Liver Flashcards

Question

Q: Which of the following statements about liver toxicology is true? A. Arsenic undergoes enterohepatic recirculation B. Microcystin disrupts the hepatic cytoskeleton C. Biliary epithelial cells possess biotransformation enzymes D. All of the above

Answer 1

Answer: D. All of the above Explanation: A. Arsenic undergoes enterohepatic recirculation – This is true. After arsenic is metabolized in the liver, it can be secreted into bile and reabsorbed in the intestines, prolonging its half-life and toxicity. B. Microcystin disrupts the hepatic cytoskeleton – Correct. Microcystins (toxins from cyanobacteria) inhibit protein phosphatases, leading to cytoskeletal collapse in hepatocytes and liver damage. C. Biliary epithelial cells possess biotransformation enzymes – Also true. Though hepatocytes are the primary site of biotransformation, biliary epithelial cells (cholangiocytes) also express some metabolizing enzymes and contribute to detoxification. Mnemonic Tip: “Arsenic cycles, microcystins collapse, and bile cells metabolize too.” – Helps you remember the three facts. Great! Here’s your flashcard for the second question:

Answer 2

Answer: C. Insulin resistance Explanation: A. Valproic acid – Can cause microvesicular steatosis, but this is rare and drug-specific, not the most common cause overall. B. Fialuridine – A nucleoside analog that caused severe hepatic failure in clinical trials, but it’s not a common cause of fatty liver. C. Insulin resistance – Correct. This is the primary driver of nonalcoholic fatty liver disease (NAFLD), which is the most common cause of fatty liver. Insulin resistance leads to increased fatty acid delivery to the liver and impaired β-oxidation. D. CCl₄ (carbon tetrachloride) – A classic hepatotoxicant causing centrilobular necrosis and steatosis, but it is not the most common cause in humans today. Mnemonic Tip: “Fatty liver loves sugar – insulin’s to blame!” (Links insulin resistance with fat accumulation in the liver.)

Answer 3

Answer: C. Insulin resistance Explanation: A. Valproic acid – Can cause microvesicular steatosis, but this is rare and drug-specific, not the most common cause overall. B. Fialuridine – A nucleoside analog that caused severe hepatic failure in clinical trials, but it’s not a common cause of fatty liver. C. Insulin resistance – Correct. This is the primary driver of nonalcoholic fatty liver disease (NAFLD), which is the most common cause of fatty liver. Insulin resistance leads to increased fatty acid delivery to the liver and impaired β-oxidation. D. CCl₄ (carbon tetrachloride) – A classic hepatotoxicant causing centrilobular necrosis and steatosis, but it is not the most common cause in humans today. Mnemonic Tip: “Fatty liver loves sugar – insulin’s to blame!” (Links insulin resistance with fat accumulation in the liver.)

Answer 4

Answer: A. Cycloheximide causes fat accumulation and cell necrosis Explanation: A. Cycloheximide causes fat accumulation and cell necrosis – False. Cycloheximide is a protein synthesis inhibitor, but it does not cause fatty liver. In fact, it can prevent the development of steatosis in some experimental models by halting protein synthesis, which is required for lipid accumulation. B. Steatohepatitis can progress to fibrosis – True. Chronic inflammation and liver cell injury in steatohepatitis can lead to fibrosis and eventually cirrhosis. C. Steatosis can increase liver sensitivity to other insults – True. A fatty liver is more vulnerable to toxins, hypoxia, and infections. D. Steatohepatitis can progress to hepatocellular carcinoma – True. Non-alcoholic steatohepatitis (NASH) is a known risk factor for liver cancer, even without cirrhosis. Memory Trick: “Fatty liver invites trouble — but not from cycloheximide!”

Answer 5

Definition: A condition where excess fat accumulates in liver cells (hepatocytes). Caused by: Insulin resistance, obesity, alcohol, certain drugs (e.g., valproic acid), and malnutrition. Key point: It’s often reversible with lifestyle changes, but it can make the liver more susceptible to other injuries.

Answer 6

Definition: Inflammation of the liver in the presence of fat accumulation. It’s a more severe form of steatosis. Types: NASH (Non-alcoholic steatohepatitis) – occurs in people who drink little or no alcohol. ASH (Alcoholic steatohepatitis) – due to chronic alcohol use. Risks: Can progress to fibrosis, cirrhosis, or even hepatocellular carcinoma.

Answer 7

Definition: The formation of excess fibrous connective tissue in the liver due to chronic damage. Cause: Chronic inflammation from infections (e.g., hepatitis), toxins, or conditions like NASH. Significance: Precursor to cirrhosis; may be reversible early on.

Answer 8

Definition: A primary liver cancer that often arises in the setting of chronic liver disease. Caused by: Chronic hepatitis B or C, cirrhosis, and NASH. Key point: Can develop even in non-cirrhotic NASH patients.

Answer 9

Definition: A laboratory chemical that inhibits protein synthesis in eukaryotic cells. Use: Research tool to stop protein production. Important note: It does not cause steatosis; in fact, it may inhibit lipid accumulation in liver studies.

Answer 10

Answer: B. Danazol Explanation: A. Amiodarone – Causes phospholipidosis and hepatocellular steatosis, but not typically peliosis hepatis. B. Danazol – Correct. Danazol, an androgenic steroid, is associated with peliosis hepatis, a condition where blood-filled cystic spaces form in the liver due to dilated sinusoids. C. Tetracycline – Can cause microvesicular steatosis, but not sinusoidal dilation. D. Halothane – Known for halothane hepatitis, a severe immune-mediated liver injury, but does not cause peliosis. Definitions: Peliosis hepatis: A rare liver condition where blood-filled cavities form in the liver due to dilated sinusoids. Can be caused by androgens (like danazol), anabolic steroids, or chronic infections. Hepatic sinusoids: Specialized capillary-like vessels in the liver that allow exchange between blood and hepatocytes. When dilated abnormally, they can contribute to peliosis. Mnemonic Tip: “Danazol dilates the liver’s lanes” (lanes = sinusoids = blood-filled spaces)

Answer 11

Answer: A. Ethanol Explanation: A. Ethanol – Correct answer (NOT associated). Chronic ethanol use causes many types of liver damage (e.g., steatosis, hepatitis, cirrhosis), but it is not typically associated with vanishing bile duct syndrome (VBDS). B. Carbamazepine – Associated. This anticonvulsant has been implicated in VBDS as a rare idiosyncratic drug reaction. C. Anabolic steroids – Associated. Can cause cholestatic liver injury, including VBDS, especially with long-term use. D. Contraceptive steroids – Associated. Estrogens and synthetic steroids can impair bile flow and contribute to bile duct loss. Definition: Vanishing Bile Duct Syndrome (VBDS) A rare condition where intrahepatic bile ducts progressively disappear, leading to cholestasis (impaired bile flow), jaundice, and liver dysfunction. Causes: Certain drugs (e.g., carbamazepine, antibiotics, anabolic/contraceptive steroids), autoimmune diseases, and graft-vs-host disease. Key feature: Histologically shows loss of interlobular bile ducts. Mnemonic Tip: “Vanishing ducts don’t drink — they’re drug-induced!”

Answer 12

Answer: D. Acetaminophen Explanation: A. Rifampicin – Known to inhibit BSEP and is associated with cholestatic liver injury. B. Bosentan – A known BSEP inhibitor, associated with liver toxicity and cholestasis. C. Troglitazone – Withdrawn from the market due to hepatotoxicity, partly via BSEP inhibition. D. Acetaminophen – Correct answer. While it causes dose-dependent hepatocellular necrosis, it does not inhibit BSEP. Its mechanism involves NAPQI-mediated oxidative stress, not bile salt transport inhibition. Definition: BSEP (Bile Salt Export Pump) Function: A liver canalicular membrane protein responsible for exporting bile acids from hepatocytes into bile. Inhibition leads to: Accumulation of toxic bile acids in the liver, resulting in cholestasis and hepatocellular injury. Drug-induced BSEP inhibition is a well-known mechanism of drug-induced liver injury (DILI). Mnemonic Tip: “Trogs, Bosentan, and Rifamp block the pump — but Tylenol doesn’t.”

Answer 13

Answer: C. Identification of apoptotic cells Explanation: A. Cell swelling – Occurs in oncotic necrosis, but also can be seen in late apoptosis, so it’s not exclusive. B. Cell content release – Happens in both oncotic and secondary necrosis (the latter following apoptosis), so this also does not distinguish them. C. Identification of apoptotic cells – Correct. Oncotic necrosis: Direct necrotic cell death with membrane rupture and inflammation. Secondary necrosis: Occurs when apoptotic cells aren’t cleared properly and undergo late-stage breakdown that resembles necrosis. You can still identify the cell as previously apoptotic, which is what sets secondary necrosis apart. D. None of the above – Incorrect because C is correct. Definitions: Oncotic necrosis: Passive, uncontrolled cell death marked by swelling, membrane rupture, and inflammatory response. Apoptosis: Programmed cell death, neat and controlled, with DNA fragmentation, cell shrinkage, and phagocytosis without inflammation. Secondary necrosis: When apoptotic cells are not cleared in time, they break down and mimic necrosis, but markers of apoptosis can still be identified. Mnemonic Tip: “Secondary necrosis = dead apoptotic cells that missed cleanup.”

Answer 14

Answer: A. Prevent apoptosis-induced liver injury Explanation: A. Prevent apoptosis-induced liver injury – Correct. Pancaspase inhibitors block multiple caspases (key enzymes in the apoptosis pathway). By doing so, they prevent the cascade of programmed cell death and reduce apoptosis-mediated liver injury. B. Induce oncotic liver injury – Incorrect. Oncotic necrosis is caused by physical or metabolic injury, not caspase activity. C. Deplete cellular ATP by damaging the mitochondrial membrane – Incorrect. This is characteristic of necrosis, not a function of pancaspase inhibition. D. None of the above – Incorrect, since A is clearly correct. Definition: Pancaspase Inhibitor A compound that broadly inhibits caspases, which are enzymes involved in apoptosis. Caspases = “executioner” enzymes in programmed cell death. Blocking them can help protect cells from apoptosis-triggered damage (e.g., in toxin exposure or ischemia-reperfusion injury in the liver). Mnemonic Tip: “Pan-caspase = pan-apoptosis blocker” (Think of it as putting a lid on cell suicide.)

Answer 15

Answer: B. Accumulate in mitochondria and inhibit beta-oxidation Explanation: A. Accumulate in lysosomes and break down cellular lipids – Incorrect. This is more related to phospholipidosis, not steatosis. B. Accumulate in mitochondria and inhibit beta-oxidation – Correct. Drugs like amiodarone and valproic acid impair fatty acid β-oxidation in mitochondria, causing accumulation of triglycerides in hepatocytes, leading to steatosis (fatty liver). C. Accumulate in cytosol and stimulate lipid synthesis – This may contribute to steatosis but is not the primary mechanism in drug-induced cases. D. None of the above – Incorrect because B is clearly correct. Definition: Drug-Induced Steatosis Also called: Fatty liver Mechanism: Most commonly caused by inhibition of mitochondrial fatty acid oxidation, leading to lipid accumulation in hepatocytes. Examples: Valproic acid, amiodarone, tetracycline. Mnemonic Tip: “Blocked beta-oxidation builds up fat.” (BBB)

Answer 16

Answer: C. The cancer cells are highly sensitive to alkylating chemotherapy Explanation: A. Malignant transformation can result from increased cell turnover and persistent inflammation – True. Chronic liver disease (e.g., hepatitis B/C, NASH) leads to inflammation and regeneration cycles, increasing mutation risk. B. DNA modifications may lead to activation of oncogenes – True. Mutations, epigenetic changes, and viral integration can activate oncogenes and promote HCC. C. The cancer cells are highly sensitive to alkylating chemotherapy – False. HCC is notoriously resistant to traditional chemotherapy, including alkylating agents. This makes treatment challenging and is why targeted therapies or immunotherapy are often preferred. D. Stimulation of proliferation expands the preneoplastic population prior to transformation – True. Cell proliferation increases the number of cells at risk for malignant transformation. Definition: Hepatocellular Carcinoma (HCC) Most common primary liver cancer Risk factors: Chronic hepatitis, cirrhosis, aflatoxin exposure, NAFLD/NASH Pathogenesis: Inflammation → regeneration → DNA damage → oncogene activation Treatment: Often resistant to chemo; treated with surgery, ablation, or targeted therapies (e.g., sorafenib) Mnemonic Tip: “HCC hides from chemo.” (Resistant to traditional treatments)

Answer 17

Correct Answer: C. The cancer cells are highly sensitive to alkylating chemotherapy Explanation: Hepatocellular carcinoma (HCC) is the most common primary liver cancer, typically arising in the context of chronic liver disease such as hepatitis or cirrhosis. Let’s go through each option: A. Malignant transformation can result from increased cell turnover and persistent inflammation – TRUE Why it’s correct: Chronic liver injury (e.g., from hepatitis B/C or alcohol) leads to ongoing cell death and regeneration, increasing the chance of mutations. Persistent inflammation also promotes an environment rich in reactive oxygen species and cytokines, contributing to DNA damage and carcinogenesis. B. DNA modifications can lead to activation of oncogenes – TRUE Why it’s correct: Mutations or epigenetic changes (like methylation or acetylation of DNA/histones) can activate proto-oncogenes into oncogenes, driving unchecked cell growth. This is a key step in cancer progression, including in HCC. C. The cancer cells are highly sensitive to alkylating chemotherapy – FALSE (Correct Answer) Why it’s incorrect: HCC cells are often resistant to chemotherapy, especially alkylating agents (e.g., cyclophosphamide). These agents work by damaging DNA, but many HCC cells have upregulated DNA repair mechanisms or drug efflux pumps (e.g., P-glycoprotein) that make them less responsive. Targeted therapies or immunotherapies are now more commonly used than traditional alkylators. D. Stimulation of proliferation expands the preneoplastic population prior to transformation – TRUE Why it’s correct: In chronic liver disease, regenerative nodules and preneoplastic cells undergo expansion due to signals promoting liver regeneration. Over time, some of these cells may acquire enough mutations to become fully transformed malignant cells. Definitions to Know: Hepatocellular carcinoma (HCC): A type of liver cancer usually linked to chronic liver disease. Alkylating chemotherapy: Drugs that add alkyl groups to DNA, causing cross-linking and DNA damage (e.g., cyclophosphamide). Oncogene: A mutated gene that drives cancer progression. Preneoplastic: Refers to cells or tissue changes that are not yet cancerous but may become so. Malignant transformation: The process by which normal cells become cancerous.

Answer 18

Correct Answer: A. Activation of hepatic stellate cells Explanation: Liver fibrosis is the result of chronic liver injury from causes like viral hepatitis, alcohol, or fatty liver disease. The central event in fibrosis is activation of hepatic stellate cells (HSCs), which transform from quiescent vitamin A–storing cells into myofibroblast-like cells that produce excess extracellular matrix (ECM), especially collagen. Let’s walk through each option: A. Activation of hepatic stellate cells – CORRECT Why it’s correct: These cells are the primary source of fibrous scar tissue in liver disease. Upon injury (e.g., inflammation, oxidative stress), HSCs get activated and start secreting ECM proteins like collagen I and III, leading to fibrosis. Remember: Chronic injury → inflammation → cytokine release (e.g., TGF-β, PDGF) → HSC activation → fibrosis. B. Suppression of Kupffer cells – INCORRECT Kupffer cells are liver-resident macrophages. In fibrosis, they are activated, not suppressed. They release pro-inflammatory cytokines (like TNF-α, IL-1) that help trigger and sustain HSC activation. Suppressing Kupffer cells would actually reduce inflammation and possibly reduce fibrosis. C. Stimulation of antibody response – INCORRECT While immune responses are part of chronic liver injury, fibrosis is more about inflammation, cytokine signaling, and fibrogenesis, not antibody-mediated immunity. This choice is more relevant to autoimmune diseases, not fibrosis per se. D. Formation of DNA adducts – INCORRECT DNA adducts are associated with carcinogenesis, especially chemical-induced cancers (e.g., aflatoxin in HCC). They are not central to fibrosis, although they can occur alongside chronic damage. Definitions to Know: Hepatic stellate cells (HSCs): Cells in the liver that, when activated, produce scar tissue (collagen) during liver injury. Fibrosis: Thickening or scarring of connective tissue, usually from chronic inflammation or injury. Kupffer cells: Specialized macrophages in the liver that mediate immune response and inflammation. DNA adducts: Segments of DNA bound to a cancer-causing chemical—early markers of mutation and carcinogenesis.

Answer 19

Correct Answer: B. It is caused by increased membrane collagen type 4 Explanation: Hepatic fibrosis refers to the excessive accumulation of extracellular matrix proteins in the liver, mainly as a result of chronic liver injury. Let’s examine each statement: A. Stimulation of apoptosis in causative cells may lead to gradual reversal – TRUE Why it’s correct: Hepatic fibrosis can be reversible, particularly in early stages. When the source of injury (like viral infection or alcohol) is removed, apoptosis (programmed cell death) of activated hepatic stellate cells (the main fibrogenic cells) can occur, leading to decreased collagen production and potential reversal of fibrosis. B. It is caused by increased membrane collagen type 4 – FALSE (Correct Answer) Why it’s incorrect: The main collagen types deposited in fibrosis are Type I and Type III, not Type IV. Type I collagen is the dominant fibrous collagen in advanced fibrosis and cirrhosis. Type IV collagen is normally found in basement membranes, not in large fibrotic scars in the liver. So, stating that increased membrane collagen type 4 causes fibrosis is inaccurate. C. It can interfere with the exchange of nutrients and waste material – TRUE Why it’s correct: Fibrosis leads to scarring and distortion of the hepatic architecture, especially in the space of Disse, where exchange occurs between hepatocytes and blood. This disruption impairs nutrient/waste exchange and contributes to hepatic insufficiency. D. Viral hepatitis is the primary cause of hepatic fibrosis/cirrhosis worldwide – TRUE Why it’s correct: Globally, chronic hepatitis B and C infections are leading causes of liver fibrosis and progression to cirrhosis. In the U.S., alcohol and nonalcoholic fatty liver disease (NAFLD) are also major causes, but viral hepatitis remains the most common worldwide. Key Definitions: Hepatic fibrosis: Scarring of liver tissue caused by chronic injury or inflammation. Apoptosis: Programmed cell death; a natural process to remove damaged or unneeded cells. Type I and III collagen: Fibrous proteins overproduced during fibrosis. Type IV collagen: Found in basement membranes; not a primary driver of fibrosis. Cirrhosis: End-stage liver fibrosis, often irreversible and linked to liver failure or cancer.

Answer 20

Correct Answer: A. Zone 1 hepatocytes Explanation: The liver acinus is divided into three functional zones based on blood supply and oxygenation: Zone 1 (periportal): Closest to the portal triad (gets first access to oxygen, nutrients, and blood-borne substances) Zone 2 (intermediate): Middle zone Zone 3 (centrilobular): Closest to the central vein (least oxygenated) So why does iron overload affect Zone 1 hepatocytes the most? Iron enters the liver through the portal vein—Zone 1 gets the highest exposure first. Iron is taken up and stored in hepatocytes, especially in Zone 1, which has high metabolic activity. In conditions like hereditary hemochromatosis, excess iron builds up primarily in Zone 1, leading to oxidative stress and damage. Over time, this leads to cell death, fibrosis, and even cirrhosis—but the first cells hit are Zone 1 hepatocytes. Other Answer Choices: B. Zone 2 hepatocytes – INCORRECT This is a transition zone. While it may be affected secondarily, it’s not the main site of initial iron damage. C. Zone 3 hepatocytes – INCORRECT Zone 3 is the most vulnerable to hypoxia and certain toxins like acetaminophen, but not iron overload. D. Zone 4 hepatocytes – INCORRECT There is no Zone 4 in classical liver zonation. This is a distractor. Quick Memory Trick: “Iron enters first = Zone 1” Think: Hemochromatosis = Iron = Hits first zone Definitions: Hepatocytes: Main liver cells that perform metabolism, detoxification, and storage. Iron overload: Condition where excess iron deposits in tissues, causing damage. Zone 1: High oxygen, high nutrients, first to receive blood from the portal triad.

Answer 21

Correct Answer: D. Bile duct cells Explanation: Methylene dianiline (MDA) is a synthetic industrial chemical used in the production of polyurethane foams. It’s known to cause a very specific type of liver toxicity called cholangiodestructive cholestasis, which targets bile duct epithelial cells. Why D is Correct (Bile Duct Cells): MDA causes destruction of bile duct epithelium, leading to cholestasis (bile flow blockage) and bile buildup in the liver. This type of injury is distinct from typical hepatocellular injury and is known for preferentially targeting cholangiocytes (bile duct cells). Seen in cases of accidental poisoning or occupational exposure. Breakdown of the Other Options: A. Hepatocytes – INCORRECT Hepatocytes are the main metabolic liver cells, often damaged by drugs like acetaminophen or alcohol—but MDA doesn’t primarily target them. B. Stellate cells – INCORRECT Stellate cells are involved in fibrosis, not commonly targeted by direct toxins like MDA. C. Kupffer cells – INCORRECT These are liver macrophages involved in immune responses. They can be activated by injury, but MDA doesn’t directly damage them. Definitions: Methylene dianiline (MDA): A toxic aromatic amine used in industry; known to cause liver injury. Cholangiocytes: Epithelial cells lining the bile ducts. Cholestasis: A condition where bile cannot flow from the liver to the duodenum. Quick Tip to Remember: “MDA = Messes up the Ducts” This links MDA with bile duct damage.

Answer 22

Correct Answer: D. Hypertension Explanation: Acetaminophen (APAP) is generally safe at therapeutic doses, but in overdose, it’s metabolized into a toxic intermediate (NAPQI) that can cause severe liver damage—especially in zone 3 hepatocytes. Let’s go through each answer: A. Malnutrition – TRUE (enhances toxicity) Malnutrition depletes glutathione (GSH), the key molecule that detoxifies NAPQI. With low GSH, NAPQI accumulates and causes oxidative damage in hepatocytes. B. Fasting – TRUE (enhances toxicity) Fasting also reduces glutathione stores, similarly making the liver more susceptible to APAP toxicity. It may also upregulate CYP2E1, increasing toxic metabolite production. C. Induction of CYP2E1 – TRUE (enhances toxicity) CYP2E1 is the main enzyme responsible for converting APAP to NAPQI. Anything that induces CYP2E1 (like ethanol, isoniazid, or fasting) increases NAPQI levels, worsening toxicity. D. Hypertension – FALSE (does not enhance toxicity) Hypertension is not directly related to acetaminophen metabolism or hepatotoxicity. It may affect other organs like the heart and kidneys, but doesn’t increase liver damage from APAP. Key Definitions: NAPQI (N-acetyl-p-benzoquinone imine): Highly toxic intermediate metabolite of acetaminophen. Glutathione (GSH): An antioxidant that neutralizes NAPQI in the liver. CYP2E1: Cytochrome P450 enzyme responsible for converting APAP into NAPQI. Quick Memory Tip: “Meds + Malnutrition + Metabolism = More NAPQI”

Answer 23

Correct Answer: B. Excess supply of acetate and NADH Explanation: Chronic alcohol intake affects liver metabolism in several key ways. A major mechanism behind alcoholic fatty liver (steatosis) is the increased production of NADH during ethanol metabolism, which shifts the liver’s metabolic balance. B. Excess supply of acetate and NADH – CORRECT Ethanol is metabolized in the liver to acetaldehyde and then to acetate, generating large amounts of NADH in the process. High NADH/NAD⁺ ratio inhibits fatty acid oxidation and promotes fat synthesis. Result: Fat accumulates in hepatocytes → steatosis. Other Options Explained: A. Stimulation of beta-oxidation of fatty acids – INCORRECT Chronic alcohol use actually inhibits beta-oxidation due to excess NADH. Fatty acids are not broken down—they’re stored in the liver. C. Excess supply of pyruvate and NADP⁺ – INCORRECT NADP⁺ is used in anabolic pathways, not directly linked to ethanol metabolism or steatosis. Pyruvate is converted to lactate under high NADH, so its availability actually drops. D. Inhibitory effect of acetaldehyde on fatty acid breakdown – PARTIALLY TRUE BUT NOT PRIMARY Acetaldehyde is toxic and contributes to liver injury, but the primary cause of steatosis is the metabolic shift caused by NADH, not acetaldehyde’s inhibition of lipid metabolism directly. Key Concepts to Know: Ethanol → Acetaldehyde → Acetate (via alcohol dehydrogenase and ALDH) Each step produces NADH High NADH blocks fat breakdown (beta-oxidation) and favors fat storage Quick Memory Tip: “Too much NADH = Too much fat in the liver”

Answer 24

Correct Answer: D. All of the above Explanation: Alcohol-induced liver disease (ALD) is complex and involves multiple overlapping mechanisms that damage liver cells and promote fibrosis and cirrhosis. Let’s break down each factor: A. Inflammation – TRUE Alcohol increases gut permeability, allowing bacterial endotoxins (e.g., LPS) to enter the liver. This activates Kupffer cells (liver macrophages), which release pro-inflammatory cytokines (like TNF-α), promoting inflammation and cell death. B. Lipid Peroxidation – TRUE Ethanol metabolism produces reactive oxygen species (ROS). These ROS cause peroxidation of cell membrane lipids, leading to membrane instability and cell damage/death. C. Oxidative Stress – TRUE Ethanol is metabolized by CYP2E1, which generates ROS. Excess ROS overwhelms antioxidant defenses (e.g., glutathione), creating oxidative stress, damaging DNA, proteins, and lipids. D. All of the above – CORRECT ALD involves inflammatory signaling, oxidative damage, and membrane lipid destruction, all working together to harm hepatocytes and promote progression to steatohepatitis, fibrosis, and cirrhosis. Key Terms: Lipid peroxidation: Free radical–driven destruction of lipids, especially in cell membranes. Oxidative stress: Imbalance between ROS and the body’s antioxidant defenses. Inflammation: Immune response that can lead to tissue injury when chronic. Quick Memory Tip: “Alcohol attacks the liver on three fronts: fire (inflammation), rust (oxidative stress), and oil (lipid peroxidation).”

Answer 25

Correct Answer: B. Kupffer cells Explanation: Kupffer cells are the liver’s resident macrophages. They play a central role in immune surveillance and inflammatory responses—especially in response to bacterial components like endotoxins (lipopolysaccharides or LPS). Why B. Kupffer cells is correct: Endotoxins (LPS) are recognized by Toll-like receptor 4 (TLR4) on Kupffer cells. This leads to activation and release of cytokines (e.g., TNF-α, IL-1β) and reactive oxygen species. Gadolinium chloride (GdCl₃) is used experimentally to modulate (either stimulate or suppress) Kupffer cell activity. Kupffer cell activation plays a key role in liver injury from sepsis, alcohol, and drug toxicity. Other Answer Choices: A. Stellate cells – INCORRECT Stellate cells get activated secondarily—often in response to signals from Kupffer cells. They are involved in fibrosis, but not directly triggered by LPS or GdCl₃. C. Zone 3 hepatocytes – INCORRECT These are vulnerable to hypoxia and toxins like acetaminophen—not primarily activated by LPS or GdCl₃. D. Bile duct cells – INCORRECT These are involved in cholangiopathies, not innate immune activation by endotoxins. Definitions: Kupffer cells: Liver-resident macrophages responsible for detecting and responding to pathogens. Endotoxin (LPS): A bacterial component that triggers strong immune activation via TLRs. GdCl₃ (Gadolinium chloride): A rare-earth compound used in research to modulate macrophage/Kupffer cell activity. Quick Memory Tip: “Endotoxins = Immune alarm → Kupffer cells sound it first”

Answer 26

Correct Answer: D. None of the above Explanation: At therapeutic doses, the vast majority of acetaminophen is safely metabolized in the liver by phase II conjugation reactions, not by the pathways listed in A–C. Here’s how acetaminophen is metabolized: Main Pathways (safe): Glucuronidation (≈60%) Via UDP-glucuronosyltransferase (UGT) Attaches glucuronic acid to acetaminophen Sulfation (≈30%) Via sulfotransferase (SULT) Attaches sulfate group Minor Pathway (toxic): Oxidation by CYP2E1 (≈5–10%) → NAPQI This forms the toxic metabolite NAPQI NAPQI is then detoxified by glutathione (GSH) Let’s break down each answer: A. Metabolized to NAPQI – INCORRECT Only a small fraction (~5–10%) goes this route. NAPQI is the dangerous byproduct, not the main pathway. B. Acetylated – INCORRECT Acetylation isn’t a major pathway for acetaminophen metabolism. It’s more relevant for other drugs (e.g., isoniazid). C. Conjugated with glycine – INCORRECT Glycine conjugation is a minor pathway for other substances (e.g., benzoic acid → hippuric acid), not acetaminophen. D. None of the above – CORRECT Because the main pathways are glucuronidation and sulfation, not any of the ones listed.

Answer 27

Correct Answer: B. Injury occurs by the killing of distressed cells that would otherwise survive Explanation: Recent research has shifted the understanding of how neutrophils contribute to liver injury. Instead of targeting only cells already destined to die, neutrophils can amplify damage by killing cells that might otherwise recover. Why B is CORRECT: Neutrophils are recruited to areas of injury, such as during alcoholic hepatitis or drug-induced liver injury. Newer studies suggest neutrophils target stressed but viable hepatocytes—cells that could survive if not attacked. This leads to excessive tissue injury and impaired liver regeneration. Analysis of Other Options: A. Detrimental liver effects can occur from neutrophil mobilization to other organs – INCORRECT Neutrophils causing damage in other organs may be true in systemic inflammatory conditions (like sepsis), but this isn’t the primary mechanism in liver-specific injury. C. Neutrophils participate in the same way in all types of toxic liver injury – INCORRECT Their role varies depending on the injury type: They are major players in alcoholic hepatitis, Less involved in acetaminophen toxicity, where oxidative stress is more dominant. D. Damage is exacerbated by the mass killing of healthy liver cells – INCORRECT Neutrophils primarily target damaged or distressed cells, not entirely healthy hepatocytes. The concern is killing recoverable (not healthy) cells, which limits regeneration. Key Concepts: Neutrophils: First-responding immune cells involved in innate immunity and inflammation. Distressed hepatocytes: Liver cells under oxidative/metabolic stress but not yet dead. Amplified injury: Damage worsens due to immune overactivation, not just the original toxin. Quick Mnemonic: “Neutrophils: rescuers gone rogue—they kill the ones that could’ve healed.”

Answer 28

Correct Answer: A. Tienilic acid Explanation: Idiosyncratic liver toxicity refers to liver injury that is unpredictable, not clearly dose-dependent, and occurs only in certain individuals due to genetic or unknown factors. It comes in two types: Immune-mediated (e.g., involving hypersensitivity or autoimmune features) Nonimmune-mediated (no signs of immune involvement) Why A. Tienilic acid is CORRECT (i.e., it’s the exception): Tienilic acid was an antihypertensive drug withdrawn from the market due to immune-mediated hepatotoxicity. It is known to form reactive metabolites that bind to liver proteins and trigger an autoimmune-like response. So it does not cause nonimmune idiosyncratic liver injury—it causes immune-mediated injury. Other Options: B. Isoniazid – INCORRECT (causes nonimmune injury) Classic example of nonimmune idiosyncratic hepatotoxicity. Metabolized by acetylation and CYP enzymes, leading to reactive intermediates in susceptible individuals. C. Amiodarone – INCORRECT (causes nonimmune injury) Can cause chronic, nonimmune liver injury, often with steatosis or phospholipidosis. Injury is related to mitochondrial dysfunction and drug accumulation, not an immune mechanism. D. Ketoconazole – INCORRECT (causes nonimmune injury) Antifungal known for nonimmune hepatotoxicity. Dose-independent and linked to mitochondrial toxicity or oxidative stress. Quick Tip to Remember: Tienilic acid = Triggers immune attack (not nonimmune)

Answer 29

Correct Answer: C. Carbon tetrachloride is an example Explanation: Idiosyncratic drug-induced liver injury (IDILI) is: Unpredictable Often not dose-dependent Can be immune or non-immune mediated Typically linked to genetic or metabolic susceptibilities Why C is INCORRECT (and thus the correct answer to the question): Carbon tetrachloride (CCl₄) causes predictable, dose-dependent, direct hepatotoxicity, particularly in zone 3 hepatocytes. It generates free radicals through CYP450 metabolism leading to lipid peroxidation and necrosis, which is not idiosyncratic. Therefore, it is not an example of idiosyncratic toxicity. Other Options: A. Involves failure to adapt to mild drug adverse effect combined with a genetic defect – TRUE Some patients have genetic polymorphisms (e.g., in drug-metabolizing enzymes or immune response genes) that prevent proper adaptation to a drug, leading to liver injury. B. Traditional animal toxicology studies may not detect it – TRUE IDILI is species-specific and rare, so standard animal testing may not reveal the risk. It often only emerges during human clinical use. D. Preclinical studies may need to be done in genetically deficient animals – TRUE Using genetically modified models (e.g., knockout mice) can help detect idiosyncratic responses linked to certain genetic vulnerabilities.

Answer 30

Correct Answer: A. CYP3A4 Explanation: Ethanol metabolism in humans primarily occurs via three main pathways, and CYP3A4 is not one of them. Correct Ethanol Metabolizing Enzymes: C. ADH (Alcohol Dehydrogenase): Primary enzyme for ethanol metabolism. Converts ethanol to acetaldehyde in the cytosol. B. CYP2E1 (Cytochrome P450 2E1): Inducible enzyme, especially during chronic alcohol use. Also converts ethanol to acetaldehyde. Produces reactive oxygen species, contributing to liver damage. D. Peroxisomal catalase: A minor pathway of ethanol metabolism. Uses hydrogen peroxide to oxidize ethanol. Not a major contributor, but does occur in peroxisomes. Why A. CYP3A4 is INCORRECT: CYP3A4 is a major drug-metabolizing enzyme, but not involved in ethanol metabolism. It does not significantly contribute to the conversion of ethanol to acetaldehyde in humans.

Answer 31

Correct Answer: B. Bile duct cells / ethanol Explanation: Each liver region or cell type tends to be selectively vulnerable to specific toxicants due to differences in oxygenation, enzyme activity, and function. Let’s walk through each pair: A. Zone 1 hepatocyte / iron – TRUE Zone 1 (periportal) is where iron preferentially accumulates, especially in hemochromatosis. It’s the first region exposed to portal blood and thus sees the most iron overload. B. Bile duct cells / ethanol – FALSE (Correct Answer) Ethanol does not primarily damage bile duct cells. Ethanol mainly targets Zone 3 hepatocytes due to high CYP2E1 activity in that region, causing oxidative stress and steatosis. Bile duct damage is more associated with cholangiopathies or toxins like methylene dianiline or alpha-naphthylisocyanate. C. Stellate cells / vitamin A – TRUE Hepatic stellate cells are the main vitamin A–storing cells in the liver. Chronic injury causes them to transform into collagen-producing myofibroblasts, central to fibrosis. D. Zone 3 hepatocyte / carbon tetrachloride – TRUE Zone 3 (centrilobular) is rich in CYP450 enzymes, especially CYP2E1. Carbon tetrachloride is metabolized to a free radical in this zone, causing lipid peroxidation and necrosis.

Answer 32

Correct Answer: B. Decreased biliary excretion of copper Explanation: Wilson’s disease is a rare autosomal recessive genetic disorder caused by a mutation in the ATP7B gene, which codes for a copper-transporting ATPase in the liver. This condition leads to: Impaired transport of copper into bile, meaning copper cannot be excreted properly, so… Copper accumulates in the liver, brain, cornea, and other tissues, leading to hepatotoxicity, neuropsychiatric symptoms, and Kayser-Fleischer rings. Why the other options are incorrect: A. Increased intestinal absorption of copper – INCORRECT Wilson’s disease is not caused by increased copper absorption; absorption is usually normal. The issue is the inability to excrete. C. Decreased renal excretion of copper – INCORRECT The kidneys are not the primary route of copper excretion; the liver excretes copper into bile. In Wilson’s, you might actually see increased urinary copper as a compensatory effect. D. Increased sensitivity to normal levels of copper – INCORRECT It’s not a sensitivity issue—it’s a build-up issue due to defective biliary copper transport.

Answer 33

Correct Answer: A. Doxycycline Explanation: Hepatocellular carcinoma (HCC) is the most common primary liver cancer and is strongly associated with chronic liver injury and regeneration, inflammation, and carcinogenic exposures. Let’s evaluate each option: A. Doxycycline – NOT associated (Correct Answer) Doxycycline is a tetracycline antibiotic. While it can cause rare cases of hepatotoxicity, there is no strong link to hepatocellular carcinoma. This makes it the correct “except” answer. B. Aflatoxin – ASSOCIATED Aflatoxins are mycotoxins produced by Aspergillus flavus, often found in contaminated grains or nuts. Aflatoxin B1 is a potent hepatocarcinogen that induces p53 mutations. Strongly linked to HCC, especially in regions with poor food storage (e.g., sub-Saharan Africa, parts of Asia). C. Viral hepatitis – ASSOCIATED Chronic infection with hepatitis B or C causes long-term inflammation and cirrhosis, which are major risk factors for HCC. Hepatitis B can also integrate into the host genome, promoting oncogenesis directly. D. Androgen abuse – ASSOCIATED Anabolic steroids (synthetic androgens) have been linked to hepatic adenomas, which can sometimes progress to HCC, especially with long-term or high-dose use. Seen in bodybuilders or performance-enhancing drug users.

Answer 34

Correct Answer: B. Decreased in chronic liver and bone disease Explanation: Albumin is a major plasma protein produced exclusively by the liver. It plays critical roles in: Maintaining oncotic pressure Binding and transporting hormones, drugs, and other molecules Why B is CORRECT : In chronic liver disease, hepatocytes lose the ability to synthesize albumin, so serum albumin decreases. Low albumin is a marker of chronic hepatic insufficiency, not acute injury. Albumin may also be decreased in protein-losing conditions, malnutrition, and possibly in severe bone disease due to associated systemic effects, although this link is more indirect. Why the Other Choices Are Incorrect: A. Elevated in liver disease and hemolysis – INCORRECT Albumin is not elevated in liver disease—it’s typically decreased. It is not affected directly by hemolysis; bilirubin levels rise in hemolysis, not albumin. C. The most sensitive indicator of acute liver disease – INCORRECT Albumin has a long half-life (~20 days), so it’s not useful for acute changes. Enzymes like ALT, AST, and bilirubin are more sensitive indicators of acute liver injury. D. Demonstrates extrahepatic bile duct dilation – INCORRECT This is a radiologic finding, not related to albumin. Imaging (like ultrasound or MRCP) is used to detect bile duct dilation.

Answer 35

Correct Answer: C. The most sensitive indicator of acute liver disease Explanation: Aspartate transaminase (AST) is a liver enzyme found in both the cytoplasm and mitochondria of hepatocytes. It is released into the bloodstream when liver cells are injured. Why C is CORRECT : AST levels rise quickly in response to acute liver injury, such as from viral hepatitis, ischemia, or toxins. It is often elevated before symptoms appear. Though alanine transaminase (ALT) is more liver-specific, AST tends to rise more dramatically in massive or mitochondrial-associated injury (e.g., alcohol-related damage). Why the Other Options Are Incorrect: A. Decreased in chronic liver disease – INCORRECT AST can be elevated or normal in chronic liver disease depending on the level of ongoing injury. It is not typically decreased. B. Distinguishes bone from liver disease – INCORRECT This is a property of alkaline phosphatase (ALP), not AST. ALP has bone and liver isoforms that can be differentiated. D. Elevated in liver and bone disease – INCORRECT AST is not associated with bone disease. It is mostly elevated in liver, heart, and muscle injury (e.g., myocarditis or rhabdomyolysis).

Answer 36

Correct Answer: A. Reflect the level of coagulation factors Explanation: Prothrombin time (PT) measures the extrinsic and common coagulation pathways and reflects the activity of clotting factors I (fibrinogen), II (prothrombin), V, VII, and X, many of which are synthesized in the liver. Why A is CORRECT : PT is a sensitive indicator of hepatic synthetic function because many clotting factors have short half-lives. In liver dysfunction, PT is prolonged due to reduced synthesis of these clotting proteins. PT is often used to assess severity of liver disease (e.g., part of MELD score). Other Options: B. Distinguish bone from liver disease – INCORRECT This is a property of alkaline phosphatase (ALP), not PT. PT has no role in differentiating bone vs liver conditions. C. Be elevated in 60–80% of patients with hepatic encephalopathy – INCORRECT PT may be elevated in hepatic encephalopathy, but it’s not a consistent feature. Encephalopathy is due to ammonia and other toxins, not clotting dysfunction directly. D. Be elevated in liver disease and hemolysis – INCORRECT PT can be elevated in liver disease, but hemolysis doesn’t directly affect clotting time. Hemolysis affects bilirubin, not coagulation factors. Summary Table: Here’s your flashcard-style breakdown for the ammonia and hepatic encephalopathy question:

Answer 37

Correct Answer: D. Elevated in 60–80% of patients with hepatic encephalopathy Explanation: Ammonia is a waste product of protein metabolism, normally detoxified in the liver via the urea cycle. When liver function is impaired, ammonia builds up and can cross the blood–brain barrier, contributing to hepatic encephalopathy (HE). Why D is CORRECT : In hepatic encephalopathy, ammonia is elevated in 60–80% of patients, although not universally. It plays a central role in the neurological symptoms seen in HE (confusion, asterixis, coma). Ammonia can come from gut bacteria, muscle metabolism, or GI bleeding. Why the Other Options Are Incorrect: A. Decreased in chronic liver disease – INCORRECT The opposite is true: ammonia levels rise due to impaired hepatic clearance. B. Elevated in liver and bone disease – INCORRECT Bone disease has no role in ammonia metabolism. Ammonia elevation is specific to liver dysfunction and not related to skeletal systems. C. Elevated in liver disease and hemolysis – INCORRECT While liver disease causes ammonia accumulation, hemolysis does not significantly affect ammonia levels.

Liver Flashcards

(61 cards)