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Chapter 33: Hepatic Physiology & Anesthesia

Michael Ramsay

KEY CONCEPTS

KEY CONCEPTS

The hepatic artery supplies about 25% of the blood supply but 45% to 50% of the liver’s oxygen requirements, and the portal vein supplies
75% of the blood supply and the remaining 50% to 55% of oxygen requirements.

All coagulation factors, with the exception of factor VIII and von Willebrand factor, are produced by the liver. Vitamin K is a necessary
cofactor in the synthesis of prothrombin (factor II) and factors VII, IX, and X.

Many “liver function” tests, such as serum transaminase measurements, reflect hepatocellular integrity more than hepatic function. Liver
tests that measure hepatic synthetic function include serum albumin, prothrombin time (PT) or international normalized ratio (INR), serum
cholesterol, and plasma pseudocholinesterase.

Albumin values less than 2.5 g/dL are generally indicative of chronic liver disease, acute stress, or severe malnutrition. Increased losses of
albumin in the urine (nephrotic syndrome) or the gastrointestinal tract (protein-losing enteropathy) can also produce hypoalbuminemia.

The PT, which normally ranges between 11 and 14 s, depending on the control value, measures the activity of fibrinogen, prothrombin, and
factors V, VII, and X. A prolonged INR reflects a patient with a dysfunctional liver. The effect on coagulation will depend on the balance between
coagulation and anticoagulation factors. If production of protein C, protein S, and antithrombin 3, are affected more than the coagulation
factors a normal or hypercoaguable state might exist. The INR was developed to monitor the effect of warfarin and that does not affect the
anticoagulant factors.

Operative procedures near the liver can reduce hepatic blood flow up to 60%. Although the mechanisms are not clear, they most likely
involve sympathetic activation, local reflexes, and direct compression of vessels in the portal and hepatic circulations.

The neuroendocrine stress response to surgery and trauma is characterized by elevated circulating levels of catecholamines, glucagon, and
cortisol and results in mobilization of carbohydrate stores and proteins, causing hyperglycemia and a negative nitrogen balance (catabolism).

All opioids can potentially cause spasm of the sphincter of Oddi and increase biliary pressure.

When liver tests are abnormal postoperatively, the usual cause is underlying liver disease or the surgical procedure itself.

FUNCTIONAL ANATOMY
The liver is the heaviest organ in the body, weighing approximately 1500 g in adults. It is separated by the falciform ligament into right and left anatomic
lobes; the larger right lobe has two additional smaller lobes at its posterior–inferior surface, the caudate and quadrate lobes.

In contrast, surgeons describe the liver based on its blood supply. Thus, the right and left surgical lobes are defined by anatomists by the point of
bifurcation of the hepatic artery and portal vein (porta hepatis); the falciform ligament therefore divides the left surgical lobe into medial and lateral
segments. Surgical anatomy defines a total of eight segments.
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is made up ofPhysiology & discrete
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cylindrically around a centrilobular vein (Figure 33–1). Four to five portal • Notice • Accessibility
composed of hepatic arterioles, portal venules, bile canaliculi,
lymphatics, and nerves, surround each lobule.
The liver is the heaviest organ in the body, weighing approximately 1500 g in adults. It is separated by the falciform ligament into right and left anatomic
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lobes; the larger right lobe has two additional smaller lobes at its posterior–inferior surface, the caudate and quadrate lobes.
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In contrast, surgeons describe the liver based on its blood supply. Thus, the right and left surgical lobes are defined by anatomists by the point of
bifurcation of the hepatic artery and portal vein (porta hepatis); the falciform ligament therefore divides the left surgical lobe into medial and lateral
segments. Surgical anatomy defines a total of eight segments.

The liver is made up of 50,000 to 100,000 discrete anatomic units called lobules. Each lobule is composed of plates of hepatocytes arranged
cylindrically around a centrilobular vein (Figure 33–1). Four to five portal tracts, composed of hepatic arterioles, portal venules, bile canaliculi,
lymphatics, and nerves, surround each lobule.

FIGURE 33–1

The hepatic lobule.

In contrast to a lobule, an acinus, the functional unit of the liver, is defined by a portal tract in the middle and centrilobular veins at the periphery. Cells
closest to the portal tract (zone 1) are well oxygenated; those closest to centrilobular veins (zone 3) receive the least oxygen and are therefore most
susceptible to ischemic injury.

Blood from hepatic arterioles and portal venules comingle in the sinusoidal channels, which lie between the cellular plates and serve as capillaries.
These channels are lined by endothelial cells and by macrophages known as Kupffer cells. The Kupffer cells remove bacterial endotoxins, viruses,
proteins, and particulate matter from the blood. The space of Disse lies between the sinusoidal capillaries and the hepatocytes. Venous drainage from
the central veins of hepatic lobules coalesces to form the hepatic veins (right, middle, and left), which empty into the inferior vena cava (Figure 33–2).
The caudate lobe is usually drained by its own set of veins.

FIGURE 33–2

Hepatic blood flow. (Modified with permission from Guyton AC. Textbook of Medical Physiology. 7th ed. Philadelphia, PA: WB Saunders; 1986.)

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The caudate lobe is usually drained by its own set of veins.
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FIGURE 33–2
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Hepatic blood flow. (Modified with permission from Guyton AC. Textbook of Medical Physiology. 7th ed. Philadelphia, PA: WB Saunders; 1986.)

Bile canaliculi originate between hepatocytes within each plate and join to form bile ducts. An extensive system of lymphatic channels also forms within
the plates and is in direct communication with the space of Disse.

The liver is supplied by T6–T11 sympathetic nerve fibers, right and left vagal nerve parasympathetic fibers, and right phrenic nerve fibers. Some
autonomic fibers synapse first in the celiac plexus, whereas others reach the liver directly via splanchnic nerves and vagal branches before forming the
hepatic plexus. The majority of sensory afferent fibers travel with sympathetic fibers.

Hepatic Blood Flow

Normal hepatic blood flow is 25% to 30% of the cardiac output and is provided by the hepatic artery and portal vein. The hepatic artery supplies
about 25% of the blood supply but 45% to 50% of the liver’s oxygen requirements, and the portal vein supplies 75% of the blood supply and the
remaining 50% to 55% (Figure 33–2). Hepatic arterial flow is dependent on metabolic demand (autoregulation), whereas flow through the portal vein is
dependent on blood flow to the gastrointestinal tract and the spleen. A reciprocal, though somewhat limited, mechanism exists, such that a decrease
in either hepatic arterial or portal venous flow results in a compensatory increase in the other.

The hepatic artery has α1-adrenergic vasoconstriction receptors as well as β2-adrenergic, dopaminergic (D1), and cholinergic vasodilator receptors.
The portal vein has only α1-adrenergic and dopaminergic (D1) receptors. Sympathetic activation results in vasoconstriction of the hepatic artery and
mesenteric vessels, decreasing hepatic blood flow. β-Adrenergic stimulation vasodilates the hepatic artery; β-blockers reduce blood flow and,
therefore, decrease portal pressure.

Reservoir Function

Portal vein pressure is normally only about 7 to 10 mm Hg, but the low resistance of the hepatic sinusoids allows relatively large blood flows through
the portal vein. Small changes in hepatic venous tone and hepatic venous pressure thus can result in large changes in hepatic blood volume, allowing
the liver to act as a blood reservoir (Figure 33–3). A decrease in hepatic venous pressure, as occurs during hemorrhage, shifts blood from hepatic
veins and sinusoids into the central venous circulation and augments circulating blood volume. Blood loss can be reduced during liver surgery by
lowering the central venous pressure, thereby reducing hepatic venous pressure and hepatic blood volume. In patients with congestive heart failure,
the increase in central venous pressure is transmitted to the hepatic veins and causes congestion of the liver that can adversely affect liver function.

FIGURE 33–3
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Chapter 33:the
The role of Hepatic
liver asPhysiology & (Modified
a blood reservoir. Anesthesia,
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permission Page 3 / 20
from Lautt WW, Greenway CV. Hepatic venous compliance and role of liver as a
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blood reservoir. Am J Physiol. 1976 Aug;231(2):292-295.)
the liver to act as a blood reservoir (Figure 33–3). A decrease in hepatic venous pressure, as occurs during hemorrhage, shifts blood from hepatic
Johns
veins and sinusoids into the central venous circulation and augments circulating blood volume. Blood loss can be reduced Hopkins
during Medicalby
liver surgery School
lowering the central venous pressure, thereby reducing hepatic venous pressure and hepatic blood volume. In patients Access Provided by:
with congestive heart failure,
the increase in central venous pressure is transmitted to the hepatic veins and causes congestion of the liver that can adversely affect liver function.

FIGURE 33–3

The role of the liver as a blood reservoir. (Modified with permission from Lautt WW, Greenway CV. Hepatic venous compliance and role of liver as a
blood reservoir. Am J Physiol. 1976 Aug;231(2):292-295.)

Metabolic Function

The abundance of enzymatic pathways in the liver allows it to play a key role in the metabolism of carbohydrates, fats, proteins, and other substances
(Figure 33–4 and Table 33–1). The final products of carbohydrate digestion are glucose, fructose, and galactose. With the exception of the large
amount of fructose that is converted by the liver to lactate, hepatic conversion of fructose and galactose into glucose makes glucose metabolism the
final common pathway for most carbohydrates.

FIGURE 33–4

Important metabolic pathways in hepatocytes. Although small amounts of adenosine triphosphate (ATP) are derived directly from some intermediary
reactions, the overwhelming majority of ATP produced is the result of oxidative phosphorylation of the reduced forms of nicotinamide adenine
dinucleotide (NADH) and nicotinamide adenine dinucleotide phosphate (NADPH).

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FIGURE 33–4

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Important metabolic pathways in hepatocytes. Although small amounts of adenosine triphosphate (ATP) are derived directly from some intermediary
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reactions, the overwhelming majority of ATP produced is the result of oxidative phosphorylation of the reduced forms of nicotinamide adenine
dinucleotide (NADH) and nicotinamide adenine dinucleotide phosphate (NADPH).

TABLE 33–1
Metabolic functions of the liver.

Creation and secretion of bile

Nutrient metabolism
Amino acids
Monosaccharides (sugars)
Lipids (fatty acids, cholesterol, phospholipids, lipoproteins)
Vitamins

Phase I and II biotransformation

Toxins
Drugs
Hormones (steroids)

Synthesis
Albumin, α1-antitrypsin, proteases
Clotting factors
Acute phase proteins
Plasma cholinesterase

Immune function
Kupffer cells

All cells utilize2020­12­20

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glycolysis. The liver and adipose tissue can also utilizeMichael
33: Hepatic Physiology & Anesthesia, Ramsay
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glucose absorbed following a meal is normally stored as glycogen, which only the liver and muscle are able to store in significant amounts. When
glycogen storage capacity is exceeded, excess glucose is converted into fat. Insulin enhances glycogen synthesis, and epinephrine and glucagon
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TABLE 33–1
Metabolic functions of the liver.

Creation and secretion of bile

Nutrient metabolism
Amino acids
Monosaccharides (sugars)
Lipids (fatty acids, cholesterol, phospholipids, lipoproteins)
Vitamins

Phase I and II biotransformation

Toxins
Drugs
Hormones (steroids)

Synthesis
Albumin, α1-antitrypsin, proteases
Clotting factors
Acute phase proteins
Plasma cholinesterase

Immune function
Kupffer cells

All cells utilize glucose to produce energy in the form of adenosine triphosphate (ATP), either aerobically via the citric acid cycle or anaerobically via
glycolysis. The liver and adipose tissue can also utilize the phosphogluconate pathway, which provides energy and fatty acid synthesis. Most of the
glucose absorbed following a meal is normally stored as glycogen, which only the liver and muscle are able to store in significant amounts. When
glycogen storage capacity is exceeded, excess glucose is converted into fat. Insulin enhances glycogen synthesis, and epinephrine and glucagon
enhance glycogenolysis. Because glucose consumption averages 150 g/d, and hepatic glycogen stores are normally depleted after 24 h of fasting. After
this period of fasting, gluconeogenesis, the de novo synthesis of glucose, is necessary to provide an uninterrupted supply of glucose for other organs.

The liver and kidney are unique in their capacity to form glucose from lactate, pyruvate, amino acids (mainly alanine), and glycerol (derived from fat
metabolism). Hepatic gluconeogenesis is vital in the maintenance of a normal blood glucose concentration. Glucocorticoids, catecholamines,
glucagon, and thyroid hormone greatly enhance gluconeogenesis, whereas insulin inhibits it.

When carbohydrate stores are saturated, the liver converts the excess ingested carbohydrates and proteins into fat. The fatty acids thus formed can be
used immediately for fuel or stored in adipose tissue or the liver for later consumption. Nearly all cells utilize fatty acids derived from ingested fats or
synthesized from intermediary metabolites of carbohydrates and protein as an energy source—only red blood cells and the renal medulla are limited
to glucose utilization. Neurons normally utilize only glucose, but, after a few days of starvation, they can switch to ketone bodies, the breakdown
products of fatty acids that have been synthesized by the liver as an energy source.

To oxidize fatty acids, they are converted into acetylcoenzyme A (acetyl-CoA), which is then oxidized via the citric acid cycle to produce ATP. The liver is
capable of high rates of fatty acid oxidation and can form acetoacetic acid (one of the ketone bodies) from excess acetyl-CoA. The acetoacetate
released by hepatocytes serves as an alternative energy source for other cell types by reconversion into acetyl-CoA. Insulin inhibits hepatic ketone
body production. Acetyl-CoA is also used by the liver for the production of cholesterol and phospholipids, which is necessary in the synthesis of
cellular membranes throughout the body.
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of urea (to eliminate the ammonia produced from deamination), interconversions
Notice between nonessential amino acids, and (4) formation
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of plasma proteins. Deamination is necessary for the conversion of excess amino acids into carbohydrates and fats. The enzymatic processes, most
commonly transamination, convert amino acids into their respective keto acids and produce ammonia as a byproduct.
To oxidize fatty acids, they are converted into acetylcoenzyme A (acetyl-CoA), which is then oxidized via the citric acid cycle to produce ATP. The liver is
JohnsThe
capable of high rates of fatty acid oxidation and can form acetoacetic acid (one of the ketone bodies) from excess acetyl-CoA. Hopkins Medical School
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released by hepatocytes serves as an alternative energy source for other cell types by reconversion into acetyl-CoA. Insulin inhibits hepatic ketone
body production. Acetyl-CoA is also used by the liver for the production of cholesterol and phospholipids, which is necessary in the synthesis of
cellular membranes throughout the body.

The liver performs a critical role in protein metabolism. The steps involved in protein metabolism include (1) deamination of amino acids, (2)
formation of urea (to eliminate the ammonia produced from deamination), (3) interconversions between nonessential amino acids, and (4) formation
of plasma proteins. Deamination is necessary for the conversion of excess amino acids into carbohydrates and fats. The enzymatic processes, most
commonly transamination, convert amino acids into their respective keto acids and produce ammonia as a byproduct.

Ammonia formed from deamination (as well as that produced by colonic bacteria and absorbed through the gut) is highly toxic to tissues. Through a
series of enzymatic steps, the liver combines two molecules of ammonia with CO2 to form urea. The urea thus formed readily diffuses out of the liver
and can then be excreted by the kidneys.

Nearly all plasma proteins, with the notable exception of immunoglobulins, are formed by the liver. These include albumin, α1-antitrypsin and other
proteases/elastases, and the coagulation factors. Albumin, the most abundant plasma protein, is responsible for maintaining a normal plasma oncotic
pressure and is the principal binding and transport protein for fatty acids and a large number of hormones and drugs. Consequently, changes in
albumin concentration can affect the concentration of the pharmacologically active, unbound fraction of many drugs.

All coagulation factors, with the exception of factor VIII and von Willebrand factor, are produced by the liver (Table 33–2 and Figure 33–5; see
Chapter 51). The liver also produces anticoagulant factors (protein C, protein S, and antithrombin III). Vascular endothelial cells synthesize factor VIII,
levels of which are therefore usually maintained in chronic liver disease. Vitamin K is a necessary cofactor in the synthesis of prothrombin (factor II)
and factors VII, IX, and X. The liver also produces plasma cholinesterase (pseudocholinesterase), an enzyme that hydrolyzes esters, including ester
local anesthetics and some muscle relaxants, including succinylcholine. Other important proteins formed by the liver include protease inhibitors
(antithrombin III, α2-antiplasmin, and α1-antitrypsin), transport proteins (transferrin, haptoglobin, and ceruloplasmin), complement, α1-acid
glycoprotein, C-reactive protein, and serum amyloid A.

TABLE 33–2
Coagulation factors.

Factor Approximate Half-Life (h)

I Fibrinogen 100

II Prothrombin 80

III Tissue thromboplastin —

IV Calcium —

V Proaccelerin 18

VII Proconvertin 6

VIII Antihemophilic factor 10

IX Christmas factor 24

X Stuart factor 50

XI Plasma thromboplastin antecedents 25

XII Hageman factor 60

XIII Fibrin-stabilizing factor 90

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FIGURE 33–5
and factors VII, IX, and X. The liver also produces plasma cholinesterase (pseudocholinesterase), an enzyme that hydrolyzes esters, including ester
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local anesthetics and some muscle relaxants, including succinylcholine. Other important proteins formed by the liver include protease inhibitors
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(antithrombin III, α2-antiplasmin, and α1-antitrypsin), transport proteins (transferrin, haptoglobin, and ceruloplasmin), complement, α1-acid
glycoprotein, C-reactive protein, and serum amyloid A.

TABLE 33–2
Coagulation factors.

Factor Approximate Half-Life (h)

I Fibrinogen 100

II Prothrombin 80

III Tissue thromboplastin —

IV Calcium —

V Proaccelerin 18

VII Proconvertin 6

VIII Antihemophilic factor 10

IX Christmas factor 24

X Stuart factor 50

XI Plasma thromboplastin antecedents 25

XII Hageman factor 60

XIII Fibrin-stabilizing factor 90

FIGURE 33–5

The intrinsic and extrinsic coagulation pathways. HMWK, high-molecular-weight kininogen.

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 Johns Hopkins Medical School
FIGURE 33–5
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The intrinsic and extrinsic coagulation pathways. HMWK, high-molecular-weight kininogen.

Drug Metabolism

Many exogenous substances, including most drugs, undergo hepatic biotransformation, and the end products of these reactions are usually either
inactivated or converted to more water-soluble substances that can be readily excreted in bile or urine. Hepatic biotransformations are often
categorized as one of two types of reactions. Phase I reactions modify reactive chemical groups through mixed-function oxidases or the cytochrome P-
450 enzyme systems, resulting in oxidation, reduction, deamination, sulfoxidation, dealkylation, or methylation. Barbiturates and benzodiazepines are
inactivated by phase I reactions. Phase II reactions, which may or may not follow a phase I reaction, involve conjugation of the substance with
glucuronide, sulfate, taurine, or glycine. The conjugated compound can then be readily eliminated in urine or bile.

Some enzyme systems, such as those of cytochrome P-450, can be induced by exposure to drugs such as ethanol, barbiturates, ketamine, and perhaps
benzodiazepines. This can result in increased tolerance to the drugs’ effects. Conversely, some agents, such as cimetidine and chloramphenicol, can
prolong the effects of other drugs by inhibiting these enzymes. Some drugs, including lidocaine, morphine, verapamil, labetalol, and propranolol,
have very high rates of hepatic extraction from the circulation, and their metabolism is therefore highly dependent upon the rate of hepatic blood flow.
As a result, a decrease in their metabolic clearance usually reflects decreased hepatic blood flow rather than hepatocellular dysfunction.
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The liver 33:
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Hepatic role in hormone,
&vitamin, and mineral
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active triiodothyronine (T3). The liver is also the major site of degradation for thyroid hormone, insulin, steroid hormones (estrogen, aldosterone, and
cortisol), glucagon, and antidiuretic hormone. Hepatocytes are the principal storage sites for vitamins A, B12, E, D, and K. Lastly, hepatic production of
 Johns Hopkins
Some enzyme systems, such as those of cytochrome P-450, can be induced by exposure to drugs such as ethanol, barbiturates, ketamine, Medical School
and perhaps
benzodiazepines. This can result in increased tolerance to the drugs’ effects. Conversely, some agents, such as cimetidine and chloramphenicol, can
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prolong the effects of other drugs by inhibiting these enzymes. Some drugs, including lidocaine, morphine, verapamil, labetalol, and propranolol,
have very high rates of hepatic extraction from the circulation, and their metabolism is therefore highly dependent upon the rate of hepatic blood flow.
As a result, a decrease in their metabolic clearance usually reflects decreased hepatic blood flow rather than hepatocellular dysfunction.

The liver plays a major role in hormone, vitamin, and mineral metabolism. It is an important site for the conversion of thyroxine (T4) into the more
active triiodothyronine (T3). The liver is also the major site of degradation for thyroid hormone, insulin, steroid hormones (estrogen, aldosterone, and
cortisol), glucagon, and antidiuretic hormone. Hepatocytes are the principal storage sites for vitamins A, B12, E, D, and K. Lastly, hepatic production of
transferrin and haptoglobin is important because these proteins are involved in iron hemostasis, whereas ceruloplasmin is important in copper
regulation.

Bile Formation

Bile (Table 33–3) plays an important role in absorption of fat and excretion of bilirubin, cholesterol, and many drugs. Hepatocytes continuously
secrete bile salts, cholesterol, phospholipids, conjugated bilirubin, and other substances into bile canaliculi.

TABLE 33–3
Composition of bile.

97% water

<1% bile salts

Pigments

Inorganic salts

Lipids
Cholesterol
Fatty acids

Lecithin

Alkaline phosphatase

Bile ducts from hepatic lobules join and eventually form the right and left hepatic ducts. These ducts, in turn, combine to form the hepatic duct, which
together with the cystic duct from the gallbladder becomes the common bile duct (Figure 33–6). The gallbladder serves as a reservoir for bile. The bile
acids formed by hepatocytes from cholesterol are essential for emulsifying the insoluble components of bile and facilitating the intestinal absorption
of lipids. Defects in the formation or secretion of bile salts interfere with the absorption of fats and fat-soluble vitamins (A, D, E, and K). Because of
limited stores of vitamin K, a deficiency of this fat-soluble vitamin can develop within a few days. Vitamin K deficiency is manifested as a
coagulopathy due to impaired formation of prothrombin and of factors VII, IX, and X.

FIGURE 33–6

The biliary system. (Modified with permission from Guyton AC. Textbook of Medical Physiology. 7th ed. Philadelphia, PA: WB Saunders; 1986.)

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coagulopathy due to impaired formation of prothrombin and of factors VII, IX, and X.
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FIGURE 33–6
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The biliary system. (Modified with permission from Guyton AC. Textbook of Medical Physiology. 7th ed. Philadelphia, PA: WB Saunders; 1986.)

Bilirubin is primarily the end product of hemoglobin metabolism, and it is formed from degradation of the heme ring in Kupffer cells. Bilirubin is then
released into blood, where it readily binds to albumin. Hepatic uptake of bilirubin from the circulation is passive, but binding to intracellular proteins
traps the bilirubin inside hepatocytes. Bilirubin is conjugated by the hepatocytes, primarily with glucuronide, and actively excreted into bile canaliculi.

LIVER TESTS
The most commonly performed liver tests are neither sensitive nor specific. No one laboratory test evaluates overall hepatic function, reflecting
instead one aspect of hepatic function that must be interpreted in conjunction with other tests and clinical assessment of the patient.

Many “liver function” tests, such as serum transaminase measurements, reflect hepatocellular integrity more than hepatic function. Liver tests that
measure hepatic synthetic function include serum albumin, prothrombin time (PT) or international normalized ratio (INR), serum cholesterol, and
plasma pseudocholinesterase. Moreover, because of the liver’s large functional reserve, substantial cirrhosis may be present with few or no laboratory
abnormalities evident.

Liver abnormalities can often be divided into either parenchymal disorders or obstructive disorders based on laboratory tests (Table 33–4).
Obstructive disorders primarily affect biliary excretion of substances, whereas parenchymal disorders result in generalized hepatocellular
dysfunction.

TABLE 33–4

Abnormalities in liver tests.1 – 3

Parenchymal (Hepatocellular) Dysfunction Biliary Obstruction or Cholestasis

AST (SGOT) ↑ to ↑↑↑ ↑

ALT (SGPT) ↑ to ↑↑↑ ↑

Albumin 0 to ↓↓↓ 0

Prothrombin time 0 to ↑↑↑ 0 to ↑↑4

Bilirubin 0 to ↑↑↑ 0 to ↑↑↑

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5′-Nucleotidase 0 to ↑ ↑ to ↑↑↑
abnormalities evident.
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Liver abnormalities can often be divided into either parenchymal disorders or obstructive disorders based on laboratory tests (Table 33–4).
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Obstructive disorders primarily affect biliary excretion of substances, whereas parenchymal disorders result in generalized hepatocellular
dysfunction.

TABLE 33–4

Abnormalities in liver tests.1 – 3

Parenchymal (Hepatocellular) Dysfunction Biliary Obstruction or Cholestasis

AST (SGOT) ↑ to ↑↑↑ ↑

ALT (SGPT) ↑ to ↑↑↑ ↑

Albumin 0 to ↓↓↓ 0

Prothrombin time 0 to ↑↑↑ 0 to ↑↑4

Bilirubin 0 to ↑↑↑ 0 to ↑↑↑

Alkaline phosphatase ↑ ↑ to ↑↑↑

5′-Nucleotidase 0 to ↑ ↑ to ↑↑↑

γ-Glutamyl transpeptidase ↑ to ↑↑↑ ↑↑↑

1Adapted with permission from Wilson JD, Braunwald E, Isselbacher KJ et al. Harrison’s Principles of Internal Medicine. 12th ed. New York, NY: McGraw-Hill

Education; 1991.

2AST, aspartate aminotransferase; SGOT, serum glutamic-oxaloacetic transaminase; ALT, alanine aminotransferase; SGPT, serum glutamic pyruvic-transferase.

3↑, increases; 0, no change; ↓, decreases.

4Usually corrects with vitamin K.

Serum Bilirubin

The normal total bilirubin concentration, composed of conjugated (direct), water-soluble and unconjugated (indirect), lipid-soluble forms, is less than
1.5 mg/dL (<25 mmol/L) and reflects the balance between bilirubin production and excretion. Jaundice is usually clinically obvious when total bilirubin
exceeds 3 mg/dL. A predominantly conjugated hyperbilirubinemia (>50%) is associated with increased urinary urobilinogen and may reflect
hepatocellular dysfunction, congenital (Dubin–Johnson or Rotor syndrome) or acquired intrahepatic cholestasis, or extrahepatic biliary obstruction.
Hyperbilirubinemia that is primarily unconjugated may be seen with hemolysis or with congenital (Gilbert or Crigler–Najjar syndrome) or acquired
defects in bilirubin conjugation. Unconjugated bilirubin is neurotoxic, and high levels may produce encephalopathy.

Serum Aminotransferases (Transaminases)

These enzymes are released into the circulation as a result of hepatocellular injury or death. Two aminotransferases are most commonly measured:
aspartate aminotransferase (AST), also known as serum glutamic-oxaloacetic transaminase (SGOT); and alanine aminotransferase (ALT), also known
as serum glutamic pyruvic-transferase (SGPT).

Serum Alkaline Phosphatase

Alkaline phosphatase is produced by the liver, bone, small bowel, kidneys, and placenta and is excreted into bile. Normal serum alkaline phosphatase
activity is 25 to 85 IU/L; children and adolescents have much higher levels, reflecting active growth. Most circulating alkaline phosphatase is normally
derived from bone; however, with biliary obstruction, more hepatic alkaline phosphatase is synthesized and released into the circulation.
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Serum Albumin
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The normal serum albumin concentration is 3.5 to 5.5 g/dL. Because its half-life is approximately 2 to 3 weeks, albumin concentration may initially be
normal with acute liver disease. Albumin values less than 2.5 g/dL are generally indicative of chronic liver disease, acute stress, or severe
Serum Alkaline Phosphatase
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Alkaline phosphatase is produced by the liver, bone, small bowel, kidneys, and placenta and is excreted into bile. Normal serum alkaline phosphatase
activity is 25 to 85 IU/L; children and adolescents have much higher levels, reflecting active growth. Most circulating alkaline phosphatase is normally
derived from bone; however, with biliary obstruction, more hepatic alkaline phosphatase is synthesized and released into the circulation.

Serum Albumin

The normal serum albumin concentration is 3.5 to 5.5 g/dL. Because its half-life is approximately 2 to 3 weeks, albumin concentration may initially be
normal with acute liver disease. Albumin values less than 2.5 g/dL are generally indicative of chronic liver disease, acute stress, or severe
malnutrition. Increased losses of albumin in the urine (nephrotic syndrome) or the gastrointestinal tract (protein-losing enteropathy) can also produce
hypoalbuminemia.

Blood Ammonia

Significant elevations of blood ammonia levels usually reflect disruption of hepatic urea synthesis. Normal whole blood ammonia levels are 47 to 65
mmol/L (80–110 mg/dL). Marked elevations usually reflect severe hepatocellular damage and may cause encephalopathy.

Prothrombin Time

The PT, which normally ranges between 11 and 14 s, measures the activity of fibrinogen, prothrombin, and factors V, VII, and X. The relatively short
half-life of factor VII (4–6 h) makes the PT useful in evaluating hepatic synthetic function of patients with acute or chronic liver disease. Prolongations
of the PT greater than 3 to 4 s from the control are considered significant and usually correspond to an INR greater than 1.5. This INR reflects liver
dysfunction but not the degree of coagulopathy. If protein C, protein S, and antithrombin 3 are more depressed than the coagulation factors the
patient may have normal clotting or be hypercoaguable. The INR was designed to reflect warfarin activity not liver function. This is of great clinical
importance as a prolonged INR after liver surgery may result in venous thromboembolic prophylaxis being withheld until the INR normalizes. This may
leave the patient at increased risk for a pulmonary embolus. Because only 20% to 30% of normal factor activity is required for normal coagulation,
prolongation of the PT usually reflects either severe liver disease or vitamin K deficiency. See Table 33–5 for a list of coagulation test abnormalities.
Patients are increasingly treated with factor Xa inhibitors (eg, apixaban, rivaroxaban) for prevention of thrombosis. Direct assays of anti-factor Xa
activity may be employed to monitor their effects. The direct thrombin inhibitor dabigatran is also currently prescribed for prophylaxis.

TABLE 33–5

Coagulation test abnormalities.1

PT PTT TT Fibrinogen

Advanced liver disease ↑ ↑ N or ↑ N or ↓

DIC ↑ ↑ ↑ ↓

Vitamin K deficiency ↑↑ ↑ N N

Warfarin therapy ↑↑ ↑ N N

Heparin therapy ↑ ↑↑ ↑ N

Hemophilia N ↑ N N
Factor VIII deficiency N ↑ N N
Factor IX deficiency

Factor VII deficiency ↑ N N N

Factor XIII deficiency N N N N

1PT, prothrombin time; PTT, partial thromboplastin time; TT, thrombin time; N, normal; DIC, disseminated intravascular coagulation.
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This technology provides a “real time” assessment of the coagulation status and utilizes thromboelastography (TEG), rotation thromboelastometry
leave the patient at increased risk for a pulmonary embolus. Because only 20% to 30% of normal factor activity is required for normal coagulation,
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prolongation of the PT usually reflects either severe liver disease or vitamin K deficiency. See Table 33–5 for a list of coagulation test abnormalities.
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Patients are increasingly treated with factor Xa inhibitors (eg, apixaban, rivaroxaban) for prevention of thrombosis. Direct assays of anti-factor Xa
activity may be employed to monitor their effects. The direct thrombin inhibitor dabigatran is also currently prescribed for prophylaxis.

TABLE 33–5

Coagulation test abnormalities.1

PT PTT TT Fibrinogen

Advanced liver disease ↑ ↑ N or ↑ N or ↓

DIC ↑ ↑ ↑ ↓

Vitamin K deficiency ↑↑ ↑ N N

Warfarin therapy ↑↑ ↑ N N

Heparin therapy ↑ ↑↑ ↑ N

Hemophilia N ↑ N N
Factor VIII deficiency N ↑ N N
Factor IX deficiency

Factor VII deficiency ↑ N N N

Factor XIII deficiency N N N N

1PT, prothrombin time; PTT, partial thromboplastin time; TT, thrombin time; N, normal; DIC, disseminated intravascular coagulation.

Point-of-Care Viscoelastic Coagulation Monitoring

This technology provides a “real time” assessment of the coagulation status and utilizes thromboelastography (TEG), rotation thromboelastometry
(ROTEM), or Sonoclot analysis to assess global coagulation via the viscoelastic properties of whole blood (Figure 33–7). A clear picture is provided of
the global effect of balance between the procoagulant and anticoagulant systems and the profibrinolytic and antifibrinolytic systems and the resultant
clot tensile strength, allowing precise management of hemostatic therapy. The rate of clot formation, the strength of the clot, and the impact of any clot
lysis can be observed. The presence of disseminated intravascular coagulation can be evaluated, as can the effect of heparin or heparinoid activity. In
addition, platelet function can be assessed, including the effects of platelet inhibition. Viscoelastic coagulation monitoring is particularly important
when assessing the coagulation and thromboembolic risk of the patient who has a prolonged INR from liver dysfunction and has undergone, or is
about to undergo, procedural care. Coagulopathy is a balance of the procoagulant and anticoagulant factors produced by the liver, and the INR only
examines the procoagulant side. A patient with an INR of 3, for example, may have also have anticoagulant factors so reduced that in fact the patient is
in a hypercoagulable state and thereby actually at increased risk for venous thromboembolism. This risk can be readily evaluated by viscoelastic
testing.

FIGURE 33–7

Examples of typical thromboelastograph tracings. A: Normal. B: Hypercoagulation. C: Hypocoagulation (eg, thrombocytopenia). D:

Fibrinolysis. (Reproduced with permission from Johansson PI, Stissing T, Bochsen L, et al. Thrombelastography and thromboelastometry in assessing
coagulopathy in trauma. Scand J Trauma Resusc Emerg Med. 2009 Sep 23:17:45.)

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FIGURE 33–7

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Examples of typical thromboelastograph tracings. A: Normal. B: Hypercoagulation. C: Hypocoagulation (eg, thrombocytopenia). D:
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Fibrinolysis. (Reproduced with permission from Johansson PI, Stissing T, Bochsen L, et al. Thrombelastography and thromboelastometry in assessing
coagulopathy in trauma. Scand J Trauma Resusc Emerg Med. 2009 Sep 23:17:45.)

EFFECT OF ANESTHESIA ON HEPATIC FUNCTION

Hepatic blood flow usually decreases during regional and general anesthesia, and multiple factors are responsible, including both direct and indirect
effects of anesthetic agents, the type of ventilation employed, and the type of surgery being performed.

Decreases in cardiac output reduce hepatic blood flow. The hemodynamic effects of ventilation can also have a significant impact on hepatic blood
flow. Controlled positive-pressure ventilation with high mean airway pressures reduces venous return and cardiac output, and can compromise
hepatic blood flow. The former increases hepatic venous pressure, whereas the latter can reduce blood pressure and increase sympathetic tone.
Positive end-expiratory pressure (PEEP) further accentuates these effects.

Operative procedures near the liver can reduce hepatic blood flow up to 60%. Although the mechanisms are not clear, they most likely involve
sympathetic activation, local reflexes, and direct compression of vessels in the portal and hepatic circulations.

β-Adrenergic blockers, α1-adrenergic agonists, H2-receptor blockers, and vasopressin reduce hepatic blood flow. Dopamine infusions (0.5–2.5
mcg/kg/min) may increase liver blood flow.

Metabolic Functions

The effects of the various anesthetic agents on hepatic metabolism are poorly defined. An endocrine stress response secondary to fasting and surgical
trauma is generally observed. The neuroendocrine stress response to surgery and trauma is characterized by elevated circulating levels of
catecholamines, glucagon, and cortisol and results in the mobilization of carbohydrate stores and protein, causing hyperglycemia and negative
nitrogen balance (catabolism). The neuroendocrine stress response may be at least partially blunted by regional anesthesia, deep general anesthesia,
or pharmacological blockade of the sympathetic system, with regional anesthesia having the most salutary effect on catabolism. All opioids can
potentially cause spasm of the sphincter of Oddi and increase biliary pressure. Naloxone and glucagon may relieve opioid-induced spasm.

Procedures in close proximity to the liver frequently result in modest elevations in lactate dehydrogenase and transaminase concentrations regardless
of the anesthetic agent or technique employed. When liver function tests are abnormal postoperatively, the usual cause is underlying liver disease
or the surgical procedure itself. Persistent abnormalities in liver tests may be indicative of viral hepatitis, sepsis, idiosyncratic drug reactions, or
surgical complications. Postoperative jaundice can result from a variety of factors (Table 33–6), but the most common cause is
overproduction of bilirubin because of resorption of a large hematoma or red cell breakdown following transfusion. Nonetheless, all
other causes should be considered. Correct diagnosis requires a careful review of preoperative liver function and of intraoperative and postoperative
events, such as transfusions, sustained hypotension or hypoxemia, and drug exposure. Desflurane, sevoflurane, and isoflurane have minimal, if any,
direct adverse effect upon hepatocytes.

TABLE 33–6
Causes of postoperative jaundice.

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Resorption of hematomas
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Hemolytic anemia transfusion
Senescent red cell breakdown
overproduction of bilirubin because of resorption of a large hematoma or red cell breakdown following transfusion. Nonetheless, all
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other causes should be considered. Correct diagnosis requires a careful review of preoperative liver function and of intraoperative and postoperative
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events, such as transfusions, sustained hypotension or hypoxemia, and drug exposure. Desflurane, sevoflurane, and isoflurane have minimal, if any,
direct adverse effect upon hepatocytes.

TABLE 33–6
Causes of postoperative jaundice.

Prehepatic (increased bilirubin production)

Resorption of hematomas
Hemolytic anemia transfusion
Senescent red cell breakdown
Hemolytic reactions

Hepatic (hepatocellular dysfunction)

Preexisting liver disease
Ischemic or hypoxemic injury
Drug-induced
Gilbert syndrome
Intrahepatic cholestasis
Halothane

Posthepatic (biliary obstruction)

Postoperative cholecystitis
Postoperative pancreatitis
Retained common bile duct stone
Bile duct injury

Miscellaneous

CASE DISCUSSION

Coagulopathy in a Patient with Liver Disease

A 52-year-old man with a long history of alcohol abuse presents for a splenorenal shunt after three major episodes of upper
gastrointestinal hemorrhage from esophageal varices (also see Chapter 51). Coagulation studies reveal a PT of 17 s (control: 12
s), INR of 1.7, and a partial PT of 43 s (control: 29 s). The platelet count is 75,000/μL .

What factors can contribute to excessive bleeding during and following surgery?

Hemostasis following trauma or surgery is dependent on three major processes: (1) vascular spasm, (2) formation of a platelet plug (primary
hemostasis), and (3) coagulation of blood (secondary hemostasis) in addition to adequate surgical control of bleeding sites. The first two are nearly
immediate (seconds), whereas the third is delayed (minutes). A defect in any of these processes can lead to a bleeding diathesis and increased blood
loss.

Outline the mechanisms involved in primary hemostasis.

Injury to smaller blood vessels normally causes localized spasm as a result of the release of humoral factors from platelets and local myogenic
reflexes. Sympathetic-mediated vasoconstriction is also operative in medium-sized vessels. Exposure of circulating platelets to the damaged
endothelial surface causes them to undergo a series of changes that results in the formation of a platelet plug. If the break in a vessel is small, the
plug itself can often completely stop bleeding. If the break is large, however, coagulation of blood is also necessary to stop the bleeding.

Formation of the platelet plug can be broken down into three stages: (1) adhesion, (2) release of platelet granules, and (3) aggregation. Following
injury, circulating platelets adhere to subendothelial collagen via specific glycoprotein (GP) receptors on their membrane. This interaction is
stabilized by a circulating GP called von Willebrand factor (vWF), which forms additional bridges between subendothelial collagen and platelets via
GPIb. Collagen (as well as epinephrine and thrombin) activates platelet membrane-bound phospholipases A and C, which, in turn, results in the
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formation
Chapter 33:ofHepatic
thromboxane A2 (TXA
Physiology 2) and
&amp; platelet degranulation.
Anesthesia, TXA2 is a potent vasoconstrictor that also promotes platelet aggregation.
Michael Ramsay Platelet
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granules contain a large number of substances, including adenosine diphosphate (ADP), factor V, vWF, fibrinogen, and fibronectin. These factors
attract and activate additional platelets. ADP alters platelet membrane GPIIb/IIIa, which facilitates the binding of fibrinogen to activated platelets.
 plug itself can often completely stop bleeding. If the break is large, however, coagulation of blood is also necessary to stop the bleeding.
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Formation of the platelet plug can be broken down into three stages: (1) adhesion, (2) release of platelet granules, andAccess
(3) aggregation.
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injury, circulating platelets adhere to subendothelial collagen via specific glycoprotein (GP) receptors on their membrane. This interaction is
stabilized by a circulating GP called von Willebrand factor (vWF), which forms additional bridges between subendothelial collagen and platelets via
GPIb. Collagen (as well as epinephrine and thrombin) activates platelet membrane-bound phospholipases A and C, which, in turn, results in the
formation of thromboxane A2 (TXA2) and platelet degranulation. TXA2 is a potent vasoconstrictor that also promotes platelet aggregation. Platelet
granules contain a large number of substances, including adenosine diphosphate (ADP), factor V, vWF, fibrinogen, and fibronectin. These factors
attract and activate additional platelets. ADP alters platelet membrane GPIIb/IIIa, which facilitates the binding of fibrinogen to activated platelets.

Describe the mechanisms involved in normal coagulation.

Coagulation, often referred to as secondary hemostasis, involves formation of a fibrin clot, which usually binds and strengthens a platelet plug.
Fibrin can be formed via one of two pathways (extrinsic or intrinsic; see Figure 33–5) that involve calcium and activation of soluble coagulation
precursor proteins in blood (see Table 33–2). Regardless of which pathway is activated, the coagulation cascade ends in the conversion of
fibrinogen to fibrin. The extrinsic pathway of the coagulation cascade is triggered by the release of a tissue lipoprotein, thromboplastin, from the
membranes of injured cells and is likely the more important pathway. The intrinsic pathway can be triggered by the interaction between
subendothelial collagen with circulating Hageman factor (XII), high-molecular-weight kininogen, and prekallikrein. The latter two substances are
also involved in the formation of bradykinin.

Thrombin plays a central role in coagulation because it not only activates platelets, but also accelerates conversion of factors V, VIII, and XIII to their
active forms. Conversion of prothrombin to thrombin is markedly accelerated by activated platelets. Thrombin then converts fibrinogen to soluble
fibrin monomers that polymerize on the platelet plug. The cross-linking of fibrin polymers by factor XIII is necessary to form a strong, insoluble
fibrin clot. Finally, retraction of the clot, which requires platelets, expresses fluid from the clot and helps pull the walls of the damaged blood vessel
together.

What prevents coagulation of blood in normal tissues?

The coagulation process is limited to injured areas by localization of platelets to the injured area and by maintenance of normal blood flow in
uninjured areas. Normal endothelium produces prostacyclin (prostaglandin I2, PGI2), which is a potent vasodilator that also inhibits platelet
activation and helps to confine the primary hemostatic process to the injured area. Normal blood flow is important in clearing activated coagulation
factors, which are taken up by the monocyte–macrophage scavenger system. Multiple inhibitors of coagulation are normally present in plasma,
including antithrombin III, protein C, protein S, and tissue factor pathway inhibitor. Antithrombin III complexes with and inactivates circulating
coagulation factors (with the notable exception of factor VII), and protein C specifically inactivates factors V and VIII. Heparin exerts its anticoagulant
activity by augmenting the activity of antithrombin III. Protein S enhances the activity of protein C, and deficiencies of protein C and protein S lead to
hypercoagulability. Tissue factor pathway inhibitor antagonizes the action of activated factor VII.

What is the role of the fibrinolytic system in normal hemostasis?

The fibrinolytic system is normally activated simultaneously with the coagulation cascade and functions to maintain the fluidity of blood during
coagulation. It is also responsible for clot lysis once tissue repair begins. When a clot is formed, a large amount of the protein plasminogen is
incorporated. Plasminogen is then activated by tissue plasminogen activator (tPA), which is usually released by endothelial cells in response to
thrombin, and by Hageman factor (XII). The resulting formation of plasmin degrades fibrin and fibrinogen, as well as other coagulation factors.
Urokinase (found in urine) and streptokinase (a product of bacteria) are also potent activators of plasminogen to plasmin. The action of tPA is
localized because (1) it is absorbed into the fibrin clot, (2) it activates plasminogen more effectively on the clot, (3) free plasmin is rapidly neutralized
by a circulating α2-antiplasmin, and (4) circulating tPA is cleared by the liver. Plasmin degrades fibrin and fibrinogen into small fragments. These
fibrin degradation products possess anticoagulant activity because they compete with fibrinogen for thrombin; they are normally cleared by the
monocyte–macrophage system. The drugs ε-aminocaproic acid (EACA) and tranexamic acid inhibit the conversion of plasminogen to plasmin.
Endothelium also normally secretes a plasminogen activator inhibitor (PAI-1) that antagonizes tPA.

What hemostatic defects are likely to be present in this patient?

Multifactorial coagulopathy often develops in patients with advanced liver disease. Three major causes are usually responsible: (1) vitamin K
deficiency due to dietary deficiency or to impaired absorption or storage, (2) impaired hepatic synthesis of coagulation factors, and (3) splenic
sequestration of platelets resulting from hypersplenism. To complicate matters further, patients with cirrhosis typically have multiple potential
bleeding sites (esophageal varices, gastritis, peptic ulcers, and hemorrhoids) and frequently require multiple blood transfusions. With severe liver
disease, patients may also have decreased synthesis of coagulation inhibitors and may fail to clear activated coagulation factors and fibrin split
products because of impaired Kupffer cell function; the resultant coagulation defect resembles, and becomes indistinguishable from, disseminated
intravascular coagulation (DIC).
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activation of factor XII by endotoxin or foreign surfaces. Widespread deposition of fibrin in the microcirculation results in consumption of
coagulation factors, secondary fibrinolysis, acute severe thrombocytopenia, and a microangiopathic hemolytic anemia. Diffuse bleeding, and, in
 sequestration of platelets resulting from hypersplenism. To complicate matters further, patients with cirrhosis typically have multiple potential
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bleeding sites (esophageal varices, gastritis, peptic ulcers, and hemorrhoids) and frequently require multiple blood transfusions. WithMedical School
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disease, patients may also have decreased synthesis of coagulation inhibitors and may fail to clear activated coagulation factors and fibrin split
products because of impaired Kupffer cell function; the resultant coagulation defect resembles, and becomes indistinguishable from, disseminated
intravascular coagulation (DIC).

What is DIC?

In DIC, the coagulation cascade is activated by the release of endogenous tissue thromboplastin or thromboplastin-like substances, or by direct
activation of factor XII by endotoxin or foreign surfaces. Widespread deposition of fibrin in the microcirculation results in consumption of
coagulation factors, secondary fibrinolysis, acute severe thrombocytopenia, and a microangiopathic hemolytic anemia. Diffuse bleeding, and, in
some cases, thromboembolic phenomena, usually follows. Treatment is generally aimed at the underlying cause. Supportive measures include
transfusion of coagulation factors and platelets. Heparin therapy is controversial but may benefit patients with thromboembolic phenomena.

What is primary fibrinolysis?

This bleeding disorder is due to uncontrolled fibrinolysis. Patients may have a deficiency of α2-antiplasmin or impaired clearance of tPA. The latter
may be common in patients with severe liver disease and during the anhepatic phase of liver transplantation. The disorder may occasionally be
encountered in patients with carcinoma of the prostate. Diagnosis is often difficult, but is suggested by a bleeding diathesis with a low fibrinogen
level but relatively normal coagulation tests and platelet count (as noted next). Treatment includes fresh frozen plasma or cryoprecipitate and
possibly either EACA or tranexamic acid.

How are coagulation tests helpful in evaluating inadequate hemostasis?

The diagnosis of coagulation abnormalities can be facilitated by measurement of the activated partial thromboplastin time (aPTT), PT, thrombin
time (TT), fibrin degradation products, and fibrinogen level (see Table 33–5). The aPTT measures the intrinsic pathway (factors I, II, V, VIII, IX, X, XI,
and XII). The whole blood clotting time and activated clotting time (ACT) also measure the intrinsic pathway. In contrast, the PT measures the
extrinsic pathway (factors I, II, V, and VII). The TT specifically measures conversion of fibrinogen to fibrin (factors I and II). The normal plasma
fibrinogen level is 200 to 400 mg/dL (5.9–11.7 μmol/L). Because heparin therapy primarily affects the intrinsic pathway, in low doses it usually
prolongs the aPTT only. In high doses, heparin also prolongs the PT. In contrast, warfarin primarily affects vitamin K–dependent factors (II, VII, IX,
and X), so the PT is prolonged at usual doses, and the aPTT is prolonged only at high doses. In vivo plasmin activity can be evaluated by measuring
circulating levels of peptides cleaved from fibrin and fibrinogen by plasmin, namely fibrin degradation products (FDPs) and D-dimers. Patients with
primary fibrinolysis usually have elevated FDPs, but normal D-dimer levels.

What tests are most helpful in evaluating inadequate primary hemostasis?

The most commonly performed tests include a platelet count and a bleeding time, but also include TEG, ROTEM, and Sonoclot analysis (see Figure
33–7 and Chapter 51). Patients with normally functioning platelets and platelet counts above 100,000/μL have normal primary hemostasis. The
normal platelet count is 150,000 to 450,000/μL, and the bleeding time is generally not affected by the platelet count when the latter is greater than
100,000/μL. When the platelet count is 50,000/μL or greater, excessive bleeding generally occurs only with severe trauma or extensive surgery. In
contrast, patients with platelet counts less than 20,000/μL often develop significant bleeding following even minor trauma. However, patients with
liver cirrhosis may be thrombocytopenic but have increased levels of vWF, resulting in very active platelets that may compensate for the low count.
Thrombocytopenia usually results from one of three mechanisms: (1) decreased platelet production, (2) splenic sequestration of platelets, or (3)
increased platelet destruction. The third mechanism may fall under one of two categories of destruction: immune or nonimmune. Nonimmune
destruction includes vasculitis or DIC.

A prolonged bleeding time with a normal platelet count implies a qualitative platelet defect. Although the bleeding time is somewhat dependent on
the technique employed, values longer than 10 min are generally considered abnormal. Significant intraoperative and postoperative bleeding may
be expected when the bleeding time exceeds 15 min. Specialized testing is required to diagnose specific platelet functional defects.

What are the most common causes of qualitative platelet defects?

The most common platelet defect is due to inhibition of TXA2 production by aspirin and other nonsteroidal antiinflammatory drugs (NSAIDs). In
contrast to aspirin, which irreversibly acetylates and inactivates cyclooxygenase for the life of the platelet (up to 8 days), enzyme inhibition by other
NSAIDs is reversible and generally lasts only 24 h. Increasingly patients with cardiac stents are treated with a variety of antiplatelet agents such as
clopidogrel, which impair platelet function for the life of the platelet. Assays of platelet function are available to determine the degree to which
platelet function is inhibited.

What is von Willebrand disease?

The most common inherited bleeding disorder (1:800–1000 patients) is von Willebrand disease. Patients with this disorder produce either a
defective vWF or low levels of a normal vWF (normal: 5–10 mg/L). Most patients are heterozygous and have relatively mild hemostatic defects that
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subjected to major surgery or trauma or following ingestion of NSAIDs. In addition to helping link
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platelets, vWF serves as a carrier for coagulation factor VIII. As a result, these patients typically have a prolonged bleeding time, decreased plasma
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vWF concentration, and decreased factor VIII activity. Acquired forms of von Willebrand disease may be encountered in patients with some immune
disorders and those with tumors that absorb vWF onto their surface. At least three forms of the disease are recognized, ranging in severity from mild
 clopidogrel, which impair platelet function for the life of the platelet. Assays of platelet function are available to determine the degree to which
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platelet function is inhibited.
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What is von Willebrand disease?

The most common inherited bleeding disorder (1:800–1000 patients) is von Willebrand disease. Patients with this disorder produce either a
defective vWF or low levels of a normal vWF (normal: 5–10 mg/L). Most patients are heterozygous and have relatively mild hemostatic defects that
become clinically apparent only when they are subjected to major surgery or trauma or following ingestion of NSAIDs. In addition to helping link
platelets, vWF serves as a carrier for coagulation factor VIII. As a result, these patients typically have a prolonged bleeding time, decreased plasma
vWF concentration, and decreased factor VIII activity. Acquired forms of von Willebrand disease may be encountered in patients with some immune
disorders and those with tumors that absorb vWF onto their surface. At least three forms of the disease are recognized, ranging in severity from mild
to severe.

Treatment with desmopressin (DDAVP) can raise vWF levels in some patients with mild von Willebrand disease (as well as normal individuals). The
drug is usually administered at a dose of 0.3 mcg/kg intravenously 30 min prior to surgery. Patients who do not respond to DDAVP should receive
cryoprecipitate or factor VIII concentrates, both of which are rich in vWF; prophylactic infusions are generally recommended before and after
surgery twice a day for 2 to 4 days to help assure surgical hemostasis.

What other hereditary hemostatic defects may be encountered in anesthetic practice?

The most common inherited secondary hemostasis defect is factor VIII deficiency (hemophilia A), an X-linked abnormality estimated to affect
1:10,000 males. Disease severity is generally inversely related to factor VIII activity. Most symptomatic patients experience hemarthrosis, bleeding
into deep tissues, and hematuria, and usually have less than 5% of normal factor VIII activity. Classically, patients present with a prolonged aPTT, but
a normal PT and bleeding time. The diagnosis is confirmed by measuring factor VIII activity in blood. Affected patients generally do not experience
increased bleeding during surgery when factor VIII levels are more than 30% of normal, but most clinicians recommend increasing factor VIII levels
to more than 50% of normal prior to surgery. Normal (fresh frozen) plasma, by definition, is considered to have 1 U of factor VIII activity per milliliter.
In contrast, cryoprecipitate has 5 to 10 U/mL, whereas factor VIII concentrates have approximately 40 U/mL. Each unit of factor VIII transfused is
estimated to raise factor VIII levels 2% per kilogram of body weight. Twice-a-day transfusions are generally recommended following surgery because
of the relatively short half-life of factor VIII (8–12 h). Administration of DDAVP can raise factor VIII levels two- to threefold in some patients. EACA or
tranexamic acid may also be used as adjuncts. Recombinant factor VIII is now undergoing clinical trials.

Hemophilia B (also known as Christmas disease) is the result of an X-linked hereditary deficiency of factor IX. It is very similar to hemophilia A, but
much less common (1:100,000 males). Measurement of factor IX levels establishes the diagnosis. Perioperative administration of fresh frozen
plasma is generally recommended to maintain factor IX activity at more than 30% of normal. Recombinant or monoclonal purified factor IX is
available.

Factor XIII deficiency is extremely rare, but notable in that the aPTT, PT, TT, and bleeding times are normal. The diagnosis requires measurement of
factor XIII levels. Because only 1% of normal factor XIII activity is generally required, patients are treated by a single transfusion of fresh frozen
plasma.

Do normal laboratory values exclude a hemostatic defect?

A bleeding diathesis may exist even in the absence of gross abnormalities on routine laboratory tests. Some hemostatic defects are often not
detected by routine testing, but require additional specialized tests. A history of excessive bleeding after dental extractions, childbirth, minor
surgery, minor trauma, or even during menstruation suggests a hemostatic defect. Conversely, there may be no excess bleeding despite abnormal
laboratory testing. A family history of a bleeding diathesis may suggest an inherited coagulation defect, but such history is often absent because the
increased bleeding is often minor and goes unnoticed.

Hemostatic defects can often be differentiated by their clinical presentation. Bleeding in patients with primary hemostatic defects usually
immediately follows minor trauma, is confined to superficial sites (skin or mucosal surfaces), and often can be controlled by local compression.
Small pinpoint hemorrhages from capillaries in the dermis (petechiae) are typically present on examination. Bleeding into subcutaneous tissues
(ecchymosis) from small arterioles or venules is also common in patients with platelet disorders. In contrast, bleeding that results from secondary
hemostatic defects is usually delayed following injury, is typically deep (subcutaneous tissues, joints, body cavities, or muscles), and is often difficult
to stop even with compression. Hemorrhages may be palpable as hematomas or may go unnoticed when located deeper (retroperitoneal).
Coagulation may be impaired by systemic hypothermia or by subnormal temperature at the site of bleeding, even when coagulation test results (PT,
aPTT, bleeding time) are normal and there is no history of hemostatic defects. Most laboratory tests are carried out at body temperature and may
not reflect the effects of hypothermia.

SUGGESTED READINGS
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Barton CA. Treatment of coagulopathy related to hepatic insufficiency. Crit Care Med . 2016;44:1927 [PubMed: 27635482]
 Coagulation may be impaired by systemic hypothermia or by subnormal temperature at the site of bleeding, even when coagulation test results (PT,
Johnstemperature
aPTT, bleeding time) are normal and there is no history of hemostatic defects. Most laboratory tests are carried out at body Hopkins Medical School
and may
Access Provided by:
not reflect the effects of hypothermia.

SUGGESTED READINGS

Barton CA. Treatment of coagulopathy related to hepatic insufficiency. Crit Care Med . 2016;44:1927 [PubMed: 27635482]

Bona R. Hypercoagulable states: What the oral surgeon needs to know. Oral Maxillofac Surg Clin N Am . 2016;28:491.

Boral BM, Williams BJ, Boral LI. Disseminated intravascular coagulation. Am J Clin Pathol . 2016;146:670. [PubMed: 28013226]

Cohen MJ, Christie SA. Coagulopathy of trauma. Crit Care Clin . 2017;333:101.

Goobie SM, Haas T. Perioperative bleeding management in pediatric patients. Curr Opin Anaesthesiol . 2016;29:352. [PubMed: 26844864]

Hackl C, Schlitt HJ, Renner P, et al. Liver surgery in cirrhosis and portal hypertension. World J Gastroenterol . 2016;22:2725. [PubMed: 26973411]

Kandiah PA, Olson JC, Subramanian RM. Emerging strategies for the treatment of patients with acute hepatic failure. Curr Opin Crit Care .
2016;22:142. [PubMed: 26849251]

Peyvandi F, Garagiola I, Biguzzi E. Advances in the treatment of bleeding disorders. J Thromb Haemost . 2016;14:2095. [PubMed: 27590165]

Tapper EB, Jiang ZG, Patwardhan VR. Refining the ammonia hypothesis: A pathology-driven approach to the treatment of hepatic encephalopathy.
Mayo Clin Proc . 2015;90:646. [PubMed: 25865476]

Wijdicks EFM. Hepatic encephalopathy. N Engl J Med . 2016;375:1660. [PubMed: 27783916]

Wikkels⊘ A, Wettersley J, M⊘ller AM, et al. Thromboelastography (TEG) or rotational thromboelastometry (ROTEM) to monitor haemostatic treatment
in bleeding patients: A systemic review with meta-analysis and trial sequential analysis. Anaesthesia . 2017;72:519. [PubMed: 28052313]

Williams B, McNeil J, Crabbe A, et al. Practical use of thromboelastometry in the management of perioperative coagulopathy and bleeding. Transfus
Med Rev . 2017;31:11. [PubMed: 27622549]

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