Week 3 Flashcards
What is the role of the liver?
- makes bile with respect to hepatobiliary system, which is made up organic and inorganic components.
Define Bile
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.
role of the Gall Bladder
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.
role of Intestine
- 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.
General functions of bile
- 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.
majority of the blood going to the liver
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
blood flow to hepatocytes - flow - sinusoids
- 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.
Bile constituents
Bile acids, phospholipids, cholesterol, bile pigments, xenobiotics, electrolytes
functional/ excretory or isotonic components of bile?
• 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.
Deficiency of which enzyme will decrease the synthesis of bile acid ? - coenzyme?
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
What turns 7- alpha hydroxylase on and off?
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-alpha hydroxylase - function - deficiency
- 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.
How do we get bile acids across the basolateral membrane-? - what about bicarb?
- 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.
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
- 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
What does the active movement of ions and these organic substrate do to the osmotic pressure of the caniculus?
increases the osmotic pressure and therefor holds the water into it which is how you form the canicular bile
What will happen if there was blockage/Destruction in the ducts
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.
What is the name of the condition where you don’t have adequate production of bile or flow to the intestines? - causes - effects
- 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.
Explain the maintenance of bile acids homeostasis
- reabsorption and reuse of the bile acids through Enterohepatic circulation
Enterohepatic circulation: mode of absorption of bile salts in the distal ileum
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.
efficiency of reabsorption of bile salts - how much is absorbed
- 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
What happens to the amount that is not reabsorbed?
- It is excreted, it goes to the colon from the small intestine and forms secondary bile acids
primary vs secondary bile acids
- 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)
What is the rate limiting enzyme in bile acid synthesis - how is it regulated?
- CYP7A1 aka 7 alpha hydroxylase - by its product
summary of process of recycling/formation of bile salts
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
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
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
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
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
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
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
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
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.
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
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
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
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
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
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
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.
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.
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
Liver and biliary system - what comes out?
- Bile, formed and secreted into common hepatic duct
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
Mycelles - importance
- So fats can be absorbed by going through aquiatic lumen and be take up into enterocytes for absorption
Gallbladder - role
Storage and concentration
Pancreas - role
- Secrete enzymes to help break down macromolecules: Lipase, Amylase, Trypsinogen, Pepsidase -Secrete bicarb/mucin: From ductal cells - Secrete glucagon and insulin
Importance of bicarb?
Pumping of this base into the duodenum will help neutralize some of acid coming from the stomach
Intestines - parts
- duodenum, jejunum, ileum
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
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
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
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
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
What’s abnormal?
- Dilations of intrahepatic bile ducts
- Primary lesion with yellow arrows-shows mass
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
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
