Tsuyoshi Kajihara

A Combination Therapy With Simvastatin and Ursodeoxycholic Acid Is More Effective for Cholesterol Gallstone Dissolution Than Is Ursodeoxycholic Acid Monotherapy

Inhibitors of 3-hydroxy,3-methylglutaryl coenzyme A (HMG-CoA) reductase have been reported to decrease the cholesterol saturation index (CSI) in duodenal bile in humans and to prevent formation of cholesterol gallstones in animal studies. We performed a prospective study to evaluate the role of HMG-CoA reductase inhibitors as gallstone-dissolving agents. Fifty patients with radiolucent gallstones in a gallbladder opacifying at drip infusion cholecystography were treated with either 10 mg/day simvastatin plus 600 mg/day ursodeoxycholic acid (group 1, n=26) or 600 mg/day ursodeoxycholic acid alone (group 2, n=24) for 12 months. The ratio of solitary to multiple gallstone cases was 21:29. Plasma lipid levels were assessed and ultrasonographic examination of the gallbladder was performed at baseline and at 3-month intervals during treatment. Duodenal bile sampling was performed in five patients in each group at baseline and after 12 months of treatment. Plasma cholesterol decreased significantly in group 1 but not in group 2. In solitary gallstone cases, no significant difference in dissolution rates was observed between groups 1 (3 of 9, 33%) and 2 (4 of 12, 33%). In contrast, the dissolution rate in multiple gallstone cases was significantly higher in group 1 (12 of 17, 71%) than in group 2 (3 of 12, 25%) (p < 0.01). Bile cholesterol saturation index was significantly decreased (p < 0.01) but did not significantly differ between the two groups. These results suggest that combination therapy with simvastatin and ursodeoxycholic acid is more effective for cholesterol gallstone dissolution than ursodeoxycholic acid monotherapy in patients with multiple gallstones.

Factors affecting gallstone recurrence after successful extracorporeal shock wave lithotripsy.

Ninety-six patients treated successively for symptomatic cholelithiasis with extracorporeal shock wave lithotripsy (ESWL) and oral bile acid therapy consisting of ursodeoxycholic acid in daily dosages of 600 mg were prospectively followed for gallstone recurrence for a median of 13 months. Ultrasonography was performed to detect stone recurrence at 3, 6, and 12 months, and then yearly after the termination of therapy. Recurrent stones were found in 17 patients (18%). The cumulative probability of gallstone recurrence was 15.8% at 12 months, 26.1% at 24 months, and 30.7% at 36 months. The probability of stone recurrence over the entire period of observation was not dependent on stone number, whereas the median interval to detection of recurrence was significantly shorter in the patients with multiple stones (2 months) than in those with solitary stones (8 months) (p < 0.05). The rate of impaired gallbladder contractility was higher in patients with recurrence (8/15, 53.3%) when compared with those with no recurrence (15/72, 20.8%) (p < 0.01). Neither age, gender, or stone characteristics predicted stone recurrence. Only one patient with a recurrence reported biliary pain. Of the 15 patients with recurrent stones who opted for further nonsurgical treatment, complete stone disappearance was achieved in 10. Impaired gallbladder function may predict gallstone recurrence after ESWL.

Role of Phospholipase A2 in Cholesterol Gallstone Formation Is Associated with Biliary Phospholipid Species Selection at the Site of Hepatic Excretion

Phospholipase A2 plays a role in cholesterol gallstone development by hydrolyzing bile phospholipids into lysolecithin and free fatty acids. Lysolecithin and polyunsaturated free fatty acids are known to stimulate the synthesis and/or secretion of gallbladder mucin via a prostanoid pathway, leading to enhancing cholesterol crystal nucleation and growth, and therefore, the action of phospholipase A2 is associated, in part, with bile phospholipid fatty acid. To clarify this hypothesis, we evaluated the effect on bile lipid metastability in vitro of replacing phospholipids with lysolecithin and various free fatty acids. Supersaturated model biles were created with an identical composition (cholesterol saturation index, 1.8; egg yolk lecithin, 34 mM; taurocholate, 120 mM; cholesterol, 25 mM) except for 5%, 10%, or 20% replacement of egg yolk lecithin with a combination of palmitoyl–lysolecithin and a free fatty acid (palmitate, stearate, oleate, linoleate, or arachidonate), followed by time-sequentially monitoring of vesicles and cholesterol crystals using spectrophotometer and video-enhanced differential contrast microscopy. Replacement with hydrophilic fatty acids (linoleate and arachidonate) reduced vesicle formation and promoted cholesterol crystallization, whereas an enhanced cholesterol-holding capacity was evident after replacement with hydrophobic fatty acids (palmitate and stearate). These results indicate that the effect of phospholipase A2 on bile lithogenecity is modulated by the fatty acid species in bile phospholipids, and therefore, that the role of phospholipase A2 in cholesterol gallstone formation is dependent, in part, on biliary phospholipid species selection at the site of hepatic excretion.

Effects of bilirubin ditaurate on biliary secretion of proteins and lipids: Influence on the hepatic vesicle transport system

Background : Several organic anions cause dissociation of biliary lipid secretion from bile acid secretion (uncoupling). As bile lipids originate from liver microsomes and are transported by carrier proteins and/or transcytotic vesicles, such a reduction of biliary lipid secretion may lead to cytosolic accumulation of vesicles. This study investigated whether bilirubin conjugate, a physiologically important organic anion, caused uncoupling and whether hepatic retention of compounds carried by transcytotic vesicles occurred subsequently, using bilirubin ditaurate, a synthetic commercially available compound.

Effects of Cerivastatin Sodium, a New HMG-CoA Reductase Inhibitor, on Biliary Lipid Metabolism in Patients with Hypercholesterolemia

The use of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors has become common in the treatment of hypercholesterolemia. The present uncontrolled study was undertaken to determine the effect of cerivastatin sodium (BAY w 6228), a new HMG-CoA reductase inhibitor, on biliary lipid levels in patients with hypercholesterolemia. Twenty-one hypercholesterolemic patients (World Health Organization type IIa = 16 patients; type IIb = 5 patients) received placebo during a 4- to 6-week observation period, after which they received cerivastatin sodium 0.2 mg/d for 12 weeks. Fasting blood samples were drawn for the measurement of serum lipid levels early in the morning before the start of treatment and once a month for each of the 12 weeks of cerivastatin sodium treatment. Gallbladder bile samples were aspirated with a duodenal tube by cerulein stimulation to assess bile lithogenicity. Serum total cholesterol levels decreased markedly after 12 weeks. However, no significant difference was found in the molar percentage composition of biliary lipids (e.g., cholesterol, phospholipids, and total bile acids) or in individual biliary bile acids. Consequently, no significant change in bile cholesterol saturation index was found. The index values before and after 12 weeks of treatment were 0.81 +/- 0.38 and 0.80 +/- 0.47, respectively, whereas when patients were grouped by type of hypercholesterolemia, there was a tendency toward decreased lithogenicity in patients with type IIb but not type IIa hypercholesterolemia. We concluded that cerivastatin sodium was an effective cholesterol-lowering drug that did not appear to worsen biliary lipid metabolism and that may decrease lithogenicity in patients with type IIb hypercholesterolemia.

A quantitative assessment of serum chylomicron by light scattering intensity: Application to the intestinal fat absorption test

A novel fat absorption test to clarify the malabsorption syndrome was developed using a micronephelometric technique and compared with the classic conventional technique using 131I‐triolein. An integrity of time‐sequential light scattered from chylomicron‐related turbidity in serum was determined between 0 and 300 min after butter fat load, being expressed in terms of the light scattering intensity (LSI). A good correlation was obtained between LSI and the serum level of chylomicron‐triglyceride determined by an ultracentrifugation technique (r=0.819, P < 0.001). The maximal LSI was consistently observed at 180 min after administration of a test meal in the normal group (n= 39), whereas the malabsorption syndrome group (n= 35) was distinctly different and could be further classified according to four patterns of LSI changes. In addition, an inverse correlation was found between this fat absorption test and the 131I‐triolein absorption test. It was concluded that the micronephelometric technique which does not use a radionuclide is advantageous in its simple and safe evaluation of fat malabsorption syndrome.

Effect of organic anions on acyl chain composition of secreted biliary lecithin in rats: relation to hepatocellular vesicle pathway☆

Abstract Organic anions can uncouple bile salt secretion from the secretion of phospholipid and cholesterol. The uncoupling mechanism appears to be dependent on the type of anion present. To investigate the effect that different uncoupling mechanisms may have on the flow of bile and its composition, rats were depleted of bile salt pool by overnight biliary diversion and reinfused intravenously with sodium taurocholate (STC) at a constant rate (160 nmol/min per 100 g b.w.). After bile salt secretion had achieved a steady state, sulfobromophthalein (BSP) or papaverine was continuously administered at a rate of 100 nmol/min per 100 g b.w. with STC. During the intravenous infusion of BSP or papaverine, the output of biliary lecithin and cholesterol decreased without affecting bile salt output. The degree of fatty acyl chain saturation in biliary lecithin was increased by BSP infusion and decreased by papaverine infusion. The mechanism by which bile salt secretion is uncoupled from the secretion of phospholipid and cholesterol affects the acyl chain composition of secreted lecithin. The changes in composition of lecithin acyl chains may reflect the intervention by different anions at different points in the lipid transport pathway.

Tauroursodeoxycholate and taurochenodeoxycholate stabilize bile lipid metastability through different mechanisms: relation to phospholipid fatty acid composition

Abstract Lecithin–cholesterol vesicles are present in bile and play a role in cholesterol metastability. Cholesterol holding capacity of vesicles is regulated by lecithin hydrophobicity. In the present study, the effect of therapeutic bile salts on biliary lipid secretion rate and phospholipid fatty acid composition was evaluated in bile duct-fistula rats to determine whether bile salts modulate biliary phospholipid species to, thereby, regulate a physico-chemical metastability of bile cholesterol. Rats were depleted with bile salt pool by overnight biliary diversion and reinfused intravenously with sodium taurocholate (TC) at a constant rate (200 nmol/min per 100 g b.w.) for 3 h, followed by infusion of either sodium taurochenodeoxycholate (TCDC) or tauroursodeoxycholate (TUDC) at a compatible rate. TCDC-infusion increased the biliary secretion rate of cholesterol and phospholipids with a decrease in molar ratio of cholesterol to phospholipid ( C / P ) when compared to values under TC-infusion, and this was associated with an increase in the molar ratio of phospholipid saturated to unsaturated fatty acids ( S / U ). In contrast, TUDC-infusion decreased such a biliary lipid secretion rate with an increase in C / P , and this was associated with a decrease in a molar ratio of arachidonate in phospholipids. These findings indicate that TCDC enhances a cholesterol packing density of biliary particulate species by decreasing C / P ratio and increasing S / U , whereas TUDC improves bile lithogenecity by decreasing biliary cholesterol and phospholipid secretion rates and reducing bile arachidonyl phospholipids.