Transcript 04. Liver Function Tests slides 2009

Liver Function
Tests
First Lecture
Learning objectives :
• Outline the structure and functions of the
liver
• Describe the metabolism of bilirubin.
• Outline different types of jaundice
LIVER ANATOMY:

The liver is the largest organ in the body.

It consists of two main lobes that together
weigh from 1400 to 1600 g in the normal
adult .

It is reddish brown in color and has a rich
blood supply 1500 ml/min from two major
vessels, the hepatic artery and the portal vein
The hepatic artery, a branch of the aorta,
contributes 20 % of the blood supply and
provides most of the oxygen requirement.

The portal vein , which drains the GIT ,
transports the most recently absorbed
materials from the intestines to the liver.

Structural Unit:
 The lobule which measures 1-2 mm in
diameter, forms the structural unit of the
liver.
 It is composed of cords of liver cells
(hepatocytes) radiating from a central vein.
 The boundary of each lobule is formed by a
portal tract made up of connective tissue
containing a branch of the hepatic artery,
portal vein and bile duct.
.No higher resolution available
Between the cords of the liver cells are vascular spaces,
called sinusoids, that are lined by Kupffer’s cells
The Kupffer’s cells are phagocytic macrophages capable
of ingesting bacteria or other foreign material from the
blood that flows through the sinusoids

Hepatocytes form 80% of liver , Kupffer’s cells ,vascular
and supporting cells form the 20% .
Liver functions:
Synthesis of plasma proteins
Metabolism of carbohydrate,lipids ,and
amino acids.
Detoxification and excretion.
Liver function tests

The routine liver function tests include the
measurement of :
- Total , direct and indirect bilirubin
- Total proteins and albumin
- Liver enzymes include :

ALT ( Alanine transaminase )

AST ( Aspartate transaminase )

ALP ( Alkaline phosphatase )

GGT (  - Glutamyl transferase )
• The routine liver function tests include the measurement of
Total and Direct Bilirubin, Total proteins and Albumin and
Liver enzymes including ALT, AST, ALP and GGT.
• Not all of these tests are related to the function of the liver.
Standard group of tests Property being assessed
Plasma albumin
Plasma bilirubin (total)
Protein synthesis
Hepatic anion transport
Plasma enzymes activities:
- ALT, AST
Hepatocellular integrity
- ALP, GGT
Presence of cholestasis
 Not all of these tests are related to the functions of the
liver.
 Except for the screening of healthy people (for
insurance examinations or occupational medicine),
liver function tests are usually employed in patients to:
 Confirm a clinical suspicion of the presence of liver
disease.
 Give an idea about the severity and prognosis of the
liver disease.
 Follow up the disease and evaluate therapy.
 Arrive at a differential diagnosis (e.g. cholestatic vs
hepatocellular liver disease).
Bilirubin Metabolism
1.Production of bilirubin in RES:

80% of bilirubin formed from haem arise from red
blood cells.

The remaining 20% comes from red cell precursors
destroyed in the bone marrow (ineffective
erythropoiesis), and from other haem proteins
such as myoglobin, cytochromes, catalase and
peroxidase.

Iron is removed from the haem molecule and the
porphyrin ring is opened to form bilirubin.
Dr. RANA -
2, transport of bilirubin in the plasma:
bilirubin is soluble in lipid solvents but almost insoluble in
water., so it is carried in plasma by protein-binding mainly to
albumin  forming indirect or unconjugated bilirubin.
So the bound form does not readily enter most tissues, nor it is
filtered at the glomerulus.
 The maximum capacity of albumin for bilirubin is 340
mol/L. the excess ,free, unconjugated bilirubin crosses the BBB
and dissolves in the lipid –rich brain tissue and leads to brain
damage to the baby( kernicterus )
3. IN THE LIVER:
a) Hepatic uptake:
The bilirubin-albumin complex appears to be
associated by receptors on the plasma
membrane of the hepatocytes, bilirubin taken
up by a specific carrier (facilitated diffusion),
leaving albumin in the plasma.
NORMAL BILIRUBIN
METABOLISM
Uptake of bilirubin by the liver is mediated by a 
carrier protein (receptor)
Uptake may be competitively inhibited by other 
organic anions
On the smooth ER, bilirubin is conjugated with 
glucoronic acid, xylose, or ribose
Glucoronic acid is the major conjugate - catalyzed by 
UDP glucuronyl tranferase
“Conjugated” bilirubin is water soluble and is secreted 
by the hepatocytes into the biliary canaliculi
Converted to stercobilinogen (urobilinogen) 
(colorless) by bacteria in the gut
Oxidized to stercobilin which is colored
Excreted in feces
Some stercobilin may be re-adsorbed by the gut and 
re-excreted by either the liver or kidney
b) Conjugation:
Conjugation of bilirubin within the hepatocytes
makes it water-soluble. The enzyme is BilirubinUDP-glucuronyl transferase forms bilirubin –
diglucuronide (direct or conjugated bilirubin).
c) Secretion of bilirubin into bile:
Occurs against a high concentration gradient,
a carrier mediated energy dependant process
(active secretion).
4. Intestine:
 Bilirubin diglucuronide is degraded by bacterial
action, mainly in the colon, being deconjugated
and then converted into a mixture of compounds
collectively termed urobilinogen
(stercobilinogen).
 Urobilinogen is water-soluble, mostly excreted
in the feces but a small percentage (20%) is
reabsorbed and then mostly re-excreted by the
liver.
 After excretion, urobilinogen (colorless) is
oxidized to urobilin (stercobilin) which is
brown gives stools its color.
 Some of the reabsorbed urobilinogen passes
through the liver into the systemic circulation
and is then excreted in the urine (urobilin)
gives the urine its yellow color .
Dr. RANA -
Jaundice


Jaundice is the yellowish coloration of the skin
and sclera due to hyperbilirubinemia.
Normal plasma bilirubin level is 2-17mol/L
,95% is indirect.

Jaundice becomes clinically apparent when the
plasma bilirubin exceeds 50 mol/L.
Latent jaundice is 17-50 mol/L
Jaundice may be classified into:
1) Pre-hepatic Jaundice:
 The production rate of bilirubin is increased, exceeding the
excretory capacity of the liver.
1. hemolytic anemia,
2. ineffective erythropoiesis (e.g. pernicious anemia).
3. Hematomas
lab; increase in plasma indirect (unconjugated) bilirubin
.Bilirubin is not excreted in urine.
2) Hepatocellular Jaundice:
 Hepatocellular damage due to viral hepatitis
or toxins may interfere with the uptake of
bilirubin, or with its conjugation or with
secretion of conjugated bilirubin into bile.
 Lab: Both indirect and direct
hyperbilirubinemia
Bilirubin is found in urine(bilirubinuria).
3) Obstructive (Cholestatic) Jaundice:
Intrahepatic cholestasis
Extrahepatic cholestasis
lab: Increased direct bilirubin in blood
bilirubinuria
Congenital Hyperbilirubinemias:
They are all due to inherited defects in the
mechanism of bilirubin transport.
1) Gilbert’s Disease :
 A common congenital disorder (autosomal
dominant) of bilirubin transport affecting
approximately 2% of the population, males more
affected than females.
 Gilbert’s disease is a benign condition and life
expectancy is normal.
 Causes: The activity of UDP-glucuronyl transferase
is reduced and defects in the uptake of bilirubin by
hepatocytes also occur.
 features: mild fluctuating jaundice .
 Investigations:
 plasma bilirubin less than 50 mol/L and increase to
double the original plasme with a 400 Kcal/day for
72 hours diet.
 liver function tests are normal
 no histological changes in the liver.
 fasting normal bile acids
Second Lecture
learning objectives
• Hepatic protein synthesis
• Albumin
• Blood Coagulation Factors
• Immunoglobulins
• Hepatic Enzymes
• ALT, AST, ALP, & GGT
• Biomarkers for hepatic fibrosis
• Other Liver Function Tests
• Tests for functional liver mass
• Bile acids
Albumin (35-50 g/l )
Albumin is synthesized in liver and is
highly dependent on the supply of amino
acids.
The biologic half-life of albumin is about •
20 days.
It present in plasma in higher •
concentration than other plasma proteins.
Functions of Albumin
The main functions of albumin are ::
1.Oncotic pressure. Albumin is responsible for
approximately 80% of the plasma oncotic
pressure (the osmotic pressure due to
proteins).This is a major determinant of the
distribution of fluid between the intravascular
and extravascular compartments and thus
plasma volume.
2. Transport.
Albumin acts as a nonspecific transport vehicle for many
substances.
Such as : Hormones (e.g.T4 and T3)
Calcium
Drugs
Free fatty acid
Billirubin
Hyperalbuminaemia is rare and is usually
caused by dehydration.
Reduced serum albumin levels are common ,
occurring in many conditions.
1.
2.
3.
Causes
of
Hypoalbumina
emia
Artefactual ..
diluted sample.. if a sample is taken from
an arm into which fluids are being infused.
Physiological..
pregnancy
Pathological..
* Decreased production :
-Decreased availability of amino acids.
Malnutrition
Malabsorption
-Defective synthesis:
Chronic liver disease
* Increased loss :
-From the kidney Nephrotic
syndrome
- Increased catabolism
Trauma
Surgery
Infection
II- Coagulation factors:
• In liver disease the synthesis of prothrombin and
other clotting factors is diminished,  prolonged
prothrombin Time (PT).
• This may be one of the earliest abnormalities
seen in hepatocellular damage, since
prothrombin has a short half-life (~ 6h).
• Deficiency of fat soluble vitamin K due to
failure of absorption of lipids  prolonged
pT.
• In vit. K deficiency the coagulation defect
can often be corrected by parentral
administration of vit. K.
III- Immunoglobulins:
• Plasma Ig measurements are of little value in
liver disease, because the changes are of low
specificity.
• In most types of cirrhosis  plasma IgA.
• In primary biliary cirrhosis  plasma IgM.
• In chronic active hepatitis   plasma IgG.
Hepatic Enzymes
a) Aminotransferases (ALT & AST):
ALT is cytomplasmic enzyme ,liver specific, raises at
an early stage in hepatic injury.
AST is cytoplamic and mitochondrial enzyme,
less liver specific, raises to greater degree in
chronic hepatitis.
 amounts of both transaminases leak from
inflamed or damaged hepatocytes due to acute
or chronic hepatitis.
Aminotransferases
AST (SGOT) (cytosol •
and mitochondria)
Liver
Cardiac Muscle
Skeletal Muscle
Kidneys
Brain
Pancreas
Lungs
Leukocytes
Erythrocytes
–
–
–
–
–
–
–
–
–
ALT(SGPT) •
(cytosol)
Liver –
b) Alkaline Phosphatase (ALP):
• Originates from the liver, bone
(reflecting osteoblastic activity) and the
placenta.
• Levels of ALP  in cholestasis, mainly
because of increased synthesis.
c)  - Glutamyl transferase (GGT):

 serum levels of GGT are found in
both hepatocellular and cholestatic disease.


Higher levels are found in cholestasis.
 synthesis of GGT is induced by excessive
ethanol intake.
N.B. Hepatic Enzymes:



ALT and AST levels are  mainly in
hepatocellular disease.
ALP level is raised mainly in obstructive
liver diseases.
Serum GGT levels are modest  in
hepatocellular disease and marked  in
obstructive disease.
Makers of fibrosis
• A Varity of markers have been described that
may be of help in measurement of hepatic
fibrosis.
• Procollagen type III terminal peptide and
hyaluronic acid (hyaluronin) are the most
commonly used tests.
Other Liver Function Tests
A. A number of liver function tests have been
described to give an indication of the
functional liver mass.
•
These tests are not often used but include :
–
–
the aminopyrine breath tests.
the galactose elimination test.
B. Bile Acids :
•
bile acids measurement is the most sensitive
test for early detection of liver disease used in:
–
Investigation of hepatic dysfunction associated with
pregnancy (increased)
investigation of Gilbert’s syndrome(normal)
The End