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 largest (internal) organ in the body. Divided into:

• Larger right lobe
• Smaller left lobe

Separated superiorly by the Falciform 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.

The 5 ligaments of the liver are:

• Falciform – connects the liver to abdominal wall
• Coronary – attaches the liver to the diaphragm
• Left and Right Triangular
• Ligamentum Venosum – Embryonic remnant of the

ductus venosus

• Ligamentum Teres Hepatis (Round) – fibrous remnant
• f the umbilical vein

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 common bile duct joins the main pancreatic duct at the Ampulla of Vater which is the opening into the duodenum which is controlled by the Sphincter of Oddi.

The Gallbladder A pouch that usually holds approximately 50ml of bile. It lives in the fossa between the right and quadrate lobes of the liver. It is divided into a fundus, body and a neck that

• pens into the cystic duct.

LIVER PHYSIOLOGY

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

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

CARBOHYDRATE METABOLISM

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

­ Fibrinogen ­ Prothrombin ­ Factors II, V, VII, VIII, IX, X, XI and XII ­ Protein C and S

Vitamin K dependent factors

­ Factors II, VII, IX and X ­ Protein C and S

Vitamin K

­ Fat soluble ­ Found in green leafy vegetables ­ Stored in hepatocytes. Also synthesised by gut bacteria.

Warfarin inhibits Vitamin K epoxide reductase, preventing the reactivation of Vitamin K and coagulation factor synthesis.

BILE

What is Bile? A green/yellow secretion, made in the liver and stored in the gallbladder. What is bile composed of? Water Bile salts/acids Phospholipids Cholesterol Bilirubin Electrolytes It is secreted: By hepatocytes By epithelial cells lining the bile ducts What are the functions of bile? To aid with:

• Digestion – neutralises gastric juice
• Absorption (of vitamins and fats by emulsifying and

solubilising them)

• Excretion of waste products e.g. Bilirubin and

cholesterol

500mg of cholesterol is converted to bile acids daily. 95% of bile is reabsorbed by enterohepatic circulation. 5% of bile is lost in faeces – giving it its brown colour.

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 (conjugated and/or unconjugated) in the extra cellular fluid. It can lead to yellowing of the skin, sclera and mucous membranes and can also cause pruritis (itching).

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

Hyperbilirubinaemia = excess bilirubin levels in the blood Normal Bilirubin levels 1mg/dl

Pre-hepatic Jaundice Hepatic Jaundice Post-hepatic Jaundice Unconjugated Bilirubin Unconjugated or conjugated Conjugated Excess breakdown of RBCs (Increased haemolysis) Decreased uptake or conjugation of unconjugated bilirubin Hepatocyte damage (>80%) Obstruction in getting to the duodenum Increased reuptake Is likely to accompany very dark urine Sickle Cell Anaemia Physiologic Jaundice

• f the Newborn

Hepatitis A,B,C,E Cirrhosis Drugs Gilbert Syndrome Gallstones Pancreatic or liver cancer Jaundice may present with:

• Pale stools
• Dark urine
• Right Upper Quadrant pain
• Steatorrhea
• Pruritis
• Weight loss

LIVER FUNCTION TESTS

ALT (Alanine aminotransferase) A Liver Test Hepatocellular damage, disease progression ↑: marker for hepatocellular injury AST (Aspartate aminotransferase) A Second Test (non-specific) ↑ ALT + AST = hepatocyte damage; ↑ AST = muscle damage/MI ALP (Alkaline phosphatase) Cholestasis (reduced/blocked flow

• f bile from liver)

↑ indication for cholestasis GGT (γ-glutamyl transpeptidase) Review if ALP ↑ ↑ ALP + ↑GGT suggestive of cholestasis PT (Prothrombin time) INR (International Normalised Ratio) Hepatic biosynthesis ↑ in advanced liver disease (↓ production of clotting factors, measuring liver’s biosynthetic function) Albumin Happy livers make albumin ↓ in advanced liver disease, marker of liver’s biosynthetic function) Bilirubin Jaundice, liver disease severity 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? The metabolism of a drug before it reaches the systemic circulation. Drugs absorbed from the GI 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

Some drugs e.g. nitrates, undergo a heavy first pass effect which means that when taken orally, very little of the drug actually reaches the systemic circulation. For this reason they should be given by alternative routes.

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

• Carbamazepine
• Rifampicin
• Alcohol (chronic use)
• Phenytoin
• Griseofulvin
• Phenobarbitone
• Smoking

Substrates

• Warfarin
• OCP
• Theophylline
• Anti-epileptic drugs

Inhibitors

• Erythromycin
• Ciproflaxacin
• Sodium Valproate
• Omeprazole
• Simvastatin
• Fluconazole/Ketoconazole
• Isoniazid

Reduce the metabolism of other drugs at the same time! Rifampicin increases the metabolism of the OCP which can increase the risk of pregnancy.

DRUG METABOLISM AND EXCRETION

Drug metabolism aims to transform drugs in order to make them easier to excrete renally. This normally involves them going from lipophilic to hydrophilic (making them water-soluble). Phase 1 of Drug Metabolism

• Reduction, oxidation and hydrolysis

reactions

• Can create active metabolites e.g.

Clopidogrel, Diazepam

• Includes the CYP450 system

*Phase 1 metabolism can be altered in elderly patients. Phase 2 of Drug Metabolism

• Conjugation – drugs get paired up with

water-soluble endogenous molecules

• Drugs that have been conjugated and

made chemically inactive and water- soluble then go to the kidney to be excreted

• Uses conjugation reactions

PARACETAMOL

First line analgesic for most acute and chronic pain. Antipyretic Mechanism of action poorly understood.

­ Weak inhibitor of COX, particularly in CNS. ­ Appears to ↑ pain threshold and ↓ PGE2 (affects thermoregulation, controlling fever) ­ Not active peripherally ­ Lack of COX-1 inhibition ≠ peptic ulceration or renal impairment

Toxic dose ~7.5g/day in adults

PARACETAMOL

Signs and symptoms

Non-specific symptoms:

­ Nausea and vomiting ­ Pallor ­ Lethargy

Signs of liver injury (usually 2-4 days

• nwards)

­ RUQ abdominal pain ­ Hepatomegaly and tenderness ­ Jaundice ­ Abnormal LFTs

Management

Supportive care Activated charcoal within the 1st hour N-acetylcysteine depending on serum level at 4 hours

ALCOHOL METABOLISM ALCOHOLIC LIVER DISEASE

Alcohol/ethanol is converted to acetaldehyde by alcohol dehydrogenase. Acetaldehyde converted to acetate. This process produces excess NADH which,

­ Shunts carbohydrate pathway: pyruvic acid converted to lactic acid ­ Shunts lipogenic pathway: ↑ production of lipids, fatty acids and glycerol.

Chronic alcohol consumption (>10 years) lead to

­ ↑ Fatty acid synthesis, ↓ fatty acid oxidation ­ Formation of scar tissue ­ Eventually leads to irreversible damage: cirrhosis

Armando Hasudungan – Alcohol Physiology https://www.youtube.com/watch?v=T8k8SgfpQ9k

QUESTIONS?

SBAs

A 55 year old woman comes into A&E after she is referred by her GP with a week’s history of jaundice and right upper quadrant abdominal pain. Associated symptoms include dark urine and pale stools. There is no history of weight loss and the patient does not drink alcohol. Her LFTs reveal a hyperbilirubinemia. What is the most likely diagnosis? A. Alcoholic hepatitis B. Autoimmune hepatitis C. Carcinoma of the head of the pancreas D. Gallstones E. Viral hepatitis

A medication is being administered that has a high first-pass effect. The prescription has been changed from IV (intravenous) route to PO (oral). Which of the following would be applicable for the new oral dosage? A. It would be higher than the IV dose because it will have a higher bioavailability B. It would be higher than the IV dose because it will have a lower bioavailability C. It would be lower than the IV dose because it will have a higher bioavailability D. It would be lower than the IV dose because it will have a lower bioavailability E. It would be the same as the IV dose

Where is bile made and stored? A. Made and stored in the gallbladder B. Made and stored in the liver C. Made in the gallbladder and stored in the liver D. Made in the liver and stored in the duodenum E. Made in the liver and stored in the gallbladder

Autoimmune Hepatitis can present with which type of jaundice? A. Hepatic B. Hepatocellular C. Post-hepatic D. Pre-hepatic E. Pre-hepatic obstructive

Unconjugated bilirubin is…? A. Unimportant B. Water insoluble C. Water soluble

Prolonged fasting causes the blood to become more acidic by… A. Production of lactic acid from anaerobic respiration B. Keto acid formation from ketone bodies C. Amino acid breakdown for energy leads to excess urea production

Which of the following is the best indicator of cholestasis A. ALT/AST B. ALP C. ALP + GGT D. Bilirubin E. GGT

A 24 year old female student, who is normally fit and well, present to ED 2 weeks before her exams. She is drowsy and confused, and on examination is jaundiced and has tender hepatomegaly. Which is the most relevant first line investigation? A. Ferritin levels B. GGT C. Hepatitis screen D. Plasma paracetamol levels

The best liver function test is: A. AST/ALT B. ALP C. Bilirubin D. PT/INR