Chapter 24: Liver & Portal Venous System

Sectors and Segments

The liver develops as an embryologic outpouching from the duodenum. The liver is one of the largest organs in the body, representing up to 2% of the total body weight. The relationship of the liver to the other abdominal organs is shown in Figure 24–1. In classic descriptions, the liver was characterized as having four lobes: right, left, caudate, and quadrate; however, this is an overly simplistic view that fails to consider the more complex segmental anatomy, which is depicted in Figure 24–2.

The anatomical right and left hemilivers are separated by an imaginary line running from the medial aspect of the gallbladder fossa to the inferior vena cava, running parallel with the fissure of the round ligament (Figure 24–3). This division is known as the Cantlie line or the principal plane and marks the course of the middle hepatic vein. The liver is divided into four sectors and eight segments based on the branching of the portal triads and hepatic veins. The structures of the portal triad (hepatic artery, portal vein, and biliary duct) are separate in their extrahepatic course but enter the hepatic hilum ensheathed within a thickened layer of the Glisson capsule.

The three main hepatic veins divide the liver into four sectors, each of which is supplied by a portal pedicle: the right posterior sector (segments VI and VII), the right anterior sector (segments V and VIII), the left medial sector (segment IV), and the left lateral sector (segments II and III) (Figure 24–2). The caudate lobe (segment I) is an exception because its venous drainage is directly into the vena cava and therefore independent of the major hepatic veins. The four sectors delimited by the hepatic veins are called the portal sectors, and these portions of the parenchyma are supplied by independent portal pedicles arising from the right or left main pedicles. The divisions separating the sectors are called portal scissurae, within each of which runs a hepatic vein. Further branching of the pedicles subdivides the sectors into segments. The liver is thus subdivided into eight segments, with the caudate lobe designated as segment I. Segments I-IV comprise the left liver, and segments V-VIII, the right. Each segment is supplied by an independent portal pedicle, which forms the basis of sublobar segmental resections.

Portal Circulation

The portal vein is formed by the confluence of the splenic and superior mesenteric veins at the level of the second lumbar vertebra behind the head of the pancreas (Figure 24–4). It runs for approximately 6-9 cm to the hilum of the liver, where it divides into the main right and left branches. The left gastric vein usually enters the portal vein on its anteromedial aspect just cephalad to the margin of the pancreas, in which case it must be ligated during the surgical construction of a portacaval shunt; in 25% of cases, the left gastric vein joins the splenic vein. Other small venous tributaries from the pancreas and duodenum are less constant but must be anticipated during surgical mobilization of the portal vein.

The inferior mesenteric vein often drains into the splenic vein to the left of its junction with the superior mesenteric vein; alternatively, it may empty directly into the superior mesenteric vein.

In the hepatoduodenal ligament, the portal vein lies dorsal and slightly medial to the common bile duct. Portacaval lymph nodes are encountered along the right lateral aspect of the portal vein, running from the level of the duodenum to the base of the liver and extending posteriorly to the common hepatic artery and celiac axis. These lymph nodes are routinely removed during resections for certain malignancies and must be dissected before a portacaval shunt can be created.

Venous Blood Supply

The anatomy of venous blood supply is shown in Figure 24–2. Both the portal and hepatic venous systems lack valves. The main portal vein terminates in the porta hepatis by dividing into right and left branches. The right branch typically has a short extrahepatic course before subsequently dividing into anterior and posterior sectoral divisions, often high within the porta hepatic or intrahepatically. The left branch has a longer extrahepatic course, running first along the base of segment IV and then entering the umbilical fissure, where it gives rise to branches to segments II, III, and IV; a large branch to the caudate lobe generally arises from the left portal vein prior to its entry into the umbilical fissure. Variations in the normal portal venous anatomy occur but are less common than aberrancies in the arterial supply or the biliary drainage. The most common anomaly of the portal venous system is separate origins of the right anterior and posterior sectoral branches. The left portal vein may drain primarily into the right anterior pedicle.

The hepatic veins represent the final common pathway for the central veins of the lobules of the liver. There are three major hepatic veins: left, right, and middle. The right hepatic vein drains into the vena cava independently, while the middle and left hepatic veins typically join just outside the liver, forming a common trunk. The middle hepatic vein runs in the principal plane (Cantlie line) and provides drainage for segment IV and the anterior sector of the right liver (segments V and VIII). The left hepatic vein drains segments II and III, while the right hepatic vein drains the posterior sector (segments VI and VII) and provides additional drainage to the anterior sector. A small venous tributary runs within the umbilical fissure, providing accessory drainage of segments III and IV and emptying into the left hepatic vein. Several small accessory veins enter the inferior vena cava directly from the posterior aspect of the right lobe and must be carefully ligated during mobilization and resection of the right liver.

Arterial Blood Supply

The common hepatic artery arises from the celiac axis, ascends in the hepatoduodenal ligament, and gives rise to the right gastric, gastroduodenal, and proper hepatic arteries; the proper hepatic artery then divides into the right and left hepatic arterial branches in the liver hilum. The hepatic artery supplies approximately 25% of the 1500 mL of blood that enters the liver each minute; the remaining 75% is supplied by the portal vein.

Variations of the standard arterial anatomy of the liver are relatively common, seen in up to 40% of patients. The most common variants involve different origins of the right or left hepatic artery. A replaced right hepatic artery arises entirely from the superior mesenteric artery and courses posteriorly and to the right of the common bile duct within the porta hepatis, which is in contrast to its normal position to the left of the duct. Recognition of this anatomical variant is critical during operations on the extrahepatic biliary tree. An accessory right hepatic artery also arises from the superior mesenteric artery and is found in the same location within the porta hepatis but supplies only a portion of the right liver; in this situation, a separate right branch arising from its normal position off the proper hepatic artery is typically present. An accessory or replaced left hepatic artery arises from the left gastric artery and enters the liver through the gastrohepatic ligament. Up to 25% of patients have a replaced or accessory right hepatic artery, and a similar proportion have a replaced or accessory left hepatic artery. Within the liver, the hepatic arterial branches travel with segmental bile ducts and portal vein branches, and remain as portal triads in subsegmentations, found at each angle of the hexagonal-shape liver lobules.

Biliary Drainage

The biliary tree arises within the liver from bile canaliculi, formed from specialized segments of the hepatocyte membrane. Bile canaliculi join to form progressively larger channels, resulting in segmental bile ducts that drain each segment. The right anterior and right posterior sectoral ducts unite to form the main right hepatic duct, while the union of ducts draining segments II, III, and IV forms the left hepatic duct. The left hepatic duct typically is longer and has a longer extrahepatic course than the right hepatic duct. Drainage of segment I (caudate lobe) is principally into the left hepatic duct, but additional smaller ducts enter the right hepatic duct or drain directly into the hepatic duct confluence, which is formed by the union of the major lobar ducts to form the common hepatic duct. The common hepatic duct descends within the hepatoduodenal ligament for a variable distance to the point of insertion of the cystic duct of the gallbladder to give rise to the common bile duct.

Anatomic variations in the biliary ductal anatomy are seen in approximately 30% of patients and most often involve the right hepatic duct. In approximately 25% of patients, the duct from the right posterior sector joins the common hepatic duct or the left hepatic duct independently. Recognition of this variation is crucial for the surgeon performing a left hepatectomy for avoiding injury of the right posterior biliary drainage. Variations are far less common on the left side.

Lymphatics

Lymphatics draining superficial lobules of the liver follow a subcapsular course to the diaphragm, to the suspensory ligaments of the liver, or to the posterior mediastinum, while others enter the porta hepatis. Lymphatics arising from lobules deep within the liver travel either with the hepatic veins along the vena cava or with the portal veins into the porta hepatis. Most of the lymphatic drainage of the liver is to the hepatoduodenal ligament.

The liver and biliary tree are innervated by sympathetic fibers arising from T7 to T10 and by parasympathetic fibers from the right and left vagus nerves. The postganglionic sympathetic nerves arise from the celiac ganglia. Fibers derived from the celiac ganglia and vagus nerves form a plexus of nerves that run along the anterior and posterior aspects of the hepatic artery.

Total hepatic blood flow (about 1500 mL/min; 30 mL/min per kg body weight) constitutes 25% of the cardiac output, though the liver accounts for only 2.5% of body weight. About 30% of the hepatic volume is blood (12% of total blood volume). Two-thirds of the flow enters through the portal vein and one-third through the hepatic artery. Pressure in the portal vein is normally low (10-15 cm H₂O [7-11 mm Hg]). The liver derives half of its oxygen from hepatic arterial blood and half from portal venous blood.

Blood flow within the liver is uniform, as demonstrated by an even distribution of microspheres injected into the hepatic artery or portal vein. Hepatic blood flow to the liver is regulated by a number of factors. Muscular sphincters at the inlet and outlet of sinusoids represent a major control point and respond to a number of different stimuli, including the autonomic nervous system, circulating hormones, bile salts, and metabolites. The cells lining the hepatic sinusoids (endothelial cells, Kupffer cells, and stellate cells) can also regulate flow to some extent.

Portal venous and hepatic arterial blood becomes pooled after entering the periphery of the hepatic sinusoid (Figure 24–5). Hepatic arterial flow increases or decreases reciprocally with changes in portal flow; however, portal venous flow does not increase with reductions in arterial flow. This arterial compensatory response is controlled largely by adenosine, which is released into the space of Mall surrounding the hepatic arterial resistance vessels. High concentrations of adenosine dilate the vessels, which increases flow and washes out the adenosine.

Sudden occlusion of the portal vein results in an immediate 60% rise in hepatic arterial flow. The total flow then gradually returns toward normal. On the other hand, sudden reductions in hepatic arterial supply are not immediately met by significant increases in portal vein flow. In both normal subjects and cirrhotics, total hepatic flow, and portal pressure drop following hepatic arterial occlusion. Arterial collaterals develop, and arterial perfusion is ultimately restored.

It is for this reason that interruption of hepatic arterial flow to the right or left liver generally has little impact on hepatic function. The one notable exception is in the setting of biliary obstruction. Decreased hepatic arterial flow to portions of the liver with impaired biliary drainage carries a high risk of hepatic necrosis. Clinically, this is an important consideration in patients undergoing hepatic arterial embolization of liver tumors and in patients undergoing resection of periampullary tumors, where jaundice is common and dissection within the porta hepatic could potentially put the hepatic artery at risk for injury. On the other hand, portal venous flow plays a critical role in maintaining normal hepatic architecture and function. This point is underscored by the observation that occlusion of the right or left portal venous branches results in profound ipsilateral hepatic atrophy and contralateral hypertrophy. Portal vein occlusion is clinically relevant in a number of disease processes, particularly carcinoma of the hepatic duct confluence (hilar cholangiocarcinoma), in which portal venous involvement is common and has important therapeutic implications. Additionally, intentional occlusion of a major portal vein branch (usually the right side) is a procedure being used with greater frequency prior to major hepatic resection, primarily when the regenerative capacity of the future liver remnant (that portion of the liver that remains behind after the resection) is questionable because of either size concerns (too small) or underlying parenchymal disease (steatohepatitis, cirrhosis). By causing atrophy of the liver to be resected, and therefore hypertrophy of the future liver remnant, the risk of postoperative hepatic failure may be reduced.

Liver resection is most commonly indicated for primary and secondary malignant tumors and symptomatic benign tumors; less common indications include traumatic injury, infection/abscesses, and living donor transplantation. Removal of as much as 80% of the normal liver can be performed with the expectation that the liver remnant will regenerate sufficiently for the patient to survive. It must be emphasized, however, that such extensive resections should be considered only in patients with normal hepatic function; those with cirrhosis or significant fibrosis or steatosis (fatty infiltration of the liver) are less likely to tolerate a major hepatic resection. Liver function may be impaired for several weeks after an extensive resection, but the extraordinary regenerative capacity of the liver rapidly provides new functioning hepatocytes. Within 24 hours after partial hepatectomy, cell replication becomes active and continues until the original volume of hepatic tissue is restored. Considerable regeneration occurs within 10 days, and the process is essentially complete by 4-5 weeks. Excised portions of liver are not re-formed; rather, the growth consists of formation of new lobules and expansion of residual lobules. The stimuli for hepatic regeneration are thought to include the following: hepatocyte growth factor, tumor growth factor (TGF)-α, heparin-binding growth factor, hepatopoietin B, and disinhibition by TGF-β₁ (ie, decreased levels of this inhibitor of hepatic growth).

Preoperative Evaluation

Several different disease-related and patient-related factors must be assessed before deciding to proceed with hepatic resection. Among the most important of these is the preoperative functional status of the liver. Cirrhosis is a relative contraindication for partial hepatectomy because the limited reserve of the residual cirrhotic liver may be insufficient to meet essential metabolic demands, and the cirrhotic liver has a reduced capacity for regeneration. Cirrhosis is a particular concern in patients with hepatocellular carcinoma, which frequently arises in the setting of chronic hepatic parenchymal disease. An increasingly important concern in patients with hepatic colorectal metastases is chemotherapy-induced liver damage, which may also impair regeneration of the liver remnant.

Several tests are available to assess hepatic function prior to operation, none of which is perfect. The Child–Pugh classification is the oldest and most widely employed and remains the most useful assessment. The Child–Pugh system classifies hepatic function on the basis of the amount of ascites, the degree of encephalopathy, albumin and total bilirubin levels, and the prothrombin time (INR) (Table 24–1). Originally used to assess mortality related to portosystemic shunts, the Child–Pugh score also predicts mortality in patients with cirrhosis after hepatic resection. In general, only Child–Pugh A and highly selected Child–Pugh B cirrhotics would be candidates for resection. More recently in the United States, to improve allocation of cadaveric liver transplant to cirrhotic patients with the highest risk of death, the Model for End-Stage Liver Disease (MELD) score has been validated. Similar to the Child–Pugh classification, the total bilirubin level, and the INR are accounted for, combined with the serum creatinine level. The MELD score was originally devised to predict mortality of patients awaiting liver transplantation but is also effective for assessing liver function in patients undergoing resection. The indocyanine green clearance test is commonly used in centers outside North America but has not been proven superior to the Child–Pugh scoring system.

Extent of Hepatic Resection

Hepatic resections are classified as anatomical (based on the segmental liver anatomy) or nonanatomical. Wedge resections, enucleations, and resectional debridement of devitalized tissue are examples of the latter. In general, anatomical resections are preferred because they are associated with lower blood loss and, when performed for malignancy, a lower incidence of positive resection margins.

Major resections must be performed in accordance with the segmental anatomy (Figure 24–2). Major resections (right or left hepatectomy or extended hepatectomy) are commonly performed; however, the segmental anatomy of the liver allows smaller resections or bilateral resections to be performed when necessary and appropriate. For example, in selected situations, a resection of the anterior (segments V and VIII) or posterior (segments VI and VII) sectors may be performed rather than sacrificing the entire right liver. Such parenchymal-sparing resections on one side would then allow a resection of part of the contralateral lobe, if necessary. Sequential, two-stage hepatectomy has also proven to benefit patients in the setting of multiple, bilateral liver metastases of colorectal cancer origin, allowing time for the liver remnant to regenerate and compensate for the second resection.

The terminology and extent of the common types of major resections are in Figure 24–2. The operation entails removal of a lobe or segment with its afferent and efferent vessels while avoiding injury to vessels and bile ducts supplying the remnant tissue.

Most elective hepatic resections can be performed through an abdominal incision, although selected situations (very large right lobe tumors) are probably best performed with a thoracoabdominal approach. Laparoscopic resections are being performed with greater frequency, although the open approach is most common and remains the standard. The best perioperative results are obtained by minimizing blood, which is accomplished by: (1) achieving vascular inflow and outflow control prior to parenchymal transaction; (2) performing careful division of the liver with precise control of intrahepatic vascular structures; and (3) using low central venous pressure anesthesia, which reduces hepatic venous blood loss. Clamping of the portal inflow pedicle (Pringle maneuver) for periods of 10-15 minutes is commonly used to minimize blood loss via intrahepatic arterial and portal venous branches, although hepatic venous bleeding is unaffected.

Preoperative Portal Vein Embolization

As discussed previously, preoperative portal vein embolization is a technique that can be used to potentially improve the safety of major hepatic resections. By inducing hypertrophy of the future liver remnant prior to operation, the risk of postoperative liver failure is potentially reduced. The risk of such complications increases significantly with resections that leave behind a liver remnant of less than 25% in patients with normal liver or less than 40% in patients with liver disease.

Postoperative Course

Patients submitted to major resections require close monitoring for the first several postoperative days; however, a prolonged stay in the intensive care unit is unnecessary in most cases. The major concern in the immediate postoperative period is hemorrhage, although in practice, reoperation for bleeding is rarely necessary. Patients without cirrhosis usually exhibit some metabolic changes consistent with mild liver insufficiency, but these quickly normalize, and they are often ready for discharge on the seventh or eighth postoperative day. In the presence of significant hepatic parenchymal disease (ie, cirrhosis, fibrosis, steatosis) or septic complications, postoperative liver function may be significantly impaired.

Many of the postoperative abnormalities can be predicted on the basis of the liver’s normal function. The serum bilirubin often increases after major resections but returns to normal as regeneration progresses. A persistent or rising serum bilirubin level should raise concern for a perihepatic fluid collection (biloma) or hepatic failure (especially if other measures of hepatic function are also deteriorating). The serum albumin level usually falls, and the prothrombin time often increases; treatment of the latter with fresh frozen plasma is generally needed only when the INR is markedly elevated (> 2). Some patients may develop ascites, which can be treated with diuresis. Although the liver’s glycogen stores are necessarily reduced after a major partial hepatectomy, hypoglycemia is almost never a problem postoperatively; normoglycemia can be easily maintained with 5% dextrose solutions, and profound hypoglycemia should raise concern for liver failure. Serum levels of phosphate, magnesium, and potassium often decrease during the first several postoperative days and require replacement. The liver enzymes (aspartate aminotransferase [AST], alanine aminotransferase [ALT]) are usually increased in the first few days after operation and then normalize. By contrast, the alkaline phosphatase is often initially normal and then increases and can remain elevated for several days to weeks after surgery.

Complications

Complications may occur in up to 40% of patients after major liver resection (≥ 3 segments), but many are relatively minor, and the overwhelming majority are readily managed and resolve without sequelae. Liver-related complications are the most frequent; perihepatic fluid collections requiring drainage occur in approximately 10%-15% of patients. Relative hepatic insufficiency (hyperbilirubinemia, ascites, coagulopathy) is common but resolves in most patients as the liver regenerates; however, hepatic failure is distinctly uncommon in high-volume centers. Pulmonary complications are also seen with some frequency, underscoring the need for aggressive pulmonary toilet postoperatively. The most common pulmonary problems are symptomatic pleural effusions or atelectasis; pneumonia is infrequent. Despite the potential complications associated with major liver resection, mortality rates are low, typically on the order of 1%-3% in high-volume centers. Less extensive liver resections (< 3 segments) are associated with even lower morbidity and mortality rates.

HEPATIC TRAUMA

The liver is injured in approximately 5% of all trauma admissions. Based on the mechanism of injury, liver trauma is classified as penetrating or blunt. Penetrating wounds, constituting more than half of cases, are typically due to projectiles (such as bullets or shrapnel) or knives. In civilian practice, most of these tend to be clean wounds that are dangerous because of intra-abdominal bleeding but do not result in much devitalization of liver tissue. In contrast, high-velocity projectiles, commonly associated with military weapons, are associated with greater energy that is transferred to the abdominal viscera and can shatter the parenchyma, even if the projectile does not enter the liver directly.

Blunt trauma can be inflicted by a direct blow to the upper abdomen or lower right rib cage or can follow sudden deceleration, as occurs with a fall from a great height. Most often a consequence of automobile accidents, direct blunt trauma tends to produce explosive bursting wounds or linear lacerations of the hepatic surface, often with considerable parenchymal destruction. The stellate, bursting type of injury tends to affect the posterior and superior aspect of the right liver (segments VI, VII, and VIII) because of its relatively vulnerable location, convex surface, fixed position, and concentration of hepatic mass. Damage to the left liver is much less common than damage to the right. Injuries that involve shearing forces can tear the hepatic veins where they enter the liver substance, producing an exsanguinating retrohepatic injury in an area difficult to surgically expose and repair.

The improvement in image quality and rapidity of execution of CT scans has transformed the initial management of trauma patients over the past few decades. For patients who can be hemodynamically stabilized with initial resuscitation, CT allows staging of the liver injury, in addition to all other structures from the neck to the pelvis. The staging system described in Table 24–2 is used to categorize liver injuries and provide a common language in order to allow comparisons of results of treatment between institutions. Patients who cannot be stabilized must go directly to the operating room.

There are two main management approaches to traumatic liver injury: nonoperative, which can be combined with angiography and selective embolization, or operative. When angiographic embolization is used as adjuvant to nonoperative management, approximately 85% of patient with blunt hepatic trauma can be successfully managed. A major limitation of arterial embolization is its inability to control bleeding from major venous injuries. Penetrating trauma, however, most often requires surgical intervention. The principal surgical goals are to stop bleeding and debride devitalized liver. Because some degree of liver failure is common postoperatively, efforts should be made during each step to maintain adequate oxygenation and perfusion of the liver. Also, when one is debriding liver tissue, care should be taken to avoid injury to the vascular supply of adjacent viable parenchyma.

Clinical Findings

A. Symptoms and Signs

The clinical manifestations of liver injury are those of hypovolemic shock: hypotension, decreased urinary output, low central venous pressure, and, in some cases, abdominal distention. Patients managed nonoperatively are admitted in a monitored setting and closely followed with serial examinations and hematocrit assessments. Patients who develop peritoneal signs on physical examination or the onset of hemodynamic instability denote the failure of nonoperative management and mandate surgical intervention.

B. Laboratory Findings

With major injuries, particularly those associated with disruption of hepatic veins, the rate of blood loss is usually so rapid that anemia does not develop. Leukocytosis greater than 15,000/μL is common following rupture of the liver from blunt trauma. Polytraumatized patients most often develop acidosis and coagulopathy.

C. Imaging Techniques

Focused abdominal sonography for trauma (FAST) in unstable patients has a sensitivity of 97% for detecting hemoperitoneum larger than 1 L and can direct surgical intervention in patients going directly to surgical management. The exact location of the injury often cannot be reliably identified with FAST. There is no defined role for FAST in stable patients.

High resolution CT scan with intravenous contrast enhancement should be obtained in all stable patients suspected of having a hepatic injury. The CT provides a detailed evaluation of the liver injury and its extent, an estimate of the amount of blood loss, and can demonstrate a contrast blush from the liver parenchyma. The findings are useful for triaging, since minor injuries rarely require surgical treatment, whereas extensive injuries usually do. One must exercise caution, however, in using CT estimates of injury grade, because they correlate poorly (ie, they both understage and overstage) with what is found at surgery. CT scanning is also useful for identifying injuries to other organs, which are not uncommon, particularly in the setting of high velocity blunt trauma.

Angiography is generally not helpful in the acute setting for the diagnosis of liver injury, but may be used as an interventional adjunct in patients who are potential candidates for nonoperative management.

Treatment

Regardless of the grade of blunt liver injury, the hemodynamic stability of patients dictates whether or not a liver trauma should be managed operatively. In contrast, only highly selected patients with penetrating trauma can be managed nonoperatively. In the absence of injury to the spleen and the kidneys, CT findings most often associated with successful nonoperative management include small hemoperitoneum, contained subcapsular or intrahepatic hematoma, unilobar fracture, absence of devitalized liver, minimal intraperitoneal blood, and absence of injuries to other intra-abdominal organs. Failure rate of the nonoperative approach increases with the grade of the liver injury, reaching one out of four patients with grade V blunt injury. Conversely, it should be kept in mind that low-grade injuries can bleed significantly. Drop in hematocrit in stable patients should prompt a CT scan to verify that the lesion is stable rather than expanding, and if a blush of intravenous contrast is associated with the liver injury, often bleeding can be addressed by angiographic embolization.

Most patients with CT or clinical evidence of active bleeding or a major injury, however, require prompt exploration. Most minor parenchymal lacerations have stopped bleeding by the time operation is performed. In the absence of active hemorrhage, these wounds should not be sutured. Active bleeding should be managed by clipping or direct suture of identifiable vessels, if possible, rather than by mass ligatures. Subcapsular hematomas often overlie an active bleeding site or parenchyma in need of debridement and should be explored even though the injury appears to be tamponaded and of limited severity. Blunt injuries associated with substantial amounts of parenchymal destruction may be particularly difficult to manage. Rarely, a very severe pulverizing injury requires formal partial hepatectomy.

Temporary occlusion of the hepatic artery and portal vein can be done quickly by placing a vascular clamp around the entire hepatoduodenal ligament (Pringle maneuver). This can be done for periods of 15-20 minutes and reduce the hemorrhage sufficiently to permit more accurate ligation of bleeding vessels. With major hepatic venous injuries, however, a Pringle maneuver has little effect, and precise repair of the injury may not be possible. Absorbable gauze mesh (eg, polyglycolic acid) can sometimes be wrapped around an injured lobe and sutured in a way that maintains pressure and tamponades the bleeding; this is difficult to accomplish without rendering the involved liver ischemic, however, and such an approach is rarely applicable. In some cases, control of arterial hemorrhage requires ligation of the hepatic artery or one of the accessible major branches (ie, right anterior or right posterior sectoral branches) in the hilum.

The most difficult problems involve lacerations of the major hepatic veins behind the liver. With such injuries, temporary clamping of the inflow vessels has no impact on back-bleeding from the inferior vena cava and does not allow adequate inspection and repair of the injured vessels. For persistent bleeding, the abdominal incision can be extended into a median sternotomy to improve exposure. An ancillary technique, which is used only rarely and has been associated with high mortality rates, is to place a tube through the atrial appendage into the inferior vena cava past the origin of the hepatic veins. Appropriately placed ligatures around the supra- and infra-hepatic vena cava combined with the Pringle maneuver permit total isolation of the liver circulation. Resection of the right liver improves exposure of the retrohepatic vena cava but is difficult to perform in the face of massive hemorrhage.

In many cases, when bleeding is difficult to control, and especially when other injuries must be addressed, damage control is the best strategy and involves packing the liver to achieve hemostasis. The packs are generally left in place for 48-72 hours, during which time the patient remains sedated and intubated in the intensive care unit where adequate resuscitative measures are undertaken to correct hypothermia, acidosis, and coagulopathy. The packs are removed in the operating room; if persistent bleeding is noted, definitive repair of the injury can then be performed in a somewhat more controlled fashion.

The majority of patients who come to operation require little in the way of surgical intervention to control bleeding; drainage of substantial liver lacerations and other injuries is reasonable, since bile leakage can occur. For superficial liver injuries, bleeding can often be controlled with direct compression, topical agents, electrocautery or argon beam coagulation. Suture ligation of bleeding hepatic vessels and debridement of devitalized tissue are indicated in about 30% and 10% of cases, respectively. More extensive procedures are indicated even less often.

Penetrating injuries that also involve the small bowel or colon may result in contamination of perihepatic fluid or devitalized liver tissue, leading to a subhepatic abscess. Placement of drains may help prevent this problem, but a high index of suspicion should be maintained during the postoperative period.

Postoperative Complications

With present techniques, hemorrhage at laparotomy is rarely uncontrollable except with retrohepatic venous injuries. Patients who rebleed early from the liver wound after initial suture ligation should be treated by reexploration and packing, in most cases; rarely is a major resection required. Angiography and CT scanning may provide useful diagnostic information preoperatively in such patients.

Bile leaks can follow both blunt penetrating liver injuries when the biliary system is disrupted. Most bilomas can be treated with image-guided percutaneous drainage. Endoscopic retrograde cholangiopancreatography may help identify the site of injury and may be therapeutic in some cases, since stents can be deployed in selected bile ducts and sphincterotomy of the sphincter of Oddi can relieve pressure in the biliary system. It should be noted, however, that such maneuvers have not been shown to expedite the resolution of biliary injuries, provided that adequate drainage of the biloma has been achieved.

Subhepatic sepsis develops in about 20% of cases; it is more frequent if a major hepatectomy has been performed. Abscess can occur after blunt trauma, especially with concomitant enteric injuries. Most abscess can be managed with percutaneous drainage and antibiotic therapy.

Hemobilia may be responsible for gastrointestinal bleeding in the postoperative period and can be diagnosed by selective angiography. Treatment consists of embolization through the arteriography catheter.

Prognosis

The death rate of 10%-15% following hepatic trauma depends largely on the type of injury and the extent of associated injury to other organs. About one-third of patients admitted to the emergency department in shock cannot be saved. Only 1% of penetrating civilian wounds are lethal, whereas a 20% death rate attends blunt trauma. The death rate in blunt hepatic injury is 10% when only the liver is injured. If three major organs are damaged, the death rate is close to 70%. Bleeding causes more than half of deaths associated with liver trauma.

SPONTANEOUS HEPATIC RUPTURE

Spontaneous rupture of the liver is not common. Most cases of ruptured diseased liver are due to hepatic tumors. Approximately 5% of hepatocellular carcinoma can rupture and manifest as hemoperitoneum. Hepatic adenoma larger than 5 cm carries a risk of spontaneous bleeding of approximately 20%-40%.

Many cases of ruptured normal liver occur during or after pregnancy and are related to preeclampsia-eclampsia and/or HELLP syndrome (hemolysis, elevated liver enzymes, low platelet count). Hepatic rupture should be suspected in any pregnant or postpartum patient (especially if hypertensive) who complains of acute discomfort in the upper abdomen.

Spontaneous rupture has also been reported in association with a number of other conditions, including hepatic hemangioma, typhoid fever, malaria, tuberculosis, syphilis, polyarteritis nodosa, and diabetes mellitus. Rupture of the liver in the newborn is related to birth trauma in larger infants after difficult deliveries. The typical progression is intrahepatic hemorrhage expanding to subcapsular hematoma and eventually capsular rupture and free intra-abdominal hemorrhage.

The diagnosis is best made by CT scanning. Angiography and hepatic artery embolization can be quite effective for controlling hemorrhage in the setting of spontaneous rupture. Emergency laparotomy and intraoperative management (as one would for a traumatic liver injury) are reserved for those who fail hepatic artery embolization or are unsuitable for the procedure. Patients who experience hemoperitoneum from spontaneous rupture of hepatocellular carcinoma appear to be at increased risk for peritoneal dissemination of tumor.

PRIMARY LIVER CANCER

Liver malignancy may arise from hepatocytes (hepatocellular carcinoma [HCC], the most common) or biliary epithelial cells (intrahepatic cholangiocarcinoma). Tumors arising from both cell types (mixed hepatocellular carcinoma/cholangiocarcinoma) have also been described. Neonates may also develop a variant of hepatocellular carcinoma called hepatoblastoma because it is morphologically similar to fetal liver and the occasional presence of hematopoiesis. Primary malignancy arising from other liver cell types (endothelial cells, stellate cells, neuroendocrine cells, or lymphocytes) is exceedingly rare.

Primary hepatic cancer is relatively uncommon in the United States, with an estimated 28,720 new cases in 2012. The incidence of HCC has tripled during the past two decades, largely the result of hepatitis C infection outbreak. The 5-year survival rate of patients with HCC remains under 16%, ranking this tumor amongst the 10 leading cause of cancer related death in both men and women in the United Sates. In Asia and Africa, primary liver cancer is extremely common and in some areas represents the single-most frequent abdominal tumor and the most common cause of cancer-related death. The etiologic factors in these high-risk areas are environmental or cultural, since persons of similar racial background in the United States are at only slightly greater risk than Caucasians.

Hepatocellular Carcinoma

Chronic hepatitis B and C virus (HBV and HCV) infection is the principal etiologic factor worldwide for HCC. Patients chronically seropositive for HBsAg constitute a high-risk group for development of hepatocellular carcinoma. Hepatitis B virus DNA has been detected integrated into the genome of host hepatocytes and hepatoma cells and has a direct oncogenic effect. Patients with chronic hepatitis B infection may therefore develop hepatocellular carcinoma in the absence of cirrhosis; by contrast, HCC arising in the setting of chronic hepatitis C infection is typically associated with cirrhotic change. Cirrhosis from almost any cause (eg, alcoholism, hemochromatosis, α₁-antitrypsin deficiency, or primary biliary cirrhosis) is associated with an increased risk of hepatocellular carcinoma, and the great majority of these tumors arise in the setting of chronic underlying liver disease. With the increase in obesity in the United States, nonalcoholic fatty liver disease (NAFLD) has become the one of the most common causes of chronic liver disease; a subgroup of these patients with nonalcoholic steatohepatitis (NASH) are at high risk of cirrhosis and malignant transformation. Certain fungal metabolites called aflatoxins have been shown experimentally to be capable of producing liver tumors. These substances are present in staple foods (eg, ground nuts and grain) in some parts of Africa where hepatocellular carcinoma has a high incidence.

HCC constitutes about 85%-95% of primary hepatic cancers. Previously, differences in morphology were used to separate tumors into three types: mass-forming type, characterized by a single predominant mass clearly demarcated from the surrounding liver, occasionally with small satellite nodules; nodular type, composed of multiple nodules, often distributed throughout the liver; and a diffuse type, characterized by infiltration of tumor throughout the remaining parenchyma. A number of staging systems for hepatocellular carcinoma are in current use when considering treatment options for patients with HCC: the Barcelona Clinic Liver Cancer (BCLC), Cancer of the Liver Italian Program (CLIP), Okuda, Chinese University Prognostic Index (CUPI), and Japan Integrated Staging (JIS); these classifications differ on their assessment of tumor burden, related symptoms, and underlying liver dysfunction, and most cannot predict the survival in patients with advanced HCC. The 7^th edition of the American Joint Commission on Cancer tumor-node-metastasis (TNM) staging system can be used after pathological examination of the resected liver for determining the prognosis of patients after transplantation. About 50% of resectable tumors are surrounded by a fibrous capsule, which develops as a result of compression of adjacent liver stroma. Encapsulated tumors exhibit a lower incidence of tumor microsatellites and venous permeation compared with nonencapsulated tumors, and the finding is a favorable sign. An uncommon variant, fibrolamellar hepatocellular carcinoma, contains numerous fibrous septa and may resemble focal nodular hyperplasia (FNH). Fibrolamellar hepatoma occurs in a younger age group (average 25 years) and is not associated with cirrhosis or hepatitis virus infection.

A large proportion of patients have intrahepatic or extrahepatic metastases at presentation. Multiple intrahepatic tumors can arise as a result of infiltration of the portal venous system with subsequent dissemination of tumor cells. Vascular invasion is more common with larger tumors (> 5 cm). The extrahepatic sites most commonly involved with metastatic disease include the hilar and celiac lymph nodes and the lungs; metastases to bone and brain are less common, and peritoneal disease (ie, carcinomatosis) is distinctly unusual. Major portal or hepatic veins are often invaded by tumor, and venous occlusion may occur as a result.

Microscopically, there is usually little stroma between the malignant cells, and the tumor has a soft consistency. The tumor may be highly vascularized, a feature that rarely can result in massive intraperitoneal hemorrhage following spontaneous rupture.

Intrahepatic Cholangiocarcinoma

Cholangiocarcinoma makes up a small fraction of primary liver cancers, although several reports have documented a marked increase in incidence worldwide. Unlike hepatocellular carcinoma, intrahepatic cholangiocarcinoma is less frequently associated with cirrhosis. Primary sclerosing cholangitis is a predisposing condition in a small minority of patients. Widespread infection with liver flukes (Clonorchis sinensis) is at least partly responsible for the higher incidence of these tumors in some parts of Asia. Emerging evidence has implicated chronic hepatitis C infection, obesity, diabetes mellitus, chronic liver disease, and cigarette smoking as risk factors for intrahepatic cholangiocarcinoma. In Western centers, the vast majority of intrahepatic cholangiocarcinomas are sporadic. Intrahepatic cholangiocarcinoma generally presents as a large mass within the liver and is therefore clinically distinct from cholangiocarcinoma arising from the extrahepatic biliary tree.

Histologically, these tumors are most often invasive adenocarcinomas, although rare variants have been reported. Intrahepatic or extrahepatic spread of disease is not uncommon by the time the tumor is detected. These tumors infrequently cause symptoms at early stages and therefore often grow to a large size before they become apparent, frequently because of pain. Infrequently, these tumors may contain cells of both cholangiocellular and hepatocellular origin. These mixed tumors are similar to intrahepatic cholangiocarcinoma in that they are infrequently associated with chronic liver disease.

Angiosarcoma of the liver, a rare fatal tumor, has been seen in workers intensively exposed to vinyl chloride for prolonged periods in polymerization plants. Hepatoblastomas are the most common primary hepatic tumors of childhood and is estimated to affect 1 child younger than 15 years in 1 million per year, and approximately 50-70 new cases are reported in the United States yearly.

Clinical Findings

A. Symptoms and Signs

The diagnosis at early and more treatable stages is often difficult, since symptoms are often absent. Screening and surveillance of high-risk patients (with cirrhosis, chronic hepatitis, etc) with ultrasonography of the liver has been recommended. Patients with more advanced tumors may have epigastric or right upper quadrant pain, which may be associated with referred pain in the right shoulder. Weight loss may be present. Jaundice is rare in patients with small tumors and good liver function; the presence of jaundice suggests either very advanced cancer or deteriorating liver function or both.

Hepatomegaly or a mass is palpable in many patients. An arterial bruit or a friction rub may be audible over the liver. Intermittent fever may be a presenting feature. Ascites or gastrointestinal bleeding from varices indicates advanced disease, and ascites fluid with blood should always suggest hepatocellular carcinoma. An acute deterioration in a previously well-compensated cirrhotic patient should also raise the suspicion of hepatocellular carcinoma.

The patterns of presentation can thus be extremely variable and may include: (1) pain with or without hepatomegaly; (2) sudden deterioration of the condition of a cirrhotic patient with the onset of hepatic failure, bleeding varices, or ascites; (3) sudden, massive intraperitoneal hemorrhage; (4) acute illness with fever and abdominal pain; (5) symptoms related to distant metastases; and (6) no clinical findings or symptoms.

B. Laboratory Findings

Depending on the disease extent and underlying hepatic function, laboratory values may range from entirely normal to suggestive of impending liver failure. Serum transaminase levels (AST and ALT) and alkaline phosphatase may be increased but are nonspecific and often seen in patients with chronic liver disease without hepatocellular carcinoma. The presence of a moderate to large liver tumor may bring about an increase in the serum alkaline phosphatase in the absence of underlying liver disease. An elevated serum bilirubin is a more ominous finding and reflects some degree of liver dysfunction, either from the underlying chronic liver disease or from a large volume of cancer within the liver. Tumor extension within the portal venous system is not uncommon, and involvement of the right and left portal trunks or the main portal vein may result in jaundice due to compromised portal venous inflow. Less often, jaundice is the result of tumor involvement of the biliary confluence by direct compression or by intrabiliary tumor extension. Other signs of compromised hepatic function include hypoalbuminemia, coagulopathy, and thrombocytopenia. A large number of patients may be positive for HBsAg or HCV antibody; the proportions of each vary somewhat by geography.

C. Liver Imaging

Liver ultrasound, CT scans, and magnetic resonance imaging (MRI) scans demonstrate the principal lesion in nearly all patients. A triple-phase (no contrast, arterial phase, and portal venous phase), contrast-enhanced helical CT scan of the chest, abdomen, and pelvis generally provides the best images of disease extent within the liver and also assesses for extrahepatic spread. Hepatocellular carcinomas are supplied primarily by the hepatic artery, and the vast majority thus enhance on arterial phase more than the adjacent nontumorous liver parenchyma (hypervascular). In some cases, the center of the tumor has become necrotic, and only the peripheral areas are hypervascular. Arterial branches supplying the tumor have an irregular appearance compared to the native hepatic artery, and arterial-venous shunting may be seen. Upon venous phase, the arterial contrast typically has washed out, and the HCC bear similar density to the adjacent parenchyma (isodense). In contrast to HCC, cholangiocarcinomas usually appear less vascular than adjacent liver parenchyma, on all phase contrast. As an adjunct to CT, MRI scans with MR angiography or CT angiography may provide more detail regarding vascular involvement and clarify if a tumor is surgically removable.

D. Angiography

Diagnostic angiography was previously used often to assess liver tumors but is now rarely needed for this purpose; it is reserved primarily for treatment (ie, transarterial chemoembolization). Angiography may be equivocal in small HCC, which may be demonstrated with greater certainty by a selective injection of iodized oil (Lipiodol) followed 1-2 weeks later by CT scanning. In a normal liver, the contrast medium is cleared quickly but HCC retains it and remains opacified.

E. Liver Biopsy

The diagnosis can be established by percutaneous core biopsy or aspiration biopsy. Fine-needle aspiration biopsy is associated with an approximately 30% false-negative rate. A negative result therefore does not rule out malignant disease, and a core biopsy should be pursued if the index of suspicion is high. Percutaneous biopsy carries some risk of bleeding, although this is rare in experienced hands; tumor dissemination by seeding resulting from a biopsy can occur in 2%-4%. In patients with cirrhosis, the presence of a hypervascular mass larger than 1 cm with typical imaging features on contrast-enhanced CT or MRI has specificity and predictive positive values of nearly 100% and a biopsy is generally not required in this setting. In other clinical scenario, a diagnostic biopsy is often requested for nonsurgical candidate to guide appropriate liver-directed or systemic treatment.

F. Surveillance

In patients with cirrhosis or chronic hepatitis B, surveillance with biannual liver sonography is recommended since early detection and treatment is the best strategy to achieve long-term survival. The optimal type and timing of imaging studies is the subject of debate, but such programs have proved useful in areas with a high incidence of chronic hepatitis, such as Asia, where a large proportion of patients are now identified with a mass 2 cm in diameter or smaller; other studies in high-risk patients have also proved valuable.

G. Tumor Markers

Alpha fetoprotein (AFP), a glycoprotein normally present only in the fetal circulation, is present in high concentrations in the serum of many patients with hepatocellular carcinoma, testicular tumors, and hepatoblastomas. Increased levels are rarely seen as a product of other tumor types, such as the lung, stomach, pancreas, and biliary tree.

The upper limit of normal in the serum is 20 ng/mL; values above 200 ng/mL are suggestive of HCC, while levels above 400 ng/mL in a cirrhotic patients with a hypervascular liver mass larger than 2 cm in diameter are diagnostic. Levels in the intermediate range are nonspecific and may occur with benign liver diseases, such as cirrhosis and chronic hepatitis, where they represent a manifestation of liver cell proliferation. As imaging methods have improved, the diagnosis of liver cancer is being made earlier, when AFP levels may be normal or only minimally elevated. Additionally, some patients may have normal AFP levels despite the presence of advanced disease. In general, AFP levels correlate with tumor size and vascular invasion, and a number of studies have shown a correlation between high AFP levels and recurrent cancer after resection. AFP levels can also provide a measure of tumor response in patients treated nonoperatively.

Differential Diagnosis

The clinical picture is often nonspecific, and the presenting symptoms may provide little in the way of diagnostic clues. Primary liver cancer may initially be confused with metastatic cancer arising from other abdominal sites. The presence of cirrhosis and findings consistent with chronic liver disease should make hepatocellular carcinoma the leading diagnosis, and this is often confirmed with further testing. In patients without cirrhosis or normal AFP levels (or both), a hypervascular mass in the liver should raise other diagnostic considerations, such as hepatic adenoma, which can be difficult to distinguish from hepatocellular carcinoma on the basis of imaging alone. In addition, certain types of cancer may give rise to hypervascular liver metastases, including melanoma, neuroendocrine carcinoma, and renal cell carcinoma.

When sudden decompensation develops in a cirrhotic patient, the possibility of HCC must always be considered. In rare instances, HCC is associated with metabolic or endocrine abnormalities such as erythrocytosis, hypercalcemia, hypoglycemic attacks, Cushing syndrome, or virilization.

Complications

Sudden intra-abdominal hemorrhage may occur from spontaneous bleeding. Obstruction of the portal vein may produce portal hypertension, and obstruction of the hepatic veins may produce the Budd–Chiari syndrome. Liver failure is a common cause of death in these situations.

Treatment

A. Partial Hepatectomy

Resection is the treatment of choice in selected patients without cirrhosis or in cirrhotics with well-preserved hepatic function. Initial diagnostic laparoscopy, immediately prior to planned laparotomy, may identify previously undetected spread of tumor within the liver or abdominal cavity that would preclude resection; however, with better imaging, the yield of laparoscopy has decreased. The minimal criteria of resectability that must be met are: (1) disease confined to the liver and (2) disease amenable to a complete resection. Multiple tumors in the liver and tumor invasion into major portal or hepatic veins are bad prognostic findings, even if resection is technically feasible; such patients generally are not good candidates for resection. For small and peripherally placed lesions, particularly in cirrhotics, sublobar, segmental resections are preferred if technically feasible. Anatomical segmentectomies are preferred to nonanatomical resections. Larger or more central tumors require more extensive resections. In Western centers, about 25%-30% of patients with hepatocellular carcinoma prove to be candidates for resection; this proportion is over 60% in Japan due largely to widespread surveillance programs.

If gross tumor is left behind or if the margins of resection are involved microscopically, progressive disease is the rule. After a complete resection, the prognosis is best for patients with a solitary, small (< 3 cm), and asymptomatic tumor and well-preserved hepatic function. Several adverse predictors of outcome have been identified, which vary somewhat among studies. However, the presence of vascular invasion (even if microscopic) has been identified in nearly all studies to predict recurrent cancer and poor outcome. Large tumor size (> 5 cm), the presence of satellite tumors, and markedly elevated AFP (> 2000 ng/mL) are also associated with a worse outcome, in part because of their correlation with vascular invasion. Additionally, patients with coexistent hepatocellular disease (ie, cirrhosis) do worse, and this is especially true in the face of significant hepatocellular dysfunction or portal hypertension.

In general, cirrhosis constitutes the major obstacle to resection in patients with hepatocellular carcinoma. Careful patient selection (Child–Pugh A, no portal hypertension) is critical in order to avoid acute liver failure and provide survival benefit to patients. In addition to this immediate perioperative concern, cirrhotic patients have a late risk of death from progression of the underlying liver disease (bleeding esophageal varices or liver failure) and a high rate (> 75%) of new tumors developing in the residual liver. For these reasons, highly selected patients may be better treated with liver transplantation rather than resection.

Overall, the rate of tumor recurrence is approximately 70% at 5 years (although it is higher, as mentioned above, in patients with cirrhosis). Some patients may be candidates for repeat resection or ablative procedures. The 5-year survival rate varies from approximately 40% to 70%, but is lower for patients with cirrhosis.

After the surgery, patients should be followed by periodic physical examinations and blood work to assess liver function. Imaging studies and AFP measurements (if elevated before resection) at regular intervals may help identify early, localized recurrences that may be amenable to repeat resection or palliative therapy.

For intrahepatic cholangiocarcinoma, resection, when possible, is the treatment of choice.

B. Liver Transplantation

Hepatocellular carcinoma is the only solid neoplasm for which transplantation plays a significant role. Liver transplantation has the advantage of treating not only the malignant disease but also the underlying cirrhosis. Previously, the selection criteria for transplanting hepatoma patients were broad and included patients with very advanced disease. Consequently, 5-year survival rates were less than 40%, too low to justify use of a scarce resource. The lessons learned from this early experience have allowed identification of patients most likely to benefit, specifically those with a single tumor no larger than 5 cm in diameter or up to three tumors with none exceeding 3 cm in diameter and no major vascular invasion. Using these strict criteria (the Milan criteria), 5-year survival rates of 70% can be achieved, a survival benefit similar to transplant patients with advanced cirrhosis but without HCC.

It should be emphasized that the benefit of transplantation is realized only when the waiting time for a new graft is under 6 months. Since waiting times can exceed 12 months in many centers, up to 50% of patients develop cancer progression or otherwise become ineligible. This problem has led a number of centers to adopt living donor transplantation as a means of increasing the donor pool, an approach that remains controversial because of donor-related morbidity and mortality. Another approach to this problem has been to increase the number of MELD points for transplantable liver disease, which effectively places eligible patients higher on the priority list.

A major concern of transplantation in cancer patients has been that the immunosuppressive therapy required to support the graft would remove an important defense mechanism against progression of residual microscopic disease. Indeed, calculated tumor doubling times for lesions in transplanted patients have been shown to be greater compared to patients not on immunosuppressive agents. Despite this possibility and although the logistical problems and expense are enormous, transplantation is a reasonable option in patients with cirrhosis who are not candidates for resection and have limited malignant disease burden, as specified in the selection criteria.

At present, transplantation has no role in patients with intrahepatic cholangiocarcinoma outside the controlled clinical trials, since the results to date have been poor.

C. Liver-Directed Therapy

Liver-directed therapies have been the subject of multiple investigations for the treatment of hepatocellular carcinoma. The effectiveness of these approaches for unresectable intrahepatic cholangiocarcinoma is being evaluated.

D. Ethanol Injection

Percutaneous ablative techniques are a reasonable option in patients with small, unresectable hepatocellular carcinoma, of which ethanol injection is the cheapest, easiest, and least morbid. Using ultrasound or CT guidance, 95% ethanol (5-20 mL) is injected through a 22-gauge needle directly into the tumor. This approach can achieve complete necrosis in 90%-100% of tumors smaller than 2 cm, but its efficacy declines rapidly as the tumor size increases. The patient is followed up and retreatment given for residual or new primary tumors. In one multi-institutional series from Italy, survival 1, 2, and 3 years after treatment for patients with solitary, small tumors was 90%, 80%, and 63%, respectively.

E. Radiofrequency Ablation

Radiofrequency ablation (RFA) is another percutaneous ablative approach, useful for treating selected patients with small tumors who are not candidate for surgery or liver transplantation. RFA has generally supplanted ethanol injection as the percutaneous treatment of choice. Under ultrasound or CT guidance, a needle is used to access the lesion; the needle is attached to a radiofrequency generator that generates thermal energy to bring about tumor destruction. RFA can be used percutaneously, laparoscopically, or at laparotomy.

The goal of RFA is the same as that of ethanol injection: to achieve complete tumor necrosis. The efficacy of RFA is limited by tumor size but may be somewhat greater than ethanol injection in this regard; RFA is less effective for tumors adjacent to major vascular structures. A randomized study comparing the two techniques found no differences in survival, although RFA may offer better local tumor control rates. In carefully selected patients, 5-year survival rates of 30%-40% have been reported. RFA has been compared with resection in early HCC in randomized controlled trials, but results have varied. Generally, RFA appear to be as effective as resection in lesions smaller than 2 cm. Ablation techniques, including RFA, have been studied in the context of controlling disease progression while on the waiting list in patients who are candidates for transplantation with some suggestion of benefit.

Microwave ablation and irreversible electroporation are two emerging ablative techniques that may prove to be alternatives to RFA.

F. Arterial Embolization

Hepatic artery embolization is another ablative technique that is more broadly applicable than RFA or ethanol injection. This approach takes advantage of the fact that primary liver cancers derive disproportionately greater blood supply from the hepatic arterial circulation compared to the surrounding liver. The strategy is to combine selective hepatic arterial injection of cancer chemotherapeutic agents with arterial embolization, the latter to produce tumor necrosis and slow the washout of the drugs. Embolization can be used in patients with much larger tumors than can be effectively treated with percutaneous procedures, and the procedure can be staged to treat bilobar disease. Patients must have adequate liver function; those with Child-Pugh C cirrhosis or thrombosis of the portal vein are not suitable candidates.

A variety of techniques have been used. Embolization is often performed with Gelfoam, which dissolves after a few weeks, but other inert agents are also used and are probably more effective for occluding vessels. Some centers use inert particles without chemotherapy (ie, bland emobolization) but most employ a chemotherapeutic component (ie, transarterial chemoembolization or TACE). Doxorubicin, mitomycin, and cisplatin in various combinations are the drugs most often given. Lipiodol, which lodges in the tumor, has occasionally been used as a carrier for the drugs. It remains unclear if the addition of chemotherapeutic agents provides much benefit beyond the necrosis produced by occlusion of the hepatic arterial supply. Many patients require multiple treatments, although the optimal schedule is ill defined. Embolization achieves partial responses in up to 55% of patients. A survival benefit of approximately 10 months has been reported with chemoembolization compared to best supportive care in randomized controlled trials, and 30%-50% of patients are reported to survive at 3 years. Of note, histologic studies of tumors resected shortly after treatment reveal viable neoplastic cells in the tumor capsule, which receives blood from the portal vein as well as the hepatic artery. Recently, a randomized prospective trial showed that the combination of RFA and chemoembolization provided superior disease control rates than either technique alone.

G. Systemic Therapy

Until recently, no systemic treatment was found able to prolong the survival of patients with metastatic hepatocellular carcinoma. The multikinase inhibitor sorafenib, that mainly blocks RAF, VEGF, PDGF, and c-Kit signaling, has however been shown to have antitumor efficacy. In two phase 3, multicenter, randomized, double-blind and placebo-controlled trials, sorafenib improved by 2-3 months the survival of patients with advanced HCC and compensated liver function. The efficacy of combining sorafenib with other biologic and chemotherapeutic agents is being evaluated, as well as its use in less advanced disease status and in the adjuvant setting in an attempt to lessen or delay cancer recurrence.

Gemcitabine-based chemotherapy, in particular with combination with cisplatin, has shown prolongation of survival in patients with metastatic biliary tract cancer.

METASTATIC NEOPLASMS OF THE LIVER

In Western countries, metastatic cancer is much more common than primary tumors in the liver. Nearly all solid tumors can potentially give rise to liver metastases; primary cancers of the gastrointestinal tract (colon, pancreas, esophagus, stomach, neuroendocrine), breast, lung, genitourinary system (kidney, adrenal), ovary and uterus, melanoma, and sarcomas account for the overwhelming majority of cases. Spread to the liver may be via the systemic or portal venous circulation. The cirrhotic liver, which often gives rise to primary hepatic tumors, seems to be less susceptible than normal liver to implantation of metastases.

Individual tumor types have characteristic patterns of spread. For example, colorectal cancer spreads to the liver as the first site of metastatic disease in a very high proportion of patients; the lung is the next most common site, but bone, brain, or adrenal metastases are distinctly unusual. By contrast, metastatic lung cancer to the liver typically occurs concomitantly with spread to other sites, with brain, bone, and adrenal among the most common. In general, the vast majority of patients with metastases to the liver also have disease at other sites. A notable exception is colorectal cancer, which in many cases involves the liver only for a prolonged period. In the past, approximately 20% of patients with hepatic metastases had additional tumor deposits in the liver not seen on preoperative imaging studies. As imaging technology has improved, however, this proportion has become increasingly smaller.

Clinical Findings

A. Symptoms and Signs

The signs and symptoms vary with the clinical scenario, the disease extent within the liver, and the presence or absence of metastatic disease to other sites. Patients with an undiagnosed primary tumor may come to attention because of symptoms caused by the metastatic disease. Weight loss, fatigue, pain, and anorexia are the presenting general complaints in many such patients. Signs of liver failure, such as ascites and jaundice, are uncommon and suggestive of very advanced cancer. Fever without demonstrable infection is present in 15% of cases. By contrast, patients with a known history of cancer undergoing routine surveillance often develop liver metastases that cause no symptoms; in a small proportion of cases, liver metastases are found on studies done for unrelated reasons.

Physical examination is frequently unrevealing. Hepatomegaly or a palpable tumor in the upper abdomen may be present, and either may be tender. Portal hypertension may be manifested by abdominal venous collaterals or splenomegaly. A friction rub is sometimes heard over the liver.

B. Laboratory Findings

Laboratory values may be entirely normal or at most reflect only minor nonspecific changes. Patients with advanced cancer can have anemia and hypoalbuminemia. The alkaline phosphatase is increased in most patients. More significant derangements in liver function occur in patients with a large volume of liver disease, although this is uncommon at initial presentation. Tumor marker levels (carcinoembryonic antigen [CEA], carbohydrate antigen [CA] 19-9, CA-125) are often elevated, depending on the tumor type, and may be helpful for monitoring treatment.

The diagnosis can be established in most cases by CT-guided or ultrasound-guided percutaneous liver biopsy or fine-needle aspiration for malignant cells.

C. Imaging Studies

The detection of liver metastases relies on CT and/or MRI scans; ultrasonography identifies tumors in the liver and distinguishes solid from cystic lesions but cannot provide the same degree of anatomical detail. MRI provides useful additional information and may help distinguish benign from malignant disease. However, a high-quality triple phase CT scan with intravenous and oral contrast medium provides excellent assessment of disease extent in the liver and elsewhere in the abdomen. In the past, CT portography was superior to ordinary contrast-enhanced CT and was obtained routinely in patients being considered for hepatic resection, but this is no longer the case. Positron emission tomography using 18-fluorodeoxyglucose (FDG-PET) is a commonly used staging study and may help identify extrahepatic disease, a finding that could change the treatment recommendations. During surgery, intraoperative ultrasound is used to assess the liver for disease not appreciated on imaging studies.

Treatment

For most patients with metastatic liver disease, chemotherapy is the only treatment option, particularly with coexisting metastases outside the liver. Such therapy is usually not curative but rather palliative in most cases. A notable exception is metastatic colorectal cancer, for which resection or other treatments aimed at the liver disease are effective and potentially curative; the recent advent of several active chemotherapeutic agents has further improved the results of treatment. Carefully selected patients with metastases from other primary tumors (sarcoma, breast, ovary, lung, neuroendocrine) may also benefit from resection but represent a small minority of cases.

A. Hepatic Resection

Hepatic resection is most commonly indicated in patients with metastatic colorectal cancer. Of the approximately 130,000 patients diagnosed with colorectal cancer annually in the United States, approximately 50% either have liver metastases at diagnosis or develop liver metastases at some point. In 40% of the latter group, the liver is the only demonstrable site of disease. Hepatic metastases from colorectal cancer thus affect approximately 20,000 patients per year, which is comparable to the annual incidence of pancreatic or esophageal carcinoma.

After a complete resection, the 5-year survival rate has historically been 25%-40%; systemic or regional chemotherapy or both are frequently given after resection and appear to enhance the results of surgery, with more recent series reporting 5-year survival figures of approximately 50%. The presence of extrahepatic metastases and inability to achieve a complete resection are contraindications to resection in most cases. However, as more effective chemotherapeutic options have emerged, the indications for resection have expanded to include selected patients with multiple bilobar tumors and even some with extrahepatic metastatic disease. Extensive use of chemotherapy prior to surgery can cause changes in the liver, particularly steatosis and steatohepatitis, which can impair the liver’s normal regenerative response. Caution is therefore needed when considering such patients for major hepatic resections, since operative morbidity and mortality may be increased; preoperative portal vein embolization may reduce the incidence of serious postoperative complications.

The following variables are associated with a worse prognosis after resection: (1) original tumor with involved lymph nodes (stage III or Dukes C); (2) multiple liver lesions; (3) less than 1-year interval between resection of the colon primary and diagnosis of liver disease (disease-free interval); and (4) CEA level higher than 200 ng/mL. Variables that do not influence the outcome include: (1) histologic grade of the tumor; (2) bilateral rather than unilateral disease; (3) site of the primary tumor within the large intestine; and (4) the gender of the patient. The mortality rate for resection of hepatic metastases is 1%-2% in hospitals where this operation is performed frequently.

The liver is the most common site of cancer recurrence after a complete resection. A small proportion of patients with hepatic recurrence may be amenable to a second resection. The use of adjuvant hepatic arterial chemotherapy appears to reduce the risk of intrahepatic recurrence.

The efficacy of liver resection for colorectal cancer has been clearly established and is the most common indication for this procedure. By contrast, for most other tumor types, particularly those arising from the gastrointestinal tract other than the colon or rectum, the benefit of liver resection is much more limited. Rare patients with metastases from renal cell carcinoma, ovarian cancer, adrenocortical carcinoma, or sarcomas appear to derive the most benefit; by contrast, liver resection for metastatic esophageal, gastric, or pancreatic cancer is almost never warranted. In selecting patients with noncolorectal liver metastases for resection, the most important factors are: (1) long disease-free interval; (2) solitary resectable liver tumor; and (3) the absence of extrahepatic metastases.

Neuroendocrine carcinomas (pancreatic islet cell tumors, carcinoids) represent a unique class of tumors that often give rise to liver metastases. Unlike patients with other metastatic tumor types, those with neuroendocrine tumors often survive for many years. Multiple liver metastases are the rule with this disease, so complete resection is usually not possible. However, debulking liver resections are sometimes indicated to palliate tumor-related pain or hormonal symptoms. Partial hepatectomy is also sometimes worthwhile to extirpate a tumor invading directly from a contiguous organ.

B. Radiofrequency Ablation

RFA has been used to treat metastases to the liver from a variety of tumor types. The indications for this procedure remain ill defined. The best candidates are those with a limited number of small liver lesions with no evidence of extrahepatic cancer.

C. Chemotherapy

In a large proportion of patients with metastatic colorectal cancer, the liver is the only evident site of disease. If the lesions cannot be resected, regional intrahepatic chemotherapy can be given by placing a catheter in the gastroduodenal artery (at its origin with the common hepatic artery) connected to an implantable, subcutaneous infusion pump, which allows the delivery of much higher concentrations of drug to the tumor than is possible with systemic administration. This regimen is generally not used for metastases from other kinds of tumors. The pump is primed with floxuridine, which is delivered by continuous infusion (0.1-0.2 mg/kg/d) for 14-day periods alternating with 14-day rests. Systemic chemotherapy is usually given concomitantly. The discovery of extrahepatic lesions at laparotomy for pump placement is a relative contraindication to proceeding with this approach. Treatment is continued until disease progression or excessive toxicity is seen or, rarely, until the response is complete. Toxicity consists mainly of gastroduodenal erosions (caused by unintentional perfusion of these areas), chemical hepatitis, or chemical sclerosing cholangitis. Survival is related principally to the initial amount of liver involvement by tumor, objective response to treatment (which is seen in about 60% of patients), and extent of prior chemotherapy. The median survival of patients with less than 30% of liver replaced by tumor is 24 months, compared with 10 months if the extent of replacement exceeds 30%. Up to 47% of patients with initially unresectable disease may respond enough to become resectable and potentially benefit from surgery. There is a general perception that hepatic artery infusion therapy improves survival, but the objective evidence is inconclusive.

Hepatic artery infusion chemotherapy may be a useful adjunctive therapy after complete tumor resection or RFA. Studies of this option are under way. Systemic chemotherapy (eg, with fluorouracil, irinotecan, or oxaliplatin) after a complete resection of liver metastases has not been proved to improve survival, although it is often prescribed.

D. Miscellaneous

Hepatic artery ligation or angiographic embolization of the tumor has been of benefit in a few patients with hepatic metastases from specific tumor types, particularly neuroendocrine tumors.

Prognosis

Survival varies with the site of origin of the primary tumor and the extent of metastatic disease. Patients with extensive hepatic replacement by multiple lesions have a dismal outlook, with a survival measured in months, compared to perhaps 2-3 years for patients with small solitary lesions. The range of treatment options and effective chemotherapeutic agents is greatest for metastatic colorectal cancer compared to most other tumor types, and survival is generally better in this group.

BENIGN TUMORS & CYSTS OF THE LIVER

Hemangiomas

Hemangioma is the most common benign hepatic tumor and has an incidence of approximately 7%. Except for the skin and mucous membranes, the liver is the most common site of origin. Women are affected more often than men—in some series, up to 75% of patients are female. Histologically, hepatic hemangiomata are of the cavernous type rather than the capillary type. Most are small, solitary subcapsular growths that are found incidentally during laparotomy or autopsy or on imaging studies. Rarely, hemangiomata grow to very large dimensions (giant hemangiomata) and cause abdominal pain or a palpable mass. Most are small to moderate-sized lesions, however; pain is uncommon in tumors smaller than 8-10 cm in diameter.

Rare complications of liver hemangiomata include hemorrhagic shock resulting from spontaneous rupture and the Kasabach–Merritt syndrome, which is usually seen in children and is associated with thrombocytopenia and a consumptive coagulopathy; both of these complications are exceedingly uncommon. Large congenital hemangiomas of the liver may be associated with others in the skin. Large hemangiomata may also give rise to large-volume arteriovenous shunting, resulting in cardiac hypertrophy and congestive heart failure.

Large-bore needle biopsy is hazardous due to bleeding risks; aspiration biopsy with a fine needle is safe but rarely helpful. Fortunately, biopsy is very rarely indicated, since the diagnosis can be made with certainty in most cases by contrast-enhanced CT or MRI scans. The hallmark features of hemangiomata are nodular peripheral enhancement on arterial phase with progressive central enhancement on the more delayed images. MRI is a particularly good study for hemangiomata, which appear very bright on the T2-weighted images, and combined with dynamic intravenous contrast, has a sensitivity and specificity of 98%. Angiography is unnecessary, and nuclear scans lack sufficient sensitivity and specificity.

Irrespective of their size, the only reasons to resect hemangiomata are for symptoms, most commonly pain, or diagnostic uncertainty (rare). Symptomatic hemangiomas should be excised by lobectomy or enucleation. Even large lesions can be safely removed. Radiotherapy or embolization via a catheter in the hepatic artery may be tried in patients who are poor candidates for surgery, but the efficacy of these approaches is limited. The natural history of asymptomatic hemangiomas, whether large or small, is benign. The vast majority of incidentally discovered hemangiomata remain stable in follow-up, do not give rise to symptoms, and therefore do not require resection. Progressive growth of asymptomatic hemangiomata over a relatively short time interval, particularly in young patients, is considered a relative indication for resection.

Cysts

A number of different cystic lesions may affect the liver. Simple hepatic cysts, the most common, are unilocular fluid-filled lesions that generally produce no symptoms. The occasionally large cyst may present as an upper abdominal mass or discomfort. Small, simple cysts may be difficult to diagnose on CT and may be confused for metastatic disease; ultrasound and MRI are better modalities to assess the character of cystic lesions. Many patients have multiple simple cysts, which should not be confused with polycystic liver disease, a progressive condition characterized by cystic replacement of virtually the entire liver. Polycystic liver disease is associated in about half of cases with polycystic renal disease. The possibility of echinococcosis should be considered in patients with cystic liver lesions and the appropriate exposure history, although their radiographic appearance is usually quite distinctive.

Most simple cysts have a serous lining and a smooth, thin wall. Intracystic hemorrhage can occur, which can confuse the radiographic appearance. Solitary cysts lined with cuboidal epithelium are classified as cystadenomas and should be resected, since they are premalignant. Cystadenomas are characterized radiographically as complex, with internal septae, an irregular lining, and papillary projections. Complex, multilocular (septated) cysts (if not echinococcal) are often neoplastic and should be resected. However, cystadenomas and cystadenocarcinomas are rare, while internal hemorrhage into a simple cyst is a more common entity and may have a similar appearance. Nevertheless, complex cysts of the liver must be approached with some caution in order to avoid inappropriate interventions. There are few indications for aspirating hepatic cysts—simple cysts reaccumulate fluid quickly, neoplastic cysts must be excised, and parasitic cysts might rupture and the parasite thus be allowed to spread. It is possible to eliminate small cysts by aspiration of the contents followed by an injection into the lumen of 20-100 mL of absolute alcohol; however, small cysts almost never cause symptoms and generally require no treatment.

Large symptomatic cysts are difficult to eradicate with alcohol injections, and serious superinfection of the cyst cavity may occur. The simplest method of treatment consists of laparoscopic cyst fenestration (wide excision of the cyst wall). A tongue of omentum may be fixed so it lies in the residual cyst cavity as an ancillary measure to prevent the edges from coapting. The operation is curative in nearly all patients.

Multiple, small, simple cysts do not usually require treatment, but large polycystic livers that cause discomfort or are associated with obstructive jaundice can be managed by partial resection or surgically unroofing the cysts on the surface of the liver and creating windows between superficial cysts and adjacent deep cysts. The opened cysts are allowed to drain into the abdominal cavity. The results of surgery for polycystic liver disease are often disappointing, with quick return of symptoms in many patients.

Hepatic Adenoma

Hepatic adenomas occur predominantly in women of childbearing age and appear to be related to the use of oral contraceptives. Mestranol-containing compounds have been associated with a disproportionate number of cases, but mestranol has been in use longer than the other agents.

The tumors are soft, yellow-tan, well-circumscribed masses that are usually of moderate size (range of 2-15 cm in diameter). Most of those that cause symptoms are in the 8-15 cm range. Two-thirds of hepatic adenomas are solitary; other benign tumors (such as FNH, see next section) are present in some cases. Transition from benign hepatic adenoma to hepatocellular carcinoma is estimated to occur in 5%, with liver cell dysplasia as an intermediate step. Histologically, hepatic adenomas consist of an encapsulated homogeneous mass of normal-appearing hepatocytes without bile ducts or central veins. Intratumoral hemorrhage or central necrosis may be present.

About half of patients are asymptomatic. Most of those with symptoms present with right upper quadrant pain. Spontaneous hemorrhage into the substance of the tumor with subsequent rupture and intraperitoneal bleeding is a well-known potential complication of adenomas estimated to occur in 20%-40% of untreated cases. The true risk of spontaneous hemorrhage is, however, difficult to know with certainty, since the overall incidence of adenomas is unknown. This risk increases with size, and there appears to be a strong association of acute bleeding episodes from adenoma with pregnancy. Patients with this life-threatening problem present with acute pain or even hemorrhagic shock.

Liver function tests and AFP levels are usually normal or minimally deranged. Adenomas typically appear hypervascular compared to the surrounding liver parenchyma, a feature that is apparent on contrast-enhanced CT or MRI scans or angiography. Adenomas can be difficult to distinguish from FNH, another benign tumor often found in young women. Differences in tumor vascularity may be demonstrated on angiography; however, MRI is probably the best study for differentiating these lesions. Adenomas often cannot be distinguished from well-differentiated hepatocellular carcinoma on imaging studies and even on biopsy specimens. Needle biopsy is generally safe but often inconclusive and is associated with a small risk of bleeding.

The general recommendation is that adenomas should be resected because of the risks of malignant change and spontaneous hemorrhage. Unfortunately, the true likelihood of these events is difficult to estimate, since most series include only treated patients. Lesion measuring less than 5 cm can be observed with serial imaging since the risk of malignant transformation or bleeding at this size appears minimal. Symptomatic and large asymptomatic adenomas clearly should be resected. Emergent resection or hepatic artery embolization should be undertaken in patients with evidence of hemorrhage. Small peripheral lesions may be removed with wedge excisions, but larger tumors require more extensive resections. Small adenomas may regress when oral contraceptive agents are discontinued, and close follow-up with imaging studies is not unreasonable in such cases; however, any change in symptoms or imaging characteristics (growth, hemorrhage) should prompt resection. The possibility that a presumed adenoma is actually a well-differentiated hepatocellular carcinoma or contains a focus of malignancy must always be kept in mind; there is no completely reliable means of making the differentiation other than pathologic analysis of the resected specimen.

Most patients recover without sequelae after surgical removal; recurrence is rare. Oral contraceptives should be proscribed permanently in all cases. Radiotherapy and chemotherapy are of no value, but elective hepatic artery embolization may be helpful in patients who are not surgical candidates. Embolization may be particularly helpful in the very rare patient with multiple hepatic adenomas (hepatic adenomatosis), since resection is usually not possible.

Focal Nodular Hyperplasia

FNH accounts for the second most common benign liver process after hemangioma. Like hepatic adenoma, FNH is much more common in young women. The average age is about 40 years, but the tumor can occur at any age. Unlike hepatic adenoma, however, the use of oral contraceptive agents does not appear to predispose to the development of FNH, although it has been suggested that these agents may stimulate growth.

Grossly, the tumor is a well-circumscribed, firm, tan, usually subcapsular mass measuring 2-3 cm in diameter. In patients with symptoms, the lesions are much larger, usually around 10 cm. Multiple tumors can occur; 80% are solitary. The gross appearance on cut section is quite characteristic, consisting of a central stellate scar (which is actually an aggregation of blood vessels) with radiating fibrous septa that compartmentalize the lesion into lobules. Histologically, there are nodular aggregations of normal-appearing hepatocytes without central veins or portal triads. Bile duct proliferation is present in the nodules.

Most patients with FNH are asymptomatic. The few with symptoms present with a right upper quadrant discomfort. Unlike hepatic adenomas, these lesions rarely, if ever, bleed, and the natural history of asymptomatic lesions is benign. Very rare patients with diffuse FNH develop portal hypertension.

Hepatic function tests and AFP levels are usually normal. Hepatic scintiscans usually do not show a filling defect but are of little practical value. CT scans demonstrate the tumor and may also show the central stellate scar. The arteriographic pattern is one of hypervascularity. In most cases, the diagnosis of FNH can be made with noninvasive studies, although distinguishing FNH from hepatic adenomas can be difficult, even for experienced radiologists. MRI scanning is the best modality, but the imaging features of both tumors overlap somewhat, and they occur in similar patient populations. Fine-needle aspiration biopsies are generally not helpful.

Symptomatic lesions should be removed, while asymptomatic tumors (the majority) should be left undisturbed, provided that the diagnosis has been made confidently. In the latter circumstance, a period of observation with imaging studies is recommended to ensure stability. Inability to distinguish FNH from adenoma or malignant disease is an indication for resection in some patients. Discontinuation of oral contraceptives probably has no impact. FNH can be reliably identified on examination of frozen sections.

CIRRHOSIS

Hepatic cirrhosis remains a major public health problem worldwide, with an annual mortality of approximately 23,000 per year in the United States alone. The incidence of cirrhosis is increasing, due in large measure to hepatitis C, and at present is the third-most common cause of death in men in the fifth decade of life. Another contributing factor is the epidemic of obesity, which is associated with NAFLD and progression to cirrhosis in many patients.

Alcohol abuse remains the leading cause of cirrhosis in most Western countries. Alcohol exerts direct toxic effects on the liver that are magnified in the presence of protein and other dietary deficiencies that are often present. Even still, cirrhosis develops in a small minority of patients who abuse alcohol. Alcohol induces a specific cytochrome P450 in the liver (ie, P450 2E1) that participates in its metabolism to acetaldehyde, which has a number of deleterious effects, including antibody formation, decreased DNA repair, enzyme inactivation, and alterations in microtubules, mitochondria, and plasma membranes. Acetaldehyde also promotes glutathione depletion, free radical–mediated toxicity, lipid peroxidation, and hepatic collagen synthesis. Hepatic steatosis and alcoholic hepatitis are stages of alcoholic liver injury that may precede cirrhosis. Alcoholic hyalin, a glycoprotein, accumulates in centrilobular hepatocytes of patients with alcoholic hepatitis. There is some evidence that immunologic responses to alcoholic hyalin may be important in the pathogenesis of cirrhosis.

Regardless of the cause (Table 24–3), collagen deposition in cirrhosis results from increased fibroblastic activity as well as from repair following hepatocellular injury and necrosis. The ultimate result is a liver containing regenerative nodules and connective tissue septa linking portal fields with central canals, which can be graded by severity on pathologic assessment of liver biopsy.

The natural history of cirrhosis is difficult to predict. Once the diagnosis has been established, up to 30% of patients die within a year from hepatic failure or complications of portal hypertension, of which bleeding esophageal varices is the most feared. In newly diagnosed cirrhotics, the chances of dying within the subsequent 2-3 years are influenced by the status of liver function (as reflected by the Child–Pugh classification, [Table 24–1]), the presence of varices, and the portal pressure. A group of cirrhotics with varices followed by the Boston Interhospital Liver Group experienced a 1-year death rate of 66%. Cirrhotics without varices may benefit substantially by abstaining from alcohol. Bleeding episodes occur in up to 40% of all patients with cirrhosis, and the initial episode of variceal hemorrhage is fatal in 50% or more. At least two-thirds of those who survive their initial hemorrhage bleed again, and the risk of dying from the second is similarly high. It is principally for such patients that portal decompressive procedures are recommended.

Other main complications of cirrhosis include ascites, hepatorenal syndrome with hyponatremia and renal insufficiency, coagulopathy, and encephalopathy. Those processes are mainly managed medically to maintain a state of relative physiological compensation. Liver transplantation for appropriate candidates provides the most effective treatment option associated with prolongation of survival.

Etiology

The major causes of portal hypertension are listed in Table 24–4. In all but a few instances, the basic lesion is increased resistance to portal flow. Those associated with increased resistance can be subclassified according to the site of the block as prehepatic, hepatic, and posthepatic; hepatic causes of portal hypertension are further subclassified as presinusoidal, sinusoidal, and postsinusoidal. Cirrhosis accounts for about 85% of cases of portal hypertension in the United States, most commonly from heavy alcohol use. Postnecrotic cirrhosis is next in frequency, followed by biliary cirrhosis. The other intrahepatic causes of portal hypertension are relatively rare in Western countries, although in some parts of the world, hepatic schistosomiasis constitutes the largest single group. Idiopathic portal hypertension occurs with greater frequency in southern Asia.

After cirrhosis, extrahepatic portal venous thrombosis or occlusion is the most common cause of portal hypertension in the United States. Patients with this condition are generally younger than cirrhotics, and many are children. Posthepatic obstruction due to Budd–Chiari syndrome (BCS) or constrictive pericarditis is rare.

Pathophysiology

Portal hypertension is defined as a hepatic venous pressure gradient (HVPG) (the difference between portal-vein pressure and hepatic-vein pressure) greater than 5 mm Hg, but usually become clinically significant when this gradient reaches 10 mm Hg. Portal venous pressure normally ranges from 7 to 10 mm Hg. In portal hypertension, portal pressure exceeds 10 mm Hg, averaging around 20 mm Hg and occasionally rising as high as 50-60 mm Hg. With those portal pressures, since the venous pressure in the right atrium averages 5 mm Hg, the HVPG can easily become greater than 5 mm Hg.

Since pressure in the portal venous system is determined by the relationship Pressure = Flow × Resistance, portal hypertension could result either from increased volume of portal blood flow or increased resistance to flow. Portal hypertension can be classified by pathophysiologic processes as summarized in Table 24–4.

In practice, however, the liver has tremendous reserve capacity to accommodate increased blood flow, and portal hypertension solely due to this mechanism is extremely uncommon. Increased flow may contribute to portal hypertension in patients with arterial-portal venous fistulae (traumatic, congenital). When an arteriovenous fistula occurs, portal hypertension and its clinical manifestations usually do not appear for several months, because sinusoidal capacity is so great that the immediate rise in portal pressure is only moderate. With time, however, sinusoidal sclerosis develops, resistance increases, and portal pressure gradually reaches high levels, leading to the formation of varices.

Nearly all clinically relevant cases of portal hypertension result from increased resistance, in itself due to both structural distortion of the liver vascular architecture by fibrosis and dynamic increases in hepatic vascular tone. In addition to increased vascular resistance in the liver, splanchnic vascular bed resistance decreases, a consequence of local production of vasodilators (eg, nitric oxide) and mesenteric angiogenesis, paradoxically worsening the portal hypertension by increasing the splanchnic blood flow to the liver.

The average portal flow in cirrhotic patients with complications of portal hypertension is nonetheless about 30% of normal, ranging from 0 to 700 mL/min. Hepatic arterial flow is usually reduced by a similar proportion. The range of portal flow rates in different patients may vary greatly; in some, blood in the portal vein moves sluggishly or the direction of flow may even be reversed (hepatofugal) so that the portal vein functions as an outflow tract from the liver. These states of low flow predispose to spontaneous thrombosis of the portal vein, a complication of cirrhosis seen in 16% per year in patients with advanced liver disease. Portal thrombosis usually is associated with acute clinical deterioration and renders the portal vein unsuitable for a shunt to decompress the portal venous system.

Fluctuations in the level of portal hypertension may occur in conjunction with changes in blood volume. This is almost never a problem in patients with a normal liver. However, administration of colloid solutions to a patient with underlying liver disease and a normal or expanded blood volume could theoretically aggravate the clinical manifestations of portal hypertension.

A. Disease-Specific Pathophysiology

In alcoholic liver disease, the abnormal resistance is predominantly hepatic and postsinusoidal, as indicated by the results of wedged hepatic vein pressure studies.^* The causes of increased resistance in this disease are thought to be: (1) distortion of the hepatic veins by regenerative nodules and (2) fibrosis of perivascular tissue around the hepatic veins and the sinusoids.

Even in the absence of cirrhosis, acute alcoholic hepatitis can raise portal pressure by producing centrilobular swelling and fibrosis. Sinusoidal resistance to flow is also increased by engorgement of adjacent hepatocytes with fat and resultant distortion and narrowing of vascular channels. Documented cases of normalization or reduction in portal pressure have occurred with resolution of the pathologic changes.

Schistosomiasis can produce a unique form of hepatic presinusoidal obstruction to blood flow from deposition of parasite ova in small portal venules. The subsequent chronic inflammatory reaction leads to fibrosis and cirrhosis. Many patients with schistosomiasis are also at risk for chronic hepatitis, which can exacerbate the liver damage.

BCS (hepatic vein thrombosis) results from obstruction of flow through the hepatic veins. The resulting sinusoidal hypertension produces prominent ascites and hepatomegaly. Conditions (veno-occlusive disease, inferior vena cava obstruction by tumor or congenital webs, right-sided heart failure) that reduce flow through the hepatic veins result in a similar clinical picture.

Banti syndrome was defined as liver disease secondary to primary splenic disease and was incorrectly considered as the cause of portal hypertension now known to result from cirrhosis and other hepatic disorders rather than a consequence of such conditions. Portal hypertension from splenomegaly and increased splenic vein flow has been described in patients with hematologic diseases or tropical splenomegaly and apparently normal liver function. This is extremely uncommon, however, and given the great reserve of the liver to handle increases in portal flow, many such patients probably have some component of liver disease. In cirrhosis, the increased splenic blood flow accompanying “congestive” splenomegaly may occasionally be great enough to warrant splenic artery ligation or splenectomy to decrease portal pressure and improve symptoms, but this situation is rare.

B. Development of Portosystemic Collaterals and Varices

The obstacle to flow through the liver promotes expansion of collateral channels between the portal and systemic venous systems. As the pathologic process develops, portal pressure increases until a level of about 40 cm H₂O (30 mm Hg) is reached. At this point, increasing hepatic resistance, even to the point of occlusion of the portal vein, diverts a greater fraction of portal flow through collaterals without significant increments in portal pressure.

The type of portosystemic collaterals that develops depends partly on the cause of the portal hypertension. In extrahepatic portal vein thrombosis (without liver disease), collaterals in the diaphragm and in the hepatocolic, hepatoduodenal, and gastrohepatic ligaments transport blood into the liver around the occluded vein (hepatopetal). In cirrhosis, collateral vessels circumvent the liver and deliver portal blood directly into the systemic circulation (hepatofugal); these collaterals give rise to esophageal and gastric varices. Other common spontaneous collaterals are through a recanalized umbilical vein to the abdominal wall, from the superior hemorrhoidal vein into the middle and inferior hemorrhoidal veins, and through numerous small veins (of Retzius) connecting the retroperitoneal viscera with the posterior abdominal wall.

Isolated thrombosis of the splenic vein causes localized splenic venous hypertension and gives rise to large collaterals from spleen to gastric fundus (sinistral, or left-sided, portal hypertension). From there, the blood returns to the main portal system through the coronary vein. In this condition, gastric varices are often present without esophageal varices.

Of the many large collaterals that form as a result of portal hypertension, spontaneous bleeding is relatively uncommon except from those at the gastroesophageal junction; spontaneous bleeding from gastric varices can sometimes occur and carries a higher rate of death than gastroesophageal varices. Compared with adjacent areas of the esophagus and stomach, the gastroesophageal junction is especially rich in submucosal veins, which expand disproportionately in patients with portal hypertension. The cause of variceal bleeding is most probably rupture due to sudden increases in hydrostatic pressure. Esophagitis is usually mild or absent.

ACUTELY BLEEDING VARICES

Varices develop in 5%-15% of cirrhotic patients per year. Most patients with cirrhosis develop varices, but only about one-third experience variceal hemorrhage. Each bleeding episode is associated with a mortality rate of up to 25%, and 70% of untreated patients die within a year of the first episode. This high death rate reflects not only the massive hemorrhage but also the frequent presence of severely compromised liver function and other systemic disease that may or may not be related to alcohol abuse. Malnutrition, pulmonary aspiration, infections, and coronary artery disease are frequent coexisting conditions. Additional complicating factors in this patient population include lack of cooperation with treatment and acute alcohol withdrawal, which in its worst manifestation (delirium tremens) adds greatly to the already high mortality rate.

Clinical Findings

A. Symptoms and Signs

If cirrhosis or varices have been documented on previous examinations, hematemesis would strongly suggest bleeding varices as the cause. Patient with significant hemorrhage present with alteration of mental status, hypotension, and tachycardia, often in hypovolemic shock. It must be emphasized that bleeding from varices cannot be accurately diagnosed on clinical grounds alone even though the history or the appearance of the patient may strongly suggest the presence of cirrhosis or portal hypertension. Most patients with bleeding varices have alcoholic cirrhosis, and the diagnosis may seem obvious in a patient with hepatomegaly, jaundice, and vascular spiders who admits to recent binge drinking. Splenomegaly, the most constant physical finding, is present in 80% of patients with portal hypertension regardless of the cause. Ascites is frequently present. Massive ascites and hepatosplenomegaly in a nonalcoholic would suggest the much less common BCS.

B. Laboratory Findings

Most patients with alcoholic liver disease and acute upper gastrointestinal bleeding have compromised liver function. The bilirubin is usually elevated, and the serum albumin is often below 3 g/dL. The leukocyte count may be elevated. Anemia may be a reflection of chronic alcoholic liver disease or hypersplenism as well as acute hemorrhage. The development of a hepatoma by a cirrhotic may first manifest by hemorrhage from varices; CT scan and marked elevation of the serum α-fetoprotein make the diagnosis. Thrombocytopenia and coagulopathy are common.

Treatment of Acute Bleeding

The general goal of treatment is to control the bleeding as quickly and reliably as possible using methods with the fewest possible side effects. The methods in use for acute variceal bleeding are listed in Table 24–5 and presented into a current treatment algorithm in Figure 24–6. Over the past decades, improvement in medical, endoscopic, and endovascular technique studied in the setting of randomized control trials has lessened the need for surgical interventions.

The initial management of the patient with massive gastrointestinal hemorrhage is discussed in Chapter 23. Critical initial steps include airway protection, particularly in patients with altered mental status or those with hemodynamic instability, and resuscitation with fluid and blood products. In the cirrhotic patients, correction of coagulopathy and thrombocytopenia should also be initiated early. Patients admitted with variceal hemorrhage are often bacteremic as a result of a concomitant infectious process (spontaneous bacterial peritonitis, urinary tract infection, or pneumonia). Clinical trials have shown better outcomes when empiric antibiotic therapy is initiated during an episode of variceal bleed, and usually a third-generation cephalosporin such as ceftriaxone is favored.

Vasoconstrictive drugs which reduce portal pressure (somatostatin and vasopressin analogs) and endoscopic variceal ablation (ligation and sclerotherapy) are the mainstay of initial management. The combined pharmacologic and endoscopic therapy has been shown in single trials and meta-analysis to be more effective in controlling acute bleeding than endoscopic treatment alone. With this initial strategy, control of bleeding can be achieved in 80%-85% of episodes. Endoscopic intervention requires a skilled endoscopist; banding has been shown effective and is considered the treatment of choice, although very profuse bleeding makes ligation a challenge, and sclerotherapy with cyanoacrylate may be useful in this setting if special expertise is available. Balloon tamponade is no longer used routinely but is rather reserved for failure of the pharmacologic/endoscopic therapy for the hemodynamically unstable patients, and when the next line of treatment cannot readily be implemented.

The failure rate of the standard medical therapy for all comers is of 10%-20%, highest in patients with Child-Pugh class C disease, and early rebleeding rate has been reported in up to 30% of patients. Placement of a transjugular intrahepatic portosystemic shunt (TIPS) is currently considered the salvage therapy of choice in this situation. TIPS may not be an option in some cases, for example in face of portal thrombosis, in which situation surgical shunt or devascularization procedures are indicated.

Death rates rise rapidly in patients requiring more than 10 units of blood, and in general, patients still bleeding after 6 units—or those whose bleeding is still unchecked 24 hours after admission—should be considered for portal decompression procedures. Even when the bleeding is brought under control by the initial intervention, the mortality rate remains high (about 35%) as a result of liver failure and other complications.

Specific Measures

1. Acute endoscopic sclerotherapy or ligation

Emergency esophagogastroscopy is the most useful procedure for the diagnosis and the treatment of bleeding varices and should be performed as soon as the patient’s general condition is stabilized by blood transfusion, correction of coagulopathy, administration of vasoconstrictors, and antibiotics are given. Endotracheal intubation is usually necessary for airway control. Varices appear as three or four large, tortuous submucosal bluish vessels running longitudinally in the distal esophagus. The bleeding site may be identified, but in some cases the lumen fills with blood so rapidly that the lesion is obscured. Using fiber-optic endoscopy, 13 mL of sclerosant solution is injected into the lumen of each varix, causing it to become thrombosed. Variations in the type of endoscope or sclerosant solution or whether or not the varices are physically compressed appear to have little influence on the outcome. Endoscopy is usually repeated within 48 hours and then once or twice again at weekly intervals, at which time any residual varices are injected.

Sclerotherapy controls acute bleeding in 80%-85% of patients, and rebleeding during the same hospitalization is about half (25% vs. 50%) the rebleeding rate of patients treated with a combination of vasopressin and balloon tamponade. Even though controlled trials show improvement in the control of bleeding with sclerotherapy, the evidence for increased patient survival is conflicting.

A similar effect is achieved by endoscopic ligation of the varices. The varix is lifted with a suction tip, and a small rubber band is slipped around the base. The varix necroses to leave a superficial ulcer. Several controlled trials have reported rubber band ligation to be more effective in controlling long-term bleeding episodes compared to sclerotherapy, although comparisons in the acute setting are limited. Band ligation is associated with fewer complications and fewer procedures are needed for complete eradication and has thus emerged as the initial endoscopic treatment of choice.

2. Somatostatin and analogs

Octreotide (brand name Sandostatin), is an octapeptide that mimics the hormone somatostatin pharmacologically. Purified somatostatin is not available in the United States. Somatostatin infusion reduces portal pressure without any impact on systemic hemodynamics; this effect may be less pronounced for octreotide. Somatostatin has been shown, in a prospective randomized trial, to effectively control acute bleeding, although other studies have had equivocal results. A meta-analysis of all studies using somatostatin or its analogs did show a significant risk reduction in control of hemorrhage. The efficacy of octreotide remains uncertain, but it appears to reduce the rebleeding rate when used in conjunction with endoscopic therapy. It should be emphasized that no study of somatostatin or octreotide has shown improved survival after an acute bleeding episode. Octreotide is given as an initial bolus of 50 μg followed by a continuous infusion of 50 μg/h for 2-5 days.

3. Vasopressin and analogs

Vasopressin and its analog terlipressin (triglycyl lysine vasopressin) lower portal blood flow and portal pressure by directly constricting splanchnic arterioles, thereby reducing inflow. Vasopressin or terlipressin alone controls acute bleeding in about 80%-85% of patients, and this rate is increased when combined with endoscopic therapy or balloon tamponade. Cardiac output, oxygen delivery to the tissues, hepatic blood flow, and renal blood flow are also decreased—effects that occasionally produce complications such as myocardial infarction, cardiac arrhythmias, and intestinal necrosis. These unwanted side effects may sometimes be prevented without interfering with the decrease in portal pressure by simultaneous administration of nitroglycerin or isoproterenol. Terlipressin has fewer untoward cardiovascular side effects than vasopressin.

Although the results are somewhat contradictory, controlled trials generally indicate that vasopressin plus nitroglycerin is superior to vasopressin alone and that vasopressin alone is superior to placebo in controlling active variceal bleeding. Survival is not increased, however. In fact, while several vasoactive agents effectively stop acute hemorrhage, only terlipressin has been shown to improve survival after an acute event. Vasopressin is given as a peripheral intravenous infusion (at about 0.4 units/min), which is safer than bolus injections. Nitroglycerin can be given intravenously or sublingually. Terlipressin undergoes gradual conversion to vasopressin in the body and is safe to give by intravenous bolus injection (2 mg intravenously every 6 hours); this drug is, however, not available in the United States.

4. Balloon Tamponade

Tubes designed for tamponade have two balloons that can be inflated in the lumen of the gut to compress bleeding varices. There are three or four lumens in the tube, depending on the type: two are for filling balloons within the stomach and the esophagus, and the third permits aspiration of gastric contents. A fourth lumen in the Minnesota tube is used to aspirate the esophagus orad to the esophageal balloon. The main effect results from traction applied to the tube, which forces the gastric balloon, generally inflated first and with 200 mL of air, to compress the collateral veins at the cardia of the stomach. Inflating the esophageal balloon probably contributes little, since barium x-rays suggest that it does not actually compress the varices (Figure 24–7).

The most common serious complication is aspiration of pharyngeal secretions and pneumonitis. Another serious hazard is the occasional instance of esophageal rupture caused by inflation of the esophageal balloon. The esophageal balloon is therefore infrequently used.

About 75% of actively bleeding patients can be controlled by balloon tamponade, usually applied for 6-12 hours. When bleeding has stopped, the balloons are left inflated for another 24 hours. They are then decompressed, leaving the tube in place. If bleeding does not recur, the tube should be withdrawn. The efficacy of other therapies combined with potential complications associated with balloon catheters have led to a marked reduction in the use of the latter approach, which is now reserved as a salvage treatment or temporary bridge in patients who fail medical and endoscopic therapy.

5. Transjugular Intrahepatic Portosystemic Shunt

TIPS is a minimally invasive means of creating a portosystemic shunt by creating a direct communication between the portal and hepatic venous systems within the liver parenchyma. A catheter is introduced through the jugular vein and, under radiologic control, positioned in the hepatic vein. From this point, the portal vein is accessed through the liver, the tract is dilated, and the channel is kept open by inserting an expandable metal stent, which is left in place. This technique is of great value in controlling portal hypertension and variceal bleeding and is used most commonly as a salvage therapy to stop acute bleeding for the 10%-20% of patients in whom medical and endoscopic therapy fails. TIPS is also indicated to prevent rebleeding in patients with advanced liver disease at high risk for recurrent variceal bleeding. In this latter category of patients, early use of TIPS has been shown in randomized controlled trial to improve survival. The shunt remains open in most patients for up to a year, at which point intimal overgrowth lead to thrombosis and occlusion in many cases. The use of polytetrafluoroethylene (PTFE)-covered stents now appears to have improved the patency rate.

TIPS should not be regarded as definitive therapy, however, even though the shunt usually remains patent for many months. Patients with advanced liver disease are the principal candidates for TIPS, proved most useful as a bridge to transplantation. Patients with less severe cirrhosis should generally be considered for beta-blocker therapy and in some cases for surgical devascularization procedure when transplantation is not a suitable option.

6. Surgery

The operative procedures to control active bleeding are emergency portosystemic shunt and variceal ligation or esophageal transection.

a. emergency portacaval shunt

Although TIPS, when technically feasible, has largely supplanted more invasive surgical shunts as a salvage procedure for variceal bleed, emergency portacaval shunt success has a success rate of 95% in stopping bleeding in this context. The death rate of the operation is not insignificant, generally related to the status of the patient’s liver function (eg, Child–Pugh classification; Table 24–1) as well as the rate and amount of bleeding and its effects on cardiac, renal, and pulmonary function. Some patients with advanced liver disease, especially those with severe encephalopathy and ascites, have an extraordinarily poor survival regardless of the treatment. In such patients, surgery is usually not warranted, even in the face of continued bleeding. On the other hand, patients with good liver function usually recover after an emergency shunt. A controlled trial showed that the death rate in acutely bleeding Child–Pugh C patients was insignificantly lower after endoscopic sclerotherapy (44%) than after emergency portacaval shunt (50%).

For active bleeding, a nonselective end-to-side portacaval shunt is most commonly performed (Figure 24–8C). A side-to-side portacaval shunt might be preferable in an acutely bleeding patient with severe ascites (Figure 24–8B), and this approach (or a variant such as an H-mesocaval shunt) would be required for someone with BCS.

The central splenorenal shunt, in which the portal vein is decompressed via the splenic vein into the left renal vein, is more complicated than portacaval shunts and has no specific advantages. Selective shunts, such as the distal splenorenal (Warren) shunt, in which the gastrosplenic collaterals are decompressed via the splenic vein into the left renal vein, leaving the portal vein intact, are usually too time-consuming for use in emergency operations.

Although the risk of variceal rebleeding is low, approximately 40% of patients develop encephalopathy after portacaval surgical shunting. Hepatic insufficiency is accelerated and liver failure is the cause of death in about two-thirds of those who die after an emergency portacaval shunt. Portacaval shunts can also render liver transplantation more difficult. Renal failure, which is often accompanied by ascites, is another potentially lethal problem. Metabolic alkalosis and delirium tremens are not uncommon postoperatively in alcoholics.

b. esophageal transection

Varices may be obliterated by firing the end-to-end stapler in the distal esophagus after tucking a full-thickness ring of tissue into the cartridge with a circumferential tie. This procedure has gained popularity in the past decade, and in many surgical units it is considered a last resort therapy when nonsurgical methods fail.

If transection is performed, it must be done as soon as it is recognized that a second attempt at sclerotherapy or band ligation has failed. The results (eg, survival) are better in patients with nonalcoholic cirrhosis. Stapled transection has replaced the older technique of direct suture ligation of the varices. Transection must be viewed as an emergency measure to stop persistent bleeding—not as definitive treatment—since the underlying portal hypertension is not corrected and varices recur months later in many patients.

NONBLEEDING VARICES

Gastroesophageal varices are present in almost half of patients with cirrhosis at the time of diagnosis. Development and growth of esophageal varices each occur at a rate of 7% per year. Patients with varices that have never bled have a 30% chance of bleeding at some point; of those who bleed, 50% die. For patients who do not bleed during the first year after diagnosis of varices, the risk of bleeding subsequently decreases by half and continues to drop thereafter. Patients who have bled once from esophageal varices have a 60%-70% chance of bleeding again, and about two-thirds of repeat bleeding episodes are fatal.

Evaluation

A. Portal Flow and Pressure Measurements

Measurements of pressure and flow in the splanchnic vasculature have been used for diagnosis and as a guide to therapy and prognosis in portal hypertension. Portal pressure can be measured directly at surgery or preoperatively by any of the following techniques:

1. Wedged hepatic venous pressure (WHVP) accurately reflects free portal pressure when portal hypertension is caused by a postsinusoidal (or sinusoidal) resistance, as in cirrhosis. The portal pressure can be determined with the catheter in the wedged position, corrected by subtracting the free hepatic venous pressure; the HVPG (the pressure gradient from the portal to the hepatic venous systems) can also be determined. This is the most commonly used technique.

2. Direct measurement of splenic pulp pressure is obtained by a percutaneously placed needle.

3. Percutaneous transhepatic catheterization of the intrahepatic branches of the portal vein is the method of choice in patients thought to have presinusoidal block or BCS.

4. Catheterization of the umbilical vein is accomplished through a small incision, and the catheter is threaded into the portal system. With each of these methods, one may also obtain anatomic information by performing angiography through the catheter.

HVPG predicts decompensation and death. Reduction in the HVPG, either spontaneously or after therapy, may help predict the risk of rebleeding in some patients. It has therefore been suggested that HVPG can be used to guide therapy. However, its value currently has been shown primarily in alcoholic liver disease. Also, it is an invasive study that requires special expertise and is not always readily available. Duplex ultrasonography is an accurate noninvasive means of assessing the amount and direction of flow in the portal vein. Preoperatively, duplex ultrasonography is useful to determine patency of the portal vein and direction of flow. Because of spontaneous thrombosis, about 10% of patients with cirrhosis have a portal vein unsuitable for a portacaval shunt. If flow in the portal vein is reversed (hepatofugal), a selective shunt (eg, splenorenal, distal) is not recommended, because it compromises the ability of portal tributaries to serve as an outflow tract for liver blood. Duplex ultrasonography can also be used to follow changes in portal perfusion after shunt operations.

B. Portal Angiography

The portal venous anatomy is often studied preoperatively by angiographic techniques. The objectives are to determine the patency, location, and size of the veins tentatively chosen for a shunt, to demonstrate the presence of varices, and to estimate the degree of prograde portal flow. Some of this information can now be obtained less invasively by duplex ultrasonography. When a splenorenal shunt is contemplated, the left renal vein should be opacified, either by injection of the renal artery or renal vein.

Treatment

The treatment options consist of expectant management, endoscopic sclerotherapy, nonselective beta-blocker (eg, propranolol, nadolol), portosystemic shunts, devascularization of the esophagogastric junction, and miscellaneous rarely used operations. The treatment of patients with varices that have never bled is usually referred to as prophylactic therapy (eg, prophylactic endoscopic variceal ligation (EVL) or prophylactic propranolol). By convention, procedures performed on patients who have bled previously are referred to as therapeutic (eg, therapeutic shunts).

A. Prophylactic Therapy

Prophylactic therapy is of value, since the mortality rate of variceal bleeding is high (25%), the risk of bleeding in patients with varices is relatively high (30%), and varices can often be diagnosed before the initial episode of bleeding. In patients who have never had a bleeding episode, the following have been shown to be related to the risk of hemorrhage: Child–Pugh classification, the size of the varices, and the presence of red wale markings (longitudinal dilated venules resembling whip marks) on the varices. This information can be used to identify high-risk patients (up to 65% risk of bleeding within a year) who are most likely to benefit from prophylactic treatment.

In cirrhotic patients without varices, treatment with nonselective beta-blockers is not recommended because they do not prevent the development of varices and are associated with side effects. In patients with low-risk varices (small, no red wale marks, no severe liver dysfunction), nonselective beta-blockers may delay variceal growth and thereby prevent hemorrhage. The alternative is to schedule periodic endoscopic screening for detection of variceal growth, at what time medical treatment can be initiated.

In patients who have never bled but have a high risk (medium to large varices or small varices with red wale markings and/or decompensated cirrhosis), EVL, or nonselective beta-blockers are considered equally adequate, as high-quality randomized controlled trial have concluded to similar survival of patients with either approaches. It has been suggested that beta-blocker therapy should be the first-line treatment, with EVL used in patients who cannot tolerate or have contraindications to beta-blockade. Endoscopic sclerotherapy is no longer routinely used as primary prophylaxis. More recently, low-dose carvediol as shown lower rates of first variceal hemorrhage when compared to EVL (10% vs. 23%), but those results needs to be validated in other trials.

B. Therapy of Patients Who Have Bled Previously

As noted earlier, patients who recover from an episode of variceal bleeding have an approximately 60%-70% chance of bleeding again. Much effort has been expended to ascertain the best treatment for these patients. The methods of greatest interest include nonselective beta-blocker therapy, endoscopic band ligation, and portosystemic shunts.

1. Nonselective beta-blocker therapy

As with patients with esophageal varices who have never bled, nonselective beta-adrenergic blocking agents (propranolol, nadolol) effectively reduce the risk of recurrent bleeding episodes. These agents work by decreasing cardiac output and splanchnic blood flow and consequently portal blood pressure. Chronic propranolol therapy, 20-160 mg twice daily (a dose that reduces resting pulse rate by 25%), decreases by about 40% the frequency of rebleeding from esophageal or gastric varices, deaths from rebleeding, and overall mortality. The benefits are greater in Child–Pugh A and B than in Child–Pugh C cirrhotics. Beta-blocker therapy has been compared to endoscopic sclerotherapy, with no difference in rebleeding or mortality seen but with higher complications in the sclerotherapy group. On the other hand, randomized controlled trials have shown that the combined use of EVL and nonselective beta blockers could further lower the risk of rebleeding. The addition of nitrate drugs to beta-blocker therapy appears to result in a greater reduction of portal pressure compared to beta-blockade alone. This approach is often favored in patients who are not candidates for EVL. Abstinence from alcohol should always be emphasized and may help prevent further bleeding but may not necessarily decrease the mortality related specifically to variceal hemorrhage, as was previously thought.

2. Endoscopic band ligation

Endoscopic band ligation, as described earlier, is an effective means of preventing recurrent bleeding episodes and has been shown to be superior to sclerotherapy in this regard. Both band ligation and beta-blocker therapy appear to be similarly effective in preventing rebleeding. However, the combination of both therapies has been shown to significantly reduce not only the risk of rebleeding but also the recurrence of varices. Thus, combination therapy appears to be the most effective treatment after an initial bleeding episode.

3. Endoscopic sclerotherapy

The technique of endoscopic sclerotherapy was described earlier in this chapter. Sclerotherapy was previously used routinely to reduce the risk of rebleeding but has been replaced by band ligation.

4. Transjugular intrahepatic portosystemic shunt

The TIPS technique is described in the preceding section. TIPS is effective in preventing rebleeding episodes, more so than either endoscopic or pharmacologic therapy alone. However, this advantage is offset by its higher morbidity and mortality rate from the development of hepatic encephalopathy and liver failure. For this reason, as well as the lack of a clear survival or cost-benefit advantage, TIPS is used mainly to salvage patients who fail endoscopic and/or pharmacologic treatment.

TIPS has generally superseded shunt surgery in most patients who fail first-line therapy. A recent large multicenter randomized trial showed that TIPS and surgical shunts had similar rates of rebleeding, encephalopathy, and mortality in Child–Pugh A and B cirrhotic patients. There was a higher incidence of shunt dysfunction in the TIPS patients, perhaps because of the type of stent used, the first generation not being covered with PTFE. The use of TIPS covered with PTFE has significantly lower occlusion rate. The choice between TIPS and surgical shunts therefore currently depends on expertise, anatomical considerations, and patient’s preference.

C. Surgical Approaches

The objective of surgical procedures used to treat portal hypertension is either to obliterate the varices or to reduce blood flow and pressure within the varices (Table 24–6). A third option, liver transplantation, can treat both the underlying liver dysfunction and the portal hypertension.

1. Liver transplantation

Any relatively young patient with cirrhosis who has survived an episode of variceal hemorrhage should be considered a candidate for liver transplantation, since any other form of therapy carries a much higher (about 80%) mortality rate within the subsequent 1-2 years as a result of repeat bleeding or complications of hepatic failure. Obviously, continued alcohol use is a contraindication to transplantation in most patients. The good transplantation candidates, however, should not be subjected to portosystemic shunts or other procedures if it appears that they will come to transplantation in the near future. In general, Child-Pugh A patients are candidates for portal decompression; Child-Pugh C patients are candidates for a transplant. A TIPS (see previous section) is an excellent way to control bleeding while the patient is being prepared for a transplant.

2. Portosystemic shunts

The advent of TIPS has resulted in a marked decline in the number of shunt operations performed. However, surgical shunts are durable, and good risk patients appear to benefit from these procedures.

Portosystemic shunts can be grouped into those that shunt the entire portal system (total shunts) and those that selectively shunt blood from the gastrosplenic region while preserving the pressure-flow relationships in the rest of the portal bed (selective shunts). All of the shunt operations commonly used today reduce the incidence of rebleeding to less than 10%, compared with about 75% in unshunted patients. Unfortunately, the price of this achievement is an operative mortality rate of 5%-20% (depending on the Child–Pugh classification), further impairment of liver function, and an increase in encephalopathy (greater with total shunts). Therefore, since shunts have these potential drawbacks, clinical trials are needed to pinpoint their place within an overall treatment strategy.

In one well-designed trial, patients who had bled previously were randomized to chronic sclerotherapy or a distal splenorenal shunt (Warren shunt, Figure 24–8F). Patients randomized to chronic sclerotherapy who had recurrent episodes of bleeding during treatment (ie, treatment failures, which amounted to 30% of the sclerotherapy group) were then treated surgically (ie, shunted). The results showed that 2-year survival was better among those originally randomized to sclerotherapy (90%) than among those originally assigned to the shunt group (60%). This trial supports a general treatment plan consisting initially of endoscopic therapy and reserving portosystemic shunts for the patients in whom the former fails to control bleeding adequately (Figure 24–6).

The choice of shunt has been the subject of much debate and several randomized trials. The principal question in recent years has been whether encephalopathy and survival are better with a selective shunt (eg, a distal splenorenal shunt, Figure 24–8F) than with a total shunt (eg, a mesocaval or an end-to-side portacaval shunt, Figure 24–8C and 24–8D). The results are conflicting, but in general they support the contention that there is about half as much severe encephalopathy following selective shunts. None of the trials have shown any particular shunt to be associated with longer survival.

3. Severity of hepatic disease and operative risk

The immediate death rate of an elective shunt procedure can be predicted from the patient’s hepatic function as reflected by the Child–Pugh classification (Table 24–1). In addition to operative death rate, the figures also correlate with the death rate in the first postshunt year. Thereafter, survival curves of the different risk classes become reasonably parallel.

The severity of histopathologic changes in liver biopsies correlates with the immediate surgical death rate, the most ominous findings being hepatocellular necrosis, polymorphonuclear leukocyte infiltration, and the presence of Mallory bodies. The extent of histologic change also correlates with the more easily obtained data in the Child–Pugh classification (ie, severe changes occur in class C patients), so results of biopsies have no independent predictive value.

Figure 24–8 depicts the various shunts in use currently. Although they differ technically, physiologically there are only three different types: end-to-side, side-to-side, and selective.

The end-to-side shunt completely disconnects the liver from the portal system. The portal vein is transected near its bifurcation in the liver hilum and anastomosed to the side of the inferior vena cava. The hepatic stump of the vein is oversewn. Postoperatively, the WHVP (sinusoidal pressure) drops slightly, reflecting the inability of the hepatic artery to compensate fully for the loss of portal inflow. The side-to-side portacaval, mesocaval, mesorenal, and central splenorenal shunts are all physiologically similar, since the shunt preserves continuity between the hepatic limb of the portal vein, the portal system, and the anastomosis. Flow through the hepatic limb of the standard side-to-side shunt is nearly always away from the liver and toward the anastomosis. The extent to which hepatofugal flow is produced by the other types of side-to-side shunts listed previously is not known.

The end-to-side portacaval shunt gives immediate and permanent protection from variceal bleeding and is somewhat easier to perform than a side-to-side portacaval or central splenorenal shunt. Encephalopathy may be slightly more common after side-to-side than end-to-side portacaval shunts. Side-to-side shunts are required in patients with BCS or refractory ascites (when the latter is treated by a portosystemic shunt).

The mesocaval shunt interposes a segment of prosthetic graft or internal jugular vein between the inferior vena cava and the superior mesenteric vein where the latter passes in front of the uncinate process of the pancreas. The mesocaval shunt is particularly useful in the presence of severe scarring in the right upper quadrant or portal vein thrombosis, and in some cases it may be technically easier than a conventional side-to-side portacaval shunt if a side-to-side type of shunt is necessary. In most cases, portal flow to the liver is lost after this shunt. Evidence has been presented, however, that by limiting the diameter of the prosthetic graft to 8 mm (compared with 12- to 20-mm grafts), prograde flow is preserved in the portal vein, which decreases the incidence of postoperative encephalopathy while still preventing variceal hemorrhage.

Selective shunts lower pressure in the gastroesophageal venous plexus while preserving blood flow through the liver via the portal vein.

The distal splenorenal (Warren) shunt involves anastomosing the distal (splenic) end of the transected splenic vein to the side of the left renal vein, plus ligation of the major collaterals between the remaining portal and isolated gastrosplenic venous system. The latter step involves division of the gastric vein, the right gastroepiploic vein, and the vessels in the splenocolic ligament. The operation is more difficult and time consuming than conventional shunts and except for the experienced operator is probably too complex for emergency portal decompression. If mobilization of the splenic vein is hazardous, the renal vein may be transected and its caval end joined to the side of the undisturbed splenic vein. The segment of splenic vein between the anastomosis and the portal vein is then ligated. Surprisingly, this seems to have little permanent effect on renal function as long as the remaining tributaries are preserved on the oversewn renal vein stump.

In contrast to total shunts, the Warren shunt does not improve ascites and should not be performed in patients whose ascites has been difficult to control. Preoperative angiography should be performed to determine if the splenic vein and left renal vein are large enough and close enough together for performance of this shunt. Recent pancreatitis may preclude safe dissection of the splenic vein from the undersurface of the pancreas.

Another type of selective shunt (Inokuchi shunt) consists of joining the left gastric vein to the inferior vena cava by a short segment of autogenous saphenous vein. The procedure has not become popular, perhaps because of its technical complexity.

Selective shunts tend to become less selective over several years as new collaterals develop between the high-pressure and low-pressure regions of the portal system. This is accompanied by a gradual decrease in portal pressure (measured by WHVP) and evolution of the procedure into a version of side-to-side total shunt. The enlargement postoperatively of small venous tributaries entering the distal splenic vein from the pancreas suggests that this is the path by which nonselectivity develops. It is possible that this can be avoided by mobilizing the splenic vein all the way to the hilum (dividing these small vessels) before performing the splenorenal anastomosis.

A reasonable approach to shunt selection is as follows.

The distal splenorenal shunt is the first choice for elective portal decompression. If ascites is present or the anatomy is unfavorable, an end-to-side portacaval shunt is preferred. Side-to-side shunts would be done for patients with severe ascites or BCS. The H-mesocaval and central splenorenal shunts are reserved for special anatomic situations in which the above operations are unsuitable. An end-to-side shunt or H-mesocaval shunt is performed for emergency decompression.

Portacaval and distal splenorenal shunts are often followed by a rise in platelet count in patients with secondary hypersplenism. The response is unpredictable, however, and hypersplenism need not necessarily dictate the type of shunt since it rarely produces clinical manifestations. A central splenorenal shunt, in which splenectomy is performed, should not be considered preferable to other kinds of shunts just because the patient has a low platelet count.

Over 90% of portosystemic shunts remain patent, and the incidence of recurrent variceal bleeding is less than 10%. The 5-year survival rate after a portacaval shunt for alcoholic liver disease averages 45%. Some degree of encephalopathy develops in 15%-25% of patients. Severe encephalopathy is seen in about 20% of alcoholics following a total shunt; its occurrence is not related to the severity of preshunt encephalopathy.

D. Devascularization Operations

The objective of devascularization is to destroy the venous collaterals that transport blood from the high-pressure portal system into the veins in the submucosa of the esophagus.

The Sugiura-Futugawa procedure initially described in 1973 was done in two stages. The first stage was performed through a thoracotomy and consisted in division of the dilated venous collaterals between esophagus and adjacent structures, transection of the esophagus at the level of the diaphragm, and reanastomosis. The second stage, a laparotomy, was performed immediately after the thoracotomy if the patient was actively bleeding or deferred 4-6 weeks in elective cases. In the second stage of the operation, the upper two-thirds of the stomach was devascularized, and selective vagotomy, pyloroplasty, and splenectomy performed.

More recently, an analogous one-stage operation has been described in many series and performed through laparotomy that consists of splenectomy, devascularization of 8-10 cm of distal esophagus, devascularization of the lesser and greater curvature with ligation of the left gastric and gastroepiploic vessels, transection and end-to-end anastomosis of the lower esophagus 4-5 cm above the gastroesophageal junction (EEA-stapler), pyloroplasty, and insertion of a feeding jejunostomy.

In Eastern and Western series published between 1980 and 1999, the operative mortality ranged from 0% to 36%, up to 80% in Child C patients, the variceal rebleeding rate from 0% to 37%, encephalopathy from 0% to 22%, and esophageal stenosis ranged from 2% to 37%. For cirrhotic patients with extensive portal thrombosis, for who portosystemic shunt cannot be performed, devascularization operations can offer a good alternative.

E. Miscellaneous Operations

Attempts have also been made to decrease portal pressure by decreasing splanchnic inflow through splenectomy or splenic artery ligation. Diseases characterized by marked splenomegaly may rarely be associated with portal hypertension as a consequence of increased splenic blood flow, which has been known to reach levels as high as 1000 mL/min. Splenic blood flow may occasionally be increased enough in patients with cirrhosis to contribute significantly to the portal hypertension. However, splenectomy or splenic artery ligation in cirrhosis most often gives only a transient decrease in portal pressure, and over half of patients having these operations bleed again. Some workers have suggested that the absolute size of the splenic artery (a crude index of splenic flow) correlates with the clinical effectiveness of splenic artery ligation, a good result being predictable if the diameter of the artery is 1 cm or greater.

EXTRAHEPATIC PORTAL VENOUS OCCLUSION

Extrahepatic portal vein obstruction is one of many causes of noncirrhotic portal hypertension, the other common cause being noncirrhotic portal fibrosis. These disorders are distinct but appear to share several similar etiological and pathogenetic features, the most notable of which is the clinical manifestation of portal hypertension in the absence of significant hepatic parenchymal dysfunction.

Idiopathic portal vein thrombosis (in the absence of liver disease) is a relatively common cause of portal hypertension in developing countries but is less prevalent in the West. This diagnosis accounts for most cases of portal hypertension in childhood (80%-90%) and for a smaller proportion of cases in adults. Neonatal septicemia, omphalitis, umbilical vein catheterization for exchange transfusion, and dehydration have all been incriminated as possible causes, but collectively they can be implicated in less than half of cases. The causes of portal vein thrombosis in adults include hepatic tumors, cirrhosis, trauma, pancreatitis, pancreatic pseudocyst, myelofibrosis, thrombotic states (eg, protein C deficiency), and sepsis; in particular, cirrhosis and/or hepatocellular carcinoma need to be considered in adult patients. In adult, systemic anticoagulation result in complete portal vein recanalization in approximately 38.3% of cases and partial recanalization in 15%.

Although clinical manifestations may be delayed until adulthood, 80% of patients with idiopathic portal vein thrombosis present between 1 and 6 years of age with variceal bleeding, although hemorrhage from ectopic varices at other locations in the gastrointestinal tract is not uncommon. About 70% of hemorrhages are preceded by a recent upper respiratory tract infection. Some of these children first come to medical attention because of splenomegaly and pancytopenia. Failure to recognize the underlying problem has occasionally led to splenectomy, with the result that portal decompression using the splenic vein is precluded. Ascites is uncommon except transiently after bleeding. Liver function is either normal or only slightly impaired, which probably accounts for the low incidence of overt encephalopathy. There is an increased frequency of neuropsychiatric problems, which may be a subtle form of encephalopathy.

Portal biliopathy refers to abnormalities of the extrahepatic bile ducts, usually the result of bile duct compression from large, dilated venous collaterals within the porta hepatis. These changes result in marked irregularities of the biliary wall that can progress to strictures and even obstructive jaundice and cholangitis in some cases; secondary biliary cirrhosis has been reported. Biliopathy is commonly seen on imaging studies, but most patients remain free of related symptoms.

Because the patient’s general condition and liver function are good, the death rate for sudden massive bleeding is below that for other types of portal hypertension. The diagnosis can be confirmed with cross-sectional imaging or direct mesenteric angiography. WHVP is normal to slightly elevated; liver biopsies are normal or may show mild to moderate periportal fibrosis.

Bleeding episodes in children under age 8 years are usually self-limited and often do not require endoscopic sclerotherapy, administration of vasopressin, or balloon tamponade. Even if such interventions are necessary, however, the bleeding episodes are self-limited and uncommonly fatal, so emergency operations are rarely necessary.

Thrombosed portal veins are unsuitable for shunt procedures. Cavomesenteric shunts are best for young children, whose vessels are small. In older individuals, treatment should be started with sclerotherapy; if that fails to control the bleeding, a distal splenorenal shunt is preferred. Splenectomy alone has no permanent effect and sacrifices the splenic vein, which might be needed later for a shunt operation. Shunts in small children have a high rate of spontaneous thrombosis and should be avoided, if possible, until approximately 8-10 years of age, when the vessels are of larger caliber. Even still, using precise technique, some surgeons have obtained a high rate of anastomotic patency in the very young. Encephalopathy and hepatic dysfunction many years after a total shunt may be improved if converted to a selective shunt.

Splenectomy alone is never indicated in this disease, either for hypersplenism or in an attempt to reduce portal pressure, because the rebleeding rate is 90% and fatal postsplenectomy sepsis is not uncommon. If it is not possible to construct an adequate shunt, expectant management is the best strategy. Repeated severe bleeding episodes should be treated by transendoscopic sclerosis. Esophagogastrectomy with colonic interposition may be effective but should be considered a last resort.

SPLENIC VEIN THROMBOSIS

Isolated thrombosis of the splenic vein is a rare cause of variceal bleeding that can be cured by splenectomy. The splenic venous blood, blocked from its normal route, flows through the short gastric vessels to the gastric fundus and then into the left gastric vein, continuing toward the liver. This phenomenon is called left-sided (or sinistral) portal hypertension. As the blood traverses the stomach, large gastric varices are produced that may rupture and bleed. Characteristically, the collateral pattern does not involve the esophagus, so esophageal varices are uncommon.

The principal causes of this syndrome are pancreatitis, pancreatic pseudocyst, neoplasm, and trauma. The mean incidence of splenic vein thrombosis associated with chronic and acute pancreatitis is estimated at 12.4% and 22.6% respectively, with an overall bleeding rate of 12.3%. Splenomegaly is present in two-thirds of patients. Diagnosis can be made by selective splenic arteriography that opacifies the venous phase, but more commonly nowadays on CT scan with portal phase imaging. Splenectomy is curative. Many cases of splenic vein thrombosis are unaccompanied by bleeding varices, and in such cases, no therapy is required. Treatment of acute bleeding from gastric varices is generally endoscopic, and endoscopic variceal obturation with tissue glue appears to be superior to band ligation or sclerotherapy.

BUDD–CHIARI SYNDROME

BCS is a rare disorder resulting from obstruction of hepatic venous outflow, which can arise at several different levels, from the small hepatic venous tributaries within the liver parenchyma to the major hepatic venous trunks to the inferior vena cava up to the level of the right atrium. The prevalence of BCS is estimated as 1:100,000, and the largest published series reported on 237 patients treated at four centers in the United States, the Netherlands, and France between 1984 and 2001. Most cases are caused by spontaneous thrombosis of the hepatic veins, often associated with myeloproliferative disorders (polycythemia vera, essential thrombocytosis) or the use of birth control pills. Other common associated conditions include factor V Leiden and factor II gene mutations. Other predisposing factors include protein C and S deficiencies, antiphospholipid syndrome, antithrombin III deficiency, paroxysmal nocturnal hemoglobinuria, Behçet syndrome, and trauma. Some patients present with idiopathic membranous stenosis of the inferior vena cava located between the hepatic veins and right atrium, which is usually associated with secondary thrombosis of the hepatic veins; this condition appears to be more common in Asia than in Western countries. Many patients with BCS are HBsAg-positive, and others have malignancies (eg, hepatocellular carcinoma). Vena caval webs were once thought to be congenital, but more recent evidence suggests that they are the consequence of thrombus formation. Primary BCS originates from within the lumen of the hepatic veins or venules, and occlusion results from thrombosis, webs, or endophlebitis. By contrast, secondary BCS results from extrinsic compression of the venous outflow tract, usually related to a neoplasm or abscess.

Veno-occlusive disease and congestive hepatopathy are two conditions that can cause hepatic venous outflow obstruction, and although the clinical picture of both may be indistinguishable from that of BCS, they differ in the level of obstruction and in predisposing conditions. Veno-occlusive disease is primarily a problem affecting the sinusoids and terminal venules, while congestive hepatopathy reflects a problem at the level of the heart.

Posthepatic (postsinusoidal) obstruction raises sinusoidal pressure, which is transmitted proximally to cause portal hypertension. Because the parenchyma is relatively free of fibrosis, filtration across the sinusoids and hepatic lymph formation increase greatly, producing marked ascites.

Symptoms usually begin with a mild prodrome consisting of vague right upper quadrant abdominal pain, postprandial bloating, and anorexia. After weeks or months, a more florid picture develops consisting of gross ascites, hepatomegaly, and hepatic failure. At this stage, the AST is usually markedly increased, the serum bilirubin is slightly elevated, and the alkaline phosphatase is inconsistently abnormal.

Except in patients with membranous obstruction of the vena cava, liver scans (CT or MRI) usually demonstrate a marked perfusion abnormality throughout most of the liver except for a small central area representing the caudate lobe, whose venous outflow is spared (it goes directly to the vena cava through multiple small tributaries). CT scans show pooling of intravenous contrast media in the periphery of the liver; patent hepatic veins cannot be seen on ultrasound scans. An enlarged azygos vein may be seen on chest x-rays of patients with caval obstruction. Liver biopsy reveals grossly dilated central veins and sinusoids, pericentral necrosis, and replacement of hepatocytes by red blood cells. Centrilobular fibrosis develops late. The clinical diagnosis should be confirmed by venography, which shows the hepatic veins to be obstructed, usually with a beaklike deformity at their orifice. The inferior vena cava should be opacified to verify its patency, which is a requirement for a successful portacaval shunt. Previously, direct venography was used, but the required information may now be obtained using noninvasive methods, such as CT or MR angiography. The x-rays may show compression of the intrahepatic cava by the congested liver.

Treatment of BCS relies on expert consensus given the low incidence of this disease. Anticoagulation is recommended in the presence of recent or long-standing thrombosis to allow recanalization or to avoid propagation of venous thrombosis. Management of ascites and treatment or prevention of portal hypertension and variceal hemorrhage follows the same algorithms as for cirrhotic patients. Surgical or radiological approaches to relieve sinusoidal pressure have been advocated and are now considered appropriate only for symptomatic patients who do not improve with medical management. In recent years, the development of interventional radiology techniques using thrombolysis and angioplasty has shown possible to insert TIPS in selected patients with recent thrombosis or with short-length stenosis of the IVC or hepatic veins with good outcomes. Portosystemic surgical shunts are considered effective for relieving sinusoidal hypertension with the potential to reverse hepatic necrosis and prevent cirrhosis.

Focal membranous obstruction of the suprahepatic cava may be treated by excision of the lesion with or without the addition of a patch angioplasty. Some cases may be managed nonsurgically by percutaneous transluminal balloon dilation of the stenosis. Occlusion of the inferior vena cava by thrombosis or compression from the liver requires a mesoatrial shunt using a prosthetic vascular graft. Because the incidence of graft thrombosis is relatively high, it may be advisable to perform a second-stage side-to-side portacaval shunt a few months after mesoatrial shunt decompression of the liver in patients with hepatic vein thrombosis whose vena cava was originally blocked by a congested liver. Development of hepatocellular carcinoma is common in patients with membranous obstruction of the vena cava. The postoperative results are excellent in patients without malignant neoplasms.

Liver transplantation is required when medical treatment and portosystemic shunts fail in patients presenting progressive liver failure either from cirrhosis or as part of the acute syndrome. The 1-, 5-, 10-year survival rates with transplantation are of 76%, 71%, and 68%, respectively, and the risk of later hepatocellular carcinoma is eliminated.

ASCITES

Ascites is a common manifestation of chronic liver disease, resulting from sinusoidal hypertension as the specific pathophysiologic abnormality. Ascites in hepatic disease results from (1) increased formation of hepatic lymph (from sinusoidal hypertension), (2) increased formation of splanchnic lymph (from splanchnic vasodilatation), (3) hypoalbuminemia, and (4) salt and water retention by the kidneys. Before therapy is started, paracentesis should be performed and the following examinations made on a sample of ascitic fluid: (1) Culture and leukocyte count—spontaneous bacterial peritonitis is common and may be clinically silent. A white count above 250/μL is highly suggestive of infection. (2) LDH levels—a ratio of LDH in ascites to serum that exceeds 0.6 suggests the presence of cancer or infection. (3) Serum amylase—a high level suggests pancreatic disease. (4) Albumin—the ratio of serum to ascites albumin concentrations is above 1.1 in liver disease and below 1.1 in malignant ascites. (5) Cytology—this is pertinent only in patients with a cancer diagnosis or a suspicion of cancer.

Nonhepatic ascites can result from congestive heart failure, chylous leak, peritoneal carcinomatosis, infections such as tuberculosis, coccidiomycosis, and chlamydia, and some autoimmune disease involving the connective tissues, such as systemic lupus erythematosus. Treatments of ascites in these contexts depend on the underlying cause and are not discussed in this chapter.

Medical Treatment

In general, the intensity of medical therapy required to control ascites can be predicted from the pretreatment 24-hour urine Na⁺ output as follows: A Na⁺ output below 5 mEq/24 h requires strong diuretics; 5-25 mEq/24 h, mild diuretics; and above 25 mEq/24 h, no diuretics. Initial treatment is usually with spironolactone, 200 mg/d. The objective is to stimulate a weight loss of 0.5-0.75 kg/d except in patients with peripheral edema who can mobilize fluid faster. If spironolactone alone is insufficient, another drug such as furosemide should be added. A loop diuretic (eg, furosemide, ethacrynic acid) should be given only in combination with a distally acting diuretic (eg, spironolactone, triamterene). Alternatively, massive ascites may be treated by one or more large volume (eg, 5-L) paracenteses; this is often accompanied by an intravenous infusion of albumin, although the benefits of albumin remain controversial. Caution is required in patients with evidence of renal dysfunction, since aggressive fluid removal can result in renal failure. Close monitoring of serum electrolytes should be done. Because the development of ascites in cirrhosis is a result of renal sodium retention, dietary sodium restriction is a mainstay of treatment. A typical American diet contains 4-6 g of sodium per day. Patients are educated to have a diet of maximum 2 g of sodium per day. Fluid restriction is only indicated in patients with severe hyponatremia, but all should avoid excessive fluid intake.

Surgical Treatment

A. Portacaval Shunt

A history of ascites that has been easy to control need not influence the choice of shunt operation intended to treat variceal bleeding. When ascites has been severe, however, a side-to-side shunt (eg, side-to-side portacaval, H-mesocaval, central splenorenal) may be considered, because it reduces sinusoidal as well as splanchnic venous pressure. A side-to-side portacaval shunt is rarely indicated just to treat ascites (eg, in patients in whom several LeVeen shunts have thrombosed), although the incidence of severe postoperative encephalopathy is high under these circumstances. TIPS is another effective intervention for refractory ascites, probably a better option than repeated paracentesis in good-risk patients, although there is an associated risk of hepatic encephalopathy.

B. Peritoneal-Jugular Shunt (LeVeen Shunt, Denver Shunt)

Refractory ascites can be treated with a LeVeen shunt—a subcutaneous Silastic catheter that transports ascitic fluid from the peritoneal cavity to the jugular vein. A small unidirectional valve sensitive to a pressure gradient of 3-5 cm H₂O prevents backflow of blood. A modification called the Denver shunt contains a small chamber that can be used as a pump to clear the line by external pressure. In practice, Denver shunts become blocked more often than LeVeen shunts.

In patients with ascites due to cirrhosis, use of a LeVeen shunt should be confined to those who fail to respond to high doses of diuretics (eg, 400 mg of spironolactone and 400 mg of furosemide daily) or who repeatedly develop encephalopathy or azotemia during diuretic therapy.

Peritoneovenous shunts may also be used for ascites associated with cancer. The best results occur in patients whose ascitic fluid contains no malignant cells. A LeVeen shunt is of benefit in BCS but is ineffective for chylous ascites. Because the incidence of complications and early shunt thrombosis is high, a LeVeen shunt is relatively contraindicated if the ascitic fluid is grossly bloody, contains many malignant cells, or has a high protein concentration (> 4.5 g/dL). The incidence of tumor embolization is low (5%).

The ascitic fluid should be cultured a few days before the shunt is inserted. Antibiotic coverage should be given for the procedure. The operation can be done with local anesthesia.

Postoperatively, the patient is outfitted with an abdominal binder and instructed to perform respiratory exercises against mild pressure to increase abdominal pressure and flow through the shunt. Dietary salt should not be restricted. A functioning LeVeen shunt alone is unable to fully eliminate the ascites, but it improves symptoms related to distention and renders the patient much more responsive to diuretics. Therefore, furosemide should be administered postoperatively.

An average of 10 kg of weight is lost during the first 10 days after the operation, and eventually the abdomen assumes a normal configuration. Nutrition and serum albumin levels often improve postoperatively. Urinary sodium excretion increases promptly, and renal function may improve in patients with the hepatorenal syndrome. Serious complications and deaths are most common in patients with advanced hepatorenal syndrome or a serum bilirubin level greater than 4 mg/dL. Although some patients eventually bleed from varices following insertion of a LeVeen shunt, the shunt itself does not increase the risk of bleeding and actually decreases portal pressure. Thus, a previous episode of variceal bleeding is not a contraindication for this procedure. Disseminated intravascular coagulation (manifested by increased fibrin split products, decreased platelet count, etc) occurs in more than half of cases but is clinically relevant in only a few. The frequency and severity of disseminated intravascular coagulation may be minimized by emptying most of the ascitic fluid from the abdomen during operation and partially replacing it with Ringer lactate solution. Lethal septicemia may occur if the ascitic fluid is infected at the time the shunt is inserted. In about 10% of cases, the valve becomes thrombosed and must be replaced.

Hydrothorax, usually on the right side, may develop in patients with cirrhosis and ascites. The fluid reaches the chest through a pinhole opening in the membranous portion of the diaphragm, a pathway that can be demonstrated by aspirating the thoracic fluid, injecting technetium ^99mTc colloid into the ascites fluid, and observing rapid accumulation of the label in the chest. Treatment consists of a peritoneovenous shunt and injection of a sclerosing agent into the pleural cavity after it has been tapped dry. If a leak persists, it may be closed surgically by thoracotomy.

HEPATIC ENCEPHALOPATHY

Central nervous system abnormalities may be seen in patients with chronic liver disease and are especially likely after portacaval shunts. Portosystemic encephalopathy, ammonia intoxication, hepatic coma, and meat intoxication are older terms used to refer to this condition. The manifestations range from lethargy to coma—from minor personality changes to psychosis—from asterixis to paraplegia. Hypothermia and hyperventilation may precede coma. The changes may be quite subtle and detectable only with the use of neuropsychological or neurophysiological testing.

Pathogenesis

Hepatic encephalopathy is a reversible metabolic neuropathy that results from the action of chemicals absorbed from the gut on the brain. Increased exposure of the brain to these agents is the result of impaired hepatic metabolism due to cirrhosis or spontaneous or surgically created shunts of portal venous blood around the liver and increased permeability of the blood-brain barrier. The chemical agents responsible for encephalopathy form from the action of colonic bacteria on protein within the gut. Potential aggravating factors include gastrointestinal hemorrhage, constipation, azotemia, hypokalemic alkalosis, infection, excessive dietary protein, and sedatives (Table 24–7). Four main chemical mediators of this syndrome currently attract the most attention. Low-grade cerebral edema appears to be a major component of the pathophysiologic process.

A. Amino Acid Neurotransmitters

Gamma-aminobutyric acid (GABA), the principal inhibitory neurotransmitter in the brain, produces a state similar to hepatic encephalopathy when given experimentally. It is normally synthesized in the brain and by bacteria within the colon; GABA in the gastrointestinal tract is normally degraded by the liver and is found in increased levels in the serum of patients with hepatic encephalopathy. The passage of GABA across the blood-brain barrier is increased in hepatic encephalopathy. Experiments also indicate the presence of increased numbers of GABA receptors in encephalopathy and increased GABA-ergic tone, perhaps due to a benzodiazepine receptor agonist ligand on the receptor complex (GABA/benzodiazepine receptor). This has raised the possibility of treating encephalopathy with benzodiazepine antagonists, and the drug flumazenil has shown promise in preliminary trials.

B. Ammonia

Ammonia is produced in the colon by bacteria and is absorbed and transported in portal venous blood to the liver, where it is extracted and converted to glutamine. Ammonia concentrations are elevated in the arterial blood and cerebrospinal fluid of patients with encephalopathy, and experimental administration of ammonia produces central nervous system symptoms.

C. False Neurotransmitters

According to this theory, cerebral neurons become depleted of normal neurotransmitters (norepinephrine and dopamine), which are partially replaced by false neurotransmitters (octopamine and phenylethanolamine). The result is inhibition of neural function. Serum levels of branched-chain amino acids (leucine, isoleucine, valine) are decreased, and levels of aromatic amino acids (tryptophan, phenylalanine, tyrosine) are elevated in patients with encephalopathy. Because these two classes of amino acids compete for transport across the blood-brain barrier, the aromatic amino acids have increased access to the central nervous system, where they serve as precursors for false neurotransmitters. Trials of therapy with supplements of branched-chain amino acids have given conflicting results.

D. Synergistic Neurotoxins

This theory postulates that ammonia, mercaptans, and fatty acids, none of which accumulate in the brain in amounts capable of producing encephalopathy, have synergistic effects that produce the full-blown syndrome in patients with liver disease.

Prevention

Encephalopathy is a major side effect of portacaval shunt and is to some extent predictable. Elderly patients are considerably more susceptible. Patients with alcoholic liver disease fare better than those with postnecrotic or cryptogenic cirrhosis, apparently owing to the invariable progression of liver dysfunction in the latter. Good liver function partially protects against encephalopathy. If the liver has adapted to complete or nearly complete diversion of portal blood before operation, a surgical shunt is less apt to depress liver function further. For example, patients with thrombosis of the portal vein (complete diversion and normal liver function) rarely experience encephalopathy after portosystemic shunt. Encephalopathy is less common after a distal splenorenal (Warren) shunt than after other kinds of shunts.

Increased intestinal protein, whether of dietary origin or from intestinal bleeding, aggravates encephalopathy by providing more substrate for intestinal bacteria. Constipation allows more time for bacterial action on colonic contents. Azotemia results in higher concentration of blood urea, which diffuses into the intestine, is converted to ammonia, and is then reabsorbed. Hypokalemia and metabolic alkalosis aggravate encephalopathy by shifting ammonia from extracellular to intracellular sites where the toxic action occurs.

Laboratory Findings

Arterial ammonia levels are usually high, although encephalopathy can certainly be present with a normal ammonia level. The presence of high levels of glutamine in the cerebrospinal fluid may help distinguish hepatic encephalopathy from other causes of coma. Electroencephalography is more sensitive than clinical evaluation in detecting minor involvement. The changes are nonspecific and consist of slower mean frequencies. Studies performed at different times can be compared to assess the effects of therapy.

Treatment

Acute encephalopathy is treated by controlling precipitating factors, halting all dietary protein intake, cleansing the bowel with purgatives and enemas, and administering antibiotics (neomycin or ampicillin) or lactulose. Neomycin may be given orally or by gastric tube (two to four times daily) or rectally as an enema (1% solution one or two times daily). At least 1600 kcal of carbohydrate should be provided daily, along with therapeutic amounts of vitamins. Blood volume must be maintained to avoid prerenal azotemia. After the patient responds to initial therapy, dietary protein may be started at 20 g/d and increased by increments of 10-20 g every 2-5 days as tolerated.

Chronic encephalopathy is treated by restriction of dietary protein, avoidance of constipation, and elimination of sedatives, diuretics, and tranquilizers. To avoid protein depletion, protein intake must not be chronically reduced below 50 g/d. Vegetable protein in the diet is tolerated better than animal protein. Lactulose, a disaccharide unaffected by intestinal enzymes, is the drug of choice for long-term control. When given orally (20-30 g three or four times daily), it reaches the colon, where it stimulates bacterial anabolism (which increases ammonia uptake) and inhibits bacterial enzymes (which decreases the generation of nitrogenous toxins). Its effect is independent of colonic pH. A related compound outside the United States, lactitol (β-galactoside sorbitol), is also effective and appears to work faster. As a powder, it is easier to use than liquid lactulose. Intermittent courses of oral neomycin or metronidazole may be given if lactulose therapy and preventive measures are inadequate.

HEPATIC ABSCESS

Hepatic abscesses may be bacterial, parasitic, or fungal in origin. In the United States, pyogenic abscesses are the most common, followed by amebic abscesses (see Chapter 8). Unless otherwise indicated, the remarks in this section refer to bacterial abscesses.

Cases are about evenly divided between those with a single abscess and those with multiple abscesses. About 90% of right lobe abscesses are solitary, while only 10% of left lobe abscesses are solitary.

In most cases, the development of a hepatic abscess follows a suppurative process elsewhere in the body. Many abscesses are due to direct spread from biliary infections such as empyema of the gallbladder or protracted cholangitis. Abdominal infections such as appendicitis or diverticulitis may spread through the portal vein to involve the liver with abscess formation. About 40% of patients have an underlying malignancy. Other cases develop after generalized sepsis from bacterial endocarditis, renal infection, or pneumonitis. In 25% of cases, no antecedent infection can be documented (cryptogenic abscesses). Rare causes include secondary bacterial infection of an amebic abscess, hydatid cyst, or congenital hepatic cyst.

In most cases, the organism is of enteric origin.

Escherichia coli, Klebsiella pneumoniae, bacteroides, enterococci (eg, Streptococcus faecalis), anaerobic streptococci (eg, Peptostreptococcus), and microaerophilic streptococci are most common. Staphylococci, hemolytic streptococci, or other gram-positive organisms are usually found if the primary infection is bacterial endocarditis or pneumonitis.

Clinical Findings

A. Symptoms and Signs

When liver abscess develops in the course of another intra-abdominal infection such as diverticulitis, it is accompanied by increasing toxicity, higher fever, jaundice, and a generally deteriorating clinical picture. Right upper quadrant pain and chills may appear.

In other cases, the diagnosis is much less obvious, since the illness develops insidiously in a previously healthy person. In these, the first symptoms are usually malaise and fatigue, followed after several weeks by fever. Epigastric or right upper quadrant pain is present in about half of cases. The pain may be aggravated by motion or may be referred to the right shoulder.

The course of fever is often erratic, and spikes to 40-41°C are common. Chills are present in about 25% of cases. The liver is usually enlarged and may be tender to palpation. If tenderness is severe, the condition may be confused with cholecystitis.

Jaundice is unusual in solitary abscesses unless the patient’s condition is worsening. Jaundice is often present in patients with multiple abscesses and primary disease in the biliary tree and in general is a bad prognostic sign.

B. Laboratory Findings

Leukocytosis is present in most cases and is usually over 15,000/μL. A small group of patients, usually the most seriously ill, may fail to develop leukocytosis. Anemia is present in most. The average hematocrit is 33%.

Serum bilirubin is usually normal except in patients with multiple abscesses or biliary obstruction or when hepatic failure has supervened. Alkaline phosphatase is often elevated even in the presence of a normal bilirubin.

C. Imaging Studies

X-ray changes present in the right lung in about one-third of cases consist of basilar atelectasis or pleural effusion. The right diaphragm may be elevated and less mobile than the left.

Plain films of the abdomen are usually normal or show only hepatomegaly. In a few patients, an air-fluid level in the region of the liver reveals the presence and location of the abscess. Distortion of the contour of the stomach on upper gastrointestinal series may be seen with large abscesses involving the left lobe.

Ultrasound and CT scans are the most useful diagnostic tests, providing accurate information regarding the presence, size, number, and location of abscesses within the liver. CT scans have the added advantage of being able to demonstrate abscesses or neoplasms elsewhere in the abdomen. The radioisotope liver scintiscan is able to demonstrate most liver abscesses but is nonspecific, gives little other useful information, and is therefore not helpful.

Differential Diagnosis

In many cases, early findings may be so vague that hepatic abscess is not even considered. The multiple other causes of malaise, weight loss, and anemia would enter into the differential diagnosis. With spiking fevers, one must consider all the causes of fever of unknown origin. Failure to entertain the idea of hepatic abscess and to obtain the necessary scans leads to most errors in diagnosis.

Once imaging tests have demonstrated the abscess, the responsible organisms must be identified. Amebiasis should be considered in cases of a solitary abscess. Compared with amebic abscesses, pyogenic liver abscesses are seen more often in patients older than 50 years and are associated with jaundice, pruritus, sepsis, a palpable mass, and elevated bilirubin and alkaline phosphatase levels. Patients with amebic abscesses more often have been to an endemic area and have abdominal pain and tenderness, diarrhea, hepatomegaly, and positive serologic tests for amebiasis.

Complications

Intrahepatic spread of infection may create multiple additional abscesses and is responsible for some failures after treatment of an apparently solitary abscess. As the untreated abscess expands, rupture may occur in the pleural or peritoneal cavity, usually with catastrophic results. Septicemia and septic shock are common terminal complications of diffuse hepatic infection. Hepatic failure may develop in addition to uncontrolled sepsis, or it may predominate over signs of infection.

Hemobilia may follow bleeding from the vascular wall into the abscess cavity. In this case, hepatic artery embolization or ligation may be required to control bleeding.

Treatment

Antibiotics should be started promptly. Initial coverage, before culture results are available, should be adequate for E coli, K pneumoniae, bacteroides, enterococci, and yanaerobic streptococci and consequently would usually include an aminoglycoside, clindamycin or metronidazole, and ampicillin. The regimen may be modified later according to the results of cultures.

About 80% or more of patients with liver abscesses are adequately treated by drainage catheters inserted percutaneously under ultrasound or CT guidance. Whether the patient has a single abscess or multiple abscesses, this is usually the most appropriate initial therapy. The catheters can be removed in 1-2 weeks after output becomes nonpurulent and scant.

In about 40% of patients, the catheters do not drain well following initial placement and must be repositioned. The principal advantage of percutaneous drainage is lower morbidity compared to open drainage, although not necessarily lower mortality. It is easier to provide thorough drainage surgically, so when difficulties are encountered with percutaneous drainage, laparotomy should be performed promptly. Surgical intervention is more often necessary in cases of multiple, loculated collections or when the abscess cavity contains a large amount of necrotic debris. In such cases, open debridement should be considered early. Likewise, early surgical intervention is indicated for patients who are seriously ill (APACHE II score ≥ 15). Rarely, multiple abscesses are confined to a single lobe and can be cured by lobectomy. Biliary obstruction or other causes of sepsis must also be corrected.

Prognosis

The overall mortality rate of 15% is more closely related to the underlying disease than to any other factor. The mortality rate is about 40% in patients with malignant disease. Pleural effusion, leukocytosis over 20,000/μL, hypoalbuminemia, and polymicrobial infection correlate with a poor outcome. In the United States, whether the abscess is solitary or multiple no longer has a major influence on survival, but where benign biliary disease remains a major cause of this disease, multiple hepatic abscesses are associated with a worse prognosis. Death is rare in patients with a cryptogenic liver abscess.