Chapter 31: Liver

1. When operating on the liver, gallbladder, pancreas, or ­adjacent organs, recognition of the normal or variant vascular and biliary anatomy is essential to avoiding surgical ­complications.

2. The liver is the largest gland in the body and performs a diverse spectrum of functions.

3. Computed tomography and magnetic resonance imaging with contrast enhancement constitute the mainstays for the radiologic evaluation of the liver.

4. Acute liver failure rapidly progresses to hepatic coma and death even with maximal medical therapy. The only definitive treatment is orthotopic liver transplantation.

5. Cirrhosis is the end result of chronic hepatic insult, and further deterioration can lead to the development of end-stage liver disease, which carries a high mortality rate.

6. Acute variceal bleeding should be managed with aggressive resuscitation and prompt endoscopic diagnosis with hemorrhage control. The transjugular intrahepatic portosystemic shunt procedure can be considered for cases refractory to medical treatment.

7. Common benign lesions of the liver include cysts, hemangiomas, focal nodular hyperplasia, and hepatocellular ­adenomas. In most instances, these lesions can be reliably diagnosed by their characteristic features on imaging.

8. Many options exist for the treatment of hepatocellular carcinomas, and these cases are best managed by a multidisciplinary liver transplant team.

9. Surgical resection is the treatment of choice for hilar cholangiocarcinoma. Under a protocol with strict eligibility criteria, patients with unresectable tumors can be considered for liver transplantation following neoadjuvant chemoradiation, with survival rates that compare favorably with the rates for resection.

10. The resectability of colorectal cancer metastases to the liver is primarily determined by the volume of the future liver remnant and the health of the background liver and not actual tumor number.

11. Laparoscopic liver resections can be performed safely by experienced surgeons in selected patients and have been shown to produce comparable morbidity and mortality rates to open resections.

The ancient Greek myth of Prometheus reminds us that the liver is the only organ that regenerates. According to Greek mythology, Zeus was furious with the Titan Prometheus because he gave fire to mortals. In return, Zeus chained Prometheus to Mount Caucasus and sent his giant eagle to eat his liver during the day, only to have it regenerate at night. Although this is folklore, the principles are correct that after hepatic resection, the remnant liver will hypertrophy over weeks to months to regain most of its original liver mass. It is interesting to note that the ancient Greeks seem to have been aware of this fact, because the Greek word for the liver, h¯epar, derives from the verb h¯epaomai, which means “mend” or “repair.” Hence h¯epar roughly translates as “repairable.”¹ The importance of the liver dates back to even biblical times, for the Babylonians (c. 2000 B.C.) considered the liver to be the seat of the soul. There are scattered reports of liver surgery for battlefield injuries, but the first recorded elective hepatic resection was done in 1888 in ­Germany by Langenbuch. There followed reports of liver resections in the United States (Tiffany, 1890) and Europe (Lucke, 1891), as well as the first large series of hepatic resections by Keen in 1899.^2,3 In 1908, Pringle described in Annals of Surgery the “arrest of hepatic hemorrhage due to trauma” by compression of the porta hepatis, a maneuver that now bears his name.⁴ Possibly due to the potential for massive hemorrhage during liver surgery, very little progress in surgical techniques was recorded for the next half-century. Work by Rex, Cantlie, and others laid the groundwork for experimental and clinical reports in the 1950s by Couinaud, Hjortsjo, Healey, Lortat-Jacob, and Starzl.^5,6 These seminal contributions paved the way for the modern era of hepatic resection surgery.

The liver is the largest organ in the body, weighing approximately 1500 g. It resides in the right upper abdominal cavity beneath the diaphragm and is protected by the rib cage. It is reddish brown and is surrounded by a fibrous sheath known as ­Glisson’s capsule. The liver is held in place by several ligaments (Fig. 31-1). The round ligament is the remnant of the obliterated umbilical vein and enters the left liver hilum at the front edge of the falciform ligament. The falciform ligament separates the left lateral and left medial segments along the umbilical ­fissure and anchors the liver to the anterior abdominal wall. Deep in the plane between the caudate lobe and the left lateral segment is the fibrous ligamentum venosum (Arantius’ ligament), which is the obliterated ductus venosus and is covered by the plate of Arantius. The left and right triangular ligaments secure the two sides of the liver to the diaphragm. Extending from the triangular ligaments anteriorly on the liver are the coronary ligaments. The right coronary ligament also extends from the right undersurface of the liver to the peritoneum overlying the right kidney, thereby anchoring the liver to the right retroperitoneum. These ligaments (round, falciform, triangular, and coronary) can be divided in a bloodless plane to fully mobilize the liver to facilitate hepatic resection. Centrally and just to the left of the gallbladder fossa, the liver attaches via the hepatoduodenal and the gastrohepatic ligaments (Fig. 31-2). The hepatoduodenal ligament is known as the porta hepatis and contains the common bile duct, the hepatic artery, and the portal vein. From the right side and deep (dorsal) to the porta hepatis is the foramen of Winslow, also known as the epiploic foramen (see Fig. 31-2). This passage connects directly to the lesser sac and allows complete vascular inflow control to the liver when the hepatoduodenal ligament is clamped using the Pringle maneuver.

Segmental Anatomy

The liver is grossly separated into the right and left lobes by the plane from the gallbladder fossa to the inferior vena cava (IVC), known as Cantlie’s line.⁵ The right lobe typically accounts for 60% to 70% of the liver mass, with the left lobe (and caudate lobe) making up the remainder. The caudate lobe lies to the left and anterior of the IVC and contains three subsegments: the Spiegel lobe, the paracaval portion, and the caudate process.⁷ The falciform ligament does not separate the right and left lobes, but rather it divides the left lateral segment from the left medial segment. The left lateral and left medial segments also are referred to as sections as defined in the Brisbane 2000 terminology, which is outlined later in the section titled “Hepatic Resection.” A significant advance in our understanding of liver anatomy came from the cast work studies of the French surgeon and anatomist Couinaud in the early 1950s. Couinaud divided the liver into eight segments, numbering them in a clockwise direction beginning with the caudate lobe as segment I.⁶ ­Segments II and III comprise the left lateral segment, and segment IV is the left medial segment (Fig. 31-3). Thus, the left lobe is made up of the left lateral segment (Couinaud’s segments II and III) and the left medial segment (segment IV). Segment IV can be subdivided into segment IVA and segment IVB. Segment IVA is cephalad and just below the diaphragm, spanning from segment VIII to the falciform ligament adjacent to segment II. Segment IVB is caudad and adjacent to the gallbladder fossa. Many anatomy textbooks also refer to segment IV as the quadrate lobe. Quadrate lobe is an outdated term, and the preferred term is segment IV or left medial segment. Most surgeons still refer to segment I as the caudate lobe, rather than segment I. The right lobe is comprised of segments V, VI, VII, and VIII, with segments V and VIII making up the right anterior lobe, and segments VI and VII the right posterior lobe.

Additional functional anatomy was highlighted by ­Bismuth based on the distribution of the hepatic veins. The three hepatic veins run in corresponding scissura (fissures) and divide the liver into four sectors.⁸ The right hepatic vein runs along the right scissura and separates the right posterolateral sector from the right anterolateral sector. The main scissura contains the middle hepatic vein and separates the right and left livers. The left scissura contains the course of the left hepatic vein and separates the left posterior and left anterior sectors.

Hepatic Artery

The liver has a dual blood supply consisting of the hepatic artery and the portal vein. The hepatic artery delivers approximately 25% of the blood supply, and the portal vein approximately 75%. The hepatic artery arises from the celiac axis (trunk), which gives off the left gastric, splenic, and common hepatic arteries (Fig. 31-4). The common hepatic artery then divides into the gastroduodenal artery and the hepatic artery proper. The right gastric artery typically originates off of the hepatic artery proper, but this is variable. The hepatic artery proper divides into the right and left hepatic arteries. This “classic” or standard arterial anatomy is present in only approximately 76% of cases, with the remaining 24% having variable anatomy. It is critical to understand the arterial (and biliary) anatomic variants to avoid surgical complications when operating on the liver, gallbladder, pancreas, or adjacent organs.

The most common hepatic arterial variants are shown (Fig. 31-5). Approximately 10% to 15% of the time, there is a replaced or accessory right hepatic artery arising from the superior mesenteric artery (SMA). When there is a replacement or accessory right hepatic artery, it travels posterior to the portal vein and then takes up a right lateral position before diving into the liver parenchyma. This can be recognized visually on a preoperative computed tomography (CT) or magnetic resonance imaging (MRI) scan, and confirmed by palpation in the hilum where a separate right posterior pulsation is felt distinct from that of the hepatic artery proper that lies anteriorly in the hepatoduodenal ligament to the left of the common bile duct. In approximately 3% to 10% of cases, there exists a replacement (or accessory) left hepatic artery coming off of the left gastric artery and running obliquely in the gastrohepatic ligament anterior to the caudate lobe before entering the hilar plate at the base of the umbilical fissure. Other less common variants (approximately 1% to 2% each) are the presence of both replaced right and replaced left hepatic arteries, as well as a completely replaced common hepatic artery coming off the SMA (see Fig. 31-5). Although not well demonstrated in the illustration, the clue for a completely replaced common hepatic artery coming off the SMA is the presence of a strong arterial pulsation to the right of and posterior to the common bile duct, rather than the left side and anterior, in the porta hepatis. Another important point is that the right hepatic artery passes deep and posterior to the common bile duct approximately 88% of the time but crosses anterior to the common bile duct in approximately 12% of cases. The cystic artery feeding the gallbladder usually arises from the right hepatic artery in Calot’s triangle.

Portal Vein

The portal vein is formed by the confluence of the splenic vein and the superior mesenteric vein. The inferior mesenteric vein usually drains into the splenic vein upstream from the confluence (Fig. 31-6). The main portal vein traverses the porta hepatis before dividing into the left and right portal vein branches. The left portal vein typically branches from the main portal vein outside of the liver with a sharp bend to the left and consists of the transverse portion followed by a 90° turn at the base of the umbilical fissure to become the umbilical portion before entering the liver parenchyma (Fig. 31-7). The left portal vein then divides to give off the segment II and III branches to the left lateral segment, as well as the segment IV branches that supply the left medial segment. The left portal vein also provides the dominant inflow branch to the caudate lobe (although branches can arise from the main and right portal veins also), usually close to the bend between the transverse and umbilical portions. The division of the right portal vein is usually higher in the hilum and may be close to (or inside) the liver parenchyma at the hilar plate. Twenty percent to thirty-five percent of individuals have aberrant portal venous anatomy, with portal vein trifurcation or an aberrant branch from the left portal vein supplying the right anterior lobe being the most frequent.

The portal vein drains the splanchnic blood from the stomach, pancreas, spleen, small intestine, and majority of the colon to the liver before returning to the systemic circulation. The portal vein pressure in an individual with normal physiology is low at 3 to 5 mmHg. The portal vein is valveless, however, and in the setting of portal hypertension, the pressure can be quite high (20 to 30 mmHg). This results in decompression of the systemic circulation through portocaval anastomoses, most commonly via the coronary (left gastric) vein, which produces esophageal and gastric varices with a propensity for major hemorrhage. Another branch of the main portal vein is the superior pancreaticoduodenal vein (which comes off low in an anterior lateral position and is divided during pancreaticoduodenectomy). Closer to the liver, the main portal vein typically gives off a short branch (posterior lateral) to the caudate process on the right side. It is important to identify this branch and ligate it during hilar dissection for anatomic right hemihepatectomy to avoid avulsion.

Hepatic Veins and Inferior Vena Cava

There are three hepatic veins (right, middle, and left) that pass obliquely through the liver to drain the blood to the suprahepatic IVC and eventually the right atrium (Fig. 31-8). The right hepatic vein drains segments V through VIII; the middle hepatic vein drains segment IV as well as segments V and VIII; and the left hepatic vein drains segments II and III. The caudate lobe is unique because its venous drainage feeds directly into the IVC. In addition, the liver usually has a few small, variable short hepatic veins that directly enter the IVC from the undersurface of the liver. The left and middle hepatic veins form a common trunk approximately 95% of the time before entering the IVC, whereas the right hepatic vein inserts separately (in an oblique orientation) into the IVC. There is a large inferior accessory right hepatic vein in 15% to 20% of cases that runs in the hepatocaval ligament. This can be a source of torrential bleeding if control of it is lost during right hepatectomy. The hepatic vein branches bisect the portal branches inside the liver parenchyma (i.e., the right hepatic vein runs between the right anterior and posterior portal veins; the middle hepatic vein passes between the right anterior and left portal vein; and the left hepatic vein crosses between the segment II and III branches of the left portal vein).

Bile Duct and Hepatic Ducts

Within the hepatoduodenal ligament, the common bile duct lies anteriorly and to the right. It gives off the cystic duct to the gallbladder and becomes the common hepatic duct before dividing into the right and left hepatic ducts. In general, the hepatic ducts follow the arterial branching pattern inside the liver. The right anterior hepatic duct usually enters the liver above the hilar plate, whereas the right posterior duct dives behind the right portal vein and can be found on the surface of the caudate process before entering the liver. The left hepatic duct typically has a longer extrahepatic course before giving off segmental branches behind the left portal vein at the base of the umbilical fissure. Considerable variation exists, and in 30% to 40% of cases, there is a nonstandard hepatic duct confluence with accessory or aberrant ducts (Fig. 31-9). The cystic duct itself also has a variable pattern of drainage into the common bile duct. This can lead to potential injury or postoperative bile leakage during cholecystectomy or hepatic resection, and the surgeon needs to expect these variants. The gallbladder sits adherent to hepatic segments IVB (left lobe) and V (right lobe).

Neural Innervation and Lymphatic Drainage

The parasympathetic innervation of the liver comes from the left vagus, which gives off the anterior hepatic branch, and the right vagus, which gives off the posterior hepatic branch. The sympathetic innervation involves the greater thoracic splanchnic nerves and the celiac ganglia, although the function of these nerves is poorly understood. The denervated liver after hepatic transplantation seems to function with normal capacity. A common source of referred pain to the right shoulder and scapula as well as the right side or back is the right phrenic nerve, which is stimulated by tumors that stretch Glisson’s capsule or by diaphragmatic irritation.

Lymph is produced within the liver and drains via the perisinusoidal space of Disse and periportal clefts of Mall to larger lymphatics that drain to the hilar cystic duct lymph node (Calot’s triangle node), as well as the common bile duct, hepatic artery, and retropancreatic and celiac lymph nodes. This is particularly important for resection of hilar cholangiocarcinoma, which has a high incidence of lymph node metastases. The hepatic lymph also drains cephalad to the cardiophrenic lymph nodes, and the latter can be pathologically identified on a staging CT or MRI scan.

The liver is the largest gland in the body and has an extraordinary spectrum of functions. These include processes such as storage, metabolism, production, and secretion. One crucial role is the processing of absorbed nutrients through the metabolism of glucose, lipids, and proteins. The liver maintains glucose concentrations in a normal range over both short and long periods by performing several important roles in carbohydrate metabolism. In the fasting state, the liver ensures a sufficient supply of glucose to the central nervous system. The liver can produce glucose by breaking down glycogen through glycogenolysis and by de novo synthesis of glucose through gluconeogenesis from noncarbohydrate precursors such as lactate, amino acids, and glycerol. In the postprandial state, excess circulating glucose is removed by glycogen synthesis or glycolysis and lipogenesis. The liver also plays a central role in lipid metabolism through the formation of bile and the production of cholesterol and fatty acids. Protein metabolism occurs in the liver through amino acid deamination, resulting in the production of ammonia as well as the production of a variety of amino acids. In addition to metabolism, the liver also is responsible for the synthesis of most circulating plasma proteins. Among these proteins are albumin, factors of the coagulation and fibrinolytic systems, and compounds of the complement cascade. Furthermore, the detoxification of many substances through drug metabolism occurs in the liver, as do immunologic responses through the many immune cells found in its reticuloendothelial system.⁹

Bilirubin Metabolism

Bilirubin is the breakdown product of normal heme catabolism. Bilirubin is bound to albumin in the circulation and sent to the liver. In the liver, it is conjugated to glucuronic acid to form bilirubin diglucuronide in a reaction catalyzed by the enzyme glucuronyl transferase, making it water soluble. This glucuronide is then excreted into the bile canaliculi. A small amount dissolves in the blood and is then excreted in the urine. The majority of conjugated bilirubin is excreted in the intestine as waste, because the intestinal mucosa is relatively impermeable to conjugated bilirubin. However, it is permeable to unconjugated bilirubin and urobilinogens, a series of bilirubin derivatives formed by the action of bacteria. Thus, some of the bilirubin and urobilinogens are reabsorbed in the portal circulation; they are again excreted by the liver or enter the circulation and are excreted in the urine.¹⁰

Formation of Bile

Bile is a complex fluid containing organic and inorganic substances dissolved in an alkaline solution that flows from the liver through the biliary system and into the small intestine. The main components of bile are water, electrolytes, and a variety of organic molecules including bile pigments, bile salts, phospholipids (e.g., lecithin), and cholesterol. The two fundamental roles of bile are to aid in the digestion and absorption of lipids and lipid-soluble vitamins and to eliminate waste products (bilirubin and cholesterol) through secretion into bile and elimination in feces. Bile is produced by hepatocytes and secreted through the biliary system. In between meals, bile is stored in the gallbladder and concentrated through the absorption of water and electrolytes. Upon entry of food into the duodenum, bile is released from the gallbladder to aid in digestion. The human liver can produce about 1 L of bile daily.

Bile salts, in conjunction with phospholipids, are responsible for the digestion and absorption of lipids in the small intestine. Bile salts are sodium and potassium salts of bile acids conjugated to amino acids. The bile acids are derivatives of cholesterol synthesized in hepatocytes. Cholesterol, ingested from the diet or derived from hepatic synthesis, is converted into the bile acids cholic acid and chenodeoxycholic acid. These bile acids are conjugated to either glycine or taurine before secretion into the biliary system. Bacteria in the intestine can remove glycine and taurine from bile salts. They can also convert some of the primary bile acids into secondary bile acids by removing a hydroxyl group, producing deoxycholic acid from cholic acid and lithocholic acid from chenodeoxycholic acid.

Bile salts secreted into the intestine are efficiently reabsorbed and reused. Approximately 90% to 95% of the bile salts are absorbed from the small intestine at the terminal ileum. The remaining 5% to 10% enter the colon and are converted to the secondary salts, deoxycholic acid and lithocholic acid. The mixture of primary and secondary bile salts and bile acids is absorbed primarily by active transport in the terminal ileum. The absorbed bile salts are transported back to the liver in the portal vein and re-excreted in the bile. Those lost in the stool are replaced by synthesis in the liver. The continuous process of secretion of bile salts in the bile, their passage through the intestine, and their subsequent return to the liver is termed the enterohepatic circulation.¹⁰

Drug Metabolism

The liver plays an important role in providing mechanisms for ridding the body of foreign molecules (xenobiotics) that are absorbed from the environment. In most cases, a drug is relatively lipophilic to ensure good absorption. The liver participates in the elimination of these lipid-soluble drugs by transforming them into more readily excreted hydrophilic products. There are two main reactions important for drug metabolism. Phase I reactions include oxidation, reduction, and hydrolysis of molecules. These result in metabolites that are more hydrophilic than the original chemicals. The cytochrome P450 system is a family of hemoproteins important for oxidative reactions involving drugs and toxic substances. Phase II reactions, also known as conjugation reactions, are synthetic reactions that involve addition of subgroups to the drug molecule. These subgroups include glucuronate, acetate, glutathione, glycine, sulfate, and methyl groups. These drug reactions occur mainly in the smooth endoplasmic reticulum of hepatocytes.

Many factors can affect drug metabolism in the liver. When the rate of metabolism of a drug is increased (i.e., enzyme induction), the duration of the drug action will decrease. However, when the metabolism of a drug is decreased (i.e., enzyme inhibition), then the drug will circulate for a longer period of time. It is important to note that some drugs may be converted to active products by metabolism in the liver. An example is acetaminophen when taken in larger doses. Normally, acetaminophen is conjugated by the liver to harmless glucuronide and sulfate metabolites that are water soluble and eliminated in the urine. During an overdose, the normal metabolic pathways are overwhelmed, and some of the drug is converted to a reactive and toxic intermediate by the cytochrome P450 system. Glutathione normally reacts with this intermediate, leading to the production and subsequent excretion of a harmless product. However, as glutathione stores are diminished, the reactive intermediate cannot be detoxified and it combines with lipid membranes of hepatocytes, which results in cellular necrosis. Thus, treatment of acetaminophen overdoses consists of replenishing glutathione stores by supplementing with sulfhydryl compounds such as acetylcysteine.

Liver Function Tests

Liver function tests is a term frequently used to refer to measurement of the levels of a group of serum markers for evaluation of liver dysfunction. Most commonly, levels of aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (AP), γ-glutamyltranspeptidase (GGT), and bilirubin are included in this panel. This term is a misnomer, however, because most of these tests measure not liver function but rather cell damage. More accurate measurement of the liver’s synthetic function is provided by serum albumin levels and prothrombin time (PT). Although measuring liver enzyme levels is important in the assessment of a patient’s liver disease, these test results can be nonspecific. Thus, evaluation of patients with suspected liver disease should always involve careful interpretation of abnormalities in these liver test results in the context of a thorough history and physical examination. The approach to evaluating abnormal laboratory values also can be simplified by categorizing the type of abnormality that predominates (hepatocellular damage, abnormal synthetic function, or cholestasis).

Hepatocellular Injury

Hepatocellular injury of the liver is usually indicated by abnormalities in levels of the liver aminotransferases AST and ALT. These enzymes participate in gluconeogenesis by catalyzing the transfer of amino groups from aspartic acid or alanine to ketoglutaric acid to produce oxaloacetic acid and pyruvic acid, respectively (these enzymes are also referred to as serum glutamic-oxaloacetic transaminase [SGOT] and serum ­glutamic-pyruvic transaminase [SGPT]). AST is found in liver, cardiac muscle, skeletal muscle, kidney, brain, pancreas, lungs, and red blood cells and thus is less specific for disorders of the liver. ALT is predominately found in the liver and thus is more specific for liver disease. Hepatocellular injury is the trigger for release of these enzymes into the circulation. Common causes of elevated aminotransferase levels include viral hepatitis, alcohol abuse, medications, genetic disorders (Wilson’s disease, hemochromatosis, α₁-antitrypsin deficiency), and autoimmune diseases.

The extent of serum aminotransferase elevations can suggest certain etiologies of the liver injury. However, the levels of the enzymes in these tests correlate poorly with the severity of hepatocellular necrosis, because they may not be significantly elevated in conditions of hepatic fibrosis or cirrhosis. In alcoholic liver disease, an AST:ALT ratio of >2:1 is common. Mild elevations of transaminase levels can be found in nonalcoholic fatty liver disease, chronic viral infection, or medication-induced injury. Moderate increases in the levels of these enzymes are common in acute viral hepatitis. In conditions of ischemic insults, toxin ingestions (i.e., acetaminophen), and fulminant hepatitis, AST and ALT levels can be elevated to the thousands.

Abnormal Synthetic Function

Albumin synthesis is an important function of the liver and thus can be measured to evaluate the liver’s synthetic function. The liver produces approximately 10 g of albumin per day. However, albumin levels are dependent on a number of factors such as nutritional status, renal dysfunction, protein-losing enteropathies, and hormonal disturbances. In addition, level of albumin is not a marker of acute hepatic dysfunction due to albumin’s long half-life of 15 to 20 days.

Most clotting factors (except factor VIII) are synthesized exclusively in the liver, and thus their levels can also be used as a measure of hepatic synthetic function. Measurements of the prothrombin time (PT) and international normalized ratio (INR) are some of the best tests of hepatic synthetic function. PT measures the rate of conversion of prothrombin to thrombin. To standardize the reporting of PT and avoid interlaboratory variability, the INR was developed. The INR is the ratio of the patient’s PT to the mean control PT. Because vitamin K is involved in the γ-carboxylation of factors used to measure PT (factors II, VII, IX, and X), values also may be prolonged in other conditions such as vitamin K deficiency and warfarin therapy.

Cholestasis

Cholestasis is a condition in which bile flow from the liver to the duodenum is impaired. Disturbances in bile flow may be due to intrahepatic causes (hepatocellular dysfunction) or extrahepatic causes (biliary tree obstruction). Cholestasis often results in the release of certain enzymes and thus can be detected by measuring the serum levels of bilirubin, AP, and GGT. Bilirubin is a breakdown product of hemoglobin metabolism. Unconjugated bilirubin is insoluble and thus is transported to the liver bound to albumin. In the liver, it is conjugated to allow excretion in bile. Measured total bilirubin levels can be normal or high in patients with significant liver disease because of the liver’s ability to conjugate significant amounts of bilirubin. Thus, to help aid in the diagnosis of hyperbilirubinemia, fractionation of total bilirubin is usually performed to distinguish between conjugated (direct) and unconjugated (indirect) bilirubin. Indirect bilirubin is a term frequently used to refer to unconjugated bilirubin in the circulation because the addition of another chemical is necessary to differentiate this fraction from the whole. Normally, >90% of serum bilirubin is unconjugated. The testing process for conjugated bilirubin, in contrast, is direct without the addition of other agents. The direct bilirubin test measures the levels of conjugated bilirubin and δ bilirubin (conjugated bilirubin bound to albumin).

The patterns of elevation of the different fractions of bilirubin provide important diagnostic clues as to the cause of cholestasis. In general, an elevated indirect bilirubin level suggests intrahepatic cholestasis, and an elevated direct bilirubin level suggests extrahepatic obstruction. Mechanisms that can result in increases in unconjugated bilirubin levels include increased bilirubin production (hemolytic disorders and resorption of hematomas) or defects (inherited or acquired) in hepatic uptake or conjugation. The rate-limiting step in bilirubin metabolism is the excretion of bilirubin from hepatocytes, so conjugated hyperbilirubinemia can be seen in inherited or acquired disorders of intrahepatic excretion or extrahepatic obstruction. Conjugated bilirubin that cannot be excreted accumulates in hepatocytes, which results in its secretion into the circulation. Because conjugated bilirubin is water soluble, it can be found in the urine of patients with jaundice.

AP is an enzyme with a wide tissue distribution but is found primarily in the liver and bones. In the liver, it is expressed by the bile duct epithelium. In conditions of biliary obstruction, levels rise as a result of increased synthesis and release into the serum. Because the half-life of serum AP is approximately 7 days, it may take several days for levels to normalize even after resolution of the biliary obstruction.

GGT is another enzyme found in hepatocytes and released from the bile duct epithelium. Elevation of GGT is an early marker and also a sensitive test for hepatobiliary disease. Like AP elevation, however, it is nonspecific and can be produced by a variety of disorders in the absence of liver disease. Increased levels of GGT can be induced by certain medications, alcohol abuse, pancreatic disease, myocardial infarction, renal failure, and obstructive pulmonary disease. For this reason, elevated GGT levels are often interpreted in conjunction with other enzyme abnormalities. For example, a raised GGT level with increased AP level supports a liver source.

Jaundice

Jaundice refers to the yellowish staining of the skin, sclera, and mucous membranes with the pigment bilirubin. Hyperbilirubinemia usually is detectable as jaundice when blood levels rise above 2.5 to 3 mg/dL. Jaundice can be caused by a wide range of benign and malignant disorders. However, when present, it may indicate a serious condition, and thus knowledge of the differential diagnosis of jaundice and a systematic approach to the workup of the patient is necessary. Workup of a patient with jaundice is simplified by organizing the possible causes of the disorder into groups based on the location of bilirubin metabolism. As mentioned previously, bilirubin metabolism can take place in three phases: prehepatic, intrahepatic, and posthepatic. The prehepatic phase includes the production of bilirubin from the breakdown of heme products and its transport to the liver. The majority of the heme results from red blood cell metabolism and the rest from other heme-containing organic compounds such as myoglobin and cytochromes. In the liver, the insoluble unconjugated bilirubin is then conjugated to glucuronic acid to allow for solubility in bile and excretion. The posthepatic phase of bilirubin metabolism consists of excretion of soluble bilirubin through the biliary system into the duodenum. Dysfunction in any of these phases can lead to jaundice.¹⁰

Prehepatic

Jaundice as a result of elevated levels of unconjugated bilirubin occurs from faulty prehepatic metabolism and usually arises from conditions that interfere with proper conjugation of bilirubin in the hepatocyte. Insufficient conjugation is often seen in processes that result in excessive heme metabolism. Subsequently, the conjugation system is overwhelmed, which results in unconjugated hyperbilirubinemia. Causes of hemolysis include inherited and acquired hemolytic anemias. Inherited hemolytic anemias include genetic disorders of the red blood cell membrane (hereditary spherocytosis and eliptocytosis), enzyme defects (glucose-6-phosphate dehydrogenase deficiency), and defects in hemoglobin structure (sickle cell anemia and thalassemias). Hemolytic anemias can also be acquired, and these can be further divided into those with immune-mediated and those with non–immune-mediated causes. Immune-mediated hemolytic anemias result in a positive finding on a direct Coombs’ test and have a variety of autoimmune and drug-induced causes. In contrast, direct Coombs’ test results are negative in nonimmune hemolytic anemias. The causes in this latter category are varied and include drugs and toxins that directly damage red blood cells, mechanical trauma (heart valves), microangiopathy, and infections. Prehepatic dysfunction of bilirubin metabolism also can result from failure in the transport of unconjugated bilirubin to the liver by albumin in any condition that leads to plasma protein loss. A poor nutritional state or excess protein loss as seen in burn patients can lead to elevated levels of unconjugated bilirubin in the circulation and jaundice.

Intrahepatic

Intrahepatic causes of jaundice involve the intracellular mechanisms for conjugation and excretion of bile from the hepatocyte. The enzymatic processes in hepatocytes can be affected by any condition that impairs hepatic blood flow and subsequent function of the liver (ischemic or hypoxic events). Furthermore, there are multiple inherited disorders of enzyme metabolism that can result in either unconjugated or conjugated hyperbilirubinemia. Gilbert’s syndrome is a genetic variant characterized by diminished activity of the enzyme glucuronyltransferase, which results in decreased conjugation of bilirubin to glucuronide. It is a benign condition that affects approximately 4% to 7% of the population. Typically, the disease results in transient mild increases in unconjugated bilirubin levels and jaundice during episodes of fasting, stress, or illness. These episodes are self-limited and usually do not require further treatment. Another inherited disorder of bilirubin conjugation is Crigler-Najjar syndrome. It is a rare disease found in neonates and can result in neurotoxic sequelae from bilirubin encephalopathy.

In addition to defects in conjugation, disorders in bilirubin excretion in hepatocytes can also lead to jaundice. Rotor’s syndrome and Dubin-Johnson syndrome are two uncommon genetic disorders that disrupt secretion of conjugated bilirubin from the hepatocyte into the bile and result in conjugated hyperbilirubinemia. There are also multiple acquired conditions that result in inflammation and intrahepatic cholestasis by affecting hepatocyte mechanisms for conjugation and excretion of bile. Viruses, alcohol abuse, sepsis, and autoimmune disorders all can result in inflammation in the liver with subsequent disruption of bilirubin transport in the liver. In addition, jaundice can also occur from the cytotoxic effects of many medications, including acetaminophen, oral contraceptives, and anabolic steroids.

Posthepatic

Posthepatic causes of jaundice are usually the result of intrinsic or extrinsic obstruction of the biliary duct system that prevents the flow of bile into the duodenum. There is a wide spectrum of pathologies that may present with obstructive jaundice. Intrinsic obstruction can occur from biliary diseases, including cholelithiasis, choledocholithiasis, benign and malignant biliary strictures, cholangiocarcinoma, cholangitis, and disorders of the papilla of Vater. Extrinsic compression of the biliary tree is commonly due to pancreatic disorders. Patients with pancreatitis, pseudocysts, and malignancies can present with jaundice due to external compression of the biliary system. Finally, with the growing armamentarium of endoscopic tools and minimally invasive surgical approaches, surgical complications are becoming more frequent causes of extrahepatic cholestasis. Misadventures with surgical clips, retained stones, and inadvertent ischemic insults to the biliary system can result in obstructive jaundice recognized at any time from immediately postoperatively to many years later.

Ultrasound

Abdominal ultrasound is a commonly applied imaging modality used to evaluate abdominal symptoms. Ultrasound technology is based on the pulse-echo principle. The ultrasound transducer converts electrical energy to high-frequency sound energy that is transmitted into tissue. Although some of the ultrasound waves are transmitted through the tissue, some are reflected back, and the ultrasound image is produced when the ultrasound receiver detects those reflected waves. This real-time gray scale (B-mode) imaging is augmented by Doppler flow imaging. Doppler ultrasound not only can detect the presence of blood vessels but also can determine the direction and velocity of blood flow. Ultrasonography is a useful initial imaging test of the liver because it is inexpensive, widely available, involves no radiation exposure, and is well tolerated by patients. It is excellent for diagnosing biliary pathology and focal liver lesions. In addition, liver injury can be evaluated in trauma patients using the focused abdominal sonography for trauma examination. Limitations of ultrasound include incomplete imaging of the liver, most often at the dome or beneath ribs on the surface, and incomplete visualization of lesion boundaries. Moreover, obesity and overlying bowel gas also can interfere with image quality. Thus, ultrasonographically detected masses usually require further evaluation by other imaging modalities due to the lower sensitivity and specificity of ultrasound compared with CT and MRI.

The advent of contrast-enhanced ultrasound has improved the ability of this modality to differentiate among benign and malignant lesions. The injection of gas microbubble agents can increase the sensitivity and specificity of ultrasound in detecting and diagnosing liver lesions. Microbubbles are <10 μm and, when given intravenously, allow for more effective echo enhancement. Contrast-enhanced ultrasound imaging of the liver improves delineation of liver lesions through identification of dynamic enhancement patterns and the vascular morphology of the lesion. In addition, some agents exhibit a late liver-specific phase in which the bubbles are taken up by cells in the reticuloendothelial system and accumulate in normal liver parenchyma after the vascular enhancement has faded.

The use of intraoperative ultrasound of the liver has rapidly expanded over the years with the increasing number and complexity of hepatic resections being performed.¹¹ It has the ability to provide the surgeon with real-time accurate information useful for surgical planning. Intraoperative ultrasound is considered the gold standard for detecting liver lesions, and studies have shown that it can identify 20% to 30% more lesions than other preoperative imaging modalities. Importantly, it has been shown to influence surgical management in almost 50% of planned liver resections for malignancies. Applications for intraoperative ultrasound of the liver include tumor staging, visualization of intrahepatic vascular structures (Fig. 31-10), and guidance of resection plane by assessment of the relationship of a mass to the vessels. In addition, biopsy of lesions and ablation of tumors can be guided by intraoperative ultrasound.

Ultrasound elastography, also referred to as transient elastography, can be used to assess the degree of fibrosis or cirrhosis in the liver. Low-frequency vibrations transmitted through the liver induce an elastic shear wave that is detected by pulse-echo ultrasonography as the wave propagates through the liver. The velocity of the wave correlates with the stiffness of the organ—the wave travels faster through fibrotic or cirrhotic tissues. Ultrasound elastography has been found in large cohorts of individuals to have a sensitivity of 87% and a specificity of 91% for the diagnosis of cirrhosis when compared with liver biopsy.¹² Unlike liver biopsy, ultrasound elastography is noninvasive and can be repeated often without additional risk to the patient. Furthermore, this rapid test can acquire information from a larger area of the tissue relative to needle biopsy, providing a better understanding of the entire hepatic parenchyma and reducing sampling error.

Computed Tomography

CT produces a digitally processed cross-sectional image of the body from a large series of x-ray images. The introduction of helical (spiral) CT has improved the imaging capabilities of this technique compared to earlier conventional axial CT by combining a continuous patient-table motion with continuous rotation of the CT gantry and allowing rapid acquisition of a volume of data within a single breath hold. With the recent advent of multi-detector row CT scanners, high-resolution images can be obtained in submillimeter section thickness within a short scan time, with virtually no penalty in increased radiation dose. Together, these technologic advances have led to reduced motion artifacts due to variations in inspiration, facilitated optimal contrast delivery, and allowed for the capability to generate high-resolution reformations in any desired plane. In a single examination, modern-day CT scans provide detailed morphologic information on the number, size, distribution, and vascularity of liver lesions, all of which are vital in guiding the clinical management and therapeutic plan.

Contrast medium is routinely used in CT evaluation of the liver because of the similar densities of most pathologic liver masses and normal hepatic parenchyma. A CT scan with a ­dual- or triple-phase bolus of intravenous contrast agent is performed to achieve the greatest enhancement of contrast between normal and pathologic tissues.¹³ Ideally, contrast media should be selectively delivered to either the tumor or the liver, but not both. Radiologists use the dual blood supply of the liver and the hemodynamics of hepatic tumors to achieve this goal. The liver is unique in that it has a dual blood supply. As previously noted, the portal vein supplies approximately 75% of the blood flow and the hepatic artery the remaining 25%. However, many liver tumors receive the majority of their blood supply from the hepatic artery. After injection of the contrast agent, the rapid scan time of helical CT allows for CT sections through the liver in both the arterial dominant phase (20 to 30 seconds after the beginning of contrast delivery) and venous or portal dominant phase (60 to 70 seconds after contrast injection) (Fig. 31-11). Thus, many hepatic tumors that derive the majority of their blood supply from the hepatic artery as well as other hypervascular lesions are well delineated in the arterial phase. On the other hand, the portal phase provides optimal enhancement of the normal liver parenchyma because the majority of its blood supply is derived from the portal vein. This allows for detection of hypovascular lesions because they will appear hypoattenuated in relation to the brighter normal liver parenchyma.³ Furthermore, the arterial and portal phase images allow for noninvasive mapping of the hepatic arterial and venous anatomy, information that is crucial in the preoperative planning for patients undergoing liver surgery.

CT cholangiography has emerged as a new imaging modality for biliary disease. This technique usually involves the use of contrast agents, which are excreted by hepatocytes into the bile ducts. CT cholangiography, therefore, provides information on hepatocyte function and bile flow, in addition to high-resolution depiction of the biliary tree. It has compared well to endoscopic retrograde cholangiopancreatography (ERCP) in identifying obstructive biliary disease.¹⁴ One of the major advantages of CT cholangiography over other imaging modalities is the ability to depict small nondilated peripheral biliary radicals. This technique may be useful in the context of live liver donation or complex biliary surgery to aid in the preoperative depiction of biliary anatomy. It also may be applicable in the postoperative setting for the detection of biliary leakage or obstruction. A limitation of CT cholangiography is that the biliary tree may not be well visualized in patients with excessively dilated bile ducts or in those with hyperbilirubinemia, as bilirubin excretion is impaired in these cases.

Magnetic Resonance Imaging

MRI is a technique that produces images based on magnetic fields and radio waves. The MRI scanner creates a powerful magnetic field that aligns the hydrogen atoms in the body, and radio waves are used to alter the alignment of this magnetization. Different tissues absorb and release radio wave energy at different rates, and this information is used to construct an image of the body. Most tissues can be differentiated by differences in their characteristic T1 and T2 relaxation times. T1 is a measure of how quickly a tissue can become magnetized, and T2 measures how quickly it loses its magnetization. As with CT technology, advances in MRI now provide the opportunity to perform single-breath T1-weighted imaging and respiration-triggered T2-weighted imaging. The development of breath-hold imaging techniques has eliminated many of the motion artifacts that previously limited the sensitivity and application of MRI for imaging of the liver. Compared with CT scanning, the major advantages of MRI pertain to higher soft tissue contrast resolution and excellent depiction of fluid-containing structures, while obviating the need for ionizing radiation.

As with the iodinated contrast media use in CT scanning, multiple contrast agents have been developed for MRI to increase the difference in signal intensity between normal liver and pathologic lesions. Various gadolinium-based compounds have been used as MRI contrast agents that behave in a manner very similar to iodine in CT. Liver-specific MRI contrast agents also have been developed that rely either on excretion by Kupffer cells, such as ferumoxide (Feridex, Advanced Magnetics, Cambridge, MA), or on secretion in bile by hepatocytes, including gadoxetate (Eovist or Primovist, Bayer-Schering, Berlin, Germany). These agents combine the information obtained during a standard MRI with additional functional data, which in turn yields improved detection and characterization of lesions within the liver.¹⁵

Just as ultrasound elastography is useful in the diagnosis of hepatic fibrosis and cirrhosis, magnetic resonance (MR) elastography appears promising as an imaging modality in reducing the need for liver biopsy. In this technique, a vibration device is used to induce a shear wave in the liver. A modified MRI machine detects the shear wave, then generates a color-coded image that depicts the wave velocity, and hence stiffness, throughout the organ. Although preliminary studies have shown that MR elastography can detect cirrhosis with a high degree of accuracy, the clinical utility of this modality, especially given its relatively high cost, remains to be determined.

Magnetic resonance cholangiopancreatography (MRCP) enables rapid, noninvasive depiction of both the biliary tree and the pancreatic duct without the use of ionizing radiation or intravenous contrast media. One of the most common clinical indications for MRCP is biliary obstruction. MRCP provides visualization of dilated bile ducts, and the high spatial and contrast resolution often enables accurate assessment of the level of occlusion in the biliary tree. MRCP also can be enhanced with liver-specific MRI contrast agents that are actively secreted into the bile, but the clinical indications for such studies are still a matter of intensive investigation.¹⁶

Positron Emission Tomography

Positron emission tomography (PET) is a nuclear medicine test that produces images of metabolic activity in tissues by detecting gamma rays emitted by a radioisotope incorporated into a metabolically active molecule. Fluorodeoxyglucose (FDG) is the most common metabolic molecule used in PET imaging. Although traditional imaging such as CT, ultrasound, and MRI provide anatomic information, PET offers functional imaging of tissues with high metabolic activity, including most types of metastatic tumors. PET imaging increasingly is used as a tool in the diagnostic evaluation of a patient with potentially resectable hepatic disease. In nonrandomized trials, PET demonstrated better sensitivity and specificity than CT scanning for the detection of both intrahepatic and extrahepatic disease.¹⁷ Integrated PET/CT improves diagnostic accuracy over standard PET or CT alone and has been shown to be sensitive in the detection of liver metastases derived from a wide range of cancers, including colorectal (Fig. 31-12), breast, or lung primaries.¹⁷

More than 20% of patients with colorectal cancer initially present with hepatic metastasis, and a large percentage of patients undergoing resection for their primary colorectal cancer eventually experience disease recurrence in the liver. The role of FDG-PET/CT in colorectal cancers lies predominantly in tumor staging and follow-up, particularly in the detection of occult intrahepatic metastases or extrahepatic disease. Although hepatic resection of colorectal metastases provides survival rates nearing 50%, the presence of extrahepatic disease is a poor prognosticator and usually precludes aggressive surgical intervention. Thus, accurate information regarding the extent of the disease is necessary for management of patients with colorectal metastases. PET/CT has also been shown to be more accurate than contrast-enhanced CT in tumor surveillance after radiofrequency ablation.¹⁸ The sensitivity of FDG-PET, however, is lowered by neoadjuvant chemotherapy, most likely secondary to reduced metabolic activity within the tumor.

Although the role of PET/CT in the clinical management of liver metastases has been well-established, its utility in the diagnostic workup of primary liver tumors is still debated. In hepatocellular carcinoma (HCC), FDG uptake correlates with the degree of differentiation—high-grade HCC lesions have increased FDG uptake compared to low-grade HCCs. As a result, the overall sensitivity of FDG-PET/CT in the detection of HCCs is reported to be only 50% to 65%, rendering this modality insufficient when used alone in the diagnosis of primary HCCs. For this reason, dual-tracer PET has been introduced to improve sensitivity in detecting all HCC. This modality combines the use of FDG, which accumulates in poorly differentiated tumors, with ¹¹C-acetate, a tracer preferentially accumulated by well-differentiated HCC lesions. Although the clinical benefits of dual-tracer PET/CT have yet to be fully established, this combined modality has the potential to become a valuable tool in the diagnosis and staging of HCC. In cholangiocarcinoma tumors, FDG avidity depends on the morphologic characteristics and location of the lesion. Therefore, FDG-PET and FDG-PET/CT have not been shown to be highly beneficial in the diagnosis of primary cholangiocarcinoma, but they may be beneficial in the detection of regional and distal metastases, which can affect clinical decision making and patient management.

Acute liver failure (ALF) occurs when the rate and extent of hepatocyte death exceeds the liver’s regenerative capabilities. It was initially described as a specific disease entity in the 1950s. It also has been referred to as fulminant hepatic failure. ALF is a rare disorder affecting approximately 2000 patients annually in the United States. ALF is defined by the development of hepatic encephalopathy occurring within 26 weeks of severe liver injury in a patient without a history of previous liver disease or portal hypertension.¹⁹ The manifestations of ALF may include cerebral edema, hemodynamic instability, increased susceptibility to bacterial and fungal infections, renal failure, coagulopathy, and metabolic disturbances. Even with current medical care, ALF can progress rapidly to hepatic coma and death. The most common cause of death is intracranial hypertension due to cerebral edema, followed by sepsis and multisystem organ failure. The causes of ALF, which are the most important variables in determining outcome, are numerous and can include viral infection as well as drug overdose, reaction, and toxicity. It has been determined that the etiologic factor leading to ALF varies according to geographic location.²⁰ Before the introduction of orthotopic liver transplantation (OLT), the chance for survival was <20%. Currently, most series report 5-year survival rates of >70% for affected patients.²¹

Etiology

Differences in etiology, management, and patient outcomes have been described for various regions of the globe. In the East and developing portions of the world, the most common causes of ALF are viral infections, primarily hepatitis B, A, and E.²⁰ In these areas, there are a relatively small number of drug-induced cases. In contrast, 65% of cases of ALF in the West are thought to be due to drugs and toxins, with acetaminophen (paracetamol) being the most common etiologic agent in the United States, Australia, United Kingdom, and most of Europe. In France and Spain, where acetaminophen sales are restricted, the rate of acetaminophen-induced ALF is quite low.²² Acetaminophen-induced ALF is also uncommon in South America. The U.S. Acute Liver Failure Study Group identified several other causes of ALF, including autoimmune hepatitis, hypoperfusion of the liver (in cardiomyopathy or cardiogenic shock), pregnancy-related conditions, and Wilson’s disease.²³ Even with exhaustive efforts to identify a cause, approximately 20% of all cases of ALF remain indeterminate in origin.

Clinical Presentation

In a multicenter study involving 17 tertiary care centers and 308 patients in the United States, 73% of all patients with ALF were female, with a median age of 38 years.²⁴ The most common ethnic group affected was whites (74%), followed by Hispanics (9%) and African Americans (3%). Patients were ill for a median of 6 days before the onset of encephalopathy and had a median of 2 days between the onset of jaundice and the development of encephalopathy. Hepatic coma grade at presentation was approximately equally distributed across grades I to IV. Eighty-four percent of the patients in the study were referred from outside hospitals, 40% had a serum creatinine level exceeding 2.0 mg/dL, and 14% had an arterial pH of <7.30. In addition, 44% of the patients acquired a culture-proven infection.

Diagnosis and Clinical Management

When the medical history is obtained, it is important to address the possibility of exposure to viral infections, medications, and other possible toxins. The possibility of previous liver disease needs to be explored. The physical examination must assess and document the patient’s mental status as well as attempt to identify findings of chronic liver disease. The initial laboratory examination must evaluate the severity of the ALF as well as attempt to identify the cause (Table 31-1). A liver biopsy should be performed if certain disease entities such as autoimmune hepatitis or lymphoma are a possibility. Because of the associated coagulopathy, if a liver biopsy is needed, it is usually safest to obtain the tissue via a transjugular approach. Patients with ALF should be admitted to the hospital and monitored frequently. Due to the rapidity with which this disease process may progress, a liver transplant center should be contacted and the affected patient transferred to the center early in the evaluation period.

If acetaminophen overdose is suspected to have occurred within a few hours of presentation, administration of activated charcoal may be useful to reduce the volume of acetaminophen present in the gastrointestinal (GI) tract. N-acetylcysteine (NAC), the clinically effective antidote for acetaminophen overdose, should be administered as early as possible to any patient with suspected acetaminophen-associated ALF.²⁵ NAC also should be administered to patients with ALF of unclear etiology, because replenishing glutathione may be beneficial in this patient population as well.²⁶ NAC can be administered either orally (140 mg/kg initial dose, followed by 70 mg/kg every 4 hours × 17 doses) or via the intravenous route (loading dose of 150 mg/kg, followed by a maintenance dose of 50 mg/kg every 4 hours × 12 doses). For patients who are suspected of having drug-induced hepatotoxicity, it is important to obtain details regarding all prescription and nonprescription drugs, herbs, and dietary supplements that may have been taken in the previous year. Most instances of drug-induced hepatotoxicity occur in the first 6 months after drug initiation. Any suspected offending agent must be discontinued, and an attempt should be made to administer only essential medications.

The majority of patients with ALF need to be monitored in the intensive care unit (ICU) setting, and specific attention needs to be given to fluid management, ulcer prophylaxis, hemodynamic monitoring, electrolyte management, and surveillance for and treatment of infection. Surveillance cultures should be performed to identify bacterial and fungal infections as early as possible. Serum phosphorus levels need to be monitored. Hypophosphatemia, a sign of hepatic regeneration, may indicate a higher likelihood of spontaneous recovery and needs to be corrected via intravenous (IV) administration of phosphate. Sedation should be avoided, and the head of the bed should be elevated at least 30°. Neurologic examinations should be ­performed frequently. Intracranial pressure monitoring is reserved for patients in whom a neurologic examination is no longer reliable. CT scans of the head should be performed to rule out mass lesion or hemorrhage, but they provide only limited information regarding increased intracranial pressure. The administration of blood products for thrombocytopenia and prolonged PT is recommended only in the setting of hemorrhage or before invasive procedures. Acute renal failure is a frequent complication in patients with ALF, and efforts should be made to protect renal function by maintaining sufficient perfusion and avoiding nephrotoxic medications. Should renal replacement therapy become necessary, continuous venovenous hemodialysis should be used rather than intermittent hemodialysis, because continuous venovenous hemodialysis provides better hemodynamic and intracranial pressure stability. The most severely affected patients have a poor prognosis with medical management alone and require liver transplantation. Identifying these patients early in the clinical course is important both to maximize the time available to obtain a donor liver allograft for those in need and to avoid transplant in those who will recover without it.

Prognosis

Accurate identification of ALF patients who will recover spontaneously is important because of the severe shortage of donor liver allografts and the potential complications of lifelong nonspecific immunosuppression. The most widely applied prognostic scoring system is the King’s College Hospital ALF criteria.²⁷ This scoring system has separate criteria predicting a poor medical management outcome for acetaminophen-related and non–acetaminophen-related forms of ALF (Table 31-2). Many other prognostic models exist such as the Acute Physiology and Chronic Health Evaluation II (APACHE II) score, the Clichy criteria,²⁸ and actin-free Gc-globulin serum concentration.²⁹ Overall, prognostic scoring systems have proven to have acceptable specificity but low sensitivity in determining patient outcome and therefore should not replace the judgment of an experienced clinician.³⁰

Liver Transplantation

Despite advances in medical management, OLT remains the only definitive therapy for patients unable to regenerate sufficient hepatocyte mass in a timely manner. The advent of OLT has coincided with a rise in overall ALF survival rates from approximately 20% in the pretransplantation era to >70% at the present time. One-year posttransplantation survival for patients with ALF has been reported to be as high as 80% to 90%.²¹ Although these improvements in survival rates are impressive, it should be noted that 10% of patients still die while awaiting OLT, which confirms that the potential for improved patient outcome still has not been realized because of the ongoing liver allograft shortage.

Emerging Technologies

As mentioned earlier, patient survival could be improved if additional time could be gained for the patient while awaiting liver replacement or hepatocyte regeneration. The development of a support device to replace the acutely failing liver has been a highly sought after (and elusive) goal. Several systems have been tested without definitive evidence of efficacy. Transient improvement in hepatic encephalopathy has been observed in several trials, but improvement in hepatocyte function and long-term benefit have not been realized.³¹ Liver support trials are difficult to perform due to access to liver replacement, the rarity of affected patients, and the heterogeneous causes and varying levels of disease severity. Therefore, additional data are necessary, and liver support systems should be used only as part of an approved clinical trial. Focus has now shifted toward xenotransplantation,³² organ engineering, and cell transplantation.³³ In the meantime, living donation and auxiliary liver transplantation can help overcome the organ shortage.³⁴

Cirrhosis, the final sequela of chronic hepatic insult, is characterized by the presence of fibrous septa throughout the liver subdividing the parenchyma into hepatocellular nodules (Fig. 31-13).³⁵ Cirrhosis is the consequence of sustained wound healing in response to chronic liver injury. Approximately 40% of cirrhotic patients are asymptomatic, but progressive deterioration leading to the need for liver transplantation or death is typical after the development of end-stage liver disease (ESLD). The complications of ESLD include progressive hyperbilirubinemia, malnutrition, decreased synthetic function of the liver, coagulopathy, portal hypertension (i.e., ascites and variceal bleeding), hepatic encephalopathy, and life-limiting fatigue. ESLD carries a 5-year mortality of 50%, with 70% of deaths due to liver failure.³⁶ In the United States, cirrhosis accounts for 30,000 deaths per year and is the most common nonneoplastic cause of death among patients with hepatobiliary and digestive diseases. An additional 10,000 to 12,000 deaths occur annually due to HCC, the most rapidly increasing neoplasm in the United States.³⁶.

Morphologic Classification of Cirrhosis

Morphologically, cirrhosis can be described as micronodular, macronodular, or mixed. Micronodular cirrhosis is characterized by thick regular septa, small uniform regenerative nodules, and involvement of virtually every hepatic lobule. Macronodular cirrhosis frequently has septa and regenerative nodules of varying sizes. The regenerative nodules consist of irregularly sized hepatocytes with large nuclei and cell plates of varying thickness. Mixed cirrhosis is present when regeneration is occurring in a micronodular liver and over time converts to a macronodular pattern. This morphologic categorization is limited, and cirrhosis is a dynamic process in which nodule size varies over time. The three patterns correlate poorly with etiology, and the same pattern can result from a variety of disease processes. Conversely, a single disease process can demonstrate several morphologic patterns. Irrespective of etiology and morphologic pattern, the cirrhotic liver frequently demonstrates right hepatic lobe atrophy, caudate lobe and left lateral segment hypertrophy, recanalization of the umbilical vein, a nodular surface contour, dilatation of the portal vein, gastroesophageal varices, and splenomegaly on radiographic evaluation.

Etiology of Cirrhosis

Cirrhosis can result from a wide range of disease processes, including viral, autoimmune, drug-induced, cholestatic, and metabolic diseases (Table 31-3). In the diagnosis of alcoholic liver disease, documentation of chronic alcohol abuse is imperative. Liver biopsy will reveal the typical findings of alcoholic hepatitis, including hepatocyte necrosis, Mallory bodies, neutrophil infiltration, and perivenular inflammation. Patients with nonalcoholic steatohepatitis (NASH) often endorse a history of diabetes mellitus or metabolic syndrome. The diagnosis of NASH requires the demonstration of steatohepatitis on biopsy, the lack of a history of significant alcohol consumption, and exclusion of other causes of hepatic steatosis. Although cryptogenic cirrhosis, or cirrhosis without an apparent cause, accounted for a third of all cases in the past, this proportion has declined over time as it becomes increasingly apparent that many of such patients may actually have unrecognized NASH.

Chronic hepatitis C infection is the most common cause of chronic liver disease and the most frequent indication for liver transplantation in the United States. The identification of chronic hepatitis C infection is facilitated by serologic assays that detect antibody to hepatitis C and molecular assays that quantify hepatitis C viral RNA. Chronic hepatitis B, on the other hand, can be diagnosed based on the detection of hepatitis B surface antigen (HBsAg) more than 4 to 6 months after initial infection. Additional tests of hepatitis B viral replication, such as the hepatitis B e antigen (HBeAg) and hepatitis B viral DNA, can be used to confirm ongoing infection and to guide appropriate antiviral therapy.

Autoimmune causes of cirrhosis include primary biliary cirrhosis, primary sclerosing cholangitis, and autoimmune hepatitis. Patients with primary biliary cirrhosis may be asymptomatic or may present with a history of fatigue, pruritus, and skin hyperpigmentation that is not related to jaundice. Antimitochondrial antibodies will test positive in the vast majority of cases. Affected patients also may have marked elevations in serum cholesterol, while hyperbilirubinemia is seen late in the course of the disease. Primary sclerosing cholangitis is a chronic cholestatic disease of the liver associated with ulcerative colitis and Crohn’s disease. The clinical presentation can include pruritus, steatorrhea, fat-soluble vitamin deficiencies, and metabolic bone disease. The diagnosis is often established by imaging of the biliary tree, which reveals a characteristic picture of diffuse, multifocal strictures with focal dilation of the bile ducts resulting in a beaded appearance. Complications are common and can include biliary strictures, cholangitis, cholelithiasis, and cholangiocarcinoma. Autoimmune hepatitis is often accompanied by an elevation in serum globulins, particularly gamma globulins. Liver biopsy will show nonspecific changes such as a portal mononuclear cell infiltrate with the characteristic presence of plasma cells. Many patients with autoimmune hepatitis will respond to treatment with prednisone with or without azathioprine.

Hereditary hemochromatosis is the most common metabolic disorder causing cirrhosis. This entity should be suspected if the patient’s clinical presentation includes skin hyperpigmentation, diabetes mellitus, pseudogout, cardiomyopathy, or a family history of cirrhosis. Elevated plasma ferritin and increased iron saturation levels suggest the presence of iron overload, but these findings also can be seen in other diseases of the liver. Confirmatory testing can be achieved by means of genetic testing, liver biopsy, or by assessing the response to phlebotomy. Other uncommon metabolic disorders leading to cirrhosis include Wilson’s disease and α₁-antitrypsin deficiency.

Clinical Manifestations of Cirrhosis

The clinical history associated with cirrhosis can include fatigue, anorexia, weight loss, jaundice, abdominal pain, peripheral edema, ascites, GI bleeding, and hepatic encephalopathy. On physical examination, a number of findings have been described in patients with cirrhosis. Spider angiomata and palmar erythema are believed to be caused by alterations in sex hormone metabolism. Finger clubbing may be a consequence of hypoalbuminemia, while the pathogenesis of white nail beds and Dupuytren’s contractures are less well understood. Males may develop features of feminization such as gynecomastia, loss of chest and axillary hair, and testicular atrophy. Splenomegaly is common, whereas the cirrhotic liver itself may be enlarged, normal sized, or small. Ascites and pleural effusion can be seen with fluid accumulation. Portal hypertension can manifest as caput medusae and/or the presence of the ­Cruveilhier-Baumgarten murmur, a venous hum that can be auscultated in the epigastrium resulting from collaterals between the portal system and the remnant of the umbilical vein. Jaundice usually does not appear until the bilirubin rises above 2 to 3 mg/dL. Asterixis can be detected in patients with hepatic encephalopathy. Other manifestations include fetor hepaticus, as well as features suggestive of malnutrition such as weakness, weight loss, and temporal muscle wasting.

Although fat stores and muscle mass are reduced, resting energy expenditure is increased. Muscle cramps occur frequently in the cirrhotic patient and are felt to correlate with ascites, low mean arterial pressure, and plasma renin activity. Abdominal hernias are common with ascites and should be electively repaired only in patients with well-compensated cirrhosis; otherwise, the hernia should be repaired at the time of or after hepatic transplantation. HCC can occur in all forms of cirrhosis, and every cirrhotic patient should undergo screening for the development of HCC every 6 months via imaging and measurement of a serum α-fetoprotein (AFP) level. Cirrhosis is associated with increased cardiac output and heart rate as well as decreased systemic vascular resistance and blood pressure. Patients with cirrhosis are more prone to infections due to impaired phagocytic activity of the reticuloendothelial system. Bacterial infections, often of intestinal origin, are common and must be suspected in a patient with unexplained pyrexia or clinical deterioration. Spontaneous bacterial peritonitis also is seen in cases of cirrhosis with ascites. Intrinsic drug metabolism is reduced in the cirrhotic liver, and this fact needs to be recognized when prescribing medications.

Laboratory Findings Associated with Cirrhosis

Laboratory findings vary in the cirrhotic patient depending on the degree of compensation; however, in general, a number of trends are seen. The cirrhotic patient usually has a mild normocytic normochromic anemia. The white blood cell and platelet counts are reduced, and the bone marrow is macronormoblastic. The PT is prolonged and does not respond to vitamin K therapy, and the serum albumin level is depressed. Urobilinogen is present and urinary sodium excretion is diminished in the presence of ascites. The serum levels of bilirubin, transaminases, and alkaline phosphatase may all be elevated. However, normal liver function test results do not eliminate the possibility of cirrhosis.

Liver Biopsy

The diagnosis of cirrhosis can be made in many cases from a constellation of clinical features, laboratory values, and radiographic findings. Histopathologic examination of liver tissue is occasionally needed to confirm the diagnosis of cirrhosis and in determining disease etiology, activity, and progression. Liver biopsy can be performed via a percutaneous, transjugular, or laparoscopic approach. If needed, ultrasound or CT guidance can be helpful in obtaining an adequate sample and avoiding other viscera.

Various serologic markers of hepatic fibrosis are currently being investigated to help predict the presence of cirrhosis without the need for liver biopsy. However, no currently available marker is sufficiently accurate for clinical use. Ultrasound elastography, which measures the stiffness of the liver by inducing an elastic shear wave that propagates through the tissue, shows promise as a noninvasive test in identifying patients with advanced fibrosis and cirrhosis. (See earlier section, “Radiologic Evaluation of the Liver.”)

Hepatic Reserve and Assessment of Surgical Risk in the Cirrhotic Patient

Assessing the hepatic reserve of the cirrhotic patient is important, because cirrhosis and portal hypertension can have a negative impact on the outcome of nontransplant surgical procedures. Patients with liver disease undergoing surgery are at increased risk for surgical and anesthesia-related complications. The actual risk depends on the type of anesthetic used, the specific surgical procedure performed, and the severity of liver disease. Previous studies have demonstrated that emergency operations, cardiac surgery, hepatic resections, and abdominal surgery, particularly cholecystectomy, gastric resection, and colectomy, generate the highest operative risk among cirrhotic patients. Additionally, preoperative patient characteristics such as anemia, ascites, encephalopathy, malnutrition, hypoalbuminemia, hypoxemia, infection, jaundice, portal hypertension, and prolonged PT have also been associated with inferior outcomes after surgery. Nontransplant surgical procedures are contraindicated in patients with acute fulminant hepatitis and those with severe decompensated chronic hepatitis.

A number of laboratory tests have been used to assess hepatic reserve in patients with cirrhosis. Tests of indocyanine green, sorbitol, and galactose elimination capacity as well as the carbon-13 galactose breath test and carbon-13 aminopyrine breath test have all been disappointing clinically due to their dependence on flow to the liver as well as the unavailability and complexity of the tests. The monoethylglycinexylidide (MEGX) test, which measures MEGX formation after the administration of lidocaine, has been shown to be approximately 80% sensitive and specific in diagnosing cirrhosis. However, this test loses both sensitivity and specificity as the serum bilirubin level rises and interferes with the fluorescent readout system.

Child-Turcotte-Pugh Score

The Child-Turcotte-Pugh (CTP) score was originally developed to evaluate the risk of portocaval shunt procedures performed for portal hypertension and subsequently has been shown to be useful in predicting surgical risks of other intra-abdominal operations on cirrhotic patients (Table 31-4). Numerous studies have demonstrated overall surgical mortality rates of 10% for patients with class A cirrhosis, 30% for those with class B cirrhosis, and 75% to 80% for those with class C cirrhosis.³⁷ The CTP score is derived from five variables as shown in Table 31-4. The problems with the CTP score are the presence of subjective variables (encephalopathy and ascites), its narrow range (5 to 15 points), and the equal weighting given to each variable. Multiple retrospective studies have demonstrated that perioperative mortality and morbidity rates correlate well with the CTP score, and for over 30 years, this measure had been used as the principal predictor of operative risk.

Model for End-Stage Liver Disease Scoring System

The Model for End-Stage Liver Disease (MELD) is a linear regression model based on objective laboratory values (INR, bilirubin level, and creatinine level). It was originally developed as a tool to predict mortality after transjugular intrahepatic portosystemic shunt (TIPS) but has been validated and used as the sole method of liver transplant allocation in the United States since 2002. The MELD formula is as follows:

where Ln represents natural logarithm, SCr is serum creatinine level (in milligrams per deciliter), and Tbil is serum bilirubin level (in milligrams per deciliter).

A number of studies have examined the relative values of MELD and CTP scores in predicting postoperative mortality in cirrhotic patients undergoing nontransplant surgical procedures. Northup and colleagues demonstrated that MELD score was the only statistically significant predictor of 30-day mortality.³⁸ In this study, mortality increased by approximately 1% for each MELD point up to a score of 20 and by 2% for each MELD point above 20. A comparison of the MELD model with the CTP classification showed good correlation between the two measures in predicting mortality, especially in the setting of emergency surgery.³⁹ In these studies, the relative risk of mortality increased by 14% for each 1-point increase in MELD score. As a result, it has been proposed that patients with a MELD score below 10 can safely undergo elective surgery, those with MELD between 10 and 15 may undergo surgery with caution, while those with MELD scores in excess of 15 should not be subjected to elective surgical procedures.⁴⁰

Portal Hypertension

The portal venous system contributes approximately 75% of the blood and 72% of the oxygen supplied to the liver. In the average adult, 1000 to 1500 mL/min of portal venous blood is supplied to the liver. However, this amount can be significantly increased in the cirrhotic patient. The portal venous system is without valves and drains blood from the spleen, pancreas, gallbladder, and abdominal portion of the alimentary tract into the liver. Tributaries of the portal vein communicate with veins draining directly into the systemic circulation. These collateral communications occur at the gastroesophageal junction, anal canal, falciform ligament, splenic venous bed and left renal vein, and retroperitoneum (Fig. 31-14). The normal portal venous pressure is 5 to 10 mmHg, and at this pressure, very little blood is shunted from the portal venous system into the systemic circulation. As portal venous pressure increases, however, the collateral communications with the systemic circulation dilate, and a large amount of blood may be shunted around the liver and into the systemic circulation.

Imaging of the Portal Venous System and Measurement of Portal Venous Pressure

The patency of the portal vein and the nature of the collateral circulation should be established. An understanding of portal vein patency and anatomy is crucial before undertaking portosystemic shunts, hepatic resection, or hepatic transplantation. The simplest initial investigation is abdominal ultrasonography. A large portal vein suggests portal hypertension but is not diagnostic. Doppler ultrasound is capable of outlining the anatomy of the portal vein, excluding the presence of thrombosis, and identifying the direction of portal venous blood flow. Doppler ultrasound also is useful in evaluating blood flow through surgical shunts and TIPS. Abdominal CT and magnetic resonance angiography both are capable of revealing portal vein anatomy as well as patency. Visceral angiography and portal venography are reserved for cases that cannot be evaluated satisfactorily by noninvasive methods and require further clarification of portal patency or anatomy.

The most accurate method of determining portal hypertension is hepatic venography. The most commonly used procedure involves placing a balloon catheter directly into the hepatic vein and measuring the free hepatic venous pressure (FHVP) with the balloon deflated and the wedged hepatic venous pressure (WHVP) with the balloon inflated to occlude the hepatic vein. The hepatic venous pressure gradient (HVPG) is then calculated by subtracting the free from the wedged venous pressure (HVPG = WHVP – FHVP). The HVPG represents the pressure in the hepatic sinusoids and portal vein and is a measure of portal venous pressure. Clinically significant portal hypertension is evident when HVPG exceeds 10 mmHg.

Etiology and Clinical Features of Portal Hypertension

The causes of portal hypertension can be divided into three major groups: presinusoidal, sinusoidal, and postsinusoidal.⁴¹ Although multiple disease processes can result in portal hypertension (Table 31-5), in the United States, the most common cause of portal hypertension is usually an intrahepatic one, namely, cirrhosis. The most significant clinical finding associated with portal hypertension is the development of gastroesophageal varices, which are mainly supplied by the anterior branch of the left gastric (coronary) vein.

Portal hypertension also results in splenomegaly with enlarged, tortuous, and even aneurysmal splenic vessels. Splenomegaly is frequently associated with functional hypersplenism, causing leukopenia, thrombocytopenia, and anemia. Ascites occurs in the setting of severe portal hypertension in combination with hepatocyte dysfunction. The umbilical vein may recannulate and dilate, leading to visible collaterals on the abdominal wall. Anorectal varices are present in approximately 45% of cirrhotic patients and must be distinguished from hemorrhoids, which do not communicate with the portal system and are not present at increased incidence in patients with portal hypertension. Large spontaneous venous shunts may form between the portal venous system and the left renal vein or the IVC, but these shunts are ineffective in reducing portal venous pressures and preventing bleeding from gastroesophageal varices.

Management of Gastroesophageal Varices

The most significant manifestation and the leading cause of morbidity and mortality related to portal hypertension is variceal bleeding. Approximately 30% of patients with compensated cirrhosis and 60% of patients with decompensated cirrhosis have esophageal varices. One third of all patients with varices will experience variceal bleeding. Each episode of bleeding is associated with a 20% to 30% risk of mortality. If left untreated, 70% of patients who survive the initial bleed will experience recurrent variceal hemorrhage within 2 years of the index ­hemorrhage.

Prevention of Variceal Bleeding

Current measures aimed at preventing variceal bleeding include the administration of nonselective β-blockers and prophylactic endoscopic surveillance with variceal band ligation. Meta-analyses have demonstrated that nonselective β-blockers such as propranolol and nadolol reduce the index variceal bleed by approximately 45% and decrease bleeding mortality by 50%.⁴² However, approximately 20% of patients do not respond to β-blockade, and another 20% cannot tolerate β-blockade due to medication side effects. Endoscopic surveillance with prophylactic variceal band ligation has been associated with a lower incidence of a first variceal bleed.⁴³ Variceal band ligation is recommended for patients with medium to large varices, performed every 1 to 2 weeks until obliteration, followed by esophagogastroduodenoscopy (EGD) 1 to 3 months later and surveillance EGD every 6 months to monitor for recurrence of varices.

Management of Acute Variceal Hemorrhage

Patients with acute variceal hemorrhage should be admitted to an ICU for resuscitation and management. Blood resuscitation should be performed carefully to reach a hemoglobin level of approximately 8 g/dL. Overzealous replacement of blood products and administration of saline can lead to both rebleeding and increased mortality. Administration of fresh frozen plasma and platelets can be considered in patients with severe coagulopathy. Use of recombinant factor VIIa has not been shown to be more beneficial than standard therapy and therefore is not recommended at this time. Cirrhotic patients with variceal bleeding have a high risk of developing bacterial infections, which are associated with increased risks of rebleeding and mortality. Spontaneous bacterial peritonitis accounts for approximately half of these infections, with urinary tract infections and pneumonias comprising the remainder. The use of short-term prophylactic antibiotics (e.g., ceftriaxone 1 g/d intravenously) has been shown both to decrease the rate of bacterial infections and to increase survival.

Vasoactive medications decrease blood flow to the gastroesophageal varices and can be initiated as soon as the diagnosis of variceal bleeding is made. Although vasopressin is the most potent available vasoconstrictor, its use is limited by its systemic vasoconstrictive effects that can produce hypertension, myocardial ischemia, arrhythmias, ischemic abdominal pain, and limb gangrene. Octreotide, a somatostatin analog, has the advantage that it can be administered for 5 days or longer, and it is currently the preferred pharmacologic agent for initial management of acute variceal bleeding. In addition to pharmacologic therapy, endoscopy with variceal band ligation should be carried out as soon as possible. This combination of pharmacologic and endoscopic therapy has been shown both to improve the initial control of bleeding and to increase the 5-day hemostasis rate.⁴³

Luminal Tamponade

When medical and endoscopic measures fail to control variceal hemorrhage, balloon tamponade using a Sengstaken-Blakemore tube will control refractory bleeding in up to 90% of patients. However, its application is limited due to the potential for complications, which include aspiration, airway obstruction, and esophageal perforation due to overinflation or pressure necrosis. Therefore, the use of a Sengstaken-Blakemore tube should not exceed 36 hours to avoid tissue necrosis, and this treatment modality should only be considered a temporary bridge to more definitive measures of variceal hemorrhage control.

Transjugular Intrahepatic Portosystemic Shunt

The TIPS procedure involves implantation of a metallic stent between an intrahepatic branch of the portal vein and a hepatic vein radicle. The needle track is dilated until a portal pressure gradient of ≤12 mmHg is achieved. TIPS can be performed in 95% of patients by an experienced interventional radiologist, controls variceal bleeding in >90% of cases refractory to medical treatment, and should not affect subsequent hepatic transplantation. Possible complications include bleeding either intra-abdominally or via the biliary tree, infections, renal failure, decreased hepatic function, and hepatic encephalopathy, which occur in 25% to 30% of patients after the TIPS procedure. A high rate of thrombosis is seen and can be attributed to intimal hyperplasia of the metallic stent. Frequent follow-up with repeated interventions such as dilation or restenting often are needed to maintain TIPS patency.

Balloon-Occluded Retrograde Transvenous Obliteration

The balloon-occluded retrograde transvenous obliteration (BRTO) procedure has been used for the specific management of bleeding gastric varices in patients with spontaneous gastrorenal or splenorenal shunts shown on ­contrast-enhanced cross-sectional imaging. Using a transjugular or transfemoral approach, a balloon-occlusion catheter is directed through the left renal vein into the spontaneous shunt, which is then obliterated with the use of a sclerosing agent. BRTO effectively controls hemorrhage from gastric varices and preserves portal flow to the liver, thereby reducing the risk of hepatic encephalopathy relative to TIPS. The occlusion of spontaneous shunts, however, can theoretically exacerbate portal hypertension, precipitate hemorrhage from esophageal varices, and exacerbate the accumulation of ascites.

Surgical Shunting

The need for surgical shunts has been reduced since the introduction of the TIPS procedure and hepatic transplantation. At this time, the recommendation is that surgical shunts be considered only in patients who have MELD scores of <15, who are not candidates for hepatic transplantation, or who have limited access to TIPS therapy and the necessary follow-up. The aim of the surgical shunt is to reduce portal venous pressure, maintain total hepatic and portal blood flow, and avoid the high incidence of complicating hepatic encephalopathy. Patient survival is determined by hepatic reserve.

The portacaval shunt, as first described by Eck in 1877, either joins the portal vein to the IVC in an end-to-side fashion and completely disrupts portal vein flow to the liver, or joins it in a side-to-side fashion and thereby maintains partial portal venous flow to the liver. Currently this shunt is rarely performed due to the high incidence of hepatic encephalopathy and decreased liver function resulting from the reduction of portal perfusion. The Eck fistula also makes subsequent hepatic transplantation much more technically difficult.

The mesocaval shunt uses an 8- or 10-mm polytetrafluoroethylene (PTFE) graft to connect the superior mesenteric vein to the IVC. The mesocaval shunt is technically easier to perform and can be easily ligated during subsequent hepatic transplantation. The smaller caliber of the shunt avoids the deleterious effects of portal blood flow deprivation on hepatic function. Small-diameter portosystemic shunts have been reported to reduce the incidence of encephalopathy but at the expense of increased risks of shunt thrombosis and rebleeding.

The surgical shunt currently used most often is the distal splenorenal or Warren shunt (Fig. 31-15). This shunt is technically the most difficult to perform. It requires division of the gastroesophageal collaterals and allows venous drainage of the stomach and lower esophagus through the short gastrosplenic veins into the spleen, and ultimately decompresses the left upper quadrant by allowing the splenic vein to drain directly into the left renal vein via an end-to-side splenic to left renal vein anastomosis. This shunt has the advantages of being associated with a lower rate of hepatic encephalopathy and decompensation and not interfering with subsequent liver transplantation.

Nonshunt Surgical Management of Refractory Variceal Bleeding

In the patient with extrahepatic portal vein thrombosis and refractory variceal bleeding, the Sugiura procedure may be considered. The Sugiura procedure consists of extensive devascularization of the stomach and distal esophagus along with transection of the esophagus, splenectomy, truncal vagotomy, and pyloroplasty. As with performance of surgical shunts, patient survival is dependent on hepatic reserve at the time of the surgical procedure. Experience in Western countries is somewhat limited, and a number of modifications have been made to the original Sugiura procedure over time.

Hepatic Transplantation

Patients with cirrhosis, portal hypertension, and variceal bleeding usually die as a result of hepatic failure and not acute blood loss. Therefore, hepatic transplantation must be considered in the patient with ESLD, because it represents the patient’s only chance for definitive therapy and long-term survival. Hepatic transplantation also can be considered for the patient with variceal bleeding refractory to all other forms of management. Survival after hepatic transplantation is not affected adversely by the previous performance of endoscopic variceal band ligation, TIPS, or splenorenal or mesocaval shunts. Previous creation of an Eck fistula, however, does make hepatic transplantation much more technically difficult, and therefore this procedure should be avoided in the transplant candidate. In addition to saving the patient’s life, hepatic transplantation reverses most of the hemodynamic and humoral changes associated with ­cirrhosis.

Budd-Chiari Syndrome

Budd-Chiari syndrome (BCS) is an uncommon congestive hepatopathy characterized by the obstruction of hepatic venous outflow. The incidence of BCS is 1 in 100,000 of the general population worldwide.⁴⁴ Patients may present with acute signs and symptoms of abdominal pain, ascites, and hepatomegaly or more chronic symptoms related to long-standing portal hypertension. BCS is defined as primary when the obstructive process involves an endoluminal venous thrombosis. BCS is considered as a secondary process when the veins are compressed or invaded by a neighboring lesion originating outside the vein.

A thorough evaluation demonstrates one or more thrombotic risk factors in approximately 75% to 90% of patients with primary BCS.⁴⁴ Primary myeloproliferative disorders, such as essential thrombocythemia or polycythemia rubra, account for approximately 35% to 50% of the primary cases of BCS. All known inherited thrombophilias also have been implicated in the development of BCS. Activated protein C resistance, generally related to factor V Leiden mutation, is present in approximately 25% of patients. Anticardiolipin antibodies, hyperhomocysteinemia, and oral contraceptive use all have been shown to be risk factors for BCS.⁴⁴

Clinically significant BCS is usually the result of obstruction of two or more of the major hepatic veins. The obstruction results in hepatomegaly, liver congestion, and right upper quadrant pain. In addition, liver perfusion via the portal vein may be decreased, and 70% of affected patients have noninflammatory centrilobular necrosis on biopsy. Although ALF is rare, most patients will go on to develop chronic portal hypertension and ascites. Caudate lobe hypertrophy occurs in approximately 50% of cases and is due to the fact that the caudate lobe has direct venous drainage into the IVC. This caudate lobe hypertrophy, in turn, can result in further obstruction of the IVC.

Abdominal ultrasonography is the initial investigation of choice and can demonstrate the absence of hepatic vein flow, spider web hepatic veins, and collateral hepatic veins.⁴⁵ CT or MRI of the abdomen also is capable of demonstrating hepatic vein thrombosis and evaluating the IVC but is limited in that it cannot show direction of blood flow. The definitive radiographic study to evaluate BCS is hepatic venography to determine the presence and extent of hepatic vein thrombus as well as measure IVC pressures.

Initial treatment consists of diagnosing and medically managing the underlying disease process and preventing extension of the hepatic vein thrombosis through systemic anticoagulation. The BCS-associated portal hypertension and ascites can be medically managed in a manner similar to that in most cirrhotic patients. Radiologic and surgical intervention should be reserved for patients whose condition is nonresponsive to medical therapy. Percutaneous angioplasty and TIPS, in combination with thrombolytic therapy, are the preferred strategies to restore the outflow of blood from the liver. Thrombolytic therapy alone may be attempted for acute thrombosis. Surgical shunting, namely with the side-to-side portacaval shunt, essentially turns the portal vein into a hepatic outflow tract. Most patients with a portacaval shunt show improvement in hepatic function and fibrosis at 1 year without significant hepatic encephalopathy.⁴⁵ However, the enthusiasm for this procedure has been curbed due to the relatively high rate of operative mortality and shunt dysfunction. Patients with progressive BCS and manifestations of ESLD will ultimately require hepatic transplantation.

The liver contains the largest portion of the reticuloendothelial system in the human body and is therefore able to handle the continuous low-level exposure to enteric bacteria that it receives through the portal venous system. Due to the high level of reticuloendothelial cells in the liver, nonviral infections are unusual.

Pyogenic Liver Abscesses

Pyogenic liver abscesses are the most common liver abscesses seen in the United States. They may be single or multiple and are more frequently found in the right lobe of the liver.⁴⁶ The abscess cavities are variable in size and, when multiple, may coalesce to give a honeycomb appearance. Approximately 40% of abscesses are monomicrobial, an additional 40% are polymicrobial, and 20% are culture-negative. The most common infecting agents are gram-negative bacteria; Escherichia coli is found in two thirds of cases, and other common organisms include Streptococcus faecalis, Klebsiella, and Proteus ­vulgaris. Anaerobic organisms such as Bacteroides fragilis also are seen frequently. In patients with endocarditis and infected indwelling catheters, Staphylococcus and Streptococcus species are more commonly found.

In the past, pyogenic liver abscesses often resulted from infections of the intestinal tract such as acute appendicitis and diverticulitis, which then spread to the liver via the portal circulation. With improved imaging modalities and earlier diagnosis of these intra-abdominal infections, this particular etiology of pyogenic liver abscesses has become less common. Pyogenic liver abscesses also occur as a result of impaired biliary drainage, subacute bacterial endocarditis, infected indwelling catheters, dental work, or the direct extension of infections such as diverticulitis or Crohn’s disease into the liver. There appears to be an increasing incidence due to infection by opportunistic organisms among immunosuppressed patients, including transplant and chemotherapy recipients as well as patients with acquired immunodeficiency syndrome (AIDS).

Patients commonly present with right upper quadrant pain and fever. Jaundice occurs in up to one third of affected patients. A thorough history and physical examination are usually helpful in identifying the underlying cause of the liver abscess. Leukocytosis, an elevated sedimentation rate, and an elevated AP level are the most common laboratory findings. Significant abnormalities in the results of the remaining liver function tests are unusual. Blood cultures will only reveal the causative organism in approximately 50% of cases. Ultrasound examination of the liver reveals pyogenic abscesses as round or oval hypoechoic lesions with well-defined borders and a variable number of internal echoes. CT scan is highly sensitive in the localization of pyogenic liver abscesses, which appear hypodense with peripheral enhancement and may contain air-fluid levels indicating a gas-producing infectious organism (Fig. 31-16). MRI of the abdomen can also detect pyogenic abscesses with a high level of sensitivity but plays a limited role because of its inability to be used for image-guided diagnosis and therapy.

The current cornerstones of treatment include correction of the underlying cause and IV antibiotic therapy. Empiric antibiotic therapy should cover gram-negative and anaerobic organisms; percutaneous needle aspiration and culture of the aspirate may be useful in guiding subsequent antibiotic therapy. IV antibiotic therapy should be continued for at least 8 weeks and can be expected to be effective in 80% to 90% of patients. Placement of a percutaneous drainage catheter is beneficial only for a minority of patients, as most pyogenic abscesses are quite viscous and catheter drainage is often ineffective.

Surgical drainage either via the laparoscopic or open approach may become necessary if initial therapies fail. Anatomic surgical resection can be performed in patients with recalcitrant abscesses. It must be kept in mind throughout the evaluation and treatment of the presumed pyogenic abscess that a necrotic hepatic malignancy must not be mistaken for a hepatic abscess. Therefore, early diagnosis and progression to surgical resection should be advocated for patients who do not respond to initial antibiotic therapy.

Amebic Abscesses

Entamoeba histolytica is a parasite that is endemic worldwide, infecting approximately 10% of the world’s population. Amebiasis is most common in subtropical climates, especially in areas with poor sanitation. E. histolytica exists as cysts in a vegetative form that are capable of surviving outside the human body. The cystic form passes through the stomach and small bowel unharmed and then transforms into a trophozoite in the colon. Here it invades the colonic mucosa forming typical flask-shaped ulcers, enters the portal venous system, and is carried to the liver. Occasionally, the trophozoite will pass through the hepatic sinusoid and into the systemic circulation, which results in lung and brain abscesses.

Amebae multiply and block small intrahepatic portal radicles with consequent focal infarction of hepatocytes. They contain a proteolytic enzyme that also destroys liver parenchyma. The abscesses formed are variable in size and can be single or multiple. The amebic abscess is most commonly located in the superior-anterior aspect of the right lobe of the liver near the diaphragm and has a necrotic central portion that contains a thick, reddish brown, pus-like material. This material has been likened to anchovy paste or chocolate sauce. Amebic abscesses are the most common type of liver abscesses worldwide.

Amebiasis should be considered in patients who have traveled to an endemic area and present with right upper quadrant pain, fever, hepatomegaly, and hepatic abscess.⁴⁶ Leukocytosis is common, whereas elevated transaminase levels and jaundice are unusual. The most common biochemical abnormality is a mildly elevated AP level. Even though this disease process is secondary to a colonic infection, the presence of diarrhea is unusual. Most patients have a positive fluorescent antibody test for E. histolytica, and test results can remain positive for some time after a clinical cure. This serologic test has a high sensitivity, and therefore amebiasis is unlikely if the test results are negative.

Ultrasound and CT scanning of the abdomen are both very sensitive but nonspecific for the detection of amebic abscesses.⁴⁶ Amebic abscesses usually appear on CT as well-defined low-density round lesions that have enhancement of the wall, somewhat ragged in appearance with a peripheral zone of edema. The central cavity may have septations as well as fluid levels. CT scanning is also useful in the detection of extrahepatic involvement.

Metronidazole 750 mg three times a day for 7 to 10 days is the treatment of choice and is successful in 95% of cases. Defervescence usually occurs in 3 to 5 days, but the time necessary for the abscess to resolve depends on the initial size at presentation and varies from 30 to 300 days.⁴⁶ Both ultrasound and CT of the liver can be used as follow-up after the initiation of medical therapy. Aspiration of the abscess rarely is needed and should be reserved for patients with large abscesses, those who do not respond to medical therapy, or those who appear to be superinfected. Furthermore, abscesses of the left lobe of the liver at risk for rupture into the pericardium should be treated with aspiration and drainage.

Hydatid Disease

Hydatid disease is due to infection by the tapeworm Echinococcus granulosus in its larval or cyst stage.⁴⁷ The tapeworm lives in canids, which are infected by eating the viscera of sheep that contain hydatid cysts. Scolices, contained in the cysts, adhere to the small intestine of dogs and become adult taenia, which attach to the intestinal wall. Each worm sheds approximately 500 ova into the bowel. The infected ova-containing feces of dogs contaminate grass and farmland, and the ova are ingested by intermediate hosts such as sheep, cattle, pigs, and humans. The ova have chitinous envelopes that are dissolved by gastric juice. The liberated ovum then burrows through the intestinal mucosa and is carried by the portal vein to the liver, where it develops into an adult cyst. Most cysts are caught in the hepatic sinusoids, and therefore 70% of hydatid cysts form in the liver. A few ova pass through the liver and are held up in the pulmonary capillary bed or enter the systemic circulation, forming cysts in the lung, spleen, brain, or bones.

Hydatid disease is most common in sheep-raising areas, where dogs have access to infected offal. These include South Australia, New Zealand, Africa, Greece, Spain, and the Middle East. Hydatid cysts commonly involve the right lobe of the liver, usually the anterior-inferior or posterior-inferior segments. The uncomplicated cyst may be silent and found only incidentally or at autopsy. Occasionally, the affected patient presents with symptoms such as dull right upper quadrant pain or abdominal distention. Cysts may become secondarily infected, involve other organs, or even rupture, which leads to an allergic or anaphylactic reaction.

The diagnosis of hydatid disease is based on the findings of an enzyme-linked immunosorbent assay (ELISA) for echinococcal antigens, and results are positive in approximately 85% of infected patients.⁴⁷ The ELISA results may be negative in an infected patient if the cyst has not leaked or does not contain scolices or if the parasite is no longer viable. Eosinophilia is seen in approximately 30% of infected patients. Ultrasonography and CT scanning of the abdomen are both quite sensitive for detecting hydatid cysts. The appearance of the cysts on images depends on the stage of cyst development. Typically, hydatid cysts are well-defined hypodense lesions with a distinct wall. Ring-like calcifications of the pericysts are present in 20% to 30% of cases. As healing occurs, the entire cyst calcifies densely, and a lesion with this appearance is usually dead or inactive. Daughter cysts generally occur in a peripheral location within the main cyst and are typically slightly hypodense compared with the mother cyst. MRI of the abdomen may be useful to evaluate the pericyst, cyst matrix, and daughter cyst characteristics.

Unless the cysts are small or the patient is not a suitable candidate for surgical resection, the treatment of hydatid disease is surgically based because of the high risk of secondary infection and rupture. Medical treatment with albendazole relies on drug diffusion through the cyst membrane. The concentration of drug achieved in the cyst is uncertain but is better than that of mebendazole, and albendazole can be used as initial treatment for small, asymptomatic cysts. For most cysts, surgical resection involving laparoscopic or open complete cyst removal with instillation of a scolicidal agent is preferred and usually is curative. If complete cystectomy is not possible, then formal anatomic liver resection can be undertaken. During surgical resection, caution must be exercised to avoid rupture of the cyst with release of protoscolices into the peritoneal cavity. Peritoneal contamination can result in an acute anaphylactic reaction or peritoneal implantation of scolices with daughter cyst formation and inevitable recurrence.

Echinococcus multilocularis occurs in the Northern Hemisphere and can infect the liver in a fashion similar to that described earlier, although the cysts are multilocular. Infection of the lung also is common (alveolar echinococcosis). Canine species such as wolves, foxes, and dogs ingest infected viscera of an intermediate host (e.g., rodents, moose) and become infected; humans become infected incidentally by ingesting contaminated food or water. Treatment consists of albendazole; however, infection in the lung produces a more generalized granulomatous reaction, can present in a manner similar to that of a malignancy, and often requires resection.

Ascariasis

Ascaris infection is particularly common in the Far East, India, and South Africa. Ova of the roundworm Ascaris lumbricoides arrive in the liver by retrograde locomotion in the bile ducts from the GI tract. The adult worm is 10 to 20 cm long and may lodge in the common bile duct, causing partial bile duct obstruction and secondary cholangitic abscesses. The Ascaris may serve as a nidus for the development of intrahepatic gallstones. The clinical presentation in an affected patient may include biliary colic, acute cholecystitis, acute pancreatitis, or hepatic abscesses.⁴⁸ Plain abdominal radiographs, abdominal ultrasound, and ERCP can demonstrate the Ascaris as linear filling defects within the bile ducts. Occasionally, worms can be seen moving into and out of the biliary tree from the duodenum. Treatment consists of the administration of piperazine citrate, mebendazole, or albendazole in combination with endoscopic extraction of the worms. Surgical intervention may become necessary if the Ascaris cannot be removed via ERCP.

Schistosomiasis

Schistosomiasis affects >200 million people in 74 countries. Hepatic schistosomiasis occurs when emboli of the ova in the intestines reach the liver via the mesenteric venous system. Eggs excreted in the feces hatch in water to release free-swimming embryos, which enter snails and develop into fork-tailed cercariae. They then re-enter human skin during contact with infected water. They burrow down to the capillary bed and enter the bloodstream, leading to widespread hematogenous dissemination. Those entering the intrahepatic portal system grow rapidly, resulting in a granulomatous reaction. The degree of consequent portal fibrosis is related to the adult worm load.

Schistosomiasis has three stages of clinical symptomatology: the first includes itching after the entry of cercariae through the skin; the second includes fever, urticaria, and eosinophilia; and the third involves hepatic fibrosis followed by presinusoidal portal hypertension. During this third phase, the liver shrinks, the spleen enlarges, and the patient may develop complications of portal hypertension while hepatic function is maintained. Active infection is detected by stool examination. Serologic tests indicate past exposure but do not provide information regarding the timing of infection. A negative serologic test result excludes the presence of schistosomal infection. Serum levels of transaminases are usually normal, but the AP level may be mildly elevated. A decreased serum albumin level is usually the result of frequent GI bleeds and malnutrition.

Medical treatment of schistosomiasis includes education on hygiene and the avoidance of infected water. Treatment with praziquantel 40 to 75 mg/kg as a single dose is the treatment of choice for all forms of schistosomiasis and produces few side effects. GI bleeding usually is controlled by endoscopic variceal ligation. However, in a patient with refractory GI portal hypertensive bleeding, distal splenorenal shunt or gastric devascularization and splenectomy may be considered.

Viral Hepatitis

The role of the surgeon in the management of viral hepatitis is somewhat limited. However, the disease entities of hepatitis A, B, and C need to be kept in mind during any evaluation for liver disease. Hepatitis A usually results in an acute self-limited illness and only rarely leads to fulminant hepatic failure. Patients can present with fatigue, malaise, nausea, vomiting, anorexic fever, and right upper quadrant abdominal pain. The most common physical findings are jaundice and hepatomegaly. Because the disease is self-limited, the treatment is usually supportive. Patients who develop fulminant infection require aggressive therapy and should be transferred to a center capable of performing liver transplantation.

Hepatitis B and C, on the other hand, can both lead to chronic liver disease, cirrhosis, and HCC. The prevalence of chronic hepatitis B infection in the U.S. population is estimated to be 0.27%, but hepatitis B remains a major burden in resource-limited countries, accounting for 30% of cirrhosis and 53% of HCC cases. The ultimate goal of treatment for chronic hepatitis B is viral suppression, thereby preventing the development of clinical outcomes such as cirrhosis, liver failure, and HCC. The cornerstone of current antiviral therapy includes pegylated interferon and nucleoside analogs such as tenofovir or entecavir.⁴⁹ These agents have been proven to reduce complications of cirrhosis and HCC and perhaps reverse previous damage to the liver. Interferon therapy produces various side effects including fatigue, flu-like symptoms, mood changes, bone marrow suppression, and stimulation of autoimmunity. On the other hand, the nucleoside analogs are generally well-tolerated by patients. Compared with lamivudine, the nucleoside analogs are less likely to produce resistance and are more likely to be clinically effective. Despite its high rate of viral resistance, lamivudine may be the preferred treatment in some countries because of its relatively low cost.

Acute hepatitis C viral (HCV) infection typically develops 2 to 26 weeks after exposure to the virus, and presenting symptoms can include jaundice, nausea, dark urine, and right upper quadrant abdominal pain. Diagnosis is confirmed by testing for the presence of HCV RNA and anti-HCV antibodies in the serum; viral RNA is first detectable in the serum by polymerase chain reaction (PCR) within days to weeks following the exposure, whereas antibodies will not appear until 2 to 6 months after. If the diagnosis of acute hepatitis is established and the virus is not spontaneously cleared within 12 weeks, patients should generally be treated with pegylated interferon monotherapy. High rates of sustained viral response, in excess of 80%, have been achieved with the early treatment of acute HCV infection.⁵⁰ Unfortunately patients with acute HCV infection are typically asymptomatic, and the vast majority of cases go undetected. Untreated, most of these patients will eventually develop chronic infection.

Chronic HCV infection often follows a progressive course over many years and can ultimately result in cirrhosis, HCC, and the need for liver transplantation. Cirrhosis secondary to hepatitis C remains the leading indication for liver transplantation in the United States, Europe, and Japan. The decision to treat a patient with chronic HCV infection is complex and involves consideration of multiple factors including the natural history of the ­disease, stage of fibrosis, and the efficacy and adverse effects related to the treatment regimen. Patients with genotype 1 are now treated with triple-agent therapy including pegylated interferon, ribavirin, and a protease inhibitor. The protease inhibitors telaprevir and boceprevir were recently approved for the treatment of chronic HCV genotype 1 infection, and their addition to the treatment regimen has been shown to increase the rate of sustained viral response from 40% to 70%. These protease inhibitors do no exhibit significant antiviral activity against other HCV genotypes, and therefore genotypes 2, 3, and 4 are treated with interferon and ribavirin alone. Genotypes 2 and 3 are generally more responsive to treatment than genotypes 1 and 4, but the therapeutic response also is dependent on other factors such as baseline viral load, ethnicity, and the patient’s genetic background and compliance with the regimen.

A liver mass often is identified incidentally during a radiologic imaging procedure performed for another indication. For example, a liver mass may be discovered during evaluation for gallbladder disease or kidney stones. In addition, with advances in imaging technology, previously undetected lesions not infrequently are now identified. Although many of these lesions are benign and will require no further treatment, the concern for malignancy requires a thorough evaluation. Thus, an orderly approach should be taken to the workup of an incidental liver lesion to minimize unnecessary testing.⁵¹

The evaluation of an incidental liver mass begins with a history and physical examination (Fig. 31-17). The patient should be asked about abdominal pain, weight loss, previous liver disease, cirrhosis, alcohol use, viral hepatitis, blood transfusions, tattoos, oral contraceptive use (in women), and personal or family history of cancer. On physical examination, jaundice, scleral icterus, hepatomegaly, splenomegaly, palpable mass, or stigmata of portal hypertension should be noted. After completion of the history and physical examination, blood work should be performed, including complete blood count; platelet count; measurement of levels of electrolytes, blood urea nitrogen, creatinine, glucose, and albumin; liver function tests; serum ammonia level; coagulation ­studies; hepatitis screen; and measurement of levels of the tumor markers carcinoembryonic antigen, AFP, and cancer antigen 19-9.

The differential diagnosis for an incidental liver mass includes cysts, benign solid lesions, and primary or metastatic cancers (Table 31-6). Ultrasound or CT is commonly performed to evaluate respiratory or abdominal symptoms, and these imaging studies usually lead to the discovery of an incidental liver lesion. Further radiologic evaluation by dual- or triple-phase CT scan or MRI is often necessary to fully characterize the extent and nature of the lesion. Different types of liver masses have distinct appearances and patterns of contrast enhancement on these studies, facilitating the clinician in the diagnosis and formulation of the treatment plan. The use of liver-specific contrast agents in MRI provides information on hepatocyte function in combination with the structural data obtained during a standard MRI, and yields improved detection and characterization of liver lesions. CT cholangiography or MRCP can be obtained, particularly when visualization of the biliary tract is desired. These modalities may be useful in the depiction of benign or malignant strictures resulting in biliary obstruction. In the evaluation of metastases to the liver from a variety of primary cancers, FDG-PET/CT has emerged as an indispensable tool in disease staging and in the follow-up after treatment. The techniques available for imaging of liver lesions are described in detail earlier in the section “Radiologic Evaluation of the Liver.”

Liver biopsy is indicated when biochemical analysis and diagnostic imaging fail to lead to a definitive diagnosis. Percutaneous liver biopsy with ultrasound or CT guidance is the simplest, fastest, and most commonly performed approach to obtain hepatic tissue for histologic examination. Absolute contraindications to percutaneous liver biopsy include significant coagulopathy (as in patients with decompensated cirrhosis), biliary dilatation, and suspicion for hemangioma or echinococcal cyst. Obesity and the presence of ascites are relative contraindications that can present a challenge to the percutaneous approach. In these patients, laparoscopic liver biopsy can be considered. The laparoscopic technique is likely to have a higher diagnostic yield in cirrhotic patients with ascites and/or coagulopathy, in whom bleeding risk is excessive by the percutaneous route. Laparoscopy also offers the opportunity to stage the extent of disease in patients with various intra-abdominal malignancies.

Congenital Cysts

The majority of hepatic cysts are asymptomatic. Hepatic cysts are usually identified incidentally and can occur at any time throughout life. The most common benign lesion found in the liver is the congenital or simple cyst. The exact prevalence of simple hepatic cysts in the U.S. population is not known, but the female:male ratio is approximately 4:1, and the prevalence is approximately 2.8% to 3.6%.⁵² Simple cysts are the result of excluded hyperplastic bile duct rests. Simple cysts usually are identified in hepatic imaging studies as thin-walled, homogeneous, fluid-filled structures with few to no septations. The cyst epithelium is cuboidal and secretes a clear nonbilious serous fluid. With the exception of large cysts, simple cysts are usually asymptomatic. Large simple cysts may cause abdominal pain, epigastric fullness, and early satiety. Occasionally the affected patient presents with an abdominal mass.

Asymptomatic simple cysts are best managed conservatively. The preferred treatment for symptomatic cysts is ­ultrasound- or CT-guided percutaneous cyst aspiration followed by sclerotherapy. This approach is approximately 90% effective in controlling symptoms and ablating the cyst cavity. If percutaneous treatment is unavailable or ineffective, treatment may include either laparoscopic or open surgical cyst fenestration. The laparoscopic approach is being used more frequently and is 90% effective. The excised cyst wall is sent for pathologic analysis to exclude the presence of carcinoma, and the remaining cyst wall must be carefully inspected for evidence of neoplastic change. If such change is present, complete resection is required, either by enucleation or formal hepatic resection.

Biliary Cystadenoma

Biliary cystadenomas are slow-growing, unusual, benign lesions that most commonly present as large lesions in the right lobe of the liver. Although these lesions are usually benign, they can undergo malignant transformation. Patients with biliary cystadenomas commonly present with abdominal pain. An abdominal mass occasionally can be identified on physical examination. In contrast to simple cysts, biliary cystadenomas have walls that appear thicker with soft tissue nodules and septations that usually enhance. The protein content of the fluid can be variable and can affect the radiographic images on CT and MRI. Surgical resection is the preferred mode of treatment.

Polycystic Liver Disease

Adult polycystic liver disease (PCLD) occurs as an autosomal dominant disease and usually presents in the third decade of life. Approximately 44% to 76% of affected families are found to have mutations of PKD1, and approximately 75% have mutations of PKD2.⁵³ The prevalence and number of hepatic cysts are higher in females and increase with advancing age and with increasing severity of renal cystic disease and renal dysfunction. Patients with a small number of cysts or with small cysts (<2 cm) usually remain asymptomatic. In contrast, patients who develop many or large cysts, with a cyst-to-parenchymal volume ratio of >1, usually develop clinical symptoms, including abdominal pain, distension, shortness of breath, and early satiety. Disease progression often results in renal failure and the need for hemodialysis. In most patients, the liver parenchymal volume and synthetic function are preserved despite extensive cystic disease. Hepatic decompensation, variceal hemorrhage, ascites, and encephalopathy develop rarely in patients with PCLD and only in those with massive cystic disease. The most common liver-specific complications associated with PCLD are intracystic hemorrhage, infection, and posttraumatic rupture. The most common abnormal biochemical test finding is a modestly elevated γ-glutamyltransferase level, and the most useful imaging tests are CT or MRI of the abdomen, which will demonstrate the characteristic polycystic appearance. Other conditions that may be associated with PCLD include cerebral aneurysm, diverticulosis, mitral valve prolapse, and inguinal hernia.

The principal aim of treatment for PCLD is to ameliorate symptoms by decreasing liver volume. Medical therapy options for PCLD remain experimental at this time. Somatostatin analogs such as octreotide and lanreotide have been shown to modestly reduce liver volume and are generally well tolerated. Sirolimus and other mammalian target of rapamycin (mTOR) inhibitors possess antiproliferative effects and thus have been postulated to slow disease progression. The effectiveness of these medical measures in relieving symptoms among patients with PCLD, however, remains to be proven.⁵⁴

Cyst aspiration and sclerotherapy entail puncture of a cyst with an aspiration needle followed by injection of a sclerosing agent that causes destruction of the epithelial lining thereby inhibiting fluid production. Common agents used for sclerosis include ethanol, minocycline, and tetracycline. This technique may be considered if the patient has one or a few dominant cysts, each measuring over 5 cm. Appropriate candidates for sclerotherapy can experience a complete resolution of symptoms, but patients with numerous cysts often do not improve when this technique is used. This procedure is generally well tolerated, with the most common complication being pain from the instillation of ethanol.

Cyst fenestration, or surgical unroofing of the cyst, can be performed via an open or laparoscopic approach in symptomatic patients.⁵⁵ This approach allows multiple cysts to be treated during a single procedure, but carries the risk of potential surgical complications, including ascites, pleural effusion, hemorrhage, and biliary leakage. Immediate symptom relief can be achieved in up to 92% of cases, but 22% of patients eventually develop recurrence of their symptoms.

Hepatic resection can be considered for PCLD patients with massive hepatomegaly, when fenestration alone is unlikely to significantly reduce liver volume. Appropriate candidates are those with portions of liver that harbor numerous cysts, but have at least one spared segment with predominantly normal liver parenchyma. Because the intrahepatic vascular and biliary anatomy can be distorted by the cysts, PCLD patients undergoing hepatic resection are at increased risk for hemorrhagic and biliary complications. Furthermore, adhesion formation after liver resection can increase the technical complexity of future OLT. Significant symptom relief has been reported in up to 86% of PCLD patients following hepatic resection.

OLT represents the only definitive therapy for patients with symptomatic PCLD. This therapeutic option is indicated in patients with severely disabling symptoms that lead to a poor quality of life or in those who have developed untreatable complications such as portal hypertension and nutritional deprivation. If the patient has severe renal insufficiency from polycystic kidney disease, consideration should be given to combined liver-kidney transplantation. Because of the genetic basis of PCLD, living-donor transplantation should be considered only if the presence of PCLD in the donor can be ruled out.

Caroli’s Disease

Caroli’s disease is a syndrome of congenital ductal plate malformations of the intrahepatic bile ducts and is characterized by segmental cystic dilatation of the intrahepatic biliary radicals.⁵⁶ Caroli’s disease also is associated with an increased incidence of biliary lithiasis, cholangitis, and biliary abscess formation. Caroli’s disease usually occurs in the absence of cirrhosis and is associated with cystic renal disease.⁵⁶ The most common presenting symptoms include fever, chills, and abdominal pain. Most patients present by the age of 30 years, and males and females are affected equally. Rarely, patients can present later in life with complications secondary to portal hypertension. Approximately 33% of affected patients develop biliary lithiasis and 7% develop cholangiocarcinoma. The diagnosis of Caroli’s disease is made based on imaging studies. Magnetic resonance cholangiopancreatography, ERCP, and percutaneous transhepatic cholangiography provide more detailed imaging of the biliary tree and confirm communication of the intrahepatic cysts with the biliary tree, which is necessary to solidify the diagnosis. Treatment consists of biliary drainage, with ERCP and percutaneous transhepatic cholangiography serving as first-line therapeutic modalities. If the disease is limited to a single lobe of the liver, hepatic resection can be beneficial. Liver resection can be considered in the patient with hepatic decompensation or unresponsive recurrent cholangitis and possibly in the patient with a small (T1 or T2) cholangiocarcinoma.

The liver is an organ that is commonly involved either primarily or secondarily with vascular, metabolic, infectious, and malignant processes. Many classification schemes are used to help narrow the differential diagnosis of liver lesions: solid or cystic, single or multiple, cell of origin (hepatocellular, cholangiocellular, or mesenchymal), and benign or malignant. Benign liver lesions occur in up to 20% of the general population and are much more common than malignant tumors. The most common benign lesions are cysts, hemangiomas, focal nodular hyperplasia (FNH), and hepatocellular adenomas (see Table 31-6). Many of these lesions have typical features in imaging studies that help confirm the diagnosis.

Cyst

Hepatic cysts are the most frequently encountered liver lesion overall and are described in detail in the section “Hepatic Cysts.” Cystic lesions of the liver can arise primarily (congenital) or secondarily from trauma (seroma or biloma), infection (pyogenic or parasitic), or neoplastic disease. Congenital cysts are usually simple cysts containing thin serous fluid and are reported to occur in 5% to 14% of the population, with higher prevalence in women. In most cases, congenital cysts are differentiated from secondary cysts (infectious or neoplastic origin) in that they have a well-defined thin wall and no solid component and are filled with homogeneous, clear fluid. For benign solid liver lesions, the differential diagnosis includes hemangioma, adenoma, FNH, and bile duct ­hamartoma.

Hemangioma

Hemangiomas (also referred to as hemangiomata) are the most common solid benign masses that occur in the liver. They consist of large endothelial-lined vascular spaces and ­represent congenital vascular lesions that contain fibrous tissue and small blood vessels that eventually grow. They are predominantly seen in women and occur in 2% to 20% of the population. They can range from small (≤1 cm) to giant cavernous hemangiomas (10 to 25 cm). Most hemangiomas are discovered incidentally with little clinical consequence. However, large lesions can cause symptoms as a result of compression of adjacent organs or intermittent thrombosis, which in turn results in further expansion of the lesion. Spontaneous rupture (bleeding) is rare, but surgical resection can be considered if the patient is symptomatic. Resection can be accomplished by enucleation or formal hepatic resection, depending on the location and involvement of intrahepatic vascular structures and hepatic ducts.

The majority of hemangiomas can be diagnosed by liver imaging studies. On biphasic contrast CT scan, large hemangiomas show asymmetrical nodular peripheral enhancement that is isodense with large vessels and exhibit progressive centripetal enhancement fill-in over time (Fig. 31-18). On MRI, hemangiomas are hypointense on T1-weighted images and hyperintense on T2-weighted images.⁵⁷ With gadolinium enhancement, hemangiomas show a pattern of peripheral nodular enhancement similar to that seen on contrast CT scans. Caution should be exercised in ordering a liver biopsy if the suspected diagnosis is hemangioma because of the risk of bleeding from the biopsy site, especially if the lesion is at the edge of the liver.

Adenoma

Hepatic adenomas are benign solid neoplasms of the liver. They are most commonly seen in premenopausal women older than 30 years of age and are typically solitary, although multiple adenomas also can occur. Prior or current use of estrogens (oral contraceptives) is a clear risk factor for development of liver adenomas, although they can occur even in the absence of oral contraceptive use. On gross examination, they appear soft and encapsulated and are tan to light brown. Histologically, adenomas lack bile duct glands and Kupffer cells, have no true lobules, and contain hepatocytes that appear congested or vacuolated due to glycogen deposition. On CT scan, adenomas usually have sharply defined borders and can be confused with metastatic tumors. With venous phase contrast, they can look hypodense or isodense in comparison with background liver, whereas on arterial phase contrast, subtle hypervascular enhancement often is seen (see Fig. 31-18). On MRI scans, adenomas are hyperintense on T1-weighted images and enhance early after gadolinium injection. With the use of liver-specific MRI contrast agents such as gadoxetate (Eovist or Primovist, Bayer-Schering, Berlin, Germany), hepatic adenomas can be better distinguished from FNH by their enhancement characteristics during the hepatobiliary phase of imaging. The new MRI contrast agent, gadobenate dimeglumine (MultiHance, Bracco Diagnostics, Milan, Italy), is eliminated through both renal and biliary excretion. Therefore, liver lesions that contain hepatocytes with intact biliary excretion mechanism will take up this contrast agent and be easily distinguished from lesions that do not. This contrast agent has improved our ability to differentiate hepatic adenoma from FNH with a high degree of accuracy.

Hepatic adenomas carry a significant risk of spontaneous rupture with intraperitoneal bleeding. The clinical presentation may be abdominal pain, and in 10% to 25% of cases, hepatic adenomas present with spontaneous intraperitoneal hemorrhage. Hepatic adenomas also have a risk of malignant transformation to a well-differentiated HCC. Therefore, it usually is recommended that a hepatic adenoma (once diagnosed) be surgically resected.

Focal Nodular Hyperplasia

FNH is a solid, benign lesion of the liver believed to be a hyperplastic response to an anomalous artery. Similar to adenomas, they are more common in women of childbearing age, although the link to oral contraceptive use is not as clear as with adenomas. A good-quality biphasic CT scan usually is diagnostic of FNH, on which such lesions appear well circumscribed with a typical central scar (see Fig. 31-18). They show intense homogeneous enhancement on arterial phase contrast images and are often isodense or invisible compared with background liver on the venous phase. On MRI scans, FNH lesions are hypointense on T1-weighted images and isointense to hyperintense on T2-weighted images. After gadolinium administration, lesions are hyperintense but become isointense on delayed images. The fibrous septa extending from the central scar are also more readily seen with MRI. Unlike adenomas, FNH lesions usually do not rupture spontaneously and have no significant risk of malignant transformation. Therefore, the management of FNH is usually reassurance and prospective observation irrespective of size. Surgical resection can be recommended, however, when patients are symptomatic or when hepatic adenoma or HCC cannot be definitively excluded. Oral contraceptive or estrogen use should be stopped when either FNH or adenoma is diagnosed.

Bile Duct Hamartoma

Bile duct hamartomas are typically small liver lesions, 2 to 4 mm in size, visualized on the surface of the liver at laparotomy. They are firm, smooth, and whitish yellow in appearance. They can be difficult to differentiate from small metastatic lesions, and excisional biopsy often is required to establish the diagnosis.

Malignant tumors in the liver can be classified as primary (cancers that originate in the liver) or metastatic (cancers that spread to the liver from an extrahepatic primary site) (see Table 31-6). Primary cancers in the liver that originate from hepatocytes are known as hepatocellular carcinomas (HCCs or hepatomas), whereas cancers arising in the bile ducts are known as cholangiocarcinomas.

In the United States, approximately 150,000 new cases of colorectal cancer are diagnosed each year, and the majority of patients (approximately 60%) will develop hepatic metastases over their lifetime. Hence, the most common tumor seen in the liver is metastatic colorectal cancer. This compares with approximately 18,000 new cases of HCC diagnosed annually in the United States. Interestingly, in a Western series of 1000 consecutive new liver cancer patients seen at a university medical center, 47% had HCC, 17% had colorectal cancer metastases, 11% had cholangiocarcinomas, 7% had neuroendocrine metastases, and 18% had other tumors.⁵⁸ Although these figures do not reflect the incidence or prevalence of these liver cancers, they are indicative of referral patterns in a tertiary academic medical center with a large liver transplantation team and active hepatology clinic.

Hepatocellular Carcinoma

HCC is the fifth most common malignancy worldwide, with an estimated 750,000 new cases diagnosed annually. Because of its high fatality, it is the third most common cause of cancer death worldwide.⁵⁹ Major risk factors are viral hepatitis (B or C), alcoholic cirrhosis, hemochromatosis, and NASH. In Asia, the risk is as high as 35 to 117 per 100,000 persons per year, whereas in the United States, the risk is only 7 per 100,000 persons per year.⁵⁹ Although cirrhosis is not present in all cases, it has been estimated to be present 70% to 90% of the time. In a person with cirrhosis, the annual conversion rate to HCC is 2% to 6%.⁶⁰ In patients with chronic HCV infection, cirrhosis usually is present before the HCC develops; however, in cases of hepatitis B virus infection, HCC tumors can occur before the onset of cirrhosis. HCCs are typically hypervascular with blood supplied predominantly from the hepatic artery. Thus, the lesion often appears hypervascular during the arterial phase of CT studies (Fig. 31-19) and relatively hypodense during the delayed phases due to early washout of the contrast medium by the arterial blood. MRI imaging also is effective in characterizing HCC. HCC is variable on T1-weighted images and usually hyperintense on T2-weighted images. As with contrast CT, HCC enhances in the arterial phase after gadolinium injection because of its hypervascularity and becomes hypointense in the delayed phases due to contrast washout. HCC has a tendency to invade the portal vein, and the presence of an enhancing portal vein thrombus is highly suggestive of HCC.

The treatment of HCC is complex and is best managed by a multidisciplinary liver transplant team. A complete algorithm for the evaluation and management of HCC is shown (Fig. 31-20). For patients without cirrhosis who develop HCC, resection is the treatment of choice. For patients with Child’s class A cirrhosis with preserved liver function and no portal hypertension, resection also is considered. If resection is not possible because of poor liver function and the HCC meets transplant criteria (discussed later), liver transplantation is the treatment of choice.^61,62

The Barcelona-Clinic Liver Cancer Group has refined its HCC management strategy and has developed the American Association for the Study of Liver Diseases Practice Guidelines.⁶³ Management guidelines vary slightly in Asia, Europe, the United States, and other countries based in part on availability of organ donors for liver transplantation. Living donor liver transplantation also is an alternative for patients with HCC awaiting transplantation to avoid dropout as a candidate for cadaveric donor liver transplantation due to tumor progression.⁶² Specific treatment options are described in the next section.

Cholangiocarcinoma

Cholangiocarcinoma, or bile duct cancer, is the second most common primary malignancy of the liver. Cholangiocarcinoma is an adenocarcinoma of the bile ducts; it forms in the biliary epithelial cells and can be subclassified into peripheral (intrahepatic) bile duct cancer and central (extrahepatic) bile duct cancer. Extrahepatic bile duct cancer can be located distally or proximally. When proximal, it is referred to as a hilar cholangiocarcinoma (Klatskin’s tumor). Hilar cholangiocarcinoma originates in the wall of the bile duct at the hepatic duct confluence and usually presents with obstructive jaundice rather than an actual liver mass. In contrast, a peripheral (or intrahepatic) cholangiocarcinoma represents a tumor mass within a hepatic lobe or at the periphery of the liver. A biopsy specimen from the cholangiocarcinoma will show adenocarcinoma, but pathologists are often unable to differentiate metastatic adenocarcinoma to the liver from primary bile duct adenocarcinoma. Therefore, a search for a primary site should be undertaken in cases in which an incidentally discovered liver lesion is proven to be an adenocarcinoma on biopsy.

Hilar cholangiocarcinoma is difficult to diagnose and typically presents as a stricture of the proximal hepatic duct causing painless jaundice. It preferentially grows along the length of the bile ducts, often involving the periductal lymphatics with frequent lymph node metastases. Surgical resection offers the only chance for cure of cholangiocarcinoma.⁶⁴ The location and extent of tumor dictate the operative approach. In one series of 225 patients with hilar cholangiocarcinoma, 65 (29%) were deemed to have unresectable tumors by initial imaging.⁶⁵ Of the remaining 160 patients who underwent exploratory surgery with curative intent, 80 (50%) were found to have inoperable tumors. Histologically negative margins, concomitant hepatic resection, and well-differentiated tumor histology were associated with improved outcome after resection. In another series of 61 patients undergoing surgical exploration for hilar cholangiocarcinoma, the 5-year actuarial survival rates for an R0 or R1 resection were 45% and 26%, respectively.⁶⁶ In a large series reported by Nagino and colleagues, 132 patients with hilar cholangiocarcinoma underwent extended hepatectomy with resection of the caudate lobe and extrahepatic bile duct, and/or portal vein resection (n = 63) after portal vein embolization.⁶⁷ The 3- and 5-year survival rates were 41.7% and 26.8%, respectively.

In the absence of associated primary sclerosing cholangitis (PSC), surgical resection is the treatment of choice for hilar cholangiocarcinoma. However, approximately 10% of patients with cholangiocarcinoma have PSC.⁶⁸ Furthermore, cholangiocarcinoma in the setting of PSC is frequently multicentric and often is associated with underlying liver disease, with eventual cirrhosis and portal hypertension. As a result, experience has shown that resection of cholangiocarcinoma in patients with PSC yields dismal results. This led transplant centers to consider OLT for patients with hilar cholangiocarcinoma. The initial results of transplantation were disappointing, however, with high recurrence and overall 3-year survival rates of <30%.⁶⁹

Because the growth of hilar cholangiocarcinoma indicates that this disease spreads in a locoregional manner, a rationale for the use of neoadjuvant chemoradiation was developed by the transplant team at the University of Nebraska in the late 1980s. This was adapted in 1993 by the transplant team at the Mayo Clinic, which led to the current Mayo Clinic protocol.⁷⁰ The pretransplant Mayo protocol consists of external-beam radiation therapy plus a protracted course of intravenous 5-fluorouracil followed by iridium-192 brachytherapy.⁷¹ Patients then undergo an abdominal exploration with staging. If findings are negative, patients are given capecitabine for 2 of every 3 weeks until transplantation. Even after restaging with CT/MRI and endoscopic ultrasonography, approximately 15% to 20% of patients will have positive findings for tumor on abdominal exploration.^68,71 The 5-year survival rate for those undergoing transplantation for cholangiocarcinoma at the Mayo Clinic is approximately 70% and compares favorably with the rate for resection.^68,71 Current eligibility criteria for this Mayo Clinic protocol include unresectable hilar cholangiocarcinoma or hilar cholangiocarcinoma with PSC. The tumor must have a radial dimension of ≤3 cm with no intrahepatic or extrahepatic metastases, and the patient must not have undergone prior radiation therapy or transperitoneal biopsy.⁷¹ Many centers have adopted similar protocols with comparable results.⁷²

Peripheral, or intrahepatic, cholangiocarcinoma is less common than hilar cholangiocarcinoma. In a series of 53 patients at Memorial Sloan-Kettering Cancer Center who underwent surgical exploration for a diagnosis of intrahepatic cholangiocarcinoma, 33 (62%) were found to have resectable tumors.⁷³ Actuarial 3-year survival for patients undergoing resection was 55%. Factors predictive of poor survival included vascular invasion, histologically positive margins, and multiple tumors. In a large series in Taiwan, 373 patients with peripheral cholangiocarcinoma underwent surgical treatment from 1977 to 2001. Absence of mucobilia, nonpapillary tumor type, tumor of advanced stage, nonhepatectomy, and lack of postoperative chemotherapy were five independent prognostic factors that adversely affected overall survival.⁷⁴ Liver transplantation has been performed for peripheral cholangiocarcinoma⁷⁵; however, currently all but one center in the United States have eschewed this approach because of organ shortages and relatively high recurrence rates.

Gallbladder Cancer

Gallbladder cancer is a rare aggressive tumor with a very poor prognosis. Over 90% of patients have associated cholelithiasis. In one study examining the mode of presentation over a 10-year period from 1990 to 2000 in 44 patients diagnosed with gallbladder cancer, the diagnosis was found to be made preoperatively in 57%, intraoperatively in 11%, and incidentally after cholecystectomy in 32%.⁷⁶ Surgical approaches can be classified into (a) reoperation for an incidental finding of gallbladder cancer after cholecystectomy, and (b) radical resection in patients with advanced disease. The results are dismal for radical resection in patients with advanced disease and positive hilar lymph nodes.^77,78 For incidental gallbladder cancer beyond stage T1, reoperation with central liver resection, hilar lymphadenectomy, and evaluation of cystic duct stump is most commonly performed.^79,80 The role of formal lobectomy or extended lobectomy as well as common bile duct resection is more controversial. In a single-center study of 23 patients undergoing attempted curative treatment by surgical resection, survival was 85% at 1 year, 63% at 2 years, and 55% at 3 years.⁸⁰ In a multicenter study encompassing 115 patients with incidentally discovered gallbladder cancer who underwent ­re-resection,⁷⁹ residual disease in the liver was identified in 46% of patients (0% of those with stage T1 disease, 10% of those with T2 tumors, and 36% of those with T3 disease). T stage also was associated with the risk of metastasis to locoregional lymph nodes (lymph node metastasis for T1 of 13%; for T2, 31%; and for T3, 46%). In another study, a German registry of incidental gallbladder cancer identified 439 patients. Patients with tumors staged as T2 or T3 after cholecystectomy had better survival if they underwent reoperation than if they were managed with observation.⁸¹ Hence, reoperation should be considered for all patients who have T2 or T3 tumors or for whom the accuracy of staging is in question.

Metastatic Colorectal Cancer

Over 50% to 60% of patients diagnosed with colorectal cancer will develop hepatic metastases during their lifetime. Resection for hepatic metastases has been a routine part of treatment for colorectal cancer since the publication of a large single-center experience demonstrating its safety and efficacy.⁸² Predictors of poor outcome in that study included node-positive primary, disease-free interval <12 months, more than one tumor, tumor size >5 cm, and carcinoembryonic antigen level >200 ng/mL. Traditional teaching suggested that hepatic resection for metastatic colorectal cancer to the liver, if technically feasible, should be performed only for fewer than four metastases.⁸³ However, later studies challenged this paradigm. In a series of 235 patients who underwent hepatic resection for metastatic colorectal cancer, the 10-year survival rate of patients with four or more nodules was 29%, nearly comparable to the 32% survival rate of patients with only a solitary tumor metastasis.⁸⁴ In the Memorial Sloan-Kettering Cancer Center series of 98 patients with four or more colorectal hepatic metastases who underwent resection between 1998 and 2002, the 5-year actuarial survival was 33%.⁸⁵ Furthermore, improved chemotherapeutic regimens and surgical techniques have produced aggressive strategies for the management of this disease. Many groups now consider volume of future liver remnant and the health of the background liver, and not actual tumor number, as the primary determinants in selection for an operative approach.^86,87 Hence, resectability is no longer defined by what is actually removed, but indications for hepatic resection now center on what will remain after resection.⁸⁸ Use of neoadjuvant chemotherapy, portal vein embolization, two-stage hepatectomy, simultaneous ablation, and resection of extrahepatic tumor in select patients have increased the number of patients eligible for a surgical approach.^89,90

Neuroendocrine Tumors

Hepatic metastases from neuroendocrine tumors have a protracted natural history and commonly are associated with debilitating endocrinopathies. Several groups have advocated an aggressive surgical approach of debulking surgery, both to control symptoms and to extend survival.^91,92 In a series of 170 patients undergoing resection of hepatic metastases from neuroendocrine tumors between 1977 and 1998 at the Mayo Clinic, overall survival was 61% and 35% at 5 and 10 years, respectively.⁹³ There was no difference in survival between patients with carcinoid tumors and those with islet cell tumors. Major hepatectomy was performed in 91 patients (54%), and recurrence rate was 84% at 5 years. Belghiti’s group has described a two-stage strategy used in 41 patients with a primary neuroendocrine tumor and synchronous bilobar liver metastases.⁹⁴ In the first stage, the primary tumor is resected and limited resection of metastases in the left hemiliver, combined with right portal vein ligation, is performed. After 8 weeks of hypertrophy, a right hepatectomy or extended right hepatectomy (also referred to as a right trisectionectomy; resection of Couinaud’s segments IV, V, VI, VII, and VIII of the liver) is performed.⁹⁴ In patients treated using this strategy, the 2-, 5-, and 8-year Kaplan-Meier overall survival rates were 94%, 94%, and 79%, respectively, and disease-free survival rates were 85%, 50%, and 26%, respectively. Because systemic therapy has had little success in the treatment of advanced tumors, a broader approach using multimodal therapy has been used to increase survival and improve hormone-related symptoms. These therapies include radiofrequency or microwave ablation and intra-arterial therapy with chemoembolization or radioembolization (yttrium-90). Some centers perform liver transplantation for selected patients (carcinoid histology; primary tumor removed with curative resection; primary tumor drained by portal system; ≤50% hepatic parenchyma involved; good response or stable disease for at least 6 months during pretransplantation period; and age 55 years or younger), although this is not routine.⁹⁵

Other Metastatic Tumors

Nearly every cancer has the propensity to metastasize to the liver. Historically, enthusiasm was low for resecting metastases other than those from a colorectal cancer primary. This was due in part to the recognition that many other primary cancers (such as breast cancer) represent a systemic disease when liver metastases are present. However, more recent studies have shown acceptable 5-year survival rates in the 20% to 40% range for resection of hepatic metastases from breast, renal, and other GI tumors.^96,97 In a large study of hepatic resection for noncolorectal, nonendocrine liver metastases in 1452 patients, negative prognostic factors were nonbreast origin, age >60 years, disease-free interval of <12 months, need for major hepatectomy, performance of R2 resection, and presence of extrahepatic metastases.⁹⁶

In general, the major treatment options for liver cancer can be categorized as shown in Table 31-7. The decision making for any given patient is complex and is best managed by a multidisciplinary liver tumor board. The treatments listed in Table 31-7 are not mutually exclusive; the important point is to select the most appropriate initial treatment after a complete evaluation. In general, surveillance imaging (CT or MRI) is performed every 3 to 4 months during the first year after diagnosis to observe for response, progression, or recurrence. The treatment plan is individualized and modified according to the response of the patient.

Hepatic Resection

For primary liver cancers or hepatic metastases, hepatic resection is the gold standard and treatment of choice. Although there are anecdotal reports of long-term survival after ablation and other regional liver therapies, liver resection remains the only real option for cure. For HCC in the setting of cirrhosis, liver transplantation also offers the potential for long-term survival, albeit with the consequences of immunosuppression. Hepatic resection also has been advocated for HCC in select patients with cirrhosis before secondary liver transplantation, although not without some controversy.⁹⁸ Many large series of patients undergoing major hepatectomy now report mortality rates of <5%.^{99,100,101,102} Previously, a 1-cm tumor margin was considered desirable; however, recent studies have reported comparable survival rates with smaller margins.^103,104,105 Technical innovation in liver surgery and a better understanding of perioperative care have even allowed surgeons to perform resections in cases with IVC involvement with extracorporeal liver surgery.¹⁰⁶ The technical aspects of anatomic hepatic lobectomies are described later.

Liver Transplantation

The rationale supporting OLT for HCC includes the fact that most HCCs (>80%) arise in the setting of cirrhosis.^69,107 The cirrhotic liver often does not have enough reserve to tolerate a formal resection. Also, HCC tumors are commonly multifocal and are underestimated by current CT or MRI imaging.¹⁰⁸ Furthermore, recurrence rates are high at 5 years after resection (>50%). Hence, OLT is an appealing treatment, because it removes both the cancer and the cirrhotic liver that leads to cancer. More than 6000 liver transplantations are performed each year in the United States, with 1-year survival rates approaching 90%. In June 2013, approximately 15,800 patients were on the waiting list for liver transplantation.¹⁰⁹

Initial series of OLT for HCC reported in the 1990s included advanced cases of HCC, and the 5-year survival rates were only 20% to 50%.⁶⁹ This compared poorly with overall 5-year survival rates of 70% to 75% for OLT in the Organ Procurement and Transplantation Network/United Network for Organ Sharing (OPTN/UNOS) database. Mazzaferro and colleagues at Milan subsequently showed that survival rates were markedly improved when OLT was limited to patients with early-stage HCC (stage I or stage II) with one tumor ≤5 cm, or up to three tumors no larger than 3 cm, along with the absence of gross vascular invasion or extrahepatic spread.¹¹⁰ Multiple studies have validated these findings, and many groups have proposed an expansion of the Milan criteria.⁶²

As noted previously, the 6- to 40-point MELD score was adopted by OPTN/UNOS in 2002 for allocation of deceased donor liver organs in the United States. In an attempt to prioritize patients with preserved liver function and progressive HCC, patients with stage I or stage II HCC are allocated exception points (currently 22 MELD points, increasing every 3 months as long as they continue to meet transplant criteria). This allocation has had a positive effect for HCC liver transplant candidates, leading to decreased waiting list dropout and increased transplant rates with excellent long-term outcomes.¹¹¹ The goal is to better equate death rates on the liver transplant waiting list for patients with stage I or stage II HCC with rates for patients with chronic liver disease without HCC. Although indications for liver transplantation have increased, the supply of donor livers has failed to keep pace with the numbers of potential recipients. A partial solution has been the use of living donor grafts. This is especially true in Asia where the incidence of HCC is high and the rate of cadaveric donation is low. Living donor grafts include right and left lobes, as well as dual grafts from separate donors to provide adequate hepatic mass to the recipient. The use of living donor grafts also allows for transplant programs to push the boundaries by accepting patients beyond the Milan criteria with good results.¹¹²

Radiofrequency Ablation

In 1891, d’Arsonval discovered that radiofrequency (RF) waves delivered as an alternating electric current (>10 kHz) could pass through living tissue without causing pain or neuromuscular excitation. The resistance of the tissue to the rapidly alternating current produced heat. This discovery contributed to the development of the surgical application of electrocautery. In 1908, Beer used RF coagulation to destroy urinary bladder tumors. Cushing and Bovie later applied RF ablation to intracranial tumors. In 1961, Lounsberry studied the histologic changes of the liver after RF ablation (RFA) in animal models. He found that RF caused local tissue destruction with uniform necrosis. In the early 1990s, two groups proposed that RFA can be an effective method for destroying unresectable malignant liver tumors.^113,114 Both groups found that RFA produced lesions with well-demarcated areas of necrosis without viable tumor cells present. Clinical reports after short-term follow-up suggested that RFA was safe and effective in the treatment of liver tumors.^115,116,117 However, Abdalla and colleagues examined data for 358 consecutive patients with colorectal liver metastases treated with curative intent over a 10-year period (1992 to 2002).¹¹⁸ Liver-only recurrence after RFA was four times the rate after resection (44% vs. 11% of patients), and RFA alone or in combination with resection did not provide survival rates comparable to those with resection alone. Other studies have corroborated this trend.¹¹⁹ Nonetheless, RFA remains a common procedure that can be performed by a percutaneous, minimally invasive laparoscopic, or open approach.^120,121 It also has been used successfully to ablate small HCCs as a bridge to liver transplantation.¹²² Recently, results were reported for the first randomized clinical trial involving RFA treatment for HCC in 291 Chinese patients with three or fewer HCC tumors ranging in size from 3 to 7.5 cm.¹²³ Patients were randomly assigned to treatment arms of RFA alone (n = 100), transarterial chemoembolization (TACE) alone (n = 95), or combined TACE plus RFA (n = 96). At a median follow-up of 28.5 months, median survival was 22 months in the RFA group, 24 months in the TACE group, and 37 months in the TACE plus RFA group. Patients treated with TACE plus RFA had significantly better overall survival than those treated with TACE alone (P < .001) or RFA alone (P < .001).

Ethanol Ablation, Cryosurgery, and Microwave Ablation

Percutaneous ethanol injection has been shown to be a safe and effective treatment for small HCCs.¹⁰⁷ The ethanol usually is delivered by percutaneous injection under ultrasound or CT guidance. Percutaneous ethanol injection also is used to treat small HCC tumors as a bridge to liver transplantation in some centers to avoid patient dropout.⁶¹ Although cryosurgery was used in the late 1980s and 1990s for ablation of liver tumors, many have abandoned this approach in favor of RFA because of the latter’s fewer side effects and ease of use. Microwave ablation is a thermal ablative technique used in the management of unresectable liver tumors to produce a coagulation necrosis. In a multicenter phase II U.S. trial using a 915-MHz microwave generator, 87 patients underwent 94 ablation procedures for 224 hepatic tumors.¹²⁴ Forty-five percent of the procedures were performed using an open approach, 7% laparoscopically, and 48% percutaneously. The average tumor size was 3.6 cm (range, 0.5 to 9.0 cm). At a mean follow-up of 19 months, 47% of the patients were alive with no evidence of disease. Local recurrence at the ablation site occurred in 2.7% of tumors, and regional recurrence occurred in 43% of patients. There were no procedure-related deaths. Further studies are required to define the role of this technology in relation to the other ablation options available.

Chemoembolization and Hepatic Artery Pump Chemoperfusion

Chemoembolization is the process of injecting chemotherapeutic drugs combined with embolization particles into the hepatic artery that supplies the liver tumor using a percutaneous, transfemoral approach. It is most commonly used for treatment of unresectable HCC. Three randomized trials and a meta-analysis have shown a survival benefit with chemoembolization.^{125,126,127,128} In a study by Lo and colleagues, 80 Asian patients were randomly assigned to receive either chemoembolization with cisplatin in lipiodol or symptomatic treatment only.¹²⁵ Chemoembolization resulted in a marked tumor response, and the actuarial survival was significantly better in the chemoembolization group (1- and 3-year survival of 57% and 26%, respectively) than in the control group (1- and 3-year survival of 32% and 3%, respectively). In another randomized trial, a Barcelona group compared chemoembolization with doxorubicin versus supportive care and showed that chemoembolization significantly improved survival.¹²⁶ Finally, in a large prospective cohort study of 8510 patients with unresectable HCC in Japan who received transcatheter arterial lipiodol chemoembolization, the 5-year survival rate was 26% and median survival time was 34 months.¹²⁷ The TACE-related mortality rate after the initial therapy was 0.5%. Complications of TACE include liver dysfunction or liver failure, hepatic abscess, and hepatic artery thrombosis. Multiple studies also have shown promising results for chemoembolization with drug-eluting beads in treatment of HCC.¹²⁹

In the 1990s, hepatic artery pump chemoperfusion with floxuridine for colorectal cancer metastases to the liver was used both for treatment of inoperable disease and in the adjuvant setting.¹³⁰ However, in the modern era of improved chemotherapeutic options, this treatment modality is seldom used outside of a clinical trial.

Yttrium-90 Microspheres

Selective internal radioembolization or transarterial radioembolization (TARE) is a promising new treatment modality for patients with inoperable primary or metastatic liver tumors. The treatment is a minimally invasive transcatheter therapy in which radioactive microspheres are infused into the hepatic arteries via a transfemoral percutaneous approach. The yttrium-90 microspheres are directly injected into the hepatic artery branches that supply the tumor. Once infused, the microspheres deliver doses of high-energy, low-penetration radiation selectively to the tumor. The main indications are inoperable HCC¹³¹ and colorectal cancer hepatic metastases for which systemic chemotherapy has failed.^132,133 In a recent study involving 137 patients with unresectable chemorefractory liver metastases treated with radioembolization, there was a response rate of 42.8% (2.1% complete response, 40.7% partial response) according to World Health Organization criteria.¹³³ One-year survival rate was 47.8%, and 2-year survival rate was 30.9%. Median survival was 457 days for patients with colorectal tumor metastases, 776 days for those with neuroendocrine tumor metastases, and 207 days for those with noncolorectal, nonneuroendocrine tumor metastases. The two products available in the United States are SIR-Spheres (Sirtex, Sydney, Australia) and TheraSphere (Nordian, Ottawa, Canada).

Stereotactic Radiosurgery and Intensity-Modulated Radiation Therapy

Although stereotactic radiosurgery (with CyberKnife and other systems) is in widespread use for brain and spinal tumors, body application to HCC or metastatic liver tumors has only recently occurred. In a phase I study, 31 patients with unresectable HCCs and 10 with unresectable cholangiocarcinomas completed a six-fraction course of stereotactic body radiotherapy.¹³⁴ The treatment was well tolerated, and median survival was 11.7 and 15.0 months for the two groups, respectively. A similar safety profile was observed in a study in the Netherlands.¹³⁵ Further clinical trials are required to define the future role of stereotactic radiosurgery in treatment of HCC and metastatic tumors. Intensity-modulated radiation therapy (IMRT) is another technologic advancement that facilitates the targeted delivery of external-beam radiation. Early clinical data suggested favorable outcomes with IMRT for the treatment of patients with unresectable HCC, and ongoing trials are further examining the role of IMRT for these locally advanced tumors.

Downstaging

In more advanced-stage patients not eligible for MELD exception points, hepatic-directed therapy including TACE and tumor ablation with radiofrequency, microwave, and ethanol ablation have been found to be effective in shrinking tumors to meet Milan criteria (downstaging). Multiple centers have used downstaging to allow for OLT in patients whose tumors responded and shrank to meet eligibility criteria.^136,137

Systemic Chemotherapy

Chemotherapy has not demonstrated great efficacy in patients with HCC, especially in patients with significant cirrhosis. For treatment of HCC, the multikinase inhibitor sorafenib has shown some efficacy in a phase III randomized international multicenter trial. The SHARP trial (Sorafenib HCC Assessment Randomized Protocol) enrolled 602 patients with Child’s class A cirrhosis and inoperable HCC. At interim analysis, the trial was discontinued because a survival benefit was found in the treatment group. The median overall survival for patients receiving sorafenib was 10.7 months versus 7.9 months for patients in the control arm. Based on these findings, sorafenib received accelerated Food and Drug Administration approval for the treatment of advanced unresectable HCC.¹³⁸ Future studies will likely examine the role of other molecularly targeted agents and combinations of sorafenib with other treatment modalities.

Nomenclature

Due to the confusion in language with regard to anatomic descriptions of hepatic resections, a common nomenclature was introduced at the International Hepato-Pancreato-­Biliary Association meeting in Brisbane, Australia, in 2000 (Table 31-8).^139,140 The goal was to provide universal terminology for liver anatomy and hepatic resections, because there was much overlap among the designations for hepatic lobes, sections, sectors, and segments used by surgeons worldwide (Fig. 31-21). The most common or prevailing anatomic pattern was used as the basis for naming liver anatomy, and the surgical procedure nomenclature adopted for hepatic resections was based on the assigned anatomic terminology.¹⁴¹ Adoption of a common language should enable hepatic surgeons to better understand and interpret liver surgery publications from different continents and disseminate their knowledge to the next generation of hepatobiliary surgeons. Nonetheless, even today, the literature is full of both old and new liver resection terminology, so the surgeon in training must be familiar with all the various classifications.

Techniques and Devices for Dividing the Hepatic Parenchyma

Hepatic resection surgery has evolved over the past 50 years. A better understanding of liver anatomy and physiology, coupled with improved anesthesia techniques and widespread use of ­intraoperative ultrasound, has led to virtually “bloodless” liver surgery in the modern era (the year 2000 to the present). Innovations in technology have expanded the list of liver parenchymal transection devices^142,143,144 and hemostatic agents (Table 31-9). Use of each device or agent has a learning curve, and undoubtedly every experienced hepatic surgeon has his or her personal preferences.

One major trend has been the application of vascular stapling devices for division of the hepatic and portal veins.^145,146,147 Based on early reports of successful stapling of extrahepatic vessels, stapling devices are now being used in the parenchymal transection phase, which remains a source of potential blood loss due to back bleeding from the middle hepatic vein.^148,149 One advantage of the stapling technique is the speed with which the transection can be performed, which minimizes surface bleeding and period of ischemia for the remnant liver. However, a major disadvantage of the stapling technique is the cost of multiple stapler cartridges. This is balanced by the decreased expenses reported with avoidance of ICU admission and blood transfusion, as well as shortened operating room time. Another consideration in the use of staplers for parenchymal transection is the potential for bile leaks. However, in a large series of 101 consecutive right hemihepatectomies performed using the stapling technique, there was only one reported bile leak (1%), which sealed after ERCP.¹⁴⁹

Steps in Commonly Performed Hepatic Resections

A fundamental understanding of hepatic anatomy is vital for any surgeon with the desire to perform hepatobiliary surgery. Each hepatic resection surgery can be broken down into a series of orderly steps. The key to being a proficient hepatic surgeon is not to operate swiftly but rather to accomplish the operation by completing the steps in an orchestrated fashion. Mastery of the operative steps coupled with knowledge of liver anatomy and the common anatomic variants provides the foundation for safe hepatic surgery. There are many different techniques and sequences for accomplishing each of the anatomic (and nonanatomic) hepatic operations. The authors present their preferred approach in a stepwise fashion for right hepatic lobectomy (right hemihepatectomy), left hepatic lobectomy (left hemihepatectomy), and left lateral segmentectomy (left lateral sectionectomy). Provision of a detailed approach for every type of liver resection is beyond the scope of this chapter, and readers are referred to several excellent descriptions.¹⁵⁰

Steps Common to All Open Major Hepatic Resections

1. Make the skin incision—right subcostal with or without a partial or complete left subcostal extension across the midline, depending on the patient’s habitus and liver/tumor anatomy.

2. Open and explore the abdomen, and place a fixed table retractor (e.g., Thompson or Bookwalter).

3. Examine the liver with bimanual palpation. Perform liver ultrasound, and confirm the operation to be performed.

4. Take down the round and falciform ligaments, and expose the anterior surface of the hepatic veins.

5. For a left hepatectomy, divide the left triangular ligament; for a right hepatectomy, mobilize the right lobe from the right coronary and triangular ligaments.

6. Open the gastrohepatic ligament, palpate the porta hepatis, and assess for accessory or replaced hepatic arteries.

7. Perform a cholecystectomy; leave the gallbladder with the cystic duct intact if the gallbladder is involved by the tumor.

Right Hepatic Lobectomy (Right Hepatectomy or ­Hemihepatectomy)

1. Mobilize the liver from the anterior aspect of the IVC in “piggyback” fashion; ligate the short hepatic veins up to the right hepatic vein (RHV).

2. Perform a right hilar dissection—gently lower the hilar plate, then doubly ligate and divide the right hepatic artery (RHA), superior to the right side of the common bile duct.

3. Doubly ligate and divide a replaced or accessory RHA if present.

4. Expose the portal vein, identifying its right and left branches. There is a small lateral portal vein branch off the right portal vein (RPV) to the caudate lobe that should be controlled and ligated to allow the exposure of additional length on the RPV. Divide the RPV either with a vascular stapler or between vascular clamps.

5. Dissect the avascular tissue along the suprahepatic vena cava between the right and middle hepatic veins. Pass a silastic tube of a Jackson-Pratt drain through this gap.

6. Notch or divide the caudate process crossing to the right hepatic lobe, and bring the drain up and through this notch.

7. Hang the liver over the drain by pulling up as you divide through the liver parenchyma.

8. Repeat ultrasound and confirm the transection plane, staying just to the right of the middle hepatic vein (MHV) unless the tumor extends over it.

9. Cauterize approximately 1 cm into the liver parenchyma, then switch to a hydro-jet dissection device in combination with Bovie electrocautery and suture ligation.

10. Continue parenchymal division until the RHV is encountered. During this division, identification, control, ligation, and transection of the right hepatic duct (RHD) are obtained late in the parenchymal transection process.

11. Divide the RHV between vascular clamps and suture ligate the RHV.

12. Examine the transected liver edge for bleeding; place a figure-of-eight ligating vascular suture if bleeding is encountered.

13. Ensure hemostasis of the transected liver edge with an argon beam coagulator and suture ligation.

14. Inspect the transection surface for bile leaks. These should be clipped or suture ligated. Applying a dilute solution of hydrogen peroxide can facilitate the visualization of bile leaks.

15. Inspect the IVC and right retroperitoneal space for ­hemostasis.

16. Perform completion ultrasound to confirm left portal vein (LPV) inflow and outflow in the remaining hepatic veins.

17. Fix the proximal falciform ligament back to the diaphragm side with figure-of-eight sutures.

18. Apply tissue sealant to the cut surface of the liver, and place a Jackson-Pratt drain in the right subphrenic space and close the abdomen (Fig. 31-22).

Comments

Although some liver surgeons advocate a one-step division of the entire intrahepatic Glissonian pedicle as described by Launois and Jamieson,¹⁵¹ it is the authors’ preference to divide the RHA, RHD, and RPV in an extrahepatic ­fashion. As for the transection plane, the key is to perform ­accurate ultrasound visualization and mapping of the MHV and to stay just to the right of it. Weaving in and out or bisecting the MHV can leading to torrential back bleeding. Also, for bulky right lobe tumors adherent to the diaphragm or retroperitoneum, an anterior approach with division of the parenchyma can be performed before right lobe mobilization.^152,153

Left Hepatic Lobectomy (Left Hepatectomy or ­Hemihepatectomy)

1. Widely open the gastrohepatic ligament flush with the undersurface of the left lateral section and the caudate lobe.

2. Doubly ligate and divide a replaced or accessory left hepatic artery (LHA) if present.

3. Clamp the round ligament (ligament teres) and pull it anteriorly as a handle to expose the left hilum.

4. Divide any existing parenchymal bridge between segments III and IVB.

5. Dissect the left hilum at the base of the umbilical fissure and lower the hilar plate anterior to the left portal pedicle.

6. Incise the peritoneum overlying the hilum from the left side, and doubly ligate the LHA (after test clamping and confirming a palpable pulse in the RHA).

7. Dissect the portal vein at the base of the umbilical fissure (it will take a nearly 90° bend from the transverse to the umbilical portion).

8. Expose the portal vein, identifying the right and left branches. Control the small portal vein branch off the LPV to the caudate lobe to allow the exposure of additional length. Divide the LPV either with a vascular stapler or between vascular clamps.

9. Ligate and divide the ligamentum venosum caudally.

10. Identify the long extrahepatic course of the left hepatic duct (LHD) behind the portal vein. Ligate and divide the LHD at the umbilical fissure.

11. Fold the left lateral segment up and back to the right, exposing the window at the base of the left hepatic vein (LHV) as it enters the IVC. This is facilitated by dividing any loose areolar tissue overlying the ligamentum venosum, which is divided proximally.

12. Pass a large, blunt right-angle clamp in the window between the RHV and the MHV, and hug the back of the MHV, aiming for the deep edge of the LHV. Do not force it or perforate the IVC or MHV.

13. Pass the silastic tube of a Jackson-Pratt drain through this window.

14. Notch or divide the caudate process crossing to the left hepatic lobe and bring the drain up and through this notch.

15. Hang the liver over the drain by pulling up as you divide through the liver parenchyma.

16. Repeat ultrasound and confirm the transection plane on the anterior surface, staying close to the demarcated line. Do not bisect the MHV as it passes tangentially from the left to the right lobe.

17. Cauterize down approximately 1 cm in the liver parenchyma, then switch to a hydro-jet dissection device in combination with Bovie electrocautery and suture ligation.

18. Continue parenchymal division until the left/middle hepatic veins are encountered.

19. Divide the LHV and MHV between vascular clamps and suture the ligate the LHV/MHV.

20. Check the transected edge of the liver for surgical bleeding; ensure hemostasis of the transected edge with an argon beam coagulator and suture ligation.

21. Inspect the transection surface for bile leaks. These should be clipped or suture ligated. Apply dilute solution of hydrogen peroxide to facilitate the visualization of bile leaks.

22. Perform completion ultrasound to confirm RPV inflow and RHV outflow.

23. Apply tissue sealant to the transected surface of the liver. Place a Jackson-Pratt drain in the left subphrenic space and close the abdomen (Fig. 31-23).

Comments

Because the right posterior duct arises from the left hepatic duct (LHD) in approximately 20% of cases (see Fig. 31-9) and the right anterior duct comes off the LHD in approximately 5% of cases,⁶ it is vital to divide the LHD at the base of the umbilical fissure and not more centrally in the hilum as it bifurcates. If the LHD were divided as it appears to bifurcate from the right hepatic duct, then approximately 20% to 25% of the time, either the right posterior or right anterior duct would be transected. After the LHD is divided as described earlier (Step 17), the liver parenchyma is scored and divided horizontally approximately 1 cm above the left hilum; the surgeon thus assumes that an aberrant right anterior or posterior duct is coming off the LHD in the hilum and preserves it. Then as the parenchymal transection reaches the left side of the gallbladder fossa, the transection plane turns vertical to run parallel to Cantlie’s line (or the left edge of the gallbladder bed). The left lobe of the liver will be well demarcated at this point (after the vascular inflow has been divided), which guides the transection plane on the anterior surface. In general, the transection plane should be close to the demarcation line to minimize the amount of devascularized liver remaining. When dividing the LHV and MHV, the surgeon should keep in mind that they have a common trunk approximately 90% of the time. If it is not easy to open the window deep to the MHV and LHV, then division of the MHV and LHV can be accomplished after the parenchymal transection.

Left Lateral Segmentectomy (Left Lateral Sectionectomy)

1. Widely open the gastrohepatic ligament flush with the undersurface of the left lateral section and the caudate lobe.

2. Doubly ligate and divide a replaced or accessory LHA if present.

3. Clamp the round ligament and pull it anteriorly as a handle to expose the left hilum.

4. Divide any existing parenchymal bridge between segments III and IVB.

5. Carry the dissection down from the end of the round ligament, and the segment III pedicle will be encountered.

6. Incise the peritoneal reflection on the left side of the round ligament as it inserts into the umbilical fissure. This will facilitate encircling the segment III and II pedicles, which can be divided separately. When encircling the segment II pedicle, take care to avoid injury to the caudate inflow vessels coming off the LPV.

7. Divide the liver parenchyma, staying flush on the left side of the falciform ligament using Bovie electrocautery.

8. Divide the LHV as the parenchymal transection is ­complete.

9. A Pringle maneuver usually is not required for a left lateral sectionectomy because complete devascularization occurs before transection and little back bleeding is encountered.

Comments

If the segment III and II LHA branches are large, they can be individually ligated in the left hilum before the pedicles (with portal vein and hepatic duct branches) are taken. If the tumor is more peripheral in the left lateral segment, then the segment III and II pedicles can be divided with a vascular stapler inside the liver during the parenchymal transection.

Pringle and Ischemic Preconditioning

Pringle described clamping of the portal triad a century ago in the landmark paper “Notes on the Arrest of Hepatic Hemorrhage Due to Trauma.”⁴ Although the Pringle maneuver was initially described for controlling bleeding due to traumatic liver injury, it is commonly used during elective hepatic resections.^154,155 The goal is to minimize blood loss and hypotension, which add significant morbidity to the operation. Furthermore, intraoperative blood transfusion has been shown to be an independent risk factor for increased postoperative infection as well as worse patient survival in some studies. Therefore, all efforts should be made to minimize blood loss during hepatic resection.

Although the liver has been shown to tolerate up to 1 hour of warm ischemia, some technical variations of the Pringle maneuver include intermittent vascular occlusion with cycles of approximately 15 minutes on and 5 minutes off. Experimental and clinical studies have demonstrated the efficacy of intermittent vascular occlusion in decreasing ischemia/reperfusion injury compared with continuous vascular occlusion, with less elevation of postoperative liver enzyme levels.¹⁵⁶ Another variation is selective hemihepatic vascular occlusion, which can reduce the severity of visceral congestion and total liver ischemia. In one prospective trial of total versus selective portal triad clamping, both techniques of inflow clamping were found to be equally effective for patients with normal livers, but greater liver damage was observed with total inflow occlusion in patients with cirrhotic livers.¹⁵⁷

In an attempt to decrease the ischemic damage associated with inflow occlusion, some hepatic surgeons have advocated the use of ischemic preconditioning.¹⁵⁸ Ischemic preconditioning refers to the brief interruption of blood flow to an organ, followed by a short reperfusion period, and then a more prolonged period of ischemia. In a randomized clinical trial involving 100 patients undergoing major hepatic resection, Clavien and colleagues reported significantly less liver injury in the group who received ischemic preconditioning with a 10-minute clamp, a 10-minute reperfusion, and then a 30-minute clamp than in those who received a 30-minute clamp alone.¹⁵⁹ Patients with steatosis also were especially protected by ischemic preconditioning, and the mechanism was shown to be related in part to preservation of the adenosine triphosphate content of liver tissue.

Preoperative Portal Vein Embolization

The observation that tumor thrombosis of a major portal vein branch induced ipsilateral lobar atrophy and contralateral lobe hypertrophy led to the concept of intentional preoperative portal vein embolization (PVE) to induce compensatory hypertrophy of the remnant liver. This procedure was first described in the 1980s and is accomplished via a percutaneous, transhepatic route.^160,161 Numerous studies have subsequently confirmed that PVE is effective in inducing hypertrophy of nonembolized hepatic segments.^67,162 PVE usually is performed in the setting of a planned right trisectionectomy or extended left hepatectomy (also referred to as a left trisectionectomy; resection of Couinaud’s segments II, III, IV, V, and VIII of the liver) or extended hepatic lobectomy when it is thought that the patient’s remnant liver will be too small to support liver function. The future liver remnant volume (e.g., the volume of segments II, III, and I) in a patient undergoing a planned right trisectionectomy can be directly measured by helical CT and then divided by the total estimated liver volume to calculate the percentage of the future liver remnant. If the future liver remnant is thought to be too small, then PVE should be considered to increase the size of the future liver remnant.¹⁶³ In general, surgery is planned approximately 4 weeks after PVE to allow adequate time for hypertrophy.

There is no universal agreement on what constitutes a future liver remnant adequate to avoid postoperative liver failure. It is thought that 25% to 30% of the total liver volume is adequate in patients with a normal liver.¹⁶⁴ Vauthey and associates reported that major postoperative complications were increased when the estimated future liver remnant was <25%.¹⁶⁵ Farges and colleagues conducted a prospective study to assess the benefits of PVE before right hepatectomy. They demonstrated that PVE had no beneficial effect on the postoperative course in patients with normal livers but significantly reduced postoperative complications in patients with chronic liver diseases.¹⁶⁶ A larger remnant may be necessary even in patients with normal livers when a complex hepatectomy is planned or when the background liver is steatotic.¹⁶⁷ This is especially relevant with the increased incidence of fatty liver disease. A larger remnant may also be needed when patients have received preoperative chemotherapy. Some have suggested that 40% of the total hepatic volume should remain to minimize postoperative complications in patients who have underlying liver disease or who have received preoperative chemotherapy for colorectal cancer metastases.^168,169 In a recent study encompassing 112 patients who underwent PVE, major complications, hepatic insufficiency, length of hospital stay, and 90-day mortality rate were significantly greater in patients with a standardized future liver remnant of ≤20% or a degree of hypertrophy of <5% than in patients with higher values.¹⁷⁰ In another study, the authors performed PVE during neoadjuvant chemotherapy for colorectal cancer metastases. After a median wait of 30 days after PVE, patients receiving neoadjuvant chemotherapy showed median liver growth of 22% in the contralateral (nonembolized) lobe compared with 26% for those not receiving chemotherapy (not a statistically significant difference), which indicated that liver growth occurs after PVE even when cytotoxic chemotherapy is administered.¹⁷¹ PVE-related complications occur at a relatively low rate and include bleeding, hemobilia, liver abscess, incomplete embolization, and small bowel obstruction. To augment the ability to increase liver function reserve in patients who have undergone PVE, some groups have added ipsilateral hepatic artery embolization and ipsilateral hepatic vein embolization.¹⁷²

Staged Hepatectomy and Repeat Hepatic Resection for Recurrent Liver Cancer

A two-stage hepatectomy is a sequential resection strategy to remove all metastatic liver tumors when it is impossible to resect all disease in a single operative procedure. The first-stage hepatectomy usually consists of clearance of the left hemiliver by nonanatomic resection, followed by right portal vein ligation or embolization to induce left lobe hypertrophy.^173,174 This is followed by a second-stage major right hepatectomy or extended right hepatectomy to resect the right liver metastases. This approach is most commonly used in cases of initially unresectable colorectal hepatic metastases and has yielded very good results.¹⁷⁴ Another possibility is to potentiate the effect of PVE on increasing future liver remnant by performing an in situ liver transection along the future line of resection leaving the arterial and hepatic vein branches intact.¹⁷⁵

The majority of patients undergoing hepatic resection for colorectal cancer metastases experience a recurrence. For those with limited disease recurrence confined to the liver, repeat hepatectomy is a reasonable option and can be performed with low morbidity and mortality in experienced hands.¹⁷⁶ In one study, 126 patients who underwent a second liver resection for colorectal cancer metastases had 1-, 3-, and 5-year survival rates of 86%, 51%, and 34%, respectively. By multivariate analysis, the presence of more than one lesion and a tumor size of >5 cm were independent prognostic indicators of reduced survival.¹⁷⁷ In another study, 40 patients underwent a second hepatectomy for liver metastases from colorectal cancer and experienced a survival benefit similar to that from the first hepatectomy; however, the results suggested that this approach should be limited to those patients who do not have extrahepatic disease and for whom >1 year has elapsed since the first operation.¹⁷⁸ A meta-analysis of 21 studies examining clinical outcomes after first and second liver resections for colorectal cancer metastases showed that repeat hepatectomy was safe and provided a survival benefit equal to that from the first liver resection.¹⁷⁹

Repeat hepatectomy also has been performed in patients with HCC. Nakajima and colleagues reported on follow-up of 94 patients who underwent curative liver resection for HCC from 1991 to 1996.¹⁸⁰ Of these, 57 patients had isolated recurrent disease in the liver. Twelve of these 57 patients underwent repeat hepatic resection, whereas the other 45 patients received ablation therapy. The overall survival rate in those undergoing a second hepatectomy was 90% at 2 years; however, the disease-free survival rate was only 31% at 2 years, significantly lower than the 62% rate after initial hepatectomy. Likewise, in another group of 84 patients who underwent second hepatectomy for recurrent HCC, the overall 5-year survival rate was 50%, but the recurrence-free survival rate was only 10%.¹⁸¹ In a report of 67 patients undergoing a second resection for HCC, overall 1-, 3-, and 5-year survival rates were 93%, 70%, and 56%, respectively.¹⁸² Multivariate analysis showed that absence of portal invasion at the second resection, single HCC at primary hepatectomy, and disease-free interval of ≥1 year after primary hepatectomy were independent prognostic factors after the second resection.

Cherqui and colleagues first reported in 2000 that laparoscopic hepatic surgery was feasible.¹⁸³ Since this initial report, laparoscopic liver surgery has expanded from the simple unroofing of hepatic cysts to resection of peripheral benign lesions to formal anatomic lobectomies for malignancy and laparoscopic hepatectomy for living donor liver transplantation. While minimally invasive approaches have been widely adopted in other areas of abdominal surgery, there was initial apprehension regarding laparoscopic liver resection (LLR), hampering its widespread adoption.¹⁸⁴ First, the elementary maneuvers of open hepatic surgery, such as manual palpation, organ mobilization, vascular control, and parenchymal transection, were thought to be difficult to reproduce laparoscopically. Second, there was concern that hemorrhage may be more difficult to control laparoscopically and that the risk of gas embolism may be increased by the use of pneumoperitoneum. Third, there was apprehension concerning the possibility of oncologic inadequacy and tumor seeding, but data regarding long-term oncologic outcomes were lacking at the time.

Because of the increased technical demands in LLR, stringent criteria based on surgeon experience and lesion size and location must be used. Surgeons should have an advanced understanding of liver anatomy, extensive experience in open liver surgery, and the technical skills to control major vascular and biliary structures laparoscopically before embarking on LLR. Familiarity with laparoscopic ultrasonography is needed to help confirm the number and size of lesions, demarcate transection planes, and define relationships to major intrahepatic and extrahepatic structures intraoperatively. Smaller, more peripheral lesions, particularly those located in the anterolateral segments (segments II to VI) are most amenable to LLR. Several centers have reported large series consisting of laparoscopic resections of the left lateral and anterior hepatic segments. Laparoscopic major hepatectomy, such as lobectomies, trisegmentectomies, and the resection of difficult posterior segments, has been described and can be performed by expert centers, but should not be considered standard practice at the current time.

As in open hepatic resections, various different technical approaches for performing major laparoscopic liver resection have been described. Hepatic resection can be achieved using either electrosurgical devices to transect the parenchyma, reserving staplers for larger vascular and biliary structures, or staplers alone to divide parenchyma and major structures without the aid of portal triad clamping. As in open liver surgery, no single method of parenchymal transection has been shown to be superior.

Three general techniques have been used for laparoscopic hepatectomy. The pure laparoscopic method is suitable for experienced surgeons to achieve better cosmetic outcomes, whereas the hand-assisted method has been associated with a reduced conversion rate to open procedures. The addition of the assisting hand allows for tactile feedback while palpating the liver and may help in abdominal exploration, parenchymal transection, mobilization of the liver, and providing gentle retraction. Additionally, in cases when significant bleeding is encountered, hand compression allows for easier hemostasis. The specimen is then removed from the hand-port incision. Hand assistance allows the laparoscopic approach to be extended to lesions in posterosuperior segments. Finally, the laparoscopic-assisted method, or the hybrid procedure, is used by surgeons for difficult or unique resections such as resection in cirrhotic livers, laparoscopic resection of tumors in unfavorable locations, and living donor hepatectomies.¹⁸⁵ With the hybrid procedure, the liver is first mobilized laparoscopically, and the hilar dissection and parenchymal transection are then carried out under direct vision through an 8- to 12-cm midline or subcostal incision, through which the specimen is removed.

Results with laparoscopic liver resections have been excellent. Advantages of laparoscopic liver resection include reduced operative blood loss and need for portal triad clamping, decreased postoperative pain and narcotic requirements, faster return of bowel function, and shorter length of hospital stay.¹⁸⁶ The actual occurrence of gas embolism in clinical practice has proven to be extremely low. Carbon dioxide pneumoperitoneum minimizes the risk of gas embolism as compared to air, and lowered pneumoperitoneum pressures further reduce its incidence. The occurrence of gas embolism has been also related to argon beam coagulation, which increases intra-abdominal pressure, leading to an increased risk of gas embolism.

Comparative studies between open resection and LLR for malignant lesions have revealed no difference in overall or disease-free survival after short- and medium-term follow-up, and no difference in the width of resection margins. Some series have even reported fewer positive resection margins with LLR compared to open resection for malignant lesions.¹⁸⁷ No port site recurrences or tumor seeding has been reported to date after LLR. It has been proposed that LLR may allow for more timely start of adjuvant chemotherapy because of a quicker postoperative recovery and fewer wound-related complications.

In particular to LLR for HCC, hypothesized advantages include avoidance of collateral vessel ligation, resulting in reduced portal hypertension, decreased need for intravenous fluids, and improved reabsorption of ascites. The reduced occurrence of postoperative ascites and hepatic insufficiency in cirrhotic patients has led to decreased morbidity in these high-risk patients operated through a laparoscopic approach. The persisting underlying liver disease in these patients, however, dictates that HCC will recur in 40% to 90% of this population after resection, necessitating salvage liver transplantation.¹⁸⁸ Laurent and colleagues¹⁸⁹ reported that prior LLR for HCC compared to open resection facilitated subsequent salvage liver transplantation with decreased morbidity. In this study, patients with previous LLR had shorter hepatectomy and total operative times, less blood loss, and reduced need for blood transfusions after liver transplantation, possibly due to less arduous adhesiolysis.

Zhou and colleagues¹⁹⁰ published a meta-analysis of 10 nonrandomized controlled studies to compare surgical and oncologic outcomes following LLR or open resection for HCC. Compared with perioperative results of open liver resection, reports of LLR demonstrate advantageous outcomes related to blood loss, transfusion requirements, postoperative morbidity, and hospital length of stay. There were significantly lower rates of cirrhotic decompensation and ascites, as well as a trend toward lower rates of postoperative liver failure following LLR. There were no differences in operative time or postoperative mortality. With regard to specific oncologic outcomes, there were no differences in pathologic resection margin or in 3- and 5-year overall and disease-free survival. There were no reported cases of port site recurrences or peritoneal dissemination. This meta-analysis suggests that LLR is comparable, and in some parameters superior, to open resection for HCC.

Regarding LLR for metastatic colorectal cancer, multiple retrospective series have reported the safety, feasibility, and oncologic integrity of the laparoscopic approach. Castaing and colleagues¹⁹¹ reported a matched prospective comparison in patients undergoing resection of colorectal cancer liver metastases via laparoscopic and open approaches. There were no differences in resection margins, whereas the incidence of positive margins was greater in the open group. There were no differences in 1- or 3-year overall, recurrence-free, and disease-free survival, indicating that equivalent oncologic outcomes can be achieved with LLR in selected patients.

Initial experience with laparoscopic living-donor hepatectomy for transplantation was with left lateral segmentectomy during liver allograft procurement for pediatric transplants. With continued advances in laparoscopic liver surgery, this approach has been applied to adult-to-adult donor right hepatectomy using the hybrid procedure. Complication rates are comparable to those reported for open living-donor hepatectomies.

Laparoscopic liver resection can now be performed safely by experienced surgeons in selected patients. Benefits of the laparoscopic approach include less operative blood loss, reduced postoperative pain and narcotic requirements, a shorter length of hospital stay, and comparable postoperative morbidity and mortality rates to open liver resection. Although small peripheral lesions in anterolateral segments are most amenable to laparoscopic resection, surgeons with extensive experience can embark on major hepatic resections using the laparoscopic approach. Comparative studies have identified similar oncologic outcomes for laparoscopic and open resections for malignant lesions such as HCC and colorectal liver metastases.