The liver

30.1 Surgical anatomy of the liver and biliary tree

Adrian Savage and Julian Britton

Development

The liver and biliary tree develops as a hollow endodermal bud, the hepatic diverticulum, from the distal foregut in the 3-week embryo. The rapidly proliferating cells of the bud penetrate the septum transversum and eventually develop into the liver, while the connection between the hepatic diverticulum and the foregut is preserved to form the bile duct. A ventral outgrowth of the bile duct gives rise to the gallbladder and cystic duct. With the rotation of the gut, the opening from the bile duct into the intestine migrates to a posterior position and the common bile duct comes to lie behind the duodenum and pancreas.

Surgical anatomy of the liver

The external appearance of the mature liver shows its division into two lobes by the umbilical fissure and falciform ligament. Further subdivisions are made on other superficial features. The quadrate lobe is a subdivision of the right lobe and lies to the left of the gallbladder fossa and to the right of the umbilical fissure. The transverse hilar fissure forms the posterior boundary of the quadrate lobe and divides it from the caudate lobe posteriorly

Fig. 1 Divisions of the liver by its external features.

The internal architecture of the liver bears only a superficial relation to its external appearance. Cast studies of the biliary tree and portal venous radicles show that the liver is divided into right and left halves, according to the territories of drainage of the right and left hepatic ducts and the areas of supply of the right and left branches of the portal vein and hepatic artery. This principal division is called Cantlie's line, after its first description in 1898, but it is not readily visible on external examination. It runs from the medial edge of the gallbladder fossa to the inferior vena cava posteriorly. The nomenclature of hepatic anatomy has become confused by the use of the term 'lobe', which has been applied to both the division of the liver by its external features and the territories of drainage of the right and left hepatic ducts.

Glisson's capsule, a peritoneal and fibrous covering, invests the liver. The reflections of the capsule on to the right hemidiaphragm form the coronary ligament and right triangular ligament, and the reflection from the left liver on to the left hemidiaphragm forms the left triangular ligament. Glisson's capsule is also reflected over the falciform ligament. The structures at the hilum of the liver are invested in dense fibrous tissue continuous with Glisson's capsule; here this covering is known as the hilar plate. The hilar plate is continuous with the peritoneal layers investing the common hepatic and common bile duct, cystic duct, and gallbladder.

The liver is supplied by blood 80 per cent of which comes via the portal vein and 20 per cent via the hepatic artery. Venous drainage is by three, large, short, hepatic veins that pass posteriorly to the inferior vena cava, which lies on the posterior surface of the liver. Drainage of bile occurs from the left and right hepatic ducts to the common hepatic and bile duct, and then to the second part of the duodenum.

The portal vein is formed by the confluence of the superior mesenteric vein and the splenic vein in front of the inferior vena cava and behind the neck of the pancreas. The portal vein runs behind the pancreas to the free border of the lesser omentum, where it traverses to the hilum of the liver in the hepatoduodenal ligament behind the common bile duct and to the right of the hepatic artery. At the hilum of the liver, the portal vein divides into left and right branches. The vein, with its accompanying branches of the biliary tree and hepatic artery, is invested in a fibrous sheath continuous with the hilarplate.

The common hepatic artery usually arises from the coeliac axis and travels across the posterior abdominal wall to lie just above the pylorus. Here it gives off the gastroduodenal artery before continuing as the hepatic artery proper, which then runs in the gastroduodenal ligament medial to the common bile duct and anterior to the portal vein to the hilum of the liver. The hepatic artery divides into the left and right hepatic artery well below the hilum of the liver. Sixteen per cent of individuals have an aberrant right hepatic artery arising from the superior mesenteric artery that runs in the groove to the right of the portal vein and common bile duct. Less commonly, the arterial supply to the left half of the liver comes from the left gastric artery.

The venous radicles in the liver give rise to three hepatic veins, the right, middle, and left, which are short and large. The middle hepatic vein usually joins the left hepatic vein before entering the inferior vena cava. In addition, a number of unnamed short veins enter the inferior vena cava directly. These arise in the caudate lobe, which, because of its embryological development form the dorsal mesogastrium, has a different venous drainage

Segmentation of the liver

The three hepatic veins divide the liver into four sectors, each of which is further subdivided into two segments. The whole liver is therefore divisible into eight segments: four are in the right half, and three in the left half.The remaining segment is the caudate lobe, which should be considered separately because of its different embryological origin, variable blood supply, and venous drainage. Two differing descriptions of the segmentation of the liver are in common use, that of Couinaud and that of Goldsmith and Woodburne. These differ mainly in nomenclature, and the description of Couinaud will be used here.

Fig. 2 Schematic representation of the segmentation of the liver.

The segments are numbered anticlockwise I to VIII, starting with the caudate lobe. Each segment is supplied by a named portal venous radicle and is drained by a segmental bile duct, forming the smallest anatomical unit of hepatic resection. Removal of segments II to IV is described as 'left hepatectomy' and removal of segments V to VIII, 'right hepatectomy'. Removal of segment IV (the quadrate lobe) in addition to right hepatectomy is described as extended right hepatectomy. The use of this nomenclature avoids the confusion inherent in the use of the terms 'hepatic lobectomy' and 'trisegmentectomy'.

Fig. 3 The segments of the liver, showing the segmental biliary tree and venous drainage.

The intrahepatic bile ducts

The interlobular bile canaliculi join to form segmental bile ducts that eventually drain into the right or left hepatic ducts. On the right, ducts from segments VI and VII join to form the right posterior sectoral duct, which runs horizontally across the gallbladder fossa, where it is surgically accessible after localization by needle puncture or intraoperative ultrasonography. The right anterior sectoral duct runs more vertically and is formed by the confluence of the ducts from segments V and VIII.

Segmental ducts from segments II, III, and IV merge to form the left hepatic duct at the base of the umbilical fissure. Although there are variations in the exact anatomy of this confluence of bile ducts, these are of little clinical relevance. The duct from segment III is surgically accessible by dissection in the groove to the left of the umbilical ligament, where it lies anterior to its accompanying branch of the portal vein and hepatic artery. The left hepatic duct runs from the base of the umbilical fissure to the hilum in the transverse hilar fissure, invested by the fibrous tissue of the hilar plate with the left portal vein lying posterior and the left hepatic artery lying inferior. The left duct is surgically accessible by division of the peritoneal fold under the quadrate lobe (segment IV), a procedure known as lowering the hilar plate.

At the hilum of the liver, the right and left hepatic ducts join to form the confluence of the bile ducts. Anatomical variations of both the intrahepatic and extrahepatic biliary tree are so common that a 'normal' pattern is seen in less than 60 per cent of individuals. In 57 per cent, the right anterior and posterior sectoral ducts join to form a right hepatic duct, whereas in the remainder, the right anterior and posterior sectoral ducts join the confluence individually. One important variation is the presence of an anomalous subvesical duct, the duct of Luschka, which runs in the gallbladder fossa. It is found in 12 to 50 per cent of individuals, drains a variable portion of the right liver, and is potentially vulnerable during cholecystectomy.

Fig. 4 Anomalies of the confluence of the bile ducts: ra, right anterior sectoral duct; rp, right posterior sectoral duct; lh, left hepatic duct; roman numerals refer to hepatic segments.

The gallbladder

The gallbladder, a pear-shaped reservoir 5 to 12 cm in length, lies in a fossa on the lower surface of the liver. Four parts of the gallbladder are described: the fundus, the body, the infundibulum, and the neck. In addition, a Hartmann's pouch often develops as a pathological feature in the neck and infundibulum of the gallbladder in the presence of gallstones. Various congenital abnormalities have been described, including double, bilobed, and intrahepatic gallbladder, and congenital absence. The occasional presence of a long mesentery is of significance since it may allow torsion. The gallbladder drains by the cystic duct to the junction of the common hepatic duct and common bile duct. The wall of the cystic duct contains muscle fibres that form the sphincter of Lutkens, while the mucosa of the cystic duct forms crescentic folds known as the spiral valve of Heister.

Calot's triangle

Calot's triangle is formed by the common hepatic duct to the left and the cystic duct below. Although the original description of this area gave the cystic artery as the superior border, the inferior surface of the liver is now accepted as this border. The cystic artery usually arises from the right hepatic artery behind the common hepatic duct and runs behind the right hepatic duct and through Calot's triangle to the gallbladder. In 20 per cent of individuals the cystic artery arises from a right hepatic artery that runs anterior to the common hepatic duct, and the right hepatic artery forms a loop or 'caterpillar hump' with the cystic artery originating from the apex in 7 per cent of individuals. In the latter case, the right hepatic artery may be mistaken for the cystic artery during cholecystectomy. In 10 per cent of individuals the cystic artery arises proximally from the right hepatic artery and runs anterior to the common hepatic duct, while the right hepatic artery runs posterior to this duct.

There are no discrete veins draining the gallbladder and bile duct, although all arteries are normally accompanied by a small vein or venous plexus. Some veins drain directly from the gallbladder into the liver. Lymphatic drainage is first to the cystic lymph node, which is usually seen adjacent to the cystic artery during cholecystectomy, and thence to the retroduodenal lymph nodes. Some lymphatic channels from the fundus drain to the lymphatic channels in the liver capsule. Motor and sensory sympathetic nerves from the coeliac plexus reach the gallbladder along the hepatic artery, and the parasympathetic motor supply comes from the right and left vagus nerves.

Two other major anomalies may be encountered during the course of dissection in Calot's triangle for cholecystectomy. An aberrant right hepatic artery from the superior mesenteric artery occurs in 16 per cent of individuals, running in the groove between the common hepatic duct and the portal vein. It can be seen in the medial border of Calot's triangle in 90 per cent of these individuals. The right posterior or anterior sectoral ducts may also run through Calot's triangle and may be mistaken for the cystic duct.

The bile ducts

From the confluence of the bile ducts, the common hepatic duct runs for some 2.5 to 3.5 cm down to its confluence with the cystic duct, resulting in the formation of the common bile duct. This junction is variable. In 5 per cent of people the cystic duct spirals behind the common hepatic duct and enters the bile duct low down within the pancreas. In 2 per cent the cystic duct opens directly into the confluence of the bile ducts. The common bile duct is normally 10 to 12 cm in length and about 6 mm in diameter in anatomical specimens. In life, the upper limit of normal measured by ultrasonography is 7 mm, whilst on direct cholangiography, when the duct is deliberately distended, it may be 10 mm in diameter.

Fig. 5 The relations of the extrahepatic biliary tree.

The common hepatic and bile ducts are supplied by adjacent arteries that supply two axial arteries that run at 3 o'clock and 9 o'clock along the bile duct wall. Other small arteries run in the mesentery around the bile duct to form a plexus. About 60 per cent of blood flow to the duct arises inferiorly from the retroduodenal and gastroduodenal arteries, while 38 per cent comes from the cystic and hepatic arteries superiorly.

The common bile duct passes behind the first part of the duodenum. It may be exposed by division of the peritoneal fold over the superior aspect of the first part of the duodenum and by drawing the duodenum downwards. It then runs either in a groove in the back of the head of the pancreas or in the loose areolar tissue behind the head of the pancreas. Here it may be exposed by Kocher's manoeuvre, that is, division of the peritoneum lateral to the duodenum and reflection of the duodenum and head of the pancreas medially. It curves to the right to enter the medial duodenal wall about 2 cm below the duodenal cap, where it is joined by the main pancreatic duct of Wirsung to form the sphincter of Oddi, which discharges into the duodenum through the ampulla of Vater.

Some 2 cm of the terminal portion of the common bile duct lies within the wall of the duodenum, where it is surrounded by the smooth muscle fibres of the sphincter of Oddi. The pancreatic duct may be closely applied to the common bile duct at this point and may similarly be invested in smooth muscle of the sphincter of Oddi. The exact anatomy of the terminal common bile duct and pancreatic duct follows one of three patterns. They may unite outside the wall of the duodenum and traverse the duodenal wall to the papilla as a common channel; they may join within the duodenal wall and have a short common terminal channel; and separate orifices have been described.

Fig. 6 Anatomy of the sphincter of Oddi.

30.2 Hepatic trauma

David V. Feliciano

Mechanism of injury

Compressive injuries to the liver from the overlying ribs occur most frequently in frontal motor vehicle crashes in which the victim has an impact with the lower rim of the steering wheel or the dashboard. Compression against a shoulder belt restraint may be a cause, as well, particularly if the device is worn improperly under the right upper extremity. In 'T-bone' side impacts, the front seat passenger is at significant risk for a hepatic injury.

Patients with penetrating wounds to the right thoracoabdominal area (nipples to costal margin and medial to right anterior axillary line) are at risk of a hepatic injury if the diaphragm is penetrated. This occurs in approximately 15 per cent of patients with penetration of the body wall by a stab wound and in 45 to 48 per cent of those with gunshot wounds.

Diagnosis

In hypotensive patients who have suffered blunt abdominal or multisystem trauma, either surgeon-performed ultrasound or a standard infraumbilical diagnostic peritoneal lavage is appropriate. Using a 3.5 mHz transducer in the right midaxillary line between ribs 10 and 11, the visualization of fluid (blood unless ascites is present) in Morison's pouch mandates a laparotomy in the absence of other overt sites of hemorrhage. An experienced surgeon-sonographer may visualize a hepatic injury, also. When no fluid is present in Morison's pouch, the ultrasound probe is moved to image the left subphrenic area/splenorenal recess and the pelvis. A diagnostic peritoneal tap that yields 10 to 20 ml of gross blood or a formal lavage whose effluent is cloudy enough to obscure the print on the bag of intravenous fluids mandates laparotomy in the hypotensive patient, also. In any patient undergoing emergency laparotomy after suffering blunt abdominal trauma, the most likely sources of hemorrhage are injuries to the liver, spleen, or mesentery.

A patient who is hemodynamically stable and without peritonitis after suffering blunt abdominal trauma is evaluated by a spiral contrast CT if the physical examination is equivocal or compromised or if there is intra-abdominal fluid on the preliminary ultrasound. The volume of intraperitoneal fluid (blood), magnitude of injury to the liver or other organ, and the presence or absence of active hemorrhage on the contrast CT will determine whether nonoperative or operative management is chosen in the stable patient.

Penetrating wounds to the abdomen in patients with peritonitis, hypotension, or significant evisceration mandate laparotomy. Stab wounds to the right thoracoabdominal area in patients without fluid in the right subphrenic space or Morison's pouch on ultrasound undergo in-hospital serial physical examinations for 24 h after admission. An occasional stable patient with a gunshot wound to this area and minimal tenderness may be evaluated by a contrast spiral CT to determine the magnitude of hepatic and pulmonary injuries.

Nonoperative management

Approximately 80 to 85 per cent of all patients with hepatic trauma are stable upon arrival in the emergency center, and, in the absence of other indications for an emergency laparotomy, nonoperative management is appropriate after a contrast spiral CT. Contraindications to nonoperative management include a period of hypotension in the field or in the emergency center, persistent significant tachycardia despite aggressive resuscitation, the presence of active hemorrhage from the liver, spleen, or kidney on the contrast CT, or the presence of another organ injury mandating laparotomy. Patients are kept at bed rest, and their vital signs are monitored in the surgical intensive care unit if a significant injury is present (American Association for the Surgery of Trauma—Organ Injury Scale Grades III, IV, V). A falling hematocrit or continuing need for transfusion during the nonoperative period should prompt an emergency hepatic arteriogram or laparotomy. New onset peritonitis and hypotension are followed by an emergency laparotomy. In stable patients a repeat spiral CT is appropriate at 5 to 7 days following injury to determine whether progression of the injury or some healing has occurred. With some healing, discharge to a home situation in which a family member is available to the patient is indicated if a Grade III, IV, or V injury was present. Return to vigorous physical activity or contact sports is prohibited until a late follow-up spiral CT shows healing.

Nonoperative management fails in approximately 2 to 7 per cent of patients with blunt hepatic injuries. The hepatic injury, itself, will be the cause in 50 to 75 per cent of the failures, and 65 to 85 per cent of the hepatic failures will be in patients with Grade IV or V injuries on the original CT.

Nonoperative management of gunshot wounds of the liver is practiced in a similar fashion. The success rate is similar to that described above for blunt trauma as missile tracks from civilian handguns are significantly smaller than many of the Grade IV or V hepatic injuries presently undergoing nonoperative management.

General principles of operative management

A midline incision is used, and blood and clots are evacuated manually or with a suction device. A vascular clamp is applied to the porta hepatis (Pringle maneuver) if a significant (Grade III, IV, V) hepatic injury is present. The injured lobe is compressed between laparotomy pads in the hands as the surgeon informs the anesthesiologist about the need to contact the blood bank. Also, the surgeon should request that an upper hand retractor, various sizes of metal clips, O-chromic sutures on blunt needles, and a 36–38 French thoracostomy tube be available in the operating room. When blood and appropriate equipment is available in the operating room, the packs around the liver are removed and the hepatic injury is inspected. Posterior lobar injuries or Grade III, IV, or V injuries are best visualized by division of the ipsilateral triangular ligament and the anterior coronary ligament at the edge of the liver. Folded dry laparotomy pads are then placed beneath the injured lobe to elevate it into the midline incision. In obese patients or in those with a high likelihood of an injury to the extrahepatic veins or retrohepatic vena cava (dark venous hemorrhage as the injured lobe is mobilized), a median sternotomy is also performed.

Fig. 3 Mobilization of the right lobe of the liver by division of the triangular and anterior coronary ligaments. (Reproduced with permission from Baylor College of Medicine.)

Simple techniques of hemostasis

Approximately 90 per cent of penetrating injuries and 60 per cent of blunt injuries can be managed with 5 min of compression, the application of topical hemostatic agents, or simple suture hepatorrhaphy. Currently available topical hemostatic agents include oxidized regenerated cellulose, microfibrillar collagen hemostat, and fibrin sealant. Fibrin sealant, only recently available in the United States, contains human fibrinogen and thrombin, aprotinin, and calcium chloride. Five minutes of compression is performed after the application of a topical agent. After releasing compression, the electrocautery is used for any remaining bleeders when only Grade I or Grade II hepatic injuries are present. Suture hepatorrhaphy with O-chromic material is appropriate for Grade II and Grade III injuries. An interrupted or continuous suture technique is used, with the caveat that crushing sutures cause postoperative hepatic necrosis and 'liver fever'. Drainage is not necessary in the absence of further hemorrhage or obvious leakage of bile.

Advanced techniques of hemostasis

Advanced techniques are necessary in 10 per cent of penetrating wounds and in 40 per cent of blunt hepatic injuries. These patients have Grade III, IV, or V injuries that will require the use of one or more of the following techniques: (1) extensive hepatorrhaphy; (2) hepatotomy with selective vascular ligation; (3) viable omental pack; (4) resectional debridement with selective vascular ligation; (5) absorbable mesh compression; (6) formal resection; (7) selective hepatic artery ligation; (8) intrahepatic balloon tamponade; (9) perihepatic packing; and (10) atriocaval shunt. The most important adjunct to these techniques is avoiding intraoperative hypothermia using the maneuvers listed in

Extensive hepatorrhaphy

Extensive hepatorrhaphy is indicated in 'damage control' situations in which intraoperative hypothermia (<34–35°C), metabolic acidosis (pH < 7.1–7.2), and/or a coagulopathy (PT or PTT > 50 per cent normal) mandate a rapid operation. Large figure-of-eight sutures or a continuous O-chromic suture is used to reapproximate the sides of hepatic lacerations in the hope that hemorrhage from small hepatic arteries and low pressure hepatic veins or portal veins will be controlled by compression. Extensive postoperative hepatic necrosis is likely when such sutures are tied too tight in the presence of a prolonged Pringle maneuver.

Hepatotomy with selective vascular ligation

Gaining further exposure of a deep hepatic laceration or connecting the entrance and exit wounds of a penetrating wound with the finger fracture technique or the electrocautery is known as hepatotomy. Once completed, large Deaver or Harrington retractors are used to maintain visibility in the depths of the hepatotomy as selective vascular clipping or suture ligation of injured vessels is performed. This technique should be utilized prior to the onset of hypothermia and only by surgeons with sufficient experience in elective or traumatic hepatic surgery.

Viable omental pack

The gastrocolic omentum mobilized off the transverse colon with its blood supply intact is used to fill Grade III, IV, or V hepatic injuries or hepatotomy sites. Intrahepatic omentum is effective in controlling venous hemorrhage, managing dead space, and in bringing mobile macrophages to the site of injury. While it does not appear to aid healing, postoperative bleeding and drainage of bile are much decreased in the experience of most trauma surgeons. The viable omental pedicle is held in place by compressing hepatic sutures tied under moderate tension.

Fig. 4 Viable omental pack used to fill hepatic laceration after selective vascular ligation. (Reproduced with permission from Baylor College of Medicine.)

Resectional debridement with selective vascular ligation

With disrupted hepatic tissue on the edge of an injured liver, the finger fracture technique or the electrocautery should be used to create a new fresh edge of the liver around the area of injury. Vessels and biliary ducts can then be clipped or suture ligated where they are intact, and all disrupted tissue outside this new line is then debrided. The application of a viable omental pedicle to this new raw surface is controversial, though this is appropriate when a coagulopathy makes hemostasis difficult.

Fig. 5 Resectional debridement of portion of segments II and III of liver with selective vascular ligation using clips and sutures.

Absorbable mesh compression

Wrapping an injured hepatic lobe in which all fragments are viable with a large sheet of absorbable mesh tailored around the porta hepatis and inferior vena cava has been used in some centers. The technique is time-consuming, but eliminates the need for reoperation as when perihepatic packs are used for compression.

Formal resection

Anatomic lobectomy is used in approximately 3 per cent of patients undergoing operative management. No dissection is performed in the porta hepatis, and the lobectomy is performed with a Pringle maneuver in place using finger fracture or electrocautery and metal clips. The large right hepatic vein can usually be controlled inside the liver as the lobectomy is completed. Anatomic segmentectomy is much more commonly utilized, especially with extensive lacerations beneath the falciform ligament mandating resection of Couinaud's segments II and III (left lateral segment).

Fig. 6 Resection of segments II and III after avulsion injury beneath falciform ligament.

Selective hepatic artery ligation

Selective hepatic artery ligation is used in about 1 per cent of patients undergoing operative management. It is indicated when arterial hemorrhage in a deep hepatic laceration cannot be directly controlled, but stops whenever a Pringle maneuver is applied. Extrahepatic ligation of the artery to the injured lobe in the porta hepatis will fail to control hemorrhage when the wrong artery is ligated or when intrahepatic or retrohepatic venous hemorrhage is present.

Intrahepatic balloon tamponade

The passage of a Foley or Fogarty balloon catheter into the hepatic track of a knife or missile may allow for balloon compression of the site of parenchymal hemorrhage. This technique is particularly useful when the novice trauma surgeon has little experience in completing an extensive hepatotomy through one or both lobes. The inflated balloon catheter is passed through the body wall away from the midline incision at the completion of the first laparotomy. After 48 to 72 h of balloon compression, the balloon is deflated and removed through the body wall in the surgical intensive care unit. Rebleeding is extraordinarily rare when a parenchymal track has been tamponaded for this period of time.

Perihepatic packing

The insertion of folded dry laparotomy pads over and, occasionally, below an injured hepatic lobe is used in approximately 5 per cent of patients undergoing operative management. Packs should be used to tamponade minor hepatic injuries or subcapsular hematomas when a damage control procedure is performed. They are also useful for any major hepatic parenchymal injury when advanced techniques of hemostasis fail secondary to intraoperative hypothermia or a coagulopathy. The use of a plastic sheet beneath the packs to prevent sticking to raw edges of parenchyma has been useful in the author's experience. Packs are removed at a reoperation 48 to 72 h after the original laparotomy when hypothermia, acidosis, and any coagulopathy are corrected and the cardiovascular, respiratory, and renal systems are stable. Perihepatic packs have also been used with success in patients with unruptured retrohepatic hematomas from presumed injuries to the retrohepatic vena cava.

Fig. 7 Perihepatic packing with folded dry laparotomy pads over plastic sheet (Reproduced with permission from Baylor College of Medicine.)

Atriocaval shunt

A no. 36 French thoracostomy tube or no. 8 endotracheal tube inserted through the right atrial appendage into the infrarenal inferior vena cava is an atriocaval shunt. An extra hole at the level of the right atrium is cut before insertion. By pulling circumferential umbilical tape tourniquets tight around the shunt at the suprarenal inferior vena cava and intrapericardial inferior vena cava, venous return from the lower body and renal veins is diverted into the shunt. This causes a 40 to 60 per cent decrease in hemorrhage from an injury in the retrohepatic vena cava and should allow for a rapid repair.

Fig 8 After decision to insert atriocaval shunt is made, a median sternotomy is performed. Also, the suprarenal infrahepatic inferior vena cava (B) and intrapericardial inferior vena cava (C) are looped with umbilical tapes to act as tourniquets. (Reproduced with permission from Baylor College of Medicine.)

Fig. 9 A no. 36 French thoracostomy tube is inserted through right atrial appendage to act as atriocaval shunt. Blood in the infrahepatic inferior vena cava is diverted into the shunt by tightening the umbilical tape tourniquets. (Reproduced with permission from Baylor College of Medicine.)

When there has not been a preoperative or intraoperative cardiac arrest from exsanguination, use of the atrocaval shunt has resulted in a 33 to 50 per cent survival in the modern era. Alternative approaches for injuries to the retrohepatic vena cava include direct approach behind an injured lobe, total hepatic vascular isolation, and deep hepatotomy.

Drainage

Closed suction drains above and below an injured lobe are used when an intraoperative coagulopathy or the extent of hepatic repair suggests that postoperative drainage of blood and bile is likely.

Complications

Postoperative hyperpyrexia occurred in nearly two-thirds of patients with Grade III, IV, or V injuries in one review. Early postoperative coagulopathies occur in 15 per cent of patients, while reoperations for persistent or late hemorrhage used to be necessary in 3 to 7 per cent of patients. Self-limited biliary fistulas occur in 8 to 10 per cent of patients, while intra-abdominal abscesses develop in 4 to 10 per cent.

The embolization of disrupted intrahepatic arteries or pseudoaneurysms to control postoperative bleeding or late hemobilia by the interventional radiologist has caused a significant decrease in reoperations for hemorrhage. Reoperations for perihepatic abscesses have essentially disappeared in the modern era for the same reason.

Fig. 10 Percutaneous drainage of right subphrenic abscess (A) led to significant decrease in size over 7 days (B).

30.3 Abscesses - pyogenic and amoebic

Robert H. Rubin

Pyogenic abscesses

Epidemiology

The incidence of pyogenic liver abscess in developed countries has not changed appreciably over the past 50 years, being estimated at 8 to 16 cases/100 000 admissions, with a prevalence at autopsy of 0.3 to 1.5 per cent. A slight male predominance of cases has remained during this period, and no ethnic group appears to be at increased risk.

What has changed over this time is the age of the patients, the underlying cause of the liver infection, and the increasing role of malignancy in the pathogenesis of the abscess. Fifty years ago, the majority of patients were under the age of 40 years and appendicitis was the leading cause of the disease; today the average age is between 43 and 60 years, with an increasing proportion of patients over the age of 60. This change corresponds to the finding that appendicitis has been replaced by biliary tract disease as the most common underlying etiology. The increasing age of patients has been associated with an increased incidence of malignancy in patients with liver abscesses, with malignancy playing a role in a number of ways: tumors invading or compressing the biliary tract; secondary infection of primary or metastatic tumors within the liver; and gastric and intestinal malignancies providing a portal of entry for infection to gain access to the liver. Indeed, with the improvement in management of these patient that has occurred over the past 50 years, the presence or absence of underlying cancer is now the most important prognostic determinant.

Etiology and pathogenesis

Pyogenic liver abscesses may be divided into two general categories, based upon the size and distribution of the focal sites of inflammation, the acuity of clinical presentation, and the nature of the therapy that is required. Macroscopic abscesses are usually restricted to one lobe of the liver, are frequently single or confluent, present subacutely with symptoms of several days to weeks' duration, and require some form of primary drainage. Microscopic abscesses are multiple, widely distributed throughout the hepatic parenchyma, usually manifest themselves acutely over a few days, and require primarily medical therapy, with any surgery that is carried out being aimed at the underlying process, rather than the hepatic parenchymal inflammation.

Focal infection within the liver can be divided into six general categories, based upon the pathogenetic route by which infecting organisms were introduced into the liver.

Biliary tract disease

Hepatic abscess may arise due to cholangitis whenever bile flow is obstructed. In general, total obstruction is associated with elevated pressure within the biliary tree, an acute septic course, and miliary microabscesses throughout the hepatic parenchyma—a process that has been termed 'acute suppurative cholangitis'. Infection associated with less complete obstruction is associated with normal biliary tract pressure, a subacute course, and macroscopic abscesses. In older patients, malignancy of the liver, biliary tree, or pancreas is the most common cause of biliary obstruction, with a resulting dismal prognosis for such patients.

Portal vein pylephlebitis

Liver abscess may arise because of suppurative thrombophlebitis in the portal venous system that is secondary to such intra-abdominal inflammatory processes as appendicitis (the classical cause), diverticulitis, infected hemorrhoids, or any other cause of intra-abdominal or pelvic infection that impacts upon the portal venous system. In the older population, colonic malignancy is particularly common as the portal of entry, often with a clinical presentation of diverticulitis. A clinical curiosity which remains unexplained is that although portal vein bacteremia is common in patients with inflammatory bowel disease, hepatic abscess is uncommon.

Hepatic arterial infection

Two subcategories of liver abscess should be considered. Systemic bacteremias may occasionally seed the liver, resulting in either macro-scopic abscesses (usually in the setting of some form of antimicrobial therapy that permits the individual to survive, although not to be cured of the systemic process) or, more commonly, miliary microabscesses. Typically, these infections occur in children with such underlying conditions as chronic granulomatous disease, leukemia, or other disturbances of granulocyte number or function, and are caused by such organisms as Staphylococcus aureus. In other patients the primary process affecting the hepatic artery is thrombosis, with hepatic injury then becoming superinfected with micro-organisms of local or systemic origin. With the increasing prevalence of liver transplantation, particularly in young children in whom the hepatic arterial anastomosis is especially vulnerable, this entity is becoming more common.

In recent years there have been increasing attempts to embolize hepatic tumors as part of treatment programs. Secondary infection of the resulting infarcted tumor and surrounding tissue can occur.

Post-traumatic

Both penetrating and non-penetrating trauma to the liver can result in liver abscess formation. The common denominator is hepatic necrosis, intrahepatic hemorrhage, and intraparenchymal bile extravasation. Such areas of devitalized tissue commonly become infected, even if they are initially sterile, resulting in macroscopic abscesses. Prevention of this form of hepatic abscess is dependent upon an aggressive surgical approach to devitalized hepatic tissue, wide excision of such necrotic tissue being essential.

Direct extension of infection

Contiguous sites of infection involving the gallbladder, subphrenic space, or pleural space and disease processes in which gallbladder, gastric, or intestinal perforation occur directly into the liver can result in macroscopic hepatic abscesses. Malignancy is commonly found in these tissues as the cause of the perforation that results in liver abscess formation.

Miscellaneous causes

The etiology of the liver abscess remains obscure in about 5 per cent of patients, even after extensive evaluation. Presumably, a minor injury to the liver renders such individuals susceptible to seeding by a transient bacteremia. Other unusual causes of liver disease, such as cysts (including polycystic liver disease), intrahepatic malignancy (including hepatic injury from cryosurgery of tumors), amebic abscesses, and hydatid disease, may become secondarily infected, resulting in a pyogenic liver abscess. The common denominator, as in the post-traumatic cases, is the microbial seeding of a locus minoris resistentiae within the liver.

Bacteriology

The majority of the organisms that invade the liver to cause hepatic abscesses are derived from the gastrointestinal tract: gastrointestinal flora account for more than 75 per cent of these abscesses. Polymicrobial infection occurs in 22 to 64 per cent of cases, usually involving both facultative and anaerobic flora of gastrointestinal origin. Escherichia coli is the most common facultative organism isolated from liver abscesses, being demonstrated in specimens from 35 to 45 per cent of patients, with Klebsiella pneumoniae being the second most frequent isolate in this category. In general, infection with K. pneumoniae tends to be more severe, be associated with gas formation in the involved liver or portal vein, have concomitant infection at such sites as the eye (endophthalmitis), and be particularly common in diabetic individuals. Other facultative or aerobic Gram-negative bacteria, including Proteus spp., Enterobacter cloacae, Citrobacter spp., Pseudomonas aeruginosa, Morganella morganii, Serratia marsecens, and Acinetobacter and Eikenella spp. may also be isolated, usually in association with other gut flora. These are particularly common in patients with biliary tract disease.

Anaerobic and microaerophilic organisms, either alone or in conjunction with aerobic organisms, are isolated from up to 60 per cent of pyogenic liver abscesses. Bacteroides fragilis (particularly sp. fragilis) is the most common anaerobe isolated, but such others as other Bacteroides spp., Fusobacterium spp., anaerobic streptococci, Clostridium spp., and Actinomyces spp. may be found on occasion. An important group of organisms are the microaerophilic streptococci, particularly Streptococcus milleri. If appropriate microbiologic techniques are employed (especially the provision of an environment enriched with carbon dioxide), microaerophilic streptococci may be found to be the most common causes of pyogenic liver abscess. S. milleri is especially virulent and likely to cause suppuration of the liver and other organs, even in the absence of the usual predisposing anatomic abnormalities commonly associated with hepatic abscess formation.

Other Gram-positive organisms account for less than 25 per cent of isolates. Staphylococcus aureus and group A streptococci occur most commonly after trauma and in children with the previously delineated granulocyte disorders. Seeding of the liver in these individuals usually is secondary to a systemic bacteremia.

Focal candidal infection of the liver and/or spleen has been reported in an increasing number and variety of patients, most notably in those undergoing chemotherapy for leukemia or liver transplantation. In the patient with leukemia, in particular, a subacute-chronic entity that has been termed hepatosplenic candidiasis has been defined. This is characterized by persistent fevers and macroscopic abscesses due to Candida spp., most notably C. albicans and C. tropicalis. This process is usually initiated when the patient is neutropenic due to chemotherapy, presumably due to the entrance of the yeast into the portal vein through gut mucosal ulcerations induced by the chemotherapy; alternatively, systemic candidemia from infected intravascular access devices could have the same result. The abscesses and the clinical symptoms persist even after hematological remission has been achieved, and require prolonged antifungal therapy.

A variety of organisms, once they reach the bloodstream, can seed the liver, becoming unusual causes of hepatic abscess. The most frequent are those whose portal of entry is the gastrointestinal tract, most commonly Salmonella spp., but also including Yersinia enterocolitica, Campylobacter jejuni, Listeria monocytogenes, and, rarely, Brucella spp. Rarely, mycobacterial infection can present as a liver abscess. Finally, it is important to point out that in developing areas of the world, such parasitic infections as schistosomiasis, ascariasis, and toxocariasis can cause liver injury sufficient to enhance the localization of bacteria, and increase the risk of liver abscess.

Clinical presentation

Patients with microscopic liver abscesses usually have an acutely septic clinical presentation, with fever, rigors, and, not uncommonly, hypotension, as well as right upper quadrant discomfort that can be quite severe. Other manifestations depend upon the underlying condition producing the microabscesses: rapidly progressing jaundice in the presence of biliary tract disease, congestive heart failure if the systemic sepsis is associated with endocarditis.

In contrast, the clinical presentation of macroscopic liver abscesses is more subacute, developing over several days to weeks, with fever, night sweats, anorexia, weight loss, and malaise far more common than rigors and hypotension. Fever is present in 90 per cent of these patients with macroscopic liver abscesses; nausea, vomiting, and abdominal pain occur in 50 to 75 per cent; and symptoms such as pleurisy, diarrhea, dyspnea, and cough are seen in 5 to 25 per cent of patients. Uncommonly, intra-abdominal rupture of the liver abscess will occur, transforming the illness into an acute one, characterized by manifestations of septic shock, peritonitis, and increasing jaundice.

Other than fever, abdominal tenderness, usually localized to the right upper quadrant, is the most common physical finding, being demonstrable in 50 to 75 per cent of affected individuals. Hepatomegaly is demonstrable in approximately 50 per cent of patients with macroscopic liver abscesses. Jaundice is uncommon, unless biliary obstruction is present.

Almost all patients with pyogenic hepatic abscesses have abnormal hematologic and liver function tests. Leukocytosis, usually of a moderate extent, is noted in 70 to 80 per cent, an elevated erythrocyte sedimentation rate in at least 90 per cent, and anemia in 50 to 65 per cent of patients with liver abscess. The most characteristic liver function test abnormality observed in patients with hepatic abscess is an elevated alkaline phosphatase level, which is observed in more than 75 per cent of these individuals. An elevated serum bilirubin level is seen in 40 per cent of patients, with elevated aminotransferases being found in approximately 30 per cent. Other abnormalities that are not uncommon include a prolonged prothrombin time and a raised serum vitamin B12 level. Laboratory abnormalities associated with a poor prognosis include an elevated bilirubin and a serum albumin level of 2 g/dl or less.

Positive blood cultures are obtained in approximately 50 per cent of all patients. Although up to 65 per cent of abscesses are polymicrobial when aspirated pus is cultured from the liver, it is unusual to retrieve more than one organism from the blood cultures.

Chest radiographs are abnormal in about 50 per cent of patients, usually because the inflammatory process within the liver impinges on the diaphragm, producing a variety of 'sympathetic' responses. These include a right-sided pleural effusion, right lower lobe atelectasis and pneumonitis, and elevation of the right hemidiaphragm. Occasionally, if a gas-forming organism is present in the abscess, air-fluid levels are discernible on chest or abdominal radiographs. Rarely, a liver abscess presents by discharging itself into the chest, with both clinical symptoms (cough, chest pain, hemoptysis, dyspnea) and chest radiographic appearances which reflect this.

Diagnostic evaluation

Clinical suspicion of a liver abscess (either pyogenic or amebic) is aroused when a patient has fever, right upper quadrant abdominal pain and tenderness, and abnormal liver function tests. The differential diagnosis includes acute cholecystitis, cholangitis, subphrenic or subhepatic abscess, malignancy, and hepatitis.

Fig. 1 Diagnostic scheme for suspected liver abscess.

Ultrasonography is the initial procedure of choice to assess a suspected liver abscess because it is non-invasive, 80 to 90 per cent accurate, and capable of delineating liver lesions as small as 2 cm in diameter. Ultrasound is more useful than computed tomography (CT) for distinguishing solid masses from cystic lesions. However, ultrasonography may miss lesions in the dome of the right liver lobe or multiple microscopic abscesses. Fatty infiltration can produce an echogenic liver, making detection of small abscesses difficult. Although some features of amebic abscesses differ on ultrasound from those of pyogenic origin, the differences are not sufficient to permit a specific diagnosis.

Abdominal CT can detect intrahepatic collections as small as 0.5 cm in diameter and can be particularly useful in identifying multiple small abscesses or abscesses located near the hemidiaphragm. The diagnostic accuracy of CT is 90 to 95 per cent. Another advantage of CT is that it may identify other abdominal pathology responsible for the pyogenic liver abscess.

Although radionuclide scans of the liver have a sensitivity comparable with that of ultrasonography in detecting liver abscesses, nuclide scans have largely been replaced by ultrasonography and by CT, at least in part because either sonography or CT allows the clinician to proceed directly to percutaneous aspiration for either diagnosis or therapy. Any material obtained by aspiration should be examined microscopically after Gram staining, cultured aerobically and anaerobically, and, if there is any suspicion clinically or epidemiologically, submitted for examination for Entamoeba histolytica trophozoites. Fungal and mycobacterial cultures should also be carried out, particularly in immunosuppressed patients.

Treatment

The traditional approach to the therapy of pyogenic liver abscesses has been open surgical drainage of the abscess, correction, whenever possible, of the underlying pathology that led to the abscess, and a 4- to 6-week course of parenteral antibiotics. Such antibiotics have usually included a b-lactam, an aminoglycoside, and either metronidazole or clindamycin (aimed at the anaerobic organisms), but treatment could be modified on the basis of microbiologic results. In recent years, such drugs as pipercillin-tazobactam, imipenem, and meropenem have largely replaced aminoglycosides in the therapy of these patients. Over the past decade, the majority of patients with macroscopic pyogenic abscesses have been managed with antibiotics and percutaneous drainage, thus avoiding more surgery in typically debilitated patients. Recently, laparoscopic drainage has been introduced as a 'middle level' alternative to open surgery for those patients not amenable to percutaneous drainage.

Fig. 2 Treatment of pyogenic liver abscesses.

Percutaneous drainage is carried out under CT or ultrasound guidance, with the insertion of a pigtail catheter using the Seldinger technique. Samples are then withdrawn for microbiologic examination, the abscess cavity is gently irrigated with saline, and the catheter is left in place to provide continuing drainage. More than one catheter may need to be placed to provide complete drainage. Such percutaneous aspiration and drainage does not correct the problem in 10 to 30 per cent of patients, and open drainage is then necessary. Failure to achieve drainage may be due to poor catheter placement, the presence of a multiloculated abscess, excessive viscosity of the abscess contents causing plugging of the drainage catheters, thick abscess walls that do not collapse with drainage, and inadequate anatomic localization of the abscess. Follow-up ultrasonography or CT scanning is necessary to ensure complete resolution of the process.

Percutaneous drainage is less likely to be of value when there are multiple abscesses, a known intra-abdominal source of infection that requires surgical correction, an abscess of unknown cause, ascites, or when the abscess requires a transpleural drainage route.

Patients with biliary tract disease, diverticulitis, and appendicitis as the source for their liver abscesses are better treated with open surgical drainage, than by percutaneous drainage. Guidelines other than those mentioned to recommend percutaneous or an open surgical approach to these patients are still being formulated.

Mortality rates of patients with macroscopic liver abscesses reported in the 1960s and early 1970s were 65 to 79 per cent. Recent studies have noted a marked improvement, with mortality rates being as low as 11 per cent. Such improvement is due to the widespread availability of ultrasonography and CT scanning and hence earlier diagnosis, and the utility of the percutaneous approach to drainage, especially in debilitated patients, who tolerate conventional surgery poorly. The major determinants of mortality are the nature of the underlying process causing the abscess, the anatomy of the intrahepatic infection, and the presence or absence of such comorbidity factors as cancer, diabetes, heart disease, and renal failure.

Amebic abscesses

Epidemiology

Entamoeba histolytica infection affects an estimated 10 per cent of the world's population, with the great majority of such infections occurring in people living in sub-Saharan Africa, the Indian subcontinent, Asia, and parts of Central and South America. In these endemic areas approximately 50 per cent of the population is infected, with 90 per cent or more being asymptomatic cyst passers. In more developed countries, amebic infection occurs predominantly in immigrants or travelers returning from endemic areas, in sexually active male homosexuals, in residents of Indian reservations, and in people institutionalized for mental or emotional disability. The common denominator in these last groups is an increased opportunity for person-to-person spread via the fecal-oral route.

Amebic liver abscess occurs in less than 10 per cent of individuals infected with this organism. Whereas amebic infection of the liver is far less common than is pyogenic infection in the United States, in other areas of the world such as India, amebic abscesses are three to five times as frequent as pyogenic liver abscesses. The average age of patients with amebic liver abscess is between 28 and 48 years, which is significantly younger than patients with pyogenic infection. Although infection rates are similar in men and women, there is a striking male predominance (up to 20:1) in patients who develop hepatic abscesses from amebiasis. Particularly severe invasive disease occurs in patients with compromised cellular immunity, in young infants, in the malnourished, in pregnant women, andin patients receiving corticosteroids.

Etiology and pathogenesis

Amebiasis is initiated by the ingestion of E. histolytica cysts. Once these cysts reach the small intestine, motile trophozoites are released and migrate to the colon, where they proliferate along with the resident bacterial flora. It is now apparent that the E. histolytica complex is made up of two distinct species: E. histolytica, which is capable of invading the colonic mucosa and causing extraintestinal disease; and E. dispar, which remains a gut commensal, neither invading nor causing extraintestinal manifestations. E. histolytica differs strikingly from E. dispar: genetically, resistance to complement-mediated lysis, and the presence of cysteine proteinases, which are essential for virulence. Other important determinants of invasiveness probably include diet, the constituents of the bacterial flora of the gut, and both humoral and cell-mediated host resistance.

Once intestinal infection is established, amebas may be carried to the liver via the portal vein. The ability to adhere to endothelial cells, and to bind to laminin, a component of the extracellular matrix, is an important virulence factor in the pathogensis of an amebic liver abscess. Within the liver these organisms multiply and block small intrahepatic portal radicles, causing focal infarction of hepatocytes. A proteolytic enzyme produced by the invading trophozoites causes coalescence of the invaded areas and abscess formation. Necrosis rather than apoptosis appears to be the primary form of liver injury induced, and polymorphonuclear leukocytes are the first line of host defense. Some authorities differentiate between so-called amebic hepatitis and amebic hepatic abscess, depending upon whether or not a macroscopic abscess has formed. We regard this differentiation as a difficult one, as this process might best be regarded as a continuum rather than as two separate entities.

At the time of clinical presentation, approximately 80 per cent of amebic liver abscesses are solitary; 83 per cent of them are located in the right lobe of the liver, characteristically high in the dome subjacent to the diaphragm. The propensity for this site reflects the fact that venous return from the right side of the colon (amebic infection having a particular impact on the cecum and right colon) into the portal vein is predominantly delivered to the right lobe of the liver. The juxtaposition of these abscesses to the diaphragm explain the common occurrence of thoracic symptoms in these patients. Discharge of amebic hepatic abscesses into the subphrenic, pleural, and even into pericardial spaces is not uncommon, with frank rupture into the lung as an uncommon complication.

Amebic abscesses can become extremely large, containing several liters of fluid that is classically described as 'anchovy sauce' but may be yellow or green. This fluid is primarily necrotic liver tissue and blood, with a paucity of inflammatory cells unless bacterial superinfection has occurred. Because bile appears to have a deleterious effect on amebas, infection of the gallbladder and bile ducts does not occur.

Clinical presentation

Amebic liver abscess has a more subacute presentation than that of pyogenic liver abscess in the majority of patients. Symptoms typically evolve over a few weeks to months (as opposed to several days to weeks for a pyogenic process) before medical attention is sought. Initial symptoms are non-specific: fever, anorexia, night sweats, malaise, nausea and vomiting, and weight loss. As the disease becomes established, right upper quadrant abdominal pain becomes a dominating symptom in at least two-thirds of these patients. Approximately 25 per cent of patients exhibit thoracic symptoms, such as pleurisy, non-productive cough, right shoulder pain, and/or hiccups as an important part of the symptom complex. Characteristically, simultaneous intestinal complaints such as dysentery or diarrhea are not present. Uncommonly, patients may have a more fulminant presentation, suggesting an acute abdominal surgical emergency.

The patients typically appear chronically ill, with fever, abdominal tenderness, and hepatomegaly. Chest findings (rales, decreased breath sounds, dullness to percussion, impaired diaphragmatic movement) are observed in 50 per cent of patients. Jaundice is rare (less than 15 per cent of individuals).

Anemia and an elevated erythrocyte sedimentation rate are present in at least 80 per cent of patients, as well as a moderate leukocytosis in 60 to 75 per cent. More extreme white blood cell responses suggest the presence of bacterial superinfection. Eosinophilia is not observed in patients with amebic liver abscesses; if present, another explanation should be sought. Normal liver function tests do not exclude the diagnosis of an amebic abscess, although slight to moderate elevations of the alkaline phosphatase, reduction in the serum albumin, and minimal changes in aminotransferase values are generally observed.

Immune complex glomerulonephritis has been reported in the setting of an amebic liver abscess. Prognostic factors connoting a high risk for mortality include size of abscess, the presence of multiple abscesses, a bilirubin level of more than 3.5 mg/dl, and hypoalbuminuria (serum albumin less than 2.0 g/dl). Positive blood cultures are obtained in up to 20 per cent of patients with amebic abscess with secondary bacterial infection. Aspirated abscess fluid may also be culture positive for bacteria. Stool examination may reveal trophozoites or cysts in up to 25 per cent of patients.

The typical location of an amebic abscess in the dome of the right lobe of the liver produces not only thoracic symptoms, but also abnormalities on chest radiograph: an elevated right hemidiaphragm, pleural effusion, and atelectasis are the most common. Uncommonly a bronchohepatic fistula develops, with the characteristic expectoration of sputum that resembles 'anchovy sauce'. Left hepatic lobe abscesses can produce not only left-sided pleuropulmonary signs and symptoms, but also can rupture into the pericardium, producing tamponade and/or mediastinal infection.

Diagnostic evaluation

In areas of the world free of endemic amebiasis, serologic testing is extremely useful in evaluating the patient for an amebic liver abscess (Fig. 1). The indirect hemagglutination test is positive in 90 to 95 per cent of patients with an amebic abscess, and in areas of low prevalence a positive result strongly suggests the presence of acute infection. False-negative tests are usually obtained early in the disease course. Levels of hemagglutinating antibodies remain elevated for many years after an episode of invasive disease, and the indirect hemagglutination test is therefore less useful in diagnosing acute disease in endemic regions, where 50 per cent of the general population may be seropositive. Newer ELISA assays appear to be at least as sensitive and specific. Levels of antibodies detectable by counterimmunoelectrophoresis and indirect immunofluorescence usually become undetectable within 6 months of acute infection; they may be more useful in evaluating patients in endemic areas.

Since amebic abscesses, unlike most pyogenic liver abscesses, respond to antimicrobial therapy without drainage, a non-invasive approach to diagnosing amebic infection is needed. In the patient with subacute disease in whom the problem is a diagnostic dilemma rather than a therapeutic emergency, amebic serology should be performed and a therapeutic trial is initiated if the patient has an appropriate epidemiologic history. If the patient is unstable, if there is reason to suspect a pyogenic component to the illness on the basis of clinical or epidemiologic findings, if the amebic serology is negative, or if the patient has failed to respond clinically to several days of antiamebic therapy, a percutaneous needle aspiration should be performed.

Treatment

Most amebic abscesses are cured with a regimen of metronidazole 750 mg orally or intravenously three times per day, for 10 days, followed by treatment with an agent that is effective in eradicating the cysts which may persist in the intestine after treatment with metronidazole. Agents effective in the treatment of such luminal disease include iodoquinol 650 mg orally, three times per day, for 20 days; diloxanide furoate 500 mg orally, three times per day, for 10 days; or paramomycin 25 to 30 mg/kg per day orally, in three divided doses, for 7 days.

Fig. 3 Treatment of amebic liver abscesses. *Luminal agents include: iodoquinol 650 mg orally, thrice daily, for 20 days; diloxanide furoate 500 mg orally, thrice daily, for 10 days; or paramomycin 25 to 30 mg/kg per day orally, in three divided doses, for 7 days. +Other indications for percutaneous drainage are abscess in the left lobe of the liver and a possible large abscess. Indications for open surgical drainage are perforation to peritoneum, possible bacterial superinfection, and if the diagnosis is uncertain and percutaneous drainage is impossible.

Most patients show a prompt therapeutic response to metronidazole, with defervescence and decreased abdominal pain within 3 or 4 days. This response is useful for differentiating amebic and pyogenic abscesses in situations where serologic testing is unavailable or uninterpretable. Fewer than 10 per cent of patients with amebic liver abscess fail to respond to metronidazole therapy. Treatment in the non-responders is with dihydroemetine (1 to 1.5 mg/kg per day, maximum dose 90 mg/day, intramuscularly for 5 days) plus chloroquine phosphate (600 mg base/day for 2 days, followed by 300 mg of chloroquine base orally daily for 2 to 3 weeks). This regimen should be followed by treatment with an agent active against luminal disease.

Considerable controversy surrounds the role of percutaneous drainage in the management of amebic liver abscesses. Proposed indications for such drainage include liver abscesses in the left lobe of the liver, because of the risk of rupture into the pericardial sac; drainage of large abscesses to facilitate more rapid healing with chemotherapy; and lack of response to metronidazole therapy. However, because of the risk of introducing bacteria during catheter drainage, we reserve a drainage procedure for patients in whom the differentiation between pyogenic and amebic infection is unclear, for acutely ill patients, for patients who have failed to respond to therapy, and for patients whose infection has spread into adjoining structures.

Treatment of an amebic hepatic abscess is usually successful, mortality being associated only with delayed diagnosis or complications such as bacterial superinfection, or rupture into adjoining structures.

30.4 Cancers of the liver

George W. Daneker Jr and Mark S. Talamonti

Introduction

The liver is a common site for the development of primary malignancies as well as a favorite target organ for metastatic cancers. Despite its common involvement by cancers, the liver has remained a formidable object of respect to surgeons. Some apprehension in dealing with the liver undoubtedly stems from our earliest references to hepatic surgery. Prometheus, who incurred the wrath of Zeus following his creation of men from clay and the theft of fire, was chained to a rock and underwent daily hepatectomy by a vulture. Although this ritual was described as torture, Prometheus showed that the liver has amazing regenerative powers and could be a beneficial object of surgical attention. The modern era of liver surgery began in 1888 when Langenbuch performed the first left hepatic lobectomy. Tiffany was credited with performance of the first liver resection for a solid tumor 2 years later. Since that time, the surgical treatment of liver cancers, including resection and transplantation, has become commonplace and can be performed with low morbidity and mortality.

The emergence of successful treatments for cancers of the liver has resulted from improvements in imaging and tumor staging, in surgical techniques as a result of a better understanding of hepatic anatomy, in anesthesia and critical care, and in the ability to assess hepatic tolerance and maximize hepatic reserve. Selection of the appropriate therapy in each clinical situation is based on a sound understanding of the biologic behavior of the tumor, familiarity with the indications for and limitations of each therapeutic modality, and a thorough knowledge of hepatic anatomy.

Surgeons have long had a predominant role in the management of liver cancers. This position is a result of two factors: (i) surgery, including transplantation, is the sole modality that can produce a long-term disease-free survival or cure from primary and metastatic liver cancers; and (ii) surgeons have had a discriminating appreciation for the appropriate treatment modality, even non-surgical, due to their understanding of hepatic anatomy and procedural morbidity and mortality. At the present time, we are witnessing a proliferation of new treatments. While some treatments are surgical, the majority are not, and are primarily under the control of our non-surgical colleagues. In order to maintain our influence on the treatment of liver cancers, it is essential that we remain fully informed of all the latest developments. Equally important, we should then critically assess and integrate promising treatments, including non-surgical, into the overall multimodality management of liver cancers. An essential component of this integration is our participation in clinical trials. In this way, we can maintain our role as experts in the overall treatment of patients with liver cancers, not just experts on surgery for liver cancers.

Anatomy

A thorough knowledge of anatomy is essential for the hepatic surgeon. Armed with this knowledge, intelligent decisions can be made about resectability, surgical planning, and operative conduct. Modern hepatic surgery should be efficient, controlled, and with limited blood loss. Failure to adhere to anatomic principles portends an opportunity for massive blood loss and a poor surgical outcome.

The liver, which is the largest gland in the body, principally occupies the right subcostal and epigastric regions with an extension into the left subcostal region and the right lumbar region. The liver lies directly beneath diaphragm and is hidden behind a cage of ribs over the majority of its anteriolateral surface. A small portion of the liver's anterior surface is in contact with the anterior abdominal wall. Only that portion of the anterior surface of the liver is normally palpable, the remainder the liver is hidden behind its protective rib cage and away from the inquiring hand.

The anteriosuperior surface of the liver is convex and shaped by the overlying diaphragm. In a similar fashion, the inferior surface of the liver is imprinted by and conforms to the surrounding intra-abdominal organs. The liver's inferior surface is covered by a peritoneal continuation of the gastrohepatic omentum. The peritoneum envelops the liver and extends from the anterior, anteriosuperior, and lateral surfaces to reflect on to the diaphragm. This hepatic envelope, which is reinforced with fibrous tissue, is called Glisson's capsule. The reflections of Glisson's capsule off the liver and on to the diaphragm leave most of the posterior surface of the right lobe and a strip of the posterior surface of the left lobe in direct contact with the diaphragm. This 'bare area' of the liver is contained within these peritoneal reflections, called coronary ligaments, and the lateral fusion of the coronary ligaments called triangular ligaments. Of importance, the inferior vena cava and hepatic veins are fully contained within the bare area. The liver's lateral surface lies beneath the costal margin at the midaxillary line and is covered by a portion of the thoracic wall comprised of the seventh to eleventh ribs.

The liver is functionally divided into lobes, sectors, and segments based on the arterial and portal venous blood supply, hepatic venous drainage, and biliary drainage. The main anatomic division of the liver is into the right and left lobe. Branching of the proper hepatic artery, portal vein, and common bile duct into major right and left branches define each lobe. The division between these lobes follows a plane running vertically, through the liver, connecting the anterior border of the gallbladder fossa to the left side of the inferior vena cava posteriorly. This plane is known by an eponym as 'Cantlie's line'.

Fig. 1 Overview of intrahepatic vascular and biliary anatomy.

The right and left lobes can be further subdivided into sectors based on the distribution of portal pedicles and hepatic veins. Using a plane of division along each of the three main hepatic veins, the liver is divided into four sectors, known as the right anterior, right posterior, left medial, and left lateral sectors. Each sector is supplied by a vascular and biliary pedicle comprised of the major lobar hepatic artery branch, portal vein branch, and bile duct branch. No clear topographic features or morphologic boundaries exist between the sectors in the right lobe. Within the left lobe, the umbilical fissure and falciform ligament defines a plane of division between the medial and lateral sectors.

Fig. 2 Sectoral anatomy of the liver

Each hepatic sector can be further subdivided into numbered segments as described by Couinaud. This segmentation is one step further beyond the division of liver into sectors and is based on the bifurcation of portal pedicles within the sectors. The liver's segmental anatomy can be remembered as follows: in a clockwise fashion beginning at the vena cava (12 o'clock) are segments 2, 3, and 4, which comprise the left lobe of the liver. Segment 4, the portion of liver between the falciform ligament and Cantlie's line, can be further divided into a superior half (segment 4a) and an inferior half (segment 4b). Continuing clockwise, the right lobe comprises segments 5, 6, 7, and 8. No clear boundaries exist between the segments of the right lobe. The caudate lobe is assigned segment 1 by this system. The caudate lobe is considered an autonomous segment from the standpoint of functional anatomy. It receives branches from both hepatic arteries and portal veins, although the majority of its blood supply comes from the left. Its venous drainage is not into a hepatic vein but rather through a variable number of bridging veins directly into the inferior vena cava.

Fig. 3 Segmental anatomy of the liver (after Couinaud).

The common bile duct branches into the main right and left hepatic ducts on the right side of the liver hilum, anterior to the portal vein bifurcation, and overlying the origin of the right main portal trunk. The right hepatic duct is short and ascends into the parenchyma after the bifurcation. In 28 per cent of cases, one of the main right segmental ducts crosses to join the main left hepatic duct. Due to its length, orientation, and the variable anatomy of the biliary tree, the right duct is more vulnerable to injury then the more horizontally oriented left duct.

The hepatic veins arise from the inferior vena cava as it emerges from the liver immediately below the diaphragm. The suprahepatic inferior vena cava has a very short course before it passes through the diaphragm into the chest. In a similar fashion, the hepatic veins have a short extrahepatic course before they enter the liver. The right hepatic vein is usually single (61 per cent) and drains the anterior and posterior sectors of the right lobe. In 61 per cent of patients there are an additional one or two large veins draining from the posterior or posterioinferior right lobe directly into the inferior vena cava. The middle hepatic vein runs along Cantlie's line and drains the right anterior and left medial sector. The left hepatic vein drains the left lateral sector and a small portion of the left medial sector. In 84 per cent of patients the left and middle hepatic veins arise from a common trunk. The bifurcation of this common trunk usually occurs near its origin from the vena cava and makes extrahepatic division of both the left and middle hepatic veins potentially hazardous.

Physiology

The hepatic surgeon must remain cognizant of the liver's normal and pathophysiologic functions. This information is not just of academic interest, but is also practically important because the sequelae of hepatic dysfunction must be addressed during the perioperative evaluation and management, particularly for patients with chronic liver diseases. A more in-depth discussion of hepatic function is not within the scope of this chapter and the reader is referred to other sources for that information.

In contrast to its relatively formless and bland appearance, the liver is amazing in its performance of a plethora of critical functions. Underscoring this claim is the fact that the liver constitutes only 5 per cent of the total body weight but expends approximately 20 per cent of the body's energy and consumes up to 25 per cent of the body's total oxygen.

In general, the liver's main functions include anabolic and catabolic metabolism, vitamin and mineral storage, reticuloendothelial clearance, and maintenance of plasma volume and electrolyte concentrations. Within the context of anabolic function, the liver is responsible for synthesis of a number of integral proteins including serum albumin and a-globulin. In addition, the liver synthesizes 11 proteins critical for hemostasis involving both the intrinsic and extrinsic coagulation pathways. Additional critical anabolic functions include maintenance of serum glucose by glycogenolysis and gluconeogenesis, as well as lipoprotein and cholesterol metabolism. The liver has a key role in the metabolism of vitamins A, B, C, D, E, and K. Among the most significant vitamin deficiency syndromes associated with hepatic dysfunction is coagulopathy resulting from vitamin K deficiency. In addition to its effects on the extrinsic pathway, chronic liver disease may produce coagulopathy due to insufficient absorption of vitamin K as a result of bile salt deficiency.

The liver also has a primary role in the metabolism and detoxification of drugs and other metabolic by-products. Drug catabolism occurs principally by the cytochrome P-450 system. The most significant metabolic by-product produced by the liver is bilirubin, a breakdown product of hemoglobin that is excreted almost entirely in the bile.

The liver can perform immunologic functions by means of the fixed reticuloendothelial Kupffer cells as well as through the activities of the sinusoidal endothelial cells.

Among the amazing synthetic functions of the liver is its regeneration after partial hepatectomy. The liver can routinely reconstitute its normal mass following a hepatectomy of up to 75 per cent, provided the regenerating parenchyma is normal. In humans, the time-frame for complete regeneration is from weeks to several months. Studies have shown that hepatic regeneration results from a combination of compensatory hypertrophy and hyperplasia of the cells within the hepatic remnant. A number of growth factors are involved, but the exact role of these growth factors is not well known. The anatomy of regeneration is such that the new parenchyma expands and deforms the residual liver. After a right hepatectomy, the regenerated liver is centered to the left near the epigastrium. After a left hepatectomy, the bulk of the regenerative liver is in the right subcostal region. The physiologic importance of regeneration is the reserve it supplies after a cancer is resected. As a neoplasm grows, it displaces the normal liver tissue but does not destroy it. In the unlikely event that parenchyma is damaged by the neoplasm, regeneration can compensate. Enormous neoplasms can therefore be removed from the liver with little compromise of the hepatic mass.

Patient evaluation

Clinical

Routinely, all patients seen for evaluation of a primary or metastatic liver tumor undergo an initial complete history and physical examination. The history and physical examination are important for two reasons: an evaluation of the patient's general health and comorbid conditions which impact on the choice of proposed treatment, and the initial clinical staging of the patient with preliminary selection of the appropriate treatment option(s). Although simple, these evaluations are important because the detection of advanced comorbid disease, such as cirrhosis, or more extensive tumor spread, usually extrahepatic metastases, will often eliminate the patient from further consideration of surgery as the principal therapy.

Laboratory

Patients presenting with a liver tumor should also have blood taken for laboratory studies. These studies should include a complete blood count, platelet count, serum electrolytes, and 'liver function tests'. The 'liver function tests' should include aminotransferases, alkaline phosphatase, bilirubin, and lactate dehydrogenase; these studies will provide information as to the overall health of the liver. In addition to these classic liver function tests, measurement of the albumin level, prothrombin time, and partial thromboplastin time are included. These tests are important because they reflect hepatic synthetic function. In patients with primary liver tumors or a history of hepatitis, levels of anti-hepatitis B antibody, hepatitis B surface antigen, and anti-hepatitis C antibody should be measured. If these hepatitis B and C screening studies are positive, they should be confirmed by quantitative assessment of viral DNA or RNA by polymerase chain reaction.

Tumor markers

Tumor cells may also synthesize and secrete substances, usually glycoproteins, which can be clinically useful in screening for the tumor, or for monitoring tumor status following treatment. In the case of primary and metastatic liver tumors, the markers a-fetoprotein and carcinoembryonic antigen are the most useful.

Measurement of a-fetoprotein levels (normal range 1 to 10 ng/ml) has been used extensively in the management of hepatocellular carcinoma. Despite its widespread use, this test is beset with both false-positive and false-negative results. At present, elevation of serum a-fetoprotein has a sensitivity of 68 per cent and a specificity of only 20 per cent in detecting small early hepatocellular carcinomas (less than 3 cm in diameter). Even with these limitations, measurement of a-fetoprotein remains an essential component of screening high-risk patients for hepatocellular carcinoma. Currently, the recommendations are for measurement of serum a-fetoprotein levels every 4 months, along with trans-abdominal hepatic ultrasound every 16 months in patients with chronic viral hepatitis, especially those with established cirrhosis. Overall, elevation of a-fetoprotein above normal has a true-positive rate of 80 per cent and a false-negative rate of 20 per cent, when all hepatocellular carcinomas are taken into consideration. False-negative elevations of a-fetoprotein usually result from chronic active hepatitis or cirrhosis. If the cut-off for an abnormally elevated a-fetoprotein is raised to 500 ng/ml, the sensitivity is decreased to 60 per cent but specificity for hepatocellular carcinoma is increased to 100 per cent. In addition, a sharp steady rise in serum a-fetoprotein levels is highly diagnostic for hepatocellular carcinoma. As with most tumor markers, rising a-fetoprotein levels after definitive treatment are usually a sensitive indicator of recurrence, provided that the primary tumor could secrete a-fetoprotein. Another tumor marker useful in hepatocellular carcinoma is abnormal prothrombin or PIVKA-II. Because PIVKA-II levels are elevated in 65 per cent of patients with hepatocellular carcinoma, and can be elevated when a-fetoprotein levels are normal, this marker may be useful for diagnosis and monitoring of therapy in patients with normal serum a-fetoprotein levels.

Carcinoembryonic antigen (normal range 1 to 5 ng/ml) is one of the longest known and most extensively studied of all the tumor markers. Since most (65 to 90 per cent) colorectal cancers are able to synthesize and secrete carcinoembryonic antigen, the measurement of carcinoembryonic antigen levels is most commonly used in the management of colorectal cancer, even though this antigen may be elevated in other cancers such as breast and lung. Overall, serum carcinoembryonic antigen levels are an indirect reflection of tumor mass, although the threshold for detection of the antigen in the serum is high. This fact is reflected in the finding that up to 25 per cent of early stage tumors (Duke's A and B) have an elevated carcinoembryonic antigen level, while 85 to 90 per cent of patients with hepatic metastases (Duke's D) have elevated antigen levels. In addition, some investigators believe that carcinoembryonic antigen production is associated with a more aggressive biologic behavior and that cells producing this antigen have a greater ability to become both locally invasive and metastatic than cells not producing the antigen.

The high threshold for detection of carcinoembryonic antigen elevation makes it poorly suited for colorectal cancer screening. This antigen's main usefulness is as an initial staging study and, more importantly, as a marker of response to therapy (for both primary colorectal cancer and metastases) and of recurrence following therapy. The serum carcinoembryonic antigen level, collected at the time of an initial evaluation, will give a general indication of prognosis based on the degree of elevation. Many investigators have reported that higher serum levels are associated with an increased incidence of recurrence following treatment, but correlations between specific values and outcome are controversial. The measurement of carcinoembryonic antigen levels is far more helpful in the management of a patient with an elevated level on initial screening, whose level returns to normal following resection of the primary tumor. In this patient, a progressive rise of the antigen level is virtually diagnostic of recurrence and will serve as the first indicator of recurrence in approximately two-thirds of patients. However, on a cautionary note, an isolated elevation in carcinoembryonic antigen may be falsely positive and should be confirmed by an additional two or three measurements at separate times (usually during the following 2 to 3 months). Since serum carcinoembryonic antigen levels are often an indirect reflection of tumor burden, measurement of these levels is an indicator of response to therapy independent of imaging studies. In particular, for those patients undergoing chemotherapy, 90 per cent of those who respond will have a decrease in their carcinoembryonic antigen levels, while 90 per cent of those with progression of their tumor will have increasing levels.

Recently developed tumor markers, which include CA19–9 and CA 125, have also been used in the management of colorectal cancer. Although these markers can be helpful, particularly in patients who are negative for carcinoembryonic antigen, both their sensitivities and specificities are inferior to carcinoembryonic antigen. Because of these factors, plus the easy commercial availability of the test for the carcinoembryonic antigen, routine use of these markers cannot be recommended at this time.

Imaging studies

The importance of imaging studies in the management of patients with liver malignancies cannot be overemphasized. These studies provide the most specific and detailed staging information and are indispensable for clinical decision making. While improvements in the understanding of hepatic anatomy, surgical technique, and perioperative care have made major contributions to the current success of liver-directed therapy, the single most important factor in improved survival is better patient selection due to the accuracy of modern imaging studies.

When used for evaluating the patient contemplated for liver-directed therapy, imaging studies have the following goals: (i) determination of the number and distribution of the liver lesion(s); (ii) anatomic and functional characterization of liver lesion(s); (iii) delineation of the lesion(s) relationship to significant vascular and biliary structures; and (iv) detection of extrahepatic and extra-abdominal tumor.

Nuclear scans

Normal liver tissue contains Kupffer cells, which are able to take up 99Tcm-sulfur colloid, thereby displaying the liver on liver–spleen scans. Tumors, on the other hand, lack Kupffer cells, and are visualized as photopenic defects on liver–spleen scans. Although these differences are theoretically useful, in practicality the details provided by liver–spleen scans are inadequate for staging and this procedure was largely abandoned for staging of the liver with the advent of computed tomography (CT) in the 1980s. For the evaluation of liver lesions, the most commonly used nuclear scan, at present, is the tagged red blood cell scan. The study is used to determine whether a liver lesion, usually detected by another imaging modality, is a hemangioma and contains many tagged red blood cells or a solid lesion with few red blood cells. On tagged red blood cell scans, a hemangioma is imaged as a photodense area in the liver while, in contrast, a tumor is imaged as a photopenic area within the liver.

Ultrasound

Percutaneous ultrasound is the most readily available, least expensive, and least invasive of the imaging modalities for the liver. Unfortunately, the consistency of results from percutaneous ultrasound is limited, in up to 50 per cent of cases, by dependence on operator expertise and the inability to obtain a complete study due to interference from air in the lung or gastrointestinal tract, patient body habitus, and motion artifact. In addition, small tumors, either primary hepatocellular or metastatic carcinoma, can be difficult to detect and differentiate from regenerating nodules in the cirrhotic liver (this can be a difficult problem with CT as well). None the less, percutaneous ultrasound remains the most popular liver screening modality worldwide. The United States is an exception, where an abundance of CT scanners has caused CT to be favored over ultrasound. In the hands of experts, results from percutaneous ultrasound are as accurate as those obtained by CT or magnetic resonance imaging (MRI) with respect to lesion size, distribution, and relationship to intrahepatic anatomy. In addition, greater detail about intratumoral anatomy and tissue characteristics is provided by ultrasound when compared with CT. Percutaneous ultrasound has also had a valuable therapeutic role when used in the ablation of liver lesions, particularly in alcohol ablation for patients with hepatocellular carcinoma. The advantage of ultrasound over CT or other imaging modalities during therapeutic interventions is the real-time information obtained by ultrasound, particularly during placement and positioning of intrahepatic wires or needles.

Intraoperative ultrasound is an invaluable tool for the hepatic surgeon. In this type of ultrasound, the probe is placed directly on the parenchymal surface of the liver following its mobilization. Because the probe is in direct contact with the liver surface, transducers (5 to 10 MHz) with a shorter depth of penetration but capable of displaying greater anatomic detail are used. In general, the higher the transducer frequency the greater the anatomic detail, but at the expense of a reduced depth of penetration. Dedicated intraoperative ultrasound probes are usually small, easily hand-held, and configured in either an 'I' or 'T' shape. During hepatic examination by intraoperative ultrasound, the following information is obtained: definition of portal vascular and biliary anatomy, definition of hepatic vein anatomy, identification of occult and non-palpable tumors, and definition of tumor(s) and its relationship to intrahepatic vascular and biliary anatomy. Once a surgeon has become experienced with the techniques of intraoperative ultrasound, it should become a routine part of any liver procedure. Overall, ultrasound can improve the sensitivity for detection of tumors larger than 1 cm in size to over 95 per cent. Ultrasound findings may alter the planned operation or lead to abandonment of the procedure in up to 30 per cent of patients.

Computed tomography

Since its development in the 1980s, CT has been the most widely used modality for definitive imaging of liver tumors. Initially, CT sensitivity was poor, owing to similarities in density between tumor and the surrounding liver. To overcome this obstacle, techniques were developed that used timed scanning following rapid administration of intravenous contrast. Despite the use of intravenous contrast, the sensitivity for detection of liver metastases by planar CT remained between 40 and 75 per cent. In the 1990s, a major advance in CT technology occurred with the introduction of spiral (helical) CT. This technology allows for continuous data acquisition from rapid uninterrupted scanning during a single breath hold. The helical data set results in improved visualization of the lesion and the ability to reconstruct overlapping images at variable intervals. Studies have shown that an additional 20 per cent of liver lesions could be identified, when compared with planar CT. The greater sensitivity of spiral CT was mostly a result of detecting additional lesions of less than 2 cm. As a result of reduced scan times, newer CT techniques have focused on optimization of the intravenous contrast bolus and timing of image acquisition, so that the arterial and portal venous phase of liver enhancement can be captured. Using this 'biphasic' technique, up to 40 per cent of additional smaller liver lesions may be detected. A further benefit of spiral CT is the ability to merge the overlapping slices retrospectively to produce three-dimensional reconstructions. These reconstructions can be used to image anatomically complex areas, such as the porta hepatis, with more clarity and precision.

Fig. 4( (a) Biphasic spiral CT of the liver showing colorectal metastases. (b) Angiographically assisted CT of the liver showing a colorectal metastasis. (c) MRI of the liver showing colorectal metastases.

The liver is unique in that it receives vascular inflow from both the hepatic artery (30 per cent) and the portal vein (70 per cent), while metastases receive their blood flow almost exclusively from the hepatic artery. Angiographically assisted CT was developed to capitalize on this differential perfusion of liver metastases. In this technique, CT is performed during transcatheter infusion of contrast material into the hepatic artery (CT hepatic angiography) or during portal venous enhancement following infusion of contrast material into the superior mesenteric or splenic artery (CT angioportography). Since its introduction, angiographically assisted CT has consistently demonstrated an 85 to 90 per cent sensitivity for detection of intrahepatic lesions and has become the 'gold standard' imaging study for the assessment and planning of surgical resections. The greater sensitivity of angiographically assisted CT has also primarily resulted from improved detection of lesions less than 2 cm in size. Angiographically assisted CT not only improves lesion detection, but it also very clearly depicts relevant intrahepatic vascular anatomy critical to operative planning. Although it remains the current 'gold standard' study, criticisms of this technique include a high false-positive rate (up to 20 per cent) from benign perfusion defects and more frequent technical problems than CT or MRI. Furthermore, the angiographically assisted CT is an invasive examination with risks and significant expense. An additional important feature is the delineation of hepatic arterial anatomy provided by celiac and superior mesenteric artery angiograms. Angiographically assisted CT still remains the definitive preoperative liver staging study. As spiral CT and MRI technology have improved, the need for angiographically assisted CT has diminished and will, in all likelihood, eventually disappear.

For patients with hepatocellular carcinoma, the contrast agent lipiodol can be delivered during hepatic angiography. Lipiodol, which is an ethiodized oil emulsion, is unique in that it is retained (indefinitely) within tumors but not normal or cirrhotic liver. While useful radiographically, this property of lipiodol can also be exploited for therapeutic purposes. Lipiodol is mixed with chemotherapeutic drugs so that these drugs will have both a higher concentration and duration of action when retained within the tumor (see section below on embolization and chemoembolization).

Magnetic resonance imaging

MRI has not achieved the same widespread popularity as CT for routine imaging of the liver. Historically, this has largely been due to problems with motion artifact, inferior spatial resolution when compared with enhanced CT, and lack of suitable intravenous and intestinal contrast agents for MRI. As MRI technology has improved, in particular with the routine use of higher field strength (1.5 T) magnets, improved gradients, improved pulse sequences, and refinements in motion suppression techniques, many of these criticisms are no longer relevant. Unenhanced hepatic MRI has been shown to have a sensitivity for detection of hepatic lesions that is equal to, or slightly better than, contrast-enhanced CT. MRI does offer excellent delineation of lesion morphology and characteristics as a result of using multiple pulse sequences. In fact, the ability to characterize reliably benign liver lesions, such as cysts or hemangiomas, from malignant lesions is a major advantage of MRI. Also, MRI can depict the relationship of lesions to major vascular structures without the use of contrast agents. Because of rapid technologic advances, differences between various MRI manufacturers, and the continued evolution of pulse sequences, hepatic MRI techniques vary widely between institutions. Despite these differences, a combination of T1- and T2-weighted sequences are routinely used for lesion detection and characterization. The T2-weighted sequences, with tumors appearing hyperintense, appear to be the most efficient for detecting intrahepatic tumor, although the combination of T1- and T2-weighted images usually provides complementary information. In an effort to improve sensitivity for lesion detection, contrast agents for hepatic MRI have been developed. The efficacy of these agents, including gadolinium and ferumoxide, has yet to be shown conclusively; although recent studies have shown the superiority of lesion detection for ferumoxide-enhanced over unenhanced MRI. Despite improvements in hepatic imaging, questions about the ability of MRI to detect extrahepatic tumor still remain. An additional criticism of hepatic MRI stems from the current image quality. Although MRI has continued to improve in clarity with technologic advances, it generally remains inferior to CT with respect to depiction of intrahepatic vascular and biliary anatomy. As noted above, CT holds the current principal role for definitive staging of liver.

Positron emission tomography (PET)

The alteration of biochemical processes within tumors usually precedes their detection by gross anatomic changes. Positron emission tomography is one of the functional modalities that images by exploiting tumor-related biochemical processes, in contrast to the anatomic and structural information provided by most imaging modalities. Because of its emphasis on biochemical changes, PET scanning is theoretically more sensitive than CT or MRI for detection of occult or low-volume cancers. Enhanced glycolysis and glucose retention in tumor cells was first described by Warburg in the 1930s and is the basis for 18F-fluorodeoxyglucose PET imaging in the diagnosis, staging, and follow-up of patients with colorectal cancer. In recurrent colorectal cancer, the presence of extrahepatic metastases has a profound negative impact on surgical curability. The limitations of CT and MRI for detection of extrahepatic tumor recurrence is well recognized and, at best, these studies may detect only 60 per cent of extrahepatic recurrences. In early studies on patients with metastatic colorectal cancer, there was a greater than 90 per cent sensitivity and specificity for detection of both intra- and extrahepatic recurrences by whole-body PET scans. In addition, these studies showed that surgical management was altered in up to 30 per cent of patients according to the findings on PET scan. Before PET can be recommended as a routine part of staging for patients with recurrent colorectal cancer, the impressive results of these series will have to be duplicated. Unfortunately, the widespread use of PET may be limited by the prohibitive costs associated with the production of radiolabeled metabolic substrates.

Diagnostic laparoscopy

Because of the aforementioned limitations of CT and MRI for detection of extrahepatic tumor recurrences, diagnostic laparoscopy has been considered as an initial step in surgical exploration. Small older series have shown that up to one-third of patients with metastatic colorectal cancer or hepatocellular carcinoma will be deemed unresectable by laparoscopy due to the detection of unrecognized intrahepatic tumor spread or peritoneal seeding. Although promising, contributions from the routine use of laparoscopy must be weighed in light of modern CT, MRI, and PET. In addition, adequate laparoscopic staging in the setting of a previous laparotomy may necessitate a time-consuming lysis of adhesions to examine the entire abdomen fully. At present, diagnostic laparoscopy cannot be recommended as a routine staging study in patients with recurrent colorectal cancer or hepatocellular carcinoma.

Primary liver tumors

Hepatocellular carcinoma

Hepatocellular carcinoma is the most common liver malignancy worldwide, causing an estimated one million deaths annually. The geographic distribution of hepatocellular carcinoma shows distinct variation with areas of high, intermediate, and low incidence in the general population. In endemic 'hot spots,' including sub-Saharan Africa, South-East Asia, and southern China, incidence rates may run as high as 150 per 100 000 persons. At the other end of the spectrum, North America, northern Europe, and Australia have incidence rates of less than 2 per 100 000 persons. The high mortality from hepatocellular carcinoma is largely due to both patient presentation at a late stage of the disease and poor hepatic function/reserve resulting from cirrhosis.

Etiology

The two major groupings of etiologic factors for hepatocellular carcinoma are environmental and viral. The best studied and most potent natural carcinogen is a product of Aspergillus fungus called aflatoxin B1. In humid parts of the world, where grain is stored in unrefrigerated conditions, fungal overgrowth produces contamination with aflatoxin. Epidemiologic studies in hyperendemic areas have shown the close correlation between aflatoxin exposure and the development of hepatocellular carcinoma. It is unclear whether aflatoxin exposure alone is adequate for the development of hepatocellular carcinoma, or whether it acts as a cocarcinogen with hepatitis B virus (HBV) infection. In low-incidence areas, alcohol-induced hepatic cirrhosis has a major etiologic association with hepatocellular carcinoma and 10 per cent of patients dying from alcoholic cirrhosis will have hepatocellular carcinoma. The exact role of alcohol is not known, but evidence supports its role as a cocarcinogen rather than a direct carcinogenic agent. Other environmental factors include mycotic toxins, plant alkaloids, anabolic steroids, and pollutants including pesticides and insecticides.

The most prominent factor worldwide linked to the development of hepatocellular carcinoma is chronic hepatitis from HBV or hepatitis C virus (HCV) infection. These infections result from contact with contaminated blood or bodily fluids. In particular, one common source of HCV infections in developed countries has been transfusion with contaminated blood in the era prior to routine HCV testing. Chronic viral infection contributes to the high incidence of cirrhosis (75 per cent) or chronic hepatitis (10 per cent) in the majority of patients with hepatocellular carcinoma. The annual cumulative risk of developing hepatocellular carcinoma in the setting of chronic viral hepatitis without cirrhosis is approximately 1 per cent, while the risk of developing hepatocellular carcinoma with cirrhosis ranges from 3 to 10 per cent. This significant risk has prompted aggressive screening programs in high-incidence countries, like Japan, where patients with cirrhosis are evaluated by ultrasonography and measurement of a-fetoprotein levels every 3 months. In addition, a campaign of immunization against HBV may have a significant impact on the development of hepatocellular carcinoma in endemic areas. Differences in hepatocellular carcinoma due to HBV compared with HCV include: a 10-year earlier age of onset (50 instead of 60 years) for HBV, a shorter interval from infection to development of hepatocellular carcinoma with HCV, and more advanced cirrhosis and poorer hepatic function with HCV.

Clinical presentation

Presenting symptoms and signs are related to the tumor stage and are an indirect reflection of the intensity of screening and ease of access to medical care. Common symptoms include abdominal pain, shoulder pain, abdominal swelling, weight loss, malaise and weakness, and anorexia/nausea/vomiting. Common physical findings include hepatomegaly, abdominal pain and tenderness, splenomegaly, ascites, jaundice, fever, hepatic bruit, muscle wasting, and signs of portal hypertension. In areas with limited medical care, patients are more likely to present with abdominal pain, abdominal mass or swelling, and hepatomegaly. Patients in screening programs are more likely to be asymptomatic from the tumor per se and will be predominantly symptomatic from cirrhosis and hepatic dysfunction. Up to 10 per cent of patients, particularly in Asia, will present with atraumatic acute hemoperitoneum from bleeding into a necrotic tumor. Jaundice is commonly due to hepatic dysfunction, however it may also be due to tumor compression of the main intrahepatic or extrahepatic biliary tree. A large number of paraneoplastic syndromes, usually biochemical in nature, are seen with hepatocellular carcinoma. These include hypoglycemia, hypercalcemia, hypercholesterolemia, hypertriglyceridemia, porphyria, pseudohyperparathyroidism, sexual changes, hypertrophic pulmonary osteoarthropathy, and carcinoid syndrome. Associated hematologic abnormalities include erythrocytosis, plasmacytosis, dysfibrinogenemia, and antifibrinolysis. Abnormalities in serum levels of globulins, haptoglobin, ceruloplasmin, and a-antitrypsin and increased thyroid-binding globulin are also seen.

Diagnosis

As noted above, a-fetoprotein was the first and is the most widely used serologic assay for hepatocellular carcinoma. By using radioimmunoassay, 70 to 90 per cent of patients from Asia and 75 per cent of patients from the United States with hepatocellular carcinoma will have significant a-fetoprotein elevations. This number decreases for patients with hepatocellular carcinoma in non-cirrhotic livers. In general, a sharp, steady rise in serum a-fetoprotein, especially in a patient at risk for hepatocellular carcinoma, is highly diagnostic. It is noteworthy, however, that serum a-fetoprotein is normal in 40 per cent of patients with tumors smaller than 3 cm. Ultrasonography is particularly useful in covering the weaknesses of a-fetoprotein measurements, especially in screening programs. Unfortunately, percutaneous ultrasound is rarely able to detect lesions smaller than 1 cm in diameter.

Although ultrasound is useful for screening, it is supplanted by biphasic spiral CT as the principal imaging study for hepatocellular carcinoma. Because of the distorted intrahepatic anatomy resulting from cirrhosis, MRI, particularly with ferumoxide enhancement, can be helpful for distinguishing between small hepatocellular carcinoma and adenomatous hyperplastic nodules when CT is inconclusive in answering this question. Unfortunately, the accuracy for detection of hepatocellular carcinoma with MRI falls off dramatically for tumors less than 2 cm in diameter. Angiographically assisted CT can be difficult to interpret because of perfusion abnormalities from cirrhosis and is not routinely obtained. Angiography can be helpful as a route to deliver lipiodol into the hepatocellular carcinoma. Lipiodol retention within small tumors may improve their detection by CT. PET imaging has enjoyed only modest success in hepatocellular carcinoma and is not recommended as a preoperative screening study. Ultrasound or CT have also been useful for directing a core biopsy of suspicious liver lesions, but routine biopsy for at-risk patients with an elevated a-fetoprotein and a clearly defined liver mass(es) is not indicated. In addition, a core liver biopsy in patients with cirrhosis and the resultant coagulopathy poses a risk of severe bleeding, in addition to the mostly theoretical risk of abdominal contamination by tumor cells.

Patient evaluation and selection

In contrast to other patients with primary and metastatic liver malignancies, the prognosis of patients with hepatocellular carcinoma is determined not only by the tumor's stage, but also by the functional status of the patient's liver. Often, liver function will loom as an important, if not the most important, factor in treatment decisions. In order to deal with the difficulties imposed by the tumor biology and hepatic dysfunction of hepatocellular carcinoma, a number of treatment modalities have been developed and are detailed below.

Patients evaluated for treatment of hepatocellular carcinoma undergo a history, physical examination, laboratory studies, and imaging studies as detailed above. The studies, particularly those grouped together in Child's classification of liver function, give an excellent initial idea of treatment limitations imposed by hepatic dysfunction. The chest should be imaged by routine posterioanterior and lateral chest radiographs. If these are abnormal, they should be followed by chest CT. Further pretreatment quantitative assessment of liver function is usually required. A number of quantitative assessments have been developed that measure the disappearance of a test substrate from the blood, principally as an indirect reflection of hepatic function. Unfortunately, the kinetics involved with these tests are dependent on, and affected by, hepatic blood flow. The studies include indocyanine green clearance, galactose elimination, and the radiolabeled aminopyrine breath test. Indocyanine green clearance has been shown to be an accurate indicator of hepatic reserve and is currently the most favored test in clinical use.

Accurate information about the tumor, obtained principally from laboratory and imaging studies, is critically important for the selection of appropriate treatment and prognosis. Adverse tumor factors include multicentricity, bilobar distribution, size greater than 5 cm, absence of tumor capsule, capsular invasion, portal vein thrombosis, extrahepatic metastases, and vascular invasion or thrombosis. The ominous significance of vascular invasion cannot be overemphasized; many studies have demonstrated this factor as the most important determinant of survival following resection. Although biopsy is not routinely recommended for hepatocellular carcinoma, biopsy information can be useful for modifying surgical aggressiveness. In particular, the fibrolamellar variant of hepatocellular carcinoma has a much better prognosis than other histopathologic types. This cancer usually occurs in patients in their 20s and is not associated with elevated serum a-fetoprotein levels, chronic viral hepatitis, or cirrhosis. Survival following surgical resection is significantly better than for other types of hepatocellular carcinoma, even in patients with extrahepatic metastases.

Surgical resection

Surgical extirpation, either by resection or liver transplantation, is the only curative treatment for hepatocellular carcinoma. At present, 5-year survival rates following resection average from 20 to 30 per cent worldwide, while survival rates as high as 50 per cent have been reported by several groups from Asia, Europe, and North America. In both American and European experiences, there has been reported a 75 per cent 3-year survival for stage II disease, 50 per cent 3-year survival for stage III disease, and 10 to 20 per cent 3-year survival for stage IVa (non-metastatic)disease. These data probably reflect differing populations, with the best results in patients with a lower incidence of cirrhosis and smaller tumors. Overall, the survival rates for patients with cirrhosis are approximately one-half that of patients without cirrhosis. As noted above, surgical selection criteria not only include the tumor stage, but also the functional status of the liver. In general, patients selected for resection should meet the following criteria: a solitary hepatocellular carcinoma less than 10 cm in diameter or up to three smaller hepatocellular carcinomas in a surgically accessible location(s); no vascular invasion of the lobar portal trunk, main portal trunk, or main hepatic vein(s); no extrahepatic tumor (with the exception of fibrolamellar hepatocellular carcinoma in highly selected patients); Child's class A or well compensated B; confirmation of adequate liver function by quantitative studies; intact performance status; and absence/excellent control of significant comorbid medical illnesses, particularly diabetes mellitus and renal insufficiency. The operative goal is as limited a resection as possible to achieve a 1-cm margin of normal tissue. The resection is limited to prevent the increased morbidity and mortality, mostly from hepatic failure in patients with cirrhosis, associated with progression from a non-anatomic resection to a segmental resection to a formal lobectomy (without a clear increase in disease-free survival). Operative mortality following liver resection is directly related to underlying liver function and ranges from 3 per cent for patients without cirrhosis up to 25 per cent for patients with cirrhosis. Despite resection of all detectable disease, intrahepatic recurrence rates can run a high as 80 per cent within 5 years of resection. These data strongly argue for more effective adjuvant chemotherapy rather than condemning surgical therapy as ultimately ineffective.

Principles of surgical resection

The initial operative step is a thorough exploration for extrahepatic metastases through a limited right subcostal incision. If no extrahepatic metastases are found, or limited extrahepatic metastases are found for a fibrolamellar hepatocellular carcinoma, the incision is then extended down the right subcostal margin to the lateral peritoneal reflection and down the left subcostal margin to the lateral rectus sheath. For large and/or posteriorly situated tumors, a midline extension to the xiphoid improves access to the vena cava and hepatic veins. Self-retraining retractors are then placed to retract the lower rib cage in anterior, cephalad, and lateral directions. The falciform, triangular, and coronary ligaments are divided and the appropriate lobe is mobilized. The liver is then thoroughly examined by intraoperative ultrasound (see above). If the patient is to undergo a formal lobectomy, the caudate lobe is mobilized from the vena cava by ligation of the bridging veins. The portal pedicle is then divided, taking great care to avoid encroachment on the bile duct and portal vein bifurcations. Attempts are then made at extrahepatic isolation and division of the lobar hepatic vein. This maneuver is potentially dangerous, and intrahepatic division of the hepatic veins should be pursued if any trouble is encountered. The parenchyma is then cautiously transected. A number of transection techniques are available, but use of the Cavitron Ultrasonic Surgical Aspirator is preferred.

A partial lobectomy or non-anatomic resection is frequently used, particularly in patients with hepatic dysfunction from cirrhosis. After the liver has been mobilized, vascular inflow is occluded by intermittent clamping of the main portal triad. No formal division of lobar pedicles or lobar hepatic veins is required. The parenchyma is then divided using the Cavitron Ultrasonic Surgical Aspirator device. An attempt is made to limit inflow occlusion to less than 60 min for cirrhotic livers. Regardless of technique, the principal goal during parenchymal transection is to maintain more than a 1-cm margin between the tumor and the transection margin.

Liver transplantation

Orthotopic liver transplantation has potential advantages over liver resection, including correction of the underlying liver dysfunction/cirrhosis (at least transiently in the case of viral hepatitis) and removal of the entire organ at risk for development of metastatic or recurrent primary hepatocellular carcinoma. Results from transplantation have rivaled those of resection, with survival rates ranging from 40 to 50 per cent in series with 3-year follow-up data and 15 to 35 per cent in series with 5-year data. Recurrence rates within the transplanted liver are approximately one-half of those seen with liver resection. The results of transplantation eclipse those of resection in the patient with a small T1 (80 per cent 3-year survival) or T2 (65 per cent 3-year survival) hepatocellular carcinoma and cirrhosis. This improvement in survival over resection is due to the abovementioned factors. Overall, a number of comparative studies have shown a significant survival advantage of transplantation over resection for patients with smaller tumors in conjunction with cirrhosis. This advantage is not seen for patients without cirrhosis. An additional indication for transplantation, as treatment of choice, is in patients with technically unresectable or recurrent hepatocellular carcinoma. Direct comparison of results from transplantation with resection is complicated by the use of aggressive multiagent chemotherapy in the liver transplantation group. The efficacy of chemotherapy in this setting is promising, but lacks confirmation in prospective randomized trials. More widespread adoption of liver transplantation, solely as a means of treating hepatocellular carcinoma, is limited by the high cost, 'poor' results of transplantation for hepatocellular carcinoma when compared with transplantation for benign diseases, and the scarcity of donor livers. A current practice is to transplant patients with hepatocellular carcinoma and cirrhosis for hepatic dysfunction if the following conditions are met: the hepatocellular carcinoma is solitary and 5 cm or less in size or there are up to three tumor nodules (each up to 3 to 5 cm). Overall, liver transplantation for hepatocellular carcinoma remains an unsettled issue. In the future, if improved immunomodulatory agents or genetically engineered xenografts become readily available, there may be an expansion of transplants for the treatment of hepatocellular carcinoma.

Ablation

Ablative techniques to treat hepatocellular carcinoma range from simple (alcohol injection) to exotic (interstitial radiofrequency), but have as a common goal the direct mechanical destruction of all cells within the ablated field. Hepatocellular carcinoma ablation by percutaneous ethanol injection has gained widespread popularity, especially in Europe and Asia, due to its excellent efficacy coupled with simple administration and low cost. Most investigators report excellent disease-free survival following treatment of tumors of 3 cm or less, with results only surpassed by surgical resection for patients with excellent liver function. While more than 90 per cent necrosis may be obtained with these small tumors, the efficacy decreases with increasing tumor size, due to the exponential increase in the volume of ethanol needed for tumor treatment [V = 4/3 p (r + 0.5)3] and the heterogeneous dispersion of ethanol within the tumor. In the United States, enthusiasm for percutaneous ethanol injection has been dampened by diminishing patient compliance with repeated biopsies and sequential injections; the inability of radiologic studies to distinguish accurately between scar, necrotic tumor, and viable tumor; and a complication rate of up to 35 per cent (major and minor). Currently, percutaneous ethanol injection is useful for tumors of less than 4 cm in patients with Child's class B or C liver function.

Cryoablation is currently available in clinical practice and used widely for treatment of unresectable liver metastases. This technique uses super-cooled liquid nitrogen to create a freeze zone surrounding a probe placed into the hepatic parenchyma under ultrasound guidance (see details in the cryoablation and radiofrequency ablation section of colorectal liver metastases). The advantage of cryoablation over percutaneous ethanol injection is that much larger tumors (up to 6 cm) can be treated with good local control. A recent study from China reported a 5-year survival of 38 per cent for patients with tumors of less than 5 cm. Because multiple treatment modalities were used in this group of patients, the contribution of cryotherapy alone is difficult to assess. Unfortunately, cryoablation requires a laparotomy for safe conduct of the ablation. The need for open laparotomy may be averted with the developing technique of radiofrequency ablation. Radiofrequency ablation uses microwave energy radiated from a probe placed in the parenchyma of the liver, also under ultrasound guidance. The radiofrequency technique lends itself to a minimally invasive (laparoscopic) or percutaneous approach. Because of its ease of use and significantly lower cost, when compared with cryoablation, and its potential use for larger tumors inadequately treated by percutaneous ethanol injection, radiofrequency ablation may prove to be superior to the other ablative techniques, however more experience with this technique is required before it can be recommended further.

Embolization and chemoembolization

The vascular supply to a hepatocellular carcinoma, in significant contrast to the normal surrounding liver, is almost completely derived from the hepatic artery. This fact can be exploited to produce ischemic necrosis of the hepatocellular carcinoma following occlusion of its arterial branches. Occlusion is achieved by transcatheter embolization of segmental feeding vessels using gelfoam or metal coils and enhanced by concurrent administration of lipiodol, which adheres preferentially to (or is unable to be cleared from) the tumor endothelium within the hepatocellular carcinoma. Embolization can be repeated on a monthly schedule based on the degree of lipiodol retention in the tumor and according to the tumor response. The addition of chemotherapeutic agents, including doxorubicin, cisplatin, and mitomycin C, to lipiodol was shown to improve the response to embolization in several non-randomized trials. In contrast, a recent prospective randomized French trial and meta-analysis of smaller trials failed to reveal a statistical benefit of chemoembolization over simple embolization (or supportive therapy). One reason for the lack of effect in the French study was the high incidence of hepatic failure after chemoembolization. Unfortunately, the incidence of liver failure following chemoembolization, as reported in the literature, is widely variable (4 to 60 per cent) and the threat of this post-procedural complication is difficult to assess. Despite the results of the French trial and meta-analysis, many investigators still feel that the addition of chemotherapy to embolization may enhance its effects. Further prospective randomized trials, stratified for tumor stage and patient performance characteristics, will be needed if accurate conclusions are to be drawn. Side-effects from the embolization are common and include abdominal pain and tenderness, anorexia, nausea and vomiting, and fever. These symptoms and signs usually resolve within 2 to 3 weeks, although lasting effects may linger for several months. Patients with significant intrahepatic venous shunting can have an extrahepatic distribution of chemotherapy and may experience side-effects for this reason. Patients who may benefit from embolization include those with moderate liver dysfunction (Child's class B) who are not candidates for resection/cryoablation because of liver dysfunction or percutaneous ethanol injection because of tumor size. Patients who have occlusion of their main portal vein or main lobar trunks are not candidates for embolization.

Chemotherapy

The results of systemic chemotherapy for hepatocellular carcinoma have been disappointing. Doxorubicin has been shown to be the most effective single agent against hepatocellular carcinoma and the majority of randomized trials have used it alone or in combination with other agents. These trials have shown response rates in the 20 per cent range with little increase in median survival. The addition of other agents to doxorubicin has not significantly improved the response rates or the duration of response. There was a brief flurry of interest over estrogen-receptor blockade by tamoxifen, however the benefit of this drug was not supported by follow-on randomized controlled trials. At present, there is little justification for the use of chemotherapy for patients with hepatocellular carcinoma outside the setting of a clinical trial.

Radiotherapy

Although used in the treatment of hepatocellular carcinoma, external beam radiotherapy is limited by the lack of differential radiosensitivity between tumor and normal liver. Several small studies have shown poor results with the use of external beam radiotherapy for palliation. The administration of transcatheter radiopharamaceuticals including 131I lipiodol or 90Y microspheres has been described, but these series are small and recommendations are still pending.

Gene therapy

With the expansion of molecular biology techniques, the presence of specific intercellular genetic abnormalities within the hepatocellular carcinoma cells has been identified. At present, the most frequently identified genetic abnormality is the loss of p53, a tumor suppressor gene. The percentage of hepatocellular carcinomas with p53 deletions was shown to be increased in areas with higher incidence rates. In vitro studies have shown that when p53 is reintroduced into hepatocellular carcinoma cells, the growth rate is slowed and programmed cell death, called apoptosis, will occur. The potential use of replacement gene therapy is currently being explored for patients with hepatocellular carcinoma.

Cholangiocarcinoma

Cholangiocarcinomas account for 10 per cent of all primary hepatic malignancies and are second to hepatocellular carcinoma in incidence. They may occur anywhere in the biliary tree; however, cholangiocarcinoma within the liver parenchyma (known as peripheral cholangiocarcinoma) accounts for up to 5 per cent of these tumors. Peripheral cholangiocarcinoma develops in the small intrahepatic bile ducts and is associated with etiologic factors including hepatobiliary parasites, particularly flukes, and intrahepatic lithiasis. Peripheral cholangiocarcinoma is 10 times more common in Asia than in Western countries.

Although cholangiocarcinoma is usually considered one entity, peripheral cholangiocarcinoma has different clinical characteristics and tends to have a more aggressive biologic behavior than hilar cholangiocarcinoma. While hilar cholangiocarcinoma presents with obstructive jaundice, usually due to a small tumor within the common duct or lobar ducts, peripheral cholangiocarcinoma often presents with jaundice from multilevel intraparenchymal ductal obstruction late in the disease course. When compared with hepatocellular carcinoma or liver metastases, peripheral cholangiocarcinoma is far more diffusely infiltrative with a higher incidence of intrahepatic metastases. These characteristics are significant factors accounting for the low resectability rate of peripheral cholangiocarcinomas.

The evaluation of patients with a peripheral cholangiocarcinoma is similar to that described for patients with hepatocellular carcinoma. There are no tumor markers specific for peripheral cholangiocarcinoma. Accurate intrahepatic staging of peripheral cholangiocarcinoma can be extremely difficult, even with modern CT and MRI. Part of the difficulty lies with differentiation between infiltrative peripheral cholangiocarcinoma and hepatic congestion and fibrosis due to chronic biliary obstruction from peripheral cholangiocarcinoma.

Surgical resection is the mainstay of treatment for peripheral cholangiocarcinoma. The surgeon should be aware that intraoperative findings may require expansion or abandonment of the originally planned procedure in up to one-half of patients. Operative mortality rates range from 0 to 14 per cent. Operative morbidity is elevated due to hepatic fibrosis with atrophy and segmental cholangitis with abscess formation. Five-year survival rates range from 30 to 40 per cent. Poor outcome is associated with multiple tumors and incomplete resection. Liver transplantation can also be performed for peripheral cholangiocarcinoma. Five-year survival rates in the largest series range from 27 to 40 per cent. Poor outcome after transplantation was seen in patients with positive margins, multiple tumors, and lymph node involvement. Currently, transplantation is reserved for highly selected patients with a small single peripheral cholangiocarcinoma without associated malignant adenopathy.

Results from the palliative treatment of patients with chemotherapy have been disappointing. 5-Fluorouracil has been the mainstay of treatment with response rates ranging from 10 to 24 per cent. Use of other agents alone or in combination with 5-fluorouracil has shown a minimal effect or additive benefit. The combination of radiation with chemotherapy may have some promise for hilar cholangiocarcinoma but cannot be used for peripheral cholangiocarcinoma because of hepatic toxicity.

Hepatoblastoma

Hepatoblastoma is the most common primary hepatic malignancy in children. This rare tumor (1 per 100 000 children) is usually diagnosed before the age of 3 years. Males are affected twice as often as females. Common presenting symptoms include abdominal swelling or mass, anorexia, nausea, weight loss, and pain. Hepatomegaly, due to a mass, is commonly seen on physical examination. The serum a-fetoprotein level is elevated in 75 to 95 per cent of patients. Abdominal CT scans will show an isolated enhancing hepatic tumor in the majority of patients. Surgical resection is the mainstay of therapy. Complete resection is possible in up to 65 per cent of children and is associated with cure for 30 to 70 per cent. Preoperative chemotherapy with cisplatin, 5-fluorouracil, and vincristine has been shown to be effective for improving resectability and decreasing recurrence rates. Adjuvant chemotherapy following liver resection has shown promise, however the results are difficult to interpret because of small series size. Small series of liver transplantations for hepatoblastoma have also been promising, with 5-year survival rates of 50 per cent. Present recommendations are for surgical resection of early stage tumors. More advanced tumors should be considered for resection or transplantation and strong consideration for preoperative adjuvant chemotherapy should be entertained. Late-stage tumors should be treated initially with chemotherapy and a recommendation for resection or transplantation pending the tumor response.

Epithelioid hemangiendothelioma

Epithelioid hemangiendothelioma is a rare tumor arising from intrahepatic endothelium. These tumors are relatively indolent, with a clinical behavior between hemangioma and angiosarcoma. Epithelioid hemangiendothelioma may arise in a wide age range, with the average age at presentation of 50. There is a slight female predominance. Patients may have a history of vinyl chloride exposure. The preferred treatment is surgical resection. Patients with extensive epithelioid hemangiendothelioma may undergo liver transplantation. The survival of a small group of patients, undergoing transplantation, was 40 per cent at 5 years.

Hepatic sarcomas

Angiosarcomas are interesting not because they are rare and incurable, but mainly because their etiology is usually specific and obvious. They usually arise following injection of Thorotrast decades ago, following arsenic exposure of agricultural workers (especially in the vineyards of the Moselle Valley), following testosterone in boys with Fanconi syndrome, and after exposure to vinyl chloride (the monomer of many plastics). The peak incidence of angiosarcoma occurs in patients in their 60s and 70s. There is a pronounced male predominance. Most patients present with abdominal pain and hepatomegaly. Hepatic angiosarcomas are extremely aggressive with a median survival of 6 months. The results of surgical resection have been disappointing, as has the use of chemotherapy and radiation. Because most patients will present with advanced tumors, transplantation has been used in a small series of patients. Although the 2-year survival rate was 15 per cent, no patient survived more than 28 months after transplantation. Other rare hepatic sarcomas including leimyosarcomas and rhabdomyosarcomas may arise within the liver. They are commonly treated by surgical resection.

Hepatic adenomas

Hepatic adenomas are benign, but large adenomas may rupture and bleed thereby coming to surgical attention. Contemporary publicity has now alerted physicians and patients to the role of oral contraceptives in fostering the development of adenomas, although both pristine liver cell adenomas and the ruptured variety are infrequent. It is not yet determined whether hepatic adenomas progress to carcinoma. Although the risk is small, some adenomas, without doubt, undergo carcinomatous transformation. The majority of hepatic adenomas are situated within the right liver. No one can predict which adenomas will rupture, nor why. When adenomas in the right liver rupture, they are often deep seated and immediate partial hepatectomy, with its attendant risk, is sometimes required.

From a clinical viewpoint, any source of hormonal stimulation should be withdrawn from a man or woman receiving hormone treatment who is thought to have a hepatic adenoma. If the neoplastic mass regresses by 50 per cent over the next 3 months, no treatment is likely to be needed. Adenomas that do not regress upon stopping hormonal therapy should be removed. Because of the possibility of carcinomatous transformation, albeit small, imaging studies over 6-month intervals for a total of 5 years, then yearly ad infinitum should probably be pursued to assess unresected adenomas for malignant growth.

Hemangiomas

Although benign cavernous hemangiomas are frequent, they are rarely important. Those less than 8 cm in diameter seldom need treatment, except when an ill-advised biopsy provokes hemorrhage. Intervention is required only when the hemangioma (usually best diagnosed by MRI) causes symptoms of a mass lesion, displacing or irritating other organs, or if it ruptures. Leaks or rupture are uncommon, fewer then 50 cases of ruptured hemangioma have been recorded. All of those that ruptured were over 8 cm in diameter, although a few smaller ones have leaked. The common hemangioma is resectable along non-anatomic lines. Most, including giant hemangiomas, can and should be enucleated rather than resected. There is no cause for concern if the resection margin contains evidence of hemangioma, since they do not recur.

Liver metastases

Successful management of the patient with liver metastases is dependent on matching the appropriate treatment to the tumor and its stage. Liver metastases may arise as an isolated site of regional failure or herald the development of generalized metastatic spread. The key element is selection of that biologically privileged subset of patients with favorable isolated liver metastases who can be cured by aggressive therapy. For as yet undetermined reasons, liver-directed therapy, particularly resection, of isolated liver metastases from only a limited number of primary tumor sites has been shown to be beneficial. These sites include the colon, rectum, neuroendocrine (pancreas) and carcinoid, and highly selected patients with metastases from other primary tumors. Unfortunately, liver metastases from more common primary sites, such as the lung, breast, or pancreatic adenocarcinoma, are usually only a part of more widespread metastases and herald a poor prognosis. Aggressive surgical treatment for an apparent isolated liver metastasis from these primary sites is considered only in highly selected patients, as discussed below.

In general, survival rates following resection of liver metastases have improved over the preceding 10 years. The most significant reason for this improvement is better patient selection. Better selection is a direct reflection of more accurate tumor staging, resulting from technologic improvements in imaging studies and refinement of preoperative clinical selection criteria.

Colorectal liver metastases

The most frequent indication for surgical involvement in the management of a patient with liver metastases is in the setting of colorectal cancer. This is principally because colorectal cancers, among the common gastrointestinal and extra-abdominal malignancies, have the highest incidence of liver metastases as the sole site of regional failure. In addition, the problem is commonplace with over 50 000 patients per year developing colorectal liver metastases in the United States alone. For these reasons, the biology, clinical features, and indications for a variety of therapeutic interventions and their results are best understood for liver metastases from colorectal cancer.

An aggressive and invasive (surgical) approach to this problem is reasonable only if it can significantly alter the tumor's natural history and better the results from less invasive (systemic chemotherapy) therapy. The 5-year survival rates following resection of colorectal liver metastases average from 25 to 49 per cent in modern series. Natural history studies show that the median survival of untreated colorectal liver metastases is from 5 to 10 months. If this data is analyzed more closely, the 5-year survival rate for patients with a solitary unresected (but potentially resectable) liver metastasis was 2 per cent. The 3-year survival for patients with unresected multiple metastases was 1 per cent. Tumor response rates from chemotherapy based on 5-fluorouracil range from 22 to 25 per cent. The median survival in these series ranges from 9 to 12 months with few patients surviving longer than 3 years. These data show that an aggressive surgical approach can both alter the natural history and significantly improve survival when compared with supportive care or systemic therapy for patients with colorectal liver metastasis.

Patient evaluation

The majority of patients referred for evaluation and management of their liver metastases will be diagnosed by a rising serum level of carcinoembryonic antigen or routine surveillance imaging, principally abdominal CT. Patients presenting with symptoms related to their metastatic disease or who have metastatic disease suspected because of symptoms and signs have a significantly poorer survival than asymptomatic patients do. Patients should undergo an initial evaluation including thorough history, physical examination, and routine laboratory studies including a complete blood count, platelet count, serum electrolytes, and 'liver function tests'. A current serum level of carcinoembryonic antigen should also be collected. The chest should be imaged by routine posterioanterior and lateral radiographs. If these are abnormal, they should be followed by a chest CT. The routine preoperative use of chest CT is costly and not currently recommended. The patient should also have undergone a routine colonoscopy within the previous 6 months. Following this initial evaluation, the liver should be imaged by a biphasic spiral CT scan enhanced with intravenous contrast. This scan uses a different contrast technique than routine CT scans enhanced with intravenous contrast that are performed for screening. These routine screening CTs are not adequate for definitive preoperative staging of the liver. Ill-defined liver abnormalities can be further characterized by ferumoxide-enhanced MRI. Angiographically assisted CT should be obtained if there remain any lingering questions about parenchymal abnormalities or in the rare circumstance that the anatomic detail provided by the biphasic CT/MRI is not adequate. Angiographically assisted CT can also be used to confirm the findings from biphasic CT during the initial institutional experience with this study. A celiac and superior mesenteric artery 'angiogram' is obtained from vascular reconstruction of the CT's biphasic data set.

The definitive staging of intra-abdominal extrahepatic metastasis remains controversial. CT and MRI are marginally adequate studies, with sensitivities for detection of extrahepatic metastasis less than 60 per cent. 18F-fluorodeoxyglucose PET imaging holds great promise, and should be considered if there is access to a linear accelerator. PET provides definitive evidence of metastatic disease if a 'hot spot' located by PET corresponds to a defined anatomic abnormality on CT or MRI. Unfortunately, the cost associated with PET can be prohibitive and will limit its widespread application. Radionuclide-tagged monoclonal antibody scans have been used with variable success. The efficacy of tagged antibody scans needs to be shown in a larger patient population before recommendations for their use can be made.

Patient selection

The majority of patients with metastatic liver disease, referred for surgical opinion, will be accompanied by a screening abdominal CT scan. The next step in an initial evaluation is assessment of the adequacy of the screening CT. Cardiology and pulmonary consultations are obtained for older patients with significant cardiopulmonary disease. At this point, patients with severe comorbid illnesses and documented extrahepatic tumor are excluded from further consideration of liver-directed therapy. Depending on physician preference and institutional expertise, patients will then undergo a radiologic evaluation as detailed above. Following these definitive staging procedures, final treatment decisions are made. Patients with well-controlled comorbid illnesses, no definitive evidence of extrahepatic tumor, and four or fewer metastases arrayed within the liver so that they can be resected without compromise of hepatic function are scheduled for resection. Patients with well-controlled comorbid illnesses including mild hepatic dysfunction, no definitive evidence of extrahepatic tumor, and six or fewer metastases arrayed within the liver so that they could not be resected without compromise of hepatic function are scheduled for cryoablation/resection or radiofrequency ablation/resection. Patients with well-controlled comorbid illnesses, no definitive evidence of extrahepatic tumor, but more than six metastases within the liver are referred for systemic chemotherapy or are considered for hepatic artery infusion therapy.

Surgical resection

The principles and conduct of surgical resection for metastatic cancer are very similar to those described for treatment of hepatocellular carcinoma. Again, the underlying goal of resection is to obtain a greater than 1 cm resection margin of normal liver around the metastases. The type of resection is geared to that goal, and there is no clearly demonstrated superiority of larger (lobectomies) over more limited resections.

Surgical resection in the modern era can be performed safely with acceptable morbidity and mortality. In the centers with a large experience, the operative mortality is 2 to 4 per cent. The complication rates range from 15 to 50 per cent and include hemorrhage, liver dysfunction or failure, biliary leak or fistula, and cardiac and pulmonary complications. Median hospital stays following liver resection average approximately 2 weeks; however, the length of stay is decreasing, with stays of 1 week now common.

The 5-year survival rates from pooled large series range from 25 to 40 per cent. The series with lower survival rates tend to be older with less accurate imaging technology, and less stringent patient selection criteria. Using current imaging technology and careful patient selection, 5-year survival rates as high as 49 per cent are seen. The 10-year survival rates drop to approximately 20 per cent, but these are older series and an improvement should be seen as the current 5-year data matures.

Determinants of prognosis after resection

Data from large resection series has been subjected to statistical analysis so that associations with survival could be identified. As expected, the results are not uniform between series but comparisons show a number of similarities. Most, if not all, series show poor long-term outcomes for patients with the following tumor-related factors: extrahepatic metastases, particularly malignant portal adenopathy; intrahepatic 'satellite' metastases; symptomatic presentation; tumors larger than 10 cm; more than 50 per cent of the liver involved with tumor; more than four metastases; and synchronous presentation of liver metastases and the primary tumor. Poor outcomes were also seen within the following intervention-related factors: positive margin or margin less than 1 cm following resection and perioperative blood transfusion.

Adjuvant systemic chemotherapy, following liver resection, has been used without the benefit of a prospective randomized trial. No benefit has been shown in retrospective reviews of chemotherapy based on 5-fluorouracil used in this setting. A small trial has shown that adjuvant hepatic intra-arterial chemotherapy was beneficial, but the numbers are too small to permit any definitive conclusion. The results of a larger American trial comparing observation with adjuvant intra-arterial fluorodeoxyuridine and systemic 5-fluorouracil following liver resection are currently pending. In the best series, 55 to 60 per cent of patients will develop recurrent colorectal cancer within 5 years. Examination of recurrences in these patients show that half will recur in the liver, with 85 per cent of these recurrences isolated to the liver. Other common sites of recurrence include the abdomen and pelvis (25 per cent) and lungs (25 per cent). Less than 5 per cent of recurrences develop in the bone or brain. The majority of recurrences will occur within 2 years following resection. By considering the pattern and time course of recurrences, a postoperative surveillance program focusing on the abdomen, particularly the liver, and the lungs, which is most intense during the initial 2 postoperative years, is both logical and fruitful.

A measure of the relevance of any postoperative surveillance program is its ability to find recurrences that are treatable. Patients with isolated liver recurrences, detected at follow-up, are re-evaluated as described above and re-resected if they meet the criteria. Series of re-resections have shown that patients can be treated safely, with 5-year survival rates (25 to 30 per cent) rivaling those of the initial resection.

Hepatic artery infusion chemotherapy

Hepatic artery infusion chemotherapy exploits the preferential blood supply to neoplastic lesions in the liver. Thus, hepatic artery infusion theoretically increases the exposure of neoplastic cells to chemotherapy relative to normal hepatocytes. Regional therapy to the liver has several advantages over systemic therapy. Intra-arterial infusions can produce elevated hepatic drug concentrations relative to systemic levels for agents that have a high hepatic extraction. This characteristic results in high local exposure to the drug while limiting systemic toxicity. This situation is advantageous for drugs with steep dose–response rates, such as 5-fluorouracil and fluorodeoxyuridine, where higher drug concentrations result in increased measurable responses. Direct arterial perfusion of active agents such as fluorodeoxyuridine allows smaller infusion volumes to be used and facilitates treatment via implantable drug delivery systems. Regional hepatic chemotherapy for patients without evidence of extrahepatic disease may slow the development of systemic disease. One theory of colorectal carcinoma metastases postulates that there is a stepwise progression. Malignant cells initially spread via lymphatic and hematogenous routes to the liver, and cells from these metastases subsequently disseminate to the lung and the systemic circulation.

5-Fluorouracil and fluorodeoxyuridine have been the agents primarily used for intra-arterial therapy. Fluorodeoxyuridine appears to be the best agent for this use, since it has a high first-pass clearance rate with a hepatic extraction ratio of 0.7 to 0.9. The high first-pass clearance results in hepatic drug levels that are 400 times higher than systemic values. Pilot studies, using percutaneous catheters to deliver the drug continuously for 1 to 2 weeks, were able to show response rates as high as 30 to 50 per cent. With the development of an implantable infusion device, it became possible to deliver concentrated and prolonged infusions in the ambulatory setting.

Several randomized phase III trials have been performed comparing hepatic artery infusion with systemic chemotherapy. In general, these reports demonstrate significantly higher complete and partial response rates in patients receiving intrahepatic infusions relative to systemic chemotherapy. None of the American studies has shown improvement in overall survival.The inability to show a survival advantage in these trials probably resulted from the enrollment of small numbers of patients and the practice of 'crossing-over' patients to hepatic artery infusion if they failed to respond to systemic therapy. The two largest American studies allowed patient crossover to hepatic artery infusion therapy after failure of systemic therapy, thereby confounding the impact of hepatic artery infusion therapy on survival. Both studies did demonstrate a significant increase in survival for the crossover group compared with those who never received hepatic artery infusion.Certain trials also included patients with extrahepatic disease who were unlikely to derive any survival benefit from liver-directed therapy. In addition, many of these trials were started before the nuances of surgical pump placement and the significance of hepatobiliary toxicity due to fluorodeoxyuridine were appreciated. Treatment-limiting toxicities were seen in the hepatic artery infusion arms of many of the trials. For example, in the Mayo trial, nearly one-third of the patients randomized to hepatic artery infusion therapy never received any significant treatment.One recent meta-analysis of six randomized studies suggested small but significant improvements in 1- and 2-year survival rates for patients receiving hepatic artery infusion therapy. Two European studies demonstrated improved survival in patients treated with hepatic artery infusion; however, less than half of the patients in the control arms received systemic chemotherapy. Thus, definitive statements concerning the survival benefit of hepatic artery infusion over systemic therapy cannot yet be made. Some investigators, however, have clearly demonstrated improved symptom control and quality of life with hepatic artery infusion compared with systemic chemotherapy and supportive care.The toxicities of hepatic artery infusion noted in these trials include direct hepatic toxicity, biliary sclerosis, and gastric/duodenal irritation and ulceration. Systemic effects such as myelosuppression and mucositis are rarely seen after infusion therapy. Nausea, vomiting, and diarrhea may be noted following hepatic artery infusion but are attributable to local gastrointestinal inflammation rather than systemic effects.

One approach to decrease toxicity has been to lower the fluorodeoxyuridine dose. A phase II trial explored this option, decreasing the dose from 0.3 mg/kg.day to 0.1 mg/kg.day. Measured responses were equivalent to those seen with conventional doses with a 50 per cent complete response rate and median survival of 22.4 months.None of the patients treated with the lower dose of fluorodeoxyuridine required treatment termination as a result of hepatic artery infusion toxicity.

A different approach was attempted with the goal of reducing toxicity while maintaining the fluorodeoxyuridine dose. A randomized trial using fluorodeoxyuridine with or without dexamethasone was performed. Although no significant decrease in toxicity was documented, patients in the dexamethasome arm were able to receive greater overall drug doses, which resulted in improved response rates, well over 50 per cent in previously untreated patients.

New approaches designed to improve hepatic artery infusion responses have also included the addition of fluoropyrimidine modulators, such as leucovorin and interferon-a. Encouraging phase II data have been reported with this combination, but the addition of leucovorin to intra-arterial fluorodeoxyuridine therapy increased the rate of hepatic toxicity. Concurrent dexamethasone has helped to reduce biliary toxicity in this setting from 21 to 3 per cent while maintaining good response rates. In a recently published trial, this combination of fluorodeoxyuridine, leucovorin, and Decadron led to an objective response rate of 70 per cent with a median survival of nearly 25 months.Studies comparing hepatic artery infusion therapy with fluorodeoxyuridine, leucovorin, and dexamethasone against systemic 5-fluorouracil and leucovorin are ongoing.

The recognition of several important surgical considerations is fundamental during hepatic artery pump placement if one is to achieve the goals of bilobar hepatic perfusion while avoiding misperfusion of the stomach and duodenum. Preoperative angiography is essential to define variations in hepatic artery anatomy, which are estimated to occur in up to 50 per cent of patients. Conventional intra-arterial biplanar angiography is currently recommended, although it will probably be replaced by vascular reconstructions from biphasic CT in the near future. Specific methods have been described to achieve complete hepatic perfusion via either the gastroduodenal artery or anomalous branches of the hepatic artery.Maneuvers including ligation of non-dominant vessels and placement of dual-lumen pump devices have been described. The surgeons placing these pumps must recognize when these techniques are called for if they are to be assured of optimal delivery of drug to the liver. Evidence of extrahepatic disease is sought during the initial exploration of the abdomen and should include sampling of any suspicious peritoneal or omental nodules and frozen-section biopsies of the porta hepatis nodes or any suspicious nodes in the celiac axis. If any extrahepatic tumor is identified, especially in the portal nodes, the procedure is terminated. Misperfusion of the stomach and duodenum is avoided by performing a meticulous dissection and ligation of the right gastric artery and the small branches of the common hepatic artery along the superior border of the antrum and proximal duodenum. A cholecystectomy is then performed, but care is taken to avoid injuring the axial blood supply to the distal common bile duct. In most situations, the gastroduodenal artery is cannulated approximately 2 cm below its origin off the hepatic artery, and the tip of the catheter is secured just distal to the origin of the vessel to avoid disrupting arterial flow to the liver. Bilobar liver perfusion and absence of flow to the stomach and duodenum are verified by injection of 5 ml of fluorescein and examination with a Wood's lamp.

Cryoablation and radiofrequency ablation

Cryoablation refers to the in situ destruction of liver tumors by precisely and rapidly cooling the tumor and a zone of normal hepatic parenchyma to extreme subzero temperatures. By circulating a coolant, such as liquid nitrogen, through the core of the tumor, temperatures as low as –100°C can be achieved. Such profound tissue hypothermia results in both direct and indirect mechanisms of cell destruction. Details of the lethal effects of cryoablation have been well described, but essentially involve the formation of extracellular ice crystals leading to protein denaturation and the rupture of cell membranes. Indirectly, subzero temperatures result in microvascular thrombosis and tissue anoxia. Further damage occurs if the cells are allowed to thaw slowly and are then rapidly refrozen. Clinical studies have suggested that two such freeze–thaw cycles may be necessary for optimal tissue destruction. Fundamental to the implementation of cryoablation as a viable treatment option for patients with unresectable liver metastases has been the development of intraoperative ultrasonography and refinement of the equipment used to deliver the coolant to the tumor.

Early reports demonstrated the feasibility and safety of treating liver metastases by cryoablation, while follow-up series have now helped to define the indications for this modality. The most significant clinical limitation of surgical resection is usually the number of lesions that can be safely removed while sparing sufficient hepatic parenchyma to avoid postoperative liver failure. Thus, the major indications for cryoablation are metastatic lesions that are not amenable to resection due to liver dysfunction from cirrhosis or because the number of lesions or the location of the tumors, usually bilobar, would risk insufficient postoperative hepatic function. For colorectal metastases, most centers with sufficient cryosurgical experience will limit this technique to patients with fewer than six metastases (generally less than 40 per cent of the liver volume), and tumors smaller than 6 to 8 cm in greatest diameter. Most surgeons will avoid large, central tumors near the hilum of the liver and major bile ducts, which are easily damaged by freezing.

Similarly to other forms of liver-directed therapy, cryoablation probably offers little advantage to patients with extrahepatic metastatic disease. The operative technique involves intraoperative ultrasound localization and monitoring of the cryoprobe placement into the tumor. In addition, intraoperative ultrasound allows detection of tumors not recognized on preoperative scans and is essential for monitoring the freeze margins of the 'iceball'. The cryoprobe is a vacuum-insulated device that circulates supercooled liquid nitrogen through the probe's tip. A 3-mm blunt-tipped probe creates a freeze zone up to 4 cm, and the 8-mm trocar point probe creates a freeze zone of up to 6 cm. A single probe or combination of probes can be utilized to achieve complete freezing of the tumor and an additional 1 cm beyond the margin to ensure complete cryoablation. The entire process of probe introduction, freeze–thaw cycles, and probe extraction is monitored with real-time intraoperative ultrasound.

Major complication rates are reportedly between 10 and 40 per cent, and mortality rates are 2 per cent. Complications may include hemorrhage, biliary fistulas, hepatic or subphrenic abscesses, and more rarely, hepatic failure, coagulopathy, and cardiac arrest. Disease-free survival rates and patterns of failure have now been reported from several centers. With median follow-up times of 18 to 36 months, most series report 5-year actuarial disease-free survival rates of 15 to 28 per cent. These rates are comparable with those reported for liver resection, and in light of the reported mortality rates of less than 2 per cent, it becomes obvious why cryoablation has generated such interest and enthusiasm. In one series, postoperative carcinoembryonic antigen changes were extremely predictive of ultimate outcome. For the group in which carcinoembryonic antigen levels returned to the normal range, median survival exceeded 3 years.

Tumor destruction due to thermal damage, as opposed to freezing, is the goal of radiofrequency ablation. The radiofrequency technique uses high-frequency alternating current that passes from an electrode into the tumor and surrounding tissue. With application of an alternating current, ions within the tumor attempt to follow the change in direction of the current, resulting in frictional heating and coagulation necrosis within the tumor. Radiofrequency ablation uses monopolar or bipolar needle electrodes placed into the tumor under radiologic guidance. These electrodes can be placed in the operating room under ultrasound guidance by minimally invasive (laparoscopic) techniques or percutaneously by using CT or ultrasound-directed imaging. Preliminary results from treatment of hepatic tumors have been promising. These techniques can be safely applied, with mortality rates under 1 per cent and morbidity rates under 3 per cent. Radiofrequency ablation also appears to be effective, with local recurrence rates after treatment between 2 and 3 per cent in larger series. Careful attention must be paid to tumor size in order to prevent local recurrence. Studies have shown that as tumor size increases over 3 cm, the local recurrence rates rise sharply. The adequacy of treating larger liver tumors by multiple ablations is unproved and ongoing improvements in radiofrequency technology are directed towards treatment of these larger tumors. What is clear from these early studies is the substantially lower morbidity and mortality rates from radiofrequency ablation compared with cryoablation. These are principally due to the need for laparotomy associated with cryoablation. At present, though, cryoablation is superior for tumors ranging in size between 3 and 6 cm.

Systemic chemotherapy

An in-depth discussion of systemic chemotherapy for metastatic colon cancer is beyond the scope of this chapter and readers are referred elsewhere. Despite two decades of intense clinical investigation, cancer metastatic to the liver remains relatively resistant to systemic chemotherapy. Only the fluoropyrimidines (5-fluorouracil and fluorodeoxyuridine) and irinotecan, a topoisomerase I inhibitor, have been shown to have consistent therapeutic activity, and numerous studies have not demonstrated other agents to be superior to these drugs. The best and most consistent results with 5-fluorouracil have been obtained when it is combined with the folate modulator leucovorin. Response rates for this combination range from 10 to 60 per cent with the average partial response rate of 30 to 40 per cent and complete response rate of under 5 per cent. Median survival from this combination therapy is from 12 to 14 months. Irinotecan is useful as a salvage therapy by virtue of its 15 to 25 per cent response rate in patients with progression of tumor on 5-fluorouracil. Wider use of irinotecan has been limited by its substantial gastrointestinal and hematologic toxicity. Overall, chemotherapy is purely palliative and a poor substitute for the potentially curative therapies discussed previously.

Embolization

Liver metastases can be treated by embolization of the blood supply. A cannula is introduced into the femoral artery and advanced until the celiac axis has been cannulated. An angiogram is then performed and the vessels supplying the metastases identified. If possible, these vessels are then superselectively cannulated. Absolute alcohol, gelfoam, or steel coils may be introduced to occlude the blood supply. Embolization is most effective for patients with hepatic metastases from neuroendocrine tumors and sarcomas because of their rich blood supply and the resultant reduction of symptoms attributable to the secretion of a hormonally active substance from neuroendocrine tumors. Embolization has not been shown to improve survival of patients with metastases from colorectal carcinoma and other gastrointestinal malignancies.

Radiotherapy

The efficacy of radiotherapy in the treatment of metastases of the liver is limited by the radiosensitivity of normal hepatocytes and the relative insensitivity of metastatic carcinoma. The maximum dose that can be administered before inducing radiation hepatitis is 35 Gy; this dose is too low for curative irradiation of metastatic carcinoma. Radiotherapy is occasionally useful in the palliation of severe pain from hepatic metastases, but does not prolong survival.

Gene therapy

Using modern molecular techniques, many of the genetic abnormalities in cancer are now partially understood. In general, both genes that potentiate the malignant phenotype, called oncogenes, are functioning and/or genes that suppress the malignant phenotype, called tumor suppressor genes, are lost within tumor cells. Gene therapy strategies that target and inhibit oncogene function or replace lost tumor suppressor gene function are being developed. Liver metastases are potentially good targets for gene therapy, since the gene can be delivered directly into the tumor via the hepatic artery. A key field of investigation is focused on the tumor suppressor gene p53, which is mutated in up to 50 per cent of patients with colorectal cancer. When p53 is reintroduced into p53 mutant tumor cells, these cells undergo programmed cell death called apoptosis. Ongoing studies are examining the possible intra-arterial delivery of 'normal' p53 into hepatic metastases with mutated p53. This and other gene therapy trials will be expanding rapidly as the clinical use of gene therapy moves more into mainstream medicine.

Neuroendocrine (including carcinoid) metastases

Both primary gastrointestinal neuroendocrine and carcinoid malignancies metastasize to the liver as the most common site of extranodal dissemination. Metastases from these malignancies pose unique features that make them excellent candidates for liver-directed therapy. These features include: a less aggressive behavior manifested as a more indolent clinical course and prolonged survival when compared with hepatic metastases from adenocarcinoma; and endocrinopathy, related to the secretion of active hormones from liver metastases directly into the systemic circulation. In general, the severity of endocrinopathy is directly related to the hepatic tumor burden.

The evaluation of patients with neuroendocrine metastases is similar to that described for patients with colorectal cancer. An exception to the similarity is the evaluation of tumor markers. Since endocrinopathy from ectopic hormone oversecretion is common, the selective sampling of serum hormone levels is indicated. The selection of hormones to be sampled should be based on suggestive clinical symptoms, signs, and routine laboratory studies. The use of imaging studies is also similar to that described above, with the exception of 18F-fluorodeoxyglucose PET imaging, which remains experimental for neuroendocrine tumors. Somatostatin receptor scintigraphy plays the same role in the management of neuroendocrine metastases as does 18F-fluorodeoxyglucose PET imaging in the management of colorectal metastases. Overall, the sensitivity for detection of intrahepatic and extrahepatic metastases from neuroendocrine tumors by somatostatin receptor scintigraphy has been shown to be from 85 to 92 per cent. The specificity for detection of intrahepatic metastases by somatostatin receptor scintigraphy has also been shown to be as high as 93 per cent. These data support the contention that somatostatin receptor scintigraphy has a potentially important role in the imaging of neuroendocrine malignancies, particularly for the detection of extrahepatic and occult intrahepatic metastases.

Patient selection is less well defined for patients with neuroendocrine liver metastases when compared with colorectal carcinoma. In general, patients with neuroendocrine liver metastases that are potentially resectable should be resected. The 5-year survival rates following resection for this tumor are excellent, with an average of 70 per cent. The survival rate is double when compared with patients who are not resected. Equally as important, resolution of the associated endocrinopathy was seen in 90 to 95 per cent of these patients. Patients with small to moderate-sized low-volume metastases who are not candidates for resection, for anatomic reasons, should be considered for either cryoablation or radiofrequency ablation. For patients with disseminated liver metastases, which are not amenable to resection or ablation, hepatic transplantation is an alternative. In a recent review of 103 patients undergoing liver transplantation for neuroendocrine metastases there was a 5-year survival rate of 47 per cent. The disease-free survival in this group was unfortunately only 24 per cent. Those patients who did well were under the age of 50 with metastases isolated to the liver. These data support the conclusion that transplantation can provide good long-term palliation and occasional cure in selected patients with hepatic metastases from neuroendocrine tumors.

Non-surgical palliative options have also been successful for treatment of neuroendocrine liver metastases. Hepatic artery emboliza-tion without chemotherapy has been able to produce an objective tumor response in from 50 to 60 per cent of patients, with a median duration of response of approximately 12 months and a 5-year survival rate of 60 per cent. The addition of chemotherapy, usually doxorubicin, mixed with lipiodol and coinjected with the occlusive substance improves the tumor response rate to 60 to 100 per cent and improves symptoms (from tumor and endocrinopathy) in 70 to 100 per cent of patients. Side-effects following embolization are common and are as described for treatment of hepatoma. The incidence of liver failure (10 to 15 per cent) is much lower than for hepatoma and is a reflection of normal liver function in patients with neuroendocrine metastases.

Neuroendocrine tumors have been relatively responsive to chemotherapy, particularly streptozotocin. Response rates for single-agent streptozotocin range from 40 to 60 per cent. The addition of doxorubicin to streptozotocin improves the response rates up to 70 per cent and the median duration of survival to 18 months. These results are slightly better than the combination of streptozotocin and 5-fluorouracil, except for gastrinoma. The combination of streptozotocin, 5-fluorouracil, and doxorubicin may produce the highest response rates, but the data from several series show a wide range of variation. Major side-effects from streptozotocin include renal dysfunction (20 to 70 per cent) and hepatic dysfunction (30 per cent). Hormonal therapy with the somatostatin analog octreotide is effective in controlling symptomatic endocrinopathy in most patients. This drug has some therapeutic effect with tumor stabilization, seen in up to 50 per cent of patients.

Liver metastases from other primary tumors

Liver metastases from primary malignancies, others than colorectal and neuroendocrine, are usually a part of a systemic metastatic dissemination and rarely the focus of liver-directed therapy. On those rare occasions, surgical opinion will be sought about a patient with an excellent performance status who has low-volume metastases confined to the liver. The data on these patients are limited to a few small retrospective studies of very highly selected patients. In these studies, the overall 5-year survival rates range from 15 to 37 per cent. Analysis of prognostic criteria is difficult, although patients who underwent a curative resection, had a single metastasis, had no extrahepatic metastases, and presented with metachronous not synchronous metastasis had a better survival. In general, treatment of a single or low-volume metastasis may be considered in highly selected patients. Selection criteria include: the patient has been or is being treated with standard therapy for the particular metastasis; the metastasis has been stable in size or slowly growing over the period of chemotherapy or observation; there is no evidence of extrahepatic metastases following thorough clinical and radiologic evaluation; the patient has an excellent performance status; and the liver metastasis will determine patient survival far in advance of other potential metastatic disease. The relative roles of resection and ablation are not well defined, therefore resection should be pursued whenever possible.

Of the tumor types resected, patients with Wilm's tumors, renal cell carcinoma, and testicular tumors had the best results. Patients with breast carcinoma, sarcomas, adrenocortical carcinoma, and gynecologic cancers had less favorable results, but appeared to do better than those patients with gastrointestinal primaries, particularly those of the stomach and pancreas.

Patients with malignant gastrointestinal stromal tumors (gastro-intestinal sarcomas) commonly present with metastases confined to the liver. Although resection in these patients is palliative, it may extend their median survival up to 5 years and is indicated, given the variable natural history of this tumor and lack of effective alternative therapy.

Fifty per cent of patients with uveal melanoma may present with liver metastases as the sole or initial site of dissemination. Although the median survival of these patients is only 5 months, selected patients benefit from liver-directed therapy. The majority of patients are treated with chemoembolization and a 36 per cent response rate has been shown using cisplatin-based regimens. Palliative resection may be considered for those patients with large symptomatic metastases or who are not candidates for chemoembolization. Prolonged survival following resection has been seen in rare anecdotal reports.

30.5 The Budd-Chiari syndrome

J. Michael Henderson

Budd–Chiari syndrome encompasses a group of disorders caused by obstruction to hepatic venous outflow. The range of presentations of the clinical syndrome is from mild, non-specific, upper abdominal symptoms to a fulminant course with extensive hepatic necrosis. Budd originally described the pathologic features of hepatic vein thrombosis in 1846 while the clinical syndrome of hepatomegaly, ascites, and abdominal pain was described by Chiari in 1899. However, the syndrome now more broadly includes any thrombotic or non-thrombotic occlusion at the hepatic veins or the suprahepatic inferior vena cava leading to liver outflow obstruction. The venous outflow obstruction results in marked elevation of sinusoidal pressure, intense congestion of the liver, progressive necrosis of the hepatic parenchyma, and hepatocellular death.

The investigation and management of Budd–Chiari syndrome depends on a multidisciplinary approach with input from hepatology, hematology, radiology, and surgery. The rarity of this syndrome often leads to a delay in diagnosis, but suspicion of hepatic venous outflow obstruction mandates a careful work up with the priorities of defining the following.

1.                               Is there a mechanical outflow obstruction?

2.                               Is there ongoing acute or chronic liver damage?

3.                               What is the underlying etiology for the syndrome?

4.                               What are the treatment options?

This chapter will define a method for working through these steps based on current data.

Pathophysiology

Budd–Chiari syndrome is caused by obstruction to hepatic venous outflow. This obstruction means that the liver sinusoids cannot drain while blood continues to flow into the liver. This results in congestion of the sinusoids, increased sinusoidal pressure, hepatocyte necrosis, and progressive liver damage. If this passes to the chronic phase, centrilobular fibrosis results. Untreated, patients die from progressive liver damage over several months to years.

The normal physiology of hepatic venous drainage is through the right, middle, and left hepatic veins, with the caudate lobe having separate short veins draining into the inferior vena cava. In addition, there are usually several small hepatic veins passing directly from the right lobe into the intrahepatic inferior vena cava. In Budd–Chiari syndrome, if outflow obstruction only affects some of these veins, the segments of the liver that maintain venous drainage may be spared, will hypertrophy significantly, and there is therefore a more chronic rate of progression of the total syndrome. The extent of hepatic venous thrombosis correlates with the clinical manifestations of the syndrome and its prognosis. When there is total obstruction to all hepatic venous outflow, the severe congestion and swelling will stretch Glisson's capsule with severe pain and a fulminant course. On the other hand, the more common sequence is for one or two of the major hepatic veins to occlude and the symptoms may be less severe leading to delay in diagnosis until there is further obstruction of other major venous outflow.

Veno-occlusive disease of the liver presents with different pathophysiology but has similar outcomes. Most common in patients undergoing bone marrow transplantation, this syndrome results in a non-thrombotic occlusion of small sublobular branches of the hepatic veins causing a sinusoidal outflow obstruction. This in turn can lead to hepatocyte necrosis and a full-blown syndrome.

Etiology

Etiologies are listed in

Chronic myeloproliferative disorders

These are the most common etiologic factor in Budd–Chiari syndrome. Polycythemia rubra vera is the most common of these although other myeloproliferative disorders such as myelofibrosis, essential thrombocythemia, and chronic lymphocytic leukemia may cause hepatic vein thrombosis. These disorders are characterized by a common origin of a malignant stem cell change followed by proliferation. The outcome of this process is an increased viscosity, a low-grade disseminated intravascular coagulation, and intravascular thrombosis. The liver is the main site of clearance of plasminogen activator, and a deficiency of hepatic antiplasmin may contribute to localization of thrombosis in the hepatic veins. Evaluation and detection of these hematologic disorders is more difficult in patients with Budd–Chiari syndrome than in their usual occurrence because of associated portal hypertension with increased plasma volume and splenomegaly which may mask the increased red blood cell mass and changes of thrombocythemia. Early detection of an underlying myeloproliferative disorder can be made using spontaneous endogenous erythroid colony formation in vitro and/or in bone marrow biopsies. Up to three-quarters of patients with 'idiopathic' Budd–Chiari syndrome have been shown to fall into this category.

Webs

Webs in the suprahepatic inferior vena cava or hepatic venous outflow are a common cause of Budd–Chiari syndrome in the Far East and South Africa. In the United States, webs should be considered in immigrants from that region but are not frequently seen in the native populations.

Tumors

Tumors as a cause of Budd–Chiari syndrome account for approximately 10 per cent of cases. Most of these tumors are intrahepatic hepatocellular carcinomas that directly invade the hepatic veins. However, other tumors such as renal and/or adrenal tumors may involve the vena cava and/or the hepatic veins themselves. It is the mechanical obstruction caused by these tumors with intrinsic or extrinsic compression of the hepatic veins that lead to Budd–Chiari syndrome.

Pregnancy and oral contraceptives

Pregnancy and oral contraceptives are cited in the etiology of Budd–Chiari syndrome and it is usually in the first 2 months after delivery that pregnancy is implicated as a risk factor. It has been postulated that increased levels of factors VII and VIII along with increased fibrinogen may be etiologic. While the reported risk in patients on the oral contraceptive pill is 2.4 over age-matched controls, other etiologic factors should be sought as some of these patients may have an underlying hematologic disorder.

Paroxysmal nocturnal hemoglobinuria

Paroxysmal nocturnal hemoglobinuria may accompany other severe hematologic disorders such as aplastic anemia and the acute leukemias. Characterized by complement-induced platelet activation, these patients are markedly hypercoagulable with extensive thrombosis of all outflow tracts and a devastating fulminant course.

Hypercoagulable states

Hypercoagulable states account for a relatively low percentage of patients with Budd–Chiari syndrome. However protein C, protein S, and antithrombin III deficiencies should all be sought in patients with hepatic venous thrombosis and no other defined etiology. More recently, the factor V Leiden mutation has been shown to be a frequent cause of hereditary thrombophilia. A recent analysis has documented a significantly increased prevalence of this mutation in Budd–Chiari syndrome, so it is a further factor which should be sought.

Clinical presentation

Budd–Chiari syndrome is relatively uncommon in Europe and the United States, being much more common in India, South Africa, and the Orient. It can occur at any age, but is most common in the third and fourth decades; it is slightly more common in women than in men. Budd–Chiari syndrome may present in acute, subacute, or chronic forms depending on the factors outlined in the pathophysiology above.

Acute fulminant Budd–Chiari syndrome

This is uncommon and only occurs when there is total obstruction of all venous outflow with severe congestion, hepatocyte necrosis, and liver failure. This usually implies a severe underlying hematologic disorder which must be fully defined in making management decisions.

Subacute Budd–Chiari syndrome

This presents with symptoms over several weeks. Right upper quadrant pain and ascites are the dominant symptoms, but the absence of other stigmas of liver disease such as jaundice, muscle wasting, and spider angiomas often result in failure to make the diagnosis. Hepatomegaly is present, but may be difficult to detect in the face of significant ascites. Splenomegaly is not a feature in early Budd–Chiari syndrome, only occurring as portal hypertension develops later in the course. The most frequent misdiagnoses are of a gynecologic or gastrointestinal malignancy or an intra-abdominal inflammatory process causing the ascites.

Chronic Budd–Chiari syndrome

This presents with portal hypertension and stigmas of chronic liver disease. Ascites, variceal bleeding, and muscle wasting may all be present, and it is usually because 'something does not fit' in the work up that Budd–Chiari syndrome is considered and diagnosed as outlined below.

In all stages of the disease, non-specific symptoms such as general malaise, tiredness, anorexia, and nausea are unhelpful. In considering the clinical presentation of disorders in the differential diagnosis such as malignancies listed above, right-sided cardiac problems, or early diagnosis of other liver diseases, these non-specific symptoms will be similar. It cannot be overemphasized that the diagnosis of Budd–Chiari syndrome depends on a high index of suspicion.

Diagnosis

Laboratory studies, as with the clinical presentation, are overall unhelpful in making a diagnosis of Budd–Chiari syndrome. Liver tests usually show minimal elevation of aminotransferases and bilirubin, a marginal decrease in serum albumin, and a mild prolongation of prothrombin time. Considering the degree of hepatocellular damage that is often seen at biopsy, it is surprising how minimal these laboratory changes appear. The one exception is the unusual patient with fulminant Budd–Chiari syndrome who may show marked laboratory abnormalities. Ascites fluid analysis should be done but the findings are highly variable with total protein from 1.5 to 3 g. The serum to ascites albumin gradient of greater than1.1 g/dl is usually found, but is not diagnostic. The ascites cell count is variable with most patients having fewer than 100 white blood cells/mm3. Spontaneous bacterial peritonitis does not occur in Budd–Chiari syndrome.

Diagnosis depends on a combination of appropriate radiologic imaging and liver biopsy. If the diagnosis is confirmed, then full hematologic evaluation becomes important. The sequence to be followed can therefore be divided into the phases of: (i) Is there a mechanical outflow obstruction? (ii) Is there ongoing or chronic hepatic damage? and (iii) Is there an underlying hematologic disorder?

Radiologic investigation

Radiologic investigation must follow an appropriate sequence. Clinical suspicion of Budd–Chiari syndrome should lead to hepatic ultrasound with Doppler flow studies of the main hepatic veins. In a normal subject, the three major hepatic veins can be readily visualized and phasic flow documented within them. Inability to demonstrate these veins or to only show small and stenotic vessels with no phasic flow raises a high index of suspicion of hepatic vein occlusion. shows ultrasound imaging of hepatic vein with appropriate phasic flow within it. If this can be demonstrated for all major hepatic veins, Budd–Chiari syndrome is excluded. Concurrent with hepatic vein imaging, the portal vein should be visualized to document patency and presence of prograde flow to the liver within it. This is an important further piece of information for management decisions.

Figure 1 Doppler ultrasound of hepatic veins. The patent hepatic vein can be seen and the tracing shows normal phasic flow pattern. If these two components are absent, the diagnosis of Budd–Chiari syndrome must be entertained.

Other radiologic imaging modalities such as hepatic scintigraphy, computed tomography, and magnetic resonance imaging have all been used both to assess liver morphology and for vascular imaging in Budd–Chiari syndrome. While each of these may provide some supportive evidence for Budd–Chiari syndrome, they are not first-line diagnostic modalities and by and large are unnecessary.

The gold standard for radiologic diagnosis of Budd–Chiari syndrome is hepatic venography and this should be performed if the Doppler ultrasound is equivocal or strongly supports the diagnosis. Hepatic venography may be done either through a transfemoral or a transjugular approach, and should attempt to cannulate each of the major hepatic veins directly. Pressure measurements are of little value in making the diagnosis as reliable pressures cannot be measured in the occluded or stenotic veins. Contrast material should be injected at each site and will give the typical spider's web appearance that is characteristic of Budd–Chiari syndrome. The spider's web represents contrast in recannulized vessels coursing on the surface of the liver which are collaterals that are attempting to decompress the congested sinusoids. In involved segments, no normal named hepatic vein can be identified. As indicated above, the disease may only affect one or two of the three major hepatic veins, and it is for this reason that all the major veins must be studied. Venography also includes visual and pressure assessment of the inferior vena cava which may be compressed by the swollen liver or thrombosed. This information helps plan decompressing therapy.

Fig. 2 The typical spider's web of Budd–Chiari syndrome seen by hepatic venography. The interconnecting small branches represent collaterals attempting to decompress the sinusoids. No major hepatic vein is visualized.

Fig. 3 Inferior vena caval compression. The swollen liver of Budd–Chiari syndrome has compressed the inferior vena cava with a resultant pressure gradient from the infrahepatic cava to the right atrium.

The role of celiac and/or superior mesenteric arteriography is more controversial in the work up of patients with Budd–Chiari syndrome. These studies should be used when Doppler ultrasound fails to demonstrate an open portal vein with flow. Arteriography, followed through to the venous phase, is important to document if there is thrombosis of the portal vein and its major tributaries as this may obviate some of the surgical options.

Liver biopsy

This must be performed if the radiologic imaging studies confirm or are highly suspicious for Budd–Chiari syndrome. This is the confirmatory test for a histologic diagnosis in addition to assessing the degree of ongoing hepatocyte necrosis and liver fibrosis. It is often said that the presence of massive ascites and a degree of coagulopathy may make biopsy difficult, but if that is the case, ascites should be drained and the coagulopathy corrected to allow this essential diagnostic step to be taken. Separate biopsies of the right and left lobe should be done to evaluate the degree of involvement of both sides of the liver. Transjugular liver biopsy is not a good option in these patients unless the biopsy needle can be advanced some distance into the occluded hepatic veins to assure adequate tissue samples. The essential features on liver biopsy to be evaluated by the pathologist are the degree of centrilobular congestion, hepatocellular necrosis, degree of lobular collapse, and finally extent of fibrosis and/or cirrhosis.

Laparoscopy has been suggested as a diagnostic modality in evaluating Budd–Chiari syndrome. Its use should be limited to cases where there remains a diagnostic dilemma although it does provide an alternative way for bilobar biopsies under direct vision. Laparoscopy is an adjunctive rather than a primary diagnostic tool.

Hematologic evaluation

Hematologic evaluation is the third major diagnostic step. This is summarized in  and requires the input of an experienced hematologist who understands the interrelation of the Budd–Chiari syndrome with the pathophysiologic changes of portal hypertension and the impact of this on the hematologic diagnostic tests. The newer modalities of spontaneous endogenous erythroid colony formation and measurement of factor V gene for the Leiden mutation should be performed where available.

Management

The management of Budd–Chiari syndrome is divided into two phases, first the treatment of the liver and second the treatment of the underlying etiology. Treatment of the liver damage component is based on biopsy findings. Treatment of any underlying hematologic disorder is an ongoing process that includes management of the underlying hematologic disorder and may include anticoagulation.

The three options in the management of the liver injury are:

·                                 non-surgical management

·                                 surgical decompression

·                                 liver transplantation.

illustrates the main categories of biopsy findings and the associated therapies. The decision on non-surgical treatment or surgical management is based on the biopsy.

Figure 4 Liver biopsy findings. The three broad categories of liver biopsy findings in this figure dictate the management courses.

Non-surgical management must be used with caution as the disease may result in progressive liver damage. shows a liver biopsy with mild Budd–Chiari syndrome with some sinusoidal dilata-tion but minimal evidence of ongoing necrosis. Management of ascites in patients such as this with salt restriction and diuretics is appropriate, but further follow-up with repeat ultrasound and repeat liver biopsies in 3 to 6 months is mandatory. In the acute setting, providing the biopsy does not show significant ongoing necrosis, thrombolytic therapy with streptokinase or urokinase can be undertaken, but again requires careful invasive follow-up. A peritoneal venous shunt does nothing to deal with the basic pathophysiology of Budd–Chiari syndrome and is a purely palliative measure that should not be used unless all other options have been eliminated. Web dilatation with angioplasty may play a role, but again requires reassessment of liver pathology. When non-surgical management is embarked upon, there must be a low index for moving forward to surgical decompression if the follow-up biopsies show progression to necrosis or there is refractory ascites.

Figure 5 Mild Budd–Chiari syndrome of this biopsy shows sinusoidal dilation with minimal evidence of necrosis.

shows an example of acute Budd–Chiari syndrome with ongoing hepatocyte necrosis under both high- and low-power views. This patient needs sinusoidal decompression by side-to-side portal systemic shunt. The principle in the management of this patient is that the sinusoids can be decompressed by using the portal vein as an outflow track from the obstructed sinusoids and any side-to-side type of shunt will suffice. The options are broad. A side-to-side portacaval shunt will be adequate if the inferior vena cava is not obstructed. Equally, a mesocaval shunt is an infrahepatic shunt that will decompress the sinusoids when there is no caval obstruction. However, if there is severe caval obstruction, as shown by a cava to atrial pressure gradient greater than 20 mmHg, a mesoatrial shunt may be required to decompress the sinusoids. These shunts are illustrated in. Other options are available to decompress the sinusoids. Transjugular intrahepatic portal systemic shunts (TIPS) have been used in Budd–Chiari syndrome, applying the same principle of the portal vein being the outflow track from the obstructed sinusoids. In the enlarged liver of Budd–Chiari syndrome, TIPS need to be long, often with two or three stents, and if there is an underlying thrombotic problem, careful monitoring is required to assure continued patency. Are mesoatrial shunts still indicated? The issue is important in that this is a complex procedure with a long synthetic graft. The availability of intravascular stents to stent open an obstructed inferior vena cava may obviate the need for mesoatrial shunts by combining an infrahepatic portacaval or mesocaval shunt with an intrahepatic inferior vena cava stent.

Figure 6 Acute Budd–Chiari syndrome. The low- and high-power views show the marked sinusoidal congestion, ongoing hepatocyte necrosis, and evidence of severe liver injury.

Fig 7 Side-to-side infrahepatic shunts. Portacaval, mesocaval, and mesorenal shunts are illustrated that all serve to use the portal vein as a decompressive route from obstructed sinusoids in Budd–Chiari syndrome.

Fig. 8 Mesoatrial shunt. A long synthetic poly(tetrafluoroethene) (PTFE) graft is taken from the superior mesenteric vein in front of the liver, through the diaphragm, and anastomosed to the right atrium for decompression of the liver using the portal vein as an outflow tract from the sinusoids.

From the pathophysiologic point of view, any type of decompression of the sinusoids will halt the ongoing necrosis, stabilize the liver disease, and relieve the symptoms of Budd–Chiari syndrome in the acute setting illustrates the third type of biopsy that may be seen in Budd–Chiari syndrome with severe fibrosis and cirrhosis. There are only small islands of regenerative nodules of hepatocytes in this densely fibrotic liver. This patient requires a liver transplant. No attempt to decompress this liver will relieve the obstruction or alleviate the symptoms. Progression to this degree of scarring is usually the result of recurrent thrombotic episodes involving progressively more hepatic veins over several years. The liver has progressively attempted to compensate for loss of hepatic segments by hypertrophy of the remaining segments before they too become involved in the process. Marked distortion of gross liver anatomy is therefore usually seen on ultrasound, CAT scan, or direct visualization of the liver. Transplant is often difficult in these patients with the recipient hepatectomy being complicated by the many collaterals which have formed from the surface liver to the diaphragm in an attempt to decompress the sinusoids spontaneously. The transplant surgeon needs to be aware of this and take appropriate intraoperative precautions to move through his phase.

Figure 9 Chronic Budd–Chiari syndrome. This liver biopsy shows the liver is almost entirely fibrotic with small islands of hepatocytes as regenerative nodules. This Budd–Chiari syndrome has reached endstage liver disease.

Hematologic management

This must proceed in parallel with management of the liver disease. It is important that any underlying hematologic disease is identified preoperatively, therapy initiated, and decisions made as to optimal timing for surgery considering the risk to the liver and the risk of further vascular thrombosis. Management must be continued long term, and, in addition to specific therapy aimed at any underlying blood disorder, may require long-term anticoagulation.

Outcomes

Budd–Chiari syndrome is rare, and there are no prospective, randomized, controlled trials looking at outcomes. Large series amount to approximately 50 patients. Reports have largely been based on local available expertise. However, in the last two decades there has been increasing recognition of the need to use different therapies and to tailor the management to the findings as outlined in this chapter. The reported experience with non-surgical methods is largely anecdotal with case reports of thrombolytic therapy, or web dilatations, and of conservative management of symptoms.

Experience with TIPS for Budd–Chiari syndrome is growing as exemplified by the Freiburg experience. In this series of 12 patients managed by TIPS, the stent could be placed successfully in all patients and alleviated symptoms in the 10 patients with subacute and chronic disease. The two patients with fulminant disease progressed to liver failure and died. Long-term follow-up with TIPS is still awaited in the series or other reports.summarizes reported experience of some of the larger series of surgical decompression by side-to-side shunts. These series include both infra- and suprahepatic shunts depending on the status of the inferior vena cava. However, some have also included infrahepatic shunts combined with caval stent. Overall, reasonable outcomes have been achieved with survival as indicated in this table, but it has been increasingly recognized that decompression with a surgical shunt may not be optimal therapy when there is significant fibrosis and cirrhosis.

Experience with liver transplantation for Budd–Chiari syndrome is summarized from five centers in. While early experience had fairly significant hospital mortality, usually related to the preoperative treatments used and technically difficult procedures as outlined above, the overall results have improved. The major issue in facing a decision for transplantation is the severity of any underlying hematologic disorder and the potential impact of post-transplant immunosuppression on that disease. Equally, the need for anticoagulation has to be carefully considered in these patients as the correct timing in initiating this is essential to avoid early graft thrombosis. Some of the transplant series have reported significant retransplant rates related to vascular thrombosis following initial transplantation.

Summary

The algorithm in summarizes the overall approach to the diagnosis and management of Budd–Chiari syndrome. Clinical suspicion of Budd–Chiari syndrome should lead to a Doppler ultrasound of the main hepatic veins. Failure to identify these vessels or lack of phasic flow should lead to further evaluation with venography. Liver biopsy should be performed at the same time to evaluate both lobes of the liver. Confirmation of a diagnosis of Budd–Chiari syndrome should lead to definitive management based on the severity of the findings on the biopsy. Treatment options range from minimal intervention for patients with sinusoidal congestion but no ongoing hepatocyte necrosis, through surgical decompression for those with acute Budd–Chiari syndrome and ongoing liver damage, to liver transplantation for those with endstage liver disease.

Fig. 10 Algorithm for the management of Budd–Chiari syndrome.