HEPATOTOXICITY

Jinu Janet Varghese4th Group, 3rd Year

TSMU

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.

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.

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.

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

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).

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

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

• 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).

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

• 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.

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

CELLULAR TARGETS OF LIVER DAMAGE

• HEPATOCYTES - Paracetamol toxicity;Viral Hepatitis

• BILE DUCTS - Primary Biliary Cirrhosis, Sclerosing Cholangitis.

• ENDOTHELIAL CELLS - Drugs.

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

Images showing liver damage

Images(contd.)

Ultrastructural Images

Images (contd.)

References

• Wikipedia: http://en.wikipedia.org/wiki/Liver_disease

• Medicine Net: http://www.medicinenet.com/liver_disease/article.htm

• Robbins Basic Pathology• Google Images

THANKS