Hepatic Physiology PDF - Liver Functions, Metabolism, Anatomy

Section 13: Hepatic Physiology I. Functional Anatomy of the Liver Functions: Nutrient metabolism Detoxification Fig. 62 Bile production A. Blood supply 1. 80% from portal vein Nutrient-rich blood (CHO,...

Section 13: Hepatic Physiology I. Functional Anatomy of the Liver Functions: Nutrient metabolism Detoxification Fig. 62 Bile production A. Blood supply 1. 80% from portal vein Nutrient-rich blood (CHO, AAs, peptides from GI tract) 2. 20% from hepatic artery O2-rich blood and chylomicra 3. Blood drains via sinusoids over hepatocytes into central vein centrilobular hepatocytes more susceptible to ischemia and toxins - centrilobular necrosis B. Bile drainage 1. Hepatocytes arranged in “plates” radiating from a central vein. 2. Bile canaliculi are formed between the basolateral membranes of opposite-facing hepatocytes and connect to bile ductules. Bile flows in the opposite direction of blood flow II. Nutrient Metabolism by the Liver the liver is important for maintaining constant blood nutrient levels A. Carbohydrate metabolism * A primary function of the liver is to maintain euglycemia Normoglycemia = 80-120mg/dL (dog, cat) Does this by maintaining a constant input of glucose into the blood by: 3 mechanisms 1. Glycogenolysis (glycogen is a glucose polymer): Large glycogen store in liver Glycogen lysis > glucose released = increase blood glucose Glycogen stores can be depleted by intense demant )e.g, marathon runner 'hiting a wall' = glycogen depleted > decrease blood glucose 88  2. Gluconeogenesis slower process than glycogenolysis Synthesizes glucose from non-CHO sources 1. Deaminated AA - dietary or muscle breakdown (removes nitrogen group and uses CHO skeleton) 2. Glycerol - triglyceride backbone 3. Propionic acid - VFA Regulated by endocrine sys: glucagon, glucocorticoids, epi, thyroxine 3. Interconversion of other monosaccharides Also, slower than. glycoproteins Ex: Galactose or fructose → glucose B. Nitrogen metabolism * The liver is the primary site of amino acid, uric acid and ammonia metabolism. Uric acid: purine breakdown (form nucleic acids) Ammonia: protein processing/breakdown Specific dynamic action of dietary protein Protein metabolism generates heat as a byproduct (Energy expenditure) Meat sweats: profuse sweating that follows a meat-rich meal Liver Consumes 20-40% of daily O2 intake 1. Amino acid metabolism. The 4 fates of amino acids absorbed from the intestine: a. Used to synthesize hepatic and plasma proteins 1) Hepatic proteins Metabolic and structural proteins to maintain liver structrue and function 2) Plasma proteins - 90% of plasma proteins from liver synthesis. other 10% are circulating anitbodies from WBCs Major categories of plasma proteins made in liver: a) Albumin - Main protein in plasma Carrier protein for hydrophobic substances and primary contributor to COP b) Clotting Factors Fibronogen and prothrombin; liver disease can cause abnormal clotting c)  and  Globulins Specilized proteins; carriers (e.g., steriod hormones, cholestrol, copper) and substrates (e.g., angiotensinogen) 89  b. Transamination - Used in the synthesis of non-essential amino acids Essential AAs not synthesized by the body, must be acquired via diet c. Deamination (when amino acids in excess) - Used for gluconeogenesis Ammonia (NH3) liberated from this process enters the urea cycle. carbon skeleton used for glucose synthesis d. Bypass liver - Enter general circulation to make other tissue proteins increase blood NH3 toxic to CNS; detoxified by conversion to urea Fig. 62a. 2. Ammonia metabolism a. NH3 in the blood Sources of NH3: 1) Formed by hepatic deamination 2) Absorbed from the large intestine or rumen b. NH3 enters the urea cycle in hepatocytes urea enters circulation Increase BUN sign c. Fate of urea in the blood (BUN): 1) 75% excreted in urine of kidney disease BUN = blood urea nitrogen 2) 25% enters into GI tract Lipid soluble compound = - Diffusion from blood across the epithelium - Saliva (Ruminants) d. Bacterial ureases (in LI or rumen) breakdown urea to NH3 LI and/or rumen microbes use NH3 and CHO skeletons to synthesize microbial proteins (some NH3 absorbed into the animinal body) Clinical Relevance:. Ammonia intoxication NH3 is toxic to CNS. CNS signs coma. lethargy, head pressing (sign of CNS damage) Causes: 1) Liver Disease Hepatic insufficiency Hepatic encephalopathy Damaged liver unable to synthesize NH3 into urea 2) Urea poisoning - Cattle Nonprotein nitrogen feeding without sufficient dietary carbohydrate NPN supplementns w/o sufficient CHO source > 3) Ornithine deficiency - Cats bacteries cannot convert AAs > NH3 absorboed and overwhelms urea cycle Essential amino acid in feline diet. Ornithine required in urea cycle. AA from meat, fish, dairy and eggs Fish: NH3 excreted as glutamiine from gills (detoxify NH3 to glutamine) 90 UREA IS NOT URIC ACID Sources of uric acid: - diet ~ red meat, organ meats, seafood, bacterial flora 3. Uric acid metabolism - endogenous -- sloughed intestinal cells a. Most species - Purines (from nucleic acid catabolism and dietary sources) are metabolized by the small intestine and other tissues to uric acid. → At the liver, uric acid is transported into the hepatocytes by the uric acid transporter (SLC2A9) → Hepatic uricase converts uric acid to allantoin Excreted in urine At the kidney, uric acid transporter also removes some uric acid from the urine b. Dalmation dogs - Inherited mutations in urate transporter (SLC2A9) prevents uric acid from entering the hepatocyte for metabolism to allantoin. Uric acid in blood is filtered at the kidney into the urine→ Lack of urate resorption in renal tubule (due to same transporter defect) → High levels of urate in urine → High potential for urate stones in urinary bladder Gout: Humans, higher primates lack uricase enzymes > increase blood UA C. Lipid metabolism > predisosed to UA crystal deposittion in joints/joint capsules (arthritis) Birds: excrete urate via kidneys > cloaca > renal disease > increase blood UA > gout * Normally, the liver maintains an equilibrium of lipid input and output Healthy liver is ~3% fat Increase hapatic fat interferes with liver function, causes inflammation 1. Lipid Input to the Liver – 3 Inputs a. Dietary: Chylomicra from intestinal fat absorption: i. Circulating chylomicra from intestinal absorption carry triglycerides (TGs) clears chylomicra from circulation ii. Lipoprotein lipase synthesized in adipose, cardiac, skeletal muscle and hepatic tissues. Lipoprotein lipase is transported and affixed to capillary surface endothelium of these tissues. LL hydrolyzes triglycerides in chylomicrons > remnants pass through fenestae of the liver sinusoids into space of Disse > cleared by uptake by hepatocytes iii. Apolipoproteins of chylomicra bind to lipoprotein lipase on capillary endothelium and TGs are digested to liberate free fatty acids for use by tissue. iv. After digestion, smaller chylomicron remnants in the circulation pass through sinusoid fenestra of liver and pass into the space of Disse (contains lymph) and cleared by hepatocyte for metabolism or bile excretion. 91  b. Hepatic lipid synthesis: Hepatic cells convert excess de-aminated amino acids and sugars to free fatty acids for metabolism and lipoprotein formation c. Lipid mobilization from adipose tissue: > trigylcerides for storage i. Mobilizing lipase (several isoforms) located in body fat stores (adipose tissue) ii. In a negative energy balance, mobilizing lipase liberates FFA from stored TG which enter circulation Liver for metabolism can overwhelm liver fat handling > fattu liver in 'well-conditioned' cattle and cats iii. Mobilizing lipase activity is regulated by endocrine system (glucocorticoids, glucagon) 2. Lipid output from the liver - The 3 fates of fat: a. Hepatic lipoprotein formation i. Hepatic cells synthesize FFA into triglycerides, phospholipids, and cholesterol ii. Hepatic cells package lipids with apolipoproteins into hepatic lipoproteins - Lipoprotein formation requires lipotrophic substances that include phospholipids, choline and methyl group donors (e.g., methionine). iii. Lipoproteins enable transport to other tissues via the circulation lipotrophic = catalyze fat breakdown 92  Types of lipoproteins: Very low density lipoprotein (VLDL) Low density lipoprotein (LDL) - More triglycerides, less protein Intermediate density lipoprotein (IDL) High density lipoprotein (HDL) - Less triglycerides, more protein HDL ('good' cholesterol) and LDL ('bad' cholesterol, associated with atherosclerosis) Cholesterol: -Most cholesterol synthesized in the liver (80%) Hepatic synthesis inversely related to dietary cholesterol input Can also be synthesized at low levels by cells in many tissues -Important use of cholesterol esters is hepatic synthesis of bile acids. b. Hepatic catabolism of lipid for energy: i. oxidation of FFA in liver yields acetyl coenzyme A (acetyl CoA- 2C) -Acetyl CoA enters Kreb's citric acid cycle for oxidation - Requires sufficient oxaloacetic acid (OAA -4C) from glucose metab. BOTH OAA and Acetyl CoA are needed for the Kreb's cycle c. Ketone body formation in the liver i. When sufficient OAA is not available in hepatic cells, acetyl CoA is synthesized into.3 or 4 C units called ketone bodies: Acetone (3C) Brain uses glucoses as main energy Acetoacetate (4C) soucre, but can use ketones during -hydroxybutyrate (4C) fasting and starvation ii. Ketone bodies enter circulation and used as energy source by muscle and neurons Excess ketones can be toxic Clinical Relevance: Negative energy balance mild increase circulating ketones Mild: Decreased OAA + FFA mobilized to liver → AcCoA → Ketone bodies Elevated circulating ketone bodies (Ketosis) Acetone order to breath (nail polish remover smell) Severe: Very low OAA +  FFA mobilized→  AcCoA→  Ketone bodies (Ketoacidosis) Metabolic acidosis - excessive ketones decrease blood pH > CNS signs e.g., untreated diabetes (diabetic ketoacidosis) 93  Clinical Relevance: Fatty liver Fatty liver - Increased percentage of fat in liver impairs liver function. >3% Causes: 1. Choline deficiency - Decreased apolipoprotein synthesis Rare Fat cat or fat cow goes off feed > 2. Excessive fat input to liver Increase mobilization of FFAs > a. Excess dietary fat not a common casue of fatty liver fatty liver > liver dysfunction, CNS b. Starvation and mobilization of body stores signs, jaundice 3. Excessive dietary protein and CHO Rare -Foie gras Cats: hepatic lipidosis, cattle: fat cow syndrome Fatty liver from force-fed geese D. Vitamin and mineral metabolism liver invovled in synthesis, activation, and storage of some vitamins 1. Fat-soluble vitamins a. Bile salts improves absorption efficiency..but, not necessary b. Liver is main site of storage for fat-soluble vitamins A and D Vitamin A Storage for 1-2 years in hepatic stellate cells Vitamin D Storage and 1st activation step (vitamin D > 25-OH vitamin D > kidney (1,25-OH vitamin D) Vitamin E Antioxidant; little stroage Prothrombin - protein produced Vitamin K little storage ;used to sunthesize prothrombin by liver - clotting factor 2. Water-soluble vitamins a. Water-soluble B vitamins are required in the diet of most mammals (except adult foregut fermentors and coprophagous animals). Some water-soluble vitamins are activated in the liver. b. Water-soluble vitamin C is synthesized in the liver by most species except: Primates Scurvy - vitamin C deficiency Guinea pigs Vitamin C - protein metabolism, biosynthesis of collagen, some NTs 94  3. Iron - Stored as ferritin in liver and other tissues Fe retention is very efficient; lost mainly via hemorrhage Sources of Fe in circulation: Hemoglobin breakdown (from old RBCs) Intestinal absorption Trapped by apoferritin in liver, muscle, spleen, bone Fe apoferritin = no bound Fe Ferritin used as needed for heme production O2-binding proteins:: ferritin = bound Fe Hemoglobin - bone marrow Myoglobin - muscle Excess dietary Fe in intestine is toxic Soil with high Fe content (grazing animals) Increase O2 radical porduced in gut > tissue damage/inflammation III. Detoxification Function of the Liver A. Metabolizes (detoxifies) a number of compounds: 1. Exogenous = xenobiotics Drugs Toxins 2. Endogenous cause disease if not cleared by liver - Endotoxins from GI tract - Hormones (particularly steroids, thyroxine) - Pigments (heme) usally conjugated with glucuronic acid > soluble > bile > feces 3. Many are conjugated (often with glucuronic acid) and excreted via bile Coffee (not caffeine) > increase hepatic glucuronyl transferase experssion > increase detox > decrease liver cancer risk by 60% (2-6 cups/day) B. Degradation of heme pigments and excretion as bilirubin 1. Heme pigment - Porphyrin rings complexed with iron. Hemoglobin - In RBC Myoglobin - In muscle O2 binds reversibly with heme good for O2 transport RBCs turnover ~120 days (varies by species) Varies with species; RBC lyse > heme released 95 Sim: Ammonia to Urea Released porphyrin is toxic (porphyria). Porphyria - rare hereditary disease; neuological signs, skin lesion (photosensitization) Detoxified by conversion to bilirubin. Billirubin = breakdown producte (found in bile, but NOT BILE) **Bilirubin  BileBile = mostly water, w/ bile salts, bilirubin, some fats and inorganic salts 2. Formation of conjugated bilirubin (main way for porphyrin excretion) a. RBCs lyse and release hemoglobin b. Hemoglobin (Hb) binds to haptoglobin in plasma. FYI: haptoglobin is an alpha-globulin c. Hb-haptoglobin complex is cleared and phagocytized by reticuloendothelial system (RES). RES = Tissue resident phagocytes in spleen, bone marrow, liver marginated along vessels and liver sinusoids (i.e, Kupffer cells) d. Within RES phagocyte: 1) Heme oxygenase action causes release of Fe (enters circulation) and converts porphyrin ring to biliverdin (a blue- green pigment). massive hemolysis can overwhelm this process; pigment is visible 'green jaundice' 2) Biliverdin reductase converts biliverdin to unconjugated bilirubin (yellow-red pigment). not in birds, low in rabbits - green bruises 3) Unconjugated bilirubin is released to circulation bound to albumin (unconjugated bilirubin is poorly soluble in aqueous solution). unconjugated bilirubin is measurable in blood e. At liver, unconjugated bilirubin cleared from plasma by hepatocytes f. Bilirubin is conjugated with glucuronic acid (makes soluble) in heptocyte and in bile conjugated bilirubin enter bile for excretion 3. Excretion: Conjugated bilirubin excreted in bile but a small % enters the blood (measureable) -Bacterial action in large intestines converts conjugated bilirubin to urobilinogen. Most urobilinogen converted to stercobilin - Brown color of feces Obstructed bile flow > no bilirubin in gut > no stercobilin > gray feces (acholic feces) 96  Some urobilinogen absorbed from bowel, undergoes oxidation in blood and filtered at kidney as urobilin - Yellow color of urine Clinical Relevance: Jaundice Jaundice = Yellow color of skin when excess bilirubin in blood 1. Typically caused by either: - Excessive hemolysis toxin - or immune-mediated (e.g., neonatal isoerythrolysis in foals) - Biliary obstruction cirrhosis, gall stones, cancer - Liver parenchymal disease cirrhosis; decrease conjugation 2. Certain causes of jaundice can be differientiated by van den Bergh test Indirect = Unconjugated bilirubin pre-hepatocyte Direct = Conjugated bilirubin post-hepatocyte Dx: Hemolytic jaundice Increase indirect (overwhelms liver conjugation) Dx: Obstructive jaundice increase direct (increase bilirubin leaks into blood) Neonatal jaundice (preterm infants) - low glucuronyl transferase in liver; any increase in bilirubin formation overwhelms conjugation capacity (increase direct) ~~~~ TX: phototherapy, blue light helps off set IV. Bile synthesis, secretion and reabsorption 3rd major liver function A. Functions of bile: 1. Emulsification of dietary lipids/micelle formation 2. Excretion of toxic products e.g., bilirubin 97  B. Bile constituents are formed and exported by hepatocytes into canaliculi Bile composed of: 1. Bile acids (75% of total solids) 2. Cholesterol 3. Excretory products including blood pigments (ex, conjugated bilirubin) 4. Electrolytes and water (NaHCO3 - alkaline pH) biliey duct like pancreatic ducts C. Bile acid synthesis 1. Bile acids synthesized from cholesterol in the liver (steroid backbone) only 5% is newly synthesize bile acids Cholesterol Primary bile acids: Cholate Chenodeoxycholate Fig. 63 2. Primary bile acids are conjugated with either taurine or glycine in liver to make secondary bile acids (makes amphipathic) FYI: pKa (acid dissociation Example: Taurocholic acid constant): a measure of the Lowers pKa of bile acid. Ionized at intestinal pH (Trapped in lumen) strength of an acid becomes amphipathic (has hydrophobic and hydrophilic moieties) ~ to make it more water soluble Conjugation of bile salts makes water-soluble D. Enterohepatic recycling (or circulation) of bile acids 1. After bile enters intestinal lumen, bile salts form micelles with dietary fat 2. Bile salts are released from micelles when dietary lipids (that have been digested) are absorbed from intestine 3. Released bile salts travel to terminal ileum where absorbed by Na-coupled active transport: a. 95% reabsorbed to complete enterohepatic cycle 98  -Enter portal circulation - Cleared by liver - Secreted into bile b. 5% pass to large intestine 1) Part lost in feces Bile salts have laxative action endogenous laxative 2) Bacteria deconjugate some bile acids Enter circulation Reconjugated in liver E. Control of hepatic biliary secretion 1. Modes of secretion: Tonic secretion Choleresis = Augmented bile secretion (meal) 2. Choleresis Secretion of bile by the liver ~ by heptaocytes a. Bile salts - **Main choleretic (after bile acid absorbed, ie, recycled) b. Acetylcholine - Vagus to cholinergic effectors - Mild choleretic c. Secretin - Stimulates HCO3 and water secretion from bile ducts like prancreatic ducts V. Gallbladder function A. Bile is stored in gallbladder until meal intake in species with a gallbladder, that is: 1. NaHCO3 + H2O absorption during storage: a. Concentrates bile salts 99  prevents Ca2+ precipation, which can form a b. Lowers bile pH nidus for stone formation B. Control of gallbladder contraction/emptying 1. CCK-PZ - Main cholegogue. 2. Acetylcholine - Vagus to cholinergic effectors - Mild cholegogue. Species without gallbladder: Horse, Rat, Pigeon increase bile flow when eating > exits via bile duct Objectives: 1. Describe the relationship of the hepatic blood supply to the hepatocyte and to the secretion of bile from the liver. 2. Know the three ways that the liver maintains euglycemia. 3. Know the four fates of amino acids after absorption from the intestine. 4. Know the sources of ammonia for urea synthesis and the fate of urea. 5. Know why dalmation dogs are prone to urate stones in the bladder. 6. Know the sources of lipid input to the liver. 7. Know the three fates of lipid output from the liver. 8. Know how ketosis develops. 9. Describe the role of the liver in vitamin and mineral metabolism. 10. Describe the steps in bilirubin formation from RBC lysis to excretion. 11. Know how the van den Bergh test is used in diagnosis of types of jaundice. 12. Know the functions of bile and describe enterohepatic recycling of bile salts. 13. Describe how bile salt secretion is controlled. 14. Describe the function of the gallbladder and the neuroendocrine control of gallbladder emptying. 15. Relate the hormonal control of bile secretion and gallbladder contraction to the secretion of enzymes and buffer from the pancreas. 100