Neville Hoffman

Dynamics of the enterohepatic circulation of bile acids. Postprandial serum concentrations of conjugates of cholic acid in health, cholecystectomized patients, and patients with bile acid malabsorption.

Abstract The effect of three liquid meals on the serum level of conjugates of cholic acid was determined by radioimmunoassay. In eight healthy subjects, these bile acids peaked 90 to 120 minutes after each meal, and returned to base line by four hours. This pattern was meal related because the values remained at base line in four subjects undergoing a 22-hour fast. In five patients with cholecystectomy, conjugates of cholic acid increased to lower maxima after the first meal, and then remained elevated throughout the day, returning to base line 14 hours after the evening meal. In six patients with bile acid malabsorption (after ileal resection), the postprandial increase after the first meal was smaller than in health; an increase was barely detectable after the mid-day meal and occurred after the evening meal. In subjects with normal liver function, postprandial conjugates of cholic acid appear to indicate the dynamics of the enterohepatic circulation of bile acids; the level depends in part on intestina...

Five-Year Efficacy and Safety Analysis of the Adenoma Prevention with Celecoxib Trial

The Adenoma Prevention with Celecoxib Trial examined the efficacy and safety of the cyclooxygenase (Cox)-2 inhibitor, celecoxib, for sporadic colorectal adenoma prevention in patients at high risk for colorectal cancer. The trial randomized 2,035 subjects to receive either placebo, celecoxib 200 mg twice daily, or celecoxib 400 mg twice daily. The primary study safety and efficacy analyses involved 3 years of treatment. The results showed significant antitumor effect but also indicated increased cardiovascular adverse events in patients treated with celecoxib compared with placebo. A total of 933 patients participated in an extension of the Adenoma Prevention with Celecoxib Trial, with a planned total treatment and surveillance duration of 5 years. Study medication was stopped early, resulting in a median treatment duration of 3.1 years for those with a year 5 colonoscopy. Patients treated on the placebo arm had a cumulative adenoma incidence of 68.4% over 5 years of observation. This figure was 59.0% (P < 0.0001) for those receiving low-dose celecoxib, and 60.1% (P < 0.0001) for those receiving high-dose celecoxib. The cumulative incidence of advanced adenomas over 5 years was 21.3% of those taking placebo, 12.5% (P < 0.0001) of those taking low dose celecoxib and 15.8% (P < 0.0001) of those taking high-dose celecoxib. Investigator reported treatment emergent adverse events were similar across all treatment groups for categories including renal and hypertensive events and gastrointestinal ulceration and hemorrhage events. For a category composed of cardiovascular and thrombotic events, the risk relative to placebo was 1.6 (95% confidence interval, 1.0, 2.5) for those using 200 mg twice daily celecoxib and 1.9 (95% confidence interval, 1.2, 3.1) for those using 400 mg twice daily celecoxib. Secondary analysis showed an interaction between a baseline history of atherosclerotic heart disease and study drug use with respect to cardiovascular and thrombotic adverse events (P = 0.004). These results confirm the inhibitory effect of celecoxib on colorectal adenoma formation, and provide additional safety data indicating an elevated risk for cardiovascular and thrombotic adverse events, particularly for patients with preexisting atherosclerotic heart disease.

A Double-Blind Placebo-Controlled Study of the Effects of the Bisphosphonate Risedronate on Bone Mass in Patients with Inflammatory Bowel Disease

BACKGROUND:Low bone density and fractures are common in patients with inflammatory bowel disease (IBD).OBJECTIVE:To determine whether the bisphosphonate risedronate and calcium are safe and effective in preserving bone mass compared to calcium alone in IBD patients with low bone mass.PATIENTS:Sixty-one ambulatory patients with Crohns disease (n = 31) or ulcerative colitis (n = 30) and low bone density.METHODS:Using a double-blind placebo-controlled trial format, patients were randomized to 12 months of therapy with risedronate 5 mg or placebo. All received a 600 mg calcium supplement. Bone density using dual energy X-ray absorptiometry was performed at baseline and at 12 months. Disease activity, use of corticosteroid, and adverse events were noted.RESULTS:Forty-eight patients completed the trial. Compared to the placebo group risedronate resulted in a 2.0% (95%CI, 0.02–3.97) and 1.9% (95%CI, 0.21–3.62) improvement in bone density at the spine and hip, respectively. IBD diagnosis, gender, therapy, and disease status had no effect on the results. There were no significant differences in the adverse events.CONCLUSIONS:Risedronate improved bone density at the spine and hip in patients with either Crohns disease or ulcerative colitis and low bone mass. These data suggest that risedronate is a safe and effective therapy to improve bone mass in these patients.

Routine colonic mucosal biopsy and ileoscopy increases diagnostic yield in patients undergoing colonoscopy for diarrhea

Background and Aims: In patients undergoing colonoscopy for diarrhea, when the examination is normal, the role of routine mucosal biopsy remains controversial, particularly in the open‐access setting. It is uncertain whether routine ileoscopy adds anything to colonoscopy alone. We aimed to assess the yield of mucosal biopsy and ileoscopy in patients with diarrhea.

Metabolism of Steroid and Amino Acid Moieties of Conjugated Bile Acids in Man: V. Equations for the perturbed enterohepatic circulation and their application

Equations previously developed to describe the enterohepatic circulation of the major biliary bile acids in man (Gastroenterology 67:887, 1974) were modified in order to predict the effect on biliary bile acid composition and pattern of amino acid conjugation after prototypic perturbations of the enterohepatic circulation in man. For the steroid moiety, the effects of bile acid feeding, increased recycling frequency, decreased intestinal conservation, and increased dehydroxylation were simulated. For the glycine or taurine moiety, the effect of increased deconjugation or preferential loss of one of the amino acid moieties was simulated. For the steroid moiety, the steady state biliary bile acid composition reflects the balance between input and conservation for each bile acid. Similarly, the distribution of bile acids between glycine and taurine conjugates reflects the balance between conjugation and conservation for each amino acid moiety. Because these values may vary widely and independently, analysis of biliary bile acid composition in terms of the steroid moiety or the glycine-taurine ratio per se cannot be used to infer the relative rates of input or conjugation.

Colonoscopic surveillance after surgery for colorectal cancer

Background:  Intensive colonoscopic surveillance after resection of colorectal cancer (CRC) has been shown not to improve outcome. The National Health and Medical Research Council of Australia (NHMRC) has recently published guidelines recommending appropriate surveillance intervals after CRC resection. The aims of the present study were to assess current and past patterns of postoperative CRC surveillance and to determine the yield of neoplasia from such surveillance.

4479 Is routine mucosal biopsy of value in patients with diarrhoea and normal colonoscopy in an open access setting

BACKGROUND: Routine mucosal biopsy in patients undergoing colonoscopy for diarrhoea, in whom macroscopic examination is normal, remains controversial and practice varies widely without clear guidelines. Reported rates of clinically significant microscopic abnormalities vary from 2-27%.It is unclear if ileal biopsy adds anything to colonic biopsy alone. OBJECTIVES: We sought to evaluate the diagnostic yield of colonic and ileal mucosal biopsy in patients undergoing colonoscopy for diarrhoea in whom the macroscopic examination was normal. METHODS: We retrospectively reviewed all colonoscopies performed over a nine year period in a tertiary referral centre with an open access endoscopy service. Cases were selected where the sole indication for colonoscopy was diarrhoea, the musosa was macroscopically normal (other than diverticulosis) and biopsies were performed. Cases were excluded if the examination was inadequate. The histopathology reports of the selected cases were then reviewed. RESULTS: 362 cases were identified. Colonoscopy and biopsy was normal in 260 patients.Ileal biopsies were performed (in addition to colonic biopsies) in 158 cases, none of which revealed clinically significant abnormalities. Clinically significant histological findings were present in 18 cases (5%). Findings included collagenous colitis (5 cases), lymphocytic colitis (1 case), possible lymphocytic colitis (1 case), possible collagenous colitis (1 case), inflammatory bowel disease (2 cases), melanosis coli (2 cases) and significant eosinophil mucosal infiltration (6 cases). 28 patients (8%) had minor histological abnormalities with no specific diagnostic features. The diagnostic yield was highest in patients above 60 years old, where 10% had clinically significant histological abnormalities. All patients with collagenous colitis were female and only 1 was less than 60 years old. CONCLUSIONS: When colonoscopy is normal in patients with diarrhoea, routine colonic biopsy identifies significant pathology in 5% of cases. The diagnostic yield is highest in patients over 60 years old. Routine ileal biopsy is unhelpful.