The liver performs many critical physiological functions: 1. It regulates carbohydrate, lipid, and protein metabolism, producing glucose and ketone bodies and breaking down toxins. 2. The liver synthesizes proteins involved in blood clotting and transports iron, vitamins, and hormones. 3. The liver metabolizes and detoxifies drugs and other xenobiotics through phase I and phase II reactions and transports them out of the body. Impairment of these functions can lead to drug accumulation and toxicity.

1. PHYSIOLOGICAL FUNCTIONS
OF THE LIVER
DR ZIKRULLAH MALLICK
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
Lactate
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.

6. Carbohydrate metabolism
Gluconeogenesis
• Liver glycogen stores depleted - hepatic gluconeogenesis
to replenish blood glucose.
• Substrates-
- lactate
- glycerol from hydrolysis of triglycerides
- gluconeogenic amino acid , alanine , glutamine

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
•  Oxidation of fatty acids
• Fatty acids derived from plasma

• Enter into mitochondria

•  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,
 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  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.

26. Bilirubin
Metabolism

27. Plasma
Fragile RBCs
RE System
unconjugated bilirubin (protein – bound)
Liver
Liver
Kidneys
Urobilinogen
Conjugated bilirubin Absorbed
Bacterial
action
Urobilinogen
Stercobilinogen
Stercobilin
Intestinal Contents
Oxidation
Urobilinogen
Urobilin
Urine
Oxidation
BILIRUBIN METABOLISM

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

35. Signs of Liver Disease
• Jaundice
• Hepatomegaly
• Spider Naevi
• Splenomegaly
• Scratch Marks
• Ascites
• Palmer Erythema
• Dilated Abdominal
Veins
• Peripheral Oedema
• Finger Clubbing
• Testicular Atrophy
• Bruising
• Gynaecomastia
• Confusion/Coma

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

38. THANK YOU