Liver Metabolism Flashcards
What are the liver metabolic contributions?
• Maintains acceptable plasma glucose
o Gluconeogenesis, glycogenolysis
• Synthesis & breakdown of plasma proteins
• Disposal of amino groups of AAs as urea
• Ketone body synthesis (upregulated in starvation)
• Catabolises ethanol
• Provides cholesterol for other organs (LDL)
• Breaks down haem
• Metabolises drugs
• Storage of vitamins & minerals
• Excretion of lipid soluble waste products (via bile)
Desribe some Liver function tests
Medical diagnostics
• Assess aspects of liver operation
Series of serum/plasma measurements :
o Enzyme activity (liver function tests – serum samples) • Alanine aminotransferases • Aspartate aminotransferases • Alkaline phosphatase • Gamma-glutamyl transferase
o Plasma protein concentrations
• Liver key in making certain plasma proteins
• Albumin, coagulation proteins, immunoglobulins
o Plasma bilirubin concentrations
Describe some of the livers role in protein metabolism
• Responsible for a number of key processes in protein metabolism
o Formation of plasma proteins, deamination, formation of urea, inter-conversion of amino acids, conversion of amino acids to other intermediates
• The liver is responsible for making key proteins (approx. 25g/day)
o Albumin, coagulation proteins, immunoglobulins
Albumin!
ALBUMIN
o T1/2 = 20 days (hence if liver isn’t making it will see a quick drop off)
o Most abundant plasma protein (approx. 40g/L)
Liver makes 9-12g/day
o Crucial in retaining fluid in blood vessels, transports hormones, metals, bilirubin, fatty acids & drugs
o If it is low => Oedema
Not making enough of the protein due to insufficient dietary protein (doesn’t have the aa substrates)
• Not functioning correctly
o No storage, no reserves, not catabolized in starvation
o Levels reflect long term nutritional status & liver function
How are amino acids metabolised by the liver?
Metabolism of nitrogen (urea cycle) requires:
• Aspartate aminotransferase (AST)
o Also found in RBC, cardiac and skeletal muscle, kidney, brain& lung
o If this is raised look for CK (skeletal muscle damage) or troponin (cardiac muscle damage)
• Alanine aminotransferase (ALT)
o Enzyme is specific to the liver, involved in urease cycling
o Increased in serum means it specific to liver rupture releasing this into serum
• Intracellular enzymes – normally low concentrations in serum
• An increase (20-100x) in serum levels of the enzymes may indicate liver cell damage (lysis of hepatocytes)
o Look at ALT/AST ratio
How is haem synthesised by the liver?
Haem Synthesis
• Haem is the prosthetic group of heamoglobin, myoglobin & cytochromes
o 85% of synthesis occurs in bone marrow at a constant rate
• For hb & oxygen transport around blood
o Haemoglobin = 4 proteins together, with 4 haem groups – the functionality of haem is determined by the protein structure that surrounds it (iron must be in 2+ state to carry oxygen)
o Liver also synthesises haem at a more variable rate, responding to alterations in cellular concentrations caused by demand for haem protein production
• Synthesised by using ALA synthase – so if we have low haem, ALA is upregulated.
• Haem is not a carb, lipid or protein. It is a ring structure with iron in the middle, which attaches to each of these rings (can be in a 2+ or 3+ form)
• Role of the haem group is dictated by the protein structure
o Oxidation-reduction reactions
• Eg: cytochrome P45 proteins
o Part of the active site of enzymes
• Eg peroxidase, catalase, NO synthase
o Reversibly binds oxygen
• Eg Haemoglobin, myoglobin
Explain CYP450!!
• One of the key liver families
• Coded for by 27 genes, 18 different families etc => over 11500 distinct CYP proteins
• Contains haem group
o around it is the protein structure that gives it the function
• Located on the smooth ER of cells (or mitochondrial membrane) with the largest concentrations in the liver
• Enzymes with low substrate specificity (infinite range of substances)
• Involved in metabolism of a wide variety of exogenous & endogenous compounds (chemicals) => may activate or deactivate
o Lipid metabolism
o Steroid hormones (eg testosterone, oestrogen)
o Fat soluble vitamins (hydroxylation of vitamin D3 to active form)
o Drug metabolism (activation or degradation)
o Toxic chemicals/xenobiotics
• Food, drugs, toxins which interfere with metabolism
Describe the process of haem degradation
Livers big role. RBCs damage quite easily, life span 120 days. Must recycle all the material that was in the RBCs (macrophages)
1. Haem – Ring cleavage
Requires Haem oxygenase, O2 & NADPH
Releases Fe3+ & CO
- Oxidised to Biliverdin
Green, water soluble molecule
3. Reduced to Bilirubin Free/unconjugated bilirubin Not water soluble Orangey colour Requires NADPH and Biliverdin reductase Not very water soluble therefore travels in blood with albumin ⇒ liver
This bilirubin is free/unconjuged
• Not very soluble hence travels in blood with albumin to the liver for processing
Bilirubin in the liver
• Bilirubin (unconjugated) enters the hepatocyte by facilitated diffusion (need concentration gradient)
• Two molecules of glucuronic acid are added to bilirubin forming bilirubin diglucuronide
“Conjugated” bilirubin
Requires glucoronyl transferase
Increases solubility of bilirubin
• Bilirubin diglucuronide is actively transported into the bile canaliculi ⇒ bile
Energy dependent and rate limiting step
Describe bilirubin in the SI
‘Conjugated bilirubin’ (bilirubin diglucuronide) released with bile into SI
Hydrolysed to Unconjugated bilirubin
This is reduced by intestinal bacteria => urobilinogen
Urobilinogen
o Oxidised by intestinal bacteria => Stercobilin (brown colour) => excreted in faeces
o May circulate to the kidney producing a brownish coloured urobilin which is excreted in the urine
Hence there are a number of ways you can get rid of bilirubin.
What is the cause of jaundice? and what are the types?
• Caused by an imbalance between bilirubin production & excretion
o Prehepatic/haemolytic jaundice
o Hepatic/hepatocellular jaundice
o Post-hepatic/obstructive jaundice
Explain prehepatic/haemolytic jaundice
Increased production of bilirubin
Increased haemolysis o Sickle cell anaemia o Defective RBC metabolism o Infection o Autoimmune disease
Production exceeds livers capacity to conjugate & excrete bilirubin
Results in elevated levels of unconjugated bilirubin levels in the blood
o Conjugated levels may also rise, with increased urinary and faecal urobilinogen levels
Explain Hepatic Jaundice
Impaired ability to conjugate bilirubin
Caused by damage to the liver cells
o Cirrhosis, hepatitis, drugs, autoimmune, neonatal
• Increased blood concentrations of unconjugated bilirubin
o Conjugated levels in blood may also rise
o Usually associated with increased serum alanine aminotransferase (ALT) – indicative of liver damage
• Increased urobilinogen in urine
o Hepatic damage decreases enterohepatic circulation ⇒ more in blood ⇒ More excreted in urine
o Urine darker, stool may be a pale clay colour
explain neonatal jaundice
• Affects 50% of normal babies
Low activity of bilirubin glucuronyl transferase at birth
o Bilirubn production exceeds liver capacity to conjugate
o If bilirubin levels exceed capacity of albumin it may diffuse into the basal ganglia causing toxic encephalopathy
• Normal after 4 weeks
• Treated with blue florescent light
o Converts bilirubin to a more water soluble isomer which can be excreted in bile without the need for conjugation
Explain post hepatic/obstructive jaundice
• Due to obstruction of the bile duct
o Tumour, gallstones
• Causes an accumulation in the bile duct ⇒ spills back into the blood
• Increased conjugated bilirubin in blood (hyperbilirubinemia) and is excreted in urine (as bilirubin, not urobilinogen)
o Pale stool
o No enterohepatic circulation ⇒ no urinary urobilinogen
o The conjugated bilirubin is merely absorbed into the kidneys and excreted (unconjugated bilirubin bound to albumin cannot be filtered through as albumin is too big)
• Associated increase in serum alkaline phosphatase (ALP)
o Enzyme concentrated in liver & bile duct (also kidney, bone & placenta)
o If raised indicates it has spilled back
