The effect of dietary calcium supplementation on intestinal lipid metabolism.

Population studies in man and experimental animal work support the contention that dietary supplementation with calcium may prevent the development of colorectal cancer. The mechanism of action is postulated to be bile acid chelation in the small-bowed forming non-toxic calcium soap compounds but such substances have yet to be isolated and quantified. In this 2-part study faecal concentrations of acidic lipids and neutral sterols were measured in 93 Sprague-Dawley rats whose calcium intake was modulated by enriching the chow and adding calcium lactate (24 milligrams) to the drinking water. In study-1 (dietary calcium intake doubled from 0.4-0.8%) small bowel resection was used to manipulate colonic lipid concentration for comparison with control rats who had undergone transection with immediate restoration of bowel continuity at an equivalent point. Faecal concentrations of free bile acids were 53-67% less in animals receiving added calcium [1.76 +/- 1.33 vs 0.82 +/- 0.65 mg/g (transection); 2.74 +/- 3.73 vs 1.03 +/- 1.27 mg/g (small bowel resection): P less than 0.001]. In study-2 (dietary calcium intake trebled to 1.21%) faecal bile acid concentration was reduced by 32% (1.86 +/- 0.57 vs 1.27 +/- 0.34 mg/g: NS) whereas long chain fatty acid concentrations were increased by 117% (6.77 +/- 2.39 vs 14.67 +/- 4.82 mg/g: P less than 0.001) in animals receiving added calcium. Serum calcium levels remained unchanged in these animals. Calcium soaps of the bile acids were not detected in faeces and therefore contrary to popular theory these results indicate that conditions within the intestinal lumen favour calcium chelation of long chain fatty acids rather than bile acids.

Bile acids and trypsin are unimportant in alkaline esophageal reflux.

We recorded esophageal alkaline exposure time (AET) in 52 patients with gastroesophageal reflux and in 20 control subjects to determine whether esophageal pH monitoring can measure reflux of bile acids and trypsin from the duodenum. Patients underwent a further 16-h study (divided into 2-h periods) in which AET was correlated with bile acid and trypsin concentrations in esophageal aspirates. Patients had greater nocturnal AET than controls (22.7 versus 0.9%, p = 0.005). Patients with a stricture had a greater AET than patients with erosive esophagitis (25.2 versus 13%, p less than 0.05). There was no relationship between esophageal bile acid concentrations and AET, and total bile acid concentrations were similar regardless of whether a 2-h period contained alkaline episodes. Esophageal bile acid concentrations were no different, in patients with a normal esophagus, esophagitis, stricture, or Barrett's esophagus. Trypsin was found in only 5% of aspirates, and could not be predicted by AET. We conclude that measurement of AET is not useful in the clinical evaluation of duodeno-esophageal bile reflux, and bile acids and trypsin are not important in the pathogenesis of reflux esophagitis.

Effect of dietary calcium on the colonic luminal environment.

Dietary supplementation with calcium may prevent the development of colorectal cancer. This mechanism may be related to fatty acid and bile salt chelation in the small bowel forming non-toxic calcium-soap compounds. Calcium may also act locally or systemically on the colonic mucosa. Faecal concentrations of free fatty acids and free bile acids were measured in 17 Sprague-Dawley rats (weighing 472 (39 g)) whose daily calcium intake had been trebled by enriching the chow and adding calcium lactate (24 g/l) to the drinking water. Mean (SEM) faecal concentrations of free bile acids were 33% less than in 19 controls (1.23 (0.15) v 1.82 (0.20) mg/g; p less than 0.001), whereas free fatty acid concentrations were 117% higher (14.68 (3.59) v 6.76 (2.41) mg/g; p less than 0.02). The 'direct' effect of calcium was assessed by organ culture of rat colonic explants in three different concentrations of calcium. Crypt cell production rate (measured by a stathmokinetic technique), which was (mean (SEM)) 4.80 (0.23) cells/crypt/h in control medium (Ca2+ = 2.14 mmol/l), fell by 43% when calcium concentration was doubled (p less than 0.05) and by a further 43% when the concentration was trebled (p less than 0.02). Calcium binds free fatty acids but not free bile acids intraluminally. Calcium has a direct antitropic action on colonic crypts.

Validation of organ culture in colonic adaptation to surgical manipulation.

Valuable information on intestinal adaptation can be gained by using the technique of organ culture to measure the crypt cell production rate. It is not known, however, whether the production rate in organ culture accurately represent that in vivo. Colonic crypt cell production rate, determined by a standard method in vivo, was compared with that in vitro in organ culture in 56 rats. Extensive jejunoileal bypass was used to stimulate colonic hyperplasia, and colonic defunction (by transverse colostomy) led to hypoplasia. There were no differences in crypt cell production rates between in vivo and in vitro groups in normal colon (4.62 (0.39) v 4.80 (0.23) cells/crypt/hour), after 80% jejuno-ileal bypass (7.81 (0.71) v 6.75 (0.72) cells/crypt/hour), or after defunction (2.11 (0.39) v 1.81 (0.35) cells/crypt/hour). Adapting colonic mucosa does not undergo appreciable readaptation in vitro in short term organ culture (10-24 hours). Crypt cell production rate results obtained in man probably reflect in vivo values.

Effect of defunction on cytokinetics and cancer at colonic suture lines.

An intestinal suture line potentiates experimental carcinogenesis in its vicinity, probably due to adaptive hyperplasia. By contrast, a defunctioning colostomy causes distal hypoplasia, and fewer tumours develop. Male Sprague-Dawley rats (n = 160) were used to study adaptation (assessed by a stathmokinetic technique) and carcinogenesis (induced by azoxymethane) at an end-to-end anastomosis that was raised in either functioning or defunctioned left colon. Controls had no procedure and other rats had proximal colostomy alone. Defunction had a profound antitropic effect on the colon, reducing bowel length and weight and crypt cell production rate (CCPR) by 22-56 per cent. Anastomotic CCPR was increased by a factor of 2.6 over controls: mean(s.e.m.) values of 12.71(2.85) versus 4.87(0.41) cells/crypt/h (P less than 0.01), but defunction reduced this by 76 per cent to a mean(s.e.m.) value of 3.00(0.52) cells/crypt/h below that in the intact colon. In the left colon, 39-50 per cent of tumours were sited at the anastomosis. Compared with controls there were 77 per cent fewer tumours in defunctioned colon, but they still favoured the site of anastomosis. Neoplasms at the colostomy site accounted for 74-77 per cent of all right-sided tumours. Anastomosis and defunction have powerful but contrasting effects on colonic adaptation and carcinogenesis; when combined they tend to cancel each other out.

Hypoplasia of defunctioned rectum.

The adaptive response of the large bowel to surgical defunction in man is essentially unknown, although in the rat there is progressive hypoplasia and a reduced propensity to experimental carcinogenesis. Mucosal biopsies were taken from the upper rectum completely defunctioned by a proximal stoma from 2 months to 5 years earlier in 11 patients and from 14 controls without abdominal operations or disease. Samples were established in organ culture and, after 16 h, crypt cell production rate (CCPR) was determined by a stathmokinetic technique. Crypt morphometry was also undertaken. CCPR in defunctioned large bowel was less than half that of controls: (mean (s.d.)-1.96 (0.68) versus 4.65 (0.54) cells crypt-1 h-1, P less than 0.0001). Likewise, crypt length was 24 per cent lower (0.34 (0.05) versus 0.44 (0.04) mm, P less than 0.0001) and crypt width was 38 per cent lower (0.04 (0.01) versus 0.07 (0.01) mm, P less than 0.0001). Rectal defunction causes profound and persistent hypoplasia in man.

The value of angiography in the surgical management of pancreatic disease.

Selective visceral angiography should help to determine the nature and extent of pancreatic lesions and their suitability for resection. Between 1980 and 1987 coeliac and superior mesenteric angiograms were obtained in 76 patients considered for pancreatic resection. Anomalous arterial anatomy was delineated in 25%. Among arterial abnormalities observed in 42 patients (55%), increased or decreased vascularity and displacement were of limited diagnostic value, but encasement correctly predicted cancer in 18 of 21 cases and irresectability in nine of these. When present (17%), invasion or occlusion of the portal or superior mesenteric vein was even more accurate, indicating cancer in 12 of 13 cases and irresectability in 11 of these. Hepatic metastases were only detected in 7 of 15 patients (47%). Overall, angiography confirmed the diagnosis in 54%, localised the lesion in 64% and correctly forecast irresectability in 58%. Misleading data were obtained in five patients. There were no complications.

Rectal hyperplasia after jejunoileal bypass for morbid obesity.

Jejunoileal bypass (JIB) has been widely used to treat patients with morbid obesity for the past 20 years. In rats JIB causes adaptive colonic hyperplasia and enhances colorectal neoplasia. In this study crypt cell production rate (CCPR) was measured stathmokinetically in cultured rectal biopsies from nine patients with JIB and seven controls without intestinal operations or disease. Crypt cell production rate in the group with JIB was more than double that of controls (12.80 (2.67) v 6.23 (1.49) cells/crypt/h: p less than 0.001). There were no significant differences in crypt morphometry and histological examination of rectal biopsies was normal. Patients with JIB have a marked and persistent increase in cell proliferation in the large intestine and may be at increased risk of developing colonic cancer.

Inhibition of intestinal carcinogenesis by dietary supplementation with calcium.

Dietary supplementation with calcium reduces colonic crypt cell production rates in both normal and hyperplastic mucosa. Calcium can bind intraluminally with bile salts and fatty acids thus reducing their mitogenic effect. The protective role of oral calcium on intestinal carcinogenesis (induced by azoxymethane) was tested in 60 male Sprague-Dawley rats submitted to either 80 per cent mid jejuno-ileal resection (n = 30) or jejunal transection (n = 30). Half the rats in each group received calcium lactate 24 g/l added to their drinking water. Rats were killed 25-27 weeks postoperatively. Enterectomy increased colonic tumour yield by 60-106 per cent (P = 0.002-0.005) and duodenal tumour yield by 70-86 per cent. Calcium abolished this effect at both sites, halving intestinal tumour yields in rats with both transection and resection (P less than 0.05). Doubling the dietary intake of calcium inhibits experimental carcinogenesis.

Proximal enterectomy provides a stronger systemic stimulus to intestinal adaptation than distal enterectomy.

Enteroglucagon has been implicated as a tropic hormone in the control of intestinal adaptation. Because cells producing enteroglucagon are located mainly in the distal small bowel (and colon), ileal resection might be expected to produce less adaptive change than a jejunal resection of equivalent length. This hypothesis was tested in male Sprague-Dawley rats (n = 40) weighing 184.0 +/- 7.3 g and receiving a Thiry-Vella fistula (TVF) of the mid-60% of the small intestine. One group had concomitant resection of the jejunum proximal to the TVF (n = 12), another had resection of the ileum distal to the TVF (n = 13), while controls had a TVF alone (n = 15). When killed 10 days postoperatively rats with ileal resection weighed only 81% of controls (p less than 0.001) and 85% of those with jejunal resection (p less than 0.01). Jejunal resection produced an 81% increase in crypt cell production rate (measured by a stathmokinetic technique) over control values (28.5 +/- 4.2 v 15.8 +/- 2.3 cells/crypt/h: p = 0.025), whereas ileal resection had no demonstrable effect (17.5 +/- 2.3 cells/crypt/h). Adaptive hyperplasia in isolated small bowel is modulated by factors localised to the distal small intestine, enteroglucagon being a plausible candidate.

Increased dietary calcium and small bowel resection have opposite effects on colonic cell turnover.

Oral supplements of calcium reduce the mitogenic effects of fatty acids and bile acids on large bowel mucosa. The cytokinetic effects of intraluminal calcium were tested in normal and adapting colonic epithelium. Male Sprague-Dawley rats (n = 60) weighting 356.7 +/- 24.9 g were submitted to either an 80 per cent jejuno-ileal resection or simple transection and resuture of the jejunum. Within each group, half the animals had 24 g/l calcium lactate added to the drinking water. Seven weeks postoperatively crypt cell production rate (CCPR) was determined in the lower descending colon. Among controls with transection CCPR was 4.49 cells crypt-1 h-1; calcium supplements reduced this figure by 26 per cent (P less than 0.05). As expected jejuno-ileal resection increased CCPR (by 51-61 per cent), but again calcium reduced this response by 31 per cent (P less than 0.02). Increased dietary levels of calcium thus inhibit colonic cell turnover and blunt the adaptive response to massive enterectomy, conceivably by binding tropic factors such as bile acids.

A 5-year follow-up of undiagnosed haematuria.

Eighty-four patients with haematuria were seen during 1976 and 1977. This symptom was investigated but no definite cause could be found. Five or more years later they were followed up. Although some patients had experienced further urological symptoms, none was found to have developed a malignancy in the genito-urinary tract. Possible causes of their bleeding are discussed.