HbA NH2

H 2O 2 Cl2O7
KClO3

NAOH
CH2O
PO4

KMnO4

MEDICINE
KING SAUD UNIVERSITY
COOH
Co2
MgCl2

H 2O

SO2
Important Doctors slides
HCN
Extra Information Doctors notes CCl4
CuCl2
SiCl4

Biochemistry Work hard in silence,

let your success be
Liver Function Tests (LFTs) your noise
Editing file
OBJECTIVES Upon completion of this lecture, the
students should be able to:
• Understand the major metabolic functions of
the liver and causes of liver dysfunction.

• Discuss markers of liver function tests such as

liver enzymes, bilirubin, albumin and
prothrombin time that can diagnose hepatic
injury and assess hepatic function.

you don't have to memorize any number.

Just the numbers that we tell you to memorize
This video is recommended by Dr.
sumbul
Information that Dr. Sumbul recalled at the beginning of the lecture:

-The liver is an important organ, everything we take in the body has to go through the liver .
whether we’re eating food (no need)

-Functions of the liver:

1-detoxification, which clears the ammonia from the blood and converts it into urea (less toxic) . Also
bilirubin + cholesterol + drugs are all cleared out through the liver.
2-Synthesis of the majority of plasma proteins, some enzymes, bile (which helps in digestion) ,and
cholesterol (which is a parent molecule for all the steroids in the body).
3-Storage of fat soluble vitamins such as vitamin A,K,D and E

-so anything that causes damage to the liver by any disease that associated with it assess that we do the liver
function test ,so the major metabolic functions of the liver for ex plasma protein albumin + cholesterol +
triglycerides.
-which lipoprotein synthesized in the liver ? VLDL, so the triglycerides is carried to the liver and then the liver
transport it to the rest of the tissues as VLDL
Lecture Overview
Major Metabolic Functions of the Liver

Major Metabolic
Functions of the Liver

Detoxification and Production of bile

Synthetic Function Storage Function
excretion salts

Plasma proteins Ammonia to urea

(albumin, globulins), (urea cycle),
Vitamins A, D, E,
cholesterol, bilirubin, Helps in digestion
K and B12
triglycerides and cholesterol, drug
lipoproteins (VLDL) metabolites
Some example of liver dysfunction

Cholestasis
Hepatocellular
disease (obstruction of bile
flow)

Steatosis (fatty liver)

Cirrhosis quite common in a lot Hepatitis
of people

Jaundice Liver cancer

Some example of liver dysfunction:
To differentiate between hemochromatosis
Genetic Disorders : and hemosiderosis
Hemochromatosis
(iron storage disease)

Disease Hemochromatosis Hemosiderosis

Etiology: Genetic Repeated blood transfusion
Cause: Due to iron overload disorders
Iron gets stored in the organ and it’s toxic to the organ
Mechanism:
majority stored in the liver
Complications: Causes damage to the liver and other thing
Hemochromatosis storage
or the accumulation of the Iron ( hemosiderin) is
Storage:
iron is happening in the stored in macrophages.
liver.
Liver Function Tests (LFTs)
• We have to check a list of tests to detect a liver disease The good thing is that there are non invasive
and we will discuss the major ones. and invasive so, baiscally it’s not a liver
• Noninvasive methods for screening of liver dysfunction function test it’s liver dysfunction test (don’t
think this is necessary)
• Help in identifying general types of disorder
• Assess severity and allow prediction of outcome We are basically testing and screening for liver
dysfunction.
• Disease and treatment follow up
Broadly classified as : what are the indications for doing a liver
1. Tests to detect hepatic injury: (affecting structure) function test?
• Mild or severe; acute or chronic 1-When there are symptoms like (Jaundice or
abdominal pain or anorexia or nausea and
• Nature of liver injury (hepatocellular or cholestasis)
vomiting)
2-If a person is on drugs which cause liver
2. Tests to assess hepatic function (affecting function) toxicity or if you want to start a treatment and
you want to make sure that the patient's liver
is healthy or not ( so by knowing that you can
change the treatment or modify the dose) .
3- Alcoholism
Classification

Classification of
LFTs:

Group I: Markers Group II: Markers Group III:

of liver of hepatocellular Markers of
dysfunction injury cholestasis
Classification

Group I: Markers of liver dysfunction

▫ Serum bilirubin: total and conjugated

▫ Urine: bile salts and urobilinogen
▫ Total protein, serum albumin and
albumin/globulin ratio
▫ Prothrombin Time

Group II: Markers of hepatocellular injury

Group III: Markers of cholestasis
(at the level of the cells) conditions that
markers of obstruction
cause damage to hepatocytes .
▫ Alanine aminotransferase (ALT)
▫ Alkaline phosphatase (ALP)
▫ Aspartate aminotransferase
▫ g-glutamyltransferase (GGT)
(AST)
Limitations of LFTs
There are some limitations because
non of the markers are perfect and
Limitations of LFTs can tell you exactly what is wrong
with the liver. That’s why we have
more the one marker

Liver is a big organ so a lot of times

if the cell injury wasn’t severe (even
if we choose more than one marker)
Normal LFT values do not we may not see a difference in the
Asymptomatic people may levels of the markers. Unless the
always indicate absence of
have abnormal LFT results injury has gone for a long time or
liver disease
the injury is really severe . (because
the liver is a large organ that
compensates ).

* There could be something wrong

Liver a has very large reserve Diagnosis should be based on in the liver but it may not reflect on
capacity * clinical examination the values.
Common serum liver chemistry tests
Bilirubin

Bilirubin

• A byproduct of red blood cell

(hemoglobin) breakdown

• It is the yellowish pigment observed in

jaundice in sclera, skin and mucous

• High bilirubin levels are observed in:

 Gallstones, acute and chronic hepatitis

Bilirubin cycle
-The life span of RBC’S is 120 days. The RBC’S keeps on dying in
the system and are cleared up by the macrophages (of RES) in
the spleen and the liver ,so these macrophages produce
bilirubin as byproduct.
-The bilirubin is not soluble it requires a lot of water or fluids to
be soluble so it has to go to the liver to become soluble. From
the macrophages it goes to the liver as a complex with albumin
- Albumin carries the bilirubin to the liver and once it goes to
the liver, the hepatocytes take it in with the help of ……ligandin
……..( it facilitate the transport of bilirubin inside the
hepatocyte). Once inside the hepatocyte they are conjugated
with a carbohydrate called glucuronic acid. 2 molecules of
glucuronic acid are bound to 1 molecule of bilirubin and that is
done by the enzyme glucuronyl transferase ( it’s microsomal
enzyme present in the endoplasmic reticulum) .
- After that it is actively secreted into bile and enters the bile
duct to reach the intestine. Once in the intestine, it’s acted
upon by the intestinal bacteria which removes the glucuronic
acid from the bilirubin and convert it into a molecule called
urobilinogen.
-Majority of urobilinogen gets oxidized ( by intestinal bacteria)
to stercobilin which is excreted with the feces (gives the feces
it’s brown color) .
-The remaining urobilinogen are reabsorbed into the blood and
goes back to the liver through the portal circulation ( known as
enterohepatic circulation) . Some of it goes to the kidney where
it is converted to urobilin ( that gives urine it’s yellow color) and
get excreted in urine. Side note: Bilirubin makes a complex with
Albumin and is conjugated with glucuronic acid
Bilirubin cycle

Summary:

Urobilinogen has 3 fates:

1- Oxidized by intestinal bacteria into stercobilin and excreted

into feces (majority)

2_ Reabsorbed from the gut and enters the portal blood to go

back to the liver ( enterohepatic circulation) (Some)

3- Reabsorbed from the gut and enters the blood to reach the
kidney where they are converted into urobillin and excreted in
urine.
Bilirubin metabolism

The role of the liver is basically

conjugation which turns the non
soluble bilirubin into a soluble
form that can be easily excreted
out of the body.
Serum bilirubin levels
Unconjugated Conjugated Latent
Normal Jaundice
(indirect) (direct) jaundice
0.2 – 0.8 0.2 – 0.7 0.1 – 0.4
Above 1 mg/dL Above 2 mg/dL
mg/dL mg/dL mg/dL

Bilirubin levels and jaundice

Class of Jaundice Causes

Abnormal red cells; antibodies; drugs and

Pre-hepatic or hemolytic (mainly toxins; thalassemia
unconjugated bilirubin in the serum) Hemoglobinopathies, Gilbert’s, Crigler-
Najjar syndrome

Hepatic or Hepatocellular (both Viral hepatitis, toxic hepatitis, intrahepatic

conjugated and unconjugated) cholestasis
Extrahepatic cholestasis; gallstones;
Post-hepatic (Conjugated) tumors of the bile duct, carcinoma of
pancreas
Urobilinogen (UBG), bile salts and serum albumin
Urobilinogen (UBG) and bile salts Serum Albumin

• Most UBG is metabolized in the large • The most abundant protein

intestine but a fraction is excreted in synthesized by the liver
urine (less than 4 mg/day) • One of the most important and
• If there is too much bilirubin present abundant protein synthesis in the
then this fraction gets increased liver the half life of it is 20 days.
• Normally bile salts are NOT present in • Normal serum levels: 3.5 – 5 g/dL
urine • Synthesis depends on the extent of
• Normally 95% of bile salts are functioning liver cell mass
reabsorbed and only 5% gets excreted. • Since the liver is a large organ and
• Obstruction in the biliary passages the 1/2 life of albumin is long . The
causes: disease should be either chronic or
1. Leakage of bile salts into circulation acute (but really severe) in order to
2. Excretion in urine see change in the level of albumin.
• Obstruction leads to regurgitation of • Its levels decrease in all chronic liver
bile salts into the blood and there for diseases
excreted in urine
Serum Globulin

Globulin Albumin to globulin (A/G) ratio

 Normal serum levels: 2.5 – 3.5g/dL • Normal A/G ratio: 1.2/1 – 1.5/1
 a and b-globulins mainly synthesized by the
• Globulin levels increase in hypoalbuminemia as a
liver
compensation
 They constitute immunoglobulins
(antibodies) • When the synthetic function of the liver is affected,
 High serum g-globulins are observed in the albumin levels falls . So in order to maintain the
chronic hepatitis and cirrhosis : osmosis of the system and compensate for the loss of
1. IgG in autoimmune hepatitis albumin, there is a compensatory increase in the
globulin synthesis. you start making lots of globulin
2. IgA in alcoholic liver disease that leads to a change in the ratio of
albumin/globulin. The ratio will be decreased.
Prothrombin Time (PT)

• Prothrombin time is the time needed for blood clot to form.

• Prothrombin is clotting factor number 2
• Prothrombin: synthesized by the liver, a marker of liver function .. We should
say dysfunction not function
• Half-life: 6 hours. (indicates the present function of the liver)
• PT is prolonged only when liver loses more than 80% of its reserve capacity
• Vitamin K deficiency also causes prolonged PT
• Intake of vitamin K does not affect PT in liver disease
• You have to give an injection of vitamin K to make sure if it's due to Vit k or
liver injury
• PT is affected by vitamin K or liver injury
AST and ALT These numbers are
important

Aspartate aminotransferase (AST) Alanine aminotransferase (ALT)

• More liver-specific than AST

• Normal range: 8 – 20 U/L • Normal range (U/L):
 Male: 13-35
• A marker of  Female: 10-30
hepatocellular damage • High serum levels in acute hepatitis (300-1000U/L)
• Moderate elevation in alcoholic hepatitis (100-300U/L)
• High serum levels are • Minor elevation in cirrhosis, hepatitis C and non-alcoholic
observed in: steatohepatitis (NASH) (50-100U/L)
• Appears in plasma many days before clinical signs appear
 Chronic hepatitis, (good thing about it)
cirrhosis and liver cancer • A normal value doesn’t always indicate absence of liver
• AST and ALT are both damage
produced by the liver but • Obese but otherwise normal individuals may have
AST is less specific elevated ALT levels (minor elevation will appear in obese
people)
Alkaline phosphatase (ALP) Not specific because :
1- it is present in bone
2- synthesized in the placenta
therefore pregnant females have
• A non-specific marker of liver disease
elevated ALP levels.
• Produced by bone osteoblasts (for bone calcification) 3- hepatocyte membrane
• Present on hepatocyte membrane
• Normal range: 40 – 125 U/L
• Moderate elevation observed in:
• Infective hepatitis, alcoholic hepatitis and hepatocellular carcinoma

• High levels are observed in:

• Extrahepatic obstruction (obstructive jaundice) and intrahepatic cholestasis

• Very high levels are observed in:

• Bone diseases
gamma-glutamyltransferase (GGT)

GGT
• It’s a marker for alcohol abuse
• Used for glutathione synthesis

• Normal range: 10 – 30U/L

• Moderate elevation observed in:

• Infective hepatitis and prostate cancers

• GGT is increased in alcoholics despite

normal liver function tests
• Highly sensitive to detecting alcohol
abuse
Take Home Messages

 LFTs help detect liver injury and function.

 LFTs do have some limitations.

Summary
Marker Normal levels Abnormal levels Causes
Pre-hepatic: abnormal RBC,
Thalassemia, hemoglobinapothies
Hepatic: viral hepatitis, toxic
0.2-0.8 mg/dL
Latent jaundice: above 1 mg/dL hepatitis, and intrahepatic
Bilirubin Unconjugated: 0.2-0.7 mg/dL
Jaundice: above 2 mg/dL cholestasis
Conjugated: 0.1-0.4 mg/dL
Post-hepatic: extra hepatic
cholestasis, tumors of bile duct,
and pancreatic carcinoma
UG: less than 4 mg/day in
Urobilinogen and bile salts urine -- Obstruction of biliary passage
Bile salts: never in urine
Albumin 3.5-5 g/dL decreased All chronic liver diseases
Chronic hepatitis and cirrhosis
Serum Globulin 2.5-3.5 g/dL elevated IgG: autoimmune
IgA: alcoholic liver disease
Globulin increases in
Albumin/Globulin ratio 1.2-1.5/1 --
hypoalbuminemia
When liver loses 80% of
capacity
Prothrombin Time (PT) -- --
Vitamin K deficiency prolongs
PT
Summary
Marker Normal values Abnormal value Causes

Chronic hepatitis, cirrhosis,

liver cancer
AST 8-20 U/L High levels
Signifies hepatocellular
damage
300-1000 (high): acute
hepatits
100-300 (mod): alcoholic
Male: 13-35 U/L
ALT hepatitis --
Female: 10-30 U/L
50-100 (minor) in cirrhosis,
hepatitis C, non alcoholic
steatohepatitis
Mod. Elevation: infective
hepatitis, alcoholic hepatitis,
hepatocellular carcinoma
ALP 40-125 U/L -- High levels: extra-hepatic
obstruction, intrahepatic
cholestasis
Very high levels: bone disease
Mod. In infective hepatitis
GGT 10-30 U/L -- Increased naturally in
alcoholics
 QUIZ
Q1 : Which ONE of the following enzymes is more liver Q4 : Jaundice has no clinical manifestation when the bilirubin
specific? serum levels are?
A. ALT A. Less than 1 mg /dL
B. AST B. Between 2 and 3 mg /dL
C. LD C. More than 3 mg/dL
D. None of them D. Both (B&C)

Q2 : Which of these enzymes are highly sensitive in Q5 : ALT & AST are markers of ?
detecting alcohol abuse? A. Markers of cholestasis
A. Alkaline phosphatase (ALP) B. Markers hepatocellular damage
B. gamma–glutamyl-transferase (GGT) C. Markers for biliary obstruction
C. Alanine aminotransferase (ALT) D. All of the above
D. Aspartate aminotransferase (AST)
Q6 : Which ONE of the following has a (very high absorbed)
Q3 : Increased conjugated bilirubin is due to? level in bone diseases ?
A. Pre hepatic A. Alkaline phosphatase (ALP)
B. Post hepatic B. Aspartate aminotransferase (AST)
C. Hepatic C. Gamma–glutamyl-transferase (GGT)
D. Both (B&C) D. Both (A&C)
 QUIZ
Q7 : Explain why Prothrombin Time (PT) is good as a
prognostic tool ?
Q10 : A 26 year old male comes to the clinic with
It has a short half life of 6 hours. a yellowish tinge to the eyes and skin and
complains of abdominal pain, fatigue and
Q8 : What does Prothrombin Time (PT) means? And how is weakness, liver function tests only shows mildly
that relevant to liver dysfunction ? elevated bilirubin (mostly unconjugated) and
the rest of the parameters were all normal.
PT means how much time it takes for the blood to clot, PT is Which ONE of the following is the most likely
synthesized by the liver diagnosis ?

Q9 : Explain why albumin is not a good indicator of an acute Gilbert's Syndrome

hepatic dysfunction ?

It has a long half life of 20 days. It’s good in detecting chronic

liver diseases.

Suggestions and
recommendations
1) A 2) B 3) D 4) D 5) B 6) A
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