KEY POINTS

1. The liver receives roughly one fourth of the cardiac output in healthy adults at rest. The portal vein delivers nearly 75% of the hepatic blood flow, and the hepatic artery provides the rest. Each of these vessels supplies about half of the O₂ consumed by the liver. Blood enters the hepatic sinusoids (capillaries of the liver) by terminal portal venules and hepatic arterioles and exits through hepatic venules (often called "central veins"). Hepatic veins (downstream to the sinusoids) are the major source of intravascular resistance within the liver.
2. The acinus (the functional microvascular unit of the liver) has three circulatory zones, defined by relative distances of hepatocytes from the portal axis. Hepatocytes in zone 1 (periportal region) receive oxygen- and nutrient-rich blood, whereas the blood that perfuses zone 3 (centrilobular region) delivers less oxygen and contains metabolites from zone 1 and zone 2 (midzonal region). Centrilobular hepatocytes have the greatest density of cytochrome P450 proteins and are the most vulnerable to ischemia, hypoxia, venous congestion, and reactive drug metabolites.
3. The hepatic arterial buffer response is the main intrinsic regulator of hepatic blood flow. Arterial hypotension causes portal venous flow to decrease since pressure-flow autoregulation is absent in the liver (i.e., in the fasted state). When this occurs, the buffer response increases hepatic arterial flow, which helps preserve the hepatic oxygen supply. Advanced liver disease disrupts the buffer response, increasing the risk that protracted hypotension (e.g., from controlled hypotensive anesthetic techniques) will cause hypoxic liver damage.
4. The liver is an essential part of the splanchnic circulation. In normovolemic adults, sympathoadrenal stimulation rapidly transfers roughly a liter of splanchnic blood to the systemic circulation. Splanchnic reservoir dysfunction, such as occurs in patients with advanced liver disease, will worsen hypotensive responses to sudden losses of intravascular volume.
5. A 12- to 24-hour fast exhausts liver glycogen stores, making the production of blood glucose dependent on hepatic gluconeogenesis. Starvation stimulates lipolysis, beta-oxidation of fatty acids, and ketone synthesis by the liver. Ketones promote the pancreatic release of insulin, which decreases lipolysis and fatty acid oxidation. Starvation- or stress-induced ketosis is therefore self-limited—except in insulin-deficient states, when diabetic ketoacidosis ensues.
6. Albumin accounts for 15% of the protein made by the liver and plays key roles in maintaining plasma oncotic pressure and transporting endogenous (e.g., bilirubin, free fatty acids) and exogenous substances to the liver. Hepatocytes convert amino acids to ammonia and intermediary metabolites and transform ammonia and other nitrogenous compounds to urea. Thus, in patients with severe liver disease (and normal renal function), the blood urea nitrogen (BUN) level typically remains low, whereas nitrogenous wastes increase in blood and other tissues.
7. The liver makes most coagulant factors (except III, IV, and VIII) and inserts γ-carboxylate groups into many of them (II, VII, IX, X, protein C, protein S) in vitamin K-dependent, post-translational reactions. γ-Carboxylation enables activation of these zymogens in plasma.
8. Bile acids are produced by hepatocytes and facilitate the gastrointestinal absorption of many lipophilic molecules, including vitamin K. In cholestatic disorders, the liver synthesizes, but does not γ-carboxylate, clotting factors. Parenteral vitamin K therapy will rapidly correct the resultant coagulopathy, unless liver failure supervenes. In such cases, patients need frozen plasma because the γ-carboxylation pathway is dysfunctional.
9. The liver is the major organ for metabolizing and removing a wide variety of substances through phase 1 (mostly oxidations with cytochrome P450), phase 2 (conjugations), and phase 3 (ATP transport proteins) reactions. The major pharmacokinetic parameters of hepatic drug clearance are liver blood flow, protein binding, intrinsic clearance, and extraction ratio (ER). Generally, decreases in liver blood flow only lower the hepatic clearances of drugs that have a high ER, whereas decreases in drug metabolizing capacity or increases in protein binding only lower hepatic clearances of drugs that have a low ER.
10. The liver filters venous blood from the gastrointestinal tract. Porto-systemic shunting—whether caused by intrinsic liver disease or a procedure to decompress portal hypertension—circumvents the hepatic filter. Shunting decreases the hepatic clearance of drugs, nitrogenous wastes, and toxins and therefore increases the concentrations of such substances in arterial blood (greater bioavailability) and their effects on the body (e.g., hepatic encephalopathy).

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11. The panel of biochemical tests typically used to evaluate the liver (liver function tests) will not reveal specific hepatic diseases. Rather, these tests identify broad categories of pathology: namely hepatocellular injury, hepatobiliary dysfunction, and hepatic synthetic dysfunction. A sudden decrease in the ability of the liver to synthesize proteins is detectable within days as a prolongation of the PT owing to the short half-life of factor VII. Serum albumin concentration is useful for evaluating the status of chronic, but not acute, liver dysfunction because plasma albumin has a half-life of 3 weeks.
12. Kupffer cells, which account for nearly 10% of the hepatic mass, phagocytose and process antigens absorbed from the gastrointestinal tract. In sepsis, these cells scavenge bacteria, inactivate toxins, and remove inflammatory mediators. When activated, Kupffer cells produce reactive oxygen species, nitro-radicals, leukotrienes, proteases, and cytokines and recruit neutrophils to the liver to augment the inflammatory response. Activated Kupffer cells also play a role in the pathogenesis of hepatocellular disease.
13. Portal hypertension is responsible for severe complications of advanced liver disease, such as variceal bleeding, hepatic encephalopathy, and renal failure. Cirrhosis and portal hypertension cause a hyperdynamic circulatory state characterized by high cardiac output, low total peripheral resistance, and low-normal arterial blood pressure. Pathophysiologic hallmarks include extensive arteriovenous communications, hypervolemia within the splanchnic vasculature, and hypovolemia of the extrasplanchnic circulation (decreased effective plasma volume). The cardiovascular responsiveness to vasopressors decreases, which usually reflects increased concentrations of endogenous vasodilators and occasionally myocardial dysfunction (e.g., cirrhotic cardiomyopathy).