Liver Diseases

C H A P T E R
5
Liver Diseases
ANAHAT DHILLON, MD n
RANDOLPH H. STEADMAN, MD n
KEY POINTS
Normal Hepatic Anatomy
Hepatic Function in Health n The liver receives a dual afferent blood supply; the portal
Carbohydrate Metabolism vein provides 75% and the hepatic artery 25% of hepatic
Lipid Metabolism and Transport inflow. With differences in oxygen content, each source
Protein Synthesis contributes about 50% of the liver's oxygen supply.
Detoxification and Transformation n Hepatocytes make up 80% of the liver. Nonparenchymal
Bilirubin Metabolism cells include Kupffer cells, members of the monocyte-
The Injured Liver phagocyte system that play a key role in immunity. Stellate
Cellular Responses cells undergo transformation to fibroblasts and produce
Laboratory Manifestations of Hepatobiliary Dysfunction collagen in response to injury, fundamental to fibrosis and
Etiology of Liver Dysfunction cirrhosis.
Viral Hepatitis n Hepatic dysfunction affects most organ systems because of
Hydatid Cyst Disease the liver's extensive metabolic, detoxification, and digestive
Nonalcoholic Steatohepatitis functions; alterations cause encephalopathy, coagulopathy,
Genetic Causes of Liver Disease and muscle wasting.
Drug-Associated and Other Toxic Liver Disease n Liver injury leads to fibrosis and portal hypertension,
Ischemic Liver Injury which is responsible for ascites, gastrointestinal bleed-
Liver Function in the Geriatric Patient
ing, and renal dysfunction, the characteristic manifesta-
Biliary Cirrhosis
tions of cirrhosis.
Pregnancy-Associated Liver Disease
n The major causes of liver disease include noncholestatic
Systemic Effects of Liver Disease
cirrhosis, cholestatic cirrhosis, acute hepatic necrosis, bili-
Cardiovascular Effects
ary atresia, metabolic diseases, malignant neoplasms, and
Portal Hypertension and Ascites
drug-induced injury. Noncholestatic cirrhosis includes
Renal Effects
hepatitis; hepatitis C is the most common diagnosis in U.S.
Pulmonary Effects
Hepatic Encephalopathy
liver transplant recipients.
Assessment of Perioperative Risk n Nonalcoholic steatohepatitis is increasing in incidence
Anesthetic Management in the United States, possibly secondary to the obesity
Abnormal Laboratory Values in Asymptomatic Patients epidemic.
Acute Hepatitis n Alagille's syndrome is the most common form of familial
Cirrhosis intrahepatic cholestasis; 90% of patients have associated
Acute Liver Failure congenital heart disease, most often pulmonic stenosis.
Transjugular Intrahepatic Portosystemic Shunt n Alpha-1-antitrypsin deficiency, the most common meta-
Biliary Tract Procedures bolic disorder of the liver, is associated with decreasing
Hepatic Resection FEV1 and exacerbated by smoking.
Liver Transplantation n Hemochromatosis first affects the liver, then the pancreas
Postoperative Liver Dysfunction with diabetes mellitus, the skin with bronze pigmentation,
Conclusion and iron deposition in the heart with restrictive cardiomy-
opathy and arrhythmias.
162
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Chapter 5 Liver Diseases 163
n Mucopolysaccharidoses affect enzymes in glycosaminogly- depends on the normal variations in splanchnic blood flow, as
can metabolism. Each presents differently, but all may be regulated by the arterioles and capillary flow of the splanch-
associated with difficult intubation from immobility and nic bed. Hepatic artery blood flow demonstrates autoregula-
macroglossia. tory changes in response to blood pressure, as well as to portal
n Postoperative jaundice can result from increased production blood flow and sinusoidal oxygen levels.
of bilirubin, hepatocellular injury, and cholestasis. Causes The liver comprises two lobes of unequal size, the right and
include hemolysis of transfused red blood cells, reabsorp- left lobes, as divided by the falciform ligament. These lobes can
tion of hematomas, liver hypoperfusion, and drug-induced be further subdivided into the eight segments of Couinaud
injury. (Fig. 5-1), based on separate vascular and biliary branches.
n Further key points are noted throughout the chapter. Vascular outflow through the hepatic veins crosses between
segments. Segments may be surgically resected to excise patho-
logic lesions or living-directed donation for transplantation.
The liver is a complex organ system with myriad functions that Microscopically, the classic concept of the hepatic histologic
is susceptible to dysfunction as a result of disease p
rocesses and structure is that of the hepatic lobule (Figs. 5-2 and 5-3). This
physiologic abnormalities. A dysfunctional liver can affect the model is that of a polygon, typically a hexagon, with branches
function of almost every organ system in the body. Anesthesia of the portal triad (hepatic artery, portal vein, and bile duct)
and surgery can stress the reserve of the liver, resulting in at the vertices. A central vein, technically a venule, marks the
worsening function even without overt evidence of cause. central axis of the lobule. Mixed arterial and portal blood flows
These factors can make the preoperative, intraoperative, and from the vessels at each vertex, through the sinusoids, to the
postoperative care of patients with liver disease challenging. common central vein. The sinusoids are formed by one-cell-
An understanding of normal hepatic structure and function, thick plates of hepatocytes and lined with endothelial cells.
the acute and chronic responses of the liver to v arious types of These sinusoids differ from normal capillaries because of the
injury, and the behavior of the healthy or diseased liver dur-
ing perioperative events helps structure an approach to anes-
thetic management issues. Representative disease processes
Extended left hepatectomy
are examined for unique aspects of perioperative evaluation (left trisegmentectomy)
and care for patients with specific liver diseases.
Extended right hepatectomy
NORMAL HEPATIC ANATOMY (right trisegmentectomy)
Certain aspects of hepatic anatomy and physiology with

Right hepatectomy Left hepatectomy
implications for perioperative care of the patient with liver
disease include (1) the dual blood supply of systemic blood Right Right Left Left
via the hepatic artery and portal venous blood from the posterior anterior medial lateral
splanchnic circulation; (2) histologic arrangement of hepato- section section section section
cytes, including the unique hepatic sinusoids and the result- Hepatic vein Middle hepatic vein
ing blood-hepatocyte interface; and (3) isolation of biliary Left hepatic vein
and blood compartments with regulation of enterohepatic
circulation.1,2 VII II
VIII
The liver is the largest parenchymal organ in the human I IVa
body, representing approximately 2% of total body weight in
the adult. Blood flow to the liver is normally 100 mL/100 g of
tissue per minute, or 25% to 30% of the resting cardiac out- III
put. The metabolic functions of the liver are facilitated by the IVb
interposition of the liver between the splanchnic and systemic V
VI
venous systems. Approximately 75% of the blood supply to Umbilical vein
the liver is delivered by the portal vein. This blood is partially (remnant)
deoxygenated as a result of oxygen extraction by the splanch- Gallbladder Cystic Inferior vena cava
duct Hepatic artery
nic organs. After coursing through capillary beds of the
Bile duct Portal vein
stomach, pancreas, spleen, and intestines, portal venous blood Hepatic duct
contains high concentrations of nutrients, as well as secreted FIGURE 5-1 Liver segments. Schematic depiction of Couinaud
and ingested exogenous substances. Under normal circum- segmental liver anatomy and the normal portal venous structures.
stances, this portal blood provides 35% to 50% of the oxygen Bracketed text shows hepatic segments resected during partial
delivered to the liver. The well-oxygenated blood of the hepatic hepatectomies. (Modified from Curley SA, Barnett CC, Abdalia EK:
artery delivers the remaining 50% to 65% of oxygen, despite Surgical resection for hepatocellular carcinomas, Up-to-date.
being only 25% of the liver's blood supply. Portal venous flow www.uptodate.com; accessed 1/15/12.)
164 ANESTHESIA AND UNCOMMON DISEASES
Bile duct mixture of portal venous and arterial blood. They also lack a
Portal vein Central vein Sinusoids basement membrane, and their endothelium has fenestrations
Hepatic artery typically ranging in size from 50 to 200 nm. These fenestrations
and the low sinusoidal pressure allow a multitude of solutes,
including macromolecules, to enter the perisinusoidal space
of Disse. Here, molecules are in direct contact with the micro-
villi of the hepatocyte's basolateral membrane. The hepatocyte
also has specialized canalicular membrane portions with dis-
tinct microvilli. In combination with the adjacent hepatocyte,
this specialized area forms the wall of the bile canaliculi, its iso-
lation completed by tight intercellular junctions. Intracellular
actin and myosin filaments along the canalicular channel are
presumed to promote drainage of bile into the canals of Hering
and subsequently into the interlobar bile ducts.
Concentric zones radiating from the portal triad out to the
draining venule, numbered 1 to 3, reflect decreasing oxygen
content in the sinusoidal blood and decreasing concentrations
of nutrients arriving from the gut. These zones correlate with
Hepatic
artery
differential enzyme concentrations, metabolic activities, and
Bile duct Portal vein degree of cellular damage caused by a variety of agents and
situations (Fig. 5-4).
FIGURE 5-2 Hepatic lobule seen as three-dimensional
Although hepatocytes make up about 80% of the liver, a host
polyhedral unit. Terminal portal triads (hepatic artery, portal vein,
and bile duct) are at each corner and give off branches along the of other cells are found in the liver. Two important nonparen-
sides of the lobule. Hepatocytes are in single-cell sheets with chymal cells are Kupffer and stellate cells. Kupffer cells are mem-
sinusoids on either end, aligned radially toward a central hepatic bers of the monocyte-phagocyte system (macrophage derived)
venule. (Modified from Ross MH, Reith EJ, Romrell LJ: The liver. In and typically reside on the luminal aspect of sinusoidal endo-
A text and atlas, Baltimore, 1989, Williams & Wilkins. www.lww.com; thelial cells. Their phagocytic and inflammatory responses are
accessed 2/27/11.) important in sepsis, eliminating bacteria and clearing inflam-
matory mediators. Thus, patients with liver disease tend to be
prone to infectious complications. Stellate cells (Ito cells) are
found in the space of Disse and, in health, store lipids and vita-
min A. In the fibrogenic response to injury, however, the stel-
late cells undergo transformation to fibroblasts and produce
Bile Bile collagen, which leads to loss of fenestrations and creation of a
ductule canaliculus pseudo–basement membrane. This is believed to be a funda-
mental step in the development of hepatic fibrosis and cirrhosis.
KEY POINTS
n The liver is the largest parenchymal organ.
n Blood flow is normally 25% to 30% of cardiac output.
n Portal vein is responsible for 75% of blood flow and 35% to
50% of oxygen delivery.

n Hepatic artery is responsible for 25% of blood flow and 50%
Portal Hepatic Kupffer cell Sinusoids Central vein to 65% of O2 delivery.

vein artery n Hepatocytes are arranged in zones leading away from
portal triad; each zone shows varying degrees of O2 con-

Terminal
branches
tent, enzyme concentrations, metabolic activity, and cellular
damage.
FIGURE 5-3 Portal triad in cross section. Blood enters
n Through the liver, carbohydrate and lipid metabolism
sinusoids (blue with black arrows) and egresses through central
vein (blue). Sinusoids contain Kupffer cells (purple). Hepatocytes provides an energy source for the body.
n The liver produces proteins in plasma (except for immuno-
(pinkish tan) produce bile and secrete it into bile canaliculi
(green with black arrows), which drain into bile ductule of portal globulins), detoxifies and transforms endogenous and exog-
triad. (Modified from The Internet Encyclopedia of Science. http:// enous substances, metabolizes heme, and provides immune
daviddarling.info/encyclopedia/L/liver.html; accessed 2/27/11.) function of Kupffer cells.
Nodal Nodal
point point
Central Terminal
vein hepatic venule
Portal
tract
Nodal Nodal 1 2 3
point point
Portal tract
FIGURE 5-4 Liver architecture. At left is classic hepatic lobule, with central vein as its center and portal tracts at three corners. In
middle is portal unit, with portal tract at its center, and central veins and nodal points at its periphery. At right is liver acinus, center of
which is terminal afferent vessel (in portal tract) and periphery of which is drained by terminal hepatic venule, or central vein. Zones 1,
2, and 3 extending from portal tract to terminal hepatic venule are shown. (Modified from Misdraji M: Embryology, anatomy, histology, and
developmental anomalies of liver. In Feldman M, Friedman L, Brandt LL, editors: Sleisenger & Fordtran's gastrointestinal and liver disease,
ed 9, Philadelphia, 2010, Saunders-Elsevier, p 1201.)
HEPATIC FUNCTION IN HEALTH Acute liver injury (e.g., viral hepatitis) is often associated
with mild hypoglycemia despite normal or depressed insu-
Carbohydrate Metabolism lin levels. Hypoglycemia can be pronounced in the alcoholic
The liver provides for the body's varying energy requirements patient despite apparently minimal hepatic decompensation;
under the modulation of neural and endocrine regulators. ethanol cannot be used in gluconeogenesis, and its metabo-
Complex interacting systems of energy storage and utiliza- lism can c ritically reduce the availability of pyruvate. In ful-
tion are required to compensate for asynchronous periods of minant hepatic failure of any cause, hypoglycemia can be life
nutritional ingestion and energy demand. Figure 5-5 presents threatening.
a simplified diagram of carbohydrate and lipid metabolism in Glucose intolerance, conversely, is often observed in chronic
the hepatocyte. liver disease. Although insulin levels may actually be elevated
Many cells of the body are glucose dependent (e.g., eryth- because of decreased hepatic clearance, peripheral receptors
rocytes, renal medullary and retinal cells) or glucose prefer- are decreased in number. Additionally, receptor-binding char-
ential (e.g., brain cells). Maintenance of blood glucose levels acteristics and activity may be altered. Hepatocytes may also
depends on nutritional circumstances. Glucose is eventually be isolated from the usual concentrated levels of portal pan-
released from stored glycogen through glycogenolysis, as pro- creatic insulin release because of portosystemic shunting.
moted by epinephrine and glucagon. The liver and the skel-
etal muscle contain the vast majority of the body's glycogen.
Lipid Metabolism and Transport
Glycogen stores in the adult liver during fasting are capable
of providing adequate glucose levels for 24 to 48 hours, repre- Fatty acids provide the most efficient energy source for both
senting 250 to 500 mg of glucose. During fasting the brain will intrahepatic and extrahepatic storage and utilization. The
transition from glucose dependency to ketone metabolism liver's central role in lipid metabolism, beyond utilization,
and thus sustain itself while greatly decreasing the body's daily involves regulated conversion of excess carbohydrates to fatty
glucose utilization. Gluconeogenesis is the creation of glucose acids, esterification of free fatty acids to form triglycerides for
from lactate, pyruvate, and amino acids, the products of anaer- transport and storage, and synthesis of transport proteins.
obic and catabolic metabolism, as stimulated by the depletion In normal circumstances, the liver takes up a relatively fixed
of glycogen stores. amount of free (nonesterified) fatty acids regardless of dietary
The liver can rapidly switch from glycogen breakdown to intake. This provides the major energy source for hepato-
glycogen formation, depending on the current nutritional cytes. The nutritional state determines the subsequent balance
state and energy requirements. Disruption of carbohydrate between synthesis and esterification of fatty acids in the fed
homeostasis can be a manifestation of liver dysfunction. state versus oxidation in the fasting state (Fig. 5-6).
Blood
Glucose
Fructose
Hepatocyte Pho Glut 2
Glycogen sp
Glucose
ho
Glu-6-Pase GK Regulatory protein
ryla
Glucogen Glucose-6-P
se
cycle
UDPG Pentose phosphate pathway Fru-1-K

Fructose 6-P
Glucose-1-P 6-Fru Kinase/Pase Fructose-1-P
6 PF-1-K
Fruc-1,6-P2ase
Fructose-2,6-P2
Fructose-1,6-P2
Triglycerides
Dihydroxyacetone phosphate D-glyceraldehyde 3-phosphate
Acetyl CoA Fatty Acyl-CoA -glycerol

Glycerol
Peroxisomal H2O2
oxidation Fatty acid
O2 synthase
Fatty Acyl-CoA PEP
Fatty acids Malonyl-CoA
PEPCK OAA
Fatty acid Fatty Acyl PYR PK Acetyl CoA
carnitine
Acyl-CoA PYRDH carboxylase
Carnitine
synthase
T Mitochondrion Acetyl CoA
TI
Fatty Acyl-CoA CP Fatty Acyl
Carnitine carnitine PYR
I
TI ATP citrate lyase
CP Fatty Acyl-CoA Acetyl CoA
FAD Acetyl CoA
FADH2 oxidation Tricarboxylic

OAA Citrate Citrate
acid cycle
CO2 energy
FIGURE 5-5 Hepatic carbohydrate and lipid metabolism. Gluconeogenic pathways are identified by dashed lines. 6-Fru Kinase/Pase,
6-phosphofructo-2-kinase/fructose-2,6-biphosphatase; 6 PF-1-K, 6-phosphofructo-1-kinase; ATP, adenosine triphosphate; CoA, coenzyme
A; CPT, carnitine palmitoyltransferase; FAD, flavine adenine dinucleotide; FADH2, reduced flavine adenine dinucleotide; Fru-1-K, hepatic
fructokinase; Fruc-1,6-P2ase, fructose-1,6-biphosphatase; 1-P, 1-phosphate; 1,6-P2, 1,6-diphosphate; 2,6-P2, 2,6-diphosphate; 6-P, 6-phosphate;
GK, glucokinase; Glu-6-Pase, glucose-6-phosphatase; Glut 2, glucose transporter 2; OAA, oxaloacetate; PEP, phosphoenol pyruvate; CK,
carboxykinase; PK, pyruvate kinase; PYR, pyruvate; PYRDH, pyruvate dehydrogenase; T, carnitine:acylcarnitine transferase; UDPG, uridine
diphosphate glucose. (Modified from Roy-Chowdury N, Roy-Chowdury J: Liver physiology and metabolism. In Feldman M, Friedman L, Brandt LL,
editors: Sleisenger & Fordtran's gastrointestinal and liver disease, ed 9, Philadelphia, 2010, Saunders-Elsevier, p 1217.)
Hepatic steatosis (“fatty liver”) refers to abnormal accu-

Protein Synthesis
mulation of predominantly triglycerides with fatty acids in
hepatocytes. Previously defined in terms of weight percentage With the exception of immunoglobulins, the liver produces
(>5%) or number of hepatocytes affected (>30% in a lobule), the vast majority of proteins found in plasma, including pro-
the diagnosis is now also grossly correlated to findings of teins of coagulation, plasma-binding proteins involved in
noninvasive imaging. Conditions associated with steatosis
transport (e.g., albumin, transferrin, lipoprotein, haptoglo-
include obesity, alcohol ingestion, pregnancy, nonalcoholic bin), and acute-phase reactants. These proteins share many
steatohepatitis, and certain drug toxicities, as discussed later. common synthetic pathways but have distinguishing charac-
Cholesterol is not a direct energy source but serves as a teristics of substrate, modulation, and kinetics that explain the
structural unit of membranes and is a precursor for steroid clinically variable response to injury and disease. For exam-
production. Most cholesterol is synthesized in the liver and, ple, the clotting factors dependent on vitamin K for post-
in combination with dietary cholesterol, is either secreted in translational modification can be affected by K's nutritional
the bile, incorporated into lipoproteins for plasma transport, intake or absorption, whereas inflammatory mediators stim-
or converted to bile acids. ulate acute-phase reactants. Serum albumin levels reflect not
Dietary cholesterol
and triglyceride
Intestine Chylomicrons
FA
storage FA energy
Nascent
Feces Remnants
HDL
Bile
FFA acids Scavenger
receptor
Hepatic HDL
Triglyceride Cholesterol LDL Cholesterol
lipase binding LCAT
ACAT site
Cholesteryl
VLDL ester
Liver LDL
receptor
FFA
Macrophage
Hormone- VLDL IDL HDL3

sensitive Triglyceride
lipase LCAT
Lipoprotein CETP HDL2

Triglyceride
lipase
Cholesteryl
Adipose tissue ester
FIGURE 5-6 Lipoprotein metabolism. FA, Fatty acid; FFA, free fatty acid; LDL, low-density lipoproteins; VLDL, very-low-density lipoproteins;
IDL, intermediate-density lipoprotein; HDL, high-density lipoproteins; CETP, cholesteryl ester transfer protein; ACAT, acylcholesterol
acyltransferase; LCAT, lecithin-cholesterol acyltransferase. (Modified from Roy-Chowdury N, Roy-Chowdury J: Liver physiology and
metabolism. In Feldman M, Friedman L, Brandt LL, editors: Sleisenger & Fordtran's gastrointestinal and liver disease, ed 9, Philadelphia,
2010, Saunders-Elsevier, p 1217.)
only production from available amino acids but also volume transformation actually renders substances toxic, as discussed
of distribution, abnormal losses (e.g., ascites, pleural effu- later. The pathways involved are categorized into three phases.
sion, proteinuria), and regulators responding to parameters Phase 1 metabolism alters the molecule by reactions, usually
such as serum oncotic pressure. Another protein monitored involving the cytochrome P450 enzyme system (CYP450),
in patients with liver disease is alpha fetoprotein (AFP). Its role such as oxidation, reduction, and hydrolysis. Phase 2 metabo-
is primarily in neonatal life, with most of it being replaced by lism conjugates the parent molecule or its metabolite with a
the first year. Hepatocellular proliferation in adulthood will polar molecule (e.g., acetate, amino acid, sulfate, glutathione)
result in an increase in AFP levels. High levels are seen in acute and thus further enhances water solubility. Phase 3 elimina-
hepatitis and liver failure and are a marker for hepatocellular tion is an energy-dependent excretion. A particular molecule
carcinoma. Altered protein levels, which actually reflect liver may undergo any or all of these processes. Changes in the
disease, will develop after variable periods, depending on the pathway(s) utilized may occur as dictated by substrate concen-
synthetic rates and plasma half-life of the particular proteins. trations, enzyme induction, disease, and nutritional status.
Thus, although it is generally true that serum protein levels
will be decreased with liver dysfunction, the specific l aboratory
Bilirubin Metabolism
abnormality and time frame (hours or days for coagulation
factors vs. weeks for albumin) are important d iagnostic clues Bilirubin is a tetrapyrrole produced from the breakdown of
in liver disease. heme at the rate of about 250 mg/day in the normal adult.
About two-thirds comes from hemoglobin of senescent eryth-
rocytes processed by the reticuloendothelial system, and the
Detoxification and Transformation
remainder mostly from nonhemoglobin hemoproteins (e.g.,
The liver is the major site in which both xenobiotics (foreign CYP450 enzymes). The turnover of myoglobin is slow enough
chemicals) and endogenous substances undergo detoxification that its substantial hemoprotein content does not contrib-
and transformation. These changes usually generate less active ute significantly to bilirubin production. Heme is first con-
and more hydrophilic compounds. In notable exceptions, verted to biliverdin by heme oxygenase and then to bilirubin
by biliverdin reductase. This unconjugated bilirubin, which is since the Greek myth of Prometheus, has a reputation for its
water insoluble and neurotoxic at high levels, is bound to albu- unparalleled ability to regenerate. When its connective tissue
min and transported to the hepatocyte, where it is conjugated framework is left intact, the liver can actually re-form itself
with glucuronic acid to form bilirubin monoglucuronide and from less than half of its original size, as demonstrated in
diglucuronide. After secretion into canaliculi, bilirubin is living-directed liver donors. Similarly, the liver that has under-
incorporated into bile and remains unchanged through the gone extensive necrosis may subsequently recover essentially
gallbladder and most of the small intestine. In the terminal normal structure, except for minor abnormalities of bile duct-
ileum and colon, hydrolysis by bacterial enzymes produces ules and parenchymal arrangement. Stimulating factors thus
urobilinogen, which is reabsorbed, and re-excreted predomi- far identified in the human include epidermal, transforming,
nantly in bile, with a small fraction filtered by the kidney into and hepatocyte growth factors.
the urine. Fibrosis is a much different consequence of injury response.
It is generally irreversible and will compromise function.
Fibrosis results from the deposition of collagen within the
THE INJURED LIVER space of Disse, around portal tracts, or around the central
vein by transformed stellate cells. Previously healthy hepato-
Cellular Responses
cytes are eventually replaced with connective tissue. Cirrhosis
The liver can sustain injury from a variety of processes, both is the term applied to nodules of regenerating hepatocytes
primary to the organ (e.g., viral hepatitis) and secondary (e.g., within such scar tissue, reflecting the impact of disruption of
right-sided heart failure or metastatic cancer). Regardless of the normal connective framework before or during regenera-
the cause, general categories of cellular consequences are typi- tion. This architectural disruption results in increased resis-
cally observed. tance to hepatic blood flow, with eventual portal hypertension
Hepatitis is simply liver injury associated with the incur- and decreased functional mass with impaired metabolic and
sion of inflammatory cells. Depending on the type of hepatitis, excretory function. Box 5-1 outlines causes of hepatic fibro-
hepatocyte injury may stimulate the inflammatory response sis and cirrhosis, which represent the consequences of a wide
(e.g., toxic injury) or may be secondary to it. Degeneration is range of diseases. In the Western world, about 90% of cirrho-
defined in terms of microscopic findings. Foamy degeneration sis of known etiology is related to alcoholic liver disease, viral
occurs with ineffective biliary excretion, whereas ballooning hepatitis, or biliary disease. Approximately 10% of cases are of
degeneration is found in toxic and immunologically m ediated unknown etiology and are termed cryptogenic cirrhosis.
injury. Steatosis specifically represents accumulation of fat
droplets in the cell. Multiple small accumulations are seen in
microvesicular steatosis (e.g., acute fatty liver of pregnancy),
Laboratory Manifestations of Hepatobiliary
whereas macrovesicular steatosis is defined as a large nucleus-
Dysfunction
displacing droplet (e.g., obese and diabetic patients).
Necrosis can occur after a variety of injuries. Necrosis Most common tests have limitations of sensitivity and
results in poorly stained cells with lysed nuclei, frequently specificity and assess narrow aspects of hepatic function. The
exhibiting zonal distributions. Centrilobular necrosis is a com- concept of a panel of tests that represent a measure of hepatic
mon pattern in which the most severe damage immediately reserve or “liver function tests” is flawed. However, different
surrounds the central vein. This is characteristic of toxins and patterns of abnormalities do often correlate with the under-
ischemic injury, the latter presumably reflecting the decreas- lying pathology and allow further targeted investigation.
ing oxygen content of the sinusoidal blood as it flows to the Table 5-1 summarizes common tests used to evaluate liver
terminal venule, whereas the toxic pattern may reflect not only disease. These tests can be broadly divided into two catego-
relative hypoxia but also regions of high metabolic a ctivity ries, those that reflect liver injury and those that reflect liver
and biotransformation. Periportal necrosis, conversely, is function. The markers of direct injury include released hepatic
exceedingly unusual but may be found in pre-eclamptic enzymes. Synthetic function can be reflected in protein levels
patients for unknown reasons. With most injuries, a variety and clotting times, whereas dye clearance and drug transfor-
of necrotic and inflammatory patterns are seen. Focal necro- mation can be used to investigate blood flow and metabolic
sis denotes scattered necrosis within lobules, whereas more capacity.
severe bridging necrosis spans adjacent lobules. Apoptosis is the
energy-dependent deconstruction of cells with an attenuated TESTS THAT REFLECT HEPATIC CLEARANCE
inflammatory response and salvage of cell components that Ammonia
can be reused. The conditions and regulators that influence The liver normally clears ammonia from the blood and
apoptosis in the liver are being elucidated.3,4 Whether the bal- converts it to urea for renal excretion. With severe liver dys-
ance between necrosis and apoptosis can be predicted or even function or portosystemic shunting, ammonia levels may be
manipulated clinically remains to be seen. elevated. Although typically used in the evaluation of possible
Regeneration and fibrosis represent two different outcomes hepatic encephalopathy, ammonia levels correlate poorly with
in the liver's attempt to replace injured liver units. The liver, the severity of clinical presentation.
BOX 5-1 n CAUSES OF HEPATIC FIBROSIS AND CIRRHOSIS
Medications and Toxins Chronic hepatitis (B, C, and D) Tyrosinosis

Alcohol Cytomegalovirus Wilson's disease
α-Methyldopa Echinococcosis Wolman's disease
Amiodarone Schistosomiasis
Arsenic Syphilis (tertiary and congenital)
Other Causes
Autoimmune chronic hepatitis
Carbon tetrachloride
Chlordecone
Metabolic and Genetic Disorders Biliary obstruction (chronic)
α1-Antitrypsin deficiency Budd-Chiari syndrome
Isoniazid
Alagille's syndrome Cystic fibrosis
Methotrexate
Biliary atresia Idiopathic portal hypertension
Methylene diamine
Fanconi's syndrome Jejunoileal bypass
Nitrofurantoin
Fructose intolerance Nonalcoholic steatohepatitis
Oral contraceptives
Galactosemia Primary biliary cirrhosis
Pyrrolizidine alkaloids
Gaucher's disease Primary sclerosing cholangitis
Sulfa antibiotics
Glycogen storage disease Right-sided heart failure and tricuspid
Vitamin A
Hemochromatosis regurgitation (chronic)
Infections Hereditary tyrosinemia Sarcoidosis
Brucellosis Ornithine transcarbamylase
Capillariasis Porphyrias
TABLE 5-1 n Characteristic Biomarkers in Liver Disease
HEPATOCELLULAR NECROSIS BILIARY OBSTRUCTION

Etiologies and Lab Results Toxin or Ischemia Viral Alcohol Complete* Partial Chronic Infiltration
Transaminases 50-100× 5-50× NL to 5× NL to 5× 1-3×

(aminotransferases) 2-5×
Alkaline phosphatase (ALP) 1-3× 1-3× 1-10× 2-20× 2-20× NL to 20×
Bilirubin 1-5× 1-30× 1-30× 1-30× 1-5× NL to 5×
Prothrombin time (PT) Prolonged; minimal or no improvement with Often prolonged; may improve Normal
vitamin K with parenteral vitamin K
Albumin Decreased in chronic disease Often normal; may be Usually normal

decreased
Illustrative disorders Shock liver, Hepatitis Pancreatic Hilar tumor, Sarcoid, metastatic
acetaminophen A or B cancer sclerosing carcinoma
toxicity cholangitis
Modified from Daven TJ, Sxharschmidt B: Biochemical liver tests. In Feldman M, Friedman LS, Sleisenger MH, editors: Sleisenger & Fordtran's gastrointestinal and liver
disease, ed 7, Philadelphia, 2002, Saunders, p 1231.
*Acute onset of complete biliary obstruction may result in massive elevations in transaminases that are transient and in the range of 20 to 50 times normal.
×, Times elevation from normal, NL, normal.
Bilirubin TESTS THAT REFLECT SYNTHETIC FUNCTION

As discussed with normal metabolism, bilirubin is a product Albumin
of heme breakdown. It exists in conjugated (water soluble) and Albumin is synthesized only in the liver, typically at a rate of 100
unconjugated (lipid soluble) forms, which are reported impre- to 200 mg/kg/day in the adult, and under normal circumstances
cisely as the direct and indirect fractions, respectively. Serum bil- the plasma half-life is 3 weeks. Abnormalities are poorly specific
irubin is usually less than 1 mg/dL and primarily unconjugated. for liver disease, however, because many factors affect its produc-
Elevated serum levels occur in most significant liver diseases; tion and turnover. For example, nutritional state, plasma osmotic
degree of elevation correlates with prognosis in primary bili- pressure, and thyroid levels all affect the rate of albumin produc-
ary cirrhosis, alcoholic hepatitis, and fulminant liver failure. The tion. The increased albumin losses seen in nephrotic syndrome,
appearance of conjugated bilirubin in the blood is thought to be burns, and protein-wasting enteropathies also affect the balance
caused by reflux from the hepatocyte, but this does not discrimi- between production and loss of albumin. Hypoalbuminemia can
nate between obstructive and parenchymal causes. Other causes be helpful in assessing chronic liver disease when nonhepatic
of elevated bilirubin include Gilbert's syndrome, increased pro- causes are excluded. Its prolonged half-life means that measured
duction (e.g., hemolysis, ineffective erythropoiesis, hematoma changes are slow to develop and slow to revert to normal in rela-
resorption), and inherited d isorders of bilirubin transport. tion to the onset and resolution of the causative process.
Prothrombin Time elevated in many forms of liver disease, presumably as a result

Prothrombin time (PT) determinations depend on serum of leakage from damaged cells. Substantial hepatic necrosis as
concentrations of fibrinogen, prothrombin, and factors V, VII, found in chemical and ischemic injury appears to be partic-
and IX, all of which are products of the liver. Furthermore, the ularly associated with elevation of these enzymes. Advanced
half-life of these factors is short enough (<24 hours) that the cirrhosis can exist without significant elevations if active cell
PT changes rapidly. Given their short half life, factor V and VII injury is absent or minimal at the time of evaluation.
levels can also be followed in evaluating liver f unction in ful- The relative increase in AST compared with ALT can be use-
minant liver failure. An abnormal PT can result from reduced ful in supporting a diagnosis of alcohol injury (AST/ALT >2)
factor synthesis (e.g., vitamin K deficiency, liver failure, versus most other acute liver injuries (AST/ALT ≤1), although
warfarin therapy) or increased factor loss (e.g., disseminated cirrhosis is also associated with AST/ALT ratio greater than 1.
intravascular coagulation). Absolute levels can be diagnostic when extreme and helpful
Vitamin K deserves special mention in the context of the when moderately elevated (see Table 5-1).
PT. Prothrombin and factors VII, IX, and X undergo post-
Lactate Dehydrogenase
translational carboxylation of glutamic acid residues that
Because of its presence in tissues throughout the body, lactate
is necessary for activity and requires vitamin K as a cofac-
dehydrogenase (LDH) usually offers little diagnostic discrimi-
tor. Deficiency of vitamin K or antagonism of this process by
nation beyond that of the transaminases. However, LDH does
warfarin (Coumadin) alters the PT. Additionally, in the jaun-
demonstrate a short-lived but exceptionally high elevation in
diced patient, a favorable response to parenteral vitamin K
ischemic injury, as well as a moderate but sustained increase
implies that intake or absorption of vitamin K is abnormal,
in some malignancies.
versus a nonresponse, which implies that parenchymal disease
is at least partly the basis for the abnormality (see Table 5-1).
KEY POINTS
SERUM ENZYME TESTS
n No single test is specific for hepatic reserve.
Alkaline Phosphatase
n Hepatic clearance may be tested with ammonia and biliru-
Hepatic alkaline phosphatase (ALP) is concentrated in the
bin levels.
canalicular hepatocyte membrane and bile duct epithelial
n Bilirubin can be elevated secondary to hemolysis, hema-
cells, and increased production and release appear to cause the
toma resorption, and disorders of biliary transport.
elevated ALP levels seen in cholestasis. However, ALP exists in
n Synthetic function can be tested with albumin and pro-
normal tissues throughout the body as well as in extrahepatic
thrombin time.
neoplasms. Elevated levels are not specific for biliary disease
n Albumin is made only in the liver, but many factors affect
because states of increased metabolic activity are associated
production and turnover.
with increased ALP activity in the affected tissue. Therefore,
n Abnormal PT can result from reduced factor synthesis or
young adults with rapid bone growth and gravid patients with
increased factor loss.
placental production routinely have elevated ALP levels. ALP
n Serum enzymes may reflect hepatocyte or injury, but none
levels as high as three times normal occur in many liver dis-
is isolated to the liver; GGTP is more specific for the liver
eases. More pronounced increases suggest infiltrative pro-
than ALP.
cesses or biliary obstruction, which can be intrahepatic (e.g.,
tumor) or extrahepatic. Even if the entire biliary tree is not
obstructed, ALP can be greatly elevated.
ETIOLOGY OF LIVER DYSFUNCTION
Gamma-Glutamyl Transpeptidase
Liver dysfunction has been categorized in a variety of ways.
γ-Glutamyl transpeptidase (GGTP) has a tissue distribution
Clinical presentation (e.g., jaundice), etiology (e.g., viral
similar to alkaline phosphatase except that it has low concen-
hepatitis), circumstances (e.g., postoperative liver dysfunc-
trations in bone. Thus, GGTP may be helpful in discriminat-
tion), time frame, and severity (e.g., subfulminant liver failure)
ing the source of ALP elevations. However, GGTP can also be
are common descriptors, but none offers a complete descrip-
quite sensitive to the ingestion of alcohol and drugs, including
tion. For example, acute liver failure may have an infectious
several anticonvulsants.
or toxic etiology, whereas viral hepatitis may result in abrupt,
Transaminases (Aminotranferases) severe liver dysfunction or may proceed along a chronic, sub-
Aspartate transaminase (AST, formerly known as SGOT [serum clinical course.
glutamic-oxaloacetic transaminase]; also called aspartate ami-
notransferase) and alanine transaminase (ALT, formerly SGPT
[serum glutamic-pyruvic transaminase]; also alanine amino-
Viral Hepatitis
transferase) are participants in gluconeogenesis. Both enzymes Although a vast number of viruses can produce hepatitis
are plentiful in the cytosol of the hepatocyte, and an AST iso- (Table 5-2), only five viruses produce liver disease as their
zyme is present in the mitochondria as well. AST is also found primary clinical manifestation.5 Each of the five hepatitis

in a variety of tissues, including heart, brain, and skeletal viruses has been designated with a letter (e.g., hepatitis A, hep-
muscle; ALT is more specific to the liver. These enzymes are atitis B) according to their clinical manifestations (Table 5-3).
fecal-oral route after ingestion of contaminated food or drink.

TABLE 5-2 n Uncommon Causes of Viral Hepatitis
The virus is absorbed through the small bowel and trans-
Virus Vaccine Available ported by the portal blood flow to the liver.7 HAV replicates in
the liver and is then shed into the blood or, more frequently,
Epstein-Barr virus (EBV) No through the bile and into the stool. Viral shedding begins as
Cytomegalovirus (CMV) No early as the second week of infection and consequently may
occur before the patient experiences any clinical signs or symp-
Human herpesvirus type 1 (HHV-1) In development
toms of hepatitis. Viral shedding may continue until 2 weeks
Human herpesvirus type 2 (HHV-2) In development after the onset of jaundice. Although the virus is shed into the
Coxsackievirus type B No
stool in high titers, viral titers in the blood remain low dur-
ing the short (1-2 weeks) viremic phase.8 As such, transmis-
Echoviruses No sion of HAV by blood transfusion is extremely rare, although
Adenovirus Yes, for certain subtypes;, transmission from a single donor has been reported.9,10 The
limited to military use virus has also been transmitted to hemophiliac patients with
contaminated factor VIII concentrates.11
Yellow fever virus Yes
After an incubation of 15 to 50 days, patients may experi-
Varicella-zoster virus Yes ence the acute onset of systemic complaints, including fever,
Measles Yes malaise, nausea, vomiting, and abdominal pain. Patients may
also note the appearance of dark urine and jaundice. Mild
hepatic enlargement and tenderness is noted in approxi-
mately 85% of patients, with splenomegaly in up to 15%.12
It is important to remember that although each virus infects Coagulopathy, encephalopathy, and renal failure are rare in
the liver, the hepatitis viruses have different biochemical, patients with acute HAV infection.12,13 The infection is nor-
biologic, and clinical characteristics. Indeed, the viruses do mally a self-limited illness, with complete recovery usually
not form a phylogenetic family and are not actually related. in less than 2 months; however, serious complications can
Although infection with each virus can be associated with occur.14 Underlying liver disease is associated with increased
significant morbidity and mortality, infection with any virus risk of fulminant hepatic failure with HAV superinfection.15,16
may result in an anicteric illness and may not be diagnosed as Chronic hepatitis does not occur, but an atypical, relapsing
hepatitis.6 course has been described in both children and adults.17
Diagnosis of HAV infection is usually confirmed by sero-
HEPATITIS A logic testing. Anti-HAV immunoglobulin M (IgM) is detect-
The hepatitis A virus (HAV) is a 27 to 32–nm, nonenveloped able in the serum approximately 3 weeks after exposure.
virus (Picornaviridae) with a 7.5-kilobase genome of single- Early diagnosis is also possible with the detection of HAV
stranded (ss) RNA. HAV is almost always transmitted by the in stool using electron microscopy or the detection of viral
TABLE 5-3 n Characteristics of Human Hepatitis Viruses A (HAV) to E (HEV)
Hepatitis A B C D E
Virus family Picornaviridae Hepadnaviridae Flaviviridae Viroid Caliciviridae
Genome ssRNA Partially dsDNA SsRNA ssRNA ssRNA
Transmission:
Fecal-oral Yes No No No Yes
Sexual No Yes Rare Rare No
Blood/percutaneous Rare Yes Yes Yes No
Incubation period 15-50 days 4-26 wk 2-26 wk 3-7 wk 15-60 days
Immunity IgG anti-HAV IgG HBsAB Unknown IgG HBsAb IgG anti-HEV
Chronic hepatitis No Yes Yes Yes No
Fulminant failure <1% <1% Rare 2%-10% 1% (30% in pregnancy)
Cirrhosis No Yes Yes Yes No
Modified from Ryder SD, Beckingham IJ: BMJ 322:151-153, 2001; and Berenguer M, Wright T: Viral hepatitis. In Feldman M, Friedman L, Sleisenger M, editors:
Sleisenger & Fordtran's gastrointestinal and liver diseases, ed 7, Philadelphia, 2002, Saunders.
Ss, Single-stranded; ds, double-stranded; Ig, immunoglobulin.
RNA; however, both methods are impractical. Although 75% of HBeAg is an important biochemical predictor of progres-
of adult patients with HAV have clinical manifestations, up sion to chronic hepatitis. IgM antibodies to hepatitis core
to 70% of infections in children younger than 6 years are antigen (HBc), a viral protein not detected in the serum, can
asymptomatic.18 Their bowel hygiene and capacity to act as be detected in the serum shortly before the onset of acute ill-
asymptomatic carriers make children the principal reservoir ness. IgM anti-HBc is gradually replaced by IgG anti-HBc over
for the virus. several months. IgG anti-HBs does not appear until after the
Hepatitis A infections occur throughout the world but are resolution of jaundice and clinical symptoms and after the dis-
more common in developing countries with poor sanitation. appearance of HBsAg. During this “core window” after the
In the United States, the incidence of HAV infection is 9 to disappearance of HBsAg and before the appearance of anti-
10 per 100,000 population, with an overall seroprevalence of HBs, IgM anti-HBc (and IgM anti-HBe) are the only labora-
30%. Two highly effective vaccines18 available in the United tory markers of HBV infection.
States since 1996 are recommended for children19 and adults18 Of the approximately 325,000 new HBV infections in the
with chronic liver disease. Anesthesiologists and all health United States each year, approximately 60% of patients will
care providers should consider immunization. In the event of develop subclinical disease without jaundice and completely
possible transmission of HAV to a health care provider, a sin- recover. About 25% of infected patients develop acute hepati-
gle dose of 0.02 mL/kg immune globulin is highly effective in tis, characterized by fever, nausea, vomiting, anorexia, abdom-
preventing infection if given within 14 days of exposure.18 inal pain, and jaundice. Almost all patients who develop acute
hepatitis recover completely, although about 1% of patients
HEPATITIS B develop fulminant hepatic failure, which can be fatal with-
The hepatitis B virus (HBV) is a 42-nm, enveloped virus out liver transplantation. From 5% to 10% of patients become
(Hepadnaviridae) with 3.2-kb genome of partially double- “healthy carriers” of HBV disease. These individuals do not
stranded (ds) DNA. Worldwide, more than 400 million people normally manifest signs or symptoms of hepatitis but are
have chronic HBV infection.20,21 Unlike HAV, HBV is primar- able to transmit the disease to others. Less than 5% of HBV-
ily transmitted by blood, blood products, and sexual con- infected patients will develop a persistent infection, character-
tact. Perinatal infection can occur, with evidence of infection ized by mild but persistent elevation of serum transaminases
occurring across mucous membranes through semen, saliva, for months to years. Most patients with persistent infection
and breast milk.22 Intravenous (IV) drug use remains a major ultimately recover; however, 20% to 30% will develop chronic
mode of HBV transmission,23 and outbreaks among IV drug hepatitis and cirrhosis. Patients who develop chronic hepati-
abusers are frequently reported.24 Nosocomial transmission tis may have a defective immune response.30-32 HBV c irrhosis
has occurred through use of multidose vials of local anesthet- is a significant risk factor for hepatocellular carcinoma, and
ics.25 Acupuncture has been linked to occasional outbreaks of approximately 10% of patients with HBV cirrhosis will develop
HBV infection.26 Fortunately, transfusion-related HBV infec- hepatocellular carcinoma.
tion is rare because HBV screening of donated blood has been Unlike HAV, HBV infection tends to be more severe in
routine for almost two decades.21 Nevertheless, an estimated younger patients. In neonates and children younger than 1 year,
1:50,000 to 1:63,000 transfused units transmits HBV.27 risk of an infection becoming chronic is 90%. For children age
In the United States, Canada, Europe, and Australia, sexual 1 to 5 years, risk of chronic infection is 30%. For children older
transmission is the most important mode of HBV infection.28,29 than 5 years, risk of chronic infection approaches that of
Both heterosexual and homosexual activities can transmit adults.21,33 Transplacental passage of HBeAg from an infected
HBV, but heterosexual activity accounts for the majority of mother to the fetus is thought to induce immune tolerance in
HBV infections. Prostitutes, their clients, and individuals with the neonate.34
many sexual partners are at an increased risk of HBV infec- Highly effective HBV vaccines have been available for
tion. The risk of heterosexual transmission is greater when the more than 20 years. In 1991 the U.S. Centers for Disease
infected person is female than when male.5 In endemic regions Control and Prevention (CDC) recommended universal
such as China and sub-Saharan Africa, most HBV infections childhood vaccination against HBV in the United States.
occur neonatally or in early childhood,21 and sexual transmis- Broad-based vaccination initiatives have been effective in
sion is less important. reducing the incidence of HBV infection in Alaska35 and
After parenteral exposure, an asymptomatic incuba- reducing the incidence of hepatocellular carcinoma in
tion period ranges from 4 to 26 weeks (average, 6-8). During Taiwan.36 Before HBV vaccination was widespread, the inci-
this period, infected hepatocytes synthesize and secrete dence of anti-HBs among anesthesiologists was greater than
large quantities of noninfective hepatitis B surface antigen fourfold higher that of the general population.37 As such, the
(HBsAg). Consequently, HBsAg is detectable before the onset practice of anesthesiology is an independent risk factor for
of signs and symptoms of hepatitis. Hepatitis B DNA (HBV- the development of HBV infection.38,39 All anesthesiologists
DNA) is detectable in the serum by polymerase chain reaction should be vaccinated against HBV.
(PCR) shortly after HBsAg and indicates active viral replica- In the event of possible transmission of HBV to a non-
tion. HBeAg, another important indicator of active viral rep- immunized individual (e.g., accidental needlestick), passive
lication, is also detectable at this time. Continued expression immunization with hepatitis B immune globulin (HBIG) is
available. Current recommendations are to administer HBIG and vaccination reliably prevents HBV infection, vaccina-
in a dose of 0.05 to 0.07 mL/kg immediately after exposure. A tion against HBV remains the best method to prevent HDV
second dose 30 days after exposure may further reduce the risk infection.
of HBV infection. If HBIG is not given within 7 days of infec-
tion, antiviral treatment should be considered.
KEY POINTS
Most antiviral therapy in HBV is directed toward the treat-
ment of chronically infected patients.40 Therapy with inter- n Hepatitis A virus is transmitted by the fecal-oral route,
feron alfa has proved effective in the elimination of HBeAg with rare progression to liver failure. Superinfection with
in patients with chronic infection.41,42 Therapy normally con- underlying liver disease can result in hepatic failure, and
sists of a 16-week course of 5 mU daily or 10 mU three times vaccination is recommended.
weekly. Lamivudine, a nucleoside analog, is available orally n Hepatitis B virus is transmitted by body fluids; 60% of
for HBV therapy.43 Long-term lamivudine therapy reduces patients have subclinical disease, and 1% with acute HBV
fibrosis and necrosis in patients with chronic HBV infec- infection develop fulminant liver failure.
tion.44 Despite these impressive results, however, lamivudine- n About 1% of HBV patients develop chronic hepatitis and
resistant mutants have emerged.45 Adefovir dipivoxil, another cirrhosis, with 10% risk of hepatocellular carcinoma.
nucleoside analog, is also effective against HBV.46 Adefovir n Superinfection of HBV-infected patients with hepatitis D
seems to have efficacy against lamivudine-resistant mutants.47 increases the risk of fulminant hepatic failure.
n Hepatitis C is transmitted by body fluids; 80% of patients
HEPATITIS D (DELTA AGENT) develop chronic hepatitis, 25% with cirrhosis.

Hepatitis D virus (HDV) is a 35-nm viroid with a 1.7-kb
genome of ssRNA. The viroid is enveloped with HBsAg and HEPATITIS C
requires coinfection with hepatitis B virus for HDV infection The hepatitis C virus (HCV) is a 55-nm enveloped virus
and replication. Delta agent was first noted in 1977,48 and its (Flaviviridae) with 9.4-kb genome of ssRNA. Worldwide,
unique structure was described in 1986.49 As with HBV, HDV more than 170 million people have chronic HCV infection.56
is transmitted parenterally. IV drug abuse remains the most HCV was not identified until 1989.57 As with HBV, HCV is
common mode of transmission in North America, Europe, primarily transmitted by blood, blood products, and sexual
and Australia.50-52 Sexual transmission of HDV can occur,53 contact. The two main risk factors for HCV infection are IV
but may be less efficient than for HBV. Perinatal infection of drug use and blood transfusion before 1990.58,59 Indeed, HCV
HDV is rare. has been identified as the etiologic agent in more than 85% of
Hepatitis D infection can occur in two settings.54 In acute all cases of posttransfusion “non-A, non-B” hepatitis before
coinfection, HDV occurs at the same time as acute HBV infec- 1991.5 Since routine screening for anti-HCV and blood donor
tion, usually when a patient has been exposed to blood or risk factor assessment by most blood donor centers in 1991,
serum from a patient harboring both infections. Superinfection transfusion-related infection of HCV is a rare event.58,59 An
can occur when a patient with a persistent HBV infection or estimated 1 in 103,000 transfused units transmits HCV.27
chronic hepatitis becomes infected with HDV. Coinfection Consequently, IV drug use has emerged as the principal
with HBV and HDV results in a more severe course of acute risk factor for HCV infection in North America, Europe, and
hepatitis and increased risk (3%-4%) of fulminant hepatic fail- Australia.60 Perinatal transmission is rare and occurs exclu-
ure. Nevertheless, approximately 90% of coinfected patients sively from mothers who are HCV-RNA positive at delivery.61,62
have complete recovery and develop immunity. Secondary to Perinatal transmission may be more common if coinfection
defective immunity, patients with chronic HBV infection pro- with human immunodeficiency virus (HIV) exists.63 It is
vide the ideal host for HDV superinfection. About 10% of unclear whether cesarean birth increases or decreases the risk
patients superinfected with HDV develop fulminant hepatic of perinatal transmission.61,64-66 Breastfeeding appears to pose
failure that rapidly progresses. Most of the remaining 90% little risk to the infant.67,68 As noted earlier, sexual transmis-
develop an accelerated cirrhotic picture.55 A small percentage sion of HCV is possible; however, transmission is significantly
of patients will recover and develop immunity. less efficient than for HBV. Nevertheless, prostitutes and their
The diagnosis of HDV infection is normally made by the clients, men who have sex with men (MSM), and individuals
detection of IgM anti-HDV. IgM anti-HDV is not normally with multiple sexual partners are at increased risk for HCV
detectable in patient serum until the onset of acute hepatitis infection. Some suggest that coinfection with HIV69 or her-
and jaundice. It is possible to detect HDV antigen in patient pes simplex virus type 2 (HSV-2)58 may increase the likelihood
serum before the onset of hepatitis during the late incubation of HCV infection. Although the virus is present in saliva of
period; however, HDVAg is present only transiently, and thus chronically infected persons,70 transmission through casual
testing may be unreliable. HDV-RNA is the earliest marker of contact seems an unusual means of transmission.71 Patient-to-
infection and can be detected by PCR, but this is rarely used to patient transmission has occurred during colonoscopy,72 and
establish HDV infection. patients have been infected during surgery.73 In one hospital,
There is no specific treatment for HDV infection. Because an anesthesia assistant became infected from a patient and
HDV infection is only possible in the case of HBV infection, subsequently spread the infection to five other patients.74
In contrast to HBV, HCV has a high rate of progression to fecal contamination.87 Compared with HAV, there is a low
chronic disease and eventual cirrhosis. After infection, HCV rate of person-to-person transmission of household contacts.
has a long incubation period that ranges from 2 to 26 weeks Nosocomial infection has been reported.88 After ingestion,
(average, 7-8 weeks).56 Of the approximately 175,000 persons HEV is absorbed through the small bowel and transported by
infected in the United States each year, 75% will develop sub- the portal blood flow to the liver. After an incubation period of
clinical disease. The remaining 25% develop a symptomatic 15 to 60 days (average, 35-42) a preicteric phase characterized
disease characterized by fever, nausea, vomiting, abdominal by fever and malaise is reported by 95% to 100% of patients.
pain, anorexia, and jaundice. Approximately 1% of patients An icteric phase characterized by abdominal pain, nausea,
with symptomatic disease develop fulminant hepatic fail- vomiting, anorexia, and jaundice follows shortly thereafter.
ure that rapidly progresses to death without transplantation. Symptoms normally resolve in less than 6 weeks, although ful-
Almost 80% of all patients infected with HCV develop chronic minant hepatic failure is a rare but reported complication. A
hepatitis, characterized by mild, episodic elevations in trans- characteristic feature of HEV is the high incidence of progres-
aminases and occasional jaundice.56 More than 25% of patients sion to fulminant hepatic failure in pregnant women. If con-
with chronic hepatitis develop cirrhosis. HCV cirrhosis is a tracted in the third trimester, HEV mortality may exceed 20%.
significant risk factor for hepatocellular carcinoma, with an The diagnosis of HEV is normally made by exclu-
estimated risk of 1% to 4% per year.56,75 sion after travel to an endemic area (South and Central
The detection of antibodies against HCV is both sensi- America; Southeast Asia, including China, India, and Africa).
tive and specific for HCV infection. Newer, third-generation Nevertheless, assays to detect both IgM anti-HEV and IgG
enzyme immunoassays (EIAs) can detect antibodies within 4 anti-HEV are commercially available. PCR can be used to
to 10 weeks of infection.75 Unlike HBV, PCR to detect HCV- detect HEV-RNA; however, this is usually done for research
RNA is often used in clinical practice to determine viral load, purposes.
a significant predictor of antiviral therapy efficacy.76 Detection Currently, no vaccine is available for HEV infection. The
of HCV-RNA is the most sensitive and specific test of HCV administration of immune globulin from endemic areas has
infection.77 Significant controversy surrounds the use of liver not decreased infection rates during epidemics.89 Health care
biopsy in HCV-infected patients.78–81 providers should use universal precautions when dealing with
Various treatment regimens are available for HCV infec- patients with suspected HEV infection. Pregnant women
tion. Standard interferon three times weekly for 24 to 48 weeks should avoid any type of exposure to HEV.
(approved in 1990) is successful in treating HCV infection.75
Interferon alfa (2a or 2b), 3 MU three times weekly for 24 HEPATITIS G
to 48 weeks, has shown response rates as high as 40%76 and Hepatitis G virus (HGV) was first described in the serum of
seems to be more effective than standard interferon. Pegylated a patient with “non-A, non-B, non-C” hepatitis.90 HGV and
interferons have been used to treat HCV since the late 1990s, so-called GB viruses have been described.91 HGV and GB are
with superior results compared with interferon alfa.82 When detectable in a substantial number of blood donors92 and have a
pegylated interferons are combined with ribavirin, studies genomic sequence similar to HCV. However, HGV/GB does not
have shown response rates as high as 88% in certain patient appear to cause liver disease.93 Indeed, the initial patient was later
groups.83,84 found to have HCV infection. Interestingly, patients coinfected
No vaccine is available for HCV infection. Therefore, avoid- with HIV and HGV/GB seem to have prolonged survival.94
ing exposure is the best prevention. For anesthesiologists and
other health care professionals, adherence to universal pre-
Hydatid Cyst Disease
cautions is critical. Prophylaxis after an accidental exposure is
not currently recommended. There are no randomized, con- Hydatid cyst disease is caused by an infection of the animal
trolled trials examining the efficacy of therapy in acute HCV tapeworm Echinococcus. As with all tapeworms, Echinococcus
infection; however, one study showed that after treatment with lives in the small bowel of hosts. Definitive hosts include car-
interferon alfa-2b for 24 weeks, 43 of 44 patients did not have nivorous animals such as dogs, wolves, and other canines.
detectable HCV-RNA.85 Tapeworm-infected canines pass eggs in their feces, which
contaminate the environment. Sheep, cattle, and humans
HEPATITIS E become intermediate hosts when they ingest the eggs by eating
The hepatitis E virus (HEV) is a 32-nm, nonenveloped virus contaminated foodstuffs. Infected domestic dogs remain the
(Caliciviridae) with 7.5-kb genome of ssRNA. HEV was dis- most important vector for transmission of hydatid disease.95,96
covered in 1983 and is part of the alpha supergroup of viruses. Once the eggs are ingested, gastric acid and digestive pancre-
HEV is responsible for the majority of cases of what was pre- atic enzymes dissolve the egg's external shell. The larvae then
viously called “enterically transmitted non-A, non-B hepa- penetrate the bowel wall, enter the portal circulation, and are
titis” (ET-NANBH).86 As with HAV, HEV is almost always carried to the liver. Approximately 70% of the larvae remain in
transmitted via the fecal-oral route through the ingestion the liver, with 20% infecting the lungs, although other organs
of contaminated food or drink. During epidemics, the most can be infected, including the brain,97 spinal cord,98,99 kidney,100
common mode of transmission is the ingestion of water with and heart.101
In the liver, Echinococcus infection results in virtually no

symptoms until the cysts become very large. Although pain is
the most common complaint, a large cyst may cause obstruc-
tive jaundice, cholangitis, pancreatitis, or portal hyperten-
sion.95,96 Blunt trauma may cause cyst rupture.102 Diagnosis is
normally made by serologic testing after abdominal imaging
reveals hepatic cysts. An eosinophilia may also be present.
The treatment of large hydatid cysts is surgical, and the
anesthesiologist is likely to encounter patients scheduled for
cyst drainage. The surgical approach may be attempted by
laparoscopy,103 laparotomy, or thoracotomy if a subdiaphrag-
matic cyst is present. There are multiple case reports of an
anaphylactic reaction to hydatid fluid during surgical exci-
sion.104-106 Preoperative steroids and antihistamines107 should
be considered.
Nonalcoholic Steatohepatitis FIGURE 5-7 Photomicrograph shows histology of

nonalcoholic steatohepatitis in 62-year-old woman. Mallory
Although the incidence of chronic viral or alcoholic hepa- hyaline bodies (pink filamentous structures, black arrowhead) are
titis has not increased significantly in the past few years, cytoplasmic inclusions in hepatocytes consisting of abnormal
the overall number of patients with liver dysfunction has keratin, hyaline, and other proteins. They are usually found in
increased secondary to the well-recognized obesity epidemic. hepatocytes that are ballooned (black arrow) and are morphologic
Nonalcoholic steatohepatitis (NASH) is becomingly increas- hallmarks of alcoholic and nonalcoholic steatohepatitis. Mallory
bodies are not cause but rather consequence of cellular injury.
ingly recognized as the most common cause of liver disease
Usually, hepatocytes with Mallory bodies do not contain large
in the United States.108 Few of these patients progress to cir- fat vacuoles, although microvesicular fat may be seen. In this
rhosis but often have moderate degrees of dysfunction. The frame, other hepatocytes are present, containing macrovesicular
diagnosis of NASH is based on a liver biopsy showing steato- fat globules (white arrow), which occupy almost all cytoplasm,
sis that is often indistinguishable from alcoholic liver disease displacing nucleus (white arrowhead) to periphery. (Hematoxylin-
(Fig. 5-7), evidence of negligible alcohol consumption, and eosin stain, ×400.) (From Lall C, et al: Nonalcoholic fatty liver
absence of HBV or HCV infection.109,110 The etiology of NASH disease, AJR Am J Roentgenol 190:993-1002, 2008.)
is unknown, but it is often associated with obesity, type 2 dia-
betes, and hyperlipidemia.111 on the short arm of chromosome 20; others have a mutation
Patients may present with fatigue, malaise, and right in NOTCH-2.117,118 AGS has an incidence of approximately
upper quadrant discomfort with elevated enzyme levels. Most 1:100,000 live births. Most patients present with jaundice, clay-
patients have only increased enzymes, but a few will progress colored stools, and other symptoms of mild cholestasis during
to cirrhosis. To date, no good predictors of disease progres- the neonatal period. Patients might also present with rapidly
sion exist, but presence of inflammation on biopsy, diabetes, progressive, fulminant hepatic failure. AGS is slowly progres-
and high AST may be associated factors.112,113 NASH has a bet- sive, and treatment is generally supportive. Approximately
ter overall prognosis than alcoholic liver disease, with fewer 15% of patients will require transplantation.119 A Kasai pro-
patients progressing to transplantation and improved 10-year cedure is generally not considered beneficial and thus is not
survival. However, NASH is associated with hepatocellular recommended, especially because the risk during liver trans-
carcinoma.114 There is no proven therapy, although weight plantation may increase with previous Kasai surgery.120
loss may result in improved enzyme levels and histologic find- Although the primary manifestation is cholestasis, AGS is of
ings.115 Modification of risk factors for hyperlipidemia and particular interest to anesthesiologists because of the high mor-
diabetes is also recommended. bidity of its associated conditions. More than 90% of patients
with AGS have congenital heart disease. Approximately 67%
of patients have uncomplicated peripheral pulmonic steno-
Genetic Causes of Liver Disease
sis; however, the remaining 33% have more serious defects,
ALAGILLE'S SYNDROME (ARTERIOHEPATIC DYSPLASIA) including tetralogy of Fallot (16%), patent ductus arteriosus
Alagille's syndrome (AGS) is a rare inherited disorder char- (5%), ventricular septal defect (4%), and atrial septal defect
acterized by the progressive loss of the intralobular bile ducts (4%). The presence of significant cardiovascular disease is
and narrowing of extrahepatic bile ducts.108 It is the most com- associated with increased perioperative mortality during liver
mon form of familial intrahepatic cholestasis, and more than transplantation.119 As many as 85% of patients have “butterfly
90% of patients experience chronic cholestasis.116,117 AGS has vertebrae” resulting from clefting abnormalities.111,116 Patients
an autosomal dominant pattern of inheritance, and more than are described as having a characteristic facies, and as many
90% of patients have a mutation in the jagged 1 (JAG1) gene as 90% of patients have ophthalmologic abnormalities, usually
anterior chamber defects.108,121 The facial features are defined The low serum protein concentrations observed in individ-
by a broad nasal bridge, triangular facies, and deep-set eyes, uals with α1-antitrypsin deficiency do not occur secondary to
but are not specific to Alagille's syndrome.122 Patients have a defective protein synthesis, but rather to ineffective processing
characteristically short stature, and resistance to growth hor- and secretion.130,131 These ineffective processes leave the hepa-
mone has been described.123 tocyte with large quantities of defective protein that accumu-
A meticulous preoperative evaluation of patients with arte- late in the cell. Defective processing is particularly severe in
riohepatic dysplasia is critical for perioperative planning and the Z mutation, where processing errors lead to the formation
optimal care. Severity and type of dysfunction can be highly of long polymers of Z–α1-antitrypsin.130 In both mutations,
variable, so associated conditions are evaluated, with partic- the excess of defective α1-antitrypsin is visible under light
ular attention to each patient's cardiac,124 hepatic, renal, and microscopy as large cytoplasmic inclusions. Stores of excessive
orthopedic disease.125 In some patients, vitamin K deficiency defective protein ultimately can interfere with normal hepatic
results from malabsorption. If blood loss is possible, preop- function.132
erative clotting studies may be indicated. Malnutrition can be The abnormal accumulation of defective protein leads to
a major concern, and proactive treatment with high-energy hepatocyte death and eventual cirrhosis. In general, the sever-
supplements and fat-soluble vitamins is recommended. Severe ity of hepatic disease is closely associated with the amount of
postoperative cholestasis has been reported in patients with accumulated protein. Liver disease does not occur in patients
Alagille's syndrome.126 with unusual mutations of α1-antitrypsin that do not result
in the accumulation of defective protein in the hepatocyte.
ALPHA1-ANTITRYPSIN DEFICIENCY Clinical presentation and age at onset vary significantly among
Deficiency of α1-antitrypsin is the most common metabolic patients with α1-antitrypsin deficiency, even among individu-
disease affecting the liver. The disease is most common among als with the same genotype. The variation in age at onset of
white Europeans, in whom the incidence may be as high as 1 in liver disease may result from variations in the rate of synthe-
1500 persons.127 The disease is somewhat less common among sis between individuals.133 Indeed, the appearance of jaun-
North American and Australian whites, about 1 in 2000 per- dice in infants with ZZ α1-antitrypsin deficiency may reflect
sons. The incidence among African, Asian, and Hispanic indi- a chronic infection resulting in increased synthesis of defec-
viduals is low. The precise geographic distribution depends on tive protein.134 Regardless, the appearance of jaundice dur-
the specific genotype. ing the neonatal period is a poor prognostic sign. Although
A potent serine protease inhibitor, α1-antitrypsin is synthe- α1-antitrypsin deficiency has other manifestations, it is well
sized in the liver and secreted into the blood. As it circulates, accepted that liver disease most influences survival. The
it binds to and promotes the degradation of serine proteases other primary clinical manifestations occur secondary to the
produced throughout the body. One of the most important absence of normal protease inhibition, which is most appar-
proteases inhibited by α1-antitrypsin is elastase. Indeed, α1- ent in the lung; patients with α1-antitrypsin deficiency have
antitrypsin is responsible for more than 90% of all the serum early onset of panlobular emphysema. All individuals experi-
antielastase activity and is principally involved in the degrada- ence an age-related decline in the forced expiratory volume in
tion of alveolar elastase. Once bound to its protease target, the 1 second (FEV1) after age 30; however, this decline is acceler-
α1-antitrypsin/protease complex binds to a receptor on hepa- ated by α1-antitrypsin deficiency. This acceleration is further
tocytes and is removed from the circulation.128 exacerbated by tobacco smoke, which can double the rate of
The α1-antitrypsin gene has been localized to chromo- decline.135
some 14 and is part of the serine protease inhibitor (SERPIN) The diagnosis is made by the measurement of serum α1-
supergene. This gene cluster also encodes for corticosteroid- antitrypsin concentration. The genotype is confirmed by
binding globulin, C1 inhibitor, and antithrombin III.127 At protein electrophoresis. There is no specific therapy for α1-
least 17 different mutant alleles of α1-antitrypsin have been antitrypsin deficiency, and liver transplantation may be
described; however, two mutations account for the major- required.
ity of disease. Individuals homozygous for the more com-
mon S mutation (Glu264Val) have a 40% decrease in serum CYSTIC FIBROSIS
α1-antitrypsin concentration.129 The S mutation is more Cystic fibrosis (CF) is the most common lethal inherited dis-
common among Southern Europeans, with peak inci- ease among white populations, with an incidence of approx-
dences recorded in the Iberian peninsula.127 Individuals imately 1 in 3300 persons in the United States. CF was one
homozygous for the more serious Z mutation (Glu342Lys) of the first genetic diseases to be characterized. The gene for
have an 85% decrease in serum α1-antitrypsin concentra- CF, the cystic fibrosis transmembrane conductance regula-
tion.129 Unlike the S mutation, the Z mutation is more com- tor (CFTR), resides on chromosome 7. Presence of the gene
mon among Northern and Western Europeans, with peak results in defective cellular chloride conductance. Although
incidences in northern France, the United Kingdom, and the principal manifestation of CF is pulmonary with associ-
Scandanavia.127 In general, the S mutation only produces ated viscid secretions, atelectasis, emphysema, and chronic
clinically significant disease when combined with the Z infections with Pseudomonas aeruginosa, hepatic abnormali-
mutation (SZ genotype). ties may complicate 20% of cases. Portal hypertension and
eventual hepatic cirrhosis may complicate up to 10% of all CF Galactosemia may present the anesthesiologist with several
cases and represent the second most common cause of death unique challenges. Newly diagnosed newborns who have been
after respiratory failure. As the median age of CF patients treated for a short time may have elevated clotting times and
increases secondary to a reduction in mortality, the concern is may be prone to bleeding. Some patients may have hemoly-
increased incidence of liver disease. sis, and preoperative evaluation of hemoglobin may be valu-
Although pathologic elevation of liver enzymes is fre- able in any jaundiced patient. Also, albuminuria may cause an
quently observed in infants, most patients with CF do not osmotic diuresis, and thus urine volume may be a poor indica-
progress to cirrhosis.136 Nevertheless, certain genotypes are tor of intravascular volume.
clearly associated with liver dysfunction and an increased inci-
dence of cirrhosis.137 There is also an increased incidence of
KEY POINTS
liver disease in patients with certain major histocompatibil-
ity complex (MHC) genotypes,138 male gender, coexisting liver n Infants with galactosemia may have elevated clotting times,
disease, and poor nutrition (especially fatty acid deficiency). hemolysis, and albuminuria.
Major liver disease is rarely noted in the absence of pancreatic n Glycogen storage disorders types I, II, and IV are associated
insufficiency. When hepatic disease advances to cirrhosis, it with severe hepatic disease; type III with muscular disease;
normally presents during the first decade of life. Portal hyper- and type IV with cardiomyopathy.
tension is usually manifested by splenomegaly, hypersplenism n Careful glucose monitoring is mandatory in patients with
with thrombocytopenia, and ascites.139 Bleeding of esophageal type I or III glycogen storage disease.
varices is also noted in some patients.
Transjugular intrahepatic portosystemic shunt (TIPS) GLYCOGEN STORAGE DISEASES
has been used with success in children and adolescents with Glycogen is the principal storage form for glucose in the human
refractory esophageal bleeding.140,141 In severe cases, liver body. It is composed of long chains of glucose joined together
transplantation has been performed.142,143 The anesthesiolo- by α-1,4 linkages. The chains intermittently branch to form
gist should be aware that the metabolism of certain drugs144 long, treelike strands of stored glucose. Glycogen stands as a
may be increased in CF secondary to increased hepatic drug ready reserve for glucose in times of metabolic need. Glycogen
clearance.145 metabolism principally occurs in skeletal muscle and liver.
Skeletal muscle glycogen provides exercising muscles with a
GALACTOSEMIA ready source of fuel while hepatic glycogen serves to main-
Galactosemia is an inherited deficiency of the enzyme tain plasma glucose during fasting. The glycogen storage dis-
galactose-1-phosphate uridyltransferase, which catalyzes
orders comprise a family of 10 different diseases. Each disease
the conversion of galactose-1-phosphate to UDP-galactose; is characterized by a glycogen metabolism enzyme deficiency.
deficiency leads to the abnormal accumulation of galactose- Only glycogen storage disorder types I, III, and IV are associ-
1-phosphate in cells. The enzyme is normally present in liver ated with severe hepatic disease (Table 5-4).
and erythrocytes. Galactosemia is a rare disorder, approxi- The perioperative management of any patient with a
mately 1 in 60,000 live births. Galactose-1-phosphate is directly glycogen storage disorder requires meticulous care and plan-
toxic to cells, and accumulation is most notable in the kid- ning. Obviously, the blood glucose level should be carefully
ney, liver, and brain. Breast milk contains lactose, a disaccha- monitored in any patient with a type I or III glycogen stor-
ride consisting of glucose and galactose. As newborn infants age disorder. Nothing by mouth (NPO) guidelines should
receive up to 20% of their caloric intake in the form of lac- be followed, and patients may require preadmission for IV
tose, infants with galactosemia rapidly accumulate galactose- administration of glucose-containing fluids. Case reports of
1-phosphate. Routine newborn screening normally makes the successful anesthetic management of patients with a type I
diagnosis of galactosemia. If the diagnosis is not made, the glycogen storage disease have been reported.151-153 Patient-
accumulation of galactose-1-phosphate can ultimately lead to controlled sedation with propofol during spinal anesthesia has
cataracts, severe mental retardation, and cirrhosis. also been successfully employed.154 Patients with a type III gly-
Treatment involves the avoidance of lactose in the diet; cogen storage disease may pose a special challenge to anesthe-
however, patients treated appropriately still develop long- siologists secondary to muscle disease.155 Liver transplantation
term complications, including cognitive impairment, cata- has been used to treat type I, III, and IV glycogen storage dis-
racts, speech abnormalities, and primary ovarian failure.146,147 eases,156 but cardiomyopathy may persist in type IV secondary
Infants born with galactosemia have an increased incidence to cardiac amylopectin deposition.157
of Escherichia coli neonatal sepsis that normally precedes the
diagnosis of galactosemia.148 Without treatment, the disease is HEREDITARY FRUCTOSE INTOLERANCE
generally fatal, although case reports of adult patients present- Hereditary fructose intolerance (HFI) is an inherited defi-
ing with decompensated cirrhosis exist.149 Galactokinase deficiency of the enzyme fructose-1,6-bisphosphate aldolase
ciency, another inherited disorder of galactose metabolism, is (aldolase B). Aldolase B catalyzes the conversion of fructose-
less common than galactosemia and generally has a milder 1,6-bisphosphate to two triose phosphates, dihydroxyace-
course.150 tone phosphate and glyceraldehyde-3-phosphate. Deficiency
TABLE 5-4 n Glycogen Storage Diseases
Enzyme Main Clinical

Disease Deficiency Features Liver Disease Treatment Notes
Type Ia (von Glucose-6- Profound Hepatomegaly (normal Portal diversion Type Ib (10% of
Gierke's phosphatase hypoglycemia spleen) shunting type I disease)
disease) Growth failure Hepatic adenomas (by Glucose also associated
Metabolic acidosis second decade of life) supplements with neutropenia
Hyperlipidemia Occasional hepatocellular (cornstarch, and neutrophil
Renal failure (by carcinoma nocturnal glucose dysfunction
second decade infusion)
of life) Liver transplantation
Diagnosis in infancy
Type IIIa Liver and Profound Hepatomegaly (normal High-protein, low- Type IIb (15% of
(Cori- muscle hypoglycemia spleen) carbohydrate diet type III) has
Forbe's debranching Growth failure Hepatic adenomas (less Glucose normal muscle
disease) enzyme Progressive muscle common than type I) supplementation debranching
weakness with Rare hepatocellular (cornstarch, enzyme and
activity carcinoma nocturnal glucose no muscular
Muscle atrophy infusion) rarely symptoms
More tolerant to necessary Generally improves
fasting than type I with age
Type IV Branching Failure to thrive Hepatosplenomegaly Death without liver Rare

(Andersen's enzyme Abdominal distention Progressive transplantation
disease) Miscellaneous macronodular cirrhosis
gastrointestinal Hepatic failure
complaints
Cardiomyopathy
Hypoglycemia rare
leads to the abnormal accumulation of fructose-1-phosphate nutritional disorder; however, the gene was later found to
and initiates severe symptoms when patients are exposed to reside on the short arm of chromosome 6, closely linked to the
fructose. The enzyme is normally present in liver, kidney, genes encoding for human leukocyte antigen (HLA).161,162 It
and small bowel. HFI is a rare disorder, with an incidence of was not until 1996 that the gene responsible for hemochroma-
approximately 1 in 23,000 live births. tosis (HFE) was discovered, allowing for formal genetic test-
When patients consume fructose or sucrose (a disaccharide ing and diagnosis.163 A variety of conditions, both acquired
consisting of glucose and fructose), the acute presentation of and idiopathic, can be characterized by excessive total body
abdominal pain, malaise, hypoglycemia, nausea, and vomiting iron (Box 5-2). In many cases, these diseases mimic hereditary
is often noted. Continued ingestion of fructose yields jaundice, hemochromatosis and may be superficially indistinguishable
hepatomegaly, and renal dysfunction.158 Persistent fructose in their clinical manifestations. Nevertheless, it is universally
consumption results in fulminant hepatic failure. Treatment accepted that hereditary hemochromatosis refers specifically
consists of the avoidance of fructose and sucrose in the diet. to increased iron absorption secondary to HFE-related genetic
Unlike galactosemia, patients are normally without symptoms mutations.
if fructose is avoided, and intellectual development is unim- As specific HFE mutations are identified and investigated,
paired. Some investigators believe that HFI is underdiag- it has become increasingly clear that hereditary hemochroma-
nosed, and formal testing yields the diagnosis among patients tosis represents a spectrum of clinical disease. Indeed, some
with unexplained, chronic abdominal pain.159 Secondary to homozygotes may manifest disease without a substantial
an almost-complete absence of dietary sucrose, patients with increase in iron stores,164 whereas others do not manifest clini-
HFI have excellent dentition.160 Oral medications containing cal symptoms in any appreciable way. In addition, although
sucrose or fructose are avoided in patients with HFI. HFE is equally distributed between the genders, clinical dis-
ease is two to eight times more common in men than women.
HEREDITARY HEMOCHROMATOSIS Patients with hereditary hemochromatosis can be classified
Hereditary hemochromatosis is an autosomal recessive dis- into four groups: (1) genetic predisposition without abnor-
ease characterized by an inappropriately high degree of iron malities, (2) iron overload without symptoms, (3) iron over-
absorption. In the past, it had been theorized that the disor- load with early symptoms, and (4) iron overload with end
der occurred due to alcohol abuse and was merely a secondary organ damage.165 Other factors, genetic and environmental,166
secondary to pancreatic iron deposition, may also occur,

BOX 5-2 n IRON OVERLOAD CONDITIONS although it is rare in the absence of cirrhosis. Iron deposition
Primary Iron Overload in skin may give patients a bronze coloration; hemochroma-
Hereditary hemochromatosis (HFE) tosis has been referred to as “bronze diabetes.” Iron deposi-
Non-HFE related tion in the heart can lead to fibrotic changes and most often
Juvenile hemochromatosis
to a restrictive cardiomyopathy. An increase in fatal and non-
Transferrin receptor-2 mutations
Ferroportin-1 mutation
fatal arrhythmias is also noted. An arthropathy, especially of
African iron overload the hands, is noted in about 50% of patients but does not usu-
ally present before age 50.
Secondary Iron Overload
Red blood cell transfusions As iron accumulates in the liver, significant hepatocyte
Iron-loading anemias damage occurs. The fundamental disease mechanism results
Thalassemia major from direct iron toxicity and the consequent increase in
Sideroblastic anemia iron-generated free-radical production.174-177 The increased
Chronic hemolytic anemia
oxidative stress results in lipid peroxidation,176,177 mitochon-
Aplastic anemia
Pyruvate kinase deficiency drial injury,165 and impaired calcium homeostasis.174,175 This
Long-term dialysis results in an inflammatory response, fibrin deposition, and
Chronic liver disease ultimately cirrhosis. Further oxidative stress may result in
Hepatitis B DNA damage and an increased risk of hepatocellular carci-
Hepatitis C
noma.175 Hepatocellular carcinoma is the most common cause
Alcoholic liver disease
Nonalcoholic steatohepatitis of death in patients with hereditary hemochromatosis, and
Portocaval shunting the risk is 200 times greater than in the general population.178
Complications arising from cirrhosis and congestive heart
Modified from Harrison SA, Bacon BR: J Hepatol 38:S14-S23, 2003. failure are other common causes of death.
Once the diagnosis of hereditary hemochromatosis is made,
treatment with phlebotomy and reduction in alcohol and
certainly influence the development of clinical disease. The dietary iron intake should be initiated. The goal of therapy is
early observation of the link among hereditary hemochroma- to make the patient non–iron deficient or nonanemic.165 Thus,
tosis, cirrhosis, and alcohol abuse may be explained by alcohol careful monitoring of hemoglobin, iron levels, ferritin, and
further increasing iron absorption.167 transferrin saturation should guide therapy. Although phle-
The normal adult has a total body iron content of 3 to 5 g. botomy and careful monitoring of dietary intake effectively
Most iron is recycled through the phagocytosis of senescent reduce iron stores, therapy does not reverse cirrhosis or totally
erythrocytes, and only 1 to 2 mg of iron is normally lost each eliminate the risk of hepatocellular carcinoma. This is espe-
day.168 Losses may be greater among menstruating women cially true among patients diagnosed at an advanced age. As
and in the case of acute or chronic blood loss. Consequently, such, early diagnosis and treatment, ideally before the onset of
dietary iron absorption is tightly regulated, with the amount symptoms, is critical. Liver transplantation may represent the
absorbed paralleling the body's needs. In hereditary hemo- only treatment in patients with advanced disease or with hepa-
chromatosis, regulatory processes fail.169,170 This results in an tocellular carcinoma; however, many studies reveal decreased
abnormal increase in dietary iron absorption with iron depo- survival in transplant patients with hereditary hemochroma-
sition in the skin, heart, pancreas, joints, and liver. Hereditary tosis compared with other indications.179
hemochromatosis is surprisingly common. In some white
European populations, 10% to 12% of people are heterozy- HEREDITARY TYROSINEMIA TYPE 1
gous carriers of the disease.170 The incidence of homozygous There are four known deficiencies in the catabolism of tyro-
hereditary hemochromatosis ranges between 1:100 and 1:400 sine: alkaptonuria and tyrosinemia types 1, 2, and 3. Only
in whites of European descent.171,172 hereditary tyrosinemia type 1 (HT-1) is associated with
The primary presentation of symptomatic hereditary liver disease. HT-1 is an inherited deficiency of the enzyme
hemochromatosis is becoming rare. Most patients are asymp- fumarylacetoacetate hydrolase (FAH). The enzyme catalyzes
tomatic and report for evaluation and genetic testing after the final step in phenylalanine and tyrosine catabolism, the
a family member develops the disease. Nevertheless, most conversion of fumarylacetoacetate to acetoacetate and fuma-
symptomatic patients present in the fifth or sixth decade of rate. FAH deficiency leads to the abnormal accumulation of
life. The liver is the first organ to be affected in hemochro- “upstream” tyrosine metabolites fumarylacetoacetate (FAA)
matosis, and hepatomegaly is noted in almost 100% patients. and maleylacetoacetate (MAA). Both FAA and MAA are con-
The most common presenting symptoms include generalized verted to two toxic products, succinyl acetoacetate (SAA) and
weakness, malaise, arthralgias, abdominal pain, and impo- succinylacetone (SA). SAA and SA interfere with DNA ligase
tence (in men).173 Physical examination may reveal hepa- activity,180 reduce blood and liver stores of glutathione,181 and
tomegaly and, in advanced cases, signs and symptoms of interfere with heme metabolism. These effects combine to
cirrhosis, including ascites and jaundice. Diabetes mellitus, decrease the body's ability to deal with oxidative stress and
directly result in mutagenic damage and chromosomal break- coronary, and valvular heart disease are common.188 Corneal
age.182 Initially, liver biopsy reveals steatohepatitis; however, “clouding” is an expected complication, and patients may pres-
this advances to fibrosis and cirrhosis. ent for corneal transplant. Patients frequently require surgical
Although a rare disorder affecting approximately 1 in intervention for orthopedic abnormalities. A stiff neck, large
100,000 births, the incidence of HT-1 may be higher in north- tongue, and tonsillar hypertrophy may make intubation diffi-
ern Europe (1:8000) and in Quebec, Canada (1:1846).183,184 cult.189,190 Copious airway secretions may be treated with anti-
Essentially, two forms exist, acute and chronic. In acute HT-1, cholinergics. Fiberoptic intubation through a laryngeal mask
patients present with symptoms of severe hepatic dysfunction airway (LMA) may represent a useful technique, especially in
during the first 6 months of life. Liver biopsy reveals steato- children.191 Patients should be considered at risk for airway
hepatitis that advances to fibrosis and micronodular cirrho- obstruction and postobstructive pulmonary edema.192 Failure
sis with bile duct proliferation. In general, the acute form is of epidural anesthesia has been reported and may be related to
rapidly fatal within the first year of life without hepatic trans- the accumulation of glycosaminoglycans (GAGs) in the epi-
plantation. The chronic form of HT-1 presents more slowly, dural space.193 Perioperative antibiotics may be indicated in
with patients rarely seeking medical care before age 1 year. The patients with valvular disease.
progress of hepatic dysfunction tends to occur more slowly, Mucopolysaccharidosis type II (MPS-II, Hunter's disease)
and patients develop other symptoms, including nephropa- results from the deficiency of iduronate sulfatase and has an
thy, rickets, and serious neurologic problems.185 Secondary to X-linked recessive pattern of inheritance. Both a severe infan-
continued DNA damage, a substantial risk of hepatocellular tile and a mild juvenile form of the disease exist. In addi-
carcinoma exists. Liver biopsy reveals less cholestasis than the tion to massive hepatosplenomegaly, GAGs accumulate in
acute form; however, macronodular and micronodular cirrho- the head and neck, and patients have a short neck and large
sis are eventually noted. tongue. Unlike MPS-I, corneal disease is rare. Nevertheless,
Liver transplantation is normally indicated within the endotracheal intubation can be difficult,189,190 and acute airway
first decade of life in patients with chronic HT-1; how- obstruction has been reported.194 Failure of the LMA to secure
ever, advances in treatment are promising.186,187 Patients may the airway in a patient with MPS II has been reported.195
develop hypertrophic cardiomyopathy. Anemia, thrombocy- Again, however, fiberoptic LMA intubation may be useful in
tosis, and prolonged clotting times may be observed. No spe- children,191 and sleep apnea and pulmonary edema have been
cific information addresses anesthetic care in patients with reported.192
HT-1, although preoperative assessment of cardiac, hepatic, Mucopolysaccharidosis type VII (MPS-VII, Sly's syn-
metabolic, and hematologic function should be considered. drome) results from the deficiency of β-glucuronidase and
has an autosomal recessive pattern of inheritance. At least
four phenotypes exist.196 The neonatal form of MPS-VII pres-
LYSOSOMAL STORAGE DISEASES
ents as hydrops fetalis and is uniformly fatal.197 An infantile
Lysosomal storage diseases are a heterogenous group of dis-
form presents as hepatosplenomegaly, jaundice, and inguinal
eases resulting from different defects in lysosomal function.
and umbilical hernias. It is rapidly progressive and has a poor
Each disease normally reflects a lysosomal enzyme deficiency
prognosis. A second infantile form also presents as hepato-
and a consequent inability to metabolize various biomole-
splenomegaly, but seems to have a milder course.198 The adult
cules. Most diseases follow an autosomal recessive pattern of
form of MPS-VII presents in adolescence and is not normally
inheritance. Of the more than 30 well-classified diseases, only
complicated by hepatic involvement. Patients may have car-
a small number result in hepatic impairment.
diac involvement with mitral and aortic insufficiency. Acute
Mucopolysaccharidoses aortic dissection has been reported. Because of the accumu-
Each mucopolysaccharidosis (MPS) results from the defi- lation of GAGs in the head and neck, patients with Sly's syn-
ciency of an enzyme responsible for glycosaminoglycan drome may also be difficult to intubate, although this has not
(GAG) metabolism. GAGs are complex, long-chain carbohy- been specifically reported with MPS-VII. Intraoperative com-
drates that are normally linked to proteins to form proteogly- plete heart block has been observed.199 Patients with aortic
cans. Proteoglycans are common constituents of connective or mitral insufficiency may require perioperative antibiotic
tissue. prophylaxis.
Mucopolysaccharidosis type I (MPS-I) results from the
deficiency of α-l-iduronidase. At least three phenotypes exist. LIPID STORAGE DISORDERS
MPS-IH (Hurler's disease) has an acute course characterized by Each of the lipid storage disorders results from the deficiency
hepatosplenomegaly, mental retardation, and death normally of an enzyme responsible for lipid metabolism. The lipid stor-
occurring in the first decade. MPS-IS (Scheie's disease) has a age disorders include Fabry's disease, Gaucher's disease, and
less severe course characterized by hepatosplenomegaly after Niemann-Pick disease; only the latter two have hepatic mani-
age 5 years and normal life span without mental retardation. festations and are discussed here.
MPS-IH/S (combined Hurler/Scheie) follows an intermediate Gaucher's disease (GD) results from the deficiency of
course. In all these MPS-I diseases, hepatosplenomegaly can acid β-glucosidase and has an autosomal recessive pattern
be massive, with profound skeletal dysplasia.188 Myocardial, of inheritance. GD is the most common lysosomal storage
disease. Three phenotypes have been described: adult, infan- develop pulmonary disease characterized by severe diffusion
tile, and juvenile.200,201 Adult Gaucher's disease (GD type 1) limitations. Such patients may have low Pao2 and develop cor
represents 99% of cases and has a variable onset. It is charac- pulmonale and right ventricular failure in the second decade of
terized by thrombocytopenia,202 anemia, and hepatospleno- life. Patients with type C NPD have a deficiency in cholesterol
megaly. Bone pain is a common complaint, and pathologic transport that leads to a disease that is phenotypically similar
fractures can occur. Although hepatosplenomegaly may be to types A and B NPD.210 Patients with type C disease present
the most prominent feature, most morbidity results from with prolonged neonatal jaundice. Hepatosplenomegaly is less
bone pain. Intelligence is normal, and neurologic symptoms severe than in types A and B, and patients normally undergo
are rare. The availability of placental and now recombinant slowly progressive neurodegeneration.
glucocerebrosidase has improved morbidity in many patients Airway management may be more difficult in patients with
and can result in decreased liver volume.202,203 Blood coagula- NPD.211 Pulmonary disease may complicate perioperative care,
tion abnormalities have also improved.204 Adult GD has a car- especially in individuals with type B disease. Liver transplan-
rier rate of approximately 1:18 among Ashkenazi Jews and an tation has successfully reduced some of the clinical manifesta-
annual incidence of approximately 1:1000 live births in the tions in patients with type A and B NPD. However, morbidity
United States.190 and mortality of liver transplantation may be extremely high
The accumulation of glycosphingolipids in the head and secondary to pulmonary and neurologic disease.212,213
neck may make endotracheal intubation difficult, and patients
may require a smaller-than-predicted endotracheal tube. OTHER LYSOSOMAL STORAGE DISEASES
Patients should be considered at risk for upper airway obstruc- Mannosidosis results from the deficiency of α-mannosidase.214
tion.205,206 A small mouth may make LMA insertion difficult.205 An infantile form of the disease is characterized by progres-
Preoperative evaluation should include a baseline hemoglo- sive mental retardation and hepatosplenomegaly. Cataracts
bin and platelet count, because patients are at risk for anemia and corneal clouding may also be observed. An adult form has
and thrombocytopenia. Spinal anesthesia has been used with a delayed onset and allows for longer survival. A small mouth
success.207 and a large tongue may make intubation difficult. Death nor-
Infantile Gaucher's disease (GD type 2) is characterized by mally occurs before age 5. An autosomal recessive pattern of
hepatosplenomegaly and severe developmental delay. Stridor inheritance is noted in this rare disease.
and laryngospasm are frequent complications. The disease Wolman's disease results from the deficiency of acid lipase
progresses rapidly, and death occurs before age 2. Juvenile and is characterized by the deposition of cholesterol esters
Gaucher's disease (GD type 3) is characterized by ataxia, hep- throughout the body.215 Hepatosplenomegaly and eventual
atosplenomegaly, and mental retardation. The typical onset cirrhosis are among the more prominent manifestations; how-
occurs during childhood, and patients normally die before age ever, pulmonary disease with a high alveolar diffusion gradi-
15. Juvenile GD has a peak incidence in the Swedish Norrbotten ent may be severe. Adrenal calcification is a unique feature.
population, with an incidence of 1 in 50,000 persons. Neonatal survival is impossible without total parenteral nutri-
Gastroesophageal reflux and chronic aspiration can compli- tion, and death occurs within the first year of life. Bone marrow
cate both type 2 and type 3 GD. As in type 1 GD, the airway transplantation has been used successfully to treat Wolman's
management of patients with types 2 and 3 may be difficult, disease.216 No specific information is available on anesthesia in
and patients are at risk for postoperative respiratory compro- patients with Wolman's disease.
mise.208 Regional anesthesia has been used with success and
should be considered. PORPHYRIA
Niemann-Pick disease (NPD) results from the deficiency The porphyrias make up a family of inherited diseases result-
of sphingomyelinase and has an autosomal recessive pattern ing from deficiencies in one or more of the enzymes required
of inheritance. At least six phenotypes of NPD have been for heme synthesis. The enzymatic deficit results in the accu-
described, but three types (A, B, and C) make up the majority mulation of “upstream” metabolites and consequent symp-
of cases.209 Infantile neuropathic NPD (NPD type A) normally toms (Fig. 5-8). More than 75% of heme synthesis occurs in
presents before 6 months of age and is characterized by hepa- the bone marrow, and thus porphyrias are associated with
tosplenomegaly, lymphadenopathy, seizures, and mental retar- variable hepatic disease. Traditionally, porphyrias are gener-
dation. A progressive loss of intellectual capacity and motor ally divided into erythropoietic or hepatic types, depending
function results from increased deposition of sphingomy- on whether the excess production of metabolic intermediates
elin in the central nervous system (CNS). Non-neuronopathic takes place in the liver or in the bone marrow. Porphyrias can
NPD (NPD type B) has a variable age of presentation and a be further divided into those with neurovisceral symptoms
more heterogenous expression. Nevertheless, most patients (acute porphyrias) and those characterized by photosensitivity
are diagnosed in childhood with hepatosplenomegaly. Unlike and cutaneous symptoms (cutaneous porphyrias). Table 5-5
type A, patients with type B NPD are neurologically intact, summarizes the characteristics of the various porphyrias.217
and systemic deposition of sphingomyelin is more promi- Acute intermittent porphyria (AIP) is the most common
nent. Hepatic cirrhosis may develop, and portal hypertension type of porphyria, with a prevalence of about 1:10,000 to
and ascites can complicate the disease. Many type B patients 1:20,000 people. Secondary to the disease's ability to cause
Cytosol Mitochondria
XLSA
ALA synthase Succinyl CoA

ALA
Glycine
ADP ALA dehydratase
HEME
PBG
AIP PBG deaminase

Ferrochelatase EPP
HMB
Protoporphyrin IX
CEP Urogen III
cosynthase
Protogen oxidase VP
Urogen I Urogen III
Urogen
decarboxylase Coprogen oxidase
PCT
HEP
Protogen IX
Coprogen I Coprogen III
HCP
FIGURE 5-8 Heme synthesis and enzymatic defects in porphyrias. Defects begin with formation of δ-aminolevulinic acid (ALA) from
succinyl coenzyme A (CoA) and glycine. The enzymatic defect in each porphyria is shown by a red broken line. In patients, the substrate
for the defective enzyme accumulates and is excreted into urine or stool. XLSA, X-linked sideroblastic anemia; ADP, ALA dehydratase
porphyria; PBG, porphobilinogen; AIP, acute intermittent porphyria; HMB, hydroxymethylbilane; CEP, congenital erythropoietic porphyria;
Uro'gen, uroporphyrinogen; Copro'gen, coproporphyrinogen; Proto'gen, protoporphyrinogen; PCT, porphyria cutanea tarda; HEP,
hepatoerythropoietic porphyria; HCP, hereditary coproporphyria; VP, variegate porphyria; EPP, erythropoietic protoporphyria. (Anderson K:
Porphyrias: an overview. Up-to-date. www.uptodate.com; accessed 2/27/11.)
neuronal damage, the incidence of AIP among patients with An acute attack is normally heralded by the presence of
psychiatric disorders may be as high as 1:500.218,219 AIP may colicky abdominal pain, nausea, and vomiting, followed by
be considered the prototype for all acute porphyrias, because the appearance of dark urine.220 Patients with AIP may also
the presentation of all acute porphyrias is similar, with spe- complain of diarrhea or constipation. Classically, neurologic
cific diagnosis requiring laboratory analysis. In AIP, patients symptoms follow the onset of visceral complaints and may
have a deficiency of porphobilinogen (PBG) deaminase activ- be highly variable. Patients may experience seizures, periph-
ity. Because a complete deficiency would be incompatible with eral neuropathy, and cranial nerve deficits. They may become
life, most patients have approximately 50% of normal PBG psychotic. Hyponatremia may be observed secondary to the
deaminase activity. The deficiency results in an increase in syndrome of inappropriate secretion of antidiuretic hormone
cellular δ-aminolevulinic acid (ALA). Most patients are gen- (SIADH).
erally asymptomatic until some event stimulates the produc- The cornerstone of treatment in AIP, as all acute porphyr-
tion of ALA. The deficiency of PBG deaminase activity results ias, includes the recognition and avoidance of precipitating
in relative ALA overproduction and consequent symptoms. factors. Once precipitating factors have been eliminated,
Precipitating factors that lead to an acute exacerbation include glucose therapy (400 g/day) and/or heme arginate (3 mg/kg/
(1) stimulation of ALA synthetase production in the liver; day for 3 days) may be instituted.217 Glucose and heme argin-
(2) endocrine factors, including the female reproductive cycle; ate work to decrease ALA synthetase activity and reduce the
(3) fasting, especially in combination with alcohol intake; urinary excretion of ALA and shorten the length of an acute
(4) induction of hepatic CYP450 that leads to ALA synthe- attack.
tase production through a reduction in inhibitory heme; and In the patient with a history of acute porphyria, optimal peri-
(5) emotional stress, including surgery and chronic illness.217 operative care includes careful planning and communication
Clinical onset occurs most often after puberty and is more among surgeons, anesthesiologists, and internists. Presurgical
common in women, likely secondary to the effects of hor- admission for IV hydration with glucose-containing fluids is
mones and corticosteroids on the liver. an important step in the patient with a history of acute attacks.

TABLE 5-5 n Classification of the Human Porphyrias
MAJOR BIOCHEMICAL FINDINGS*

Site/Clinical Enzyme
Disease Features Affected Inheritance Urine Plasma RBCs Feces
ADP HepaticΔ/Acute ALAD Autosomal recessive ALA, copro III ALA, copro III Zinc proto and low —
ALAD activity
AIP Hepatic/Acute PBGD Autosomal dominant ALA, PBG, copro — Low PBGD activity —
HCP Hepatic/Acute and CPO Autosomal dominant ALA, PBG, copro III — — Copro III
cutaneous
VP Hepatic/Acute and PPO Autosomal dominant ALA, PBG, copro III Fluorescence — Copro III and proto
cutaneous peak at 626 nm
PCT Hepatic/Cutaneous UROD Autosomal dominant¸ Uro and hepta-CP Uro and hepta-CP — Isocopro
HEP HepaticΔ/Cutaneous UROD Autosomal recessive Uro and hepta-CP Uro and hepta-CP Zinc proto and low Isocopro
UROD activity
CEP Erythropoietic/ UROS Autosomal recessive Uro I and copro I Uro I and copro I Uro I and copro I Copro I
Cutaneous
EPP classic Erythro/Cutaneous FECH Autosomal dominant — Proto Free proto Proto
EPP variant Erythro/Cutaneous ALAS-2 X-linked recessive — Proto Free and zinc proto Proto
Modified from Anderson K: Porphyrias: an overview. Up-to-date. February 2011.

* Increases of importance for diagnosis in most cases.
Δ, These hepatic porphyrias also have erythropoietic features, including increases in erythrocyte zinc protoporphyrin.
¸, UROD inhibition in PCT is mostly acquired, but an inherited deficiency of the enzyme predisposes in familial (type 2) disease.
ADP, δ-Aminolevulinic acid dehydratase porphyria; RBCs, red blood cells, erythrocytes; ALAD, aminolevulinic acid dehydratase; Copro, coproporphyrin; Proto, protoporphyrin; AIP, acute intermittent porphyria; PBGD,
porphobilinogen deaminase; HCP, hereditary coproporphyria; CPO, coproporphyrinogen oxidase; VP, variegate porphyria; PPO, protoporphyrinogen oxidase; PCT, porphyria cutanea tarda; UROD, uroporphyrinogen
decarboxylase; Uro and hepta-CP, uroporphyrin and heptacarboxyl porphyrin; Isocopro, isocoproporphyrin HEP, hepatoerythropoietic porphyria; CEP, congenital erythropoietic porphyria; Erythro, erythropoietic; UROS,
uroporphyrinogen III synthase; EPP, erythropoietic protoporphyria; FECH, ferrochelatase; ALAS-2, δ-aminolevulate synthase, erythroid-specific form.
Chapter 5 Liver Diseases
183
n Anesthetic management of porphyria patients includes

TABLE 5-6 n Porphyria and Safety of Anesthetics
avoiding precipitating drugs, early IV hydration and glucose
Generally administration, and avoidance of hypothermia.
Considered Generally n Acute exacerbation may be treated with glucose and heme
Safe Unclear Considered Unsafe arginate.
INTRAVENOUS AGENTS
WILSON'S DISEASE (HEPATOLENTICULAR DEGENERATION)
Midazolam Ketamine Barbiturates Wilson's disease (WD) is an autosomal recessive disease that
Lorazepam Diazepam Etomidate results in the abnormal accumulation of copper in the liver,
Propofol
kidney, and CNS. One of the oldest diseases to be recognized
INHALED AGENTS as familial, WD was first described by Kinnear Wilson in 1912
Nitrous oxide Isoflurane Enflurane
as a progressive disease characterized by hepatic cirrhosis and
Desflurane Halothane softening of the lenticular nucleus.231 Over the past century,
WD has changed from a universally fatal familial disease to a
ANALGESICS
treatable disease with multiple therapeutic options. WD is pres-
Fentanyl Alfentanil ent in all populations and has an incidence of approximately
Morphine Sufentanil 1 in 30,000 persons. The gene responsible has been located in
MUSCLE RELAXANTS chromosome 13. The disease is more common among Jewish
eastern Europeans and certain Asian populations.232
Succinylcholine Atracurium Copper is an essential metal required for the normal func-
Vecuronium Pancuronium
tion of a variety of enzymes, including lysyl oxidase, super-
LOCAL ANESTHETICS oxide dismutase, tyrosinase, and monoamine oxidase.233,234
Bupivacaine Lidocaine
Copper metabolism is a complex process.235 Briefly, copper is
Procaine absorbed from the small intestine and bound to albumin. More
than 90% of copper-bound albumin is taken up by the liver.234
VARIOUS
In the liver, copper binds to apoceruloplasmin to form cerulo-
Atenolol Glucocorticoids plasmin. It is noteworthy that the incorporation of copper into
Atropine Hydralazine apoceruloplasmin is an ATP-dependent process. Saturated
Droperidol with six molecules of copper, ceruloplasmin is released into
Labetalol
Neostigmine
the blood. Ceruloplasmin is also an acute-phase reactant, with
increased levels found in various inflammatory conditions.
Modified from Jensen NF, Fiddler DS, Striepe V: Anesth Analg 80:591-599, Throughout the body, copper is taken up by cells and deliv-
1995; and Stevens JJ, Kneeshaw JD: Anesth Analg 82:416-418, 1996.
ered to its target enzymes after binding to various thiol-rich
metallochaperones.236 The only physiologic means of copper
A large carbohydrate load may suppress the synthesis of ALA excretion is through the bile. In WD, patients lose the ability
synthetase and may be beneficial.221 The selection of appropri- to mobilize copper for biliary excretion.237 This defect leads to
ate anesthetics and analgesics is important, because many drugs increased serum levels of copper. High levels of copper induce
frequently used in anesthesia have the capacity to induce ALA metallochaperone production. Because metallochaperones are
synthetase and CYP450.222,223 Table 5-6 summarizes the safety of able to sequester copper in a nontoxic form, patients normally
various drugs frequently used in anesthesia. Many otherwise- remain asymptomatic until copper supply overwhelms the
asymptomatic patients with AIP (or any acute porphyria) may absorptive power of metallochaperones. Ceruloplasmin levels
present for anesthesia with a misdiagnosed “surgical” abdomen. are low in patients with WD, as in patients with liver cirrhosis
Patients should be kept warm because cold-induced stress may of any cause.238
precipitate an acute crisis. Regional anesthesia has been used The presentation of hepatolenticular degeneration varies
with success.224 Liver transplantation has been used success- widely. In general, patients present with symptoms of liver dis-
fully to cure AIP.225 Attempts to treat other porphyrias with liver ease before the onset of neurologic symptoms.239 Normally,
transplantation have met with mixed success.226-230 WD presents in children and young adults with nonspecific
symptoms, including nausea, vomiting, and abdominal pain.
Patients may give a history of mild, intermittent jaundice,
KEY POINTS
and some patients may present with hepatomegaly or hepato-
n Porphyrias are divided into acute and cutaneous forms. splenomegaly. WD may also present as fulminant hepatic fail-
n Acute intermittent porphyria is most common (1:10,000 to ure240,241 or as an incidental, asymptomatic elevation of serum
1:20,000). transaminases. WD can imitate a variety of liver diseases,
n Porphyria exacerbation can be precipitated by stimulation including autoimmune hepatitis. WD should be considered in
of ALA synthetase, endocrine factors (female reproductive the differential diagnosis of established liver disease, even in
cycle), fasting, induction of CYP450, and emotional stress. the preschool-aged child.242
Most patients present with the neurologic manifesta-

Drug-Associated and Other Toxic Liver Disease
tions of WD in adulthood. Pseudosclerosis is noted, and Drug induced liver injury is a common problem, with an
patients present with parkinsonian features or rigid dys- annual incidence of approximately 1 in 10,000 to 100,000
tonia. The classically described lenticular degeneration of p
opulation.252 Up to 10% of all adverse drug reactions are liver
WD tends to present in childhood and is more often asso- injury, and drug-induced hepatic injury is the most common
ciated with dystonia. Children are often described as hav- cause of acute liver failure in the United States.253,254 The liver
ing a “sardonic smile.” The clinical hallmark of WD is the receives high concentrations of ingested compounds by portal
presence of a Kayser-Fleischer ring, a yellow-brown ring blood flow from the splanchnic bed. Hepatocytes in turn take
around the cornea. The Kayser-Fleischer ring is caused up such compounds and subject them to metabolic processes
by copper deposition in Descemet's membrane. The ring with detoxification and biotransformation.
is best demonstrated under slit-lamp examination; how- Drug-induced liver injury can be classified according to
ever, the ring may be plainly visible. The Kayser-Fleischer clinical presentation and laboratory findings, the mechanism
ring is present in more than 98% of patients with neuro- of toxicity, or the histologic findings.255 An exhaustive list of
logic manifestations of WD and more than 80% of patients naturally occurring substances, manufactured chemicals, and
with WD.243 Approximately 30% of patients with WD will pharmacologic agents has been implicated in liver disease,
have psychiatric symptoms. The most common symptoms with pharmaceuticals being the most common. Table 5-7 pro-
include depression and irritability; however, patients may vides examples of the types of damage caused by represen-
present with frank catatonia.243,244 tative agents and is by no means a complete listing. Clinical
The diagnosis of hepatolenticular degeneration requires manifestations range from minor asymptomatic biochemi-
a high index of suspicion, because the presentation is simi- cal changes to cholestatic signs and symptoms to massive
lar to many causes of cirrhosis. Indeed, WD may underlie liver necrosis, depending not only on the agent but also on
coexisting liver disease. In general, the diagnosis should the patient's pre-exposure condition, concurrent disease, and
be considered in any patient younger than 40 with the extent of exposure. Clinical presentation is not limited to acute
signs and symptoms of hepatic dysfunction, especially in
cirrhotic patients with unexplained CNS dysfunction. As
noted earlier, the presence of a Kayser-Fleischer ring and a TABLE 5-7 n Types of Toxic Hepatic Injury
low serum ceruloplasmin level virtually seals the diagno-
Hepatocellular Damage Representative Agents
sis. In patients with normal ceruloplasmin levels, high uri-
nary copper and high copper on liver biopsy may support Microvesicular fatty change Tetracycline, salicylates, yellow
the diagnosis. phosphorus, ethanol
d-Penicillamine is considered the “gold standard” in the Macrovesicular fatty change Ethanol, methotrexate,
medical treatment of WD, capable of reversing the hepatic, amiodarone
neurologic, and psychiatric manifestations. Penicillamine
Centrilobular necrosis Bromobenzene, carbon
therapy is not likely to be effective in patients with fulmi- tetrachloride, acetaminophen,
nant failure, dystonia, or severe lenticular degeneration. halothane, rifampin
Adverse reactions to penicillamine include rashes, lymph-
Diffuse or massive necrosis Halothane, isoniazid,
adenopathy, and a lupuslike syndrome. Life-threatening acetaminophen, methyldopa,
thrombocytopenia245 or leukopenia246 is uncommon. trinitrotoluene, Amanita
Because penicillamine has an antipyridoxine effect, pyri- phalloides (mushroom) toxin
doxine should be supplemented. Trientine may be effective
Hepatitis, acute and chronic Methyldopa, isoniazid,
in penicillamine-sensitive patients.247,248 Zinc, which may nitrofurantoin, phenytoin,
induce more metallochaperone production, is also effec- oxyphenisatin
tive.249 Liver transplantation may be required in cases of
Fibrosis-cirrhosis Ethanol, methotrexate,
fulminant liver failure and will reverse the hepatic manifes- amiodarone, most drugs
tations of WD.249,250 Improvement of neurologic symptoms that cause chronic hepatitis
has been inconsistently reported.249,251
Granuloma formation Sulfonamides, methyldopa,
Anesthesia in patients with Wilson's disease should
quinidine, phenylbutazone,
include a careful preoperative assessment with regard to the hydralazine, allopurinol
multiple organ systems that can be affected. A preopera-
tive platelet count should be obtained in any patient taking Cholestasis (with or without Chlorpromazine, anabolic
hepatocellular injury) steroids, erythromycin
d-penicillamine. Because metoclopramide may exacerbate estolate, oral arsenicals
a patient's extrapyramidal symptoms, it should be avoided. contraceptives, organic
Droperidol, promethazine, and prochlorperazine should arsenicals
also be avoided in patients with hepatolenticular degenera-
Data from Crawford JM: The liver and biliary tract. In Cotran RS, Kumar V,
tion because these agents may aggravate pre-existing move- Collins T, editors: Robbins pathologic basis of disease, ed 6, Philadelphia, 1999,
ment disorders. Saunders, p 869.
hepatitis; some drugs will cause a chronic histologic inflam- INHALATIONAL ANESTHETICS
matory change with a syndrome resembling autoimmune Hepatic injury associated with the administration of inhala-
hepatitis. Still others can cause endothelial damage leading tional anesthetic agents is especially important to the anesthe-
to vascular complications such as sinusoidal obstruction syn- siologist. Halothane was introduced into practice in 1956 and
drome or Budd-Chiari malformation. Toxic injury can thus be was rarely associated with hepatic necrosis. It is now accepted
included in virtually every differential diagnosis in the patient that halothane actually produces at least two types of hepato-
with liver disease. The diagnosis of drug-induced liver injury toxicity. Up to 20% of adult patients who receive a halothane
can be difficult given the variability in presentation and time anesthetic exhibit slight increases in transaminases and vari-
course of the disease. Key factors that suggest the diagnosis able clinical complaints of fever, nausea, and malaise. From
include exposure preceded the onset of liver injury, no under- 1:7000 to 1:35,000 patients, depending on risk factors, will
lying liver disease, injury improving when drug is discontin- have fulminant hepatic necrosis termed halothane hepati-
ued, and injury recurring more rapidly and with increased tis. Transaminases and bilirubin levels are elevated, and the
severity after repeated exposure.256 patient is jaundiced and often encephalopathic. The classic
Several distinctions are important in considering toxic histologic examination reveals hepatitis with centrilobular
liver disease. One issue concerns the type of toxicity of a necrosis; zonal, bridging, and panlobular forms of necrosis
substance. Although certain chemicals enter the body in have been described. Risk factors include age (rare in child-
toxic form, injury in most cases results from metabolites hood), gender (twice as common in women), repeated expo-
that, ironically, are the result of hepatic transformation. sure within 3 months (up to 15-fold increase), and perhaps a
Another categorization of toxins is based on the consistency history consistent with the milder postoperative hepatotoxic
with which they cause disease. Intrinsic hepatotoxins con- symptoms listed earlier. Mortality has been reported at 10%
sistently produce damage in a dose-dependent manner in to 50%, although recovery is typically complete in survivors.
otherwise healthy patients, most often with a short latency. Halothane hepatitis is a model for idiosyncratic hepato-
Amanita mushrooms and trichlorethane are examples of toxicity, and thus its mechanisms have been extensively inves-
intrinsic hepatotoxins. Idiosyncratic hepatotoxin exposure, tigated. A variety of observations, including increased risk
in contrast, produces liver disease infrequently with variable from re-exposure and the often-reported fever, rash, arthral-
severity and after a variable latent period. The idiosyncratic gias, and eosinophilia, led to research supporting the theory
pattern can obviously be extremely challenging diagnosti- of an immunologic basis for halothane hepatitis. Cytochrome
cally. Some idiosyncratic hepatotoxins produce mild symp- P450 2E1 (CYP2E1) metabolizes halothane to trifluoroacetyl
toms or asymptomatic biochemical changes with routine chloride. This reactive molecule was initially investigated as
exposure (e.g., isoniazid, halothane) but can cause severe a direct hepatotoxin. The current immunogenic theory, how-
liver disease in susceptible individuals and in certain cir- ever, focuses on its acetylation of endoplasmic reticulum pro-
cumstances. Also, under certain conditions, even intrinsic teins. These trifluoroacetylated (TFA) proteins in turn are
hepatotoxins can produce variable injury in exposures oth- thought to serve as neoantigens that elicit an antibody response
erwise considered safe (e.g., acetaminophen in patient with to both the altered proteins and the native hepatocyte proteins
alcoholic hepatic injury). in susceptible patients. Corroborating evidence includes the
Many drugs will cause an increase in ALT up to three detection of TFA proteins in patients with a history of halo-
times the upper limit of normal, which is considered sub- thane exposure, as well as antibodies to the TFA hapten (and
clinical.257 Most of these abnormalities are benign and resolve carrier protein components) in patients with actual halothane
with discontinuation of the medication. Acute injury is the hepatitis. Further support can be found in reports of cross-
most common, but the pattern may be hepatocellular (cyto- sensitization to methoxyflurane and perhaps enflurane by
toxic) damage (resembling hepatitis), cholestatic (resembling prior halothane exposure. Further, although as much as 20%
extrahepatic obstructive jaundice), mixed, or steatotic (resem- of absorbed halothane may be metabolized, newer agents
bling Reye's syndrome).258 Acetaminophen and antibiotics, undergo significantly less biodegradation (approximate val-
in particular amoxicillin-clavulanate, are the most frequently ues: enflurane 2%-3%, sevoflurane 1%-2%, isoflurane 0.2%,
implicated medications for acute injury.259 Chronic injury can and desflurane 0.02%) and are believed to be rarely or never
primarily be categorized as chronic hepatitis and steatosis. A the cause of hepatitis.
subtype of chronic hepatitis is similar to type I autoimmune
hepatitis, with a female preponderance, serologic markers, and
Ischemic Liver Injury
histologic features.260 Steatotic injury can be difficult to differ-
entiate from nonalcoholic steatohepatitis; both types of injury The manifestations of ischemic injury to the liver have been
can progress to fibrosis and cirrhosis. Chronic liver disease labeled as hepatic infarction, shock liver, centrilobular necro-
can also result from vascular obstructive lesions, chronic cho- sis, and most commonly, the inaccurate term “ischemic hep-
lestasis, and related tumors. atitis” (inflammatory changes are minimal). As might be
The treatment for drug-induced liver injury is initially expected, hypotension and hypoxemia are the usual precip-
withdrawal of the drug. N-acetylcysteine is recommended for itating factors and result from processes ranging from obvi-
acetaminophen toxicity and l-carnitine for valproic acid.261 ous cardiac dysfunction, intraoperative events, and trauma to
less apparent causes. Diagnosis depends on identification of Western countries. ALP elevation, fatigue, and pruritus are
an offending episode and typical biochemical response. LDH typical but nonspecific early findings. Diagnosis is based on
usually is greatly increased both in terms of absolute values antimitochondrial antibodies with confirmatory liver biopsy.
and relative to transaminase elevations. Biopsy is not typi- A variety of autoantibodies may be present, especially rheu-
cally required but, when performed, demonstrates widespread matoid factor, anti–smooth muscle, and thyroid specific; these
necrosis of the central lobule with minimal inflammation. may occur without obvious coexisting disease. Advanced dis-
Severity ranges from subclinical biochemical changes to ful- ease leads to portal hypertension and cirrhosis.
minant failure. Treatment is supportive with correction of the Liver failure typically occurs 5 to 10 years after diagnosis of
instigating process. PBC. Prognostic models appear to be more accurate than in
many types of progressive liver disease and are helpful in con-
sidering the appropriate time for consideration of liver trans-
Liver Function in the Geriatric Patient
plantation. Immunosuppressive drugs have had limited success
The liver exhibits functional and structural changes with in controlling the progression of PBC. Ursodeoxycholic acid
aging. Decreased liver weight with fibrosis and proportion- (UDCA), a hydrophilic bile acid, has been shown to increase
ally decreased blood flow has been described. Functionally, survival time without transplantation in PBC patients.265 A
reduced regenerative capacity, altered response to endocrine multicenter trial, however, did not find this benefit; patients
stimulation, and altered drug metabolism are relevant to the were allowed to continue UDCA or switch from placebo to
perioperative physician.262 Overall function, however, is rela- UDCA on completion of the trial and did not experience sig-
tively resilient to these changes. Data are conflicting on the nificant improvement of transplant-free survival.266 UDCA
impact of age on risk in the geriatric patient undergoing anes- currently remains a standard treatment for PBC, but further
thesia. For example, one series in the 1980s of portosystemic evaluation through large-scale studies is anticipated.267
procedures showed better mortality in patients age 55 and
younger,263 although differences in disease severity and comor- SECONDARY BILIARY CIRRHOSIS
bidities were either pronounced or not described. General Prolonged biliary obstruction, whether intrahepatic or extra-
survival of cirrhotic patients with bleeding varices in differ- hepatic (also known as extrinsic or mechanical obstruction),
ent eras have correlated with Child-Pugh classification but not can lead to cirrhosis regardless of etiology. Many diseases
age.20,264 There is little evidence that age is an important peri- can cause secondary biliary cirrhosis. Primary sclerosing chol-
operative risk factor compared with actual hepatic function. angitis is the most common cause of secondary intrahepatic
cholestasis but is still less common than PBC. In infancy and
early childhood, cholestatic syndromes associated with atre-
Biliary Cirrhosis
sia of intrahepatic and extrahepatic ducts often demonstrate
Biliary cirrhosis is simply cirrhosis caused by biliary obstruc- rapid progression to fibrosis. Even when relief of obstruction
tion of any type, regardless of location in the biliary tree. is possible, this progression is not reliably halted. Adults more
Primary biliary disease is defined as immunogenic disease of often have extrahepatic cholestasis, such as chronic pancreati-
the intrahepatic bile ducts. Secondary biliary cirrhosis occurs tis with stricture, pancreatic cancer, and choledocholithiasis.
with prolonged obstruction from mechanical causes, scleros- Presentation and diagnosis depend on the instigating
ing cholangitis, and diseases that promote cholestasis, such as process, but jaundice and pruritus are often present. ALP is
biliary atresia and cystic fibrosis. typically highly elevated both absolutely (>4 times normal)
and relative to other liver panel abnormalities. Treatment
PRIMARY BILIARY CIRRHOSIS involves diagnosis and treatment of the cause of cholestasis.
Primary biliary cirrhosis (PBC) is an autoimmune disease Extrahepatic obstruction is often successfully relieved by sur-
usually occurring with other autoimmune diseases (e.g., rheu- gical or endoscopic procedures. Intrahepatic obstruction is
matoid arthritis, CREST syndrome, pernicious anemia, sicca more problematic, with limited curative options.
complex). In the modern era, PBC is often diagnosed before Biliary atresia, for example, is an idiopathic fibroprolif-
actual cirrhotic changes, and thus primary biliary “cirrhosis” erative disease that affects the extrahepatic biliary tree. The
has become something of a misnomer. PBC follows a progres- cause of biliary atresia is unknown, but viral, toxic, genetic,
sion through four stages. It is first characterized by periductu- and immune etiologies have been proposed. Splenomegaly,
lar inflammation and interlobular duct injury with granuloma jaundice, acholic stool, dark urine, and hyperbilirubinemia all
formation, then reactive ductular proliferation with cholesta- suggest the disease. These symptoms should prompt imme-
sis. Decreasing inflammation follows, but with development diate evaluation for biliary atresia because the success of sur-
of septal fibrosis and architectural disruption with worsening gical intervention improves at a younger age.268,269 The Kasai
cholestasis. Finally, cirrhosis occurs with obliteration of nor- procedure (hepatoportoenterostomy), in which a hilar core is
mal bile ducts, continued inflammation, and cholestasis. opened to allow the cut bile ducts to drain unobstructed, can
Primary biliary cirrhosis has a 10:1 predilection for women, delay cirrhosis until age 3 to 4 years. Biliary atresia, however,
usually of middle age. Although found in populations world- remains the most common reason for liver transplantation
wide, PBC is more prevalent and increasing in incidence in in younger children, with 60% to 80% of patients requiring
a transplant. Of note for the anesthesiologist, 70% of infants attention has focused on disruption of endothelial produc-
have no other anomalies, and 10% to 15% have biliary atre- tion of nitric oxide (NO), prostacyclin, and tissue plasmino-
sia splenic malformation, which may include situs inver- gen activator (TPA). This approach emphasizes the change in
sus, asplenia or polysplenia, and cardiac anomalies. These vascular tone as well as coagulation changes.
patients tend to have a poorer outcome. The remaining 10% Serum transaminases ranging from several times normal
to 15% of patients have associated congenital malformations, to as high as 100 times normal are found in almost 25% of
including renal abnormalities, choledochal cysts, and cardiac pre-eclamptic patients and 90% of women with eclampsia.
defects.270,271 Symptoms include epigastric or right upper quadrant dis-
comfort. Complications believed to be associated with pre-
eclampsia and eclampsia include hepatic rupture or infarction,
Pregnancy-Associated Liver Disease
fulminant hepatic failure, and subcapsular hematoma. Biopsy
Most biochemical tests remain within the normal ranges of has demonstrated periportal fibrin deposition and areas of
the general population during pregnancy. Exceptions include necrosis. Treatment is delivery, after which rapid normaliza-
alkaline phosphatase and albumin. ALP production by the tion of laboratory values is typical. This decision is relatively
placenta causes elevations in early pregnancy, eventually straightforward when the fetus has an adequate maturity pro-
reaching levels that are three to four times normal nongravid file to ensure viability, but is problematic earlier in pregnancy.
values. Although albumin production is thought to be normal Delay in delivery entails risk of progression of pre-eclampsia
in pregnancy, increased blood volumes result in serum albu- but is thought to improve outcome in the fetus.
min decreases of about 1 g/dL.
HELLP SYNDROME
INTRAHEPATIC CHOLESTASIS OF PREGNANCY The syndrome of hemolysis, elevated liver enzymes, and low
Intrahepatic cholestasis of pregnancy (IHCP) occurs fre- platelets occurs in late pregnancy and usually with at least
quently in pregnancy, with great variation between popula- some of the signs of pre-eclampsia. Moderate transaminase
tions. Its cause is unknown, but associated factors include a elevations and thrombocytopenia are defining conditions of
personal or family history of IHCP and history of cholestasis HELLP. Microangiopathic hemolysis is thought to be related
with oral contraceptives. Onset is usually in the third trimes- to fibrin deposition; it produces schistocytes and fragment
ter, typically with symptoms of pruritus, nausea, and in some cells on peripheral smear, elevated serum LDH, and decreased
cases, abdominal pain. Jaundice occurs in about one fourth hemoglobin. Biopsy, although rarely required, reveals peri-
of patients, typically weeks after the onset of pruritus. ALP is portal or focal necrosis and sinusoidal fibrin deposition with
usually elevated beyond the normal increases of pregnancy, hemorrhage. Maternal complications of HELLP include sei-
and transaminases are usually normal but may occasionally be zures (eclampsia), placental abruption, and disseminated
slightly elevated. In rare cases when liver biopsy is performed, intravascular coagulation (DIC). Fetal complications include
histologic findings are usually limited to cholestasis without prematurity, intrauterine growth retardation, and increased
inflammatory or necrotic changes. perinatal mortality (as high as 30% in some earlier series).
Intrahepatic cholestasis usually has minimal maternal Treatment, as with pre-eclampsia, is delivery. Liver trans-
impact; resolution of symptoms and laboratory abnormali- aminases typically normalize within 1 week, whereas platelet
ties is typically complete within 1 month of delivery. The inci- counts continue to decline for 24 to 48 hours postpartum and
dence of premature delivery and perhaps perinatal mortality eventually normalize in 2 weeks.
is increased. Treatment includes observation of mother and
fetus; UDCA, which decreases pruritus and may slow IHCP HEPATIC INFARCTION OR RUPTURE
progression; and prophylactic vitamin K to compensate for Hepatic rupture is thought to occur in about 1 in 200,000
cholestatic malabsorption. pregnancies, most often in association with pre-eclampsia
or eclampsia, less often with acute fatty liver of pregnancy
PRE-ECLAMPSIA AND ECLAMPSIA or HELLP syndrome, and rarely without associated hepatic
Pre-eclampsia occurs in up to 10% of pregnancies in general. disease. Clinically, infarction or rupture presents as acute
Pre-eclampsia is the triad of hypertension (>140/90 mm Hg), abdominal pain and distention, vomiting, and shock in the
proteinuria (>300 mg/24 hr), and edema, usually occurring in third trimester or immediately postpartum. Elevated trans-
the late second or the third trimester, that cannot be attributed aminases, anemia, and DIC are common, but the diagnosis
to other causes. Eclampsia occurs when seizures are superim- can be confirmed with magnetic resonance imaging (MRI)
posed on pre-eclampsia, which occurs in about 0.3% of pre- or computed tomography (CT) when time allows. Bedside
eclamptic patients. The pathophysiology of pre-eclampsia ultrasound may be invaluable as a time-saving diagnostic tool.
remains undefined, although often-overlapping proposed Survival requires early diagnosis and rapid treatment. Surgical
mechanisms include endothelial cell injury, abnormal spi- intervention has included packing of the liver, resection of the
ral artery development with compromised placental perfu- involved segment or lobe (usually right), and even transplan-
sion, thromboxane imbalance with prostacyclin, intravascular tation. Radiographically guided embolization has also been
volume contraction, and abnormal renal function. Recent described in cases limited to a single lobe.
ACUTE FATTY LIVER OF PREGNANCY of the cirrhotic patient is decreased. Available data show that
Acute fatty liver of pregnancy (AFLP) occurs in the third tri- cirrhotic patients undergoing exercise testing respond with
mester and is of variable severity but can be fatal. It occurs in lower-than-normal peak heart rates, lack of increased left ven-
about 1 in 15,000 pregnancies and is more likely to occur in tricular ejection fraction, abnormally increased end-diastolic
pre-eclamptic patients. Clinical presentation reflects the sever- volumes with subnormal maximal cardiac output, and auto-
ity of the disease and ranges from nausea, abdominal pain, and nomic reflex abnormalities.272 Ability to compensate for the
general malaise to progressive liver failure with jaundice, coag- vasodilation is exhausted, with systemic blood pressure often
ulopathy, encephalopathy, and uremia. Expected laboratory maintained by vasoconstriction in the renal and hepatic beds.
abnormalities include elevated transaminases, prolonged clot- These patients are affected by anesthetic choices and surgery;
ting times, hypoglycemia, and uremia. Liver biopsy will dem- those with end-stage cirrhosis are often unable to tolerate the
onstrate centrilobular microvesicular fatty deposition with stress of surgery.
either absent or minimal inflammation and necrosis. Essential Absolute intravascular volume is usually increased in cir-
hepatic architecture is preserved, and eventual regression rhotic patients, but coexisting renal disease, the impact of syn-
to normal hepatic tissue is found in survivors. Treatment is thetic failure through decreased oncotic pressure, treatment
delivery, the delay of which must include a thoughtful assess- of ascites with paracentesis or diuretics, and other factors may
ment of fetal viability balanced against the possibility of rapid dramatically affect intravascular volume. Even with increased
deterioration. Liver transplantation has been described as a intravascular volume, the actual clinical behavior of the
treatment for AFLP, but timely delivery appears to result in patient is often that of relative hypovolemia. General vasodila-
complete reversibility of the disease in most cases. tion, widespread arteriovenous shunting, and depressed car-
diac response are presumably major factors. Decompensation
with abrupt decreases in volume may be related to attenuated
KEY POINTS
sympathetic effects on the heart and the systemic vasculature.
n Alkaline phosphatase can be elevated 3 to 4 times nor- Furthermore, although the healthy liver can displace a portion
mal values in normal pregnancy, and albumin levels may of its blood volume into the central circulation with sympa-
decrease by 1 g/dL. thetic simulation, this compensatory mechanism is impaired
n Pre-eclampsia is hypertension, proteinuria, and edema in or absent in the setting of cirrhosis.273,274
the late second or third trimester; 0.3% of patients develop Cirrhotic cardiomyopathy has increasingly been recognized
seizures. Delivery is definitive treatment. as an important entity separate from alcoholic cardiomyop-
n The HELLP syndrome is complicated by seizures, placental athy.273 Cirrhotic cardiomyopathy is characterized by systolic
abruption, and DIC; delivery is definitive treatment. and diastolic dysfunction as well as electromechanical abnor-
n Of gravid patients, 1% to 3% will have liver test abnormali- malities. As the incidence of NASH increases, it is important
ties sometime during pregnancy. Patients with pre-existing to note that these patients are at increased risk for athero-
liver disease may experience deterioration during preg- sclerotic disease, independent of obesity, as well as increased
nancy, and pregnant patients can develop coincident liver mortality.275-278 Therefore, it may be advisable to have a lower
disease. threshold for preoperative cardiac testing in cirrhotic patients.
An electrocardiogram (ECG) that shows an increased QT
interval may indicate severe liver disease, increased brain
SYSTEMIC EFFECTS OF LIVER DISEASE
natriuretic peptide, and decreased survival.279 Dobutamine
The diseased liver's pervasive impact on the function of other echocardiography may be a better stress test in advanced cir-
organ systems might be predicted by its myriad roles in health. rhosis because patients may not be able to vasodilate further
This discussion briefly outlines systemic abnormalities associ- with dipyridamole.
ated with hepatic dysfunction that are of particular concern to
the anesthesiologist in the perioperative period.
Portal Hypertension and Ascites
The appreciation of esophageal variceal bleeding from cir-
Cardiovascular Effects
rhotic obstruction of portal blood flow and the actual term
The impact of chronic liver disease on the cardiovascular sys- “portal hypertension” are more than 100 years old. The conse-
tem is extremely complex and variable from patient to patient quences of portal hypertension, such as ascites, variceal hem-
and under different circumstances within the same patient. orrhage, and encephalopathy, still cause significant morbidity
The cardiovascular profile of the cirrhotic patient is classi- and mortality in patients with advanced liver disease.
cally described as a hyperdynamic state with greatly increased In Western societies, portal hypertension is most often
cardiac output low systemic vascular resistance, and mod- associated with cirrhosis. Portal hypertension can actually be
estly reduced arterial blood pressure. These effects worsen found in a variety of situations, however, and its causes have
with progression of disease, possibly related to increased pro- been categorized by mechanism and location. This way of con-
duction of NO and splanchnic vasodilation. Despite this sus- sidering portal hypertension incorporates both the forward
tained increase in cardiac output, functional exercise capacity and backward models of portal hypertension that have been
variously favored in the past. Elevated pressure can result pri- Variceal bleeding is believed to be possible with an HPG of
marily from increased flow, increased resistance to flow, or greater than 12 to 15 mm Hg, although the degree of elevation
both. If increased resistance is present, it may be prehepatic, above this threshold is poorly related to bleeding risk. HPG of
intrahepatic (presinusoidal, sinusoidal, or postsinusoidal), or greater than 10 mm Hg is a strong predictor of clinical decom-
posthepatic. Box 5-3 and Figure 5-9 demonstrate this categori- pensation.281 Variceal bleeding is associated with 6-week mor-
zation schema with several examples. The relative resistance of tality of 15% to 20%, depending on the degree of underlying
portosystemic collateral pathways, while not causal, will affect cirrhosis.282-284
the degree of portal hypertension. Whether by the development of varices or intentional por-
Pressure within the portal vein is usually less than 10 mm tosystemic shunt procedures, significant portal blood flow
Hg, although variability is introduced by the influence of can bypass the liver to the systemic venous circulation. This
intra-abdominal pressure on the absolute venous pressure. circumvention of hepatocyte processing has been implicated
The hepatic venous pressure gradient (HPG) can be used to in the prolonged and exaggerated effects of medications with
control for this variability and attempt to localize the cause of high hepatic extraction, persistence of endogenous vaso-
increased portal venous pressure. HPG is the gradient between dilating substances usually cleared by the liver, and hepatic
hepatic venous pressure and the wedged hepatic venous pres- encephalopathy.
sure. The latter, in a manner analogous to pulmonary artery Ascites is often present in the setting of severe cirrhosis
occlusion pressure, estimates the intrasinusoidal pressures of and portal hypertension. As described previously, the nor-
the liver. Shortcomings of this measurement include variable mal sinusoid is lined with fenestrated endothelium and has no
sinusoidal communications arising from different pathologic basement membrane. The normal sinusoidal pressure is low
processes, causing variability in pressures, and measurement enough as to be almost balanced by oncotic pressure. With
from the efferent vessel, causing occlusion artifact. When increasing sinusoidal pressure, however, protein and fluid
available, HPG can be used to localize etiology (e.g., HPG move into the interstitium, with increased volume and increas-
would be normal if the cause of portal hypertension were pre- ing protein content of hepatic interstitial fluid and lymph. This
hepatic) and monitor therapeutic interventions (e.g., sequen- flow eventually exceeds lymphatic return and accumulates in
tial HPG can be used to verify improvement after β-blockade). the abdomen as ascites. Interestingly, as the sinusoids develop
Portal hypertension is typically defined as an absolute pressure a pseudo–basement membrane (so-called capillarization), less
greater than 10 mm Hg or an HPG of greater than 5 mm Hg. protein transudes through the now partially obstructed fenes-
The HPG at which portosystemic collaterals begin to develop trations. As a result, the protein content of the ascitic fluid can
appears to be 10 to 12 mm Hg in alcoholic cirrhosis.280 These decrease with advancing disease.
are most often gastroesophageal varices. The long-standing treatment of ascites includes diuretic
therapy and paracentesis in conjunction with sodium restric-
tion. IV infusion of albumin with paracentesis has decreased
the rapidity of ascites reaccumulation in some patients, per-
BOX 5-3 n CATEGORIZATION AND EXAMPLES haps because of the sinusoidal changes. The treatment of
OF PORTAL HYPERTENSION ETIOLOGIES ascites results in intravascular depletion. During laparotomy,
Increased Flow Predominates the loss of large volumes of ascites can result in the activa-
Arterial-portal fistula tion of the renin-angiotensin-aldosterone system through an
Splenic hemangiomatosis acute increase in splanchnic vasodilation resulting in circula-
Increased Resistance Predominates tory dysfunction. This hemodynamic effect can be mitigated
Prehepatic by the preemptive administration of albumin at 8 g/L of ascites
Portal vein thrombosis removed.273,285 Preoperative paracentesis with appropriate vol-
Splenic vein thrombosis
ume replacement may also reduce hemodynamic effects.
Intrahepatic Refractory ascites may be treated with TIPS without an
Presinusoidal increase in mortality compared to paracentesis. However,
Schistosomiasis
Azathioprine
there is a significant increase in encephalopathy, particularly
Sinusoidal in patients with a history of encephalopathy, older patients,
Cirrhosis and those with renal insufficiency.286,287 TIPS may also play a
Alcoholic hepatitis role in patients that have severe portal hypertension that is a
Methotrexate contraindication to surgery.288,289
Postsinusoidal
Budd-Chiari syndrome
Posthepatic Renal Effects

Caval web
Cardiogenic
Renal function is usually reduced in advanced liver disease.
Right-sided heart failure Processes such as infection or immune-mediated disease may
Tricuspid regurgitation primarily affect both the liver and kidneys. However, in cir-
rhosis and sometimes in acute liver failure, renal function can
Cirrhosis
Resistance to Hepatic dysfunction

Backward theory intrahepatic blood flow
Vasodilators Hypoalbuminemia
Portal Portal systemic Nitric oxide, glucagon,
hypertension shunt prostacyclin, activation of K
channels, cytokines,
endotoxemia, adenosine
Forward theory Peripheral and splanchnic PVBF Plasma

vasodilatation HABF oncotic
Splanchnic AV shunting THBF pressure
GI bleeding
Liver and
intestinal Effective blood volume
lymph flow
Ascites and
edema
Volume receptor stimulation
Ascites and
edema
Neural factors Humoral factors Intrarenal factors
Sympathetic Renin Endothelin
nervous activity Aldosterone Urinary kallikrein
Role of Angiotensin II or PGs
hepatorenal ADH Thromboxane
reflex Refractory to ANF Leukotrienes
PAF
Adenosine
Tubular sodium retention and reduced renal blood flow
FIGURE 5-9 Pathways for cirrhosis-induced portal hypertension: forward and backward theories. Cirrhosis and portal
hypertension induce circulatory changes that decrease effective blood volume. This activates volume receptors and stimulates
neurohumoral and intrarenal reflexes, which decreases renal blood flow and increases renal retention of sodium. K+, Potassium ion; GI,
gastrointestinal; AV, arteriovenous; PVBF, portal venous blood flow; HABF, hepatic arterial blood flow; THBF, total hepatic blood flow; ADH,
antidiuretic hormone; ANF, atrial natriuretic factor; PGs, prostaglandins; PAF, platelet-activating factor. (Modified from Mushlin PS, Gelman S:
Anesthesia and the liver. In Barash PG, Cullen BF, Stoelting RK, editors: Clinical anesthesia, ed 4, Philadelphia, 2001, Lippincott Williams &
Wilkins, p 1088.)
deteriorate as a consequence of liver dysfunction. This phe- a patient with generalized vasodilation are active topics of dis-
nomenon is termed hepatorenal syndrome (HRS). Prerenal cussion. Suggested mediators include prostaglandins, NO, cat-
failure and acute tubular necrosis can also occur in the setting echolamines, and endothelins.291,292 HRS is typically designated
of severe liver disease. These conditions are discussed with as type I or type II. Type I occurs acutely over days in patients
emphasis on their differentiation from hepatorenal syndrome. with marginal hepatic function and is associated with instigat-
Hepatorenal syndrome is the type of renal failure specifi- ing factors such as gastrointestinal bleeding, infection, or hypo-
cally associated with advanced liver disease. It usually occurs volemia in about half of cases. Type II HRS is slowly progressive
in patients with ascites. As previously discussed, advanced liver and occurs in patients with better-preserved and more stable
disease often produces a cardiovascular profile of high car- hepatic function who often have refractory ascites. Diagnostic
diac output with low peripheral resistance and a relative, if not criteria for HRS are (1) advanced liver disease with portal
absolute, hypovolemia. This can predictably result in renal dys- hypertension, (2) elevated serum creatinine or decreased cre-
function of hypoperfusion (“prerenal”) etiology. However, in atinine clearance, (3) absence of other etiology, (4) lack of
HRS, the decrease in renal cortical flow appears exaggerated. response to volume expansion, and (5) absence of proteinuria,
Cortical blood flow can actually be significantly decreased, obstructive uropathy, or parenchymal renal disease.293 Despite
even with normal glomerular filtration rates. Such patients, criteria, accurate diagnosis can be problematic.294
with an increased resistive index by Doppler studies, are at Although the kidney in HRS remains unchanged histologi-
high risk to progress to renal insufficiency.290 The proposed cally and function may return to normal after liver transplanta-
sites and mechanisms of renal vasoconstriction occurring in tion,295 spontaneous recovery is rare, and there is currently no
other definitive treatment. The goals of pharmacologic treat- effusions are initially transudative and more often occur on the
ment are as a bridge to transplant. Treatment with arterial vaso- right side. Effusion can occasionally occur in isolation but is
constrictors and volume expansion are the more promising most often associated with ascites. In the latter case, transdia-
approach. The mechanism of this treatment appears to be related phragmatic communications between the peritoneal and pleu-
to vasoconstriction of the splanchnic circulation and reversal of ral cavities are thought to allow movement of fluid into the
the decreased effective circulating volume. This is theorized to chest. The impact on lung mechanics includes decreased lung
improve effective blood volume and perhaps suppress renin- volumes and pulmonary compliance, as well as elevated pleu-
angiotensin and sympathetic activity to more normal ranges. ral pressures (abnormalities also caused by massive ascites).
Interestingly, simple volume expansion is not particularly effec- Moderate hypoxemia, thought to be an effect predominantly
tive,296 but colloid infusion may improve the response to V1 vaso- of intrapulmonary shunt, is common, but improvement after
pressin agonists.297 Increasing experience suggests promising evacuation of the effusion is unpredictable.305 Without resolu-
results with the combination of a vasopressin agonist and albu- tion of the hepatic process, repeated thoracenteses and perhaps
min;297-302 however, concerns exist about increased incidence of portosystemic shunting may be required.
ischemic complications. The combination of midodrine, octreo- Some diseases that affect the liver will also primarily affect
tide, and albumin is also a promising treatment strategy.303,304 the lung, including cystic fibrosis, α1-antitrypsin deficiency,
The diagnosis of prerenal failure should be considered because sarcoidosis, and primary biliary cirrhosis. Several reports also
it may well be reversible if treated promptly. The question of describe patients undergoing sclerosis of esophageal varices
whether prerenal failure can progress to HRS in some patients who develop a range of pulmonary deterioration. These prob-
is unanswered. Acute tubular necrosis (ATN), when it occurs, is lems range from worsening hypoxemia and decreased vital
often precipitated by a combination of sustained hypoperfusion capacity to full-blown adult respiratory distress syndrome
and nephrotoxic agents such as nonsteroidal anti-inflammatory (ARDS). The etiology of these problems may have been embo-
drugs (NSAIDs), contrast dye, and aminoglycoside antibiotics. lization of sclerosants.306
Elevated bilirubin, which itself has been postulated to be nephro- Two syndromes that are sometimes confused but have
toxic, is associated with an increased incidence of ATN. very different findings and implications are hepatopulmonary
Characteristics helpful in distinguishing prerenal failure and syndrome and portopulmonary hypertension (Table 5-8).
HRS are limited. HRS sometimes demonstrates tubular dam-
age with proteinuria and, in fact, may progress to ATN. Urine
sodium will be low in both processes, whereas urinary creatinine TABLE 5-8 n Distinguishing Hepatopulmonary Syndrome
and Portopulmonary Syndrome
will be high compared with levels in the plasma. Proteinuria,
high urine sodium, and low urine creatinine are typical of ATN. Hepatopulmonary Portopulmonary
Volume challenge of the patient with renal dysfunction is a logi- Syndrome Hypertension
cal approach to diagnose and begin treatment of prerenal failure. Defining Liver dysfunction Lack of general
characteristics Intrapulmonary agreement
vascular dilations Commonly cited
KEY POINTS (IPVDs) criteria:
Abnormal alveolar- Portal
n Cirrhotic patients have depressed response to sympathetic
arterial oxygen hypertension
stimulation, abnormalities with autonomic reflex, diastolic gradient (>15 mm Resting mPAP
dysfunction, and possible systolic dysfunction. Hg with room air) >25 mm Hg
n Relative intravascular depletion may be exacerbated by Other PAOP <15 mm
paracentesis for ascites and diuretic therapy. cardiopulmonary Hg
causes excluded Other causes
n Hepatorenal syndrome may be treated with albumin,
excluded
octreotide, midodrine, and albumin.
n Hepatopulmonary syndrome is characterized by room-air Common Platypnea Orthopnea
Pao2 less than 60 mm Hg partially corrected with oxygen, symptoms Orthodeoxia Dyspnea on
Arterial desaturation exertion
with evidence of intrapulmonary shunting; HRS is an indi- Fatigue
cation for transplantation.
n Portopulmonary syndrome is characterized by elevated PAP Common Clubbing Hypoxemia with
signs and Decreased DLco exertion
and PVR and may be treated with sildenafil and IV epopros-
diagnostics CE-Echo positive* Elevated PAP
tenol. Severe pulmonary hypertension is a contraindication
to transplantation. Management Oxygen Vasodilator trial
supplementation
Liver transplantation
Pulmonary Effects
mPAP, Mean pulmonary artery pressure; PAOP, pulmonary artery occlusion
The diseased liver impacts lung function in a variety of ways. pressure; DLco, carbon monoxide diffusing capacity.
*Contrast-enhanced echocardiography: positive when contrast appears in left
Almost 10% of patients with cirrhosis, for example, will develop side of heart within three to six cardiac cycles of appearance in right side of
pleural effusion. Classically termed “hepatic hydrothorax,” such heart and in the absence of another cause.
Hepatopulmonary syndrome (HPS) is defined by the presence

of liver disease, an increase alveolar-arterial gradient on room BOX 5-4 n THEORIZED PATHOGENIC SUBSTANCES IN
HEPATIC ENCEPHALOPATHY
air, and evidence of intrapulmonary vascular dilations.307,308 A
room-air Pao2 less than 60 mm Hg is highly suggestive of HPS. Ammonia
A contrast-enhanced echocardiogram will detect intrapulmo- γ-Aminobutyric acid (GABA)
True neurotransmitters
nary shunting. Peripheral pulmonary vasculature (precapillary
False neurotransmitters (aromatic amino acid excess)
and capillary) has characteristic vascular dilations, thought to Serotonin
increase the distance between red blood cells and the alveoli, Manganese
which impairs oxygenation. This effect is exaggerated in the Endogenous opioids
sitting position with increased basilar blood flow, accounting
for the symptoms of platypnea (worsened shortness of breath
in upright position) and orthodeoxia. Supplemental oxygen encephalopathy. Ammonia is produced by colonic bacterial
will typically improve saturation. To date, multiple medical activity and small-bowel deamination of glutamine, absorbed
therapies have been attempted for HRS without benefit. Liver into the portal circulation, and in health, removed by the liver.
transplantation is usually effective, although improvement Hepatic dysfunction, especially in association with portosys-
may be seen only after several months.309,310 temic shunting, allows increased systemic ammonia concen-
Portopulmonary hypertension (POPH) is a distinctly dif- trations. Glutamine synthetase inhibition can blunt cerebral
ferent process that appears histologically similar to primary edema and intracranial hypertension in animals with portoca-
pulmonary hypertension with medial hypertrophy. POPH val shunting and ammonia infusions.317 This observation has
is defined by the presence of pulmonary arterial hyperten- supported the concept that CNS metabolism of ammonia with
sion (mean PAP >25 mm Hg) in the setting of portal hyper- resultant increases of glutamine leads to an osmotic gradient
tension. Because patients with liver disease generally have capable of causing cerebral edema. Ammonia is also capable
high cardiac output, peripheral vascular resistance of greater of altering the blood-brain barrier and influencing glutamate-
than 240 dynes/sec/cm-5 is often used.311 POPH is thought to associated neurotransmission.
be secondary to an imbalance of vasomediators resulting in Despite these interesting findings, however, blood ammo-
vasoconstriction, endothelial damage causing remodeling, nia levels have not consistently correlated with the severity of
and microthrombosis.312 Patients with symptoms of pulmo- hepatic encephalopathy. Lactulose, however, is still a main-
nary hypertension (e.g., dyspnea) should be evaluated with a stay of treatment for hepatic encephalopathy. The therapeutic
screening test of echocardiography. Pulmonary artery pres- mechanisms of lactulose are purportedly both acidification of
sures (PAPs) may respond to vasodilators such as IV or inhaled the gut and catharsis resulting in decreased ammonia absorp-
epoprostenol or inhaled NO.313 The mortality of liver trans- tion. Ammonia load can be further decreased with poorly
plantation in patients with POPH and mean PAP greater than absorbed antibiotics that decrease bacterial activity, decreased
40 mm Hg is considered prohibitively high, although there protein ingestion, and control of gastrointestinal bleeding.
are scattered case reports of survivors.314 Aggressive preop- γ-Aminobutyric acid (GABA) has received attention because
erative therapy315 of POPH may be associated with improved in animal models of hepatic encephalopathy, both expression
outcome. Other prostanoids, endothelin receptor antagonists, of GABA receptors and blood-brain GABA movement were
and phosphodiesterase-5 inhibitors have all been associated increased. The “false neurotransmitter” or amino acid imbal-
with positive results.316 ance theory is based on the increased proportion of aromatic
versus branched-chain amino acids often found in patients
with hepatic encephalopathy. Increased aromatic amino acids
Hepatic Encephalopathy
are proposed to be the precursors for false neurotransmitters,
Hepatic encephalopathy can be associated with acute or such as octopamine, tyramine, and phenethylamine.
chronic liver disease and can itself be slowly progressive Clinically, branched-chain amino acid supplementation has
or can deteriorate rapidly. It is a neuropsychiatric disorder been reported to improve hepatic encephalopathy.318 Poorly
that should be a diagnosis of exclusion. Differential diagno- absorbed antibiotics such as neomycin and rifaximin have
ses include intracranial processes (e.g., hemorrhage, tumor, also shown to be of benefit.319 The severity of hepatic encepha-
abscess), hypoxemia, neurologic infection, sepsis, and meta- lopathy is assessed on the basis of cognitive function, behav-
bolic encephalopathy. Primary neuropsychiatric disorders can ior, motor function, and level of consciousness. As shown in
have similar presentations. Figure 5-10, a stage of 1 through 4 can be assigned according
Clinical observation and limited animal models have led to these changes.
to the generally accepted concept that hepatic encephalopa-
thy is caused by the failure of the liver to clear neurotoxins
ASSESSMENT OF PERIOPERATIVE RISK
or their precursors arising from the gut. Box 5-4 lists sev-
eral substances considered in the development of hepatic Up to 10% of patients with advanced liver disease require a sur-
encephalopathy, which help explain current treatments. gical procedure in the final 2 years of life.320 Estimation of peri-
Ammonia is generally believed to play a central role in hepatic operative risk in the patient with liver disease is problematic.
STAGES OF HEPATIC ENCEPHALOPATHY
0 1 2 3 4
Normal
Hypersomnia, insomnia, or inversion of sleep pattern

Slow responses
Lethargy
Minimal disorientation
Somnolence
State of consciousness Confusion
Semi-stupor
Stupor
Coma
Subtly impaired computations

Shortened attention span
Loss of time
Grossly impaired
Loss of place
Intellectual function Inability to compute
Loss of self
No intellect
Exaggeration of normal behavior

Euphoria or depression
Garrulousness
Irritability
Decreased inhibitions
Overt change in personality computations
Anxiety or apathy
Inappropriate behavior
Personality-behavior Bizarre behavior
Paranoia or anger
Rage
No personality-
behavior
Metabolic tremor
Muscular incoordination
Asterixis
Impaired handwriting
Slurred speech
Ataxia
Hypoactive and hyperactive reflexes
Nystagmus
Neuromuscular abnormalities Babinski clonus
Rigidity
Dilated pupils
Opisthotonos
Coma
FIGURE 5-10 Progression of hepatic encephalopathy. Diagram depicts grades of hepatic encephalopathy and clinical features
associated with advancing stages. (Modified from Ferenci P : Clinical manifestations and diagnosis of hepatic encephalopathy. Up-to-date.
www.uptodate.com; accessed 2/27/11.)
TABLE 5-9 n Approach to Patient with Liver Disease Steatohepatitis. Fatty liver itself does not contraindicate
for Elective Surgery elective surgery, whether of alcoholic or nonalcoholic (NASH)
etiology. It is important to verify that acute alcoholic injury
Disease Approach to Surgery
is not also present and further emphasize to the patient the
Acute hepatitis Postpone surgery until normalization of importance of alcohol abstinence in avoiding direct paren-
biochemical profiles. chymal damage and worsening of perioperative liver abnor-
Chronic hepatitis Proceed with surgery if clinical course malities. Patients with severe steatohepatitis tend to show
and laboratory parameters have increased morbidity and mortality in major hepatobiliary sur-
been stable; unspecified increased gery,328 although other associated factors are surgical time and
perioperative risk.
body mass index. NASH is the presumed etiology of increased
Obstructive jaundice Proceed with surgery, with attention to cirrhosis in morbidly obese patients. Among patients under-
fluid resuscitation. Endoscopic or going gastric bariatric surgery, a voluntary multi-institutional
percutaneous preoperative biliary survey329 reported an incidence of previously undiagnosed
drainage is controversial.
cirrhosis of almost 6% and mortality of 4%, with all deaths
Cirrhosis: occurring postoperatively. More recent data from a single
Child's classes A Optimize and proceed with surgery. institution's 48 consecutive bariatric patients found 33% to
and B (See text for special concern in cases
have NASH and a further 12% to have advanced fibrosis.330
requiring cardiopulmonary bypass.)
Coagulation: Goal of prothrombin Mortality was not reported, but NASH and fibrosis were both
time within 2 seconds of normal. associated with diabetes mellitus but not body mass index in
Parenteral vitamin K; if ineffective, this obese population.
fresh-frozen plasma or cryoprecipitate.
Ascites: If conservative management Cirrhosis. Cirrhosis is the liver abnormality for which most
(fluid restriction/diuretics) is perioperative data exist and for which a generally accepted clas-
ineffective, use paracentesis. sification has been developed and verified. Specifically, the
Encephalopathy: Evaluate and
Child-Turcotte and Child-Turcotte-Pugh (CTP) classifications
treat triggering processes (e.g.,
gastrointestinal bleeding, uremia, of cirrhosis have been shown to correlate well with perioperative
medications); consider lactulose. mortality rates (Table 5-10). Data from the 1980s331 and 1990s332
show remarkably similar mortalities of approximately 10% for
Child's class C Postpone surgery while improving
Child's classification, or cancel surgery
Child's class A, 30% for Child's B, and 80% for Child's C disease
for nonsurgical management in patients undergoing open abdominal procedures. Recent
experience indicates that laparoscopic cholecystectomy333-335 is
Modified from Rizvon MK, Chou CL: Surgery in the patient with liver disease,
Med Clin North Am 87:211-227, 2003.
better tolerated in Child's A and B cirrhotic patients, even con-
sidering higher conversion to open procedures than controls.
Endoscopic intervention is often chosen for Child's C patients.
Available data are often either outdated, retrospective, non- The distinction between Child's A and Child's B dis-
specific to etiology, or of limited subject size. While acknowl- ease may be important in patients undergoing cardiopulmo-
edging these shortcomings, generally accepted guidelines are nary bypass. Two very small series indicate that Child's A
summarized in Table 5-9 and Figure 5-11 and expanded here. patients will experience a marginal increase in complications,
but reported a 50% to 80%336,337 mortality in their Child's B
Acute Hepatitis. High mortality rates from older studies are
patients.
often quoted for patients with acute hepatitis undergoing elec-
The subjective nature of measurement of ascites and
tive surgery. Patients were predominantly undergoing explor-
encephalopathy in the CTP has led to increasing investigation
atory laparotomy for possible surgically correctable jaundice
on the model for end-stage liver disease (MELD) (Table 5-11).
in an era before the availability of accurate noninvasive diag-
The MELD is used for organ transplant allocation but is an
nostic techniques. These studies showed mortality of approx-
effective predictor of mortality in patients with cirrhosis.338
imately 10%321,322 for viral hepatitis and almost 55%323,324 for
The other major concern with the Child scoring system is the
alcoholic hepatitis. Acute hepatitis has thus been considered a
lack of inclusion of renal status. Renal dysfunction is associ-
contraindication to elective surgery, although these outcomes
ated with perioperative complications and thus should be con-
have not been retested in the setting of modern anesthetics
sidered in decision making. A cutoff MELD score of 14 has
and techniques.
been proposed, with better positive and negative predictive
Chronic Hepatitis. The patient's clinical and biochemical values than with CTP.339 Others have used a MELD of 8 as a
status should be used to assess perioperative risk. In the symp- cutoff. There is still no consensus as to which of the two scor-
tomatic patient with synthetic or excretory abnormalities, data ing systems should be used. The benefit of the CTP is the ease
from different eras indicate increased perioperative risk.325,326 of use and the length of experience. Not surprisingly, emer-
Conversely, well-compensated, asymptomatic chronic hepati- gency surgery and intra-abdominal surgery carry a signifi-
tis appears to add minimal perioperative risk.327 cantly higher risk of perioperative morbidity and mortality.340
Suspect liver disease from

history/physical
Blood tests: Bilirubin, INR,

Imaging:
creatnine, albumin, Endoscopy
CT/MRI/US
ALT/AST/ALP
No evidence
of cirrhosis or Cirrhosis and/or portal
portal hypertension hypertension: Assess
(PHTN) or acute severity with MELD
hepatitis/acute score/Child’s score.
liver failure Imaging/EGD for PHTN
MELD10, MELD10-15, MELD15,

Proceed with Child’s A, Child’s B,/ Child’s C,
surgery No PHTN PHTN PHTN
Prefer for outpatient Proceed Low-Risk High-Risk Emergency: Consider

GI/hepatology with Surgery: Surgery: Proceed with evaluation for
assessment surgery Proceed Consider caution and liver
with caution evaluation for inform patient transplantation
and close liver of risk. and
perioperative transplantation. alternatives
monitoring Defer surgery to surgery.
until clinical
situation changes.
FIGURE 5-11 Algorithm for preoperative assessment of patients with suspected liver disease. MELD, Model for end-stage liver
disease; see text.
TABLE 5-10 n Child-Turcotte-Pugh Classification of Cirrhosis*
Factor and Score 1 2 3
Serum bilirubin (mg/dL) <2 2-3 >3
Serum albumin (g/dL) <3.5 3-3.5 >3
Ascites None Easily controlled Poorly controlled
PT prolongation (seconds) 0-4 4-6 >6
(INR) (<1.7) (1.7-2.3) (<2.3)
*The Child-Turcotte-Pugh score is calculated by adding the scores of the five factors (possible scores therefore range from 5 to 15).
Child's Class is A (5 or 6), B (7, 8, or 9), or C (10 and greater).
PT, Prothrombin time; INR, international normalized ratio.
ANESTHETIC MANAGEMENT
TABLE 5-11 n Model for End-Stage Liver Disease
(MELD) Score* Concern for liver function may arise in a variety of clinical
scenarios. An asymptomatic patient presenting for any elec-
Score Surgical Risk
tive procedure may have previously undetected laboratory
<10 Low risk abnormalities. The patient with obvious jaundice or asci-
10-15 Intermediate risk
tes, on the other hand, may present for related diagnostic
or therapeutic interventions. Patients with advanced or life-
>15 High risk threatening hepatic dysfunction may require interventions
*MELD score = (9.6 × loge[creatinine]) + (3.8 × loge[bilirubin]) + (11.2 × such as biliary decompression, partial hepatic resection, and
loge[INR]) + 6.4 liver transplantation; alternatively, these patients may require
unrelated emergency procedures such as appendectomy, frac- evaluation. Conversely, acute hepatitis is still considered a
ture repair, or cesarean delivery, with significant risk posed by contraindication to elective surgery. The cautious and often-
their hepatic process. recommended path is to postpone elective surgery until
The dilemmas faced by clinicians in these situations are further evaluation and signs and symptoms allow either deter-
cited in earlier sections. Laboratory value profiles are helpful, mination of etiology or resolution of the undefined process.
but not specific, in diagnosing disease processes. Perioperative Others advocate a tiered response;347 for example, if transami-
data for specific diseases are limited and often reflect a vari- nases were elevated less than two times normal, risk factors
ety of diagnostic criteria, anesthetic management techniques, for acute hepatitis would be reassessed. If the absence of risk
and eras. Additionally, assessment of hepatic reserve is prob- factors was confirmed, this algorithm would then proceed to
lematic. Although extraction tests have been used to assess elective surgery. Regardless of the approach chosen, careful
hepatic function (particularly in transplant candidates),341,342 reassessment of the patient's history is indicated (Box 5-6).
and newer nuclear imaging techniques show promise for risk The divided opinion of experts reflects the unanswered
stratification in the future,343,344 neither is well correlated with dilemma for the clinician, which is to determine when acute
surgical risk or universally available. hepatitis has been adequately excluded to justify the delivery
Anesthetic management is discussed from two perspec- of an anesthetic for elective surgery.
tives: management issues ranging from asymptomatic lab-
oratory abnormalities to fulminant failure and anesthetic
Acute Hepatitis
considerations for procedures directly involving the liver.
Supporting data, when available, are cited. Management rec- Patients with acute hepatitis should not be subjected to an
ommendations are otherwise based on common practice, anesthetic for an elective procedure. Some patients will require
available reports, and the authors’ opinions. urgent surgery (1) without time for a definitive diagnosis or
resolution of asymptomatic laboratory abnormalities or (2)
with known acute hepatitis. It seems prudent to manage the
Abnormal Laboratory Values in Asymptomatic
former group with the same principles that would be applied
Patients
for known acute hepatitis; thus these situations are discussed
Previous series have reported the incidence of elevated trans- together. (Acute hepatic failure is an entirely different entity
aminases in asymptomatic patients without prior diagnostic that is discussed separately.)
abnormality to range from less than 1% to greater than 10%. It is generally accepted (with supporting data but without
In the 1970s, an often-quoted study345 found that 11 of 7620 absolute proof) that decreased hepatic blood flow is an impor-
patients (0.14%) scheduled for elective surgery had unexpected tant cause of perioperative hepatic dysfunction in patients
significant elevations of liver function studies. Of particular with acute hepatitis, and that efforts should therefore be made
interest, three patients developed jaundice even though their to maintain total blood flow to the liver. Peripheral procedures
surgical procedures were canceled. A large series of asymp- will have less impact than abdominal procedures, but proce-
tomatic patients undergoing nondirected screening indicates dure location is usually mandated by circumstance. In ani-
that the prevalence of asymptomatic elevation in liver values mal models and humans, it appears that halothane decreases
may be much higher three decades later. Approximately 15% of total hepatic blood flow by decreasing both portal venous
2294 patients had transaminase levels greater than normal, and and hepatic arterial blood flow348,349 and should be avoided.
almost 4% had levels greater than twice normal.346 A high prev- Isoflurane is the best studied alternative and appears to preserve
alence of NASH was considered a likely cause for the findings. hepatic blood flow much better than halothane. Total intra-
Other likely and important diagnoses are listed in Box 5-5. venous anesthesia (TIVA) may prove to be another reason-
Approximately one third of asymptomatic patients with- able alternative in these patients. Positive-pressure ventilation
out risk factors will have normal values on repeated laboratory
BOX 5-6 n LABORATORY ABNORMALITIES IN
ASYMPTOMATIC PATIENTS WITH
BOX 5-5 n DIFFERENTIAL DIAGNOSIS IN ASYMPTOMATIC HEPATITIS: DIAGNOSTIC STRATEGY
PATIENTS WITH LIVER DYSFUNCTION*
1. Reassess risk factors for acute hepatitis.
False positive (especially likely in asymptomatic patients without risk n Viral hepatitis exposures
factors) n Toxic exposures
Early and/or subclinical hepatitis n Alcohol history
Nonalcoholic steatohepatitis n Medication history
Drug or toxic effect 2. Repeat liver panel laboratory studies (LFTs).

Ischemic injury n Order viral hepatitis laboratory studies, especially with even
Infiltrative process marginal indication from history.

Biliary disease 3. Consider hepatology consultation.
n Worsening LFTs and/or positive viral serology
*Elevated levels or abnormal findings on liver function studies. n Transaminases that remain more than twice normal
BOX 5-7 n ACUTE HEPATITIS FOR URGENT SURGERY: BOX 5-9 n COMORBIDITIES AND COMPLICATIONS OF
INTRAOPERATIVE MANAGEMENT CIRRHOSIS
1. Preserve hepatic blood flow. Portal hypertension

n Avoid halothane (isoflurane is best-studied alternative and Ascites
better preserves flow). Variceal bleeding
n Consider regional anesthesia if procedure and coagulation Hypoalbuminemia
allow. Coagulopathy
n Maintain normocapnia. Renal dysfunction (hepatorenal syndrome as extreme presentation)
n Avoid positive end-expiratory pressure (PEEP) if possible. Central nervous system effects (hepatic encephalopathy as extreme
n Provide generous volume maintenance. presentation)
2. Avoid medications with situational potential hepatotoxicity Hepatopulmonary syndrome
whenever possible. Pleural effusion(s)
n Halothane Portopulmonary hypertension
n Acetaminophen, particularly in alcoholic patient Glucose intolerance
n Sulfonamides, tetracycline, and penicillins Circulatory changes: high cardiac output and low systemic vascular
n Amiodarone resistance
3. Perform postoperative surveillance clinically and biochemically for
progression of hepatic dysfunction.
n Consider postoperative intensive care admission for 24 to 48
hours. Ironically, the cirrhotic patient often suffers more from

4. Suspect infectious etiology. extrahepatic manifestations of the disease than from loss of
n Provider exposures are treated as high risk for viral hepatitis. hepatic parenchyma. Such issues as coagulopathy and altered
drug metabolism are important considerations, but the anes-
thesiologist must be cognizant of a wide range of comorbidi-
(PPV) and positive end-expiratory pressure (PEEP) would ties and complications that occur with cirrhosis (Box 5-9).
be expected to decrease liver flow,350 but spontaneous venti- Portal hypertension has already been discussed in terms of
lation with an elevated carbon dioxide and splanchnic sym- its role in the development of significant varices and ascites.
pathetic stimulation could also be detrimental. Drugs with The patient's history should be reviewed for portosystemic
known or suspected hepatotoxicity should be avoided, if pos- shunts, such as a surgical splenorenal shunt or the now more
sible (Box 5-7); examples are also provided in the prior discus- common TIPS procedure. Ascites is important preoperatively
sion of hepatotoxins. for many reasons. Its presence may have led to treatment with
spironolactone, paracentesis, or in resistant cases, even the
Cirrhosis placement of a peritoneal-systemic shunt. All these treatment
modalities may result in blood volume and electrolyte abnor-
As previously described, cirrhosis is a sequela of many differ- malities, which should be assessed preoperatively. Enthusiastic
ent types of liver injury and represents a histologic diagno- paracentesis can also cause or exacerbate hypoalbuminemia.
sis rather than a single disease process. The key elements of All patients with cirrhosis and portal hypertension should
disruption of normal architecture by scarring with nodules of be considered at risk for esophageal varices. These dilated veins
regenerating parenchyma are common to all causes, but some communicating blood from the hypertensive portal system to
causes have typical associated findings (Box 5-8). These and lower-pressure systemic veins can be the source of massive
several less common causes are detailed in previous sections, bleeding. Esophageal varices may be treated with endoscopic
and Box 5-1 provides a more complete list. sclerotherapy. Blind instrumentation of the esophagus should
be undertaken with caution.
BOX 5-8 n COMMON CAUSES OF CIRRHOSIS Abnormal PT and hypoalbuminemia reflect decreased syn-
thetic reserve. If time permits, the response to vitamin K can be
Alcohol determined; otherwise, fresh-frozen plasma (FFP) is often used
Viral hepatitis: hepatitis B, C, and D (delta) to bring the PT within acceptable range. Hypofibrinogenemia
Nonalcoholic steatohepatitis or dysfibrinogenemia from altered synthesis and fibrinolysis
Metabolic
may also be responsible for coagulopathy and may be treated
Wilson's disease
Hemochromatosis
with cryoprecipitate. Thrombocytopenia, thought to be
α1-Antitrypsin deficiency caused by both splenic sequestration and decreased peripheral
Diabetes mellitus survival, should be addressed as required by the procedure
Galactosemia in question. Qualitative abnormalities of platelet function,
Autoimmune
including abnormal activation, may also exist but are difficult
Drug or toxin other than alcohol
Primary biliary cirrhosis
to assess.
Cholestasis (prolonged) Review of the patient's history must recognize the multi-
Cystic fibrosis systemic impact of cirrhosis. If time allows, correctable abnor-
malities of coagulation, metabolic status, and intravascular
status should be addressed preoperatively. Child's classifica-

tion and MELD scoring should be evaluated for stratification BOX 5-11 n ANESTHETIC PREPARATION AND
MANAGEMENT OF PATIENTS WITH CIRRHOSIS
of perioperative risk (see Tables 5-10 and 5-11). It is important
to remember that most patients with significant cirrhosis have 1. Consider same issues as in acute hepatitis (see Boxes 5-8, 5-9,
at least some degree of cognitive dysfunction and memory and 5-10):
2. Preserve hepatic blood flow.
lapse; verification of history and signs of early encephalopa-
n Avoid halothane (isoflurane is best studied alternative and
thy should be sought from objective observers. Box 5-10 lists better preserves flow).
other important considerations. n Consider regional anesthesia if procedure and coagulation allows.
The course of cirrhosis can be stable for long periods, but n Maintain normocapnia.
this belies the minimal systemic reserve that is often present. n Avoid high PEEP if possible.
n Provide generous volume maintenance.

Perturbations that would be minor and well tolerated in the
3. Avoid medications with situational potential hepatotoxicity when
healthy patient may precipitate decompensation in the cir- possible.
rhotic patient. Dietary indiscretions, infection, minor trauma, n Halothane
and medication interruptions may not be tolerated. Also, pro- n Acetaminophen, particularly in the alcoholic patient
cedures considered minor in most patients may be major chal- n Sulfonamides, tetracycline, and penicillins
n Amiodarone
lenges to the cirrhotic patient, especially in the case of high
4. Anticipate presence or development of abnormalities.
Child's classification or significant preoperative deterioration.
Cirrhotic patients should be managed perioperatively with Coagulation
n Attempt to correct prothrombin time to within 2 seconds of normal.
many of the same considerations as the patient with acute
n Consider cryoprecipitate if fresh-frozen plasma ineffective or
hepatitis (see previous section), except that elevated intra- fibrinogen abnormality.
cranial pressure or severe hypoglycemia is not as high a con- n Correct thrombocytopenia appropriately for procedure.
cern. Box 5-11 includes common additional cardiovascular, n Anticipate higher-than-normal blood loss for procedure.
coagulation, and metabolic abnormalities that must also be Hemodynamics

n Anticipate relative hypovolemia, worsened by treatment of ascites.
addressed. Correction of PT to within 2 seconds of normal
n Assess for presence of high cardiac output and low peripheral
is generally recommended for invasive procedures. Portal resistance.
hypertension and ascites may be present. Changes in pharma- n Suspect portal hypertension and variceal bleeding, even without
cokinetics and pharmacodynamics should be expected but are history.

often unpredictable. Drugs with high hepatic extraction are n Anticipate depressed response to ionotropes and vasopressors.
n Consider invasive monitoring.

especially affected by portosystemic shunting of blood. Highly
Pharmacokinetics and Pharmacodynamics
protein-bound medications are affected by hypoalbuminemia, n Altered volume of distribution may occur.
and the pharmacodynamic effects of drugs such as vasopres- n Decreased serum albumin and increased gamma globulins are
sors (decreased) and sedatives (increased) may be altered. seen.

▪n Intravascular volume is unpredictable, especially with ascites
treatment.
Acute Liver Failure n Portosystemic shunted blood bypasses liver.
n Drugs highly extracted by liver are especially affected.

Acute liver failure or fulminant hepatic failure can occur n Increased sensitivity to sedative medications may be present.
rarely with any number of insults to the liver that result

in the loss of sufficient hepatic parenchyma to precipitate
acute decompensation. Diagnosis of the syndrome requires
acute hepatocellular failure (without prior significant liver correlated with both etiology and prognosis. Ischemic hep-
disease) and encephalopathy. The time interval between atitis and many toxic injuries progress to encephalopathy
onset of illness and progression to encephalopathy may be in days, whereas viral hepatitis and cryptogenic failure are
more typically associated with 1 month between onset and
the development of encephalopathy. Also, the presence of
jaundice for more than 1 week before encephalopathy may
BOX 5-10 n ANESTHETIC CONSIDERATIONS IN indicate a poor prognosis. These observations have led to
CIRRHOTIC PATIENTS the use of various nomenclatures for acute hepatic failure
Etiology of cirrhosis (Box 5-12).
Complications of cirrhosis, particularly related to Child's Worldwide, the most common causes of acute liver fail-
classification ure are drugs, particularly acetaminophen, and viral hepati-
History of disease progression tis. Box 5-13 lists the more common causes in approximate
History of therapeutic interventions
Current medications
order of likelihood for centers in the United Kingdom and
Deterioration of status associated with current illness United States. The differential diagnosis of acute liver failure
Seek reliable confirmation: suspect patient's cognitive function and is limited. Sepsis may be associated with cholestasis, DIC, and
memory. encephalopathy without actual hepatocellular destruction.
Decompensation of chronic liver disease can also be confused
BOX 5-12 n NOMENCLATURE FOR ACUTE LIVER BOX 5-14 n COMORBIDITIES AND COMPLICATIONS

FAILURE SEEN WITH ACUTE LIVER FAILURE
Encephalopathy
Original Definition of Acute Hepatic Failure or Fulminant Hepatic
Cerebral edema with elevated intracranial pressure
Failure
Consider other causes (hypoxemia, electrolyte abnormality,
Hepatocellular failure (jaundice or coagulopathy)
hypoglycemia.
No prior diagnosis of significant liver disease
Hemorrhage
Encephalopathy within 8 weeks of onset
Gastrointestinal: typically gastric ulceration and not variceal origin
Nomenclature Refinements Based on Syndrome Development Coagulopathy
Subfulminant hepatic failure Respiratory failure
Encephalopathy develops between 2 weeks and 3 months after Adult respiratory distress syndrome
jaundice. Pneumonia and/or aspiration in encephalopathic patient
Fulminant hepatic failure Renal failure
Encephalopathy develops within 2 weeks of jaundice. Hypovolemia
Hyperacute liver failure Acute tubular necrosis
Encephalopathy develops within 1 week of jaundice. Hepatorenal syndrome
Acute liver failure Hypoglycemia
Encephalopathy develops between 1 and 4 weeks of jaundice. Hypotension
Subacute liver failure Relative hypovolemia
Encephalopathy develops between 5 and 12 weeks after jaundice. Generalized vasodilation
Sepsis
Anesthesia should not be administered to patients with

BOX 5-13 n ETIOLOGY OF ACUTE LIVER FAILURE acute liver failure, except for potentially lifesaving emergency
procedures. Management issues encompass not only the
Common
issues previously discussed for acute hepatitis, but also atten-
Acetaminophen toxicity
Hepatitis B tion to often-severe neurologic, hemodynamic, and metabolic
Cryptogenic derangements. Box 5-14 outlines relevant systemic effects of
Hepatitis A (most common worldwide cause) acute liver failure.
Toxicity other than acetaminophen Direct measurement of intracranial pressure (ICP) can be
Uncommon invaluable for advanced encephalopathy. However, placement
Wilson's disease of a monitoring device does have substantial risk of bleed-
Vascular disease ing and infection in these patients, and clinical indicators of
Pregnancy associated
Ischemia
damaging ICP increase under anesthesia may be both delayed
Reye's syndrome and insensitive. If direct monitoring is not available, patients
Infections other than hepatitis A and B should be presumed to have elevated ICP with poor intracra-
nial elastance. Maintenance of adequate cerebral perfusion
pressure may be problematic because of relative hypovolemia
and generalized vasodilation.
with acute liver failure, particularly when a reliable patient his- Hemorrhage should be anticipated in acute liver failure.
tory is not available. Severe coagulopathy often requires extensive transfusion.
Acute liver failure is a medical emergency. Etiology- Gastrointestinal bleeding tends to be related to stress ulcer-
specific therapy should be implemented when present. ations, rather than the variceal bleeding found in chronic liver
N-Acetylcysteine, for example, is used to treat acetamino- disease. Hypoglycemia can be profound because of decreased
phen toxicity, whereas emergency delivery is indicated for fail- intake and loss of hepatic release. ARDS occurs frequently in
ure associated with fatty liver of pregnancy. A major dilemma acute liver failure and can present a dilemma in attempting
occurs for the intensivist managing acute liver failure. With to avoid hypercapnia for ICP concerns while avoiding ventila-
appropriate supportive care, some patients can survive with tory pressure and volume lung injury in ARDS. Renal failure
recovery of hepatic function, especially patients with acet- has been attributed to prerenal mechanisms, hepatorenal syn-
aminophen toxicity and hepatitis A. Other patients are unlikely drome, and ATN. Regardless of etiology, patients with acute
to survive without liver transplantation. Much effort has been liver failure frequently require hemofiltration or hemodialy-
expended in devising,351 verifying,352-354 and refining355 meth- sis, and nephrotoxic medications should be avoided whenever
ods to separate these two patient groups. The patient who may possible.
be a candidate for transplantation should be transported to Invasive hemodynamic monitoring must be considered to
an experienced transplant center without delay. This allows incur a higher-than-normal risk in the patient with acute liver
implementation of the dual processes of constant reassess- failure. Considering the interplay of systemic abnormalities
ment of prognosis for recovery and transplant candidacy. just outlined, however, management of these patients typically
requires invasive monitoring. Finally, it is unlikely that coagu- observed after shunting, and the cirrhotic patient with poor
lation abnormalities can be fully corrected. The possibility of cardiac function may decompensate; myocardial infarction
large-volume transfusion requirements should be anticipated, has been reported. Encephalopathy is a risk of any portosys-
with adequate venous access, fluid-warming devices, person- temic shunting procedure. Modern TIPS procedures maintain
nel, and blood bank support. Box 5-15 summarizes anesthetic a patency rate of greater than 90% per year. When necessary,
management issues. revision or repeat TIPS has become commonplace in active
centers.
Anesthetic considerations for patients undergoing TIPS
Transjugular Intrahepatic Portosystemic Shunt
are, in essence, those of managing the patient with cirrhosis
The TIPS procedure, in use since 1989, is sometimes referred to complicated by ascites and portal hypertension, except for
as “transjugular intrahepatic portosystemic stent shunt” in ear- the rare patient who presents with presinusoidal or venous
lier literature. This terminology emphasized the importance of causes of portal hypertension. Although some centers per-
stenting open hepatic tissue, to avoid the loss of patency expe- form TIPS with the patient under sedation, most cases are
rienced with the original technique of ballooning without stent performed using general anesthesia. Sedated patients report
placement. With the refinement of this procedure, patients were significant pain during intrahepatic dilation and stent
provided with portosystemic shunting to relieve portal hyper- deployment. The unpredictable response of patients with
tension without undergoing major surgery. Box 5-16 lists char- advanced cirrhosis to sedative and narcotic medications
acteristics of patients presenting for TIPS. The essentials of should also be considered in choosing between sedation and
TIPS involve placing a catheter into the hepatic vein through general anesthesia.
the right jugular approach, passage of a specialized needle and
then guidewire into a major tributary of the portal vein, and
passage of an angioplasty balloon and metallic stent over this BOX 5-16 n PATIENTS REQUIRING TRANSJUGULAR
wire to create and maintain a tract through the hepatic tissue. INTRAHEPATIC PORTOSYSTEMIC SHUNT (TIPS)
Mortality is increased in patients undergoing emergency
Diagnoses
TIPS. Early mortality may approach 80% in patients with risk Portal hypertension, most frequently from cirrhosis, with:
factors.356 In one small series, patients with Child-Pugh class C Bleeding varices and/or
disease not only failed to have resolution of ascites but also had Ascites failing medical management
higher mortality than patients randomized to repeated para- Comorbidities of Cirrhosis
centesis.357 In a larger series of 60 patients, mortality without Bleeding varices
liver transplant was similar in TIPS and paracentesis groups Emergency procedure associated with increased mortality
at 1 and 2 years, although multivariate analysis demonstrated Ascites
Recent paracentesis and/or diuretic therapy may cause
association of TIPS with survival not requiring listing for liver
hypovolemia
transplantation.358 Cardiovascular
Complications that can lead to significant morbidity include Typically high cardiac output and low peripheral vascular resistance
puncture of the liver capsule or injury to a hepatic artery with Depressed response to inotropes and vasopressors
extensive bleeding. Increased central venous pressure has been
BOX 5-15 n ANESTHETIC MANAGEMENT AND PREPARATION OF PATIENTS WITH ACUTE LIVER FAILURE
1. Preserve hepatic blood flow. n Preserve cerebral perfusion pressure.
n Avoid halothane (isoflurane is best studied alternative and better 5. Consider electroencephalography (EEG) to detect seizure activity
preserves flow). perioperatively.
n Consider regional anesthesia if procedure and coagulation allow. 6. Anticipate hypoglycemia, sometimes profound, with added
n Maintain normocapnia. perioperative stress.
n Avoid high positive end-expiratory pressure (PEEP) if possible. 7. Prepare for adult respiratory distress syndrome.
n Provide generous volume maintenance. n Consider PEEP (in conflict with ICP concerns and hepatic
2. Avoid medications with situational potential hepatotoxicity whenever perfusion).

possible (halothane, amiodarone, acetaminophen). n Consider decreased tidal volumes with permissive hypercapnia
3. Suspect infectious etiology. (balance with ICP concerns).
n Treat provider exposures as high risk for viral hepatitis. 8. Anticipate hypotension.
4. Anticipate elevated intracranial pressure (ICP) with compromised n Relative hypovolemia
cerebral perfusion pressure. n Hemorrhage
n Assess with direct ICP monitoring if available. n Extensive vasodilation
n Elevate the patient's head. 9. Prepare for massive transfusion requirements.

n Consider osmotic diuresis. n Alert blood bank.
n Consider barbiturates. n Secure adequate venous access.
n Consider hypertonic saline. 10. Utilize invasive hemodynamic monitoring.

n Avoid systemic hypotension.
Biliary Tract Procedures

Anesthetic preparation should focus on any coexisting dis-
Biliary tract procedures include cholecystectomy, choledochal eases and complications, with medical optimization as time
cyst excision, and biliary tumor resection. General character- allows (Box 5-18). Even healthy patients with biliary disease
istics of patients undergoing procedures of the biliary tract will often be profoundly hypovolemic and may be actively
are listed in Box 5-17. Although open cholecystectomy is still experiencing nausea and vomiting. Narcotics should be titrated
performed in select patients with anticipated technical diffi- with the awareness that their stimulation of the sphincter of
culties or coexisting disease (e.g., advanced cirrhosis, bleeding Oddi may precipitate worsened pain in the conscious patient
diathesis), most institutions now prefer laparoscopic chole- preoperatively and technical failure of cholangiography intra-
cystectomy. Indications for cholecystectomy are cholelithiasis, operatively. Atropine, glycopyrrolate, naloxone, and glucagon
choledocholithiasis, and cholecystitis. Patients in this group have all been reported to reverse this narcotic-induced spasm.
are often otherwise healthy, although cirrhotic patients often Transfusion and special monitoring are typically not required.
require cholecystectomy and may present the challenges of
coagulopathy and portal hypertension. Patients with severe
Hepatic Resection
cardiopulmonary disease may poorly tolerate the pneumo-
peritoneum required for laparoscopic surgery; conversely, A wide range of patients undergo hepatic resection. Living-
pulmonary function after laparoscopy is superior to that of directed donors are healthy individuals whose excised lobes
open, high abdominal surgery. will be transplanted into another patient. Most other patients
The extrahepatic biliary tree infrequently may be the site of have benign or malignant primary hepatic tumors or meta-
primary tumors or cystic dilation (choledochal cysts) that may static tumors to the liver. This large group may have a variety
present as symptoms of cholangitis, pancreatitis, or cholecystitis. of associated disease processes such as cirrhosis and any num-
Surgical excision is required and, depending on location, may be ber of unrelated diseases. More rarely, patients near extremis
technically challenging and result in extensive blood loss. may require resection for problems such as trauma or preg-
Endoscopic retrograde cholangiopancreatography (ERCP) nancy-associated rupture with uncontrolled bleeding.
has become a cornerstone in the assessment and often the Technologic applications such as intraoperative sonog-
management of patients with suspected biliary obstruction. raphy, ultrasonic suction aspiration, harmonic scalpels, and
It is typically implemented after suspicious ultrasound, CT, the argon laser coagulator have become a routine part of
or MRI. Institutional variation in the anesthetic management liver resections in many centers. Hepatic cryotherapy, orig-
of patients undergoing ERCP ranges from sedation to general inally as an open procedure360 and now under radiologic
anesthesia. Trends include the increased use of sedation or guidance, has been used for lesions otherwise unresectable
general anesthesia in referral centers undertaking more com- because of underlying liver disease or anatomic position.
plex procedures and the cooperative development by involved
professional societies of national management guidelines.359
BOX 5-18 n ANESTHETIC CONSIDERATIONS IN PATIENTS
UNDERGOING BILIARY TRACT SURGERY
BOX 5-17 n PATIENTS REQUIRING BILIARY TRACT
PROCEDURES 1. Check for elevated prothrombin time (PT).
n Vitamin K may correct if time allows; otherwise, use fresh-frozen
Diagnoses plasma.
Cholecystectomy 2. Pay attention to volume status when vomiting, decreased oral
Cholelithiasis intake, or fever is present.
Cholecystitis 3. Consider rapid-sequence induction or awake intubation in patients
Choledocholithiasis with nausea and vomiting.
Biliary duct tumor 4. Perioperative opioids may cause spasm of sphincter of Oddi.
Choledochal cyst 5. Blood loss typically is minimal unless complex biliary repair or
coagulopathy.
Comorbidities/complications*
Open Procedures
Respiratory embarrassment from abdominal pain
Pain can significantly affect respiratory status and can be difficult to
Obstructive jaundice
manage.
Coagulopathy from vitamin K malabsorption with chronic biliary
Consider epidural analgesia or intercostal nerve blocks.
obstruction
Cholelithiasis associated with: Laparoscopic Procedures
Female gender Pneumoperitoneum associated with:
Obesity Increased incidence of pneumothorax and pneumomediastinum
Cystic fibrosis Subcutaneous emphysema
Crohn's disease Decreased venous return
Sickle cell anemia Increased peak inspiratory pressures
Hypercapnia from insufflated CO2 and decreased pulmonary
*Associated with biliary tract disease. compliance
Liver Transplantation
BOX 5-19 n ANESTHETIC MANAGEMENT AND ORTHOTOPIC LIVER TRANSPLANT
PREPARATION FOR PATIENTS
UNDERGOING HEPATIC RESECTION Liver transplantation has made a remarkable transition from
a procedure of desperate last resort to a commonly recom-
1. Define volume management strategy (restrictive volume vs. mended therapy (Table 5-12). In the United States, data indi-
euvolemia). cate 80% to 90% 1-year survival across all groups and 70%
2. Consider risk and benefits of epidural catheter placement.
3. Consider invasive hemodynamic monitoring.
to 80% 5-year survival. With improved survival, recurrences
4. Secure adequate intravenous access for massive transfusion. of infection (first hepatitis B, now hepatitis C) as well as the
5. Alert blood bank of potential for extensive transfusion morbidities of long-term immunosuppression have become
requirements. management issues. Indeed, transplantation can be viewed as
6. Consider use of cell salvage and rapid infusion device. exchanging an otherwise untreatable disease (e.g., cirrhosis or
7. Anticipate possibility of postoperative hepatic insufficiency.
n Hypoglycemia
acute liver failure) with the treatable disease of immunosup-
n Coagulopathy pression. Box 5-20 lists the most common diagnoses of U.S.
8. Anticipate postoperative complications such as atelectasis, liver transplant candidates for adult and pediatric patients.
effusion, pneumonia, and renal insufficiency. Box 5-21 provides important anesthetic considerations in liver
transplant cases.
Overall morbidity and mortality of patients undergoing THE PREVIOUSLY TRANSPLANTED PATIENT
tumor resection or destruction have improved remarkably The remarkable improvement in patients surviving liver trans-
in recent experience. plantation and the number of transplantations performed
The anesthetic management of patients undergoing liver means that more patients will present for surgery who have
resection does have two areas of controversy (Box 5-19). The had a liver transplant. Many of these patients seek all health
first involves fluid management. Traditionally, the patient is care at their transplant center. For practical and economic rea-
kept relatively euvolemic or even slightly hypervolemic dur- sons or medical urgency, however, many patients likely will
ing dissection; as in any procedure with the risk of sudden seek care elsewhere. Faced with this situation, the anesthesi-
blood loss, the patient can be more rapidly resuscitated if ologist should evaluate the function of the transplanted liver
hemorrhage occurs. The other approach is to minimize flu- through history, examination, and routine liver panel stud-
ids throughout dissection in order to achieve a low central ies as described for patients in general. Within a few months
venous pressure (CVP). Some surgeons augment this by of transplantation, serum bilirubin and transaminase levels
intermittent occlusion of vascular inflow. Because CVP is a should return toward or to normal range. AST changes in par-
critical determinant in hepatic venous pressures, the lower ticular are monitored as indications of graft rejection. ALP
the CVP, the lower is the bleeding from cut hepatic surfaces. and GGTP are more likely to remain elevated after liver trans-
Many centers have adopted this approach.361-365 Importantly, plant and must be considered in their trends rather than abso-
after resection and confirmation of hemostasis, fluid resusci- lute values.
tation is undertaken. Proponents of this approach believe that Conservative management of the patient with the trans-
the presumed increased risks of organ hypoperfusion, possi- planted liver applies the principles discussed for the patient
ble hemorrhage in a hypovolemic patient, and even air embo- with acute hepatitis. However, minimal data exist to indicate
lism are outweighed by the improved surgical conditions and that the transplanted liver is at particularly increased risk for
decreased blood loss and transfusion requirements reported. perioperative dysfunction. Immunosuppressive protocols
Postoperative analgesia is the second area of controversy should be maintained and their pharmacologic interactions
in the anesthetic management of patients undergoing liver with perioperative medications considered.
resection.366-368 Many centers routinely place epidural cath-
eters for pain management; others do not. Although postop-
Postoperative Liver Dysfunction
erative pain is significant in this upper abdominal chevron
incision, many anesthesiologists are concerned that the Every anesthesiologist should be prepared to provide at least
postoperative fluctuations of coagulation seen in any major initial consultation and care for the postoperative patient
abdominal procedure will be dangerously accentuated with with liver dysfunction. The specter of hepatic necrosis from
the resection of large amounts of hepatic tissue. Data are lim- halothane exposure still looms large in the minds and liter-
ited to guide the clinician in weighing the risk of epidural ature of many colleagues in other specialties. As discussed
catheter placement in a patient who may become coagulo- previously, halothane is rarely a cause of severe hepatic
pathic against the presumed benefits of epidural analge- injury, and newer volatile agents have never been convinc-
sia.369-371 The possibility of massive blood loss always exists ingly implicated. The anesthesiologist can help to ensure
in these procedures. The blood bank should be alerted and that the more likely, although perhaps less dramatic, causes
appropriate venous access attained. Cell salvage may be used of postoperative dysfunction are considered based on their
if cancer and infection are not present. relative probability.
TABLE 5-12 n Anesthetic Management Issues for Patients Undergoing Liver Transplantation
Management Issues Comments
CENTRAL NERVOUS SYSTEM MONITORING
Intracranial pressure (ICP) monitoring Used most often in fulminant hepatic failure
There is a risk of hemorrhage
LABORATORY MONITORING
Hemoglobin, ABGs Frequent monitoring assists in resuscitation
Calcium, potassium Abnormalities in both are common and can result in cardiac disturbances
Coagulation tests PT, PTT, fibrinogen, and platelet count
Thromboelastography Some centers routinely use to identify fibrinolysis early
POTENTIAL FOR MASSIVE TRANSFUSION
Venous access Large-bore central access and large peripheral access are routine
Blood bank protocols 10 to 20 units of RBCs and fresh-frozen plasma should be ready at start of case, and more
should always be available
Cryoprecipitate and platelets may be needed
HEMODYNAMIC MONITORING
Blood pressure monitoring Arterial lines in radial or femoral site are recommended
Pulmonary artery catheter Continuous cardiac output and mixed venous saturation catheters allow rapid assessment
of oxygen delivery and utilization
Pulmonary artery pressures allow for diagnosis of pulmonary hypertension and acute
intraoperative changes
Transesophageal echocardiography Useful in assessment of cardiac function, especially during reperfusion as well as for
tamponade
Risk of bleeding in patients with varices must be considered
ABGs, Arterial blood gases; PT, prothrombin time; PTT, partial thromboplastin time; RBCs, red blood cells (erythrocytes).
The reported incidence of hepatic abnormalities after anes-

thesia depends on pre-existing state of health, population, pro-
BOX 5-20 n MOST COMMON DIAGNOSES IN U.S.
PATIENTS REQUIRING LIVER cedure, era, and the defining criteria for dysfunction. Studies
TRANSPLANTATION report that 25% to 75% of postoperative patients develop
abnormal laboratory values, but a much smaller percentage
Adult
progress to clinically significant disease or jaundice. Box 5-22
Cirrhosis from hepatitis C
Cirrhosis from alcohol lists causes of postoperative jaundice. Three general categories
Cryptogenic cirrhosis of postoperative abnormalities are increased bilirubin produc-
Primary biliary cirrhosis tion, hepatocellular injury, and cholestatic disorders.
Autoimmune cirrhosis Bilirubin overproduction can cause jaundice in the pre-
Cirrhosis from hepatitis B
viously healthy patient when bilirubin production exceeds
Acute liver failure
Primary sclerosing cholangitis hepatic processing capacity. About 250 mg of bilirubin
is usually conjugated daily, but the healthy liver can con-
Pediatric
Biliary atresia (extrahepatic)
jugate up to three times that amount. Several periopera-
Autoimmune cirrhosis tive situations can exceed this production. About 10% of
Acute liver failure transfused red blood cells (RBCs), if older than 2 weeks, are
Obstructive biliary disease destroyed within 1 day of administration. Similarly, RBCs
Cystic fibrosis
within hematomas are rapidly hemolyzed during resorp-
Cirrhosis
Neonatal hepatitis
tion. The placement of stents (e.g., as discussed with early
Congenital hepatic fibrosis TIPSS series) and mechanical valves can result in frag-
Inborn errors of metabolism mentation or so-called mechanical hemolysis. Laboratory
values usually show a pattern of mildly elevated AST and
BOX 5-21 n ANESTHETIC CONSIDERATIONS IN PATIENTS UNDERGOING LIVER TRANSPLANTATION
Coagulation* Pericardial effusion may require preoperative or early intraoperative

Decreased or abnormal factor synthesis drainage.
Fibrinolysis Portopulmonary hypertension confers exceptionally high perioperative risk.
Disseminated intravascular coagulation
Respiratory
Thrombocytopenia
Hypoxemia is common.
Metabolic Abnormalities† Ascites and pleural effusions occur with respiratory compromise.
Hypoglycemia in acute hepatic failure; glucose intolerance in cirrhosis Intrapulmonary shunting results from endogenous vasodilators.
Respiratory alkalosis common with hypoxemia-driven tachypnea Hepatopulmonary syndrome is associated with intrapulmonary vascular
Metabolic acidosis from peripheral shunting, causing tissue dilations.
hypoperfusion Adult respiratory distress syndrome may be present, particularly in acute
Metabolic alkalosis from volume contraction of paracentesis; diuresis, failure.
or vomiting
Neurologic
Cardiovascular Encephalopathy is common, with variable severity.
High cardiac output with low peripheral resistance is typical. Encephalopathy of acute liver failure is often associated with critical ICP
Peripheral arteriovenous shunting causes paradoxical tissue ischemia. elevation.
Increased endogenous vasodilators are usually metabolized by liver. Direct ICP measurement is invaluable for intraoperative management.
Formation of true arteriovenous fistulas occurs.
Renal
Cardiomyopathy may occur with such disorders as alcoholism and
Dysfunction is common; severity ranges from mild to hepatorenal
Wilson's disease.
syndrome.
Cardiac reserve must be adequate to tolerate rigorous challenges of
Osmotic diuretics and dopamine are often used, but without proven
transplantation.
efficacy.
*Almost universally abnormal; severity and direct causes are variable. Preoperative or intraoperative dialysis may be considered in anuric
†
Arise from variety of causes; overall picture is unpredictable. patients.
BOX 5-22 n CLASSIFICATION AND EXAMPLES OF POSTOPERATIVE JAUNDICE
Pre-Existing Limitation of Capacity for Bilirubin Metabolism Hemolysis

Chronic liver disease Mechanical (e.g., stents, cell-salvage processing)
Gilbert's disease Pre-existing disease (e.g., G6PD deficiency)
Transfusion reaction
Unappreciated Pre-Existing Disease with Natural or Accelerated
Progression Intrahepatic Cholestasis
Viral hepatitis Benign postoperative cholestasis
Cirrhosis Medication associated
Autoimmune hepatitis
Extrahepatic Biliary Obstruction
Hepatocellular Injury Postoperative pancreatitis
Ischemic hepatitis Biliary stricture
Viral hepatitis
Cholecystitis
Drug hepatotoxicity
Calculous
Increased Bilirubin Load Acalculous
Breakdown of hemoglobin from transfused erythrocytes
Resorption of large hematomas
LDH, reduced haptoglobin, unconjugated hyperbilirubine- be insignificant stress. Table 5-13 compares laboratory pat-
mia, and reticulocytosis. The peripheral smear may reveal terns that may be seen in postoperative liver dysfunction.
schistocytes. Unrecognized pre-existing diseases can result Hepatocellular necrosis can account for postoperative jaun-
in a relative or absolute overproduction of bilirubin. The dice and transaminase abnormalities. Ischemic liver injury
amount of hemoglobin that can be conjugated decreases typically manifests 1 to 10 days after the insult. Hypoperfusion
in Gilbert's disease. Glucose-6-phosphate dehydrogenase from hypotension, cardiopulmonary bypass, and mechanical
(G6PD) deficiency, sickle cell disease, and the thalassemias interruption of flow as well as hypoxemia have been associated
can result in increased hemolysis with what would usually with this type of injury. Venous congestion from right-sided
TABLE 5-13 n Biochemical Patterns of Postoperative Liver Dysfunction
Dysfunction AST and ALT ALP LDH Bilirubin Others
Bilirubin AST (↑) Other ↑ ↑Unconj ↑Reticulocytes

overproduction ALT NL medications ↑Schistocytes
Ischemic injury ↑ 5×-100× (↑) 2× ↑↑ (↑) 2-3× —
Viral infection ↑ >10× (↑) (↑) ↑ Serologies and RNA

analysis
Anesthetic associated; ↑ to ↑↑ — — ↑ Leukocytosis,

severe eosinophilia
Benign postoperative (↑) ↑ 3× — ↑ 3× PT (↑)

cholestasis
Extrahepatic ↑ ↑ — ↑ —
cholestasis
AST, Aspartate transaminase; ALT, alanine transaminase; ALP, alkaline phosphatase; LDH, lactate dehydrogenase; unconj, unconjugated; PT, prothrombin time.
NL, Normal; (↑), mild or no increase; ↑, increased; ↑↑, marked increase; ×, times normal; —, not applicable or unavailable.
heart failure may exacerbate the damage. As previously dis- nomenclature, infection should be considered in the differen-
cussed, liver blood flow is decreased with most anesthetics. In tial diagnosis of postoperative cholestasis.
the case of unrecognized chronic disease, small decreases in Extrahepatic cholestasis is a rare cause of postoperative
blood pressure and cardiac output may not allow the hepatic jaundice but should be considered. Causes include cholecys-
arterial flow to compensate for decreased portal venous flow titis (with or without cholelithiasis), postoperative pancreati-
to the liver. Transaminase levels are greatly elevated, as is tis, and complications of surgery that disrupt the biliary tract.
LDH, as previously described in patterns of hepatic injury. If AST/ALT, ALP, and total bilirubin are typically mildly to mod-
liver biopsy is performed, centrilobular or panlobular necro- erately elevated. Total parenteral nutrition (TPN) has been
sis is found. The injury can progress to acute liver failure. associated with both acalculous cholecystitis and cholelithia-
Treatment is supportive with maintenance of perfusion and sis, as well as steatohepatitis and even micronodular cirrhosis
oxygen delivery. with long-term administration.
Viral hepatitis is an unusual but important cause of post- A general approach to the patient with postoperative liver
operative jaundice. Some percentage of patients will have an dysfunction is to review the history for any overlooked evidence
acute infection with a time course that conspires to manifest of pre-existing liver disease. A biochemical liver profile, com-
perioperatively, or a chronic infection that results in hepatic plete blood cell count, and clotting times should be assessed.
deterioration postoperatively. Transfusion-borne disease is Elevations of unconjugated bilirubin can arise from break-
less likely than preoperative infection in the current era. The down of transfused RBCs, hemolysis from mechanical devices
disease can present anytime in the first 2 postoperative weeks or pre-existing disease, hematoma resorption, or Gilbert's syn-
with typical laboratory findings; previously discussed sero- drome. Haptoglobin, reticulocyte count, and LDH can be used
logic studies and RNA analysis are indicated. to help confirm the etiology. In the case of conjugated hyper-
Anesthetic-associated injury is discussed earlier with hep- bilirubinemia, further discriminating laboratory testing should
atotoxins. The newer inhalational anesthetics are rarely, if be pursued. Greatly increased transaminases and LDH with-
ever, associated with hepatic injury of consequence, because out evidence of obstruction are consistent with ischemic injury,
of decreased biotransformation and improved hepatic per- drug-associated injury, or active viral infection. Abdominal
fusion compared with halothane. Other drugs that should sonography can be used to evaluate obstruction. Sepsis, TPN,
be considered in postoperative liver dysfunction are tetracy- medication effects, and acalculous cholecystitis can also cause
cline, isoniazid, phenytoin, penicillin, acetaminophen, and cholestasis and conjugated hyperbilirubinemia.
sulfonamides.
Benign postoperative cholestasis occurs with or without
CONCLUSION
jaundice. It tends to occur in critically ill patients. Its causes
are believed to be multifactorial, having significant over- The vital roles of the liver, even in health, are of a complexity
lap with issues such as increased bilirubin load and hypo- and number beyond current understanding. Patients with liver
perfusion. Treatment is supportive, and mortality is related disease, or those without liver disease undergoing procedures
to processes other than cholestasis. Major infection can also affecting the liver, can present great challenges to the anesthe-
cause intrahepatic cholestasis. In fact, some authors consider siologist. With the current epidemic of patients deteriorating
this simply to be another cause of benign postoperative cho- from chronic hepatitis C and the limited number of organs
lestasis, whereas others distinguish the two. Regardless of available for transplantation, anesthesiologists can expect
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C H A P T E R

Certain aspects of hepatic anatomy and physiology with

50% of oxygen delivery.

Portal Hepatic Kupffer cell Sinusoids Central vein to 65% of O2 delivery.

­portal triad; each zone shows varying degrees of O2 con-

Dihydroxyacetone phosphate D-glyceraldehyde 3-phosphate

Acetyl CoA Fatty Acyl-CoA -glycerol

FADH2  oxidation Tricarboxylic

Hepatic steatosis (“fatty liver”) refers to abnormal accu-

Hormone- VLDL IDL HDL3

Lipoprotein CETP HDL2

BOX 5-1 n CAUSES OF HEPATIC FIBROSIS AND CIRRHOSIS

Medications and Toxins Chronic hepatitis (B, C, and D) Tyrosinosis

TABLE 5-1 n Characteristic Biomarkers in Liver Disease

HEPATOCELLULAR NECROSIS BILIARY OBSTRUCTION

Transaminases 50-100× 5-50× NL to 5× NL to 5× 1-3×

Alkaline phosphatase (ALP) 1-3× 1-3× 1-10× 2-20× 2-20× NL to 20×

Bilirubin 1-5× 1-30× 1-30× 1-30× 1-5× NL to 5×

Albumin Decreased in chronic disease Often normal; may be Usually normal

Bilirubin TESTS THAT REFLECT SYNTHETIC FUNCTION

Prothrombin Time elevated in many forms of liver disease, presumably as a result

fecal-oral route after ingestion of contaminated food or drink.

TABLE 5-3 n Characteristics of Human Hepatitis Viruses A (HAV) to E (HEV)

Virus family Picornaviridae Hepadnaviridae Flaviviridae Viroid Caliciviridae

Genome ssRNA Partially dsDNA SsRNA ssRNA ssRNA

Blood/percutaneous Rare Yes Yes Yes No

Incubation period 15-50 days 4-26 wk 2-26 wk 3-7 wk 15-60 days

Chronic hepatitis No Yes Yes Yes No

Fulminant failure <1% <1% Rare 2%-10% 1% (30% in pregnancy)

Cirrhosis No Yes Yes Yes No

HEPATITIS D (DELTA AGENT) develop chronic hepatitis, 25% with cirrhosis.

In the liver, Echinococcus infection results in virtually no

Nonalcoholic Steatohepatitis FIGURE 5-7 Photomicrograph shows histology of

TABLE 5-4 n Glycogen Storage Diseases

Enzyme Main Clinical

Type IV Branching Failure to thrive Hepatosplenomegaly Death without liver Rare

secondary to pancreatic iron deposition, may also occur,

ALA synthase Succinyl CoA

AIP PBG deaminase

TABLE 5-5 n Classification of the Human Porphyrias

MAJOR BIOCHEMICAL FINDINGS*

Modified from Anderson K: Porphyrias: an overview. Up-to-date. February 2011.

n Anesthetic management of porphyria patients includes

Most patients present with the neurologic manifesta-

Posthepatic Renal Effects

Resistance to Hepatic dysfunction

Forward theory Peripheral and splanchnic PVBF Plasma

Tubular sodium retention and reduced renal blood flow

Hepatopulmonary syndrome (HPS) is defined by the presence

STAGES OF HEPATIC ENCEPHALOPATHY

Hypersomnia, insomnia, or inversion of sleep pattern

Subtly impaired computations

Exaggeration of normal behavior

Suspect liver disease from

Blood tests: Bilirubin, INR,

MELD10, MELD10-15, MELD15,

Prefer for outpatient Proceed Low-Risk High-Risk Emergency: Consider

TABLE 5-10 n Child-Turcotte-Pugh Classification of Cirrhosis*

Factor and Score 1 2 3

Serum bilirubin (mg/dL) <2 2-3 >3

Serum albumin (g/dL) <3.5 3-3.5 >3

Ascites None Easily controlled Poorly controlled

PT prolongation (seconds) 0-4 4-6 >6

portal triad; each zone shows varying degrees of O2 con-

Acetyl CoA Fatty Acyl-CoA -glycerol

FADH2 oxidation Tricarboxylic

BOX 5-1 n CAUSES OF HEPATIC FIBROSIS AND CIRRHOSIS

MELD10, MELD10-15, MELD15,

BOX 5-12 n NOMENCLATURE FOR ACUTE LIVER BOX 5-14 n COMORBIDITIES AND COMPLICATIONS