Chapter Outline
Hepatic Drug Metabolism and Excretion
Anesthetic Pharmacology and the Liver
Liver Disease: Etiologies and Severity
Cirrhosis and Perioperative Risk: Nonhepatic Surgery
In perioperative management, the hepatic and gastrointestinal (GI) systems usually receive consideration after the cardiovascular and respiratory systems. However, potential perioperative problems such as aspiration, ileus, and nausea and vomiting are common and significant. Additionally, end-stage liver disease—often associated with multisystem organ failure—can be life threatening. It is incumbent in anesthesiology to understand the physiologic basis of these conditions to minimize associated complications and optimize patient outcomes.
Liver
The liver weighs approximately 1.5 kg, or about 2% of total body weight in an adult. Functionally, the liver metabolizes carbohydrates, proteins, fats, hormones, and foreign substances. In addition, it filters and stores blood; stores vitamins, glycogen, and iron; and produces bile and blood coagulation factors.
Anatomy
The functional unit of the liver is the lobule, or liver acinus, a structure roughly 1 × 2 mm that consists of plates of hepatocytes located in a radial distribution about a central vein ( Fig. 31.1 ). Bile canaliculi are located between the plates and collect bile formed in the hepatocytes. The canaliculi drain into bile ducts located at the periphery of the lobule next to portal venules and hepatic arterioles. The bile ducts join to form the common hepatic duct. The cystic duct from the gallbladder and the pancreatic duct join the common hepatic duct before entering the duodenum. The sphincter of Oddi controls the flow of bile into the small intestine.
Portal venules empty blood from the GI tract into the hepatic sinusoids, the space between the plates of hepatocytes that serve as the capillaries of the liver. Hepatic arterioles supply well-oxygenated blood to the septa located between the plates of hepatocytes and the sinusoids. The liver typically contains between 50,000 and 100,000 lobules.
The large pores of endothelium lining the sinusoids allow plasma and its proteins to move readily into the tissue spaces surrounding hepatocytes, an area known as the space of Disse, or perisinusoidal spaces. This fluid drains into the lymphatic system. The liver is responsible for generating about half of the lymph.
Macroscopically the liver is divided unequally into right and left lobes by the falciform ligament ( Fig. 31.2A ). More recently a segmental, or surgical, anatomy has been described, known as the Couinaud classification. The liver is divided into eight segments based on the anatomy of the portal and hepatic veins ( Fig. 31.2B ).
Blood Supply
The liver receives almost 25% of cardiac output via a dual supply. The portal venules conduct blood from the portal vein that drains the GI tract. The portal vein supplies 75% of liver blood flow, about 1 L/min. The hepatic arterioles supply 25% of blood flow. Each system contributes about 50% of hepatic oxygen supply ( Fig. 31.3 ).
The high hepatic blood flow is due to low vascular resistance in the portal vein. The average portal vein pressure is 9 mm Hg, whereas hepatic venous pressure averages 0 mm Hg for a 9-mm Hg perfusion pressure gradient. However, when hepatocytes are injured and replaced by fibrous tissues, blood flow is impeded, resulting in portal hypertension, the hallmark of cirrhosis. Sinusoidal pressures greater than 5 mm Hg are abnormal and define portal hypertension (see later text). Sympathetic innervation from T3 to T11 controls resistance in the hepatic venules. Changes in compliance in the hepatic venous system help regulate cardiac output and blood volume. In the presence of reduced portal venous flow, the hepatic artery can increase flow by as much as 100% to maintain hepatic oxygen delivery. The reciprocal relationship between flow in the two afferent vessels is termed the hepatic arterial buffer response .
The microcirculation of the liver lobule is divided into three zones that receive varying oxygen content. Zone 1 receives oxygen-rich blood from the adjacent portal vein and hepatic artery. As blood moves through the sinusoid, it passes from the intermediate zone 2 into zone 3, which surrounds the central vein. Zone 3 receives blood that has passed through zones 1 and 2, reducing the oxygen content. Pericentral hepatocytes have a greater quantity of cytochrome P450 (CYP) enzymes and are the site of anaerobic metabolism. Hypoxia and reactive metabolic intermediates from biotransformation affect this zone more prominently than other zones.
Volatile anesthetics decrease hepatic blood flow; however, newer agents (isoflurane, desflurane, and sevoflurane) reduce flow less than older agents such as halothane.
Liver Function
Storage
Owing to its ability to distend, the liver is capable of storing up to 1 L of blood. Thus the liver serves as a reservoir capable of accepting blood, as in the presence of heart failure, or releasing blood at times of low blood volume. The liver also stores vitamins, particularly vitamins B 12 (1-year supply), D (3-month supply), and A (10-month supply). Excess body iron is transported via apoferritin to the liver for storage as ferritin, which is released when circulating iron levels are low. Thus the liver apoferritin system serves for iron storage and as a blood iron buffer.
Filtering and Cleansing
Kupffer cells, a type of reticuloendothelial cell, line the venous sinusoids. Kupffer cells are macrophages that phagocytize bacteria that enter the sinusoids from the intestines. Less than 1% of bacteria that enter the liver pass through to the systemic circulation.
Metabolism of Nutrients
The liver is involved in energy production and storage from nutrients absorbed from the intestines. The liver helps regulate blood glucose concentrations through its glucose buffer function. This is accomplished by storing glucose as glycogen, converting other carbohydrates (principally fructose and galactose) to glucose, and synthesizing glucose from glucogenic amino acids and from glycerol derived from triglycerides (gluconeogenesis). In patients with altered liver function, glucose loads are poorly tolerated, and blood glucose concentration can rise severalfold higher than postprandial levels found in patients with normal hepatic function.
The liver synthesizes fat, cholesterol, phospholipids, and lipoproteins. It also metabolizes fat efficiently, converting fatty acids to acetyl coenzyme A (CoA), an excellent energy source. Some of the acetyl-CoA enters the citric acid cycle to liberate energy for the liver. The liver generates more acetyl-CoA than it consumes, so it packages the excess as acetoacetic acid for use by the rest of the body via the citric acid cycle. The majority of cholesterol synthesized in the liver is converted to bile salts and secreted in the bile. The remainder is distributed to the rest of the body where it is used to form cellular membranes. Fat synthesis from protein and carbohydrates occurs almost exclusively in the liver, and the liver is responsible for most fat metabolism.
The liver also plays a key role in protein metabolism. The liver synthesizes all of the plasma proteins with the exception of gamma globulins, which are formed in plasma cells. The liver is capable of forming 15 to 50 g of protein per day, an amount sufficient to replace the body’s entire supply of proteins in several weeks. Albumin is the major protein synthesized by the liver and is the primary determinant of plasma oncotic pressure. The liver also synthesizes the nonessential amino acids from ketoacids, which it also synthesizes.
The liver can deaminate amino acids, a process required before their use for energy production or conversion to carbohydrates or fats. Deamination results in the formation of ammonia, which is toxic. Intestinal bacteria are an additional source of ammonia. The liver is responsible for the removal of ammonia through the formation of urea.
Synthesis of Coagulation Factors
Blood clotting factors, except factors III (tissue thromboplastin), IV (calcium), and VIII (von Willebrand factor), are synthesized in the liver. Vitamin K is required for the synthesis of the calcium ion (Ca 2+ )-binding proteins prothrombin (factor II) and factors VII, IX, and X (see Chapter 43 ).
Bile Secretion
Hepatocytes produce roughly 500 mL of bile daily. Between meals the high pressure in the sphincter of Oddi diverts bile to the gallbladder for storage ( Fig. 31.4 ). The gallbladder holds 35 to 50 mL of bile in concentrated form. The presence of fat in the duodenum causes release of the hormone cholecystokinin from duodenal mucosa, which reaches the gallbladder via the circulation and stimulates gallbladder contraction. Bile contains bile salts, bilirubin, and cholesterol. Bile salts serve as a detergent, solubilizing fat into complexes called micelles, which are absorbed. Bile salts are returned to the liver via the portal vein, completing the enterohepatic circulation. Bile salts are needed for fat absorption, and cholestasis can result in steatorrhea and vitamin K deficiency.
Bilirubin and Jaundice
Bilirubin is the major end product of hemoglobin breakdown, which occurs when red blood cells reach the end of their 120-day life span. After phagocytosis by reticuloendothelial cells, hemoglobin is split into globin and heme. The heme releases iron and a four-pyrrole nucleus that forms biliverdin, which is converted to free, or unconjugated, bilirubin. Unconjugated bilirubin is conjugated in the liver, primarily with glucuronic acid, before it is secreted into bile for transport to the intestines. In the intestines, a portion of conjugated bilirubin is converted to urobilinogen by bacteria. Some urobilinogen is reabsorbed from the intestines into the blood, but most is excreted back into the intestines. A small amount is excreted into urine as urobilin. Urobilinogen that remains in the intestines is oxidized to stercobilin and excreted in feces.
Jaundice is the yellow-green tint of body tissues that results from bilirubin accumulation in extracellular fluid. Skin discoloration is usually visible when plasma bilirubin reaches three times normal values. Bilirubin accumulation can occur as the result of increased breakdown of hemoglobin (hemolysis) or obstruction of bile ducts. Hemolytic jaundice is associated with an increase in unconjugated (indirect) bilirubin, whereas obstructive jaundice is associated with increases in conjugated (direct) bilirubin.
Liver Regeneration
The liver has the unique ability to restore itself after injury or partial hepatectomy. As much as two-thirds of the liver can be removed with regeneration of the remaining liver in a matter of weeks. Control over this process is not completely understood, but hepatocyte growth factor, produced by mesenchymal cells in the liver, is involved. Other growth factors, such as epidermal growth factor and cytokines, tumor necrosis factor, and interleukin (IL)-6 can also stimulate regeneration. The mechanism responsible for returning the liver to a quiescent state might involve transforming growth factor β, a known inhibitor of hepatocyte proliferation. The signal for cessation of regeneration appears to be related to the ratio of liver to body weight. In the presence of inflammation, as with viral hepatitis, regeneration is significantly impaired.
Portal Hypertension
Ongoing inflammation results in fibrosis that constricts blood flow in the sinusoids, creating increased portal pressures. Portal hypertension is formally diagnosed by measurement of the hepatic venous gradient (HVG), defined as the difference between hepatic venous and portal venous pressures. Because direct measurement of portal venous pressures is not easily accomplished, it is estimated by the wedge pressure of the hepatic veins as measured by a balloon catheter introduced into (typically) the right hepatic vein. The difference between that wedge pressure and the free pressure in the hepatic vein is the HVG, normally 1 to 5 mm Hg. Subclinical portal hypertension appears when the HVG rises to 6 to 9 mm Hg. When HVG reaches 10 to 12 mm Hg, portal hypertension becomes a systemic condition affecting hemodynamics, fluid balance, renal function, and cognition.
Resistance to portal blood flow causes collateral vessels to develop between portal and systemic veins. With increased pressure in the splenic vein, collateral vessels to esophageal veins develop. These enlarge and protrude into the esophageal lumen, producing esophageal varices. Variceal size and HVG predict both the likelihood of rupture and ability to control variceal bleeding and rebleeding. Within 2 years of diagnosis of portal hypertension, approximately 30% of patients have a variceal hemorrhage. The 6-week mortality after variceal hemorrhage is 30%, which increases to 50% with a second episode of bleeding. Prophylaxis to prevent bleeding includes nonselective β blockers, long-acting nitrates, endoscopic obliteration, and endoscopic ligation.
Portal hypertension results in portosystemic shunting. Shunted blood circumvents the filtering system of the liver. This results in the entry of drugs, ammonia, and other toxins normally handled by the liver into the systemic circulation; hepatic encephalopathy often ensues. Splanchnic vasodilatation reduces renal perfusion, resulting in renal failure (hepatorenal syndrome). During the early stages of acute renal injury the kidneys can be functionally normal and the changes reversible. In the absence of improvement in liver function, renal injury can become permanent.
Systemic vasodilatation leads to hyperdynamic circulation characterized by low normal blood pressure, low systemic vascular resistance, and high cardiac output. Response to vasoconstrictors is often attenuated owing to endogenous vasodilators, an ineffective splanchnic reservoir, and increased sympathetic tone.
Hepatic Drug Metabolism and Excretion
The liver metabolizes and excretes many drugs into the bile. The liver is also responsible for metabolism of a number of hormones, including thyroxine and the steroids estrogen, cortisol, and aldosterone.
Intrinsic hepatic clearance of a compound divided by the hepatic blood flow determines the extraction ratio. The extraction ratio indicates the efficiency with which various drugs are cleared. Efficiently extracted drugs include many opioids, β blockers (except atenolol), calcium channel blockers, and tricyclic antidepressants. Poorly extracted drugs include warfarin, aspirin, ethanol, and phenobarbital. Elimination of poorly extracted drugs is limited by intrinsic clearance and/or protein binding rather than hepatic blood flow, whereas elimination of highly extracted drugs is dependent on blood flow (see Chapter 4 ).
Anesthetic Pharmacology and the Liver
Volatile anesthetic agents decrease hepatic blood flow. Agents currently in use—isoflurane, sevoflurane, and desflurane—affect hepatic blood flow less than older agents. Despite reductions in hepatic blood flow, liver function testing fails to show alterations of hepatic function after administration of current inhaled anesthetics. Fewer data exist on the effects of inhaled anesthetics on patients with chronic liver disease. Central neuraxial blockade decreases hepatic blood flow proportionally to the decrease in systemic blood pressure. Hepatic blood flow can be restored by administration of vasopressors.
Hepatic dysfunction affects the pharmacokinetics of intravenous anesthetics through alterations in protein binding (as the result of reduced plasma proteins), increases in the volume of distribution, and reductions in hepatic metabolism. The pharmacodynamic effects of opioids and sedatives can be enhanced in patients with end-stage liver failure who have encephalopathy. Although opioids have been used successfully to treat biliary colic, they can also produce spasm of the sphincter of Oddi. Glucagon, opioid antagonists, nitroglycerin, and atropine reverse this effect. Intermediate-duration neuromuscular blocking agents that undergo hepatic elimination have a prolonged duration of action in the presence of liver disease. Atracurium and cisatracurium are not dependent on hepatic elimination, so dosing alterations are not required in patients with hepatic disease (see Chapter 22 ).
Liver Disease: Etiologies and Severity
The most common causes of hepatic cirrhosis are hepatitis C, alcoholic liver disease, and nonalcoholic fatty liver disease. Other causes include biliary cirrhosis, autoimmune disease, hemochromatosis, drug-induced liver disease, metabolic disorders, and hepatocellular cancer. Biliary cirrhosis is associated with several forms of cholestatic disease, including primary biliary cirrhosis, sclerosing cholangitis, and biliary atresia. Nonalcoholic fatty liver disease (also called steatohepatitis), an increasingly recognized cause, is associated with obesity, type 2 diabetes mellitus, and the constellation of risk factors known as the metabolic syndrome. The severity of cirrhosis can be graded using the Child-Turcotte-Pugh (CTP) scoring system ( Table 31.1 ). Patients with the most severe disease have a CTP score of 10 points or more (class C). These patients have exceedingly high perioperative mortality (up to 75%). Class B (7–9 points) patients also have significant perioperative mortality (30%). Preoperative risk modification, through treatment of encephalopathy and ascites, appears to reduce risk.
| Parameters | 1 Point | 2 Points | 3 Points |
|---|---|---|---|
| Albumin (g/dL) | >3.5 | 2.8–3.5 | <2.8 |
| Prothrombin time | |||
| Seconds prolonged | <4 | 4–6 | >6 |
| International normalized ratio | <1.7 | 1.7-2.3 | >2.3 |
| Bilirubin (mg/dL) b | <2 | 2-3 | >3 |
| Ascites | Absent | Slight-moderate | Tense |
| Encephalopathy | None | Grade I-II | Grade III-IV |
a Class A = 5.6 points, B = 7 to 9 points, and C = 10 to 15 points.
b For cholestatic diseases (e.g., primarily biliary cirrhosis), the bilirubin level is disproportionate to the impairment in hepatic function and an allowance should be made. For these conditions, assign 1 point for a bilirubin level less than 4 mg/dL, 2 points for a bilirubin level of 4 to 10 mg/dL, and 3 points for a bilirubin level more than 10 mg/dL.
An alternative mortality risk stratification for patients with liver disease undergoing nonhepatic surgery is the Model for End-Stage Liver Disease (MELD) score. The MELD score was developed to predict 90-day mortality in patients undergoing transjugular intrahepatic portosystemic shunt procedures. It has since been validated for risk stratification of patients with liver disease in a number of different settings, including patients awaiting liver transplantation. The MELD score is used to allocate donor grafts to liver transplant candidates with the greatest urgency (highest predicted 90-day mortality). It is calculated as follows: MELD = 3.78 × ln bilirubin (mg/dL) + 11.2 × ln INR + 9.57 × ln creatinine (in milligrams per deciliter) + 6.43, where ln INR is the natural logarithm and INR is the international normalized ratio. In January 2016, serum sodium (Na) was added to the MELD score to account for the impact of hyponatremia on wait list mortality, particularly at lower MELD scores. The resulting formula is MELD-Na = MELD + 1.32 × (137 − Na) − [0.033 × MELD × (137 − Na)]. Online calculators are convenient and commonly used to ascertain the MELD score.
Cirrhosis and Perioperative Risk: Nonhepatic Surgery
Patients with cirrhosis frequently require nonhepatic surgery for abdominal wall hernias, peptic ulcer disease, biliary, small bowel, colon and pancreatic disease, in addition to cardiac, vascular and orthopedic surgery. In the perioperative period cirrhosis can decompensate owing to the effects of surgery and anesthesia, which results in decreased hepatic blood flow and an increased risk of bacterial infection. Risk factors for perioperative mortality and morbidity include the severity of liver disease as determined by the CTP or MELD score, and the anatomic location of procedure, with upper abdominal surgery associated with considerable risk.
A pioneering study included 140 peripheral, intraabdominal, and intrathoracic procedures in 131 patients whose MELD scores ranged from 6 to 43. Overall 30-day mortality was 16%, which correlated with MELD score and was confined to nonperipheral procedures. Abdominal surgery carries more risk than nonabdominal surgery owing to significant reductions in hepatic blood flow. A more recent study, which included 138 patients with cirrhosis undergoing general surgical procedures, found an overall hospital mortality of 28%. As in other series, mortality was stratified by CTP group, with mortality highest in CTP class C patients. Laparoscopic surgery, which is controversial because of the requirement for pneumoperitoneum, appears to reduce perioperative risk.
Hepatic Surgery
Hepatic resection surgery, most commonly for hepatocellular carcinoma and metastatic cancer, evolved over the past several decades of the 20th century. In a single-center series, the overall mortality was 4%, although subgroups with cirrhosis and biliary obstruction had higher mortality (9% and 21%, respectively). This improvement in survival after hepatic resection is attributed to a number of factors, including improved patient selection, volumetric studies designed to assess predicted remnant liver mass, portal vein embolization (to decrease the mass of resected tissue and stimulate regeneration of the liver remnant), and use of intraoperative ultrasound to delineate vascular anatomy and the extent of pathology. Additionally, the success of liver transplantation, with a 5-year patient survival of 73%, has given rise to a generation of hepatobiliary surgeons skilled in liver resection. Since 2000, perioperative mortality for hepatic resection has not seen further reductions, remaining at about 3%, because of expanded indications for surgery in a patient population that is older and more likely to have cirrhosis.
Liver transplantation is recognized as definitive management for patients with acute and chronic liver failure. The liver is the second most commonly transplanted organ, after the kidney. Anesthetic management for patients undergoing liver transplantation is challenging because of unpredictable, sometimes massive, blood loss; coagulation abnormalities; electrolyte and acid-base disturbances; and hemodynamic, pulmonary, renal, neurologic, and infectious derangements.
Gastrointestinal Tract
The GI, or alimentary, tract provides the body with substrates for energy needs and essential nutrients through food digestion and absorption. Water, electrolytes, vitamins, and nutrients are supplied to the body via the exclusive function of the GI tract. Control of the process requires local, nervous system, and hormonal input.
Anatomy
The anatomy of the digestive tract consists of one continuous tube connected with the external environment. It is separated into distinct sections, each adapted to specialized functions ( Fig. 31.5 ). A typical cross section of the gut consists of multiple layers ( Fig. 31.6 ). Moving from the outside to within, the gut is made up of the serosa, a longitudinal muscle layer, a circular muscle layer, submucosa, and mucosa. The enteric nervous system plexuses lie within the gut layers. As a barrier to the external environment, an epithelial layer lines the innermost portion of the gut.
