Functions of the liver

Assessment and interpretation of liver

function tests

Dr. Neha Kanojia

University College of Medical Science & GTB

Hospital, Delhi

WHY ?

 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.

Physiological functions of liver

Intermediary metabolism
a.
b.
c.
d.

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

Physiological functions of liver

Intermediary metabolism
a.
b.
c.
d.

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

Hormonal regulation of carbohydrate metabolism

Glycogenolysis
+
+

Glycogenesis

Glucose 6-PO4
Insulin

Glucagon
Epinephrine

B. Glucose

B. Glucose

 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

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

 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

LDLs and HDLs

Liver produces them in a small amount

 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

 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

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

 Bile salts undergo enterohepatic circulation (20-30 times/day)

intrahepatic bile duct

common hepatic duct

cystic duct

gall bladder

CBD

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.

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.

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

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

- 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

Ceruloplasmin binds with copper and helps in its transport and

storage
Wilsons disease
Deficiency of ceruloplasmin free Cu2+ in circulation
deposited in brain and liver

Coagulation
Synthesize most of the procoagulants excepta.
b.
c.

factor III ( tissue thromboplastin)

Factor IV ( calcium)
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

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 malabsorption of lipid vitamin K deficiency
Storage in liver- limited hypoprothrombinemia can develop within a
few weeks.
Treatment
FFP
Antidote- parenteral vit K

Vitamin K cofactor & - 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.

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.

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 )

biliverdin IX + CO + free divalent iron

( biliverdin reductase)
bilirubin

Plasma
Fragile RBCs

BILIRUBIN METABOLISM

RE System

unconjugated bilirubin (protein bound)

Liver
Urobilinogen
Kidneys

Liver

Conjugated bilirubin

Absorbed

Bacterial
action

Urobilinogen
Oxidation
Urobilin

Urobilinogen
Stercobilinogen
Oxidation
Stercobilin
Intestinal Contents

Urine

CO produced has many physiological roles

Vasodilation ( regulation of vascular tone)
Platelet aggregation
Vascular myocyte proliferation
Neurotransmitter release
Cytoprotective , antiapoptotic, antioxidant effects

Biliverdin confers protection from oxidative effects

rapidly converts to bilirubin

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.

 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

 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

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

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

 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

 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

 Uses

Liver Function Tests

To detect the presence of liver disease

To distinguish among different type of liver disorders
To guage the extent of known liver damage
To follow the response to treatment

 Classification of LFTs
Tests based on detoxification and excretory functions
Serum bilirubin
Breakdown product of porphyrin ring of heme containing proteins
2 fractions -

conjugated (direct 30%)

unconjugated (indirect 70%)

Normal total serum bilirubin 1 mg/dl
in unconjugated fraction is rarely due to liver disease

Fractionate bilirubin
>15% direct

<15% direct

Dubin Johnson syndr

Rotors syndr

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

Enzymes that reflect damage to hepatocytes

Aminotransferases
Aspartate aminotransferase (AST or SGOT): Liver, cardiac muscle, skeletal
muscle, kidneys, brain, pancreas, etc.
Alanine aminotransferase (ALT or SGPT): 1 in liver
Sensitive indicators of liver cell injury
Normal levels <35-45 IU/L

 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

Moderate 250-1000 IU/l

Disorder that produces hepatocellular necrosis
e.g. Acute viral hepatitis, drug induced hepatitis, exacerbation of
chronic hepatitis (alcoholic)

Large - >1000 IU/l

Viral or drug induced liver damage superimposed on ALD, autoimmune
hepatitis

 Extreme - >2000 IU/l

Massive hepatic necrosis, usually from drugs (acetaminophan),
halothane hepatitis, toxins, ischemic hepatitis (shock liver), acute viral
hepatitis

AST/ALT ratio DERITIS QUOTIENT

Normal - 1 or slightly > 1
<1 non-alcoholic steatosis or hepatitis without cirrhosis
2-4 ALD
>4 Wilsonian hepatitis

AST/ ALT not in purely obstructive disorder

except
Acute biliary obstruction caused by passage of
gallstones to CBD

 LDH
Normal level -25-100 IU/L
Massive but transient - Ischemic hepatitis
Massive, sustained - Malignant infiltration of liver

Other causes of LDH

Hemolysis
Renal infarction
Acute stroke
Myocardial damage
Skeletal muscle injury

 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

 Bromosulphathein excretion test

BSP dye- same mechanism as bilirubin

-binding
-conjugation
-excretion

BSP i/v 45 mins- levels in venous blood

Normally- <5%.
Slightly higher in old age
Sensitive test to detect mild impairement of liver

Enzymes reflecting cholestasis

Alkaline phosphatase- present in cells of the bile duct
Isoenzymes- bone , liver, intestine, placenta , kidney , leukocytes.
Normal levels- 42-122 IU/L

- 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

 in serum ALP in an apparently healthy pt.

Fractionate the ALP to identify source of isoenzyme
ALP from different tissues differ in susceptibility inactivation by
heat
Measure - 5' NT, GGT

 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

 Tests for bio-synthetic function of the liver

Estimation of plasma proteins
Tests for reversal of A:G ratio
Tests for coagulability of blood
Plasma protein
Total

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

Reversal of A : G ratio chronic liver dysfunction.

 Serum globulin
in gamma globulin chronic liver disease
Ig M - Primary billiary cirrhosis.
Ig A Alcoholic liver disease.
Ig G - Auto immune hepatitis.

Thymol turbidity test

Test for reversal of A:G ratio
Marked turbidity liver insufficiency

 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

HBV- HBsAg , HBcAg, HBeAg

Antibody to Entamoeba histolytica
Antibody to CMV, HCV, EBV

Non specific antibodies

Antimitochondrial antibody- PBC

Antismooth muscle antibody- Auto immune hepatitis
pANCA- Primary sclerosing cholangitis

 Serum tumor markers

feto-protein - in HCC.

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

Blood tests & D/D of hepatic dysfunction

Bilirubin overload
(hemolysis)

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)

Blood urea nitrogen

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

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

III. Bile secretion

Bile salts & acids
Conjugation of
bilirubin

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.

THANK YOU