Liver and its toxic responses... liver cell death, cholestasis, ductal damage, sinusoidal damage and liver cancer

1. TOXIC REPONSE
OF
LIVER
RVS Chaitanya Koppala
Assistant professor
Vignan Institute of Pharmaceutical Technology
Visakhapatnam

2. TOXIC RESPONSE OF LIVER
Liver is the largest internal organ of the body where exogenous chemical are
metabolized and eventually excreted. It is the first port of call for ingested nutrients, vitamins,
metals, drugs and environmental toxicants as well as waste bacterial products that enter portal
circulation.
Acute or chronic exposure to chemicals can leads to liver dysfunction, cell injury and even
organ failure. The liver responds to chemical insult in different ways depending upon the type
of exposure (acute/chronic), intensity and the population of cells affected. The major toxic
responses of the liver were discussed below.
1. Fatty liver (steatosis):
 It is a reversible condition characterized by accumulation of fat (mainly triglycerides)
in liver cells. Biochemically, it is described as increased in hepatic lipid content to more
than 5% of the organ weight. It can stem from disruptions in fat metabolism.
 Obesity and sedentary lifestyle or upon acute exposure to hepatoxicants (E.g. CCl4) and
certain drugs. Among drugs, excessive intake of alcohol is most commonly associated
to liver fatty liver.
 Fatty liver does not lead to cell death but may be accompanied by progressive
inflammation called steatohepatitis.
2. Liver cell death:
 Death of liver cells typically takes place via apoptosis or necrosis. It can occur in focal
(single or small cluster), zonal (specific zones) or panacina (massive death of most
hepatocytes) patten.
 Apoptotic cell death is characterized by membrane blebbing, cell shrinkage, nuclear
collapse and formation of apoptotic bodies which are later engulfed by WBCs. In
contrast, necrosis is characterized by nuclear disintegration and an influx of
inflammatory cells.
 Mechanism by which toxicant cause hepatocyte death includes lipid peroxidation,
mitochondrial damage, ATP depletion, Ca influx, cytoskeletal derangement, cell
blebbing and cell lysis.

3. 3. Cholestasis:
 Physiological, cholestasis denotes a decrease in volume of bile formed or disruption in
secretion of specific solutes into bile.
 Bile helps emulsify the fats and rid the circulation of endogenous waste products,
xenobiotics and their metabolites. These cores hepatic function is disrupted by some
specific hepatotoxicants as a result of which bile substances (particularly bile and
bilirubin) that are normally excreted in bile accumulate in liver and escape into blood.
 When hepatic clearance of bilirubin and biliverdin is impaired, they accumulate in blood
and blood tissues like skin, eyes causing jaundice.
 Structural changes include dilation and presence of bile plugs in canaliculi or bile ducts.
 Many toxoids cause cholestasis. Six potential mechanism for toxicant induced
cholestasis have been identified.
a) Impaired hepatic intake
b) Impaired secretion
c) Decreased canalicular contractility
d) Decreased transcytosis
e) Leaky paracellular junctions
f) Concentrations of reactive forms of chemicals in the peri canalicular area.
 Toxicant may produce cholestasis by a single or multiple mechanism. Example,
chlorpromazine alters bile acid uptake and canalicular contractility, unresolved
cholestasis can lead to cell swelling. Cell death and inflammation.
4. Bile duct damage:
 Mechanical blockage of intrahepatic bile ducts that transport bile from the liver to the
GIT is termed as cholangio destructive cholestasis.
 It is characterized biochemically by elevated serum levels of alkaline phosphate, bile
salts and bilirubin. The changes consist of swollen biliary cells within biliary tract,
accumulation of debris of damaged cells within biliary tract lumen and inflammatory
cell infiltration of postal tracts.
 Administration of chemicals in large doses may leads to biliary proliferation and fibrosis
similar to cirrhosis. Rarely, vanishing bile duct syndrome (i.e. loss of bile ducts) has
also been reported.

4. 5. Sinusoidal damage:
 Liver sinusoids are specialized capillaries lined by this discontinuous endothelium with
numerous fenestrae for greater penetration/ permeation.
 They serve as a site for mixing of O2 rich and nutrient rich blood from hepatic artery
and portal vein respectively
 Sinusoidal damage is considered as early sign of vernacular disease caused upon
exposure to pyrrolizidine alkaloids. Functioning of sinusoids Is impaired in the
following conditions.
 Dilation of sinusoidal lumen: this occurs when hepatic blood flow is blocked. It has
been linked to exposure to anabolic steroids.
 Blockade of sinusoidal lumen: this occurs because when sinusoids become engorge
with RBCs due to enlargement of fenestrae. Such changes have been associated with
acetaminophen overdose.
 Progressive destruction of endothelial cell wall: damage to endothelial cell wall of
sinusoids leads to loss of membrane integrity.
6. Fibrosis and cirrhosis:
 Cirrhosis may define as chronic injury to the liver involving fibrosis of hepatic cell
within in the liver accompanied with regenerative nodule formation.
 The nodules protrude and make the surface of liver uneven and turn it into pale brown.
Cirrhosis may be due to various causes and lead to decreased hepatic function.
 Almost all the chronic disease progress to cirrhosis. Cirrhosis initiate with in the release
of cytokines during inflammation and necrosis of hepatocytes.
 These cytokines stimulate fibrogenesis. After subsiding of inflammation, the destroyed
liver tissue gets replaced by fibrous tissue. The fibrous tissues lead to a consequent loss
of normal function, later hyperplasia of hepatocytes occurs leads to the formation of
nodules consisting of hepatocytes confined within sheet of fibrous tissue.
 As the condition progresses, there is a decreased flow of blood to the liver leading to a
rise in portal pressure. This is known as portal hypertension which can leads to severe
complications such as ascites, esophageal varices, hepatic encephalopathy and rarely
hepatorenal syndrome.

5. 7. Liver cancer:
 Chemically induced liver cancer arises from hepatocytes, bile duct progenitor cells, the
ductular bipolar progenitor cells, periductular stem cells and rarely sinusoidal lining
cells, it has been associated with abuse of alcohol, androgens, exposure to radioactive
thorium dioxide and a high prevalence of aflatoxin contaminated diet.
Types of injury Toxicants involved
Fatty liver Ethanol, CCl4, valproic acid
Hepatocyte death Ethanol, allyl alcohol, copper, acetaminophen, DMF
Cholestasis Cyclosporin A, estrogens, manganese, chlorpromazine
Bile duct damage Amoxicillin, alpha naphthyl isocyanate, sporidesmin
Sinusoidal damage Cyclophosphamide, microcystin, anabolic steroids
Fibrosis and cirrhosis CCl4, ethanol, Vit A, vinyl chloride
Liver cancer Androgens, arsenic, thorium, aflatoxin