Hepatotoxicity

1. HEPATOTOXICITY
Jinu Janet Varghese
4th Group, 3rd Year
TSMU

2. Introduction
Liver plays a key role in detoxifying harmful
substances that you may eat, drink, inhale or rub
on your skin. However, the liver is no match for
certain toxins, including some common
medications. Toxic hepatitis is liver inflammation
that occurs when your liver is damaged by toxic
chemicals, drugs or certain poisonous
mushrooms.

3. Located in the right upper quadrant of the abdominal
cavity, resting just below the diaphragm. The liver lies to
the right of the stomach and overlies the gallbladder.

4. Mechanism of liver damage
• Due to its unique metabolism and close relationship with the
gastrointestinal tract, the liver is susceptible to injury from drugs and
other substances.
• 75% of blood coming to the liver arrives directly from gastrointestinal
organs and then spleen via portal veins which bring drugs and xenobiotics
in concentrated form.
• Several mechanisms are responsible for either inducing hepatic injury or
worsening the damage process.
• Many chemicals damage mitochondria, an intracellular organelle that
produce energy.
• Its dysfunction releases excessive amount of oxidants which in turn
injures hepatic cells.
• Injury to hepatocyte and bile duct cells lead to accumulation of bile acid
inside liver. This promotes further liver damage.
• Non-parenchymal cells such as Kupffer cells, fat storing stellate cells and
leukocytes (i.e. neutrophil and monocyte) also have role in the
mechanism.

5. Signs and symptoms:-
• Yellowing of the skin and whites of the eyes
(jaundice)
• Fatigue
• Loss of appetite
• Nausea and vomiting
• Weight loss
• Dark or tea-colored urine

6. AGENTS WHICH CAUSE OF LIVER DAMAGE
• Toxins - Drugs, Chemicals, Fe,Cu, alpha-1-AT.
• Ischaemia - venous or arterial thrombosis,
hypertension.
• Infection - viral,protozoal, bacterial.
• Immunological - autoimmune, response to infection.
• Cholesterol or triglycerides can accumulate (such as
in steatosis; steat=fat + osis=accumulation).
• Obstruction of bile flow (such as in cholestasis:
chole=bile + stasis=standing).

7. Drugs causing Liver damage
• Acetaminophen:-
(Paracetamol, also known
by the brand name Tylenol
and Panadol) is usually well
tolerated in prescribed dose
but overdose is the most
common cause of drug
induced liver disease and
acute liver failure
worldwide. Acetaminophen (3D structure)
overdose is the most common cause
of drug induced liver disease

8.  Nonsteroidal anti-inflammatory drugs- Aspirin,
phenylbutazone, ibuprofen, sulindac, phenylbutazone,
piroxicam, diclofenac and indomethacin.
 Glucocorticoids- Glucocorticoids are so named due to
their effect on carbohydrate mechanism. they promote
glycogen storage in liver. The classical effect of prolonged
use both in adult and paediatric population is steatosis.
 Isoniazid- Isoniazide (INH) is one of the most commonly
used drug for tuberculosis; it is associated with mild
elevation of liver enzymes in up to 20% of patients and
severe hepatotoxicity in 1-2% of patients

9. • Natural products- Amanita
mushroom, particularly the
destroying angels, aflatoxins.
• Industrial toxin- Arsenic,
Carbon tetraChloride, Vinyl
Chloride.
• Herbal and alternative
remedies- Ackee fruit,
Camphor, Pyrrolizidine
alkaloids, Horse chestnut leaf,
Valerian, Comfrey (often used
in herbal tea).

10. Forms of liver toxicity:-
 Zonal Necrosis- This is the most common type of
drug induced liver cell necrosis where the injury
is largely confined to a particular zone of the
liver lobule.
 Hepatitis- Disease of the liver causing
inflammation.
 Cholestasis- Cholestasis is a condition where bile
cannot flow from the liver to the duodenum.
 Steatosis- Steatosis is a condition characterised
by the build up of fat within the liver, sometimes
triggering inflammation of the liver

11. • Granuloma- A granuloma is one of a number
of forms of localized nodular inflammation
found in tissues.
• Vascular lesions- They result from injury to
the vascular endothelium.
• Neoplasm- Neoplasm or tumor, tissue
composed of cells that grow in an abnormal
way.

12. Complications:-
Except for gallstone disease and some viral infections
such as Hepatitis A and infectious mononucleosis, most
liver diseases are managed and not cured.
Liver disease can progress to cirrhosis and liver failure.
Associated complications may include increased risk of
bleeding and infection, malnutrition and weight loss, and
decreased cognitive function.
Some liver diseases are associated with an increased risk
for developing liver cancer

13. CELLULAR TARGETS OF LIVER DAMAGE
• HEPATOCYTES - Paracetamol toxicity;Viral Hepatitis
• BILE DUCTS - Primary Biliary Cirrhosis, Sclerosing
Cholangitis.
• ENDOTHELIAL CELLS - Drugs.

14. Treatment:-
 No specific treatment exists for most kinds of toxic
hepatitis
For most other cases of drug-induced toxic hepatitis,
stopping the medication is the only treatment.
Other treatments include:
 Supportive therapy. People with severe symptoms are
likely to receive supportive therapy in the hospital,
including intravenous fluids and medication to relieve
nausea and vomiting.
 Liver transplant. When liver function is severely impaired,
a liver transplant may be the only option for some people

15. Images showing liver damage

16. Images(contd.)

17. Ultrastructural Images

18. Images (contd.)

19. References
• Wikipedia:
http://en.wikipedia.org/wiki/Liver_disease
• Medicine Net:
http://www.medicinenet.com/liver_disease/article.• Robbins Basic Pathology
• Google Images

20. THANKS