Minor term - liver
45 important questions on Minor term - liver
What role does the liver play in metabolism and bioavailability?
- Most metabolism of food and drugs occurs in the liver
- Primary organ for metabolizing and excreting exogenous chemicals.
- High chemical exposure can lead to liver dysfunction, cell injury, and organ failure (hepatotoxicity).
What are the stages in the progression of liver disease due to unbalanced diets or drug intake?
- Healthy liver
- Fatty liver: Enlarges with fatty deposits in cells.
- Fibrosis liver: Tissue replaced by connective tissue.
- Cirrhosis liver: Connective tissue growth, restructuring, necrosis.
- Liver cancer: Malignant transformation of hepatocytes.
What are the functions and characteristics of the liver?
- Located in the upper-right abdominal cavity
- Second largest organ (1.5 kg)
- Metabolic and detoxifying roles
- Produces bile for fat absorption and waste excretion
- Blood filtration rate: ~1.8 L/min (men), ~1.5 L/min (women)
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What are some key anatomical features of the liver?
- Cone-shaped and weighs 1.5 kg
- Contains ~450 ml blood
- Composed primarily (~80%) of hepatocytes
- Located on top of the stomach and gallbladder
- Divided into left and right lobes
- Has a dual blood supply
What are the features of the liver's dual blood supply?
- First pass clearance
- Portal vein: 70% of blood; nutrient/pathogen-rich, oxygen-deprived; from GI tract
- Hepatic artery: 30% of blood; oxygen-rich; systemic
- Hepatic vein: Venous blood exit
What are the key functions of the liver related to metabolism and storage?
- Metabolic Homeostasis:
- - Glucose metabolism
- - Cholesterol metabolism
- - Lipid distribution
- - Protein (Nitrogen) metabolism
- Storage and Regulation:
- - Vitamin A storage
- - Blood volume regulation
- Other Functions:
- - Bile production
- - Clearance of xenobiotics
What is the flow of blood and bile in liver architecture?
- Blood flows from portal region to central region via liver sinusoids.
- Bile flows from central to portal region in bile ductules.
- Portal region includes branches of portal vein and hepatic artery.
What are the zonation of metabolic processes in the lobule?
- Zone 1: High oxygen concentration, TG synthesis, β-oxidation
- Zone 2: Lipogenesis/Ketogenesis, Gluconeogenesis, Glycolysis
- Zone 3: Glycogen synthesis from lactate, glucose, Ureagenesis
What is the function of liver sinusoids and their structural features?
- Blood flows from the portal area to the central vein via sinusoids.
- Sinusoids are larger and more irregular than normal capillaries.
- They are lined by endothelial cells with fenestrae (pores).
- Fenestrae facilitate the exchange of metabolites like glucose between blood and hepatocytes.
What are the main functions and characteristics of hepatocytes in the liver?
- Hepatocytes make up approximately 80% of the liver's volume.
- There are about 130 million hepatocytes per gram of liver.
- Functions include:
- - Glucose, lipid, and protein metabolism.
- - Bile synthesis.
- - Detoxification.
What are the components of the liver's non-parenchymal cells?
- Liver Sinusoidal Endothelial Cells (LSEC)
- Stellate cells:
- - Fibroblasts containing 80% of total body vitamin A.
- Kupffer cells (macrophage)
- Dendritic cells
- Cholangiocytes (bile duct)
What are the key components of liver anatomy shown?
- Liver: Central organ with hepatic ducts.
- Right and left hepatic ducts: Drain bile.
- Hepatic portal vein: Blood supply.
- Common hepatic duct: Bile flow.
- Gallbladder: Stores bile.
- Stomach and pancreas: Nearby organs.
Describe the components of the portal triad shown.
- Portal triad: Includes branches of bile duct, hepatic portal vein, and hepatic artery.
- Reticuloendothelial cell: Part of defense.
- Hepatic sinusoid: Blood channel.
- Hepatocyte: Liver cell.
Where is bile synthesized and what does it contain?
- Synthesized by hepatocytes
- Contains bile acids, water, lipids, and bilirubin
- Specialized function of the liver
What is the role of bile in nutrient uptake and excretion?
- Essential for uptake of lipid nutrients from the small intestine
- Bile acids assist uptake of fat and fat-soluble vitamins (A, D, E, K)
- Serves as an excretion route for xenobiotic compounds
What is the process of enterohepatic circulation of bile salts?
- Bile enters the intestine via the common bile duct.
- Bile salts emulsify fats and fat-soluble compounds, aiding absorption by micelle formation (chylomicrons).
- Waste products are excreted in feces.
- Bile salts cycle 5-7 times a day and are efficiently reabsorbed in the ileum, with only 5% lost in feces per day.
How do chylomicrons enter systemic circulation and what compounds bypass first-pass clearance?
- Chylomicrons enter systemic circulation through the lymphatic system.
- They bypass first-pass clearance.
- Bile salts and water-soluble compounds return to the liver via the portal vein.
- Lipophilic compounds (LogP > 5) use the lymphatic system to bypass first-pass clearance.
What is the first-pass effect/elimination?
- A pharmacological phenomenon
- Drug metabolism occurs at a specific body location
- Reduces drug concentration and bioavailability
- Varies by patient (genetics, gender)
- Bypass by altering route, formulation, or dose
Where do Phase I and Phase II reactions occur, and how are xenobiotics transported?
- Occur in hepatocytes.
- Xenobiotics transported via multi-drug transporters: OATP, MRP, MDR.
- Transporters facilitate bioconversion, conjugation, and excretion.
- Examples: OATP1A2, OATP1B1, MDR1, MRP4.
What are the key roles and characteristics of Phase I enzymes?
- Superfamily of proteins for detoxification.
- Responsible for ~75% of drug metabolism.
- Consists of thousands of different CYP450 enzymes.
- Involves oxidation (via cytochrome P450), reduction, and hydrolysis reactions.
- Converts drugs to polar metabolites by adding functional groups (e.g., -OH, -SH, -NH2).
What are the major functions of the liver?
- Biotransformation: Processes ammonia, hemoglobin, drugs, xenobiotics.
- Storage: Stores glucose, vitamins, glycogen, lipids.
- Synthesis: Produces albumin, growth factors, urea.
What is the role of the liver in drug metabolism?
- Majority of drug metabolism occurs in the liver.
- It involves activation/inactivation of toxic substances/drugs.
- First pass metabolism occurs when oral medications are processed by the liver before reaching systemic circulation.
How is codeine bio-activated and what are its active metabolites?
- Codeine is a prodrug activated by cytochrome P450 (CYP2D6).
- Active metabolites include:
- - 6-glucuronide
- - Morphine (5% conversion)
- - Norcodeine
What are the possible problems associated with high CYP2D6 activity?
- Abnormally high CYP2D6 activity
- Enhanced morphine production
- Lethal effects in hypermetabolizer children with codeine (Koren et al., 2006)
- Death of a breast-fed baby from a mother using codeine (Kelly et al., 2012)
- Affects the respiratory system
How is acetaminophen metabolized and what risks are associated with it?
- Acetaminophen is primarily conjugated (80-90% non-toxic).
- Small amount processed by CYP450 into NAPQI (toxic).
- NAPQI is inactivated by conjugation with glutathione (GSH).
- Chronic alcohol use lowers GSH, increasing NAPQI risk.
What factors influence the liver's response to chemical exposure in toxin-induced injury?
- Intensity of exposure
- Cell population affected
- Duration: acute vs. chronic exposure
What are some representative toxins for fatty liver and fibrosis?
- Fatty liver toxins: Amiodarone, CCl₄, ethanol, tamoxifen, valproic acid
- Fibrosis and cirrhosis toxins: CCl₄, ethanol, thiocetamide, vitamin A, vinyl chloride
What are the three enzymatic pathways to metabolize ethanol in the liver?
- Cytochrome p450 (MEOS)
- Alcohol dehydrogenase (ADH)
- Catalase
These pathways convert ethanol to acetaldehyde, then to acetate.
What is the role of CYP2E1 in ethanol metabolism?
- CYP2E1 increases reactive oxygen species (ROS) formation.
- Leads to oxidative stress in hepatocytes.
What is significant about ALDH2 and its polymorphisms?
- Polymorphisms with reduced ALDH2 activity are common in the Asian population.
- ALDH2 converts acetaldehyde to acetate.
What are some results of ethanol metabolism mentioned?
- Increased acetaldehyde adducts formation.
- Increased reactive oxygen species (ROS) formation.
- Increased NADH:NAD⁺ ratio.
Why are some Asian people more susceptible to alcohol?
- ADH (alcohol dehydrogenase) functions differently.
- Leads to higher amounts of acetaldehyde.
- Results in Alcohol Flush Reaction/Asian glow.
- Similar effects seen with alcohol abuse treatments like disulfiram.
What is the major cause of liver disease in most western countries?
- Alcohol abuse is the primary cause.
- Initial effect: fatty liver (steatosis).
- Ethanol exposure induces steatosis.
- Effect: increased susceptibility to inflammation.
- Consequences: cell death, scar tissue, hepatic cirrhosis.
What is the relationship between FFA, obesity, and insulin resistance?
- Free Fatty Acids (FFA) are synthesized, released from adipose tissue, and uptake/generation happens in hepatocytes.
- Equilibrium in liver involves FFA synthesis, consumption, and storage.
- Chronic excess food, obesity, insulin resistance lead to overload of FFA in liver, causing steatosis (fatty liver).
Why is liver toxicology significant in drug development?
- Liver toxicology is crucial for drug development.
- It's a common reason for drug withdrawal.
- Liver toxicity risk increases with herbal medicines.
- Two types of drug reactions: intrinsic and idiosyncratic.
What role does the CYP450 enzyme have in relation to ROS?
- CYP450 enzyme catalyzes the production of Reactive Oxygen Species (ROS).
- ROS are harmful reactive molecules.
- Capable of causing cell damage and death.
- Involves lipid peroxidation, DNA fragmentation, enzyme inactivation.
What role do antioxidants play in liver hepatocytes, and what can excessive ROS formation lead to?
- Liver hepatocytes contain antioxidants, such as Glutathione (GSH).
- Antioxidants prevent cell damage from reactive oxygen species (ROS).
- Excessive ROS formation can exhaust antioxidants.
- Exhaustion leads to necrosis, impacting liver cell health.
What characterizes necrosis in cell death?
- Uncontrolled cell death
- Caused by toxic compounds, mechanical stress, infection
- Cells and mitochondria swell, disrupting the plasma membrane
- Apoptosis may lead to necrosis if damaged
- Necrosis triggers an immune response
- Many cells involved
What are the changes in liver tissue during chronic liver toxicity?
- Normal Liver:
- - Presence of hepatocytes, endothelial cells, quiescent HSCs, Kupffer cells.
- - Hepatic sinusoid structure maintained.
- Liver Injury:
- - Loss of hepatocyte microvilli and fenestrae.
- - HSC activation, deposition of scar ECM.
- - Activated Kupffer cells.
What is the progression of liver damage leading to cirrhosis?
- Healthy Liver: Normal function and appearance.
- Fibrotic Liver: Scarring begins.
- Cirrhotic Liver: Extensive scarring, leading to liver failure.
- Liver Cancer: Possible outcome of chronic liver damage.
What factors are linked to liver cancer (Hepatocellular cancer)?
- Linked to:
- - Chronic androgen (male hormones) abuse
- - Alcohol consumption
- - Aflatoxin-contaminated diets
- - Hepatitis & Metabolic diseases
What are the results and genetic alterations leading to liver cancer?
- Results from:
- - Chronic liver injury, persistent inflammation, cirrhosis
- Genetic alterations:
- - Impaired DNA repair
- - Oncogene activation
- - Tumor suppressor gene inactivation
How do carcinogens and their metabolites directly affect DNA in liver cancer?
- Mechanism:
- - Direct DNA binding of carcinogens or their reactive metabolites, e.g., aflatoxin metabolites
What are some in vitro models for liver toxicology studies?
- Cell lines: human carcinomas, animal
- Single cells versus an organism
- Liver slices
- Organoids
- Animal models: rats, mice, pigs
- - Focus on gallbladder, CypP450 enzymes, transporters
- Lab on a chip
What is the key message about liver redox homeostasis?
- Liver redox homeostasis depends on a balance between ROS generation and elimination.
- ROS Generation:
- - Catalyzed by P450 cytochrome, lipoxygenase.
- - Sources: Mitochondrial electron transport chain, NADPH oxidase.
- - Forms: \(O_2^-\), \(OH\), \(H_2O_2\), ROO\(\cdot\), ROOH, HOCl, \(ONOO^-\).
- ROS Elimination:
- - Antioxidants like GSH, GSH-Px, SOD, CAT.
- - Vitamins C/E, enzymes, proteins, amino acids.
- Emphasizes: "Stay in balance!"
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