Pathophysiology Of Gallstones Research Articles

Gallstones: Prevention, Diagnosis, and Treatment.

Gallstones are common and affect up to 20% of the general adult population and >20% of them will develop symptoms or complications of cholelithiasis. The high risk of gallbladder stone formation can be reduced by ursodeoxycholic acid in the case of significant weight reduction resulting from diet or bariatric surgery. Laparoscopic cholecystectomy is indicated for symptomatic gallstones, as the risk of recurrence or complications increases over the course of the disease. Biliary colic is treated with nonsteroidal anti-inflammatory drugs and spasmolytics; opioids can also be used in cases of severe acute pain. Acute cholecystitis represents a common complication of gallbladder stones and a cholecystectomy should be performed early electively, i.e., within 24 hours of admission to hospital. Symptomatic bile duct stones are primarily treated endoscopically. Immediate anti-infective therapy is mandatory in acute cholangitis. Although knowledge on the genetics and pathophysiology of gallstones has increased, current treatment algorithms remain predominantly invasive, based on interventional endoscopy and surgery. Future efforts should focus on novel strategies to prevent the development of gallstones.

Gallstone disease - interdisciplinary treatment

Gallstones develop in the gallbladder or the bile ducts. According to their chemical composition, gallstones can be divided into cholesterol stones, which are common, and the rare bile pigment stones. Altogether, up to 20 % of all adults develop gallstones and more than 20 % of them symptoms or complications. Female sex, age, pregnancy, physical inactivity, obesity, overnutrition and genetic factors such as ABCB4 deficiency of the hepatic lecithin transporter are kown risk factors for gallstone formation. In about one half of all patients biliary symptoms precede the three common and potentially life-threatening complications (acute cholecystitis, acute cholangitis and biliary pancreatitis). Although our knowledge about the genetics and pathophysiology of gallstones has improved, current treatment algorithms are predominantly invasive (ERC and surgery). Thus, better strategies are needed to prevent the formation of gallstones in general.

Mouse models of gallstone disease.

The establishment of mouse models of gallstones, and the contribution of mouse models to genetic studies of gallstone disease, as well as the latest advances in the pathophysiology of gallstones from mouse experiments are summarized. The combined uses of genomic strategies and phenotypic studies in mice have successfully led to the identification of many Lith genes, which pave the way for the discovery of human LITH genes. The physical-chemical, genetic, and molecular biological studies of gallstone disease in mice with knockout or transgene of specific target genes have provided many novel insights into the complex pathophysiological mechanisms of this very common hepatobiliary disease worldwide, showing that interactions of five primary defects play a critical role in the pathogenesis of cholesterol gallstones. Based on mouse studies, a new concept has been proposed that hepatic hypersecretion of biliary cholesterol is induced by multiple Lith genes, with insulin resistance as part of the metabolic syndrome interacting with cholelithogenic environmental factors to cause the phenotype. The mouse model of gallstones is crucial for elucidating the physical-chemical and genetic mechanisms of cholesterol crystallization and gallstone formation, which greatly increase our understanding of the pathogenesis of this disease in humans.

Gallstones.

Gallstones grow inside the gallbladder or biliary tract. These stones can be asymptomatic or symptomatic; only gallstones with symptoms or complications are defined as gallstone disease. Based on their composition, gallstones are classified into cholesterol gallstones, which represent the predominant entity, and bilirubin ('pigment') stones. Black pigment stones can be caused by chronic haemolysis; brown pigment stones typically develop in obstructed and infected bile ducts. For treatment, localization of the gallstones in the biliary tract is more relevant than composition. Overall, up to 20% of adults develop gallstones and >20% of those develop symptoms or complications. Risk factors for gallstones are female sex, age, pregnancy, physical inactivity, obesity and overnutrition. Factors involved in metabolic syndrome increase the risk of developing gallstones and form the basis of primary prevention by lifestyle changes. Common mutations in the hepatic cholesterol transporter ABCG8 confer most of the genetic risk of developing gallstones, which accounts for ∼25% of the total risk. Diagnosis is mainly based on clinical symptoms, abdominal ultrasonography and liver biochemistry tests. Symptoms often precede the onset of the three common and potentially life-threatening complications of gallstones (acute cholecystitis, acute cholangitis and biliary pancreatitis). Although our knowledge on the genetics and pathophysiology of gallstones has expanded recently, current treatment algorithms remain predominantly invasive and are based on surgery. Hence, our future efforts should focus on novel preventive strategies to overcome the onset of gallstones in at-risk patients in particular, but also in the population in general.

Influence of Insulin Resistance Status on the Development of Gallstones Following Roux-En-Y Gastric Bypass: a Prospective Cohort Study.

The occurrence of gallstones following Roux-en-Y gastric bypass (RYGB) has been extensively reported. As RYGB promotes improvement in insulin resistance (IR), which is one of the factors enrolled in the pathophysiology of gallstones, this study aims to determine the influence of IR and its post-RYGB course on the development of gallstones. This is a prospective cohort study that enrolled 108 morbidly obese subjects free of gallstones which underwent RYGB and were followed up for 24 months, through clinical, laboratory, and ultrasound examinations. IR was assessed through the surrogate marker homeostasis model assessment (HOMA). Of the individuals evaluated, 29 (26.8%) developed gallstones following RYGB. In the univariate analysis, postsurgical gallstones were associated with preoperative HOMA (p < 0.0001), preoperative fasting glucose (p = 0.0019), preoperative fasting insulin (p = 0.0001), and preoperative triglycerides (p = 0.0001). Multivariate analysis revealed that preoperative HOMA was the only factor independently associated with gallstones (p < 0.0001). The incidence of gallstones among individuals with IR was 46.8%; in the non-IR subjects, the incidence was 7.4% (p < 0.0001). Preoperative IR led to a relative risk of 6.02 (95% CI = 2.1-17.3; p = 0.0009) of gallstones. As gallstones often occur following RYGB, there is controversy regarding their management. Some authors propose systematic cholecystectomy along with RYGB, while others suggest that the aggregate risk of the concomitant approach is significantly higher. As IR was a significant risk factor in this study, an individualized approach for this population may be proposed. Further research is needed to confirm these findings.

Gallstones

Gallstones are estimated to affect over 20 million people in the United States. Recent studies have clarified the role of various dietary components in gallstone disease. Also, insulin resistance has been demonstrated to be a risk factor for gallstones. Other research has focused on the pathophysiology of gallstones and on clarifying the underlying mechanisms of previously noted risk factors for gallstones. New techniques for the noninvasive diagnosis of bile duct stones continue to be developed and tested. These techniques include computed tomography and magnetic resonance cholangiography. The impact and appropriateness of laparoscopic cholecystectomy continue to debated, and studies point to both overuse and underuse of this operation in the management of the disease.

Effect of phospholipids and their molecular species on cholesterol solubility and nucleation in human and model biles.

Much research in the pathophysiology of gall stones has been devoted to various molecular species of bile salts. Recent findings have shown the importance of phospholipids in biliary pathophysiology. In the present study the addition of increasing doses of egg lecithin to human and model biles progressively prolonged the nucleation time. Concurrently biliary cholesterol was shifted from the vesicular to the non-vesicular carrier(s) while the cholesterol/phospholipid ratio of the remaining vesicles was progressively lowered. Model bile solutions of identical lipid concentration were prepared using phosphatidylcholine, phosphatidylserine, and phosphatidylethanolamine as the only phospholipid. With phosphatidylethanolamine most of the cholesterol was shifted to the vesicular carrier while phosphatidylserine shifted most of the cholesterol to the non-vesicular carrier(s). With phosphatidylcholine the cholesterol was distributed in both carriers. Phosphatidyl choline species composed of various acyl fatty acids in the sn-1 and sn-2 positions were used as the sole phospholipid in otherwise identical model bile solutions. With palmitic acid in the sn-1 position and arachidonic acid in the sn-2 position most of the cholesterol was found in the non-vesicular carrier. When stearic acid was used in sn-2 position instead of arachidonic acid most of the cholesterol was found in the vesicular carrier. These and other variations in phospholipid molecular species shifted cholesterol among its carriers and also modified the nucleation time of model biles. Most of these effects were also found upon addition of the various phospholipid species to human biles. These findings show the importance of phospholipid species in biliary pathophysiology and may be useful when trying to manipulate cholesterol carriers and solubility in bile.

Role of gallbladder mucin in pathophysiology of gallstones.

A critical step in the formation of cholesterol gallstones in nucleation (i.e., the formation of cholesterol monohydrate crystals from supersaturated bile). The rate of nucleation of cholesterol depends upon a critical balance between pronucleating and antinucleating factors in bile. Mucin, a high molecular weight glycoprotein secreted by the gallbladder and biliary duct epithelium, is a pronucleating agent in experimental and human gallstone disease. Gallbladder mucin shares with other epithelial mucins the ability to bind lipids and bile pigment. The hydrophobic binding sites in the polypeptide core of mucin may provide a favorable environment for nucleation of cholesterol monohydrate from supersaturated bile. In nearly all animal models of cholelithiasis, mucin hypersecretion is prominent. The stimulus for gallbladder mucin hypersecretion appears to be a component of lithogenic bile. Prostaglandins regulate mucin release in gallbladder epithelium in vitro and probably in vivo. In the cholesterol-fed prairie dog, blockage of mucin release with aspirin inhibits gallstone formation. These findings suggest that inhibition of mucin release may prevent cholesterol stone formation during high-risk periods or after dissolution therapy with bile salts.

Role of gallbladder mucus hypersecretion in the evolution of cholesterol gallstones.

Because mucin glycoproteins may be important in the pathophysiology of gallstones, we studied the relationship among biliary lipids, gallbladder mucin secretion, and gallstone formation in cholesterol-fed prairie dogs. Organ culture studies of gallbladder explants revealed that the incorporation of [(3)H]glucosamine into tissue and secretory gallbladder glycoproteins was significantly increased at 3, 5, 8, and 14 d of feeding. Peak secretion of labeled mucin occurred at 5 d, when total tissue and secreted glycoprotein production was fivefold greater than control. Gel filtration of the secreted glycoprotein on Sepharose 4B indicated that the majority of radioactivity was present in a macromolecule of > 1 million molecular weight. The increased secretion of gallbladder mucin was organ specific, in that [(3)H]glucosamine incorporation into glycoproteins of stomach and colon was unaffected by cholesterol feeding. Similarly, the incorporation of [(3)H]mannose into gallbladder membrane glycoproteins was not altered by cholesterol feeding. The rate of glycoprotein synthesis and secretion returned to normal upon withdrawal of the cholesterol diet, and ligation of the cystic duct before cholesterol feeding prevented gallbladder mucin hypersecretion. Both results indicate that the stimulus to mucin secretion was a constituent of bile. Gallbladder bile after 5 d contained cholesterol in micelles, liquid crystals, and crystals, whereas hepatic bile remained a single micellar phase throughout cholesterol feeding. For this reason the cholesterol-saturation indices of gallbladder bile were compared in both homogenized and centrifuged samples. The micellar phase of gallbladder bile was appreciably less saturated than homogenized bile at 5 and 8 d, which reflects the continuous nucleation of cholesterol in the gallbladder. Purified human gallbladder mucin gels were shown to induce nucleation of lecithin-cholesterol liquid crystals from supersaturated hepatic bile. These in turn gave rise to cholesterol monohydrate crystals within 18 h. Control supersaturated hepatic bile could not be nucleated by the addition of other proteins, and was stable for days upon standing. These results suggest that the increase in cholesterol content of bile in cholesterolfed prairie dogs stimulates gallbladder mucus hypersecretion, and that gallbladder mucus gel is a nucleating agent for biliary cholesterol.