Physiological functions of liver - and liver function test
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The liver performs many critical physiological functions: 1. It regulates carbohydrate, lipid, and protein metabolism, producing glucose and ketone bodies and breaking down toxins. 2. The liver synthesizes proteins involved in blood clotting and transports iron, vitamins, and hormones. 3. The liver metabolizes and detoxifies drugs and other xenobiotics through phase I and phase II reactions and transports them out of the body. Impairment of these functions can lead to drug accumulation and toxicity.
Physiological functions of liver - and liver function test
- 1. PHYSIOLOGICAL FUNCTIONS OF THE LIVER DR ZIKRULLAH MALLICK Department of Anaesthesiology & critical Care JAWAHARLAL NEHRU MEDICAL COLLEGE,ALIGARH
- 2. • Liver is the largest internal organ & largest gland in the human body. • Liver is at the epicenter of intermediary metabolism. • It performs versatile & massive biochemical pathways. • It destroys bacteria, inactivate antigens, detoxify harmful chemicals. • Thus multiple & diverse functions of liver have an impact on every tissue in the body.
- 3. Physiological functions of liver • Intermediary metabolism a. Carbohydrate metabolism b. Lipid metabolism c. Bile metabolsim and entero- hepatic circulation d. Protein metabolism • Coagulation • Heme metabolism • Bilirubin metabolism • Xenobiotics metabolism • Storage • Endocrine functions • Immune & inflammatory response • Blood reservoir
- 4. Carbohydrate metabolism • Liver is an important homeostatic regulator of blood glucose. • It can either produce glucose or store glucose • In fed state- polymerize glucose to glycogen • In unfed state- depolymerize glycogen to glucose • Glucose → hepatocytes → glycogen ↑ →glucose Lactate Glycerol aminoacids
- 5. Carbohydrate metabolism • Glycogen metabolism • Regulation – 2 rate limiting enzymes 1. Glycogen synthase- synthesis of glycogen from monomers of UDP glucose. 2. Glycogen phosphorylase- clevage of glycogen to glucose-1- phosphate.
- 6. Carbohydrate metabolism Gluconeogenesis • Liver glycogen stores depleted - hepatic gluconeogenesis to replenish blood glucose. • Substrates- - lactate - glycerol from hydrolysis of triglycerides - gluconeogenic amino acid , alanine , glutamine
- 8. • Blood glucose regulation within a narrow limit (70-100 mg/dl) not affected in liver disease due to large reserve of hepatic function Effects of anaesthesia on carbohydrate metabolism • Halothane – release of insulin – rate of glycogenolysis – Inhibition of gluconeogenic response • Isoflurane – Impaired insulin secretion
- 9. Lipid Metabolism • Oxidation of fatty acids • Fatty acids derived from plasma • Enter into mitochondria • oxidation: fatty acids AcetylCoA citric acid cycle • Regulators - Glucagon - activates - Insulin - inhibits
- 10. • Synthesis of lipoproteins • One of the major functions of the liver • Major classes – VLDL – LDL – HDL
- 11. • VLDL • Acute or chronic liver disease – ability to produce VLDL is markedly compromised • Liver VLDLs are associated with an important class of proteins, the apo B protein • Apo B100 - important for hepatic secretion of VLDL. • Decreased in ABETALIPOPROTEINEMIA • LDLs and HDLs • Liver produces them in a small amount
- 12. • Production of ketone bodies • Most organs except the liver- use ketone bodies as fuel • Ketone bodies – acetoacetic acid, acetone, hydroxybutyrate • Their formation by the liver is normal and physiologically important, e.g. – Fasting rapid depletion of glycogen stores in the liver shortage of substrates for citric acid cycle – AcetylCoA formed from oxidation ketone bodies • Ketosis - conc. of ketone bodies in blood – Starvation – DM – After high fat diet
- 13. • Synthesis of cholesterol • Important role in cholesterol homeostasis • Liver cholesterol has both exogenous and endogenous source Uses of hepatic cholesterol • Formation of bile acids- conjugated with other substances to form cholic acid. • Synthesis of VLDLs
- 14. Bile metabolism & enterohepatic circulation • Bile salts are end products of cholesterol synthesis • Daily production – 600- 800 ml/d • Functions- - activate lipase - promote micelle formation - intestinal uptake of fat soluble vitamins, cholesterol & lipids - facilitate excretion of xenobiotics, lipophillic substances, bilirubin, amphipathic steroid hormone derivative
- 15. • Bile salts undergo enterohepatic circulation (20-30 times/day) intrahepatic bile duct ↓ common hepatic duct cystic duct CBD ↓ ↓ gall bladder small intestine ( terminal ileum) • Clinical implication – Opioids can induce spasm of bile duct & spinter of oddi – Reversed by – glucagon, opioid antagonists ( naloxone), smooth muscle relaxant (NTG), antimuscarinic drugs( atropine), volatile anaesthetics.
- 16. Protein and amino acid metabolism • Deamination of amino acids – Required before they can be used for energy or before they can be converted into carbohydrates or fats • Formation of urea for removal of ammonia from the body fluids • Production of proteins and peptides.
- 17. Krebs- Hanseleit cycle Major pathway for removing NH3 & other nitrogenous wastes from body Captures nitrogen in form of urea. Failing liver- BUN remain low - ammonia accumulates in liver ↓ Hepatic encephalopathy
- 18. Proteins & peptides Albumin • Most abundant protein • Normal plasma conc- 3 - 5 g% • Daily production -12-15 g/d • Plasma half life – 15-20 days • Functions – • maintains plasma oncotic pressure (80% by albumin) • binds ions, bilirubin, hormones & drugs • Hypoalbuminemia – Colloid oncotic pressure edema
- 19. ᾳ- feto protein • Resembles albumin genetically & functionally • Formation sites- yolksac, hepatocytes, enterocytes • Fetal & neonatal life- major determinant of plasma oncotic pressure • 1 year of age- albumin largely replaces AFP • ↑ ↑ AFP- HCC
- 20. Fibrinogen • Synthesized exclusively by hepatocytes • Plasma fibrinogen – 100-700 mg/dl • Functions – polymerizes into long fibrin threads by the action of thrombin formation of clot
- 21. • Haptoglobins – Forms stable complexes with free Hb prevents loss of iron through urinary excretion, protects kidney from damage • Ceruloplasmin – binds with copper and helps in its transport and storage • Wilson’s disease – Deficiency of ceruloplasmin free Cu2+ in circulation deposited in brain and liver
- 22. Coagulation • Synthesize most of the procoagulants except- a. factor III ( tissue thromboplastin) b. Factor IV ( calcium) c. Factor VIII ( von Willebrand factor ) • Produce protein regulators of coagulation & fibrinolytic pathways – Protein C, protein S ( protein C – inactivate F VIIIa- Va complex) – protein Z ( degradation of Factor Xa ) – plasminogen activator inhibitor (PAI) ( inhibits tissue plasminogen activators to convert plasminogen to plasmin ) – antithrombin III
- 23. Liver as a Storage Organ • Vitamin A • Important role in the uptake, storage and maintenance of vitamin A levels by mobilizing its vitamin A store • Vitamin K • Vitamin K dependent factors II, VII, IX, X • Absorption of Vit K depends on normal fat absorption: any mal- absorption of lipid vitamin K deficiency • Storage in liver- limited hypoprothrombinemia can develop within a few weeks. • Treatment – • FFP • Antidote- parenteral vit K
- 24. Vitamin K cofactor & ỳ- carboxylation – Factor II, VII., IX, X , protein C & S- undergo Vit K dependent post translational modifications – Enables procoagulants to form complexes with calcium or other divalent cations for participation in the clotting cascade. Clinical implication Warfarin inhibits vit K epoxide reductase ↓ traps Vit K in epoxide form ↓ Inhibits y- carboxylation T/T- Enteral / parenteral Vit K.
- 25. Storage & Homeostasis of Iron • Major site of synthesis of proteins (Transferrin, Ferritin) involved in iron transport & metabolism. Heme metabolism Clinical implication • Porphyrias • Acute Intermittent Porphyria – commonest – Defects in the heme pathway- accumulation of porphyrinogens – Trigger substances- barbiturates, sex hormones, glucocorticoides, cigarette smoke, CYP inducers.
- 27. Plasma Fragile RBCs RE System unconjugated bilirubin (protein – bound) Liver Liver Kidneys Urobilinogen Conjugated bilirubin Absorbed Bacterial action Urobilinogen Stercobilinogen Stercobilin Intestinal Contents Oxidation Urobilinogen Urobilin Urine Oxidation BILIRUBIN METABOLISM
- 28. Metabolism of Drugs (Xenobiotics) Phase-I reactions • Alter the parent drug by inserting or unmasking a polar group • Converts drugs to more polar compounds • Reactions – oxidations, reduction, hydrolysis • Cytochrome P450 – substrate binding site, located in the endoplasmic reticulum • Drugs– barbiturates, benzodiazepines, halogenated volatile anaesthetics, pethidine etc.
- 29. • Phase-II reactions • Creates conjugates of parent compound or its metabolite with endogenous hydrophilic substrate Reactions • Glucoronidation • Sulphation • Methylation • Acetylation Glucoronidation • Most common type • Hepatic microsomal enzyme, UDPglucuronyl transferase mediates the transfer of glucoronic acid from UDP glucuronic acid to the functional group on the xenobiotics
- 30. • Drug handled by phase-II – morphine, propofol, thiopentone (initially oxidized subsequently conjugated) Phase-I reaction enzymes – more susceptible to destruction in cirrhosis Phase-II reactions enzymes – more resistant, function even in advanced liver disease Phase-III reactions • Involves ATP-binding cassette transport proteins (ABC) • These proteins use the energy of ATP hydrolysis to drive molecular transport • Dysfunction of ABC proteins hinders flow of bile predisposing to drug accumulation and cholestatic liver injury
- 31. Microsomal enzyme induction • Anticonvulsants, rifampicin, isoniazid, glucocorticoids, chronic alcohol consumption Consequences of enzyme induction duration of action of drugs that are inactivated by metabolism intensity of action of drugs that are activated by metabolism
- 32. Endocrine functions • Liver can modify or amplify hormone action • Metabolic conversion of Vitamin D to form 25(OH)D • 25(OH)D 1,25(OH)2D in kidney • Peripheral conversion of T4 to T3 Pseudocholinesterase • Hydrolysis of succinylcholine • Plasma t½ - 14 days • Severe liver disease duration of action of succinylcholine
- 33. • Insulin-like growth factors or somatomedins – growth hormone like action • Important role in cartilage function by promoting uptake of sulphate and synthesis of collagen Removes circulating hormones • Insulin, glucagon, growth hormone, gastrointestinal hormones, e.g. gastrin
- 34. • Blood reservoir – Liver is an expandable organ – 10 -15 % of total blood volume can be sequestered and quickly released after sympathetic stimulation . • Immune & inflammatory responses – kuffer cells protect against foreign intrutions, degrade toxins, process antigens, and phagocytose bacteria. – Induce & intensify inflammation by recruiting neutrophils – Release proinflammatory mediators
- 35. Signs of Liver Disease • Jaundice • Hepatomegaly • Spider Naevi • Splenomegaly • Scratch Marks • Ascites • Palmer Erythema • Dilated Abdominal Veins • Peripheral Oedema • Finger Clubbing • Testicular Atrophy • Bruising • Gynaecomastia • Confusion/Coma
- 36. Summary • Functions of liver I. synthetic Plasma protein (albumin) Hypoproteinimea → oedema Coagulants Haemorrhagic disorders Enzymes Hepatocellular disorders Urea / removal of NH3 ↓ bld urea, ↑bld NH3 II. Metabolic Carbohydrate ↓ glycogen – more damage ↓ bld. Glucose – muscle weakness, personality changes, tremors, slurred speech, convulsion, coma , death → pre hepatic coma Protein metabolism ↑ blood ammonia – aminoaciduria lipid metabolism Acc. Of FA in liver → fatty liver →pre hepatic hepatitis→ fibrosis→ cirrhosis→ ↑ portal pressure→ portal hypertension
- 37. III. Bile secretion Bile salts & acids steatorrhea Conjugation of bilirubin Hepatocellular jaundice IV. Miscellaneous Vit A, K Deficiency- ↓vit A , K Antibacterial action Prevent infections Destruction of RBCs Anemia , ↑ bilirubin
- 38. THANK YOU