Liver Physiology Module PDF

Liver Physiology Module October 30, 2023 8:25 AM Modules Page 1 - Weighs 3lbs, 1.5kg - Accessory organ - below diaphragm in RUQ of abdo, surrounded by diaphragm, rib cage, bones, muscles of abdo wall - R lobe larger than L - Liver anchored to stomach via lesser omentum - GB on R side of liver, a...

Liver Physiology Module October 30, 2023 8:25 AM Modules Page 1 - Weighs 3lbs, 1.5kg - Accessory organ - below diaphragm in RUQ of abdo, surrounded by diaphragm, rib cage, bones, muscles of abdo wall - R lobe larger than L - Liver anchored to stomach via lesser omentum - GB on R side of liver, and bulk of liver on R; thus kidney on R is lower than L - Smooth and firm surface - feel smooth liver border under R rib cage on physical exam. ○ Inferior side has GB attached to it - Bile ducts are through the hilus, and connected to the duodenum - Liver covered by visceral peritoneum, same covering over other abdo organs - Liver surrounded by dense, irregular CT = Glisson's capsule ○ Surrounds liver and contains nerve fibers or endings  People experienced pain if have inflammation of cancer of liver b/c causes distention of this capsule = severe pain - Can regenerate after hepatic injury or surgery or infection or inflammation. No other organ can regenerate ○ Ex. If up to 70% of liver is removed during partial hepatectomy, the remaining lobe will enlarge and expand the blood supply to original size within couple of weeks  However with fibrosis, inflammation or viral infection, liver is unable to regenerate and overall function deteriorates Modules Page 2 - Human liver contains 50-100 thousand lobules, organized into hexagonal units around a central vein - Central vein empties into hepatic veins, and then IVC - Lobules organized into cellular plates or sheets extending from portal tracts to central vein. - Between plates are functional liver cells, hepatocytes, and the sinusoids - Hepatocytes make up 90% of total mass of liver, with large RER and SER, golgi complexes, peroxisomes, and mitochondria - Hepatocytes can secrete ~ 1L of bile per day through bile canaliculi, towards portal triads - L image: 2 liver cellular plates radiating from central vein like wheel spokes, the blood vessels, the bile-collecting system between 2 adjacent hepatocytes, and lymph system composed of spaces of Modules Page 3 - - - bile-collecting system between 2 adjacent hepatocytes, and lymph system composed of spaces of Disse and interlobular lymphatics Sinusoidal epithelial cells and large star-shaped Kupffer cells (reticuloendothelial cells or hepatic macrophages) ○ Kupffer cells - scavenger cells that eradicate foreign matter or microbes 3 vessels -- hepatic artery, portal vein and bile duct = portal triad or tract Liver blood flow = 27% of resting cardiac output, as liver is expandable and capable of being a venous blood reservoir ○ Most richly perfused cells in the body With inc RA and RV pressure in heart, liver can expand and store 0.5-1L of extra blood, leading to hepatomegaly Liver has high lymph flow, and accounts for about 1/2 of all lymph formed in the body - Liver gets blood supply from 2 sources: ○ O2 blood from hepatic artery, branched off of unpaired celiac artery, from the aorta ○ Nutrient-rich deoxygenated blood from hepatic portal vein - Together, these 2 blood sources mix in the sinusoid spaces, so that O2 and nutrients and other substances are taken up by hepatocytes. ○ Hepatocytes also release products i.e. albumin, clotting proteins back into the blood, going to the central vein and then draining into the hepatic vein, then IVC Modules Page 4 - Portal venous circulation that drains blood from GI tract, specifically the stomach, pancreas, small and large intestines - This very nutrient rich blood goes directly to liver first before it gets released into the rest of circulation - The hepatocytes have access to the nutrients and drugs first, including microbes or toxins from the GI tract ○ Important b/c it is called first pass effects-->liver gets the first shot at detoxifying metabolites or medications before they go to circulation Modules Page 5 - enterohepatic circulation: hepatic secretion, intestinal absorption, hepatic resecretion of bile acids ○ Efficient recycling mechanism, with less than 5% loss per day - Bile, which contains bile salts, is made by the hepatocytes and is essential for digestion and absorption of fats - Recycling of bile salts conserves bile salts--> normal healthy adult has 2-4g of bile salts in their total bile acid pool - Cycling of bile acids is done several times during meal, and it can provide body enough bile salts to promote lipid absorption - Light eaters may circulate pool 3-5times/d, and heavy eater may circulate same pool 14-16 times per day - ~95% of bile salts secreted and reabsorbed in terminal ileum - Bile salts are recycled by 4 mechanisms: ○ Passive diffusion along enter small intestine (minor role with very small fraction absorbed this way) ○ Carrier-mediated active absorption in terminal ileum (most important absorption route with less than 5% escaping into colon) ○ Bacteria in colon deconjugates the bile salts to bile acids before being absorbed passively or actively ○ Bacteria converts primary bile acids to secondary bile acids with subsequent absorption of deoxycholic acid  Lithocholic acid is poorly absorbed, so approximately 500mg of bile acids are lost daily - If there is inflammation in terminal ileum, this can result in loss of large quantities of bile salts in feces, which is problematic ○ Depending on the severity, this can lead to malabsorption of fat Modules Page 6 - GB has 4 parts: ○ Fundus ○ Main portion of body ○ Infundibulum between body and neck ○ Neck or narrow distal segment that joins with the cystic duct  This small pouch-like structure is responsible for storing and concentrating bile - Wall of GB has 3 main layers: ○ Mucosa with epithelial cells that have microvilli to absorb water and the lamina propria ○ The muscularis layer with 3 layers of SM fibres and CT ○ The outer layer or serosa that covers the entire unattached portion of GB surface - Mucosa layer has small honeycomb-like folds that expand as the sacs fill with bile - When there is accumulation and solidification of bile, this can lead to bile or gallstones, which get caught in folds and then can cause trouble - The SM in the muscularis layer contracts to expel the bile into the cystic duct ○ This links with the common hepatic duct, which empties into duodenum via the ampulla of vater (or the hepatopancreatic ampulla), and past the major duodenal papilla, which is surrounded by the sphincter of Oddi Modules Page 7 - Neurohumoral control of GB contraction and biliary secretion: - GB contractions are regulated to coordinate bile availability with the timing of meals - The endocrine release of CCK occurs in response to nutrients, particularly FA and AA in chyme ○ As these reach the duodenum, the GB contracts - Also, CCK activates vagal afferent pathways to trigger a vasovagal reflex, reinforcing the GB contraction (via parasympathetic activity and Ach) ○ Both facilitate relaxation of sphincter of Oddi to permit bile outflow (via nitric oxide and vasoactive intestinal polypeptide - VIP) - Also, secretin released from enteroendocrine cells in the duodenal wall can lead to more bile production Modules Page 8 - Metabolism of carbs, lipids, and proteins - Liver is complex and has high rate of metabolism, shares substrates and energy from one metabolic system to another, processes and synthesizes multiple substances that are transport to other areas of the body, plus other functions - Stores dietary carbohydrates - Regulates level of glucose in blood - Brain function depends on constant supply of glucose for its metabolism, but has no ability to store the glucose in the brain - Liver can store excess glucose and then return it to the blood when the levels drop, thus ensuring a constant supply for the body - Liver is capable of gluconeogenesis, turning proteins or AA into glucose, or TG or glycerol into glucose, both in conditions when glucose levels fall Modules Page 9 glucose, both in conditions when glucose levels fall - Liver converts and stores excess glucose into glycogen and can reverse this by changing glycogen back into glucose as needed, all of which are important mechanisms for keeping glucose homeostasis - When venous blood first comes to the liver via portal circulation, it arrives, and any non-glucose sugars are rapidly converted to glucose - Initially, glucose from the portal vein is not stored there, but it passes through rest of body - In the general circulation, some glucose is used by the brain, but most can be taken up and stored by insulin sensitive tissues, especially muscle - When glucose returns to liver, via hepatic artery, unlike the glucose entering the portal vein, the glucose entering the artery can be stored as glycogen--a large polymer of glucose - When the glucose levels are high, the liver will form glycogen from the extra glucose, and this is called glycogenesis - when glycogen is broken down to re-form glucose, this is called glycogenolysis ○ Both processes use enzymes found in hepatocytes to accomplish these reactions - The liver uses many different metabolic pathways and employs dozens of enzymes to adjust the circulating glucose levels to keep this in the normal range - Hepatocytes: ○ store some TGs ○ break down FA to make E in the form of ATP ○ synthesize phospholipids which get transported as lipoproteins  synthesize lipoproteins to transport FAs, TGs, cholesterol to all body cells ○ Synthesize cholesterol and use cholesterol to make bile salts - 80% of cholesterol synthesized in liver is converted to bile salts, which is secreted into the bile - The remainder is transported as lipoproteins and carried by blood - Both phospholipids and cholesterol are used by all cells to form membranes, intracellular structures, and multiple chemical substances important for cell function - All fat synthesis in body from carbohydrates and proteins occur in liver - After fat is synthesized, it is transported in lipoproteins to adipose tissue to be stored - Digestible fats are complicated--liver plays important role - Some proteins produced by liver and some in small intestines help with transformation of TGs and ability for TGs to pass through membranes - Fat is not water soluble, thus body develops ways for fat to be transported and absorbed since body contains large amounts of water - TGs are very hydrophobic and don’t dissolve in water, thus need to become water soluble - To absorb these fats, pancreas secretes lipase to break down monoglycerides and Fas ○ The bile salts from liver form micelles (a complex that is made of bile salts + monoglycerides + Fas) ○ These micelles are taken to the epithelial cell membrane and then Fas diffuse across - Inside intestinal cell, the TG is reprocessed, repackaged, then combined with glycerol, phospholipids, cholesterol, Fas to make chylomicrons - These chylomicrons are moved to lacteals via exocytosis - The role of bile salts is to emulsify fats to form micelles, to make the cholesterol soluble, and then Modules Page 10 - The role of bile salts is to emulsify fats to form micelles, to make the cholesterol soluble, and then facilitate cholesterol absorption ○ Overall,, emulsification is breaking down fat droplets into smaller droplets and making these droplets soluble in water - Emulsification of fat drops with bile salts for absorption ○ Micelles move to SI cell and then monolglycerides and Fas cross the membrane ○ These components are repackaged with other substances i.e. glyverol, choelster and proteins by the golgi apparatus, and then released as a chylomicron that is taken up by the lymph lacteal Modules Page 11 - Liver must deaminate or remove amine groups from proteins before AA can be used for E or converted to carbs or fats - As liver removes amine group, this results in toxic ammonia that is then required to be converted into the much less toxic urea, to be excreted in urine - If liver is unable to form urea (i.e. liver failure), the plasma ammonia concentration levels would rise rapidly and could result in hepatic coma and death - Drug given to bring down ammonia levels in liver failure = lactulose ○ Also a laxative, but can also draw ammonia from blood into colon to be excreted ○ Pt may experience some diarrhea - Hepatocytes also synthesize 90% of all plasma proteins i.e. albumin, alpha and beta globulins, prothrombin, fibrinogen - The liver has the ability to synthesize all non-essential AA and other important chemical compounds or precursors from AA Modules Page 12 - Liver can also be a filter, b/c contains detox systems - Main detox system is cytochrome P450 ○ Pathway of 50-60 enzymes, able to change active metabolites to an inactive form for most toxins and medications - 2 pathways to detoxification of alcohol ○ Alcohol dehydrogenase enzyme breaks down alcohol into acetaldehyde, which is a highly toxic substance and known carcinogen  Acetaldehyde must be further metabolized to acetate, then broken down to water and CO2 for easy elimination ○ MEOS: microsomal ethanol-oxidizing system, is an alternate pathway to metabolize alcohol and some other drugs - Liver can excrete many drugs i.e. penicillin, erythromycin, and sulfonamides into bile - Major route for excreting calcium is when liver secretes it into bile, which then passes into gut and lost in feces - Liver can chemically alter, activate, or excrete thyroid hormones and steroid hormones such as estrogen, cortisol, and aldosterone to prevent excessive accumulation and adverse effects ○ Ex. TH - liver plays major role in converting T4 or thyroxine to biologically more potent hormone of T3 (triiodothyronine) - For other hormones, liver can chemically alter them to form then can excreted in urine Modules Page 13 - Bilirubin is byproduct of destruction of aged RBCs and this makes up main bile pigment found in bile - Bilirubin on its own is useless and a toxic metabolite of Hb generated in large quantities, so must be constantly disposed of since every couple of minutes roughly 20 million RBCs are pulled out of circulation and replaced - Bilirubin gives bile the greenish black colour and produces yellow tinge of jaundice. - Some old RBCs are destroyed in spleen, and rest of them are taken up and destroyed by Kupffer cells in liver - In Kupffer cells, the Hb is broken down to heme and globin, with the globin part degraded into AA ready for recycling to form new proteins ○ The heme component is broken into iron and rest gets converted to biliverdin, which is then enzymatically converted to bilirubin (unconjugated) and released into blood - In blood, this lipid soluble form of bilirubin binds to albumin = unconjugated or free bilirubin - In liver hepatocytes, albumin is removed and it conjugates the free bilirubin to join the bilirubin with glucoronic acid, which then forms conjugated bilirubin ○ In this form, it becomes water soluble and is excreted into bile canaliculus as part of bile, thus delivered to SI Modules Page 14 thus delivered to SI - In distal ileum and colon, the resident bacteria metabolize this form of bilirubin to urobilinogen and the majority of this is eliminated in the feces as stercobilin, giving the stool its brownish colour with smaller amount reabsorbed as urobilin to be excreted int the urine, giving the urine a yellowish colour - If too much free or conjugated bilirubin accumulates in the extracellular fluid, a yellow discolouration of the skin, sclera and mucous membranes can occur, called clinical icterus or jaundice - Bile and bile salts produced in liver, essential for fat absorption - Bile salts made from 2 pathways: ○ Primary pathway: bile salts directly synthesized and conjugated from cholesterol ○ Secondary/alternative: from SI bacteria that get absorbed and go back to liver Modules Page 15 - Glycogen storage, which can be readily broken down to mobilize glucose if levels drop - Large vitamin storage ○ Largest is vitamin A, with up to 2 year's supply ○ Large quantities of vit D and B12 ○ Very little vit K, but some stays in liver and more can be found in spleen and skeletal muscles ○ Vit E is metabolized in liver, so only a small amount stored here, but more of this lipid soluble vitamin is found in adipose tissue - Liver can store small amounts of trace element copper ~ 80% of copper absorbed from jejunum is excreted in bile, preventing accumulation in plasma (preventing toxic effects in liver, kidney, cornea, and other tissues) - Ex. Wilson Disease caused by genetic mutation that impairs biliary excretion of copper leading to accumulation leading to liver disease - Dietary iron absorbed in duodenum and is transported in blood and bound to a protein produced by the liver called transferrin ○ Hepatocytes take up, secrete, and store iron ○ Small amount of asoluble irone is maintained for intracellular enzymatic reactions ○ Iron is toxic to cells, so hepatocytes contain large amounts of apoferrin, which can reversible combine with iron to form ferritin, an intracellular iron storage protein that is non-toxic to cells  If iron levels drop, the ferritin releases the iron  If the iron storage mechanisms are overwhelmed and too much iron stays in the system, this can be problematic and cause toxicity aka hemochromatosis Modules Page 16 - Skin, liver, and kidneys help synthesize active form of vit D - Vit D3 comes from cutaneous skin, other forms of vit D2 and D3 can come from diet - Liver converts vit D to 25-hydroxycholcalciferol or 25(OH)D ○ This is the form that is usually measured as indication of vit D levels (test no OHIP-covered) - Kidney converts 25OHD to active hormone, 1-alpha, 25dihydroxyvitami D or calcitriol - Thus need the liver to help convert it to the active form Modules Page 17 Modules Page 18 Modules Page 19 Modules Page 20 Modules Page 21 Modules Page 22 Modules Page 23 Modules Page 24 Modules Page 25 Modules Page 26 Modules Page 27 Modules Page 28 Modules Page 29 Modules Page 30 Modules Page 31 Modules Page 32 Modules Page 33 Modules Page 34 Match with above: Modules Page 35 Modules Page 36 Modules Page 37