Hepatic Physiology, Pathophysiology, and Anesthetic Considerations

Surgical Anatomy, Hepatic Blood Flow, and the Biliary Tree

The adult liver can range from around 600 to over 1800 g making the liver one of the heaviest organs in the body. In healthy females the liver ranges in size from 603 to 1767 g, while in healthy males, the liver ranges in size from 968 to 1860 g. In newborns, infants, and children, the liver is also one of the largest organs and the contribution of its weight to total body weight decreases with age. Thus the liver in a term 3 to 3.5 kg newborn can weigh 150 to 170 g, which represents around 5% of the total body weight. In sharp contrast the adult liver represents 2% to 2.5% of the total body weight.

The liver receives approximately 25% of the resting cardiac output (CO). The blood supply is through both the arterial and venous systems in the form of the hepatic artery and the portal vein ( Fig. 16.1 ). The hepatic artery is responsible for 25% to 30% of the blood supply to the liver whereas the portal vein is responsible for 70% to 75%. The hepatic artery arises from the celiac trunk in 80% of the population. In the remainder, it arises from the superior mesenteric artery. After giving rise to the gastroduodenal artery, the common hepatic artery enters the hilum of the liver (porta hepatis) where it further branches into the right and left hepatic arteries, supplying the right and left sides of the liver, respectively. The right hepatic artery gives rise to the cystic artery that supplies the gallbladder. The arteries continue to branch throughout the liver ultimately running through the portal tracts and terminating in the hepatic sinusoids (capillaries). Although part of the venous system, the portal vein is the primary source of oxygenated blood to the liver. The portal vein carries blood from the gastrointestinal tract, pancreas, and spleen to the liver. It drains the superior mesenteric, splenic, and inferior mesenteric veins. It also drains the gastric, cystic, and pancreaticoduodenal veins. The portal vein enters the hilum and, like the hepatic artery, branches into the right and left portal veins, supplying the respective sides of the liver. The portal veins continue to branch throughout the liver in conjunction with the hepatic arteries. As with the arteries, they terminate in the hepatic sinusoids.

Venous drainage of the liver is through the hepatic veins directly into the inferior vena cava (IVC). The right and middle hepatic veins serve the right half and middle portions of the liver, respectively, while the left hepatic vein drains the left half of the liver. The biliary system removes bile from the liver and delivers it to the duodenum through the ampulla of Vater. The intrahepatic bile ducts typically travel with the portal veins, draining into right and left collections systems that ultimately form the common bile duct (CBD; see Fig. 16.1 ).

From a historical perspective, the description of the gross anatomy of the liver has evolved from being rooted in the surface anatomy of the organ to its functional organization. Traditionally, the liver was divided into four lobes based on its surface features: right lobe, left lobe, quadrate, and caudate. The right and left lobes were divided by the falciform ligament, when viewed anteriorly. When viewed from below, the quadrate lobe was bounded by the porta hepatis posteriorly, the gallbladder fossa on the right, and the ligamentum teres on the left. The caudate lobe was bounded by the porta hepatis anteriorly, the IVC on the right, and the ligamentum venosum fissure on the left. In the late 1800s, Sir James Cantlie demonstrated that the right and left hemilivers were defined by independent portal circulations and thus the functional midline of the liver was at the bifurcation of the portal vein, along a line connecting the gallbladder bed and the IVC (“Cantlie’s line”), lateral to the falciform ligament. Cantlie recognized that the line defined a vascular watershed and described its implications for surgical resection of the liver. With advances in hepatic surgery, anatomic descriptions of the liver were developed that further divided the hemilivers into segments based on the vascular distribution and biliary drainage. Each segment has its own independent vascular inflow and outflow, and biliary drainage. As a result, surgical resection of a segment does not compromise adjacent segments. The most commonly used organizational system was developed by Couinaud (see Fig. 16.1 ). In the Couinaud model, the liver is divided into eight segments. The right and left hemilivers are divided at the bifurcation of the portal vein, along the middle hepatic vein. The right, middle, and left hepatic veins divide the liver vertically into four sectors: right posterior, right anterior, left medial, and left lateral sectors. The four sectors are divided in the horizontal plane by the branches of the portal vein, giving rise to the eight segments. In this system, the caudate lobe is referred to as segment 1 and the remainder of the segments are numbered in a clockwise fashion. Segments 2 and 3 are medial to the left hepatic vein, with segment 2 superior to segment 3. Segment 4 lies between the middle and left hepatic vein and is subdivided into 4a (superior) and 4b (inferior) subsegments. Segments 8 (superior) and 5 (inferior) are located between the middle and right hepatic veins. Segments 6 (inferior) and 7 (superior) are located between the right hepatic vein and the edge of the liver. In clinical practice, contrast-enhanced computed tomography (CT) scanning and intraoperative ultrasound are used to define the anatomy unique to each individual and plan for the appropriate resection. To standardize the nomenclature used to describe hepatic resections, the International Hepatopancreatobiliary Association published consensus terminology in 2000 based on the Couinaud segments, known as the Brisbane 2000 terminology. This system of terminology has gained traction but has not yet been uniformly adopted.

Cellular Anatomy

Liver Lobule and Acinus

The cellular architecture of the liver supports its functions of detoxifying the blood and metabolizing nutrients. Histologically, the liver parenchyma can be organized into anatomic units (liver lobules) or functional units (liver acinus). The liver lobule is the basic structural unit of the hepatic parenchyma ( Fig. 16.2 ). The lobule typically appears hexagonal in shape with a portal canal at each corner and a hepatic venule (central vein) located in the center. Through each portal canal run the lymphatics, nerve fibers, and a portal triad. Each portal triad consists of a bile ductule, hepatic arteriole, and portal venule. From a functional standpoint, the acinus is the smallest unit of the liver ( Fig. 16.3A ). It is comprised of a portal tract at the center with central vein at the periphery. Oxygenated and nutrient-rich blood flows from the portal triads to the central hepatic veins through the hepatic sinusoids (see Fig. 16.3B ). The walls of the sinusoids are composed of sinusoidal endothelial cells (SECs) that are separated by fenestrations of 50 to 150 nm in diameter. The fenestrations allow the passage of metabolites, plasma proteins, pharmaceutical molecules, lipoproteins, and other solutes into the space of Disse (SD) surrounding the sinusoids while retaining blood cells in the vessels. Larger macromolecules and potentially immunogenic peptides enter the SD by transcytosis through the SECs. Once in the SD, the molecules are taken up by hepatocytes.

Myeloid Cells

The myeloid cells that can be found in the liver consist primarily of Kupffer cells (20%-30%) also known as resident tissue macrophages, in addition to dendritic cells and myeloid-derived suppressor cells. At first glance, it may seem that these cells have a less important role than hepatocytes and LSEC. However, while Kupffer cells constitute around 20% to 30% of nonparenchymal cells, they constitute 80% to 90% of all tissue macrophages. Kupffer cells reside in the portal and lobular liver sinusoids where they engulf both infectious and noninfectious particles by phagocytosis. Once phagocytosed, these particles are unable to induce proinflammatory responses in the liver. Thus by prevalence and location, these cells serve critical roles in innate and adaptive immunity by detoxification where they down-regulate potentially proinflammatory triggers that could disrupt hepatic homeostasis.

Dendritic cells and myeloid-derived suppressor cells are the least abundant of myeloid cells. Hepatic dendritic cells are present in the normal liver and reside in the portal area and are believed to promote tolerance to phagocytosed particles. Hepatic myeloid-derived supressor cells suppress immune response in the liver. In acute hepatitis they reduce inflammation and limit tissue injury. Their immune suppressive function has been associated with adverse effects in certain pathologic conditions. In chronic viral hepatitis, they may promote viral persistence. They have also been associated with suppression of immune response to hepatic tumors.

Lymphocytes

Cells of lymphatic origin that can be detected in the liver include natural killer (NK) cells, NK T cells (NKT), mucosal-associated invariant T cells, and γδ T cells in addition to major histocompatibility restricted CD4+ T cells, CD8+T cells, and B cells. These cells are distributed throughout the liver parenchyma and serve critical roles in the innate (NK, NKT, mucosal-associated invariant T cells, and γδ T cells) and adaptive (major histocompatibility restricted CD4+ T cells, CD8+T cells, and B cells) immune responses. These cells work primarily to maintain hepatic homeostasis by promoting tolerance to foreign substances. However, when necessary, these MHC-restricted cells can promote the clearance of foreign substances by expanding in response to them while recruiting additional cells from extrahepatic sources such as the lymph nodes and the spleen.

Drug Metabolism

The vast majority of drugs used in the conduct of anesthesia are metabolized in the liver. A variety of enzymes convert drug molecules into more water-soluble (hydrophilic) molecules or compounds to facilitate their excretion. These enzymes are designated as being either part of the Phase I pathway or Phase II pathway based on the types of reactions they mediate. Phase I enzymes consist of the cytochrome P450 family of enzymes that convert lipophilic drug molecules to hydrophilic molecules primarily through oxidation, reduction, or hydrolysis. Non-CYP450 enzymes include monoamine oxidases, alcohol dehydrogenases, and aldo-keto reductase. The phase II pathway consists of the conjugation of the products of the phase I pathway with hydrophilic endogenous moieties to make them more water-soluble. Polar molecules may undergo Phase II metabolism without having undergone Phase I metabolism. The most common Phase II reaction is glucuronidation, which is the conjugation of the drug compound to glucuronic acid. This reaction is carried out by a family of enzymes known as uridine 5′-diphospho-glucuronosyltransferases. Other Phase II enzymes include sulfotransferases (SULT), glutathione S-transferases (GST), and catechol O-methyltransferases. The phase III pathway involves the excretion of compounds into the sinusoids or canalicular bile by molecular transporters that are transmembrane proteins which facilitate the movement of large or ionized molecules across cell membranes. The majority of these transmembrane proteins are part of a superfamily of ATP-binding cassette (ABC) transporters that use ATP to actively transport molecules. Common ABC-transporters include multidrug resistance protein (MDR), cystic fibrosis transmembrane conductance regulator, and multidrug resistance–related protein (MRP).

Some orally administered medications undergo extensive metabolism in the gut or liver prior to entering the systemic circulation. This metabolism is termed the first-pass effect and is responsible for the lower oral bioavailability of these medications.

Drug metabolism is affected by a number of factors including genetic polymorphisms of metabolic enzymes, age, gender, pregnancy, liver disease, and concomitantly administered medications. The expression and function of Phase I and Phase II enzymes are reduced in neonates. The activities of some CYP450 enzymes are increased in women compared to men. Genetic polymorphisms in drug metabolizing enzymes and transporters can lead to wide variations in the pharmacokinetics of some drugs such as warfarin, with some patients having lower rates of metabolism based on the specific CYP450 polymorphism they carry. The concomitant administration of medications may also influence drug metabolism. A number of commonly encountered medications can serve as inducers or inhibitors of the enzymes involved in the different phases of drug metabolism. Table 16.1 lists some of the commonly used drugs, which are metabolized and excreted by each of the three phases along with drugs that may serve as inhibitors or inducers for each phase.

See the pharmacokinetics chapter for further discussion of hepatic extraction ratio.

Protein Metabolism

The liver is responsible for the synthesis and catabolism of proteins, amino acids, and peptides. It is the site of synthesis for 80% to 90% of the circulating proteins including hormones, coagulant factors, cytokines, and chemokines. As such it plays a significant role in the functioning of the body. Albumin is the predominant protein produced by the liver, accounting for over 50% of total plasma protein. It functions to transport lipids and hormones and maintain blood volume. The liver plays a central role in protein degradation. Amino acids are catabolized through one of two reactions: deamination or transamination. Both reactions lead to the production of ammonia, which the liver converts to urea through the urea cycle. Urea is then excreted by the kidneys in the urine.

Carbohydrate Metabolism

The liver is primarily responsible for storing and releasing glucose to meet the body’s needs. In the postprandial state, the liver stores glucose through glycogenesis. Once the glycogen stores are complete, the liver converts excess glucose into fat through lipogenesis. In the fasting state, the liver provides the body with glucose by breaking down glycogen (glycogenolysis) or by generating glucose from carbohydrate precursors (gluconeogenesis).

Lipid Metabolism

The liver plays an important role in lipid metabolism. Nonesterified fatty acids can arise from the lipase-mediated breakdown of complex lipids, or from thioesterase-mediated hydrolysis of fatty acid-CoA. These fatty acids can enter the liver following oral intake or they can enter the liver following the breakdown of adipose tissue. In the liver, fatty acid oxidation is regulated by two main factors: the supply of fatty acids to the liver (via lipolysis), and the amount of microsomal esterification that occurs. Lipid metabolism is also influenced by the carbohydrate metabolism, as the acetyl-CoA formed during carbohydrate metabolism can be utilized to synthesize fatty acids. Fatty acids can undergo biotransformation to supply energy for the needs of the body. Alternatively, the liver can convert amino acids and intermediate products of carbohydrates into fats and transport them to the adipose tissues.

Bile and Enterohepatic Circulation

The adult liver produces approximately 400 to 600 mL of bile each day. Bile facilitates the excretion of toxins as well as the absorption of dietary fats. It is the mechanism of excretion for compounds with molecular weights greater than 300 to 500 Daltons that are not readily excreted by the kidneys. It is used to excrete a host of endogenous and exogenous compounds, including bile acids, bilirubin, phospholipids, cholesterol, drugs, toxins, steroid hormones, and water-insoluble porphyrins. Box 16.1 lists drugs, chemicals, and their metabolites that are excreted in the bile. The other major function of bile is to assist in the digestion and absorption of dietary fats, cholesterol, and vitamins. Bile is 95% water by volume, with the remainder consisting of bile acids, phospholipids, cholesterol, bilirubin, as well as other exogenous and endogenous substances. The two primary bile acids are cholic acid and chenodeoxycholic acid. Bile acids are synthesized by hepatocytes from cholesterol. They are then conjugated to reduce hepatotoxicity and increase solubility and secreted into the canaliculi. The canaliculi drain into the biliary ductules, which connect to form hepatic ducts. The walls of the intrahepatic bile ducts are made up of cholangiocytes that modify the volume and composition of the bile. The ducts ultimately form the left and right hepatic ducts, which join into the common hepatic duct. Bile is stored and concentrated in the gallbladder, which connects to the biliary tree through the cystic duct. The common hepatic duct and cystic duct join to form the CBD, which connects to the duodenum through the sphincter of Oddi (hepatopancreatic sphincter). Following the ingestion of food, fatty acids in the duodenum stimulate the release of cholecystokinin (CCK) which causes the gallbladder to contract and the sphincter of Oddi to relax leading to the release of bile into the duodenum. The bile acids emulsify dietary fats and facilitate their absorption. The vast majority (95%) of the bile acids released into the duodenum are reabsorbed in the terminal ileum and returned to the liver to be reused. This pathway for recycling bile acids is known as the enterohepatic circulation (EHC). Enterohepatic cycling can impact the pharmacokinetics and pharmacodynamics of drugs that undergo biliary excretion by increasing their bioavailability, reducing their elimination, as well as altering their plasma concentration curves. The effect of EHC on the properties of a drug depends on the physiologic activity of the excreted form of the drug (i.e., prodrug or activated form), the ease with which the excreted form is reabsorbed through the intestines, and whether it is recycled through the liver into the bile or the systemic circulation. In the case of some drugs, EHC can lead to secondary and tertiary peaks in plasma concentration as the drug is recycled into the system.

Role of the Liver in Coagulation

The liver plays a significant role in the coagulation system. It synthesizes all coagulation factors except factors III (thromboplastin), IV (calcium), and VIII (von Willebrand factor [vWF]). It also synthesizes proteins that regulate coagulation and fibrinolysis such as protein S, protein C, plasminogen activator inhibitor, and antithrombin III. Furthermore, it removes activated clotting and fibrinolysis products through the hepatic reticuloendothelial system. A number of factors require vitamin K to become active. Coagulation factors II, VII, IX, X, as well as protein C and protein S undergo posttranslational modification with vitamin K to become active. Briefly, glutamic acid in the amino terminus of these proteins is converted to gamma-carboxyglutamic acid. These gamma-carboxylated procoagulants can then bind calcium ions and form bridges to phospholipid surfaces that are essential for the formation of activation complexes. Warfarin acts by inhibition gamma-carboxylation. In addition to these vitamin K–dependent factors, hepatocytes also synthesize factor V, XIII, fibrinogen, antithrombin, α ₂ plasmin inhibitor, and plasminogen. Thrombomodulin, tissue plasminogen activator, tissue factor plasma inhibitor, vWF, and urokinase are not synthesized in the liver. Instead these proteins are synthesized in endothelial cells, whereas urokinase is expressed by endothelial cells, macrophages, and renal epithelial cells. Tissue plasminogen activator is primarily removed from the bloodstream through the hepatic reticuloendothelial system.

Heme Metabolism, Bilirubin, and Porphyrias

The liver is involved in both heme synthesis and metabolism. Eighty to 90% of heme synthesis takes place in the bone marrow with the resultant heme used to produce hemoglobin. Most of the remainder of the heme is produced in the liver and used primarily to synthesize cytochrome P450 enzymes. Whereas the rate of heme synthesis in the bone marrow is a function of the availability of iron, the rate of synthesis in the liver is a function of the available free heme pool in the body. Heme is synthesized through an eight-step enzymatic cascade known as the Shemin pathway. Synthesis begins with glycine and succinyl CoA and proceeds through porphyrinogen intermediaries. A deficiency in any of the enzymes involved in heme synthesis leads to the development of porphyria. The specific type of porphyria and its clinical manifestations depend on the specific enzyme that is deficient and the substrate that accumulates as a result. The most common porphyria is acute intermittent porphyria with an estimated incidence of 5 to 10 per 100,000. It is caused by a deficiency in porphobilinogen deaminase, which catalyzes the conversion of porphobilinogen to hydroxymethylbilane. Patients typically have adequate levels of the enzyme for heme homeostasis; however, in response to endogenous or exogenous triggers that induce the Shemin pathway, the capacity of the system is exceeded and they accumulate precursors leading to symptoms. Common triggers include erythromycin, trimethoprim, rifampicin, phenytoin, and barbiturates. Clinical symptoms of an attack include severe, poorly localized abdominal pain (in >90% of cases), nausea, vomiting, agitation, and confusion. Hyponatremia occurs in 40% of attacks. Change in urine color to dark red (especially on exposure to light) is a common finding. Treatment consists of discontinuing the triggering agent, administering pain medication, carbohydrates, and hematin.

Bilirubin is a product of heme catabolism. The primary source is senescent erythrocytes that are phagocytosed by macrophages in the spleen, liver, and bone marrow. The released heme is metabolized by heme oxygenase into bilirubin, yielding carbon monoxide and iron in the process. Unconjugated bilirubin is water insoluble and thus tightly bound to albumin in the circulation. Hepatocytes convert bilirubin into a water-soluble form by conjugating it to glucuronic acid via the enzyme glucuronyl transferase. Conjugated bilirubin is then transported across bile canaliculi and excreted in the bile. In the colon, bilirubin is deconjugated, metabolized by bacteria, and converted into urobilinogen. Urobilinogens are either reabsorbed through the EHC or excreted in the urine and stool, giving urine and stool their characteristic colors.

Hepatic Regulation of Hormones

The liver can participate in endocrine functions through hormone synthesis or hormone degradation. Hepatocytes synthesize hormones or prohormones such as hepcidin, insulin-like growth factor, and angiotensinogen, respectively. In addition to these hormones, thrombopoietin is also synthesized by hepatocytes and LSECs. These hormones and prohormones have specialized roles in the human body. Thus hepcidin is responsible for iron homeostasis and regulates intestinal iron absorption, plasma iron concentrations, and tissue iron distribution by inducing degradation of the hepcidin receptor, ferroportin. Insulin-like growth factor promotes systemic growth, especially bone growth in children. Angiotensinogen, the precursor of all angiotensin proteins, regulates the systemic blood pressure as well as the water and sodium composition of the body. Thrombopoietin regulates platelet production by stimulating production and differentiation of megakaryocytes. In addition to hormone synthesis, the liver participates in endocrine function by inactivating many hormones, including thyroxine, aldosterone, antidiuretic hormone, estrogens, androgens, and insulin.