1

Hepatotoxicity
 Liver functions
 Structural organization of liver
 Bile formation
 Types of hepatobiliary injury
Fatty liver (steatosis)
Cirrhosis
Hepatocyte death (liver necrosis)
Hepatocanalicular cholestasis
Cholangiodestructive cholestasis (bile duct damage)
Sinusoidal damage
Tumors
2
 Introduction
• A basic understanding of chemical hepatotoxicity
requires some appreciation of :

1. Major functions of the liver

2. Structural organization of the liver
3. Processes involved in the excretory
function of the liver, namely bile 膽汁
formation

• These aspects contribute to the vulnerability of hepatic

cells to chemical insults.
3
4
Liver function – glucose metabolism
• One of its major functions is a role in glucose metabolism in which glucose is
converted to glycogen for storage following a carbohydrate meal.
• Between meals the liver responds to hypoglycemia 低血糖 to maintain normal
blood glucose levels.
• During fasting, the liver also may supply glucose by gluconeogenesis, the
synthesis of glucose from amino acids or other sources.

Glycogen degradation

5
 Liver function – lipid metabolism
• The liver is the major site for converting excess carbohydrates and proteins
into fatty acids and triglyceride, which are then exported and stored in
adipose tissue.
• The liver is extremely active in oxidizing triglycerides to produce energy.
• The liver synthesizes large quantities of cholesterol and phospholipids.

Glycogen degradation

6
 Liver function – synthesize
apoprotein for lipid transport
• Lipids such as fatty acids, triglycerides (or
triacylglycerols), steroids and fat soluble vitamins are
insoluble in water.
• To transport lipids in the blood plasma, a carrier
protein is required.
• Fatty acids are carried from the adipose tissue to the
muscle and liver tissues by serum albumin.
• Vitamin A is carried by the retinol binding protein.
• Steroids are carried to the target cells by steroid
carrier proteins.
• Dietary lipids (cholesterol, phospholipids and
triglycerides) are transported in the plasma by large
complexes called lipoproteins.
• These lipoproteins consist of a core of hydrophobic
lipids surrounded by a shell of phospholipid and
proteins (called apoprotein).
• The protein components of lipoproteins solubilize the
hydrophobic lipids. 7
 Lipoproteins
• Lipoproteins are classified according
to their density.
• The densities of these lipoproteins are
related to the relative amounts
of lipids to proteins in the
complex.
• The higher the protein content the
higher the density of the lipoprotein.
• The lowest density lipoproteins are
chylomicrons (ULDL) < VLDL < IDL
< LDL < HDL.
ULDL = Ultra low-density lipoprotein
(Chylomicrons)
VLDL = Very low-density
lipoprotein
IDL = Intermediate-density lipoprotein
LDL = Low-density lipoprotein 8
HDL = High-density lipoprotein
Liver function – protein metabolism
• Most of the albumin
白蛋白 (carrier protein) in
blood synthesizes from
the liver.
• The urea 尿素 cycle
is found within the liver.
• In this cycle, ammonia,
which arises from the
deamination of amino
acids, is processed into
the urea, which makes its
way to the kidney for
excretion into the urine. 9
Do not need to study the details of the urea cycle
Liver function – others
• Other activities which occur partly or entirely in
the liver include the:

–synthesis of some blood-clotting factors,

–metabolism of xenobiotics (Phase I and
Phase II reactions),
–synthesis of bile acids to aid lipid
absorption,
–storage of fat-soluble vitamin
10
11
Location of the liver and gallbladder
Esophagus
Liver

Stomach

Gallbladder Hepatic
duct
Spleen

Common bile
duct

12
Duodenum
Gross structure of the liver

Normal healthy liver

13
• To visualize lobules, first locate several
portal areas.
• These are recognizable as small
patches of connective tissue, each
containing a duct (bile duct), a
large vein (portal vein), and a
small artery (hepatic artery).
• These mark the corners where
lobules come together.
•Central veins are conspicuous
spaces, with no associated connective
tissue, located midway between portal
areas.
• These central veins mark the centers of
lobules.
• Lobules appear much more clearly in
pig liver, which has an envelope of
fibrous connective tissue around each
lobule.
 Hematoxylin and eosin staining

Hematoxylin and eosin staining

15
http://www.siumed.edu/~dking2/erg/liver.htm#sinusoids
 Liver structure
• Liver cells are called hepatocytes.
• They are arrayed in rows which are adjacent
to sinusoids, spaces that are supplied by
branches of the portal vein and hepatic
artery and which, in turn, supply the
hepatocytes with solutes from the blood.
• Solutes arriving through the sinusoids bathe
the hepatocytes which, in turn, absorb many
dissolved particles.
• Products of liver cell activity exit the
hepatocytes by one of the two drainage
mechanisms. Hepatocyte
• These products may enter the sinusoids or
they may drain into bile canaliculi.
• Bile acids as well as many products of toxin
metabolism move from the liver cell into the
tiny bile channels, the canaliculi, and these
merge into larger ducts, eventually forming
the bile duct which drains into the upper 16
part of the small intestine, the duodenum.
• Along the way from liver to duodenum, bile
may be temporarily sequestered in the gall
bladder.
Location of the liver and gallbladder
Esophagus
Liver

Stomach

Gallbladder Hepatic
duct
Spleen

Common bile
duct

17
Duodenum
Hepatic sinusoids 肝竇狀隙
• Hepatic sinusoids are the channels between cords of hepatocytes where blood
percolates on its way to the terminal hepatic vein (central vein).
• Sinusoids are larger and more irregular than normal capillaries.
• The three major types of cells in the sinusoids are endothelial cells,
Kupffer cells, and Ito cells .
• Sinusoids are lined by thin, discontinuous endothelial cells with numerous pores
that allow molecules smaller than 250 kDa to cross the interstitial space between
the endothelium and hepatocytes.
Biliary canaliculi Branch of
hepatic artery Bile duct

BD
Central vein
(=THV) HA

PV

Sinusoid Ito cell

Kupffer Endothelial Branch of 18
cell cell portal vein
The hepatic vascular system
• Roughly 75% of the blood
entering the liver is venous blood aorta

from the portal vein. Vena cava

• Importantly, all of the venous blood Hepatic artery
(25%)
returning from the small intestine, Hepatic
Portal vein
stomach, pancreas and spleen vein
Liver (75%)
converges into the portal vein.
• The remaining 25% of the blood
supply to the liver is arterial
blood from the hepatic Small

artery.
intestine

• Terminal branches of the hepatic

portal vein and hepatic artery
empty together and mix as they from
Hepatic
enter sinusoids in the liver. artery

• Blood flows through the Sinusoid lined with

(25%)
Central
sinusoids and empties into the
central vein of each lobule. vein endothelial cells
• Central veins coalesce into from
hepatic vein, which leaves Portal
vein
the liver and empty into the vena 19
(75%)
cava.
Kupffer cells 細胞肉瘤
• Kupffer cells are the resident macrophages 巨噬細
胞 of the liver and constitute approximately 80% of
the fixed macrophages in the body.
• Kupffer cells are situated within the lumen of the
sinusoid.
This specimen comes from an animal which
• The primary function of Kupffer cells is to ingest was injected IV with a suspension of
and degrade particulate matter. carbon particles. These particles are
scavenged by Kupffer cells whose
cytoplasm becomes packed with black
Sinusoidal Kupffer cell carbon particles.

lumen Endothelial
cell

Space of Disse Ito cell

Hepatocytes

20
Bile canaliculi
 Ito cells
• Ito cells (also known as the fat-storing cells and stellate
cells) are located between endothelial cells and hepatocytes.
• Ito cells synthesize collagen and are the major site for
vitamin A storage in the body.

Kupffer
Sinusoidal cell
lumen Endothelial
cell

Space of Disse Ito cell

Hepatocytes

21
Bile canaliculi
Structural organization (I)
• Two concepts exists for organizations of the liver into operational units, namely
the lobule and the acinus.
• Classically, the liver is divided into hexagonal lobules oriented around
central vein (also known as terminal hepatic vein).
• At the corners of the lobule are the portal triads (or portal tracts),
containing a branch of the portal vein, a hepatic artery, and a
bile duct.

Classic lobule Liver acinus Portal lobule

Portal tract
Central vein 22
 Bile duct

Portal vein Portal

Hepatic artery
triad

CV The hepatic
acinus and
surrounding
zones

CV

23
Liver operational unit
- the classic lobule concept
• The lobule is divided into three regions known as:
(1) Centrilobular
(2) Midzonal
(3) Periportal

(1) Centrilobular (2) Midzonal (3) Periportal

24
 Liver operational unit
- the acinus concept
•Perferred as a concept of a
functional hepatic unit is the acinus. LOBULE
•The acinus has three zones:
Zone 1 is closest to the entry of blood
Zone 2 is intermediate Bile duct
Zone 3 nears the central vein
Portal vein
Hepatic artery
Terminal Hepatic Vein
= CV

THV THV

Centrilobular
(close to CV)

Midzonal
(intermediate) Periportal
(closest to the
Acinus Lobule entry of blood)
terminology terminology
Zone 1 Periportal
Zone 2 Midzonal 25
Zone 3 Centrilobular
ACINUS
Functional consequences of
acinar zonation (I)
• Acinar zonation is of considerable functional
consequence regarding gradients of
components both in blood and in
hepatocytes.
• Blood entering the acinus consists of oxygen-depleted
blood from the portal vein (60-70% of hepatic blood Central vein
flow) plus oxygenated blood from the hepatic artery
(30-40%). 32
• Enroute to the terminal hepatic vein (= central vein), 1
oxygen rapidly leaves the blood and to meet the high
metabolic demands of the parenchymal cells.
•Approximate oxygen Central vein

concentrations in zone 1 are 9-13%,

compared to 4-5% in zone 3.
• Therefore hepatocytes in zone 3 are exposed to
substantially lower concentrations of oxygen than
hepatocytes in zone 1.
• In comparison to other tissues, zone 3 is hypoxic. 26
 Functional consequences
of acinar zonation (II)
• Another well-documented acinar gradient is
that of bile salts.
• Physiologic concentrations of bile
salts are efficiently extracted by
zone 1 hepatocytes with little bile salt Central vein
left in the blood flows past zone 3
hepatocytes. 32
• Hepatocytes in the mitochondria- 1
rich zone 1 are predominant in fatty
acid oxidation, gluconeogenesis, and
ammonia detoxification to urea. Central vein

• Notable gradients for hepatotoxins are the

higher levels of glutathione in
zone 1 and the greater
amounts of cytochrome P450
proteins in zone 3, particularly the
CYP2E1 isozyme inducible by ethanol. 27
 Functional consequences
of acinar zonation (Summary)
Acinus concept Zone 1 Zone 3
(Periportal) (Centrilobular)
(Classical concept)
Oxygen 9-13% 4-5% (hypoxic)
content Central vein

Bile salt High Low

content 32
1
Mitochondria Rich Scarce

Glutathione
Central vein
High Low

Cytochrome Low High

P450
content
28
29
Location of the liver and gallbladder
Esophagus
Liver

Stomach

Gallbladder Hepatic
duct
Spleen

Common bile
duct

30
Duodenum
Gall bladder and bile ducts
Hepatocyte

Lumen of sinusoid

Bile
canaliculus
Bile ductule
Portal tract bile duct

Medium and large

Interlobular ducts

31
Bile formation (I)
• Bile is a yellow fluid containing bile salts,
glutathione, phospholipids, cholesterol, bilirubin (a
breakdown pigment of red blood cells) and other
organic anions, proteins, metals, ions, and
xenobiotics.
• Formation of this fluid is a specialized function of the
liver.
• Adequate bile formation is essential for uptake of
lipid nutrients from the small intestine and for
excretion of endogenous and xenobiotic
compounds. 32
 Bile salts
• Bile acids (also known as bile salts) are steroid acids found predominantly in the bile of
mammals.
• They are produced in the liver by the oxidation of cholesterol, conjugated (with either the
amino acid taurine or glycine, or a sulfate, or a glucuronide) and are stored in the gallbladder.
• In humans taurocholic acid, and glycocholic acid (derivatives of cholic acid) represent
approximately 80% of all bile acids.
• Bile acids serve multiple functions which include elimination of cholesterol from the body,
driving the flow of bile to eliminate catabolites from the liver, and serving to emulsify lipids
and fat soluble vitamins in the intestine.

Cholic acid : R1 = OH, R2 = H

Cholesterol Glycocholic acid : R1 = OH, R2 = NH-CH2-COOH
Taurocholic acid : R1 = OH, R2 = NH-CH2-CH2-SO3H

Bile acids
33
 Excretion of bilirubin by the liver
• The life span of erythrocytes is about 120 days. 脾
• The erythrocytes are lysed inside the
reticuloendothelial cells of spleen and the
hemoglobin released. 膽紅素
• The globin is hydrolyzed into amino acid, and
the heme is metabolized to form bilirubin. Bilirubin
• The bilirubin, a water-insoluble molecule, is
released into the blood plasma and complexed
with albumin and transported to the liver.
• In the liver, it is solublized by being converted
to bilirubin diglucuronide (90%) and bilirubin
sulfate (10%).
• Bilirubin diglucuronide is excreted from the
liver via the bile into the intestine.
• Within the bowel, it is hydrolyzed, and the
bilirubin is reduced to urobilinogen and
stercobilinogen.
• These are excreted in urine as urobilin and in
feces as stercobilin and give urine and feces
their characteristic colors. 34
 Bile formation (II)
• Hepatocytes begin the process
by transporting bile salts, Hepatocyte

glutathione, and other solutes Lumen of sinusoid

into canalicular lumen, which is
a space formed by specialized
regions of the plasma
membrane between adjacent
hepatocytes. Bile
• Canaliculi form channels canaliculus
between hepatocytes that
connect to a series of larger and Bile ductule
larger channels or ducts within
the liver. Portal tract bile duct
• The large extrahepatic bile ducts
merge into the common bile
duct. Medium and large
• Bile can be stored and Interlobular ducts
concentrated in the
gallbladder before its release
into the duodenum.
35
Gall bladder and bile ducts

36
 Bile Portal Hepatic
duct vein vein

Hepatic vein
Bile duct

37

Portal vein
38
Liver injury
• All of the major functions of the liver can be
detrimentally altered by acute or chronic
exposure to toxicants.
• The types of liver injury that may occur
depend on:
1. the identity of the liver toxin
2. the degree of exposure (massive vs.
light)
3. whether the duration of exposure is
acute or chronic
39
 Patterns of lobular injury
Zone 3 Zone 2 Zone 1
Centrilobular Midzonal Periportal

•Despite the utility of the acinar concept, lobular terminology is

Portal area still used to describe regions of pathologic lesions of hepatic
parenchyma.
•Fortunately, the three zones of the acinus roughly coincide with
Central vein the three regions of the lobule.
•Centrilobular is by far the most common site of
hepatic damage due to the abundant distribution of
Area of injury cytochrome P450 enzymes.
40
 Blood tests

Liver Biopsy

Ultrasound

41
Assessment of liver dysfunction
• Liver injury from a variety of causes can lead to very
similar clinical symptoms, a common endpoint
being hepatocyte damage and scar
formation.
• However, a thorough history and physical examination
can reveal clues to the potential etiologies of liver disease.
• Laboratory studies can help establish the
pattern of injury, the functional status of the liver, and the
specific causes of disease.
• Finally, liver biopsy is a safe procedure that can
provide valuable information about the patterns and
etiologies of liver injury. 42
Common liver function tests (LFTs)

• Liver function tests are performed on blood

samples.
• Serum enzyme tests look for activity of
enzymes in the blood which are normally
found in hepatic cells.
• Increased serum activities of these
enzymes may indicate damage to hepatocytes,
and subsequent leakage of the enzymes.

43
Common liver function tests (LFTs)
Serum tests
Alanine aminotransferase (ALT)
/serum glutamic-pyruvic
transminase (SGPT)
Aspartate aminotransferase
(AST) / serum glutamic-
oxaloacetic transaminase (SGOT)
Alkaline phosphatase (AP)
Albumin
Bilirubin
Prothrombin time
Normal Clinical role
value
10 - 31 U/L Aminotransferases are enzymes that catalyze protein
transformations within hepatocytes. ALT is found
predominantly in the liver. Hepatocellular injury
usually results in the elevation of ALT in serum.
10 - 44 U/L AST is found in liver, muscle, kidney, and brain.
Hepatocellular injury usually results in the elevation of ALT
in serum.
25 - 112 Alkaline phosphatase is an enzyme in the membrane of
U/L biliary ductular cells, but it is also found in other
tissues, such as bone. Cholestatic liver injury
(obstruction of bile flow) results in elevation of the serum AP.
3.5 - 5.2 Serum albumin transports substances in the blood. It can
g/dL assess the functional status of the liver, specifically its
synthetic function.
0.1 - 1.0 Bilirubin is a breakdown pigment of red blood cells.
mg/dL Increased bilirubin occurs with cholestasis.
11.3 - 16.5 Assess the functional status of the liver, specifically its
sec synthetic function.
44
Measures the time needed for blood to clot.
Microscopic examination
of a liver biopsy specimen
usually do ultra sound before biopsy

• In order to determine the patient’s cause and

stages of liver injury, fine-needle aspiration
followed by histological examination is
necessary. study of cells

• A very narrow-bore needle is inserted through

the chest wall and into the liver.
• A specimen is drawn from the liver into the
needle.
• Microscopic examination of a liver biopsy
specimen can reveal characteristic patterns of
inflammation, necrosis, and fibrosis.
45
Hisotologic examination of a liver biopsy
specimen (Hematoxylin & eosin staining)

Normal liver
histology
CV
Zone

Zone Centrilobular
Hepatic (close to CV)
Mid-zonal
artery
Zone (intermediate)

Periportal
(closest to the
PV entry of blood

Bile duct

CV = Central vein or terminal hepatic vein (THV) 46

PV = Portal vein
 Normal liver Fatty liver
Central vein

Portal triad
Empty vacuoles

Cholestastic liver Cirrhotic liver

Bile plug
Nodule

47
Types of hepatobiliary injury
Type of injury or damage Representative toxins

Fatty liver (steatosis) CCl4, ethanol

Cirrhosis Arsenic, ethanol, vitamin A, vinyl

chloride
Hepatocyte death Acetaminophen, CCl4,
(liver cell necrosis) dimethylformamide (purification or
separation solvent in organic synthesis),
ethanol
Tumors Aflatoxin, vinyl chloride

Canalicular cholestasis Chlorpromazine (antipsychotic drug),

cyclosporin A (immune suppressant drug)
Bile duct damage Methylene dianiline (a compound used to
make epoxy resin)
Sinusoidal disorders Anabolic steroids
48
脂肪肝
脂肪積聚

49
 Steatosis (Fatty liver)
• Fatty liver is an excessive accumulation of a type of fat
(triglyceride) inside the liver cells.
• Fatty liver is called steatosis, and fatty liver with liver
inflammation is called or steatohepatitis.
• Steatosis and steatohepatitis can be caused by alcohol and
other drugs.
• Steatohepatitis can progress to cirrhosis.

Fatty acids

50
glycerol Triglyceride
Pathophysiology of fatty Liver
• The mechanism by which these diseases cause fat to accumulate within liver cells
is not known.
• The amount of fatty acid in the liver depends on the balance between the processes of
delivery and removal.
• Excess fat accumulation in the liver could result from increased transportation of
fatty acids from the peripheral organs to the liver, increased hepatic fatty acid
synthesis, impaired hepatic fatty acid oxidation, increased triglyceride synthesis in
the liver, and/or diminished export of triglycerides from the liver.
• Triglycerides are generally exported from the liver by very low-density lipoproteins (VLDL)
particles, which are assembled through a complex process and made of triglycerides,
cholesterol, phosphatidylcholine, and apoproteins.
• Inhibition of the formation of VLDL may result in accumulation of
triglycerides in hepatocytes.
• The resulting buildup of fat within the body is then stored inside the liver cells.
• Fatty liver is a potential pathologic condition and that accumulated fat can sensitize liver to
further injury such as inflammation, cirrhosis and necrosis.
51
Histological examination of fatty liver

Fatty liver
Normal liver

Reddish
brown Yellowish
In the laboratory the liver tissue is processed
for histology by conventional means, fat is
removed by the solvents used, so that in
sections stained with hematoxylin and
eosin, all that remains is an empty
vacuole within the cell.

Empty vacuole

Fatty liver
52
Normal liver
肝硬化
53
 What is cirrhosis?
• Cirrhosis is a complication of many liver diseases that is
characterized by abnormal structure and function
of the liver.
• The diseases that lead to cirrhosis do so because they injure and
kill liver cells, and the inflammation and repair that is associated
with the dying liver cells causes scar tissue to form.
• The liver cells that do not die multiply in an attempt to replace
the cells that have died.
• This results in clusters of newly-formed liver cells (regenerative
nodules) within the scar tissue.
• This results in loss of functioning hepatocytes and a significant
disruption of blood and biliary flow in the liver.
• Chronic consumption of ethanol is a leading cause of liver
cirrhosis in humans, although other chemicals may also cause
this order.
54
 Alcoholic liver cirrhosis
• Early stages of ethanol abuse are characterized by lipid
accumulation (fatty liver) due to diminished use of lipids as
fuels and impaired ability to synthesize the lipoproteins that
transport lipids out of the liver.
• As alcohol-induced liver disease progresses, occasional lipid
release from rupture of distended hepatocytes may produce a
mild localized inflammatory response.
• Appreciable cell death occurs, the functioning mass of the liver
is replaced by scar tissue, and hepatic capacity for
biotransformation of certain drugs progressively declines.
• People with hepatic cirrhosis due to chronic alcohol abuse
frequently become deficient at detoxifying both the ammonia
formed by catabolism of amino acids and the bilirubin derived
from breakdown of hemoglobin.
• Uncontrolled hemorrhage due to inadequate synthesis of
clotting factors is a common fatal complication of alcohol
cirrhosis. 55
Alcoholic cirrhosis 肝硬化 Normal liver

The surface of the liver

displays innumerable
small, regular nodules

CV

Portal
Hyperplastic triad
nodule

56
肝細胞壞死

57
Liver cell necrosis 肝細胞壞死
• Liver necrosis involved the death of hepatocytes.
• The necrosis is often described as being either focal (confined
to a limited area), zonal (centrilobular, midzonal, or periportal),
or massive (virtually all of the cells within a hepatic lobule).
• It is usually an acute injury.
• Necrosis of hepatocytes is characterized by accumulation of
vacuoles in the cytoplasm, damage to endoplasmic reticulum,
swelling of mitochondria, destruction of the nucleus, and
disruption of the plasma membrane.
• A number of chemicals such as CCl4, chloroform, and
acetaminophen have been demonstrated or reported to cause
liver necrosis.
58
 Carbon tetrachloride (CCl4)
• CCl4 is a simple molecule which, when administered to a variety of species, causes
centrilobular hepatic necrosis and fatty liver.
• It is a very lipid-soluble compound and is consequently well distributed throughout the
body, but despite this its major toxic effect is on the liver, irrespective of the route of
administration.
• The reason for the liver being the major target is that the toxicity of CCl4 is dependent on
metabolic activation by the cytochrome P450 system.
• Therefore, the liver becomes the target as it contains the greatest concentration of
cytochrome P450, especially in the centrilobular region which is where the damage is
greatest.
• CCl4 exposure had been shown to produce damage to membranes including smooth and
rough endoplasmic, thus reducing xenobiotic-metabolizing ability as well as reducing
protein synthesis.
• One possible mechanism of injury to hepatocytes is lipid peroxidation.
• Cytochrome P450-dependent conversion of CCl4 to ·CCl3 and then to CCl3OO· is the
classic example of xenobiotic bioactivation to a free radical that initiates lipid peroxidation
by abstracting a hydrogen atom from the polyunsaturated fatty acid of a phospholipid. 59
 CCl4-mediated lipid peroxidation
• Lipid peroxidation is the
initiating reaction in a cascade of CYP2E1

events, starting with the

oxidation of unsaturated fatty
acids to form lipid
in membranes
hydroperoxides, which then
break down to yield a variety of
end products, mainly aldehydes,
which can go on to produce
toxicity in distal tissues.
• For this reason, cellular damage
results not only from the
breakdown of membranes such
as those of the endoplasmic
reticulum, mitochondria, and
(aldehydes)
lysosomes, but also from the
production of reactive aldehydes
60
that can travel to other tissues.
 Mouse treated with corn oil vehicle
Hematoxylin & eosin staining

PT
PT
CV
CV
CV

Mouse treated with 1 ml/kg CCl4 for 24 h

CV

PT CV

PT CV
PT CV

61
Acetaminophen (paracetamol)
• Acetaminophen is a widely used over-the-counter pain reliever
that also has anti-inflammatory and antipyretic properties.
• It is normally safe when taken at therapeutic doses.
• Overdoses, however, may cause an acute centrilobular hepatic
necrosis that can be fatal.
• Although acetaminophen is eliminated primarily (over 90%) by
formation of glucuronide and sulfate conjugates, a small
proportion is metabolized by cytochrome P450 (including CYP2E1)
to a reactive electrophilic intermediate believed to be a N-acetyl-p-
benzoquinoneimine (NAPQI).
• This reactive intermediate is usually inactivated by conjugation
with reduced glutathione and excreted.
62
Metabolism of paracetamol
Detoxification Detoxification
Conjugation Conjugation

(acetaminophen)

Activation (CYP2E1)
(~10%) Inducible by alcohol

Conjugation

63
(NAPQI)
 Acetaminophen (II)
• Higher doses of acetaminophen will progressively deplete hepatic
glutathione levels, however, resulting in extensive covalent binding of
the reactive metabolite to liver macromolecules with subsequent
hepatic necrosis.
• Alcohol induces the cytochrome P450 enzymes (majority CYP2E1).
• Therefore, a relatively larger quantity of the acetaminophen will take
the metabolic pathway to NAPQI.
• Alcoholics have suffered acetaminophen overdose on as little as 4
acetaminophen tablets per day.
• The early administration of sulfhydryl compounds such as N-
acetylcysteine is very effective in preventing the liver damage, renal
failure, and death that would otherwise follow an acetaminophen
overdose.
• These agents are thought to act primarily by stimulating glutathione
synthesis. 64
Liver cell necrosis

65
66
Liver carcinogens
• Chemical toxins may produce liver cancer in humans.
• Many hepatoxicants, including CCl4 and chloroform
have also been shown to be hepatic carcinogens in
laboratory animals.
• Natural chemicals that have been implicated in liver
cancer include aflatoxin.
• The most well known human hepatic carcinogen is
probably vinyl chloride a chemical used in the
manufacture of polyvinyl chloride (PVC).

67
 Vinyl chloride metabolism

P450

Detoxifi-
Tumor cation

68
Hepatocellular carcinoma

69
 Biliary toxicity
Hepatocyte

Lumen of sinusoid

Canaliculi damage
(Canaliculi cholestasis)

Bile duct damage

(Cholangio-destructive
cholestasis)

• Hepatocytes perform an exocrine function through the production and

secretion of bile, and damage to this system leads to cholestasis 70
(stoppage or suppression of the flow of bile) 膽汁鬱積.
膽汁鬱積
71
 Hepatocanalicular cholestasis
• Hepatocytes perform an exocrine function
through the production and secretion of bile.
• Secretion of bile into the canaliculus and its
passage into biliary collecting system is an
active process that depends on a number of
factors.
• Interference with any of these results in
cholestasis.
• Hepatocanalicular cholestasis represents:
– a decrease in bile flow through the
canaliculus and
– a reduction in the secretion of water, bilirubin,
and bile acids by the hepatocytes.
• Many drugs including some tranquilizers 鎮靜
劑, tricyclic antidepressants 抗抑鬱藥, and
steroids 類固醇 are capable of causing 72
cholestasis.
Hepatocellular cholestasis

Deposition of
bile salts and
bilirubin
(bile plugs)

73

The morphological hallmark of hepatocellular cholestasis is the

presence of brownish bile pigment within dilated canaliculi and in
hepatocytes.
Jaundice

Bilirubin

Yellowish discoloration of the eye

resulting from the buildup of bile
pigments such as bilirubin

A consequence of cholestasis is impaired clearance of bilirubin 膽

紅素, a yellow degradation product of heme whose accumulation
leads to jaundice 黃疸. 74
75
 Bile duct damage
• Another name for damage to the intrahepatic bile
ducts is cholangiodestructive 膽管破壞 cholestasis.
• A useful biochemical index of bile duct damage is a
sharp elevation in serum activities of enzymes
localized to bile ducts, particularly alkaline
phosphatase.
• In addition, serum levels of bile salt and bilirubin are
elevated, as observed with canalicular cholestasis.
• Initial lesion following a single dose of
cholangiodestructive agents include swollen biliary
epithelium, debris of damage cells within ductal
lumen, and inflammatory cell infiltration of portal
tracts.
• Methylene dianiline, a compound used to make
epoxy resins, is a noteworthy cause of bile duct
damage. NH2 CH2 NH2

• Small doses of methylene dianiline produce 76

selective bile duct injury.
77
 Liver sinusoidal cells
Kupffer
Sinusoidal cell
lumen
Endothelial
cell

Space of Disse Ito cell

Hepatocytes

78
Bile canaliculi
 Sinusoidal damage
• The sinusoid is a specialized capillary with numerous
fenestrae for high permeability.
• The functional integrity of the sinusoid can be
compromised by dilation or blockade of its lumen or by
progressive destruction of its endothelial cell wall.
• Dilation of the sinusoid will occur whenever efflux of
hepatic blood is impeded.
• Blockage will occur when the fenestrae enlarge to such
an extent that red blood cells become caught in them or
pass through with entrapment in the interstitial space of
Disse.
• Progressive destruction of the endothelial wall of the
sinusoid will lead to gaps and then ruptures of its barrier
integrity, with entrapment of red blood cells.
• Anabolic steroid abuse has been associated with a
rare condition called peliosis hepatis, in which
blood-filled cysts form in the liver. 79
• The cysts sometimes rupture, causing internal bleeding.
Anabolic-androgenic steroids
• Anabolic steroids are synthetic derivatives
of the male hormone testosterone.
• These androgens are prescription drugs
that have legitimate, therapeutic uses.
• They are prescribed for children and
adolescents to treat delayed puberty and
hypogonadism.
• Hypogonadism is usually applied to
permanent defects, usually implies
deficiency of reproductive hormones. 80
Why do people abuse
anabolic steroids?
• One of the main reasons people give for abusing steroids
is to improve their performance in sports.
• Among competitive bodybuilders, steroid abuse has been
estimated to be very high.
• Among other athletes, the incidence of abuse probably
varies depending on the specific sport.
• Another reason people give for taking steroids is to
increase their muscle size and/or reduce their body fat.
• Steroid abuse has been associated with liver tumors and a
rare condition called peliosis hepatis, in which
blood-filled cysts form in the liver.
81
Peliosis hepatis
• Peliosis hepatis is typically an
asymptomatic disorder in which
multiple blood-filled cystic spaces
develop randomly in the liver.
• Measuring a few millimeters to about 3
cm in diameter, the cysts of peliosis
hepatis often lack a cell lining and are
surrounded by hepatocytes.
• Some have an endothelial cell lining
and occur with dilated hepatic
sinusoids.
• The cause is probably damage to the
sinusoidal lining cells.
• Peliosis hepatis is usually
asymptomatic, but occasionally cysts
rupture, resulting in hemorrhage and
sometimes causing death.
•Ultrasound or CT can detect
cysts.
82
83
Hepatotoxicity
THE END

84