Regulation of TRAIL receptor expression by ß-catenin in colorectal tumours.

Tumour-necrosis-factor-related apoptosis-inducing ligand (TRAIL) is being investigated as a targeted cancer therapeutic and the expression of its pro-apoptotic receptors, DR4 and DR5, increases during colorectal carcinogenesis. This study investigated the role of ß-catenin in the regulation of these receptors. In human colorectal adenoma and carcinoma cell lines, downregulation of ß-catenin resulted in lower total DR4 and DR5 protein levels. Similarly, cell membrane expression of DR4 and DR5 was reduced after downregulation of ß-catenin in colon carcinoma cells, whereas induction of ß-catenin in HeLa cells led to increased cell membrane expression of DR4 and DR5. Downregulation of ß-catenin decreased the recombinant human TRAIL sensitivity of human colon carcinoma cells. Activation of the transcription factor T-cell factor-4 (TCF-4) is an important function of ß-catenin. Dominant-negative TCF-4 overexpression, however, did not significantly affect TRAIL receptor expression or recombinant human TRAIL sensitivity. Human colorectal adenomas (N = 158) with aberrant (cytoplasmic and nuclear) ß-catenin expression had a higher percentage of immunohistochemical DR4 and DR5 staining per tumour (mean: 73 and 88%, respectively) than those with membranous ß-catenin staining only (mean: 50 and 70%, respectively, P < 0.01 for both). Furthermore, aberrant ß-catenin staining co-localized with DR4 and DR5 expression in 92% of adenomas. In 53 human colorectal carcinomas, aberrant ß-catenin expression was present in most cases and DR4/5 expression was largely homogenous. Similarly, in adenomas from APC(min) mice, cytoplasmic ß-catenin staining co-localized with staining for the murine TRAIL death receptor. In conclusion, the gradual increase in TRAIL receptor expression during colorectal carcinogenesis is at least partially mediated through increased ß-catenin expression, independently of TCF-4-signalling.

Quality colonoscopy and risk of interval cancer in Lynch syndrome.

PURPOSE: Despite colonoscopic surveillance, Lynch syndrome patients develop colorectal cancer (CRC). Identification of modifiable factors has the potential to improve outcome of surveillance. The aims of this study were to determine (1) characteristics of patients with CRC, (2) endoscopic and histological features of these cancers, and (3) quality of the previous colonoscopy. METHODS: Approximately 2,200 medical reports from proven and obligate mutation carriers identified at the Dutch Lynch Syndrome Registry and two large hospitals were retrospectively analyzed for the presence of an interval cancer defined as CRC diagnosed within 24 months of previous colonoscopy. RESULTS: Thirty-one interval cancers were detected in 29 patients (median age of 52 [range 35-73]), after a median time of 17 months. All were MLH1 or MSH2 mutation carriers, and 39 % had a previous CRC. In patients without previous surgery for CRC, 84 % was proximally located. Of all interval cancers, 77 % were at local stage (T1-3N0Mx). In three patients (9 %) with an incomplete previous colonoscopy, CRC was located in the unexamined colon. In six of the nine patients with an adenoma during previous colonoscopy, the cancer was detected in the same colonic segment as the previously removed adenoma. CONCLUSIONS: Interval cancers were detected in MLH1 and MSH2 mutation carriers, especially in those with a history of previous CRC and between 40 and 60 years. Interval cancer could be related to incompleteness of previous endoscopy and possibly residual adenomatous tissue. Further reduction of the interval cancer risk may be achieved by optimizing endoscopy quality and individualization of surveillance guidelines.

A role for MLH3 in hereditary nonpolyposis colorectal cancer.

We investigated a possible role of the mismatch-repair gene MLH3 in hereditary nonpolyposis colorectal cancer by scanning for mutations in 39 HNPCC families and in 288 patients suspected of having HNPCC. We identified ten different germline MLH3 variants, one frameshift and nine missense mutations, in 12 patients suspected of HNPCC. Three of the 12 also carried a mutation in MSH6.

High detection rate of adenomas in familial colorectal cancer.

BACKGROUND AND AIMS: Subjects with one first-degree relative (FDR) with colorectal cancer (CRC) <50 years old or two FDRs with CRC have an increased risk for CRC (RR 4-6). Current guidelines recommend colonoscopic surveillance of such families. However, information about the yield of surveillance is limited. The aim of the present study was to evaluate the outcome of surveillance and to identify risk factors for the development of adenomas. PATIENTS AND METHODS: Subjects were included if they fulfilled the following criteria: asymptomatic subjects aged between 45 and 65 years, with one FDR with CRC <50 years old (group A) or two FDRs with CRC diagnosed at any age (group B). Subjects with a personal history of inflammatory bowel disease or colorectal surgery were excluded. RESULTS: A total of 551 subjects (242 male) met the selection criteria. Ninety-five subjects with a previous colonoscopy were excluded. Two of 456 remaining subjects (0.4%) were found to have a colorectal tumour (one CRC and one carcinoid). Adenomas were detected in 85 (18.6%) and adenomas with advanced pathology in 37 subjects (8.1%). 30 subjects (6.6%) had multiple (>1) adenomas. Men were more often found to have an adenoma than women (24% vs 14.3%; p=0.01). Adenomas were more frequent in group B compared with group A (22.0% vs 15.6%; p=0.09). CONCLUSION: The yield of colonoscopic surveillance in familial CRC is substantially higher than the yield of screening reported for the general population.

Evaluation of management of desmoid tumours associated with familial adenomatous polyposis in Dutch patients.

BACKGROUND: The optimal treatment of desmoid tumours is controversial. We evaluated desmoid management in Dutch familial adenomatous polyposis (FAP) patients. METHODS: Seventy-eight FAP patients with desmoids were identified from the Dutch Polyposis Registry. Data on desmoid morphology, management, and outcome were analysed retrospectively. Progression-free survival (PFS) rates and final outcome were compared for surgical vs non-surgical treatment, for intra-abdominal and extra-abdominal desmoids separately. Also, pharmacological treatment was evaluated for all desmoids. RESULTS: Median follow-up was 8 years. For intra-abdominal desmoids (n=62), PFS rates at 10 years of follow-up were comparable after surgical and non-surgical treatment (33% and 49%, respectively, P=0.163). None of these desmoids could be removed entirely. Eventually, one fifth died from desmoid disease. Most extra-abdominal and abdominal wall desmoids were treated surgically with a PFS rate of 63% and no deaths from desmoid disease. Comparison between NSAID and anti-estrogen treatment showed comparable outcomes. Four of the 10 patients who received chemotherapy had stabilisation of tumour growth, all after doxorubicin combination therapy. CONCLUSION: For intra-abdominal desmoids, a conservative approach and surgery showed comparable outcomes. For extra-abdominal and abdominal wall desmoids, surgery seemed appropriate. Different pharmacological therapies showed comparable outcomes. If chemotherapy was given for progressively growing intra-abdominal desmoids, most favourable outcomes occurred after combinations including doxorubicin.

Microscopic colitis: an unfamiliar but treatable disease.

Chronic diarrhoea is a frequent complaint in clinical practice. Microscopic colitis is the cause of this symptom in 10% of these cases and the prevalence is rising. To exclude microscopic colitis a colonoscopy with multiple biopsies of different regions of the colon is mandatory. A sigmoidoscopy alone is insufficient. Two histopathological types of microscopic colitis can be distinguished: collagenous colitis and lymphocytic colitis. Nowadays, there is sufficient evidence to recommend budesonide as the first-choice treatment. Bismuth can also be recommended, but this drug is not easily available in the Netherlands. Evidence of efficacy of other drugs is scant.

Symptom experience associated with immunosuppressive drugs after liver transplantation in adults: possible relationship with medication non-compliance?

Symptom experience (occurrence and perceived distress) associated with side effects of immunosuppressive medications in organ transplant patients may well be associated with poorer quality of life and medication non-compliance. The aims of this study were: first, to assess symptom experience in clinically stable adult patients during long-term follow-up after liver transplantation; and second, to study the relationship between symptom experience and medication non-compliance. This cross-sectional study included 123 liver transplant patients. Symptom experience was assessed using the "Modified Transplant Symptom Occurrence and Symptom Distress Scale" (29-item version) at the annual evaluation. According to the duration of follow-up, patients were divided into a short-term (1-4 yr) and a long-term (5-18 yr) cohort. Medication non-compliance was measured using electronic monitoring. Results showed that increased hair growth was the most frequent symptom in both sexes. Symptom distress was more serious in women than in men. The most distressing symptom in women was excessive and/or painful periods, while in men this was impotence. Clear differences were revealed at item level between symptom occurrence and symptom distress in relationship with the two time cohorts and between sexes. No relationship was found between symptom experience and prednisolone non-compliance.

Role of endogenous secretin in acid-induced inhibition of human gastric function.

The role of secretin in the inhibition of gastric acid secretion that occurs during acidification of the gastric lumen was studied in nine healthy men. Gastric acid secretion was stimulated by 500-ml meals of 8% peptone solution, and the pH of the stomach was maintained at 5.5, 2.5, or 2.0 by intragastric titration. The increase in plasma secretin was measured, after extraction, by a new secretin radioimmunoassay. After determining the intravenous dose of secretin required to reproduce plasma secretin concentrations achieved during pH 2.5 and 2.0 meals, similar doses were given during administration of a pH 5.5 peptone meal. The doses of secretin led to plasma secretin concentrations that averaged 3.4 pM, not different from the 3.2 and 3.9 pM concentrations achieved during acidified meals. However, exogenous secretin infusion failed to inhibit acid secretion or gastrin response to peptone, although significant inhibitions occurred in both during peptone meals given at pH 2.5 or 2.0. When secretin infusions were given at fivefold higher rates, plasma gastrin responses again failed to demonstrate significant inhibition. Gastric emptying was inhibited significantly by both acidified peptone meals but only slightly (P = 0.053) during exogenous infusion of physiologic secretin doses. The decrease in acid secretion could be explained by decreased gastrin release, but neither of these findings could be explained by circulating secretin concentrations. These results cast strong doubt on a physiological role of secretin in inhibition of acid secretion in man.

Effects of different immunosuppressive regimens on regulatory T-cells in noninflamed colon of liver transplant recipients.

BACKGROUND: Regulatory T-cells (Treg) are natural suppressors of autoimmunity. Previous studies indicate that immunosuppressive drugs, especially calcineurin-inhibitors, may interfere with Treg homeostasis. Inflammatory bowel disease (IBD) can relapse or develop de novo after liver transplantation. IBD is associated with a relative deficiency of Treg. The aim of this study was to determine the effect of long-term immunosuppression on the presence of Treg in the noninflamed colonic mucosa of liver transplant recipients. METHODS: Colonic biopsies of normal mucosa of 36 liver transplant recipients on different types of immunosuppression and 11 controls were studied. Treg marker Foxp3 and Treg products transforming growth factor-beta (TGF-beta) and interleukin-10 (IL-10) were studied by quantitative polymerase chain reaction (Q-PCR) and immunohistochemistry. TGF-beta-induced Smad-protein 3 and 7 were studied by Q-PCR. RESULTS: No significant differences between controls and patients were observed in IL-10, TGF-beta, and Smad expression. Mucosal Foxp3 mRNA levels and Foxp3+CD3+ cells were significantly reduced in transplant recipients using prednisone/azathioprine/tacrolimus compared with controls but no direct relationship between Foxp3 expression and 1 specific drug was detected. CONCLUSIONS: These results challenge the hypothesis that calcineurin-induced reduction of Treg or TGF-beta expression predisposes nontransplanted tissue to inflammation, but indicate that combined immunosuppression hampers Treg development in the intestine.

Independent induction of caspase-8 and cFLIP expression during colorectal carcinogenesis in sporadic and HNPCC adenomas and carcinomas.

BACKGROUND: TNF-Related Apoptosis Inducing Ligand (TRAIL) is a promising agent for the induction of apoptosis in neoplastic tissues. Important determinants of TRAIL sensitivity are two intracellular proteins of the TRAIL pathway, caspase-8 and its anti-apoptotic competitor cellular Flice-Like Inhibitory Protein (cFLIP). METHODS: The aim of this study was to investigate basic expression of caspase-8 and cFLIP in normal colorectal epithelium (n=20), colorectal adenomas (n=66) and colorectal carcinomas (n=44) using immunohistochemistry performed on both sporadic and Hereditary Non-Polyposis Colorectal Cancer (HNPCC or Lynch syndrome)-associated adenomas and carcinomas. RESULTS: Expression of both caspase-8 and cFLIP was similar in cases with sporadic and hereditary origin. Expression of caspase-8 in colorectal adenomas and carcinomas was increased when compared to normal colon tissue (P=0.02). Nuclear, paranuclear as well as cytoplasmic localizations of caspase-8 were detected. Immunohistochemistry revealed an upregulation of cFLIP in colorectal carcinomas in comparison to normal epithelium and colorectal adenomas (P<0.001). A large variation in the caspase-8/cFLIP ratio was observed between the individual adenomas and carcinomas. CONCLUSION: Caspase-8 and cFLIP are upregulated during colorectal carcinogenesis. Upregulation of caspase-8 and/or downregulation of cFLIP may be interesting approaches to maximize TRAIL sensitivity in colorectal neoplasms.

What is the appropriate screening protocol in Lynch syndrome?

INTRODUCTION: Lynch syndrome families have a substantial risk of developing colorectal cancer (CRC). The recommended surveillance protocol includes colonoscopy every 2 years from age 20-25 years. It is yet unknown whether annual screening of patients aged 40-60 years is more effective than bi-annual screening, whether patients who had an adenoma removed should be re-examined after a year and whether surveillance of second-degree relatives is indicated. The aim of this study was to address these issues. METHODS: All carriers of a mismatch repair gene mutation who participated in the surveillance program were selected from the Dutch Lynch syndrome registry. The results of colonoscopy were prospectively collected. RESULTS: A total of 666 mutation carriers were identified in 110 families. Fourty-one CRCs were detected during endoscopic follow-up, of which 34 (83%) were diagnosed between age 40 and 60 years. In five of 34 patients, CRC was diagnosed within 1 year after colonoscopy, eight cancers were diagnosed between 1 and 2 years and the remaining tumors more than 2 years after colonoscopy. All eight CRCs detected between 1 and 2 years were at local stage. At least one adenoma was diagnosed at 141 examinations. The risk of developing CRC during follow-up in carriers with an adenoma was similar as in carriers without an adenoma at the previous colonoscopy. 280 parent-child couples with at least one Lynch syndrome-related carcinoma were identified in 110 families. In only 19 (6.8%) of these couples, CRC developed earlier in the child than an Lynch syndrome-associated cancer in the parent. CONCLUSION: The current surveillance protocol, i.e., bi-annual colonoscopy in first-degree relatives independent of age and endoscopic findings, appears to be appropriate.

Increased risk of fundic gland polyps during long-term proton pump inhibitor therapy.

BACKGROUND: It is controversial whether proton pump inhibitor use leads to fundic gland polyp development. AIM: To determine whether fundic gland polyp development is due to proton pump inhibitor use and to investigate mechanisms involved. METHODS: Proton pump inhibitor use and the presence of fundic gland polyps were assessed in consecutive patients undergoing oesophagogastroduodenoscopy. Biopsies from fundic gland polyps and gastric mucosa were taken. Dysplasia was graded as negative, low or high grade. Prevalence of parietal cell hyperplasia and parietal cell protrusions and the proportional cystic area were assessed. RESULTS: 599 patients participated, 322 used proton pump inhibitors, 107 had fundic gland polyps. Long-term proton pump inhibitor use was associated with an increased risk of fundic gland polyps (1-4.9 years use: OR 2.2, 95% CI: 1.3-3.8; > or =5 years: OR 3.8, 95% CI: 2.2-6.7) while short-term therapy (<1 year) was not (OR 1.0, 95% CI: 0.5-1.8). Low-grade dysplasia was found in one fundic gland polyp. Fundic gland polyps associated with long-term proton pump inhibitor use had a larger proportional cystic area and higher frequency of parietal cell hyperplasia and parietal cell protrusion. CONCLUSIONS: Long-term proton pump inhibitor use is associated with an up to fourfold increase in the risk of fundic gland polyps. Risk of dysplasia is negligible. Aetiologically, these polyps seem to arise because of parietal cell hyperplasia and parietal cell protrusions resulting from acid suppression.

CARD15 in inflammatory bowel disease and Crohn's disease phenotypes: an association study and pooled analysis.

BACKGROUND: Three major polymorphisms of the Caspase-Activation Recruitment Domain containing protein 15 gene have been described to be associated with Crohn's disease. Genotype-phenotype studies reported in literature provide conflicting data on disease localisation and behaviour. We investigated the relation of Caspase-Activation Recruitment Domain containing protein 15 with inflammatory bowel disease and Crohn's disease phenotypic characteristics in a large Dutch cohort and performed a pooled analysis on inflammatory bowel disease patients and Crohn's disease phenotypic characteristics reported in association studies. METHODS: We genotyped 781 cases and 315 controls for the R702W, G908R and 1007fsinsC variants and for six microsatellite markers in and close to Caspase-Activation Recruitment Domain containing protein 15. In the pooled analysis data of 7201 inflammatory bowel disease patients and 3720 controls from 20 studies were included. RESULTS: Association was found for Crohn's disease with R702W and 1007fsinsC, including several disease characteristics, and not for ulcerative colitis. In the pooled analysis all three common Caspase-Activation Recruitment Domain containing protein 15 variants showed strong association with Crohn's disease (p<0.00001; odds ratio varying from 3.0 for single heterozygotes to 14.7 for compound heterozygotes) and not with ulcerative colitis. Phenotype analysis showed association with small bowel involvement, stricturing and penetrating disease. CONCLUSION: Caspase-Activation Recruitment Domain containing protein 15 is associated with Crohn's disease and not with ulcerative colitis. All three common Crohn's disease-associated variants are associated with small bowel involvement, the G908R and 1007fsinsC alleles also being associated with a complicated disease course.

Randomized, double-blinded, placebo-controlled intervention study with supplemental calcium in families with hereditary nonpolyposis colorectal cancer.

BACKGROUND: A high-fat diet has been recognized for some time as a major risk factor for colorectal cancer. It is thought that fat promotes this disease by increasing the levels of fatty and bile acids within the colon. These acids irritate and damage the epithelial cells of the colon. As a result of this cellular destruction, an increase in the rate of cellular proliferation occurs. Oral calcium supplementation has been proposed as a dietary intervention for individuals at high risk of colorectal cancer because of its ability to reduce rectal epithelial cell proliferation through the binding of fatty and bile acids. Placebo-controlled studies, however, have yielded varying results. PURPOSE: We conducted a randomized, double-blinded, placebo-controlled trial to test oral calcium supplementation in patients at high risk of developing hereditary nonpolyposis colorectal cancer. METHODS: Thirty subjects at risk for this cancer, with an increased epithelial cell proliferation along the colon and rectum, were randomly assigned to either a placebo group (n = 15) or a treatment group (n = 15). They received either oral calcium carbonate (CaCO3) supplements (1.5 g) or placebo (cellulose and starch) three times a day during a 12-week period. Colonic biopsy specimens (rectal, sigmoidal, and descending) were obtained prior to and after the intervention trial, during endoscopy, for determination of labeling index (LI) of whole crypts and crypt compartments by 5-bromo-2'-deoxyuridine incorporation and immunohistochemistry. Proportional bile acid compositions in duodenal bile and cytolytic activity of fecal water were also determined. All P values represent two-tailed tests of statistical significance. RESULTS: Statistically significant reductions, comparing before with after intervention, in rectal whole-crypt LI after receiving either calcium supplements (from 10.9% +/- 5.2% [mean +/- SD] to 6.2% +/- 1.5%; P < .02) or placebo (from 11.7% +/- 4.7% to 8.2% +/- 3.1%; P < .05) were observed. In the three bowel segments, no statistically significant differences were observed between the supplemental calcium and placebo groups. A statistically significant reduction in cytolytic activity was determined during calcium supplementation (from 57% +/- 41% to 32% +/- 30%; P < .05), whereas in the placebo group, it did not change (from 42% +/- 41% to 36% +/- 27%; P > .10). CONCLUSIONS: Oral calcium supplementation was shown to cause only a minor nonstatistically significant reduction of epithelial cell proliferation in the rectum, compared with placebo, and to have no effect on the same parameter in the sigmoid and descending colon in first-degree relatives of hereditary nonpolyposis colorectal cancer patients. IMPLICATION: These results cast doubt on the value of calcium supplementation in the prevention of colorectal cancer, especially in individuals already consuming an adequate amount of dietary calcium.

[Screening the population for colorectal cancer: the background to a number of pilot studies in the Netherlands]. / Bevolkingsonderzoek op colorectaal carcinoom: achtergronden bij pilotstudies in Nederland.

Colorectal cancer is one of the most common cancers in the Netherlands, where it is now the second most commonly-occurring cancer in terms of both incidence (10,000 new cases each year) and mortality rate (4,400 each year). - In 40% of all cases the disease is diagnosed at a late stage, which is associated with a poor outcome. - Research has shown that screening of the general population for colorectal cancer by means of the faecal occult blood test (FOBT) results in a reduction in mortality of approximately 16%. Whether endoscopic screening will result in a greater reduction in the mortality rate is currently under investigation. - This year, the first pilot study on implementation of screening for colorectal cancer using two different types of FOBT will start in the Netherlands.

[Endoluminal treatment of gastro-oesophageal reflux disease: too early to determine a clear role]. / Endoscopische behandeling van gastro-oesofageale refluxziekte: nog te vroeg voor een duidelijke plaatsbepaling.

Gastro-oesophageal reflux disease is a chronic disorder. The most important therapeutic measure is long-term pharmacological acid inhibition. Anti-reflux surgery plays a role in cases where pharmacological treatment fails. A new development is endoluminal treatment for reflux disorders. The various methods used are based on one of the following principles: radiofrequency ablation, gastroplication and implantation of a bulking agent. Short-term results with endoluminal treatment are not very positive and longer-term results have been disappointing so far. Results from randomised studies are still largely unavailable. Longer follow-up and controlled randomised studies are needed before a well-founded judgment can be made regarding the place of endoluminal treatment in the therapeutic armamentarium.

[Treatment of servere ulcerative colitis]. / De behandeling van ernstige colitis ulcerosa.

10-15% of patients with ulcerative colitis experience a severe episode of colonic inflammation that does not respond to mesalazine and oral corticosteroids. These patients require hospitalisation and treatment with intravenous corticosteroids. However, 25% of these patients do not respond to treatment. In these cases, intravenous cyclosporin is effective. Infliximab, an antibody against tumour necrosis factor alpha, is also beneficial. With these new treatment options, the colectomy rate in the acute phase has declined to about 35%. Other new therapies are under investigation in phase 2 and 3 trials. Surgery remains an important treatment option. Patients, gastroenterologists and surgeons should be involved in the clinical decision-making process.

Red meat and colon cancer: the cytotoxic and hyperproliferative effects of dietary heme.

The intake of a Western diet with a high amount of red meat is associated with a high risk for colon cancer. We hypothesize that heme, the iron carrier of red meat, is involved in diet-induced colonic epithelial damage, resulting in increased epithelial proliferation. Rats were fed purified control diets, or purified diets supplemented with 1.3 micromol/g of hemin (ferriheme), protoporphyrin IX, ferric citrate, or bilirubin (n = 8/group) for 14 days. Feces were collected for biochemical analyses. Fecal cytotoxicity was determined from the degree of lysis of erythrocytes by fecal water. Colonic epithelial proliferation was measured in vivo using [3H]thymidine incorporation into colonic mucosa. The colonic epithelial proliferation in heme-fed rats was significantly increased compared to control rats [55.2 +/- 5.8 versus 32.6 +/- 6.3 dpm/microg DNA (mean +/- SE); P < 0.05]. The fecal water of the heme group was highly cytotoxic compared to the controls (90 +/- 2% versus 2 +/- 1%; P < 0.001), although the concentrations of cytotoxic bile acids and fatty acids were significantly lower. Organic iron was significantly increased compared to the controls (257 +/- 26 versus 80 +/- 21, microM; P < 0.001). Spectrophotometric analyses suggest that this organic iron is heme-associated. Thiobarbituric acid-reactive substances were greatly increased in the fecal water of heme-fed rats compared to the controls (177 +/- 12 versus 59 +/- 7 microM; P < 0.05). Heme itself could not account for the increased cytotoxicity because the addition of heme to the fecal water of the control group, which was equimolar to the organic iron content of the fecal water of the heme group, did not influence the cytotoxicity. Hence, an additional heme-induced cytotoxic factor is involved, which may be modulated by the generation of luminal-reactive oxygen species. Protoporphyrin IX, ferric citrate, and bilirubin did not increase proliferation and cytotoxicity. In conclusion, dietary heme leads to the formation of an unknown, highly cytotoxic factor in the colonic lumen. This suggests that, in heme-fed rats, colonic mucosa is damaged by the intestinal contents. This results in a compensatory hyperproliferation of the epithelium, which supposedly increases the risk for colon cancer.

Mechanism of the protective effect of supplemental dietary calcium on cytolytic activity of fecal water.

Dietary calcium supplementation inhibits hyperproliferation of rectal epithelium, possibly by precipitating luminal surfactants and thus preventing their cell-damaging effects. Therefore, we studied the effects of supplemental dietary calcium (35.5 mmol/day) on composition and cytolytic activity of fecal water and on the release of the epithelial marker alkaline phosphatase in 12 healthy volunteers. Fecal water was isolated by low-speed centrifugation. Cytolytic activity was determined as lysis of human erythrocytes by fecal water. Intestinal alkaline phosphatase activity in fecal water was measured with the use of the uncompetitive inhibitor L-phenylalanine. Supplemental calcium increased soluble calcium and decreased soluble P(i). The logarithm of the concentration product of calcium and phosphate was linearly dependent on pH. These observations indicate formation of insoluble calcium phosphate. Supplemental calcium did not alter the total bile acid concentration in fecal water but significantly decreased the ratio of more hydrophobic to more hydrophilic bile acids from 3.3 to 2.3. Calcium also significantly decreased the concentration of fatty acids (from 2.9 to 2.1 mM). Consistent with these decreases in hydrophobic surfactants, calcium decreased the cytolytic activity of fecal water from 47 +/- 9 to 27 +/- 8% (n = 12, P < 0.05). Analogous to the decrease in cytolytic activity, the release of the epithelial marker alkaline phosphatase was also lowered by supplemental calcium. We conclude that supplemental dietary calcium decreases luminal cytotoxic surfactant concentrations and thus inhibits luminal cytolytic activity and the release of the epithelial marker alkaline phosphatase as an indicator of intestinal epitheliolysis. This mechanism may explain how dietary calcium could decrease epithelial cell proliferation.

Changes in rectal epithelial cell proliferation and intestinal bile acids after subtotal colectomy in familial adenomatous polyposis.

Subtotal colectomy and ileorectal anastomosis in familial adenomatous polyposis patients can induce temporary regression of adenomas in the rectum. The mechanism for this phenomenon is unclear. We evaluated the effect of colectomy on rectal mucosal proliferation, in relation to changes in bile acid metabolism. Four familial adenomatous polyposis patients were studied before and 3-6 months after surgery, and eight others 7-22 years postoperatively. Within 6 months after surgery, the size of the proliferative zone of the colonic crypts was found to be reduced (P less than 0.05). The proliferative activity of total colonic crypts was not affected within this period. More than 7 years postoperatively, increased cell proliferation of total crypts (P less than 0.02), as well as mid (P less than 0.05) and basal (P less than 0.05) crypt compartments, were observed compared to shortly after colectomy. In duodenal bile, deoxycholic acid was absent shortly after operation, whereas several years after operation only a small fraction (2%) was present. Fecal secondary bile acid excretion diminished after colectomy and did not change several years postoperatively. In postoperative stools only, small proportions of ursocholic and ursodeoxycholic acids (about 5% each) were consistently found. As subtotal colectomy causes a temporary decrease in the length of the proliferative zone of rectal crypts toward a normal pattern, this may explain regression of rectal polyps. This temporary effect may be mediated, at least in part, by decreased amounts of cytotoxic secondary bile acids in the rectal lumen.