Transcript Drug and toxin Induced liver Disease hepatotoxicity from

Drug and toxin Induced
liver Disease
hepatotoxicity from chemicals
Drug Induced liver Disease
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Liver is the mayor detoxifying organ in the
body.
Liver is subjet to potential damage from
pharamceutical and environmental chemicals.
Injury may result from:
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Direct toxicity
Hepatic conversion of chemical.
Immune mechanisms.
Drug Induced liver Disease
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Liver damage from chemicals may be
immediate or take months.
Forms of liver injury:
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Hepatocyte necrosis
Cholestasis
Insidious onset of dysfunction.
Drug induced chronic hepatitis is indistinguishable
from chrinc viral hepatitis
Drug Induced liver Disease
Hepatocelular damage Chemicals
Microvesicular fatty change
Tetracycline, salicylates.
Macrovesicular fatty change Ethanol, methrotexate.
Massive necrosis
Acetaminophen,
insoniazid.
Hepatitis, acute and chronic Methyldopa, phenytoin.
Cholestasis
Anabolic steroids, oral
contraceptives.
Drug Induced liver Disease
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Reye syndrome
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Mitochonrdial dysfuntion in liver and some
other organs.
Predminantly in children given
acetylsalicylic acid cause of fever.
Produces microvesicular steatosis with
severe liver dysfuntion.
Alcholic liver disease
(Ethanol Metabolism)
Epidemiology
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It develop only after a "threshold" dose
600 kg for men and 150 to 300 kg for
women.
one must consume eight 6-oz beers, 1 L of
wine, daily for a period of 20 years
Almost all people who exceed this threshold
dose of ethanol exhibit some biochemical or
histologic abnormality suggestive of liver
injury
Epidemiology
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fewer than 50% of people who ingest
the calculated threshold dose of ethanol
eventually develop serious alcoholic
liver disease (e.g., alcoholic hepatitis or
fibrosis).
This suggest that the pathogenesis
involves hereditary and enviromental
disorders.
Metabolism
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Liver. 3 enzyme systems:
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ADH
MEOS
Catalase.
There exist several isoforms of the ADH
enzyme (alfa, beta and gamma) and its
variation changes the metabolic rate of
ethanol. Asians (beta2) 20% faster.
ADH acts alone when tissue levels do not
exceed 10 mmol/L
MEOS
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Cytochrome P-450 2E1 (CYP2E1)
also the metabolism of other drugs such as
acetaminophen, haloalkanes, and
nitrosamines
Chronic ethanol consumption up-regulates
CYP2E1
CYP2E1-mediated ethanol oxidation yields
reactive oxygen intermediates
These are capable of provoking hepatocellular
damage
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Acetaldehyde is a highly reactive and
potentially toxic compound. It is
metabolized by the ALDH .
Half of Chinese people are deficient of
this enzyme.
Gastric metabolism
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Gastric ADH is implicated in first-pass
metabolism of ethanol
This limit the ethanol delivery to the
portal circulation
This enzyme is lower in Women.
Eventos mórbidos
Oxidant Stress
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DNA is sensitive to oxidant stress.
Mitochondrial DNA is more susceptible
than nuclear DNA to oxidative damage
because of reduced protection by
histone and nonhistone proteins and
because of a decreased capacity for
repair
This causes deletion and mutations in
DNA
Alcoholic hepatitis
Hepatocyte necrosis
Infiltrate of neutrophils
+/- fatty change
+/- Mallory bodies
+/- bile stasis
Alcoholic liver disease
Traditional spectrum of injury
* Fatty change
* Alcoholic hepatitis
* Alcoholic cirrhosis
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MECHANISMS OF TISSUE DAMAGE
2 ways of damage: Indirect
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Ingestion of Ethanol
Increases the release of endotoxins, from the gram
negative bacteria in the natural flora of the intestinal
tract
Kupffer cells release toxic mediators:Reactive Oxygen
Intermediates (ROIs) and Tumor Necrosis Factor
(TNF)
Synergize to cause oxidative damage to hepatocytes.
the inflammatory response.
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Injury on structures of the liver
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A. Mitochondria
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Know as “megamitochondria”
25% of the patient with AAH.
B. citokines.
C. Kupfer Cells
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Secretes high levels of:
TNF-alpha. This is a strong factor for adherence and activation of the
leucocytes.
IL-8- main mediator for neutrophils atraction
D. Alterations of the hepatocelular protein
Aldehide and ethanol change conformation of the surface proteins. In such
way the immune system recognizes them as “Neoantigens
E. Fibrosis Irreversible
Occurs at only 10 – 15% of the alcoholics
Due to activation of the Ito Cells (Fat store cells or
perisinusoids cells) that are at Disse Spece.
Function: normally stores vitamyn A, But en presence of
Ethanol  miofibrobñastic cells and Hipersecretes
collagen fibrosis
This liver is slightly enlarged and has a pale yellow appearance,
seen
both on the capsule and cut surface. This uniform change is
consistent with fatty metamorphosis (fatty change).
Massive hepatomegaly in an elderly alcoholic; the
liver weighed 2010 grams. Note the tinge of yellow.
Micro
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ballooning degeneration of hepatocytes,
inflammation with neutrophils near mallory bodies
Mallory bodies (abnormal perinuclear aggregations of cellular intermediate filament
proteins “citokeratin”).
Mallory's hyaline is seen here, but there are also neutrophils, necrosis of
hepatocytes, collagen deposition, and fatty change. These findings are
typical for acute alcoholic hepatitis. Such inflammation can occur in a
person with a history of alcoholism who goes on a drinking "binge" and
consumes large quantities of alcohol over a short time.
Hyaline Mallory´s Bodies
In globoid hepatocyte. There
Is an interstitial infiltrate of
Neutrophils.
Mallory´s bodies are positive
For CK immunoperoxidase.
Clinical manifestations
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Vomiting
Diarrhea
Jaundice
Psychological disturbances.
Hepatic encephalopathy
Ascites
Bleeding esophageal
Varices (varicose veins in the esophagus), abnormal
blood clotting and coma.
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Main Reason for consulting:
Pathologically, it results in an enlarged liver
Painful to palpation.
Enlargement is due to the accumulation of fat
and the swelling of liver cells, and to the
accumulation of proteins that are normally
secreted.
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Lab
AST to ALT ratio = 2:1
Alkaline Phosphatase elevated
Gamma glutamyl transferase (GGT)
Hypoalbuminemia
Management
Alcohol Cessation
Increased caloric and protein intake
Vitamin supplementation (Thiamine)
Corticosteroids
Prognosis
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Mortality 10-15% from acute hepatitis
Cirrhosis develops in 50% of alcoholic
hepatitis
Alcoholic liver disease
Immediate causes of death:
* massive gastrointestinal
* variceal haemorrhage
* hepatic coma
* infection
* hepatorenal syndrome
Alcoholic Liver Disease.
The End.