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TtáxÜ `A TuwxÄté|Å? c{WTtáxÜ `A TuwxÄté|Å? c{WTtáxÜ `A TuwxÄté|Å? c{WTtáxÜ `A TuwxÄté|Å? c{W
LIVER FUNCTION TESTSLIVER FUNCTION TESTSLIVER FUNCTION TESTSLIVER FUNCTION TESTS
3/20/2018
Dr/ Aaser Abdelazim ----assistant professor
of Clinical Medical Biochemistry and
Molecular Biology
24
TtáxÜ `A TuwxÄté|Å? c{WTtáxÜ `A TuwxÄté|Å? c{WTtáxÜ `A TuwxÄté|Å? c{WTtáxÜ `A TuwxÄté|Å? c{WAssistant professor of Medical Biochemistry
Zagazig University, Egypt
University of Bisha, KSA
Liver Functions Tests
1.Functions of human liver.
2.Major tests used in diagnosis of liver
disorders.
3.Major changes in plasma enzymes and their
3/20/2018
Dr/ Aaser Abdelazim ----assistant professor
of Clinical Medical Biochemistry and
Molecular Biology
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3.Major changes in plasma enzymes and their
indication in liver diseases.
4.Major pathological changes in liver.
5.Hepatic coma.
6.Jaundice.
Functions of liver:
1. Metabolism (Lipid, Proteins,
Carbohydrates)
2. Storage (Glycogen, Vitamins,
Vitamin B12)
3. Excretory function (Bilirubin,
Cholesterol).
Liver is the master organ in the body, it serve all other organs
Cholesterol).
4. Detoxification (Phenbarbiton,
Amonia, Steroid Hormones,
Benzoic)
5. Hematological function (Blood
formation, Blood volume, Blood
coagulation).
CAH: chronic active hepatitis
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Dr/ Aaser Abdelazim ----assistant professor
of Clinical Medical Biochemistry and
Molecular Biology
Anatomical over view
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Dr/ Aaser Abdelazim ----assistant professor
of Clinical Medical Biochemistry and
Molecular Biology
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Figure (1): liver Lobule
Major tests used to diagnose Major tests used to diagnose Major tests used to diagnose Major tests used to diagnose
liver functionsliver functionsliver functionsliver functions
Major tests used to diagnose Major tests used to diagnose Major tests used to diagnose Major tests used to diagnose
liver functionsliver functionsliver functionsliver functions
•ALT 1. Albumin (cirrhosis) 1. Anti mitochondrial .
Plasma enzymes Plasma proteins Serology
3/20/2018
Dr/ Aaser Abdelazim ----assistant professor
of Clinical Medical Biochemistry and
Molecular Biology
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•ALT
•AST
•GGT
•ALP
•LDH•5` nucleosidase
1. Albumin (cirrhosis)
2. (α, ᵦ, ɣ) globulins
(Cholestasis)
3. Immunoglobulins(IGs)
- IgG: chronic active
hepatitis
- IgA: portal cirrhosis
- IgM: biliray cirrhosis, viral
hepatitis
1. Anti mitochondrial .
Ab.(CAH, Biliray
cirrhosis
2. Anti nuclear:
autoimmune
hepatitis
3. Anti smooth muscle: CAH
CAH: Chronic active hepatitis
(1) Serum ALT (sGPT)(N= up to 35 U/ml)
It presents in high concentration In:
1. Liver2. Skeletal muscles 3. Kidneys
4. Heart
Major changes in plasma enzymes and its indication in liver diseases
Causes of ALT increase 4. Heart
Marked increase(10- 100
times)
1. Viral hepatitis
2. Toxic liver hepatitis 3. Circulatory failure
Moderate increase
1. Liver cirrhosis
2. Cholestatic jaundice
3. Liver congestion
4. Secondary to cardiac failure 5. Extensive trauma
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Dr/ Aaser Abdelazim ----assistant professor
of Clinical Medical Biochemistry and
Molecular Biology
Causes of ALT increase
It present in high concentration In:
1. Heart 2. Liver 3. Muscle 4. Kidenys
(2) Serum AST (sGOT)(N= up to 40 U/ ml)
Causes of AST increase
Physiological increase
In newborn its increase= 1.5 of normal level
Marked increase (10-
100 times )
1. Myocardial infraction
2. Viral hepatitis
3. Toxic liver cirrhosis
4. Circulatory failure
due to
- Shock - Hypoxia
Artefacual increase
Due to hemolysis of
blood in lab. Led to its release
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Dr/ Aaser Abdelazim ----assistant professor
of Clinical Medical Biochemistry and
Molecular Biology
Moderate increase
1. Liver cirrhosis
2. Cholestatic jaundice
3. Liver infiltration
4. Skeletal muscle
disease
5. After trauma or surgery
Presents in high concentration In:
1. Bone 2. Liver 3. Kidneys
4. Lactating mammary glands
5. Intestinal wall 6. Placenta
(3) Serum Alkaline Phosphatase (ALP) N= (50-190 U/L)
Causes of ALP increase
Physiological
1. Children until
puberty 2.5 times
of adult level 2. Pregnancy
Bone diseases
1. Osteomalcia
2. Rickets
3. Bone carcinoma
4. Healing stage of bone fractures
Liver diseases
1. Cholestatic jaundice*
2. Hepatitis
3. Cirrhosis
4. Tumors * *5. Infiltration * *
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Dr/ Aaser Abdelazim ----assistant professor
of Clinical Medical Biochemistry and
Molecular Biology
Presents in
1. Heart
2. Skeletal muscles
3. Liver
4. Kidneys
5. Brain 6. Malignant tissues
LDH isoenzymes1. LDH1:heart, erythrocytes, blast, kidneys
2. LDH2: heart
3. LDH3:intermediate
4. LDH4:liver 5. LDH5:liver
(4) Serum Lactate Dehydrogenase (LDH) N= (60-250
IU/L)
Causes of serum LDH increase
Marked increase
1. Myocardial infarction
2. Hematological diseases
- Leukemia
- Shock - Pernicious anemia
Moderate increase
1. Viral hepatitis
2. Skeletal muscle
diseases
3. Pulmonary
embolism 4. Infections
Artefacual increase Hemolysis of samples
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Dr/ Aaser Abdelazim ----assistant professor
of Clinical Medical Biochemistry and
Molecular Biology
Causes of serum LDH increase
Presents in:
1. Liver 2. Kidneys 3. Pancreas
(5) Gamma Glutamyle transpeptidase (γ-GT) N= up
to 38 U/L
Causes of GGT increase
Liver diseases
1. Cirrhosis
2. Metastatic cancer
3. Hepatic infiltration
4. Cholestasis
Chronic alcoholism Patient with anticonvulsant therapy
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Dr/ Aaser Abdelazim ----assistant professor
of Clinical Medical Biochemistry and
Molecular Biology
3/20/2018
Dr/ Aaser Abdelazim ----assistant professor
of Clinical Medical Biochemistry and
Molecular Biology
34
Major pathological changes in liver Major pathological changes in liver Major pathological changes in liver Major pathological changes in liver
Liver cell damage Cholestasis Infiltration of liver
Impaired the secretion of bile
Then accumulated in the
1. Secondary to a disease
2. Abscess
Destruction of cell
plasma 3. Parasitic emboli
As bilhariziasis cause
destruction of cells
Acute: as viral infection Chronic : Loss of function
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Dr/ Aaser Abdelazim ----assistant professor
of Clinical Medical Biochemistry and
Molecular Biology
((((1111) Liver cell damage ) Liver cell damage ) Liver cell damage ) Liver cell damage
Causes:
•Viral infection
•Toxins (alcohol, paracetamol, acetaminophen)
•Hypoxia and congestion in chronic heart failure (CHF).•Secondary to biliray obstruction.
Biochemical effect:
1. Release of intracellular constituents into blood.1. Release of intracellular constituents into blood.
2. High sGOT (AST) and sGPT(ALT).
- Massive destruction: sudden fall after high elevation
- Chronic destruction: high level for long time
ALT than AST Means liver viral hepatitis
AST than ALTMeans excess damage,cirrhosis, hypoxia and tumors
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Dr/ Aaser Abdelazim ----assistant professor
of Clinical Medical Biochemistry and
Molecular Biology
Liver diseases and AST-to-ALT ratio
Disease Ratio
EtOH 1.5
Drugs 2.0
Cirrhosis 1.4-2.0
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Dr/ Aaser Abdelazim ----assistant professor
of Clinical Medical Biochemistry and
Molecular Biology
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Hepatocellular carcinoma (HCC) > 1.5
Intra hepatic cholestasis > 1.5
Extra hepatic cholestasis 0.7-0.8
Acute viral hepatitis < 0.65
Acute myocardial infraction (MI) > 3.0
With jaundice (Cholestatic jaundice) With out jaundice
1. Obstruction to only part of biliary
system
2. Cholengitis3. Primary biliary cirrhosis
((((2222) Cholestasis ) Cholestasis ) Cholestasis ) Cholestasis
1. Gall stones
2. Carcinoma (obstruction of bile duct)
1. Some forms of Viral hepatitis
2. Biliary cirrhosis 3. Drugs : phenothiazine.
1. Plasma Bilirubin increased to be 50 mg/dl
2. ALP increases
3. ALT, AST increases
4. Increase GGT 5. Increase 5` nucleotidase
3. Primary biliary cirrhosis
Biochemical changes
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Intra hepatic Extra hepatic
Biochemical changes:Biochemical changes:
Abscess (1)
Amyloidosis(2)
Tuberculosis (3)
((((3333) Liver infiltration ) Liver infiltration ) Liver infiltration ) Liver infiltration
(5) Carcinoma from lung or stomach
Parasitism(4)
CAUSES
1. Increase synthesis in
sinusoids
2. Regarded to circulation 3. But it highest in Cholestasis
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Dr/ Aaser Abdelazim ----assistant professor
of Clinical Medical Biochemistry and
Molecular Biology
High serum ALP
High serum GGT
Normal bilirubin
ALT and AST normal or slight raised
Why?
Case study (1):
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Dr/ Aaser Abdelazim ----assistant professor
of Clinical Medical Biochemistry and
Molecular Biology
17.1 µmol/l bilirubin=1 mg/dl
0.41 mg/dl
Casestudy (1):
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Dr/ Aaser Abdelazim ----assistant professor
of Clinical Medical Biochemistry and
Molecular Biology
1. Liver function tests indicate mild cell damage; this appeared from
normal levels of AST and Bilirubin and slight increase of ALT (38/N =
<35).
2. High serum ALP indicates one of the following:
a) Bone metastasis tumor; and this not excluded by normal level
of Ca as ALP is very high (bone scan is very important here)
Comments on case 1
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Dr/ Aaser Abdelazim ----assistant professor
of Clinical Medical Biochemistry and
Molecular Biology
42
of Ca as ALP is very high (bone scan is very important here)
b) Metastatic breast carcinoma
c) Hepatic metastatic carcinoma from breast
3. Further investigations are required
a) Bone scan
b) Tumor markers
c) Histopathological examinations
Aaser Aaser Aaser Aaser
Hepatic coma
Definition: is the occurrence of confusion, altered level of consciousness as a
result of liver failure.
Biochemical findings
High blood ammonia
3/20/2018Dr/ Aaser Abdelazim ---- lecturer of Medical
Biochemistry and Molecular Biology 43
High blood ammonia
�Serum ammonia levels are
elevated in 90% of patients.
�Not all hyperammonemia
(high ammonia levels) is
associated with coma.
Abnormal liver function tests
indicating liver failure
Causes: other causes with hepatic faliure may predispose coma like:
Type Cause
Excessive
nitrogen
load
1. Consumption of large amounts of protein
2. Gastrointestinal bleeding e.g. from esophageal varices (blood is high in protein, which
is reabsorbed from the bowel),
3. Renal failure (inability to excrete nitrogen-containing waste products such as urea),
4. Constipation
Electrolyte
or
metabolic
1. Hyponatraemia (low sodium level in the blood) and hypokalaemia (low potassium
levels)—these are both common in those taking diuretics, often used for the treatment of
ascites
2. Alkalosis (decreased acid level),
3/20/2018Dr/ Aaser Abdelazim ---- lecturer of Medical
Biochemistry and Molecular Biology 44
metabolic
disturbance2. Alkalosis (decreased acid level),
3. Hypoxia (insufficient oxygen levels),
4. Dehydration
Drugs and
medications
1. Sedatives: such as benzodiazepines (often used to suppress alcohol withdrawal or
anxiety disorder),
2. Narcotics: (used as painkillers or drugs of abuse) and sedative antipsychotics, alcohol
intoxication
Infection Pneumonia, urinary tract infection, spontaneous bacterial peritonitis, other infections
OthersSurgery, progression of the liver disease, additional cause for liver damage (e.g. alcoholic
hepatitis, hepatitis A)
Unknown In 20–30% of cases, no clear cause for an attack can be found
Hepatic failure
(NH3)
Crosses the blood-brain barrier
(NH3)
Glutamate Glutamine
Ammonia (NH3) accumulates in the systemic circulation
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Biochemistry and Molecular Biology 45
The energy to brain cells is decreasedDue to depletion of α-ketoglutarate
Excess Glutamine lead to increase the osmotic pressure in brain cells (become swollen) Increase the activity of GABA in brain due to
conversion of α-ketoglutarate in to glutamate(inhibitory neurotransmitter)
Brain edema (cytotoxic type)
1. Definition of jaundice
2. Bilirubin metabolism
3. Causes of jaundice
4. Differential diagnosis of jaundice
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Dr/ Aaser Abdelazim ----assistant professor
of Clinical Medical Biochemistry and
Molecular Biology
4. Differential diagnosis of jaundice
1) Is a yellow discoloration of skin or/and sclera due to high
concentration of plasma Bilirubin over 40 µmol/l2) Normal plasma total bilirubin is less than 22 µmol/l (3-15
µmol/l OR 0.3 -1 mg/dl )3) Normal conjugated = 0.1 mg/dl
1. See bilirubin metabolism figure (3) Jaundice
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Dr/ Aaser Abdelazim ----assistant professor
of Clinical Medical Biochemistry and
Molecular Biology
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1. See bilirubin metabolism figure (3)2. Main causes of high bilirubin are three
figure (4)• Hemolysis • Failure of conjugation mechanism in
liver • Obstruction in biliary system
17.1 µmol/l bilirubin=1 mg/dl
Jaundice
�Indicates an elevated level of
serum bilirubin .
�In neonates it is important to
determine the concentration of
Unconjugated bilirubin in order to
decide the treatment required
�In adults most common type isdue obstruction.
Water soluble
•Non water soluble (not secreted
from kidneys)
•It is neurotoxic
•Can cause permanent brain damage in neonates
Bacteria
3/20/2018
Dr/ Aaser Abdelazim ----assistant professor
of Clinical Medical Biochemistry and
Molecular Biology
48
Figure (2) Bilirubin metabolism
•Brown coloration of feces
•If not present lead to pale colored feces
Bacteria
Orange color of urine on long standing
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Dr/ Aaser Abdelazim ----assistant professor
of Clinical Medical Biochemistry and
Molecular Biology
Figure (3): Causes of jaundice
Hemolysis
Plasma Unconjugated bilirubin
Main in neonates
Extra hepatic obstruction
Both Plasma bilirubin and ALP
Partial Complete
ALP with bilirubin within reference range
Hepatocellular damage
Obstruction occurs
here secondary to
hepatic cell
damage by toxinsor infection
conjugated
Little or no
3/20/2018
Dr/ Aaser Abdelazim ----assistant professor
of Clinical Medical Biochemistry and
Molecular Biology
50
>> 200 µmol/l (12
mg/dl); need
phototherapy
>> 300 µmol/l(17
mg/dl); need exchange transfusion
Little or no urobilinogen in urine
Pale stool
Level of ALP indicate the degree of obstruction
Both Plasma bilirubin and ALP with ALT and AST
Indicates
damage of liver cells
Little or no Stercobilinogen in intestine
Laboratory differential diagnosis of jaundice
Feature Hemolytic Cholestatic Hepatocellular
Serum Bilirubin >75 µmol/l (4.38 mg/dl)
(Unconjugated)(Indirect)
Over 3 times than in
hemolytic (Conjugated) (Direct)
>75 µmol/l but later
(Unconjugated/conjugated)
Conjugated increased when obstruction occurs later on
Bilirubin in urine
Not present(Unconjugated is not water
soluble and bound to albumin and not filtered )
Present Present(high level of conjugated bilirubin)
Urine Urobilinogen
Increased Decreased /absent Decreased/absent
3/20/2018
Dr/ Aaser Abdelazim ----assistant professor
of Clinical Medical Biochemistry and
Molecular Biology
51
Stool Normal Clay/pale in color
(no bilirubin reaches the intestine)
Normal
Reticulocytosis + - -
Hemoglobin /Haptoglobin Decrease Normal Normal
Plasma enzymes LDH may increased
1. ALP over 3 times the
reference range it act
as a mirror for the
degree of obstruction.
2. High AST, ALT, GGT
and LDH
High ALP but appear later
High ALT and ASTDue to hepatocytes damage
Neonatal jaundice
Causes:
1. Inability of immature liver of neonates to produce UDPG- transferase2. Higher turnover of neonatal erythrocytes shortly after birth to replace fetal HbF
with normal HbA
Neonatal jaundice
Transient Sustained
3/20/2018
Dr/ Aaser Abdelazim ----assistant professor
of Clinical Medical Biochemistry and
Molecular Biology
52
Physiological jaundice of the newborn (PJN)
1. Hemolytic diseases
2. Biliray artesia (post hepatic type)
3. Idiopathic neonatal
hepatitis (rare) (hepatic jaundice)
1. Blood groups
incompatibility
between mother and
fetus (+ direct anti-
globulin)
2. Absorption of large
hematoma.
Blood cells of mother Blood cells of fetus
Mechanism of neonatal jaundice
Group (O) orRH-
Group (A/B) orRh+
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Dr/ Aaser Abdelazim ----assistant professor
of Clinical Medical Biochemistry and
Molecular Biology
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Both come in contact
1. Through transfusion2. Or during pregnancy
Immune system of
mother recognizedthem as foreigners
Produce antibodiesagainst them
RBCs destruction
This usually not affects the 1st
child but affects the second oneAaser
1. High amounts of IgM (anti-A, anti-B)
2. Small amounts of IgG (anti-A, anti-B)
Consequence of neonatal jaundice
Treatment
Phototherapy if the level exceed 10 mg/dl
Source of light emitted light of 450 nm
Kernicterus
Brain cell nuclei stained yellow
Damaged due to high
bilirubin can cross blood
3/20/2018
Dr/ Aaser Abdelazim ----assistant professor
of Clinical Medical Biochemistry and
Molecular Biology
54
Unconjugated
bilirubin (insoluble)
Soluble bilirubin
bilirubin can cross blood
brain barrier (not occurs in adults
why?! Here type of bilirubin is unconjugatedwhich is water insoluble).
Usually brain is damaged if
the level reaches > 20mg/dl
cerebral palsy, deafness,mental retradation
Physiological jaundice of the newborn (PJN)
Transient condition/ phenomena in whichbilirubin subsides within few weeks
Other factors affecting neonatal hyperbilirubinemia
1. Increase total and Unconjugated bilirubin
2. Near-normal conjugated bilirubin 3. Normal hepatic enzymes if there is no iflammation
Physiological jaundice of the newborn (PJN)
3/20/2018
Dr/ Aaser Abdelazim ----assistant professor
of Clinical Medical Biochemistry and
Molecular Biology
55
Other factors affecting neonatal hyperbilirubinemia
1. Decrease binding of Unconjugated bilirubin to albumin
2. reabsorption of intestinal meconium
3. constituents in mother’s milk. Progesterone and other hormones in
breast milk as well as beta-glucuronidase may suppress neonatal
conjugation of bilirubin
Case study (2):
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Dr/ Aaser Abdelazim ----assistant professor
of Clinical Medical Biochemistry and
Molecular Biology
Case study (2):
3/20/2018 57
Dr/ Aaser Abdelazim ----assistant professor
of Clinical Medical Biochemistry and
Molecular Biology
3/20/2018
Dr/ Aaser Abdelazim ----assistant professor
of Clinical Medical Biochemistry and
Molecular Biology
58