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functions-of-the-liver-lft
1. PHYSIOLOGICAL FUNCTIONS
OF THE LIVER
Varun kumar Varshney
Department of Anaesthesiology & critical Care
JAWAHARLAL NEHRU MEDICAL
COLLEGE,ALIGARH
2. • Liver is the largest internal organ & largest gland in
the human body.
• Liver is at the epicenter of intermediary metabolism.
• It performs versatile & massive biochemical pathways.
• It destroys bacteria, inactivate antigens, detoxify harmful
chemicals.
• Thus multiple & diverse functions of liver have an impact
on every tissue in the body.
3. Physiological functions of liver
• Intermediary metabolism
a. Carbohydrate metabolism
b. Lipid metabolism
c. Bile metabolsim and entero- hepatic circulation
d. Protein metabolism
• Coagulation
• Heme metabolism
• Bilirubin metabolism
• Xenobiotics metabolism
• Storage
• Endocrine functions
• Immune & inflammatory response
• Blood reservoir
4. Carbohydrate metabolism
• Liver is an important homeostatic regulator of blood
glucose.
• It can either produce glucose or store glucose
• In fed state- polymerize glucose to glycogen
• In unfed state- depolymerize glycogen to glucose
• Glucose → hepatocytes → glycogen
↑ →glucose
L a c t a t e
Glycerol
aminoacids
5. Carbohydrate metabolism
• Glycogen metabolism
• Regulation – 2 rate limiting enzymes
1. Glycogen synthase- synthesis of glycogen from monomers of
UDP glucose.
2. Glycogen phosphorylase- clevage of glycogen to glucose-1-
phosphate.
8. • Blood glucose regulation within a narrow limit (70-100 mg/dl)
not affected in liver disease due to large reserve of hepatic
function
Effects of anaesthesia on carbohydrate metabolism
• Halothane
¯ release of insulin
rate of glycogenolysis
– Inhibition of gluconeogenic response
• Isoflurane
– Impaired insulin secretion
9. Lipid Metabolism
b Oxidation of fatty acids
• Fatty acids derived from plasma
¯
• Enter into mitochondria
¯
b oxidation: fatty acids AcetylCoA citric acid cycle
• Regulators
- Glucagon - activates
- Insulin - inhibits
10. • Synthesis of lipoproteins
• One of the major functions of the liver
• Major classes
– VLDL
– LDL
– HDL
11. • VLDL
• Acute or chronic liver disease – ability to produce
VLDL is markedly compromised
• Liver VLDLs are associated with an important class
of proteins, the apo B protein
• Apo B100 - important for hepatic secretion of VLDL.
• Decreased in ABETALIPOPROTEINEMIA
• LDLs and HDLs
• Liver produces them in a small amount
12. • Production of ketone bodies
• Most organs except the liver- use ketone bodies as fuel
• Ketone bodies – acetoacetic acid, acetone,
b hydroxybutyrate
• Their formation by the liver is normal and physiologically important,
e.g.
– Fasting rapid depletion of glycogen stores in the liver
shortage of substrates for citric acid cycle
– AcetylCoA formed from b oxidation ketone bodies
• Ketosis - conc. of ketone bodies in blood
– Starvation
– DM
– After high fat diet
13. • Synthesis of cholesterol
• Important role in cholesterol homeostasis
• Liver cholesterol has both exogenous and endogenous source
Uses of hepatic cholesterol
• Formation of bile acids- conjugated with other substances to form cholic
acid.
• Synthesis of VLDLs
14. Bile metabolism enterohepatic circulation
• Bile salts are end products of cholesterol synthesis
• Daily production – 600- 800 ml/d
• Functions-
- activate lipase
- promote micelle formation
- intestinal uptake of fat soluble vitamins, cholesterol
lipids
- facilitate excretion of xenobiotics, lipophillic
substances, bilirubin, amphipathic steroid hormone
derivative
15. • Bile salts undergo enterohepatic circulation (20-30 times/day)
intrahepatic bile duct
↓
common hepatic duct
cystic duct CBD
↓ ↓
gall bladder small intestine ( terminal ileum)
• Clinical implication
– Opioids can induce spasm of bile duct spinter of oddi
– Reversed by – glucagon, opioid antagonists ( naloxone),
smooth muscle relaxant (NTG), antimuscarinic
drugs( atropine), volatile anaesthetics.
16. Protein and amino acid metabolism
• Deamination of amino acids
– Required before they can be used for energy or before they can be
converted into carbohydrates or fats
• Formation of urea for removal of ammonia from the body fluids
• Production of proteins and peptides.
17. Krebs- Hanseleit cycle
Major pathway for removing NH3
other nitrogenous wastes from body
Captures nitrogen in form of urea.
Failing liver- BUN remain low
- ammonia
accumulates
in liver
↓
Hepatic encephalopathy
18. Proteins peptides
Albumin
• Most abundant protein
• Normal plasma conc- 3 - 5 g%
• Daily production -12-15 g/d
• Plasma half life – 15-20 days
• Functions –
• maintains plasma oncotic pressure (80% by albumin)
• binds ions, bilirubin, hormones drugs
• Hypoalbuminemia – ¯ Colloid oncotic pressure edema
19. ᾳ- feto protein
• Resembles albumin genetically functionally
• Formation sites- yolksac, hepatocytes, enterocytes
• Fetal neonatal life- major determinant of plasma oncotic
pressure
• 1 year of age- albumin largely replaces AFP
• ↑ ↑ AFP- HCC
20. Fibrinogen
• Synthesized exclusively by hepatocytes
• Plasma fibrinogen – 100-700 mg/dl
• Functions – polymerizes into long fibrin threads by the action of
thrombin formation of clot
21. • Haptoglobins
– Forms stable complexes with free Hb prevents loss of iron through
urinary excretion, protects kidney from damage
• Ceruloplasmin – binds with copper and helps in its transport and
storage
• Wilson’s disease
– Deficiency of ceruloplasmin free Cu2+ in circulation deposited in
brain and liver
22. Coagulation
• Synthesize most of the procoagulants except-a.
factor III ( tissue thromboplastin)
b. Factor IV ( calcium)
c. Factor VIII ( von Willebrand factor )
• Produce protein regulators of coagulation fibrinolytic
pathways
– Protein C, protein S ( protein C – inactivate F VIIIa- Va complex)
– protein Z ( degradation of Factor Xa )
– plasminogen activator inhibitor (PAI) ( inhibits tissue plasminogen
activators to convert plasminogen to plasmin )
– antithrombin III
23. Liver as a Storage Organ
• Vitamin A
• Important role in the uptake, storage and maintenance of vitamin A
levels by mobilizing its vitamin A store
• Vitamin K
• Vitamin K dependent factors II, VII, IX, X
• Absorption of Vit K depends on normal fat absorption: any mal-absorption
of lipid vitamin K deficiency
• Storage in liver- limited hypoprothrombinemia can develop within a
few weeks.
• Treatment –
• FFP
• Antidote- parenteral vit K
24. Vitamin K cofactor ỳ- carboxylation
– Factor II, VII., IX, X , protein C S- undergo Vit K
dependent post translational modifications
– Enables procoagulants to form complexes with
calcium or other divalent cations for participation in
the clotting cascade.
Clinical implication
Warfarin inhibits vit K epoxide reductase
↓
traps Vit K in epoxide form
↓
Inhibits y- carboxylation
T/T- Enteral / parenteral Vit K.
25. Storage Homeostasis of Iron
• Major site of synthesis of proteins (Transferrin, Ferritin) involved in iron
transport metabolism.
Heme metabolism
Clinical implication
• Porphyrias
• Acute Intermittent Porphyria – commonest
– Defects in the heme pathway- accumulation of porphyrinogens
– Trigger substances- barbiturates, sex hormones, glucocorticoides,
cigarette smoke, CYP inducers.
28. Metabolism of Drugs (Xenobiotics)
Phase-I reactions
• Alter the parent drug by inserting or unmasking a polar group
• Converts drugs to more polar compounds
• Reactions – oxidations, reduction, hydrolysis
• Cytochrome P450 – substrate binding site, located in the
endoplasmic reticulum
• Drugs– barbiturates, benzodiazepines, halogenated volatile
anaesthetics, pethidine etc.
29. • Phase-II reactions
• Creates conjugates of parent compound or its metabolite with
endogenous hydrophilic substrate
Reactions
• Glucoronidation
• Sulphation
• Methylation
• Acetylation
Glucoronidation
• Most common type
• Hepatic microsomal enzyme, UDPglucuronyl transferase mediates the
transfer of glucoronic acid from UDP glucuronic acid to the functional
group on the xenobiotics
30. • Drug handled by phase-II – morphine, propofol, thiopentone
(initially oxidized subsequently conjugated)
Phase-I reaction enzymes – more susceptible to destruction in
cirrhosis
Phase-II reactions enzymes – more resistant, function even in
advanced liver disease
Phase-III reactions
• Involves ATP-binding cassette transport proteins (ABC)
• These proteins use the energy of ATP hydrolysis to drive molecular
transport
• Dysfunction of ABC proteins hinders flow of bile predisposing to
drug accumulation and cholestatic liver injury
31. Microsomal enzyme induction
• Anticonvulsants, rifampicin, isoniazid, glucocorticoids, chronic
alcohol consumption
Consequences of enzyme induction
¯ duration of action of drugs that are inactivated by metabolism
intensity of action of drugs that are activated by metabolism
32. Endocrine functions
• Liver can modify or amplify hormone action
• Metabolic conversion of Vitamin D to form 25(OH)D
• 25(OH)D 1,25(OH)2D in kidney
• Peripheral conversion of T4 to T3
Pseudocholinesterase
• Hydrolysis of succinylcholine
• Plasma t½ - 14 days
• Severe liver disease duration of action of succinylcholine
33. • Insulin-like growth factors or somatomedins – growth hormone like
action
• Important role in cartilage function by promoting uptake of sulphate
and synthesis of collagen
Removes circulating hormones
• Insulin, glucagon, growth hormone, gastrointestinal hormones, e.g.
gastrin
34. • Blood reservoir
– Liver is an expandable organ
– 10 -15 % of total blood volume can be sequestered and quickly
released after sympathetic stimulation .
• Immune inflammatory responses
– kuffer cells protect against foreign intrutions, degrade toxins,
process antigens, and phagocytose bacteria.
– Induce intensify inflammation by recruiting neutrophils
– Release proinflammatory mediators
36. Summary
• Functions of liver
I. synthetic
Plasma protein (albumin) Hypoproteinimea → oedema
Coagulants Haemorrhagic disorders
Enzymes Hepatocellular disorders
Urea / removal of NH3 ↓ bld urea, ↑bld NH3
II. Metabolic
Carbohydrate ↓ glycogen – more damage
↓ bld. Glucose – muscle weakness, personality
changes, tremors, slurred speech, convulsion,
coma , death → pre hepatic coma
Protein metabolism ↑ blood ammonia – aminoaciduria
lipid metabolism Acc. Of FA in liver → fatty liver →pre hepatic
hepatitis→ fibrosis→ cirrhosis→ ↑ portal pressure→
portal hypertension
37. III. Bile secretion
Bile salts acids steatorrhea
Conjugation of bilirubin Hepatocellular jaundice
IV. Miscellaneous
Vit A, K Deficiency- ↓vit A , K
Antibacterial action Prevent infections
Destruction of RBCs Anemia , ↑ bilirubin