Liver

How to detect cell death of liver

Histopathology

Molecular markers

What enzymes leak after hepatocyte necrosis

• ALT

• AST

What causes sinusoidal/vascular damages

Blockages of its lumen ie after large doses of paracetamol cause RBCs to get caught in the sinusoids

or destruction of its endothelial wall ie Monocrotaline

What can be the result of paracetamol and monocrotaline toxcity

• Disturbed blood flow causes ischaemia

• centrilobular necrosis

What is cholangiodestructive cholestasis

Damage to the intrahepatic bile ducts

• Increase levels of bile salts and biliruben

• Swollen biliary epithelial cells and debris of damaged cells in lumen

What is directly toxic to bile ducts?

Naphthylisothiocynate

What is fatty liver diease

It’s a reversible condition where larger deposits fo trglyceride fat accumulate in cells also known as steatosis

What causes steatosis

• bad diet

• excessive alcohol consumption

• CCl4

• Chloroform

How does alcohol induce steatosis

• increased NADH: NAD ratio caused decreased synthesis of lipoproteins

• NADH/NAD+ ratio, which promotes fatty acid synthesis and inhibits fatty acid oxidation in hepatocytes.

• This metabolic shift leads to an accumulation of triglycerides in liver cells.

What is hepatitis

Inflammation of the liver

Innate immune response

• DAMPs activate macrophages which release cytokines that can damage cells

• ie IL-8 attract neutrophils that in turn produce ROS that damage cells

Adaptive immune responses

• hepatic protein adducts can become antigenic and stimulate antibody production and activation of complement system

• repeated exposure to certain chemical may result in the development of an immune response

Hepatic fibrosis

Chronic liver injury leads to excessive collagen which forms scars around the sinusoids and portal tracts by hepatic stellate cells

Cirrhosis

When those scars disrupt liver architecture and compromise or destroy liver function

• reduced ability to detoxify xenobiotics, cellular waste, produce bile, metabolize drugs and produce plasma proteins

• Not reversible and requires transplantation

What is the name of liver cancer

hepatocellular carcinoma

• Mainly due to alcohol

Afltoxin

• Hepatic carcinogen

• By-product of fungal contamination of foodstuffs

• causes DNA damage and mutations of the p53 gene

• Humans are exposed to aflatoxin through the ingestion of mouldy foods found in susceptible grains

What are canalculi

form channels between the hepatocytes

How are lipophilic cationic toxins exported from the gall bladder

MDR transporters

Age

decreased clearance

more drug-drug interactions

reduced hepatic blood flow

infections and liver disease

Alcohol

• Induction of liver injury, cirrhosis, inflammation

• causes a reduction in glutathione

• alters metabolic enzyme activity

Types of damage leading to liver injury

Protein modification- paracetamol

lipid peroxidation- paracetamol, CCl4

DNA modification- Aflatoxins

Zone 1:

Higher oxygen levels = higher levels of B-oxidation of fats

• higher levels of GSH

• Higher levels of alcohol dehydrogenase

Zone 2

Beryllium

Zone3

• Higher levels of CYP

• less GSH

• Higher levels of lipid synthesis

• Paracetamol and CCI4