LABORATORY DIAGNOSIS
IN LIVER DISEASES
Prof. Dr. Arzu SEVEN
The metabolic pathways of glycolysis,the Krebs
cycle,amino acid synthesis and degradation and
the process of oxidative phosphorylation are all
carried out in hepatocytes,which are well
endowed with mitochondria.
 The liver contains an extensive
reticuloendothelial system for the synthesis of
blood cells.

PROTEIN SYNTHESIS IN LIVER
Albumin
 Transthyretin(prealbumin)
 Igs
 Ceruloplasmin
 α1-antitrypsin
 Haptoglobulin
 β2-microglobulin
 Transferrin
 α-fetoprotein
 Some coagulation factors

Albumin is the major protein product of the liver.
 İt has a long biological half-life in plasma
 (about 20 days )
 Hypoalbuminemia is a feature of advanced
chronic liver disease.

METABOLIC LIVER DISEASES

1.
Clinical conditions associated with abnormal
concentrations of liver_produced proteins in
plasma :
Genetic deficiency of α1-antitripsin presents in
infancy as liver disease or in adulthood as lung
disease
Hepatic α1-antitrypsin belongs to the serpins,
one of the family of serine protease inhibitors
2. Genetic deficiency of ceruloplasmin leads to
Wilson’s disease, a condition associated with
liver and CNS damage.
Ceruloplasmin is the major cupper containing
protein of liver and plasma functions as a
ferrooxidase
hepatic manifestations are fulminant hepatitis
+ chronic hepatitis + cirrhosis
Neuropsychiatric changes include behavioral
changes + psychosis + extrapyramidal/pyramidal
signs
 Cupper accumulates in liver, brain,cornea,
kidney and joints
 Corneal rings(Kayser_Fleischer)
 Hemolysis + proximal renal tubular dysfunction
+ osteopenia + osteoarthropathy

Lab:
 Serum ceruloplasmin
 Urinary Cu>100 μg/d
 Hepatic Cu>250 μg/d
 AST>ALT
 Untreated Wilson’s disease is fatal

Treatment:
 Chelation therapy with D-penicillamine(1-2g/d)

3. Liver cancer is associated with particularly high
plasma α-fetoprotein (AFP) concentrations.
AFP and albumin have sequence homology
in the fetus, AFP appears to serve physiologic
functions similiar to albumin in adult
By the end of first year of life, AFP in plasma is
replaced by albumin
4. Hemochromatosis
 Hereditary hemochromatosis (HHC) is an
autosomal recessive disorder of iron retention
that damages liver, pancreas , heart joints,
gonads and skin
 Lethargy + hepatomegaly + skin
pigmentation(grayish color) + sometimes DM

Diagnosis by analysis of serum iron, ferritin and
transferrin saturation
DRUG METABOLISM

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Most drugs are metabolized by the liver.
Low substrate specificity of some hepatic
enzymes produces a wide-ranging capability for
drug metabolism
Hepatic metabolism usually increases the
hydrophilicity of drugs and therefore their ability
to be excreted.
Metabolites produced are less pharmacologically
active than the substrate drug.
However some inactive prodrugs are converted to
their active forms as a result of liver processing
 Metabolism proceeds in 2 phases:
 Phase I-addition of the polar group:
 The polarity of the drug is increased by oxidation
or hydroxylation catalyzed by cytocrome P-450
oxidases

Phase II-conjugation
 Cytoplasmic enzymes conjugate the functional
groups introduced in the first phase by
glucuronidation/sulfation/ acetylation
/methylation
 Cytocrome P-450 enzymes :
 Heme containing proteins
 Colocalize with NADPH:cyt P 450 reductase

Present in endoplasmic reticulum
 In liver and in the epithelium of endoplasmic
reticulum
 There are 12 cyt P450 gene families
 CYP1, CYP2 and CYP3 are responsible for most
of phase I drug metabolism
 Induction and inhibition of cyt P-450 enzymes is
the mechanism of drug interactions.


Cytocrome P-450 gene polymorphisms determine
response to many drugs
ALCOHOLIC LIVER DISEASE
 Excess intake of ethyl alcohol remains the most
common cause of liver disease in the western
world.
 Alcohol leads to alcoholic hepatitis, steatosis due
to fat deposition/fibrosis(cirrhosis)
liver

failure

Alcohol
acetaldehyde
acetate
A
B
 A:alcohol dehydrogenase(NAD⁺)
 B:aldehyde dehydrogenase(NAD⁺)

Ethanol oxidation as a result of increased
NADH/NAD⁺ alters the redox potential of
hepatocyte
 This inhibits oxidation of lactate to pyruvate (a
step that requires NAD⁺ as a cofactor)
lactic acidosis + risk for hypoglycemia


NADH/NAD⁺

Hepatic steatosis
inhibition of β-oxidation
+
TG synthesis
secreted into plasma
as VLDL

Ethanol consumption affects the ubiqutin system
of protein degradation, proteosome activity is
decreased
hepatocyte signalling system is deregulated
apoptosis (feature of alcoholic liver
disease)
Liver function tests:
 Bilirubin
 Aminotransferases (AST and ALT )
 Alkaline phosphatase (ALP )
 Gamma- glutamyl transpeptidase ( γ GT )
 Plasma proteins
 Prothrombin time

AST-ALT
 Sensitive,albeit non-specific index of
 Acute damage to hepatocytes irrespective of
aetiology
 Hepatitis,toxic injury,drug overdose

ALP
 İntra-or extrahepatic cholestasis
 Tumours
 Cirrhosis
 Liver is not the sole source of ALP activity
 Substantial amounts ara present in bone,small
intestine,placenta and kidney.

In normal blood,ALP activity is derived mainly
from bone and liver,with small amounts from
intestine.
 Placental ALP appears in maternal blood in the
third trimester of pregnancy.
 The liver and bone isoenzymes can be separated
by electrophoresis.
 Elevated γ GT suggests that the liver is


the source of increased ALP.

γ GT
Microsomal enzyme,widely distributed in tissues
including liver and renal tubules
 A very sensitive index of liver pathology
 İncreases in cholastasis

Alcohol and pheytoin induce enzyme activity.
 Prothrombin time (PT )

A measure of the activities of certain coagulation
factors,made by the liver
 A very short half-life
 İncreased PT may be the earliest indicator of
reduced hepatic synthesis.


Acute liver disease
Acute liver damage occurs for one of the three
reasons:
 Poisoning
 İnfection
 İnadequate perfusion


Chronic liver disease
Three forms of chronic liver damage are:
 Alcoholic fatty liver
 Chronic active hepatitis
 Primary biliary cirrhosis



Cirrhosis is the terminal stage of chronic liver
damage and only occasionally follows an acute
course.
The most common causes of cirrhosis are
Chronic excess alcohol ingestion
 Viral hepatitis
 Autoimmune diseases
