Drug and toxin Induced liver Disease hepatotoxicity from chemicals

1
Drug and toxin Induced liver Diseasehepatotoxic
ity from chemicals
2
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.

3
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

4
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.
5
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.

6
Alcholic liver disease (Ethanol
Metabolism)
7
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

8
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.

9
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

10
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

11
(No Transcript)
12

• Acetaldehyde is a highly reactive and potentially
  toxic compound. It is metabolized by the ALDH .
• Half of Chinese people are deficient of this
  enzyme.

13
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.

14
Eventos mórbidos
15
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

16
(No Transcript)
17
Alcoholic liver disease Traditional spectrum
of injury Fatty change Alcoholic hepatitis
Alcoholic cirrhosis
18

• 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 mediatorsReactive
  Oxygen Intermediates (ROIs) and Tumor Necrosis
  Factor (TNF)
• Synergize to cause oxidative damage to
  hepatocytes.
• the inflammatory response.

19

• 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 protein
• Aldehide and ethanol change conformation of the
  surface proteins. In such way the immune system
  recognizes them as Neoantigens

20

• 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

21
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).
22
Massive hepatomegaly in an elderly alcoholic the
liver weighed 2010 grams. Note the tinge of
yellow.
23
Micro

• ballooning degeneration of hepatocytes,
• inflammation with neutrophils near mallory bodies
• Mallory bodies (abnormal perinuclear aggregations
  of cellular intermediate filament proteins
  citokeratin).

24
(No Transcript)
25
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.
26
Hyaline Mallorys Bodies In globoid hepatocyte.
There Is an interstitial infiltrate
of Neutrophils.
Mallorys bodies are positive For CK
immunoperoxidase.
27
Clinical manifestations

• Vomiting
• Diarrhea
• Jaundice
• Psychological disturbances.
• Hepatic encephalopathy
• Ascites
• Bleeding esophageal
• Varices (varicose veins in the esophagus),
  abnormal blood clotting and coma.

28

• 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.
•  

29

• Lab
• AST to ALT ratio 21
• Alkaline Phosphatase elevated
• Gamma glutamyl transferase (GGT)
• Hypoalbuminemia
• Management
• Alcohol Cessation
• Increased caloric and protein intake
• Vitamin supplementation (Thiamine)
• Corticosteroids

30
Prognosis

• Mortality 10-15 from acute hepatitis
• Cirrhosis develops in 50 of alcoholic hepatitis

31
Alcoholic Liver Disease.The End.