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Keywords:

  • bile salts;
  • cholecystitis;
  • cholesterol;
  • gallbladder;
  • lithogenic bile

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Role of lithogenic bile with excess cholesterol in the pathogenesis of cholecystitis
  5. Role of hydrophobic bile salts in the pathogenesis of chronic cholecystitis
  6. Role of sex hormones in the pathogenesis of chronic cholecystitis
  7. Role of gallbladder hypomotility in the development of acute cholecystitis
  8. Conclusions
  9. Funding
  10. Disclosures
  11. References

Background and Purpose

A large number of human and animal studies have challenged the hypothesis that cystic duct obstruction by gallstones causes cholecystitis. These studies suggest that lithogenic bile that can deliver high cholesterol concentrations to the gallbladder wall causes hypomotility and creates a permissive environment that allows normal concentrations of hydrophobic bile salts to inflame the mucosa and impair muscle function inhibiting gallbladder emptying. High concentrations of cholesterol increase its diffusion rates through the gallbladder wall where they are incorporated into the sarcolemmae of muscle cells by caveolin proteins. High caveolar cholesterol levels inhibit tyrosine-induced phosphorylation of caveolin proteins required to transfer receptor–G protein complexes into recycling endosomes. The sequestration of these receptor–G protein complexes in the caveolae results in fewer receptors recycling to the sarcolemmae to be available for agonist binding. Lower internalization and recycling of CCK-1 and other receptors involved in muscle contraction explain gallbladder hypomotility. PGE2 receptors involved in cytoprotection are similarly affected. Cells with a defective cytoprotection failed to inactivate free radicals induced by normal concentrations of hydrophobic bile salts resulting in chronic inflammation that may lead to acute inflammation. Ursodeoxycholic acid salts (URSO) block these bile salts effects thereby preventing the generation of free radicals in muscle cells in vitro and development of cholecystitis in the ligated common bile duct in guinea pigs in vivo. Treatment with URSO improves muscle contraction and reduces the oxidative stress in patients with symptomatic cholesterol gallstones by lowering cholesterol concentrations and blocking the effects of hydrophobic bile salts on gallbladder tissues.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Role of lithogenic bile with excess cholesterol in the pathogenesis of cholecystitis
  5. Role of hydrophobic bile salts in the pathogenesis of chronic cholecystitis
  6. Role of sex hormones in the pathogenesis of chronic cholecystitis
  7. Role of gallbladder hypomotility in the development of acute cholecystitis
  8. Conclusions
  9. Funding
  10. Disclosures
  11. References

The pathogenesis of chronic and clinically overt acute cholecystitis has not been conclusively established despite time-honored observations made over the past century. The most common and widely proposed hypothesis is that acute cholecystitis is caused by obstruction of the cystic duct either by gallstones or mucin-gel entrapped microcrystal aggregates (i.e., ‘biliary sludge’) present in lithogenic bile which by definitions contain increased absolute or relative concentrations of cholesterol.[1] This hypothesis, however, lacks evidentiary data from human studies and scant evidence from laboratory animal experiments.

Most of the evidence supporting the putative role of cystic duct obstruction in humans derives from imaging studies with technetium99m-labeled HIDA or PIPIDA in establishing the diagnosis of acute cholecystitis.[2, 3] Such imaging studies confirmed the clinical and pathological diagnosis of acute cholecystitis in up to 97% patients. This diagnosis assumes that the failure to visualize the gallbladder is due to obstruction of the cystic duct by gallstones or ‘biliary sludge’. However, we propose alternative explanations for these observations that are far more likely and plausible. For example, the obstruction could be due to extension of the acute inflammatory process from the gallbladder into the infundibulum and cystic duct. Alternatively, the acutely inflamed and atonic gallbladder is unable to empty its contents and therefore it does not allow entry of sufficient quantities of the radioisotope to be sensed by the radio scanner. The lithogenic state converts the gallbladder from an absorptive to a secretory organ that is filled with bile and inflammatory secretions. There are currently no objective data to confirm or refute these possibilities.

Surgical studies have reported that gallstones obstruct the cystic duct in patients with acute cholecystitis. As gallstones are infrequently found in the cystic duct, these reports have suggested that existent gallstones become dislodged during the surgical procedure and are found in the gallbladder or in the common bile duct. In contrast, it has been suggested that unless careful dissection is performed, some of the gallbladder stones may be pushed into the cystic and common bile duct during the surgical procedure. However, there is only one study that systematically examined the cystic duct during surgery performed in patients with acute cholecystitis. Despite the gallbladder being carefully manipulated during the procedure, cystic duct gallstones were found in only 12.3% of patients with acute cholecystitis.[4] Even accepting this low percentage of cystic duct stones, their presence does not prove that they were actually obstructing the cystic duct ab initio.

The hypothesis that cystic duct obstruction contributes to acute cholecystitis also fails to explain why the pathological indices of chronic cholecystitis are infrequent in patients with ‘black’ pigment gallstones.[5] The mucosa of these gallbladders does not exhibit evidence of adenomatous hyperplasia or Rokitansky–Aschoff sinuses that are common features in gallbladders containing mixed, i.e., Ca bilirubinate and cholesterol stones.[6] Moreover, the contraction of muscle strips and isolated myocytes from gallbladders with ‘black’ pigment stones induced cholecytokinin-8 (CCK-8) is not different from that observed in preparations from normal gallbladders.[7] Some patients with gallbladders with black pigment stones may have a slight reduction in postprandial gallbladder emptying probably due to the presence of a concurrent delayed gastric emptying.[8] Most of the patients included in this study had thalasemia who are commonly affected by a generalized motility abnormalities due to the anemia.

The hypothesis of cystic duct obstruction causes chronic or acute cholecystitis is further challenged by the occurrence of acalculus cholecystitis associated with lithogenic bile or a single large stone in the gallbladder several times greater than the typical diameter of the lumen of the cystic duct ≈7 mm. It is therefore unlikely that such large stones would cause recurrent episodes of obstruction by blocking the gallbladder neck. Evidence of chronic cholecystitis is frequently found in gallbladders removed because of acute cholecystitis. This would suggest that a chronic process had been in place long before the occurrence of the acute episode.[9] Such gallbladders frequently show mucosal and muscle abnormalities including mucosal thickening, hypertrophic muscle layers, and infiltration with macrophages of the lamina propria. Furthermore, chronic cholecystitis is frequently seen histopathologically in the absence of gallstones. The majority of morbidly obese subjects exhibit lithogenic bile without gallstones. However, they have mucosal abnormalities consistent with chronic cholecystitis compared with control non-obese subjects.[10] Based on these and similar studies, it is unlikely that cystic duct obstruction by gallstones is the initiating event in cholecystitis or is even a contributing factor in its pathogenesis.

It has been even more difficult to identify the pro-inflammatory agents that cause cholecystitis assuming that the initial event is the obstruction of the cystic duct by a gallstone. Gallbladder bile is sterile in the early stages of the process, and bacterial infection only develops after acute cholecystitis has been present for some time. It has been suggested that fluid secretions from epithelial cells lead to gallbladder distension resulting in inflammation.[11] However, increased fluid secretion and retention by the gallbladder lumen is likely the result and not the cause of the inflammatory process and hypomotility.

Further challenging the hypothesis that cystic duct obstruction is the initial event in the development of acute cholecystitis are experimental studies in laboratory animals. Cystic duct ligation in prairie dogs does not cause cholecystitis unless concentrated bile is injected in obstructed gallbladders.[12] Daily infusions of sterile fresh bile introduced into gallbladders of domestic dogs are necessary to cause a similar effect.[13] In contrast, severe acute cholecystitis develops quickly in untreated guinea pigs 3 days following ligation of the common bile duct.[14] Treating these animals with oral ursodeoxycholic acid (URSO) for 2 weeks prior to ligation of the common bile duct prevents the development of acute cholecystitis. In contrast, the acute gallbladder inflammatory process is aggravated if the ligation of the common bile duct is performed 2-weeks after animals are fed with a hydrophobic bile acid such as chenodeoxycholic acid compared with ligation of the common bile duct alone. These observations suggest that the entry of hydrophobic bile salts into the gallbladder is a necessary event to initiate and allow the inflammatory process to continue.

This review critically examines the hypothesis based mainly on studies obtained over the last 30 years that suggest that cholecystitis (both chronic and acute) is caused primarily by the presence of excessive cholesterol concentrations in bile that impairs the gallbladder's ability to protect itself against the deleterious effects of normal concentrations of hydrophobic bile salts. We will show below that both of these impair the cytoprotective functions of gallbladder epithelial and muscle cells.

Role of lithogenic bile with excess cholesterol in the pathogenesis of cholecystitis[15, 16]

  1. Top of page
  2. Abstract
  3. Introduction
  4. Role of lithogenic bile with excess cholesterol in the pathogenesis of cholecystitis
  5. Role of hydrophobic bile salts in the pathogenesis of chronic cholecystitis
  6. Role of sex hormones in the pathogenesis of chronic cholecystitis
  7. Role of gallbladder hypomotility in the development of acute cholecystitis
  8. Conclusions
  9. Funding
  10. Disclosures
  11. References

Lithogenic bile per se containing supersaturated concentrations of Ch molecules is the initial event not only of the pathogenesis of gallstones but also of chronic cholecystitis. Only supersaturated but not unsaturated bile can induce net delivery of Ch to gallbladders tissues. These high Ch concentrations create a permissive environment that facilitates the aggressive actions of injurious molecules present in normal concentrations in bile. Lithogenic bile with a high Ch saturation index is necessary to form Ch gallstones but it is even more relevant to the development of the initial low-grade inflammation that may progress into chronic cholecystitis. Although Ch precipitation into micro- (‘biliary sludge’) and macro-gallstones is the visual (by ultrasound and radiology, respectively) manifestation of gallbladder disease, these precipitants are unlikely to have pathological consequences for the gallbladder per se. That is unless they migrate and obstruct the common bile duct with secondary anaerobic infection (ascending cholangitis) and marked and rapid gallbladder distension. The introduction of artificial stones into the gallbladder of dogs has no pathological consequences. Thus, these two abnormalities induced by lithogenic bile appear to be independent of each other even though they may be detected simultaneously in symptomatic patients. Supersaturated concentrations of biliary Ch cause abnormalities in the mucosa and muscle layers of the gallbladder.[15] They are the result of increased transport of Ch across the gallbladder mucosa due to its high concentrations.[16] Ch molecules are then taken up by epithelial cells, macrophages in the lamina propria and also incorporated into the sarcolemmae of muscle cells.

Although most of these studies have been carried out with myocytes, few studies have examined the effects of excess Ch on epithelial cells. It is likely that they are altered by Ch in a similar manner that Ch affects the arterial intima. In the presence of lithogenic bile with Ch, epithelial cells increase PGE2 levels known to stimulate water and mucin secretion into bile before gallstones have formed.[17] PGE2 also stimulates hyperplasia of the mucosa resulting in Rokitansky–Aschoff sinuses as well as gastric and intestinal metaplasia. Moreover, these gallbladders show macrophages in the lamina propia in the absence of gallstones.

These findings in humans are supported by studies in laboratory animals. Rabbits that form glycoallodeoxycholate stones when treated with 1% dihydrocholesterol exhibit epithelial cell proliferation during the earlier stages of this process even before gallstones developed.[18] Cell proliferation also is enhanced in the gallbladder epithelium of mice fed a lithogenic diet rich in Ch and cholic acid.[19] The increase in proliferative activity preceding the formation of gallstones is another indication that these abnormalities are not necessarily related.[20] These observations explain the mucosal hypertrophy that is frequently observed with cholecystitis in humans.[19]

Lithogenic bile increases the transport of Ch through the gallbladder mucosa leading to higher Ch levels in the plasma membrane of muscle cells. This contrast strikingly to the lower Ch levels in muscle cells from gallbladders with pigment stones.[21] Most of the membrane Ch is bound to caveolar proteins of the plasma membrane.[22] Under normal conditions, cellular influx and efflux of Ch take place through these membrane invaginations, i.e., caveolae, which contain unique lipid and protein compositions.[23] These domains are rich in Ch molecules bound to caveolin proteins. These proteins participate in the internalization of most receptors following stimulation by their respective agonists. These receptor–G protein complexes phosphorylate caveolin proteins utilizing specific tyrosine kinases. This makes possible their transfer of caveolin protein-receptor–G protein complexes to the endosomes which are then recycled back to the plasma membrane.[24] High Ch levels inhibit tyrosine kinase-induced phophorylation of caveolin proteins thereby blocking the internalization of these receptors and their recycling to the plasma membrane. This inhibition leads to sequestration of receptors and caveolin proteins in the caveolae and as a result the number of receptors in the plasma membrane is reduced. The curtailed number of CCK-1 receptors in the membrane results in lower binding of 121-I-CCK-8 to the membrane of muscle cells from gallbladders with Ch stones compared with those from gallbladders with ‘black’ pigment stones that have normal or even subnormal concentrations of Ch.[24] The lower receptor binding and weaker muscle response is not unique to CCK-1 receptors as other receptors are also compromised including cholinergic types that are internalized through these domains. In contrast, receptors that internalize through clathrin-coated pit pathways like delta-opiate and erythromycin receptors express normal muscle responses in the face of high plasma membrane Ch.[24] The unaffected clathrin pathway explains why erythromycin causes a normal contraction and emptying in gallbladders with Ch stones.[25]

The pathological role of high Ch levels in the plasma membrane was further demonstrated ex vivo in muscle cells from humans and guinea pigs treated with Ch-rich or Ch-free liposomal carriers. The weak contraction of muscle cells from gallbladders with Ch stones improved after they were incubated with Ch-free liposomes, which removed the excess Ch from the plasma membranes. The opposite effect occurs when normally contracting gallbladder muscle cells are treated with Ch-rich liposomes. These cells develop a weaker contraction in response to CCK-8 when their plasma membranes are loaded with Ch molecules.[26] The abnormal inhibition is confined to the receptor level in the plasma membrane as the pathways distal to receptors are normal. Muscle cells contract normally when stimulated with GTPγS the G protein activator or inositol triphosphate that bypasses receptors to activate calmodulin.[27, 28] The small intestine also plays a role in the pathogenesis of cholecystitis in patients with Ch gallstones. Lithogenic diets fed to C57L mice impair the contractility of muscle cell layers of the small bowel resulting in slower intestinal transit. This engenders hyperabsorption of Ch from the upper small intestine generation of a secondary bile acid deoxycholic acid in the distal small intestine.[29] Inflammatory changes in the lamina propria and muscle hypertrophy occur in these mice 4 weeks after they are fed lithogenic diets but before gallstones are formed.[30] These changes do not occur when mice are pretreated with maximum doses of ezetimibe that blocks completely the intestinal absorption of Ch.

All these results are consistent with the pathophysiological findings in prairie dogs and ground squirrels fed with Ch lithogenic diets. The gallbladder muscle contraction induced by CCK-8 is impaired in these animals compared with those fed with regular chow.[31] The defective muscle cells from these experimental animals also reveal higher levels of Ch molecules in their sarcolemmae.[32]

The results of these animal studies have been confirmed in humans with symptomatic gallbladder Ch stones. Treatment with URSO for 4 weeks prior to the cholecystectomy normalizes the contractility of the gallbladder muscle cells compared with those from patients treated with placebo.[33] This improvement in muscle contractility correlates with a marked reduction in the levels of Ch in the plasma membrane and cellular free radicals and other signs of oxidative stress. We speculate that the lower Ch concentrations in the sarcolemmae were due to the URSO inhibition of Ch absorption by the gallbladder mucosa and perhaps also by the small intestinal mucosa.[34]

Another deficit in the gallbladder smooth muscle cells caused by the increase in membrane Ch is the suppression of the voltage-activated Ca2+ current.[35] Activity of these Ca2+ channels is responsible for the spontaneous rhythmic action potentials in gallbladder smooth muscle cells[36] and this Ca2+ entry is necessary for maintaining intracellular Ca2+ stores.[37] Therefore, basal tone and agonist-induced contractile properties of gallbladder smooth muscle are attenuated. Interestingly, the K+ channels in gallbladder smooth muscle are unaffected by their enrichment with Ch. It is possible that Ca2+ channels in the gallbladder smooth muscle are situated in the calveolar membranes, and are therefore more susceptible to Ch enrichment of the membranes.

The overabundance of Ch molecules in the sarcolemmae also affects PGE2 receptors involved in cytoprotective functions. PGE2 functions as cytoprotective autocoid acting on membrane receptors that mediate synthesis of increased levels of catalase. This enzyme inactivates free radicals (e.g., H2O2) in response to greater oxidative stress and prevents lipid peroxidation.[38, 39] There are no differences in the levels of PGE2 in response to oxidative stress (H2O2) in muscle cells from gallbladders with Ch or with ‘black’ pigment gallstones. However, the catalase response and degree of free radical inactivation secondary to exogenous PGE2 or to oxidative stress (using H2O2) is lower in muscle cells from gallbladders with Ch gallstones than in muscle cells from gallbladder with ‘black’ pigment stones.[39] These findings suggest that high levels of Ch molecules in the plasma membrane impair the cytoprotective response to exogenous and endogenous PGE2 because, as with CCK receptors, fewer PGE2 receptors recycle from endosomes to the plasma membrane.

Role of hydrophobic bile salts in the pathogenesis of chronic cholecystitis

  1. Top of page
  2. Abstract
  3. Introduction
  4. Role of lithogenic bile with excess cholesterol in the pathogenesis of cholecystitis
  5. Role of hydrophobic bile salts in the pathogenesis of chronic cholecystitis
  6. Role of sex hormones in the pathogenesis of chronic cholecystitis
  7. Role of gallbladder hypomotility in the development of acute cholecystitis
  8. Conclusions
  9. Funding
  10. Disclosures
  11. References

Normal gallbladders (i.e., in the absence of lithogenic bile) tolerate hydrophobic bile salts very well. A classic example is the rabbit where most of the bile salt pool is glycodeoxycolate and the amount of Ch is very small. However, bile salts are capable of inducing an inflammatory reaction either because of the presence of lithogenic bile, which induces a permissive environment, or after obstruction of the common bile duct that causes marked gallbladder distension and most likely some degree of ischemia.

These conclusions are supported by the results from experimental cholecystitis performed in normal animals. Common bile duct ligation in rabbits produces a histological picture identical to human cholecystitis without chemical or physical manipulation of the gallbladder or significant changes in the Ch lithogenic index.[19] Hydrophobic bile salts damage normal gallbladder epithelial and muscle cells in vitro and in vivo by increasing oxidative stress (H2O2) and lipid peroxidation.[40] Such bile salts also inhibit smooth muscle contraction by acting on G protein bile coupled receptors (BAR1 receptors also known as TGR5), activation of KATP channels[41] and by their tissue-aggressive effects because of their high detergency. Other tissues can be negatively impacted since prolonged exposure to hydrophobic bile salts can lead to esophagitis and gastritis. However, in healthy animals and humans, the gallbladder protects itself from the aggressive action of hydrophobic bile salts by utilizing PGE2-induced cytoprotective and motility mechanisms including regular emptying of gallbladder bile during fasting and postprandial states. Both protective mechanisms are affected by supersaturated levels of Ch molecules rendering the mucosa and muscle layers vulnerable to the effects of hydrophobic bile salts. This conclusion is supported by studies on experimental cholecystitis induced in guinea pigs by ligating the common bile ducts for 3 days.[14] In the initial stages of the inflammatory process, receptors to exogenous agonists, i.e., CCK-8 are damaged impairing muscle contraction whereas the endogenous PGE2 receptors remain unaffected.[39] Both the muscle contraction and cytoprotective response to PGE2 are normal because its receptors are protected by endogenous PGE2 that induces normal increases in catalase levels capable of inactivating free radicals. However, the effects of PGE2 are impaired in muscle cells from gallbladders with Ch stones or gallbladder muscle cells treated with Ch-rich liposomes. This is most obvious in the normal response to the effects of PGE2 or bile salts on muscle cells from gallbladders with ‘black’ pigment stones or ex vivo muscle cells from gallbladders with Ch stones treated with Ch-free liposomes.[39] These findings taken together suggest that lithogenic bile impairs the gallbladder's ability to protect itself against hydrophobic bile salts by reducing gallbladder contractility and emptying and impairing PGE2-dependent cytoprotective mechanisms that inactivate free radicals.

The protective effects of URSO on gallbladder epithelial and muscle cells in vitro and in vivo further support the potential toxic effects of hydrophobic bile salts in a permissive setting. Ursodeoxycholic acid pretreatment prevents lipid peroxidation, and mucin and water secretion by the gallbladder mucosa induced by hydrophobic bile salts.[42] Ursodeoxycholic acid also prevents the generation of free radicals and the corresponding cytoprotection responses on gallbladder muscle cells induced by chenodeoxycholate that are observed in isolated muscle cells.[43] Moreover, URSO treatment for 1 month prior to surgery improves gallbladder muscle contractility, reduces levels of sarcolemmal Ch and indices of oxidative stress in patients with symptomatic gallbladders with Ch gallstones.[33] It also reduces gallbladder inflammation as determined by the lower number of activated macrophages[44] probably by blocking the intestinal absorption of Ch[33] by antagonizing the local effects of hydrophobic bile salts and by maintaining the levels of free radicals within normal ranges.[43] Furthermore, URSO reduces the monocyte/macrophage, mast cell, and granulocyte infiltrate that was present in the gallbladder muscle layer of gallstone patients. The hydrophilic bile salt decreases the number of activated macrophages, degranulated mast cells and COX-2 expression compared with placebo-treated patients.[46] This short-term study is consistent with the results of a two-decade study demonstrating that URSO treatment reduced the incidence of biliary pain and cholecystectomy compared with untreated patients despite the persistence of gallbladder stones.[45] Although the mechanism of URSO protection from the effects of hydrophobic salts is not completely known, there is evidence that this hydrophilic bile salt protects the gallbladder epithelial and muscle cells by blocking the intestinal absorption of Ch and by acting as a bile salt receptor antagonist at the muscle cell level and by being a powerful antioxidant.

Role of sex hormones in the pathogenesis of chronic cholecystitis

  1. Top of page
  2. Abstract
  3. Introduction
  4. Role of lithogenic bile with excess cholesterol in the pathogenesis of cholecystitis
  5. Role of hydrophobic bile salts in the pathogenesis of chronic cholecystitis
  6. Role of sex hormones in the pathogenesis of chronic cholecystitis
  7. Role of gallbladder hypomotility in the development of acute cholecystitis
  8. Conclusions
  9. Funding
  10. Disclosures
  11. References

Females exhibit a higher prevalence of lithogenic bile and gallbladder disease as compared with males suggesting that sex hormones may be involved in the pathogenesis of chronic and acute cholecystitis. Most attention has been focused on the actions of progesterone as this hormone impairs gallbladder contractility by its genomic effect which downregulates G proteins (Gq/11 and Gi3) that mediate agonist-induced contraction.[46] Progestogens affect normal gallbladder muscle cells but they do not affect muscle cells from gallbladders harboring Ch stones or muscle cells treated with Ch-rich liposomes.[47] As with Ch progesterone is also transported across the sarcolemmae by caveolin proteins. Experimentally, treatment with Ch-rich liposomes blocks the entry of 3H-progesterone into the sarcolemmae of normal muscle cells compared with cells treated with Ch-free liposomes. Ch inhibits entry of this hormone into the plasma membrane possibly because of stronger hydrophobic interactions of Ch with the hydrophobic binding sites of caveolar proteins. Estrogens also play an important role in the pathogenesis of gallbladder disease because they increase the biliary secretion of Ch. Estrogen receptor alpha, but not beta, plays a major role in 17-beta-estradiol-induced murine Ch gallstones.[48] Linear increases in estrogen and progesterone levels during pregnancy explain the gallbladder hypomotility, stasis, and Ch supersaturated bile but there are only modest increases in acute cholecystitis during each of the trimesters. This scenario is reversed rapidly in the puerperium when the hormonal effects are abated. Octeotride is the only therapeutic agent commonly employed that causes gallbladder hypomotility and its chronic use is associated with an increased incidence of cholelithiasis. It is unlikely that this hormone would cause gallbladder disease with normal, i.e., Ch unsaturated bile. However, this hormone causes hyperabsorption of Ch from both dietary and biliary sources by inducing hypomotility of the small intestine.[49] This slow intestinal transit leads to the formation of more secondary and therefore more hydrophobic bile salts such as deoxycholate conjugate.[50] Higher levels of deoxycholate conjugates in bile are pro-lithogenic for two reasons – they extract more Ch from the liver and accelerate nucleation in the gallbladder bile.[51]

Role of gallbladder hypomotility in the development of acute cholecystitis

  1. Top of page
  2. Abstract
  3. Introduction
  4. Role of lithogenic bile with excess cholesterol in the pathogenesis of cholecystitis
  5. Role of hydrophobic bile salts in the pathogenesis of chronic cholecystitis
  6. Role of sex hormones in the pathogenesis of chronic cholecystitis
  7. Role of gallbladder hypomotility in the development of acute cholecystitis
  8. Conclusions
  9. Funding
  10. Disclosures
  11. References

Gallbladder hypomotility and bile stasis are essential for promoting the formation of macroscopic gallstones from Ch crystals in bile. This occurs simply because bile is retained for longer periods of time in the interdigestive and postprandial states. Unless the bile is Ch supersaturated, i.e., lithogenic there is no evidence that impaired interdigestive and postprandial emptying per se lead to gallbladder inflammation. Slower intestinal motility increases Ch absorption resulting in increased concentration of bile Ch in humans and mice[29, 50, 51] as well as pro-lithogenic secondary bile salts formation.[51]

Conclusions

  1. Top of page
  2. Abstract
  3. Introduction
  4. Role of lithogenic bile with excess cholesterol in the pathogenesis of cholecystitis
  5. Role of hydrophobic bile salts in the pathogenesis of chronic cholecystitis
  6. Role of sex hormones in the pathogenesis of chronic cholecystitis
  7. Role of gallbladder hypomotility in the development of acute cholecystitis
  8. Conclusions
  9. Funding
  10. Disclosures
  11. References

The human and animal data summarized in this review clearly show that lithogenic bile with excess Ch and hydrophobic bile acids contribute to the development of gallbladder hypomotility and chronic inflammation. Hence, the factors that contribute to the progression from low-grade inflammation to acute cholecystitis are not conclusively known. However, there are significant risk factors present in patients with high incidence of acute cholecystitis. Acute cholecystitis tends to develop in patients after major surgical trauma.[52] The incidence is also higher in patients with or without gallstones in advancing age (20% of men and 35% of women by age 75), systemic illnesses (e.g., leukemia, chemotherapy), and other debilitating conditions.[53]

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Role of lithogenic bile with excess cholesterol in the pathogenesis of cholecystitis
  5. Role of hydrophobic bile salts in the pathogenesis of chronic cholecystitis
  6. Role of sex hormones in the pathogenesis of chronic cholecystitis
  7. Role of gallbladder hypomotility in the development of acute cholecystitis
  8. Conclusions
  9. Funding
  10. Disclosures
  11. References
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