The pathogenesis of gallstone formation.
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Absorption↗
Biomedical subjects
M Z Abedin
Publications and source records attributed to M Z Abedin.
Altered Na+ and Cl- flux during diet-induced mixed gallstone formation in the prairie dog.
Recent studies suggest that altered gallbladder absorptive function may be an important and previously unrecognized factor in the pathogenesis of experimentally induced gallstones. The present study was designed to define the specific changes in gallbladder epithelial ion transport that occur during mixed gallstone formation. Fifteen prairie dogs were fed either control or corn-alfalfa chow for six months. No control animals developed gallstones or crystals. Three of eight corn-alfalfa-fed animals had large black stones, and the remaining five had crystals ("pregallstone" group). Corn-alfalfa-fed animals had significant increases in gallbladder bile cholesterol, phospholipids, and calcium as compared to controls. Gallbladders were removed and mounted in a Ussing chamber for electrophysiologic and ion flux studies. Gallbladders from animals fed corn-alfalfa demonstrated significant decreases in short-circuit current and potential difference as compared to controls (P less than 0.05). 22Na and 36Cl were used to determine unidirectional ion fluxes. While net ion fluxes were similar in pregallstone animals and controls, stone-forming animals exhibited a significant decrease in net Na+ flux and a significant reversal in the direction of net Cl- flux (from secretion to absorption) as compared to controls (P less than 0.05). These data indicate that mixed gallstone formation is associated with alterations in gallbladder ion transport. The role of these changes in the pathogenesis of mixed gallstones remains to be determined.
Animal Nutritional Physiological Phenomena↗
The effects of extracellular calcium on prairie dog gallbladder ion transport.
Recent studies suggest that experimentally induced gallstone formation is associated with altered gallbladder absorptive function. Moreover, elevated biliary levels of calcium have been implicated in the pathogenesis of cholesterol gallstones. Nonetheless, the relationship between gallbladder ion transport and biliary calcium remains obscure. We tested the hypothesis that extracellular calcium modulates gallbladder ion transport. Prairie dog gallbladders were mounted in an Ussing chamber, and short-circuit current (Isc), transepithelial potential difference (Vms), and tissue resistance (Rt) were measured. Tissues were randomly exposed to physiologic salt solutions containing the following concentrations of calcium: 0.01, 1.3, 5, and 10 mmol/L. Exposure of gallbladder epithelium to increasing calcium concentrations resulted in concomitant increases in Isc and Vms (p < 0.001), without altering Rt. Regression analysis demonstrated a curvilinear correlation between calcium and Isc (Y = 167 + 22.5x - 1.4 x 26; p < 0.001). We conclude that extracellular calcium may be a modulator of gallbladder ion transport.
Animals↗
Intrahepatic cholesterol stones: a rationale for dissolution therapy.
A case of primary cholesterol hepatolithiasis is reported. Stone composition was documented by infrared spectroscopy, and the presence of cholesterol saturated bile was demonstrated using standard biochemical techniques. The patient was treated with operative stone extraction, choledochoscopy, biliary enteric anastomosis, and oral dissolution therapy. The administration of oral dissolution agents has altered the composition of the patient's bile and may prevent further stone formation. We advocate the use of both stone and biliary biochemical analysis for patients with primary hepatolithiasis to facilitate optimal therapy.
Bile↗
Intracellular calcium modulates gallbladder ion transport.
Although experimentally induced cholesterol gallstone formation has been associated with altered gallbladder (GB) absorption and increased biliary Ca2+, the relationship between these events remains unclear. Recent studies suggest that extracellular Ca2+ ([Ca2+]ec) influences GB ion transport. Whether the effects of [Ca2+]ec are mediated by changes in intracellular Ca2+ ([Ca2+]ic) has not been determined. This study was designed to define the effects of altered [Ca2+]ic on GB ion transport. Prairie dog GBs were mounted in a Ussing chamber and short-circuit current (Isc), potential difference (Vms), and resistance (Rt) were recorded. Mucosal surfaces were exposed to either Dantrolene (Dt) or nickel (Ni2+). Dt "traps" [Ca2+]ic within intracellular organelles, thereby lowering cytosolic Ca2+; and Ni2+ prevents influx of [Ca2+]ec, presumably by binding Ca2+ channels. Although Dt reduced both Isc and Vms (P less than 0.01), these effects were transient. Transport recovery was probably due to increased [Ca2+]ec influx with restoration of [Ca2+]ic. Ni2+ resulted in sustained decreases in Isc and Vms (P less than 0.05) despite subsequent addition of 10 mM Ca2+. These findings are consistent with the prevention of [Ca2+]ec influx by Ni2+. We conclude that: (1) [Ca2+]ic may be a modulator of GB ion transport and (2) previously reported [Ca2+]ec effects on ion transport may be mediated through [Ca2+]ic concentration changes.
Animals↗
Uncoupled basal sodium absorption and chloride secretion in prairie dog (Cynomys ludovicianus) gallbladder.
1. Prairie dog gallbladders mounted in a Ussing-type chamber and bathed with symmetrical Ringer's solutions exhibited a transepithelial resistance (Rt) of 51 +/- 5 omega cm2, a lumen negative potential difference (Vms) of 11.5 +/- 0.7 mV and a short-circuit current (Isc) of 6.9 +/- 0.3 microEq/hr/cm2. 2. Radioisotopic ion flux experiments revealed that the basal Isc of 6.9 +/- 0.3 microEq/hr/cm2 was mostly accounted for by net Na+ absorption of 3.2 +/- 0.5 microEq/hr/cm2 and net Cl- secretion of 2.9 +/- 0.3 microEq/hr/cm2. 3. In HCO3- free Ringer's, net Na+ flux was virtually abolished, net Cl- flux decreased by 50% and Isc was reduced by 77%. 4. 10(-3) M mucosal amiloride and DIDS reduced Isc by 28 and 24%, respectively. 5. Mucosal NaCl diffusion potentials indicated that the paracellular pathway was cation selective. 6. Thin section electron micrographs showed a single cell population in this epithelium suggesting that net Na+ absorption and Cl- secretion may emerge from the same cells. 7. We conclude that prairie dog gallbladder epithelium is an electrogenic tissue and, in contrast to gallbladders of most other species, simultaneously but independently absorbs Na+ and secretes Cl-.
Animals↗
Lovastatin inhibits gallstone formation in the cholesterol-fed prairie dog.
The efficacy of lovastatin, an inhibitor of hepatic cholesterol synthesis in the prevention of cholesterol gallstone formation, was evaluated in the prairie dog model. Two groups of animals were maintained on either nonlithogenic or 1.2% cholesterol-enriched chow for 21 days. Seven of the animals in each group received lovastatin, and the remaining six received only distilled water. All of the cholesterol-fed/water-treated animals had crystals and 83% had gallstones, but none of the cholesterol-fed/lovastatin-treated animals had gallstones and only three had microscopic crystals. These data indicate that lovastatin inhibits cholesterol gallstone formation in a diet-induced model of gallstone disease.
Animals↗
Reoperative surgery for the morbidly obese. A university experience.
Patients who undergo surgery for morbid obesity are often subjected to reoperation for a wide array of indications. To evaluate outcome following revisional procedures, we reviewed the records of 32 such patients treated at UCLA between April 1986 and May 1989. Twenty-five women (78%) and 7 men (22%) with a mean age of 44 years underwent 76 reoperations (2.4 per patient) for complications of prior obesity surgery. Indications for initial surgical revision consisted primarily of metabolic derangements (12 patients) and weight-related problems (11 patients). In contrast, indications for the patients' final surgical procedure were commonly for bowel obstruction (41%), intra-abdominal sepsis (12%), and gastrointestinal bleeding (6%). Following initial revision, 23 patients (71.8%) required further surgery for major complications and four patients died (12.5%). While initial revisions are frequently indicated for metabolic problems, final reoperations are more frequently undertaken for urgent, life-threatening complications. Revisional procedures for morbid obesity should be carefully considered, and the potential for major complications and/or death should be weighted heavily against proposed benefits.
Adult↗
Ca2+ channel blockade inhibits gallbladder ion transport.
Recent studies suggest that cholesterol gallstone (GS) formation is characterized by altered gallbladder epithelial ion transport and increased gallbladder (GB) luminal Ca2+. Moreover, intracellular Ca2+ has been reported to be an important modulator of intestinal ion transport. The aim of the present study was to determine the effects of Ca2+ channel inhibition on GB ion transport. Prairie dog GBs were mounted in a Ussing chamber and bathed in warm oxygenated Ringer's solution, and short-circuit current (Isc), transepithelial potential difference (Vms), and tissue resistance (Rt) were recorded. Following stabilization, the mucosal surfaces of the GBs were exposed to 1 or 0.1 mM verapamil (VER). Effects on Isc were apparent within 10 sec with nadir values reached in 5 +/- 1 min. Profound (76%) inhibition of Isc was seen with 1 mM verapamil exposure (26 +/- 6 microA.cm-2) as compared to baseline values (170 +/- 6 microA.cm-2) (P less than 0.001). Verapamil exposure (1 mM) also led to a marked inhibition of Vms (P less than 0.001, vs baseline) and a significant increase in Rt (P less than 0.05 vs baseline). Similar trends were seen using 0.1 mM verapamil (Isc nadir 133 +/- 13 microA.cm-2). Verapamil-induced effects on gallbladder electrophysiology were largely reversible (75-90% recovery of baseline Isc after tissue washing). These data suggest that (1) verapamil induces rapid but reversible inhibition of ion transport and (2) Ca2+ channel blockade inhibits ion transport in a dose-dependent fashion. We would propose that intracellular Ca2+ may be a regulator of GB ion transport.
Animals↗
Early effects of colectomy and endorectal pullthrough operation on biliary lipid composition.
In order to determine the effects of total colectomy and endorectal pullthrough with ileal reservoir (ERP) on biliary lipid composition in the early postoperative period, gallbladder bile of dogs was examined after biliary cannulation alone (control); biliary cannulation and colectomy with ileorectal anastomosis (IRA); and biliary cannulation, colectomy with mucosal proctectomy, and ERP. Bile collected from 3 to 6 weeks postoperation was analyzed for total bile acids, cholesterol, phospholipids, bilirubin, and calcium concentrations. Cholesterol saturation was calculated. Serum collected over the same period was analyzed for electrolytes and liver function tests. There was no evidence of sludge or gallstones post-operatively in any animal. Significant decreases in total bile acids, phospholipids, and calcium concentrations were noted in the bile of the IRA group when compared to the bile of the controls (P less than 0.05) and in total bile acids, cholesterol, phospholipids, and calcium in ERP vs controls (P less than 0.05). Moreover, all three biliary lipids and calcium were significantly decreased in ERP animals compared to those in the IRA group (P less than 0.05). No change in cholesterol saturation was noted between any of the three groups. Other than an increase in alkaline phosphatase concentrations compared to preoperative levels (P less than 0.05) which was noted in all groups, no significant changes were noted in serum parameters. We conclude that during the early postoperative period, ERP causes a significant decrease in gallbladder bile concentrations of total bile acids, cholesterol, phospholipids, and calcium which cannot be explained by colectomy alone.(ABSTRACT TRUNCATED AT 250 WORDS)
Anal Canal↗
Increased biliary calcium in cholesterol and pigment gallstone disease: the role of altered bile acid composition.
The present study was undertaken to define the relationship between calcium metabolism and bile acid composition in animal models of diet induced cholesterol and pigment gallstones. Groups of prairie dogs were fed either a control non-lithogenic chow (N = 12), a 1.2% cholesterol enriched chow (N = 6, XOL) for two weeks, or a high carbohydrate diet deficient in iron (N = 6, CHO-FeD), or a high carbohydrate diet with normal iron levels (N = 6, CHO) for eight weeks. Hepatic (HB) and gallbladder (GB) bile samples were analyzed for total calcium, cholesterol, phospholipids, total bile acids (TBA), and individual bile acid composition. In each of the four groups, TBA concentrations were essentially similar and taurine conjugates accounted for approximately 90% of TBA in HB bile and about 98% in GB bile. In the control group, cholic acid (CA) was the predominant bile acid and comprised 76% of TBA and chenodeoxycholic (CDCA) accounted for about 13% of the total. Feeding a diet rich in cholesterol caused a significant change in the relative concentrations of individual bile acids of hepatic bile--such that CA decreased significantly (p less than 0.001) while CDCA increased by 300% (p less than 0.001). The changes in secondary bile acids were insignificant. An identical shift in individual bile acid composition was noted in animals maintained on high carbohydrate diet, irrespective of iron content. Similar changes were observed in the GB in the experimental groups.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Pigment gallstone formation and altered ion transport.
Feeding corn and alfalfa to young prairie dogs resulted in formation of gallstones composed of 45 percent cholesterol, 30 percent bile pigments, and 25 percent calcium bilirubinate in half of the animals. This diet also resulted in increased gallbladder bile concentrations of calcium, phospholipids, and cholesterol. Although the cholesterol saturation index was significantly increased compared with control subjects, it remained less than 1. In addition to the changes in biliary lipid composition, the corn and alfalfa-fed animals had significantly decreased transepithelial potential difference and short-circuit current when compared with control animals. These are changes in gallbladder mucosal function similar to those that have been reported in humans with gallstones. This model may therefore prove to be of great value in studying the pathogenesis of noncholesterol gallstones.
Animal Feed↗
Altered biliary prostaglandins and cholesterol gallstones: an in vivo study.
Recent investigations suggest that biliary prostaglandin metabolism is altered during cholesterol gallstone formation. Most of the available data, however, has been obtained from in vitro studies. The purpose of the present study was to define the effects of cholesterol gallstone formation on in vivo biliary prostaglandin metabolism. Male prairie dogs were fed either a control chow for 21 days or a 1.2% cholesterol-enriched chow for 14-21 days. Cholecystectomy was performed and gallbladder tissue and bile were collected for analysis of prostaglandin concentrations using radioimmunoassay techniques. Gallbladder bile was examined for the presence of crystals and stones. No control animals but all cholesterol-fed animals developed either cholesterol crystals or gallstones (P less than 0.001). Concentrations of prostaglandin E2, prostaglandin F2 (PGF2 alpha), and the stable metabolic products of prostacyclin and thromboxane A2, 6-keto-PGF1 alpha and thromboxane B2 (TXB2), respectively, were decreased 60-85% in the gallbladder tissue of animals with crystals and gallstones compared to controls. Additionally, gallstone containing animals and those with crystals demonstrated a significant increase in the gallbladder bile concentrations of PGF2 alpha, 6-keto-PGF1 alpha, and TXB2. These findings lend support to previously reported in vitro studies suggesting that prostaglandin synthesis increases at an early stage of experimentally induced cholesterol gallstone formation.
Animals↗
The effects of amiloride on biliary calcium and cholesterol gallstone formation.
Recent studies indicate that gallbladder absorption increases during the early stages of experimentally-induced cholesterol gallstone formation. The purpose of the present study was to ascertain whether pharmacologic inhibition of gallbladder ion transport and absorption reduces the incidence of experimentally-induced cholesterol gallstones. Prairie dogs were fed either a control chow or a 1.2% cholesterol-enriched chow for 15 days. One group of cholesterol-fed animals received saline via an orogastric tube; another group received amiloride, a drug known to inhibit in vitro ion transport in the prairie dog gallbladder. The incidence of gallstones in cholesterol-fed animals was reduced from 83% to 13% (p less than 0.025) when the animals were treated with amiloride; this occurred despite a cholesterol-saturation index comparable to that observed in gallstone animals. Additionally, although biliary calcium decreased in the gallbladder, hepatic bile did not in the amiloride-treated animals. These data provide further evidence that altered gallbladder absorption and increased biliary calcium are important factors in the pathogenesis of cholesterol gallstones.
Absorption↗
Regulation of gallbladder ion transport: role of biliary lipids.
Recent studies indicate that biliary lipids influence in vivo gallbladder absorption and solute-coupled water flow. To clarify the electrophysiologic effects that underlie this phenomenon, prairie dog gallbladders were mounted in an Ussing-type chamber, and the influence of bile acids and varying ratios of bile acids and biliary phospholipids on transepithelial potential difference (Vms), resistance (Rt), and short-circuit current (Isc) was examined. Exposure to 5 mmol/L taurodeoxycholate (TDC) resulted in inhibition of Vms (p less than 0.01) and Isc (p less than 0.01) and an increase (p less than 0.05) in Rt. Subsequent perfusion with bile acids and phospholipids (5 mmol/L TDC + 0.3 mmol/L phosphatidylcholine [PC]) led to continued inhibition of ion transport. In contrast, exposure to 5 mmol/L TDC + 1.7 mmol/L PC resulted in a significant increase in transport, as manifested by an increase in Vms (p less than 0.02) and Isc (p less than 0.01) and a decrease in Rt (p less than 0.05) compared with bile acids. These results indicate that the ratio of phospholipids to bile salts modulates ion transport across prairie dog gallbladder and that this ratio may be an important determinant of gallbladder absorption in health and disease.
Animals↗
Biliary lipids alter ion transport during cholesterol gallstone formation.
Recent studies indicate that gallbladder absorption increases during the early stages of experimentally induced cholesterol gallstone formation. The purpose of the present study was to ascertain whether this change results from an alteration in gallbladder mucosal function per se or is a response of an otherwise healthy mucosa to the presence of cholelithogenic bile. Prairie dogs were fed either a control chow or a 1.2% cholesterol-enriched chow for 9 (Pre-GS) or 21 (Chronic-GS) days. Gallbladders were mounted in an Ussing-type chamber and electrophysiologic indices of ion transport were determined. Mucosal function was assessed independently by exposing the gallbladder to Ringer's solution in the absence of biliary lipids. Ion transport was similar in control and Pre-GS gallbladders but was significantly reduced in Chronic-GS animals. Gallbladders were subsequently exposed to model bile solutions containing bile acids and phospholipids in concentrations selected so as to reflect the relative concentration of bile salts and phospholipids in normal and cholesterol gallstone animals. The cross-comparison of control gallbladders exposed to nonlithogenic bile with Pre-GS gallbladders exposed to model cholelithogenic bile, therefore, simulates the in vivo situation and directly assesses the role of biliary lipids as a determinant of ion transport. When this comparison was performed there was a significant increase in short-circuit current (P less than 0.05) and potential difference (P less than 0.05) in Pre-GS animals as compared to controls. We propose that the increase in gallbladder absorptive function results from exposure of an otherwise healthy, functioning mucosa to cholelithogenic bile, and not from a change in mucosal function per se.
Animals↗
Increased biliary calcium in cholesterol gallstone formation.
The hypothesis that biliary calcium levels increase during cholesterol gallstone formation was tested in a prairie dog gallstone model. In addition to the previously documented changes in biliary lipid composition, animals with gallstones had a significant increase in gallbladder bile concentrations of total and ionized calcium compared with control animals. The observation that hepatic bile levels of calcium remained unchanged in the cholesterol-fed animals suggests that the increase in gallbladder bile calcium is due to a gallbladder-related phenomenon, rather than an alteration in hepatic metabolism. We proposed that this increase in biliary calcium levels results from an increase in gallbladder absorption. Increased biliary calcium levels may be an important, previously unrecognized, factor in the pathogenesis of cholesterol gallstones.
Animals↗
The role of dietary iron in pigment gallstone formation.
Recent studies suggest that dietary factors may be responsible for the increasing incidence of pigment gallstones. Although iron deficiency alters the activities of several hepatic enzymes, its effects on biliary lipid metabolism are not known. The aim of this study was to define the role of dietary iron in pigment gallstone formation. Three groups of prairie dogs were maintained for 2 months on either a control chow (iron-198 ppm), a high-carbohydrate diet with normal iron levels (CHO group; iron-220 ppm), or a high-carbohydrate, iron-deficient (iron-56 ppm) diet (CHO-FeD group). Serum analysis confirmed iron deficiency in the CHO-FeD group. The CHO animals had a significant (p less than 0.01) increase in hepatic bile phospholipids, while CHO-FeD animals had increased (p less than 0.01) concentrations of phospholipids and cholesterol as compared with controls. Similar findings were noted in gallbladder bile with the addition of increased calcium levels in both carbohydrate groups. Calcium bilirubinate crystals and stones were found in only 17% of CHO animals, as compared with 67% of CHO-FeD animals. These data indicate that consumption of diets rich in carbohydrates but deficient in iron alters hepatic metabolism of cholesterol and may be an important etiologic factor in pigment gallstone formation. Iron supplementation may prevent pigment gallstones in certain high-risk groups.
Animals↗