Diseases of the gallbladder and bile ducts

The gallbladder rarely causes problems in childhood or early adulthood but, from middle age onwards, an increasing occurrence of gallstones may sometimes give rise to symptoms. The digestive system can function normally without a gallbladder, and its removal has few known long-term adverse effects.

Metabolic disorders

The principal disorder, with which most other gallbladder problems are associated, is the formation of gallstones. Every year thousands of people develop gallstones. Women are affected up to four times as often as men, depending on their age and ethnicity. The formation of gallstones results from a metabolic problem in which the chemical composition of bile (the digestive juice stored in the gallbladder) is altered.There are three main types of gallstone: stones formed from the fatty substance cholesterol; stones made from bile pigments; and mixed gallstones, which contain both cholesterol and pigments. The great majority are mixed. Only about 20 per cent of affected people experience symptoms or complications; many carry “silent’’ gallstones, producing no symptoms. Attempts by the gallbladder to expel the stone or stones, however, can cause severe biliary colic (abdominal pain).

Infection and inflammation

If a gallstone lodges in the gallbladder outlet, trapped bile may irritate and inflame the lining, and bile may become infected. This disorder is called acute cholecystitis. The first symptom may be biliary colic, followed by fever and abdominal tenderness. Repeated attacks of biliary colic and acute cholecystitis can lead to chronic cholecystitis, in which the gallbladder becomes shrunken and thick-walled and ceases to function. Rarely, it may become inflamed when no gallstones are present: a condition called acalculous cholecystitis. Cholecystitis can proceed to empyema, in which the gallbladder fills with pus; a high fever and severe abdominal pain may result.

Congenital and genetic defects

Abnormalities that may be present from birth include absence of the gallbladder, an oversized gallbladder, or two gallbladders. These defects, however, rarely cause problems.

Tumours

Gallbladder cancer usually occurs in a gallbladder that contains gallstones. This cancer is, however, extremely uncommon compared to the high prevalence of gallstones. Other disorders In rare cases where the gallbladder is empty and a stone obstructs its outlet, the gallbladder may become distended and filled with mucus secreted by its lining. A gallbladder with this problem is known as a mucocele.

Diseases of the gallbladder and bile ducts in detail - technical

Essentials

Diseases of the gallbladder and bile ducts are common, with gallstones and their complications being most frequent. Less common are biliary strictures, usually malignant, which are caused by adenocarcinomas of the pancreas, bile ducts, ampulla of Vater, and gallbladder. Rarely encountered are sclerosing cholangitis and a variety of congenital disorders.

Disorders of the biliary system usually give rise to the symptoms and signs of biliary obstruction (cholestasis), including pain (ranging from ‘dyspepsia’ to severe right hypochondrial colic), jaundice, itching, nausea and vomiting (which may be prominent in sudden obstruction of the bile duct, usually by a gallstone), fevers, and rigors (indicating bacterial infection of the biliary tract, which frequently accompanies partial obstruction). Jaundice, dark urine, and pale stools indicate obstruction of the bile duct. Weight loss may be due to fat malabsorption, but can also be caused by malignancy. Prolonged biliary obstruction leads to skin changes of increased pigmentation (due to melanin) and cholesterol deposition (xanthelasma and xanthoma). Biliary cirrhosis can cause portal venous hypertension and liver cell failure.

Disorders of the biliary system generally give rise to the biochemical picture of cholestasis: the serum (conjugated) bilirubin concentration may be normal or raised; serum alkaline phosphatase, γ-glutamyl transferase and bile acids are elevated; serum transaminases show only modest elevation. Bilirubinuria is present, with the disappearance of urobilinogen from the urine indicating complete biliary obstruction.

Imaging is critical in the diagnosis of biliary disease, initially by ultrasonography, with CT scanning and MRI then employed in more complicated cases. However, these investigations sometimes provide insufficient anatomical detail for diagnosis or planning of treatment, in which cases further imaging with the cholangiographic techniques of magnetic resonance cholangiography (MRC), endoscopic retrograde cholangiopancreatography (ERCP) or percutaneous transhepatic cholangiography (PTC) are required. ERCP and PRC can be used to place biliary stents.

Gallstones

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.

Anatomy

The biliary system comprises the collection of ducts extending from the biliary canaliculus of each hepatocyte to the ampulla of Vater opening into the duodenum. The biliary canaliculi drain into interlobular and then septal bile ducts. These further ramify to form the intrahepatic bile ducts which are visible on cholangiography. They eventually form the right and left hepatic ducts draining bile from the right and left lobes of the liver, respectively. The junction of the hepatic ducts at the porta hepatis forms the common hepatic duct. The cystic duct, linking the gallbladder to the bile duct, arises from the lower end of the common hepatic duct. The gallbladder rests in a fossa under the right lobe of the liver. Anatomical variations in the size and position of the gallbladder and the insertion of the cystic duct into the bile duct are of major surgical importance. The common hepatic duct becomes the common bile duct below the insertion of the cystic duct. The common bile duct passes through the head of the pancreas and the sphincter of Oddi to drain into the duodenum via the ampulla of Vater. The bile duct usually exits through a common channel with the pancreatic duct in the ampulla of Vater, although anatomical variations are frequent.

The investigation of biliary disease

Objectives

The clinical and laboratory features of biliary disease may also be caused by hepatic disorders. Consequently, the primary objective of investigations is to establish that the cause is due to biliary and not hepatic disease. The secondary objective is to define the anatomy of the lesion to permit a rational choice of the many surgical and nonsurgical therapeutic options which are now available. To achieve these objectives requires not only a careful history and physical examination, but also the use of various imaging techniques and sometimes aspiration liver biopsy.

Symptoms and signs

Disorders of the biliary system usually give rise to the symptoms and signs of biliary obstruction (cholestasis). The repertoire is rather limited: pain, jaundice, itching, nausea and vomiting, fevers, and rigors. The pain can range from abdominal discomfort described as ‘dyspepsia’ to severe right hypochondrial colic caused by a sudden rise in biliary pressure. Jaundice, dark urine, and pale stools indicate obstruction of the bile duct. Itching is an important sign of biliary obstruction. Nausea and vomiting may be prominent in sudden obstruction of the bile duct, usually by a gallstone. The milder symptoms of flatulence and intolerance of fatty food are more common. Fever and rigors indicate bacterial infection of the biliary tract, which frequently accompanies partial obstruction. In jaundiced patients weight loss is usual and results from fat malabsorption due to the lack of bile acids reaching the gut; it may also indicate a malignant tumour. Prolonged biliary obstruction leads to skin changes: increased pigmentation (due to melanin) and cholesterol deposits (xanthelasma and xanthoma). Finally, biliary cirrhosis may develop causing the signs of portal venous hypertension and liver cell failure.

Laboratory investigations

In general, disorders of the biliary system give rise to the biochemical picture of biliary obstruction (cholestasis). A notable exception is gallstones in the gallbladder (cholelithiasis) where the liver function tests are usually normal. In cholestasis, the serum bilirubin concentration may be normal or raised and most of the bilirubin is esterified (conjugated). Bilirubinuria is present. The disappearance of urobilinogen from the urine indicates complete biliary obstruction. Elevation of the serum alkaline phosphatase is an important but not invariable sign of biliary obstruction; the rise is usually greater than three times normal. Other biliary canalicular enzymes accumulate in the blood, including γ-glutamyl transpeptidase. This enzyme is only found in the liver and is estimated if there is doubt as to whether the alkaline phosphatase is of bony or hepatic origin. This may be required in children and patients with malignancy. Serum transaminases, such as aspartate aminotransferase, show only modest elevation in contrast to the rises which occur in hepatitis. The serum cholesterol concentration rises and may cause abnormalities of red cell shape (target cells). A raised concentration of serum bile acids is a sensitive index of biliary disease. A prolonged prothrombin time reflects intestinal malabsorption of fat-soluble vitamin K owing to a lack of bile acids. Vitamin A and D deficiency may also develop. The serum albumin and gammaglobulin levels are normal until biliary cirrhosis develops. A polymorphonuclear leucocytosis accompanies bacterial infections of the biliary system.

Imaging techniques

A plain radiograph of the abdomen may reveal an enlarged liver, calcified gallstones, or air in the biliary tree. Plain radiographs of the abdomen are now rarely done. The preferred first investigation is ultrasonography. CT and MRI are used in complicated diagnostic problems. These tests reveal dilated bile ducts and may also indicate the position of the obstruction in the biliary tree and dense structures such as gallstones. Hepatic scintiscanning with ⁹⁹Tcm-labelled HIDA (dimethyl acetanilide iminodiacetic acid) is an alternative and is of value in the diagnosis of acute cholecystitis. Oral cholecystograms are rarely done nowadays but are useful to determine whether the gallbladder is functioning in patients with gallstones being assessed for oral bile acid dissolution therapy (see below). Intravenous cholangiography is obsolete. However, these noninvasive investigations usually provide insufficient anatomical detail for diagnosis or planning of treatment. A further cholangiographic technique such as magnetic resonance cholangiography (MRC), percutaneous transhepatic cholangiography (PTC), or endoscopic retrograde cholangiopancreatography (ERCP) is necessary. MRC is now the preferred investigation in the first instance. The quality of MRC images now approaches that of ERCP and PTC. ERCP and PTC are usually reserved for patients in whom MRC fails and for therapeutic interventions. ERCP and PTC carry small risks including haemorrhage, biliary peritonitis, and cholangitis (with PTC), and bowel perforation, cholangitis, and pancreatitis (with ERCP). Should cholangiography reveal a normal biliary system in a jaundiced patient, a liver biopsy is indicated. Endoscopic ultrasound (EUS) is a new technique which appears to have promise in biliary disease.

This diagnostic approach is ideal but expensive both in terms of human and material resources. The apparatus required is costly and procedures such as ERCP require considerable expertise. Obviously local factors will determine the diagnostic pathway that is adopted. Nevertheless, these techniques have revolutionized the management of patients with biliary disease. It is now a routine matter to achieve a precise diagnosis rapidly. In addition, a series of nonoperative therapeutic options with ERCP ranging from the introduction of endoprostheses for the management of benign and malignant biliary structures to endoscopic sphincterotomy for the removal of the biliary calculi are direct consequences of these diagnostic approaches.

Bile composition and gallstone formation

Bile composition

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 1.1.1.34), 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 1.14.13.17). 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 formation

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

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.

Natural history 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.

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.

Treatment

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.

Chemical methods

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).

Physical methods

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.

Acute cholecystitis

Aetiology

Acute cholecystitis is associated with gallstones in over 90% of patients. It follows the impaction of a gallstone in the cystic duct. Continued secretion by the gallbladder leads to a rise in pressure. Inflammation of the gallbladder wall results from the toxic effects of the retained bile and bacterial infection. The gallbladder bile is usually turbid but may become frank pus (empyema of the gallbladder). Intestinal organisms, especially anaerobes, are commonly cultured from the gallbladder. Ischaemia in the distended gallbladder wall may lead to infarction and perforation. Generalized peritonitis may follow, but the leak is usually localized to form a chronic abscess cavity. Some patients have repeated attacks of acute cholecystitis which are probably exacerbations of chronic cholecystitis. Acute cholecystitis in the absence of gallstones (acalculous cholecystitis) is very rare. However, acalculous cholecystitis is a particular problem in patients with AIDS. Cytomegalovirus and cryptosporidium are the most commonly associated organisms in acalculous cholecystitis in AIDS.

Symptoms and signs

The typical patient is an obese middle-aged woman, and the acute attack is often precipitated by a large or fatty meal. However, there are many exceptions to this pattern. The principal symptom is pain, of fairly sudden onset, which is severe, continuous or minimally fluctuating, and localized to the epigastrium or right hypochondrium. The pain often radiates to the back. The constancy of the pain is in contrast to the repeated short bouts of biliary colic. In uncomplicated cases the pain gradually subsides over 12 to 18 h. Flatulence and nausea are common, but persistent vomiting suggests the presence of a stone in the common bile duct. Examination reveals an ill, sweating patient with shallow, jerky respiration. Fever indicates a complicating bacterial cholangitis. Jaundice may accompany acute cholecystitis but is usually a sign of a stone in the bile duct. The abdomen moves poorly with respiration. Right hypochondrial tenderness is present and is exacerbated by inspiration (Murphy’s sign). Muscle guarding and rebound tenderness are common. The gallbladder is usually impalpable but occasionally a tender mass of omentum and gallbladder may be felt under the liver.

Laboratory investigations

The white cell count is usually moderately elevated (12–15 × 10⁹/litre) as a result of a polymorphonuclear leucocytosis. Serum bilirubin concentrations between 17 and 68 µmol/litre (1–4 mg/dl) may be seen in uncomplicated acute cholecystitis, but should raise the suspicion of a stone in the bile duct. Modest rises in the serum alkaline phosphatase, aspartate transaminase, and amylase may also be seen. An abdominal radiograph will show gallstones in about 10% of patients. Ultrasound scanning of the gallbladder is the preferred first investigation. Scintiscanning with ⁹⁹Tcm-labelled HIDA provides similar information. It is important to establish the correct diagnosis before starting surgery.

Differential diagnosis

Acute cholecystitis may be confused with other abdominal emergencies including perforated peptic ulcer, acute pancreatitis, retrocaecal appendicitis, perforated carcinoma or diverticulum of the hepatic flexure of the colon, and liver abscess. Cardiac infarction and pneumonia with right-sided pleurisy should also be considered.

Complications

Gangrene of the gallbladder

Pain, tenderness, and fever progressively increasing or persisting for longer than 24 to 48 h are indications of gangrene of the gallbladder. The prognosis is poor if necrosis and perforation occur. In patients who are elderly and obese, perforation of the gallbladder can occur without definite signs. Perforation into an adjacent viscus may produce a cholecystenteric fistula and may lead to gallstone ileus.

Cholangitis

Intermittent high temperatures often accompanied by rigors indicate bacterial infection of the bile duct and usually follow the passage of a stone into the bile duct.

Treatment

In most patients acute cholecystitis subsides in a few days with conservative treatment. Cholecystectomy is performed either a few days after the symptoms have settled or 2 to 3 months later. In the latter event, if the symptoms recur during the interval, cholecystectomy is performed without delay. Immediate surgery is mandatory if signs of gangrene or perforation develop.

Conservative treatment

Oral feeding is stopped. Intravenous fluids, and analgesia with nalbuphine or pethidine (demerol) and atropine are administered. Antibiotics are given to all but the most mild cases; tetracycline, amoxicillin, or a cephalosporin are satisfactory for general use. The patient should be observed frequently with abdominal examination and sequential leucocyte counts to detect signs of gangrene of the gallbladder or cholangitis.

Surgical treatment

Cholecystectomy is the operation of choice. Laparoscopic cholecystectomy is the preferred approach. About 10% of patients with acute cholecystitis will have stones in the common bile duct. The bile ducts should be assessed by MRC or ERCP and bile duct stones removed by endoscopic sphincterotomy. If an open cholecystectomy is performed, intraoperative cholangiography may be performed to determine whether bile duct stones are present. In high-risk patients and when technical difficulties are encountered a cholecystotomy may be performed.

Chronic cholecystitis

This is the most common form of gallbladder disease that results from gallstones. Pathologically it is characterized by chronic inflammation and thickening of the gallbladder wall. In addition to stones the gallbladder may contain brown sediment (‘biliary mud’). A proportion of these patients have cholesterolosis of the gallbladder (‘strawberry gallbladder’). This describes the deposition of yellow specks of cholesterol in the pink gallbladder wall and is a consequence of cholesterol-saturated bile. Cholesterolosis of the gallbladder is asymptomatic but about one-half of the patients develop gallstones. Chronic cholecystitis usually develops insidiously but may follow an attack of acute cholecystitis.

Symptoms and signs

Some patients complain of bouts of constant right hypochondrial or epigastric pain. If it is intermittent, that is, biliary colic, the height of the pain is separated by 15- to 60-min intervals. The pain may last several hours or be as brief as 15 to 20 min. It may radiate to the right shoulder or the back. More commonly the symptoms are vague and ill-defined and include abdominal discomfort and distension, nausea, flatulence, and intolerance of fatty foods. Unfortunately, many patients who do not have chronic cholecystitis complain of these symptoms. Examination of the abdomen may reveal tenderness over the gallbladder and a positive Murphy’s sign. Laboratory investigations are usually unhelpful.

Imaging techniques

An ultrasound scan is used to detect gallstones. A plain radiograph of the abdomen may reveal calcified stones or opacification of the gallbladder caused by high concentrations of calcium carbonate (‘limey bile’) but is not often used now. If these investigations fail to show stones, but stones are still suspected on clinical grounds, an MRC or ERCP should be performed before surgery is undertaken.

Differential diagnosis

Dyspepsia and fat intolerance are common symptoms that may be caused by many conditions including peptic ulcers, hiatus hernia, irritable bowel syndrome, chronic relapsing pancreatitis, and tumours of the stomach, pancreas, colon, or gallbladder. Other functional disorders may also mimic chronic cholecystitis.

Complications

The complications of chronic cholecystitis include acute exacerbations (acute cholecystitis), passage of stones into the bile duct (choledocholithiasis or Mirizzi’s syndrome), pancreatitis, cholecystenteric fistula formation and gallstone ileus, and rarely carcinoma of the gallbladder. Occasionally the accumulation of mucus and gallstones produces hydrops of the gallbladder, which is characterized by a tender mass without the symptoms of acute cholecystitis.

Treatment

In established cases of chronic cholecystitis the treatment of choice is cholecystectomy. When the diagnosis is in doubt, especially when vague symptoms are associated with a well-functioning gallbladder containing stones, a conservative approach is worth trying. This includes weight reduction and a low-fat diet, especially if fatty food is associated with the symptoms. Oral bile acid therapy may also be considered (see above).

Prognosis

Chronic cholecystitis carries a good prognosis. Cholecystectomy is curative and should have a mortality below 1%. However, if cholecystectomy is performed indiscriminately on patients with ‘dyspeptic’ symptoms who happen to have incidental gallstones, the results will be unpredictable and often unsatisfactory.

Choledocholithiasis

Most stones in the common bile duct originate in the gallbladder. About 15% of patients with cholelithiasis have common duct stones. This proportion rises with age so that nearly 50% of elderly patients with cholelithiasis may have common duct stones. Stones may develop in the bile duct in diseases causing chronic biliary obstruction such as benign bile duct strictures and sclerosing cholangitis.

Clinical features

The classic triad of symptoms is right upper abdominal pain, jaundice, and fever. The abdominal pain is typically colicky, severe, and persists for hours. It is often associated with vomiting. Fever and rigors indicate cholangitis, which commonly accompanies bile duct stones. Jaundice is variable; it may be mild or deep and is often intermittent. The urine is dark due to conjugated bilirubin and the faeces are pale. Frequently, the amount of pigment in the faeces varies. Itching may be prominent. However, common bile duct stones may also be silent, especially in older people. Alternatively, only one of the triad of symptoms may be present; the patient presenting with jaundice, abdominal pain, or cholangitis. The liver is moderately enlarged and there may be tenderness in the right upper quadrant. Prolonged biliary obstruction lasting months or years eventually leads to biliary cirrhosis with portal venous hypertension and liver cell failure.

Laboratory investigations

Liver function tests show a cholestatic (biliary obstructive) pattern. The prothrombin time may be prolonged due to inadequate absorption of vitamin K. A polymorphonuclear leucocytosis is common and indicates biliary infection. Blood cultures should be performed repeatedly during the fevers to isolate the organism and determine sensitivities.

Imaging techniques

A plain radiograph of the abdomen will show calcified gallstones in 10% of patients, but is rarely performed now. Ultrasonography is useful for demonstrating the dilated biliary tree that results from obstruction and may reveal biliary gallstones. Unfortunately, an ultrasound scan frequently fails to detect common duct stones obstructing the lower end of the bile duct. Cholangiography by MRC or ERCP is required in these patients. Common bile duct stones should be removed by endoscopic sphincterotomy before the patient is submitted to cholecystectomy.

Differential diagnosis

Common duct stones are the most common cause of cholestatic (biliary obstructive) jaundice. Next in frequency are carcinomas of the head of the pancreas, bile duct, and ampulla of Vater (Bullet list 1). Intrahepatic diseases may also cause a cholestatic jaundice; the causes include viral and alcoholic hepatitis, drugs, and pregnancy.

Treatment

Common bile duct stones must be removed. The optimal treatment is endoscopic sphincterotomy to remove bile duct stones followed by laparoscopic cholecystectomy. This approach avoids the hazards of open exploration of the common bile duct. Endoscopic removal of common duct gallstones without cholecystectomy is appropriate in patients unfit for surgery. Few patients will have further problems from the gallbladder that remains. Stones overlooked at surgery (residual calculi) are best treated by endoscopic sphincterotomy or, if a T-tube is in place, removed by a steerable basket catheter manipulated down the T-tube track. Open exploration of the common bile duct is required if gallstones are too large to be removed endoscopically (>2 cm). Preoperative preparation includes appropriate antibiotics for cholangitis, the correction of fluid and electrolyte balance, nutrition, and anaemia, and if the prothrombin time is prolonged, parenteral vitamin K.

Bullet list 1 Causes of bile duct obstruction

Intrinsic causes

After cholecystectomy a proportion of patients continue to complain of symptoms such as right upper quadrant pain, flatulence, and fatty food intolerance. However, the vast majority of patients with gallstones are improved by surgery. The persistence of symptoms in many is probably a consequence of the wrong diagnosis being made before surgery, and other diseases such as oesophagitis, pancreatitis, or functional bowel disease should be sought. In others, technical problems during surgery may have resulted in a benign post-traumatic biliary stricture or residual calculi. However, there remains a group of patients where the cause appears to be due to less common biliary disorders such as long, dilated cystic duct remnants, amputation neuromas of the cystic duct, and spasm or stenosis of the sphincter of Oddi. The biliary tract must be carefully investigated in these patients, especially if colicky pain, fever, jaundice, or cholestatic liver function tests persist. Biliary tract manometry is of value when spasm or stenosis of the sphincter of Oddi is suspected.

Biliary infections

Bacterial cholangitis (suppurative cholangitis)

This is usually associated with common bile duct calculi and benign biliary structures. Malignant strictures produce complete obstruction and the bile remains sterile. Other conditions associated with cholangitis are biliary enteric fistulas—both spontaneous and surgical—sclerosing cholangitis, and congenital intrahepatic biliary dilation (Caroli’s disease). Organisms of the gut flora are usually cultured in these infections, including aerobes such as E. coli, Streptococcus faecalis, Proteus vulgaris and staphylococci, and anaerobes such as bacteroides, aerobacter, and anaerobic steptrococci.

Clinical features and treatment

The onset of malaise, fever, and rigors is followed by pain, vomiting, jaundice, and itching. The urine turns dark and the faeces pale. The biliary obstructive features are probably due to oedema of the bile duct wall. Recurrent attacks are common. Hepatic abscesses may result. Repeated blood cultures are performed during the fever to isolate the organisms. Culture of a liver biopsy fragment may also yield the organism. The main element of treatment is drainage of the biliary tract, which is best achieved by emergency endoscopic sphincterotomy. Additionally, appropriate antibiotics such as cefuroxime and metronidazole are given. For recurrent attacks of cholangitis, tetracycline, amoxicillin, or cephalexin are usually effective.

Infestations

Infestations with the roundworm Ascaris lumbricoides and the liver fluke Clonorchis sinensis are particular problems of East Asia. Both lead to cholangitis. C. sinensis infestation predisposes to bile duct carcinoma and primary liver cancer. The common sheep fluke Fasciola hepatica may be encountered as a cause of cholangitis in Europe during wet summers.

Benign biliary strictures

In about 95% of patients these are a consequence of biliary tract surgery. The remainder are caused by gallstones eroding the bile duct and, rarely, blunt injury to the abdomen. Signs of biliary stricture may be detected in the immediate postoperative period but are often delayed. Disasters such as ligation or section of the bile duct present early with jaundice and drainage of bile from the wound drains. With lesser damage to the duct the patient presents after an interval with cholangitis and jaundice. Liver function tests reveal a cholestatic pattern and blood cultures may yield an organism. The precise delineation of the stricture requires MRC, ERCP or PTC. Biliary stricture is not a benign condition; untreated, it will usually progress to biliary cirrhosis with portal venous hypertension and liver failure. Treatment is surgical and should be performed by a surgeon skilled in this difficult repair.

Malignant biliary stricture

This is most commonly due to adenocarcinoma of the head of the pancreas but may also be caused by adenocarcinomas of the bile ducts, of the ampulla of Vater, and rarely of the gallbladder. Occasionally the cause is lymph node enlargement at the porta hepatis due to malignant metastases or lymphoma.

Symptoms and signs

Cancers of the pancreas and biliary tree usually affect middle-aged and elderly individuals. The onset is insidious, with deepening jaundice, itching, and weight loss. A dull, nagging upper abdominal pain which radiates to the back is common. In contrast to choledocholithiasis and benign strictures, cholangitis is unusual. Examination reveals a deeply jaundiced patient often excoriated from scratching. The liver is enlarged but not tender. If the malignant obstruction is below the level of the cystic duct, the gallbladder is distended and may be palpable (Courvoisier’s law). The urine is dark and the stools pale. In cancer of the ampulla of Vater, a film of blood on the pale stool may give it a silvery colour (‘silver stools’).

Laboratory investigation

Liver function tests reveal a cholestatic pattern. The serum bilirubin may be very high (600 µmol/litre; 35 mg/dl). A microcytic hypochromic anaemia indicates blood loss from the tumour.

Imaging techniques

An ultrasound or CT scan examination will reveal dilatation of the biliary tree and may demonstrate the level of the obstruction. Ultrasound-guided percutaneous needle biopsy may be employed to provide a histological diagnosis. Bile duct carcinoma frequently causes obstruction at the porta hepatis and, consequently, at laparotomy the extrahepatic biliary tract appears nondilated. Even if operative cholangiography is performed, the constrast medium frequently fails to pass the obstruction and fill the dilated intrahepatic biliary tree. Therefore it is important to establish the diagnosis precisely before surgery is contemplated by performing an MRC, ERCP or PTC. This is particularly important because most of these patients are best treated by endoscopic or percutaneous biliary stents rather than surgery (see below).

Treatment

Occasionally, small tumours confined to the head of the pancreas and ampulla of Vater may be treated curatively by a Whipple’s operation. Unfortunately the great majority of pancreatic and bile duct cancers can only be treated palliatively with a bypass procedure such as a cholecystojejunostomy. The prognosis for these patients is poor. An alternative treatment is endoscopic or percutaneous transhepatic introduction of prostheses (stents) through the biliary stricture. Patients with endoscopic prostheses have the same median survival as those with surgical bypass procedures, but the operative mortality and morbidity rate is much lower for endoscopic prostheses. Endoscopic prostheses are the preferred treatment for unresectable biliary and pancreatic cancers. The prostheses may block after about 3 months and need to be replaced.

Other causes of bile duct obstruction

Pancreatitis may obstruct the common bile duct during its passage through the head of the pancreas. Transient jaundice is common in acute pancreatitis due to compression by pancreatic oedema. In chronic pancreatitis, especially alcoholic, persistent jaundice can develop requiring a surgical bypass procedure such as a cholecystojejunostomy. This biliary obstruction is probably a consequence of pancreatic fibrosis. Pancreatic cysts may rarely cause extrinsic compression of the bile duct. Haemobilia or haemorrhage into the biliary tract is uncommon but may follow trauma, liver biopsy, biliary tumours, and gallstones. In addition to jaundice, the blood clots cause biliary pain. Massive gastrointestinal haemorrhage may occur. The diagnosis of these conditions relies on accurate cholangiography (usually MRC or ERCP).

Sclerosing cholangitis

Sclerosing cholangitis is the description applied to multiple strictures and bead-like dilatations of the intrahepatic and extrahepatic biliary tree.

Primary sclerosing cholangitis

This should only be diagnosed if the following criteria are satisfied: (1) absence of gallstones; (2) absence of previous biliary surgery; and (3) sufficiently long follow-up to exclude carcinoma of the bile duct. Primary sclerosing cholangitis affects men more than women (2:1) and about 70% of patients have ulcerative colitis. The usual clinical presentation is cholestatic jaundice and cholangitis. However, a significant proportion of patients are asymptomatic or present with cirrhosis and portal venous hypertension. There is associated retroperitoneal fibrosis or Riedel’s thyroiditis in some cases. Serum biochemistry shows cholestatic liver function tests. A raised serum alkaline phosphatase is almost invariable. Consequently the diagnosis should be considered in patients with cirrhosis whose liver function tests show cholestatic features. The IgM concentration is commonly elevated. Liver biopsy may be helpful and usually indicates large bile duct obstruction. The diagnosis is established by cholangiography with ERCP or PTC. Laparotomy should not be performed. Lone tight strictures and stones can be treated by endoscopic techniques. Primary sclerosing cholangitis is being recognized more frequently as a result of the widespread use of ERCP and PTC. It may be confused with primary biliary cirrhosis, but the serum mitochondrial antibody is always negative in primary sclerosing cholangitis. Treatment is unsatisfactory, neither corticosteroids nor azathioprine are of proven value. Ursodeoxycholic acid improves liver function tests but has not been shown to prolong survival. Pruritus may be helped by cholestyramine. The prognosis is variable but most patients eventually develop cirrhosis and liver failure. Liver transplantation yields excellent results in these patients. Bile duct adenocarcinoma is a late complication.

Secondary sclerosing cholangitis

Several causes of secondary sclerosing cholangitis are now recognized. These include recurrent bacterial cholangitis due to gallstones or benign biliary strictures. Children with primary immunodeficiency syndromes and patients with AIDS also develop sclerosing cholangitis. Cytomegalovirus and cryptosporidium are the organisms most commonly associated with AIDS-related sclerosing cholangitis. Sclerosing cholangitis may also develop in patients treated by hepatic arterial infusion of cytotoxic drugs and after the introduction of caustics into hydatid cysts.

Congenital disorders of the gallbladder and biliary tract

Congenital disorders of the liver, biliary tract, and pancreas are rare or very rare.

Biliary atresias present with cholestatic jaundice starting after the first 2 weeks of life and may eventually cause biliary cirrhosis and liver failure. Prognosis depends on the type of atresia: (1) intrahepatic—both nonsyndromic (with cirrhosis usually developing in late childhood, and fatal without liver transplantation) and syndromic (e.g. Alagille’s syndrome, due to mutation in the JAG1 gene, with dysmorphic and other features, and a tendency for recovery of liver function in adolescence), or (2) extrahepatic—which is usually fatal within 6 months of birth unless treated by hepatic portoenterostomy and/or liver transplantation.

This subject is discussed further here: Congenital disorders of the biliary tract and liver

Further reading

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Angulo P, Lindor KD (1999). Primary sclerosing cholangitis. Hepatology, 30, 325–32.

Donovan JM (1999). Physical and metabolic factors in gallstone pathogenesis. Gastroenterol Clin North Am, 28, 75–97.

Ko CW, Lee SP (1999). Gallstone formation. Local factors. Gastroenterol Clin North Am, 28, 99–115.

Martin DJ, Vernon DR, Toouli J (2006). Surgical versus endoscopic treatment of bile duct stones. Cochrane Database Syst Rev, 19, CD003327.

Schiff L, Schiff ER (1993). Diseases of the liver, 7th edn. Lippincott, Philadelphia, PA.

Sherlock S, Dooley JS (1997). Diseases of the liver and biliary system, 10th edition. Blackwell Scientific Publications, Oxford.

Sherlock S, Summerfield JA (1991). A colour atlas of liver disease, 2nd edition. Wolfe Medical Publications, London.