Structure And Function Of The Liver Flashcards
What is the nature if the blood supply to the liver?
DUAL supply to the liver
- 2/3 from portal vein (i.e from gut = nutrients/substances for
metabolism)
- 1/3 from hepatic artery (supplies O2 from the heart)
Blood from the liver is via the hepatic vein
- drains into inferior vena cava which sends blood from the body back
to the heart
What is the structure of the liver lobules?
Made up of acini = the functional units
Portal triad is the bile duct the hepatic artery and the portal vein, but there are also the vagas nerves and the lymph system within the liver lobules.
Blood flows from portal vein delivering blood to hepatocytes. Bile is synthesised in hepatocytes, then drains into bile caniliculi and bile duct.
Also hepatic sinusoid spaces, through which blood flows to the central vein, are rich with macrophages called kupffer cells, these have an important detoxifying function - detoxify blood before it goes back into circulation.
Also the central vein where the arterial blood drains.
What are the hepatocytes?
- Cubic cells ~15um2 , Rich in smooth ER (and mitochondria)
- Average life span = 5 months
- Able to regenerate - compensate for damage, such as that form alcohol
Layers of hepatocytes are separated from the sinusoid spaces by epithelial cells. Solutes can pass across the sinusoidal space and through the intercellular junctions (between cells) into the space of disse.
This has fat storage cells (stellate) within, that can transform into fibroblasts cells that deposit collagen leading to fibrosis and cirrhosis.
But space is important for draining lymph into the hepatic system.
What are the major functions of the Liver?
Carbohydrate metabolism Fat metabolism Protein metabolism Hormone metabolism Drug/toxin metabolism & excretion Storage Metabolism and excretion of bilirubin Synthesis of proteins
How is carbohydrate metabolism performed?
Glycogenesis - how energy is stored
Excess glucose → glycogen
Glycogenolysis - when glucose levels are low
Glycogen → glucose
Gluconeogenesis - glucose generation from non-carbohydrates
Amino acids/lactate/glycerol → glucose
Balance of these maintains glucose homeostasis
How is fat metabolism performed?
Triglyceride oxidation → energy
Lipoprotein synthesis
Excess carbohydrate & fat → fatty acids & trigs → stored in adipose tissue
Cholesterol (& phospholipid) synthesis & excretion (only route by which cholesterol leaves the body in significant amounts)
How is protein metabolism performed?
Deamination and transamination of amino acids
- Non-nitrogenous part → glucose or lipid
- Nitrogenous part → ammonia → urea (urea cycle)
Which proteins are synthesised in the liver?
Plasma protein synthesis:
- Albumin (maintains oncotic pressure)
- Fibrinogen/Prothrombin (& other clotting factors)
- Lipoproteins (transports lipids)/Caeruloplasmin (transports copper)/
Transferrin (transports iron)/ CRP (response to acute infection)/α1AT
(protease inhibitor)/αFP (important in foetuses - instead of albumin) - Synthesis of non-essential amino acids
Which hormones are metabolised in the liver?
Insulin-like Growth Factor-1 (IGF-1) - required in developing children
Angiotensinogen - substrate for renin (BP regulation)
Thrombopoeitin - regulates synthesis of platelets
Hepcidin - regulates Fe levels
How are drugs/toxins metabolised in the liver?
Phase I reactions: Intro/unmask functional group
- Oxidation (Cytochrome P450)
- Reduction
- Hydrolysis
Phase II reactions:
- Glucuronide/Acetyl/Methyl
- Glutathione
- Glycine/Sulphate
Usually necessary to achieve renal excretion
What species are stored in the liver?
Glycogen
Vitamins A, D & B12
Iron & Copper
How is bilirubin metabolised and excreted?
Haem Proteins (15%) ]
+ ]
Senescent RBCs (80%) ] -> heam
+ ]
Ineffective erythropoiesis (5%) ]
Haem -> Biliverdin -> Bilirubin -> Bilirubin glucuronide
| | |
Haem oxygenase Biliverdin reductase Glucuronyl transferase
Biliverdin glucuronide (H2O soluble) -> Biliary excretion
OR
Renal excretion
What is the nature of liver function tests?
- Albumin
- Total Protein
- Bilirubin
- Alkaline Phosphatase (ALP)
- Alanine aminotransferase (ALT)
- Aspartate aminotransferase (AST)
- Gamma glutamyl transferase (GGT
Pattern rather than single analyte result
Abnormal ‘LFT’ not just in primary hepatic disorders
- Heart failure
- Sepsis
- Infection/inflammation
What does abnormal albumin actually show?
Crude indicator of the synthetic capacity of the liver
Liver synthesises 12g albumin per day
Half-life ~20 days (won’t show acute changes)
Maintains plasma oncotic pressure
Binds several hormones, drugs, anions and fatty acids
Decreases in the acute phase response (APR) - in infection/inflammation it moves intracellularly, so low levels aren’t necessarily due to reduced synthesis
What does abnormal total protein actually show?
Very little utility in liver function assessment
Reflects balance between synthesis & degradation
Often allows calculation of globulin fraction
- Globulin = Total Protein - Albumin
What does abnormal Bilirubin actually show?
Total Bilirubin
Direct/Conjugated Bilirubin - measured if you see a high total
Differentiate between intra-hepatic (eg liver metastasis or hepatitis) and extra obstruction (eg gall stones)
- Intrahepatic: Liver metastases, Hepatitis
- Extrahepatic: Gall stones,carcinoma of head of pancreas
High bili becomes obvious by causing jaundice:
- Visible at ~3XULN (50µmol/L)
- Unconjugated bilirubin crosses blood-brain barrier in neonates (hasn’t
formed yet) = if crosses it causes brain damage ‘kernicterus’
What is the difference between conjugated Bilirubin and unconjugated Bilirubin?
Unconjugated:
- Not water soluble=protein bound
- Not filtered at the glomerulus
- Hence does not reach the urine
- Haemolytic states
- Gilbert’s (inherited defect in UDP glucuronyl transferase - low
levels of enzyme that binds bilirubin = benign)
Conjugated:
- Water soluble
- Filtered at the glomerulus
- Hence reaches the urine= bilirubinuria
- Pathological
- Intra or extra hepatic obstruction
What does urobiligen tell us about the kidneys function?
When bilirubin reaches the gut it gets converted to urobilinogen by gut bacteria. This gets absorbed from the distal small intestine and excreted in the urine.
If urobilinogen present in urine, shows that bilirubin is reaching the gut = no obstruction
High plasma bilirubin & No urobilinogen in urine = bilirubin is not reaching the gut (cholestasis)
What does abnormal ALP actually show?
Maximum activity in pH 9-10.5 (alk range)
Removes phosphate from molecules including proteins & nucleic acids
Isoenzymes (Liver, Bone, Intestinal & Placenta)
Age dependent reference range
Liver: sinusoids & endothelium of central & periportal veins
Secreted by cells lining biliary tract
Enhanced synthesis/inducible enzyme
Raised in bone disease (↑osteoblast activity)
Raised during growth, pregnancy (different reference ranges apply)
ALP electrophoresis to determine source
What does abnormal ALT actually show?
Catalyses transfer of amino group from alanine residues
Present in wide range/All tissues - unspecific
Cytosolic
What does abnormal AST actually show?
Catalyses transfer of amino group from aspartate residues
Present in wide range/All tissues
Cytosolic and mitochondrial
High levels in heart, liver, skeletal muscle, kidney, lung & red blood cells - very unspecific
Also found in significant amounts in brain, gastric mucosa & adipose tissue
which is a better marker of liver disease, ALT or AST?
Indicators of hepatocellular damage
ALT more specific for liver than AST
AST 80% mitochondrial, 20% cytosolic - really must damage cells to access mitochrondrial AST. Whereas ALT is in cytoplasm so spills out of damaged cells more easily
High AST also seen in MI, muscle injury & CCF
ALT:AST ratio often used:
- ALT:AST >2
- Viral hepatitis
- Infectious hepatitis
- Drugs/toxins
- NASH
- Intra/extrahepatic obstruction
- ALT:AST <2
- ALD
- Cirrhosis
- Metastatic liver disease
What does abnormal GGT actually show?
Catalyses transfer of gamma glutamyl group from peptides to appropriate acceptors
Located in cell membrane of various tissues; mainly kidney, liver, biliary tract & pancreas
Found in hepatocytes & biliary epithelial cells
Kidney contains largest amount but is not released into plasma
Indicator of obstruction (intrahepatic/biliary)
Enhanced synthesis/inducible enzyme
Unregulated when people take alcohol & anticonvulsants
Useful in conjunction with ALP
- ↑ALP measured alone - ?liver/bone/other
- ↑ALP & ↑GGT – suggests hepatic cause
- ↑GGT & Normal ALP – alcohol intake
What are ‘function tests’?
Bromosulphthalein (BSP) clearance
Give as bolus, conjugated by liver for excretion, measure decrease in plasma levels
Indocyanine green
Administered intravenously, not conjugated but excretion is dependent on liver function
14C aminopyrine breath test
Given orally. Test based on cleavage of methyl group. Indirect measure of functional hepatic microsomal mass. Measures 14CO2 exhaled in breath
