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WHY ?
Carbohydrate metabolism
Lipid metabolism
Bile metabolsim and entero- hepatic circulation
Protein metabolism
Coagulation
Heme metabolism
Bilirubin metabolism
Xenobiotics metabolism
Storage
Endocrine functions
Immune & inflammatory response
Blood reservoir
Carbohydrate metabolism
Lipid metabolism
Bile metabolsim and entero- hepatic circulation
Protein metabolism
Coagulation
Heme metabolism
Bilirubin metabolism
Xenobiotics metabolism
Storage
Endocrine functions
Immune & inflammatory response
Blood reservoir
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
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
glucose1-phosphate.
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
Glycogenesis
Glucose 6-PO4
Insulin
Glucagon
Epinephrine
B. Glucose
B. Glucose
Isoflurane
Impaired insulin secretion
Lipid Metabolism
Oxidation of fatty acids
Fatty acids derived from plasma
Synthesis of lipoproteins
One of the major functions of the liver
Major classes
VLDL
LDL
HDL
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
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
gall bladder
CBD
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.
Hepatic encephalopathy
- 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
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
Haptoglobins
Forms stable complexes with free Hb prevents loss of iron through
urinary excretion, protects kidney from damage
Coagulation
Synthesize most of the procoagulants excepta.
b.
c.
antithrombin III
Clinical implication
Warfarin inhibits vit K epoxide reductase
Inhibits y- carboxylation
T/T- Enteral / parenteral Vit K.
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.
Bilirubin
Metabolism
Bilirubin metabolism
Main source of bilirubin is heme metabolism
Daily production- 300mg
80 % derived from senescent erythrocytes by macrophages in
RE system.
Heme
( heme oxygenase + o2 )
Plasma
Fragile RBCs
BILIRUBIN METABOLISM
RE System
Liver
Conjugated bilirubin
Absorbed
Bacterial
action
Urobilinogen
Oxidation
Urobilin
Urobilinogen
Stercobilinogen
Oxidation
Stercobilin
Intestinal Contents
Urine
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
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
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 t - 14 days
Severe liver disease duration of action of succinylcholine
Blood reservoir
Liver is an expandable organ
10 -15 % of total blood volume can be sequestered and quickly
released after sympathetic stimulation .
Uses
Classification of LFTs
Tests based on detoxification and excretory functions
Serum bilirubin
Breakdown product of porphyrin ring of heme containing proteins
2 fractions -
Fractionate bilirubin
>15% direct
<15% direct
Evaluation for
hemolysis
-ve
Crigler-Najjar syndr
Gilberts syndr
No further evaluation
required
+ve
Hemolysis
Urine bilirubin
Any bilirubin found in urine is conjugated, therefore bilrubinuria implies
presence of liver disease
Blood ammonia
Detection of encephalopathy, monitoring hepatic synthetic function
Very poor predictor: presence/ degree of acute encephalopathy
Serum enzymes
No known function in serum
ed level- rate of entrance into serum from damaged liver cells
Enzymes categories
Enzymes that reflect damage to hepatocytes
Enzymes that reflect cholestasis
in aminotransferases
Mild - <250 IU/l
Any pathologic process that causes hepatocellular injury, e.g. hepatic
steatosis, alcohol or drug induced liver disease, chronic viral hepatitis,
cirrhosis, hemachromatosis
LDH
Normal level -25-100 IU/L
Massive but transient - Ischemic hepatitis
Massive, sustained - Malignant infiltration of liver
Glutathione S transferase
Relatively sensitive and specific test for detecting drug-induced
hepatocellular injury
Plasma t 90 min, rapidly released into the circulation following
hepatocellular injury
Plasma GST ( isoenzyme B ) reveal time course of hepatocellular
injury from onset to resolution
GST located in the centrilobular region (zone 3), where hepatocytes
are most susceptible to injuries from hypoxia and reactive drug
metabolism
-binding
-conjugation
-excretion
- 3-13 KA units/dl
Non-pathological
Age >60 yrs
Bld group O & B
Growing children &
adolescents
Late in normal pregnancy
Pathological
1 biliary cirrhosis
Choledocholithiasis
Hepatic malignancy
1 & 2
Pagets disease
5' NT
Sensitive and specific for hepatobiliary disorders (HBD)
Normal pregnancy, bone growth and bone diseases do not affect 5' NT
In pts with HBD, changes in ALP are usually followed by similar
changes in 5' NT
GGT
Inducible microsomal enzyme. N levels 5- 40 IU/L.
Less specific than 5' NT as a marker for HBD
Unlike 5' NT, GGT may be released from many sites beside the
hepatobiliary tree
Bone important source of ALP, has little GGT thus GGT useful for
differentiating hepatic & osseous sources of ALP
Normal levels
6.4 8.3 g%
S. Albumin
3 5 g%
Serum globulin
2 3 g%
Serum fibrinogen
0.3 g%
Serum prothrombin
40 mg%
A:G ratio
1.7 : 1
Serum albumin
S. albumin <3 g/dl suspect chronic liver disease
Hypoalbuminemia not specific for liver disease
Protein malnutrition of any cause
Protein losing enteropathies
Nephrotic syndrome
Chronic infections
Burns
Serum globulin
in gamma globulin chronic liver disease
Ig M - Primary billiary cirrhosis.
Ig A Alcoholic liver disease.
Ig G - Auto immune hepatitis.
Coagulation factors
Factor I, II, V, VI, VII
Short t1/2 single best measure of acute hepatic synthetic function
Tests PT- N 11-16 sec
- PTTK N 30- 40 sec
Prognostic value PT > 5 sec above control indicative of poor prognostic sign in acute
viral hepatitis.
in hepatitis, cirrhosis, disorders leading to vit K deficiency such as
obstructive jaundice or fat malabsorption
Immunological tests
Antibodies to specific etiologic agents
Hepatobiliary imaging
USG, CT scan - 1st line investigation
ERCP, PTC- visualization of biliary tract
Doppler USG& MRI- hepatic vasculature & heamodynamics
CT & MRI- hepatic masses & tumours
Others
FNAC
Biopsy percutaneous needle liver biopsy
a) VIM SILVERMAN ( cutting ) needle
b) MENGHINIS ( aspiration ) needle
Indications
Unexplained hepatomegaly
Cholestasis of unknown cause
Persistent abnormal LFTs
Infiltrative disorders- sarcoidosis, tuberculosis
Pyrexia of unknown origin
Primary/ metastatic liver diseases
Parenchymal
dysfunction
cholestasis
Aminotransferases
Normal
( may be N or in
advanced stages
N ( may be in
advanced stages)
ALP
Normal
Normal
Increased
serum bilirubin
unconjugated
conjugated
conjugated
Serum proteins
Normal
Decreased
N (may be in
advanced stages)
Prothrombin time
Normal
(may be N in early
stages)
N (may be prolonged in
advanced stages)
Normal
N (may be in
advanced stages)
Normal
Sulfobromophthalein /
indocyanine green
Normal
Retention
Normal or retention
Shortcomings of LFTs
Can be normal in pts with serious liver disease and
abnormal in pts with diseases that do not affect the liver
Rarely suggest a specific diagnosis
Only categorises into hepatocellular or cholestatic
Summary
Functions of liver
I. synthetic
Plasma protein
(albumin)
Hypoproteinimea oedema
Coagulants
Haemorrhagic disorders
Enzymes
Hepatocellular disorders
II. Metabolic
Carbohydrate
Protein metabolism
lipid metabolism
steatorrhea
Hepatocellular jaundice
IV. Miscellaneous
Vit A, K
Deficiency- vit A , K
Antibacterial action
Prevent infections
Destruction of RBCs
Anemia , bilirubin
References
Hepatic physiology & pathophysiology. Millers Anaesthesia ,
6th ed.
Hepatic structure, function & anaesthetic effects. International
Practice of Anaesthesia. Prys- Roberts.
Evaluation of liver function tests. Harrisons Principles of
Internal Medicine. 17th ed.
Hepatic anatomy, Function, & Physiology. Clinical Anethesia
6th ed.
Liver as an organ. Textbook of Medical Physiology, Guyton &
Hall. 10th ed.
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