PATHOPHYSIOLOGY OF

LABORATORY ABNORMALITIES IN
LIVER DISORDERS
By :
Dr. MONANG SIAHAAN, SpPK(K)
Dr.CORIEJATI RITA, SpPK, MM
LABORATORY TESTS OF LIVER FUNCTION
 TESTS OF EXCRETION FUNCTION
Bilirubin metabolism:
80 % mature RBC
20 % immature RBC, other heme
Hemoglobin heme + globin
RES Heme Biliverdin + Co + Fe ++

Bilirubin

CIRCULA
Bilirubin binds with albumin (indirect bilirubin)
-TION
Bilirubin binds with y/z protein
+ glucuronic acid Monoglucuronic bilirubin
2 molecule of monoglucuronic bilirubin 1 molecule
of diglucuronic bilirubin
LIVER Mono & diglucuronic Biliar canaliculi
bilirubin bile duct
 1

2
3
4

5
6
Bilirubin  Mesobilirubinogen
Urobilinogen Urobilinogen
Stercobilinogen

Urobilinogen urine
Faeces stercobilinogen
Urobilin Stercobilin
UCB = Unconjugated bilirubin ( bilirubin)
BNG = Bilirubin mono glucuronide (  bilirubin)
BDG = Bilirubin diglucuronide bilirubin)
BR-Albumin conjugates = Bilirubin-Albumin conjugatesbilirubin)
 DIFFERENCES BETWEEN
DIRECT & INDIRECT BILIRUBIN

DIRECT BILIRUBIN INDIRECT BILIRUBIN

* POST HEPATIC * PREHEPATIC

* CONJUGATED * UNCONJUGATED

* POLAR * NON POLAR

* DISSOLVED IN WATER * NON DISSOLVED

* POSITIVE IN URINE * NEGATIVE

* REACTIVE WITH DIAZO * REACTIVE WITH DIAZO

WITHOUT ALCOHOL IF THERE IS ALCOHOL

* MONO / DIGLUCURONIDE * PURE BILIRUBIN

• Unconjugated bilirubin=alfa bilirubin

• Monoglucuronida bilirubin= beta bilirubin

• Diglucuronida bilirubin=gamma bilirubin

• Delta bilirubin=Bilirubin tightly bound

albumin=irreversible albumin bound
 1. BILIRUBIN IN SERUM
Method :
MALLOY - EVELYN

Principle
Bilirubin + diazo reagent azobilirubin (red)
Normal value in serum < 1 mg%
increased total bilirubin find in :
a. Overproduction
b. Hepatocellular dysfunction
c. Obstruction of bile duct
2. UROBILINOGEN/UROBILIN

Method :
Urobilinogen Wallace Diamond
Urobilin Schlessinger

Normal :
Morning urine (-)
Day urine (+)
 DECREASE UROBILINOGEN

* Bilirubin enter intestine

* Renal dysfunction
* Urobilinogen production disturbance

INCREASE UROBILINOGEN
* Liver dysfunction
* Bilirubin overproduction

3. STERCOBILINOGEN / STERCOBILIN
Dark stool stercobilinogen

pale stool (acholis) stercobilinogen

Find in :
* Bile duct obstruction
* Diarrhea
* Antibiotics p.o.
4. ICTERUS INDEX :

Determination of serum / plasma color as a

quantitative bilirubin concentration
Normal 4-6 U
5. Bromsulphthalein (BSP) test

- Uncolored substance in acid solution

-Colored within alkaline solution

Normal : after 30’ retention 0 – 10%
after 45’ retention < 3%
Abnormal : after 45’ retention > 5 %
 ICTERUS : if serum bilirubin > 2 mg/dl

ICTERUS / HYPERBILIRUBINAEMIA

Unconyugated Conjugated (direct bilirubin>>>)

(80 % indirect
bilirubin)

Prehepatic Hepatic Hepatic Post hepatic

(bilirubin (disturbances
overproduction) of conjugation Extrahepatal
& uptake) obstruction
Hepatocellular Cholestatic intrahepata
 Unconjugated Prehepatic Hyperbilirubinemia
( hemolytic icterus)
Pathophysiology :
Erythrocyte destruction

indirect bilirubin

in serum

direct bilirubin

intestine

Portal vein urobilinogen (stercobilinogen)

in stool
liver

in circulation

renal

urine urobilinogen
 Unconjugated Hepatichyperbilirubinemia

Pathophysiology :

Uptake & conjugation disturbance

Serum indirect bilirubin

Direct bilirubin

Urine / faeces urobilinogen

Example :
- Gilbert syndrome
- Crigler- Najjar syndrome

Laboratory :
- Icterus with indirect bilirubin
- Decrease urobilinogen
- Decrease stercobilinogen
- Urine bilirubin (-)
 Conjugated Posthepatic Hyperbilirubinemia
(extrahepatal obstruction icterus)
Etiology : cancer, pancreatitis, lithiasis
Pathophysiology :
1. Bilirubin cannot enter the intestine urobilinogen (-)

2. Regurgitation of direct bilirubin bile duct pressure

permeability leakage bilirubin into
blood circulation
• Laboratories :
Total Partial

a. Icterus with direct bilirubin

b. Faeces urobilinogen - +

c. Urine urobilinogen - +

d. Urine bilirubin + +
 Conjugated Hepatic Hyperbilirubinemia
A. Cholestatic type
Etiology : - Idiopathic
- Hepatitis virus
- Drugs : * largactil
* organic arsenical
* methyl testosteron

Pathophysiology = conjugated extrahepatal hyperbilirubinemia

B. Hepatocellular type
Etiology : - acute hepatitis virus
- chronis cirrhosis hepatis
Pathophysiology :
Inflammation

liver cell oedem

Liver cell necrosis pressed cholangioles

increased permeability

Leakage of bilirubin into blood circulation

• Billirubin excretion by hepatosit to
canaliculi billiaris decrease find in:
• Rotor syndrome
• Dubin johnson syndrome
Liver function test according to Carbohydrate Metabolism

1. Glucose Tolerance Test

2. Fructose " "
3. Galactose " "
4. Epinephrine " "

Test according to detoxification function

Detoxification can be done :

1. Conjugation : Bilirubin, Na-Benzoat

2. Destruction : Barbiturat, morphin
3. Combination : ADH, sex-hormone, corticoteroid
Test based on enzymatic system

Categories of serum enzymes according to their behavior

in
Hepatitis and obstructive jaundice :

I. Higher in obstructive jaundice than in hepatitis

Alkaline phosphatase
Leucine Aminopeptidase
5 Nucleotidase
Gamma Glutamyl Transpeptidase

II. Higher in hepatitis than in obstructive jaundice

Aspartate Transaminase
Alaine Transaminase
Isocitric dehydrogenase
Ormithine carbamyl Transferase
Aldolase
III. Normal or only slightly elevated in hepatitis
& obstructive jaundice :
Lactate dehydrogenase
Creatine Phosphokinase
Lipase
Lecithinase
Amylase

IV. Depressed in hepatitis and normal in

obstructiv jaundice :
Cholinesterase
LCAT
ALKALINE PHOSPHATASE
Produced by bone, liver, bile duct, ect.

ALP

I. Pathologic
1. Bone disease : Paget’ disease, osteosarcoma
2. Liver disease : in cholangiohepatitis. Cholestasis stimula
the synthesis of ALP in the liver
3. Non liver / bone disease : Inflammatory bowel disease,
hyperthyroidism, pancreatitis, mononucleosis infectiosa

II. Physiologic
In growing children and 3rd trimester pregnancy

ALP in hipophosphatemia
Obstructive jaundice =
Total obstruction = 3-8 X
Partial = 1-8 X

Hepatocellular jaundice = 1-3X

Isoenzyme of ALP placental is most heat stable
5. NUCLEOTIDASE
* Alkali phosphatase acts only on nucleoside 5"-phosphate, to
form adenosine and release inorganic phosphate

* Tissues of the body, secreted by the liver

Highest value :
* Post hepatic jaundice (obstructive jaundice)
* Intrahepatal cholestasis
Increased 2 - 6 X in hepatobiliary diseases

Normal levels in osseous disease

Reference value :

O : 0,07 - 16,7 µ/l

+
O : 1,27 - 14,83 µ/l
GAMMA GLUTAMYL TRANSPEPTIDASE (GGT)

* Transfer (alpha) glutamyl from (alpha) glutamyl peptide to

others peptides or amino acid

* Kidney, liver, pancreas

Elevated levels :
* chronic alcoholism
* patients taking drugs (e.g.phenytoin)

* Reference value =

O : 0,65 - 24,09 mU/mL

O : 1,41 - 14,87 mU/mL

+
 ASPARTATE AMINOTRANSFERASE(AST/GOT)

* Catalyze the inter conversions of AA and -oxoacids by

transfer amino groups
* Cardiac muscular, liver, kidney, pancreas  decrease
Reference Value :
O : 11 - 26 U/L
O : 10 - 20 U/L
Elevated levels in : * Hepatocellular disseases (hepatitis)
+ 10 - 200 x normal
* Obstructive Hep
* Cirrhosis <10 X Normal
* Olcoholic liver
This enzyme increase in leucemia,lymphoma,infark miocardial,
renal necrosis,mononucleosis infection
 ALANINE AMINOTRANSFERASE (ALT)
Catalyze the interconversions of AA and d-oxoacids by transfer of
amino groups.

Widely distributed in human tissues but in liver >> heart

Increaced in hepatic & non hepatic disease :

* Hepatocellular 10 - 200 X normal

* Obstructive <10X normal

* Cirrhosis, Metastatic carcinoma of the liver

<10X N
* Alcoholic
• De Ritis is ALT and AST ratio
• Normal < 1
• Hepatitis Viral > 1
• Non Hepatitis = 1
• Non liver disseases <1
• ALT more specific than AST for
hepatocellular disseases
ISOCITRATE DEHYDROGENASE (ICD)
Catalyzes the oxidative decarboxylation of isocitrate to
(alpha) - oxoglutarate

are found in various human tissue

Increase in hepatic & non hepatic disease

Hepatocellular : (40X)

Obstructive : (slight)

Cirrhosis : (slight)
Myocardial infraction = N

ICD more important than ALT and AST

 CREATINE KINASE (CK)

* catalyze the reversible phosphorylation of creatine by

adenosine triphosphate (ATP)
* In : striated muscle,
brain
heart tissues
* Isoenzymes : CK1 (CK BB)
CK2 (CK MB)
CK3 (CK MM)
* Activity in some diseases :
* Diseases of sceletal muscle : Increase
* Diseases of heart : increase
* Diseases of liver : normal
Normal in serum 100% CK3
Heart 40 % CK2 + 60 % CK3
Brain 90% CK1 + 10% CK3
Lactate dehydrogenase (LDH)
* Catalyzes the oxidation of L- Lactate to pyruvate

* 5 Isoenzymes : LDH 1, LDH2, LDH3, LDH4, LDH5

present in all cells of the body :

* Cardiac muscle, LDH1

Kidney, eryth LDH2

* Liver & LDH4

skeletal muscle LDH5
CHOLINESTERASE

hydrolyzes acetylcholine
choline + acetic acid

changes in liver diseases :

Parenchymatous :

Obstructive : N
Enzyme Source acethylc Acethyl butirilch benzoilc
holine betamet oline holine
hylcholi
ne
Acethylc RBC + + - -
holine
esterase
Choline Serum/p + - + +
esterase lasma
PROTEIN METABOLISM

Sintezis : albumine
fibrinogen in liver
(alpha) & B glob
* Albumin & Globulin
Reference value :
albumin : 3,5 - 4,5 g/dL
globulin : 2 - 3 g/dL

Albumin
- Normal / mildly dicrease in acute Hepatitis (virus/toxic)
- Decrease severity & prognosis
GLOBULIN
Elevated levels in liver diseases
immune response in active chronic hepatitis
& active macromodular cirrhosis
& globulin
Biliary cirrhossis
Posthepatic Jaundice Alpha & Beta Glob
Electrophoresis
Alpha 1 globulin : mucoprotein
glicoprotein
acute disease with fetoris, cancer
Alpha 2 & Beta Glob : lipoprotein

(alpha) glob : antibody

Chronic disease
Acute Hepatitis
Albumin & globulin : Normal
* If alb < 3 gr/dL without increase wide damage

* If globulin > 3,5 gr/dL without decrease cirrhosin

* If globulin & albumine convalescense

Cirrhosis :
- compensated :N
- decompensated : alb
glob
Obstructive Jaundice :
new : Normal
old : albumin
globulin
FIBRINOGEN

is sintezised in liver, may be in RES

Function : blood clotting process

Determination : quantitative
semi quantitative
qualitative

Normal : 250 - 400 mg/dL

Decrease in : severe liver disease ( acute hepatic necrosis )

Prothrombin

is synthesized in liver
Decrease :
1. Poor Vitamin K in diet
2. Vitamin K absorption is lack
3. Liver cannot synthesized proth.

Obstructive jaundice : prothrombin can be normalized by

parenteral vit. K.
Parenchymatous jaundice : prothr cannot be normalized by
parenteral vit. K

Prothrombin occurred in severe liver disease ( end stage )

very bad prognose

Prothrombin Time ( PTT ) : 10 - 14 sec.

 SPECIFIC PROTEIN
A. Haptoglobin :

- glyco protein

- concentration is expressed as Hemoglobin or

methemoglobin binding capacity

Normal : 100 - 200 mg/dl Hb binding capacity

Increase : post hepatic jaundice

Decrease : hepato - cellular disease

B. Lipoprotein-X (Lp-X)

* in cholestatic jaundice & Lecithin Cholesterol acyl transferase

deficiency
* Sensitive determinant for cholestatic (if there is no LCAT
deficiency) but cannot differentiate intra / extra hepatal
cholestatic

C. Alpha fetoprotein (AFP)

- is the principal fetal protein
- in children > 1 year until adult normal : < 30 mg/ml
can be detection only by Radioimmuno assay (RIA)
- Gross elevations of AFP serum in Hepatocellular carcinoma
Teratoblastoma testis / ovarium
* Hepato-cellular carcinoma
* Teratoblastoma lestis / ovarium
Elevation < 500 mg / ml in

Pancreatic carcioma Pancreas cancer

Colon cancer
Lung cancer
On protein electrophoresis move as fast as alpha 1 globulin

Not for liver function test, but for tumor marker

( monitoring therapy of carcinoma )

On non-neoplastic liver disease :

* Chronic active hepatitis
* alcoholic cirrhosis
* regenerative activy of hepatocyte
D. Ceruloplasmin

* Copper oxidase

* Normal : 34 mg/dl

* Decrease : - Wilson's disease

- Protein Energy Malnutrition
- Nephrosis

* Increase : Chronic infection ( tbc, pneu )

Lupus erythematous
Rheumatic arthritis / fever
Myocardial infarction
Physiological stress
ACUTE HEPATITIS

I. Preicterus stadium
Symptom : fever, anorexia, malaise, abdominal discomfort

Laboratories : Abnormal BSP

Positive CCFT
AST & ALT
Urine urobilinogen : positive
others : normal

II. Icterus Stadium :

Symptom : Icteric, liver tender, afebril

Laboratories : Abnormal liver function tests

III. Post - Icterus Stadium :
The symptoms disappear
Lab. : liver function tests decrease to normal level
serum bilirubin still , negative urine urobilinogen

Hematological lab.
* Leucopeni, lymphopeni & neutropeni in preicteric stage
* Aplastic anemi, rare
* PTT protonged
* ESR on preicteric stage
N on icteric stage
if icteric begin to disappear
N on convalescence stage
CHRONIC HEPATITIS
Chronic inflamation > 6 month
Classification :
1. Chronic persistent hepatitis
2. Chronic lobular hepatitis
3. Chronic active hepatitis
1. Chronic persistent hepatitis
Etiology : Hepatitis B virus
Hepatitis Non A Non B virus
Alcoholism
Unknown
Lab. : Normal serum bilirubin or mildly elevated serum
IgG
2. Chronic lobular hepatitis

Etiology : acute viral Hepatitis like illness

Hepatitis Non A Non B virus
Lab. : increase of transaminases
3. Chronic active hepatitis

Etiology : Hepatitis B virus

Hepatitis Non A Non B virus

Unknown

Lab. : serum bilirubin

transaminases

gamma globulin
HEPATIC CIRRHOSIS
Is a diffuse process with fibrosis and nodule formation. It has
followed hepato-cellular necrosis. Although the causes are
many, the end result is the same
Etiology :
- Hepatitis B, non A - non B virus
- Alcoholism
- Metabolic : hemochromatosis
diabetes mellitus
Wilson's disease
- Prolonged intra & extrahepatal cholestatis
- Abnormal immunity
- Toxin & therapeutic agent
Laboratory : Compensated transminases
GGT
urine urobilinogen
Decompensated :

Urine : urobilinogen
(+) bilirubin
sodium in ascites

Blood : bilirubin
albumin
gamma globulin
transaminases
alkaline phosphatase
cholesterol ester

Normochrom normocyter anaemi, PTT prolonged

HAEMOCHROMATOSIS
A. PRIMARY HAEMOCHROMATOSIS
Normal Iron Metabolism :

The normal daily diet contains about 10 - 20 mg of iron of

this 1 - 1,5 mg is absorbed depends on body stores more
being absorbed the greater the need

Fasting iron serum is 250  / dl.

The normal total body content of iron is about 4 g., of wich

3 g are present in hemoglobin, myoglobulin , catalase, etc

Storage iron comprises 0,5 g ; of this 0.3 is in the liver.

When its capacity is ezcceded, iron is deposited in other

parenchymol tissues.
Definition :
Primary Haemochromatosin is a metabolism disturbance of
elevated iron absorpstion for years.
Etiology : Genetic
Patologi : * A. fibrous tissue reaction is found where even the iron
is deposited
liver intestine
pancreas heart
spleen, gaster brain, nerve
endocrine skin
lab. : - abnormal liver function tests
- serum iron
- transferrin 90 % saturated
- hyperglycemia
HEPATOCELLULAR FAILURE
Disfunction of liver cells can cause several manifestations :
1. Jaundice
2. Hepatic coma
3. Endocrine imbalance
- testicular atrophy
Oesterogen
- gynecomastia
in
- lost of body hair
- arterial spider Oesterogen inactivation
- palmar erythem 6.disorderd blood coagulation
4. Fetor hepaticum because some factor blood
5. Ascites : coagulation are synthesa in liver
* serum osmotic coloid ( albumin )
* electrolyte retention ( hormonal imbalance )
* portal vein pressure
Serologic marker of the Hep B viral:
HBs-Ag = Hepatitis B surface antigen
Anti HBsAg = anti hepatitis B surface antigen
HBcAg = Hepatitis B core antigen
Anti HBc = anti Hepatitis B core antigen
HBeAg = Hepatitis B envelope antigen
Anti Hbe = anti Hepatitis B envelope antigen