Postprandial Serum Bile Acid Research Articles

Clinical chemical diagnosis of diseases assisted by logistic regression illustrated by diagnosis of canine primary and secondary hepatobiliary diseases.

The purpose of the present study was to demonstrate the use of logistic regression models in the prediction of diseases using the prediction of canine primary and secondary hepatobiliary diseases as an example. Briefly, in a logistic regression model independent variables (i.e. the analytical results) are combined in a linear equation that is used to estimate the logarithm of the odds (logit) of an event (i.e. having primary or secondary hepatobiliary disease). From the estimated logit given by the logistic regression model, a conditional probability of the event (i.e. having primary or secondary hepatobiliary disease) can be calculated. Twenty-six dogs with verified primary and secondary hepatobiliary diseases and 19 dogs, initially suspected to have hepatobiliary diseases, but with apparently other diseases, were included in the study. The following clinical chemical parameters were measured: alanine aminotransferase (ALAT), aspartate aminotransferase (ASAT), alkaline phosphatase (AP), bilirubin(Total) (TB), urea, glucose, retention of bromosulphthalein (BSP), fasting and postprandial total serum bile acid concentration (FSBA and PSBA). Logistic regression analysis, using the CATMOD procedure in SAS, was used to select which of the measured parameters should be included in the model, and to derive a logistic regression model using the selected parameters. To observe more closely the potential of the logistic regression model, the model was also used to classify a test group consisting of 13 dogs (6 dogs with hepatobiliary diseases and 7 dogs with other diseases). By logistic regression analysis, ASAT and PSBA were selected to be included in the final model, and the final logistic regression model was Y = -3.194 + 0.044.PSBA + 3.251.ASAT. The logistic regression model classified correctly 38 (84%) of 45 dogs in the present study. Specifically, 21 (81%) of 26 dogs with verified primary or secondary hepatobiliary diseases and 17 (90%) of 19 dogs with various other diseases were correctly classified by the logistic regression model. When the model was used on the test group, 5 (83%) of 6 dogs with hepatobiliary diseases and 7 dogs (100%) of 7 dogs with other diseases were correctly classified. Even though the logistic regression model derived in the present study only serves as an example, thus reducing the practical usefulness of the derived logistic regression model, the present study indicates a great potential of logistic models for the diagnosis of diseases.

Evaluation of diagnostic tests using relative operating characteristic (ROC) curves and the differential positive rate. An example using the total serum bile acid concentration and the alanine aminotransferase activity in the diagnosis of canine hepatobiliary diseases.

The value of a diagnostic test depends on most cases on its ability to discriminate between patients with and without a certain disease. One way of evaluating a diagnostic test is to use the relative operating characteristic curve (ROC curve) and the differential positive rate (DPR). The ROC curve displays the relationship between the true positive ratio and the false positive ratio for a range of cutoff values and it can be used to compare various diagnostic tests under equivalent conditions (equal true positive ratios or false positive ratios) and over the entire range of cutoff values. The DPR is the difference between the true positive ratio and the false positive ratio at various cutoff values and it can be used to obtain the cutoff value associated with the highest sensitivity and specificity. The purpose of this study was to describe the evaluation and comparison of diagnostic tests using ROC curves and DPR. Eventually, the positive and negative predictive values were used to assess the differences between the sensitivity and specificity obtained when the upper limit of the reference interval, or the optimal cutoff value indicated by the DPR, was used as cutoff value. To illustrate the methods, the 2 h post-prandial total serum bile acid concentration (PSBA) and the alanine aminotransferase activity (ALAT) in the diagnosis of primary or secondary hepatobiliary diseases in dogs were used. The ROC curves showed, as expected from previous studies, that PSBA was superior to ALAT in diagnosing dogs with hepatobiliary diseases. Using DPR, the optimal cutoff value for PSBA was suggested to be 15.48 mumol/l. Compared to the traditionally used cutoff value of 22.24 mumol/l, no decisive difference in the positive predictive values were observed. However, the cutoff value of 15.48 mumol/l appeared to produce higher negative predictive values compared to a cutoff value of 22.24 mumol/l. Seemingly, ROC curves and DPR are simple methods useful to the evaluation of diagnostic tests and due to the simplicity, there seems to be a great potential for these methods in the evaluation of diagnostic tests in veterinary medicine.

Predictive value of serum procollagen-III-peptide for the survival of patients with cirrhosis

The value of the aminoterminal procollagen-III-peptide (P-III-P) in predicting death or survival was evaluated in a group of 43 patients with proven postnecrotic or alcoholic cirrhosis. Patients were followed-up prospectively for 2 years. The prognostic value of P-III-P was compared with the Child classification, fasting and postprandial serum bile acids, and standard laboratory tests such as bilirubin, prothrombin index, pseudocholinesterase, albumin, GOT, GPT, gamma-GT, and clinical findings such as ascites, encephalopathy (assessed with the number connection test = NCT), and nutritional status. Between patients who died and those who survived the following 2 years, there were significant differences in the following parameters at the time of inclusion in the study: encephalopathy judged by NCT (p = 0.001), serum albumin (p = 0.0012), postprandial serum bile acids (p = 0.0024), fasting serum bile acids (p = 0.0025), pseudocholinesterase (p = 0.0044), GOT (p = 0.015), bilirubin (p = 0.016), and prothrombin index (p = 0.01). None of the other parameters investigated, including SP-III-P (p = 0.46), revealed any statistically significant differences between patients who died and survivors. The prognostic significance of laboratory tests and recorded clinical findings was evaluated, either alone or in combination with life-table analysis using the Cox model. SP-III-P, alone or in combination with other parameters, failed to improve prediction of mortality in patients with cirrhosis. In comparison to the Child classification (p = 0.0004) the combination of NCT and postprandial serum bile acids showed a similar ability (p = 0.0003) to predict patient survival.

Hepatotoxicity of phenobarbital in dogs: 18 cases (1985-1989)

Summary The medical records of 18 dogs that had hepatic disease and received phenobarbital as an anticonvulsant for 5 to 82 months were reviewed. Clinical signs included sedation and ataxia in all dogs, 5 dogs were also anorectic, 2 had coagulopathy, 3 were icteric, and 5 had ascites. Serum biochemical analysis revealed serum albumin concentration ≤ 2.2 g/dl in 12 dogs, serum alkaline phosphatase activity ≥ 169 U/L in 18 dogs, serum alanine transaminase activity ≥ 57 U/L in 15 dogs, and total bilirubin concentration ≥ 1 mg/dl (in the absence of lipemia) in 7 dogs. Serum phenobarbital concentration was ≥ 40 μg/ml in 12 of 17 dogs. Sulfobromophthalein excretion was prolonged in 8 of 10 dogs. Preprandial serum bile acid concentrations were high in 8 of 10 dogs, and 2-hour postprandial serum bile acid concentrations were high in 9 of 10 dogs. Two of 4 dogs tested had resting plasma ammonia concentrations > 200 mg/dl. An ammonia tolerance test was performed on 2 other dogs; both had ammonia concentration ≥ 200 mg/dl in the plasma 30 minutes after receiving 100 mg of ammonium chloride/kg of body weight, po. Nine dogs died, 1 was euthanatized, and necropsies were performed on these 10 dogs. Biopsies and necropsies of 6 dogs revealed chronic hepatic fibrosis with nodular regeneration (cirrhosis). One dog had hepatocellular carcinoma and mild cirrhosis. In 1 dog, after phenobarbital had been withheld, necropsy revealed complete recovery of the previously observed lesions.

Evaluation of twelve-hour preprandial and two-hour postprandial serum bile acids concentrations for diagnosis of hepatobiliary disease in dogs

Summary In samples collected from 170 dogs suspected of having hepatobiliary disease, preprandial serum bile acids (prsba) and postprandial serum bile acids (posba) concentrations were measured, using a spectrophotometric enzymatic method. Dogs were assigned to 8 disease groups and 1 control group on the basis of hepatic histopathologic findings. Pre- and postprandial sba concentrations and results of routine biochemical analyses (including total bilirubin, albumin, and bun concentrations, and serum alkaline phosphatase (alp), alanine transaminase (alt), and aspartate transaminase (ast) activities) were expressed, using 4 indices: sensitivity, specificity, positive predictive value, and negative predictive value. Single tests and combinations of tests in series were evaluated. For diagnosis of hepatobiliary disease, the specificity of prsba was 100% at values > 20 μmol/L and of posba was 100% at values > 25 μmol/L. Test combinations with the best sensitivity for diagnosing the following diseases were: prsba-posba for cirrhosis, portosystemic vascular anomaly, and glucocorticoid hepatopathy; prsba-posba or prsba-alp for cholestasis; prsba-posba or alt-ast for chronic hepatitis; prsba-alt for hepatic necrosis and passive congestion; and prsba-alp for neoplasia. Test combinations with the overall highest sensitivity and positive predictive value for the fewest number of tests were prsba-posba, and either prsba or posba combined with an enzyme activity (alt, ast, or alp). The overall test efficacy for prsba vs posba was nearly identical: for prsba, it was 82.4%, and for posba, it was 82.3%. On the basis of the results of this study, prsba > 20 μmol/L or posba > 25 μmol/L (measured by use of an enzymatic procedure) indicates histopathologic abnormalities of the hepatobiliary system or portosystemic vascular anastomosis. Seemingly, determination of sba concentrations can be used to indicate the propriety for hepatic biopsy. Pre-and postprandial serum bile acids concentrations should be evaluated in conjunction with routinely used hepatobiliary screening tests for best diagnostic advantage.

Evaluation of Fasting and Postprandial Total Serum Bile Acid Concentration in Dogs with Hepatobiliary Disorders

The fasting and 2 h postprandial total serum bile acid concentrations (FSBA and PSBA), alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, bilirubin (Total), and retention of bromosulphthalein were determined in a group of dogs with various hepatobiliary disorders as well as in a group of dogs with other diseases than hepatobiliary disorders. Although FSBA and PSBA were generally elevated in cases of hepatobiliary disorders, no distinction between different disease groups could be made based solely on FSBA and PSBA. FSBA and PSBA were found to be relatively sensitive and specific parameters compared to the other hepatic tests. PSBA tended to be superior to the other parameters investigated in terms of sensitivity, specificity, positive predictive value, and negative predictive value.

Variations in Total Bile Acid Concentration in Serum of Dogs after a Test Meal

The purpose of this study was to examine the variations in total serum bile acid (SBA) concentration following oral administration of corn oil (3.0 ml per kg body weight) to six fasted healthy dogs using a previously validated automated method (JENSEN, 1991) for the determination of SBA concentration. The preprandial SBA concentration was 2.22 mumol/l (0.64-6.41 mumol/l) (median, 0.025-0.975 fractiles). In the 2-6 hours postprandial period, all the SBA concentrations were significantly different from the preprandial value, but not significantly different from each other. For the total 2-6 hours postprandial period the SBA concentration was 7.89 mumol/l (1.39-22.24 mumol/l). From these results it may be suggested that the reference range for the preprandial SBA concentration in dogs is 0.64-6.41 mumol/l, and that the reference range for the postprandial SBA concentration in a blood sample obtained 2 hours after oral administration of corn oil is 1.39-22.24 mumol/l.

Enteric Function in Cats after Subtotal Colectomy for Treatment of Megacolon

The enteric function of four cats that had undergone subtotal colectomy for megacolon was compared with that of four normal cats. All cats were fed the same diet before and during the study. History, physical condition, body weight, blood chemistry panel, fasting and postprandial serum bile acids, serum cobalamin concentration, serum folate concentration, fecal weight, fecal water content, fecal fat content, fecal osmolality and electrolyte concentration, quantitative anaerobic fecal bacterial culture, partial thromboplastin time, prothrombin time, breath hydrogen concentration, urinary calcium, phosphorus and electrolyte concentrations, and abdominal radiographic examination with air contrast studies (pneumocolon) were examined. The four cats treated surgically were healthy and thriving and, in general, enteric function was similar to the controls. Bowel movements occurred only slightly more frequently with no significant differences in fecal volume or water content. Serum cobalamin concentrations were significantly higher in cats treated surgically. Fecal sodium concentrations were high and fecal potassium concentrations were low. Results of this study did not show any significant subclinical evidence of abnormal bowel function in cats after subtotal colectomy.

Presence of endotoxemia and its relationship to liver dysfunction in patients with typhoid fever.

Twenty-one patients with typhoid fever were studied to evaluate the presence of endotoxin in peripheral blood and its relationship to the incidence and features of hepatic dysfunction which may occur during this disease. The limulus test for endotoxin was positive in the plasma samples of all patients prior to treatment. Liver dysfunction, as assessed by fasting and postprandial serum bile acid levels and by standard biochemical tests, occurred in 90% of patients. In seven, the injury was purely cholestatic (elevation of postprandial serum bile acid levels, alone); in 12, it was of mixed cholestatic-hepatocellular type (elevation of both serum bile acids and aminotransferase levels). After recovering, the limulus test was negative and liver function tests returned to normal values in all patients. The results demonstrate that endotoxemia is present in patients with typhoid fever. In addition, since endotoxin can impair bile secretion, our results suggest that endotoxin may have a pathogenetic role in the development of liver injury during typhoid fever.

Diagnostic sensitivity of fasting and postprandial serum bile acids determined by different methods

The diagnostic sensitivities of serum bile acids determined by three different methods in the fasting and in the postprandial state were compared in 43 patients with cirrhosis of the liver. When a method with high analytical sensitivity (capillary gas-liquid chromatography, GLC, or radioimmunoassay, RIA) was used, the serum concentrations of bile acids exhibited similar diagnostic sensitivities in the fasting state (GLC, 98%; RIA, 93%) and in the postprandial state (GLC, 95%; RIA, 93%). By contrast, when an enzymatic method with limited analytical sensitivity was employed, the diagnostic sensitivity of fasting serum bile acids was lower (79%) than that of postprandial serum bile acids (93%). The measurement of individual serum bile acids by GLC did not add any further diagnostic information. The results of this study demonstrate that the diagnostic sensitivity of serum bile acids strongly depends on the analytical method used.

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.

Treatment of liver disease with malotilate. A pharmacokinetic and pharmacodynamic phase II study in cirrhosis.

Malotilate, a sulphur-containing compound with antifibrotic and hepatoprotective properties in several animal models, has been investigated in cirrhotic patients. Nine patients with cirrhosis of various aetiologies and severity, and 4 healthy volunteers, participated in a pharmacokinetic study. After a single dose of 500 mg malotilate p.o. peak malotilate plasma concentration measured by GC-MS was 35 times higher in patients (median 0.70 micrograms/ml) than in controls (median 0.019 micrograms/ml). The median apparent oral clearance was approximately 50 times lower in cirrhotics (median 2.21/min) than in healthy volunteers (1181/min). The apparent oral clearance was significantly correlated with indicators of portal-systemic shunting, such as the 2-h postprandial serum bile acids and the bioavailability of oral nitroglycerine. Urinary output of the glucuronidated metabolite-(M3), measured by HPLC, was normal in patients, whereas recovery of metabolite-M6 (resulting from ring opening and loss of sulphur) was reduced. Six patients in an open 6-month trial received malotilate 200 mg t.i.d. for 2 months and 400 mg t.i.d. for 4 months. The thrombocyte count increased and serum ferritin level fell in all patients, and serum cholinesterase rose and IgA decreased in 5 of 6. The other indicators of liver function did not show a significant change. Dry skin was the only possible adverse effect. It is concluded that first-pass elimination of malotilate is dramatically reduced in cirrhotics, and that a smaller amount of the drug reaches the liver in such patients. Malotilate was well tolerated, even in patients with advanced disease.

Fasting and postprandial serum bile acid concentration with special reference to variations in the conjugate profile.

Serum bile acids were group-separated by ion exchange chromatography on diethylaminohydroxypropyl Sephadex LH-20 into unconjugated bile acids and bile acids conjugated with either glycine, taurine, glucuronic acid or sulphuric acid. The conjugate moiety was hydrolysed by treatment with a combination of Helix pomatia and cholylglycine hydrolase and the released bile acids analysed by gas liquid chromatography/mass spectrometry. Analysis of fasting and postprandial serum from six healthy subjects showed that, in addition to the primary bile acids, cholic (C) and chenodeoxycholic acid (CDC), secondary bile acids were present to varying extents. Unconjugated serum bile acids were found in four of the six subjects. Glycine and taurine conjugates of C and CDC and their glucuronides and sulphates were found in all subjects. The postprandial increase of serum bile acids was mainly due to increase of the glycine conjugates of C and CDC. After the meal, the ratio C:CDC in glycine and taurine conjugates shifted to lower values.

Abnormalities in Liver Function and Morphology and Impaired Aminopyrine Metabolism in Hereditary Hepatic Porphyrias

The aminopyrine breath test and measurement of postprandial serum bile acids were performed in 67 patients with well-documented hereditary hepatic porphyria. Elevated postprandial serum bile acids levels were found in 75% and the aminopyrine breath test was abnormal in 42% of the patients studied. These function tests exhibited a statistically significant correlation with the excretion of porphyrin precursors in patients with acute intermittent porphyria. Furthermore, all 12 patients with acute intermittent porphyria who had a liver biopsy because of abnormalities in the aminopyrine breath test or postprandial serum bile acids measurement, or both, were found to have diffuse, moderately severe, but nonspecific ultrastructural changes of hepatocytes, indicative of significant subcellular damage. While a direct relationship between functional and morphologic abnormalities is speculative, it is possible that the defective heme biosynthesis, perhaps related to the reduced aminopyrine demethylation, could form the basis for the ultrastructural hepatic changes in porphyria. This, in turn, could be the cause of the elevated postprandial serum bile acids levels.

Diagnostic Values of Fasting and Postprandial Concentrations in Serum of 3α-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.

Serum bile acids in Gilbert's syndrome before and after reduced caloric intake.

Fasting and postprandial serum bile acids were determined before and after reduced caloric intake in patients with Gilbert's syndrome. Cholic and chenodeoxycholic acid were determined by radioimmunoassay. In all patients there was a pronounced increase in serum bilirubin (mean increase, 140%) after caloric restriction. However, both fasting and postprandial levels of serum bile acids were within the normal range before and after reduced caloric intake. The results indicate that different mechanisms are involved in the hepatic uptake and secretion of bile acids and bilirubin. Moreover, the results show that determinations of serum bile acids can be used to assess liver function in patients with Gilbert's syndrome irrespective of the degree of hyperbilirubinemia.

Influence of the gallbladder on serum bile acids.

Serum bile acids (SBA) were studied after a standard fatty meal in patients with gallbladder disease. Early postprandial bile acid values were found to be greater in patients with non-functioning gallbladders. Higher postprandial SBA values were found after cholecystectomy. Serum bile acid measurements were of no value in the assessment of gallbladder function.

The aminopyrine breath test and serum bile acids reflect histologic severity in chronic hepatitis.

To determine whether the aminopyrine breath test (ABT) and serum bile acid concentrations reflect histologic severity of chronic hepatitis, 56 patients were prospectively evaluated with liver biopsies and ABTs, and the results were compared to results of standard liver chemistry tests; 44 of these patients also had fasting and 2-hr postprandial serum bile acid measurements. Mean values for the ABT were significantly lower, and serum bile acids were significantly higher in patients with chronic active hepatitis with bridging or cirrhosis than in patients with mild chronic active hepatitis or chronic persistent hepatitis. Thirty of 35 patients with bridging or cirrhosis had ABTs less than 5.7% (mean of controls -2 S.D.) and 21 of 25 with mild chronic active hepatitis or chronic persistent hepatitis had values greater than 5.7% (sensitivity 0.86, specificity 0.84). Fasting and 2-hr postprandial bile acids were also more sensitive than standard chemistries in identifying patients with bridging or cirrhosis. Thus, the ABT and serum bile acids reflect histologic severity in chronic hepatitis patients and may be helpful in selecting patients for liver biopsy.

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

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

Postprandial serum bile acids in resected and non-resected patients with Crohn's disease.

Fasting and postprandial serum conjugates of cholic acid (CCA) and chenodeoxycholic 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 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.