Chapter 32: Gallbladder and the Extrahepatic Biliary System

1. The physiology of the gallbladder and sphincter of Oddi is regulated by a complex interplay of hormones and neuronal inputs designed to coordinate bile release with food consumption. Dysfunctions related to this activity are linked to the development of gallbladder pathologies described in this chapter.

2. In Western countries, the most common type of gallstones are cholesterol stones. The pathogenesis of these stones relates to supersaturation of bile with cholesterol and subsequent precipitation.

3. Laparoscopic cholecystectomy has been demonstrated to be a safe and effective alternative to open cholecystectomy and has become the treatment of choice for symptomatic gallstones. Knowledge of the various anatomic anomalies of the cystic duct and artery is helpful in guiding the dissection of these structures as well as avoiding injury to the common bile duct during cholecystectomy.

4. Common bile duct injuries, although uncommon, can be devastating to patients. Proper exposure of Calot’s triangle and careful identification of the anatomic structures are keys to avoiding these injuries. Once a bile duct injury is diagnosed, the best outcomes are seen at large referral centers with experienced biliary surgeons.

5. The main risk factor for gallbladder disease in Western countries is cholelithiasis. The main complications include cholecystitis, choledocholithiasis, cholangitis, and biliary pancreatitis. In addition, cholelithiasis plays the role as the major risk factor for the development of gallbladder cancer.

6. Carcinoma of the gallbladder and bile duct generally have a poor prognosis because patients usually present late in the disease process and have poor response to chemotherapy and radiation therapy. Surgery offers the best chance for survival and has good long-term survival in patients with early-stage disease.

Gallbladder

The gallbladder is a pear-shaped sac, about 7 to 10 cm long, with an average capacity of 30 to 50 mL. When obstructed, the gallbladder can distend markedly and contain up to 300 mL.¹ The gallbladder is located in a fossa on the inferior surface of the liver. A line from this fossa to the inferior vena cava divides the liver into right and left liver lobes. The gallbladder is divided into four anatomic areas: the fundus, the corpus (body), the infundibulum, and the neck. The fundus is the rounded, blind end that normally extends 1 to 2 cm beyond the liver’s margin. It contains most of the smooth muscles of the organ, in contrast to the body, which is the main storage area and contains most of the elastic tissue. The body extends from the fundus and tapers into the neck, a funnel-shaped area that connects with the cystic duct. The neck usually follows a gentle curve, the convexity of which may be enlarged to form the infundibulum or Hartmann’s pouch. The neck lies in the deepest part of the gallbladder fossa and extends into the free portion of the hepatoduodenal ligament (Fig. 32-1).

The same peritoneal lining that covers the liver covers the fundus and the inferior surface of the gallbladder. Occasionally, the gallbladder has a complete peritoneal covering and is suspended in a mesentery off the inferior surface of the liver, and rarely, it is embedded deep inside the liver parenchyma (an intrahepatic gallbladder).

The gallbladder is lined by a single, highly folded, tall columnar epithelium that contains cholesterol and fat globules. The mucus secreted into the gallbladder originates in the tubuloalveolar glands found in the mucosa lining the infundibulum and neck of the gallbladder, but are absent from the body and fundus. The epithelial lining of the gallbladder is supported by a lamina propria. The muscle layer has circular longitudinal and oblique fibers, but without well-developed layers. The perimuscular subserosa contains connective tissue, nerves, vessels, lymphatics, and adipocytes. It is covered by the serosa except where the gallbladder is embedded in the liver. The gallbladder differs histologically from the rest of the gastrointestinal (GI) tract in that it lacks a muscularis mucosa and submucosa.

The cystic artery that supplies the gallbladder is usually a branch of the right hepatic artery (>90% of the time). The course of the cystic artery may vary, but it nearly always is found within the hepatocystic triangle, the area bound by the cystic duct, common hepatic duct, and the liver margin (triangle of Calot). When the cystic artery reaches the neck of the gallbladder, it divides into anterior and posterior divisions. Venous return is carried either through small veins that enter directly into the liver or, rarely, to a large cystic vein that carries blood back to the portal vein. Gallbladder lymphatics drain into nodes at the neck of the gallbladder. Frequently, a visible lymph node overlies the insertion of the cystic artery into the gallbladder wall. The nerves of the gallbladder arise from the vagus and from sympathetic branches that pass through the celiac plexus. The preganglionic sympathetic level is T8 and T9. Impulses from the liver, gallbladder, and the bile ducts pass by means of sympathetic afferent fibers through the splanchnic nerves and mediate the pain of biliary colic. The hepatic branch of the vagus nerve supplies cholinergic fibers to the gallbladder, bile ducts, and liver. The vagal branches also have peptide-containing nerves containing agents such as substance P, somatostatin, enkephalins, and vasoactive intestinal polypeptide.²

Bile Ducts

The extrahepatic bile ducts consist of the right and left hepatic ducts, the common hepatic duct, the cystic duct, and the common bile duct or choledochus. The common bile duct enters the second portion of the duodenum through a muscular structure, the sphincter of Oddi.³

The left hepatic duct is longer than the right and has a greater propensity for dilatation as a consequence of distal obstruction. The two ducts join to form a common hepatic duct, close to their emergence from the liver. The common hepatic duct is 1 to 4 cm in length and has a diameter of approximately 4 mm. It lies in front of the portal vein and to the right of the hepatic artery. The common hepatic duct is joined at an acute angle by the cystic duct to form the common bile duct.

The length of the cystic duct is quite variable. It may be short or absent and have a high union with the hepatic duct, or long and run parallel, behind, or spiral to the main hepatic duct before joining it, sometimes as far as at the duodenum. Variations of the cystic duct and its point of union with the common hepatic duct are surgically important (Fig. 32-2). The segment of the cystic duct adjacent to the gallbladder neck bears a variable number of mucosal folds called the spiral valves of Heister. They do not have any valvular function but may make cannulation of the cystic duct difficult.

The common bile duct is about 7 to 11 cm in length and 5 to 10 mm in diameter. The upper third (supraduodenal portion) passes downward in the free edge of the hepatoduodenal ligament, to the right of the hepatic artery and anterior to the portal vein. The middle third (retroduodenal portion) of the common bile duct curves behind the first portion of the duodenum and diverges laterally from the portal vein and the hepatic arteries. The lower third (pancreatic portion) curves behind the head of the pancreas in a groove, or traverses through it and enters the second part of the duodenum. There, the pancreatic duct frequently joins it. The common bile duct runs obliquely downward within the wall of the duodenum for 1 to 2 cm before opening on a papilla of mucous membrane (ampulla of Vater), about 10 cm distal to the pylorus. The union of the common bile duct and the main pancreatic duct follows one of three configurations. In about 70% of people, these ducts unite outside the duodenal wall and traverse the duodenal wall as a single duct. In about 20%, they join within the duodenal wall and have a short or no common duct, but open through the same opening into the duodenum. In about 10%, they exit via separate openings into the duodenum. The sphincter of Oddi, a thick coat of circular smooth muscle, surrounds the common bile duct at the ampulla of Vater (Fig. 32-3). It controls the flow of bile, and in some cases pancreatic juice, into the duodenum.

The extrahepatic bile ducts are lined by a columnar mucosa with numerous mucous glands in the common bile duct. A fibroareolar tissue containing scant smooth muscle cells surrounds the mucosa. A distinct muscle layer is not present in the human common bile duct. The arterial supply to the bile ducts is derived from the gastroduodenal and the right hepatic arteries, with major trunks running along the medial and lateral walls of the common duct (sometimes referred to as 3 o’clock and 9 o’clock). These arteries anastomose freely within the duct walls. The density of nerve fibers and ganglia increases near the sphincter of Oddi, but the nerve supply to the common bile duct and the sphincter of Oddi is the same as for the gallbladder.^1,2

Anomalies

The classic description of the extrahepatic biliary tree and its arteries applies only in about one third of patients.⁴ The gallbladder may have abnormal positions, be intrahepatic, be rudimentary, have anomalous forms, or be duplicated. Isolated congenital absence of the gallbladder is very rare, with a reported incidence of 0.03%. Before the diagnosis is made, the presence of an intrahepatic bladder or anomalous position must be ruled out. Duplication of the gallbladder with two separate cavities and two separate cystic ducts has an incidence of about one in every 4000 persons. This occurs in two major varieties: the more common form in which each gallbladder has its own cystic duct that empties independently into the same or different parts of the extrahepatic biliary tree, and as two cystic ducts that merge before they enter the common bile duct. Duplication is only clinically important when some pathologic processes affect one or both organs. A left-sided gallbladder with a cystic duct emptying into the left hepatic duct or the common bile duct and a retrodisplacement of the gallbladder are both extremely rare. A partial or totally intrahepatic gallbladder is associated with an increased incidence of cholelithiasis.

Small ducts (of Luschka) may drain directly from the liver into the body of the gallbladder. If present, but not recognized at the time of a cholecystectomy, a bile leak with the accumulation of bile (biloma) may occur in the abdomen. An accessory right hepatic duct occurs in about 5% of cases. Variations of how the common bile duct enters the duodenum are described in earlier, in the Bile Ducts section.

Anomalies of the hepatic artery and the cystic artery are quite common, occurring in as many as 50% of cases.⁵ In about 5% of cases, there are two right hepatic arteries, one from the common hepatic artery and the other from the superior mesenteric artery. In about 20% of patients, the right hepatic artery comes off the superior mesenteric artery. The right hepatic artery may course anterior to the common duct. The right hepatic artery may be vulnerable during surgical procedures, in particular when it runs parallel to the cystic duct or in the mesentery of the gallbladder. The cystic artery arises from the right hepatic artery in about 90% of cases, but may arise from the left hepatic, common hepatic, gastroduodenal, or superior mesenteric arteries (Fig. 32-4).

Bile Formation and Composition

The liver produces bile continuously and excretes it into the bile canaliculi. The normal adult consuming an average diet produces within the liver 500 to 1000 mL of bile a day. The secretion of bile is responsive to neurogenic, humoral, and chemical stimuli. Vagal stimulation increases secretion of bile, whereas splanchnic nerve stimulation results in decreased bile flow. Hydrochloric acid, partly digested proteins, and fatty acids in the duodenum stimulate the release of secretin from the duodenum that, in turn, increases bile production and bile flow. Bile flows from the liver through to the hepatic ducts, into the common hepatic duct, through the common bile duct, and finally into the duodenum. With an intact sphincter of Oddi, bile flow is directed into the gallbladder.

Bile is mainly composed of water, electrolytes, bile salts, proteins, lipids, and bile pigments. Sodium, potassium, calcium, and chlorine have the same concentration in bile as in plasma or extracellular fluid. The pH of hepatic bile is usually neutral or slightly alkaline, but varies with diet; an increase in protein shifts the bile to a more acidic pH. The primary bile salts, cholate and chenodeoxycholate, are synthesized in the liver from cholesterol. They are conjugated there with taurine and glycine and act within the bile as anions (bile acids) that are balanced by sodium. Bile salts are excreted into the bile by the hepatocyte and aid in the digestion and absorption of fats in the intestines.⁶ In the intestines, about 80% of the conjugated bile acids are absorbed in the terminal ileum. The remainder is dehydroxylated (deconjugated) by gut bacteria, forming secondary bile acids deoxycholate and lithocholate. These are absorbed in the colon, transported to the liver, conjugated, and secreted into the bile. Eventually, about 95% of the bile acid pool is reabsorbed and returned via the portal venous system to the liver, the so-called enterohepatic circulation. Five percent is excreted in the stool, leaving the relatively small amount of bile acids to have maximum effect.

Cholesterol and phospholipids synthesized in the liver are the principal lipids found in bile. The synthesis of phospholipids and cholesterol by the liver is, in part, regulated by bile acids. The color of the bile is due to the presence of the pigment bilirubin diglucuronide, which is the metabolic product from the breakdown of hemoglobin and is present in bile in concentrations 100 times greater than in plasma. Once in the intestine, bacteria convert it into urobilinogen, a small fraction of which is absorbed and secreted into the bile.

Gallbladder Function

The gallbladder, the bile ducts, and the sphincter of Oddi act together to store and regulate the flow of bile. The main function of the gallbladder is to concentrate and store hepatic bile and to deliver bile into the duodenum in response to a meal.

Absorption and Secretion

In the fasting state, approximately 80% of the bile secreted by the liver is stored in the gallbladder. This storage is made possible because of the remarkable absorptive capacity of the gallbladder, as the gallbladder mucosa has the greatest absorptive power per unit area of any structure in the body. It rapidly absorbs sodium, chloride, and water against significant concentration gradients, concentrating the bile as much as 10-fold and leading to a marked change in bile composition. This rapid absorption is one of the mechanisms that prevent a rise in pressure within the biliary system under normal circumstances. Gradual relaxation as well as emptying of the gallbladder during the fasting period also plays a role in maintaining a relatively low intraluminal pressure in the biliary tree.

The epithelial cells of the gallbladder secrete at least two important products into the gallbladder lumen: glycoproteins and hydrogen ions. The mucosal glands in the infundibulum and the neck of the gallbladder secrete mucus glycoproteins that are believed to protect the mucosa from the lytic action of bile and to facilitate the passage of bile through the cystic duct. This mucus makes up the colorless “white bile” seen in hydrops of the gallbladder resulting from cystic duct obstruction. The transport of hydrogen ions by the gallbladder epithelium leads to a decrease in the gallbladder bile pH. The acidification promotes calcium solubility, thereby preventing its precipitation as calcium salts.⁶

Motor Activity

Gallbladder filling is facilitated by tonic contraction of the sphincter of Oddi, which creates a pressure gradient between the bile ducts and the gallbladder. During fasting, the gallbladder does not simply fill passively. In association with phase II of the interdigestive migrating myenteric motor complex in the gut, the gallbladder repeatedly empties small volumes of bile into the duodenum. This process is mediated at least in part by the hormone motilin. In response to a meal, the gallbladder empties by a coordinated motor response of gallbladder contraction and sphincter of Oddi relaxation. One of the main stimuli to gallbladder emptying is the hormone cholecystokinin (CCK). CCK is released endogenously from the duodenal mucosa in response to a meal.⁷ When stimulated by eating, the gallbladder empties 50% to 70% of its contents within 30 to 40 minutes. Over the following 60 to 90 minutes, the gallbladder gradually refills. This is correlated with a reduced CCK level. Other hormonal and neural pathways also are involved in the coordinated action of the gallbladder and the sphincter of Oddi. Defects in the motor activity of the gallbladder are thought to play a role in cholesterol nucleation and gallstone formation.⁸

Neurohormonal Regulation

The vagus nerve stimulates contraction of the gallbladder, and splanchnic sympathetic stimulation is inhibitory to its motor activity. Parasympathomimetic drugs contract the gallbladder, whereas atropine leads to relaxation. Neurally mediated reflexes link the sphincter of Oddi with the gallbladder, stomach, and duodenum to coordinate the flow of bile into the duodenum. Antral distention of the stomach causes both gallbladder contraction and relaxation of the sphincter of Oddi.

Hormonal receptors are located on the smooth muscles, vessels, nerves, and epithelium of the gallbladder. CCK is a peptide that comes from epithelial cells of the upper GI tract and is found in the highest concentrations in the duodenum. CCK is released into the bloodstream by acid, fat, and amino acids in the duodenum.⁹ CCK has a plasma half-life of 2 to 3 minutes and is metabolized by both the liver and the kidneys. CCK acts directly on smooth muscle receptors of the gallbladder and stimulates gallbladder contraction. It also relaxes the terminal bile duct, the sphincter of Oddi, and the duodenum. CCK stimulation of the gallbladder and the biliary tree also is mediated by cholinergic vagal neurons. In patients who have had a vagotomy, the response to CCK stimulation is diminished and the size and the volume of the gallbladder are increased.

Vasoactive intestinal polypeptide inhibits contraction and causes gallbladder relaxation. Somatostatin and its analogues are potent inhibitors of gallbladder contraction. Patients treated with somatostatin analogues and those with somatostatinoma have a high incidence of gallstones, presumably due to the inhibition of gallbladder contraction and emptying. Other hormones such as substance P and enkephalin affect gallbladder motility, but the physiologic role is unclear.⁷

Sphincter of Oddi

The sphincter of Oddi regulates flow of bile (and pancreatic juice) into the duodenum, prevents the regurgitation of duodenal contents into the biliary tree, and diverts bile into the gallbladder. It is a complex structure that is functionally independent from the duodenal musculature and creates a high-pressure zone between the bile duct and the duodenum. The sphincter of Oddi is about 4 to 6 mm in length and has a basal resting pressure of about 13 mmHg above the duodenal pressure. On manometry, the sphincter shows phasic contractions with a frequency of about four per minute and an amplitude of 12 to 140 mmHg.⁸ The spontaneous motility of the sphincter of Oddi is regulated by the interstitial cells of Cajal through intrinsic and extrinsic inputs from hormones and neurons acting on the smooth muscle cells.¹⁰ Relaxation occurs with a rise in CCK, leading to diminished amplitude of phasic contractions and reduced basal pressure, allowing increased flow of bile into the duodenum (Fig. 32-5). During fasting, the sphincter of Oddi activity is coordinated with the periodic partial gallbladder emptying and an increase in bile flow that occurs during phase II of the migrating myoelectric motor complexes.¹¹

A variety of diagnostic modalities are available for the patient with suspected disease of the gallbladder and the bile ducts. In 1924, the diagnosis of gallstones was improved significantly by the introduction of oral cholecystography by Graham and Cole. For decades, it was the mainstay of investigation for gallstones. In the 1950s, biliary scintigraphy was developed, as well as intrahepatic and endoscopic retrograde cholangiography (ERC), allowing imaging of the biliary tract. Later ultrasonography, computed tomography (CT), and magnetic resonance imaging (MRI) vastly improved the ability to image the biliary tract.¹²

Blood Tests

When patients with suspected diseases of the gallbladder or the extrahepatic biliary tree are evaluated, a complete blood count and liver function tests are routinely requested. An elevated white blood cell (WBC) count may indicate or raise suspicion of cholecystitis. If associated with an elevation of bilirubin, alkaline phosphatase, and aminotransferase, cholangitis should be suspected. Cholestasis, an obstruction to bile flow, is characterized by an elevation of bilirubin (i.e., the conjugated form) and a rise in alkaline phosphatase. Serum aminotransferases may be normal or mildly elevated. In patients with biliary colic or chronic cholecystitis, blood tests will typically be normal.

Ultrasonography

An ultrasound is the initial investigation of any patient suspected of disease of the biliary tree.¹³ It is noninvasive, painless, does not submit the patient to radiation, and can be performed on critically ill patients. It is dependent upon the skills and the experience of the operator, and it is dynamic (i.e., static images do not give the same information as those obtained during the ultrasound investigation itself). Adjacent organs can frequently be examined at the same time. Obese patients, patients with ascites, and patients with distended bowel may be difficult to examine satisfactorily with an ultrasound.

Ultrasound will show stones in the gallbladder with sensitivity and specificity of >90%. Stones are acoustically dense and reflect the ultrasound waves back to the ultrasonic transducer. Because stones block the passage of sound waves to the region behind them, they also produce an acoustic shadow (Fig. 32-6). Stones move with changes in position. Polyps may be calcified and reflect shadows, but do not move with change in posture. Some stones form a layer in the gallbladder; others a sediment or sludge. A thickened gallbladder wall and local tenderness indicate cholecystitis. The patient has acute cholecystitis if a layer of edema is seen within the wall of the gallbladder or between the gallbladder and the liver in association with localized tenderness. When a stone obstructs the neck of the gallbladder, the gallbladder may become very large, but thin walled. A contracted, thick-walled gallbladder is indicative of chronic cholecystitis.

The extrahepatic bile ducts are also well visualized by ultrasound, except for the retroduodenal portion. Dilation of the ducts in a patient with jaundice establishes an extrahepatic obstruction as a cause for the jaundice. Frequently, the site and, sometimes, the cause of obstruction can be determined by ultrasound. Small stones in the common bile duct frequently get lodged at the distal end of it, behind the duodenum, and are, therefore, difficult to detect. A dilated common bile duct on ultrasound, small stones in the gallbladder, and the clinical presentation allow one to assume that a stone or stones are causing the obstruction. Periampullary tumors can be difficult to diagnose on ultrasound, but beyond the retroduodenal portion, the level of obstruction and the cause may be visualized quite well. Ultrasound can be helpful in evaluating tumor invasion and flow in the portal vein, an important guideline for resectability of periampullary and pancreatic head tumors.¹⁴

Oral Cholecystography

Once considered the diagnostic procedure of choice for gallstones, oral cholecystography has largely been replaced by ultrasonography. It involves oral administration of a radiopaque compound that is absorbed, excreted by the liver, and passed into the gallbladder. Stones are noted on a film as filling defects in a visualized, opacified gallbladder. Oral cholecystography is of no value in patients with intestinal malabsorption, vomiting, obstructive jaundice, and hepatic failure.

Biliary Radionuclide Scanning (HIDA Scan)

Biliary scintigraphy provides a noninvasive evaluation of the liver, gallbladder, bile ducts, and duodenum with both anatomic and functional information. ^99mTechnetium-labeled derivatives of dimethyl iminodiacetic acid (HIDA) are injected intravenously, cleared by the Kupffer cells in the liver, and excreted in the bile. Uptake by the liver is detected within 10 minutes, and the gallbladder, the bile ducts, and the duodenum are visualized within 60 minutes in fasting subjects. The primary use of biliary scintigraphy is in the diagnosis of acute cholecystitis, which appears as a nonvisualized gallbladder, with prompt filling of the common bile duct and duodenum. Evidence of cystic duct obstruction on biliary scintigraphy is highly diagnostic for acute cholecystitis. The sensitivity and specificity for the diagnosis are about 95% each. False-positive results are increased in patients with gallbladder stasis, as in critically ill patients and in patients receiving parenteral nutrition. Filling of the gallbladder and common bile duct with delayed or absent filling of the duodenum indicates an obstruction at the ampulla. Biliary leaks as a complication of surgery of the gallbladder or the biliary tree can be confirmed and frequently localized by biliary scintigraphy.¹⁵

Computed Tomography

Abdominal CT scans are inferior to ultrasonography in diagnosing gallstones. The major application of CT scans is to define the course and status of the extrahepatic biliary tree and adjacent structures. It is the test of choice in evaluating the patient with suspected malignancy of the gallbladder, the extrahepatic biliary system, or nearby organs, in particular, the head of the pancreas. Use of CT scan is an integral part of the differential diagnosis of obstructive jaundice (Fig. 32-7). Spiral CT scanning provides additional staging information, including vascular involvement in patients with periampullary tumors.¹⁶

Percutaneous Transhepatic Cholangiography

Intrahepatic bile ducts are accessed percutaneously with a small needle under fluoroscopic guidance. Once the position in a bile duct has been confirmed, a guidewire is passed, and subsequently, a catheter is passed over the wire (Fig. 32-8). Through the catheter, a cholangiogram can be performed and therapeutic interventions done, such as biliary drain insertions and stent placements. Percutaneous transhepatic cholangiography (PTC) has little role in the management of patients with uncomplicated gallstone disease but is particularly useful in patients with bile duct strictures and tumors, as it defines the anatomy of the biliary tree proximal to the affected segment. As with any invasive procedure, there are potential risks. For PTC, these are mainly bleeding, cholangitis, bile leak, and other catheter-related problems.¹⁵

Magnetic Resonance Imaging

Available since the mid-1990s, MRI provides anatomic details of the liver, gallbladder, and pancreas similar to those obtained from CT. Many MRI techniques (i.e., heavily T2-weighted sequences, pulse sequences with or without contrast materials) can generate high-resolution anatomic images of the biliary tree and the pancreatic duct. It has a sensitivity and specificity of 95% and 89%, respectively, at detecting choledocholithiasis.¹⁷ MRI with magnetic resonance cholangiopancreatography (MRCP) offers a single noninvasive test for the diagnosis of biliary tract and pancreatic disease¹⁸ (Fig. 32-9). In many centers, MRCP is first performed for diagnosis of biliary and pancreatic duct pathology, reserving endoscopic retrograde cholangiopancreatography (ERCP) for therapeutic purposes only.

Endoscopic Retrograde Cholangiopancreatography

Using a side-viewing endoscope, the common bile duct can be cannulated and a cholangiogram performed using fluoroscopy (Fig. 32-10). The procedure requires intravenous (IV) sedation for the patient. The advantages of ERC include direct visualization of the ampullary region and direct access to the distal common bile duct, with the possibility of therapeutic intervention. The test is rarely needed for uncomplicated gallstone disease, but for stones in the common bile duct, in particular, when associated with obstructive jaundice, cholangitis, or gallstone pancreatitis, ERC is the diagnostic and often therapeutic procedure of choice. Once the endoscopic cholangiogram has shown ductal stones, sphincterotomy and stone extraction can be performed, and the common bile duct cleared of stones. In the hands of experts, the success rate of common bile duct cannulation and cholangiography is >90%. Complications of diagnostic ERC include pancreatitis and cholangitis and occur in up to 5% of patients.¹⁹ The development of small fiber-optic cameras that can be threaded through endoscopes used for endoscopic retrograde cholangiopancreatography (ERCP) has facilitated the development of intraductal endoscopy. By providing direct visualization of the biliary and pancreatic ducts, this technology has been shown to increase the effectiveness of ERCP in the diagnosis of certain biliary and pancreatic diseases.^20,21 Intraductal endoscopy has been shown to have therapeutic applications that include biliary stone lithotripsy and extraction in high-risk surgical patients.²² As with most endoscopic procedures, intraductal endoscopy generally is considered safe, but there are no large trials that specifically address this issue. Typical complications such as bile duct perforation, minor bleeding from sphincterotomy or lithotripsy, and cholangitis have been described.²³ Further refinement of this technology will enhance ERCP as a diagnostic and therapeutic tool.

Endoscopic Ultrasound

Endoscopic ultrasound requires a special endoscope with an ultrasound transducer at its tip. The results are operator dependent, but offer noninvasive imaging of the bile ducts and adjacent structures. It is of particular value in the evaluation of tumors and their resectability. The ultrasound endoscope has a biopsy channel, allowing needle biopsies of a tumor under ultrasonic guidance. Endoscopic ultrasound also has been used to identify bile duct stones, and although it is less sensitive than ERC, the technique is less invasive as cannulation of the sphincter of Oddi is not necessary for diagnosis of choledocholithiasis.

Prevalence and Incidence

Gallstone disease is one of the most common problems affecting the digestive tract. Autopsy reports have shown a prevalence of gallstones from 11% to 36%.²⁴ The prevalence of gallstones is related to many factors, including age, gender, and ethnic background. Certain conditions predispose to the development of gallstones. Obesity, pregnancy, dietary factors, Crohn’s disease, terminal ileal resection, gastric surgery, hereditary spherocytosis, sickle cell disease, and thalassemia are all associated with an increased risk of developing gallstones.⁸ Women are three times more likely to develop gallstones than men, and first-degree relatives of patients with gallstones have a twofold greater prevalence.²⁵

Natural History

Most patients will remain asymptomatic from their gallstones throughout life. For unknown reasons, some patients progress to a symptomatic stage, with biliary colic caused by a stone obstructing the cystic duct. Symptomatic gallstone disease may progress to complications related to the gallstones.²⁶ These include acute cholecystitis, choledocholithiasis with or without cholangitis, gallstone pancreatitis, cholecystocholedochal fistula, cholecystoduodenal or cholecystoenteric fistula leading to gallstone ileus, and gallbladder carcinoma. Rarely, complication of gallstones is the presenting picture.

Gallstones in patients without biliary symptoms are commonly diagnosed incidentally on ultrasonography, CT scans, or abdominal radiography or at laparotomy. Several studies have examined the likelihood of developing biliary colic or developing significant complications of gallstone disease. Approximately 3% of asymptomatic individuals become symptomatic per year (i.e., develop biliary colic). Once symptomatic, patients tend to have recurring bouts of biliary colic. Complicated gallstone disease develops in 3% to 5% of symptomatic patients per year. Over a 20-year period, about two thirds of asymptomatic patients with gallstones remain symptom free.²⁷

Because few patients develop complications without previous biliary symptoms, prophylactic cholecystectomy in asymptomatic persons with gallstones is rarely indicated. For elderly patients with diabetes, for individuals who will be isolated from medical care for extended periods of time, and in populations with increased risk of gallbladder cancer, a prophylactic cholecystectomy may be advisable. Porcelain gallbladder, a rare premalignant condition in which the wall of the gallbladder becomes calcified, is an absolute indication for cholecystectomy.

Gallstone Formation

Gallstones form as a result of solids settling out of solution. The major organic solutes in bile are bilirubin, bile salts, phospholipids, and cholesterol. Gallstones are classified by their cholesterol content as either cholesterol stones or pigment stones. Pigment stones can be further classified as either black or brown. In Western countries, about 80% of gallstones are cholesterol stones and about 15% to 20% are black pigment stones.²⁸ Brown pigment stones account for only a small percentage. Both types of pigment stones are more common in Asia.

Cholesterol Stones

Pure cholesterol stones are uncommon and account for <10% of all stones. They usually occur as single large stones with smooth surfaces. Most other cholesterol stones contain variable amounts of bile pigments and calcium, but are always >70% cholesterol by weight. These stones are usually multiple, of variable size, and may be hard and faceted or irregular, mulberry-shaped, and soft (Fig. 32-11). Colors range from whitish yellow and green to black. Most cholesterol stones are radiolucent; <10% are radiopaque. Whether pure or of mixed nature, the common primary event in the formation of cholesterol stones is supersaturation of bile with cholesterol. Therefore, high bile cholesterol levels and cholesterol gallstones are considered as one disease. Cholesterol is highly nonpolar and insoluble in water and bile. Cholesterol solubility depends on the relative concentration of cholesterol, bile salts, and lecithin (the main phospholipid in bile). Supersaturation almost always is caused by cholesterol hypersecretion rather than by a reduced secretion of phospholipid or bile salts.²

Cholesterol is secreted into bile as cholesterol-phospholipid vesicles. Cholesterol is held in solution by micelles, a conjugated bile salt-phospholipid-cholesterol complex, as well as by the cholesterol-phospholipid vesicles. The presence of vesicles and micelles in the same aqueous compartment allows the movement of lipids between the two. Vesicular maturation occurs when vesicular lipids are incorporated into micelles. Vesicular phospholipids are incorporated into micelles more readily than vesicular cholesterol. Therefore, vesicles may become enriched in cholesterol, become unstable, and then nucleate cholesterol crystals. In unsaturated bile, cholesterol enrichment of vesicles is inconsequential. In the supersaturated bile, cholesterol-dense zones develop on the surface of the cholesterol-enriched vesicles, leading to the appearance of cholesterol crystals. About one third of biliary cholesterol is transported in micelles, but the cholesterol-phospholipid vesicles carry the majority of biliary cholesterol²⁹ (Fig. 32-12).

Pigment Stones

Pigment stones contain <20% cholesterol and are dark because of the presence of calcium bilirubinate. Otherwise, black and brown pigment stones have little in common and should be considered as separate entities.

Black pigment stones are usually small, brittle, black, and sometimes spiculated. They are formed by supersaturation of calcium bilirubinate, carbonate, and phosphate, most often secondary to hemolytic disorders such as hereditary spherocytosis and sickle cell disease, and in those with cirrhosis. Like cholesterol stones, they almost always form in the gallbladder. Unconjugated bilirubin is much less soluble than conjugated bilirubin in bile. Deconjugation of bilirubin occurs normally in bile at a slow rate. Excessive levels of conjugated bilirubin, as in hemolytic states, lead to an increased rate of production of unconjugated bilirubin. Cirrhosis may lead to increased secretion of unconjugated bilirubin. When altered conditions lead to increased levels of deconjugated bilirubin in bile, precipitation with calcium occurs. In Asian countries such as Japan, black stones account for a much higher percentage of gallstones than in the Western hemisphere.

Brown stones are usually <1 cm in diameter, brownish-yellow, soft, and often mushy. They may form either in the gallbladder or in the bile ducts, usually secondary to bacterial infection caused by bile stasis. Precipitated calcium bilirubinate and bacterial cell bodies compose the major part of the stone. Bacteria such as Escherichia coli secrete β-glucuronidase that enzymatically cleaves bilirubin glucuronide to produce the insoluble unconjugated bilirubin. It precipitates with calcium, and along with dead bacterial cell bodies, forms soft brown stones in the biliary tree.

Brown stones are typically found in the biliary tree of Asian populations and are associated with stasis secondary to parasite infection. In Western populations, brown stones occur as primary bile duct stones in patients with biliary strictures or other common bile duct stones that cause stasis and bacterial contamination.^2,30

Symptomatic Gallstones

Chronic Cholecystitis (Biliary Colic)

About two thirds of patients with gallstone disease present with chronic cholecystitis characterized by recurrent attacks of pain, often inaccurately labeled biliary colic. The pain develops when a stone obstructs the cystic duct, resulting in a progressive increase of tension in the gallbladder wall. The pathologic changes, which often do not correlate well with symptoms, vary from an apparently normal gallbladder with minor chronic inflammation in the mucosa, to a shrunken, nonfunctioning gallbladder with gross transmural fibrosis and adhesions to nearby structures. The mucosa is initially normal or hypertrophied, but later becomes atrophied, with the epithelium protruding into the muscle coat, leading to the formation of the so-called Aschoff-Rokitansky sinuses.

Clinical Presentation

The chief symptom associated with symptomatic gallstones is pain. The pain is constant and increases in severity over the first half hour or so and typically lasts 1 to 5 hours. It is located in the epigastrium or right upper quadrant and frequently radiates to the right upper back or between the scapulae (Fig. 32-13). The pain is severe and comes on abruptly, typically during the night or after a fatty meal. It often is associated with nausea and sometimes vomiting. The pain is episodic. The patient suffers discrete attacks of pain, between which they feel well. Physical examination may reveal mild right upper quadrant tenderness during an episode of pain. If the patient is pain free, the physical examination is usually unremarkable. Laboratory values, such as WBC count and liver function tests, are usually normal in patients with uncomplicated gallstones.

Atypical presentation of gallstone disease is common. Association with meals is present in only about 50% of patients. Some patients report milder attacks of pain, but relate it to meals. The pain may be located primarily in the back or the left upper or lower right quadrant. Bloating and belching may be present and associated with the attacks of pain. In patients with atypical presentation, other conditions with upper abdominal pain should be sought out, even in the presence of gallstones. These include peptic ulcer disease, gastroesophageal reflux disease, abdominal wall hernias, irritable bowel disease, diverticular disease, liver diseases, renal calculi, pleuritic pain, and myocardial pain. Many patients with other conditions have gallstones.

When the pain lasts >24 hours, an impacted stone in the cystic duct or acute cholecystitis (see later Acute Cholecystitis section) should be suspected. An impacted stone without cholecystitis will result in what is called hydrops of the gallbladder. The bile gets absorbed, but the gallbladder epithelium continues to secrete mucus, and the gallbladder becomes distended with mucinous material. The gallbladder may be palpable but usually is not tender. Hydrops of the gallbladder may result in edema of the gallbladder wall, inflammation, infection, and perforation. Although hydrops may persist with few consequences, early cholecystectomy is generally indicated to avoid complications.

Diagnosis

The diagnosis of symptomatic gallstones or chronic calculous cholecystitis depends on the presence of typical symptoms and the demonstration of stones on diagnostic imaging. An abdominal ultrasound is the standard diagnostic test for gallstones (see earlier Ultrasonography section).³¹ Gallstones are occasionally identified on abdominal radiographs or CT scans. In these cases, if the patient has typical symptoms, an ultrasound of the gallbladder and the biliary tree should be added before surgical intervention. Stones diagnosed incidentally in patients without symptoms should be left in place as discussed previously in the Natural History section. Occasionally, patients with typical attacks of biliary pain have no evidence of stones on ultrasonography. Sometimes only sludge in the gallbladder is demonstrated on ultrasonography. If the patient has recurrent attacks of typical biliary pain and sludge is detected on two or more occasions, cholecystectomy is warranted. In addition to sludge and stones, cholesterolosis and adenomyomatosis of the gallbladder may cause typical biliary symptoms and may be detected on ultrasonography. Cholesterolosis is caused by the accumulation of cholesterol in macrophages in the gallbladder mucosa, either locally or as polyps. It produces the classic macroscopic appearance of a “strawberry gallbladder.” Adenomyomatosis or cholecystitis glandularis proliferans is characterized on microscopy by hypertrophic smooth muscle bundles and by the ingrowths of mucosal glands into the muscle layer (epithelial sinus formation). Granulomatous polyps develop in the lumen at the fundus, and the gallbladder wall is thickened and septae or strictures may be seen in the gallbladder. In symptomatic patients, cholecystectomy is the treatment of choice for patients with these conditions.³²

Management

Patients with symptomatic gallstones should be advised to have elective laparoscopic cholecystectomy. While waiting for surgery, or if surgery has to be postponed, the patient should be advised to avoid dietary fats and large meals. Diabetic patients with symptomatic gallstones should have a cholecystectomy promptly, as they are more prone to develop acute cholecystitis that is often severe. Pregnant women with symptomatic gallstones who cannot be managed expectantly with diet modifications can safely undergo laparoscopic cholecystectomy during the second trimester. Laparoscopic cholecystectomy is safe and effective in children as well as in the elderly.^33,34 Cholecystectomy, open or laparoscopic, for patients with symptomatic gallstones offers excellent long-term results. About 90% of patients with typical biliary symptoms and stones are rendered symptom free after cholecystectomy. For patients with atypical symptoms or dyspepsia (flatulence, belching, bloating, and dietary fat intolerance), the results are not as favorable.

Acute Cholecystitis

Pathogenesis

Acute cholecystitis is secondary to gallstones in 90% to 95% of cases. Acute acalculous cholecystitis is a condition that typically occurs in patients with other acute systemic diseases (see later Acalculous Cholecystitis section). In <1% of acute cholecystitis, the cause is a tumor obstructing the cystic duct. Obstruction of the cystic duct by a gallstone is the initiating event that leads to gallbladder distention, inflammation, and edema of the gallbladder wall. Why inflammation develops only occasionally with cystic duct obstruction is unknown. It is probably related to the duration of obstruction of the cystic duct. Initially, acute cholecystitis is an inflammatory process, probably mediated by the mucosal toxin lysolecithin, a product of lecithin, as well as bile salts and platelet-activating factor. Increase in prostaglandin synthesis amplifies the inflammatory response. Secondary bacterial contamination is documented in 15% to 30% of patients undergoing cholecystectomy for acute uncomplicated cholecystitis. In acute cholecystitis, the gallbladder wall becomes grossly thickened and reddish with subserosal hemorrhages. Pericholecystic fluid often is present. The mucosa may show hyperemia and patchy necrosis. In severe cases, about 5% to 10%, the inflammatory process progresses and leads to ischemia and necrosis of the gallbladder wall. More frequently, the gallstone is dislodged and the inflammation resolves.³⁵

When the gallbladder remains obstructed and secondary bacterial infection supervenes, an acute gangrenous cholecystitis develops, and an abscess or empyema forms within the gallbladder. Rarely, perforation of ischemic areas occurs. The perforation is usually contained in the subhepatic space by the omentum and adjacent organs. However, free perforation with peritonitis, intrahepatic perforation with intrahepatic abscesses, and perforation into adjacent organs (duodenum or colon) with cholecystoenteric fistula occur. When gas-forming organisms are part of the secondary bacterial infection, gas may be seen in the gallbladder lumen and in the wall of the gallbladder on abdominal radiographs and CT scans, an entity called an emphysematous gallbladder.

Clinical Manifestations

About 80% of patients with acute cholecystitis give a history compatible with chronic cholecystitis. Acute cholecystitis begins as an attack of biliary colic, but in contrast to biliary colic, the pain does not subside; it is unremitting and may persist for several days. The pain is typically in the right upper quadrant or epigastrium and may radiate to the right upper part of the back or the interscapular area. It is usually more severe than the pain associated with uncomplicated biliary colic. The patient is often febrile, complains of anorexia, nausea, and vomiting, and is reluctant to move, as the inflammatory process affects the parietal peritoneum. On physical examination, focal tenderness and guarding are usually present in the right upper quadrant. A mass, the gallbladder and adherent omentum, is occasionally palpable; however, guarding may prevent this. A Murphy’s sign, an inspiratory arrest with deep palpation in the right subcostal area, is characteristic of acute cholecystitis.

A mild to moderate leukocytosis (12,000–15,000 cells/mm³) is usually present. However, some patients may have a normal WBC. A high WBC count (above 20,000) is suggestive of a complicated form of cholecystitis such as gangrenous cholecystitis, perforation, or associated cholangitis. Serum liver chemistries are usually normal, but a mild elevation of serum bilirubin, <4 mg/mL, may be present along with mild elevation of alkaline phosphatase, transaminases, and amylase.³¹ Severe jaundice is suggestive of common bile duct stones or obstruction of the bile ducts by severe pericholecystic inflammation secondary to impaction of a stone in the infundibulum of the gallbladder that mechanically obstructs the bile duct (Mirizzi’s syndrome). In elderly patients and in those with diabetes mellitus, acute cholecystitis may have a subtle presentation resulting in a delay in diagnosis. The incidence of complications is higher in these patients, who also have approximately 10-fold the mortality rate compared to that of younger and healthier patients.

The differential diagnosis for acute cholecystitis includes a peptic ulcer with or without perforation, pancreatitis, appendicitis, hepatitis, perihepatitis (Fitz-Hugh–Curtis syndrome), myocardial ischemia, pneumonia, pleuritis, and herpes zoster involving the intercostal nerve.

Diagnosis

Ultrasonography is the most useful radiologic testfor diagnosing acute cholecystitis. It has a sensitivity and specificity of 95%. In addition to being a sensitive test for documenting the presence or absence of stones, it will show the thickening of the gallbladder wall and the pericholecystic fluid (Fig. 32-14). Focal tenderness over the gallbladder when compressed by the sonographic probe (sonographic Murphy’s sign) also is suggestive of acute cholecystitis. Biliary radionuclide scanning (HIDA scan) may be of help in the atypical case. Lack of filling of the gallbladder after 4 hours indicates an obstructed cystic duct and, in the clinical setting of acute cholecystitis, is highly sensitive and specific for acute cholecystitis. A normal HIDA scan excludes acute cholecystitis. CT scan is frequently performed on patients with acute abdominal pain. It demonstrates thickening of the gallbladder wall, pericholecystic fluid, and the presence of gallstones as well as air in the gallbladder wall, but is less sensitive than ultrasonography.

Treatment

Patients who present with acute cholecystitis will need IV fluids, antibiotics, and analgesia. The antibiotics should cover gram-negative aerobes as well as anaerobes. A third-generation cephalosporin with good anaerobic coverage or a second-generation cephalosporin combined with metronidazole is a typical regimen. For patients with allergies to cephalosporins, an aminoglycoside with metronidazole is appropriate. Although the inflammation in acute cholecystitis may be sterile in some patients, more than one half will have positive cultures from the gallbladder bile. It is difficult to know who is secondarily infected; therefore, antibiotics have become a part of the management in most medical centers.

Cholecystectomy is the definitive treatment for acute cholecystitis.³⁶ In the past, the timing of cholecystectomy has been a matter of debate. Early cholecystectomy performed within 2 to 3 days of the illness is preferred over interval or delayed cholecystectomy that is performed 6 to 10 weeks after initial medical treatment and recuperation. Several studies have shown that unless the patient is unfit for surgery, early cholecystectomy should be recommended, as it offers the patient a definitive solution in one hospital admission, quicker recovery times, and an earlier return to work.³⁷

Laparoscopic cholecystectomy is the procedure of choice for acute cholecystitis. The conversion rate to an open cholecystectomy is higher (10%–15%) in the setting of acute cholecystitis than with chronic cholecystitis. The procedure is more tedious and takes longer than in the elective setting. However, when compared to the delayed operation, early operation carries a similar complication rate.

When patients present late, after 3 to 4 days of illness, or if they are unfit for surgery, they can be treated with antibiotics with laparoscopic cholecystectomy scheduled for approximately 2 months later. Approximately 20% of patients will fail to respond to initial medical therapy and require an intervention. Laparoscopic cholecystectomy could be attempted, but the conversion rate is high and some prefer to go directly for an open cholecystectomy. For those unfit for surgery, a percutaneous cholecystostomy or an open cholecystostomy under local analgesia can be performed. Failure to improve after cholecystostomy usually is due to gangrene of the gallbladder or perforation. For these patients, surgery is unavoidable. For those who respond after cholecystostomy, the tube can be removed once cholangiography through it shows a patent ductus cysticus. Laparoscopic cholecystectomy may then be scheduled in the near future.³⁸ For the rare patients who can’t tolerate surgery, the stones can be extracted via the cholecystostomy tube before its removal.³⁹

Choledocholithiasis

Common bile duct stones may be small or large and single or multiple, and are found in 6% to 12% of patients with stones in the gallbladder. The incidence increases with age. About 20% to 25% of patients above the age of 60 with symptomatic gallstones have stones in the common bile duct as well as in the gallbladder.⁴⁰ The vast majority of ductal stones in Western countries are formed within the gallbladder and migrate down the cystic duct to the common bile duct. These are classified as secondary common bile duct stones, in contrast to the primary stones that form in the bile ducts. The secondary stones are usually cholesterol stones, whereas the primary stones are usually of the brown pigment type. The primary stones are associated with biliary stasis and infection and are more commonly seen in Asian populations. The causes of biliary stasis that lead to the development of primary stones include biliary stricture, papillary stenosis, tumors, or other (secondary) stones.

Clinical Manifestations

Choledochal stones may be silent and often are discovered incidentally. They may cause obstruction, complete or incomplete, or they may manifest with cholangitis or gallstone pancreatitis. The pain caused by a stone in the bile duct is very similar to that of biliary colic caused by impaction of a stone in the cystic duct. Nausea and vomiting are common. Physical examination may be normal, but mild epigastric or right upper quadrant tenderness as well as mild icterus are common. The symptoms may also be intermittent, such as pain and transient jaundice caused by a stone that temporarily impacts the ampulla but subsequently moves away, acting as a ball valve. A small stone may pass through the ampulla spontaneously with resolution of symptoms. Finally, the stones may become completely impacted, causing severe progressive jaundice. Elevation of serum bilirubin, alkaline phosphatase, and transaminases are commonly seen in patients with bile duct stones. However, in about one third of patients with common bile duct stones, the liver chemistries are normal.

Commonly, the first test, ultrasonography, is useful for documenting stones in the gallbladder (if still present), as well as determining the size of the common bile duct. As stones in the bile ducts tend to move down to the distal part of the common duct, bowel gas can preclude their demonstration on ultrasonography. A dilated common bile duct (>8 mm in diameter) on ultrasonography in a patient with gallstones, jaundice, and biliary pain is highly suggestive of common bile duct stones. Magnetic resonance cholangiography (MRC) provides excellent anatomic detail and has a sensitivity and specificity of 95% and 89%, respectively, at detecting choledocholithiasis >5 mm in diameter.¹⁸ Endoscopic cholangiography is the gold standard for diagnosing common bile duct stones. It has the distinct advantage of providing a therapeutic option at the time of diagnosis. In experienced hands, cannulation of the ampulla of Vater and diagnostic cholangiography are achieved in >90% of cases, with associated morbidity of <5% (mainly cholangitis and pancreatitis). Endoscopic ultrasound has been demonstrated to be as good as ERCP for detecting common bile duct stones (sensitivity of 91% and specificity of 100%), but it lacks therapeutic intervention and requires expertise, making it less available.⁴¹ PTC is rarely needed in patients with secondary common bile duct stones but is frequently performed for both diagnostic and therapeutic reasons in patients with primary bile duct stones.

Treatment

For patients with symptomatic gallstones and suspected common bile duct stones, either preoperative endoscopic cholangiography or an intraoperative cholangiogram will document the bile duct stones.⁴² If an endoscopic cholangiogram reveals stones, sphincterotomy and ductal clearance of the stones is appropriate, followed by a laparoscopic cholecystectomy. An intraoperative cholangiogram at the time of cholecystectomy will also document the presence or absence of bile duct stones⁴³ (Fig. 32-15). Laparoscopic common bile duct exploration via the cystic duct or with formal choledochotomy allows the stones to be retrieved in the same setting (see Choledochal Exploration section). If the expertise and/or the instrumentation for laparoscopic common bile duct exploration are not available, a drain should be left adjacent to the cystic duct and the patient scheduled for endoscopic sphincterotomy the following day. An open common bile duct exploration is an option if the endoscopic method has already been tried or is, for some reason, not feasible. If a choledochotomy is performed, a T tube is left in place. Stones impacted in the ampulla may be difficult for both endoscopic ductal clearance as well as common bile duct exploration (open or laparoscopic). In these cases the common bile duct is usually quite dilated (about 2 cm in diameter). A choledochoduodenostomy or a Roux-en-Y choledochojejunostomy may be the best option under this circumstance.⁴⁴

Retained or recurrent stones following cholecystectomy are best treated endoscopically (Fig. 32-16). If the stones were deliberately left in place at the time of surgery or diagnosed shortly after the cholecystectomy, they are classified as retained; those diagnosed months or years later are termed recurrent. If a common bile duct exploration was performed and a T tube left in place, a T-tube cholangiogram is obtained before its removal. Retained stones can be retrieved either endoscopically or via the T-tube tract once it has matured (2–4 weeks). The T tube is then removed and a catheter passed through the tract into the common bile duct. Under fluoroscopic guidance, the stones are retrieved with baskets or balloons. Recurrent stones may be multiple and large. A generous endoscopic sphincterotomy will allow stone retrieval as well as spontaneous passage of retained and recurrent stones. Patients >70 years old presenting with bile duct stones should have their ductal stones cleared endoscopically. Studies comparing surgery to endoscopic treatment have documented less morbidity and mortality for endoscopic treatment in this group of patients.⁴⁵ They do not need to be submitted for a cholecystectomy, as only about 15% will become symptomatic from their gallbladder stones, and such patients can be treated as the need arises by a cholecystectomy.⁴⁶

Cholangitis

Cholangitis is one of the two main complications of choledochal stones, the other being gallstone pancreatitis. Acute cholangitis is an ascending bacterial infection in association with partial or complete obstruction of the bile ducts. Hepatic bile is sterile, and bile in the bile ducts is kept sterile by continuous bile flow and by the presence of antibacterial substances in bile, such as immunoglobulin. Mechanical hindrance to bile flow facilitates bacterial contamination. Positive bile cultures are common in the presence of bile duct stones as well as with other causes of obstruction. Biliary bacterial contamination alone does not lead to clinical cholangitis; the combination of both significant bacterial contamination and biliary obstruction is required for its development. Gallstones are the most common cause of obstruction in cholangitis; other causes are benign and malignant strictures, parasites, instrumentation of the ducts and indwelling stents, and partially obstructed biliary-enteric anastomosis. The most common organisms cultured from bile in patients with cholangitis include Escherichia coli, Klebsiella pneumoniae, Streptococcus faecalis, Enterobacter, and Bacteroides fragilis.⁴⁷

Clinical Presentation

Cholangitis may present as anything from a mild, intermittent, and self-limited disease to a fulminant, potentially life-threatening septicemia. The patient with gallstone-induced cholangitis is typically older and female. The most common presentation is fever, epigastric or right upper quadrant pain, and jaundice. These classic symptoms, well known as Charcot’s triad, are present in about two thirds of patients. The illness may progress rapidly with septicemia and disorientation, known as Reynolds’ pentad (e.g., fever, jaundice, right upper quadrant pain, septic shock, and mental status changes). However, the presentation may be atypical, with little if any fever, jaundice, or pain. This occurs most commonly in the elderly, who may have unremarkable symptoms until they collapse with septicemia. Patients with indwelling stents rarely become jaundiced. On abdominal examination, the findings are indistinguishable from those of acute cholecystitis.⁴⁸

Diagnosis and Management

Leukocytosis, hyperbilirubinemia, and elevation of alkaline phosphatase and transaminases are common and, when present, support the clinical diagnosis of cholangitis. Ultrasonography is helpful, as it will document the presence of gallbladder stones, demonstrate dilated ducts, and possibly pinpoint the site of obstruction; however, rarely will it elucidate the exact cause. The definitive diagnostic test is ERC. In cases in which ERC is not available, PTC is indicated. Both ERC and PTC will show the level and the reason for the obstruction, allow culture of the bile, possibly allow the removal of stones if present, and allow drainage of the bile ducts with drainage catheters or stents. CT scanning and MRI will show pancreatic and periampullary masses, if present, in addition to the ductal dilatation.

The initial treatment of patients with cholangitis includes IV antibiotics and fluid resuscitation. These patients may require intensive care unit monitoring and vasopressor support. Most patients will respond to these measures. However, the obstructed bile duct must be drained as soon as the patient has been stabilized. About 15% of patients will not respond to antibiotics and fluid resuscitation, and an emergency biliary decompression may be required. Biliary decompression may be accomplished endoscopically, via the percutaneous transhepatic route, or surgically. The selection of procedure should be based on the level and the nature of the biliary obstruction. Patients with choledocholithiasis or periampullary malignancies are best approached endoscopically, with sphincterotomy and stone removal, or by placement of an endoscopic biliary stent.⁴⁹ In patients in whom the obstruction is more proximal or perihilar, or when a stricture in a biliary-enteric anastomosis is the cause or the endoscopic route has failed, percutaneous transhepatic drainage is used. When neither ERC nor PTC is available, an emergent operation for decompression of the common bile duct with a T tube may be necessary and lifesaving. Definitive operative therapy should be deferred until the cholangitis has been treated and the proper diagnosis established. Patients with indwelling stents and cholangitis usually require repeated imaging and exchange of the stent over a guidewire.

Acute cholangitis is associated with an overall mortality rate of approximately 5%. When associated with renal failure, cardiac impairment, hepatic abscesses, and malignancies, the morbidity and mortality rates are much higher.

Biliary Pancreatitis

Gallstones in the common bile duct are associated with acute pancreatitis. Obstruction of the pancreatic duct by an impacted stone or temporary obstruction by a stone passing through the ampulla may lead to pancreatitis. The exact mechanism by which the obstruction of the pancreatic duct leads to pancreatitis is still not clear. An ultrasonogram of the biliary tree in patients with pancreatitis is essential. If gallstones are present and the pancreatitis is severe, an ERC with sphincterotomy and stone extraction may abort the episode of pancreatitis. Once the pancreatitis has subsided, the gallbladder should be removed during the same admission. When gallstones are present and the pancreatitis is mild and self-limited, the stone has probably passed. For these patients, a cholecystectomy and an intraoperative cholangiogram or a preoperative ERC is indicated.

Cholangiohepatitis

Cholangiohepatitis, also known as recurrent pyogenic cholangitis, is endemic to the Orient. It also has been encountered in the Chinese population in the United States, as well as in Europe and Australia. It affects both sexes equally and occurs most frequently in the third and fourth decades of life. Cholangiohepatitis is caused by bacterial contamination (commonly E. coli, Klebsiella species, Bacteroides species, or Enterococcus faecalis) of the biliary tree, and often is associated with biliary parasites such as Clonorchis sinensis, Opisthorchis viverrini, and Ascaris lumbricoides. Bacterial enzymes cause deconjugation of bilirubin, which precipitates as bile sludge. The sludge and dead bacterial cell bodies form brown pigment stones. The nucleus of the stone may contain an adult Clonorchis worm, an ovum, or an ascarid. These stones are formed throughout the biliary tree and cause partial obstruction that contributes to the repeated bouts of cholangitis. Biliary strictures form as a result of recurrent cholangitis and lead to further stone formation, infection, hepatic abscesses, and liver failure (secondary biliary cirrhosis).⁵⁰

The patient usually presents with pain in the right upper quadrant and epigastrium, fever, and jaundice. Recurrence of symptoms is one of the most characteristic features of the disease. The episodes may vary in severity but, without intervention, will gradually lead to malnutrition and hepatic insufficiency. An ultrasound will detect stones in the biliary tree, pneumobilia from infection due to gas-forming organisms, liver abscesses, and, occasionally, strictures. The gallbladder may be thickened but is inflamed in about 20% of patients and rarely contains stones. MRCP and PTC are the mainstays of biliary imaging for cholangiohepatitis. They can detect obstructions, define strictures and stones, and allow emergent decompression of the biliary tree in the septic patient. Hepatic abscesses may be drained percutaneously. The long-term goal of therapy is to extract stones and debris and relieve strictures. It may take several procedures and require a Roux-en-Y hepaticojejunostomy to establish biliary-enteric continuity. Occasionally, resection of involved areas of the liver may offer the best form of treatment. Recurrences are common and the prognosis is poor once hepatic insufficiency has developed.⁵¹

Cholecystostomy

A cholecystostomy decompresses and drains the distended, inflamed, hydropic, or purulent gallbladder. It is applicable if the patient is not fit to tolerate an abdominal operation.⁵² Ultrasound-guided percutaneous drainage with a pigtail catheter is the procedure of choice. The catheter is inserted over a guidewire that has been passed through the abdominal wall, the liver, and into the gallbladder (Fig. 32-17). By passing the catheter through the liver, the risk of bile leak around the catheter is minimized.⁵³ The catheter can be removed when the inflammation has resolved and the patient’s condition improved. The gallbladder can be removed later, if indicated, usually by laparoscopy. Surgical cholecystostomy with a large catheter placed under local anesthesia is rarely required today.

Cholecystectomy

Cholecystectomy is the most common major abdominal procedure performed in Western countries. Carl Langenbuch performed the first successful cholecystectomy in 1882, and for >100 years, it was the standard treatment for symptomatic gallbladder stones. Open cholecystectomy was a safe and effective treatment for both acute and chronic cholecystitis. In 1987, laparoscopic cholecystectomy was introduced by Philippe Mouret in France and quickly revolutionized the treatment of gallstones. It not only supplanted open cholecystectomy, but also more or less ended attempts for noninvasive management of gallstones, such as extracorporeal shock wave and bile salt therapy. Laparoscopic cholecystectomy offers a cure for gallstones with a minimally invasive procedure, minor pain and scarring, and early return to full activity. Today, laparoscopic cholecystectomy is the treatment of choice for symptomatic gallstones.

Absolute contraindications for the procedure are uncontrolled coagulopathy and end-stage liver disease. In the latter instance, liver transplantation, with cholecystectomy, may be used for treatment of severe recurrent gallstone disease. Rarely, patients with severe obstructive pulmonary disease or congestive heart failure (e.g., cardiac ejection fraction <20%) may not tolerate pneumoperitoneum with carbon dioxide and require open cholecystectomy. Conditions formerly believed to be relative contraindications such as acute cholecystitis, gangrene and empyema of the gallbladder, biliary-enteric fistulae, obesity, pregnancy, ventriculoperitoneal shunt, cirrhosis, and previous upper abdominal procedures are now considered risk factors for a potentially difficult laparoscopic cholecystectomy. When important anatomic structures cannot be clearly identified or when no progress is made over a set period of time, a conversion to an open procedure is usually indicated. In the elective setting, conversion to an open procedure is needed in about 5% of patients.⁵⁴ Emergent procedures may require more skill on the part of the surgeon and be needed in patients with complicated gallstone disease; the incidence of conversion is 10% to 30%. Conversion to an open procedure is not a failure, and the possibility should be discussed with the patient preoperatively.

Serious complications are rare. The mortality rate for laparoscopic cholecystectomy is about 0.1%. Wound infection and cardiopulmonary complication rates are considerably lower following laparoscopic cholecystectomy than are those for an open procedure. However, laparoscopic cholecystectomy is associated with a higher injury rate to the bile ducts (see later section, Injury to the Biliary Tract).⁵⁵

Patients undergoing cholecystectomy should have a complete blood count and liver function tests preoperatively. Prophylaxis against deep venous thrombosis with either low molecular weight heparin or compression stockings is indicated. The patient should be instructed to empty their bladder before coming to the operating room. Urinary catheters are rarely needed. An orogastric tube is placed if the stomach is distended with gas and is removed at the end of the operation.

Laparoscopic Cholecystectomy

The patient is placed supine on the operating table with the surgeon standing at the patient’s left side. Some surgeons prefer to stand between the patient’s legs while doing laparoscopic procedures in the upper abdomen. The pneumoperitoneum is created with carbon dioxide gas, either with an open technique or by closed needle technique. Initially, a small incision is made in the upper edge of the umbilicus. With the closed technique, a special hollow insufflation needle (Veress needle) that is spring-loaded with a retractable cutting outer sheath is inserted into the peritoneal cavity and used for insufflation. Once an adequate pneumoperitoneum is established, a 10-mm trocar is inserted through the supraumbilical incision. With the open technique, the supraumbilical incision is carried through the fascia and into the peritoneal cavity. A special blunt cannula (Hasson cannula) is inserted into the peritoneal cavity and anchored to the fascia. The laparoscope with the attached video camera is passed through the umbilical port and the abdomen inspected. Three additional ports are placed under direct vision (Fig. 32-18). A 10-mm port is placed in the epigastrium, a 5-mm port in the middle of the clavicular line, and a 5-mm port in the right flank, in line with the gallbladder fundus. Occasionally, a fifth port is required for better visualization in patients recovering from pancreatitis or those with semi-acute cholecystitis, as well as in very obese patients.

Through the lateral-most port, a grasper is used to grasp the gallbladder fundus. It is retracted over the liver edge upward and toward the patient’s right shoulder to expose the proximal gallbladder and the hilar area. Exposure of the hilar area may be facilitated by placing the patient in reverse Trendelenburg position with slight tilting of the table to bring the right side up. Through the midclavicular port a second grasper is used to grasp the gallbladder infundibulum and retract it laterally to expose the triangle of Calot. Before this, it may be necessary to take down any adhesions between the omentum, duodenum, or colon, and the gallbladder. Most of the dissection is carried out through the epigastric port using a dissector, hook cautery, or scissors.

The dissection starts at the junction of the gallbladder and the cystic duct. A helpful anatomic landmark is the cystic artery lymph node. The peritoneum, fat, and loose areolar tissue around the gallbladder and the cystic duct–gallbladder junction is dissected off toward the bile duct. This is continued until the gallbladder neck and the proximal cystic duct are clearly identified. The next step is the identification of the cystic artery, which usually runs parallel to and somewhat behind the cystic duct. A hemoclip is placed on the proximal cystic duct. If an intraoperative cholangiogram is to be performed, a small incision is made on the anterior surface of the cystic duct, just proximal to the clip, and a cholangiogram catheter is passed into the cystic duct. Once the cholangiogram is completed, the catheter is removed and two clips are placed proximal to the incision, and the cystic duct is divided. A wide cystic duct may be too big for clips, requiring the placement of a pre-tied loop ligature to close. The cystic artery is then clipped and divided.

Finally, the gallbladder is dissected out of the gallbladder fossa, using either a hook or scissors with electrocautery. Before the gallbladder is removed from the liver edge, the operative field is carefully searched for bleeding points, and the placement of the clips on the cystic duct and cystic artery is inspected. The gallbladder is removed through the umbilical incision. The fascial defect and skin incision may need to be enlarged if the stones are large. If the gallbladder is acutely inflamed or gangrenous, or if the gallbladder is perforated, it is placed in a retrieval bag before it is removed from the abdomen. Any bile or blood that has accumulated during the procedure is sucked away, and if stones were spilled, they are retrieved, placed inside a retrieval bag, and removed. If the gallbladder was severely inflamed or gangrenous or if any bile or blood is expected to accumulate, a closed-suction drain can be placed through one of the 5-mm ports and left underneath the right liver lobe close to the gallbladder fossa.

Open Cholecystectomy

The same surgical principles apply for laparoscopic and open cholecystectomies. Open cholecystectomy has become an uncommon procedure, usually performed either as a conversion from laparoscopic cholecystectomy or as a second procedure in patients who require laparotomy for another reason. After the cystic artery and cystic duct have been identified, the gallbladder is dissected free from the liver bed, starting at the fundus. The dissection is carried proximally toward the cystic artery and the cystic duct, which are then ligated and divided.

Intraoperative Cholangiogram or Ultrasound

The bile ducts are visualized under fluoroscopy by injecting contrast through a catheter placed in the cystic duct (Fig. 32-19A). Their size can then be evaluated, the presence or absence of common bile duct stones assessed, and filling defects confirmed, as the dye passes into the duodenum. Routine intraoperative cholangiography will detect stones in approximately 7% of patients, as well as outlining the anatomy and detecting injury^56,57 (Fig. 32-19B). A selective intraoperative cholangiogram can be performed when the patient has a history of abnormal liver function tests, pancreatitis, jaundice, a large duct and small stones, a dilated duct on preoperative ultrasonography, and if preoperative endoscopic cholangiography for the above reasons was unsuccessful. Laparoscopic ultrasonography is as accurate as intraoperative cholangiography in detecting common bile duct stones, and it is less invasive; however, it requires more skill to perform and interpret.^58,59

Common Bile Duct Exploration

Common bile duct stones that are detected intraoperatively on intraoperative cholangiography or ultrasonography may be managed with laparoscopic choledochal exploration as a part of the laparoscopic cholecystectomy procedure. Patients with common bile duct stones detected preoperatively, but in whom endoscopic clearance was either not available or unsuccessful, should also have their ductal stones managed during the cholecystectomy.

If the stones in the duct are small, they may sometimes be flushed into the duodenum with saline irrigation via the cholangiography catheter after the sphincter of Oddi has been relaxed with glucagon. If irrigation is unsuccessful, a balloon catheter may be passed via the cystic duct and down the common bile duct, where it is inflated and withdrawn to retrieve the stones. The next attempt is usually made with a wire basket passed under fluoroscopic guidance to catch the stones (Fig. 32-20). If needed, a flexible choledochoscope is the next step. The cystic duct may have to be dilated to allow its passage. Once in the common bile duct, the stones may be caught into a wire basket under direct vision or pushed into the duodenum. When the duct has been cleared, the cystic duct is ligated and cut and the cholecystectomy completed. Occasionally, a choledochotomy, an incision into the common bile duct itself, is necessary. The flexible choledochoscope is then passed into the duct for visualization and clearance of stones. The choledochotomy is sutured with a T tube left in the common bile duct with one end taken out through the abdominal wall for decompression of the bile ducts. By managing common bile duct stones at the time of the cholecystectomy, the patients can have all of their gallstone disease treated with one invasive procedure. It does, however, depend on the available surgical expertise.⁶⁰

Common Bile Duct Drainage Procedures

Rarely, when the stones cannot be cleared and/or when the duct is very dilated (>1.5 cm in diameter), a choledochal drainage procedure is performed (Fig. 32-21). Choledochoduodenostomy is performed by mobilizing the second part of the duodenum (a Kocher maneuver) and anastomosing it side to side with the common bile duct.

A choledochojejunostomy is done by bringing up a 45-cm Roux-en-Y limb of jejunum and anastomosing it end to side to the common bile duct.

Choledochojejunostomy or, more often, a hepaticojejunostomy, also can be used to repair common bile duct strictures or as a palliative procedure for malignant obstruction in the periampullary region. If the common bile duct has been transected or injured, it can be managed by an end-to-end choledochojejunostomy.

Transduodenal Sphincterotomy

In the majority of cases, endoscopic sphincterotomy has replaced open transduodenal sphincterotomy. If an open procedure for common bile duct stones is being done in which the stones are impacted, recurrent, or multiple, the transduodenal approach may be feasible. The duodenum is incised transversely. The sphincter then is incised at the 11 o’clock position to avoid injury to the pancreatic duct. The impacted stones are removed, as are large stones from the duct. There is no need to fully clear the duct of stones, as they can pass spontaneously through the cut sphincter.

Acalculous Cholecystitis

Acute inflammation of the gallbladder can occur without gallstones. Acalculous cholecystitis typically develops in critically ill patients in the intensive care unit. Patients on parenteral nutrition with extensive burns, sepsis, major operations, multiple trauma, or prolonged illness with multiple organ system failure are at risk for developing acalculous cholecystitis. The cause is unknown, but gallbladder distention with bile stasis and ischemia has been implicated as causative factors. Pathologic examination of the gallbladder wall reveals edema of the serosa and muscular layers, with patchy thrombosis of arterioles and venules.^61,62

The symptoms and signs depend on the condition of the patient, but in the alert patient, they are similar to acute calculous cholecystitis, with right upper quadrant pain and tenderness, fever, and leukocytosis. In the sedated or unconscious patient, the clinical features are often masked, but fever and elevated WBC count, as well as elevation of alkaline phosphatase and bilirubin, are indications for further investigation.

Ultrasonography is usually the diagnostic test of choice, as it can be done bedside in the intensive care unit. It can demonstrate the distended gallbladder with thickened wall, biliary sludge, pericholecystic fluid, and the presence or absence of abscess formation. Abdominal CT scan can aid in the diagnosis of acalculous cholecystitis and additionally allows imaging of the abdominal cavity and chest to rule out other sources of infection. A HIDA scan can be useful and will show nonvisualization of the gallbladder, but it is a less sensitive test with high false-positive rates in patients who are fasting, on total parenteral nutrition, or have liver disease.⁶³ Acalculous cholecystitis requires urgent intervention. Percutaneous ultrasound- or CT-guided cholecystostomy is the treatment of choice for these patients, as they are usually unfit for surgery (see Fig. 32-17). If the diagnosis is uncertain, percutaneous cholecystostomy is both diagnostic and therapeutic. About 90% of patients will improve with the percutaneous cholecystostomy. However, if they do not improve, other steps, such as open cholecystostomy or cholecystectomy, may be required. If needed, cholecystectomy is performed after the patient has recovered from the underlying disease.

Biliary Cysts

Choledochal cysts are congenital cystic dilatations of the extrahepatic and/or intrahepatic biliary tree. They are rare—the incidence is between 1:100,000 and 1:150,000 in populations of Western countries—but are more commonly seen in populations of Eastern countries. Choledochal cysts affect females three to eight times more often than males. Although frequently diagnosed in infancy or childhood, as many as one half of the patients have reached adulthood when diagnosed. The cause is unknown. Weakness of the bile duct wall and increased pressure secondary to partial biliary obstruction are required for biliary cyst formation. More than 90% of patients have an anomalous pancreaticobiliary duct junction, with the pancreatic duct joining the common bile duct >1 cm proximal to the ampulla. This results in a long common channel that may allow free reflux of pancreatic secretions into the biliary tract, leading to inflammatory changes, increased biliary pressure, and cyst formation. Choledochal cysts are classified into five types (Fig. 32-22). The cysts are lined with cuboidal epithelium and can vary in size from 2 cm in diameter to giant cysts.

Adults commonly present with jaundice or cholangitis. Less than one half of patients present with the classic clinical triad of abdominal pain, jaundice, and a mass. Ultrasonography or CT scanning will confirm the diagnosis, but endoscopic cholangiography, transhepatic cholangiography, or MRC is required to assess the biliary anatomy and to plan the appropriate surgical treatment. For types I, II, and IV, excision of the extrahepatic biliary tree, including cholecystectomy, with a Roux-en-Y hepaticojejunostomy is ideal. In type IV, additional segmental resection of the liver may be appropriate, particularly if intrahepatic stones, strictures, or abscesses are present or if the dilatations are confined to one lobe. The risk of cholangiocarcinoma developing in choledochal cysts is as high as 15% in adults and supports complete excision when they are diagnosed. For type III, sphincterotomy is recommended.⁶⁴

Sclerosing Cholangitis

Sclerosing cholangitis is an uncommon disease characterized by inflammatory strictures involving the intrahepatic and extrahepatic biliary tree. It is a progressive disease that eventually results in secondary biliary cirrhosis. Sometimes, biliary strictures are clearly secondary to bile duct stones, acute cholangitis, previous biliary surgery, or toxic agents, and are termed secondary sclerosing cholangitis. However, primary sclerosing cholangitis is a disease entity of its own, with no known attributing cause. It is associated with ulcerative colitis in about two thirds of patients. Other diseases associated with sclerosing cholangitis include Riedel’s thyroiditis and retroperitoneal fibrosis. Autoimmune reaction, chronic low-grade bacterial or viral infection, toxic reaction, and genetic factors have all been suggested to play a role in its pathogenesis. The human leukocyte antigen haplotypes HLA-B8, -DR3, -DQ2, and -DRw52A, commonly found in patients with autoimmune diseases, also are more frequently seen in patients with sclerosing cholangitis than in controls. Patients with sclerosing cholangitis are at risk for developing cholangiocarcinoma. Eventually, 10% to 20% of the patients will develop cancer. Cholangiocarcinoma can present at any time during the disease process and does not correlate with the extent of sclerosing cholangitis or the development of liver failure, but frequently follows an aggressive course.

The mean age of presentation is 30 to 45 years, and men are affected twice as commonly as women. The usual presentation is intermittent jaundice, fatigue, weight loss, pruritus, and abdominal pain. Symptoms of acute cholangitis are rare, without preceding biliary tract intervention or surgery. More than one half of patients are symptomatic when diagnosed. In several patients with ulcerative colitis, abnormal liver function tests found on routine testing lead to the diagnosis. The clinical course in sclerosing cholangitis is highly variable, but cyclic remissions and exacerbations are typical. However, some patients remain asymptomatic for years, while others progress rapidly with the obliterative inflammatory changes leading to secondary biliary cirrhosis and liver failure. In patients with associated ulcerative colitis, the course of each disease seems independent of the other. Colectomy for the colitis makes no difference to the course of primary sclerosing cholangitis. The median survival for patients with primary sclerosing cholangitis from the time of diagnosis ranges from 10 to 12 years, and most die from hepatic failure.⁶⁵

The clinical presentation and elevation of alkaline phosphatase and bilirubin may suggest the diagnosis, but ERC, revealing multiple dilatations and strictures (beading) of both the intra- and extrahepatic biliary tree, confirms it. The hepatic duct bifurcation is often the most severely affected segment. A liver biopsy may not be diagnostic, but is important to determine the degree of hepatic fibrosis and the presence of cirrhosis. Sclerosing cholangitis is followed by ERC and liver biopsies to provide appropriate management.

There is no known effective medical therapy for primary sclerosing cholangitis and no known curative treatment. Corticosteroids, immunosuppressants, ursodeoxycholic acid, and antibiotics have been disappointing. Biliary strictures can be dilated and stented either endoscopically or percutaneously. These measures have given short-term improvements in symptoms and serum bilirubin levels and long-term improvements in only less than one half of the patients. Surgical management with resection of the extrahepatic biliary tree and hepaticojejunostomy has produced reasonable results in patients with extrahepatic and bifurcation strictures, but without cirrhosis or significant hepatic fibrosis.⁶⁶ In patients with sclerosing cholangitis and advanced liver disease, liver transplantation is the only option. It offers excellent results, with overall 5-year survival as high as 85%. Primary sclerosing cholangitis recurs in 10% to 20% of patients and may require retransplantation.^67,68

Stenosis of the Sphincter of Oddi

A benign stenosis of the outlet of the common bile duct is usually associated with inflammation, fibrosis, or muscular hypertrophy. The pathogenesis is unclear, but trauma from the passage of stones, sphincter motility disorders, and congenital anomalies have been suggested. Episodic pain of the biliary type with abnormal liver function tests is a common presentation. However, recurrent jaundice or pancreatitis also may play a role. A dilated common bile duct that is difficult to cannulate with delayed emptying of the contrast are useful diagnostic features. Ampullary manometry and special provocation tests are available in specialized units. If the diagnosis is well established, endoscopic or operative sphincterotomy will yield good results.⁶⁹

Bile Duct Strictures

Benign bile duct strictures can have numerous causes. However, the vast majority were caused by operative injury, most commonly by laparoscopic cholecystectomy (see later section, Injury to the Biliary Tract). Other causes include fibrosis due to chronic pancreatitis, common bile duct stones, acute cholangitis, biliary obstruction due to cholecystolithiasis (Mirizzi’s syndrome), sclerosing cholangitis, cholangiohepatitis, and strictures of a biliary-enteric anastomosis. Bile duct strictures that go unrecognized or are improperly managed may lead to recurrent cholangitis, secondary biliary cirrhosis, and portal hypertension.⁷⁰

Patients with bile duct strictures most commonly present with episodes of cholangitis. Less commonly, they may present with jaundice without evidence of infection. Liver function tests usually show evidence of cholestasis. An ultrasound or a CT scan will show dilated bile ducts proximal to the stricture, as well as provide some information about the level of the stenosis. MRC will also provide good anatomic information about the location and the degree of dilatation. In patients with intrahepatic ductal dilatation, a percutaneous transhepatic cholangiogram will outline the proximal biliary tree, define the stricture and its location, and allow decompression of the biliary tree with transhepatic catheters or stents (Fig. 32-23). An endoscopic cholangiogram will outline the distal bile duct. Treatment depends on the location and the cause of the stricture. Percutaneous or endoscopic dilatation and/or stent placement give good results in more than one half of patients. Surgery with Roux-en-Y choledochojejunostomy or hepaticojejunostomy is the standard of care with good or excellent results in 80% to 90% of patients.⁷¹ Choledochoduodenostomy may be a choice for strictures in the distal-most part of the common bile duct.

Gallbladder

Injuries to the gallbladder are uncommon. Penetrating injuries are usually caused by gunshot wounds or stab wounds, and rarely by a needle biopsy procedure of the liver. Nonpenetrating trauma is extremely rare. These types of injury to the gallbladder include contusion, avulsion, laceration, rupture, and traumatic cholecystitis. The treatment of choice is cholecystectomy, and the prognosis is directly related to the type and incidence of associated injury.

Extrahepatic Bile Ducts

Penetrating trauma to the extrahepatic bile ducts is rare and is usually associated with trauma to other viscera. The great majority of injuries of the extrahepatic biliary duct system are iatrogenic, occurring in the course of laparoscopic or open cholecystectomies.⁷² Less commonly, biliary injury is associated with common bile duct exploration, division or mobilization of the duodenum during gastrectomy, and dissection of the hepatic hilum during liver resections. The exact incidence of bile duct injury during cholecystectomy is unknown, but data suggest that during open cholecystectomy, the incidence is relatively low (about 0.1% to 0.2%). However, the incidence during laparoscopic cholecystectomy, as derived from state and national databases, estimates the rate of major injury to range between 0.1% to 0.55%, and the incidence of minor injuries and bile leaks to be about 0.3%, a total of 0.85%. Limited view, difficult orientation and assessment of depth on a two-dimensional image, and the lack of tactile sensation and unusual manual skills that are needed have led to the rise in bile duct injury during laparoscopic cholecystectomy.⁷³

A number of different factors are associated with bile duct injury during laparoscopic cholecystectomy. These include acute or chronic inflammation, obesity, anatomic variations, and bleeding. Surgical technique with inadequate exposure and failure to identify structures before ligating or dividing them are the most common cause of significant biliary injury. The bile ducts may be narrow and can be mistaken for the cystic duct. The cystic duct may run along side the common bile duct before joining it, leading the surgeon to the wrong place. Additionally, the cystic duct may enter the right hepatic duct, and the right hepatic duct may run aberrantly, coursing through the triangle of Calot and entering the common hepatic duct. A number of intraoperative technical factors have been implicated in biliary injuries. Excessive cephalad retraction of the gallbladder may align the cystic duct with the common bile duct, and the latter is then mistaken for the cystic duct and clipped and divided. The use of an angled laparoscope instead of an end-viewing one will help visualize the anatomic structures, in particular those around the triangle of Calot. An angled scope also will aid in the proper placement of clips. Careless use of electrocautery may lead to thermal injury. Dissection deep into the liver parenchyma may cause injury to intrahepatic ducts, and poor clip placement close to the hilar area or to structures not well visualized can result in a clip across a bile duct.^74,75

The routine use of intraoperative fluoroscopic cholangiography to prevent bile duct injury is controversial.⁷⁶ Routine use may limit the extent of injury but does not seem to prevent it entirely. Nonetheless, the frequency of bile duct injuries is cut by 50% when an intraoperative cholangiogram is performed. Critical to the successful use of cholangiography is accurate interpretation of the imaging. It is important to check that the whole biliary system fills with contrast, including both major ducts on the right and the left hepatic duct, and that there is no extravasation of contrast.

Diagnosis

Only about 25% of major bile duct injuries (common bile duct or hepatic duct) are recognized at the time of operation. Most commonly, intraoperative bile leakage, recognition of the correct anatomy, and an abnormal cholangiogram lead to the diagnosis of a bile duct injury. More than half of patients with biliary injury will present within the first postoperative month. The remainder will present months or years later, with recurrent cholangitis or cirrhosis from a remote bile duct injury. In the early postoperative period, patients present either with progressive elevation of liver function tests due to an occluded or a stenosed bile duct, or with a bile leak from an injured duct. Bile leak, most commonly from the cystic duct stump, a transected aberrant right hepatic duct, or a lateral injury to the main bile duct, usually presents with pain, fever, and a mild elevation of liver function tests. A CT scan or an ultrasound will show either a collection (biloma) in the gallbladder area or free fluid (bile) in the peritoneum (Fig. 32-24). Bilious drainage through operatively placed drains or through the wounds is abnormal. The site of the bile leak can be confirmed noninvasively with a HIDA scan. In patients with a surgical drain or a percutaneously placed catheter, injection of water-soluble contrast media through the drainage tract (sinogram) can often define the site of leakage and the anatomy of the biliary tree.⁷⁷

CT scan and ultrasound also are important in the initial evaluation of the jaundiced patient, as they can demonstrate the dilated part of the biliary tree proximal to the stenosis or obstruction, and may identify the level of the extrahepatic bile duct obstruction. In the jaundiced patient with dilated intrahepatic ducts, a percutaneous cholangiogram will outline the anatomy and the proximal extent of the injury and allow decompression of the biliary tree with catheter or stent placements. An endoscopic cholangiogram demonstrates the anatomy distal to the injury and may allow the placement of stents across a stricture to relieve an obstruction (see Fig. 32-23). MRI cholangiography, if available, provides an excellent, noninvasive delineation of the biliary anatomy both proximal and distal to the injury.

Management

The management of bile duct injuries depends on the type, extent, and level of injury, and the time of its diagnosis. Initial proper treatment of bile duct injury diagnosed during the cholecystectomy can avoid the development of a bile duct stricture. If a major injury is discovered and an experienced biliary surgeon is not available, an external drain and, if necessary, transhepatic biliary catheters are placed, and the patient is transferred to a referral center.⁷³

Transected bile ducts <3 mm or those draining a single hepatic segment can safely be ligated. If the injured duct is ≥4 mm, it is likely to drain multiple segments or an entire lobe, and thus needs to be reimplanted. Lateral injury to the common bile duct or the common hepatic duct, recognized at the time of surgery, is best managed with a T-tube placement. If the injury is a small incision in the duct, the T tube may be placed through it as if it were a formal choledochotomy. In more extensive lateral injuries, the T tube should be placed through a separate choledochotomy and the injury closed over the T-tube end to minimize the risk of subsequent stricture formation.

Major bile duct injuries such as transection of the common hepatic or common bile duct are best managed at the time of injury. In many of these major injuries, the bile duct has not only been transected, but a variable length of the duct removed. This injury usually requires a biliary enteric anastomosis with a jejunal loop. Either an end-to-side Roux-en-Y choledochojejunostomy or, more commonly, a Roux-en-Y hepaticojejunostomy should be performed. Transhepatic biliary catheters are placed through the anastomosis to stent it and to provide access to the biliary tract for drainage and imaging. Although rare, when the injury is to the distal common bile duct, a choledochoduodenostomy can be performed. If there is no or minimal loss of ductal length, a duct-to-duct repair may be done over a T tube that is placed through a separate incision. It is critical to perform a tension-free anastomosis to minimize the high risk of postoperative stricture formation.⁶⁶

Cystic duct leaks can usually be managed with percutaneous drainage of intra-abdominal fluid collections followed by an endoscopic biliary stenting (see Fig. 32-24).

Major injuries diagnosed postoperatively require transhepatic biliary catheter placement for biliary decompression as well as percutaneous drainage of intra-abdominal bile collections, if any. When the acute inflammation has resolved 6 to 8 weeks later, operative repair is performed.

Patients with bile duct stricture from an injury or as a sequela of previous repair usually present with either progressive elevation of liver function tests or cholangitis. The initial management usually includes transhepatic biliary drainage catheter placement for decompression as well as for defining the anatomy and the location and the extent of the damage. These catheters will also serve as useful technical aids during subsequent biliary enteric anastomosis. An anastomosis is performed between the duct proximal to the injury and a Roux loop of jejunum. Balloon dilatation of a stricture usually requires multiple attempts and rarely provides adequate long-term relief. Self-expanding metal or plastic stents, placed either percutaneously or endoscopically across the stricture, can provide temporary drainage and, in the high-risk patient, permanent drainage of the biliary tree.

Outcome

Good results can be expected in 70% to 90% of patients with bile duct injuries.⁷⁸ The best results are obtained when the injury is recognized during the cholecystectomy and repaired by an experienced biliary tract surgeon. The operative mortality rate varies from 0% to almost 30% in various series, but commonly is about 5% to 8%. Common complications that are specific for bile duct repairs include cholangitis, external biliary fistula, bile leak, subhepatic and subphrenic abscesses, and hemobilia. Restenosis of a biliary enteric anastomosis occurs in about 10% of patients, and may manifest up to 20 years after the initial procedure. Approximately two thirds of recurrent strictures become symptomatic within 2 years after repair. The more proximal strictures are associated with a lower success rate than are distal ones. The worst results are in patients with many operative revisions and in those who have evidence of liver failure and portal hypertension. However, previous repair does not preclude successful outcome of repeated attempts, particularly in patients with good liver function. Patients with deteriorating liver function are candidates for liver transplants.

Carcinoma of the Gallbladder

Cancer of the gallbladder is a rare malignancy that occurs predominantly in the elderly. It is an aggressive tumor, with poor prognosis except when incidentally diagnosed at an early stage after cholecystectomy for cholelithiasis. The overall reported 5-year survival rate is about 5%.⁷⁹

Incidence

Gallbladder cancer is the fifth most common GI malignancy in Western countries. However, it accounts for only 2% to 4% of all malignant GI tumors, with about 5000 new cases diagnosed annually in the United States. It is two to three times more common in females than males, and the peak incidence is in the seventh decade of life. Its occurrence in random autopsy series is about 0.4%, but approximately 1% of patients undergoing cholecystectomy for gallstone disease are found incidentally to have gallbladder cancer. The incidence of gallbladder cancer is particularly high in native populations of the United States, Mexico, and Chile. The annual incidence in Native American females with gallstones approaches 75 per 100,000, compared with the overall incidence of gallbladder cancer of 2.5 cases per 100,000 residents in the United States.⁸⁰

Etiology

Cholelithiasis is the most important risk factor for gallbladder carcinoma, and up to 95% of patients with carcinoma of the gallbladder have gallstones.⁸¹ However, the 20-year risk of developing cancer for patients with gallstones is <0.5% for the overall population and 1.5% for high-risk groups. The pathogenesis has not been defined but is probably related to chronic inflammation. Larger stones (>3 cm) are associated with a 10-fold increased risk of cancer.⁸² The risk of developing cancer of the gallbladder is higher in patients with symptomatic than asymptomatic gallstones.

Polypoid lesions of the gallbladder are associated with increased risk of cancer, particularly in polyps >10 mm.⁸³ The calcified “porcelain” gallbladder is associated with >20% incidence of gallbladder carcinoma. These gallbladders should be removed, even if the patients are asymptomatic. Patients with choledochal cysts have an increased risk of developing cancer anywhere in the biliary tree, but the incidence is highest in the gallbladder. Sclerosing cholangitis, anomalous pancreaticobiliary duct junction, and exposure to carcinogens (azotoluene, nitrosamines) also are associated with cancer of the gallbladder.

Pathology

Between 80% and 90% of the gallbladder tumors are adenocarcinomas. Squamous cell, adenosquamous, oat cell, and other anaplastic lesions occur rarely. The histologic subtypes of gallbladder adenocarcinomas include papillary, nodular, and tubular. Less than 10% are of the papillary type, but these are associated with an overall better outcome, as they are most commonly diagnosed while localized to the gallbladder. Cancer of the gallbladder spreads through the lymphatics, with venous drainage, and with direct invasion into the liver parenchyma. Lymphatic flow from the gallbladder drains first to the cystic duct node (Calot’s), then the pericholedochal and hilar nodes, and finally the peripancreatic, duodenal, periportal, celiac, and superior mesenteric artery nodes. The gallbladder veins drain directly into the adjacent liver, usually segments IV and V, where tumor invasion is common (Fig. 32-25). The gallbladder wall differs histologically from the intestines in that it lacks a muscularis mucosa and submucosa. Lymphatics are present in the subserosal layer only. Therefore, cancers invading but not growing through the muscular layer have minimal risk of nodal disease. When diagnosed, about 25% of gallbladder cancers are localized to the gallbladder wall, 35% have regional nodal involvement and/or extension into adjacent liver, and approximately 40% have distant metastasis.⁸⁴

Clinical Manifestations and Diagnosis

Signs and symptoms of carcinoma of the gallbladder are generally indistinguishable from those associated with cholecystitis and cholelithiasis. These include abdominal discomfort, right upper quadrant pain, nausea, and vomiting. Jaundice, weight loss, anorexia, ascites, and abdominal mass are less common presenting symptoms. More than one half of gallbladder cancers are not diagnosed before surgery. Common misdiagnoses include chronic cholecystitis, acute cholecystitis, choledocholithiasis, hydrops of the gallbladder, and pancreatic cancer. Laboratory findings are not diagnostic but, if abnormal, are most often consistent with biliary obstruction. Ultrasonography often reveals a thickened, irregular gallbladder wall or a mass replacing the gallbladder. Ultrasonography may visualize tumor invasion of the liver, lymphadenopathy, and a dilated biliary tree. The sensitivity of ultrasonography in detecting gallbladder cancer ranges from 70% to 100%. A CT scan is an important tool for staging and may identify a gallbladder mass or local invasion into adjacent organs. In addition, a spiral CT scan can demonstrate vascular invasion; however, CT scan is a poor method for identifying nodal spread. In jaundiced patients, a percutaneous transhepatic or endoscopic cholangiogram may be helpful to delineate the extent of biliary tree involvement, and typically shows a long stricture of the common bile duct. With newer MRI techniques, MRCP has evolved into a single noninvasive imaging method that allows complete assessment of biliary, vascular, nodal, hepatic, and adjacent organ involvement.⁸⁵ If diagnostic studies suggest that the tumor is unresectable, a CT scan or ultrasound-guided biopsy of the tumor can be obtained to provide a pathologic diagnosis.

Treatment

Surgery remains the only curative option for gallbladder cancer as well as for cholangiocarcinoma. However, palliative procedures for patients with unresectable cancer and jaundice or duodenal obstruction remain the most frequently performed surgery for gallbladder cancers. Today, patients with obstructive jaundice can frequently be managed with either endoscopic or percutaneously placed biliary stents. There are no proven effective options for adjuvant radiation or chemotherapy for patients with gallbladder cancer.

The pathologic stage of gallbladder cancer determines the operative treatment for patients with localized gallbladder cancer. Patients without evidence of distant metastasis warrant exploration for tissue diagnosis, pathologic staging, and possible curative resection.

Tumors limited to the muscular layer of the gallbladder (T1) are usually identified incidentally, after cholecystectomy for gallstone disease. There is near universal agreement that simple cholecystectomy is an adequate treatment for T1 lesions and results in a near 100% overall 5-year survival rate. When the tumor invades the perimuscular connective tissue without extension beyond the serosa or into the liver (T2 tumors), an extended cholecystectomy should be performed.⁸⁶ That includes resection of liver segments IVB and V, and lymphadenectomy of the cystic duct and pericholedochal, portal, right celiac, and posterior pancreatoduodenal lymph nodes. One half of patients with T2 tumors are found to have nodal disease on pathologic examination. Therefore, regional lymphadenectomy is an important part of surgery for T2 cancers.⁸⁷ For tumors that grow beyond the serosa or invade the liver or other organs (T3 and T4 tumors), there is a high likelihood of intraperitoneal and distant spread. If no peritoneal or nodal involvement is found, complete tumor excision with an extended right hepatectomy (segments IV, V, VI, VII, and VIII) must be performed for adequate tumor clearance. An aggressive approach in patients who will tolerate surgery has resulted in an increased survival for T3 and T4 lesions.

Prognosis

Most patients with gallbladder cancer have unresectable disease at the time of diagnosis. The 5-year survival rate of all patients with gallbladder cancer is <5%, with a median survival of 6 months.⁸⁸ Patients with T1 disease treated with cholecystectomy have an excellent prognosis (85%–100% 5-year survival rate). The 5-year survival rate for T2 lesions treated with an extended cholecystectomy and lymphadenectomy compared with simple cholecystectomy is >70% vs. 25% to 40%, respectively. Patients with advanced but resectable gallbladder cancer are reported to have 5-year survival rates of 20% to 50%. However, the median survival for patients with distant metastasis at the time of presentation is only 1 to 3 months.

Recurrence after resection of gallbladder cancer occurs most commonly in the liver or the celiac or retropancreatic nodes. The prognosis for recurrent disease is very poor. Death occurs most commonly secondary to biliary sepsis or liver failure. The main goal of follow-up is to provide palliative care. The most common problems are pruritus and cholangitis associated with obstructive jaundice, bowel obstruction secondary to carcinomatosis, and pain.

Bile Duct Carcinoma

Cholangiocarcinoma is a rare tumor arising from the biliary epithelium and may occur anywhere along the biliary tree. About two thirds are located at the hepatic duct bifurcation. Surgical resection offers the only chance for cure; however, many patients have advanced disease at the time of diagnosis. Therefore, palliative procedures aimed to provide biliary drainage to prevent liver failure and cholangitis are often the only therapeutic possibilities. Most patients with unresectable disease die within 1 year of diagnosis.⁸⁹

Incidence

The autopsy incidence of bile duct carcinoma is about 0.3%. The overall incidence of cholangiocarcinoma in the United States is about 1.0 per 100,000 people per year, with about 3000 new cases diagnosed annually. The male-to-female ratio is 1.3:1, and the average age of presentation is between 50 and 70 years.

Etiology

Risk factors associated with cholangiocarcinoma include primary sclerosing cholangitis, choledochal cysts, ulcerative colitis, hepatolithiasis, biliary-enteric anastomosis, and biliary tract infections with Clonorchis or in chronic typhoid carriers. Features common to most risk factors include biliary stasis, bile duct stones, and infection. Other risk factors associated with cholangiocarcinoma are liver flukes, dietary nitrosamines, Thorotrast, and exposure to dioxin.^90,91

Pathology

Over 95% of bile duct cancers are adenocarcinomas. Morphologically, they are divided into nodular (the most common type), scirrhous, diffusely infiltrating, or papillary. Anatomically, they are divided into distal, proximal, or perihilar tumors. Intrahepatic cholangiocarcinomas occur, but they are treated like hepatocellular carcinoma, with hepatectomy when possible. About two thirds of cholangiocarcinomas are located in the perihilar location. Perihilar cholangiocarcinomas, also referred to as Klatskin tumors, are further classified based on anatomic location by the Bismuth-Corlette classification (Fig. 32-26). Type I tumors are confined to the common hepatic duct, but type II tumors involve the bifurcation without involvement of the secondary intrahepatic ducts. Type IIIa and IIIb tumors extend into the right and left secondary intrahepatic ducts, respectively. Type IV tumors involve both the right and left secondary intrahepatic ducts.

Clinical Manifestations and Diagnosis

Painless jaundice is the most common presentation. Pruritus, mild right upper quadrant pain, anorexia, fatigue, and weight loss also may be present. Cholangitis is the presenting symptom in about 10% of patients, but occurs more commonly after biliary manipulation in these patients. Except for jaundice, physical examination is usually normal in patients with cholangiocarcinoma. Occasionally, asymptomatic patients are found to have cholangiocarcinoma while being evaluated for elevated alkaline phosphatase and γ-glutamyltransferase levels. Tumor markers such CA 125 and carcinoembryonic antigen can be elevated in cholangiocarcinoma but tend to be nonspecific because they also increase in other GI and gynecologic malignancies or cholangiopathologies. The tumor marker most commonly used to aid the diagnosis of cholangiocarcinoma is CA 19-9, which has a sensitivity of 79% and specificity of 98% if the serum value is >129 U/mL.⁹² However, mild elevations in CA 19-9 can be seen in cholangitis, other GI and gynecologic neoplasms, and patients who lack the Lewis blood type antigen.⁹³

The initial tests are usually ultrasound or CT scan. A perihilar tumor causes dilatation of the intrahepatic biliary tree, but normal or collapsed gallbladder and extrahepatic bile ducts distal to the tumor. Distal bile duct cancer leads to dilatation of the extra- and intrahepatic bile ducts as well as the gallbladder. Ultrasound can establish the level of obstruction and rule out the presence of bile duct stones as the cause of the obstructive jaundice (Fig. 32-27). It is usually difficult to visualize the tumor itself on ultrasound or on a standard CT scan. Either ultrasound or spiral CT can be used to determine portal vein patency. The biliary anatomy is defined by cholangiography. PTC defines the proximal extent of the tumor, which is the most important factor in determining resectability. ERC is used, particularly in the evaluation of distal bile duct tumors. For the evaluation of vascular involvement, celiac angiography may be necessary. With the newer types of MRI, a single noninvasive test has the potential of evaluating the biliary anatomy, lymph nodes, and vascular involvement, as well as the tumor growth itself.⁹⁴

Tissue diagnosis may be difficult to obtain nonoperatively except in advanced cases. Percutaneous fine-needle aspiration biopsy, biliary brush or scrape biopsy, and cytologic examination have a low sensitivity in detecting malignancy. Patients with potentially resectable disease should, therefore, be offered surgical exploration based on radiographic findings and clinical suspicion.⁹⁵

Treatment

Surgical excision is the only potentially curative treatment for cholangiocarcinoma. In the past one to two decades, improvements in surgical techniques have resulted in lower mortality and better outcome for patients undergoing aggressive surgical excision for cholangiocarcinoma.⁹⁶

Patients should undergo surgical exploration if they have no signs of metastasis or locally unresectable disease. However, despite improvements in ultrasonography, CT scanning, and MRI, more than one half of patients who are explored are found to have peritoneal implants, nodal or hepatic metastasis, or locally advanced disease that precludes resection. For these patients, surgical bypass for biliary decompression and cholecystectomy to prevent the occurrence of acute cholecystitis should be performed.⁹⁷

For unresectable perihilar cholangiocarcinoma, Roux-en-Y cholangiojejunostomy to either segment II or III bile ducts or to the right hepatic duct can be performed.

For curative resection, the location and local extension of the tumor dictates the extent of the resection. Perihilar tumors involving the bifurcation or proximal common hepatic duct (Bismuth-Corlette type I or II) with no signs of vascular involvement are candidates for local tumor excision with portal lymphadenectomy, cholecystectomy, common bile duct excision, and bilateral Roux-en-Y hepaticojejunostomies. If the tumor involves the right or left hepatic duct (Bismuth-Corlette type IIIa or IIIb), right or left hepatic lobectomy, respectively, should also be performed. Frequently, resection of the adjacent caudate lobe is required because of direct extension into caudate biliary radicals or parenchyma.⁹⁵

Distal bile duct tumors are more often resectable. They are treated with pylorus-preserving pancreatoduodenectomy (Whipple procedure). For patients with distal bile duct cancer found to be unresectable on surgical exploration, Roux-en-Y hepaticojejunostomy, cholecystectomy, and gastrojejunostomy to prevent gastric outlet obstruction should be performed.

Nonoperative biliary decompression is performed for patients with unresectable disease on diagnostic evaluation. Percutaneous placement of expandable metal stents or drainage catheters is usually the appropriate approach for proximal tumors. However, for distal bile duct tumors, endoscopic placement is often the preferred approach (Fig. 32-28). There is a significant risk of cholangitis with internal and external drainage, and stent occlusion is not uncommon. However, although surgical bypass offers improved patency and fewer episodes of cholangitis, an operative intervention is not warranted in patients with metastatic disease.⁹⁸

There is no proven role for adjuvant chemotherapy in the treatment of cholangiocarcinoma. Adjuvant radiation therapy has also not been shown to increase either quality of life or survival in resected patients. Patients with unresectable disease often are offered treatment with 5-fluorouracil alone or in combination with mitomycin C and doxorubicin, but the response rates are low, <10% and <30%, respectively. The combination of radiation and chemotherapy may be more effective than either treatment alone for unresectable disease, but no data from randomized trials are available. Giving chemoradiation to these patients can be difficult because of the high incidence of cholangitis. External-beam radiation has not been shown to be an effective treatment for unresected disease. The use of interstitial (intraoperative) radiation, brachytherapy with iridium-192 via percutaneous or endoscopic stents, and combined interstitial and external-beam radiation for unresectable cholangiocarcinoma has been reported with some encouraging results. However, no randomized, prospective trials have been reported.⁹⁵ A palliative measure that has been shown effective in a multicenter randomized trial is photodynamic therapy. In this trial, patients with a diagnosis of unresectable cholangiocarcinoma were randomized to biliary stenting with photodynamic therapy or stenting alone. The authors found that photodynamic therapy prolonged survival by approximately 400 days and improved quality of life on standardized questionnaire.⁹⁹

Prognosis

Most patients with perihilar cholangiocarcinoma present with advanced, unresectable disease. Patients with unresectable disease have a median survival between 5 and 8 months. The most common causes of death are hepatic failure and cholangitis. The overall 5-year survival rate for patients with resectable perihilar cholangiocarcinoma is between 10% and 30%, but for patients with negative margins, it may be as high as 40%. The operative mortality for perihilar cholangiocarcinoma is 6% to 8%. Patients with distal cholangiocarcinoma are more likely to have resectable disease and improved prognosis compared to perihilar cholangiocarcinoma. The overall 5-year survival rate for resectable disease is 30% to 50%, and the median survival is 32 to 38 months.

The greatest risk factors for recurrence after resection are the presence of positive margins and lymph node–positive tumors. Therapy for recurrent disease is palliation of symptoms. Surgery is not recommended for patients with recurrent disease.⁹⁴