Cardiovascular disease

Presented by
Dr. Mohammad Saadeh

The requirements for the Clinical Chemistry

Middle East University
Faculty of pharmacy
 Cardiac marker

Cardiac marker Start to Time after Duration

rise (hr) infraction for of rise
peak rise (hr) (days)
Troponin I &T 4-6 12-24 7-10
TnI &TnT
CK (Total) 4-6 24-48 4-6
LDH 12-24 48-72 7-12
C-reactive protein 4-6 48 3-5
Myoglobin 2-4 12-24 2-4
AST 4-6 24-48 4-6
 The liver
Presented by
Dr. Mohammad Saadeh

The requirements for the Clinical Chemistry

Middle East University
Faculty of pharmacy
 Introduction

 The liver is the largest organ in the body.

 The liver is of vital importance in intermediary metabolism and in the
detoxification and elimination of toxic substance.
 Introduction
Structure of liver:
1. 60% hepatocytes
2. 30% kupffer cell (reticuloendothelial )
3. 10% Supporting tissue
 The liver performs an astonishingly
large number of tasks that impact all
body systems.

 Liver have two channels that can

supply and oxygen nutriment:
hepatic artery and hepatic portal
vein.

 The corresponding channels is

hepatic vein and bile ducts.
 Functions of liver
① Excretory function: bile pigments, bile salts and cholesterol are
excreted in bile into intestine.
② Metabolic function: liver actively participates in carbohydrate,
lipid, protein, mineral and vitamin metabolisms.
③ Hematological function: liver is also produces clotting factors
like factor V, VII. Fibrinogen involved in blood coagulation is also
synthesized in liver. It synthesize plasma proteins and destruction
of erythrocytes.
④ Storage functions: glycogen, vitamins A, D, B12, and trace element
iron are stored in liver.
⑤ Protective functions and detoxification: Ammonia is detoxified to
urea. kupffer cells of liver perform phagocytosis to eliminate foreign
compounds. Liver is responsible for the metabolism of xenobiotic.
 Liver function tests (LFTs)
Liver function tests (LFTs or LFs) are groups of blood tests that give
information about the state of a patient's liver and can contribute to making an
accurate diagnosis of the specific liver disorder.
LFTs are divided into:
 true tests of liver function,
such as serum albumin, bilirubin, and Prothrombin time.
 tests that are indicators of liver injury or biliary tract disease.
Typically the LFT comprises of:
1. Total protein. 8. 5’-nucleotidase.
9. LDH isoenzyme (LDH4, LDH5)
2. Albumin and globulin.
3. (Prothrombin Time).
4. Transaminases such as AST & ALT.
5. Alkaline phosphatase (ALP).
6. Bilirubin.
7. Gamma Glutamyl Transpeptidase (GGT).
 Liver function tests
Most common live disease:
Hepatitis: acute or chronic damage to and destruction of liver.
Cirrhosis: fibrosis, shrinkage liver, decrease number and
function of hepatocellular.
Jaundice: high plasma concentration of bilirubin.
Cholestasis is defined as a decrease in bile flow due to
impaired secretion by hepatocytes or to obstruction of bile
flow through intra or extra-hepatic bile ducts.

Note:
 Obstruction bile duct may cause jaundice or cirrhosis.
 Chronic alcohol ingestion is a common cause of cirrhosis.
 Liver function tests

These biochemical investigation can assist in differentiating the

following:
Obstruction to the biliary tract (cholestasis).
Acute hepatocellular damage.
Chronic liver disease such as cirrhosis, fibrosis.
Liver cancer.
 Classification of liver functions test

Classified based on the major functions of liver:

① Excretion: Measurement of bilirubin.
② Serum enzymes: Transaminase (ALT, AST), GGT, alkaline phosphatase
(ALP), 5’-nucleotidase, LDH isoenzyme.
③ Synthetic function: Prothrombin time, serum albumin.
④ Metabolic capacity: Galactose tolerance and antipyrine clearance
⑤ Detoxification : urea.
 1. Excretion : Bilirubin
• Bilirubin is the main bile pigment that is formed from the
breakdown of heme in red blood cells. The broken down heme
travels to the liver, where it is secreted into the bile by the liver.
• Effective bilirubin conjugation and excretion depend on:
1. Hepatobiliary function.
2. Rate of RBCs turnover.
 1. Serum bilirubin:
 Small amount of bilirubin circulates in the blood. Serum bilirubin
is considered a true test of liver function, as it reflects the liver's
ability to take up, process, and secrete bilirubin into the bile.
 Bilirubin metabolism
serum bilirubin levels are reported as
1. Total bilirubin (conjugated and unconjugated) (normal value
= 0.3-1.2 mg/dl).
2. Direct bilirubin (conjugated bilirubin) (normal value ≤ 0.4
mg/dl), filtrated by glomerulurs.
 Bilirubin is released by Hb breakdown and is bound to
albumin as water-insoluble indirect bilirubin (unconjugated
bilirubin), which is not filtrated by glomerulurs.
 Unconjugated bilirubin travels to the liver, where it is
separated from albumin, conjugated with monoglucuronide
(25%) and diglucuronide (75%) (more water soluble), and
then actively secreted into bile as conjugated bilirubin (direct
bilirubin), which is filtrated by Glomerulurs.
Figure in the next slide
 Globin protein-heme Bilirubin metabolism

indirect bilirubin
Unconjugated bilirubin

direct bilirubin

direct bilirubin
 Difference of two bilirubin
indirect
direct bilirubin
bilirubin
(conjugated)
(unconjugated)
Binding with Glucuronic acid no yes
Reacting with the diazo Slow and Rapid and
reagent indirect direct
solubility in water small large
Discharged via kidney no yes
Pass through the
yes no
membrane of cell
 2. urine(/faeces)
A. urobilinogen :
Conjugated bilirubin is excreted via bile salts to intestine. Bacteria in
the intestine break down bilirubin to urobilinogen for excretion in the
feces (normal value for fecal urobilinogen = 40 - 280 mg/day)

Normally there are mere traces of urobilinogen in the urine. average

is 0.64mg , maximum normal 4mg/24 hours.

B. Urobilin
Urobilin is the final product of oxidation of urobilinogen by oxygen in
air. The amount change with the amount of urobilinogen excretion .
B. bilirubinurine:
 Bilirubin is not normally present in urine and faese since bacteria in
intestine reduce it to urobilinogen.
 The kidneys do not filter unconjugated bilirubin because of its avid
binding to albumin. (bilirubin-albumin complex is too large)
 conjugated bilirubin can pass through glomerular filter.
 Bilirubin is found in the urine in obstructive jaundice due to various
causes and in cholestasis.
Note:
Bilirubin in the urine may be detected even before clinical
jaundice is noted.
 Who is a candidate for the test?
Bilirubin is used to diagnosis of jaundice.
There are three major causes of increased serum bilirubin
1. Hemolytic Jaundice, increases total bilirubin; direct bilirubin
(conjugated) is usually normal. Urine color is normal, and no
bilirubin found in urine. Increase indirect bilirubin
2. Hepatic Jaundice, occur in viral hepatitis; may cause an increase
in both direct and indirect bilirubin. Urine color is dark, and
bilirubin is present in the urine.
3. Obstructive jaundice ( Cholestasis), may be intrahepatic or
extrahepatic, increase direct and normal level for indirect
bilirubin. Urine color is dark, and bilirubin is present in the urine.
 Who is a candidate for the test?
Bilirubin is used to diagnosis of jaundice.
Abnormal bilirubin levels can be found in many disorders, including:
 blocked bile ducts
 Cirrhosis
 hepatitis
 liver diseases
 immature liver development in newborns.
 Liver function tests
2. Serum enzymes
Examples:
 Increase (total bilirubin and ALP) OR (ALP and GGT) are indicate of
cholestasis (blockage of bile flow). vvi
 Increase ALT and AST measure the integrity of liver cells. vvi
 Albumin (decrease) and Prothrombin (increase) time measure the liver
synthetic capacity. (cirrhosis)
Standard group of test Property being assessed
Serum albumin, PT Protein synthesis (cirrhosis)
Serum bilirubin (total) Hepatic anion transport
Serum enzyme activity
ALT, AST Hepatocellular integrity
5’-nucleotidase, GGT, ALP, bilirubin Presence of cholestasis
 Liver function tests
2. Serum enzymes
Alkaline phosphatase (ALP) (remember)
Clinical significance:
diagnosis of two groups of conditions; increase in hepatobiliary disease
(obstructive jaundice, cirrhosis, hepatitis and metastic) and bone disease
associated with increased osteoblastic activity (child's rickets with D vitamin
deficiency, Paget's disease, hyperparathyroidism with skeletal).
extrahepatic biliary obstruction; example
• Stone in bile duct.
• Intrahepatic cholestasis.
• Biliary cirrhosis.

 ALP Physiologically increase in; Pregnancy, Childhood, Fatty meals.

 Liver function tests; 2. Serum enzymes
γ-Glutamyl transferase (GGT): levels are elevated in:(remember)
 Cholestasis (ALP, BILIRUBIN, 5´Nucleotidase)
 liver diseases such as alcoholic cirrhosis and drug such as phenytoin. (ALB)
5' nucleotidase (5'NTD):(hydrolysis of a nucleotide into a nucleoside and a phosphate)
5' Nucleotidase (5'NTD) is another test specific for cholestasis or damage to
the intra- or extrahepatic biliary system.
Elevated ALP and GGT or 5'NTD, BILIRUBIN suggest that the liver is
the source.
Aminotrasferases (remember)
1. AST (GOT) increased in
 myocardial infarction.
 Acute hepatitis (cell damage) Hepatobiliary diseases such as cirrhosis.
2. ALT (GPT) levels are elevated in:
 liver diseases such as Acute hepatitis (cell damage), cirrhosis.
ALT is considered more liver-specific than AST.
 increase level of calcium in plasma) multiple myeloma or leukemia, bone
disease, osteoporosis and Paget's disease.
 GPT (ALT) and GOT (AST) is in the different distribution of the
hepatocytes.
GPT exists primarily in the cytoplasm of liver cell. if there is a
slight liver cell damage, GPT firstly leak into the bloodstream, so that the
serum GPT increased.
The GOT mainly in the "mitochondria“ of liver cells, the
mitochondria are "bubble" in the liver cell cytoplasm. if there is a slight
liver cell damage, GOT don`t leak into the bloodstream.

When the GOT was

significantly higher,
mitochondria of liver
cells are injuries.
Liver function tests
2. Serum enzymes
Although AST (GOT) is not a specific for liver as the ALT (GPT),
ratios between GPT and GOT are useful to physicians in assessing the
etiology of liver enzyme abnormalities.
(ALP+GGT+BILIRUBIN+5 NTD) =CHOLESTASIS

 Normally: GPT (ALT) is normal, AST (GOT) is normal, GPT/GOT is

about 1.15.
 Virus hepatitis: GPT ↑↑↑, GOT ↑,GPT/GOT＞1, even more than 2.5.
 Chronic VIRAL hepatitis : GPT↑ ,GOT ↑, GPT/GOT is about 1.
 Liver cancer, cirrhosis, Alcohol-induced hepatitis: GPT↑ ,GOT ↑
GPT/GOT < 1, about 0.6~0.7.
 Acute myocardial infarct : GPT/GOT < 1
 Liver function tests
2. Serum enzymes
 Lactate dehydrogenase (LDH) is an enzyme found in nearly all living
cells.
 Increased levels of LD4 and LDH-5 in liver disease and skeletal muscle.
Example: jaundice and metastatic carcinoma, viral hepatitis.
Liver function tests
2. Synthetic function (plasma proteins)
Albumin (Alb) (normal value=4-6 g/dl)
Clinical significance:
Decrease serum level of albumin in:
 Function: Maintains serum oncotic pressure.
Serve as transport agent.
 Primarily manufactured by the liver so, liver disease can decrease
albumin levels.
 Chronic liver disease or liver cirrhosis led to decrease the
albumin level.
globulins
 Function as transport agents and play a role in certain immunological
mechanisms.
 present, in early stage rise in β –globulins (transferrin, LDL, C3)
and in later stages γ-globulins (antibodies) shows rise.
Liver function tests
2. Synthetic function (plasma proteins)
Prothrombin time (PT)
 Prothrombin is a protein made by the liver. Prothrombin helps blood
to make normal clots.
 Increase "prothrombin time" (PT) in liver disease.
Why?
 The "prothrombin time" (PT) is one way of measuring how long it
takes blood to form a clot, and it is measured in seconds (such as 13.2
seconds). A normal PT indicates that a normal amount of blood-
clotting protein is available.
 Disruption of bile flow results in inadequate absorption of vitamin K
from intestinal.
 Good indicator of intrahepatic disease due to extra-hepatic
obstruction.
CIRRHOSIS
asis0
VVI
 Signs and Symptoms for hepatitis
virus
• Individuals may have one or more of the
following symptoms, while others experience
no symptoms:
–Tiredness –Weight loss
–Nausea –Abdominal pain
–Muscle or joint pain –Itchiness
–Trouble sleeping –Depression
–Loss of appetite –Dark urine
• Gilbert's syndrome (GS) is a common genetic liver disorder found
in 3-12% of the population.
• elevated unconjugated bilirubin, while conjugated bilirubin is
usually within the normal range.

Plasma analysis Result References Units

range
Alb 45 35-50 g/l
ALP activity 126 40-125 U/L
ALT 30 10-50 U/L
Total Bilirubin 60 3-16 mmol/L
GGT activity 35 10-55 U/L

Gilbert's syndrome
GGT that is sensitive for cholestasis is normal
Case 1: A 50 years old lecturer presented to his doctor complaining of
tiredness, abdominal pain, discomfort and poor appetite. He had worked
in Africa in the past, where he had contracted hepatitis B and had
become a carrier. On examination he was jaundiced and his liver was
enlarged. Urine was positive for both bilirubin and urobilinogen the
following results were found.
Plasma analysis Result References Units
range
Alb 34 36-47 g/l
ALP activity 400 40-125 U/L
ALT 150 10-40 U/L
AST 230 10-40 U/L
Total Bilirubin 60 2-17 mmol/L
GGT activity 150 10-55 U/L
α-fetoprotein 3000 Not detected kU/L

ALT/AST=0.65; The hepatitis B virus developed to hepatocellular carcinoma. The

tumor cause obstruction so ALP and GGT are elevated
Case 2: A 40 year old houswife complained generalised severe itching
during the previous 9 months. She had no other symptoms, and she
said that her alcohol consumption was small (2-3U/week). On clinical
examination, she was slightly jaundice, and bilirubin was detected in
the urine. The results of liver function tests were as follows:

Plasma analysis Result References Units

range
Alb 38 35-50 g/l
ALP activity 450 40-125 U/L
ALT 60 10-50 U/L
Total Bilirubin 60 3-16 mmol/L
GGT activity 150 10-55 U/L

High level of GGT,ALP and bilirubin

Cholestasis jaundice, the retention of bile salts cause hepatocellular damage
Case 3: 21- year old female student who had been complaining of flu-like
illness for 2 days. The illness had become worse, with symptoms of fever,
vomiting and abdominal tenderness in the right upper quadrant. On
examining her, the doctor found that she had recently returned from long
holiday in Asia.
A sample of urine appeared dark, and bilirubin was present and urobilinogen
was increased. Blood sample was taken for liver function tests, the results of
which were as follows:
Plasma analysis Result References Units
range
Alb 40 35-50 g/l
ALP activity 190 40-125 U/L
ALT 560 10-50 U/L
AST 233 10-50 U/L
Total Bilirubin 110 3-16 mmol/L
GGT activity 60 10-55 U/L

ALT/AST= 2.4; hepatitis virus

Case 3: A 49 year old woman has been referred by her family physician to the
liver clinic for assessment of her abnormal liver enzymes. She reports remote
use of recreational drugs in high school. Including marijuana, alcohol,
occasional amphetamines, and cocaine. She still drinks alcohol occasionally
(2-4 glasses of wine once or twice week), but otherwise has been drug free
since her mid twenties when she was married. She states that she feels fine
much of the time, but sometimes has fatigue, fluid retention, headaches, and
difficulty sleeping. She tende to get dizz on exertion at times. She has lost
about 10 pounds in the last 2 months. Which she attributes to reduced
appetite. Since her activity level has no past history of liver problems and the
skin color was normal. She had a laboratory test and showed that anti HCV was
+ve.
A) What is the likely diagnosis?
B) Concerning the laboratory results for above patient indicate increase ( )
or ( ), decrease ( ) or normal (N) for the following:
Total bilirubin
Serum albumin and total protein
ALP
ALT &GGT
AST