PRIMER Gallstones Frank Lammert1, Kurinchi Gurusamy2, Cynthia W. Ko3, Juan-Francisco Miquel4, Nahum Méndez-Sánchez5, Piero Portincasa6, Karel J. van Erpecum7, Cees J. van Laarhoven8 and David Q.-H. Wang9 Abstract | 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.
Correspondence to F.L. and K.G. 1 Department of Medicine II, Saarland University Medical Center, Saarland University, Kirrberger Str. 100, 66424 Hamburg, Germany. 2 Royal Free Campus, University College London Medical School, 9th Floor, Royal Free Hospital, Rowland Hill Street, London NW3 2PF, UK.
[email protected];
[email protected] Article number: 16024 doi:10.1038/nrdp.2016.24 Published online 28 April 2016
Gallstones (cholelithiasis) are masses in the gallbladder or biliary tract that are caused by abnormally high levels of either cholesterol or bilirubin (a breakdown prod uct of haem) in bile (FIG. 1). Gallstones are common (~10–20% of the global adult population), and >20% of people with gallstones will develop symptoms in their lifetime (including biliary colic or infections), usually in adulthood. Gallstone disease is defined by the occur rence of symptoms or complications caused by gall stones in the gallbladder and/or the bile ducts. From a clinical perspective and in treatment algorithms, those with asymptomatic stones are not generally classified as having gallstone disease. Gallstone disease is among the gastrointestinal conditions associated with the highest socioeconomic costs1. Gallstones are classified based on composition and location. More than 90% of gallstones are composed mainly of cholesterol (cholesterol gallstones) (TABLE 1). The other stone types (95% cholesterol by weight
Light yellow, hard and spherical with a smooth or morular surface
Black pigment stones
Polymerized calcium bilirubinate
Black, soft and fragile, and small sphere with a smooth surface
Common bile duct
Mixed cholesterol stones
>50% cholesterol by weight plus calcium bilirubinate
Light yellow to brown, hard and spherical with a smooth surface
Intrahepatic bile duct
Brown pigment stones
Monomeric calcium bilirubinate
Brown, soft, fragile to hard and spherical with a multifaceted surface
disease risks for a 5‑unit increment in body mass index or the presence of diabetes are estimated to be 1.63 and 1.56, respectively 24,25. Rapid weight loss (that is, >1.5 kg per week by a very-low-calorie diet or after bariatric surgery) leads to the formation of gallstones in up to 30% of individuals26–29 and increases the risk of biliary symptoms and cholecys tectomy 30–32. Factors associated with gallstone formation after bariatric surgery are a higher rate of weight loss, pro longed overnight fasting, gallbladder hypomotility and reduced intake of calories and fibres33. Importantly, preg nancy is a well-recognized risk factor for gallstone forma tion34,35. Interestingly, in up to 60% of women, gallstones can disappear postpartum, indicating that pregnancy can be a transient lithogenic state34. In addition, some drugs (such as oestrogens, progesterone and the somatostatin analogue octreotide) predispose to gallstones (BOX 1). Whereas oestrogens increase the synthesis and secretion of hepatic cholesterol, progesterone and octreotide cause gallbladder hypomotility.
Genetic risk factors In addition to the risk factors listed in BOX 1, a genetic predisposition to gallstone formation is clearly evident. A study in 43,141 Swedish twin pairs with gallstone dis ease indicated that ~25% of the risk of gallstone disease is determined by genetics36. The heritability of gallstones has been reported to exceed 50% in Hispanics with high Native American ancestry 37. Associations between multiple lithogenic gene variants and gallstone formation have been observed and indicate that the contributing genes are highly heterogeneous38,39. Quantitative trait locus analysis in inbred strains of mice that were fed a lithogenic diet containing a supraphysiological concen tration of cholesterol has identified 25 lithogenic genes to date40–45. Genome-wide association studies identified a vari ant of the hepatobiliary cholesterol transporter (ABCG8 p.D19H) as the most frequent genetic risk factor in humans34,39,46. Together with the Gilbert variant of the UDP glucuronosyltransferase family member A1 (UGT1A1) gene, which is predominantly a risk factor in men, both genes confer ~15% of the population-attributable gall stone risk47. Mutations in some of the lithogenic genes may represent the cause of gallstone formation, for exam ple, the common gallstone-associated variants in ABCG5 and ABCG8 as well as UGT1A1 (REFS 46,47). In addition, rare mutations in ABCB4 (encoding the hepatobiliary
floppase), ABCB11 (encoding the bile salt export pump), CFTR (encoding cystic fibrosis transmembrane con ductance regulator) or CYP7A1 (encoding cholesterol 7α‑hydroxylase) promote gallstone formation by leading directly to altered bile composition48. By contrast, other lithogenic genes, such as polymorphisms in the genes encoding apolipoproteins, cholesteryl ester transfer pro tein, and adrenergic and nuclear receptors might repre sent modifiers that exhibit lithogenic effects only in the setting of primary genetic risk factors39,48. A small subgroup of patients with gallstones have low phospholipid-associated cholelithiasis (LPAC) syndrome. LPAC syndrome is defined by early-onset cholelithiasis (90% water. Cholesterol, phospholipids and bile salts are the three main lipid species in bile. Apart from bile pigments, bile also contains small amounts of proteins and inorganic salts. Based on chemical composition and macroscopic appearance, gallstones are mainly divided into two types (cholesterol and pigment gallstones), with two independent aetiologies. Cholesterol gallstones The formation of cholesterol gallstones is the conse quence of a failure of biliary cholesterol homeostasis (FIG. 3) , in which the physical–chemical balance of cholesterol solubility in bile is disturbed45. FIGURE 4a shows the five primary defects for cholesterol gallstone formation, which work together to promote cholesterol crystallization and gallstone formation48.
NATURE REVIEWS | DISEASE PRIMERS
VOLUME 2 | 2016 | 3 . d e v r e s e r s t h g i r l l A . d e t i m i L s r e h s i l b u P n a l l i m c a M 6 1 0 2 ©
PRIMER
Prevalence (%) ≤10 10.1–20 20.1–30 30.1–40 ≥40 No data
Figure 2 | Global prevalence of gallstones. Prevalence rates of gallstones as determined by ultrasonography in women Nature Reviews | Disease Primers 50–60 years of age (Supplementary information S1 (table)). No corresponding data are available for the grey regions.
Hepatic cholesterol hypersecretion. Cholesterol secreted in bile is derived mainly from hepatic de novo synthe sis, HDL cholesterol generated through the reverse cholesterol transport and chylomicrons (lipoprotein particles that transport cholesterol from the intestine primarily to the liver); the contribution of each of these pathways to the formation of lithogenic bile remains unclear. Insulin resistance promotes biliary cholesterol secretion by inducing ABCG5 and ABCG8 through the dysregulation of the transcription factor forkhead box protein O1 (FOXO1) in hepatocytes52. This mechanism might explain the high gallstone prevalence in patients with diabetes52. Oestrogen increases gallstone formation by enhancing hepatic synthesis and secretion of cholesterol, as well as reducing bile salt synthesis through the upregulation of oestrogen receptor 1 and G protein-coupled receptor 30 (corresponding to the lithogenic gene cluster 18 in inbred mice)53. This may explain, in part, why gallstone preva lence is higher in women than in men. The nuclear recep tors farnesoid X receptor (FXR; also known as NR1H4) and liver X receptor (LXR; also known as NR1H3) have crucial roles in cholesterol and bile salt homeostasis. Repression of Fxr in mice reduces cholesterol solubility in bile by decreasing the expression of Cyp7a1 and hence hepatic bile salt synthesis54. Activation of LXR promotes biliary cholesterol secretion by upregulating hepatic ABCG5 and ABCG8 (REF. 55). Fibroblast growth factor 19 (FGF19), which is produced by enterocytes and functions as a hormone, regulates bile salt synthesis and glucose metabolism, as well as gallbladder refilling through speci fic receptors in the liver and gallbladder, respectively 56.
Genetic variation of FGF19 signalling may contribute to the formation of gallstones57. Niemann-Pick C1‑like protein 1 (NPC1L1) is expressed in both the canalicular membrane of hepatocytes and the apical membrane of enterocytes, but its expression is profoundly higher in the small intestine than in the liver in humans. These observations indicate that hepatic NPC1L1 may have a weak role in regulating biliary cholesterol secretion. By contrast, genetic variants in NPC1L1 may be associ ated with increased absorption of intestinal cholesterol, thus augmenting the intestine-derived cholesterol to the liver for biliary hypersecretion. Nevertheless, the role of these nuclear receptors, sterol transporters and hormones in human gallstone pathogenesis needs to be investigated further. Supersaturated bile and rapid phase transition. Biliary cholesterol secretion depends on the balance of choles terol input and output in the liver (FIG. 3). Supersaturated bile contains excess amounts of cholesterol that cannot be solubilized in bile by bile salts and phospholipids at equilibrium58. Supersaturated bile can result from: (i) excessive hepatic cholesterol secretion; (ii) decreased hepatic secretion of biliary bile salts or phospho lipids with relatively normal cholesterol secretion; or (iii) a combination of cholesterol hypersecretion and bile salt or p hospholipid hyposecretion. Five different pathways to bile crystallization have been defined, depending on the different relative amounts of cholesterol, phospholipids and bile salts59. Regardless of the pathway, the rates of crystallization are invariably faster in lithogenic human bile than in
4 | 2016 | VOLUME 2
www.nature.com/nrdp . d e v r e s e r s t h g i r l l A . d e t i m i L s r e h s i l b u P n a l l i m c a M 6 1 0 2 ©
PRIMER healthy controls60,61. Rapid in vitro crystallization of cho lesterol monohydrate crystals discriminates lithogenic bile of patients with gallstones from supersaturated bile of individuals without gallstones62,63. This is attribut able mainly to increased concentrations of mucins and perhaps other heterogeneous pro-nucleating agents in patients who are prone to developing gallstones compared to patients without gallstones64. Gallbladder hypomotility. Gallbladder emptying is impaired early in gallstone formation, mostly because large amounts of cholesterol are absorbed from super saturated bile by epithelial cells that line the gallbladder. Excess cholesterol is then converted to cholesteryl esters and stored in the mucosa and lamina propria, which stiff ens the sarcolemmal membrane of smooth m uscle cells, disrupts cholecystokinin 1 receptor signalling c ascade and decouples the signal transduction mediated by G proteins, such as Gq/11α, Giα1–2 and Giα3 (REF. 65). Another early event is chronic inflammation of the gallbladder wall in response to lithogenic bile. Although aseptic inflammation has been postulated, microbiota in the gallbladder could also trigger gallbladder inflamma tion66. Chronic gallbladder inflammation is associated with wall fibrosis and both events can impair gallbladder contractility. Thus, the residence time of cholesterol- supersaturated bile in the gallbladder lumen is longer and probably promotes cholesterol crystallization and crystal growth into microlithiasis and macroscopic stones. Intestinal factors. Hypomotility of the gallbladder also leads to more secreted bile being diverted to the intestine. This leads to increased bacterial catabolism of bile salts and increased levels of biliary deoxycholate (a hydro phobic bile salt), which in turn promotes hepatic choles terol hypersecretion and cholesterol crystallization. In patients with Crohn’s disease and those who have undergone intestinal resection or total colectomy, the enterohepatic circulation of bile salts is often impaired so that hepatic secretion of biliary bile salts is greatly reduced and the solubilization of cholesterol in bile is decreased, leading to supersaturated bile48. Increased absorption of cholesterol and the western diet increase the risk for gallstones67, and augmenting intestinal cholesterol absorption enhances cholesterol stone formation in animals68. However, patients with gall stones have lower rates of intestinal cholesterol absorption and higher rates of cholesterol synthesis than controls, a phenotype that is shared by patients with type 2 diabe tes mellitus or insulin resistance. Therefore, the inhib ition of intestinal cholesterol absorption seems to have a minor role in the prevention of gallstones in humans69. Moreover, the lithogenic role of intestinal microbiota and the immune system in gallstone formation is under investigation but still far from settled70.
Pigment gallstones Pigment stones result from abnormal bilirubin metabo lism; bile of patients with black or brown pigment stones contains excess amounts of unconjugated bili rubin51. Black pigment stones are formed in uninfected
gallbladders, particularly in patients with conditions that increase the concentration of systemic bilirubin, including chronic haemolytic anaemias, ineffective erythropoiesis, ileal diseases, extended ileal resections or liver cirrhosis51,71. Black pigment stones are com posed of either pure calcium bilirubinate or polymer-like complexes consisting of unconjugated bilirubin, cal cium bilirubinate, calcium and copper. Calcium bili rubinate may also form a nidus for the development of cholesterol stones47. Brown pigment stones consist mainly of calcium salts of unconjugated bilirubin, with varying amounts of cholesterol, fatty acids, pigment, mucin glycoproteins, bile salts, phospholipids and bacterial residues. Brown pigment stones can form in all parts of the biliary tree, especially in bile ducts. Bile stasis due to obstruction of the bile duct and biliary infection, especially with Escherichia coli, are two essential conditions (FIG. 4b). E. coli produce β‑glucuronidase, phospholipase A1 and conjugated bile acid hydrolase, leading to the production of unconjugated bilirubin from bilirubin glucuronide. Unconjugated bilirubin is water insoluble and combines with calcium to form calcium bilirubinate at its carboxyl radical, forming brown pigment stones. Mucin gel traps
Box 1 | Exogenous risk factors for gallbladder stones Factors associated with metabolic syndrome • Obesity, particularly central adiposity* • Physical inactivity* • Insulin resistance and diabetes mellitus* • Nonalcoholic fatty liver disease* Dietary factors • High-calorie intake* • High-carbohydrate intake* • High-glycaemic load* • Low-fibre intake* • High-haem iron intake* Factors causing gallbladder hypomotility • Prolonged fasting* • Rapid weight loss or bariatric surgery* • Weight cycling* • Prolonged total parenteral nutrition* • Spinal cord injury* • Gastrectomy*,‡ Factors increasing enterohepatic bilirubin cycling • Liver cirrhosis*,‡ • Crohn’s disease*,‡ • Ileal resections‡ Drugs • Hormone-replacement therapy* • Octreotide* • Fibrates* • Calcineurin inhibitors* *Cholesterol stones. ‡Black pigment stones. Based on data from Stokes et al.13.
NATURE REVIEWS | DISEASE PRIMERS
VOLUME 2 | 2016 | 5 . d e v r e s e r s t h g i r l l A . d e t i m i L s r e h s i l b u P n a l l i m c a M 6 1 0 2 ©
PRIMER these complex precipitates and facilitates their growth into stones. Recent studies on susceptibility genes for pig ment gallstones have identified several candidate genes that predispose to enhance the formation of pigment stones by increasing enterohepatic cycling of bilirubin. Serum levels of bilirubin and gallstone prevalence are strongly associated with the UGT1A1 promoter variant in patients with cystic fibrosis or sickle cell disease39,51,72.
Diagnosis, screening and prevention Diagnosis In general, the diagnosis, clinical symptoms and manage ment of gallstones do not differ between cholesterol and pigment stones, but predominantly depend on the location of the stone (gallbladder versus bile ducts). CMR
LDL
HDL Basolateral membrane
LRP1
LDLR
SRB1
VLDL
Cholesteryl esters ACAT Esterification
Biosynthesis
Acetate
HMDH
Phosphatidylcholine
Cholesterol
NPC1L1
Catabolism CYP7A1 CYP27A1
Bile salt
ABCG5/ABCG8 ABCB11
ABCB4 Hepatocyte Canalicular membrane
Figure 3 | Cholesterol metabolism in the hepatocyte. The hepatic uptake of cholesterol is mediated by prolow-density lipoprotein receptor-related (LRP1) Nature Reviews |protein Disease1Primers for chylomicron remnants (CMRs), low-density lipoprotein (LDL) receptor (LDLR) for LDL, and scavenger receptor class B member 1 (SRB1) for high-density lipoprotein (HDL). Biosynthesis of hepatic cholesterol from acetate is regulated by the rate-limiting enzyme 3‑hydroxy‑3‑methylglutaryl-coenzyme A reductase (HMDH). A large proportion of cholesterol is used for the synthesis of bile salts via the classical and the alternative pathways, which are regulated by the two rate-limiting enzymes cholesterol 7α‑hydroxylase (CYP7A1) and sterol 27‑hydroxylase (CYP27A1), respectively. Bile salt synthesis is determined by farnesoid X receptor (FXR; also known as NR1H1) through a small heterodimer partner and fibroblast growth factor 19 (FGF19) through its receptor (FGFR4). In addition, some of the cholesterol is esterified by acyl-coenzyme A:cholesterol acyltransferase (ACAT; also known as SOAT1) for storage within the hepatocytes. Part of the cholesterol is used for the synthesis of very-low-density lipoprotein (VLDL), which is secreted into the circulation. A group of ATP-binding cassette (ABC) transporters located in the canalicular membrane is responsible for hepatic lipid secretion: the heterodimer ABCG5 and ABCG8 for cholesterol, ABCB11 for bile salts and ABCB4 for phosphatidylcholine. Niemann-Pick C1‑like protein 1 (NPC1L1) in the canalicular membrane might contribute to the reuptake of cholesterol from hepatic bile into hepatocytes. Liver X receptor (LXR; also known as NR1H3) has a crucial role not only in cholesterol and bile salt synthesis through cytochrome P450 51A1 (CYP51A1) and UDP glucuronosyltransferase 1–3 (UGT1A3), respectively, but also in biliary cholesterol secretion by activating ABCG5 and ABCG8 at the transcriptional level. Dysregulation of uptake, biosynthesis, catabolism and/or biliary secretion of cholesterol at the hepatocyte level results in the formation of cholesterol-supersaturated bile.
Gallbladder stones. Patients with gallbladder stones can present with characteristic symptoms called biliary colic, which is defined as episodic attacks of severe pain in the right upper abdominal quadrant or epigastrium for at least 20–30 minutes with radiation of the pain to the right back or shoulder, which improves with admin istration of analgesics. In addition, gallbladder stones can also cause nonspecific abdominal symptoms, such as epigastric pain and intolerance to fried or fatty foods (characterized by nausea, bloating and flatulence)73. However, only ~60% of patients report the absence of abdominal pain after surgery, indicating that symptoms are neither characteristic nor predictive74. Abdominal ultrasonography is the imaging method of choice for anyone who presents with any of these symptoms, as its diagnostic accuracy for the detection of gallbladder stones exceeds 95%75 (FIG. 5). In addition, abdominal ultrasonography can detect complete or patchy calcification of the gallbladder wall (also known as porcelain gallbladder). When there is a strong sus picion of gallbladder stones but a negative abdominal ultrasonography, endoscopic ultrasonography (EUS) or magnetic resonance cholangiography (MRC) can be performed to detect microlithiasis below the detection limit of abdominal ultrasonography. Acute cholecystitis (sudden inflammation of the gallbladder) should be suspected in a patient with fever, severe pain located in the right upper abdominal quadrant that lasts for several hours and/or Murphy’s sign (that is, tenderness in the right upper quad rant below the costal margin on deep inspiration)76. Considering the lower sensitivity (65%) and specificity (87%) of Murphy’s sign77 and abdominal ultrasono graphy (a sensitivity of 82% and a specificity of 81%78) to detect acute cholecystitis, a CT scan (a sensitivity of 94% and a specificity of 59%78) is warranted in patients who are critically ill to identify suspected cholecystitis and to identify complications such as gallbladder perforation, empyema or gangrenous cholecystitis (gallbladder wall necrosis). Bile duct stones. The common presentation of sympto matic bile duct stones is pain in the right upper abdom inal quadrant or epigastrium, caused by acute distention of the obstructed bile duct. Spontaneous passage of the stone into the duodenum or backflow into the dis tended duct can relieve the pain. It is often not possible, based on clinical symptoms alone, to differentiate bile duct obstruction from cystic duct obstruction by gallbladder stones. Patients with symptomatic bile duct stones exhibit dilation of the bile ducts and/or altered liver biochemistry tests. In the first days, serum aminotransferase activ ities may be increased, probably due to hepatocyte necrosis as a consequence of acute obstruction and/or dilatation of the bile ducts; aminotransferase activities of 500–1,000 IU per l were observed in 18% of patients with symptomatic bile duct stones and >1,000 IU per l in 10% of patients79. Normal liver biochemistry tests within the first 24 hours after the onset of pain make the presence of bile duct stones unlikely 80. The activities
6 | 2016 | VOLUME 2
www.nature.com/nrdp . d e v r e s e r s t h g i r l l A . d e t i m i L s r e h s i l b u P n a l l i m c a M 6 1 0 2 ©
PRIMER a
b Genetic factors and lithogenic genes
Genetic factors
Hepatic hypersection of bilirubin
Gallbladder hypomotility
Hepatic hypersection of cholesterol Cholesterol gallstones Rapid phase transitions
Brown pigment gallstones Bile stasis
Intestinal factors
Bacterial infection
Figure 4 | Aetiological factors involved in the formation of cholesterol gallstones and brown pigment gallstones. a | Hepatic hypersecretion of cholesterol is the primary cause of cholesterol gallstone formation and depends largely on genetic predisposition. Gallbladder hypomotility and rapid phase transitions are downstream consequences. The intestinal factors that contribute to cholesterol gallstone formation include increased absorption of cholesterol and reduced absorption of bile salts. b | Brown pigment gallstones are the consequence of excess bacterial β‑glucuronidase, which results in the hydrolysis of bilirubin glucuronide into free bilirubin and glucuronic acid. Free bilirubinate combines with calcium to form water-insoluble calcium bilirubinate as a consequence. Dead bacteria and parasites could act as nuclei that accelerate the precipitation of calcium bilirubinate. The mucin gel in the gallbladder traps these complex precipitates and promotes their growth into macroscopic stones.
of other liver enzymes — γ‑glutamyl transpeptidase and alkaline phosphatase — rise more slowly than that of aminotransferases. Abdominal ultrasonography accurately detects common bile duct dilation (an indirect sign of bile duct stones) and may visualize bile duct stones with lower sensitivity directly 81. Similarly, CT scan exhib its a high sensitivity for bile duct dilation but not for bile duct stones. EUS and MRC are the most reliable imaging modalities for bile duct stones. According to a recent systematic review 82, the sensitivity of EUS is 95% with a specificity of 97%, whereas the sensitivity of MRC is 93% with a specificity of 96%. In the case of small stones (90% of patients who have undergone bariatric surgery and have developed gallstones remain asymptomatic 108–110. Cholecystectomy during bari atric surgery is reserved for the subgroup of patients with symptomatic gallstones or abnormal gallbladder findings111. In addition, patients who require longterm therapy with somatostatin or various analogues
Gallbladder stones Symptomatic gallbladder stones represent an indication for surgery. Owing to the high risk of stone recurrence as long as the gallbladder is present, the dissolution of gallbladder stones by oral administration of UDCA and their fragmentation by extracorporeal shockwave lithotripsy (that is, non-invasive fragmentation of gall stones by acoustic pulses) is not generally used anymore. Surgical removal of the gallbladder (cholecystectomy) can be performed through laparoscopy, minimally invasive open surgery or invasive open surgery.
b
+ +
Figure 5 | Abdominal transcutaneous ultrasonography. a | Multiple Nature Reviews gallbladder | Disease Primers stones (arrow) with hypoechoic shadows (echoes are weakened by dense stones, resulting in darker regions behind the stones). b | Visualization of a gallstone (arrowhead) in the common bile duct (arrow). The size of the stone is indicated (12 mm; plus symbols).
Management Management of gallstones does not depend on the composition of the stone but rather on the location.
Asymptomatic gallbladder stones. Thus far, no RCTs have been performed assessing whether asymptomatic gallbladder stones should be treated in the general popu lation. In addition, meta-analyses assessing the natural course of patients with gallbladder stones are lacking. Overall, ~1–4% of individuals with previously diagnosed asymptomatic gallbladder stones develop symptoms every year, and populations with considerably differ ent gallstone prevalence may also differ in their natural history of the disease116–121. Of those who present with symptoms, biliary colic is often the main symptom117–120. No evidence currently exists showing that medical dissolution treatment with UDCA or extracorporeal shockwave lithotripsy is effective in the treatment of gall bladder stones, as the rates of cure (that is, the permanent clearance of gallstones) are low and the recurrence rates of gallstones are high122–125. Based on a balance of bene fits and harms, there is currently no evidence to support routine cholecystectomy in patients with asymptomatic gallbladder stones, except in the case of porcelain gall bladder, which is associated with an increased risk of gallbladder cancer 126. However, further studies on the natural history of asymptomatic gallbladder stones are needed, and evidence-based recommendations may differ in countries with different prevalence rates of gallstone disease and its complications, in particular, gallbladder cancer. Symptomatic gallbladder stones. Patients with sympto matic gallbladder stones should be treated, and all evi dence thus far points to cholecystectomy as the better option than medical dissolution and extracorporeal
8 | 2016 | VOLUME 2
www.nature.com/nrdp . d e v r e s e r s t h g i r l l A . d e t i m i L s r e h s i l b u P n a l l i m c a M 6 1 0 2 ©
PRIMER shockwave lithotripsy. Two small RCTs have examined cholecystectomy versus observation in patients with symptomatic gallbladder stones — one in patients with biliary colic127 and the other in patients with acute cholecystitis128. Patients with biliary colic random ized to surgery completed their designated treatment signific antly more often (P
