Liver Function Tests Flashcards
Write a note on the anatomy of the liver
(4)
A right and a left lobe
Sheets of hepatocytes embedded in capillary network
The liver has a dual blood supply - the portal vein and the hepatic artery
The liver has a huge regenerative capacity
What does the portal vein do?
It brings blood to the liver from GIT (low oxygen: high nutrients)
What does the hepatic artery do?
It supplies the liver with oxygen
List the functions of the liver
(4)
Synthesis
Storage
Detoxification and excretion
Metabolism
What does the liver synthesise
(8)
Carbohydrates
Proteins
Bile acids
Fatty acids
Cholesterol
Lipoproteins
Active vitamin D (calcitriol)
Clotting factors
The liver synthesises carbohydrates, write a note on this function
(5)
The liver uses glucose for its own cellular energy
The liver circulates glucose to peripheral tissue
The liver stores glucose as glycogen
The liver is a major player in maintaining stable glucose concentration due to glycogenesis, glycogenolysis and gluconeogenesis
Thus the liver is responsible for the synthesis, storage and release of glucose
The liver synthesises lipids, write a note on this function
(5)
The liver gathers free fatty acids from diet and breaks them down to Acetyl-CoA to form triglycerides, phospholipids or cholesterol
It converts insoluble lipids to soluble forms
The liver produces 70% pf cholesterol
It synthesises HDL, LDL and VLDL
Thus both degradation and synthesis of fats takes place in the liver
What does the liver do to free fatty acids
It breaks them down to Acetyl-CoA
What forms of cholesterol are formed by the liver?
(3)
HDL
LDL
VLDL
What does the liver do to insoluble lipids?
It converts insoluble forms to soluble forms
What % of cholesterol is produced by the liver?
70%
The liver produces proteins, write a note on this function.
(2)
The liver produces nearly all proteins bar immunoglobulins and haemoglobin
The liver synthesises enzymes and clotting factors
Write a note on the detoxification function of the liver
(3)
The liver has an immune function, Kupffer cells which serve as a gatekeeper between the circulation and absorbed substances
The liver detoxifies drugs and poisons and metabolic products like ammonia, alcohol and bilirubin
The liver can inactivate hormones such as cortisol, aldosterone, insulin, glucagon and testosterone
What are the immune cells of the liver?
Kuppfer cells
What can the liver detoxify?
(5)
Drugs
Poisons
Ammonia
Alcohol
Bilirubin
What hormones can the liver inactivate?
(5)
Cortisol
Aldosterone
Insulin
Glucagon
Testosterone
How does the liver detoxify chemicals?
(3)
By binding to material to reversibly inactive them
By chemically modifying compounds for excretion
Drug metaboliser for detoxification of drugs and poisons
The liver is responsible for ammonia metabolism and excretion, write a note on this
(3)
Ammonia must be carefully controlled because its toxic to the CNS and is freely permeable across the blood brain barrier
The liver is the only organ in which the complete Krebs cycle is expressed
In this ammonia is converted to urea which is much less toxic, water soluble and easily excreted in urine
What is ammonia converted to which is less toxic?
Urea
What does the liver store
Glycogen
Proteins
Vitamins A, B12 and C
Iron
The liver synthesises bile, write a note on this function
(5)
Bile is important for fat digestion and is also a route of excretion from the body
Bile consists of water, bile salts, cholesterol, phospholipids, electrolytes and bile pigments which give its typical yellowy-green colour
Bile is made up of bile salts, bile pigments and other substances dissolved in alkaline electrolyte solution
Metabolic wastes and drug products may form part of the bile which can be excreted from the body through the digestive tract in the faeces
e.g. bilirubin, the toxic end product of haemoglobin breakdown is excreted from the body in this way
What does bile consist of
Bile consists of water, bile salts, cholesterol, phospholipids, electrolytes and bile pigments which give its typical yellowy-green colour
Bile is made up of bile salts, bile pigments and other substances dissolved in alkaline electrolyte solution
How does bile act as a method of excretion and give an example of this method of excretion
(2)
Metabolic wastes and drug products may form part of the bile which can be excreted from the body through the digestive tract in the faeces
e.g. bilirubin, the toxic end product of haemoglobin breakdown is excreted from the body in this way
List some of the manifestations of liver disease
(6)
Jaundice
Portal hypertension
Bleeding oesophageal varices
Ascites
Altered drug metabolism
Liver failure
What is portal hypertension?
High pressure in the portal vein
What is bleeding oesophageal varices
Enlarged veins in the walls of the lower part of the oesophagus
What is ascites
Accumulation of fluid in the abdominal cavity
What is liver failure
Hepatic encephalopathy
What are the four applications of testing liver function
i.e. what are the four reasons for testing liver function
- Establish if an individual has liver disease (screening)
- Aid in making a specific diagnosis
- Establish the severity of liver damage once a diagnosis has been made
- Monitor the progression of liver disease and response to therapy
Write a note on the basis of testing liver function
(4)
Liver damage must be considerable to affect liver function
Liver function can only be assessed by means of functional assays
Liver function is assessed by looking at the ability of the liver to perform a task
True liver function tests are infrequently used
Explain why liver function is assessed by looking at the ability of the liver to perform a task
i.e. how do we measure liver function markers
We use clearance measurements of marker substances known to be metabolised by the liver
Why are true liver function tests infrequently used
(3)
They are time consuming
They are dependant on hepatic blood flow
There is huge variability
What are the two ways of non-biochemically investigating liver function
Imaging
Biopsy
What are some examples of imaging for liver function
(4)
Ultrasound scan
Endoscopic retrograde cholangiopancreatography (ERCP)
Computerised tomography (CT)
Magnetic resonance imaging (MRI)
What is endoscopic retrograde cholangiopancreatography (ERCP)
Imaging to examine the bile ducts and pancreatic ducts
What tests are used in a liver panel?
(7)
Albumin
Prothrombin Time
Bilirubin
Alanine aminotransferase (ALT)
Aspartate aminotransferase (AST)
Alkaline phosphatase (ALP)
Gamma glutamyl transferase (GGT)
Write a note on albumin
(4)
Synthesised mainly in the liver
Half life of 14-20 days
Long term marker of liver health
Poor marker in acute states
Write a note on prothrombin time to asses liver function
(2)
PTT measures measures the rate of conversion of prothrombin to thrombin in the presence of coagulation factors
It measures how long it takes a clot to form
Write a note on the formation of bilirubin
RBCs are destroyed in the liver, spleen and bone marrow
Haemoglobin is converted into haem and globin
Haem is converted into biliverdin through haem oxygenase
Biliverdin is converted into bilirubin through biliverdin oxidase
The bilirubin produced is hydrophobic and insoluble and transported to the liver in a complex with albumin (unconjugated bilirubin)
Where are rbcs destroyed
RBCs are destroyed in the liver, spleen and bone marrow
How is haemoglobin converted into bilirubin
(3)
Haemoglobin is converted into haem and globin
Haem is converted into biliverdin through haem oxygenase
Biliverdin is converted into bilirubin through biliverdin oxidase
What is unconjugated bilirubin?
The bilirubin produced from the breakdown of haemoglobin is hydrophobic and insoluble and transported to the liver in a complex with albumin (unconjugated bilirubin)
How is unconjugated bilirubin converted to conjugated bilirubin?
(4)
The hepatocytes conjugate bilirubin i.e. hepatocytes take up conjugated bilirubin
Water soluble conjugated bilirubin is taken up by the liver this is brought to the small intestine
Bacteria in the intestine deconjugate the bilirubin
Some unconjugated bilirubin is reabsorbed, the remainder is excreted
What is the equation for total bilirubin?
Unconjugated and conjugated bilirubin
What are gallstones
Deposition of cholesterol or bilirubin in the gallbladder or in the common biliary duct
How are gallstones treated
Treatment is cholecystectomy (gall bladder removal) or sometimes endoscopic approaches to remove stones from common biliary duct or sphincter of Oddi
What are the consequences of gall bladder removal?
Inability to concentrate bile, which affects fat absorption, and fatty meals may need to be avoided
What method is used to determine bilirubin concentration?
The Diazo Method
What is the Diazo method?
A chemical method to determine bilirubin concentration
What is the principle behind the Diazo method?
(4)
Diazotised sulfanilic acid + bilirubin -> two azodipyrroles
This produces a reddish-purple at neutral pH and blue at low/high pH
This measures the conjugated bilirubin (direct bilirubin)
An accelerant can be added to the reaction to measure total bilirubin
How can you determine unconjugated bilirubin (indirect)?
Total bilirubin - conjugated bilirubin
What should you do if total bilirubin is elevated
You can do a differential measurement to determine if conjugated or unconjugated bilirubin is elevated
What are the main characteristics of unconjugated bilirubin
Indirect bilirubin
Fat soluble
Can cross the blood brain barrier when in excess
What are the main characteristics of conjugated bilirubin?
Direct bilirubin
Water soluble
What is the basis of liver function tests
(2)
We measure an analyte produced by hepatocytes, which is known to change in response to hepatocyte damage
Common LFTs include markers of liver damage rather than function
List the first line LFTs
(7)
Total protein
Albumin
Bilirubin
ALT
AST
ALP
GGT
What are the benefits of running LFTs?
(5)
Cheap
Reliable
Non-invasive
Direct the use of other more expensive/invasive tests (scans, biopsy)
Useful in detecting liver problems and following progression
What are the two types of liver damage?
Hepatocyte damage pattern
Obstructive pattern (cholestasis)
What LFTs indicate hepatocyte damage pattern?
Alanine aminotransferase (ALT)
Aspartate aminotransferase (AST)
What LFTs indicate obstructive pattern (cholestasis)
Gamma glutamyl transferase
Alkaline phosphatase
Bilirubin
Some LFTs measure liver enzyme levels, these are markers of hepatocellular damage, how does measuring theses markers work?
(4)
Enzymes are inside the hepatocytes
Damage to hepatocytes results in leakage into blood
Serum levels of enzymes increase
These markers are surrogate markers of liver damage
Why is it important to carry out a panel of LFTs and not just a single test?
We need to be able to look at multiple LFTs and recognise patterns which are associated with different pathological pictures
Write a note on ALT and AST
(3)
These are sensitive biomarkers of hepatocyte damage but they’re not very specific
Useful for monitoring, indicates worsening or improvement
Assays share common indicator reaction -> decrease in NADH is detected at 340nm
Liver function enzyme assays are sensitive, what does this mean?
(2)
They increase plasma activity with relatively very few damaged cells
i.e. very little damage needs to have occurred for an elevated liver enzyme test
Liver enzyme tests are not very specific, what does this mean
(3)
Both enzymes have wide tissue distribution i.e. they are found in liver, heart, muscle and rbcs
ALT has less activity in extra-hepatic tissues than AST so it is considered more specific for liver damage
Elevation in enzyme activity need to be considered in light of other tests, signs and symptoms
Where is ALP expressed
(5)
Liver
Bone
Placenta
In adults, most circulating ALP is derived from liver
In liver cholestasis induces synthesis
In children, most circulating ALP is derived from bone
What is the principle behind measuring ALP
ALP activity liberates paranitrophenol (yellow product) from the artificial substrate paranitrophenol phosphate (substrate)
Write a note on gamma glutamyl transferase
(6)
Located in cell membranes
Expressed in liver, kidneys, pancreas, intestine
Can be elevated in all forms of liver disease
Elevated in cholestasis
Elevated GGT is a classic marker of alcohol use
Useful to measure alongside ALP when the origin of ALP is uncertain
What is cholestasis?
Any condition in which the flow of bile from the liver is slowed or blocked
Why is elevated GGT a classic marker of alcohol use?
Alcohol can induce expression of GGT without damage
How is GGT measured?
Direct assay based on production of p-nitroanilide (yellow) from artificial substrate
Why is bilirubin measured
To diagnose jaundice
Why is bilirubin fractionation measured
To distinguish conjugated from unconjugated hyperbilirubinaemia
Why is ALP measured?
Diagnosing cholestasis
Why is AST measured
Diagnosing hepatocellular damage
AST>ALT in alcoholic disease, cirrhosis
Why is ALT measured
Diagnosing hepatocellular disease
Why is albumin measured
Indication of how chronic or severe
Why is prothrombin time measured
Indication of severity
What are the tell tale signs of liver damage
(3)
Jaundice
Hepatomegaly
Upper right quadrant pain
What are six different types of liver disease?
Acute hepatitis
Chronic hepatitis
Liver failure (acute versus chronic)
Cholestasis
Non-alcoholic fatty liver disease
Cirrhosis
What does hepatitis do to the liver
(3)
Irritation/inflammation of the liver
Acute or chronic forms recognised
Chronic can be persistent or active
What may cause hepatitis - inflammation of the liver?
(5)
Viral and non-viral infections
Drugs and toxins (e.g. paracetamol overdose, alcohol)
Ischemia (lack of oxygen; hypoxia)
Autoimmune
Genetic disorders
What are the timeline of events in hepatitis?
(4)
Injury to liver cell
Cell damage or death
Release of cytosolic enzymes to plasma
Increased activity of AST and ALT in plasma
Write a note on how viral infections cause acute hepatitis
(4)
Hepatitis A, B, C, Epstein-Barr Virus, Cytomegalovirus cause hepatitis
Generally very mild and self-limiting
80% remain undiagnosed
Flu-like symptoms; fatigue, malaise, myalgia and loss of appetite
Write a note on how toxic damage cause acute hepatitis
Alcohol, drugs e.g. paracetamol or chemicals cause hepatitis
How does hepatitis lead to acute liver failure?
This happens when the rate of damage is greater than the capacity to regenerate
What causes jaundice?
Hyperbilirubinaemia
What is hyperbilirubinaemia?
(3)
Increased level of bilirubin in plasma
Yellowing of the skin and eyes due to bilirubin deposition
Need to measure if elevated conjugated or unconjugated bilirubin
What indicates conjugated bilirubin?
Dark urine
What causes an excess production of total bilirubin?
Pre-hepatic damage e.g. problem with bilirubin synthesis
What indicates hepatocyte damage?
Failure of conjugation/excretion
What indicates obstruction?
Blockage
Post-hepatic or cholestatic bilirubin
What indicates obstruction?
Blockage
Post-hepatic or cholestatic bilirubin
What are the three classifications of causes of hyperbilirubinaemia?
Pre-hapatic
Hepatic
Post-hepatic
What indicates a pre-hepatic cause for hyperbilirubinaemia?
Raised unconjugated bilirubin
What indicates a hepatic cause for hyperbilirubinaemia?
Raised unconjugated bilirubin
Raised conjugated bilirubin
What indicates post-hepatic cause of hyperbilirubinaemia
Raised conjugated bilirubin
What are the symptoms of pre-hepatic hyperbilirubinaemia
Haemolysis
Low plasma albumin
What are the symptoms of hepatic hyperbilirubinaemia
Hepatitis
Malignancy
Drug interactions
Excretion defect
What are the symptoms of post-hepatic hyperbilirubinaemia
(3)
Obstruction in the bile ducts e.g. gallstones, pancreatic carcinoma
ALP may also be up
Scans may be used to identify anatomical block
What are the diagnostic criteria for Non-Alcoholic Fatty Liver Disease?
(5)
Ultrasound scan of a fatty liver
Alcohol intake is within the recommended limits
Need at least one of the following: obesity, diabetes, high blood pressure, abnormal lipids
Gold standard method is a liver biopsy
ALT is elevated in NAFLD
What is the progression from obesity to carcinoma?
Obesity
NAFL
NASH
Cirrhosis
Hepatocellular carcinoma
What is steatosis?
The progression of fatty liver
How does steatosis progress
(4)
Normal numerous small fat vesicles -> nuclei are not displaced
Liver cells become engorged with fat nuclei displaced
NASH = inflammatory cells infiltrate tissue with or without fibrosis
Cirrhosis = disturbed architecture/fibrosis
What is NASH?
Non-alcoholic steatohepatitis
Write a note on cirrhosis
(4)
End-stage for many types of chronic liver disease
Hepatocytes become replaced by fibrous tissue
Architecture of liver becomes disrupted, this disrupts blood flow
Clinical signs due to vascular and hepatocellular effects
What are the three phases of cirrhosis?
(3)
Quiescent/compensated: no progression of disease
Active: ongoing cell death
Decompensation: severe damage; functional reserve exhausted, plasma albumin drops -> bad sign
Why is AST:ALT ratio important in Cirrhosis
The AST:ALT ratio is important to gauge the disease
As damage proceeds the capacity to synthesise and release ALT decrease
Ratio increases to above 1
What is unconjugated bilirubin converted to?
The conjugated form = glucaronic acid
