Hepatic Disease And Treatment Flashcards
What is the percentage of oxygen consumed by the liver?
20-30%
Does the liver receive a lot of blood?
Yes it is highly vascularised
What are the 4 lobes of the liver called?
2 major lobes: (right and left)
2 minor lobes: (caudate and quadrate)
What is the functional unit of the liver called?
the liver lobule
What makes up the liver lobule?
- a central terminal hepatic venule
- interconnecting plates of hepatocytes
- peripherally arranged portal triad (terminal branches of hepatic artery, portal vein and bile duct)
Functions of the liver?
1) Xenobiotic detoxification and metabolism
2) Decomposition of erythrocytes and excretion of bilirubin
3) Bile Production
4) Cholesterol synthesis and Lipogenesis
5) Carbohydrate Metabolism
6) Protein synthesis
7) Hormone production
8) Storage
Proteins synthesised by the liver?
1) albumin
2) coagulation factors
Role of albumin?
an osmolar component of blood serum
Examples of coagulation factors?
1) fibrinogen
2) prothrombin
3) factors V, VII, IX, XI
4) proteins C and S
5) antithrombin
Hormones produced by the liver?
thrombopoieitin and angiotensin
Role of thrombopoietn?
regulates platelet production by bone marrow
Role of angiotensin?
raises blood pressure following renin activation
What is stored in the liver?
- glycogen
- vitamins A,D,E,K,B12
- Iron
- Copper
What is jaundice?
A symptom of underlying diseases or physiological dysfunction
What is the normal bilirubin level?
3-17 mmol/L
What causes pre-hepatic jaundice?
red blood cell haemolysis
What causes hepatocellular jaundice?
- infection
- chemical/drug
- genetic error
- autoimmune
- neonatal
What causes posthepatic jaundice?
- intrahepatic bile ducts
- extrahepatic bile ducts
Why is bilirubin insoluble in water?
The carboxylic group on the bilirubin forms hydrogen bonds with the NH group and the lactam oxygen on the bilirubin molecule making it insoluble in water.
How is the hydrogen bonds in bilirubin disrupted?
By enzyme-catalysed esterification of the carboxylic acid group with a glycosyl moiety - glucuronic acid.
Which of the two is toxic to cells conjugated or unconjugated bilirubin?
unconjugated bilirubin because it is insoluble in water so can’t be excreted via urine, so levels can increase leading to toxicity.
what is unconjugated bilirubin?
bilirubin that isn’t glucuronidated.
Where is unconjugated bilirubin found?
circulating in the plasma reversibly bound to albumin
Which of two, conjugated or unconjugated can be excreted into urine?
conjugated
Why is conjugated bilirubin able to be excreted into urine?
because it is soluble in water unlike the unconjugated form
why is there more albumin-bound bilirubin than unbound bilirubin in plasma?
coz albumin concentration exceeds that of bilirubin concentration so more is bound but also non-toxic (aka conjugated)
How does the uptake of bilirubin happen at hepatocytes?
- at the sinusoidal surface of hepatocytes, bilirubin dissociates from albumin
- it is taken up by facilitated diffusion requiring inorganic ions e.g. Cl-
- via a transporter that is a member of the organic anion transport protein family (OATP2)
What happens once bilirubin enters the hepatocytes?
-unconjugated bilirubin is glucuronidated by esterification of the carboxylic acid groups forming bilirubin di/monoglucuronide.
What catalyses the esterification of unconjugated bilirubin?
-this reaction is catalysed by uridine diphosphoglucuronate glucuronosyltransferase (UGT) isoform, UGT1A1
What happens once the unconjugated bilirubin becomes conjugated bilirubin?
it is secreted into the biliary canaliculi and bile in a unidirectional transport so that the conc in bile is higher than the conc in the hepatocyte. This process is energy dependent (active transport)
Conjugated bilirubin isn’t absorbed in the intestines, so what happens instead?
it is degraded by intestinal bacteria generating urobilinogen.
What colour is urobilinogen?
-colourless
What is the oxidation product of urobilinogen and what effect does it have on stool and urine colour?
- the oxidation product is urobilin
- it contributes to the colour of normal urine and stool
What is most urobilinogen oxidised to and how is it excreted?
- stercobilin
- excreted in faeces, although a small amount of it enters extrahepatic circulation and excreted in urine
Why do people get pale, clay-coloured stool during severe post-hepatic jaundice or complete obstruction of bile duct?
-coz the urobilinogen and urobilin are absent in urine and stool
What happens to urinary urobilinogen excretion if an individual has a liver disease and increased bilirubin production?
urinary urobilinogen excretion is increased.
What percentage of urobilinogen is oxidised to stercobilin and excreted in faeces?
80%
What percentage of urobilinogen enters te extrahepatic circulation and is excreted in urine?
20%
How is bilirubin formed in circulation?
- erythrocytes are broken down and haemoglobin is released
- 90% of haemoglobin is removed from the circulation by phagocytic activities of macrophages in the liver, spleen and lymph nodes
- 10% of haemoglobin remains in the circulation
- Globin is metabolised to amino acids which are recycled
- iron binds to transferrin and returns to liver stores
- haem is converted to bilirubin which binds to albumin and is insoluble.
4 types of jaundice?
- neonatal
- haemolytic
- hepatocellular
- obstructive
what is neonatal jaundice?
- bilirubin accumulates because bilirubin glucuronyl transferase levels are low at birth so bilirubin can’t undergo esterification as rapidly.
- so unconjugated bilirubin levels increase in blood
- bilirubin-albumin complex difuse into basal ganglia and cause toxic encephalopathy
How is neonatal jaundice treated?
-expose newborn skin to blue fluorescent light converting bilirubin to a more water-soluble isomer. These isomers can be excreted into bile without conjugation to glucuronic acid.
What is haemolytic jaundice?
-when excessive red blood cells undergo lysis so bilirubin is produced at a faster rate than it is conjugated.
What are the effects of haemolytic jaundice?
- blood unconjugated bilirubin levels increased
- urine urobilinogen increases and no bilirubin in urine. so urine is at normal colour
- stool has normal colour
What is hepatocellular jaundice?
- liver damage by hepatitis.
- so bilirubin isn’t conjugated efficiently
- and conjugated bilirubin isn’t efficiently secreted into bile
What is the effect of hepatocellular jaundice?
- increased both conjugated and unconjugated bilirubin levels in blood
- ALT and AST levels increased
- bilirubin present in urine causing urine to be yellow/brwn
- stool is normal to pale colour due to low levels of stercobilin.
What is obstructive jaundice?
- When the bile duct is obstructed preventing conjugated bilirubin from passing to the intestine
- instead it is passed to the blood increasing circulatory conjugated bilirubin
Effect of obstructive jaundice?
- increased conjugated bilirubin in blood
- gamma-GT and ALP conc increase (but ALT is normal or mildly increased)
- bilirubin in urine causing yellow/brown urine
- urobilinogen reduced as obstruction blocks urobilinogen entering urine
- stool is pale
If stool is pale and urine is dark, what type of jaundice is caused?
post-hepatic
If stool isn’t pale and urine isn’t dark, what type of jaundice is caused?
pre-hepatic and hepatic
if a patient has post hepatic jaundice and have fatty food intolerance, what could be causing the jaundice?
Gallstones
if a patient has post hepatic jaundice and have a tender swollen abdomen, what could be causing the jaundice?
Liver damage
What can cause pre-hepatic jaundice?
- family history of bleeding
- disorders
- tendency to bleed
What can cause hepatic jaundice?
- IV drug abuse
- blood transfusion
- travel
- flu-like illness
- excess alcohol intake
- obesity
- drug history
(1st 4 cause hepatitis, next 2 cause cirrhosis or nonalcoholic steatohepatitis)
What blood tests can be done to test for jaundice?
- FBC (full blood count)- if there’s a low Hb, then suggest haemolysis occurring
- conjugated and unconjugated bilirubin levels
- Clotting factors (INR)
- Liver function tests
What is tested for in the liver function tests?
- Albumin levels
- Alanine transaminase (ALT) and Aspartate aminotransferase (AST) levels (hepatocyte markers)
- Alkaline phosphatase (ALP) and gamma-glutamyltransferase (GGT) levels (bile canaliculi markers)
What is tested for in the urine to test for jaundice?
- bilirubin levels
- urobilinogen levels
What is hepatitis?
inflammation of the liver
What is acute hepatitis?
-mild/transient changes in hepatic function due to inflammation developing quickly. Only lasts a short period of time and patient usually recovers
What is chronic hepatitis?
-when hepatic damage results in fibrosis and potentially cirrhosis. Can develop over number of years without appearance of acute hepatitis
What is viral hepatitis?
-can cause acute liver injury or chronic liver injury.
Common causes of viral hepatitis
Hepatitis A, B, C
Rare causes of hepatitis?
- Hep E
- Epstein-Barr virus
- yellow-fever virus
- herpes simplex virus
- cytomegalovirus
What type of virus is Hep A?
-RNA virus
How is Hep A transmitted?
Enterically transmitted faecal-oral spread
How is Hep A treated?
-no specific treatment but prophylactic anti-HAV immunisation can be given to people with high risks of developing HepA or to patients with HepC.
Which has a more sever liver damage, Hep A or E
Hep E due to complication by cholestasis
How is Hep E transmitted?
-not transmitted person-to-person like hep A, instead more to do with infected water supplies
Difference in immunity between Hep A and Hep E?
Hep A has a lifelong immunity unlike Hep E which isn’t lifelong
How is Hep E treated?
- No treatment but antiviral ribavirin is given in major liver diseases
- vaccine for Hep E in clinical trias
What type of virus is Hep B?
DNA virus
How does Hep B spread?
- blood
- blood products
- sexual
- vertically
How do we detect HepB infection?
identifying Hep B surface antigen (HBcAg) in serum
How does Hep B damage the liver
By an antiviral immune response
What is chronic Hep B?
Persistence of HBsAg in serum for 6 months or more after acute infection. If treatments don’t work, can do a liver transplant.
How does interferon alpha-2a work in the treatment of HepB?
- mimics interferons (glycoprotein cytokines) produced by virus-infected cells and binds to the cell surface reeceptor stimulating proteins that inhibit viral mRNA translation.
- this inhibits viral replication and augments viral clearance from hepatocyte
Side effects of interferon alpha-2a?
- headache
- myalgia
- tremors
- fever
- delayed bone marrow suppression
Why are nucleoside analogues used to treat HepB?
-used if interferon unsuccessful, poorly tolerated, contraindicated or patient relapses after successful interferon treatment.
Types of nucleoside analogues?
- lamivudine
- adefovir dipivoxi
- entecavir
side effects of lamivudine?
can cause muscle disorders
side effects of adefovir dipivoxi
can cause renal failure
Pharmacokinetics of nucleoside analogues in the treatment of hepB?
- well absorbed in GI system
- inactive prodrugs metabolised intracellularly to active phosphorylated drug
- eliminated via kidney
What is the difference between the make up of nucleosides and nucleotides?
Nucleosides consist of:
- a nucleobase (purine or pyrimidine - GCAT)
- linked to a sugar molecule
Whereas nucleotides have both of those plus a phosphate group linked to the sugar.
What is the mechanism of action of antiviral nucleosides?
- the nucleoside undergoes phosphorylation by nucleoside kinase.
- a second phosphorylation step is performed by nucleoside monophosphate kinase
- a third phosphorylation step by nucleoside diphosphate kinase
- nucleoside triphosphates compete with deoxynucleotide triphosphates for binding to reverse transcriptase.
- This reduces RNA and protein synthesis.
What type of virus is Hepatitis C?
RNA virus
How is HepC transferred?
- blood
- blood products
- sexually
How is HepC treated?
- no vaccine for HepC
- use uridine nucleotide analogue to inhibit virus polymerase protein (NS5B) preventing viral replication
- used in conjunction with ribavirin
- effectiveness of treatment depends on strain of virus and stage of disease.
- can use protease inhibitors
- can do a liver transplant
What is autoimmune hepatitis?
when the body’s antibodies attack the liver hepatocytes
What does autoimmune hepatitis cause?
- jaundice
- right upper quadrat pain
- other autoimmune conditions
What is the test for type 1 autoimmune hepatitis?
identifying anti-smooth muscle antibodies (80%) and anti-nuclear antibodies (10%)
What is the test for type 2 autoimmune hepatitis?
- more common in children
- identifying anti-liver/kidney microsomal type 1 antibodies
What investigation can be carried out for both type 1 and 2 autoimmune hepatitis?
a liver biopsy
What is used to treat autoimmune hepatitis?
- immunosuppressants (e.g. steroids and azathioprine)
- cyclosporine (in corticosteroid resistant disease)
- tacrolimus (in corticosteroid resistant disease)
- mycophenolate (in corticosteroid resistant disease)
- transplant
What is cirrhosis?
when hepatocytes are replaced by non-functional connective tissue due to scarring of the liver caused by many forms of liver diseases and conditions.
What happens to the elimination of drugs if an individual has cirrhosis?
-elimination reduced due to significant liver dysfunction and systemic blood levels of drug higher for longer and can result in toxicity
What two things does cirrhosis not increase?
- susceptibility to idiosyncratic drug reactions
- likelihood of autoimmune-mediated drug reactions
Portal vein hypertension and shunting of blood around the liver are as a result of cirrhosis. What does this mean for drug clearance?
it means greater level of drugs delivered to systemic circulation and increased levels of high clearance drugs
Causes of cirrhosis?
- alcohol
- drugs and xenobiotics
- chronic viral hepatitis
- autoimmune hepatitis
- chronic bile duct blockage
- Wilson’s disease
- Haemochromatosis
What is wilson’s disease?
abnormal storage of copper
What is Haemochromatosis?
Abnormal storage of iron
What is sclerosing cholangitis?
when the bile duct outside the liver is narrowed and blocked
Signs and symptoms of cirrhosis?
- fluid retention and oedema in legs and abdomen
- gallstones
- coagulation defects
- peripheral neuropathy
- reduced mental function
- jaundice
- oesophageal and gastric varices and bleeding
What are the pharmacological treatment methods for treating cirrhosis?
- cessation of alcohol consumption
- for oedema: salt restriction and treat with diuretics to reduce
- for chronic hepatic encephalopathy: give a laxative to reduce colonic production of neurotoxins and an oral antibacterial to reduce bacterial ammonia production.
- for variceal haemorrhage: platelet transfusion (to treat impaired coagulation), vasopressin analogue (to reduce hypertension), endoscopic tissue glue, endoscopic variceal injection with sclerosant.
What causes alcohol-induced hepatocellular steatosis (AIHS)?
- when too much NADH is produced by alcohol dehydrogenase and acetaldehyde dehydrogenase leading to increased lipid biosynthesis
- resulting in the assembly and secretion of lipoproteins
- and increased peripheral catabolism of fat
What is hepatic steatosis?
when lipid droplets accumulate in hepatocytes
What are the 2 histologic types of hepatic steatosis?
- microvesicular
2. macrovesicular
What is required in order to reverse hepatic steatosis?
-abstention (restraint in alcohol consumption)
What part of the liver lobule does hepatic steatosis occur?
starts centrilobular then later becomes panlobular
What is the pathogenesis of alcohol liver disease?
- alcohol-induced hepatocellular damage
- alcohol-induced fibrosis
- malnutrition
- vitamin deficiencies
- impaired digestive function (damage to gastric and intestinal mucosa)
How does alcohol cause hepatocellular damage?
- cytochrome p450 is induced generating free radicals
- microtubular and mitochondrial function and membrane fluidity affected by alcohol
- acetaldehyde induced lipid peroxidation and acetaldehyde-protein adduct formation hence disrupting cytoskeletal and membrane function
- antigenic alteration of hepatocytes and hepatic proteins including immunologic attack
Symptoms of alcohol-mediated hepatitis?
- hepatocyte swelling due to fat and water accumulation and cell necrosis
- neutrophil reaction
- fibrosis
- Mallory bodies formed (cytokeratin intermediate filaments)
Symptoms of alcohol-mediated cirrhosis?
- liver shrinks and non-fatty
- fibrous septa become thicker and extend through sinusoids
- regenerative nodules with entrapped hepatocytes
Clinical features of all 3 alcohol liver diseases?
Hepatic Steatosis: -asymptomatic -mild increase in serum bilirubin and ALP levels Alcoholic hepatitis -nonspecific symptoms - increase in serum bilirubin, ALP and WBCs levels Alcoholic Cirrhosis -same as alcoholic hepatitis
