5.1 Hepatotoxicity
10 min read•august 20, 2024
The liver, our body's largest internal organ, plays a crucial role in metabolism and detoxification. It processes nutrients, synthesizes proteins, and filters toxins from our blood. Understanding how the liver works is key to grasping the concept of hepatotoxicity.
Hepatotoxicity occurs when substances damage the liver. This can happen through various mechanisms, including , mitochondrial dysfunction, and immune-mediated reactions. Recognizing the signs and causes of liver damage is essential for preventing and treating hepatotoxicity.
Liver anatomy and physiology
- The liver is the largest internal organ in the human body, weighing approximately 1.5 kg in adults and located in the upper right quadrant of the abdomen
- Comprised of two main lobes (right and left) and further divided into eight segments based on blood supply and biliary drainage
- Performs over 500 vital functions, including metabolism of nutrients and drugs, synthesis of proteins and bile acids, and detoxification of endogenous and exogenous substances
- Receives dual blood supply from the hepatic artery (oxygenated blood) and portal vein (nutrient-rich blood from the intestines) which mix in the hepatic sinusoids before draining into the central vein and eventually the inferior vena cava
Mechanisms of hepatotoxicity
Intrinsic vs idiosyncratic reactions
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- Intrinsic hepatotoxicity is and predictable, occurring in most individuals exposed to a sufficient dose of the toxicant ()
- Idiosyncratic reactions are rare, unpredictable, and not clearly dose-dependent, often involving individual susceptibility factors such as genetic polymorphisms or immune-mediated responses (, )
Oxidative stress and lipid peroxidation
- Many hepatotoxicants generate reactive oxygen species (ROS) which can overwhelm the liver's antioxidant defenses and cause oxidative damage to cellular macromolecules
- Lipid peroxidation of polyunsaturated fatty acids in cell membranes leads to formation of reactive aldehydes (, ) that can further propagate oxidative injury and trigger inflammatory responses
- Antioxidants such as glutathione and vitamin E play a critical role in protecting against oxidative stress-induced liver damage
Mitochondrial dysfunction
- Mitochondria are key targets of many hepatotoxicants due to their role in energy production, fatty acid oxidation, and cell death pathways
- Toxicants can disrupt mitochondrial function by inhibiting respiratory chain complexes, uncoupling oxidative phosphorylation, or inducing mitochondrial permeability transition pore opening
- Mitochondrial dysfunction can lead to ATP depletion, oxidative stress, and release of pro-apoptotic factors () into the cytosol
Immune-mediated liver injury
- Certain drugs (diclofenac, halothane) and herbal supplements can trigger immune-mediated liver injury by acting as haptens or priming immune responses
- Activation of innate immune cells (Kupffer cells, natural killer cells) and adaptive immune responses (T-cell mediated cytotoxicity, antibody-dependent cell-mediated cytotoxicity) contribute to liver damage
- Immune checkpoint inhibitors used in cancer immunotherapy (ipilimumab, nivolumab) can also cause immune-related hepatitis
Apoptosis and necrosis
- is a regulated form of cell death characterized by cell shrinkage, chromatin condensation, and formation of apoptotic bodies that are phagocytosed by neighboring cells
- is an unregulated form of cell death characterized by cell swelling, organelle dysfunction, and plasma membrane rupture leading to release of cellular contents and
- Many hepatotoxicants can trigger both apoptosis and necrosis depending on the dose, duration, and cellular context
- Caspase activation and mitochondrial dysfunction are key mediators of apoptotic cell death in the liver
Types of hepatotoxicity
Steatosis and steatohepatitis
- refers to excessive accumulation of triglycerides in hepatocytes, often due to impaired fatty acid oxidation or increased de novo lipogenesis
- Drugs such as valproic acid, tamoxifen, and certain antiretrovirals can induce steatosis by disrupting mitochondrial function or activating lipogenic transcription factors (SREBP-1c)
- Steatohepatitis is characterized by steatosis, inflammation, and hepatocellular injury, and can progress to and cirrhosis if left untreated
- Alcoholic and non-alcoholic steatohepatitis (ASH and NASH) are common forms of steatohepatitis with similar histological features but different etiologies
Cholestasis and biliary injury
- Cholestasis refers to impaired bile flow leading to accumulation of bile acids and other toxic compounds in the liver and systemic circulation
- Drugs such as chlorpromazine, erythromycin, and anabolic steroids can cause cholestasis by inhibiting bile acid transporters (BSEP) or inducing biliary epithelial cell injury
- Biliary injury can manifest as acute cholestatic hepatitis, vanishing bile duct syndrome, or secondary sclerosing cholangitis
- Accumulation of hydrophobic bile acids during cholestasis can exacerbate hepatocellular injury and trigger inflammatory and fibrogenic responses
Fibrosis and cirrhosis
- Fibrosis is characterized by excessive deposition of extracellular matrix proteins (collagen, fibronectin) in response to chronic liver injury and inflammation
- Activated hepatic stellate cells are the primary source of collagen production in the fibrotic liver and can be activated by various cytokines and growth factors (, )
- Cirrhosis represents an advanced stage of fibrosis characterized by distortion of liver architecture, formation of regenerative nodules, and increased intrahepatic resistance to blood flow
- Drugs such as methotrexate, amiodarone, and methyldopa can cause fibrosis and cirrhosis with long-term use or in susceptible individuals
Hepatocellular carcinoma
- (HCC) is the most common primary liver cancer and often develops in the context of chronic liver disease and cirrhosis
- Risk factors for HCC include viral hepatitis (HBV, HCV), abuse, aflatoxin exposure, and certain metabolic disorders (hemochromatosis, alpha-1 antitrypsin deficiency)
- Genotoxic compounds such as and vinyl chloride can directly induce DNA damage and mutations in oncogenes or tumor suppressor genes
- Non-genotoxic carcinogens such as hormones (estrogens, androgens) and peroxisome proliferators (fibrates) can promote HCC development by altering gene expression or cell proliferation
Risk factors for hepatotoxicity
Age and gender
- Elderly individuals may be more susceptible to hepatotoxicity due to age-related changes in drug metabolism, comorbidities, and polypharmacy
- Gender differences in hepatotoxicity have been observed for certain drugs (valproic acid, isoniazid) possibly due to hormonal influences on drug metabolism or immune responses
- Pregnancy can alter drug pharmacokinetics and increase susceptibility to certain types of hepatotoxicity (tetracycline-induced fatty liver, herpes simplex virus hepatitis)
Genetic polymorphisms
- Genetic variations in drug-metabolizing enzymes (CYP450s, UGTs), transporters (BSEP, MRP2), and antioxidant enzymes (GSTM1, GSTT1) can influence individual susceptibility to hepatotoxicity
- Polymorphisms in the HLA genes have been associated with increased risk of idiosyncratic drug-induced liver injury (ximelagatran, flucloxacillin)
- Mutations in genes involved in bilirubin metabolism (UGT1A1) or mitochondrial function (POLG) can predispose individuals to certain types of drug-induced liver injury
Nutritional status
- Malnutrition and micronutrient deficiencies (vitamin E, selenium) can impair the liver's ability to handle oxidative stress and increase susceptibility to hepatotoxicity
- Obesity and (NAFLD) can sensitize the liver to the toxic effects of certain drugs (acetaminophen, methotrexate) and environmental toxicants
- High-fat and high-carbohydrate diets can modulate drug-metabolizing enzyme activity and alter the bioactivation or detoxification of hepatotoxicants
Alcohol consumption
- Chronic alcohol consumption can induce activity and increase the bioactivation of certain hepatotoxicants (acetaminophen, carbon tetrachloride)
- Alcohol can also deplete hepatic glutathione stores and impair the liver's ability to handle oxidative stress
- Alcoholic liver disease can sensitize the liver to the toxic effects of other drugs and environmental exposures
Pre-existing liver disease
- Pre-existing liver diseases such as viral hepatitis, cirrhosis, and cholestasis can alter drug pharmacokinetics and increase the risk of hepatotoxicity
- Patients with advanced liver disease may have impaired drug clearance and require dose adjustments to avoid toxicity
- Certain drugs (nonsteroidal anti-inflammatory drugs, rifampin) can exacerbate pre-existing liver conditions or trigger acute-on-chronic liver failure
Diagnosis of hepatotoxicity
Liver function tests
- Serum aminotransferases (, ) are sensitive markers of hepatocellular injury but lack specificity for etiology
- Alkaline phosphatase (ALP) and gamma-glutamyl transferase (GGT) are markers of cholestatic injury and biliary dysfunction
- Bilirubin, albumin, and prothrombin time reflect hepatic synthetic function and can be impaired in advanced liver disease
- Hy's law (ALT > 3x ULN, total bilirubin > 2x ULN, and ALP < 2x ULN) is a predictor of severe drug-induced liver injury and mortality
Imaging techniques
- is a non-invasive technique for detecting hepatomegaly, steatosis, and biliary obstruction
- Computed tomography (CT) and magnetic resonance imaging (MRI) can provide detailed information on liver morphology, tumors, and vascular abnormalities
- Magnetic resonance cholangiopancreatography (MRCP) is useful for visualizing the biliary tree and detecting biliary strictures or dilatation
- Transient elastography (FibroScan) is a non-invasive method for assessing liver stiffness and fibrosis
Liver biopsy
- is the gold standard for diagnosing and staging liver diseases, including drug-induced liver injury
- Histological features can provide clues to the etiology of liver injury (eosinophilic infiltration, granulomas, cholestasis)
- Special stains (trichrome, reticulin) and immunohistochemistry can help assess fibrosis, inflammation, and specific cell types
- Risks of liver biopsy include bleeding, infection, and sampling error, and it should be performed judiciously in selected cases
Common hepatotoxic agents
Acetaminophen overdose
- Acetaminophen is a widely used analgesic and antipyretic that can cause severe hepatotoxicity when taken in excess (>4 g/day)
- At therapeutic doses, acetaminophen is primarily metabolized by glucuronidation and sulfation, with a small fraction undergoing CYP2E1-mediated bioactivation to the reactive metabolite NAPQI
- In overdose situations, glucuronidation and sulfation pathways become saturated, leading to increased formation of NAPQI which depletes hepatic glutathione stores and binds to cellular proteins
- is an effective antidote for acetaminophen toxicity if administered within 8-10 hours of ingestion
Antituberculosis drugs
- Isoniazid, rifampin, and pyrazinamide are first-line drugs for treating tuberculosis that can cause hepatotoxicity individually or in combination
- Isoniazid undergoes acetylation and CYP2E1-mediated bioactivation to reactive metabolites that can cause oxidative stress and immune-mediated liver injury
- Rifampin is a potent inducer of CYP450 enzymes and can increase the bioactivation of other hepatotoxic agents (acetaminophen, herbal supplements)
- Pyrazinamide can cause dose-dependent hepatotoxicity characterized by a mixed hepatocellular-cholestatic pattern of injury
Anticonvulsants
- Phenytoin, carbamazepine, and valproic acid are commonly used anticonvulsants that can cause idiosyncratic liver injury in susceptible individuals
- Phenytoin and carbamazepine can trigger immune-mediated liver injury, possibly due to formation of reactive metabolites that act as haptens or priming of T-cell responses
- Valproic acid can cause microvesicular steatosis and steatohepatitis by inhibiting mitochondrial beta-oxidation and inducing oxidative stress
- Genetic polymorphisms in drug-metabolizing enzymes (CYP2C9, UGT1A6) and antioxidant pathways (GSTM1, GSTT1) have been associated with increased risk of anticonvulsant-induced hepatotoxicity
Herbal and dietary supplements
- Herbal and dietary supplements are a growing cause of hepatotoxicity due to lack of regulation, variable quality, and potential interactions with conventional medications
- Green tea extract, kava, and certain Chinese herbal medicines (Jin Bu Huan, Ma Huang) have been associated with severe hepatotoxicity and acute liver failure
- Pyrrolizidine alkaloids found in comfrey, butterbur, and other plants can cause sinusoidal obstruction syndrome and veno-occlusive disease
- Anabolic steroids and bodybuilding supplements can cause cholestatic liver injury and increase the risk of hepatocellular adenomas and carcinomas
Environmental toxins
- Aflatoxins are mycotoxins produced by Aspergillus fungi that contaminate crops such as corn, peanuts, and cottonseed
- Aflatoxin B1 is a potent hepatocarcinogen that induces DNA damage and mutations in the p53 tumor suppressor gene
- Heavy metals such as arsenic, cadmium, and mercury can accumulate in the liver and cause oxidative stress, mitochondrial dysfunction, and cellular injury
- Organic solvents (carbon tetrachloride, trichloroethylene) and pesticides (organochlorines, organophosphates) can cause acute and chronic liver damage through various mechanisms
Prevention and management strategies
Dose adjustments and drug monitoring
- Dose adjustments based on liver function tests, age, and comorbidities can help prevent hepatotoxicity in susceptible individuals
- Therapeutic drug monitoring can ensure that drug levels remain within the therapeutic range and avoid toxicity
- Pharmacogenetic testing for certain high-risk drugs (abacavir, carbamazepine) can identify patients with genetic susceptibility to hepatotoxicity
Antidotes and supportive care
- N-acetylcysteine is the antidote of choice for acetaminophen overdose and should be administered as soon as possible after ingestion
- Intravenous carnitine supplementation can be used to treat valproic acid-induced hepatotoxicity by restoring mitochondrial function
- Silymarin, a flavonoid extract from milk thistle, has antioxidant and anti-inflammatory properties and may be useful as an adjunctive therapy for various types of hepatotoxicity
- Supportive care measures (fluid resuscitation, electrolyte correction, coagulopathy management) are essential for managing acute liver failure and preventing complications
Liver transplantation
- is the definitive treatment for end-stage liver disease and acute liver failure refractory to medical management
- Indications for liver transplantation in the context of hepatotoxicity include drug-induced acute liver failure, decompensated cirrhosis, and hepatocellular carcinoma
- Contraindications to liver transplantation include active substance abuse, uncontrolled infections, and extrahepatic malignancies
- Long-term outcomes after liver transplantation for drug-induced liver injury are generally favorable, with 5-year survival rates exceeding 70%
Emerging research and future directions
Novel biomarkers of hepatotoxicity
- MicroRNAs (miR-122, miR-192) are stable, tissue-specific biomarkers that can detect early stages of drug-induced liver injury in serum or plasma
- Glutamate dehydrogenase (GLDH) is a mitochondrial enzyme that is released into circulation during hepatocellular necrosis and may be a more specific marker than ALT
- High-mobility group box 1 (HMGB1) is a nuclear protein that is released by necrotic cells and can activate innate immune responses and inflammation
- Metabolomics and lipidomics approaches can identify novel biomarkers and pathways involved in hepatotoxicity
In vitro and in silico models
- 3D hepatic organoids derived from induced pluripotent stem cells (iPSCs) can model drug-induced liver injury and assess interindividual variability in response
- Organ-on-a-chip devices can simulate the complex interactions between hepatocytes, endothelial cells, and immune cells in a microfl
Key Terms to Review (29)
4-hydroxynonenal: 4-hydroxynonenal (4-HNE) is a highly reactive aldehyde that is produced during the peroxidation of polyunsaturated fatty acids, particularly arachidonic acid. This compound is significant in the context of hepatotoxicity as it can form adducts with proteins and DNA, leading to cellular damage, inflammation, and apoptosis in liver cells.
Acetaminophen: Acetaminophen is a widely used over-the-counter analgesic and antipyretic medication, primarily used to relieve pain and reduce fever. Despite its common usage, it is associated with hepatotoxicity, particularly in cases of overdose or chronic use, which can lead to severe liver damage and failure.
Aflatoxin B1: Aflatoxin B1 is a potent naturally occurring mycotoxin produced by certain molds, particularly Aspergillus flavus and Aspergillus parasiticus. It is primarily associated with the contamination of agricultural products, such as grains and nuts, and is known for its significant hepatotoxic effects, making it a major concern in food safety and public health.
Alcohol: Alcohol refers to a class of organic compounds that are characterized by the presence of one or more hydroxyl (-OH) groups. In the context of toxicology, ethanol is the most commonly studied alcohol due to its widespread consumption and potential for abuse, leading to various health issues. The effects of alcohol on human health are significant, especially concerning liver damage, risks during pregnancy, and developmental impacts on offspring.
ALT: ALT, or alanine aminotransferase, is an enzyme primarily found in the liver that plays a crucial role in amino acid metabolism. Elevated levels of ALT in the blood are often used as a marker for liver damage, indicating potential hepatotoxicity. Understanding ALT levels is essential for assessing liver function and diagnosing various liver conditions, as it reflects hepatocyte injury.
Apoptosis: Apoptosis is a form of programmed cell death that occurs in a regulated and controlled manner, allowing for the elimination of unwanted or damaged cells without causing harm to surrounding tissues. This process is crucial for maintaining cellular homeostasis, development, and responses to cellular stress, linking it to various biological phenomena.
AST: AST, or aspartate aminotransferase, is an enzyme found in various tissues, including the liver, heart, and muscles. It plays a critical role in amino acid metabolism by facilitating the transfer of amino groups from aspartate to alpha-ketoglutarate, ultimately producing oxaloacetate and glutamate. Elevated levels of AST in the bloodstream are often indicative of hepatotoxicity or liver damage, making it an important biomarker for assessing liver health.
Chronic Use: Chronic use refers to the long-term consumption of a substance, often leading to gradual changes in health and function. This prolonged exposure can result in cumulative effects, making it crucial to understand its implications on organs, particularly the liver, where toxicity can manifest over time through various mechanisms like metabolic overload or damage to cellular structures.
Cyp2e1: CYP2E1 is an important enzyme in the cytochrome P450 family that plays a crucial role in the metabolism of various substances, including drugs and toxins. It is particularly significant in the context of hepatotoxicity, as it is involved in the bioactivation of harmful compounds, leading to potential liver damage. CYP2E1 can be induced by chronic alcohol consumption and certain xenobiotics, which may increase its activity and consequently enhance the formation of toxic metabolites that can cause liver injury.
Cytochrome c: Cytochrome c is a small heme protein found in the mitochondria that plays a crucial role in the electron transport chain, facilitating the transfer of electrons between complex III and complex IV. This protein is essential for cellular respiration and energy production, as it helps to generate ATP through oxidative phosphorylation. In the context of hepatotoxicity, cytochrome c is significant because its release from the mitochondria can trigger apoptosis, or programmed cell death, in response to cellular damage from toxic substances.
Diclofenac: Diclofenac is a non-steroidal anti-inflammatory drug (NSAID) used to relieve pain and reduce inflammation. It works by inhibiting the enzymes responsible for producing prostaglandins, which are chemicals that promote inflammation and pain. Despite its effectiveness in managing conditions such as arthritis and acute pain, diclofenac is also associated with potential hepatotoxic effects, which can lead to liver injury in some individuals.
Dose-dependent: Dose-dependent refers to the relationship where the effects of a substance, such as a drug or toxin, vary based on the amount (dose) administered. This concept highlights how increasing doses can lead to increased severity of effects, which is critical in understanding toxicity and therapeutic efficacy.
FDA Guidelines: FDA guidelines are a set of recommendations and regulations established by the U.S. Food and Drug Administration to ensure the safety and efficacy of drugs, biologics, medical devices, and other products. These guidelines help in assessing potential toxic effects, including hepatotoxicity and cardiotoxicity, providing a framework for evaluating risks associated with substances that can cause damage to the liver or heart.
Fibrosis: Fibrosis is the formation of excess fibrous connective tissue in an organ or tissue, often as a result of injury, inflammation, or chronic disease. This process leads to the scarring and stiffening of tissues, which can impair normal organ function and is a common outcome in various forms of hepatotoxicity, particularly in conditions like cirrhosis of the liver.
Hepatocellular carcinoma: Hepatocellular carcinoma (HCC) is a primary malignancy of the liver that arises from hepatocytes, the main functional cells of the liver. This type of cancer is often linked to chronic liver diseases such as hepatitis B and C infections, cirrhosis, and exposure to certain toxins, leading to significant morbidity and mortality worldwide. HCC typically develops in patients with underlying liver damage, emphasizing the importance of understanding hepatotoxicity in both prevention and treatment strategies.
Inflammation: Inflammation is a biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. This process involves the activation of immune cells, release of signaling molecules, and increased blood flow to the affected area, leading to the classic signs of redness, heat, swelling, and pain. Inflammation plays a crucial role in healing but can also contribute to various diseases if it becomes chronic or uncontrolled.
Isoniazid: Isoniazid is an antibiotic primarily used to treat tuberculosis (TB) by inhibiting the synthesis of mycolic acids in the bacterial cell wall. While effective against TB, it is also known for its potential to cause hepatotoxicity, which can lead to significant liver damage, especially in certain populations or under specific circumstances.
Liver biopsy: A liver biopsy is a medical procedure that involves the removal of a small sample of liver tissue for examination under a microscope. This procedure is crucial for diagnosing various liver conditions, including infections, fatty liver disease, and hepatotoxicity, where the liver is damaged due to exposure to toxic substances or drugs. By analyzing the liver tissue, healthcare professionals can assess the extent of liver damage and determine the appropriate treatment options.
Liver transplantation: Liver transplantation is a surgical procedure that involves replacing a diseased or failing liver with a healthy liver from a donor. This procedure is often necessary for patients with end-stage liver disease, acute liver failure, or certain liver cancers, and it highlights the critical importance of the liver in maintaining metabolic functions and detoxifying harmful substances in the body.
Malondialdehyde: Malondialdehyde (MDA) is a reactive aldehyde that is produced as a byproduct of lipid peroxidation, which occurs when free radicals attack lipids in cell membranes. It is often used as a marker for oxidative stress and tissue damage, particularly in the context of liver injury and various forms of hepatotoxicity, as it can indicate the extent of cellular damage caused by toxic substances or metabolic dysfunction.
N-acetylcysteine: N-acetylcysteine (NAC) is a medication and supplement that serves as a precursor to the antioxidant glutathione and is primarily known for its role in treating acetaminophen (paracetamol) overdose. It works by replenishing glutathione levels in the liver, which is essential for detoxifying harmful substances, thus connecting it closely to liver health and overall detoxification processes.
Necrosis: Necrosis is the process of uncontrolled cell death caused by external factors such as injury, infection, or toxins, leading to the breakdown of cellular structures and the release of cellular contents into the surrounding tissue. This process often results in inflammation and can have significant consequences for the affected organ or tissue, disrupting normal function and potentially leading to further complications.
Nonalcoholic fatty liver disease: Nonalcoholic fatty liver disease (NAFLD) is a condition characterized by the accumulation of excess fat in the liver in individuals who consume little to no alcohol. This disease can progress to more severe liver conditions, such as nonalcoholic steatohepatitis (NASH), fibrosis, and cirrhosis. It is associated with metabolic syndrome and poses significant health risks, highlighting the importance of understanding its mechanisms and impacts on liver function.
Oxidative stress: Oxidative stress refers to an imbalance between the production of reactive oxygen species (ROS) and the body's ability to detoxify these harmful compounds or repair the resulting damage. This condition can lead to significant cellular and tissue damage, contributing to various diseases and toxic effects in organs such as the liver, kidneys, brain, heart, and lungs.
PDGF: Platelet-Derived Growth Factor (PDGF) is a protein that plays a crucial role in cell growth, proliferation, and healing, particularly in the context of tissue repair and regeneration. It is secreted by platelets and helps to recruit and activate various cell types, including fibroblasts and smooth muscle cells, to areas of injury, facilitating the repair process. PDGF is especially significant in liver pathology, where it is involved in the fibrogenic response following hepatotoxicity.
REACH Regulations: REACH regulations, which stand for Registration, Evaluation, Authorisation and Restriction of Chemicals, are a European Union initiative aimed at ensuring the safe use of chemicals. The main goal is to protect human health and the environment while promoting alternative methods for the assessment of substances. This framework emphasizes the responsibility of chemical manufacturers and importers to provide comprehensive information about the properties and risks associated with their chemicals, particularly those that could cause hepatotoxicity.
Steatosis: Steatosis is the abnormal accumulation of fat within liver cells, often resulting from various factors such as excessive alcohol intake, obesity, and metabolic disorders. This condition can lead to liver dysfunction and is a precursor to more severe liver diseases, including non-alcoholic fatty liver disease (NAFLD) and cirrhosis. Understanding steatosis is crucial for recognizing the impact of toxins and lifestyle choices on liver health.
Tgf-β: TGF-β, or Transforming Growth Factor Beta, is a multifunctional cytokine that plays a critical role in regulating cell growth, differentiation, and immune responses. It is involved in various biological processes, including inflammation, fibrosis, and tissue repair, making it highly relevant in the context of liver toxicity and hepatotoxicity, as it can influence the liver's response to injury and contribute to the development of fibrosis and cirrhosis.
Ultrasound: Ultrasound is a medical imaging technique that uses high-frequency sound waves to create images of structures within the body. It is commonly used for examining soft tissues and organs, providing real-time imaging that helps in diagnosing various conditions, including those related to hepatotoxicity. The ability to visualize liver anatomy and blood flow plays a crucial role in assessing liver health and potential damage due to toxic substances.