Term
| What are the major patterns of liver necrosis? |
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Definition
Centrolobular: (zone 3). Occurs in hypoxic conditions. Also occurs with toxins; e.g. xenobiotics; that are metabolized by cytochrome P-450 system, since Zone 3 cells have higher concentration of sER (where c P-450 is found). This is despite fact that toxins first pass through Zone 1.
Periportal: (zone 1). Associated with immune hepatitis.
Midzonal: affects Zone 2.
Random: can be focal or multifocal. |
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Term
| What conditions are associated with hepatic vacuolization? |
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Definition
1. Hydropic changes (non-specific cell injury)
2. Glycogen deposition (nutritional status or metabolic disorder)
3. Fatty changes (nutritional status or metabolic disorder) |
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Term
| What are the general factors associated with hepatocellular injury/death? |
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Definition
1. Hypoxia
2. reactive oxygen metabolites
3. bile acids
4. toxins
5. death receptors (such as Fas Ligand, Granzyme B/porin) released due to autoimmune, viral, or drug-induced disease. |
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Term
| What are some physiologic situations of hepatic lipidosis? |
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Definition
| Late pregnancy or heavy lactation of ruminants; diets high in fat; fasting. |
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Term
| What are some pathologic situations where hepatic lipidosis is often seen? |
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Definition
| Starvation, protein malnutrition, ketosis, diabetes mellitus, poisoning. |
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Term
| Where in the hepatic lobule does lipid accumulation occur first, and what does it look like? |
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Definition
| In Zone 1. Small round vacuoles present initially; merge into larger ones that may displace nucleus to the side. |
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Term
| Where does hepatic amyloidosis occur, and what result can it have? |
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Definition
| In Space of Disse. Can lead to atrophy of hepatocytes. |
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Term
| What are 3 reasons for cholestasis? How can you differentiate etiologies on histopath examination? |
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Definition
1. Hepatocellular dysfunction
2. Intrahepatic biliary obstruction
3. Extrahepatic biliary obstruction
In hepatocellular etiology, bile pigment will be present in the hepatocytes only. In obstruction, pigment will be present in the bile ducts and canaliculi. |
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Term
| What is Dubin Johnson syndrome, and what species does it affect? What would a diseased liver look like grossly? |
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Definition
Hepatocellular dysfunction due to defect in canalicular membrane transport protein, resulting in impaired excretion of bilirubin glucuronidase. Grossly, liver is very dark (almost black).
Autosomal recessive condition in corriedale sheep. |
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Term
| How are fatty acids moved from the liver to tissues needing energy? |
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Definition
| Fatty acids converted to TG, then apoproteins added to make lipoproteins. Lipoproteins exported in VLDL to other tissues. |
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Term
| What are potential causes of fatty change in the liver? |
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Definition
1. Reduced lipoprotein production due to disruption of cell metabolism -> accumulation of TG
2. Increased mobilization of lipids -> cell membrane, ER, mitochondrial damage
3. Disruption of lipoprotein export (e.g. due to lack of insulin in DM) |
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Term
| What is the definition of hepatitis? |
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Definition
| Inflammation of hepatic parenchyma. |
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Term
| What are potential routes of liver infection? |
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Definition
1. Portal vein
2. Hepatic artery (in systemic infection)
3. Umbilical vein in neonates
4. Biliary tract (ascending from duodenum) |
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Term
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Definition
| Inflammation of bile ducts. |
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Term
| Define cholangiohepatitis. What are some expected gross/histo changes? |
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Definition
| Inflammation of portal tracts and adjacent hepatic parenchyma. Look for prominent, inflamed bile ducts. In chronic form, biliary hyperplasia and fibrosis occur w/ nodular scarring. |
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Term
| What species is predisposed to chronic lymphocytic cholangiohepatitis? |
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Definition
| Cats (mature cats; idiopathic). |
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Term
| What characterizes chronic active hepatitis? Species/breed predisposition? |
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Definition
| Mononuclear infiltrates in portal zones, resulting in patchy necrosis. Idiopathic in Dobermans. Can be caused by persistent viral infection (e.g. Hep B). |
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Term
| WHat can cause an aggressive inflammatory response in the liver? |
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Definition
Chronic active hepatitis (idiopathic)
Copper toxicosis (e.g. in Bedlingtons) |
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Term
| What can one say generally about liver regeneration? |
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Definition
| Usually does not result in return to normal function. |
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Term
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Definition
| A cytokine secreted by adipocytes; has a role in energy homeostasis and stimulates liver regeneration. |
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Term
| What is nodular hepatocellular hyperplasia? Breed/species? Gross changes? |
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Definition
| Common in dogs >8 yrs. 1+ well-delineated tan/yellow nodules 1-10 cm in diameter. No breed/sex predilection; not associated with neoplasia. |
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Term
| Outline the process of fibrosis in the liver. |
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Definition
| Usually happens in portal triad first (due to chronic inflammation). Stellate/Ito cells are activated by cytokines and ROS from Kupffer cells to produce ECM materials and proteases. |
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Term
| What is bridging fibrosis? |
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Definition
| When fibrous bands connect adjacent lobules. |
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Term
| Why is liver fibrosis associated with cardiovascular pathology? |
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Definition
1. Fibrosis distorts liver vasculature, sometimes resulting in portal hypertension and/or portosystemic shunts.
2. Centrilobular fibrosis (due to hypoxic necrosis) can be secondary to CHF. |
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Term
|
Definition
| Pattern of chronic liver disease that includes bridging fibrosis, nodular regeneration, and general disruption of architecture. Grossly, liver is smaller, and bands/nodules can be seen. These bands/nodules increase pressure on normal parenchyma, causing further necrosis and a vicious cycle which ends in organ failure. |
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Term
| What do cholangiolar cells do in response to chronic injury to the biliary tract? |
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Definition
| These are the "corner" cells between canaliculi and bile ducts. They act as stem cells and can proliferate into hepatocytes or bile ductular or cholangiolar cells in response to chronic irritation/injury. |
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Term
| What is granulomatous hepatitis associated with? |
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Definition
| Mycoses (systemic) such as histoplasmosis, Tb in cattle. Salmonella typhii (humans) and pullorum (chickens) can result in "typhoid nodules" in liver. |
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Term
Summarize copper transport in the body.
What is Wilson's disease? |
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Definition
40-60% taken up by stomach/duodenum. Transported to liver via albumin. In hepatocytes, complexed to ceruloplasmin and secreted into plasma.
Wilsons' disease: lack transmembrane Cu++ transporter, leading to accumulation in hepatocytes and hepatotoxicity. Bedlington terriers have inborn Cu++ metabolizing defect resulting in progressive accumulation as they age, beginning in the centrolobular area and radiating outward. Other breeds (WHW, Dobie, Lab, Dalmation, Skye terrier) develop high copper levels with chronic hepatitis (but this is not the same as Wilson's dz as the copper accumulation is self-limiting and not progressive, and does not show the centolobular pattern). |
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Term
| Is iron hepatotoxic? Direct or indirect? |
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Definition
| Direct hepatotoxin. Inflammation is characteristically absent! |
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Term
| What is alpha-1-antitrypsin, and what does it have to do with the liver? |
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Definition
| A glycoprotein synthesized by hepatocytes, with the function of neutralizing/inhibiting proteases (esp. neutrophil-secreted elastase). A defect in transport of this glycoprotein from ER to Golgi results in its accumulation in the hepatocyte cytoplasm (eosinophilic globules). |
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Term
| Glycogen storage diseases: what do they have to do with the liver? |
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Definition
4/10 genetic glycogen storage diseases affect the liver.
Type 1 and Type IV: no glycogen accumulation.
Type II: lysosomal storage of glycogen (several cattle breeds, cats, sheep, turkeys, quail)
Type III: later in life; characterized by cirrhosis |
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Term
| What are 3 lysosomal storage diseases that involve the liver? |
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Definition
1. Wolman dz: deficient acid lipase (parakeets, Donryu rats, fox terriers)
2. Gaucher dz: deficient beta-glucocerebrosidase (Silky Terrier, sheep, pig)
3. Niemann-Pick C: mutation of cholesterol-binding membrane protein (DSH cats, boxers, FM mice) |
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Term
| What is Zellweger's syndrome? |
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Definition
| Failure of peroxisome synthesis, resulting in hepatomegaly. |
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Term
| Which species often have congenital bile duct cysts? Do these result in pathology? |
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Definition
| Cats. Usually do not compromise liver function. |
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Term
| What is the most common cause of pre-hepatic icterus? |
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Definition
| Severe hemolytic anemia (excess production of bilirubin over the liver's capacity to clear it). |
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Term
| What is the most common cause of pre-hepatic hyperbilirubinemia? |
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Definition
| Severe hemolytic anemia (excess production of bilirubin over the liver's capacity to clear it). |
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Term
| What are some common causes of hepatic hyperbilirubinemia? |
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Definition
| Intrahepatic cholestasis (eg. with feline idiopathic hepatic lipidosis, hepatic lymphangiosarcoma, cholangiohepatitis). |
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Term
| What is the general cause of post-hepatic hyperbilirubinemia? |
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Definition
| Bile stasis (choleliths, pancreatitis, neoplasia [biliary/pancreatic adenocarcinoma]). |
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Term
| What is cholestasis of sepsis? |
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Definition
| Cytokine-mediated inhibition of membrane transport in hepatocytes results in intra-hepatic cholestasis without hepatic dysfunction per se. |
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Term
| What is the most consistent sign on EHBDO in cats? What is the best clinical test? |
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Definition
| Dilation of CBD (common bile duct) to >5mm. A thickened GB wall is also often seen. Ultrasound is best test. |
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Term
| Is EHBDO associated with infection? |
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Definition
| Yes, esp. cholelithiasis-caused EHBDO. |
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Term
| What's the most common cause of feline EHBDO? |
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Definition
| Chronic inflammation/fibrosis of hepatobiliary tract, pancrease, or intestinal tract (triaditis). |
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Term
| What is the protocol for the typical bile acid test? |
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Definition
TSBA is determined after 12 hr fast. A test meal is fed, and 2 hrs later postprandial TSBA is measured.
In horses, a single TSBA is taken, since they lack gall bladders. |
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Term
| What is the rate limiting step in bile acid enterohepatic circulation? |
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Definition
| Transport across bile canalicular membranes. |
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Term
| What is Budd Chiari syndrome? |
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Definition
| Obstruction to portal venous outflow (caudal vena cava or large extrahepatic veins. Obstruction can be intraluminal (tumor, thrombus, congenital fibrosis) or extraluminal (tumor). |
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Term
| What is the most important toxin involved in hepatoencephalopathy? What is the pathogenesis? |
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Definition
| Ammonia. Product of protein breakdown by colonic bacteria. Enters systemic circulation (instead of going to liver to be metabolized in the urea cycle as it should) b/c of PSS. Crosses BBB. In brain, astrocytes detoxify it by converting glutamate to glutamine. It's the increased glutamine (which is osmotically active) that leads to astrocyte swelling/death. Also, depletes glutamate, excitatory NT, leading to neuroinhibition. |
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Term
| What is lactulose and what is it used for? |
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Definition
| Nonabsorbable disaccharide that escapes metabolism in small intestine. In colon, its broken into short chain fatty acids which acidify the colon, trapping ammonia in an ionized form that cannot cross membranes. |
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Term
| Why do animals with hepatic disease have greater risk for GI ulceration? |
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Definition
1. Portal hypertension ->venous congestion ->decreased intestinal epithelium blood flow
2. Increased circulating bile acids cyctotoxic to GI epithelium
3. Increased serum gastrin due to decreased clearance by liver |
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Term
| List some cytoprotective agents that can be used to treat liver dz. |
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Definition
Ursodeoxycholate (UDCA): hydrophilic bile acid. Mechanisms mostly unknown.
SAMe (S-adenosylmethionine): Denosyl/Zentonil: basically produces more glutathione for antioxidation. Low bioavailability; must be given on empty stomach.
Silymarin: milk thistle derived flavonoids. General free radical scavenger; stabilizes membranes.
*Denamarin has silymarin + SAMe
Vitamin E also has antiinflammatory (inhibits monocyte/neutrophil adhesion; inhibits LOX) and antioxidant effects. |
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Term
| What are inducible liver enzymes? |
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Definition
Membrane-bound enzymes that increase in cholestasis:
ALP (alkaline phosphatase): many different isoenzymes.
GGT (gamma glutamyl transferase): preferred in cats (more sensitive measure) |
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Term
| What are hepatocellular leakage enzymes? |
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Definition
ALT (alanine aminotransferase): increase can also be seen in muscle necrosis and enzyme induction by drugs.
AST (aspartate aminotransferase): Not liver specific. increases with muscle necrosis.
SDH (sorbitol dehydrogenase): most liver specific enzyme |
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Term
| Is ammonia affected directly by cholestasis? |
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Definition
| No. Indirectly, cholestasis can result in hepatocellular pressure which reduces function, including ammonia metabolism. |
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Term
| Why test hemostasis before doing a liver biopsy? |
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Definition
| If liver failure is suspected, vitamin K-dependent coag factors could be reduced since produced by the liver. |
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