Upper gastrointestinal disease in patients with familial adenomatous polyposis

BACKGROUND: Upper gastrointestinal disease has become an important aspect in the management of patients with familial adenomatous polyposis (FAP). METHODS: A review of the literature was carried out using Medline. Epidemiology, pathology and treatment options are considered. RESULTS AND CONCLUSION: Despite the fact that over 90 per cent of patients with FAP develop duodenal adenomas, only 5 per cent go on to develop cancer. In the absence of methods to detect who is at risk of cancer, all patients undergo regular endoscopic surveillance at present. Chemoprevention in the form of drug therapy may be the answer to controlling the disease.     

NSAID-induced polyp regression in familial adenomatous polyposis patients

NSAIDs inhibit prostaglandin synthesis. In 1983, Waddell et al first reported that sulindac, a NSAID (Clinoril), caused regression of rectal adenomatous polyps in several patients with familial adenomatous polyposis, an inherited form of colorectal cancer. Subsequently, NSAIDs have been used as chemopreventive agents in animal carcinogenesis models and adenoma regression had been confirmed in human trials with sulindac. This article summarizes these developments and describes possible mechanisms of colorectal neoplasia chemoprevention.     

Effect of indomethacin suppositories on rectal polyposis in patients with familial adenomatous polyposis

BACKGROUND: Oral sulindac is known to reduce polyps in patients with familial adenomatous polyposis (FAP). The authors speculated that rectal administration of indomethacin would be effective therapy for adenomas in the rectal remnant of FAP. METHODS: Eight patients with FAP who had been treated by total colectomy with ileorectal anastomosis were administered an indomethacin suppository (50 mg) once or twice daily during a period of 4 or 8 weeks. The number of polyps at the same site within the rectum was counted under proctoscopy prior to, at the end of, and after the treatment. In four patients, proliferative activity of the rectal mucosa was assessed by immunohistochemical staining for MIB-1. RESULTS: In six of the eight patients who initially had ten or more polyps, the number of polyps decreased to fewer than five, whereas such a decrease could not be observed in the remaining two patients. In the six patients, the number of polyps increased after indomethacin was discontinued. The proliferative activity of the rectal mucosa was higher at the end of treatment than it was prior to indomethacin administration. CONCLUSIONS: Indomethacin suppositories may be effective in the management of rectal adenomatosis in patients with FAP.     

Tissue prostaglandin levels in familial adenomatous polyposis patients treated with sulindac

BACKGROUND: Recent work has demonstrated a correlation between frequency of aspirin ingestion and colorectal cancer prevention. Sulindac, another nonsteroidal anti-inflammatory drug (NSAID), has been shown to cause polyp regression and a fall in cell proliferation in patients with familial adenomatous polyposis, who are destined to develop colorectal cancer unless the colon is removed. However, the mode of action of NSAIDs in colorectal carcinogenesis prevention remains to be determined, although a prostaglandin-mediated mechanism seems likely. METHODS: Rectal or duodenal biopsies from 20 patients with familial adenomatous polyposis, who had been randomized to sulindac or placebo, were analyzed for prostaglandin (PG) E2 and F2 alpha levels before and after treatment. RESULTS: A significant fall in prostaglandin E2 and F2 alpha levels was seen in patients who were on sulindac; this correlated with a visual improvement in number and size of polyps in the same patients (P = 0.0096; PGE2, P = 0.036; PGF2 alpha, Spearman's rank correlation). CONCLUSIONS: Nonsteroidal anti-inflammatory drugs may prevent colorectal cancer by their inhibition of prostaglandin synthesis. Prostaglandins may be implicated in carcinogenesis through an increase in cell proliferation, through immunosuppression, by increasing neovascularization, or via a mutagenic effect.     

Ocular findings in familial adenomatous polyposis

This article describes a systematic approach to understanding the needs of the terminally ill who are also subject to serious mental health problems. A compilation of potential issues that could arise is provided along with specific techniques that could be useful to staff and volunteers who encounter them. Vignettes from clinical experience are used to provide a framework for understanding the unique aspects of cognitively impaired patients and for enhancing confidence in helpers. This article will give serious consideration to dispelling some misconceptions and to detailing resources for helpful interventions in difficult cases.     

Desmoid tumours in familial adenomatous polyposis

Desmoids are rare, benign fibromatous lesions, which can arise in patients with familial adenomatous polyposis (FAP), a disorder caused by germline adenomatous polyposis coli (APC) gene mutation. This study investigated the risk of desmoids in FAP, the relation between specific APC gene mutations and desmoid formation, and the clinical characteristics of FAP patients with desmoids. Eighty three of 825 FAP patients (10%) from 49 of 161 kindreds (30%) had desmoids. The absolute risk of desmoids in FAP patients was 2.56/1000 person years; comparative risk was 852 times the general population. APC gene mutations were similar in families with and without desmoids. The female/male ratio was 1.4 (p = NS). Previous abdominal surgery was noted in 68% of patients with abdominal desmoids (55% developed within five years postoperatively). Desmoid risk in FAP family members of a desmoid patient was 25% in first degree relatives v 8% in third degree relatives. Desmoids are a comparatively common complication of FAP associated with surgical trauma and familial aggregation. Desmoid development was not linked to specific APC gene mutations and was not found predominantly in women. Studies of chemopreventive therapy, given within five years after abdominal surgery, should be considered in FAP patients with a family history of desmoid disease.     

Management of advanced duodenal polyposis in familial adenomatous polyposis

Farmers are exposed to high levels of organic dust with a high content of bacteria, fungi and endotoxins. The main exposure takes place during the many hours of work in closed animal confinement buildings, and working in swine confinement buildings gives the highest exposure. Corresponding to this, farmers have a high prevalence of respiratory symptoms and cross-sectional studies show evidence of airways obstruction. Swine farming seems to be an important risk factor for this in the farming community. Allergy plays a minor role in the development of symptoms, the most important allergy being towards storage mites. Longitudinal studies suggest that exposure to high concentrations of organic dust is associated with an accelerated decline in forced expiratory volume in one second.     

APC intragenic haplotypes in familial adenomatous polyposis

Genetic epidemiological studies are useful for the knowledge of the association of markers and genes involved in diseases. In the present work, we studied the frequency of four adenomatous polyposis coli intragenic RFLP markers often used in risk evaluation in a population of 10 familial adenomatous polyposis patients from 10 unrelated Portuguese familial adenomatous polyposis families not sharing the same mutation, and in a population of 55 unrelated healthy Portuguese volunteers. We compared the frequency obtained to normal and affected populations and to results already reported in other populations. We observed allelic frequencies for the Portuguese population that agree with the published ones. The intragenic polymorphisms show strong gametic disequilibrium suggesting little recombination between them. We observed haplotype frequencies significantly different in patients and controls. The gametic disequilibrium may be due to a common founder for a proportion of apparently unrelated probands.     

Type I choledochal cyst in association with familial adenomatous polyposis

Choledochal cysts and familial adenomatous polyposis are infrequent disorders that are often manifest in childhood or in early adult life. The rarity and early presentation of these diseases suggests a genetic basis, which has been established for familial polyposis but not for choledochal cysts. We report a case of a 26-yr-old woman with both disorders and offer an alternative genetics-based etiology for the formation of choledochal cysts.     

Ornithine decarboxylase and polyamines in familial adenomatous polyposis

The effects of concanavalin A (Con A) on liver cytokine gene expression was studied in mice. The CD4 mRNA expression in normal liver suggests the presence of CD4+ T cells. The administration of Con A induced interleukin (IL)-1beta, IL-2 and IL-2 receptor mRNAs, which implies lymphocyte activation in the liver. Interferon-gamma and tumor necrosis factor-alpha mRNA expressions were increased gradually. The present results showed that Con A induced liver cytokine genes. This cytokine gene induction might have been the result of lymphocyte activation in the liver.     

Diagnostic value of fundus examination in familial adenomatous polyposis

BACKGROUND: Multiple, bilateral lesions of congenital hypertrophy of the retinal pigment epithelium (CHRPE) have been described in patients suffering from familial adenomatous polyposis (FAP) since 1980. This study aimed to determine a reliable diagnostic criterion, based on the size and number of retinal CHRPE lesions, allowing the screening of patient carriers of the gene responsible for FAP. METHODS: 32 control subjects and 144 patients belonging to 85 FAP families were studied, divided into 124 carriers of the genetic alteration and 20 non-carriers. RESULTS: In carriers of the deleted gene, multiple, bilateral retinal lesions were consistently observed. Lesion situation, size, shape, and degree of pigmentation were variable however. A positive criterion for FAP was defined as the presence of at least four lesions whatever their size, or at least two lesions one of which is large. This criterion showed a high sensitivity (0.68) and a maximal specificity (1). Within each family, the retinal phenotypic expression was homogeneous. CHRPE lesions were observed in two thirds of the FAP families and absent from the remaining third. CONCLUSION: By using this new positive diagnostic criterion, fundus examination allows early detection of those children carrying the gene responsible for FAP in families positive at ocular examination.     

Non-penetrance and late appearance of polyps in families with familial adenomatous polyposis

One case of non-penetrance of the familial adenomatous polyposis (FAP) gene at 59 years of age and late onset of polyps on endoscopy and biopsy in this and two other families is described. Screening protocols should include dental screening as well as indirect ophthalmoscopy and endoscopy to detect minimal manifestations of the gene. In the absence of a specific DNA predictive test, bowel screening should continue well beyond 30 years of age.     

Increased stem cell somatic mutation in the non-neoplastic colorectal mucosa of patients with familial adenomatous polyposis

Colorectal tumorigenesis in familial adenomatous polyposis (FAP) results from somatic mutation of either the normal APC allele or another growth control gene in epithelial cells bearing a germline APC defect. The rate at which tumors develop is therefore dependent on the somatic mutation frequency; it is not known whether this is normal or elevated in FAP. We aimed to quantify stem cell somatic mutation in FAP, comparing it with hereditary nonpolyposis colorectal cancer (HNPCC) and Crohn's disease (CD). Stem cell somatic mutation frequency was studied in 47 FAP patients, 5 HNPCC patients, and 13 CD patients, all younger than 49 years, by quantifying crypt-restricted loss of O-acetyltransferase activity in sections of morphologically normal colonic mucosa from individuals heterozygous for this monogenically inherited polymorphism. Median stem cell somatic mutation frequency was significantly higher in FAP than HNPCC (4.2 x 10(-4) v 1.4 x 10(-4), Mann-Whitney U, P < .02). The level in CD (4.0 x 10(-4)) was similar to FAP. Mutated crypts occurred in groups more frequently in FAP (22%) than HNPCC (12%) or CD (10%), suggesting an increase in stem cell division associated with crypt fission in FAP. We conclude that stem cell somatic mutation frequency is raised in non-neoplastic colorectal mucosa in FAP. This is probably related to increased stem cell proliferation and contributes to the high rate of tumor formation in this condition.     

Oral calcium inhibits rectal epithelial proliferation in familial adenomatous polyposis

Calcium reduces colorectal cell turnover and might therefore protect against neoplasia. The inhibitory effects of dietary calcium were tested in a double-blind controlled trial in patients with familial adenomatous polyposis who had undergone previous abdominal colectomy and ileorectal anastomosis. Patients received supplemental calcium carbonate (1500 mg/day) or placebo tablets for 6 months; sigmoidoscopy was performed before and after treatment. Rectal biopsies were maintained in short-term organ culture, and crypt cell production rate (CCPR) was measured stathmokinetically. A total of 25 patients completed the trial; polyp counts were obtained before and after treatment in all and CCPR values in 16. Calcium treatment reduced the mean (s.e.m.) CCPR from 4.72 (0.48) to 2.42 (0.48) cells per crypt per h (P < 0.05), while values for placebo were unchanged (5.46 (1.21) versus 5.08 (1.17) cells per crypt per h). Calcium had no demonstrable effect on the number, size or distribution of rectal polyps. The ability of oral calcium supplementation to suppress rectal epithelial proliferation supports its potential to prevent development of colorectal carcinoma in high-risk individuals.     

Recommendations for the molecular diagnosis of familial adenomatous polyposis

OBJECTIVES: We investigated the relationships between gastric metaplasia occurring during the healing and scarring stages of duodenal ulcers and Helicobacter pylori by examining the course of gastric metaplasia in H. pylori-eradicated and non-eradicated patients. METHODS: One hundred and six H. pylori-positive patients with active duodenal ulcers were assigned to either a non-eradication group or an eradication group. The non-eradication group received lansoprazole for 6 wk, followed by an H2-receptor antagonist. The eradication group also received amoxicillin and metronidazole for 1 wk, in addition to lansoprazole, after initial endoscopic examination. In both groups, biopsy specimens were obtained from the ulcer margin in the active stage and from the center of the scar in the scarring stage. Specimens were examined microscopically as well as by rapid urease test to assess the extent of gastric metaplasia and to detect the presence of H. pylori. RESULTS: The extent of gastric metaplasia increased as the ulcers healed. The extent of gastric metaplasia was of a lesser degree in the non-eradication group than in the eradication group at the time of healing, and this tendency became increasingly apparent in the course of follow-up, resulting in reduced defense mechanisms against acidity to promote the recurrence of ulcers. In the eradication group, among those in whom eradication was successful, gastric metaplasia presented a well-developed appearance with abundant intracellular mucus and remained in this condition for a prolonged period, resulting in adequate defense mechanisms against acidity to prevent the recurrence of ulcers. CONCLUSION: By the eradication of H. pylori, gastric metaplasia becomes well-developed and remains so for a prolonged period. Thus, the eradication of H. pylori appears to play a role in the prevention of ulcer recurrences by developing adequate defenses against acidity.