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279 Cards in this Set
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1. What are the five different types of cells in the liver?
Which is the primary cell type? |
1. *Hepatocytes
2. Endothelial cells 3. Kupffer cells 4. Hepatic stellate cells 5. Pit cells *The primary cell type of the liver is the hepatocyte, which makes up 80% of the volume of the liver and 60% of the total number of cells in the liver. |
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2. What are hepatocytes?
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Almost all pathways of metabolism are represented in the hepatocyte and these pathways are controlled thru the actions of hormones that bind to receptors located on the plasma membrane of their cells.
These cells can grow rapidly if damage occurs to them. |
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3. What are endothelial cells?
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The sinusoidal endothelial cells constitute the lining cells of the sinusoid. These cells contain fenestrations with a mean diameter of 100 nm. Therefore, they don't form a tight basement membrane barrier between themselves and the hepatocytes. This allows for free diffusion of small molecules to the hepatocytes.
These cells are capable of endocytosing many ligands and also may secrete cytokines when appropriately stimulated. |
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4. What are Kupffer cells?
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Kupffer cells are located w/in the sinusoidal lining. They contain almost 1/4 of all the lysosomes of the liver. They are tissue macrophages w/both endocytotic and phagocytic capacity.
They phagocytose many substances such as denatured albumin, bacteria, and immune complexes. They protect the liver from bacteria and particulates. They can also secrete potent mediators of the inflammatory response and play a key role in liver immune defense thru the release of cytokines. They also remove damaged RBCs from the circulation. |
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5. What are hepatic stellate cells?
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AKA perisinusoidal or Ito cells. The stellate cells are lipid filled cells and also serve as the primary storage site for vitamin A.
They also control the turnover of hepatic connective tissue and ECM, and regualte the contractility of the sinusoids. When cirrhosis of the liver is present, the stellate cells are stimulated to increase their production of ECM material. |
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6. What are pit cells?
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The hepatic pit cells, AKA liver associated lymphocytes, are natural killer cells, which are a defense mechanism against the invasion of the liver by potentially toxic agents, such as tumor cells or viruses.
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7. What are the 10 functions of the liver?
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1. Central receiving and recycling center for the body
2. Inactivation and detox of xenobiotic compounds and metabolites 3. Regulation of blood glucose levels 4. Synthesis and export of cholesterol and TAG 5. Ammonia and the urea cycle 6. Formation of ketone bodies 7. Nucleotide biosynthesis 8. Synthesis of blood proteins 9. Synthesis of glycoproteins and proteoglycans 10. Pentose phosphate pathway |
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8. What are phase I reactions?
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Phase I reactions introduce or expose hydroxyl groups or other reactive sites that can be used for conjugation reactions (the phase II reactions).
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9. What are phase II reactions?
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The conjugation reactions add a negatively charged group such as glycine or sulfate to the molecule.
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10. Why are phase I reactions important in the liver?
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Because many pharmacological and xenobiotic compounds are lipophilic, they are oxidized, hydroxylated, or hydrolyzed by enzymes in phase I reactions.
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11. What is the cytochrome P450 enzyme system?
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The p45 dependent monooxygenases enzymes are determinants in oxidative, peroxidative, and reductive degradation of exogenous and endogenous substances.
The key enzymatic constituents of this system are the flavoprotein NADPH cytochrome p450 oxidoreductase and cytochrome P450. The latter is the terminal electron acceptor and substrate binding site of the microsomal mixed-function oxidase complex. |
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12. What is the major role of the cytochrome p450 enzymes?
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To oxidize substrates and introduce oxygen to the structure.
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13. How many gnes are in the cytochrome 450 enzymes family?
How are they divided? Which is the most popular form? |
57 genes, which produces enzymes divided into six different subfamilies.
The CYP3A4 isoform accounts for 60% of p450 enzymes in the liver and 70% of cytochrome enzymes in gut wall enterocytes. |
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14. What does CYP3A4 do?
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CYP3A4 metabolizes the greatest number of drugs in humans. Furthermore, specific drugs are substrates for CYP3A4, which can potentially induce competition for the binding site.
Therefore, the drug w/the highest affinity for the enzyme will be preferentially metabolized, whereas the metabolism and degradation of the other drug will be reduced. The latter drug's concentration in the blood will then rise. |
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15. What are six common features of all cytochrome P450 isozymes?
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1. They all contain cytochrome p450, oxidize the substrate, and reduce oxygen.
2. They all have a flavin-containing reductase subunit that uses NADPH, and not NADH as a substrate. 3. They are all found in the smooth ER and are referred to as microsomal enzymes. 4. THey are all bound to the lipid portion of the membrane, probably to phosphatidylcholine. 5. They are all inducible by the presence of their own best substrate and somewhat less inducible by the substrates for other P450 isozymes. 6. They all generate a reactive free radical compound as an intermediate in the reaction. |
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16. What is the detox process for Vinyl Chloride?
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Vinyl chloride can cause angiosarcoma in the liver.
It is activated in a phase I reaction to a reactive epoxide by a P450 (CYP2E1), which can react w/guanine in DNA or other cellular molecules. However, ti also can be converted to chloroacetaldehyde, conjugated w/reduced glutathione, and excreted in a series of phase II reactions. |
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17. What is the detox process for Aflatoxin B1?
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Aflatoxin B1 is an example of a compound made more toxic by a cytochrome p450 reaction (CYP2A1).
Ingested aflatoxin B1 in contaminated food is directly involved in hepatocarcinogenesis in humans by introducing a G to T mutation into the p53 gene. Aflatoxin is metabolically activated to its 8,9-epoxide by two different isozymes of cytochrome p450. The epoxide modifies DNA by forming covalent adducts with guanine residues. In addition, the epoxide can combine with lysine residues in proteins and thus is also a hepatotoxin. |
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18. What is the detox process for acetaminophen?
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Acetaminophin can be glucuronylated or sulfated for safe excretion by the kidney. Hwoever, a cytochrome P450 enzyme produces the toxic intermediate N-acetyl-p-benzoquinoneimine (NAPQI), which can be safely excreted in the urine.
NAPQI, however, is a dangerous and unstable metabolite which can cause damage and lead to death of the hepatocytes. |
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19. Why is NAPQI dangerous in large amts if the liver can handle the detox?
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Under normal conditions, a small dose of acetaminophen forms NAPQI in an amt that can be readily handled by the glutathione detox system (phase II reactions).
However, when taken in large doses, the levels of glutathione in the hepatocytes are insufficient to detox NAPQI and hepatocyte death can result. |
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20. What about alcohol and acetaminophen?
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The enzyme that produces NAPQI, CYP2E1, is induced by alcohol. Thus, individuals who abuse alcohol have increased sensitivity to acetaminophen toxicity b/c a higher percentage of acetaminophen metabolism is directed toward NAPQI.
Treatment is N-acetylcysteine, a precursor for increased glutathione production, which enhances the phase II reactions. |
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21. How does the liver regulate blood glucose levels?
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The pancreas monitors blood glucose and secretes insulin when levels rise and glucagon when levels decrease.
These hormones initiate regulatory cascades that affect liver glycogenolysis, glycogen synthesis, glycolysis, and gluconeogenesis. |
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22. How does the liver play a role in ammonia and the urea cycle?
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The liver is the primary organ for synthesizing urea and thus is the central depot for the disposition of ammonia in the body. Ammonia groups travel to the liver on glutamine and alanine, and the liver converts these ammonia nitrogens to urea for excretion in the urine.
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23. How does the liver play a role in nucleotide biosynthesis?
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The liver can synthesize and salvage all ribonucleotides and deoxyribonucleotides for other cells to use. Certain cells have lost the capacity to produce nucleotides de novo but can use the salvage pathways to convert free bases to nucleotides. The liver can secrete free bases into the circulation for these cells to use for this purpose.
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24. How does the liver synthesize blood proteins?
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The liver is the primary site of the synthesis of circulating proteins such as albumin and the clotting factors. Therefore, the liver has a well-developed ER, Golgi system, and cellular cytoskeleton, all of which function in the synthesis, processing, and secretion of proteins.
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25. How is the liver important in the synthesis of glycoproteins and proteoglycans?
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B/c the liver is the site of synthesis of most of the blood proteins, it has a high requirement for the sugars that go into the oligosaccharide portion of glycoprotiens.
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26. Is the liver dependent on dietary glucose or hepatic glucose to generate the precursor intermediates for glycoprotein and proteoglycan synthesis?
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No; this is b/c the liver can generate carbs from dietary AAs. However, if a dietary carb is available, the liver will use that.
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27. What is the isoform of most of the sugars secreted by the liver?
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Most of the sugars secreted by the liver are O-linked, that is, the carbohydrate is attached to the protein at its anomeric carbon thru a glycosidic link to the -OH of a serine or a theronine residue.
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28. What is NANA?
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AKA sialic acid, a nine-carbon O-linked sugar that is synthesized from fructose 6-phosphate and PEP.
As circulating proteins age, NANA residues are lost from the serum proteins. This change signals their removal from the circulation and their eventual degradation. An asialoglycoprotein receptor on the liver cell surface binds such proteins, and the receptor ligand complex is endocytosed and transported to the lysosomes. The AAs from the degraded protein are then recycled within the liver. |
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29. What about the liver and the pentose phosphate pathway?
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The major functions of the pentose phosphate pathway are the generation of NADPH and five carbon sugars. All cell types, including RBCs, can carry out this pathway b/c they need to regenerate NADPH so that the activity of glutathione reductase is reduced.
The liver has a much greater demand for NADPH than do most other organs; and thus it uses more glutathione and NADPH to maintain glutathione reductase and catalase activity than any other tissue. |
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30. What five fuels does the liver use?
How does it obtain these fuels? |
1. ATP
2. UTP 3. GTP 4. Reduced NADPH 5. Acyl coenzyme A thioesters The energy for the formation of these compounds is obtained directly from oxidative metabolism, the TCA cycle, or the electron transport chain. |
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31. After a mixed meal containing carbs, what are the major fuels used by the liver?
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Glucose, galactose, and fructose
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32. During an overnight fast, what are the major fuels used by the liver?
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Fatty acids; they are oxidized to carbon dioxide or ketone bodies.
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33. The entry of glucose into the liver is dependent on what?
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A high concentration of glucose in the portal vein after a high carb meal. B/c the Km for both GLUT2 and glucokinase is so high, glucose enters the liver principally after its concentration rises to 10-40 mM in the portal blood.
In addition, the rate of glycolysis is increases (PFK-2 is active; thus PFK-1 is activated by fructose 2,6-biphosphate) so that acetyl CoA can be produced for fatty acid synthesis). |
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34. What determines the rate of glucose utilization by the liver?
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The level of activity of glucokinase. GLucokinase activity is regulated by glucokinase regulatory protein (RP), which is located in the nucleus.
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35. How does glucose regulatory protein work?
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In the absence of glucose or presence of fuctose 6-phosphate, most glucokinase is translocated to the nucleus and binds RP. This leads to the formation of the inactive form of glucokinase.
When glucose or fructose 1-phosphate levels rise, glucokinase is released from RP. It then translocates to the cytoplasm and actively converts glucose to glucose 6-phosphate. |
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36. What is the major regulatory step for liver glycolysis?
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The PFK-1 step. Thus, liver glycolysis is basically determined by modulating the levels of fructose 2,6-bisphosphate, the produce of the PFK-2 reaction.
As fructose 26-bisphosphate levels increase (which occurs in the presence of insulin), the rate of glycolysis increases; when glucagon levels increase and protein kinase A is activated so that PFK-2 is phosphorylated and inactive glycolysis slows down and gluconeogenesis is enhanced. |
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37. What is the summary for long-chain fatty acid metabolism in the liver?
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In the liver, they bind to fatty acid binding proteins and then are activated on the outer mitochondrial membrane, the peroxisomal membrane, and the smooth ER by fatty acyl CoA synthetases.
The fatty acyl group is transferred from CoA to carnitine for transport thru the inner mitochondrial membrane, where it is reconverted back into fatty acyl CoA and oxidized to acetyl CoA in the beta-oxidation spiral. |
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38. What is the summary for medium chain length fatty acid oxidation?
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The liver and the kidney are the major sites for the oxidation of MC length FAs.
These medium chain FAs are released directly into the portal circulation. In the liver, they diffuse thru the inner mitochondrial membrane and are activated to acyl CoA derivatives by medium chain length fatty acid activating enzyme. The medium chain fatty acyl CoA is then oxidized by the normal route, beginning w/medium chain length acyl CoA dehydrogenase. |
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39. How do very-long chain FAs become oxidized?
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Peroxisomes. These enzymes are present in greater numbers in the liver than in other tissues.
Liver peroxisomes contain the enzymes for the oxidation of very-long chain FAs for the cleavage of the cholesterol side chain necessary for the synthesis of bile salts, for a step in the biosynthesis of ether lipids, and for several steps in the arachidonic acid metabolism. Peroxisomes also are capable of detoxing hydrogen peroxide. |
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40. What are peroxisome proliferator-activated receptors (PPARs)?
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PPARs play an important role in liver metabolism; they induce the proliferation of peroxisomes in the liver. When activated, they stimulate new gene transcription. In the liver, the major form of PPAR regulates directly the activity of genes that are involved in fatty acid uptake and β- and ω-oxidation of fatty acids.
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41. What are the 3 major forms of PPARs?
Which is the major form found in the liver? |
α, δ/β, and γ.
PPARα is the major form found in the liver. Fatty acids are a ligand for PPARα, such that when the level of FAs increase, there is increased gene transcription for those proteins involved in regulating FA metabolism. |
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42. Lack of PPARα leads to...?
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No problems occur w/a normal diet; however, when fasting or fed a high fat diet, severe fatty infiltration of the liver develops.
The inability to increase the rate of FA oxidation in this organ leads to excessive fatty acid buildup in the hepatocytes. It also leads to an insufficient level of energy supply with which to make glucose as well as an inability to produce ketone bodies. |
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43. How are xenobiotics metabolized?
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The liver uses the pathways of FA metabolism to detox very hydrophobic and lipid-soluble xenobiotics, which like FAs, either have carboxylic acid groups or can be metabolized to compounds that contain carboxylic acids.
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44. How are benzoate and aspirin metabolized?
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Benzoate is similar in structure to salicylic acid, and both are similar in structure to medium-chain length fatty acids. They are activated to an acyl CoA derivative by medium chain length FA activating enzyme. The acyl group is then conjugated w/glycine, which targets the compound for urinary excretion.
The glycine derivatives of salicylate and benzoate are called salicylurate and hippurate, respectively. |
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45. Chronic parenchymal liver disease is associated with what change in LCAT in the liver...?
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Reduction in the activity of lethicin cholesterol acyl transferase (LCAT). This plasma enzyme catalyzes the transfer of a FA from the 2 position of lecithin to the 3β-OH group of free cholesterol to produce cholesterol ester and lysolecithin.
In severe liver disease, plasma levels of cholesterol ester are reduced and free cholesterol levels are normal or increased. |
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46. Chronic parenchymal liver disease is associated with what change in plasma TAG levels ...?
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Plasma TAGs are normally cleared by peripheral lipases (LPL and hepatic TAG lipase). B/c the activities of these enzymes are reduced in patients w/hepatocellular disease, a high level of plasma TAGs may be found.
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47. How do low LCAT activity levels and elevated TAG levels affect LDL particles?
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LDL particles have an abnormal composition. They are relatively TAG-rich and cholesterol ester-poor.
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48. How are HDL particles affected in chronic liver disease?
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HDL metabolism may be abnormal. B/c the conversion of HDL₃ (less antiatherosclerotic) to HDL₂ (more antiatherosclerotic) is catalyzed by LCAT, the reduced activity of LCAT in patients w/cirrhosis leads to a decrease in the HDL₂:HDL₃ ratio.
BUT!!! the conversion of HDL₂ to HDL₃ requires hepatic lipases and if the activity of this lipase is reduced, there is an elevation in the HDL₂:HDL₃ ratio. *Therefore, b/c the HDL₂:HDL₃ ratio is usually elevated in cirrhosis, the lipase deficiency appears to be the more dominant of the two mechanisms. |
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49. How are VLDL levels affected?
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The hepatic production of the TAG rich, VLDL lipoprotien is impaired.
Yet the total level of plasma TAGs remains relatively normal b/c the LDL particle in such patients is TAG-rich. |
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50. Who are nonesterified FA levels affected in patients w/cirrhosis?
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NEFA levels are elevated. This might be expected b/c the basal hepatic glucose output is low in these patients. As a result, more NEFA are presumably required via increased lipolysis to meet the fasting energy requirements of peripheral tissues.
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51. How are the plasma AA concentrations affected in patients w/liver disease?
Where do the excess AAs come from? |
The AA concentrations are often elevated. This is attributable to a significantly increased rate of protein turnover as well as to impaired AA uptake by the diseased liver.
B/c 18-20x more protein is present in skeletal muscle, the muscle is probably the major source of the elevated plasma levels of AAs seen in catabolic states such as cirrhosis. |
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52. What is the plasma profile of AAs in cirrhotic patients like?
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Typically shows an elevation in aromatic AAs, phenylalanine and tyrosine, and in free tryptophan and methionine.
The latter changes may be caused by impaired hepatic utilization of these AAs as well as by portosytemic shunting. The elevation in aromatic AAs and the suppression of the level of BCAAs in the blood have been implicated in the pathogenesis of hepatic encephalopathy. |
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53. What is hepatogenous diabetes?
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After glucose ingestion, many patients w/liver disease have abnormally elevated glucose levels. 60-80% of cirrhotic patients have varying degrees of glucose intolerance, and overt diabetes mellitus occurs 2-4x as often in cirrhotics than it does in subjects w/o liver disease.
The proposed mechanisms include a degree of insulin resistance in peripheral tissues and a marked impairment of insulin secretion as well. This decrease in insulin secretion leads to increased hepatic glucose output and reduced suppression of of hepatic glucose output after meals, leading to postprandial hyperglycemia as well. |
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54. What is hepatic fibrosis?
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Extensive and progressive fibrosis of the hepatic parenchyma leads to cirrhosis of the liver. A major change occurs when fibrosis is initiated; the normally spare or leaky basement membrane between the endothelial cell and the hepatocyte is replaced w/a high density membrane containing fibrillar collagen. After a sustained insult to the liver, a 3-8x increase occurs in ECM components.
The accumulation of these compounds leads to a loss of endothelial cell fenestrations and therefore a loss of the normal sievelike function of the basement membranes. These changes interfere w/normal transmembrane metabolic exchanges between the blood and hepatocytes. |
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55. What cells in the liver are the source of the increased and abnormal collagen production?
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The hepatic stellate cells. These cells are activated by growth factors whose secretion is induced by injury to the hepatocytes or endothelial cells. Growth factors include TGFβ, PDGF, and EGF.
The release of PDGF stimulates stellate cell proliferation and increases their synthesis and release of ECM materials and remodeling enzymes. |
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56. How does the release of ECM materials and remodeling enzymes causes problems?
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These enzymes include matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs, as well as converting enzymes.
This cascade leads to the degradation of the normal ECM and replacement w/a much denser and more rigid type of matrix material. These changes are in part the result of an increase in the activity of tissue inhibitors of MMPs for the new collagen relative to the original collagen in the ECM. |
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57. What is a major consequence of the increase in hepatic fibrosis (cirrhosis)?
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A greater resistance to the free flow of blood through the liver.
This increased vascular resistance leads to an elevation of intrasinusoidal fluid pressure. With increasing pressures, the shunting of portal blood away from the liver contributes further to hepatic dysfunction. If the portal hypertension cannot be reduced, blood flow will continue to bypass the liver and return to the heart thru the normally lo-pressure esophageal veins, causing esophageal varices. |
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58. What is the substrate T-galactosyl-neoglycoalbumin (NGA) used for?
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NGA was developed as a specific ligand for selective uptake via the asialoglycoprotein hepatic receptor.
The timing and extent of the assimilation of this probe into the hepatocytes, as determined by imaging of the liver at precise intervals after the admin of this isotyope, yields an estimate of hepatic blood flow as well as the transport capacity of this specific hepatic transporter protein. |
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59. What causes hepatic encephalopathy?
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Much of the protein content of the blood entering the GI tract is metabolized by intestinal bacteria, releasing ammonium ion, which enters the portal vein. B/c heaptocellular function has been compromised, the urea cycle capacity is inadequate, and the ammonium ion enters the peripheral circulation, thereby contributing to hepatic encephalopathy brain toxicity due to elevated ammonia levels.
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60. Why would you expect fructose 1-phosphate levels to promote the dissociation of glucokinase from regulatory protein (RP)?
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Fructose 1-phosphate is produced from fructose metabolism. The major dietary source of fructose, the ingestion of which would lead to increased fructose 1-phosphate levels, is sucrose. Sucrose is a disaccharide of glucose and fructose.
Thus, an elevation of fructose 1-phosphate usually indicates an elevation of glucose levels as well. |
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61. Why are medium chain TAGs an important nutritional supplement used in patients with digestion disorders?
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They can be an easily absorbed source of calories in patients who have a GI disorder that may result in malabsorption of nutrients.
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62. What is Zellweger syndrome?
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Zellweger syndrome occurs in individuals w/a rare inherited absence of peroxisomes in all tissues.
Patients accumulate C26-C38 polyenoic acids in brain tissue b/c of defective peroxisomal oxidation of the very-long-chain fatty acids synthesized in the brain for myelin formation. In liver, bile acid and ether lipid synthesis are affected, as is the oxidation of very long chain FAs. |
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63. How do fibrates work?
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Fibrates are a class of drugs that bind to PPARs. They are prescribed for patients w/elevated TAG levels b/c they increase the rate of TAG oxidation.
Through PPARα stimulation, they also suppress ApoCIII synthesis and stimulate LPL activity. ApoCIII activity normally inhibits LPL activity, so by reducing CIII synthesis overall, LPL activity is increased. ApoCIII also blocks apoE on IDL particles, causing the IDL particles to accumulate. The suppression of ApoCIII levels allows more IDL to by taken up, thereby also reducing circulating TAG levels. |
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64. What is Reye's syndrome?
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Reye's syndrome is characterized by vomiting w/signs of progressive CNS damage. In addition, there are sings of hepatic injury and hypoglycemia. There is mitochondrial dysfunction w/decreased activity of hepatic mitochondrial enzymes. Hepatic coma may occur as serum ammonia levels rise.
It is associated w/consumption of aspirin by children. The liver at autopsy shows swollen and disrupted mitochondria and extensive accumulation of lipid droplets w/fatty vacuolization of cells in both the liver and the renal tubules. |
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65. What are the five patterns of hepatic injury?
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1. Degeneration and intracellular accumulation
2. Necrosis and apoptosis 3. Inflammation 4. Regeneration 5. Fibrosis |
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66. What is ballooning degeneration?
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With more severe hepatocellular damage, swollen hepatocytes have irregularly clumped cytoplasmic organelles and large clear spaces. This is called ballooning degeneration.
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67. What is feather degeneration?
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In cholestatic liver injury, retained biliary material may impart a diffuse, foamy appearance to the swollen hepatocyte.
This lesions can be difficult to distinguish from ballooning degeneration, except for the variable yellow discoloration of the cytoplasm. |
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68. What is microvesicular steatosis?
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Multiple tiny droplets that do not displace the nucleus are called microvesicular steatosis, and appear in such conditions as acute fatty liver of pregnancy and valproic acid toxicity.
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69. What is macrovesicular steatosis?
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A single large droplet that displaces the nucleus, macrovesicular steatosis, may be seen in hepatocytes throughout the livers of obese or diabetic individuals and in scattered hepatocytes in patients w/HCV.
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70. What is ischemic coagulative necrosis?
What do hepatocytes look like in apoptotic cell death? |
In ischemic coagulative necrosis, the liver cells are poorly stained and "mummified" and often have lysed nuclei.
In apoptotic cell death, isolated hepatocytes round up to form shrunken, pyknotic, and intensely eosinophilic cells containing fragmented nuclei. |
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71. What is lytic necrosis?
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Hepatocytes may also osmotically swell and rupture, so called lytic necrosis, the outcome of ballooning degeneration.
Lytic necrosis leaves neither mummified hepatocytes nor pyknotic cells but rather shards of cellular debris. |
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72. What is centrilobular necrosis?
What about pure midzonal and periportal necrosis? |
The most obvious necrosis of hepatocytes occurs immediately around the terminal hepatic vein (called centriblobular necrosis), an injury that is characteristic of ischemic injury and a number of drug and toxic reactions.
Pure midzonal and periportal necrosis are rare; the latter may be seen in eclampsia. |
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73. What is bridging necrosis?
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With more severe inflammatory injury, necrosis of contiguous hepatocytes may span adjacent lobules in a portal-to-portal, portal-to-central, or central-to-central fashion (bridging necrosis).
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74. What is the definition of hepatitis?
What is interface hepatitis? |
Injury to the liver associated w/an influx of acute or chronic inflammatory cells is termed hepatitis.
In viral hepatitis, quiescent lymphocytes may collect in the portal tracts as a reflection of mild smoldering inflammation, spill over into the periportal parenchyma as activated lymphocytes (interface hepatitis) causing a moderately active hepatitis, or suffuse the entire parenchyma in severe hepatitis. |
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75. What is a sign of very recent hepatocyte destruction?
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Identification of apoptotic hepatocytes is a sign of very recent hepatocyte destruction.
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76. What characterizes hepatocellular proliferation?
What is the ductular reaction? |
Hepatocellular proliferation is marked by mitoses, thickening of the hepatocyte cords, and some disorganization of the parenchyma structure.
The canal of Herin-bile ductule unit constitutes a reserve compartment for restitution of severe parenchymal injury; when it is activated, innumerable serpentine profiles resembling bile ductules appear; the so called ductular reaction. |
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77. What is the most severe clinical consequence of liver disease?
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Hepatic failure.
This can result from sudden and massive hepatic destruction, but more often it is the end point of progressive damage to the liver as part of chronic liver disease. 80-90% of hepatic functional capacity must be eroded before hepatic failure ensues. In most cases, liver transplantation is the only hope for survival. |
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78. What are the three categories of morphological alterations that cause liver failure?
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1. Massive hepatic necrosis
2. Chronic liver disease 3. Hepatic dysfunction without overt necrosis |
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79. What causes massive hepatic necrosis?
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This is most often drug or toxin induced, as from acetaminophen, halothan, antituberculosis drugs (rifampin, isoniazid), antidepressant MOAIs, carbon tetrachloride, and mushroom poisoning.
The mechanism may be direct toxic damage to hepatocytes, but more often is a variable combination of toxicity and inflammation with immune mediated hepatocyte destruction. HepA and HepB also cause massive hepatic necrosis; HepC does not! |
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80. What causes hepatic dysfunction w/o overt necrosis?
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Hepatocytes may be viable but unusable to perform normal metabolic function, as with Reye syndrome, tetracycline toxicity, and acute fatty liver of pregnancy.
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90. What are the clinical features of hepatic failure?
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These include jaundice, hypoalbuminemia, hyperammonemia, fetor hepaticus, palmar erythema, spider angiomas, hypogonadism, and gynocomastia
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91. What is fetor hepaticus?
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Fetor hepaticus is a characteristic body odor that is variously described as musty or sweet and sour and occurs occasionally. It is related to the formation of mercaptans by the action of GI bacteria on the sulfur-containing AA methionine and shunting of splanchnic blood from the portal into the systemic circulation (portosystemic shunting).
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92. Why does coagulopathy develop in hepatic failure?
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This is attributable to impaired hepatic synthesis of blood clotting factors 2, 7, 9, and 10.
The resultant bleeding tendency can lead to massive GI bleeding as well as petechial bleeding elsewhere. |
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93. What are the two important complications that herald the most grave stages of hepatic failure?
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1. Hepatic encephalopathy
2. Hepatorenal syndrome |
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94. What is hepatic encephalopathy?
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Hepatic encephalopathy is a life threatening disorder of CNS and neuromuscular transmission. It is reversible if the underlying liver conditions are corrected. It is caused by loss of hepatocellular function and blood shunting around the liver, leading to an altered metabolic milieu bathing the CNS. *Excess ammonia levels appear to be important.
In a great majority of cases, there are only minor morphologic changes in the brain, such as edema and an astrocytic reaction. |
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95. What are the symptoms of hepatic encephalopathy?
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1. Disturbances in consciousness (e.g. behavioral abnormalities, confusion, stupor, coma)
2. EEG changes 3. Limb rigidity and hyperreflexia 4. Seizures 5. Asterixis (nonrhythmic, rapid extension-flexion movements of the head and extremities) |
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96. What is hepatorenal syndrome?
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Hepatorenal syndrome is life-threatening renal failure (w/o intrinsic renal pathology) in the setting of severe liver disease.
*The cause is decreased renal perfusion pressure, followed by renal vasoconstriction. Although the patients have a drop in urine output (with a corresponding rise in serum creatinine and BUN levels), the concentrating ability of the kidney is maintained. The resulting urine is hyperosmolar, devoid of proteins, and surprisingly low in sodium. Kidney function promptly improves if hepatic failure is reversed. |
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97. What causes cirrhosis?
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Cirrhosis is among the top 10 causes of death in the Western world. The chief worldwide contributors are EtOH abuse and viral hepatitis. Other causes include biliary disease, and iron overload.
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98. Cirrhosis as the end-stage of chronic liver disease is defined by what three characteristics?
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1. Bridging fibrous septae in the form of delicate bands or broad scars linking portal tracts w/one another and portal tracts w/terminal hepatic veins.
2. Parenchymal nodules, containing proliferating hepatocytes encircled by fibrosis, with diameters varying from very small (<3mm) to large (several cm). 3. Disruption of the architecture of the entire liver. |
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99. What are five important features of cirrhosis?
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1. The parenchymal injury and consequent fibrosis are diffuse, extending throughout the liver. (Focal injury does not constitute cirrhosis).
2. Nodularity is part of the Dx and reflects the balance between generative activity and constrictive scarring. 3. Vascular architecture is reorganized by the parenchymal damage and scarring, with the formation of abnormal interconnections btw vascular inflow and hepatic vein outflow channels. 5. Fibrosis is the key feature of progressive damage to the liver. |
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100. What is the pathogenesis of cirrhosis?
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The central pathogenetic processes in cirrhosis are progressive fibrosis and reorganization of the vascular microarchitecture of the liver.
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101. What is the vascular microarchitecture in the normal liver?
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In the normal liver, interstitial collages (types I and II) are concentrated in protal tracts and around central veins. The collagen (reticulin) coursing alongside hepatocytes is composed of delicate strands of type IV collagen in the space of Disse.
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102. What is the vascular microarchitecture in the cirrhotic liver?
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In cirrhosis, types I and III collagen are deposited in the lobule, creating delicate or broad septal tracts. New vascular channels in the septae connect the vascular structures in the portal region (hepatic arteries and portal veins) and terminal hepatic veins, shunting blood around the parenchyma.
Continued deposition of collagen in the space of Disse w/in preserved parenchyma is accompanied by the loss of fenestrations in the sinusoidal endothelial cells. In the process, the sinusoidal space comes to resemble a capillary rather than a channel for exchange of solutes btw hepatocytes and plasma. |
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103. What is the major source of excess collagen in cirrhosis?
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The perisinusoidal stellate cells, which lie in the space of Disse.
Although normally functioning as vitamin A fat storing cells, during the development of cirrhosis they become activated, a process that includes robust mitotic activity, a shift from the resting lipocyte phenotype to a transitional myofibroblast phenotype, and increased capacity for synthesis and secretion of ECM. |
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104. What are the four major stimuli for stellate cell activation?
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1. Chronic inflammation, w/production of cytokines such as TNF, lymphotoxin, and IL-1.
2. Cytokine production by activated endogenous cells (Kupffer cells, endothelial cells, etc...) including TGF-β, PDGF, and lipid peroxidation products. 3. Disruption of the ECM, as stellate cells are extraordinarily responsive to the status of their substrate. 4. Direct stimulation of stellate cells by toxins. |
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105. What causes the constriction in the vascular resistance associated w/cirrhosis?
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Acquisition of myofibers by perisinusoidal stellate cells also increases vascular resistance w/in the liver parenchyma, since tonic contraction of these "myofibroblasts" constricts the sinusoidal vascular channels.
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106. What are the clinical features of cirrhosis?
What are the three mechanisms of death caused by cirrhosis? |
Can be clinically silent for years; it ultimately presents w/anorexia, weight loss, weakness, osteoporosis, and debilitation.
Death is caused by: 1. Progressive liver failure 2. A complication related to portal hypertension 3. The development of HCC |
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107. What are the causes of prehepatic portal hypertension?
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The major prehepatic conditions are obstructive thrombosis and narrowing of the portal vein before it ramifies w/in the liver.
Massive splenomegaly may also shunt excessive blood into the splenic vein. |
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108. What are the causes of posthepatic portal hypertension?
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The major posthepatic causes are severe right sided heart failure (cor pulmonale), constrictive pericarditis, and hepatic vein outflow obstruction.
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109. What are the causes of intrahepatic portal hypertension?
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The dominant intrahepatic cause is cirrhosis, accounting for most cases of portal hypertension.
Fall less frequent are schistosomiasis, massive fatty change, diffuse fibrosing granulomatous disease such as sarcoidosis, tuberculosis, and diseases affecting the portal microcirculation. |
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110. What is the pathogenesis of portal hypertension?
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Portal hypertension in cirrhosis results from increased resistance to portal blood flow at the level of the sinusoids, and compression of terminal hepatic veins by perivenular scarring and expansile parenchymal nodules.
Anastomoses between the arterial and portal systems in the fibrous septa also contribute to portal hypertension by imposing arterial pressure on the low pressure hepatic venous system. |
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111. What are the four major clinical consequences of portal hypertension?
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1. Ascites
2. Formation of portosystemic venous shunts 3. Congestive splenomegaly 4. Hepatic encepalopathy |
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112. What is ascites?
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Ascites refers to the collection of excess fluid in the peritoneal cavity.
It is generally a serous fluid having less than 3 gm/dL of protein (largely albumin). The fluid may contain a scant number of mesothelial cells and mononuclear leukocytes. Influx of neutrophils suggests secondary infection, whereas red cells point to possible disseminated intra-abdominal cancer. With long standing ascites, seepage of peritoneal fluid thru lymphatics may produce hydrothorax, most often on the right side. |
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113. What are the four mechanisms involved in the pathogenesis of ascites?
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1. Hepatic sinusoidal hypertension (promoted by hypoalbuminemia)
2. Percolation of hepatic lymph into the peritoneal cavity 3. Intestinal fluid leakage 4. Renal retention of sodium and water due to secondary hyperaldosteronism |
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114. Where are the portosystemic shunts?
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1. Veins around and within the rectum (hemorrhoids)
2. Cardioesophageal junction (producing esophagogastric varices) 3. The retroperitoneum 4. The falciform ligament of the liver (involving the periumbilical and abdominal wall collaterals called caput medusae). |
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115. Can portal hypertension cause splenomegaly?
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Yes, in long standing congestion splenomegaly can result.
The degree of enlargement varies widely up to 1 kg and is not necessarily correlated w/other features of portal hypertension. |
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116. What are the definitions of:
Jaundice? Icterus? Cholestasis? |
Jaundice and icterus denote yellow skin and sclera discoloration, respectively; they both reflect systemic bilirubin retention.
Cholestasis denotes systemic retention of bilirubin, bile salts, and cholesterol due to inadequate biliary elimination of these solutes. |
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117. What is the summary of bilirubin metabolism and elimination?
Five main steps... |
1. Normal bilirubin production from heme is derived primarily from the breakdown of senescent circulation RBCs, w/a minor contribution from degradation of tissue heme containing proteins.
2. Extrahepatic bilirubin is bound to serum albumin and delivered to the liver. 3. Hepatocellular uptake via carrier mediated transfer. 4. Glucuronidation (UGT1A1) in the ER generate bilirubin monoglucuronides and diglucuronides, which are water soluble and readily excreted into bile. 5. Gut bacteria deconjugate the bilirubin and degrade it to colorless urobilinogens. The urobilinogens and the residue of intact pigments are excreted in the feces, w/some reabsorption and excretion into urine. |
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118. What is the hepatic conjugating enzyme?
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The hepatic conjugating enzyme, UGT1A1 is a member of a family of UGTs that catalyze the glucuronidation of an array of substrates such as steroid hormones, carcinogens, and drugs.
UGT1A1 is located primarily in the sER and rER of hepatocytes; and it catalyzes the glucuronidation of bilirubin to its bilirubin monoglucuronide and diglucuronide form. |
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119. What is the pathogenesis of jaundice?
How are the two forms of bilirubin distinguished btw one another? |
Both unconjugated bilirubin and bilirubin glucuronides may accumulate systemically and deposit in tissues, giving rise to the yellow color of jaundice.
The two forms of bilirubin are distinguished by pathophysiologic differences: unconjugated bilirubin is virtually insoluble in water at physiological pH and is tightly complexed to serum albumin. This form cannot be excreted in the urine even when blood levels are high. In contrast, conjugated bilirubin is water soluble, nontoxic, and only loosely bound to albumin. This form can be excreted in urine. |
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120. What are the features of erythroblastosis fetalis?
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Hemolytic disease of the newborn, (erythroblastosis fetalis) may lead to accumulation of unconjugated bilirubin in the brain, which can cause severe neurologic damage, referred to as kernitcterus.
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121. Why does jaundice occur?
What are the five mechanisms in jaundice formation? |
Jaundice occurs when the equilibrium between bilirubin production and clearance is disturbed from any of the following mechanisms:
1. *Excessive production of bilirubin 2. *Reduced hepatocyte uptake 3. *Impaired conjugation 4. Decreased hepatocellular excretion 5. Impaired bile flow *Produce unconjugated hyperbilirubinemia |
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122. What causes neonatal jaundice?
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B/c the hepatic machinery for conjugating and excreting bilirubin does not fully mature until about 2 weeks of age, almost every newborn develops transient and mild unconjugated hyperbilirubinemia,.
Breast-fed infants tend to exhibit jaundice w/greater frequency, possibly the result of β-glucuronidases present in maternal milk. These enzymes deconjugate bilirubin glucuronides in the gut, increasing intestinal reabsorption of unconjugated bilirubin. |
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123. What is Crigler-Najjar syndrome (type I)?
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In Crigler-Najjar syndrome (type I - autosomal recessive), the enzyme UGT1A1 is completely absent. The liver is incapable of synthesizing a functional enzyme, and the colorless bile contains only trace amts of unconjugated bilirubin.
The liver is morphologically normal. However, serum unconjugated bilirubin reachs very high levels, producing severe jaundice and icterus. Without liver transplant, this condition is invariably fatal, causing death within 18 mos of birth secondary to kernicterus. |
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124. What is Crigler-Najjar syndrome (type II)?
What is the treatment? |
Crigler-Najjar syndrome (type II - autosomal dominant) is a less severe, nonfatal disorder in which UGT1A1 enzyme activity is greatly reduced, and the enzyme is capable of forming only monoglucuronidated bilirubin.
Unlike Type I, the only major consequence is extraordinarily yellow skin from high levels of circulating unconjugated bilirubin. *Treatment is with phenobarbital; it can improve bilirubin conjugation via inducing hypertrophy of the hepatocellular ER. |
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125. What is Gilbert syndrome?
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Gilbert syndrome is a relatively common, benign, somewhat heterogeneous inherited condition presenting w/mild, fluctuating hyperbilirubinemia.
The primary cause is reduction in hepatic bilirubin glucuronidating activity to about 30% of normal levels. In most patients, 2 extra bases (TA) are found which results in reduced expression of UGT1A1. The mild hyperbilirubinemia may go undiscovered for years and is not associated w/functional problems. When detected in adolescence or adult life, it is typically in association with stress, illness, strenuous exercise, or fasting. |
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126. What is Dubin-Johnson syndrome?
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Dubin-Johnson syndrome results from a hereditary defect in hepatocellular excretion of bilirubin glucuronides across the canalicular membrane.
The defect is due to absence of the canalicular protein, the multidrug resistance protein 2 (MRP2), that is responsible for transport of bilirubin glucuronides and related organic anions into bile. Apart from chronic or recurrent jaundice of fluctuating intensity, most patients are asymptomatic and have a normal life expectancy. |
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127. What is the appearance of the liver in Dubin-Johnson syndrome?
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The liver is darkly pigmented owing to coarse pigmented granules within the cytoplasm of hepatocytes.
Electron microscopy reveals that the pigment is located in lysosomes, and it i appears to be composed of polymers of epinephrine metabolites, not bilirubin pigment. The liver is otherwise normal. |
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128. What is Rotor syndrome?
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Rotor syndrome is a rare form of asymptomatic conjugated hyperbilirubinemia with multiple defects in hepatocellular uptake and excretion of bilirubin pigments.
The liver is not pigmented. As w/Dubin-Johnson syndrome, patients with Rotor syndrome exhibit jaundice but otherwise live normal lives. |
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130. What are six signs of cholestasis?
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1. Jaundice
2. Pruritus, related to the elevation in plasma bile acids and their deposition in peripheral tissues, particularly skin 3. Skin xanthomas 4. Elevated ALKPHOS 5. Elevated gGTP 6. Malabsorption of fat soluble vitamines |
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131. What is the morphology of cholestasis (common to both obstructive and nonobstructive cholestasis)?
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The morphology can vary depending on the severity, duration and underlying cause.
Common to both obstructive and nonobstructive cholestasis is the accumulation of bile pigment within the hepatic parenchyma. Elongated green-brown plugs of bile are visible in dilated bile canaliculi. Rupture of canaliculi leads to extravasation of bile, which is quickly phagocytosed by Kupffer cells. Droplets of bile pigment also accumulate within hepatocytes, which can take on a fine, foamy appearance (feathery degeneration) |
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132. What is the morphology of obstructive cholestasis?
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Obstruction of the biliary tree, either intra or extrahepatic, induces distention of upstream bile ducts and ductules by bile. Ductular proliferation is confined to portal tracts. The ductules also reabsorb secreted bile salts, serving to protect the downstream obstructed bile ducts from the toxic detergents.
Associated histologic findings include protal tract edema and periductular infiltrates of neutrophils. Prolonged obstructive cholestasis leads not only to feathery degeneration but to bile lakes fill with cellular debris and pigment. |
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133. Unrelieved obstruction in cholestasis eventually leads to...?
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Portal tract fibrosis, which initially extends into and subdivides the parenchyma w/relative preservation of hepatic architecture.
Ultimately, an end-stage bile-stained, cirrhotic liver is created (biliary cirrhosis). |
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134. Can cholestasis be corrected?
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Extrahepatic biliary obstruction is frequently amenable to surgical alleviation. In contrast, choelstasis due to diseases of the intrahepatic biliary tree or hepatocellular secretory failure cannot be benefited by surgery (short of transplantation) and the patients condition may be worsened by an operative procedure.
Regardless, there is thus some urgency in making a correct diagnosis of the cause of jaundice and cholestasis. |
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135. What is familial intrahepatic cholestasis?
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This group of disorders is characterized by low bile salt secretion into bile. Unlike many other cholestatic condition, the virtual absence of bile salts within the canalicular lumen btwn hepatocytes means that gGTP levels are low for the degree of hyperbilirubinemia.
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136. What is benign recurrent intrahepatic cholestasis?
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In BRIC, there are intermittent attacks of cholestasis over life w/o progression to chronic liver disease.
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137. What is progressive familial intrahepatic cholestasis 1 (PFIC-1)?
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In progressive familial intrahepatic cholestasis 1, cholestasis begins in infancy w/severe pruritus due to high serum bile acid levels and relentlessly progresses to liver failure before adulthood.
The first major characterized family w/this syndrome are descendents from amish people. Affected members of this particular family are designated as having Byler syndrome; unrelated individuals w/different mutations have Byler disease. |
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138. What genetic alterations are common in PFIC-1?
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These conditions encompass a spectrum arising usually from mutations in the ATP8B1 gene on chromosome 18q21. The encoded protein is a canalicular P-type ATPase that probably plays a role in secretion of bile salts indirectly thru the maintenance of aminophospholipid polarity in the membrane.
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139. Mutations in the canalicular bile salt export pump (BSEP), encoded by the ABCB11 gene are the cause of...?
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Progressive familial intrahepatic cholestasis 2 (PFIC-2).
This cholestatic disorder features severely impaired bile salt secretion into bile, w/extreme pururitus, growth failure, and progression to cirrhosis in the first decade of life. |
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140. What is Progressive familial intrahepatic cholestasis 3?
|
PFIC-3 is an autosomal-recessive disorder w/high serum GGT and is due to mutations in the ABCB4 gene.
The encoded protein, MDR3, is responsible for flipping phosphatidylcholine from the internal to the external hemileaflet of the canalicular membrane. In patients w/this disorder, absence of phosphatidylcholine in bile leaves the apical surfaces of the biliary tree epithelia subject to the full detergent action of secreted bile salts, with resultant toxic destruction of these epithelia and release of GGT into the circulation. |
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141. What is 3β-hydroxysteroid dehydrogenase deficiency?
|
Children w/severe cholestasis but with absence of elevated serum GGT and absence of pruritus may also have inherited defects in bile acid synthesis.
The most common condition is a deficiency of 3β-hydroxysteroid dehydrogenase, an enzyme located early in the pathway for bile acid synthesis. |
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142. What three systemic viral infections can involve the liver?
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1. EBV (mononucleosis), which may cause a mild hepatitis during the acute phase
2. CMV, particularly in the newborn or immunosuppressed patient. 3. Yellow fever, which has been a major and serious cause of hepatitis in tropical countries. Less frequently, in children and immunosuppressed patients, the liver is affected in the course of rubella, adenovirus, herpesvirus, or enterovirus infections. |
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143. What is the hepatitis A virus?
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HAV is a self limited disease with an incubation period of 2-6 weeks. HAV does not cause chronic hepatitis or a carrier state and only rarely causes fulminant hepatitis, so the fatality rate is very low.
HAV occurs throughout the world and is endemic in countries with substandard hygiene and sanitation. |
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144. What are the characteristics of HAV?
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HAV is a small, nonenveloped, single-stranded RNA virus that is spread by ingestion of contaminated water and foods and is shed in the stool for 2-3 weeks before and 1 week after the onset of jaundice. Thus, close personal contact w/an infected individual or fecal oral contamination during this period accounts for most cases.
It can also be spread via consumption of raw or steamed shellfish which are contaminated with sewage. |
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145. How is the serologic Dx of HAV made?
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Anti HAV-IgM appears in the blood at the onset of symptoms. Fecal shedding of the virus ends as the IgM titer rises.
The IgM response usually begins to decline in a few months and is followed by the appearance of IgG anti-HAV. The latter persists for years, perhaps for life. Hence, the HAV vaccine is effective. |
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146. What are the five possible outcomes in HBV?
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1. Acute hepatitis with resolution
2. Chronic hepatitis, which may evolve to cirrhosis 3. Fulminant hepatitis with massive liver necrosis 4. The backdrop for HDV infection 5. HCC |
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147. What are the characteristics of HBV infection?
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HBC has a prolonged incubation period (4-26 weeks). Unlike HAV, HBV remains in the blood up to and during active episodes of acute and chronic hepatitis. It is also present in all physiologic and pathologic body fluids, w/the exception of stool. HBC is a hardy virus and can withstand extremes of temp and humidity.
Thus, whereas blood and body fluids are the primary vehicles of transmission, virus may also be spread via contact w/body secretions such as semen, saliva, sweat, tears, breast milk, and pathologic effusions. |
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148. What are high risks for contracting HBV?
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Transfusion, blood products, dialysis, needle-stick accidents, IV drug abuse and homosexual activity constitute the primary risk categories for HBV infection.
Also, spread from an infected mother to a neonate during birth (vertical transmission) is common. These neonatal infections often lead to the carrier state for life. |
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149. What is the HBV?
What are the four parts of the virus? |
HBV is a member of the Hepadnaviridae, a family of DNA containing viruses that cause hepatitis in multiple animal species.
It consists of: 1. A nucleocapsid core protein (HBcAg), with a precore and core region (HBeAg). The precore region directs the HbEAg toward secretion into blood, whereas HBcAg remains in hepatocytes for the assembly of complete virions. 2. Envelope glycoprotein (HBsAg) 3. A DNA polymerase that exhibits reverse transcriptase activity 4. A protein from the X region, which is necessary for virus replication and acts as a transcriptional transactivator of the viral genes and a wide variety of host genes. |
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150. What are the two phases in HBV infection of a hepatocyte?
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1. *Proliferative phase, where HBV-DNA is present in episomal form, with formation of complete virions and antigens. HBsAg and HBcAg in association MHC class I molecules leads to activation of CD8+ cytotoxic T lymphocytes. Hepatocyte destruction occurs if a cytotoxic T lymphocyte interacts w/the infected hepatocyte.
2. For the infected hepatocytes that are not destroyed by the immune system, an *integrative phase may occur in which viral DNA is incorporated into the host genome. |
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151. What is the pathogenesis of liver injury in HBV?
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HBV is not directly toxic to liver cells; instead it is the immune response to viral antigens, expressed on infected hepatocytes, that cause liver cell injury.
HBV evokes both a humoral and cellular immune response, the latter involving both CD4+ helper T cells and CD8+ cytotoxic T cells. Whereas on one hand, cytotoxic T cells mediate hepatocellular injury, on the other hand, they also help clear the infection by destroying the intracellular reservoirs of HBV. |
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152. When does HBsAg appear?
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HBsAg appears before the onset of symptoms, peaks during overt disease, and the declines to undetectable levels in 3-6 months.
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153. When does HBeAg appear?
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HBeAg, HBV-DNA, and DNA polymerase appear in the serum soon after HBsAg, and all signify active viral replication.
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154. When does IgM anti-HBc become detectable?
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IgM anti-HBc becomes detectable in serum shortly before the onset of symptoms, concurrent w/the onset of elevation of serum aminotransferases.
Over months, the IgM antibody is replaced by IgG anti-Hbc. |
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155. When does Anti-HBe become detectable?
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Anti-HBe is detectable shortly after the disappearance of HBeAg, implying that the acute infection has peaked and the disease is on the wane.
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156. When does IgG anti-Hbs become detectable?
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IgG anti-HBs does not rise until the acute disease is over and is usually not detectable for a few weeks to several months after the disappearance of HBsAg.
Anti-Hbs may persist for life, conferring protection; this is the basis for current vaccination strategies using noninfectious HBsAg. |
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157. What designates the carrier state in HBV?
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The carrier state is defined by the presence of HBsAg in serum for 6+ months after initial detection.
The presence of HBsAg alone does not necessarily indicate replication of complete virions, and patients may be asymptomatic and w/o liver damage. |
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158. What does the serologic profile look like of someone who has a chronic replication of HBV virions?
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Chronic replication of HBV virions is characterized by persistence of:
HBsAg HBeAg HBV-DNA Anti-HBc Anti-HBs |
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159. What is the HCV?
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HCV is a major cause of liver disease. It is the most common chronic blood-borne infection and accounts for almost half of all patients in the US w/chronic liver disease.
The major routes of transmission are inoculations and blood transfusions. IV drug use accounts for 60% of cases, transfusions prior to '91 account for 10%, and hemodialysis patients and healthcare workers make up less than 5%. Sexual transmission is the only presumed risk factor in 15% of cases. |
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160. What type of liver disease does HCV cause?
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Acute HCV infection is generally undetectable. In contrast to HBV, progression to chronic disease occurs in the majority of individuals infected w/HCV, and cirrhosis eventually occurs in approx 20% of patients.
**Persistent infection and chronic hepatitis are the hallmarks of HCV infection. |
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161. What type of virus is HCV?
|
HCV is a small, enveloped, single stranded RNA virus. The virus is not that hardy, however, and it is inherently unstable which gives rise to multiple genotypes and subtypes. Over time, several dozen mutant strains can be detected within one individual. THe E2 protein of the envelope is the target of many anti-HCV antibodies but it is also the most variable region of the entire viral genome, enabling emergent virus strains to escape from neutralizing antibodies.
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162. Give me more info on this variability of HCV...
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In particular, elevated titers of anti-HCV IgG occurring after an active infection do not confer effective immunity. Moreover, HCV is able to actively evade the interferon mediated cellular antiviral response, b/c E2 and NS5A inhibit the interferon induced double-stranded RNA-activated protein kinase, which is involved in the antiviral response to IFN.
A characteristic feature of HCV infection, therefore, is repeated bouts of hepatic damage, the result of reactivation of a preexisting infection or emergence of an endogenous, newly mutated strain. |
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163. What is the serologic profile for HCV?
|
HCV RNA is detectable in blood for 1-3 weeks, coincident w/elevations in serum transaminases. In symptomatic acute HCV infection, anti-HCV antibodies are detected in only 50-70% of patients; in the remaining, the anti-HCV antibodies emerge after 3-6 weeks.
In chronic HCV infection, circulating HCV RNA persists in many patients. *A clinical feature that is quite characteristic of chronic HCV infection is episodic elevations in serum aminotransferases, with intervening normal or near-normal periods. |
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164. What is HDV?
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HDV is a unique RNA virus that is replication defective, causing infection only when it is encapsulated by HBsAg. Thus, HDV is absolutely dependent on the genetic information provided by HBV for multiplication and causes hepatitis only in the presence of HBV.
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165. What are the two settings in which HDV arises?
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1. Acute coinfection occurs following exposure to serum containing both HDV and HBV. The HBV must become established first to provide the HBsAg necessary for development of complete HDV virions.
2. Superinfection of a chronic carrier of HBV w/a new inoculum of HDV (and HBV) results in disease about 30-50 days later. The carrier may have been previously healthy or may have had underlying chronic hepatitis. |
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166. What are the clinical symptoms of HDV?
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Simultaneous coinfection w/HBV and HDV results in hepatitis ranging from mild to fulminant, fulminant disease being more likely than w/HBV alone.
Chronicity rarely develops. When HDV is superimposed on chronic HBV infection, (1) acute severe hepatitis may result, (2) mild HBV hepatitis may be converted into fulminant disease, and/or (3) chronic, progressive disease may develop (in 80% of patients), often culminating in cirrhosis. |
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167. How is HDV spread?
|
HDV infection is uncommon and is largely restricted to drug addicts and hemophiliacs. Other groups at risk for HBV, such as homosexual men and health care workers are at low risk for HDV infection, for unclear reasons.
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168. What are the characteristics of the HDV?
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HDV is a double-shelled particle that resembles HBV. The external coat antigen of HBsAg surrounds an internal polypeptide assembly, designated HDAg.
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169. What is the serologic profile of HDV?
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HDV RNA is detectable in the blood and liver just prior to and in the early days of acute symptomatic disease. IgM anti-HDV is the most reliable indicator of recent HDV exposure, although its appearance is late and freq short lived.
Nevertheless, acute coinfection by HDV and HBV is best indicated by detection of IgM against both HDAg and HBcAg. |
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170. What is HEV?
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HEV hepatitis is an enterically transmitted, water-borne infection that occurs primarily in young-to middle-aged adults; sporadic infection and overt illness in children are rare.
A characteristic feature of HEV infection is the high mortality rate among pregnant women, approaching 20%. In most cases, the disease is self-limiting; HEV is not associated w/chronic liver disease or persistent viremia. The average incubation period following exposure is 6 weeks. |
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171. What type of virus is HEV?
|
HEV is an uneveloped, single-stranded RNA virus that is structually similar to the Caliciviridae. A specific antigen (HEV Ag) can be identified in the cytoplasm of hepatocytes during active infection, and virions are shed in stool during the acute illness.
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172. What is the serologic profile of HEV?
|
Before the onset of clinical illness, HEV RNA and HEV virions can be detected in stool and liver. The onset of rising serum aminotransferases, clinical illness, and elevated IgM anti-HEV titers are virtually simultaneous. Symptoms resolve in 2-4 weeks, during which time the IgM is replaced w/a persistent IgG anti-HEV titer.
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173. What is HGV infection?
|
In up to 75% of infections, HGV is cleared from plasma; in the remainder of cases, HGV infection becomes chronic.
The site of HGV replication is most likely in mononuclear cells; hence, HGV is inappropriately names, as it is not hepatotropic and does not cause elevations in serum aminotransferases. This virus commonly co-infects patients with HIV, and curiously this dual infection is somewhat protective against HIV disease. |
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174. What are four clinical syndromes that may develop following exposure to hepatitis viruses?
|
1. Acute asymptomatic infection w/recovery; serologic evidence only
2. Acute symptomatic hepatitis w/recovery; anicteric or iteric 3. Chronic hepatitis; without or with progression to cirrhosis 4. Fulminant hepatitis; with massive to submassive hepatic necrosis |
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175. What type of people fall into the acute asymptomatic infection w/recovery group?
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Patients in this group are identified only incidentally on the basis of minimally elevated serum transaminases or by the presence of antiviral antibodies.
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176. What are the four phases of acute symptomatic infection with recovery?
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1. An incubation period
2. A symptomatic preicteric phase 3. A symptomatic icteric phase 4. Convalescence |
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177. What defines the preicteric phase?
|
The preicteric phase is marked by nonspecific, constitutional symptoms. Malaise is followed in a few days by general fatigueability, nausea, and loss of appetite. Weight loss, low grade fever, headaches, muscle and joint aches, and pains and diarrhea are inconstant symptoms.
About 10% of patients w/acute hepatitis (most often HBV), develop a serum sickness like syndrome, which may be due to elevated transaminases. Physical exam reveals a mildly enlarged, tender liver. In some patients, the nonspecific symptoms are more severe, w/higher fever, shaking chills and headache, and sometimes accompanied by right upper quadrant pain and tender liver enlargement. |
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178. What defines the icteric phase?
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The icteric phase, if it appears, is caused by conjugated hyperbilirubinemia. Icteric hepatitis is usual in adults (but not children) with acute HAV infection, but it is absent in about 1/2 the cases of HBV and in the majority of HCV cases.
Dark colored urine and light gray colored stools are common. The liver may be mildly enlarged and moderately tender to percussion. Prolonged PT time and hyperglobulinemia is common. Recovery is heralded by the generation of strong T cell responses against viral antigens expressed on infected liver cells. |
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179. What defines chronic hepatitis?
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Chronic hepatitis is defined as symptomatic, biochemical or serologic evidence of continuing or relapsing hepatic disease for more than 6 mos, with histologically documented inflammation and necrosis.
Chronic viral hepatitis constitutes a carrier state, in that these individuals harbor replicating virus and therefore can transmit an organism. However, in all instance of chronic hepatitis, etiology is the single most important indicator of likelihood to progress to cirrhosis. |
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180. What populations develop chronic hepatitis after viral infection?
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HAV: none
HBV: over 90% in infected neonates; 10% of adults HCV: over 60% HDV: rarely in acute HBV/HDV coinfection but is the most freq outcome of HDV superinfection of HBV-infected patient HEV: none |
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181. What are common morphologic features found in acute and chronic hepatitis?
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These morphologic changes can be mimicked by drug reactions. Tissue alterations caused by acute infection w/HAV, HBV, HCV, and HEV are similar, as is the chronic hepatitis caused by HBV, HCV, and HBV + HDV.
HBV-infected hepatocytes may exhibit a cytoplasm packed w/spheres and tubules of HBsAg, producing a finely granular eosinophilic cytoplasm "Ground glass hepatocytes". HCV infected livers freq show lymphoid aggregates within portal tracts and focal sublobular regions of hepatocyte macrovesicular steatosis, which are to be distinguished from the extensive panlobular microvescular and macrovesicular steatosis seen in many forms of toxic hepatitis. |
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182. What are the morphologic features of acute hepatitis?
1/2 |
With acute hepatitis, hepatocyte injury takes the form of diffuse swelling ("ballooning degeneration"), so the cytoplasm looks empty and contains only scattered eosinophilic remnants of cytoplasmic organelles.
An inconstant finding is cholestasis, with bile plugs in canaliculi and brown pigmentation of hepatocytes. The canalicular bile plugs result from cessation of the contractile activity of the hepatocyte pericanalicular actin microfilament web. |
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183. What are the two patterns of hepatocyte cell death in acute hepatitis?
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1. Rupture of cell membranes leads to cytolysis and focal loss of hepatocytes. The sinusoidal collagen reticulin framework collapses where the cells have disappeared, and scavenger macrophage aggregates mark sites of hepatocyte cell loss.
2. Apoptosis, which is more consipicuous. It is caused by anti-viral cytotoxic T cells. Apoptotic hepatocytes shrink, become intensely eosinophilic, and have fragmented nuceli; effector T cells may still be present in the immediate vicinity. |
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184. What are the morphologic features of acute hepatitis?
2/2 |
In severe cases of acute hepatitis, confluent necrosis of hepatocytes may lead to bridging necrosis connecting portal-to-portal, central-to-central, or portal-to-central regions of adjacent lobules. Hepatocyte swelling and regeneration compress sinusoids, and the more or less radial array of the parenchyma is lost.
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185. What is a prominent feature of acute hepatitis?
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Inflammation is a characteristic and usually prominent feature of acute hepatitis. Kupffer cells undergo hypertrophy and hyperplasia and are often laden with lipofuscin pigment due to phagocytosis of hepatocellular debris.
*The portal tracts are usually infiltrated w/a mixture of inflammatory cells. The inflammatory infiltrate may spill over into the adjacent parenchyma to cause necrosis of periportal hepatocytes - interface hepatitis. |
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186. What are the morphologic features of chronic hepatitis?
1/3 |
The histologic features of chronic hepatitis range from exceedingly mild to severe. In the mildest forms, significant inflammation is limited to portal tracts and consists of lymphocytes, macrophages, occasional plasma cells, and rare neutrophils or eosinophils. Liver architecture is usually well preserved, but smoldering hepatocyte necrosis throughout the lobule may occur.
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187. What are the morphologic features of chronic hepatitis?
2/3 |
Common finding are lymphoid aggregates and bile duct damage in the portal tracts and focally mild to moderate macrovesicular steatosis.
In all forms of chronic hepatitis, continued interface hepatitis and bridging necrosis are harbingers of progressive liver damage. *The hallmark of irreversible liver damage is the deposition of fibrous material. At first, only portal tracts show fibrosis; but with time, periportal septa fibrosis occurs, followed by linking of fibrous septa between lobules occurs (bridging fibrosis). |
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188. What are the morphologic features of chronic hepatitis?
3/3 |
Continued loss of hepatocytes and fibrosis results in cirrhosis, with fibrous septae and hepatocyte generative nodules.
This pattern of cirrhosis is characterized by irregularly sized nodules separated by variable but mostly broad scars. |
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189. What is fulminant hepatitis?
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When hepatic insufficiency progresses from onset of symptoms to hepatic encephalopathy within 2-3 weeks, it is termed fulminant hepatic failure.
A less rapid course, extending up to 3 months, is called subfulminant failure. |
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190. What are three major causes of fulminant hepatitis?
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1. In the US, fulminant viral hepatitis is responsible for about 12% of cases of fulminant hepatic failure; almost all are due to HAV or HBV.
2. Drug and chemical toxicity account for a substantial remainder (52%). 3. Misc or unknown (18%) |
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191. What is the morphology of fulminant hepatitis?
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The entire liver may be involved or only random areas. The liver may be transformed into a limp, red organ covered by a wrinkled, too-large capsule. On transection, necrotic areas have a muddy red, mushy appearance with blotchy bile staining. Microscopically, complete destruction of hepatocytes in contiguous lobules leaves only a collapsed reticulin framework and preserved portal tracts.
There may be little inflammatory reaction; alternatively, with survival for several days, there is a massive influx of inflammatory cells to begin the phagocytic cleanup process. |
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192. If a patient with fulminant hepatitis survives for more than a week, what morphologic changes take place?
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Survival for more than a week also permits secondary regenerative activity of surviving hepatocytes and bile ducts.
A dormant stem cell population lying alongside the bile ducts and canals of Hering also proliferates, creating a population of small cells with a high nuclear:cytopalsmic ratio (so called oval cells) interspersed with surviving hepatocytes. |
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193. What morphologic changes take place in the liver when large amts of hepatotoxins are introduced, or during ischemia?
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With centrilobular zonal necrosis caused by direct hepatotoxins or ischemia, the parenchymal framework is preserved. Regeneration is directly from hepatocytes, and native liver architecture is restored in time.
With more massive destruction of confluent lobules, regeneration is disorderly, yielding nodular masses of liver cells that produce a more irregular liver on healing. |
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194. What are the clinical features of fulminant hepatic failure?
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Fulminant hepatic failure may present as jaundice, ecephalopathy, and fetor hepaticus.
Life threatening extrahepatic complications include coagulopathy and bleeding, cardiovascular instability, renal failure, ARDS, electrolyte and acid-base disturbances and sepsis. The overall mortality rate ranges from 25-90% in the absence of liver transplantation. |
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196. What is the morphology of liver abcesses?
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Liver abscesses may occur as solitary or multiple lesions, ranging in size from mm's to massive lesions many cm's in diameter. Bactermic spread thru the arterial or portal system tends to produce multiple small abscesses, whereas direct extension and trauma usually cause solitary large abscesses.
Biliary abscesses, which are usually multiple, may contain purulent material from adjacent bile ducts. The causative organism can occasionally be identified in the case of fungal or parasitic abscesses. On rare occasion, abscesses located in the subdiaphragmatic region, particularly amebic, may burrow into the thoracic cavity to produce empyema or a lung abscess. |
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197. What are the clinical features of liver abscesses?
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Liver abscesses are associated w/fever and in many instances, right upper quadrant pain and tender hepatomegaly. Jaundice may result from extrahepatic biliary obstruction. Although antibiotic therapy may control smaller lesions, surgical drainage is often necessary for the large lesions.
B/c Dx is freq delayed and b/c patients are often elderly and have serious coexistent disease, the mortality rate w/large liver abscesses ranges from 30-90%. W/early recognition and management, up to 80% can survive. |
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198. What are the five sources of infection in liver abscesses?
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1. Portal vein
2. Arterial supply 3. Ascending infection in the biliary tract (ascending cholangitis) 4. Direct invasion of the liver from a nearby source 5. A penetrating injury *The majority of hepatic primarily spread thru the biliary tree or the arterial supply in patients suffering from some form of immune deficiency. |
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199. What is autoimmune hepatitis?
|
Autoimmune hepatitis is a chronic hepatitis w/histologic features that may be indistinguishable from those of chronic viral hepatitis. This disease may run an indolent or severe course.
Clinical presentation is often similar to other forms of chronic hepatitis, and autoimmune hepatitis may progress to cirrhosis w/o clinical Dx. In untreated severe disease, as many as 40% of patients die w/in 6 months of Dx, and cirrhosis develops in at least 40% of survivors. |
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200. What are the important features of autoimmune hepatitis?
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1. Female predominance (78%), particularly in the young and perimenopausal women.
2. The absence of viral serologic markers 3. Elevated serum IgG and γ-globulin levels (>1.5x normal) 4. High serum titers of autoantibodies in 80% of cases, including antinucear, antismooth muscles, and/or antiliver/kidney microsomes antibodies 5. Negative antimitochondrial antibody |
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201. What are the two subgroups of autoimmune hepatitis?
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1. The most common, type 1, exhibiting ANA and/or SMA serum markers
2. The type 2 subgroup of younger patients exhibits antibodies to liver/kidney microsomes (anti-LKM1). |
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202. What are the three types of injuries in drug- and toxin-induced liver disease?
|
Injury may result from:
1. Direct toxicity 2. Via hepatic conversion of a xenobiotic to an active toxin 3. Through immune mechanisms, usually by a drug or a metabolite acting as a hapten to convert a cellular protein into an immunogen. |
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203. What are the two types of drug reactions?
|
1. Predictable (intrinsic)
-Occurs in anyone who accumulates a sufficient dose 2. Unpredictable (idiosyncratic) -Depends on idiosyncrasies of the host, particularly the rate at which the host metabolizes the agent and the host's propensity to mount an immune response to the antigenic stimulus. |
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204. What are four important points regarding drug and toxin induced hepatic injury?
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1. The injury may be immediate or may take weeks to months to develop, presenting only after severe liver damage has developed.
2. The injury may take the form of hepatocyte necrosis, cholestasis, or insidious onset of liver dysfunction. 3. Drug-induced chronic hepatitis is clinically and histologically indistinguishable from chronic viral hepatitis; hence, serologic markers of viral infection are critical for making the distinction. 4. In EtOH induced liver disease, the microvesicular and macrovesicular steatosis both arise form the same etiology: the production of excess reducing equivalents (NADH + H) owing to the metabolism of ethanol. |
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205. What are examples of predictable drug reactions?
|
Hepatic injury is considered predictable from overdoses of acetaminophen, and exposure to Amanita phalloides toxin, carbon tetrachloride, and alcohol.
However, individual genetic differences in the hepatic metabolism of xenobiotics thru activating and detox pathways play a major role in the susceptibility to "predictable" hepatotoxins. |
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206. What are examples of idiosyncratic drug reactions?
|
Many other xenobiotics, such as sulfonamides, α-methyldopa, and allopurinol, cause idiosyncratic reactions.
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207. What is Reye syndrome, again?
|
Reye syndrome, a potentially fatal syndrome of mitochondrial dysfunction in liver, brain, and elsewhere, occurs predominantly in children who are given acetylsalicylic acid from the relief of fever.
This disease, which features extensive accumulation of fat droplets within hepatocytes (microvesicular steatosis), is exceedingly rare. |
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208. What are the three distinctive forms of liver disease due to EtOH?
|
1. Hepatic steatosis
2. Alcoholic hepatitis 3. Cirrhosis |
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209. What is the morphology of hepatic steatosis due to EtOH disease?
1/2 |
Following even moderate intake of EtOH, small microvesicular lipid droplets accumulate in hepatocytes. W/chronic intake, lipid accumulates to the point of creating large, clear macrovesicular globules, compressing and displacing the nucleus to the periphery of the hepatocyte. This transformation is initially centrilobular but in severe cases it can involve the entire lobule.
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210. What is the morphology of hepatic steatosis due to EtOH disease?
2/2 |
Macroscopically, the fatty liver of an alcoholic is a large, soft organ that is yellow and greasy.
Although there is little or no fibrosis at the outset, w/continued EtOH intake, fibrous tissue develops around the terminal hepatic veins and extends into the adjacent sinusoids. *The fatty change is completely reversible if there is abstention from further intake of EtOH. |
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211. What are four important features of alcoholic hepatitis?
|
1. Hepatocyte swelling and necrosis
2. Mallory bodies 3. Neutrophilic reaction 4. Fibrosis |
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212. What are mallory bodies?
|
Scattered hepatocytes accumulate tangled skeins of cytokeratin intermediate filaments and other proteins, visible as eosinophilic cytoplasmic inclusions in degenerating hepatocytes. These inclusions are a characteristic but not specific feature of alcoholic liver disease, as they are also seen in primary biliary cirrhosis, Wilson disease, chronic cholestatic syndromes, and hepatocellular tumors.
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213. What is the neutrophilic reaction?
|
Neutrophils permeate the lobule and accumulate around generating hepatocytes, particularly those having Mallory bodies. Lymphocytes and macrophages also enter portal tracts and spill into the parenchyma.
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214. What is the morphologic appearance of the liver in alcoholic hepatitis?
|
Although steatotic hepatocytes are present, they are interspersed with the inflammatory cells and activated stellate cells.
In macroscopic appearance, the liver is mottled red w/bile-stained areas. Although the liver may be of normal or increased size, it often contains visible nodules and fibrosis, indicative or evolution to cirrhosis. |
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215. What is alcoholic cirrhosis?
|
The final and irreversible form of alcoholic liver disease usually evolves slowly and insidiously. At first, the cirrhotic liver is yellow-tan, fatty, and enlarged, usually over 2 kg. Over the span of years, it is transformed into a brown, shrunken, nonfatty organ, sometimes less than 1 kg in weight.
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216. What is the morphologic appearance of the liver in alcoholic cirrhosis?
|
Initially, the developing fibrous septae are delicate and extend thru sinusoids from central to portal regions as well as from portal tract to portal tract.
With time, the nodularity becomes more prominent; scattered larger nodules create a "hobnail" appearance on the surface of the liver. As fibrous septae dissect and surround nodules, the liver becomes more fibrotic, loses fat, and shrinks progressively in size. *Ischemic necrosis and fibrous obliteration of nodules eventually create broad expanses of tough, pale scar tissue ("Laennec cirrhosis"). |
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217. SUMMARIZE the morphologic appearance of the liver in alcoholic cirrhosis...
|
Bile stasis often develops; Mallory bodies are only rarely evident at this stage.
Thus, end stage alcoholic cirrhosis comes to resemble, both macroscopically and microscopically, the cirrhosis developing from viral hepatitis and other causes. |
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218. Why does alcohol cause steatosis?
|
Steatosis results from (1) shunting of substrates toward lipid biosynthesis, (2) impaired lipoprotein assembly and secretion, and (3) increased peripheral catabolism of fat.
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219. Why does alcohol sensitize the liver to oxidative injury?
|
Alcohol-induced impaired hepatic metabolism of methionine results in decreased intrahepatic glutathione (GSH) levels, thereby sensitizing the liver to oxidative injury.
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220. How does alcohol affect cellular function?
|
As a solute at millimolar levels, alcohol directly affects microtubular and mitochondrial function and membrane fluidity.
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221. How does acetaldehyde affect cellular and hepatocellular function?
|
Acetaldehyde (the major intermediate metabolite of alcohol en route to acetate production) induces lipid peroxidation and acetaldehyde-protein adduct formation, further disrupting cytoskeletal and membrane function.
Alcohol induced and acetaldehyde-induced changes in heaptocellular proteins create new epitopes to which the immune system reacts, producing inflammation and immune-mediated heaptocellular injury. |
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222. How would you define alcoholic liver disease?
|
Alcoholic liver disease is a chronic disorder featuring steatosis, hepatitis, progressive fibrosis, cirrhosis, and marked derangement of vascular perfusion.
In essence, alcoholic liver disease can be regarded as a maladaptive state in which cells in the liver respond to an increasingly pathologic manner to a stimulus (EtOH) that was only marginally harmful. |
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223. What are the five proximate causes of death in the end-stage alcoholic?
|
1. Hepatic coma
2. A massive GI hemorrhage 3. An intercurrent infection (to which these patients are predisposed) 4. Hepatorenal syndrome following a bout of alcoholic hepatitis 5. HCC in 3-6% of cases |
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224. What is nonalcoholic fatty liver disease and steatohepatitis?
|
Nonalcoholic fatty liver disease is a condition that resemble alcohol induced liver disease but occurs in patients who are not heavy drinkers.
There are strong associations w/obesity, dyslipidemia, hyperinsulinemia, and insulin resistance, and overt type 2 DM. Steatohepatitis, or NASH, is an intermediate form of liver damage. |
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225. What is the morphology of nonalcoholic fatty liver disease?
|
This condition features liver biopsy findings of steatosis. Large and small vesicles of fat, predominantly TAGs, accumulate within hepatocytes. At the most clinically benign end of the spectrum, there is no appreciable hepatic inflammation, hepatocyte death, or scarring.
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226. What is the morphology of steatohepatitis?
|
Liver biospy shows steatosis, multifocal parenchymal inflammation, Mallory hyaline, hepatocyte death (both ballooning degeneration and apoptosis), and sinusoidal fibrosis.
Cirrhosis may occur. |
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227. What is hemochromatosis?
|
Hemochromatosis is characterized by the excessive accumulation of body iron, most of which is deposited in parenchymal organs such as the liver and pancreas. B/c humans do not have a major excretory pathway for iron, hemochromatosis results either from a genetic defect causing excessive iron absorption or as a consequence of parenteral administration of iron (i.e. transfusions).
Hereditary hemochromatosis is a homozygous-recessive inherited disorder; acquired forms of hemochromatosis w/known sources of excess iron are called secondary hemochromatosis. |
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228. What features characterize hemochromatosis?
|
1. Fully developed cases exhibit (1) micronodular cirrhosis in all patients; (2) DM; and (3) skin pigmentation
2. Iron accumulation is lifelong; symptoms usually first appear in the 5th-6th decades of life 3. The hemochromatosis gene is called HFE, and regulates intestinal absorption of dietary iron; a cysteine to tyrosine substitution is the most common and this inactivates HFE 4. Males predominate with slightly earlier clinical presentation |
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229. What genetic alterations cause hemochromatosis?
|
The hemochromatosis gene is called HFE, and regulates intestinal absorption of dietary iron.
The most common HFE mutation is a cysteine to tyrosine substitution at amino acid 282 (called C282Y), which inactivates this protein. The HFEgene is in linkage disequilibrium w/HLA-A3, thus accounting for the association of this haplotype w/hereditary hemochromatosis. |
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230. How does the body balance iron levels?
|
The critical site for HFE expression appears to be the basolateral surface of the small intestinal crypt epithelial cells. HFE complexes w/the transferrin receptor, TfR, enabling the binding of plasma transferring and its bound iron.
The TfR-Tf-iron complex is endocytosed into the crypt enterocyte; acidification of the endosome releases iron into the regulatory iron pool of the crypt cell. This is a sensing mechanism for the systemic iron balance, as increased levels of circulating iron bound to transferrin will lead to an increased iron regulatory pool in enterocytes. This pool sets the level of expression of apical iron uptake systems. |
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231. What is the pathogenesis in hereditary hemochromatosis?
|
Crypt cells w/mutant HFE lack the facilitating effect on TfR-dependent iron uptake, thus decreasing the regulatory iron pool in the crypt cell.
As small intestinal crypt cells are the progenitors of villus absorptive cells, these cells are preprogrammed to absorb dietary iron regardless of the systemic iron overload. |
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232. By what three mechanisms is excessive iron toxic to host tissues?
|
1. Lipid peroxidation via iron-catalyzed free radical reactions
2. Stimulation of collagen formation 3. Interactions of ROS and iron itself w/DNA, leading to lethal injury or predisposition to HCC. |
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233. What are the most common causes of secondary hemochromatosis?
|
Hemolytic anemias associated w/ineffective erythropoiesis. In these disorders, the excess iron may result not only from transfusions, but also from increased absorption.
Transfusions alone, as in aplastic anemias, lead to systemic hemosiderosis in which parenchymal organ injury tends to occur only in extreme cases. |
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234. What is Bantu-siderosis?
|
A rather unusual form of iron overload resembling hereditary hemochromatosis occurs in sub-Saharan Africa, the result of ingesting large quantities of alcoholic beverages fermented in iron utensils.
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235. What are the three key morphologic features in hereditary hemochromatosis?
|
1. Deposition of hemosiderin in the liver, pancreas, myocardium, pituitary, adrenal, thyroid, and PTH glands, joints, and skin
2. Cirrhosis 3. Pancreatic fibrosis |
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236. How does the liver look in hemochromatosis?
|
In the liver, iron becomes evident first as golden-yellow hemosiderin granules in the cytoplasm of periportal hepatocytes, which stain blue w/the Prussian blue stain.
With increasing iron load, there is progressive involvement of the rest of the lobule, along w/bile duct epithelium and Kupffer cell pigmentation. Since iron is a direct hepatotoxin, inflammation is characteristically absent. At this stage, the liver is typically slightly larger than normal, dense, and chocolate brown. |
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237. What is the standard for quantitating hepatic iron content?
|
Biochemical determination of hepatic iron concentration in unfixed tissue is the standard for quantitating hepatic iron content.
Hepatic iron concentrations above 22,000μg per gram dry weight are associated w/the development of fibrosis and cirrhosis. |
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238. What other morphologic characteristics occur in other organs in hemochromatosis?
|
1. The pancreas becomes intensely pigmented
2. The heart is often enlarged and has hemosiderin granules within the myocardial fibers 3. Skin pigmentation due to increased epidermal melanin production, causing a slate-gay color to the skin 4. Hemosiderin deposition in the joint synovial linings causes an acute synovitis and can lead to pseudo-gout 5. The testes may be small and trophic which results indirectly from alterations at the HPA axis. |
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239. What are the clinical features of hemochromatosis?
|
Hereditary hemochromatosis presents at age 20 - 30 with hepatomegaly, abdominal pain, skin pigmentation, DM, cardiac dysfunction, arthritis, and hypogonadism.
Potentially fatal complication occur from cirrhosis (incl. HCC) and cardiac involvement. Regular phlebotomy is sufficient treatment; screening of family members of probands is important. |
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240. What is Wilson disease?
|
Wilson disease is an autosomal-recessive disorder marked by the accumulation of toxic levels of copper in many tissues and organs, principally the liver, brain, and eye.
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241. What is the pathogenesis of Wilson disease?
|
The genetic defect is in the ATP7B gene on chromosome 13. This gene encodes a hepatocyte canalicular membrane transmembrane copper-transporting ATPase.
Copper absorption and delivery to the liver is normal, but there is increased hepatic export into the circulation most likely due to defective secretion of copper into bile. |
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242. What are the common genetic defects in Wilson disease?
|
Over 30 mutations in ATP7B have been identified. The overwhelming majority of patients are compound heterozygotes containing different mutations of the Wilson disease gene on each allele.
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243. How does defective biliary excretion lead to copper accumulation?
|
Defective biliary excretion leads to copper accumulation in the liver in excess of the metallothionein-binding capacity, causing toxic liver injury thru copper-catalyzed formation of ROS.
Usually by 5 years of age, the non-ceruloplasmin-bound copper spills over from the liver into the circulation, causing hemolysis and pathologic changes in other sites. |
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244. What is the morphology of Wilson disease?
|
The liver often bears the brunt of injury in Wilson disease, with hepatic changes ranging from minor to massive damage. Fatty change may be present, with vacuolated nuclei and occasionally focal hepatocyte necrosis. Acute and chronic hepatitis (with Mallory bodies), cirrhosis, and (rarely) massive liver necrosis can occur.
Toxicity in the brain predominantly affects the basal ganglia, which becomes atrophied and even cavitated. *Nearly all patients with neurological involvement develop Kayser-Fleischer rings in the eyes. |
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245. What is the clinical course of Wilson disease?
|
Age at onset and clinical presentation are variable; typically there will be some liver disease in the first couple decades of life. Neuropsychiatric disorders are also possible, including mild behavioral changes, frank psychosis, and Parkinson disease-like symptoms.
Dx is suggested by decreased serum ceruloplasmin (a copper binding serum protein), increased hepatic copper content, and increased urinary copper excretion. Copper chelation therapy (as with D-penicillamine) can help. |
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246. What is α1-antitrypsin deficiency?
What is the major function of this protein? |
α1-antitrypsin deficiency is an autosomal recessive disorder marked by abnormally low serum levels of this important protease inhibitor.
The major function of this protein is the inhibition of proteases, particularly elastase, cathepsin G, and proteinase 3, which are normally released from neutrophils at sites of inflammation. α1-antitrypsin deficiency leads to the development of pulmonary emphysema and can also cause hepatic disease (cholestasis or cirrhosis). |
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247. What are the genetic defects in α1-antitrypsin deficiency?
What is the most common clinically significant mutation? |
α1-antitrypsin is a 394 AA serum protease inhibitor (Pi) synthesized primarily in the liver. The gene is very polymorphic and at least 75 α1-antitrypsin forms have been identified.
The most common genotype is PiMM, occurring in 90% of individuals with this disorder. *The most common clinically significant mutation is PiZ; homozygotes for the PiZZ protein have circulating α1-antitrypsin levels that are only 10% of normal. |
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248. What is the pathogenesis of α1-antitrypsin deficiency?
|
Deficiency variants exhibit a selective defect in migration of this secretory protein from the ER to Golgi apparatus; this is most marked for the PiZ polypeptide.
The mutant polypeptide α1AT-Z is abnormally folded, and polymerizes, causing its retention in the ER. All individuals w/the PiZZ genotype accumulate α1AT-Z in the ER of hepatocytes. |
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249. So... is the accumulation of α1AT-Z in the ER of hepatocytes toxic?
|
No, the accumulated α1AT-Z is not toxic per se, nor does the liver suffer from a lack of protease inhibitor activity.
***Rather, it is the intense autophagocytic response stimulated within hepatocytes, as an alternative degradative pathway, that appears to be the chief cause of liver injury, possibly by autophagocytosis of mitochrondria. |
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250. What is the morphology of α1-antitrypsin deficiency in the liver?
|
α1-antitrypsin deficiency is characterized by the presence of round-to-oval cytoplasmic globular inclusions in hepatocytes, which in routine H&E stains are acidophilic and indistinctly demarcated from the surrounding cytoplasm.
For the most part, the only distinctive features of the hepatic disease is the PAS-positive globules; infrequently, fatty change and Mallory bodies are absent. |
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251. What is the clinical course of α1-antitrypsin deficiency?
|
Neonatal hepatitis w/cholestatic jaundice occurs in 10-20% of newborns with α1-antitrypsin deficiency. Later presentation may be attributable to acute hepatitis or complications of cirrhosis.
HCC develops in 2-3% of PiZZ homozygous adults. Treatment is liver transplantation; avoidance of smoking is extremely important in patients with α1-antitrypsin deficiency, since smoking accentuates their lung emphysematous damage. |
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252. What is the name of the drug that acts as an inhibitor to viral attachment and entry?
In theory, why does it work? |
Enfuvirtide (T20)
All viruses must infect cells to replicate. Therefore, inhibiting the initial step of viral attachment and entry provides a conceptual "preventive" measure against infection and could limit the spread of virus throughout the body. |
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253. Enfuvirtide (T20)
|
MOA: Block HIV attachment and entry by inhibiting gp41-mediated fusion of the HIV envelope with the host protein.
PURPOSE: HIV ADVERSE: Guillain-Barre syndrome, renal insufficiency, thrombocytopenia, neutropenia, eosinophilia, peripheral neuropathy, sixth nerve palsy, conjuctivitis. CONTRA: Hypersensitivity NOTES: Enfuvirtide is a peptide that must be administered parenterally, w/2x daily injections. |
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254. What are the names of the two drugs that inhibit viral uncoating?
|
Amantadine and rimantadine
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255. Amantadine and Rimantadine (analogue)
|
MOA: Inhibit influenza A uncoating by blocking M2, a proton channel that acidifies the interior of the virus; acidification is necessary for dissociation of viral matrix protein from the viral ribonucleoprotein.
PURPOSE: Influenza A; Parkinsonism (amantadine) ADVERSE: Neuroleptic malignant syndrome, exacerbation of mental disorder; orthostatic hypotension, peripheral edema, GI disturbance, confusion, dizziness, insomnia, irritability, hallucination CONTRA: Hypersensitivity NOTES: Rimantadine causes fewer neurologic effects than amantadine, and it is commonly used as a prophylactic agent. |
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256. What are the names of the antiherpes nucleoside analogues?
|
1. Acyclovir
2. Valacyclovir 3. Famciclovir 4. Penciclovir 5. Ganciclovir 6. Valganciclovir |
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257. What is acyclovir?
How does it work? |
Acyclovir is a drug used against HSV and VZV. It is a nucleoside analogue that is selectively phosphorylated by HSV or VZV thymidine kinase to generate acyclovir monophosphate. Host cellular enzymes then sequentially phosphorylate acyclovir monophosphate to its diphosphate and triphosphate forms.
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258. What is the three step mechanism in which acyclovir triphosphate works to inhibit HSV virus DNA polymerase?
|
1. It acts as a competitive inhibitor of dGTP binding
2. It acts as a substrate and is base paired with dC in the template strand to become incorporated into the growing DNA chain, causing chain termination 3. It traps (or freezes) the polymerase on the ACV-terminated DNA chain when the new deoxyribonucleoside triphosphate binds ("dead end complex") |
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259. Acyclovir and valacyclovir
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MOA: Phosphorylation of drug by viral kinases leads to inhibition of DNA synthesis in virus infected cells
PURPOSE: HSV and VZV ADVERSE: Renal failure (IV admin), TTP in immunocompromised patients, encephalopathic changes, HUS, GI disturbance, agitation, dizziness CONTRA: hypersensitivity NOTES: Valacyclovir is a prodrug of acyclovir with better oral bioavailability. |
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260. Famciclovir and penciclovir
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MOA: Similar to that of acyclovir, (inhibits viral DNA polymerase) with only quantitative differences; it is more efficiently activated by HSV and VZV TK than is acyclovir, but penciclovir triphosphate is a less selective inhibitor of the viral DNA polymerases than is ACV triphosphate.
PURPOSE: HSV and VZV ADVERSE: Erythema multiforme, GI disturbance, headache CONTRA: Hypersensitivity NOTES: Famciclovir is a diacetyl 6-deoxy prodrug analogue of penciclovir, the active form of the drug. Penciclovir ointment is used to treat cold sores. |
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261. Ganciclovir and valganciclovir
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MOA: Also inhibit viral DNA polymerase. Ganciclovir more closely resembles the natural compound, dG, and this accounts for its greater toxicity and potency in treating CMV.
PURPOSE: CMV ADVERSE: Neutropenia, thrombocytopenia, anemia, fever, phlebitis CONTRA: Severe neutropenia or thrombocytopenia NOTE: Valganciclovir is a prodrug with better oral availability. *Ganciclovir is so toxic that it should be sued only for serious infections |
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262. What is an antisherpesvirus nucleoTide analogue?
How does it work? |
Cidofovir
With its phosphonate group, cidofovir mimics dCMP, and thus in effect, it is already phosphorylated. Therefore, it does not require viral kinases for its phosphorylation and therefore it is active against kinase-deficient viral mutants that are resistant to ganciclovir. It is further phosphorylated by cellular enzymes to yield an analogue of dCTP, which inhibits HSV DNA polymerases more potently than cellular DNA polymerases. |
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263. Cidofovir
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MOA: Cidofovir is phosphorylated by cellular enzymes, but then inhibits CMV DNA polymerase.
PURPOSE: CMV retinitis ADVERSE: Nephrotoxicity, neutropenia, metabolic acidosis, decreased intraocular pressure, GI disturbance, headache, rash CONTRA: Renal insufficiency, concomitant nephrotoxic agents, direct intraocular injection NOTES: ***Must be coadministered w/probenecid (probenecid inhibits a proximal tubule anion transporter and therefore decreases cidofovir excretion). It has a long half life, and requires only once weekly dosing. |
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264. Vidarabine, idoxuridine, and trifluridine
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MOA: Early anti-HSV drugs w/increased toxicity relative to other agents
PURPOSE: HSV keratitis, rarely vidarabine for severe HSV or VZV ADVERSE: Eye irritation, lacrimation, light intolerance CONTRA: Hypersensivity NOTES: Trifluidine is used as ophthalmic preparation |
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265. What are the anti-HIV and HBV nucleoside and nucleotide analogues?
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1. Zidovudine (AZT)
2. Stavudine (d4T) 3. Zalcitabine (ddC) 4. Lamivudine (3TC) 5. Emtricitabine (FTC) 6. Didanosine (ddI) 7. Abacavir 8. Tenofovir 9. Adefovir 10.. Entecavir |
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266. What is zidovudine (AZT)
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Zidovudine (AZT) is a nucleoside analogue. It is an obligatory chain-terminator.
AZT accumulates in almost all dividing cells int he body, not just infected cells. AZT triphosphate targets HIV RT and is a substantially more potent inhibitor of HIV RT than of the human DNA polymerases. |
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267. Selectivity of action of antiviral nucleoside analogues for viral and cellular kinases
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In order of selectivity of action against kinases:
Acyclovir : Viral TK >> Cellular kinases Ganciclovir: Viral UL97(kinase) > cellular kinases Zidovudine (AZT): Cellular kinase |
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268. Selectivity of action of antiviral nucleoside analogues for viral and cellular polymerases
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In order of selectivity of action against polymerases:
Acyclovir : Viral DNA polymerase >> Cellular DNA polymerase Ganciclovir: Viral DNA polymerase > Cellular DNA polymerase Zidovudine (AZT): Viral RT >> Cellular DNA polymerase |
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269. What is lamivudine (3TC)?
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Like AZT, 3TC is an obligatory chain terminator. Most analogues exhibit toxicities that are thought to be due to inhibition of mitochondrial DNA polymerase by drug triphosphates. Of these analogues, lamivudine appears to exhibit the least toxicity.
This may be related to its highly unusual structure: 3RC is an L-stereoisomer, not the standard D-stereoisomer, and it contains a sulfur atom in its five-membered ring. In addition to treating HIV infections, 3TC is also used in patients w/chronic HBV infections. |
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270. What is emtricitabine (FTC)?
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Emtricitabine (FTC) is a structural relative of 3TC. This compound can be administered just one daily.
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271.
1. Zidovudine (AZT) 2. Stavudine (d4T) 3. Zalcitabine (ddC) 4. Lamivudine (3TC) 5. Emtricitabine (FTC) 6. Didanosine (ddI) 7. Abacavir |
MOA: The anti-HIV nucleoside analogues are phosphorylated by cellular kinases, and then inhibit viral RT. Anti-HBV nucleoside analogues are also phosphorylated by cellular enzymes, but then inhibit HBV polymerase.
PURPOSE: HIV, HBV (lamivudine 3TC) ADVERSE: Neutropenia, anemia, pancreatitis, lactic acidosis, hepatomegaly with steatosis, optic neuritis, peripheral neuropathy, fatal hypersensitivity (abacavir) CONTRA: Hypersensitivity NOTES: Most toxicity is due to inhibition of mitochondrial DNA polymerase by drug triphosphates. |
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272. Tenofir, adefovir, and entacavir
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MOA: Anti-HIV ncueloside analogues are phosphorylated by cellular kinases, and then inhibit viral RT. Anti-HBV nucleoside analogues are also phosphorylated by cellular enzymes, but then inhibit HBV polymerase
PURPOSE: HIV (tenofovir), HBV (adefovir, entecavir) ADVERSE: Lactic acidosis, hepatotoxicity (tenofovir), renal toxicity (adefovir) CONTRA: Hypersensitivity NOTES: Entecavir dose should be adjusted for patients with moderate renal insufficiency. |
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273. What is the name of the nonnucleoside DNA polymerase inhibitors?
How does it work? |
Foscarnet.
Foscarnet inhibits both DNA and RNA polymerases encoded by a wide variety of viruses. It does not require activation by cellular or viral enzymes; rather, it inhibits viral DNA polymerase directly by mimicking the pyrophosphate product of DNA polymerization. It is used clinically for certain serious HSV and CMV infections where therapy with acyclovir or ganciclovir has not succeeded. |
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274. Foscarnet
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MOA: Inhibits viral DNA polymerase directly by mimicking the pyrophosphate product of DNA polymerization reaction.
PURPOSE: HSV and CMV ADVERSE: **Renal impairment**, electrolyte imbalance, seizures, anemia, fever, GI disturbances CONTRA: Concurrent administration of arsenic trioxide and other drugs.... NOTES: **Renal impairment is the major dose limiting toxicity. |
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275. What are the nonnucleoside reverse transcriptase inhibitors (NNRTIs)?
How do they work? |
Efavirenz, nevirapine, and delavirdine.
These drugs inhibit their target directly, w/o the need for chemical modification. They bind near the catalytic site of RT, and thereby prevent the enzyme from joining deoxyribonucleotides w/the primer-template strand. The main limitation of NNRTI use is that resistance develops rapidly, requiring the use of these drugs in combo with other anti-HIV drugs. |
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276. Efavirenz, nevirapine, and delavirdine
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MOA: Bind near the catalytic site of RT, and thereby prevent the enzyme from joining deoxyribonucleotides w/the primer-template strand.
PURPOSE: HIV ADVERSE: Rash, psychiatric effects (suicidal ideation, depression), dizziness, insomnia CONTRA: Concurrent admin of drugs metabolized by P450 CYP3A4; **must verify metabolism of concurrent medications before prescribing NNRTIs!!! NOTES: Resistance develops rapidly, requiring combo w/other anti-HIV drugs; Efavirenz was the first once daily dosing available |
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277. What are four reasons why combination therapy with multiple RT inhibitors work?
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1. Combining allows for greater efficacy.
2. Mutations conferring resistance to one drug do not necessarily confer resistance to the others. 3. Mutations conferring resistance to one drug can suppress the effects of mutations conferring resistance to another drug. 4. Certain resistance mutations decrease the "fitness" of the virus; thus it may be beneficial to provide combo therapy that includes a drug to which the virus is resistant, in order to maintain selective pressure in favor of that drug-resistance virus. |
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278. What are the inhibitors of viral maturation?
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1. Saquinavir
2. Ritonavir 3. Amprenavir 4. Indinavir 5. Nelfinavir 6. Lopinavir 7. Atazanavir 8. Tipranavir 9. Darunavir |
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279.
Saquinavir Ritonavir Amprenavir Indinavir Nelfinavir Lopinavir Atazanavir Tipranavir Darunavir |
MOA: Inhibit HIV protease required for viral maturation; HIV virions replicate and do bud from the cell, but these particles are noninfectious
PURPOSE: HIV ADVERSE: Dyslipidemia (↑ cholesterol, ↑ TAGs), lipodystrophy, hyperglycemia CONTRA: Severe hepatic impairment; concurrent administration of CYP3A4 substrates with narrow therapeutic indices, including ergot derivatives, pimozide, midazolam, triazolam. NOTES: Many protease inhibitors are inducers and/or inhibitors of CYP3A4, with numerous pharmacokinetic drug interactions. |
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280. What is coadminstered with lopinavir?
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Lopinavir is coadministered in combo with ritonavir; ritonavir inhibits CYP3A4, thus increasing plasma levels of lopinavir
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281. What are the inhibitors of viral release?
How do they work? |
Zanamivir and oseltamivir.
Influenza virus encodes an envelope-bound enzymes, called neuraminidase, which cleaves sialic acid from the membrane glycoproteins and thereby permits release of the virus. W/o neuraminidase, the virus remains tethered and cannot spread to other cells. Thus, inhibitors of viral release inhibit neuraminidase. |
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282. Zanamivir and oseltamivir (tamiflu)
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MOA: Inhibit influenza virus neuraminidase, causing newly-synthesized virions to remain attached to host cell.
PURPOSE: Influenza A & B ADVERSE: Bronchospasm, respiratory depression, headache, GI disturbance, nasal symptoms. CONTRA: Hypersensitivity NOTES: Inhibit both influenza A and B; Zanamivir is administered via inhaler; Oseltamivir is approved for both prophylaxis and treatment while zanamivir is only for treatment. |
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283. What is fomivirsen?
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Fomivirsen is an antisense oligonucleotide that targets specific RNAs. It binds to an mRNA that encodes IE2, a gene-regulatory protein of CMV. However, its MOA is uncertain.
It is approved for the treatment of ophthalmic CMV disease and it is used mainly to treat CMV retinitis. The patient must be highly motivated to receive therapy, however, b/c the drug is administered intravitreally. |
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284. Fomivirsen
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MOA: Antisense oligonucleotide that targets specific RNAs
PURPOSE: CMV retinitis (second line) ADVERSE: Inflammatory disorder of the eye, transiently elevated intraocular pressure CONTRA: IV or intravitreal cidofovir therapy w/in 2-4 weeks |
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285. What is Ribavirin?
How does it work? |
Ribavirin exhibits activity against many viruses. It is approved only in aerosol form for severe RSV infection, and only in combo with an interferon for chronic HCV infection.
It may inhibit IMP dehydrogenase, leading to lower cellular GTP levels; it may also inhibit viral RNA polymerases or make the polymerases more error-prone. |
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286. Ribavirin
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MOA: It may inhibit IMP dehydrogenase, leading to lower cellular GTP levels; it may also inhibit viral RNA polymerases or make the polymerases more error-prone.
PURPOSE: RSV, HCV (in combo w/interferons) ADVERSE: Bradyarrhythmia, hypotension, pancreatitis, hemolytic anemia, TTP, hepatotoxicity, bacterial infection, suicide, rash, GI disturbance, headache, conjunctivitis, fatigue. CONTRA: Pregnancy or women of child bearing potential, creatinine clearance less than 50 mL/min, significant cardiac disease, hemoglobinopathies, autoimmune hepatitis, severe hepatic decompensation. |
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287. What are the three antiviral drugs that modulate the immune system?
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1. Interferon-α
2. Interferon-β 3. Imiquimod (Aldara cream) |
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288. Interferon-α
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MOA: Interferons activate signaling cascades that lead to production of anti-viral proteins, including protein kinase R, which turn off host translational machinery in virus infected cells.
PURPOSE: HCV, HBV, Kaposi's sarcoma, CML, hairy-cell leukemia, malignant melanoma, renal cell carcinoma ADVERSE: Gastric hemorrhage, aplastic anemia, neutropenia, thrombocytopenia, increased liver enzymes, autoimmune diseases, psychotic disorder, depression, altered mental status, influenza like flu symptoms CONTRA: Hypersensitivity NOTES: Modified w/polyethylene glycol to improve pharmacokinetic profile |
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289. Interferon-β
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MOA: Interferons activate signaling cascades that lead to production of anti-viral proteins, including protein kinase R, which turn off host translational machinery in virus infected cells
PURPOSE: Multiple sclerosis ADVERSE: Same as Interferon-α CONTRA: Hypersensitivity to Interferon-β or human albumin products |
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290. Imiquimod (Aldara)
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MOA: Imiquimod interacts w/Toll like receptors to boost innate immunity, including the secretion of interferons.
PURPOSE: HPV, basal cell carcinoma, actinic keratosis ADVERSE: Skin irritation including erythema, superficial erosion and crusting, and burning sensation CONTRA: Hypersensitivity NOTES: Wash hands before and after application. |
