Drug and toxin Induced liver Disease

hepatotoxicity from chemicals

Drug Induced liver Disease Liver is the mayor detoxifying organ in

the body. Liver is subjet to potential damage from

pharamceutical and environmental chemicals.

Injury may result from: Direct toxicity Hepatic conversion of chemical. Immune mechanisms.

Drug Induced liver Disease Liver damage from chemicals may be

immediate or take months. Forms of liver injury:

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

Reye syndrome 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 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

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 Liver. 3 enzyme systems:

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 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

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

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

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

MECHANISMS OF TISSUE DAMAGE 2 ways of damage: Indirect  

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.

Injury on structures of the liver

A. Mitochondria Know as “megamitochondria” 25% of the patient with AAH. B. citokines. C. Kupfer Cells

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 proteinAldehide 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

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. ThereIs an interstitial infiltrate ofNeutrophils.

Mallory´s bodies are positiveFor CK immunoperoxidase.

Clinical manifestations Vomiting Diarrhea Jaundice Psychological disturbances. Hepatic encephalopathy Ascites Bleeding esophageal Varices (varicose veins in the esophagus),

abnormal blood clotting and coma.

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.

 

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

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.