Effect of cholecystectomy on mouth-to-cecum transit of a liquid meal

Mouth-to-cecum transit and serum bile acid profile after ingestion of a lactulose-labeled liquid meal (440 kcal) were measured in eight patients with gallstones and a radiologically functioning gallbladder before and three to five months after cholecystectomy and in 15 controls. In the patients mouth-to-cecum transit was longer after the operation, 87.5±18.5 (mean±sem)min vs 57.5±9.7 min (P<0.05). Mouth-to-cecum transit times before and after the operation were not different from controls (58.0±6.7 min). Serum bile acid AUCs were similar (P = NS) in patients and controls, while total bile acid and cholylglycine fasting concentrations were higher after cholecystectomy (P<0.05 andP<0.01 respectively). Cholecystectomy prolongs mouth-to-cecum transit of a liquid meal.     

Bacterial Flora of the Small Intestine and Bile Acid Metabolism in Patients with Hepatico-Jejunostomy Roux-en-Y

Duodenal and jejunal bacterial flora and bile acid metabolism were investigated in 14 patients with hepatico-jejunostomy Roux-en-Y. Anaerobic culture procedures were based on the use of a glove-box with an oxygen-free atmosphere and pre-reduced, anaerobically sterilized media. Anaerobic transport was based on evacuation of atmospheric air from transport-tubes and transport-time less than 30 minutes. Bile acid metabolism was evaluated from concentrations of total bile acids and deconjugated bile acids, glycine/taurine ratio and breath test. In 92 per cent of the patients an abnormal flora containing anaerobic and/or aerobic bacteria was found in the most proximal part of the jejunum at the site of the entero-entero anastomosis (cf. Fig. 1 and Table I). Total bile acid concentrations were low in half of the patients, whereas deconjugated bile acids or elevated glycine/taurine ratio was found in one patient only (cf. Table II). An abnormal breath test was found in 5 patients, but without any clear correlation between the breath test and the bacterial flora.     

Triolein breath test of fat absorption in patients with chronic liver disease

We have compared the [¹⁴C]triolein breath test for fat malabsorption with fecal fat excretion corrected for marker pellet recovery in 23 subjects with chronic liver disease. The breath test identified 15 of the 17 subjects with abnormal fecal fat excretion (sensitivity 88%). However, four of the six subjects with normal fecal fat excretion gave abnormal breath test results (specificity 33%). While three of the four subjects with falsely abnormal breath tests had alcoholic liver disease, the explanation for the low specificity is unclear and may not be confined to patients with alcohol-related disease. We are therefore unable to recommend the breath test as a screen for steatorrhea in patients with chronic liver disease.     

Influence of Cholestasis on Absorption of Ursodeoxycholic Acid

Ursodeoxycholic acid (UDCA) has beneficialeffects in cholestatic liver diseases. Absorption ofUDCA is slow and incomplete. In the present study theeffect of cholestasis on absorption was evaluated in 10 patients with pancreatic carcinoma andextrahepatic biliary drainage. At days 3 and 10 afterinsertion of the biliary drain, all patients received750 mg UDCA in three divided doses. On both occasions intestinal absorption of UDCA was determined toevaluate the influence of cholestasis. Serum bilirubinwas used as indicator of cholestasis. Biliary output ofUDCA served as measure of absorption and was determined by gas-liquid chromatography. Atdays 4 and 11 bile consisted of less than 2% of UDCA,indicating that UDCA excretion was complete within 24 hrand no accumulation of UDCA had occurred. After insertion of the drain, serum bilirubindecreased from 12.2 ± 2.4 mg/dl at day 3 to 5.4± 0.9 mg/dl at day 10. Biliary secretion of bileacids increased from 2.0 ± 0.3 to 3.1 ±0.4 mmol/day, whereas percentage of ursodeoxycholic acid in bile didnot significantly increase (41.1% vs 42.1%). Absorptionof UDCA increased from 39.8 ± 5.0% to 61.1± 6.2% of the administered dose, indicating animprovement of the absorption rate after decrease ofcholestasis by 53.65% (P < 0.05). In conclusion, insevere cholestasis absorption of orally administeredUDCA is markedly reduced. This may have implications in the treatment of patients with cholestaticdisease.     

Meal-Stimulated Secretin Release in Man: Effect of Acid and Bile

Nine normal subjects were studied before and after intragastric instillation of a liquid meal. Gastric emptying rates of acid and pancreaticobiliary secretions were quantitated by means of a dilution indicator technique. A significant, positive correlation was found between load of acid to the duodenum and the concentration of secretin in plasma. No correlation was found between load of bile acids and plasma secretin. The buffering capacity of gastric contents should bc taken into account when fasting and postprandial period are compared. Plasma secretin concentration remained low during the first postprandial hour. Maximum secretin concentrations and duodenal disappearance rate of acid was observed 1 1/2-2 h after instillation of the meal. In contrast, trypsin output was maximum within 10 min. The data support the concept that in man release of secretin is governed principally by the amount of hydrogen ions emptied into duodenum and indicate the importance of secretin in the late postprandial period, when the acidity of the gastric contents is high.     

Ursodeoxycholic acid and in vitro vasoactivity of hydrophobic bile acids

Lipophilic bile acids, such as deoxycholic acid (DCA), are nonspecific endothelium-independent vasorelaxants whose underlying basis is complex, involving membrane calcium channels blockade and receptor antagonism. The vasorelaxant action of these acids has also been linked to the generation of reactive oxygen species and an increased extent of lipid peroxidation. Ursodeoxycholic acid (UDCA) is a naturally occurring tertiary dihydroxy hydrophilic acid whose mechanism of action has been attributed to minimizing the effects of lipophilic bile acids. Hence, we considered UDCA might be a useful pharmacological tool to delineate the role of enhanced lipid peroxidation in lipophilic bile acid-induced vasorelaxation. UDCA abrogates in vitro DCA-induced vasorelaxation in rat aortic rings and can suppress DCA-initiated lipid peroxidation in vascular smooth muscle microsomal membrane fractions prepared from the rat aortae. Three different studies were performed. In study 1, the ability of UDCA to restore the DCA-blunted contractile response to the ₁-adrenoceptor, phenylephrine in rat aortic rings, was evaluated. In study 2, the ability of UDCA to restore DCA-induced vasorelaxation in precontracted rat aortic rings was assessed. In study 3, the ability of UDCA to suppress the increased extent of lipid peroxidation effected by DCA in vascular smooth muscle microsomal membrane fractions prepared from rat aortae was measured using the thiobarbituric acid reactive substance (TBARS) assay. UDCA, at a concentration equivalent to that seen in the plasma of patients with cholestatic liver disease treated with the bile acid, partially restored DCA-induced impaired contractility, prevented DCA-induced vasorelaxation, and abolished DCA-induced increases in the extent of lipid peroxidation. In conclusion, these data suggest that DCA-induced vasorelaxation is mediated by increasing the extent of lipid peroxidation in vascular tissue.     

Intestinal Absorption of Reduced Folate Compounds in Man

S ummary . Oral administration of folate compounds was followed by a rise in L. casei active factors in blood. This was due to reduction and methylation of the folate compounds in the small gut and this was demonstrated by the use of dihydropteroylglutamic acid labelled with tritium.
Parenteral administration of tritium-labelled folate analogues was followed by a rapid exchange with unlabelled L. casei active folate from tissues.     

The Effect of Vasoactive Intestinal Polypeptide on Meal-Stimulated Gastric Acid Secretion in Man

The effect of vasoactive intestinal polypeptide (VIP) on meal-stimulated gastric acid secretion was studied in six healthy volunteers. Acid secretion was stimulated by instillation of a 10% solution of peptone, which was adjusted to pH 5.5, circulated through the stomach via a double-lumen gastric tube by a peristaltic pump. The acid secretion was estimated by continuous titration by a pH-stat. The subjects were studied twice on separate days, receiving an intravenous infusion of either VIP (1 μg/kg/h or saline. No effect on acid secretion was found. Mean serum gastrin concentration rose from 42 pmol/l to 150 pmol/l during meal stimulation and was unaffected by infusion of VIP. Plasma VIP concentration during infusion of saline was 6.8 pmol/l and during VIP infusion, 82.8 pmol/l. Plasma VIP concentration was unaffected by the peptone meal.     

Ursodeoxycholic acid reduces CpG-induced IgM production in patients with primary biliary cirrhosis

Aim:  Ursodeoxycholic acid (UDCA) treatment reduces IgM serum levels in patients with primary biliary cirrhosis (PBC) without affecting serum antimitochondrial antibody (AMA) titers. We previously reported that PBC-associated hyper-IgM is secondary to a disease-specific hyperproduction following bacterial stimulation by B cells.
Methods:  We isolated peripheral blood mononuclear cells (PBMC) from patients with PBC and controls and evaluated whether bacterial CpG challenge in the presence of UDCA at concentrations consistent with those achieved in treated patients led to changes in total IgM, IgG-AMA, and IgM-AMA production. Further, p65 phosphorylation and CD38 cell expression were analyzed as measures of activation of the NF-kB signaling pathway and B cell subsets, respectively.
Results:  UDCA significantly reduced CpG-induced total IgM and IgM-AMA production, but had no impact on IgG-AMA production. UDCA also significantly reduced the activation ofnaïve and IgM memory, but not IgG memory, B cells, as represented by CD38 expression levels. Further, p65 phosphorylation was significantly reduced in the presence of UDCA.
Conclusion:  UDCA reduces total and IgM-AMA production in PBMC from patients with PBC by downregulating B cell activation and NF-kB signaling. These data ultimately suggest novel mechanisms of action for UDCA in chronic autoimmune cholestasis.     

Comparison of Three Bile Acid Provocation Tests: Intravenous Cholecystokinin,a Standard Test Meal,and an Oral Bile Acid Load in Healthy Subjects

Three different bile acid provocation tests—an intravenous stimulation with cholecystokinin (CCK), a test meal, and an oral bile acid load of 500 mg chenodeoxycholic acid (CDAF—were compared in 12 healthy subjects. Blood samples were drawn every 30min for 3 h, and serum bile acids (SBA) were measured by an enzymatic method (Enzabile®). The CCK stimulation gave significant SB A elevations only at 30 min. After the test meal and the CDA loading tests SB A elevations were observed from 30 min and throughout the observation period. Maximal increases were obtained at 120 min after the test meal but already at 30 min after the CDA loading test. We conclude that among these three bile acid provocation tests the oral CDA loading test is to be preferred because it gives marked and rapid elevation of SBA in all subjects and is independent of bile acid pool size and normal function of the gallbladder.     

A Computer Model Simulating the Intestinal Absorption of Bile Acids

Mathematical models were developed for assessment of the absorption kinetics of compounds passing down the length of a perfused intestinal segment. The models considered the intestinal segment as a cylinder composed of a large number of very small (infinitesimal) cylinders and described the concentration decline of the compound in situations with active, passive and combined active and passive transport. The maximal velocity of active transport, V_max, the Michaëlis-Menten constant, K_m and the permeability coefficient, P, were calculated. A computer program was developed to operate the mathematical expressions. The models were validated by jejunal and ileal perfusions of various bile acids in six healthy volunteers. The fit between the mathematical models and the actually measured data showed an average standard deviation of 0.14mmol/l (substrate infusion concentration ranging from 0.25 mmol/1 to 3.0 mmol/1). It was concluded that the computer models were feasible for practical purposes. Moreover, the models reduced the number of perfusions necessary to determine the absorption kinetics of a given bile acid.     

Effect of 3-Hydroxy-3-Methylglutaric Acid Administration on Bile Lipid Composition in Humans

The effects of the lipid-lowering agent 3-hydroxy-3-methylglutaric acid (HMGA) on serum lipids and on biliary lipid composition were evaluated in a double-blind, placebo-controlled study in normolipidemic volunteers. After 4 weeks of HMGA administration (1 g three times a day orally) serum total cholesterol showed a significant decrease with regard to both pretreatment values and corresponding values of controls. The bile lipid molar percentage composition and the cholesterol saturation index showed no modification after HMGA and did not differ from the values obtained in the placebo group. These findings indicate that HMGA exerts no adverse effects on bile lipid composition in humans, differing from other hypolipidemic drugs currently in clinical use, which increase the bile cholesterol saturation index.     

Ursodeoxycholic Acid in the Treatment of Chronic Liver Disease

Recent data have suggested that ursodeoxycholic acid (UDCA) is useful in the treatment of a variety of chole-static and chronic liver diseases. Symptomatic and biochemical improvement have heen ohserved in diseases such as primary biliary cirrhosis, primary sclerosing cholangitis, and cystic fibrosis, but data on histological improvement and survival are limited. The purpose of this article is to review the proposed mechanisms of action of UDCA and to critically evaluate the existing literature reporting a heneficial therapeutic effect of UDCA in the treatment of chronic liver disease.     

Ursodeoxycholic Acid for Treatment of Enlarged Polycystic Liver

Patients with autosomal dominant polycystic kidney disease and polycystic liver disease (PLD) often have elevated serum levels of alkaline phosphatase (ALP) and gamma‐glutamyl transpeptidase (GGT). Ursodeoxycholic acid (UDCA) is used to treat biliary tract diseases, but its effect on PLD remains unclear. UDCA was administered for 1 year at a dose of 300 mg daily to seven PLD patients with elevated ALP or GGT levels who were selected for this treatment by experienced clinicians. Laboratory data and liver volumes were compared among three time points: 1 year before UDCA treatment, at the start of UDCA therapy, and 1 year after the start of therapy. Median GGT did not show a significant change between 1 year before UDCA (180 IU/L) and the start of UDCA therapy (209 IU/L), but it decreased significantly to 98 IU/L after 1 year of UDCA therapy (P = 0.015 vs. the start of therapy). ALP showed a significant increase from 1 year before UDCA (456 IU/L) to the start of UDCA therapy (561 IU/L), and then decreased significantly after 1 year of UDCA therapy (364 IU/L). Median liver volume did not show any significant changes among these three time points of assessment. UDCA may be effective for reducing biliary enzyme levels and inhibiting the growth of liver cysts in patients with PLD.     

Physiology of Intestinal Absorption and Secretion

Virtually all nutrients from the diet are absorbed into blood across the highly polarized epithelial cell layer forming the small and large intestinal mucosa. Anatomical, histological, and functional specializations along the gastrointestinal tract are responsible for the effective and regulated nutrient transport via both passive and active mechanisms. In this chapter, we summarize the current state of knowledge regarding the mechanism of intestinal absorption of key nutrients such as sodium, anions (chloride, sulfate, oxalate), carbohydrates, amino acids and peptides, lipids, lipid- and water-soluble vitamins, as well as the major minerals and micronutrients. This outline, including the molecular identity, specificity, and coordinated activities of key transport proteins and genes involved, serves as the background for the following chapters focused on the pathophysiology of acquired and congenital intestinal malabsorption, as well as clinical tools to test and treat malabsorptive symptoms.     

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.     

Intestinal absorption of bile acid glucuronides in rats

While the intestinal absorption of taurine, glycine, and sulfate conjugates of bile acids has been studied extensively, nothing is known about the absorption of bile acid glucuronides. In the present study, the intestinal phase of the enterohepatic circulation of two bile acid glucuronides was examined. [3-³ H]cholic acid 3-O--d-glucuronide or [3^–3 H]lithocholic acid 3-O--d-glucuronide was perfused through isolated segments of ileum or jejunum with intact blood supply in rats prepared with a biliary fistula. [¹⁴C]Taurocholic acid was perfused simultaneously with each glucuronide to compare glucuronide absorption with that of an actively transported bile acid. Intestinal absorption was determined by measuring the rate of secretion of labeled bile acid in bile. The absorption of [³H]cholic acid glucuronide by the ileum and jejunum was one fortieth and one eighth, respectively, that of [¹⁴C]taurocholic acid. Comparison of the two glucuronides show that [³H]lithocholic acid glucuronide absorption was 18 and 10 times greater than [³H]cholic acid glucuronide absorption from the jejunum and ileum, respectively. Collectively, the above observations suggest that glucuronidation of bile acids markedly reduces absorption from the small intestine.This work was supported in part by the National Institutes of Health, grant HD-14198, and the March of Dimes Foundation, grant G-305.