MICHAELA RUMSEY LIVER WEEK Rebekah Rocker Suraiya Chowdhury - PowerPoint PPT Presentation

MICHAELA RUMSEY LIVER WEEK Rebekah Rocker Suraiya Chowdhury

OVERVIEW Liver anatomy Liver physiology Bile and Jaundice Liver function tests Overview of drug metabolism Paracetamol and alcohol metabolism SBAs

THE LIVER: GROSS ANATOMY

The 5 ligaments of the liver are: The largest (internal) organ in the • Falciform – connects the liver to abdominal wall body. • Coronary – attaches the liver to the diaphragm Divided into: • Left and Right Triangular • Larger right lobe • Ligamentum Venosum – Embryonic remnant of the • Smaller left lobe ductus venosus • Ligamentum Teres Hepatis (Round) – fibrous remnant Separated superiorly by the Falciform of the umbilical vein Ligament There are 2 additional lobes arising from the right lobe: • Quadrate lobe (looks like a square- ish) • Caudate lobe These additional lobes are separated by the Porta Hepatis – a central fissure that is the exit and entrance of the portal vein , hepatic artery , hepatic ducts and nerves.

Blood Supply The liver has 2: Hepatic Portal vein - 75% – brings nutrient rich blood from the GI tract. Also brings the toxins that need getting rid of. ( Intestines → Portal Vein → Liver → IVC via the hepatic veins) Hepatic artery – 25% - oxygen-rich blood from the heart. ( Aorta → Celiac trunk → Common Hepatic Artery → Liver → IVC )

Liver Lobules The functional unit of the liver Hexagonal plates of hepatocytes around a central hepatic vein Each corner of the lobule has a portal triad Liver Cells Hepatocytes – 60% - Most of the metabolic functions Kupffer cells – 30% - macrophages Stellate cells Endothelial

THE BILIARY TREE (SYSTEM) The Biliary System is made up of: Right and Left hepatic ducts fuse in the porta hepatis to form the… Common Hepatic Duct - this joins with the… Cystic Duct which drains the… Gallbladder and forms the… Common bile duct . The Gallbladder The common bile duct joins the main A pouch that usually holds approximately 50ml of pancreatic duct at the Ampulla of bile. Vater which is the opening into the It lives in the fossa between the right and duodenum which is controlled by the quadrate lobes of the liver. Sphincter of Oddi . It is divided into a fundus, body and a neck that opens into the cystic duct.

Metabolism and Synthesis and Storage and detoxification secretion filtration Metabolises Clotting factors Vitamin storage products of digestion LIVER Glucose regulation Cholesterol and Blood reservoir PHYSIOLOGY triglyceride synthesis Drug and alcohol Bile Iron storage metabolsm Bilirubin metabolism Proteins and B12 storage hormones

LIVER PHYSIOLOGY CARBOHYDRATE METABOLISM Glycogenesis ­ Glucose ⟶ glycogen ­ Stimulated by insulin Glycogenolysis ­ Glycogen ⟶ glucose ­ Stimulated by glucagon and adrenaline Gluconeogenesis ­ Lactate/amino acids/glycerol ⟶ glucose (when glycogen reserves are depleted) Glycolysis ­ Glucose ⟶ pyruvate (releases energy in the form of ATP and NADH)

LIVER PHYSIOLOGY PROTEIN METABOLISM Deamination and transamination of amino acids Synthesising non-essential amino acids Synthesising plasma proteins ­ Albumin ­ Acute phase proteins Excretion of ammonia (toxic) via urea cycle ­ Ammonia buildup ⟶ hepatic encephalopathy

LIVER PHYSIOLOGY - LIPID METABOLISM FF FFA – fr free fatty acids HD HDL – Hi High gh density lipoproteins MG MG – Mo Monoglycerides LD LDL L – Lo Low d density ty l lipoproteins VL VLDL – Ve Very low density lipoproteins

LIVER PHYSIOLOGY – CLOTTING FACTORS The liver synthesizes Vitamin K ­ Fibrinogen ­ Fat soluble ­ Prothrombin ­ Found in green leafy vegetables ­ Factors II, V, VII, VIII, IX, X, XI and XII ­ Stored in hepatocytes. Also synthesised by gut bacteria. ­ Protein C and S Warfarin inhibits Vitamin K epoxide Vitamin K dependent factors reductase, preventing the reactivation of ­ Factors II, VII, IX and X Vitamin K and coagulation factor synthesis. ­ Protein C and S

BILE What are the functions of bile? To aid with: • Digestion – neutralises gastric juice • Absorption (of vitamins and fats by emulsifying and What is Bile? solubilising them) A green/yellow secretion, made in the liver and • Excretion of waste products e.g. Bilirubin and stored in the gallbladder. cholesterol What is bile composed of? Water Bile salts/acids Phospholipids Cholesterol 500mg of cholesterol is converted to bile Bilirubin acids daily. Electrolytes 95% of bile is reabsorbed by It is secreted: enterohepatic circulation. 5% of bile is lost in faeces – giving it its By hepatocytes brown colour. By epithelial cells lining the bile ducts

BILIRUBIN AND BILIRUBIN METABOLISM What is Bilirubin? A product formed during the breakdown of haemoglobin. It is a yellow pigment responsible for the yellow colour of urine and contributes to the brown colour of faeces.

JAUNDICE (ICTERUS) What is Jaundice? An increased amount of bilirubin Hyperbilirubinaemia = (conjugated and/or unconjugated) in excess bilirubin levels in the extra cellular fluid. the blood It can lead to yellowing of the skin, sclera and mucous membranes and Normal Bilirubin levels can also cause pruritis (itching). 1mg/dl There are 3 types of jaundice: • Prehepatic (Haemolytic) – Excess unconjugated bilirubin • Hepatic/Hepatocellular – Excess unconjugated and/or conjugated bilirubin • Post-hepatic/Obstructive – Excess conjugated bilirubin

Pre-hepatic Jaundice Hepatic Jaundice Post-hepatic Jaundice Unconjugated Unconjugated or Conjugated Bilirubin conjugated Excess breakdown of Hepatocyte damage Obstruction in getting to RBCs (Increased (>80%) the duodenum haemolysis) Increased reuptake Decreased uptake or conjugation of unconjugated bilirubin Is likely to accompany very dark urine Sickle Cell Anaemia Hepatitis A,B,C,E Gallstones Physiologic Jaundice Cirrhosis Pancreatic or liver cancer of the Newborn Drugs Gilbert Syndrome Jaundice may present with: • Pale stools • Dark urine • Right Upper Quadrant pain • Steatorrhea • Pruritis • Weight loss

LIVER FUNCTION TESTS ALT (Alanine aminotransferase) ↑ : marker for hepatocellular injury A L iver T est Hepatocellular damage, disease progression AST (Aspartate aminotransferase) ↑ ALT + AST = hepatocyte damage; ↑ AST = muscle damage/MI A S econd T est (non-specific) ↑ indication for cholestasis ALP (Alkaline phosphatase) Cholestasis (reduced/blocked flow Review if ALP ↑ GGT ( γ -glutamyl transpeptidase) of bile from liver) ↑ ALP + ↑ GGT suggestive of cholestasis PT (Prothrombin time) ↑ in advanced liver disease ( ↓ production of clotting factors, INR (International Normalised Ratio) measuring liver’s biosynthetic function) ↓ in advanced liver disease, marker of liver’s biosynthetic Albumin Hepatic biosynthesis Happy livers make albumin function) Jaundice, liver disease severity Bilirubin Examples – biliary obstruction, alcoholic/viral hepatitis, cirrhosis) GeekyMedics – Interpretation of LFTs - https://geekymedics.com/interpretation-of-liver-function-tests-lfts/

DRUG ELIMINATION – ZERO AND FIRST ORDER Zero Order • Saturated process • Constant rate of elimination per time • No dependence/variation with the drug • No half life • Example drugs – Alcohol, Phenytoin and Aspirin First Order (Most drugs) • Unsaturated process • Rate varies with the concentration of the drug • The percent change with time is constant (the half life)

DRUG ELIMINATION - FIRST PASS METABOLISM What is First Pass Metabolism? Some drugs e.g. nitrates, undergo a heavy first pass effect which means that when taken orally, very little of The metabolism of a drug before it reaches the the drug actually reaches the systemic circulation. For systemic circulation. Drugs absorbed from the GI this reason they should be given by alternative routes. tract arrive in the liver via the portal vein before entering the systemic circulation. In the liver some of the drug is metabolised which reduces the amount available to get to other parts of the body therefore reducing its bioavailability. Outcomes of Drug Metabolism Active molecules → Inactive molecules (Can also happen the other way) Toxic → Non-toxic (Can also happen the other way ) Lipid drug → Water soluble

CYTOCHROME P450 SYSTEM A group of extracellular enzymes: Found abundantly in the liver Help metabolise many drugs (via REOX and hydrolysis reactions) If inhibited they can increase drug levels If induced they can decrease drug levels Inducers – CRAP GPS Inhibitors • Carbamazepine • Erythromycin Substrates • Rifampicin • Ciproflaxacin • Warfarin • Alcohol (chronic use) • Sodium Valproate • OCP • Phenytoin • Omeprazole • Theophylline • Griseofulvin • Simvastatin • Anti-epileptic drugs • Phenobarbitone • Fluconazole/Ketoconazole • Smoking • Isoniazid Rifampicin increases the metabolism of the OCP which can increase the risk of Reduce the metabolism of other drugs pregnancy. at the same time!