Term
| what is unique about hepatocytes genetically? |
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Definition
| the nucleus of hepatocytes are polyploid - meaining they have more than 2n amount of DNA (up to 8n). this is thought to be b/c of: injurious processes/CA, premature cell senescence/apoptosis/self-limited repair, or as part of strategy for high cell growth and high metabolic output |
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Term
| what do the RERs found in hepatocytes produce? |
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Definition
| *proteins such as albumin (transporter, osmotic gradient maintenance), haptoglobin/ceruloplasmin (carry metals through blood), blood proteases/clotting factors (all made in the liver except for factor VIII), protease inhibitors (such as alpha1-antitrypsin/alpha1-protease inhibitor), and acute phase proteins (fibrinogen) |
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Term
| what are the SERs found in hepatocytes responsible for? |
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Definition
| synthesis of longer lipids (past 16 C - such as those used for myelination), detoxification via P450 system, and storage of Ca++ (similar to the sarcoplasmic reticulum in muscle) |
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Term
| what does the nuclear envelope (part of the endoplasmic reticulum) do? |
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Definition
| the nuclear envelope lets things such as tRNA/mRNA in and out of the nucelus. it can also be used to synthesize proteins. |
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Term
| what is the golgi apparatus's relationship with the endoplasmic reticulum? |
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Definition
| the golgi receives whatever the ER sends out and processes it, for example proteins/lipids going into circulation are made more soluble via sugars, phosphorylation, etc, some proteins are cleaved, and everything is *concentrated in the golci. |
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Term
| what is the function of the peroxisomes/microsomes in the hepatocyte? |
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Definition
| perioxisomes detox the cell via formation of hydrogen peroxide which can oxidize long chain FAs and *convert cholesterol into bile |
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Term
| what is the function of lysosomes in the hepatocyte? |
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Definition
| lysosomes are the "stomach of the cell" which have a low pH (4.5-5) and perform hydrolytic functions. their low pH is maintained by hydrogen ATPase. |
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Term
| what is the function of mitochondria in hepatocytes (which make up 20% of cellular volume)? |
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Definition
| oxidative phosphorylation (ATP creation), the TCA cycle, beta-oxidation of FAs, parts of: the urea cycle, gluconeogenesis, and FA synthesis, and finally Ca++ concentrations are regulated. |
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Term
| what is the function of the cytosol in hepatocytes? |
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Definition
| the cytosol has the majority of the metabolic processes along with the mitochondria. this includes: signal transduction, glycolysis, nucleotide synthesis (either de novo/salvage - impt for use by other tissues and WBCs), the pentose phosphate shunt (makes ribose -> nucleotides), glycogenesis/glycogenolysis, and parts of: gluconeogenesis, FA synth, TG synth, and the urea cycle. |
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Term
| what characterizes the handling of carbs by the liver in the fed state? |
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Definition
| fed state: glucose is high, insulin is high, glucagon is low. glucose enters the liver via *GLUT2, which has a high km/low affinity - requires high level of glucose to function (liver waits until the rest of the body already has glucose). |
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Term
| what does it mean to say the liver is a "donator organ"? |
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Definition
| the liver converts extra glucose to glycogen to be stored until it is needed (released later) or converts it to FAs, then TGs, then VLDLs for use by other tissues. |
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Term
| what is the liver's role in regulation of blood glucose? |
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Definition
| the liver keeps blood glucose low and stores it when it gets high |
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Term
| what characterizes the handling of carbs by the liver in the fasting state? |
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Definition
| glycogen is mobilized back into glucose and sent to other tissues. gluconeogenesis is the denovo production of glucose from lactate (from pyruvate which is often from RBCs), AAs (muscle breakdown), glycerol (TG backbone, high glucagon stimulates hormone sensitive lipase in adipose to release this). FAs are also converted to ketone bodies. |
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Term
| what is the summary of carb homeostasis as carried out by the liver? |
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Definition
| 1) liver processes glucose into glycogen storage (source of blood glucose), fatty acids, and VLDL. 2) liver spares energy for other tissues by design: its own glucokinase (first step of glycolytic pathway) is only activated in the presence of high carbs, while hexokinase in other tissues is always on and its GLUT2 transporter (high km/low affinity) only functions in high glucose conditions. 3) liver provides glucose through gluconeogenesis and glycogenolysis. |
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Term
| what characterizes the handling of proteins/AAs by the liver in the fed state? |
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Definition
| the gut sends proteins/AAs to the liver directly through the portal vein, which are *all used by the liver if needed* (including BCAAs, but not for energy). the liver does not have the enzymes for branch chain AA deamination, so it sends these out to other tissues that do. the liver also removes nitrogen from AAs and synthesizes urea. |
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Term
| what characterizes the handling of proteins/AAs by the liver in the fasted state? |
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Definition
| AAs are broken down and converted to glucose. via transamination reactions, nitrogen from these AAs are sent to other tissues by alanine/glutamine (major N carriers). after ~ 4 days, muscle stops breaking down AAs - so there is less substrate for gluconeogenesis. the liver continues to synthesize urea, but less than before. the brain switches and starts to use ketone bodies and glucose is mainly sent to RBCs. |
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Term
| what is the glucose-alanine cycle? |
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Definition
| glucose goes to tissue, goes through glycolysis to pyruvate which is converted to alanine via transamination. alanine then goes to the liver, is deaminated (amino group can be used in the urea cycle) back to pyruvate - which is converted back to glucose by gluconeogenesis. *thus the liver can provide the rest of tissues w/a continous, low level, fasting glucose supply. |
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Term
| what is the summary of protein homeostasis as carried out by the liver? |
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Definition
| the liver uses all but the branched chain AAs. the urea cycle removes extra ammonia/amino groups, glutamine/alanine carry extra amino groups, and the glucose-alanine cycle allows continuous glucose supply. |
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Term
| what characterizes the handling of lipids/TGs by the liver in the fed state? |
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Definition
| bile is synthesized by the liver to assist lipid uptake in gut through formation of micelles which are broken down by lipase/colipase into 2 monoglycerides and 1 FA. these enter GI enterocytes and are then formed into chylomicrons which go through circulation to various tissue and are broken down by lipoprotein lipase (controlled by insulin/activated by apoCII) releasing the FAs for use by muscle or adipose while the glycerol goes back to the liver for gluconeogenesis. the chylomicron remnants also go back to the liver, where everything is repackaged. TGs are repackaged in the liver as VLDLs, sent into circulation and broken down by lipoprotein lipase and FAs/glycerol are used by the body's tissues as needed. |
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Term
| what characterizes the handling of lipids/TGs by the liver in the fasted state? |
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Definition
| glucagon levels are high which stimulates hormone sensitive lipase. HSL breaks down stored TGs in the liver into FAs/glycerol which are sent out from the liver on albumin (not lipoproteins b/c its less efficient when energy is needed immediately). FAs are also broken down to ketone bodies in the liver (no ATP produced for liver in this process) which can be sent to muscles |
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Term
| what receptors in the liver allow chylomicron retrieval? what is another important apo protein found on chylomicrons? |
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Definition
| the apoE receptors in the liver allow it to receive chylomicrons. apoB48 is another important apoprotein found on chylomicrons along with ApoCII. |
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Term
| what is the apoprotein found on VLDLs? |
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Definition
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Term
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Definition
| VLDLs are packaged in the liver full of TGs (composed of FAs from excess glucose) and chylo remnants during the fed state. VLDLs circulate and are broken down by LPLs in the lumen of blood vessels in target organs. LPL is controlled by insulin secretion and activated by ApoCII. |
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Term
| what are LDLs? what do they do? |
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Definition
| VLDLs missing most of their TGs that still have apoB100, but not apotCII or apoE. LDLs carry cholesterol are recognized by LDL receptors throughout the body, which when they meet, a pit forms and an endosome forms which combines with a lysosome that frees the cholesterol into the cell (along with AAs and apoproteins) |
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Term
| what is familial hypercholesterolemia? |
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Definition
| a problem with the LDL receptors - meaning a lot of cholesterol remains in circulation. |
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Term
| what does the cell do once a high amount of cholesterol enters? |
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Definition
| de novo synthesis of cholesterol in the cell is turned off (involves HMG-CoA reductase) and LDL receptors are down-regulated. |
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Term
| what apoprotein is associated with HDL? where does it come from? |
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Definition
| apoA-1 - which is released from the liver |
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Term
| what does ABCA-1 do? where is it found? |
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Definition
| ABCA-1 is found in peripheral tissue and has 2 functions. 1) process apoA-1 coming from the liver to create nascent HDL. 2) take cholesterol across the cell membrane and have it ready for HDL to pick up and take back to the liver |
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Term
| when nascent HDL is created by ABCA-1 in peripheral tissue, how does it appear? what changes it? |
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Definition
| nascent HDL is flat like a pancake due to the amphipathic nature of cholesterol. PCAT (phosphatidylcholine acyltransferase), puts lipids on the cholesterol OH group - making them non-polar cholesterol esters and allowing the HDL particle to become round |
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Term
| can HDL and VLDL exchange material? |
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Definition
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Term
| what 2 things can HDL do after it has accumulated some cholesterol? |
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Definition
| 1) go into a receptor on the liver and be re-incorporated. 2) pass by the surface of the liver and drop off some cholesterol via hepatic lipase |
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Term
| why does the liver need cholesterol more than any other tissue? |
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Definition
|
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Term
| what are the 2 functions of HDL? |
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Definition
| 1) transfer apoproteins among other lipoproteins. 2) remove excess cholesterol from peripheral tissues. |
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Term
| what synthesizes cholesterol? what is the rate-limiting step in its production? |
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Definition
| acetyl CoA synthesizes cholesterol and HMG-CoA reductase enacts the rate limiting step (target of drug therapy) |
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Term
| what are the 2 functions of bile? |
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Definition
| 1) bile is amphipathic, meaning it emulsifies dietary lipids. 2) bile also serves as a disposal for toxins |
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Term
| how efficient is bile recycling? what are the 2 forms of bile recycling? |
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Definition
| very efficient. 1) 95% of bile is actively transported out of the ileum to the portal vein. 2) 5% is passively transported to the poral vein in the jejunum after bacteria deconjugate it (remove AAs). |
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Term
| what is the summary of fat/cholesterol homeostasis as carried out by the liver? |
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Definition
| the liver uses FA for energy, but also sends out ketones to the rest of the body. the liver forms VLDLs from chylomicron remnants/stored FAs. the liver synthesizes all apoproteins for HDL, VLDL. the liver synthesizes cholesterol de novo and either uses it or makes bile. |
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Term
| what is heme (produced by the liver, other tissues) used for? |
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Definition
| hemoglobin, electron transport, CYP |
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Term
| what is the role of the CYP in drug metabolism? |
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Definition
| cytochrome P450 puts an OH on things (oxidative reaction). this usually inactivates drugs, but can activate some. this also oxidizes ethanol and conjugates glutathione. |
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Term
| which of the LFTs reflect hepatobiliary injury/integrity? |
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Definition
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Term
| which of the LFTs reflect cholestasis/biliary excretory function? |
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Definition
| bilirubin, alk phos, GGT, 5'nucleotidase |
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Term
| which of the LFTs reflect hepatic synthetic function?? |
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Definition
| serum albumin, PT, coag factors, etc |
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Term
| how can protein electrophoresis tell you about liver function? |
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Definition
| total protein will tell you protein quantity and electrophoresis will tell you about protein quality |
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Term
| what kinds of disease would you see a mild increase in aminotransferases (AST/ALT) in? |
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Definition
| non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, and chronic viral hepatitis. |
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Term
| what kinds of disease would you see a moderate increase in aminotransferases (AST/ALT) in? |
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Definition
| chronic viral hepatitis, alcoholic hepatitis, and biliary obstruction |
|
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Term
| what kinds of disease would you see a marked increase in aminotransferases (AST/ALT) in? |
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Definition
| acute viral hepatitis, toxic/drug induced hepatic injury |
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Term
| how do the 2 aminotransferases compare? what is the ratio typically? |
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Definition
| ALT is specifically made in the liver. AST is synthesized in the liver/heart/muscle. the ratio is typically between 1:1 and 2:1 (w/AST being slightly higher), but it will be ~1:1 in liver inflammation. |
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Term
| what is the AST:ALT ratio in alcoholic liver disease? |
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Definition
| high - from 2:1 to 10:1. in alcoholic hepatitis, the cofactor PLP (pyridoxal phosphate) may be missing, so if administered this ratio can be brough down some. |
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Term
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Definition
| when the liver retains solutes such as bile salts, cholesterol and bilirubin - keeping them from going into bile |
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Term
| where does bilirubin come from? |
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Definition
| the breakdown of RBCs, CYP proteins, or electron transport chain proteins |
|
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Term
| where does bilirubin come from? |
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Definition
| the breakdown of RBCs, CYP proteins, or electron transport chain proteins |
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Term
| what does it mean if indirect (unconjugated) bilirubin is increased? |
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Definition
| there is increased production, decreased hepatic uptake, and/or decreased conjugation of bilirubin |
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Term
| what does it mean if direct (conjugated) bilirubin is increased? |
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Definition
| there is decreased secretion from hepatocytes to bile or there is bile duct obstruction (if it backs up too much, you can have direct BR in the bloodstream) |
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Term
| what is the path of bilirubin from RBC to bile? |
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Definition
| dead RBCs release hemoglobin in the spleen, which the globin is then removed from. heme is converted to biliverdin by heme oxygenase, which is then broken down into bilirubin by biliverdin reductase. bilirubin is then bound to albumin and taken to the liver, where glucuronyl transferase conjugates it. (the liver also produces BR from heme) |
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Term
| what is gilbert's disease? |
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Definition
| a mild inherited form of unconjugated hyperbilirubinemia. |
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Term
| what 2 situations can lead to jaundice (hyperbilirubinemia)? |
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Definition
| 1) increased bilirubin production (hemolysis, ineffective erythropoiesis, resorption of a hematoma). 2) decreased hepatic uptake or hepatobiliary elimination (cholestasis/bile duct obstruction or acute hepatocellular injury) |
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Term
| what is the significance of alk phos levels? |
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Definition
| alk phos levels reflect cholestasis/biliary excretory function, but cannot determine whether the etiology is extra- or intrahepatic. alk phos is also found in other tissues and may increase w/growth spurts. |
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Term
| what is the significance of GGT (gamma-glutamyl-transpeptidase) levels? |
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Definition
| if this is high, and alk phos levels are also high, then it confirms that alk phos levels are high b/c of liver disease and not another organ system. (reflects cholestasis/biliary excretory function) |
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|
Term
| what is the significance of 5'-nucleotidase levels? |
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Definition
| this enzyme breaks down nucleotides and its levels in serum reflect problems with cholestasis/biliary excretory function |
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|
Term
| how does serum albumin reflect hepatic synthetic function? |
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Definition
| the liver synthesizes a lot of albumin. abnormal albumin levels may indicate: liver disease, nephrotic syndrome, and protein malnutrition |
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Term
| how does prothrombin time reflect hepatic synthetic function? |
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Definition
| this tells you if there are enough clotting factors being produced by the liver |
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Term
| when would cytochrome P450 testing be esp important? |
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Definition
| if pts are on chemo, elderly, obese, have metabolic syndrome or are taking something like st. john's wort (induces CYP3A4) |
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Term
|
Definition
| accumulation of fat in the liver |
|
|
Term
| what are the 3 ways that steatosis can occur? |
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Definition
| extrahepatic, intrahepatic, and hepatic insuling resistance. |
|
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Term
| how can steatosis be due to extrahepatic causes? |
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Definition
| if there are increased FAs in circulation, but there is low oxidative requirement in the liver (sedentary) and underexpressed LPL (responds to insulin=problem in DM) - fat can build up in the liver |
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Term
| how can steatosis be due to intrahepatic causes? |
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Definition
| increased dietary carbs, which are converted to FAs in the liver accumulate w/decreased VLDL synthesis and/or inhibited FA oxidation (like w/carnitine deficiency) |
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Term
| how can hepatic insulin resistance lead to steatosis? |
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Definition
| insulin normally suppresses hepatic glucose and helps TG production to VLDL, but if the body becomes resistant to insulin - fat can accumulate in the liver. defects in nuclear receptors such as PPARS are involved in this. |
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Term
| what is non-alcoholic fatty liver disease/non-alcoholic steatohepatitis? |
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Definition
| the former is a condition and the latter is when it becomes inflamed. non-alcoholic fatty liver disease is associated with insulin resistance, metabolic syndrome, and obesity. LFTs can't really indicate the onset of this well, usually the occurrence of something like metabolic syndrome is the first sign. the mitochondria not properly oxidizing fat can lead to this if it does not package well. |
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Term
| how can hereditary hemochromatosis lead to liver disease? |
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Definition
| if a pt has a mutation on the HFE gene on chr 6 (regulates hepcidin, the iron hormone produced by the liver), this can lead to an excessive accumulation of iron in various tissues. this requires a pint of blood to be drawn 1x/2 mos |
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|
Term
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Definition
| copper accumulation in the liver due to hereditary transport issues, eventually damaging it. tx is avoidance of Cu in diet. |
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Term
| what are the 2 kinds of alpha1-antitrypsin deficiency? which is worse? |
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Definition
| *null: no alpha1-antitrypsin is made at all, big problem with elastase in the lungs and clotting and *z allele: alpha1-antitrypsin is being made, but incorrectly folded so it gets stuck in the RER (worse b/c will damage liver as well) |
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Term
| how does the liver relate to thyroid disorders? |
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Definition
| T4 is the major thyroid hormone produced, but the liver converts it to T3, the most active thyroid hormone. the liver also synthesizes binding proteins to carry thyroid hormones through the blood. (damage to the liver can cause thyroid problems) |
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Term
| what hematologic disorders can involve the liver? |
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Definition
| thalassemia and sickle cell disease create more bilirubin than normal. DIC (disseminated intravascular coagulation) produces such high levels of coagulation, that the liver cannot keep up w/supply of coag factors. |
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