What is liver injury?

Liver injury refers to damage or impairment of liver function due to various causes, resulting in structural and functional abnormalities within the liver tissue. Liver injury can range from mild, reversible damage to severe, life-threatening conditions, depending on the extent and duration of the insult.


Causes of liver injury include:


  • Viral Hepatitis: Infections with hepatitis viruses, such as hepatitis A, hepatitis B, hepatitis C, hepatitis D, and hepatitis E, can cause acute or chronic inflammation of the liver, leading to liver injury and hepatocellular damage.


  • Alcohol: Chronic alcohol consumption can result in alcoholic liver disease, characterized by fatty liver (steatosis), alcoholic hepatitis (inflammation of the liver), fibrosis (accumulation of scar tissue), and cirrhosis (irreversible scarring of the liver tissue).


  • Non-alcoholic Fatty Liver Disease (NAFLD): Accumulation of fat in the liver, often associated with obesity, insulin resistance, metabolic syndrome, and dyslipidemia, can lead to non-alcoholic fatty liver disease (NAFLD), which encompasses a spectrum of conditions ranging from simple fatty liver to non-alcoholic steatohepatitis (NASH) and cirrhosis.


  • Medications and Drugs: Certain medications, drugs, and toxins can cause liver injury, either through direct hepatotoxic effects or idiosyncratic reactions. Common hepatotoxic agents include acetaminophen (paracetamol), nonsteroidal anti-inflammatory drugs (NSAIDs), certain antibiotics, antiepileptic drugs, and herbal supplements.


  • Autoimmune Disorders: Autoimmune hepatitis, primary biliary cholangitis, and primary sclerosing cholangitis are autoimmune disorders characterized by immune-mediated inflammation and damage to liver tissue, resulting in liver injury and dysfunction.


  • Metabolic Disorders: Metabolic disorders, such as hemochromatosis (excessive iron accumulation), Wilson’s disease (copper accumulation), alpha-1 antitrypsin deficiency, and glycogen storage diseases, can lead to liver injury and hepatocellular damage.


  • Vascular Disorders: Vascular disorders affecting the liver, such as Budd-Chiari syndrome (obstruction of hepatic veins) and portal vein thrombosis, can cause liver injury and impair blood flow to the liver tissue.


What is the relationship between liver injury and oxidative stress?

The relationship between liver injury and oxidative stress is significant and intricate. Liver injury, regardless of its cause, often involves the generation of reactive oxygen species (ROS) and the imbalance between pro-oxidants and antioxidants, leading to oxidative stress. Here’s how liver injury and oxidative stress are interconnected:


  • ROS Production: Liver injury triggers the production of reactive oxygen species (ROS) within hepatocytes (liver cells) and other liver resident cells. ROS, including superoxide anion (O2−), hydrogen peroxide (H2O2), and hydroxyl radical (OH·), are highly reactive molecules that can cause oxidative damage to lipids, proteins, and DNA within liver cells.


  • Mitochondrial Dysfunction: Liver injury, such as that caused by alcohol consumption, viral hepatitis, or drug toxicity, can lead to mitochondrial dysfunction. Mitochondria are the primary sites of ROS generation within cells, and impaired mitochondrial function can result in electron leakage from the respiratory chain, leading to increased ROS production and oxidative stress.


  • Inflammation: Liver injury is often associated with inflammation, characterized by the infiltration of immune cells and the release of pro-inflammatory cytokines and chemokines. Inflammatory processes can stimulate the production of ROS by activating immune cells, such as macrophages and neutrophils, and inducing the expression of NADPH oxidases (NOX) and inducible nitric oxide synthase (iNOS), which generate ROS as byproducts.


  • Activation of Hepatic Stellate Cells: Liver injury can activate hepatic stellate cells (HSCs), which play a central role in the pathogenesis of liver fibrosis and cirrhosis. Activated HSCs produce ROS as part of their fibrogenic response, leading to oxidative stress and contributing to the progression of liver injury and fibrosis.


  • Hepatocellular Damage: Liver injury results in hepatocellular damage and necrosis, releasing intracellular components, such as cytochrome c and ROS, into the extracellular environment. ROS released from damaged hepatocytes can further exacerbate oxidative stress and induce oxidative damage to neighboring cells and tissues.


  • Impaired Antioxidant Defenses: Liver injury can impair the antioxidant defense mechanisms that protect cells from oxidative damage. Antioxidant enzymes, such as superoxide dismutase (SOD), catalase, and glutathione peroxidase, may be depleted or dysfunctional in the setting of liver injury, reducing the capacity of the liver to neutralize ROS and mitigate oxidative stress.


  • DNA Damage and Cell Death: Oxidative stress resulting from liver injury can cause DNA damage and promote apoptotic or necrotic cell death pathways. ROS-induced DNA damage can lead to mutations and genomic instability, contributing to the development of liver cancer and other complications of liver injury.


Overall, oxidative stress is a common feature of liver injury and contributes to the progression of liver disease by promoting inflammation, fibrosis, cell death, and DNA damage.