Week 3 Flashcards
1
Q
What is the role of the liver?
A
- makes bile with respect to hepatobiliary system, which is made up organic and inorganic components.
2
Q
Define Bile
A
Bile is made up a lot of organic and inorganic components like bile acids or bile salts which is a critical component of bile, they are structurally different but used synonymously.
3
Q
role of the Gall Bladder
A
It stores and concentrates the bile in between meals. Bile is used in fatty acid digestion and absorption so it is released right after meals and stored in between meals because the liver is constantly synthesizing the components of bile at a slow pace.
4
Q
role of Intestine
A
- It is the site of action of the bile, so it helps to perform its function and it is also the site of reabsorption. - also the site of absorption of nutrient more specifically the reabsorption of bile acids with respect to the hepatobiliary system. The distal part of the intestine reabsorbs the bile and recirculates it back to the liver for reuse.
5
Q
General functions of bile
A
- Aides in digestion and absorption of fats and fat soluble vitamins. - It has antimicrobial properties or function - Excretion of bilirubin which is a metabolite of heme, cholestrol, drug metabolites, etc.
6
Q
majority of the blood going to the liver
A
coming from the portal circulation and it is mostly venous. It does get some venous and hepatic arterial blood but the majority of it is coming from the portal circulation and that is what is shown on the diagram
7
Q
blood flow to hepatocytes - flow - sinusoids
A
- blood flow goes in one direction while bile flow goes in the opposite direction. Blood flow, both venous and arterial are both going towards the central vein while the bile flow is going in the opposite direction. - sinusoids are low resistant cavities that are in the hepatocytes themselves. At rest they are collapsed but during digestion, you increase the blood flow that actually causes the recruitment of the sinusoids till you get more and more perfusion but it tries to keep the pressure low so that you still have constant blood flow.
8
Q
Bile constituents
A
Bile acids, phospholipids, cholesterol, bile pigments, xenobiotics, electrolytes
9
Q
functional/ excretory or isotonic components of bile?
A
• functional components: Bile salts or bile acids which are structurally different but synonymous and Phospholipids which aide in the emulsification of fats and facilitate absorption. • Cholestrol, bile pigments, xenobiotics are excretory products. • The electrolytes maintain isotonicity.
10
Q
Deficiency of which enzyme will decrease the synthesis of bile acid ? - coenzyme?
A
7- alpha hydroxylase is the rate limiting enzyme. It is a predominant cytochrome P450 enzyme and also called CYP7A1( New name) . Its function is to adds OH to the 7th carbon of the steroid ring. - NADPH a derivative of Vit. B3
11
Q
What turns 7- alpha hydroxylase on and off?
A
the products, so it is product inhibition. If the liver has too much cholic or chenodeoxycholic acid it will turn off or slow down the transcription of 7-alpha hydroxylase.
12
Q
12-alpha hydroxylase - function - deficiency
A
- adding OH to the 12th carbon and this step is important to the synthesis of cholic acid and not chenodeoxycholic acid - will affect the ratio of cholic acid to chenodeoxycholic acid. It will lead to a decrease in cholic acid will cause an increase in chenodeoxycholic acid synthesis leading to a disrupted ratio of cholic acid to chenodeoxycholic acid which might lead to precipitation of a lot of the components of bile.
13
Q
How do we get bile acids across the basolateral membrane-? - what about bicarb?
A
- We can transport bile acids across the basolateral membrane through a number of ways. Both conjugated and unconjugated bile can cross through with sodium and that’s your NTCP which is the sodium taurocholate co-transport polypeptide which uses sodium, and that’s the main one. - Bicarb can also help with the movement of bile so you can also have the movement of bile acid coming in through the movement of bicarb coming out. Since bicarb is being released we have carbonic anhydrase to break down water and CO2 into bicarb and hydrogen ions to replace it.
14
Q
How does bile salts cross into the canicular membrane after going through modifications? - What other components of bile need to be moved across the cuniculus membrane
A
- It uses the bile salts export pump- this is an active movement so it uses ATP and moves the bile salts into the cuniculus - cholestrol which is coming from the diet and hepatocyte through the ABC transporter. Also need phospholipids through the MDR3 transporter and ions
15
Q
What does the active movement of ions and these organic substrate do to the osmotic pressure of the caniculus?
A
increases the osmotic pressure and therefor holds the water into it which is how you form the canicular bile
16
Q
What will happen if there was blockage/Destruction in the ducts
A
you get bile formation but no bile flow. The absence of bile flow will elevate plasma levels of bile and cholestrol. If there was a mutation of the bile salt exit pump, there will be increase in bile salts in the hepatocyte which can lead to cytoplasticity. We will have some bile formation but without bile salts since it cant get into the canicular.
17
Q
What is the name of the condition where you don’t have adequate production of bile or flow to the intestines? - causes - effects
A
- Cholestasis: - there are mult causes including obstructive cholestasis where the ducts are obstructed due to a gall stone or any type of stone, tumor or metabolic. -will cause bile back-up with a lot of bile overflow into the blood which will cause jaundice, increased color in urine, change of color to stool, lack of fat absorbtion producing smelly fatty stool and, abdominal pain after eating fatty foods.
18
Q
Explain the maintenance of bile acids homeostasis
A
- reabsorption and reuse of the bile acids through Enterohepatic circulation
19
Q
Enterohepatic circulation: mode of absorption of bile salts in the distal ileum
A
start in the hepatocyte and then get released into the canaliculi down the ductules into the hepatic bile duct then you combine to the common bile duct into the duodenum, you’re gonna go through the small intestine and get reabsorbed in the ileum back to the circulation which then takes you back up to the hepatocytes.
20
Q
efficiency of reabsorption of bile salts - how much is absorbed
A
- highly efficient, about 95% is reabsorbed back, released into the portal circulation, and then brought back to the liver where they are reconjugated w/ the AAs to make bile salts and they are then released back into the body
21
Q
What happens to the amount that is not reabsorbed?
A
- It is excreted, it goes to the colon from the small intestine and forms secondary bile acids
22
Q
primary vs secondary bile acids
A
- Primary bile acids: Formed in the hepatocytes; more polar bc they have a hydroxyl group and this increases polarity - secondary bile acids: Formed in the colon; bacteria will work on it and it will first deconjugate it (get rid of the AA) and then dehydroxylate it (remove the hydroxyl group at the 7 carbon of the steroid ring)
23
Q
What is the rate limiting enzyme in bile acid synthesis - how is it regulated?
A
- CYP7A1 aka 7 alpha hydroxylase - by its product
24
Q
summary of process of recycling/formation of bile salts
A
so you have the conjugated bile acid that get absorbed back they bind to the farnisoid X receptor and that is gonna activate the FGF19 (Fibroblast growth factor 19) and this is gonna go back to the portal blood (via the portal blood it goes to the hepatocytes) and shuts off the senses. We’re at FGF 19 coming back to the hepatocyte. So then it binds to FGFR4 and this receptor activates. What kind of signaling pathway will it activate? this will activate a MAP kinase pathway that will activate. MAP kinase will help in the production of a repressor protein which will bind to the promotor of your CYP7A1 and slow its transcription down. So as you’re have more and more absorption by enterohepatic circulation this is the process by which the end-product actually inhibits CYP7A1
25
If the normal process of recycling bile acids fails, what is the backup process?
- Repression can happen btwn the enterocytes and hepatocytes or CDCA can directly come back into the hepatocytes, get reabsorbed, activate FXR activation which will make a protein called SHP (small heterodimeric partner) which is a repressor, and this repressor will bind to the promotor of CYP7A1 and turn down its expression - Bc there is a back up mechanism, this process is constantly happening to give the liver a little bit of relieve from constantly synthesizing the bile acids
26
Why do you think, that when we talk about recycling, that it is actually occurring at the ileum and not the duodenum or the jejunum? - What happens if you have removal of the ileum?
- The whole point of the intestinal system is to digest and assimilate (absorb). So, if recycling were to occur and it were to recycle back at the duodenum or jejunum would you have enough nutrient absorption of fats? No, so it's at the iluem and so now they way you get the recycling is when you've had really complete assimilation of those nutrients that are needed - You don’t have this process going on so you don’t have proper formation of bile acid synthesis. This is needed for lipid digestion. So when a pt doesn’t have this, you wouldn’t have bile acids or the amount of bile acid secretion that you would have in a normal individual. Lipid digestion would be reduced and so if it is not being digested it is going out into the stool. So when you're putting this together, this is another thing that you need to start putting in the biochemistry on top of now the physiology and how does this affect digestion
27
Phosphatidylcholine - what is it? - what kind of compound? - what is the polarity? - What is mixed micelles? - Where does it come from? how is it released? - what happens with absence of transporter
- 40% of the bile is composed of phosphatidylcholine - It is a fatty acid derivative. It is a membrane lipid. - It is amphipathic (has a nonpolar tail which is composed of unsaturated fatty acids & has a polar head composed of an amine alcohol called choline which is attached by a phosphate group to the fatty acid. The phosphate group and the choline imparts negative charges which makes the head charged) - Phosphatidylcholine and bile salts together form these structures. Helps hide the hydrophobic parts from water and therefore helps in emulsification and later on digestion. - Membrane of the hepatocytes released by the MDR3 transporter - mixed micelles wont form so then you would have problems w/ the solubility of diff compounds, probable precipitation of diff compounds w/in the bile
28
Explain cholesterol homeostasis w/ reference to the role of bile in the process - routes of elimination - What is the liver going to do w/ the excess carbs that is coming into the liver? - what else can contribute to cholesterol pool - what happens when elimination and accumulation are not balanced
- § Intact cholesterol is secreted in bile and eliminated along with bile through the feces and also a lot of cholesterol is used to make bile acids and a portion of them are eliminated - he liver will convert the carbs into fats (diff types of fat which include cholesterol and fatty acids) so they will all contribute to the total body cholesterol pool. So in a person who has bad food habits and does not exercise much, the total cholesterol pool is going to be increased - steroid supplements - In terms of bile, the liver will try to dump a lot of cholesterol in the bile, so the bile will be super saturated w/ a lot of cholesterol in comparison to normal. So if you have too much cholesterol in the bile there will chances of cholesterol precipitating as cholesterol rich stones
29
Treatment of cholesterol rich stones - what happens when you supplement for a long time
○ Lifestyle changes ○ Supplement w/ bile acids (ex ursodeoxycholic acid) which will help to dissolve the precipitation of cholesterol and will also prevent the future possibilities of cholesterol precipitation - cholesterol is going to down regulate CYP7A1 and therefor now bile acid synthesis slows down so cholesterol is not getting converted into bile acids and the cholesterol pool will increase so over time the pt will get back to where they started from. So there will be elevated cholesterol levels, increased cardiovascular disease risk, etc
30
Heme - 3 compounds that contain - How can we correlate heme to bile - why does degradation of heme occur - site of metabolism of heme to billirubin - steps of conversion of heme to bilirubin
- Hemoglobin, Cytochromes & ETC, Myoglobin - Heme is metabolized into biliverdin and then bilirubin and the bilirubin is the pigment of bile which is drained in bowel for elimination - RBCs live 120 days and the senescent RBCs, the heme part of it, is metabolized constantly into billirubin - Macrophages will engulf it which will take it to the spleen where heme will be converted to bilirubin (If pt has hemolytic anemia, the liver will jump in so both the spleen and liver will do it together) - Biliverdin is the product of oxidation of heme. Biliverdin is a straight chain strx and then it gets reduced to bilirubin
31
Bilirubin - water soluble? - what is it conjugated to? - what enzyme is used?
- No, so in order to drain it into bile, conjugation occurs in the liver - Glucuronic acid - UDP glucoronosyl transferase
32
What happens after conjugation of bilirubin? - after bile formation? - fate of urobilinogens
- conjugated bilirubin is highly polar and soluble so it is now drained into the bile - bile goes into the intestine where it undergoes deconjugation and reduction which converts it into urobilinogens and some of these are reabsorbed through the enterohepatic circulation, brought back to the liver, and dumped in bile one more time (form that is found in the blood often times) - further oxidized in the intestines to make urobilins which is brown in color and urobilins are eliminated through the fecal mater.
33
What happens when there is a total absence of UDP glycoronosyl transferase? - syndrome? types? - symptoms - differential
- Crigler-najjar syndrome: Type 1 is complete deficiency of the enzyme (Worse prognosis and is associated w/ some neuropathy which we call kernicterus ); Type 2 is quantitative deficiency of the enzyme (Better prognosis) - Main symptoms: blood work will reveal high amount of unconjugated bilirubin - Gilbert syndrome: mutation in the tata box w/in the promoter of that transferase enzyme. They have very similar clinical presentations
34
Secretion of the bile
- not many transporters but there is active transport across the canicular membrane with a MDR (multi drug resistant) which transports bilirubin, so actively secreting particles to create osmotic gradient and help draw the water in and so that helps to make the canicular body
35
What happens when MDR does not work? - pt presentation?
- Dublin Johnson or Rotors syndrome - characterized by the transporter that secretes the bilirubin into the bile being non functional and these are diff mutations causing 2 diff kinds of diseases. - The blood will have conjugated hyperbilirubinemia
36
Conjugated bilirubin - what is it? - easy to measure in blood?
- bilirubin + glucuronic acid - Yes bc it is water soluble; so we can assay conjugated bilirubin
37
Unconjugated bilirubin - what is it? - how do you measure?
- one that does not have the glucoronic acid - We subtract the conjugated proportion from the total bilirubin
38
Direct bilirubin vs indirect bilirubin
- Direct: any bilirubin that can react to the reagents and can be analyzed from blood (90% of it is conjugated but some unconjugated bilirubin can also be analyzed and become a part of direct) - Indirect: forms of bilirubin that cannot be analyzed very quickly, does not react w/ the components of the assay reagents and therefore you cannot get them
39
Biosynthesis of heme - What are the starting materials? - rate limiting enzyme? - coenzyme of delta ALA synthase - How is delta ALA synthase regulated? - End product inhibition. - steps
○ Glycine and succinyl CoA (TCA intermediate) ○ Delta ALA synthase ○ Vitamin B6 (pyridoxine) ○ If there is a lot of heme then it will turn down - 2 Delta ala (product of the first reaction) will condense together to form a pyrole ring and 4 of these pyrole rings condense together to form uropophyrinogen which leads to decarboxilation step with mitochondrial oxidation steps which leads to formation of your protoporphyrinogen IX and then you have ferrochelatease which adds the ion to form your heme.
40
What can cause high levels of delta ala? - what enzyme is inhibited? why? - what does that lead to? why? - What is causing the neurologic symptoms?
- licking paint chips - ALA dehydratase because of lead poisoning - anemia, affects dehydratase and ferrochelatase so it prevents the attachment of the ferrous iron to the protoporphyrin IX. So anemia is due to inhibition of this entire step and anemia will lead to the fatigue. - accumulation of these intermediates in large amounts can cross the blood brain barrier and affect neurons.
41
Porphyria's - what is it? - types? - effects on body
- Group of diseases, which are caused by inactivity or low activity or quantitative deficiency of multiple of these enzymes in the heme biosynthesis pathways - There are different type which have diff effects on the body - Some of the intermediates have severe effects on the skin (itchy skin, blistering of the skin, changes in color, etc), others can cross the blood brain barrier and lead to neurological symptoms
42
Liver and biliary system - what comes out?
- Bile, formed and secreted into common hepatic duct
43
Bile - components - function, where? - why do we care?
- Bile salt, Cholesterol, Phospholipid, Water, Bilirubin, Electrolytes - Helps emulsify fat in the Duodenum, Jejunum, Ileum - Need an increased surface area for lipase to work on and bile acids help to form mycelles since fats are lipophilic and are protected in water environment
44
Mycelles - importance
- So fats can be absorbed by going through aquiatic lumen and be take up into enterocytes for absorption
45
Gallbladder - role
Storage and concentration
46
Pancreas - role
- Secrete enzymes to help break down macromolecules: Lipase, Amylase, Trypsinogen, Pepsidase -Secrete bicarb/mucin: From ductal cells - Secrete glucagon and insulin
47
Importance of bicarb?
Pumping of this base into the duodenum will help neutralize some of acid coming from the stomach
48
Intestines - parts
- duodenum, jejunum, ileum
49
digestion and assimilation occurs? - carbs - fat/lipids - Vit B12 and bile acids absorbed
-Duodenum; does happen in jejunum but not as much - Heavier in Duodenum but does occur in jejunum and ileum - ileum
50
where are things ingested in the small intestine in relation to the enterocyte? - Fat - Carbs - Proteins
- Lumen - Lumen, brush border: Broken down 1st in lumen but there are more enzymes at the brush border that will break down carbs into monosaccharides (glucose, galactose, fructose) then they can cross over into cell using their specific transporters. - Lumen, brush border, cytosol of enterocyte
51
Osmolarity in gallbladder vs liver - how?
○ Hepatic: osmolarity is isotonic ○ Gallbladder: also isotonic, will have same amount of solute as the bile from the liver but as it gets concentrated the mycelles get bigger in size. The amount of solute in the bile does NOT increase with concentration. - In unit 1 we talked about osmolarity and how the number of particles it what changes the osmolarity, so, since the number of particles in bile stays the same the osmolarity stays the same.
52
What does concentration of bile mean
Removal of water
53
What happens to cholesterol in bile
- Cholesterol is lipophilic so it can cross the membrane - The more cholesterol in the gallbladder and the longer it sits there then the greater the ability of it to form crystals which will lead to formation of stones. As you age there is increased secretion of cholesterol which aids in formation of stones
54
How does gallbladder fill? - how - when and what else happens at that same time? - what else can mediate filling?
- Due to pressure gradient - In between meals; There is high pressure at the common hepatic duct from trying to secrete the bile, and there is high pressure at the sphincter of Oddi because it is closed and so it has increased tone. The gallbladder would be going through receptive relaxation and would have decreased tone which would lead to decrease in pressure so the only area with low pressure is the galbladder so the bile moves into there. - Neuro-hormonal regulators: Fibroblast growth factor 19 (FGF19// talked about on Monday): Produced in illeal enterocytes and as bile acid is uptaken you get increase in FGF19 and it helps in relaxation of gallbladder.
55
Patient has fibrosis of cystic duct; Explain effect on gallbladder filling and justify answer.
- Fibrosis of the cystic duct leads to hardening which reduces the elasticity of the vessel, causing increased pressure in the cystic duct/gallbladder area so the bile wouldn't be able to flow into gallbladder and filling would be impaired
56
Role of CCK? - At level of gallbladder?
-At level of gallbladder-- it induce contraction by binding to smooth muscle of gallbladder - Parasympathetic: stimulates the vagus nerve which then causes the vagus nerve to release Ach which will further stimulate the galbladder contraction; through dorsal vagal complex--vagovagal response; vagal afferent to vagal efferent - Relaxes the sphincter of Oddi (Induce through NO or VIP) - Stimulates pancreatic enzyme release - Causes receptive relaxation of the stomach which will decrease gastric emptying - It will decrease potentiation
57
review: what is potentiation
potentiation is acid secretion with gastrin, histamine and acetylcholine
58
Galbladder receptor for CCK
This is a Gq receptor just like in all other smooth muscle contractions; it will activate myosin light chain kinase and increase intracellular Ca
59
Types of gallstones
○ Cholesterol ○ Bilirubin
60
How can you get formation of cholesterol stones?
- hypersecretion of cholesterol - hyposecretion of bile acids - hypomotility of gallbladder (biliary stasis): bile just sitting there causing formation of crystals - hypersecretion of mucus: locks crystals in to form gallstones
61
blockage at Cystic duct
- will not have as much concentration of the bile because there is not gallbladder filling - Bile will still be made in the liver, but will be released into the biliary tree as unconcentrated; will still have lipid digestion but will be a little bit hampered since the bile is unconcentrated
62
blockage at Common bile duct - How does this affect fat digestion/absorption? - How does this affect micelle formation?
- more difficult with lipid digestion because no bile from liver or gallbladder into the duodenum - fat would not be able to be emulsified, so there wouldn’t be increased surface area for the lipases from the pancreas to act on the fat - micelles would be decreased because there are no bile acids to help with formation; wont be able to travel through aqueous lumen and taken into enterocyte
63
blockage at Sphincter of Oddi
- No digestive enzymes from liver, gallbladder, or pancreas - Lower lipid digestion with same reasoning as in B - Also, would not have any pancreatic amylase, lipase, peptidase causing impaired digestion and absoprtion of proteins, fats, carbs. - also bicarb would not be released
64
significance of bicarb
inability to release bicarb into duodenum would cause inability to buffer gastric acid, pH remaining acidic would prevent enzymes that are only activated at more basic pH to not be able to activate, for example salivary amylase needs alkalotic pH in order to be turned on
65
2 pharmacologic agents used with bile/pancreatic dysfunction
- Ursodiol - Pancrelipase
66
Ursodiol - Used for - What is it? - MOA - What does it replace? - How often is that used? - importance
- gallstones - acid derivative that can be used for prophylaxis/treatment of gallstones - Reduce hepatic cholesterol secretion by stabilizing hepatic membranes, Induce expansion of bile acid pool - Replaces endogenous bile acid-- anti-inflammatory - Not used all that often because with patients that have significant gallstone disease it is more common to use cholecystectomy because it will get rid of production of stones to start with so don’t have to worry about treatment after the fact. The medication is still used but not as much as cholecystectomy. ○ Still need to know because not all patients want/ are good candidates for surgery but still have gallstones that are causing symptoms and need to be treated
67
Pancrelipase - what is it - Site of action - Factors that may contribute to lack of therapeutic affect
○ Concentrated pancreatic enzymes; specifically amylase, lipase, and protease ○ duodenum ○ pH- acidic can: inactivate enzyme; PPIH2 administration- reduce acid; Enteric coated capsule; only dissolved in alkaline pH of duodenum; Administration of drug should be taken with each meal
68
Cholelithiasis - what is it? - what does it prevent? - presentation? why?
- stone stuck in cystic duct - bile from going in or out of galbladder - biliary colic: abdominal pain from spasm of gallbladder trying to push stones out against highs pressure
69
Choledocholithiasis - what is it? - what does it cause?
- stone stuck in common bile duct - bile cannot exit and wil make its way back up to liver and cause damage/ inflammation since it has emulsifying properties
70
Acute Pancreatitis - what is it? - what does it cause?
- Blockage at ampulla (previously ampulla of vater) - bile will back up into liver and pancreas and there will be autodigestion of pancreas. Will have both liver and pancreatic manifestations
71
Murphys sign - what is it?
- pain from inflammation of gallbladder that increases when pushing on gallbladder
72
Hepatocyte blood flow vs bile flow
• Blood flow is going toward the central vein while Bile flow is going the opposite direction
73
Liver blood flow characteristics - where is it coming from? - how does it get there? - sinusoids and characteristics that allow for blood flow - how can this system be messed up?
- bloodflow to liver is mainly coming from the portal vein, Only a small amount is coming from the hepatic artery.) - Since veins have decreased pressure compared to arteries, you can conclude that blood supply to hepatocytes is low pressure - in order to get blood supply from the portal vein to the sinusoids, sinusoidal pressure has to be even lower. The pressure of these sinusoids are so low that they are collapsed at rest. - fibrosis is a fast and easy way to increase pressure around hepatocytes, impeding blood flow to the liver
74
Zones of blood flow in the liver - zones and amount of oxy - why?
- Zone I has the highest amount of oxygen, Zone II is intermediate, and Zone III has the least amount of oxygen • The differing oxygen levels help regionalize different enzymes based on characteristics pertaining to both digestion and xenobiotics (detoxification of foreign chemicals like drugs and alcohol). ○ Zone I will contain enzymes that require oxidative metabolism. You may have gluconeogenesis or cholesterol synthesis here because these enzymes need oxygen. ○ Zone III will contain enzymes that require less oxygen and may undergo glycolysis and ketogenesis.
75
Cells of the Liver
- Hepatocytes - Couper Cells: macrophages - Sinusoidal endothelial cells: lies adjacent to bloodflow; They are fenestrated with spaces in between so that macromolecules can be removed from the blood. - Stellate Cells: Store vitamin A and have contractile properties which help create a pressure gradient for bile secretion
76
Alcoholic Liver Disease - how does ethanol in high amounts damage liver? - what does it lead to? - CDC definition - women vs men - alcohol-related health curve - AST vs ALT
- Impaired hepatocytes, oxidative stress, protein adducts, and immune reaction. - This can lead to cell damage and death. - The CDC defines moderate alcohol consumption as 1 drink/day for women and 2/day for men. - nothing to do with body weight… It has to do with sex-related physiologic difference in metabolism of alcohol. Males can start digesting alcohol earlier in the stomach and females can not. - U-curve: relatively healthy with zero daily consumption of alcohol, but there is an increase in benefit at 1-2 drinks/day. If you exceed this amount, the curve of the U starts to go back up, indicating decreased health benefit. - AST higher because ALT is MORE vitamin B6 dependent than AST. Alcohol can cause vitamin deficiency (including vitamin B6 deficiency), causing ALT levels to drop below AST levels.
77
Fatty Liver - cause? - reversible?
- This can happen if alcohol consumption exceeds the CDC recommended amount. - yes, However, continued insults to the liver can progress into an irriversible state.
78
Injured hepatocytes release? - which causes?
- ROS and DAMP (damage associated molecular patterns) - a cascade of events including Kupffer cells and Stellate cells and involvement/ recruitment of the immune system. This causes inflammation, collateral damage, and ultimately fibrosis.
79
Stages of liver disease
- Step one from alcohol damage is fat deposition/steatosis - Step two from alcohol damage is fibrosis which can progress into cirrhosis which is characterized by fibrous bands separating lobules which is irreversible.
80
Cirrhosis
- characterized by fibrous bands separating lobules which is irreversible. - Bands are so thick that they can't be resorbed anymore.
81
AST and ALT -indicate? - what are they? - difference in levels
- Indicating liver (hepatocyte) damage - AST and ALT are both transaminases that are concentrated in the liver hepatocytes. If hepatocytes die, they leak out into the bloodstream. •Hepatitis: ALT is higher than AST; Alcoholic liver disease: AST will be greater than ALT (usually double or triple the amount of ALT)
82
Hepatocellular predominance
AST and ALT are what is predominately elevated
83
ALP and GGT - indicates - what are they? - where are they located? - causes for elevation?
- biliary damage (bile canaliculi and cholangiocytes, respectively) - enzymes are in areas close to the liver, but are located in more specific tissues that can help differentiate hepatic damage from biliary damage. - Alkaline phosphatase (ALP) is located in the bile canaliculus; GGT is found further down in the ductules, within cholangiocytes - may be elevated a little bit when there is damage to the surrounding liver, but they will be VERY high when there is damage within the biliary tree specifically (such as a biliary obstruction/ gallstone stuck in the tree)
84
Cholestatic Predominance
If ALP and GGT are predominately elevated (higher than AST and ALT)
85
Bilirubin - how is it made? - increased levels can indicate? - conjugated (direct) vs unconjugated (indirect)
- liver takes the unconjugated form of bilirubin and conjugates it into a water-soluble form so it can be excreted in the bile. - decreased liver function, but doesn't tell us why - If unconjugated/ indirect bilirubin is high, this could mean that RBC lysis is happening quickly and the liver can't keep up fast enough or there could be an underlying genetic condition such as Gilbert's syndrom in which conjugation occurs slowly. while elevated conjugated/direct bilirubin is more of a concern pertaining to hepatobiliary etiology. If we have high levels of conjugated bilirubin, this means the liver is successfully doing its' job but for some reason the bilirubin is not getting out. It could be getting stuck in the liver or biliary tree due to fibrosis of the liver or blockage/obstruction of the biliary tree.
86
Albumin and Coagulation - where are they made? - half lives? - decreased albumin vs clotting factors indicates?
- made by the liver - Albumin has a longer half life than clotting factors. - a long-term issue of hepatocyte function while decreased coagulation factors are more indicative of short-term hepatocyte function.
87
Lifestyle Changes to help with alcohol induced liver disease
- Stop drinking to reduce ongoing insult to hepatocytes! - Avoid other liver toxins. - Stress reduction: correlation with inflammation so as one is reduced the other one can also be lowered - exercise: improve blood supply to hepatocytes as well as reduce inflammation involved in the mechanism of sclerosis that we covered earlier.
88
Ascites and Edema from liver damage - what is happening - what is normal? - what is this condition
- The fenestrations from the sinusoidal epithelium have closed up to an extent because the stellate cells are releasing collagen--\> collagen builds up----\> compresses the sinusoids---\> increases sinusoidal pressure---\> causes leakage of fluid into other areas • Normally, the fluid should move into the space of disse (perisinusoidal space) and on toward the lymphatics. However, this is not happening due to the collagen buildup in the perisinusoidal space and the fluid ends up in the abdominal cavity. ○ This condition is known as portal hypertension and resulting ascites.
89
Med treatments portal hypertension and resulting ascites
-Diuretics are recommended since fluid is accumulating in the tissues - S-adenosylmethionine: synthesized from all body tissue and concentrated in liver, primary methyl group in transmethylation reactions which are integral to phase II hepatic detox - Vitamin E is an antioxidant so it can help combat the ROS that we saw earlier in the mechanism of fibrosis; also supports glutathione which is one of the most important phase I detoxification enzymes • Alpha Lipoic Acid also helps with antioxidant functions
90
Lifestyle changes for portal hypertension and resulting ascites
- unsaturated fat: decrease biliary cholesterol saturation; enhance bile flow, increase bile acid synthesis and solubility - fiber: reduces formation of deoxycholic acid - coffee: stimulates CCK release and decreases cholesterol crystalization - water: 6-8 cups a day to prevent crystal agglomeration - alcohol: 1/ day for women 2/ day for men - avoid simple sugars: increase cholesterol saturation and reduce ratio of beneficial colic acid - consider elimination diet
91
Supplements and botanicals for portal hypertension and resulting ascites
- Vit C: involved in conversion of cholesterol to bile acids - Magnesium: supplemental or dietary - calcium: binds secondary bile acids - vitamin E: mixed tocopherols - botanicals: peppermint oil, tumeric, globe artichoke, milk thistle, dandeloin
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Conventional considerations for gallstone disease
- Ursodeoxycholic acid: lowers bile cholesterol saturation - chole: definitive treatment of gallstones; impairs coordinated secretions of bile needed to digest fatty meal, changes ration of bile acids, sphincter of Oddi dysfunction - Sphincterotomy: f the stone is too big to pass through the sphincter, the sphincter of oddi may have to be opened up a little bit surgically. The smooth muscle is slightly cut, allowing it to open up so the biliary tree can be cleared out.
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Where does the common bile duct go? Where does it end up?
passes through the pancreas and joins up with the pancreatic duct
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cholangiocarcinomas
- biliary tract carcinomas -
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Magnetic resonance cholangiopancreatography
technique for viewing the bile ducts and the pancreatic duct. It can also show the pancreas, gallbladder and liver. MRCP uses magnetic resonance imaging (MRI) to produce detailed pictures of these ducts and organs.
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Endoscopic retrograde cholangiopancreatography - what is it - problems with it - common complication
procedure that enables your physician to examine the pancreatic and bile ducts. A bendable, lighted tube (endoscope) about the thickness of your index finger is placed through your mouth and into your stomach and first part of the small intestine - It's invasive - Pancreatitis
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precursor to a pancreatic mass
- What about serous cystic neoplasm? Are serous cysts of the pancreas malignant?
Pancreatic intraepithelial neoplasia (PanIN); most common precursor lesion, but mucinous cystadenomas and intraductal papillary mucinous neoplasms can become cancer
- No, they're virtually always benign, serous carcinomas exist, but they're exceptionally rare, especially in the pancreas
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What is intraepithelial neoplasia in general? What happens here with PanIN?
- You have a lot of mutations, such as telomere shortening and KRAS mutations, that can lead to a lot of overgrowth in the pancreas, and that can cause inactivation of CDKN2A, and that leads to more inactivation of tumor suppressor genes
- more than one precursor lesion for this tumor including Intraepithelial neoplasias, Neoplasia within the epithelium
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EUS
- what is it?
- how is it performed?
- can cancer be diagnosed with imaging?
- why is this perferred? what else could you do?
- endoscopic ultrasound
- GI guy is going to drop the scope, it's got an US probe on the end and while they're in there looking they can also get tissue
- No matter how pathognomonic something is on imaging some insurances won't pay for expensive cancer drugs until there's tissues.
- This is probably the least invasive way to get tissues, however you still do a CT-guided biopsy or FNA to get to the pancreas
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What are the imaging modality, orientation, and window depicted?What kind of contrast? Explain. How do you know that it's dense? Abnormality? Why does the gallbladder have the same density as the intrahepatic ducts?DX? explain.
- C+CT Abdomen/Axial/Soft-tissue;
- there are questionable trace of oral seen in one bowel, and IV contrast because the kidneys are a little denser than they normally would be and the liver is relatively dense.
- There's actually an abnormal structure inside the liver that really stands out
- intrahepatic biliary ductal dilation and big gallbladder
- Because it's filled with the same stuff, which is bile
- adenocarcinoma of the pancreas; There is a mass at the head of the pancreas, If you see a mass at the head of the pancreas, the patient has pancreatic cancer until proven otherwise
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What do we see in this image?What's another entity that looks like this? Why is there fibrosis? Does the image support your diagnosis of adenocarcinoma?
- We see a lot of glands that do not look normal, All of the pink stuff is fibrosis and there are no acinar cells
- Chronic pancreatitis : since there is usually pancreatitis around the tumor, it can be exceptionally difficult to tell the difference between chronic pancreatitis and a very low grade adenocarcinoma
- pancreatitis will cause autodigestion of the pancreas and cytokines get activated and the fibrosis ensues its called a desmoplastic response and it's believed to be the body trying to fight back and wall it off but it doesn't generally work
- Yes, this is an adenocarcinoma, it's a ductal adenocarcinoma because it kind of looks like ducts
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Serous cystic neoplasm
- where is it prevalent?
- duct system
- predominate in what sex?
- malignancy?
- prevalent in the tail of the pancreas
- does not involve the duct system
- female predominant
- almost always benign
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Mucinous cystic neoplasm
- where is it prevalent?
- what sex?
- malignancy
- description
- prevalent in the tail of the pancreas
- female predominant
pre-malignant
- associated with ovarian-type stroma ( stroma around it that looks like the stroma of the ovary and it even stains like the stroma of the ovary, )
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intraductal papillary mucinous neoplasm
- where is it prevalent?
- where does it arise? specifically?
- name when it is side duct?
- prevalent in the head of the pancreas
- arises in the duct; main pancreatic duct;
- branched-duct IPMN
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Serology for Hep B
- Susceptible to hep B
- immune from past infection
- immune from Hep B bc of vaccination
- acute infection
- chronic infection
- Susceptible to hep B: HBsAg neg, antiHBc neg, and anti HBs negative
- immune from past infection: HBsAG negative, anti-HBc positive, anti-HBs positive
- immune from Hep B bc of vaccination: HBsAg negative, anti-HBc negative, anti-HBs positive
- acute infection: HBsAg positive, anti-HBc positive, anti-HBs negative, IgM anti-HBc positive
- chronic infection: HBsAg positive, anti-HBc positive, anti-HBs negative, IgM anti-HBc negative
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Imagining to order with Hep B
CT, U/S, MRI,
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imaging modality, body region, orientation, window? Abnormality?
CT 3 phase; CT abdomen, axial, soft tissue window
- In liver, if you see lesion that lights up quickly in arterial phase then on other two phases it's dark, it's a hepatocellular carcinoma
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What is a 3 phase CT? phases? where do you find portal vein?
- used for lesions in liver that are suspicious for cancer
- First phase-arterial phase: Look at aorta on image on left-looks very bright (arterial phase)
2nd phase-portal venous phase; final phase: delayed phase
- Anterior inferior portion of liver there are a bunch of little bright spots in liver-that's portal venous phase
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Which image shows hepatocellular carcinoma with no evidence of background cirrhosis?
- Left: shows HCC; cells look like hepatocyte (big, pink, fluffy).
- Right: looks like cholangiocarcinoma-a bunch of glands ; Poorly differentiated HCC can look like poorly differentiated cholangiocarcinoma
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Risk factors for HCC
- Chronic hep B and C
- alcoholic liver disease
- aflatoxin
- metabolic disease: non-alcoholic fatty liver disease, metabolic syndrome, diabetes mellitus, obesity
- genetic liver disease: hereditary hemochromatosis, alpha-1-anti-trypsin deficinecy, wilson disease
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two most common molecular/genetic alterations associated with development of hepatocellular carcinoma?
activation of beta catenin and inactivation of p53
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entities considered potential precurosr lesions to HCC?
Hepatocellular adenoma, small cell change, large cell change, high-grade dysplastic nodule
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liver lesion suggested by abdominal pain that started as discomfot and is now severe, use of nabolic steroids?
- malignant?
- why are they more common?
- Hepatocellular adenoma
- benign but can be premalignant with beta catenin mutation
- rare lesion until the advent of oral contraceptives and then steroid use
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imaging modality, body region, orientation, and window of the displayed images? difference between the images? abnormaltiy? dx? next step?
- CT abdomen soft tissue window, axial; Left vs right image: contrast, IV. There's oral contrast. Look for white stuff in colon on left; Black arrows pointing at a solitary mass; Adenoma; Biopsy
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what is complication of adenomas
they can rupture
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Liver Fluke
- symptoms, labs, Clinical concern, secondary host, imaging
- symptoms: unintended weight loss, jaundice
- labs: cholestatic pattern of liver enzyes, elevated CA19-9, stool positive for eggs
- Clinical concern: an cause cholangiocarcinoma
- secondary host: fish
- imaging: Fluoroscopy-ERCP , Ultrasound, CT
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cholangiocarcinoma
- what is it?
- cause?
- how does cholangiocarcinoma present on ultrasound?
- Second most common primary malignant tumor of liver is a ductal carcinoma of bile duct
- Chronic irritation of any kind (including this worm) predisposes to malignancy
- carcinoma obstructs the bile duct, which causes dilated bile ducts above level of obstruction. If you also have pancreatitis, tumor would have to be distal to the ampulla
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What's abnormal?
- Dilations of intrahepatic bile ducts
- Primary lesion with yellow arrows-shows mass
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imaging modality, body part, view, window? abnormality?
- CT abdomen axial soft tissue window
- Liver-enlarged, intrahepatic duct dilation, mass extending beyond arrow heads. Mass is low density-poorly defined low density mass, clearly obstructing the intrahepatic ducts
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imaging modality, body part, abnormality
MRCP; predominantly T2 W
Several intrahepatic ducts affected. Dilation of common hepatic duct, so it's a pretty good size mass
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cholangiocarcinoma risk factors
hep B. Hep C
Primary sclerosing chlangitis
primary biliary cirrhosis
liver flukes
polycystic liver disease
fatty liver disease
biliary intraepithelial neoplasia
