Gallstones are lumps of solid matter found in the gallbladder (the sac under the liver where bile is stored) or in the bile ducts (which connect the gallbladder and liver to the duodenum). Most gallstones are made of cholesterol and bile pigments from the breakdown of red blood cells.
Causes and incidence
Gallstones develop due to a disturbance in the chemical composition of bile. They are rare in childhood and become increasingly common with age. Women are affected more than men. Risk factors for developing gallstones include a high-fat diet and being overweight.
Most gallstones cause no symptoms. Any symptoms often begin when a stone lodges in the gallbladder outlet. This problem causes biliary colic (intense pain in the upper right area of the abdomen or between the shoulder blades), nausea, and sometimes indigestion and flatulence. Possible complications include cholecystitis (inflammation of the gall-bladder) and bile duct obstruction.
Diagnosis and treatment
Gallstones are usually diagnosed by ultrasound scanning, X-ray oral cholecystography, or cholangiography. Stones that are not causing symptoms are usually left alone. In other cases, the gallbladder and stones may be surgically removed by cholecystectomy. Ultrasonic shock waves (lithotripsy) are sometimes used to shatter gallstones; the fragments pass into the intestines and cause no further problems. Drugs such as ursodeoxycholic acid can dissolve some gallstones if taken over several months, but further stones may form once the treatment is stopped.
Gallstones in more detail
Cholesterol gallstones account for 75% of gallstones in Europe and the United States of America. They result from the secretion of cholesterol-saturated bile by the liver, the cause of which is unclear. Pure cholesterol stones are usually solitary; mixed stones—which contain cholesterol in a matrix of calcium bilirubinate, calcium phosphate, and protein—are usually multiple and faceted.
Bile pigment stones consist of mucoprotein matrix, calcium bilirubinate, cholesterol, and calcium compounds: in east Asia they tend to be soft, friable, and brown and are associated with biliary infection; in the West they tend to be hard, brittle, and black and are found in patients with cirrhosis, chronic bile duct obstruction and chronic haemolytic anaemias.
Some 10 to 20% of the population have gallstones, most of which remain in the gallbladder (cholelithiasis) and give rise to no symptoms, but clinical presentations include (1) acute or chronic cholecystitis—due to impaction of a gallstone in the neck of the gallbladder; (2) choledocholithiasis—when gallstones pass through the cystic duct into the bile duct resulting in biliary obstruction and jaundice, and which may be complicated by bacterial infection (cholangitis); and less commonly, (3) perforation—through the inflamed gallbladder wall to form an internal fistula, usually to the small intestine or colon, and (4) gallstone ileus—a large gallstone passing into the small intestine may impact in the ileum and cause intestinal obstruction.
The usual treatment for symptomatic gallstones is cholecystectomy, performed (when available) laparoscopically. It is also appropriate to offer this to young patients with asymptomatic gallstones (who, with many years ahead of them, will have a greater likelihood of developing complications), but to advise against treatment in older people with other major medical problems. Chemical agents that dissolve gallstones (e.g. oral bile acid therapy, contact dissolution after transhepatic catheterization of the gallbladder) and physical methods (e.g. extracorporeal shock-wave lithotripsy) have a role to play in a very few patients. Endoscopic sphincterotomy is used to remove gallstones from the common bile duct.
Bile composition and gallstone formation
Bile is secreted by the hepatocytes and its water and electrolyte composition altered during its passage down the biliary system. Between meals much of the bile is diverted to the gallbladder where it is concentrated by the removal of sodium, chloride, bicarbonate, and water. In response to food, the gallbladder contracts, emptying bile into the duodenum. Apart from water (97%) the major components of bile are bile acids, phospholipids, and cholesterol. Bile is also the major excretory route of other compounds including bilirubin and certain drugs and their metabolites. Cholesterol is insoluble in water but is held in solution by the detergent action of bile acids with the aid of phospholipids.
Cholesterol is synthesized primarily in the liver and small intestine. The rate-limiting enzyme for cholesterol production is hydroxymethylglutaryl-CoA reductase (EC 22.214.171.124), which catalyses the first step, the conversion of acetate to mevalonate. Subsequently, nonesterified (free) cholesterol is secreted into bile. Dietary cholesterol also contributes to biliary cholesterol secretion. The control of cholesterol metabolism is complex. It is not yet clear what proportion of biliary cholesterol is derived from circulating lipoproteins and what proportion is newly synthesized by the liver.
The primary bile acids, cholic and chenodeoxycholic acid, are synthesized in the liver from cholesterol. The economy of the bile acid pool is preserved by efficient reabsorption, principally in the terminal ileum. About 95% of the bile acids are reabsorbed and pass back to the liver in the portal venous system (enterohepatic circulation). The remainder enters the colon where bacteria form the secondary bile acids, deoxycholic and lithocholic acid, from cholic and chenodeoxycholic acid, respectively. Some of the secondary bile acids are absorbed from the colon but most are excreted in the faeces. The normal bile acid pool is about 3 to 5 g and circulates 6 to 10 times each day. Synthesis is controlled by the negative feedback of bile acids returning in the portal venous blood which act on the rate-limiting hepatic enzyme, cholesterol-7α-hydroxylase (EC 126.96.36.199). The principal phospholipid in bile is lecithin. It is produced in the liver and secreted into the bile. In the intestine lecithin is hydrolysed to lysolecithin by pancreatic phospholipase and is subsequently reabsorbed.
Above a certain level (the critical micellar concentration) bile acids coalesce to form micelles that have a hydrophilic external surface and hydrophobic internal surface. Cholesterol is incorporated into the hydrophobic interior. Phospholipids are inserted into the micellar wall so that the micelles are enlarged; these ‘mixed micelles’ are thus able to hold more cholesterol.
Consequently, the solubility of cholesterol in bile depends on the concentrations of bile acid and phospholipid. In the presence of a relative excess of bile acids and phospholipid (on a molar basis) the cholesterol-holding capacity of bile is increased and it is said to be unsaturated. However, if there are insufficient micelles of bile acid and phospholipid to hold the cholesterol, the solution is referred to as saturated and the excess cholesterol tends to precipitate. With a knowledge of the molar concentration of cholesterol, phospholipid, and bile acids, the cholesterol saturation of bile can be predicted using triangular coordinate diagrams.
Gallstone disease is common and afflicts between 10 and 20% of the world’s population. Gallstones are classified according to their composition into two main groups: cholesterol stones and bile pigment stones. Cholesterol stones are composed mainly of cholesterol (>70%) and can be subdivided into pure cholesterol stones (usually solitary) and mixed stones which contain cholesterol in a matrix of calcium bilirubinate, calcium phosphate, and protein. Mixed stones are usually multiple and faceted. Bile pigment stones can also be divided into two main groups. Brown pigment stones are soft and friable and consist of calcium bilirubinate, cholesterol, and calcium soaps. Pure pigment stones (‘black stones’) are black, hard, and brittle and contain an insoluble black pigment, calcium bilirubinate, calcium carbonate and phosphate, calcium salts of fatty acids, and bile acids. All pigment stones contain a large amount of mucoprotein matrix (up to 70%). Gallstones are rare before the age of 10 years. The incidence increases progressively with age. Cholesterol gallstones account for about 75% of the gallstones in Europe and the United States of America.
Cholesterol gallstones result from the secretion of cholesterol-saturated bile by the liver. The cause of the saturation is unclear. Patients with gallstones usually have a smaller bile acid pool than controls and it circulates more frequently. The rapid recycling of bile acids may be responsible for the smaller bile acid pool by excessive inhibition of the enzyme that controls bile acid synthesis, cholesterol-7α-hydroxylase. However, diminished bile acid synthesis is probably not the most important factor in the production of saturated bile. This appears to be an elevated biliary cholesterol secretion rate, due either to increased hepatic cholesterol synthesis or to increased transfer of plasma lipoprotein cholesterol into bile. Nevertheless, saturated bile may be encountered in normal subjects, especially during fasting. It is therefore likely that other factors such as the condition of the gallbladder, the mechanism of seeding (nucleation) of gallstones, and the control of gallstone growth are important. Furthermore, racial differences, advancing age, female sex, obesity, diet, drugs (such as the contraceptive pill and clofibrate), and gastrointestinal disease (such as Crohn’s disease) are known to have a significant influence on the development of gallstones.
Bile pigment gallstones
In contrast to cholesterol stones, little is known of the aetiology of bile pigment stones. The soft, friable, brown-pigmented stones are especially common in the east Asia and are associated with Escherichia coli, bacteroides, and clostridium infection of the biliary tract. It is probable that these bacteria contribute to stone formation by producing β-glucuronidase that deconjugates bilirubin diglucuronide to form free unconjugated bilirubin. This combines with calcium to form sparingly soluble calcium bilirubinate that precipitates.
The black, hard, and brittle pure-pigment stones are the type commonly encountered in the West. The incidence of pure pigment stones increases with age and they are found in patients with cirrhosis, chronic bile duct obstruction (such as biliary strictures), chronic haemolytic anaemias including haemolysis induced by prosthetic heart valves, and malaria. Pure pigment stones affect both sexes equally. The mechanism of stone production is unclear, but does not appear to be due to cholesterol saturation of hepatic or gallbladder bile. About 50% of all pigment stones are radio-opaque and they account for about 70% of all opaque stones.
Natural history of gallstones
The majority of gallstones remain in the gallbladder (cholelithiasis) and may give rise to no symptoms (‘silent’ gallstones), being discovered incidentally during investigation or at autopsy. Impaction of a gallstone in the neck of the gallbladder results in gallbladder inflammation and the symptoms and signs of acute or chronic cholecystitis. Acute cholecystitis will subside if the stone spontaneously disempacts, or may progress to gangrene and perforation of the gallbladder or empyema of the gallbladder. Gallstones may pass through the cystic duct into the bile duct (choledocholithiasis), resulting in biliary obstruction and jaundice. Bacterial infection (cholangitis) commonly accompanies choledocholithiasis and can lead to a liver abscess. Gallstones may perforate through the inflamed gallbladder wall to form an internal fistula, usually to the small intestine or colon. A large gallstone passing into the small intestine may impact in the ileum resulting in intestinal obstruction (gallstone ileus). Finally, surgical treatment for gallstones, while usually curative, may result in a postcholecystectomy syndrome or a benign stricture of the bile duct.
The usual treatment for gallstones remains cholecystectomy although medical treatments may be employed in selected patients (see below). The advent of laparoscopic cholecystectomy has swung the balance in favour of surgery since this technique carries so little morbidity and a very short hospital stay. Treatment is obviously indicated for symptomatic gallstones and for their complications. However, in patients in whom ‘silent’ gallstones are discovered incidentally and in patients with minimal symptoms it is by no means clear that treatment is always the best solution. The problem revolves around the probability of serious complications in the future. It is appropriate to offer treatment to young patients (who, with many years ahead of them, will have a greater likelihood of developing the complications of gallstones) and to advise against treatment in older people with other major medical problems. However, in fit middle-aged patients with no or minimal symptoms it is reasonable to tell the patient of the finding and to withhold surgery until it is warranted by symptoms or complications.
Gallstone dissolution and disruption
Cholesterol gallstones can be removed from the gallbladder and bile ducts in a proportion of patients by medical treatments. These techniques avoid the discomfort, disability, and risks of general anaesthesia and surgical exploration of the abdomen and bile ducts. However, with the widespread availability of laparoscopic cholecystectomy these techniques are now used rarely. There are two types of medical method: chemical agents that dissolve gallstones, and physical methods such as endoscopic sphincterotomy and extracorporeal shock-wave lithotripsy (ESWL). Judicious combinations of chemical and physical methods yield the best results.
Oral bile acid therapy
Oral treatment with chenodeoxycholic acid or ursodeoxycholic acid can dissolve cholesterol gallstones. These bile acids, normal constituents of bile, reduce the cholesterol saturation of bile and result in the leaching of cholesterol from gallstones. They act by reducing the hepatic synthesis and biliary excretion of cholesterol. Ursodeoxycholic acid has advantages over chenodeoxycholic acid in that it does not cause diarrhoea or elevations of serum transaminases. These bile acids differ in the way that they remove cholesterol from gallstones and have been shown to dissolve gallstones better in combination than singly. Combination therapy is the preferred treatment.
Cholesterol stones in the gallbladder can be dissolved by the direct instillation of methyl tertbutyl ether (MTBE) into the gallbladder via a percutaneous catheter. MTBE is a foul-smelling, volatile, inflammable colourless substance that remains liquid at body temperature. The gallbladder is catheterized by the transhepatic route, entering it through the area of attachment of the gallbladder to the liver and MTBE is continually infused and aspirated with vigour until the stones have disappeared (which typically takes 5–7 h).
This is a noninvasive and safe but expensive way of rapidly shattering gallstones into a coarse powder. The gallbladder must contain no more than three stones to allow accurate focusing of the shock waves.
Endoscopic sphincterotomy can remove gallstones from the bile duct. The bile duct is entered by a cannula passed via a duodenoscope and the bile duct is opened by diathermy cutting of the ampulla of Vater. Stones are removed by balloon or wire catheters.
Patient selection and results
Medical treatment with oral bile acid therapy, ESWL, or contact dissolution is suitable for patients with cholesterol gallstones in a functioning gallbladder (as judged by an oral cholecystogram). Calcified gallstones do not dissolve. Radiolucent gallstones are usually, but not always, composed of cholesterol. CT scans are useful for detecting low levels of gallstone calcification. These treatments should be reserved for patients with mild or no symptoms in whom the risk of cholecystectomy is high, including those with pre-existing disease, older people, and very obese individuals. They are also of value in patients who refuse surgery. Drugs which increase the cholesterol saturation of bile should be avoided; these include oestrogens, the oral contraceptive pill, and clofibrate.
Oral bile acid therapy is protracted but safe. It dissolves gallstones in about 25% of patients fulfilling the selection criteria by 6 months. It should not be taken during pregnancy. The preferred treatment is combination therapy with chenodeoxycholic acid (7 mg/kg) and ursodeoxycholic acid (7 mg/kg). Proprietary combination tablets are available. Gallstone dissolution usually requires 6 to 24 months of therapy depending on stone size. Oral cholecystograms are performed every 6 months to assess progress. Combining oral bile acid therapy with ESWL speeds up the process greatly: gallstones will be cleared in more than 90% of patients within 18 months. Furthermore, slightly calcified gallstones can be treated in this way. MTBE therapy is invasive and the ether is unpleasant to use, but dissolution is rapid. Endoscopic sphincterotomy removes gallstones from the common bile duct. Any type of stone can be removed up to about 20 mm in diameter.
Side effects and toxicity
The most frequent side effect of oral bile acid therapy is diarrhoea. It is dose related and usually mild and transient. It can be minimized by slowly increasing the dose to the required level. Transient elevations of serum transaminase activity are also common; liver function tests should be monitored. Ursodeoxycholic acid may cause calcification of gallstones. Gallstone recurrence remains a major problem with oral bile acid therapy. About 30% of patients will have had a recurrence 1 year after gallstone dissolution. Unwanted effects of ESWL include biliary colic, skin petechias, and haematuria. The principal unwanted side effects of MTBE are sedation, burning upper abdominal pain, nausea, and vomiting. Endoscopic sphincterotomy can cause gastrointestinal haemorrhage and acute pancreatitis.