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

RES

Bilirubin metabolism:
80 % mature RBC
20 % immature RBC, other heme
Hemoglobin
heme + globin
Heme
Biliverdin + Co + Fe ++
Bilirubin

CIRCULA
-TION

Bilirubin binds with albumin (indirect bilirubin)

Bilirubin binds with y/z protein

+ glucuronic acid
Monoglucuronic bilirubin
2 molecule of monoglucuronic bilirubin
1 molecule
of diglucuronic bilirubin
Biliar canaliculi
LIVER Mono & diglucuronic
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

DIFFERENCES BETWEEN
DIRECT & INDIRECT BILIRUBIN
DIRECT BILIRUBIN
* POST HEPATIC

INDIRECT BILIRUBIN
* PREHEPATIC

* CONJUGATED

* UNCONJUGATED

* POLAR

* NON POLAR

* DISSOLVED IN WATER

* NON DISSOLVED

* POSITIVE IN URINE

* NEGATIVE

* REACTIVE WITH DIAZO

WITHOUT ALCOHOL

* REACTIVE WITH DIAZO

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
Urobilin
Normal :
Morning urine (-)
Day urine (+)

Wallace Diamond
Schlessinger

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)

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

stercobilinogen

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
(80 % indirect
bilirubin)

Conjugated (direct bilirubin>>>)

Post hepatic
Hepatic
Prehepatic
Hepatic
(bilirubin
(disturbances
Extrahepatal
overproduction) of conjugation
obstruction
& uptake)
Cholestatic intrahepata
Hepatocellular

Unconjugated Prehepatic Hyperbilirubinemia

( hemolytic icterus)
Pathophysiology :
Erythrocyte destruction
indirect bilirubin
in serum
direct bilirubin
intestine
Portal vein
liver
in circulation
renal
urine urobilinogen

urobilinogen (stercobilinogen)
in stool

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
2. Regurgitation of direct bilirubin
permeability
blood circulation

urobilinogen (-)
bile duct pressure
leakage bilirubin into

 Laboratories :
Total

Partial

b. Faeces urobilinogen

c. Urine urobilinogen

d. Urine bilirubin

a. Icterus with direct 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
- chronis

hepatitis virus
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
2. Destruction
3. Combination

: Bilirubin, Na-Benzoat
: Barbiturat, morphin
: 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
Iditol dehydrogenase

III. Normal or only slightly elevated in hepatitis &

obstructive jaundice :
Lactate dehydrogenase
Creatine Phosphokinase
Lipase
Lecithinase
Amylase
IV. Depressed in hepatitis and normal in obstructive
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 =
Partial
=

3-8 X
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 /l

O
+

: 1,27 - 14,83 /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
:
Myocardial infraction = N

(slight)

ICD more important than ALT and AST

CREATINE KINASE (CK)

* catalyze the reversible phosphorylation of creatine
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

by

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,
Kidney, eryth

LDH1
LDH2

* Liver &
skeletal muscle

LDH4
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
esterase

Serum/p
lasma

PROTEIN METABOLISM
Sintezis :

albumine
fibrinogen
(alpha) & B glob

in liver

* 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
* If globulin

& albumine

Cirrhosis :
- compensated
- decompensated

:N
: alb
glob
Obstructive Jaundice
:
new
: Normal
old
: albumin
globulin

cirrhosin

convalescense

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
pancreas
spleen, gaster
endocrine

intestine
heart
brain, nerve
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
- gynecomastia
- lost of body hair

Oesterogen
in

- arterial spider
- palmar erythem

Oesterogen inactivation
6.disorderd blood coagulation

4. Fetor hepaticum
5. Ascites :

because some factor blood

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