Liver and gallbladder Flashcards
What 4 factors can affect the livers ability to metabolise drugs?
Age
Liver disease
Genetic constitution
Drug interactions
Which veins form the portosystemic anastamoses responsible for forming caput medusae in portal hypertension?
Para umbilical veins - portal
Superior and inferior epigastric veins - systemic
Why should the initial dose of a drug prescribed to an elderly person be lower than for a normal adult?
Relative liver mass and hepatic blood flow are reduced so reduced clearance
What should you try to do with polypharmacy?
Rational prescribing - try to minimise the total number of drugs that the patient is taking
Why might children need a higher dose than adults for certain drugs?
Metabolic clearance of the drugs is faster due to mature CYPs and relatively large liver mass and hepatic blood flow
What do phase 1 reactions do to a drug in the liver?
Add a functional group to make it more reactive and therefore provide a site for phase 2 reactions
Which is the most common phase 1 reaction?
Oxidation
Which family of enzymes are largely responsible for oxidation reactions in the liver?
Cytochrome P450
What 3 things do cytochrome P450 enzymes require to function?
Oxygen, NADPH and NADPH cytochrome P450 reductase
What do phase 2 reactions do to a drug in the liver?
Add a large molecule to make it more water soluble and therefore easier to excrete. Also tend to inactivate it. Conjugation
Which drugs are more likely to be excreted via the bile?
Highly ionised or large molecules >500 Da
What are multi drug resistance proteins?
Efflux transporters for removing drug metabolism products from hepatocytes
Give 4 reasons why patients with liver disease are at risk of toxic drug effects at low doses
Reduced functioning of hepatocytes/reduced number to metabolise
Decreased plasma binding proteins so increased bioavailability
If portal hypertension - reduced first pass metabolism and shunting of drug back into systemic circulation
Increased susceptibility to hepatotoxic drugs
What happens in paracetamol induced liver injury?
Overdose of paracetamol causes a saturation of phase 2 enzymes so more phase 1 reactions occur. This causes an accumulation of NAPQBI which is toxic to hepatocytes. At first, glutathione inactivates this toxic product but once it runs out, liver damage occurs.
What would you use acetylcysteine and methionine for?
As antidote to paracetamol overdose as they increase liver synthesis of the cytoprotective glutathione
How can genetics affect people taking codeine?
Some people have low levels of CYP2D6 which is responsible for converting the codeine prodrug into morphine. Codeine itself is a very weak analgesic so patients report little pain relief with many side effects
Why is it important to ask about herbal remedies eg St. John’s wort when taking a history?
Drug interactions
St. John’s wort induces CYP3A and so leads to increased metabolism of drugs such as oral contraceptives, benzodiazepines and warfarin. This reduces their bioavailability
List 5 functions of the liver
Energy metabolism Production of plasma proteins Synthesis, storage and secretion of bile Drug metabolism Immune functions Cholesterol processing Excretion of bilirubin
What are Kupffer cells?
Immune cells of liver
Present in sinusoids attached to endothelial cell lining
Ingest bacteria and inflammatory mediators
What 5 types of plasma proteins are made by the liver?
Binding proteins - albumin Carriage proteins - thyroid binding globulin Clotting factors - fibrinogen Pro hormones Apolipoproteins
What are the 6 components of bile?
Bile salts Bile pigments HCO3 Cholesterol Lecithin Trace metals
Which enteric hormone acts to increase bile production of liver?
Secretin
What do cholangioctyes secrete and where are they?
Lining bile duct, secrete HCO3 and water
What 4 things are bile salts involved in?
Elimination of cholesterol
Emulsification of fats in SI so available to pancreatic lipases
Facilitates absorption of fat soluble vitamins
Prevention of cholesterol precipitation in gallbladder
What are primary bile acids conjugated with to form bile salts?
Taurine
What are primary bile acids made from?
Cholesterol
During recycling of bile salts from terminal ileum, what do bacteria do?
Deconjugate bile salt to bile acid
Which 2 bile components are taken from the blood?
Bile pigments
Trace metals
What are bile pigments?
Excretory products being disposed of by liver via gut
What is bilirubin?
Bile pigment formed by breakdown of haem in spleen and bone marrow. Transported in blood by albumin
What does glucuronyl transferase catalyse?
Conjugation of drugs and bilirubin with glucuronic acid
What 4 things is cholesterol used for?
Plasma membranes
Producing steroid hormones
Formation of bile acids
Myelin
What do lipoprotein complexes transport in the blood?
Cholesterol
What is different about zone 1 and zone 3 hepatocytes within a lobule?
Zone 1 specialised in oxidative metabolism, gluconeogenesis and urea synthesis
Zone 3 specialised in drug metabolism, glycolysis and lipogenesis
What lies in centre of each lobule in liver?
Central vein
What are vascular spaces between plates of hepatocytes called?
Sinusoids
What 3 cell types are found in sinusoids?
Endothelial
Kupffer
Lipocytes
What happens to lipocytes when things go wrong in liver?
They differentiate and fibrose
How many functionally independent segments does the liver have?
8
Describe the blood supply to the liver
2 sources: Portal vein (70%) & hepatic artery (30%)
Where does the hepatic artery run?
In free edge of lesser omentum
Describe the blood supply to the gallbladder
Right hepatic artery branches into cystic artery
Describe the branching of the common hepatic artery
Branches from coeliac trunk Gastroduodenal branches from here Changes into hepatic Branches into left and right hepatic Right hepatic branches into cystic
What vessels contribute to forming the portal vein?
Splenic vein
Super mesenteric vein
Inferior mesenteric vein
Where would you find the fundus of the gallbladder?
9th costal cartilage, L1
What vessels join to form the bile duct?
Common hepatic and cystic ducts
Where does the bile duct drain into?
Major duodenal papilla
What is Murphys sign?
Acute cholecystitis
Palpate, pain on inspiration. Patient will stop breathing in
Where does gallbladder pain referral cover?
Right hypochondrium
Right shoulder - diaphragm irritation
Epigastrium
How much blood flows into the liver?
25% of cardiac output
1.5L/min
What is the splanchnic circulation?
Includes blood flow through the stomach, small intestine, large intestine, pancreas, spleen and liver
Portal vein carries venous blood draining from all of these organs except the liver itself
What are the functional units of the liver called?
Lobules
What is each lobule of the liver arranged around?
Central vein
Describe the organisation of a liver lobule
Plates of hepatocytes, lying in a cage of reticuloendothelial cells
The plates are separated by vascular spaces called sinusoids
Blood from the sinusoids converges on the central vein
In turn, the central veins converge on the hepatic vein
The reticuloendothelial cell meshwork includes diverse cell types:
Endothelial cells, Kupffer cells, lipocytes (stellate cells)
What processes of energy metabolism is the liver involved in?
Glycogenolysis Gluconeogenesis Glycogen synthesis Glycolysis, citric acid cycle and fatty acid synthesis Lipid metabolism Ketogenesis Triglyceride synthesis from fatty acids Protein metabolism Deamination Urea formation
What plasma proteins does the liver synthesise?
Major plasma proteins - albumin
Factors involved in haemostasis/ fibrinolysis: coagulation e.g. fibrinogen, coagulation inhibitors e.g. a1-antitrypsin, fibrinolysis e.g. plasminogen
Carriage proteins (binding proteins) e.g. transferrin, sex hormone binding globulin (SHBG), thyroid-binding globulin (TBG)
Pro-hormones
Apolipoproteins
How much bile does the liver secrete each day?
0.7-1.2L per day
What is the man function of the gallbladder?
Storage and concentration of bile
What effect does secretin have on the liver and pancreas?
Stimulates bile production
Stimulates HCO3 secretion from pancreas
What effect does CCK (cholecystokinin) have on the gallbladder and pancreas?
Gallbladder contraction to release bile
Enzyme secretion from pancreas
What are bile salts and what do they do?
Bile acids conjugated with taurine or glycine
Solubilise fat in small intestine
Which components of bile are secreted by hepatocytes into bile canaliculi?
Bile salts
Cholesterol
Lecithin
Bile pigments
What do cholangioctyes secrete?
Bicarbonate
Water
What are primary bile acids formed from?
Cholesterol
Where do secondary bile acids come from?
Recycled from entero hepatic circulation from terminal ileum back to liver
Of the bile salts that are recycled back to the liver, what can happen to them?
Recycled intact - 75%
Deconjugated by bacteria in terminal ileum to form primary bile acids, some are dehydroxylated to secondary bile acids - 25%
How much cholesterol comes from our diet and how much is synthesised in the body?
15% diet
85% synthesised
What do hepatocytes do to bilirubin to aid its excretion?
Conjugate it with glucuronic acid to form a polar water soluble molecule which is exported into bile
Describe the excretion process of bilirubin
Taken into liver via sinusoid from blood Conjugated with glucuronic acid Excreted into bile canaliculus Excreted into small intestine Converted to urobilinogen by bacterial proteases 90% excreted in faeces 10% excreted via kidneys
What is a portal triad?
Portal arterioles
Portal venule
Bile duct
What occurs with a filter failure of the liver?
Portal hypertension
What happens with an elimination failure of the liver?
Jaundice
What occurs with metabolic failure of the liver?
Acidosis
Muscle loss
Coagulopathy
Hepato renal syndrome
What is hepatic encephalopathy?
Failure of elimination, filter and metabolism of the liver
Confusion, altered level of consciousness, coma
Hallmark of liver failure
Caused by ammonia and other toxins build up
What do LFTs test for?
ALT/AST - hepatocyte damage
Alk Phos/gamma GT - bile duct damage
What are some true tests of liver function?
Prothrombin time Bilirubin (excretion) Albumin Urea/Creatinine pH
What can cause decompensation in chronic liver disease?
Infection Toxins - inc alcohol Trauma - inc surgery Drugs - sedatives Variceal bleed Dehydration - diuretics Malignant transformation - hepatoma
What are main causes of liver injury?
Fat
Alcohol
Virus
Iron
What is jaundice?
Failure of body to excrete bile
Clinically apparent when serum Bilirubin is twice above the normal concentration ~ 34uM/L
What are the medical terms for gallbladder and bile duct stones?
Gallbladder stones - cholelithiasis
Bile duct stones - choledocolithiasis
What does the wall of the gallbladder consist of?
Epithelium
Lamina propria
Fibromuscular layer
What are gallstones?
Most are cholesterol based associated with high fat diets/ hypercholesterolaemia
Can be formed by reduced bile secretion or defective reabsorption of bile salts
Pigment stones found in those with Haemolytic disorders (high serum bilirubin levels)
What techniques can be used to see gallstones?
Ultrasound
ERCP - endoscopic retrograde cholangio pancreatography
What is laproscopic cholecystectomy?
Keyhole removal of the gallbladder
What are 4 causes of metabolic liver injury?
Alcohol
Haemochromatosis
Wilson disease
Alpha1 anti trypsin deficiency
What are 3 inflammatory causes of liver injury?
Autoimmune hepatitis
Primary biliary cirrhosis
Primary sclerosing cholangitis
What are 4 types of non alcoholic fatty liver disease?
Fatty liver
Non alcoholic steatohepatitis
Cryptogenic cirrhosis
Liver cancer
What are 3 types of phase 1 reaction?
Oxidation
Reduction
Hydrolysis
Where are cytochrome p450 enzymes located?
On smooth ER
What 2 types of cytochrome p450 exist?
Constitutive - present all the time
Inducible - synthesised in response to appropriate stimulus
What are cytochrome p450s?
Haem proteins
What is the mixed function oxidase system?
Molecular oxygen, NADPH and NADPH cytochrome P450 reductase Combination of factors required for functioning of cytochrome p450 enzymes
What occurs during oxidation of a drug by cytochrome p450 enzymes?
Cytochrome P450 catalyzes the transfer of one oxygen atom to the substrate while the other oxygen atom is reduced to water
Give an example of a drug metabolised by a reduction reaction
Inactivation by warfarin by CYP2A6
Give examples of oxidations that do not involve the P450 system
Ethanol is metabolized by alcohol dehydrogenase (cytosolic enzyme)
Monoamine oxidase inactivates many biologically active amines (e.g. noradrenaline, 5-HT)
Give examples of hydrolytic reactions which metabolise drugs
Hydrolytic reactions are not restricted to the liver and occur in plasma and in many tissues. Aspirin (acetylsalicylic acid) is hydrolyzed to salicylic acid
Which chemical groups most often involved in conjugate formation?
Glucuronyl, acetyl, methyl, sulphate and glutathione
Name 2 drugs whose rate of action is determined by their renal excretion rather than liver metabolism
Digoxin
Atenolol
Give an example of a drug which is activated by liver metabolism
ACE inhibitors - activated by esterases
Diamorphine to morphine
What factors affect drug metabolism?
Age Genetics Drug interactions Environmental influences Liver disease
Describe the effect of age on drug metabolism
Neonates - low doses required as hepatic enzymes are immature and renal clearance is inefficient
Children - Metabolic clearance quicker in children because CYPs are mature and relative liver mass and hepatic blood flow are higher
Dosages of medicines should be obtained from a paediatric dosage handbook. Prescribed dosage judged by age and body surface area
Elderly - capacity for drug metabolism, particularly phase I is reduced because the relative liver mass and hepatic blood flow are lower. Polypharmacy is common. Start drug treatment with the smallest
effective dose. Rational prescribing to minimize the number of drugs
What is polymorphic distribution?
A trait that has differential expression in >1% of the population
Which drugs inhibit metabolism by CYP3A and therefore reduce clearance of calcium channel blockers, benzodiazepines, HIV protease inhibitors, HMG-CoA-reductase inhibitors, Cyclosporine, non-sedating antihistamines and oral contraceptives?
-azole antifungal drugs e.g. fluconazole
macrolide antibiotics e.g. erythromycin
cimetidine – a histamine H2 receptor antagonist
grapefruit juice
Give examples of CYP3A inducers which increase clearance of many drugs
Carbamazepine anti-convulsant rifampicin antibacterial rifabutin antibacterial ritonavir antiviral St. John’s Wort
Which drugs should not be taken with St. John’s wort due to it inducing activity of CYPs and therefore increasing clearance of these drugs?
Warfarin
antiepileptics
oral contraceptives
What is bioavailability?
The proportion of administered drug which reaches the systemic circulation unchanged and is thus available for distribution to the site of action
What is first pass metabolism?
Orally-administered drugs, which are usually absorbed in the small intestine, reach the liver via the portal circulation. At this stage the drugmay be extensively metabolized
Why is bioavailability of drugs increased in liver disease?
Drug metabolising capacity is reduced where hepatocytes are either sick or reduced in number
Hepatocytes that metabolise drugs are by-passed when portal-to-systemic shunts develop in cirrhosis - reduced first pass metabolism
Hypoproteinaemia leads to reduced drug-binding capacity which allows more unbound and pharmacologically active drug to circulate
Name 3 drugs whose bioavailability is increased in liver disease
Nicardipine - calcium channel antagonist
Propranolol - b-adrenoceptor antagonist
Verapamil - calcium channel antagonist
Name a drug that requires first pass activation
ACE inhibitors
Name drugs which are highly protein bound and therefore their pharmacologically active dose will be much greater in liver disease
Diazepam (benzodiazepine sedative)
Tolbutamide (hypoglycaemic sulphonylurea)
Phenytoin (anticonvulsant)
Valproic acid (anticonvulsant)
At what dose can paracetamol be lethal?
2/3 times maximum therapeutic dose
In paracetamol induced liver injury, what is hepatotoxicity caused by?
Accumulation of toxic metabolite NAPBQI
In paracetamol-induced liver injury, how soon after overdose does fatal hepatocellular necrosis occur?
48-72 hours
Who is particularly at risk of paracetamol overdose?
Patients taking P450-inducing drugs inc alcohol and St. John’s wort
Patients with glutathione depletion e.g. patients with eating disorders
What are functions of the liver?
Carbohydrate/lipid/protein metabolism Processing dead red blood cells Cholesterol/phospholipid/lipoprotein production Immune function Bile production and secretion Drug metabolism/detoxification Vitamin storage Steroid hormone production Plasma protein production
Why do gallstones cause dark urine and pale stools?
Pale stools occur as no bilirubin reaches the gastrointestinal tract and dark urine results from reflux of conjugated bilirubin into blood which is excreted in the urine
Explain how varices are formed
Portal hypertension causes back up of blood into systemic circulation. At points of anastamoses, vessels under high pressure and swell up. In the oesophagus, these varices are delicate and can rupture easily
