Download 11/17/06

ENVR 430
Hepatic Physiology and Toxicology
Nov 17, 2006
Jane Ellen Simmons, 919-541-7829
[email protected]
Hepatoxicity
Hepatotoxin - of plant, animal or natural origin
Hepatotoxicant - of human origin
Categories of Hepatotoxicants
Type I (intrinsic)
Type II (idiosyncratic)
Characteristics of Type I Hepatotoxins/Hepatotoxicants
• High incidence in the exposed population
• Good correspondence between human and
experimental animal lesions - lesions typical of human
injury are produced in experimental animals
• Predictable dose-response relationship
•Incidence increases with dose
• Severity increases with dose
• Time-response relationship is predictable
• Predictable lesions
• Lesion type is predictable
• Lesion location is predictable
Characteristics of Type II Hepatotoxins/Hepatotoxicants
• Low incidence in the exposed population
• Poor correspondence between human and experimental
animal lesions - lesions typical of human injury are not
reliably produced in experimental animals
• Unpredictable dose-response relationship
•Incidence may not increase with dose
• Severity may not increase with dose
• Time-response relationship may not be predictable
• Unpredictable lesions
• Lesion type may not be predictable
• Lesion location may not be predictable
Types of Lesions Caused by Type I toxins/toxicants
Necrosis
Steatosis
Cholestatis
Sinusoidal damage
Types of Lesions Caused by Type II toxins/toxicants
Necrosis
Steatosis
Cholestatis
Sinusoidal damage
Categories of Lesions
1. Steatosis
2. Necrosis
3. Cholestasis
4. Cirrhosis
5. Sinusoidal damage
6. Tumors
1. Steatosis (aka ‘fatty liver’)
• Characterized by accumulation of lipids in the
liver, more specifically, in the hepatocyte
• Accumulation of triglyceride results in the
formation of fat droplets in the liver
• Liver weight increases with steatosis – increase is
indication of severity – in humans with severe
steatosis, liver weight can increase by 30 – 50 %
and in very severe cases, liver weight can double.
1. Steatosis (aka ‘fatty liver’)
Two principal types
a. microvesicular
- hepatocytes filled with numerous tiny vesicles that
contain fat
- the fat vesicles can be so small they are
overlooked under light microscopy and require
special fat stains to be observed
- less common than macrovesicular (?)
b. macrovesicular
- hepatocytes contain several large droplets of fat
that can become so large the nucleus is
displaced
- observed on hemoxylin and eosin stained
sections as vacuoles – the fixing/staining process
removes fat, leaving the empty vesicle – hence
the term vacuolar degeneration
1. Steatosis (aka ‘fatty liver’)
Possible mechanisms (chemical dependent)
• Imbalance between triglyceride rate of synthesis
and rate of release
• Decreased protein synthesis
• Decreased phospholipid synthesis
• Nonassociation of triglyceride and protein
• Oversupply of free fatty acids to liver
Common response to many hepatotoxic agents.
Usually reversible (does not cause hepatocyte death)
exceptions to this rule
2. Necrosis
Necrosis is cell death. Typically, considering hepatocyte death.
Necrosis is the sum of morphological changes that occur with cell
death inside a living tissue.
Necrosis
Apoptosis
cell enlargement (swelling)
cell shrinkage
non-rapid removal
rapid removal
influx of inflammatory cells
lack of inflammatory response
nuclear disintegration
nuclear fragmentation
plasma membrane leakage
‘lack’ of membrane leakage
Plasma membrane leakage results in elevated serum levels of
AST (aspartate aminotransferase), ALT (alanine
aminotransferase) and SDH (sorbitol dehydrogenase)
2. Necrosis - Characterization of Necrosis by Location
a. Zonal Necrosis – distribution characterized by where
in the lobule or acinus damage is observed
Centrilobular (zone 3) – most frequently observed type
of necrosis
Midzonal (zone 2) – the ill-defined zone between the
centrilobular and the periportal regions. Rare in
humans
Periportal (zone 1) – less common than centrilobular
but more common than midzonal
Generally, but not always, Type I hepatoxicants
produce zonal lesions
2. Necrosis -Characterization of Necrosis by
Location
b. Focal (diffuse) Necrosis – characterized by single
cell necrosis or small clusters of dead cells that
occur randomly throughout the lobule w/o a
distinct zonal relationship
Generally, but not always, Type II hepatoxicants
produce focal lesions
c. Massive (panacinar, panlobular) Necrosis –
necrosis that encompasses entire lobules (acini)
and even lobes.
Massive, diffuse and zonal necrosis appear to have
different pathogenesis.
3. Cholestasis
Cholestasis is stoppage or slowing of the flow of bile.
This results in an increase in the liver and blood
concentration of bilirubin – hyperbilirubinemia
Serum bilirubin:
normal:
0.01 – 1.0 mg/dl serum
jaundice:
2 – 4 mg/dl serum
Jaundice may have many different underlying
mechanisms but the common element is increased
serum bilirubin.
3. Cholestasis
Two major types of cholestasis
intrahepatic - stoppage or slowing of bile
flow within the liver
extrahepatic – stoppage or slowing of bile
flow external to the liver
3. Cholestasis
Intrahepatic cholestasis
Mechanisms
decreased cellular ATP
damage to the canalicular membrane
damage to the intrahepatic bile ducts
(cholangiodestructive cholestasis)
conformational changes to carrier proteins
binding of chemicals to carrier proteins
Canalicular cholestasis – a form of intrahepatic
cholestasis. It is characterized by a decrease in the
volume of bile formed or impaired secretion of
compounds into bile.
3. Cholestasis
Extrahepatic cholestasis mechanisms
most commonly due to mechanical
blockage of bile flow
gallstones
tumors of the extrahepatic biliary tree
fibrosis of the Sphincter of Oddi
4. Cirrhosis
Cirrhosis is scarring of the liver
No universally accepted definition of cirrhosis
Cirrhosis: fibrosis and the associated conversion of
normal liver architecture into structurally
abnormal nodules
If liver injury not too severe, the liver recovers.
Mechanisms of recovery are hypertrophy and
hyperplasia
When injury becomes too severe or chronic, fibrosis
occurs.
4. Cirrhosis
Fibrosis is replacement of hepatocytes with collagen.
Collagen is a dense tough protein that supports and
holds tissue together. Secreted by fibroblasts and Ito
cells.
Fibrous tissue lacks the functions of hepatocytes.
Fibrous tissue lacks the flexibility and elastic
properties of normal tissue
The liver has a large reserve capacity, so at first
fibrosis results in a decrease in the functional reserve
capacity.
Eventually, sufficient fibrosis occurs for overt
cirrhosis to be recognized.
4. Cirrhosis
Consequences of cirrhosis
•Hepatic failure – complete or almost complete
shutdown of the functions of the liver
• Portal hypertension – increased resistance to
venous blood flow from the GI tract through the
liver.
Typically P(portal vein) <<< P(coronary vein)
In portal hypertension
P(portal vein) > P(coronary vein)
With the pressure gradient reversed, blood can’t
flow from the coronary vein to the portal vein
4. Cirrhosis
Under portal hypertension, collateral circulation
develops. Blood that normally flows through the liver is
shunted into small blood vessels (anastomoses) that
connect the arterial and the venous blood systems.
Development of Esophageal Varices
Normal Blood Flow
Coronary vein > portal vein > liver > inferior vena cava > heart
Collateral Circulation
Coronary vein > esophageal varices > azygous vein > superior vena cava >
heart