FUnctions of liver.docx

FUNCTIONS OF THE LIVER https://www.hepatitis.va.gov/HEPATITIS/course/index.asp?page=/provider/courses/livertests/livertests-final-quiz&  What are the liver’s key functions? Maintaining normal blood glucose concentration Synthesizing plasma proteins Storing nutrients (carbohydrates, lipids, vitam...

FUNCTIONS OF THE LIVER https://www.hepatitis.va.gov/HEPATITIS/course/index.asp?page=/provider/courses/livertests/livertests-final-quiz&  What are the liver’s key functions? Maintaining normal blood glucose concentration Synthesizing plasma proteins Storing nutrients (carbohydrates, lipids, vitamins, trace metals) Metabolizes ammonia & bilirubin How does the liver maintain normal blood [glucose]? Regulated by insulin, glucagon, growth hormone Stores carbohydrates as glycogen in anabolism, breaks it down to glucose in catabolism Also produces glucose from lactate (from glycolysis) via gluconeogenesis Also breaks down triglycerides into ketone bodies in a pinch How does lactic acidosis occur? Ischemia or hypoxia: tissues to rely on glycolysis, which generates lots of lactate that isn’t being processed by the Krebs Cycle Excessive muscle glycolysis: from seizure, medication Impaired gluconeogenesis: from liver failure or genetics Electron transport chain disorder: primary (genetic) or acquired (e.g. toxins such as ASA, HAART therapy) What types of plasma proteins does the liver manufacture? Basically everything The only plasma proteins they don’t make are immunoglobulins, which are made by bone marrow What regulates plasma protein production? Low oncotic pressure: production Acute phase reaction (interleukin 6): some proteins, albumin & transferrin (anemia of chronic disease) Estrogen:   hormone-binding & coagulation proteins What nutrients does the liver store? How is the liver involved in fat metabolism? Receives cholesterol, triglycerides, fatty acids from chylomicrons Exports above as very low density lipoproteins Also oxidizes above for energy Receives cholesterol via high density lipoproteins  How is ammonia generated & metabolized? Amino groups are released during amino acid metabolism  Forms ammonia, which is detoxified by urea cycle in the liver into non-toxic, water-soluble urea that is excreted by kidneys Urea cycle only occurs in liver’s mitochondria & cytoplasm Urea cycle dysfunction → ammonia accumulation → lethargy, slurred speech, cerebral edema, asterixis How is bilirubin generated & metabolized in the liver? Generated as end-product of heme metabolism, from destruction of old RBCs in spleen Transported in blood bound to albumin, since free bilirubin is toxic to cells Metabolized only in the liver: hepatocytes conjugate bilirubin to glucuronic acid to make it water soluble Conjugated bilirubin is actively transported across bile canaliculi → concentrates bile Can accumulate in blood if excretion is impaired by biliary obstruction or intrahepatic cholestasis How is bilirubin generated & metabolized in the intestines? Enters small intestine via common bile duct Glucuronic acid residues are hydrolyzed Bilirubin is converted into urobilinogens Small intestines reabsorbs it  GI & kidneys eliminate it as feces & urine (urobilinogens give poo & pee their colour) How does the liver metabolize drugs? Chemical modification by cytochrome P-450 system (e.g. hydroxylation, oxidation) Conjugation & excretion: adding polar group (e.g. glucuronic acid, sulfate) so it can be excreted as bile or urine What is bile & what does it do? Yellow-brown or green fluid, made of bile salts, electrolytes, phospholipids, proteins, cholesterol, bilirubin Produced by hepatocytes, excreted into bile canaliculi Drained into hepatic duct, storied in gallbladder Major functions: digestion, excretion, hepatic cell signaling What are bile salts & what do they do? Derived from cholesterol & conjugated to glycine or taurine Amphoteric to form micelles to solubilize excreted lipids in bile & dietary lipids in small intestines Take a lot of energy to make so they are reabsorbed in terminal ileum & recycle to the liver What are liver enzyme & function tests? Liver enzymes: indicate liver injury or cholestasis; does not indicate liver function or degree of cirrhosis AST & ALT (aminotransferases) Markers of hepatocellular injury ALT: liver specific (cuz it has an “L” for liver) AST: not as liver specific; found in a lot of other cells Liver cells can be damaged by: viral infection, autoimmune disease, drugs, toxins, alcohol, metabolic conditions, ischemia / congestion ALT: 17–63 IU/L AST: 15–37 IU/L ALP (Alkaline Phosphatase),  GGT  (Glycoprotein gamma- glutamyltransferase) Markers of of cholestasis (damage to biliary tree) ALP found in many tissues, mainly in liver, biliary tree & bone GGT confirms elevated ALP is from liver / biliary tree, not bone or other sources (e.g. placenta) 50–136 IU/L Liver function: measure liver’s ability to produce proteins Albumin INR: elevated INR in liver disease often means easy bleeding & clotting, since liver makes factors for both Bilirubin:  Glucose: Marker of portal hypertension Platelets: portal HTN can cause splenomegaly, which causes low platelets (thrombocytopenia) In systemic anabolic states – Hepatocyte storage of energy rich nutrients from the portal circulation In systemic catabolic states – Hepatocyte release of glucose into the systemic circulation Glucose obtained from glycogen and Gluconeogenesis Enzyme expression and enzyme activity is regulated by multiple factors – Hormonal Insulin / Glucagon / Cortisol / Growth Hormone – Exercise – Diurnal Causes of Lactic Acidosis numbered below: Lack of Oxygen in Muscle tissue (aka Type A) caused by hypoxia or ischemia. Excessive muscle glycolysis caused by seizures or medications. Impaired gluconeogenesis caused by liver failure or genetics. – Liver Failure – Genetic Electron transport chain (ETC) Disorder (i.e. mitochondrial) caused by ASA or HAART therapy. PLASMA PROTEINS – regulators – 3 outlined below and numbered: 1) Low Oncotic pressure All plasma proteins are produced at an increased rate with low plasma oncotic pressure 2) Acute Phase reaction (Il-6 regulated) Positive regulation with regard to: -A1AT, ceruloplasmin, C3, C4 Negative regulation with regard to: - albumin and transferrin 3) Estrogen LIPID METABOLISM Uptake from the intestine Synthesis within hepatocytes – free fatty acids – triglycerides – cholesterol Export into blood (lipoproteins) Oxidation of fatty acids (energy production) LIPOPROTEINS Chylomicrons – Intestine generated particles that deliver dietary triglycerides to tissues – Chylomicron remnants deliver cholesterol to the liver Very-low-density lipoprotein (VLDL) – exports triglycerides and cholesterol from the liver to tissues Low-density lipoprotein (LDL) – derived from VLDL after it has delivered triglycerides to tissues High-density lipoprotein (HDL) – reverse transport of cholesterol from tissues back to the liver METABOLIC WASTES Ammonia – by-product of amino acid metabolism – amino groups released to form ammonia, which is toxic – ammonia is detoxified in the urea cycle – product is urea non-toxic and very water-soluble excreted by the kidneys Bilirubin – end-product of heme metabolism – produced mainly in RE cells from destruction of aged erythrocytes – transported in blood bound to albumin – free bilirubin would be toxic to cells – metabolized only in the liver HEPATIC METABOLISM OF BILIRUBIN Uptake into hepatocyte Intracellular binding to ligandin Conjugation to glucuronic acid Excretion into bile Bilirubin enters small intestine via common bile duct Glucuronic acid residues hydrolyzed Conversion to urobilinogens Reabsorption from intestine, mostly taken up by liver (enterohepatic circulation) Re-excreted by liver, eliminated in feces PRODUCTION OF BILE Yellow-brown or green fluid excreted into bile canaliculi by individual hepatocytes Drained by hepatic duct, stored in gallbladder Three major functions of Bile below: – digestion – Excretion – Hepatic cell signalling BILE SALTS Derived from cholesterol – conjugated to glycine or taurine Contain both hydrophilic and hydrophobic surfaces to solubilize – excreted lipids in bile – dietary lipids in small intestine Reabsorbed in terminal ileum and returned to the liver (enterohepatic circulation)