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Discussion post – Adv. Patho
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Question: The liver is a complex organ with many contributions to homeostasis that are often not appreciated until liver function declines. The liver has the capacity to rebound and regenerate after a variety of acute chemically or virally induced insults, but it is vulnerable to chronic chemical or infectious damage.
What blood tests are appropriate for a patient with a suspected acute liver injury?
Explain the rationale for ordering these tests, and patterns of results that you might see in a patient with acute HAV infection.
Book: Advanced Physiology and Pathophysiology
Essentials for Clinical Practice
Tkacs, Nancy C., PhD, RN |
Herrmann, Linda L., PhD, RN, AGACNP-BC, GNP-BC, ACHPN, FAANP |
Johnson, Randall L., PhD, RN
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14
LIVER
Jennifer Andres, Adam Diamond, Kimberly A. Miller, Nicole E. Omecene, and Dusty Lisi
THE CLINICAL CONTEXT
T
he liver is a complex organ with many
contributions to homeostasis that are often not
appreciated until liver function declines. The liver
has the capacity to rebound and regenerate after a
variety of acute chemically or virally induced insults,
but it is vulnerable to chronic chemical or infectious
damage. Liver diseases span a spectrum of severity
from acute self-limited episodes like some hepatitis
A virus infections or mild drug-induced liver injury,
to chronic insults that result in cirrhosis and require
liver transplantation. The most common causes of
chronic liver disease in the developed world are
alcohol-induced liver disease, nonalcoholic fatty
liver disease (NAFLD), and hepatitis C. These disorders may progress to hepatocellular carcinoma,
or may be cured by abstinence from alcohol, weight
loss, and antiviral therapy, respectively.
The rate of deaths due to liver disease increased
from 11.3 to 17.8 per 100,000 population between
1950 and 1970, before falling to a low of 8.9 per
100,000 in 2005.1 Since then, the death rate from
chronic liver disease and cirrhosis has once again
been rising in the United States; 1.9% of adults
reported receiving a diagnosis of liver disease
in the 2016 National Health Interview Survey.2
Much of this increase is attributed to the obesity
epidemic and the associated rise in nonalcoholic
fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). Primary care providers are
ideally positioned to counsel patients about management of lifestyle factors (alcohol intake, obesity) to reduce liver disease prevalence and about
screening for silent hepatitis C.
Management of liver disease is often supportive,
as many chronic, progressive liver disorders can
Copyright Springer Publishing Company. All Rights Reserved.
From: Advanced Physiology and Pathophysiology
DOI: 10.1891/9780826177087.0014
only be cured by liver transplantation. The development of effective treatments for hepatitis C virus
(HCV) infection is one of the few exceptions to this
challenging clinical scenario. Clinicians are best
positioned to deliver patient teaching regarding
HCV screening and appropriate follow-up.
OVERVIEW OF LIVER STRUCTURE
AND FUNCTION
The liver is the largest solid internal organ in the body
and is located in the right upper quadrant (RUQ) of the
abdomen. The primary cell types of the liver are hepatocytes, sinusoidal endothelial cells, Kupffer cells, stellate
cells, and cholangiocytes. The liver receives dual blood
flow: 25% of the blood is fully oxygenated blood provided
by the hepatic artery. The remaining 75% comes from the
portal vein, which combines the relatively deoxygenated
venous drainage of the intestines, pancreas, and spleen.
This arrangement makes the liver literally the “portal,” or
gate, between the intestines and the systemic circulation.
The liver is connected back to the intestines through the
production and secretion of bile, which is delivered to the
duodenum via the bile duct. Thus, the liver is uniquely
positioned to
• Absorb the primary products of carbohydrate and
protein digestion and absorption
• Use the abundant amino acid supply to synthesize a
large number of proteins of different classes, including most plasma proteins
• Regulate glucose homeostasis under the influence of
insulin or glucagon, enriched by the blood draining
the pancreas
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Advanced Physiology and Pathophysiology: Essentials for Clinical Practice
• Be the first line of immune defense against bacteria
LIVER STRUCTURE
that enter the blood across the intestinal wall
• Detoxify or metabolize drugs and toxins ingested orally
• Synthesize and secrete bile acids needed for fat
digestion and absorption
• Secrete detoxified endogenous and exogenous
compounds into the bile for eventual fecal
excretion
The liver has four lobes: right, left, caudate, and quadrate.
Each lobe is made up of lobules, and lobules are made up
of hepatocytes, sinusoids, and a central vein. The structures of a segment of a liver lobule and a representative
sinusoid are depicted in Figure 14.1. The liver accounts
for only 2.5% of the body’s total weight but receives
nearly a quarter of the cardiac output. This abundant
Dendritic cell
Plate of hepatocytes
Arteriole
Portal
vein
Central
vein
Sinusoid
(a)
Kupffer cell
Lymphocyte
Bile duct
Lymph drains from space of Disse and enters
lymphatic capillaries in the portal area
Hepatocyte
LSEC
Hepatic
sinusoid
qHSC
PC
Kupffer
cell
Immature
DC
Space of Disse
(b)
Blood from
portal vein
Blood to
central vein
FIGURE 14.1 (a) Detail of the structure of the liver. The liver is made up of lobules in which blood
flows from branches of the portal vein and arterioles from the hepatic artery, to the central vein,
through large modified capillaries (sinusoids). (b) Sinusoid structure. Sinusoid walls are made
up of specialized LSECs. Rather than a basement membrane, the sinusoid is separated from the
surrounding plate of hepatocytes by a space of Disse, which is directly connected to lymph drainage.
The immune and reticuloendothelial function of the liver is conducted by Kupffer cells, resident
macrophages residing in the sinusoids, as well as lymphocytes called PCs and DCs. These cells
provide constant immune surveillance for molecules and pathogens entering the body through the
gut wall and traveling through the portal vein, capturing them before they can enter the systemic
circulation. Stellate cells in the space of Disse are normally quiescent (qHSCs), but can become
activated in response to liver damage and contribute to liver fibrosis.
DC, dendritic cell; LSEC, liver sinusoid endothelial cell; PC, pit cell.
Chapter14 • Liver
blood supply is integral to the liver’s complex metabolic functions. Liver blood flow is approximately 800 to
1,200 mL/min.3
The structure of a liver lobule is shown in Figure 14.2,
including branches of the hepatic artery, portal vein, and
bile duct. Blood from the hepatic artery and portal vein
meets in the sinusoids. The sinusoids are surrounded
by plates of hepatocytes, allowing robust exchange of
compounds between blood and liver cells. The sinusoids
coalesce to form the central vein of each hepatic lobule.
Blood flows from the central veins to one of three hepatic veins and ultimately empties into the inferior vena
cava. Blood flow to the liver is shown in Figure 14.3.
The biliary tree is crucial to liver function (see
Figures 14.4 and 14.5). Each hepatocyte has apical
membranes with direct secretory sites to microscopic
bile canaliculi (Figure 14.4). Bile canaliculi coalesce
into bile ductules and increasingly larger channels,
finally coming together as the right and left hepatic
ducts, which merge and become the common hepatic
duct. The cystic duct connects the hepatic duct to the
gallbladder, where bile is stored between meals. Bile
then flows into the bile duct, which joins the pancreatic
duct, and through the sphincter of Oddi into the duodenum (Figure 14.5). Bile and blood flow in opposite
directions and in separate tracts between hepatocyte
plates of the lobule.
Liver Cells
Hepatocytes are the functional cells of the liver and
are the most abundant cell type. Hepatocytes perform
metabolic, storage, and synthetic processes. They surround sinusoids that are specialized capillaries with
high permeability. In order to protect the liver from
Sinusoids
Bile
canaliculi
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Hepatic
cells
Central
vein
Bile duct
(hepatic
bile duct)
Portal vein
(branch)
Hepatic artery
(branch)
FIGURE 14.2 Structure of a liver lobule. Liver lobules are roughly hexagonal structures with
corners demarcated by the “portal triad” made up of branches of the hepatic artery, portal vein,
and bile duct. Blood flows in through the sinusoid to the central vein of the lobule, while bile flows
out to the bile duct branch.
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Heart
Inferior vena
cava
Abdominal
aorta
Hepatic
veins
Proper hepatic
artery
Hepatic
portal
vein
Liver
Splenic
vein
Tributaries from portions
of stomach, pancreas. and
portions of large intestine
Superior
mesenteric
vein
Tributaries from
small intestine and
portions of large intestine,
stomach, and pancreas
FIGURE 14.3 Hepatic blood flow. Two vascular streams supply the liver with blood. The hepatic artery
branches from the abdominal aorta, providing fully oxygenated arterial blood to the liver. The portal
vein combines the venous drainage from many of the abdominal organs, making up 75% to 80% of the
liver blood flow with blood that is rich in nutrients after meals, but is oxygen poor.
Source: From Tortora GJ, Derrickson BH. Principles of Anatomy & Physiology. Hoboken, NJ:
Wiley; 2011:862.
Central vein
Biliary
Deoxygenated blood
Bile to canaliculus
from GI tract via
gallbladder
branch of portal vein
Oxygenated blood
from aorta via branch
of hepatic artery
Sinusoid
Interlobular
bile duct
Kupffer cells
FIGURE 14.4 Hepatic blood and bile flow within the liver lobule. Blood flows from the periphery
of the lobule toward the central vein, while bile flows in the opposite direction, to the periphery of
the lobule.
GI, gastrointestinal.
Chapter14 • Liver
513
Bile duct
Liver
Left hepatic duct
Right hepatic duct
Stomach
Common
hepatic duct
Cystic duct
Pancreas
Gallbladder
Duodenum
Common bile duct
Gallbladder
Distal common bile duct
FIGURE 14.5 The biliary tree is formed as small bile canaliculi draining plates of hepatocytes
coalesce to progressively larger channels. Ultimately, these vessels form the bile duct that drains
bile from the liver and gallbladder into the duodenum.
potential foreign pathogens, sinusoids contain many
Kupffer cells, tissue macrophages that destroy foreign
pathogens. The space of Disse, between sinusoids and
hepatocytes, contains hepatic stellate cells (see Figure
14.1b). Stellate cells store vitamin A, and are normally
inactive, but become activated as a consequence of
liver inflammation. When activated, they contribute to
the fibrosis and cirrhosis associated with chronic liver
disease.
Hepatocytes have a distinct polarity, with basolateral surfaces facing the space of Disse and sinusoid, and apical surfaces adjacent to bile canaliculi
( Figure 14.6 ). The apical surfaces of adjoining
cells are sealed with tight junctions that prevent the
leakage of damaging bile away from the canaliculi.
Hepatocytes have abundant smooth endoplasmic
reticulum (SER) and rough endoplasmic reticulum
(RER). SER contains many enzymes for drug detoxification and for cellular metabolism; RER is the site of
synthesis of proteins that will be secreted. There are
many mitochondria, as well as stores of glycogen, fat
droplets, iron, and vitamin B12. Large fenestrations
(pores) between sinusoidal endothelial cells allow
free interchange of molecules between plasma and
hepatocytes. This is critical for the ability of plasma
proteins synthesized in hepatocytes to make their
way to the circulation.
Thought Questions
1. How do the vascular input and output pathways
of the liver differ from those of most other
organs?
2. What are some of the functional consequences
of these differences?
LIVER FUNCTION
Energy Metabolism
The liver is the main organ of energy metabolism of
carbohydrates, lipids, and amino acids as shown in
Figure 14.7. After meals, the portal vein blood is rich
in absorbed nutrients from the gastrointestinal (GI)
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Advanced Physiology and Pathophysiology: Essentials for Clinical Practice
SER
1
2
RER
Bile
canaliculus
Tight (occluding)
junctions
Golgi
Lysosome
Mitochondria
Desmosome
Glycogen
Lipid
3
Microvilli
Perisinusoidal
space
Endothelium
Fenestration
Reticular fibers
FIGURE 14.6 Hepatocyte structure and function. The microscopic hepatocyte structure gives
clues to the varied processes carried out by these cells. There are abundant RER and Golgi
apparatus for protein synthesis and secretion (1). Protein transfer is assisted by large gaps
(fenestrations) between liver sinusoidal endothelial cells. Apical membranes of adjacent
hepatocytes are sealed with tight junctions around the site of bile secretion into the canaliculus
to prevent toxic bile components from damaging the hepatocytes or leaking into the blood (2).
SER contains enzymes of drug metabolism and metabolic processes. Fuels are stored in the
form of glycogen deposits and lipid droplets. The cells are polarized, with basolateral surfaces
enriched by folds where they contact the space of Disse for interchange of proteins between
blood and hepatocyte (3).
RER, rough endoplasmic reticulum; SER, smooth endoplasmic reticulum.
tract and pancreatic hormones, positioning the liver
to conduct the reactions allowing energy storage for
times of fasting. Although a more detailed description of the processes of energy metabolism appears
elsewhere in this book, an overview is included here.
Carbohydrate metabolism aimed at maintaining stable
blood glucose is a key responsibility of the liver. The
liver regulates blood glucose by controlling the uptake,
production, and release of glucose. In periods of excess
glucose (high blood sugar), it sequesters glucose as
glycogen (glycogenesis). During fasting, glycogen is
broken down (glycogenolysis), releasing glucose for
use by the body. The liver also has the ability to synthesize glucose from amino acids and other precursors
during periods of low blood glucose through the process termed gluconeogenesis.
The liver is the dominant organ of lipid metabolism.
When it has stored sufficient glucose, excess glucose is
converted to triglycerides, which are then packaged as
very low-density lipoproteins (VLDLs) to travel through
the bloodstream. The triglycerides are broken down
by capillary lipase, and the free fatty acids (FFAs) are
then re-formed into triglycerides and stored in adipose
tissue. The liver can also use glucose to synthesize
Chapter14 • Liver
Small intestine
Bile
Cholesterol
Bile acids
Bilirubin
Fatty acids
Bilirubin
Ketone bodies
RES
Monosaccharides
VLDL,
HDL
Amino acids
Lipids
515
Glycogen
HDL
Blood glucose
Uric acid
Blood plasma proteins
Amino acids
Urea
Lactate
FIGURE 14.7 Principal metabolic liver functions.
HDL, high-density lipoprotein; RES, reticuloendothelial system; VLDL, very low-density lipoprotein.
cholesterol, which is essential for the production of
plasma membrane components, bile, hormones, and
certain vitamins. The liver takes up low-density lipoproteins (LDLs) and intermediate-density lipoproteins
(IDLs) that are formed after tissues remove triglyceride from VLDLs. The liver also synthesizes high-density
lipoproteins (HDLs) that are integral to cholesterol distribution and uptake throughout the body and return
to the liver.
Synthetic Processes of the Liver
The liver synthesizes and breaks down amino acids in
support of protein synthesis and in the process of gluconeogenesis, respectively. Hepatocyte processes of
metabolic homeostasis, drug metabolism, and bile salt
production require an extraordinary number of intracellular, membrane, and secreted proteins. Liver ranks
third in the number of tissue-enriched messenger ribonucleic acids (mRNAs) and proteins, behind brain and
testis.4 Additionally, the liver synthesizes and secretes
the majority of plasma proteins (Table 14.1).
Dietary fat absorption depends on the fat-solubilizing properties of bile, which is synthesized in the
liver, secreted into the biliary tree, and stored in the
gallbladder. Bile is composed of water, bile salts, phospholipids, conjugated bilirubin, and other compounds
detoxified by the liver and destined for fecal excretion. Bile serves two main functions: fat digestion and
toxin excretion. Bile salts are amphipathic molecules,
containing both hydrophobic and hydrophilic parts,
synthesized from cholesterol. Bile salts are required for
digestion of fats through emulsification and for absorption of fat digestion products and fat-soluble vitamins
from the intestines. Bile is also a route of excretion for
bilirubin, xenobiotics, and endogenous compounds that
have been detoxified by liver enzymes. Bile is the major
route of excretion for potentially detrimental lipophilic
substances, and the major elimination route for cholesterol. Additionally, bile may protect against intestinal
infections through the secretion of immunoglobulin A
and stimulation of cytokine release. Approximately 500
to 600 mL of bile is produced per day.
The liver is responsible for detoxifying ammonia
through the synthesis of urea, producing a compound
that is readily cleared by the kidneys. Ammonia produced by gut bacteria reaches the liver through the portal vein. The liver also forms ammonia through amino
acid metabolism. In the urea cycle, chemical reactions
occur in the mitochondria and cytosol of the hepatocytes to convert ammonia to urea, which improves
water solubility for ease of renal excretion. Ammonia
is toxic to the brain and can impair brain function, leading to a change in mental status that can eventually
result in seizures and coma. When the liver is unable
to detoxify ammonia, as in chronic liver disease, the
result is central nervous system dysfunction. Excess
levels of ammonia are thought to contribute to hepatic
encephalopathy. Consequently, management of hepatic
encephalopathy typically aims to reduce ammonia levels. This is often achieved with the administration of
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TABLE 14.1 Major Proteins Secreted by the Liver
Protein Category
Proteins
Function
Plasma proteins
Albumin
Maintains colloid osmotic pressure, carrier protein
Acute phase proteins
C-reactive protein
Enhances endogenous immune responses, marker of
inflammation and illness
Coagulation cascade proteins
Prothrombin (factor II) and factors
V, VII, VIII, IX, X, XI, XIII; fibrinogen;
α2-antiplasmin
Hemostasis, prevention of blood loss
Regulators/inhibitors of
coagulation proteins
Protein C, protein S, antithrombin III,
plasminogen
Prevent excessive clotting, clot lysis
Stimulator of platelet production
Thrombopoietin
Stimulates bone marrow to increase platelet synthesis
and release
Complement cascade proteins
C1–C9
Host defense, innate immunity
Carrier proteins
Transferrin, transcobalamin,
transcortin, thyroxine-binding
globulin, sex hormone–binding
globulin, others
Transport of lipid-soluble or toxic substances, extends
half-life of steroid and thyroid hormones
Protective proteins, antioxidants,
other roles
α1-Antitrypsin, glutathione,
angiotensinogen
Diverse roles in homeostasis
lactulose, a disaccharide that is retained in the gut.
Lactulose reduces pH, increases stool production, and
lowers the levels of gut nitrogenous compounds that
increase circulating ammonia.
Thought Questions
3. What are the major synthetic reactions carried
out by the liver?
4. How do these reactions contribute to
homeostasis?
Liver Clearance Mechanisms
The liver has a wide range of protective and clearance functions. As mentioned, it is responsible for the
metabolism of xenobiotics, including drugs and toxins.
The passage of blood from intestines through the portal
vein to the liver allows the liver to process and absorb
ingested substances before they reach the systemic circulation by removing unwanted compounds.
Metabolism of Bilirubin
The liver is responsible for the conjugation of bilirubin and its excretion via bile ducts. As red blood cells
are broken down in the spleen, the heme component
of hemoglobin is released. Heme is metabolized into
biliverdin, which is subsequently converted to bilirubin. Bilirubin, a nonpolar substance, is released into the
bloodstream and binds with albumin. This form is called
unconjugated or indirect bilirubin. When this compound
reaches the liver, it is taken up and conjugated in hepatocytes. As with other drugs and substances discussed previously, the addition of glucuronide makes the bilirubin
molecule polar, water soluble, and able to be excreted.
Conjugated bilirubin is also referred to as direct bilirubin and can freely travel through the bloodstream
to the kidneys for excretion. Conjugated bilirubin can
also be secreted into the bile and eventually excreted
in feces. While the kidney can excrete excess levels of conjugated bilirubin, most is excreted through
the feces after reduction to urobilinogen and stercobilin in the intestine. Figure 14.8 summarizes the
production, metabolism, and excretion of bilirubin.
Hyperbilirubinemia produces the characteristic yellowing of the skin termed jaundice. Such elevations
can be caused by excess production of bilirubin,
decreased uptake by liver cells, decreased conjugation,
decreased secretion into the canaliculi, and bile duct
obstruction. Hemolytic anemia is a common cause of
excess production of bilirubin. Laboratory measurements of conjugated and unconjugated bilirubin are
used to determine the cause of jaundice and the site of
liver impairment (Table 14.2).
Chapter14 • Liver
517
Reticuloendothelial system
RBCs
Heme
Heme
oxygenase
Biliverdin
Bilirubin
Bilirubin-albumin
Uptake
Bilirubin
(unconjugated)
UDP-glucuronyl
transferase
Bilirubin
glucuronide
(conjugated)
Secretion
Defective secretion is
seen in cholestasis
Small amounts
in urine
Bilirubin glucuronide
Portal circulation
Urobilinogen
Stercobilin
(gives brown
color to
feces)
FIGURE 14.8 Bilirubin metabolism. Bilirubin is constantly generated from heme released upon
breakdown of aging RBCs by the reticuloendothelial system. Unconjugated (indirect) bilirubin is
initially hydrophobic and nonpolar, and travels in the circulation bound to albumin. Hepatocytes take
up bilirubin and conjugate it to glucuronic acid. Conjugated (direct) bilirubin glucuronide is hydrophilic
and is secreted into the bile. In the gut, bacteria further metabolize bilirubin to urobilinogen, a fraction
of which is reabsorbed and ultimately excreted by the kidneys. Much of the remaining urobilinogen is
converted to stercobilin and is excreted in the feces, adding the characteristic brown color.
RBCs, red blood cells; UDP, uridine 5′-diphospho-glucuronosyltransferase.
TABLE 14.2 Patterns of Bilirubin Elevation in
Hepatic Injury
Assay
Component
Bile Duct
Obstruction
Hemolytic
Anemia
Liver
Failure
Total bilirubin
↑
↑
↑
Direct bilirubin
↑
WNL
↑
Indirect bilirubin
WNL
↑
↑
↑ indicates that the level will be increased.
WNL, within normal limits.
Hormone and Drug (Xenobiotics) Metabolism
Endogenous hormones and xenobiotics (exogenous compounds foreign to the human body) are
detoxified and excreted by the liver. The outcome of
hepatic metabolism is to make a substance easier to
excrete. In general, this occurs by making a product
more water soluble. Figure 14.9 shows the basics of
drug metabolism and excretion. Metabolism occurs
through microsomal oxidase enzymes, such as the
highly active cytochrome P450 (CYP) system, or
through enzymatic conjugation that makes the compound or its metabolite more hydrophilic for renal
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Conjugation
(glucuronidation,
etc.)
Nonpolar
species
Stable adducts
Conjugation
Biliary elimination
(stool)
Drug
Oxidation
(cytochrome
P450s)
Metabolite
Polar
species
Renal elimination
(urine)
FIGURE 14.9 Metabolism of an exogenous drug. Phase 1 reactions are carried out by enzymes of
the cytochrome P450 (CYP) class. These reactions add a hydroxyl or other chemically reactive,
oxygen-containing group to the drug. Phase 2 reactions conjugate the drug or its phase 1 metabolite
with a larger hydrophilic group, increasing water solubility and renal elimination. Compounds with
nonpolar metabolites are usually eliminated by the biliary–fecal route.
excretion, or both. The SER in hepatocytes contains
most of the enzymes responsible for drug and hormone metabolism.
Most substances are metabolized in two processes,
referred to as phase 1 and phase 2 reactions. Some
substances may be metabolized by only one of the
phases. CYP enzymes conduct phase 1 metabolism,
converting their substrates through oxidation, reduction, or hydrolysis reactions. Many exogenously
administered drugs are lipid soluble, which facilitates
absorption and distribution, but reduces excretion. In
phase 1 metabolism, a polar functional group, most
often a hydroxyl group, is added to the parent compound to make the product polar and hydrophilic and
thus easier to excrete. There are several potential
outcomes of phase 1 metabolism. In some cases, the
intermediate metabolite can be toxic, such as with
ethanol and acetaminophen, and can cause hepatic
injury. In other cases, the administered compound
is a prodrug, and phase 1 metabolism converts it to
an active drug. Finally, some drug metabolites may
be physiologically active, prolonging the time of drug
effect on the body.
In the case of a toxic metabolite, phase 2 metabolism will often detoxify the metabolite and allow it to
be excreted. If phase 2 metabolism is altered, these
toxic intermediates can build up and cause hepatic
damage. Phase 2 reactions, or conjugation reactions,
result in the covalent attachment of a water-soluble
group, such as glucuronic acid, to the drug compound
in order to further increase the metabolite’s water
solubility and renal excretion. If the metabolite is
unable to be excreted by the kidneys, it can also be
eliminated through bile.
There are 57 identified CYP enzymes in humans.
Five of these enzymes are responsible for the majority of drug metabolism, with 3A4 metabolizing the
largest number of drugs (Table 14.3). 5 Metabolism
varies from person to person owing to a number of
factors. Genetic polymorphisms cause differences in
CYP enzyme functionality; enzyme induction or inhibition can be caused by other prescribed or over-thecounter drugs or supplements, and comorbidities can
alter drug metabolism.
Genetic polymorphisms that alter drug metabolism are the focus of pharmacogenomic research.
Polymorphisms in the genes coding for phase 1
enzymes may alter these proteins, causing a patient to
TABLE 14.3 Common Cytochrome P (CYP) Enzymes
Contributing to Drug Metabolism
CYP Enzyme
Drug Metabolized (%)
1A2
5
2C9
15
2C19
7–9
2D6
20–30
3A4
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Chapter14 • Liver
be a poor metabolizer or a rapid metabolizer, and leading to changes in drug effective concentrations or halflife of elimination. Induction increases the amount of
a CYP enzyme, thus increasing the metabolism of its
substrate drugs, and resulting in lower drug levels and
reduced effectiveness. Inhibition decreases the activity of a CYP enzyme, thus decreasing the metabolism
of the substance, resulting in higher drug levels and
increasing risk of toxicity. Enzyme induction and inhibition are common sources of drug interactions. Phase
2 metabolism can also be affected by genetic polymorphisms. The phase 2 enzyme N-acetyltransferase
catalyzes the addition of an acetyl group to a drug or
its phase 1 metabolites. Some patients have a genetic
polymorphism that reduces N-acetyltransferase activity, with a phenotype described as “slow acetylator.”
They are at increased risk of toxic effects from drugs
requiring acetylation for elimination. Genetic tests
are available to assess phase 1 and phase 2 enzyme
polymorphisms; however, such tests are not widely
used in clinical practice. Drug metabolism is altered in
patients with liver or kidney disease, or both; in these
patients, dosages must be adjusted to reduce adverse
drug events.
Liver metabolism may diminish the blood levels
of drugs administered orally, through the first-pass
effect. Once a drug is absorbed from the GI tract, the
portal vein delivers the drug to the liver. The liver can
metabolize some of the drugs before it exits through
the hepatic vein to systemic circulation, as shown in
Figure 14.10. This first-pass effect can reduce the
Oral
medication
Systemic circulation
Hepatic
vein
Hepatic
artery
Intestinal
tract
Portal
vein
FIGURE 14.10 First-pass effect. Oral medications absorbed
in the gastrointestinal tract circulate via the portal vein to
the liver prior to entering the systemic circulation. Liver
metabolism may either activate a prodrug or inactivate a
portion of administered drug, reducing the amount of active
drug that reaches the circulation.
519
amount of active drug available to the body for pharmacologic action as well as delaying the onset of drug
effect. This drug has lower bioavailability than a drug
that does not undergo this initial metabolism. Drugs
administered through the intravenous route do not
undergo absorption through the GI tract, and thus will
not undergo first-pass effect, leading to higher levels of
the active drug, and high bioavailability. Drug absorption through the GI tract and hepatic metabolism takes
time, so drugs administered intravenously reach effective blood levels almost immediately, far more quickly
than drugs administered orally. Other routes can also
bypass the first-pass effect. For example, orally administered nitroglycerin has a high rate of hepatic metabolism that substantially reduces bioavailable drug.
Sublingual administration provides rapid absorption
and avoids the first-pass effect.
Thought Question
5. How is the way the liver processes bilirubin
similar to the way it processes drugs, and how
do these processes differ?
Other Functions of the Liver
Reticuloendothelial System
As part of the reticuloendothelial system, the liver
contains the largest number of fixed tissue macrophages, also known as Kupffer cells, making it an
important component of the immune system. Kupffer
cells are responsible for the clearance of gut bacteria and foreign proteins. If the liver is damaged, then
the immune system may be unable to defend against
foreign proteins and bacteria. This is evident with
the high rate of infection in patients with acute liver
failure.
Vitamin and Mineral Storage
The liver can store iron in the form of ferritin and
can store several vitamins, including A, E, and B12.
The liver is responsible for maintaining systemic iron
homeostasis by producing the iron transport protein
transferrin, storing excess iron as ferritin, and mobilizing iron from hepatocytes to the circulation in times of
need. The liver also synthesizes hepcidin, a plasma protein that blocks cellular transport of stored iron back to
the circulation, thus decreasing circulating iron levels.
Hereditary hemochromatosis, discussed later in this
chapter, is a disorder of abnormal hepcidin.
Regenerative Capacity
The liver has the ability to regenerate after an acute
injury. In instances of hepatocyte necrosis from acute
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Advanced Physiology and Pathophysiology: Essentials for Clinical Practice
pathological processes, the hepatocytes can regenerate. Unfortunately, once a patient has severe liver
disease, or cirrhosis, the liver loses this ability. If a
person has a partial hepatectomy, as in the case of living liver donors, after removal of a portion of the liver,
that donor liver will then regrow in another region and
restore normal levels of liver tissue and function.
LIVER DISORDERS
Concerns in patients with liver disorders include abnormalities in blood glucose, lipid, and protein levels; the
inability to detoxify and excrete drugs and endogenous
toxins such as ammonia and bilirubin; and abnormal
clotting. In severe and chronic disorders, blood flow
through the sinusoids is restricted, leading to portal
hypertension. The development of portal hypertension produces manifestations of decompensated liver
disease, including ascites, esophageal varices, and
increased risk of infection.
MEASURES OF LIVER FUNCTION
AND DYSFUNCTION
Laboratory evaluation can be performed to determine the
function and health of the liver. Evaluation techniques
encompass methods that assess damage to hepatocytes
or indicate loss of liver homeostatic functions. Often the
levels of enzymes, results of other tests, and clinical findings are pathognomonic for type of liver disease.
As hepatocytes are damaged, enzymes of liver function are released into the systemic circulation, allowing for quantification in the serum. Elevation of these
enzymes is a marker for hepatocyte damage or death,
and not necessarily liver function. Examples of these
enzymes are aspartate aminotransferase (AST), alanine
aminotransferase (ALT), gamma-glutamyl transferase
(GGT), and alkaline phosphatase (ALP). Of these tests,
ALT is the most specific marker for liver damage because
it is found mainly in hepatocytes. AST is found in multiple organs and tissues, including the liver, cardiac and
skeletal muscle, and kidney. AST is released from cell
ular and tissue damage in amounts proportional to the
amount of injury that has occurred. GGT is sensitive
to hepatocellular damage caused by alcohol in
