Lecture 31-Metabolic Processes in the Liver PDF

Liver Physiology Dr. Kelly Roballo Learning Objectives 1. Describe the meaning of different liver function tests (ALT, AST, Alk phosphatase, albumin, ammonia) *only need to know those 5* 2. Discuss the immune function of the liver and the important role it plays in monitoring the portal blood. 3....

Liver Physiology Dr. Kelly Roballo Learning Objectives 1. Describe the meaning of different liver function tests (ALT, AST, Alk phosphatase, albumin, ammonia) *only need to know those 5* 2. Discuss the immune function of the liver and the important role it plays in monitoring the portal blood. 3. Discuss conjugation of Bile salts and their digestive function. 4. Discuss the different causes of pre-hepatic, hepatic and posthepatic jaundice. The Liver The Liver • Purpose: to process absorbed nutrients and other substances from the GI tract and secrete bile (GI) • Stimuli: substances received from portal circulation and systemic circulation (venous blood) • Result: • Nutrient metabolism • Storage • Excretion • The liver is a complex organ with multiple functions including GI. The overall functions are: • Vascular • Immune • Metabolism • Storage • Synthesis • Modification and detoxification • Bile secretion 3 Liver Anatomy • The liver is located in the abdominal cavity and receives portal blood from the stomach, small and large intestines, pancreas, and spleen Liver’s blood supply • liver’s blood supply is venous blood from the gastrointestinal tract (spleen, stomach, small and large intestines, and pancreas), which is delivered to the liver via the portal vein Liver Functional Anatomy Review • At the porta hepatis: ‒ Liver receives dual blood supply: • Hepatic arteries (30%) ‒ Oxygen rich ‒ From systemic circulation (celiac trunk) • Portal Vein (70%) ‒ Nutrient rich ‒ From venous drainage of abdominal GI system and spleen ‒ Hepatic bile ducts exit the liver • Venous drainage ‒ Hepatic veins drain the liver into the Inferior vena cava ‒ This arrangement is maintained at the cellular level 6 Functional Anatomy of the Liver Review • The portal tract contains branches of the portal vein, hepatic arteries, intrahepatic bile ducts, lymphatics and nerves • Portal vein and hepatic arteries empty into the sinusoids (capillaries) • Sinusoids drain into the central veins (which in turn drain into hepatic veins) • Hepatocytes: • • Arranged in cords and are surrounded by sinusoids (basolateral surface) and bile canaliculi (apical surface) Hepatocytes carry out most of the functions of the liver Other cell types: • Macrophages (Kupffer cells) ‒ Immune properties • Hepatic stellate cells (Ito cells) ‒ Vitamin A storage, involved in pathogenesis of cirrhosis • Cholangiocytes (bile duct cells) ‒ Modify secreted bile • Endothelial cells (lining blood vessels) 7 Functional Anatomy of the Liver -Review • Functionally, the liver has 3 zones: • Zone 1 is closest to the portal tract and richest in O2 • Examples of reactions: Amino acid catabolism, gluconeogenesis, glycogenolysis, ureagenesis, oxidative energy metabolism • Zone 2 is intermediate • Zone 3 is closest to the central vein (hepatic venule) and lowest in O2 and exposed to modifications made by hepatocytes in earlier zones • Examples of Reactions: Glycolysis, glycogen synthesis, liponeogenesis, bile acid synthesis, biotransformation of drugs 8 Liver functions: 1) processing of absorbed substances; 2) synthesis and secretion of bile acids; 3) bilirubin production and excretion; 4) participation in metabolism of key nutrients including carbohydrates, proteins, and lipids; 5) detoxification and excretion of waste products. Vascular function of the liver • Stores blood (10% of volume) • Storage can expand by 1 liter • Can be a reservoir in hemorrhage • Portal system is key for being able to use absorbed nutrients • 50% of lymph is formed in the body Right Heart Failure Congested liver Clinical correlation: Right heart failure Right heart failure can result in congestion of the liver and is one of the causes of hepatomegaly. Congested liver has a characteristic 10 “nutmeg” appearance Immune Function of the Liver • Macrophages (Kupffer Cells) lining the sinusoids can remove pathogens and particles in the blood • Cultured portal blood has significant bacteria and contaminants that breached the gastrointestinal barrier • “the world is a dirty place and we eat it and absorb it” • Approximately 99% of pathogens in portal blood are removed and the systemic blood is relatively pathogen free Liver injected with India Ink, taken up by macrophages 11 The Liver as a Storage Organ • Vitamins • Vitamin A (10 months worth) • Stored in hepatic stellate cells (Ito Cells) • Since it is a fat-soluble vitamin, there is a risk of excess • Vitamin D (3-4 months worth) • Vitamin B12 (>1 year) Beware Eating Polar Bear Liver (lots of Vitamin A) Hemochromatosis (zone 1 deposition) • Iron storage (as ferritin) • Blood iron buffer • Note there is no good iron excretion pathway so iron can be extremely toxic (hemochromatosis) • Glycogen Clinical correlation: Fibrosis Activation of hepatic stellate cells can lead to deposition of collagen and result in severe fibrosis, compromising liver function. Etiologies of cirrhosis include hemochromatosis, infections (Hep C), and many, many more. 12 Bile formation and secretion • bile acids are synthesized from cholesterol by the hepatocytes Bilirubin Metabolism • Source: Hemoglobin metabolism • Heme is metabolized to biliverdin and then bilirubin by mononuclear phagocyte system (reticuloendothelial system) • Transport to liver: • Bound to albumin, taken up by OATP transporter • In liver • Bilirubin is conjugated with glucuronic acid • Key enzyme: UDP glucuronosyl transferase (UGT) • Conjugated bilirubin is actively excreted into bile • MRP2 transporter • In intestines: • Deconjugated in ileum and colon • Metabolized to urobilinogen by bacteria • Urobilinogen fates: • Resorbed into the blood and then • Resecreted into bile • Excreted by kidneys (oxidized to urobilin accounting for yellow color of urine • Remains in intestine and is converted to stercobilin and excreted in feces (accounting for brown color of feces) 14 Clinical Correlation: Jaundice DEFINITION: excess bilirubin in blood leading to yellow discoloration CLASSIFICATION: • Pre-hepatic: • Excessive breakdown of red cells • Hepatic • Liver failure • Hepatocyte injury (hepatitis) • Hereditary disorders • • Crigler-Najjar syndrome (UDP glucuronyl transferase deficiency) Dubin-Johnson syndrome (MRP2 transporter defect) • Post-hepatic • Obstruction of the extrahepatic biliary system (tumor, stones) LABORATORY EVALUATION: • Total bilirubin • Unconjugated “indirect” bilirubin • Seen in pre-hepatic disorders and in Crigler-Najjar • Conjugated “direct” bilirubin • Seen in post-hepatic disorders and in Dubin-Johnson syndrome 15 Bile Acids/Bile Salts • Amphipathic molecules • Synthesized from cholesterol • Function: • • • • Induce bile flow Detergent for fat digestion Facilitate absorption of fat and fat soluble vitamins Important part of cholesterol homeostasis • Liver synthesizes 6g/day • Rate limiting step: 7α-hydroxylase • Primary bile acids: synthesized in the liver • Cholic and Chenodeoxycholic acid • Secondary bile acids: modified by intestinal bacteria • Deoxycholic and lithocholic acid • BILE SALTS: bile acids are conjugated in the liver with glycine or taurine • • ­ Polarity: Improves function ¯ pKa: Dissociation important to keep salts in the lumen and soluble • 90% of bile acids are recycled through enterohepatic circulation 16 Enterohepatic Circulation • Bile secreted from hepatocytes into canaliculi • Modified in intrahepatic ducts • Exits liver • Stored in gallbladder • Stimulation leads to contraction of gallbladder and relaxation of sphincter of Oddi so bile enters the duodenum • Bile salts are involved in fat digestion in the small intestine • Bile salts are taken up in the terminal ileum by active transport • Bile salts return to the liver via the portal circulation Intrahepatic ducts D si o u iff n ABST To colon 17 BAs Na+ Bile secretion: Intrahepatic Component • AT THE BASOLATERAL MEMBRANE • Bile acids (BAs) are taken up with sodium (cotransport) • IN THE HEPATOCYTE: • Bile acids synthesized (see previous slide) and conjugated to bile salts • AT THE APICAL MEMBRANE OF HEPATOCYTES: • Active secretion: • Bile acids are actively transported via the bile salt export pump (BSEP) • Conjugated bilirubin is transported by MRP2 transporter (see previous slide) • Cholesterol, drug metabolites and heavy metals also actively transported • Passive secretion: • Water, calcium, other components enter bile by passive paracellular transport • IN THE INTRAHEPATIC DUCTS: • Mixed micelles are formed to suspend lipid • Bile is modified by cholangiocytes • Water and HCO3- are added to bile increasing volume and alkalinity • Some resorption of solutes • Stimulus for secretion: SECRETIN • Bile acid synthesis Adapted from Berne and Levy Intrahepatic ducts Bile exits the liver and flows into extrahepatic ducts 18 Bile Secretion: Gallbladder • • • • Liver secretes 450-900 ml of bile a day Up to 12 hours worth is stored in the bile The gallbladder has a 30-60ml capacity GALLBLADDER MUST CONCENTRATE! • Mechanism: active absorption of sodium • Water and Cl follow sodium • Bile remains isotonic and alkaline, bile acids and products for excretion remain in the lumen • Stimulus for contraction: CCK and Ach • CCK also leads to relaxation of sphincter of Oddi. This coordination allows for controlled delivery of bile in response to fat in the duodenum. Recall CCK is released from I cells in response to fatty acids 19 Bile Secretion: Intestines Bile salts in the intestines: • Bile salts function in fat digestion in the intestines (see previous lecture) • In the terminal ileum, bile salts are actively absorbed with sodium via the apical sodium dependent bile salt transporter (ABST) • Bile salts return to the liver via portal circulation • Some bile salts get deconjugated by bacteria and are subject to passive diffusion earlier in the intestine • In the liver, bile salts are taken up with sodium (see previous slide) Clinical correlation review: Bacterial overgrowth can lead to deconjugation of bile salts to the point and lead to early uptake. Insufficient effective bile salts can lead to fat malabsorption. 20 Bile Acid Regulation Bile acid regulation and the importance of enterohepatic circulation: • The circulating pool of bile acids is 2.5g. The liver synthesizes approximately 25% of the pool each day to account for what is lost in the colon • Bile acid synthesis is regulated by negative feedback loop. Bile acids in the liver inhibit 7α-hydroxylase. • The liver can upregulate synthesis up to 10x. ‒ This is taken advantage of by cholesterol medications designed to “waste” bile acids (bile acid sequestrants) ‒ Severe terminal ileum disease overwhelms the liver’s capacity to synthesize new bile acids 21 Protection from stone formation: Mechanisms to prevent stone formation: • Appropriate balance of bile acids, phospholipids and cholesterol • Gallbladder motility Stones can form when: • Increased secretion of cholesterol relative to bile acids and phospholipids • Decreased bile acid resorption • Bile stasis (reduced contractility) Pathophysiology and risk factors for cholelithiasis will be extensively covered in other courses If you see gallstones on an ultrasound, do you need to take the gallbladder out? Something to consider when stones are seen on ultrasound: • There are about 50,000-100,000 pounds of gallstones in America. • >80% are asymptomatic (total weight of a DC-9 jet airliner) 22 Metabolic functions of the liver • The liver participates in the metabolism of carbohydrates, proteins, and lipids Carbohydrate metabolism • the liver performs gluconeogenesis, stores glucose as glycogen, and releases stored glucose into the bloodstream, when needed Carbohydrate metabolism CARBOHYDRATE TRANSPORT IN TO LIVER: • Monosaccharides enter the liver via GLUT2 CARBOHYDRATE FATE IN THE LIVER: • Glucose buffering: After a meal: • • Insulin increases and glucagon decreases Glucose fates: • Can be broken down for energy (glycolysis) • Can be stored as glycogen (glycogen synthesis) • • • Key enzymes in glycolysis: glucokinase, phosphofructokinase, pyruvate kinase Galactose and fructose can be converted to glucose Excess carbohydrates are converted to fat Between meals: • • Insulin decreases and glucagon increases Glycogen is broken down into glucose for energy • • • Key enzyme: Glucose 6-Phosphatase (only in liver) allows glucose to exit the hepatocyte via GLUT2 Gluconeogenesis allows for alternate sources of glucose (amino acids, glycerol, lactate) Intermediaries: Carbohydrates can also be used and intermediaries in various hepatic reactions such as synthesis of compounds with carbohydrate moieties Protein metabolism • liver synthesizes the nonessential amino acids and modifies amino acids so that they may enter biosynthetic pathways for carbohydrates • synthesizes almost all plasma proteins including albumin and the clotting factors • The liver also converts ammonia, a byproduct of protein catabolism, to urea, which is then excreted in the urine. Persons with liver failure develop hypoalbuminemia (which may lead to edema due to loss of plasma protein oncotic pressure) and clotting disorders. Protein metabolism AMINO ACID TRANSPORT INTO LIVER • Na-dependent and Na-independent transport AMINO ACID FATE IN THE LIVER: • AA’s need to be utilized or broken down immediately • NO STORAGE FORM • Synthesis of non-essential amino acids (transamination) • Key enzymes: TRANSAMINASES • Deamination of AAs yields a-keto acids and ammonia • a-keto acids can be used for the Krebs cycle, gluconeogenesis and ketogenesis • Ammonia is converted to urea (urea cycle). • • Urea leaves the cell at the basolateral membrane Excreted in urine • Synthesis of plasma proteins: Key Examples • Albumin (oncotic pressure and carrier protein) • Blood Clotting factors (fibrinogen, some are vitamin K dependent- II, VII, IX, X) • Apolipoproteins for fat metabolism • Glutathione: drug metabolism and protection against oxidative stress Lipid metabolism • liver participates in fatty acid oxidation and synthesizes lipoproteins, cholesterol, and phospholipids Lipid Transport CHYLOMICRON TRANSPORT IN LYMPH AND BLOOD • • Chylomicrons enter lymphatics in the intestines and then enter the venous system at the root of the neck, thus ending up in the systemic circulation before reaching the liver From the systemic circulation, fat and muscle endothelium lipoprotein lipases partially digest the triglycerides to fatty acids and glycerol for use in the cell CHYLOMICRON TRANSPORT TO LIVER • Chylomicrons reach the liver as chylomicron remnants – – Chylomicron remnants contain less triglycerides and higher ratio of fatty acids and cholesterol Chylomicrons remnants are taken up by the liver using the LDL-related receptor Other products of fat digestion: Glycerol and some fatty acids enter the liver through the portal circulation without traveling in the lymphatics 29 Triglycerides Metabolic Functions of the Liver: Lipids b-oxidation Cholesterol Synthesis FATTY ACIDS FATE IN THE LIVER • b-oxidation of fatty acids yields Acetyl CoA • Can enter the Krebs cycle and be a source of ATP • Or can form ketone bodies (Acetoacetate, bhydroxybutyric acid, acetone) • Used by muscle, kidney and brain during fasting states • Fatty acids can be re-esterified to form triglycerides which are stored or exported as very-low-density lipoprotein (VLDLs) • Recall that Glucose and amino acids can also be synthesized into triglycerides (see figure below right) • Synthesis: Liver uses lipids in the synthesis of phospholipids, lipoproteins • Cholesterol synthesis 30 Metabolic Functions of the Liver: Lipids Cholesterol Homeostasis • Cholesterol is vital to membrane integrity and a substrate for several compounds but it needs to be kept at a steady state (hypercholesterolemia can be detrimental to the body) • To maintain steady state liver must excrete an amount of cholesterol equal to that which is synthesized or ingested • Cholesterol can be synthesized “de novo” from Acetyl CoA when needed • Key enzyme (rate limiting step): HMG-CoA reductase Only a relatively small portion of cholesterol comes directly from diet • Fate of cholesterol: • Synthetic reactions (bile acids, steroid hormones) • Excretion in bile • Excretion in feces as free cholesterol or sloughed cells 31 Detoxification of substances • liver protects the body from potentially toxic substances • These substances are presented to the liver via the portal circulation, and the liver modifies them in socalled “first pass metabolism,” ensuring that little or none of the substances make it into the systemic circulation. For example, bacteria absorbed from the colon are phagocytized by hepatic Kupffer cells and thus never enter the systemic circulation. Biotransformation in the Liver • “First Pass Metabolism” • What gets transformed? • • Endogenous compounds: bilirubin, hormones Exogenous compounds: drugs, toxins, Vitamin D • Purpose of transformation: • • Detoxification • Conversion of toxic chemicals to non-toxic metabolites • Conversion of active drugs to inactive drugs • Some hormones are degraded in the liver Bioactivation/Toxification • Vitamin D activation • Prodrugs to active drugs or more active metabolites • Non-toxic chemicals can become toxic after biotransformation! • Mechanism: • • Phase I: oxidation and reduction catalyzed by cytochrome P-450 enzymes Phase II: conjugation of phase I products with sulfate, glucuronate and glutathione • Key enzymes: sulfotransferases, uridine diphosphate glucoronosyl transferases, glutathione-S-transferases • Phase II is critical for detoxification as it makes molecules more hydrophilic and able to be excreted. 33 Clinical Evaluation of Liver Function “LFTs” of Liver Function tests include: • Total protein: Measure of circulating serum proteins • Albumin: Most circulating protein is albumin which is synthesized in the liver • Total bilirubin: total includes unconjugated and conjugated • Unconjugated bilirubin (indirect): Elevated in pre-hepatic jaundice and certain liver conditions (where liver can’t conjugated) • Conjugated bilirubin (direct): Elevated in post-hepatic jaundice and certain liver conditions (where liver may be able to conjugated by bilirubin can be excreted) Normal Liver Panel: • Alkaline phosphatase: Enzyme found in bone and the biliary system. Elevation could mean problem in the biliary system (intrahepatic or extrahepatic) • Aspartate aminotransferase (AST): Enzyme found in hepatocytes (and other cells). Elevation could mean active hepatocyte injury. • Alanine aminostransferase (ALT): Enzyme found in hepatocytes (and other cells). Elevation could mean active hepatocyte injury. Other tests to evaluate liver function: • Prothrombin time (“PT” a measurement of blood clotting): Prolonged in certain clotting disorders. Can be prolonged in liver disease because clotting factors synthesized in the liver • Ammonia: Elevated if there is a problem with the urea cycle or liver failure • Additional tests to establish etiology 34 THANK YOU