Increased Bile Acid Concentrations Research Articles

Alkaline gastroesophageal reflux: Assessment by ambulatory esophageal aspiration and pH monitoring

The pathophysiologic effect of duodenal contents in the refhned gastric juice of patients with gastroesophageal reflux disease (GERD) is controversial. We evaluated the composition of the refluxed gastric juice in 43 normal volunteers and 52 patients with GERD using a newly developed device that allows ambulatory esophageal aspiration. The findings were correlated with the results of 24-hour esophageal pH monitoring and the presence of complications of GERD. Compared with bile concentrations in normal volunteers, the total bile acid concentration in the reflux aspirates was higher in patients with GERD (p < 0.01). There was a significant correlation between the bile acid concentration in the aspirates and the percentage of time the pH was above 7 on ambulatory 24-hour esophageal pH monitoring (r = 0.59, p = 0.006), and both were highest during the night (p < 0.01). The bile acid concentration and the percentage of time pH was greater than 7 were particularly increased in patients with strictures or Barrett's esophagus (p < 0.01). Both an increased bile acid concentration in aspirates and the percentage of time with pH greater than 7 on pH monitoring were observed primarily in patients with a destroyed gastroduodenal barrier [status post Billroth II resection (BII), Billroth I resection (BI), or pyloroplasty] or after cholecystectomy. An increased bile acid concentration also occurred in a substantial number of patients without previous foregut surgery, although this did not usually result in an increase in the time that pH was above 7. These data suggest that contamination of the refluxed gastric juice with bile acids predisposes the patient to the development of strictures and Barrett's esophagus. An increased time that pH is greater than 7 on esophageal pH monitoring indicates biliary reflux and occurs primarily after previous foregut surgery. A normaltime pH above 7 does, however, not exclude contamination of the refluxed gastric juice with duodenal contents.

Reflux gastritis in the intact stomach.

Gastric biopsy specimens from patients who have undergone gastric surgery frequently exhibit foveolar hyperplasia, oedema, vasodilatation and congestion, and a paucity of inflammatory cells as consequences of entero-gastric reflux. Similar, albeit generally milder, changes were found in 47 of 316 (15%) non-surgical patients undergoing endoscopy for dyspeptic symptoms. To relate these changes to bile reflux or other potential gastric irritants the total bile acid concentration was measured in samples of fasting gastric juice, and the use of a symptom questionnaire ascertained the patients' cigarette consumption, use of non-steroidal anti-inflammatory drugs (NSAIDs), and alcohol intake. When patients with reflux gastritis were compared with normal controls (n = 91), significant increases in associated peptic ulceration and NSAID use were found in the group with reflux, but no increases in bile acid concentrations. Indeed, only one patient had evidence of duodenogastric reflux. It is concluded that most cases of "reflux gastritis" in the intact stomach are not due to reflux of bile. Our findings indicate an important pathogenic role for long term NSAID use, in what might be usefully termed type C or "chemical" gastritis.

DEFECTIVE BILE ACID AMIDATION: PREDICTED FEATURES OF A NEW INBORN ERROR OF METABOLISM

Biochemical and clinical features are predicted for an as yet unreported inborn error of metabolism, in which bile acids cannot be conjugated with glycine or taurine. Unconjugated cholic acid will be secreted into bile, be absorbed from the intestine, and become the predominant bile acid in bile and plasma. Other bile acids will be esterified with glucuronate and secreted into bile, but undergo little enterohepatic circulation. Cholestasis will not be present; the bile acid pool will be diminished and lipid absorption, especially that of fat-soluble vitamins, will be impaired. A secretory diarrhoea may occur, caused by increased bile acid concentrations in the colon. Awareness of this possible syndrome should aid in its identification; oral administration of bile acids conjugated with glycine or taurine should correct the metabolic and clinical abnormalities.

EFFECT OF DUODENAL ULCER SURGERY AND ENTEROGASTRIC REFLUX ON GAMPYLOBACTER PYLORIDIS

To assess the effect of duodenal ulcer surgery on Campylobacter pyloridis gastric biopsies were done and fasting bile acid concentrations in gastric aspirates were measured in 35 patients with active duodenal ulceration and 54 who had undergone surgery at some time. Biopsy specimens were assessed blind for the presence of C pyloridis and scored for severity of reflux gastritis by the use of a histological grading system. Among patients who had undergone highly selective vagotomy the proportion who were C pyloridis-positive was similar to that in the unoperated group, but among those who had undergone Billroth I partial gastrectomy, Billroth II partial gastrectomy, or truncal vagotomy and gastroenterostomy it was significantly lower (p < 0·001). The absence of C pyloridis correlated strongly (p<0·001) with high reflux scores and increased bile acid concentrations in the stomach. Reflux scores and bile acid concentrations were significantly higher (p<0·01) after Billroth I and Billroth II partial gastrectomies and truncal vagotomy and gastroenterostomy than in the active duodenal ulcer or highly selective vagotomy groups. There was a highly significant correlation (p<0·001) between reflux scores and bile acid concentrations. These results suggest that reflux may disrupt mucus and thus cause the death of campylobacters that live beneath it. They also suggest that reflux may produce a reflux-specific gastritis. Highly selective vagotomy may protect against these changes in the gastric mucosa.

Reflux gastritis: distinct histopathological entity?

A total of 98 patients who had either undergone gastric surgery (23) or who had peptic ulcers (56), or who had normal endoscopic findings (19), all underwent gastric biopsy, together with measurement of pH and total bile acid concentration in their fasting gastric juice. The biopsy specimens were graded "blind" for the presence of foveolar hyperplasia; oedema and smooth muscle fibres in the lamina propria; vasodilation and congestion of superficial mucosal capillaries; and a paucity of both acute and chronic inflammatory cells in the brief that these features constituted a distinctive histological picture related to reflux of alkaline duodenal content into the stomach. We found a strong association between severe grades of each of these histological variables and both hypochlorhydria (pH greater than or equal to 4) and increased bile acid concentrations in the stomach. Furthermore, when the individual grades were added together to give a composite "reflux score," there was a significant difference in the incidence of hypochlorhydria (p less than 0.01) and raised bile acid concentrations (p less than 0.005) between those patients with a reflux score above and below 10. Although we do not claim that reflux is invariably accompanied by a distinctive histological picture, we suggest that recognition of this hitherto poorly documented combination of features as reflux gastritis may assist in the selection of patients for specific treatment and minimise the overdiagnosis of premalignant dysplasia (with which the lesion may be confused) in the postoperative stomach.

Campylobacter like organisms and reflux gastritis.

A total of 98 patients, who had undergone gastric surgery (23), or who had peptic ulcers (56), or who had normal endoscopic findings (19) underwent gastric biopsy, together with measurement of pH and total bile acid concentration, in their fasting gastric juice. The biopsy specimens were stained by the Warthin-Starry method for Campylobacter like organisms and were also graded "blind," as described in the preceding paper, for the five features that we believe may constitute the histological picture of reflux gastritis. The individual grades were added together to give a composite "reflux score" (0-15) for each patient. We found a notable association between the absence of Campylobacter like organisms and previous surgery for peptic ulceration, high reflux scores (greater than 10), hypochlorhydria (pH greater than or equal to 4), and increased bile acid concentrations (greater than or equal to 1 mmol/l) in the stomach. These findings further support our contention that reflux gastritis represents a distinct histopathological entity causally related to the effects of enterogastric reflux on the gastric mucosa and suggest that there may be two major categories of chronic gastritis: chronic superficial, or atrophic gastritis related to Campylobacter like organisms and reflux gastritis. Our data also imply that patients with peptic ulceration may, after gastric surgery, revert from being positive for these organisms to being negative and may undergo a possible transition from Campylobacter related chronic gastritis to reflux gastritis.

Conjugated bile acids in serum and secretions in response to cholecystokinin/secretin stimulation in children with cystic fibrosis.

More than 80% of patients with cystic fibrosis have poor pancreatic function, and have large daily faecal bile acid losses. This has been postulated to lower luminal bile acid concentrations and adversely affect fat absorption. We studied, for the first time, quantitative individual conjugated duodenal bile acid secretion rates into the duodenum during cholecystokinin/secretin infusion in 55 cystic fibrosis patients and six controls, using a quantitative non-absorbable marker technique. We were able to show adequate duodenal total bile acid concentrations and normal secretion rates in these children. The bile acid secretion pattern in cystic fibrosis patients showed a marked increase in bile acid concentration during cholecystokinin/secretin infusion, to levels which were above the critical micellar concentration indicating that the gall bladder is a functional organ in this disease. The subsequent fall in secretion rate was similar to controls. We have documented a significantly raised glycine/taurine bile acid conjugation ration in duodenal juice from cystic fibrosis patients and suggest that the combined effects of lowered ileal pH and increased glycine conjugated proportion of bile acids may cause precipitation of bile acids leading to decreased fat absorption and large faecal bile acid losses. To further investigate bile acid secretion in children with cystic fibrosis, we modified the high performance thin layer chromatography/densitometry method to enable measurement of individual glycine and taurine conjugates in serum. In comparing cystic fibrosis patients and controls, we were able to determine a group of 18 (36%) with bile acid evidence of liver damage who also showed reduced bile acid secretion into the duodenum. We were unable to study changes in serum bile acids during cholecystokinin/secretin infusion because of the high level of bile acid contamination in Boots Secretin. Some patients showed raised fasting serum bile acid concentrations more than two years before changes in conventional liver function tests or clinically evident liver disease. We have shown fasting serum bile acids to be a sensitive measure of liver dysfunction in cystic fibrosis and postulate that raised proportions of glycine conjugated bile acids may be responsible for the high incidence of liver disease in cystic fibrosis.

LIVER DAMAGE AFTER PARACETAMOL OVERDOSE COMPARISON OF LIVER-FUNCTION TESTS, FASTING SERUM BILE ACIDS, AND LIVER HISTOLOGY

54 patients have been studied after paracetamol (acetaminophen) overdose. Liver-function tests and fasting serum bile-acids were measured daily; liver biopsy was done in all cases, and slides were examined "blind" to assess liver damage. The plasma-paracetamol was measured on one occasion. A histological abnormality was present in the livers of 53 of the 54 patients, and was minor in 23, moderate in 16, and severe in 14. In 6 patients with moderate and 18 with mild histological abnormality liver-function tests were normal. A serum-aspartate-aminotransferase above 400 units/1 was always associated with severe histological liver damage. Fasting serum bile-acids were raised in 51 of the patients with abnormal liver histology; the serum-bileacid seemed to be a more sensitive indicator of mild liver-cell damage than was the transaminase level. There was, however, little correlation between increase in bile-acid concentration and the degree of histological abnormality. As a result of these investigations empirically determined levels of plasma-paracetamol have been drawn which give a guide to the likelihood of liver damage after paracetamol overdose.