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Surgery_Schwartz. 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 defin-itive treatment is orthotopic liver transplantation.5 Acute variceal bleeding should be managed with aggres-sive resuscitation and prompt endoscopic diagnosis with hemorrhage control. The transjugular intrahepatic por-tosystemic shunt procedure can be considered for cases refractory to medical treatment.6 Common benign lesions of the liver include cysts, hem-angiomas, focal nodular hyperplasia, and hepatocellular adenomas. In most instances, these lesions can be reliably diagnosed by their characteristic features on imaging.7 Many options exist for the treatment of hepatocellular car-cinomas, and these cases are best managed by a


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Surgery_Schwartz. these lesions can be reliably diagnosed by their characteristic features on imaging.7 Many options exist for the treatment of hepatocellular car-cinomas, and these cases are best managed by a multidis-ciplinary liver transplant team.8 Surgical resection is the treatment of choice for hilar chol-angiocarcinoma. Under a protocol with strict eligibility criteria, patients with unresectable tumors can be con-sidered for liver transplantation following neoadjuvant chemoradiation, with survival rates that compare favorably with the rates for resection.9 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.10 Laparoscopic liver resections can be performed safely by experienced surgeons in selected patients and have been shown to produce short-term patient benefits with com-parable long-term oncologic results compared to open hepatic


Surgery_Schwartz

Surgery_Schwartz. can be performed safely by experienced surgeons in selected patients and have been shown to produce short-term patient benefits with com-parable long-term oncologic results compared to open hepatic resections.Brunicardi_Ch31_p1345-p1392.indd 134620/02/19 2:36 PM 1347LIVERCHAPTER 31Figure 31-1. Hepatic ligaments suspending the liver to the diaphragm and anterior abdominal wall.Liver in situForamen ofWinslowGastrohepaticligamentOpen hepato-duodenal ligamentFigure 31-2. In situ liver hilar anatomy with hepatoduodenal and gastrohepatic ligaments. Foramen of Winslow is depicted.Right lobeLeft lobeRight lobeLeft lobeVIIIIVaIVbIIIIIVVIIVIIVCCaudate lobeIIIIVVIIVIIIIVbFigure 31-3. Couinaud’s liver segments (I through VIII) num-bered in a clockwise manner. The left lobe includes segments II to IV, the right lobe includes segments V to VIII, and the caudate lobe is segment I. IVC = inferior vena cava.the Spiegel lobe, the paracaval portion, and the caudate process.7 The falciform ligament


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Surgery_Schwartz. IV, the right lobe includes segments V to VIII, and the caudate lobe is segment I. IVC = inferior vena cava.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 direc-tion 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


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Surgery_Schwartz. 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 cepha-lad 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 DiaphragmRight triangularligamentLeft triangularligamentFalciformligamentRoundligamentcaudate lobe, rather than segment I. The right lobe is comprised of segments V, VI, VII, and VIII, with segments V and VIII mak-ing up the right anterior lobe and segments VI and VII making up the


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Surgery_Schwartz. lobe, rather than segment I. The right lobe is comprised of segments V, VI, VII, and VIII, with segments V and VIII mak-ing up the right anterior lobe and segments VI and VII making up the right posterior lobe.Brunicardi_Ch31_p1345-p1392.indd 134720/02/19 2:36 PM 1348SPECIFIC CONSIDERATIONSPART IIAdditional functional anatomy was highlighted by Bis-muth 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 ArteryThe liver has a dual blood supply consisting of the hepatic artery and the portal vein. The hepatic artery delivers


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Surgery_Schwartz. vein and separates the left posterior and left anterior sectors.Hepatic ArteryThe 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


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Surgery_Schwartz. 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 in Fig. 31-5. Approximately 10% to 15% of the time there is a replaced or accessory right hepatic artery arising from the supe-rior mesenteric artery (SMA). When there is a replacement or accessory right hepatic artery, it travels posterior to the por-tal 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 reso-nance 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


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Surgery_Schwartz. 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 replace-ment (or accessory) left hepatic artery coming off of the left gastric artery and running obliquely in the gastrohepatic liga-ment anterior to the caudate lobe before entering the hilar plate at the base of the umbilical fissure. Other less common variants (approximately 1–2% 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 com-ing 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


Surgery_Schwartz

Surgery_Schwartz. 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 VeinThe 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 conflu-ence (Fig. 31-6). The main portal vein traverses the porta hepa-tis 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


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Surgery_Schwartz. 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 enter-ing the liver parenchyma (Fig. 31-7). The left portal vein then divides to give off the segment II and III branches to the left lat-eral segment, as well as the segment IV branches that supply the left medial segment. The left portal vein also provides the domi-nant 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 35% of individuals have aberrant por-tal venous anatomy, with portal vein trifurcation or an aberrant branch from the left portal


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Surgery_Schwartz. inside) the liver parenchyma at the hilar plate. Twenty percent to 35% of individuals have aberrant por-tal 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 stom-ach, 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 1Figure 31-4. Arterial anatomy of the upper abdomen and liver, including the celiac trunk and hepatic artery branches. a. = artery; LHA = left hepatic artery; RHA = right hepatic artery.RHALHAHepatic arteryproperRight gastricarteryCommon hepatic arteryLeft gastricarteryCeliac trunkSplenic arteryGastroduodenal arteryBrunicardi_Ch31_p1345-p1392.indd 134820/02/19


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Surgery_Schwartz. hepatic artery.RHALHAHepatic arteryproperRight gastricarteryCommon hepatic arteryLeft gastricarteryCeliac trunkSplenic arteryGastroduodenal arteryBrunicardi_Ch31_p1345-p1392.indd 134820/02/19 2:36 PM 1349LIVERCHAPTER 31quite 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 hem-orrhage. 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 pancreaticoduodenec-tomy). 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 CavaThere are three hepatic veins


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Surgery_Schwartz. 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 CavaThere are three hepatic veins (right, middle, and left) that pass obliquely through the liver to drain the blood to the suprahe-patic 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 Replaced right hepaticartery from SMA (10%–15%)Replaced left hepatic artery from left gastric artery (3%–10%)Replaced right and replaced left hepatic arteries (1%–2%)Completely replaced commonhepatic artery from SMA (1%–2%)Figure 31-5. Common hepatic artery anatomic variants. SMA = superior mesenteric artery.Coronary v.Portal v.Superior mesenteric v.Inferiormesenteric v.Splenic v.Figure 31-6. Portal vein anatomy. The portal vein is formed by the


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Surgery_Schwartz. artery anatomic variants. SMA = superior mesenteric artery.Coronary v.Portal v.Superior mesenteric v.Inferiormesenteric v.Splenic v.Figure 31-6. Portal vein anatomy. The portal vein is formed by the confluence of the splenic and superior mesenteric veins. The inferior mesenteric vein drains into the splenic vein. The coronary (left gastric) vein drains into the portal vein in the vicinity of the confluence. v. = vein.Main portal veinRightportal veinLeftportal veinUmbilicalportion LPVIIIIIIIVAIVBVVIVIIVIIIVIIITransverseportion LPVFigure 31-7. Anatomy of the left portal vein (LPV). Note the transverse and umbilical portions of the LPV.Brunicardi_Ch31_p1345-p1392.indd 134920/02/19 2:36 PM 1350SPECIFIC CONSIDERATIONSPART IIis 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


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Surgery_Schwartz. 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 hepa-tocaval 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 DuctsWithin the hepatoduodenal ligament, the common bile duct lies


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Surgery_Schwartz. vein; and the left hepatic vein crosses between the segment II and III branches of the left portal vein).Bile Duct and Hepatic DuctsWithin 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 divid-ing 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 pro-cess 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 acces-sory or aberrant ducts (Fig.


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Surgery_Schwartz. 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 acces-sory 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 DrainageThe 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


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Surgery_Schwartz. 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 Right lobePosteriorsegmentstructuresMiddlehepaticv.Anterior segmentstructuresGall bladderPortal v.Hepatic a.FalciformligamentLeft lobeMedialsegmentstructuresLateralsegmentstructuresMiddle HVRight HVLeft HVIVC and 3 HVsIVC Figure 31-8. Confluence of the three hepatic veins (HVs) and the inferior vena cava (IVC). Note that the middle and left HVs drain into a common trunk before entering the IVC. a. = artery; v. = vein. (Adapted with permission from Cameron JL: Atlas of Surgery. Vol. I, Gallbladder and Biliary Tract, the Liver, Portasystemic Shunts, the Pancreas. Toronto: BC Decker; 1990.)Brunicardi_Ch31_p1345-p1392.indd 135020/02/19 2:36 PM


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Surgery_Schwartz. Cameron JL: Atlas of Surgery. Vol. I, Gallbladder and Biliary Tract, the Liver, Portasystemic Shunts, the Pancreas. Toronto: BC Decker; 1990.)Brunicardi_Ch31_p1345-p1392.indd 135020/02/19 2:36 PM 1351LIVERCHAPTER 31nerve, which is stimulated by tumors that stretch Glisson’s cap-sule 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 par-ticularly 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 stag-ing CT or MRI scan.LIVER PHYSIOLOGYThe liver is the largest gland in the body and has an extraordi-nary spectrum of


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Surgery_Schwartz. lymph nodes, and the latter can be pathologically identified on a stag-ing CT or MRI scan.LIVER PHYSIOLOGYThe liver is the largest gland in the body and has an extraordi-nary 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 con-centrations in a normal range over both short and long periods by performing several important roles in carbohydrate metabo-lism. 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


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Surgery_Schwartz. 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 rpA: Normal bifurcation 57%B: Trifurcation of 3 ducts 12%C: R anterior (C1, 16%) or R posterior (C2, 4%) duct draining into CHDD: R posterior (D1, 5%) or R anterior duct (D2, 1%) draining into the left hepatic ductE: Absence of hepatic duct confluence 3%F: Drainage of R posterior duct into cystic duct 2%rprprprprprprprplhlhlhlhlhlhlhrararararararararaIVIVIIIIIIIIIIIIF2%E3%D6%C20%A57%B12%4%1%1%2%5%16%C2C1D2E2E1D1Figure 31-9. Main variations of hepatic duct confluence. As


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Surgery_Schwartz. duct into cystic duct 2%rprprprprprprprplhlhlhlhlhlhlhrararararararararaIVIVIIIIIIIIIIIIF2%E3%D6%C20%A57%B12%4%1%1%2%5%16%C2C1D2E2E1D1Figure 31-9. Main variations of hepatic duct confluence. As described by Couinaud in 1957, the bifurcation of the hepatic ducts has a vari-able pattern in approximately 40% of cases. CHD = common hepatic duct; lh = left hepatic; R = right; ra = right anterior; rp = right posterior. (Reproduced with permission from Blumgart LH, Fong Y: Surgery of the Liver and Biliary Tract, 3rd ed, Vol. I. London: Elsevier; 2000.)Brunicardi_Ch31_p1345-p1392.indd 135120/02/19 2:36 PM 1352SPECIFIC CONSIDERATIONSPART IImetabolism, 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 metabo-lism occurs in the liver, as do immunologic responses


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Surgery_Schwartz. and fibrinolytic systems, and compounds of the complement cascade. Furthermore, the detoxification of many substances through drug metabo-lism occurs in the liver, as do immunologic responses through the many immune cells found in its reticuloendothelial system.9Bilirubin MetabolismBilirubin 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 glucuro-nide 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


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Surgery_Schwartz. 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.10Formation of BileBile is a complex fluid containing organic and inorganic sub-stances 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, phospho-lipids (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


Surgery_Schwartz

Surgery_Schwartz. 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 gallblad-der and concentrated through the absorption of water and elec-trolytes. 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 respon-sible 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 cho-lesterol 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


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Surgery_Schwartz. 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 secre-tion 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 reab-sorbed 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


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Surgery_Schwartz. 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 reexcreted 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.10Drug MetabolismThe 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 par-ticipates in the elimination of these lipid-soluble drugs by trans-forming them into more readily excreted hydrophilic products. There are two main reactions important for drug metabolism. Phase 1 reactions include


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Surgery_Schwartz. elimination of these lipid-soluble drugs by trans-forming them into more readily excreted hydrophilic products. There are two main reactions important for drug metabolism. Phase 1 reactions include oxidation, reduction, and hydrolysis of molecules. These result in metabolites that are more hydro-philic than the original chemicals. The cytochrome P450 system is a family of hemoproteins important for oxidative reactions involving drugs and toxic substances. Phase 2 reactions, also known as conjugation reactions, are synthetic reactions that involve addition of subgroups to the drug molecule. These sub-groups include glucuronate, acetate, glutathione, glycine, sul-fate, 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. How-ever, when the metabolism of a drug


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Surgery_Schwartz. 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. How-ever, 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, acet-aminophen 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 path-ways 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 prod-uct. However, as glutathione stores are diminished, the reactive intermediate cannot be detoxified and


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Surgery_Schwartz. with this intermediate, leading to the production and subsequent excretion of a harmless prod-uct. 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 replen-ishing glutathione stores by supplementing with sulfhydryl compounds such as acetylcysteine.Liver Function TestsLiver function tests is a term frequently used to refer to mea-surement of the levels of a group of serum markers for evalu-ation of liver dysfunction. Most commonly, levels of aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (AP), γ-glutamyltranspeptidase (GGT), and biliru-bin are included in this panel. This term is a misnomer, how-ever, 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


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Surgery_Schwartz. term is a misnomer, how-ever, 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 pro-thrombin 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 interpreta-tion of abnormalities in these liver test results in the context of a thorough history and physical examination. The approach to 2Brunicardi_Ch31_p1345-p1392.indd 135220/02/19 2:36 PM 1353LIVERCHAPTER 31evaluating abnormal laboratory values also can be simplified by categorizing the type of abnormality that predominates (hepa-tocellular damage, abnormal synthetic function, or cholestasis).Hepatocellular InjuryHepatocellular injury of the liver is usually indicated by abnor-malities in levels of the liver


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Surgery_Schwartz. (hepa-tocellular damage, abnormal synthetic function, or cholestasis).Hepatocellular InjuryHepatocellular injury of the liver is usually indicated by abnor-malities in levels of the liver aminotransferases AST and ALT. These enzymes participate in gluconeogenesis by catalyz-ing 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


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Surgery_Schwartz. 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, hemochroma-tosis, α1-antitrypsin deficiency), and autoimmune diseases.The extent of serum aminotransferase elevations can sug-gest 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 alco-holic liver disease, an AST to ALT ratio of >2:1 is common. Mild elevations of transaminase levels can be found in nonal-coholic fatty liver disease, chronic viral infection, or medica-tion-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 ful-minant


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Surgery_Schwartz. 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 ful-minant hepatitis, AST and ALT levels can be elevated to the thousands.Abnormal Synthetic FunctionAlbumin 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. How-ever, albumin levels are dependent on a number of factors such as nutritional status, renal dysfunction, protein-losing enteropa-thies, 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 pro-thrombin time (PT) and international normalized ratio


Surgery_Schwartz

Surgery_Schwartz. synthesized exclusively in the liver, and thus their levels can also be used as a measure of hepatic synthetic function. Measurements of the pro-thrombin 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 standard-ize 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.CholestasisCholestasis 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


Surgery_Schwartz

Surgery_Schwartz. 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 measur-ing 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 abil-ity 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


Surgery_Schwartz

Surgery_Schwartz. 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 nec-essary 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 addi-tion of other agents. The direct bilirubin test measures the lev-els of conjugated bilirubin and δ bilirubin (conjugated bilirubin bound to albumin).The patterns of elevation of the different fractions of bili-rubin provide important diagnostic clues as to the cause of cho-lestasis. 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


Surgery_Schwartz

Surgery_Schwartz. 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 dis-orders 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.


Surgery_Schwartz

Surgery_Schwartz. 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


Surgery_Schwartz

Surgery_Schwartz. 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.JaundiceJaundice refers to the yellowish staining of the skin, sclera, and mucous membranes with the pigment bilirubin. Hyperbilirubi-nemia 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 Brunicardi_Ch31_p1345-p1392.indd 135320/02/19 2:36 PM 1354SPECIFIC CONSIDERATIONSPART IIthe 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 metabo-lism. As mentioned previously, bilirubin metabolism can take place


Surgery_Schwartz

Surgery_Schwartz. with jaundice is simplified by organizing the possible causes of the disorder into groups based on the location of bilirubin metabo-lism. 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.10Prehepatic. Jaundice as a result of elevated levels of uncon-jugated bilirubin occurs from faulty prehepatic metabolism and


Surgery_Schwartz

Surgery_Schwartz. the duodenum. Dysfunction in any of these phases can lead to jaundice.10Prehepatic. Jaundice as a result of elevated levels of uncon-jugated bilirubin occurs from faulty prehepatic metabolism and usually arises from conditions that interfere with proper conju-gation 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 hemoly-sis 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 thalas-semias). Hemolytic anemias can also be acquired, and these can be further divided into those with immune-mediated and those with non–immune-mediated causes.


Surgery_Schwartz

Surgery_Schwartz. structure (sickle cell anemia and thalas-semias). 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 hemo-lytic 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


Surgery_Schwartz

Surgery_Schwartz. 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 dis-ease results in transient mild increases in unconjugated bilirubin levels and jaundice during


Surgery_Schwartz

Surgery_Schwartz. It is a benign condition that affects approximately 4% to 7% of the population. Typically, the dis-ease 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 fur-ther treatment. Another inherited disorder of bilirubin conjuga-tion 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 syn-drome 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 hyperbilirubi-nemia. There are also multiple acquired conditions that result in inflammation and intrahepatic cholestasis by affecting hepato-cyte mechanisms for conjugation and excretion of bile.


Surgery_Schwartz

Surgery_Schwartz. hyperbilirubi-nemia. There are also multiple acquired conditions that result in inflammation and intrahepatic cholestasis by affecting hepato-cyte 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 acetamino-phen, oral contraceptives, and anabolic steroids.Posthepatic. Posthepatic causes of jaundice are usually the result of intrinsic or extrinsic obstruction of the biliary duct sys-tem 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 malig-nant biliary strictures, cholangiocarcinoma, cholangitis, and disorders of the papilla of Vater.


Surgery_Schwartz

Surgery_Schwartz. can occur from biliary diseases, including cholelithiasis, choledocholithiasis, benign and malig-nant 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 complica-tions are becoming more frequent causes of extrahepatic cho-lestasis. 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.MOLECULAR SIGNALING PATHWAYS IN THE LIVERAcute Phase ReactionThe liver is the site of synthesis of acute phase proteins that consists of a group of plasma proteins that are


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Surgery_Schwartz. to many years later.MOLECULAR SIGNALING PATHWAYS IN THE LIVERAcute Phase ReactionThe liver is the site of synthesis of acute phase proteins that consists of a group of plasma proteins that are rapidly released in response to inflammatory conditions elsewhere in the body. The synthesis of these proteins in the liver is mediated by a num-ber of inflammatory mediators. Cytokines such as tumor necro-sis factor alpha (TNF-α), interferon-γ (IFN-γ), interleukin-1 (IL-1), interleukin-6 (IL-6), and interleukin-8 (IL-8) are released by inflammatory cells into the circulation at sites of injury and modulate the acute phase response. In response to these cyto-kines, the liver increases synthesis and release of a wide vari-ety of proteins including ceruloplasmin, complement factors, C-reactive protein (CRP), d-dimer protein, alpha 1-antitrysin, and serum amyloid A. There are proteins, such as serum albu-min and transferrin, that also decrease (negative acute phase proteins) in response to


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Surgery_Schwartz. protein (CRP), d-dimer protein, alpha 1-antitrysin, and serum amyloid A. There are proteins, such as serum albu-min and transferrin, that also decrease (negative acute phase proteins) in response to inflammation.The acute phase response of the liver can be initiated in response to infection, trauma, or malignancy. The purpose of the release of these proteins from the liver is to contain infectious processes, prevent further tissue damage and to begin repara-tive and regeneration processes to restore body homeostasis. For example, products of the complement pathways can attach to microbes to allow for phagocytosis and act as chemoattractants to the areas of inflammation. CRP is an important acute phase protein that is also involved in the clearance of microorganisms by binding to their membranes and functioning as an opsonin to Brunicardi_Ch31_p1345-p1392.indd 135420/02/19 2:36 PM 1355LIVERCHAPTER 31facilitate phagocytosis. Other proteins such as α1-antitrypsin are protease


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Surgery_Schwartz. membranes and functioning as an opsonin to Brunicardi_Ch31_p1345-p1392.indd 135420/02/19 2:36 PM 1355LIVERCHAPTER 31facilitate phagocytosis. Other proteins such as α1-antitrypsin are protease inhibitors and restrict the protease activity of enzymes of inflammatory cells. Thus, the secretion of acute phase pro-teins from the liver during the acute phase response is an early defense measure against harmful stimuli prior to the full activa-tion of the immune response.11LPS SignalingThe liver is a complex organ with an important function in immune surveillance and clearance of bacteria and their prod-ucts. This function is facilitated by the fact that the liver receives all the drainage of the gastrointestinal tract via the portal blood flow, making it the last barrier preventing bacteria and their toxins from reaching the systemic circulation. The importance of preventing bacteria and their products from reaching the systemic blood stream is evident in patients who are infected with


Surgery_Schwartz

Surgery_Schwartz. and their toxins from reaching the systemic circulation. The importance of preventing bacteria and their products from reaching the systemic blood stream is evident in patients who are infected with gram-negative bacteria. Gram-negative bacteria infection produces an acute inflammatory reaction that can lead to septic shock and multiple organ failure. The complications of gram-negative sepsis are initiated by endotoxin (lipopolysaccharide [LPS]). LPS is a glycolipid constituent of gram-negative bacte-ria outer membranes composed of a hydrophilic polysaccharide portion and a hydrophobic domain called lipid A. The lipid A structure is the LPS component responsible for the biological effects of LPS. Mere nanogram amounts of LPS injected into humans are needed to result in the manifestations of septic shock. The profound effects of LPS are caused not only by the direct effect of LPS itself but also by the activation of LPS-sensitive cells, resulting in the excessive release of cytokines


Surgery_Schwartz

Surgery_Schwartz. of septic shock. The profound effects of LPS are caused not only by the direct effect of LPS itself but also by the activation of LPS-sensitive cells, resulting in the excessive release of cytokines and other inflammatory mediators.Since sepsis from gram-negative bacterial infection con-tinues to be a major cause of morbidity and mortality, significant efforts have been made to identify the molecules involved in LPS-binding and signaling. Lipopolysaccharide binding protein (LBP), CD14, MD2, and Toll-like receptors have all been iden-tified as important mediators in the pathway of LPS stimulation. LBP is an acute-phase protein synthesized by hepatocytes that binds the lipid A moiety of LPS and forms a soluble LBP-LPS complex. This LBP-LPS complex then interacts with CD14, a receptor identified as important in LPS recognition, resulting in the release of inflammatory cytokines and mediators. Studies have shown that although LBP is important, it is not required for LPS to interact with


Surgery_Schwartz

Surgery_Schwartz. as important in LPS recognition, resulting in the release of inflammatory cytokines and mediators. Studies have shown that although LBP is important, it is not required for LPS to interact with CD14; however, its presence markedly decreases the concentration of LPS necessary for cellular acti-vation. This may be important especially at the low concentra-tions of LPS found under physiological conditions. CD14 exists in two forms, membrane (mCD14) and soluble (sCD14) form. The interaction of LPS with membrane CD14 or soluble CD14 is important in host clearance of LPS. This interaction is also responsible for the toxic effects of LPS seen in the liver and systemic circulation after the release of inflammatory cytokines and mediators. While membrane CD14 is a membrane protein found on the surface of myeloid lineage and mediates the activa-tion of these cells by LPS, soluble CD14 is found in the serum and enables responses to LPS by cells that do not express CD14. In addition to its


Surgery_Schwartz

Surgery_Schwartz. surface of myeloid lineage and mediates the activa-tion of these cells by LPS, soluble CD14 is found in the serum and enables responses to LPS by cells that do not express CD14. In addition to its important role in the release of LBP as an acute phase reactant during LPS-mediated inflammatory insults, the liver is also one of the major sources of soluble CD14 into the circulation.The binding of the LBP-LPS complex to CD14 is not enough to transduce an intracellular LPS signal. Membrane CD14 is a glycosyl phosphatidylinositol-anchored protein without a membrane-spanning domain. Thus, signaling fur-ther downstream of LPS requires additional elements. In stud-ies using chemically modified, radioiodinated LPS capable of cross-linking to nearby proteins, LPS has been shown to cross-link specifically to two other molecules, TLR4 and MD-2. TLR4 is a member of the family of proteins called Toll-like receptors and has been identified as the transmembrane corecep-tor to CD14. TLR4 was


Surgery_Schwartz

Surgery_Schwartz. specifically to two other molecules, TLR4 and MD-2. TLR4 is a member of the family of proteins called Toll-like receptors and has been identified as the transmembrane corecep-tor to CD14. TLR4 was originally identified as the molecular sensor for bacterial LPS when studies demonstrated that muta-tions in the tlr4 gene were responsible for defective LPS sig-naling in mutant mice. Thus, initiation of LPS signal cascade requires the interaction of LPS directly with the heteromeric receptor complex of CD14, TLR4, and MD-2. Activation of this complex senses the presence of bacterial LPS at the cell sur-face and then transmits a signal into the cytoplasm through two distinct pathways. One pathway is dependent upon an adaptor known as myeloid differentiation factor 88 (MyD88). The other pathway is MyD88-independent and relies on an adaptor known as Toll/IL-1 receptor domain-containing adaptor-inducing IFNβ (TRIF).The liver is the main organ involved in the clearance of LPS from the


Surgery_Schwartz

Surgery_Schwartz. pathway is MyD88-independent and relies on an adaptor known as Toll/IL-1 receptor domain-containing adaptor-inducing IFNβ (TRIF).The liver is the main organ involved in the clearance of LPS from the bloodstream and so plays a critical role in the identification and processing of LPS. Kupffer cells are the resident macrophages of the liver and have been shown to par-ticipate in LPS clearance. Studies have demonstrated that the majority of radiolabelled LPS injected intravenously is quickly cleared from the circulation and found in the liver, primarily localized to the Kupffer cells. Kupffer cells also contribute to the inflammatory cascade by producing cytokines in response to LPS. Interestingly, hepatocytes, the parenchymal cells of the liver, also have all the components required for LPS recognition and signaling and can participate in the response to LPS and process LPS for clearance.Although the liver is essential in the host response to gram-negative bacteria infection by


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Surgery_Schwartz. for LPS recognition and signaling and can participate in the response to LPS and process LPS for clearance.Although the liver is essential in the host response to gram-negative bacteria infection by contributing to LPS clearance and to the LPS-induced inflammatory reaction, evidence reveals that LPS may actually have a reciprocal role in the pathogenesis of liver disorders. The relationship between LPS and liver disease is not a novel concept. Early studies have shown the correlation between the presence or absence of gut-derived LPS and the development of liver injury. Attempts to eliminate gut-derived LPS have had protective effects in various animal models of liver injury, including alcohol-induced liver disease. Other stud-ies have shown the synergism between LPS and hepatotoxins in worsening liver injury.In summary, the liver is essential in the clearance of LPS, but it can also contribute to the negative systemic effects seen in gram-negative bacterial sepsis by excessive


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Surgery_Schwartz. in worsening liver injury.In summary, the liver is essential in the clearance of LPS, but it can also contribute to the negative systemic effects seen in gram-negative bacterial sepsis by excessive activation of the LPS signaling pathway. In addition, there is evidence that this signaling pathway may participate in the pathogenesis of a vari-ety of liver disease. An understanding and characterization of the LPS pathway within the liver is an important step to under-standing the molecular basis for the lethal effect of LPS during sepsis and liver disorders.12,13Nitric OxideNitric oxide (NO) is a diffusible, free radical gas that was first identified in 1980 as endothelium-derived relaxing factor. Its physiologic and pathophysiologic importance was first discov-ered in the cardiovascular system with its vital role as a vaso-dilator. However, its mediation in a variety of other diverse biological activities has since been discovered. In the liver, the Brunicardi_Ch31_p1345-p1392.indd


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Surgery_Schwartz. with its vital role as a vaso-dilator. However, its mediation in a variety of other diverse biological activities has since been discovered. In the liver, the Brunicardi_Ch31_p1345-p1392.indd 135520/02/19 2:36 PM 1356SPECIFIC CONSIDERATIONSPART IIinfluence of NO on normal physiology as well as in states of disease has been extensively studied. The activation of inflam-matory cascades in the liver almost universally includes the upregulation of the inducible or inflammatory isoform of nitric oxide synthase (iNOS) and subsequent NO production. The functions of iNOS and NO in the liver is complex, and a clear dichotomy of their roles in liver dysfunction, whether being pro-tective or detrimental, has been demonstrated.Nitric oxide can be produced by one of three NO synthases: (NOS)-neuronal NOS (nNOS), inducible or inflammatory NOS (iNOS), and endothelial NOS (eNOS). These enzymes catalyze the conversion of l-arginine to NO and l-citrulline. Neuronal and endothelial NOS are


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Surgery_Schwartz. NOS (nNOS), inducible or inflammatory NOS (iNOS), and endothelial NOS (eNOS). These enzymes catalyze the conversion of l-arginine to NO and l-citrulline. Neuronal and endothelial NOS are constitutively expressed in a wide range of tissues. The activity of iNOS and eNOS are primarily controlled by calcium-mediated signaling that results in transient activation of these enzymes to produce small amounts of NO. Inducible NOS, as the name implies, is not normally expressed in rest-ing states in most tissues but is upregulated by gene transcrip-tion under conditions of stress. In contrast to nNOS and eNOS, the amount of NO produced by iNOS is large and sustained. Although first identified in macrophages, the expression of iNOS has been shown in most cell types if appropriately stimulated. Interestingly, studies on the liver with hepatocytes provided the first evidence that parenchymal cells could express iNOS. It is now known that iNOS can be expressed in all cell types of the liver, but


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Surgery_Schwartz. studies on the liver with hepatocytes provided the first evidence that parenchymal cells could express iNOS. It is now known that iNOS can be expressed in all cell types of the liver, but hepatocyte expression appears to be the most promi-nent. Studies have shown that many inflammatory mediators, including cytokines, microbial products, and oxidative stress, are all capable of stimulating iNOS expression in the liver.The chemical action of NO in biological systems has been difficult to study due to its short-lived nature. NO is highly reac-tive with other molecules due to its one unpaired electron. These interactions can either result in nitrosation or oxidation with subsequent varied effects on cellular processes. Nitric oxide can also signal through cyclic nucleotides by activating the soluble isoform of guanylyl cyclase, increasing levels of cGMP. The functions of cGMP include acting as second messengers that transmit signals by activating downstream kinases or through the


Surgery_Schwartz

Surgery_Schwartz. the soluble isoform of guanylyl cyclase, increasing levels of cGMP. The functions of cGMP include acting as second messengers that transmit signals by activating downstream kinases or through the activation of cyclic nucleotide-gated channels. In addition to cGMP signaling, NO has also been found to modulate the expression of many genes.The role of NO in inflammatory states of the liver is complex and is at times conflicting. Under physiologic condi-tions, NO is important in maintaining hepatic perfusion. How-ever, in inflammatory conditions, such as ischemia/reperfusion (I/R), nitric oxide can play either a protective or harmful role depending on the enzymatic source (inducible versus endothe-lial nitric oxide synthase) and the type of ischemia reperfusion (cold vs. warm). It appears that the low level of constitutively expressed eNOS-derived NO is primarily beneficial in models of I/R injury with vasodilation and subsequent improvement in hepatic microcirculation as the proposed


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Surgery_Schwartz. that the low level of constitutively expressed eNOS-derived NO is primarily beneficial in models of I/R injury with vasodilation and subsequent improvement in hepatic microcirculation as the proposed mechanism of protec-tion. Interestingly, activation of iNOS in similar models sug-gests a potentially harmful role for iNOS. Nitric oxide, through its reaction with reactive nitrogen and oxygen intermediates generated in the course of reperfusion injury, can contribute to much of the hepatocellular damage depending on the intracellu-lar ratio of these intermediates to nitric oxide. The production of iNOS and NO are also closely tied to multiple other inflamma-tory mediators in the liver, and activation of these downstream signals may explain some of the detrimental effects of NO in I/R injury of the liver. Thus, given its diverse biological effects as a signaling molecule, it is not surprising that NO plays both pro-tective and potentially harmful role in the setting of hepatic I/R


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Surgery_Schwartz. injury of the liver. Thus, given its diverse biological effects as a signaling molecule, it is not surprising that NO plays both pro-tective and potentially harmful role in the setting of hepatic I/R injury. The final effect of NO varies in different liver diseases and depends on the overall hepatic environment. The potential use of NO pharmacologic manipulation to treat hepatic disease will require careful balance of the risks and benefits of this sim-ple, yet extremely complicated, molecule.14,15Heme Oxygenase SystemThe heme oxygenase (HO) is the rate-limiting enzyme in the degradation of heme to yield biliverdin, carbon monoxide (CO), and free iron. The HO system, which is activated in response to multiple cellular stresses, has been shown to be an endogenous cytoprotectant in a variety of inflammatory conditions. There are currently three heme oxygenase isozymes identified. HO-1 is the inducible form of heme oxygenase, while HO-2 and HO-3 are constitutively expressed. The function


Surgery_Schwartz

Surgery_Schwartz. of inflammatory conditions. There are currently three heme oxygenase isozymes identified. HO-1 is the inducible form of heme oxygenase, while HO-2 and HO-3 are constitutively expressed. The function of HO in heme deg-radation is essential due to the potentially toxic effects of heme. An excess of heme can cause cellular damage from oxidative stress due to its production of reactive oxygen species. Thus, the HO system is an important defense mechanism against free heme-mediated oxidative stress.HO-1 has been shown to be induced in a variety of organs during diverse conditions such as hypoxia, endotoxemia, ischemia/reperfusion (I/R), hyperthermia, and radiation. It is thought that HO-1 is involved in maintaining redox homeostasis during cellular stress. In the liver, HO-1 is thought to normally modulate hepatic microvasculature tone through its generation of CO and, like nitric oxide, its activation of guanylyl cyclase. This important role is demonstrated in animal models of por-tal


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Surgery_Schwartz. modulate hepatic microvasculature tone through its generation of CO and, like nitric oxide, its activation of guanylyl cyclase. This important role is demonstrated in animal models of por-tal hypertension where inhibition of HO-1 exacerbates hyper-tension. Since HO-1 is induced as a protective mechanism in response to various stimuli, targeted induction of HO-1 has been studied as a therapeutic strategy for protection against inflam-matory processes. HO-1 overexpression exerts hepatoprotective effects in models of I/R injury, hemorrhagic shock and resus-citation, acetaminophen-induced hepatonecrosis, and sepsis-mediated liver injury.Although HO-1 has been shown to provide protective effects in a variety of inflammatory states, the specific mecha-nisms by which HO-1 mediates its protective effects are remains to be fully elucidated. Originally thought to be only potentially toxic waste, the byproducts generated during heme catabolism now appear to play important roles against cellular


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Surgery_Schwartz. effects are remains to be fully elucidated. Originally thought to be only potentially toxic waste, the byproducts generated during heme catabolism now appear to play important roles against cellular stress. The well-known hazardous effects of high doses of CO are attribut-able to its ability to bind hemoglobin and myoglobin, preventing the release of oxygen to tissues. However, only recently have the physiological and beneficial roles of CO been identified. CO is produced in injured tissues via induction of HO-1 and contrib-utes to the attenuation of proinflammatory processes. Similar to NO, CO plays an important role in maintaining the micro-circulation though its activation of soluble guanylyl cyclase and subsequent elevation of intracellular cyclic 3’5’-guanosine monophosphate (cGMP). The signaling activities of cGMP lead to smooth muscle relaxation and inhibition and platelet aggre-gation. In addition, CO has also been shown to inhibit proin-flammatory cytokines (TNF-α, IL-1) and


Surgery_Schwartz

Surgery_Schwartz. The signaling activities of cGMP lead to smooth muscle relaxation and inhibition and platelet aggre-gation. In addition, CO has also been shown to inhibit proin-flammatory cytokines (TNF-α, IL-1) and chemokines while simultaneously inducing anti-inflammatory cytokines (IL-10). Exogenous low-dose CO has been shown to protect the liver from I/R injury and endotoxemia.Biliverdin and bilirubin are other metabolites of heme that are also recognized as possible mediators of HO-1’s protective Brunicardi_Ch31_p1345-p1392.indd 135620/02/19 2:36 PM 1357LIVERCHAPTER 31function. The cytosolic enzyme biliverdin reductase catalyzes the reduction of biliverdin to bilirubin. Both biliverdin and bilirubin have important endogenous antioxidant properties. Free iron, the third byproduct of heme oxidation is known to be cytotoxic by catalyzing the production of hydroxyl radicals. However, HO-1 induction is associated with increased levels of ferritin, the free iron sequestering protein. Thus, the


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Surgery_Schwartz. is known to be cytotoxic by catalyzing the production of hydroxyl radicals. However, HO-1 induction is associated with increased levels of ferritin, the free iron sequestering protein. Thus, the increase in ferritin with the subsequent decrease in intracellular concentra-tions of free iron results in a net antioxidant effect. Importantly, both bilirubin and ferritin have been shown to protect against liver injury in a variety of I/R models.In summary, HO-1 is upregulated and protective in mul-tiple conditions of hepatic stress. Until recently, the degradation products of the HO system were thought to only be potentially toxic waste. It now appears that CO, biliverdin/bilirubin, ferritin are important in the maintenance of cellular redox homeostasis and may play a role in the mechanism of hepatoprotection in disease. Studies involving induction of HO-1 expression and use of its metabolic products hold therapeutic promises for novel protective agents against disorders of hepatic


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Surgery_Schwartz. of hepatoprotection in disease. Studies involving induction of HO-1 expression and use of its metabolic products hold therapeutic promises for novel protective agents against disorders of hepatic inflammation.16,17Toll-Like ReceptorsThe liver is a central regulator of the systemic immune response following acute insults to the body. Not only does it play a cru-cial role in modulating the systemic inflammatory response to infection or injury, it is also subject to injury and dysfunc-tion from these same processes. Recent advances in the study of mechanisms for the activation of the innate immune system have pointed to the Toll-like receptors (TLRs) as a common pathway for immune recognition of microbial invasion and tis-sue injury. By recognizing either microbial products or endog-enous molecules released from damaged sites, the TLR system is capable of alerting the host of danger by activating the innate immune system. Initially, this is manifested by the production of inflammatory


Surgery_Schwartz

Surgery_Schwartz. molecules released from damaged sites, the TLR system is capable of alerting the host of danger by activating the innate immune system. Initially, this is manifested by the production of inflammatory mediators and the rapid uptake of invading microbes and their products. When excessive, this inflamma-tory response can contribute to organ damage and dysfunction.To date, 13 TLRs have been described in mice, and 11 in humans. TLRs are a family of proteins that are mammalian homologues to the Drosophila Toll, a protein that functions in development and immunity. The cytoplasmic portion of Toll-like receptors is similar to that of the IL-1 receptor (IL-1R) fam-ily and is called the Toll/IL-1 receptor (TIR) domain. Unlike the IL-1 receptor extracellular portion that consists of an immuno-globulin-like domain, the Toll-like receptors have leucine-rich repeats in their extracellular portion. The TLR receptors have many structural similarities both extracellularly and intracel-lularly, but


Surgery_Schwartz

Surgery_Schwartz. domain, the Toll-like receptors have leucine-rich repeats in their extracellular portion. The TLR receptors have many structural similarities both extracellularly and intracel-lularly, but they differ from each other in ligand specificities, expression patterns, and with some variability in the signaling pathways they activate.The TLR receptors were initially identified as compo-nents of the innate immune system that acted as a front-line defense mechanism against infections. Their recognition of patterns on pathogens, such as microbial peptides, lipopolysac-charide, lipoteichoic acids, bacterial DNA, and single-stranded RNA, resulted in the activation of an inflammatory response meant for controlling the invading organisms. In situations of noninfectious inflammation such as seen in trauma, clinicians have long recognized similar activation of the same inflamma-tory pathways and systemic manifestations. This observation, among others, led to the hypothesis that the immune system is


Surgery_Schwartz

Surgery_Schwartz. clinicians have long recognized similar activation of the same inflamma-tory pathways and systemic manifestations. This observation, among others, led to the hypothesis that the immune system is designed to recognize any threats, whether from pathogens or tissue damage, that may lead to disruption of homeostasis. In conditions of sterile inflammation, the activation of immune cells is through the release of endogenous danger molecules, normal cell constituents released by damage or dying cells or components of the extracellular matrix, released by the action of proteases at the site of tissue damage. Recent observations show that both microbial products and endogenous danger molecules can be recognized through the TLR system.Perhaps more than any of the other TLR family members, TLR4 sits at the interface of microbial and sterile inflammation. Whereas the role of TLR4 in the recognition of lipopolysac-charide (LPS) is well established, only recently has it become apparent that TLR4


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Surgery_Schwartz. at the interface of microbial and sterile inflammation. Whereas the role of TLR4 in the recognition of lipopolysac-charide (LPS) is well established, only recently has it become apparent that TLR4 also participates in the recognition of endogenous danger molecules. In vivo evidence for TLR4-mediated danger signaling comes from studies of acute tissue injury in hemorrhagic shock, trauma, and I/R models. In each case, TLR4-mutant animals exhibited reduced injury or inflam-mation compared to wild-type controls. In efforts to identify the ligands responsible for TLR4-dependent signaling in noninfec-tious insults, multiple molecules have been suggested. These include heat shock proteins, fibrinogen, hyaluronic acid, hepa-ran sulfate, and high mobility group box-1. Although a central role for TLR4 in recognizing tissue injury is building, studies are beginning to suggest that other TLR family members may also participate in the recognition of endogenous molecules released by tissue injury.


Surgery_Schwartz

Surgery_Schwartz. in recognizing tissue injury is building, studies are beginning to suggest that other TLR family members may also participate in the recognition of endogenous molecules released by tissue injury. The very recent realization that certain TLR family members also respond to endogenous molecules released from stressed or damaged tissues points to a molecular basis for a shared mechanism of innate immune activation by infection and injury.18-20RADIOLOGIC EVALUATION OF THE LIVERUltrasoundAbdominal ultrasound is a commonly applied imaging modal-ity used to evaluate abdominal symptoms. Ultrasound tech-nology 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)


Surgery_Schwartz

Surgery_Schwartz. 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 pres-ence of blood vessels but also can determine the direction and velocity of blood flow. Ultrasonography is a useful initial imag-ing 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


Surgery_Schwartz

Surgery_Schwartz. 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 com-pared 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 Brunicardi_Ch31_p1345-p1392.indd 135720/02/19 2:36 PM 1358SPECIFIC CONSIDERATIONSPART IIincrease the sensitivity and specificity of ultrasound in detect-ing 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 identifica-tion of dynamic


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Surgery_Schwartz. μm and, when given intravenously, allow for more effective echo enhancement. Contrast-enhanced ultrasound imaging of the liver improves delineation of liver lesions through identifica-tion of dynamic enhancement patterns and the vascular mor-phology 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 rap-idly expanded over the years with the increasing number and complexity of hepatic resections being performed.21 It has the ability to provide the surgeon with real-time accurate informa-tion 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. Impor-tantly, it has been shown to


Surgery_Schwartz

Surgery_Schwartz. 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. Impor-tantly, 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


Surgery_Schwartz

Surgery_Schwartz. 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.22 Unlike liver biopsy, ultrasound elastography is non-invasive 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, provid-ing a better understanding of the entire hepatic parenchyma and reducing sampling error.Computed TomographyCT 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


Surgery_Schwartz

Surgery_Schwartz. TomographyCT 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 multidetector 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, facili-tated 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,


Surgery_Schwartz

Surgery_Schwartz. 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 dualor triple-phase bolus of intravenous contrast agent is performed to achieve the greatest enhancement of contrast between nor-mal and pathologic tissues.23 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


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Surgery_Schwartz. 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 Figure 31-10. Intraoperative liver ultrasound images of the portal veins, hepatic veins, and inferior vena cava (IVC). Upper panel shows the portal vein bifurcation with echogenic Glissonian sheath. The confluence of the three hepatic veins (right hepatic vein [RHV], middle hepatic vein [MHV], and left hepatic vein [LHV]) and the IVC is shown in the middle panel. An accessory LHV is present in this patient. Lower panel is a color Doppler image showing flow.Brunicardi_Ch31_p1345-p1392.indd 135820/02/19 2:36 PM 1359LIVERCHAPTER 31flow 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


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Surgery_Schwartz. 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 por-tal dominant phase (60 to 70 seconds after contrast injection) (Fig. 31-11). Thus, many hepatic tumors that derive the major-ity 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 enhance-ment 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 paren-chyma. Furthermore, the arterial and portal phase images allow for noninvasive mapping of the hepatic arterial and venous


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Surgery_Schwartz. will appear hypoattenuated in relation to the brighter normal liver paren-chyma. Furthermore, the arterial and portal phase images allow for noninvasive mapping of the hepatic arterial and venous anat-omy, information that is crucial in the preoperative planning for patients undergoing liver surgery.CT cholangiography has emerged as a new imaging modal-ity 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.24 One of the major advantages of CT cholangiography over other imaging modalities is the abil-ity to depict small nondilated peripheral biliary radicals. This technique may be useful in the context of live liver donation or


Surgery_Schwartz

Surgery_Schwartz. of CT cholangiography over other imaging modalities is the abil-ity 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 postopera-tive 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 ImagingMRI 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 magnetiza-tion. Different tissues absorb and release radio wave energy at different rates, and this information is used to construct an


Surgery_Schwartz

Surgery_Schwartz. body, and radio waves are used to alter the alignment of this magnetiza-tion. 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 differ-ences 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


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Surgery_Schwartz. 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 Magnet-ics, 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 characteriza-tion of lesions within the


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Surgery_Schwartz. Germany). These agents combine the information obtained during a standard MRI with additional functional data, which in turn yields improved detection and characteriza-tion of lesions within the liver.25Just as ultrasound elastography is useful in the diagno-sis of hepatic fibrosis and cirrhosis, magnetic resonance (MR) elastography appears promising as an imaging modality in 3Figure 31-11. Computed tomographic (CT) images of hepatic veins and Couinaud’s liver segments. The images show the three hepatic veins and inferior vena cava (IVC) (upper panel), as well as Couinaud’s liver segments (lower panels). LHV = left hepatic vein; MHV = middle hepatic vein; RHV = right hepatic vein.Brunicardi_Ch31_p1345-p1392.indd 135920/02/19 2:36 PM 1360SPECIFIC CONSIDERATIONSPART IIreducing 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


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Surgery_Schwartz. 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 con-trast resolution often enables accurate assessment of the level of occlusion in the biliary tree. MRCP also can be enhanced with liver-specific MRI contrast


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Surgery_Schwartz. bile ducts, and the high spatial and con-trast 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.26Positron Emission TomographyPositron emission tomography (PET) is a nuclear medicine test that produces images of metabolic activity in tissues by detect-ing 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


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Surgery_Schwartz. 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 bet-ter sensitivity and specificity than CT scanning for the detec-tion of both intrahepatic and extrahepatic disease.27 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.27More than 20% of patients with colorectal cancer ini-tially 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 predomi-nantly in tumor staging and follow-up, particularly in the detec-tion of occult


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Surgery_Schwartz. eventually experience disease recurrence in the liver. The role of FDG-PET/CT in colorectal cancers lies predomi-nantly in tumor staging and follow-up, particularly in the detec-tion of occult intrahepatic metastases or extrahepatic disease. Although hepatic resection of colorectal metastases provides survival rates nearing 50%, the presence of extrahepatic dis-ease 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.28 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


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Surgery_Schwartz. 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 com-bined modality has


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Surgery_Schwartz. 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 com-bined 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 FAILUREAcute 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. Figure 31-12. Computed tomography (CT)–positron emission tomography (PET) scans before and after resection of liver