related survival.
1,2-Dimethylhydrazine (DMH) is a potent procarcinogen with selectivity for the colon. Recently, it has been demonstrated that levels of N1-acetylspermidine were elevated 2-3-fold in colonic tumors induced by this agent compared to control tissues. To determine whether alterations in the urinary levels of this acetylated polyamine or other polyamines were useful biochemical markers for colon cancer in this experimental model, rats were given s.c. injections of DMH (20 mg/kg body weight/week) or diluent for 26 weeks. One week after the last injection, control and DMH-treated animals were placed in separate metabolic cages and their urine was collected for 24 h. The urinary levels (expressed as nmol/mg creatinine) of putrescine, spermidine, spermine, N1-acetylspermidine, and N8-acetylspermidine were then analyzed by high-performance liquid chromatography. Animals from each group were then sacrificed and their colons were examined for tumors. The results of these studies demonstrated that the urinary level of N1-acetylspermidine was an excellent biochemical marker for colonic tumors induced by DMH. At 18.3 nmol/mg creatinine, N1-acetylspermidine was 100% sensitive and specific for colon cancer. Moreover, urinary levels of N1-acetylspermidine were better for this purpose than the N1-acetylspermidine/N8-acetylspermidine molar ratio, a marker previously suggested to be more specific for certain cancers than free polyamines.
The risk of colon cancer in patients with ulcerative colitis is related to the duration and extent of disease. Prior reports have suggested that patients with onset of disease in childhood have a high risk of cancer. These risk factors were analyzed in 99 patients in a surveillance program of annual colonoscopy to detect mucosal dysplasia. All patients had pancolitis for at least eight years. The mean age at symptom onset was 23.2 years and the mean duration of disease at entry was 17 years. An average of 4.2 tests/patient were performed, and 91% were completely followed through 1985. Cancer risk was expressed as the hazard rate or the annual probability that a patient free of cancer would develop cancer after survival to a given time period. The hazard rate for high-grade dysplasia or cancer in patients with pancolitis measured from symptom onset was 2.5% at 20 years, 4% at 25 years, 7% at 30 years, 13% at 35 years, and 20% at 40 years. Sex was not a significant predictor of cancer, but older age at symptom onset was a predictor of dysplasia and cancer. From these data, the annual hazard rate of developing high-grade dysplasia or cancer can be estimated in patients with pancolitis based on an individual's age at symptom onset and duration of disease.
To examine the effect of preoperative total parenteral nutrition (TPN) on patients with Crohn's disease undergoing bowel resection, an historical cohort was assembled of 103 patients resected between 1982 and 1984 by a single surgical team. Preoperative, perioperative, and postoperative variables were compared between patients receiving TPN and patients not receiving TPN. Analysis was stratified for three surgical procedures: segmental small bowel resection, ileocectomy, and segmental or total colectomy The effect of TPN was most pronounced in patients having small bowel surgery. For segmental small bowel resection, 12 of 17 patients had TPN, and these patients had 20.4 +/- 14.3 cm less bowel resected than did those in the non-TPN group, an effect not dependent on duration of TPN. For ileocectomy patients, 31 of 62 patients received TPN, and these patients had 11.2 +/- 4.2 cm less small bowel resected than the non-TPN group, an effect not dependent on the duration of TPN. For large bowel resection patients, 6 of 24 patients had TPN, and there was no difference in length of bowel resection, preoperative and perioperative variables, or recurrence. The total hospital stay was 13.5 +/- 2.6 days longer for those having TPN; 3.5 +/- 1.9 days of the longer stay was postoperative. In conclusion, TPN was associated with reduced length of small bowel resection at the expense of longer hospital stay.
Folate deficiency has been associated with dysplasia in human cancer models. Patients with ulcerative colitis commonly have decreased folate levels, which are partially due to sulfasalazine, a competitive inhibitor of folate absorption. To study the effect of folate supplementation on the risk of dysplasia or cancer (neoplasia) in ulcerative colitis, records from 99 patients with pancolitis for greater than 7 yr and enrolled in a surveillance program were reviewed. Thirty-five patients with neoplasia were compared with 64 patients in whom dysplasia was never found to determine the effect of folate supplementation on the rate of development of neoplasia using case-control methodology. At the time of the index colonoscopy, patients with neoplasia were older (43 +/- 11 vs. 39 +/- 12 yr) and had disease of longer duration (20 +/- 8 vs. 15 +/- 7 yr, p less than 0.05). Folate supplementation was associated with a 62% lower incidence of neoplasia compared with individuals not receiving supplementation (odds ratio, 0.38; 95% confidence interval, 0.12-1.20). There was no appreciable change in this effect when models were fit to adjust for sulfasalazine dose, duration of disease, age at symptom onset, prednisone dose, sulfa allergy, sex, race, or family history of colon cancer. The statistical power of the association between folate supplementation and neoplasia was 72%. Correction of risk factors before the development of neoplasia may prevent this serious complication. Pending a larger case-control study, folate supplementation during sulfasalazine administration is recommended to possibly prevent the complication of dysplasia or cancer in ulcerative colitis.