Postprandial changes in serum concentrations of individual bile salts in normal subjects and patients with acute viral hepatitis

A sensitive gas-liquid chromatographic assay has been used to analyze serum concentrations of the four major bile acids in both sulfated and nonsulfated forms. Twelve control subjects have been compared with 40 patients with acute viral hepatitis whose symptoms had been present from 6 to 34 days. In all subjects blood samples were collected fasting and 2 hr after a standard meal. In addition half-hourly samples were assayed for 3 hr after the meal in 6 controls and 5 patients with acute viral hepatitis. In both the control and hepatitis groups, serum concentrations of nonsulfated bile acids, especially cholic and chenodeoxycholic acids, increased after the meal. The peak levls usually occurred between 60 and 120 min in the half-hourly studies. In contrast, sulfated bile acids fell in both groups with minimum levels 60–120 min after the meal. Serum total bilirubin, aspartate aminotransferase, and alkaline phosphatase concentrations in hepatitis patients correlated significantly with postprandialitotal bile acid concentrations but were more frequently abnormal than serum total or individual bile acids. Unconjugated bile acids were not detected in control subjects but were found in 17 of the 40 hepatitis patients. Significantly higher levels of sulfated bile acids and chenodeoxycholic acid were present in hepatitis patients compared to controls. In this group of patients with acute viral hepatitis, studied soon after presentation to hospital but in some cases, some time after the onset of their disease, measurement of serum bile salts was not helpful as an index of hepatocellular function. Postprandial variation in the time of peak concentrations of the individual bile acids resulted in the postprandial bile acid studies being no more useful than fasting assays in distinguishing patients with acute viral hepatitis from control subjects.Supported by the NH and MRC of Australia and the MRC New Zealand.     

Octreotide in the treatment of refractory ascites of cirrhosis

The serum levels of conjugated cholic (CA) and chenodeoxycholic acid (CDA) were studied in 15 healthy individuals before and during 3 h after two different test meals and an oral load of CDA. The solid test meal containing 35 g fat gave less and earlier increases of CA and CDA than the liquid test meal containing 50 g fat. These findings demonstrate that the postprandial pattern of serum bile acids depends on the test meal used. After oral intake of 1 g CDA, serum levels of CDA rose faster than after the test meals, and mean maximal levels were reached after 90 min. The oral CDA loading test was also performed in 11 patients with chronic hepatitis. The results indicate that in patients with normal fasting CDA levels, this test may detect liver dysfunction. The advantages of an oral bile acid load over test meals are pointed out.     

Serum bile acids in the diagnosis of hepatobiliary disease.

The value of serum bile acids (SBA) in the diagnosis of hepatobiliary disease has been investigated. A modified GLC method was used, with an overall coefficient of variation of +/- 11% in the control range. Serum was obtained after a 12 hour fast, and two hours after a fatty meal from 73 patients and 14 control subjects. In controls the total fasting SBA of 2.17 +/- 0.86 mumol/l increased significantly (p less than 0.001) to 3.81 +/- 1.14 mumol/l after a meal. All icteric patients had raised SBA, but in 23 anicteric patients there was no significant difference in the detection of chronic liver disease by fasting SBA, postprandial SBA, AST, or gamma GTP. Compared with controls, serum in patients contained proportionately less deoxycholic acid (p less than 0.001), there was proportionately more cholic acid in extrahepatic obstruction (p less than 0.001), and proportionately more chenodeoxycholic acid in patients with cirrhosis, viral hepatitis, and neoplasia (p less than 0.001). In control subjects, the fasting cholic:chenodeoxycholic acid ratio ranged from 0.5-1.0, and differed significantly (p less than 0.001) from patients with extrahepatic obstruction 0.96-3.6, and cirrhosis 0.1-0.5. It is concluded that serum bile acids measured by sensitive methods can provide useful diagnostic information.     

Diagnostic effectiveness of serum bile acids in liver diseases as evaluated by multivariate statistical methods

The aims of this study were to determine the diagnostic effectiveness of fasting and postprandial serum bile acid determinations in liver diseases, and to compare results with those of conventional liver function tests. In 322 patients with biopsy-proved liver disease and 93 healthy subjects, fasting and postprandial (2 hr) serum levels of cholic, chenodeoxycholic, and lithocholic acid conjugates and conventional liver function tests were evaluated. Data were subjected to variance and discriminant and factor analyses. Fasting serum bile acids were higher in patients when compared to controls and were significantly higher in severe than in mild liver diseases. Determination of cholic plus lithocholic acid provided the highest discrimination capacity. The percent of correct allocation was 75.4% for conventional liver function tests, 70.1% for fasting serum bile acids and increased to 79.6% when liver function tests plus serum bile acids were considered. Postprandial percentages were always lower than fasting. Factor analysis identified two factors possibly related to cytolysis and protein synthesis. The serum bile acid concentrations highly correlated with both factors. We conclude that serum bile acid determinations increase the diagnostic and discriminant capacities of liver function tests and are more sensitive and discriminant when obtained in fasting than postprandially.     

Do bile acids reflux into the esophagus? A study in normal subjects and patients with gastroesophageal reflux disease

To determine if bile acids reflux into the esophagus in patients with gastroesophageal reflux disease and in normal subjects during physiological gastroesophageal reflux episodes, esophageal aspiration and pH monitoring were performed simultaneously in 16 patients with gastroesophageal reflux disease and 8 normal subjects. Esophageal samples were collected for 30 min in the fasting state and for 3 h (as hourly samples) after the ingestion of a test meal (egg salad sandwich, peaches, and milk). Bile acids were assayed by a standard enzymatic assay and also by a sensitive and specific assay, liquid secondary ion mass spectrometry. Bile acids were not detected by enzymatic assay in any of the fasting samples. In 6 of the 8 normal subjects and 15 of the 16 patients with gastroesophageal reflux disease, bile acid-like reactivity was detected by the enzymatic assay in postprandial samples. However, bile acid-like reactivity was also found by enzymatic assay in aliquots of the homogenized test meal in concentration similar to the highest concentrations detected in esophageal aspirates. Bile acids were not detected by the liquid secondary ion mass spectrometry method in any of the fasting or postprandial esophageal aspirates (limit of detection greater than 2 microM). However, this assay accurately identified samples to which exogenous bile acids were added as controls. Our results suggest that bile acids did not reflux into the esophagus of patients with gastroesophageal reflux disease whom we studied and caution must be exercised in the use of enzymatic assay for bile acids in postprandial gastrointestinal fluids, as the commonly used hydroxysteroid dehydrogenase assay is not specific for bile acids alone.     

Bile acid concentrations in the gastric juice of patients with erosive oesophagitis.

Intragastric total bile acid concentrations were measured before and after a corn oil test meal in 16 patients with erosive oesophagitis and symptoms of gastro-oesophageal reflux. Sixteen age and sex matched control subjects were also studied. No significant difference was detected between fasting or postprandial gastric bile acid concentrations in patients and in control subjects although a wide range of bile acid concentrations was detected among individuals in both groups. Gastric juice pH was less than 3.5 in seven patients when intragastric bile acid concentrations were greater than 200 mumol/l. These results do not support a role for abnormal duodenogastric reflux in the pathogenesis of erosive oesophagitis. The detection of acid reflux in such patients during intra-oesophageal pH monitoring, however, does not exclude the presence of bile acids which may contribute to the cytotoxic potential of gastric juice.     

Fasting and postprandial serum bile acid concentrations in normal persons using an improved GLC method

An improved GLC method was employed to study individual serum bile acids in 14 control subjects after a 12-hour fast followed by a standard fatty meal. Peripheral venous blood samples were obtained at 15-min intervals for up to 2 h in 7 subjects, and 4 h in 2 subjects. The fasting total bile acids, and cholic:chenodeozycholic acid ratio fell within a narrow range. The total bile acids and chenodeoxycholic acid increased significantly within 30 min of the meal, to reach peak values within 75-120 min. The extent of the increase was variable, and the range of values increased progressively after the meal.     

Cholecystokinin-Stimulated and Postprandial Serum Concentrations of Bile Acids in Alcoholic Liver Cirrhosis

This investigation was undertaken to examine the alterations in serum bile acid concentration after intravenous administration of cholecystokinin and a standard meal in 13 patients with alcoholic cirrhosis. Total 3α-hydroxy bile acids in serum (SBA) were monitored for 2 h after injection of cholecystokinin and for 3 h after the standard meal. The median fasting value of SBA was 39.9 μmol/l (range, 3.2–148 μmol/l). The increase in SBA after cholecystokinin started earlier and lasted shorter than after standard meal stimulation (median, 30 min and 120 min, respectively). The appropriate relative peak levels of SBA were 173% and 212% of the fasting value. The increments were significant (P < 0.01) within groups but insignificant between groups. Day-to-day variation of postprandial SBA was more pronounced than after cholecystokinin stimulation. The difference, however, was insignificant. An inverse correlation was detected between both fasting and stimulated peak levels of SBA and P-coagulation factors 2, 7, and 10.     

Fasting and postprandial serum concentrations of glycine- and taurine-conjugated bile acids in Crohn's disease

Fasting and postprandial serum concentrations of glycine and taurine conjugates of cholic, chenodeoxycholic, and deoxycholic acid were measured with a high-pressure liquid chromatographic-enzymatic assay in 17 patients with ileal Crohn's disease and in 17 controls. The postprandial concentrations of the taurine-conjugated bile acids in the patients were significantly lower than in the controls, whereas the concentrations of the glycine conjugates were not significantly different. The total glycine to taurine ratios of serum bile acids were significantly higher in the patients (means, 2.9 fasting and 4.8 postprandial) than in the controls (1.9 and 2.6). Of the patients, 65% had a postprandial total G/T ratio of serum bile acids which was above the control interval.     

Carbohydrate tolerance improves with fasting in obese subjects with noninsulin-dependent (type II) diabetes

To determine the effects of short-term fasting on carbohydrate tolerance, 10 obese women with noninsulin-dependent diabetes mellitus (NIDDM) were studied with meal tolerance tests before and after 3 days of fasting. After 3 days' fast, basal serum glucose declined from 15.2 +/- 0.9 to 7.5 +/- 0.7 mmol/L (273 +/- 17 to 135 +/- 13 mg/dL) (mean +/- SEM, p less than 0.001) and the glycemic response to the test meal (area under the glucose curve) improved by 31%. There were no changes in basal or postprandial insulin levels but a slight increase in serum c-peptide. Resting metabolic rate and the thermic effect of food were unchanged. There was a slight but insignificant change in basal and postprandial free fatty acid levels and a significant elevation of basal beta-hydroxybutyrate levels. Blood lactate rose significantly (from 0.9 to 2.0 mM) during the initial meal tolerance test, but no rise in lactate was seen in the meal tolerance test after fasting. Two subgroups of patients were identified based on the degree of glycemic improvement after short-term fasting. Those with lesser improvement in serum glucose showed overnight rises in serum glucose during the period of fasting (the dawn phenomenon), while those patients who normalized serum glucose showed a steady fall in serum glucose. This finding may help to predict the glycemic response to long-term calorie restriction. Carbohydrate tolerance improves in obese diabetic (NIDDM) women after 3 days of fasting, in contrast to the impairment of glucose tolerance seen in lean or obese nondiabetic subjects after fasting.(ABSTRACT TRUNCATED AT 250 WORDS)     

Diagnostic values of fasting and postprandial concentrations in serum of 3 alpha-hydroxy-bile acids and gamma-glutamyl transferase in hepatobiliary disease

Fasting and postprandial concentrations in serum of 3 alpha-hydroxy-bile acids and gamma-glutamyl transferase were measured in 138 consecutive patients, 62 with (D) and 76 without (D) hepatobiliary disease. The maximum efficiencies of the three tests--that is, the fractions of patients allocated correctly to the D or D group at the optimum discrimination values--were 0.85, 0.84, and 0.83, respectively. Furthermore, the predictive values and nosographic sensitivities and specificities were rather similar. When the three tests were combined, the nosographic sensitivity increased significantly to a value of 0.84, and the corresponding specificity was 0.91. The diagnostic value of the absolute postprandial increase in serum bile acid concentration was slightly inferior to the diagnostic values of the fasting and postprandial serum bile acid concentrations and, finally, the relative postprandial serum bile acid increase was of no diagnostic value at all.     

Assessment of cerulein effects on serum bile acids concentration in liver disease. Comparison with the test meal.

Twenty-four liver patients and seven healthy subjects underwent the enzymatic-fluorimetric assay of total serum bile acids during fasting and after a hyperlipidic meal, both alone and with the intramuscular administration of 0.3 microgram/kg of cerulein. A third test with cerulein alone was carried out on the control group and on 12 liver patients. The liver patients were divided into two groups; those with moderate and severe liver disease, according to the degree of liver function impairment and the clinical data. The best discriminant efficiency was observed in the test with the meal alone, even if, in the liver patients, the meal with cerulein caused a greater percentual increase of serum bile acids. After taking into account the most significant correlations between serum bile acids and liver function tests, the addition of cerulein to the meal may be recommended for liver patients with previous cholecystectomy or gallbladder pathology.     

Ileal dysfunction in Crohn's disease assessed by the postprandial serum bile acid response.

We assessed ileal functional integrity in 20 consecutive patients with Crohn's disease by sequential measurement of the postprandial serum bile acid concentration. In all 14 patients with active Crohn's disease involving the terminal ileum, the mean (+/- SEM) peak response in the cholylglycine (0.4 +/- 0.04 mumol/l, n = 14) as well as in the total serum bile acid concentration (2.0 +/- 0.4 mumol/l, n = 10) was similar to that seen in a group of children who had undergone ileal resection. A significantly greater increase in the cholylglycine (1.8 +/- 0.18 mumol/l, n = 16, P less than 0.01) and in the total serum bile acid concentration (9.8 +/- 2.4 mumol/l, n = 11, P less than 0.025) was noted in normal children. In five of the six remaining patients (three with Crohn's disease shown not to involve the ileum and two of three with asymptomatic, treated Crohn's ileitis) and in seven patients with ulcerative colitis, the meal stimulated responses were normal. These preliminary results suggest that measurement of the serum bile concentration after a meal stimulus may provide a valuable index of ileal inflammation in patients with Crohn's disease.     

Fasting and postprandial ileal function in adapted ileostomates and normal subjects.

The output of 11 established ileostomies was compared with ileal flow measured by intestinal perfusion in five normal volunteers when fasting and during the ileal passage of test meals containing different proportions of medium chain triglyceride and long chain triglyceride. Oroileal transit of the meal was the same in the two groups, but ileostomy output was less than ileal flow of normal persons both fasting (16.3 +/- 10.9 vs 62.4 +/- 24.7 ml/h, p less than 0.001) and after the long chain triglyceride rich meal (35.4 27.0 vs 96.1 +/- 20.2 ml/h, p less than 0.001). After ingestion of the medium chain triglyceride rich meal, ideal flow failed to increase in normal subjects but in ileostomates the changes in flow after medium chain triglyceride and long chain triglyceride rich meals were not significantly different. The fasting ileostomy effluent composition differed from that of normal fasting ileal content in having a higher concentration of potassium (8.0 +/- 2.9 vs 4.7 +/- 0.6 mmol/1, p less than 0.04) and a higher osmolality (353 +/- 63 vs 287 +/- 5 mosm/kg, p less than 0.05). Sodium concentration tended to be lower in ileostomy effluent, but in contrast to previous reports, ileostomy effluent was of consistently alkaline pH (7.2 +/- 0.3). These concentrations were not significantly altered by either type of meal. The long chain triglyceride rich meal increased the ileal flow of bile acids in both normal subjects and ileostomates, whereas the medium chain triglyceride rich meal increased bile acid flow in ileostomates but not in normal subjects, possibly reflecting a different amount of the bile acids in the ileum of the ileostomate. In the adapted ileostomate, the low volume and high potassium concentration of fasting effluent suggest that sodium and water absorption are continuously stimulated by chronic salt depletion.     

Portal venous bile acids in cholesterol gallstone disease: effect of treatment with chenodeoxycholic and cholic acids

We determined the serum concentrations of cholic, chenodeoxycholic and deoxycholic acids in portal and peripheral venous blood in 9 gallstone-free patients and 39 patients with cholesterol gallstones during standardized cholecystectomy. An accurate and specific gas chromatographic-mass spectrometric technique was used. The portal venous concentration of total bile acids was similar in gallstone-free and untreated gallstone patients (n = 20); there was no evidence of a reduced hepatic uptake of bile acids in the latter. Treatment with cholic acid (n = 10) was associated with a 70% increase in cholic acid and normal concentration of total bile acids. In chenodeoxycholic acid-treated patients (n = 9), the portal venous concentration of this bile acid was increased 3-fold; total bile acids were increased about 60%. The estimated hepatic uptake of cholic acid was slightly decreased during chenodeoxycholic acid treatment. The results indicate that neither bile acid inflow to the liver nor hepatic bile acid uptake is reduced in fasting patients with cholesterol gallstones, and treatment with chenodeoxycholic acid increases fasting inflow of bile acids to the liver. The latter may contribute to unsaturation of fasting hepatic bile during treatment with chenodeoxycholic acid.     

Evaluation of postprandial serum bile acid response as a test of hepatic function

Commercial assays for serum bile acids (SBA) have made this measurement practical. The purpose of this study was to examine the utility of SBA measured every 30 min after a standardized meal in controls and in patients with acute viral hepatitis, cholestasis, and anicteric cirrhosis. In five controls, repeated examination of the area under the bile acid curve (AUC) was not statistically different, whereas the fasting and 2-hr postprandial levels were significantly different. In the group of patients with anicteric cirrhosis, AUC identified disease in 18/20 using total serum bile acids (TSBAs) and in 15/20 using cholylglycine (CG). AUC can be calculated from three samples obtained at 0, 60, and 120 min without losing the sensitivity achieved with seven serial samples. SGOT, alkaline phosphatase, and serum albumin were compared for sensitivity to the total SBA response curve in 20 patients with anicteric cirrhosis. SGOT and alkaline phosphatase identified only 50% and 55% as abnormal and serum albumin was less sensitive. Using total SBA, combining the fasting level and AUC identified 100% as abnormal; using CG, 85% of these patients were detected. As a stepwise cost-effective approach, the fasting level of SBAs can identify most patients with anicteric liver disease. In cases with normal fasting levels where liver disease is suspected, the three-point AUC determination may identify additional patients.Supported in part by a grant from the Diagnostic Division, Abbott Laboratories, North Chicago, Illinois.     

Serum bile acids in relation to disease activity and intake of dietary fibers in juvenile ulcerative colitis.

Serum concentrations of primary bile acids were determined at different disease activities in juvenile ulcerative colitis and in healthy age-matched controls. In patients with ulcerative colitis in clinical remission, serum levels of bile acids were also studied after long-term intake (6 months) of dietary fibers (wheat fiber and ispaghula, respectively) in a double-blind randomized cross-over study. Blood samples were taken in the morning after an overnight fasting and for 4 h postprandially after a standardized test meal. Determinations of bile acids were made by radioimmunoassays. Patients with total colitis in the active phase had significantly higher serum levels of cholic and chenodeoxycholic acids 4 h postprandially compared with control children. After long-term intake of ispaghula, significantly higher (although not different from controls) serum levels of cholic acid were found 2 and 3 h postprandially, whereas wheat fibers did not affect serum bile acid concentrations. These results may suggest an increased absorption of unconjugated bile acids in the diseased colon and a minimal influence of dietary fibers on serum bile acid concentrations.     

Fasting and postprandial serum bile acids as a screening test for hepatocellular disease

Postprandial serum bile acid estimation was recently proposed as the most sensitive test of liver function. In our study, the fasting and postprandial serum bile acid measurements were performed on 19 normal subjects, 20 patients with cirrhosis, 10 with acute hepatitis, 4 with resolving viral hepatitis, and 6 with chronic active hepatitis. A gas-chromatographic method was used. One healthy subject had postprandial serum bile acid levels above the normal range, while 7 patients with liver disease had postprandial levels within normal limits. Of the latter group, 2 had chronic active hepatitis in remission and 3 had resolving viral hepatitis. Significant correlations were seen between serum bile acid levels and most of the conventional liver function tests. Our data indicate that the postprandial serum bile acid determination is better than any of the other conventional tests taken separately, but no better than their combined use. No significant modification of the cholic acid/chenodeoxycholic acid ratio was observed between the fasting and the postprandial determinations.     

Diagnostic value of serum primary bile acids in detecting bile acid malabsorption.

Serum cholic and chenodeoxycholic acid conjugates were measured in fasting conditions and after meals in 14 patients with bile acid malabsorption due to ileal resection. Mean serum fasting levels of both primary bile acids did not differ from the controls. After meals, serum cholic acid peaks were lower in patients with ileal resection than in control subjects (p less than 0.001), while chenodeoxycholic acid peaks were reduced in colectomised patients (p less than 0.01). In the sera from patients with ileal resection, the glycine/glycine + taurine ratio for cholic and chenodeoxycholic acid increased (p less than 0.001) from morning to evening, and glycine/glycine + taurine ratio for chenodeoxycholic acid was significantly (p less than 0.01) different from the controls in the sera collected in the evening. The results are consistent with the concept of a better intestinal conservation of chenyl, mainly of the glycine conjugated from, than of cholylconjugates, in patients with ileal resection; this is probably because of passive absorption in the intestine. The postprandial peaks of serum cholic acid conjugates may therefore be regarded as a test of ileal dysfunction, while peaks of chenodeoxycholic acid conjugates suggest colonic impairment.     

Postprandial Serum Bile Acids in Resected and Non-Resected Patients with Crohn's Disease

Fasting and postprandial serum conjugates of cholic acid (CCA) and chenodeoxy-cholic acid (CCDA) were determined by radioimmunoassay in 46 healthy individuals and 15 patients with Crohn's disease (CD), 7 bowel-resected and 8 non-resected. All patients had normal conventional liver test results, and fasting values of CCA and CCDA were within the reference ranges. Two findings appeared: the mean postprandial increases in CCA and CCDA were both lower in CD patients than in healthy individuals, and the postprandial increase in CCA was lower in the resected patients than in the non-resected, whereas the postprandial increase in CCDA was the same in the resected and the non-resected patients. These findings show that in CD patients, whether resected or not, the postprandial levels of bile acids are low. This could reflect a decreased absorptive capacity of bile acids in the small intestine. The finding that postprandial CCA, but not CCDA, was lower in resected than in non-resected patients may reflect different sites of CCA and CCDA absorption.