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Prof. Dr. Kefaya El-Sayed Mohamed
Professor of Clinical Pathology, (Clinical Chimstry)
Clinical Pathology Dep.
Faculty of Medicine, Mansoura University
1-Circulatory function:
Transfer blood from portal to systemic
circulation.
Immune mechanism (RECs in the liver).
Regulate blood volume (blood storage).
Blood formation in faetus and anemic
condition & also it stores antianemic
factors).
Blood coagulation : Synthesis of clotting
factors .
2- Excretory Function:
Bile Function and excretion into intestine.
Bilirubin conjugates.
Bile salts.
Cholesterol.
Excretion of substance into blood.
Heavy metals.
Alkaline phosphatase.
Dyes.
3-Metabolic Functions:
The liver is the central organ for metabolism of :
Carbohydrate:
glycogenesis,
gluconeogenesis, glycogenolysis.
Protein: deamination of blood ammonia
(urea formation) protein synthesis (plasma
protein and coagulation factors).
Lipids: cholesterol, bile salts formation and
secretion and VLDL with synthesis of
apolipoprotein.
Formation of ketone bodies from fat,
protein and pyruvic acid.
Minerals: e.g iron, copper, zinc, Mg.
Vitamins: A, K, B12 and vit. D.
4- Detoxication Function :
Liver cells detoxify metabolic products (bilirubin,
hormones, NH3) and toxic substances by the
following:
Kupfer, cells: phagocytose foreign bodies.
Conjugation with glucuronic acid, glycine,
cysteine, sulphate, glutamine, acetate and
glutathione.
Demethylation, hyolrlysis, hyolroxylation and
carboxylation.
Oxidation and reduction processes.
The biotrans formation of foreign compounds
(e.g. Drugs) this biotransformation consists of
two phases. Phase I involves oxidation or other
reations that introduce a polar group into the
molecule. Phase II consists of conjugation of the
product of phase I or the original compound, if
it already has a polar group, with glucuronate,
glycine, or other moieties (e.g. aminopyrine,
lidocaine, indocyanine green, caffeine and
galactose).
Aim of Liver Function Tests:
Detection of liver disease.
D.D. of jaundice.
Severity and degree of liver damage.
Diagnosis of occult liver diseases.
A number of pitfalls can be encountered in the
interpretation of common blood liver function
tests:
These tests can be normal in patients with
chronic hepatitis or cirrhosis.
The normal range for aminotransferase
levels is slightly higher in males, and
obese persons.
Severe alcoholic hepatitis is sometimes
confused with cholecystitis or cholangitis.
Patients who present soon after passing
common bile duct stones can be
misdiagnosed with acute hepatitis.
Asymptomatic patients with isolated,
mild elevation
of
either
the
unconjugated bilirubin or the Gammaglutamyltransferase value usually
do
not have liver disease and
generally
do not require extensive evaluation.
The commonly used liver function tests (LFTs)
primarily assess liver injury rather than
hepatic function. Indeed, these blood tests may
reflect problems arising outside the liver:
Hemolysis.
Bone diseases.
Liver Function Tests are not always testes of liver function.
Condition
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Pneumococcal pneumonia.
Toxic shock.
Sever heart failure.
Gm negative systemic
infection.
Sickle cell disease.
Toxoplasmosis.
Biochemical pattern
- Bilirubin:  or normal
- ALT and AST: 
Acute
hepatitis
- With or without jaundice
•
Sarcoidosis.
• Hodjkins disease.
• Ulcerative colitis
• Amyloidosis
Bilirubin:  or N.
ALP: 
ALT and AST: slight increase
Granulomatous disease.
• Amyloidosis.
• Abscess.
•Lymphoma.
ALP: 
AST and ALT: slight 
Bilirubin: letter or no 
•
Suggestion
Chronic
hepatic
disease
Infiltrative
lesion of the
liver
Abnormal LFTs often, but not always, indicate that
something is wrong with the liver, and they can
provide clues to the nature of the problem. However,
normal LFTs do not always mean that the liver is
normal.
Patients
with
cirrhosis
and
esophageal varices can have normal LFTs.
bleeding
Markers of Hepatocellular Injury
The most commonly used markers of hepatocyte
injury are (AST) and (ALT).
Elevated ALT or AST in symptomatic patients:
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A Autoimmune hepatitis
B Hepatitis B
C Hepatitis C
D Drug or toxins
E Ethanol
F Fatty liver
G Growths (i.e., tumors)
H Hemodynamic disorder (congestive heart failure)
I Iron (hemochromatosis), copper (Wilson's disease) or
Alpha,-antitrypsin deficiency
M Muscle injury
In hepatitis C, liver cell death occurs by
apoptosis (programmed cell death) as well
as by necrosis. Hepatocytes dying by
apoptosis presumably synthesize less AST
and ALT as they wither away. This
probably explains why at least one third of
patients infected with hepatitis C virus
have persistently normal serum ALT levels
despite the presence of inflammation on
liver biopsy.
Various liver diseases are associated with
typical ranges of AST and ALT levels.
ALT levels often rise to several thousand
units per liter in patients with acute viral
hepatitis. The highest ALT levels--often
more than 10,000 U per L--are usually
found in patients with acute toxic injury
subsequent
to,
for
example,
acetaminophen overdose or acute
ischemic insult to the liver. AST and ALT
levels usually fall rapidly after an acute
insult.
AST and ALT lack some sensitivity in
detecting chronic liver injury. Patients with
cirrhosis often have normal or only slightly
elevated serum AST and ALT levels.
AST and ALT also lack some specificity as
markers of hepatocellular injury.
Elevated levels are found in:
- Sever muscular excertion.
- Polymyositis.
- Hypothyrodism.
Rare individuals have chronically elevated AST
levels because of a defect in clearance of the
enzyme from the circulation.
The elevated AST/ALT ratio in alcoholic liver
disease results in part from the depletion of vitamin
B6 (pyridoxine) in chronic alcoholics. ALT and AST
both use pyridoxine as a coenzyme, but the
synthesis of ALT is more strongly inhibited by
pyridoxine deficiency than is the synthesis of AST.
Alcohol also causes mitochondrial injury, which
releases the mitochondrial isoenzyme of AST,
which explain increase AST/ALT ratio in cirrhosis.
Markers of Cholestasis
Cholestasis (lack of bile flow) results from:
Blockage of bile ducts: AP and (GGT) rise to
several times the normal level rise to several times
the normal level, several days of bile duct
obstruction or intrahepatic cholestasis.
Disease that impairs bile formation in the liver itself
(diffuse infiltrative diseases of the liver such as
infiltrating tumors and fungal infections): AP and
(GGT) rise to greater than 1,000 U per L, or more
than six times the normal value.
Common bile duct stone:
Condition can simulate acute hepatitis
AST and ALT become elevated immediately up to
500U/L on the first hour.
Elevation of AP and GGT is delayed several days
after.
Isolated elevation of GGT level:
This situation may be induced by alcohol and
aromatic medications, usually with no actual liver
disease.
Isolated elevation of AP level
(asymptomatic patient with normal
GGT level)
Consider bone growth or injury.
Primary biliary cirrhosis.
AP level rises in late pregnancy.
Indicators of How Well the
Liver Function
Bilirubin
Albumin
Prothrombin time
Blood Ammonia
Bilirubin
The secretion of conjugated bilirubin into
bile is very rapid in comparison with the
conjugation step, healthy persons have
almost no detectable conjugated bilirubin in
their blood.
The serum conjugated bilirubin level does
not become elevated until the liver has lost at
least one half of its excretory capacity.
The delta-bilirubin phenomenon:
When a patient has prolonged, severe biliary
obstruction followed by the restoration of bile flow,
the serum bilirubin level often declines rapidly for
several days and then slowly returns to normal over
a period of weeks.
Isolated elevation of unconjugated bilirubin level:
- Consider Gilbert syndrome.
- Hemolysis.
Albumin
Although the serum albumin level can serve as an
index of liver synthetic capacity, several factors
make albumin concentrations difficult to interpret:
1) The liver can synthesize. Albumin at twice the
healthy basal rate and thus partially compensate
for decreased synthetic capacity or increased
albumin losses.
2.Albumin has a plasma half-life of
three weeks;
therefore,
serum
albumin
concentrations
change
slowly in
response to alterations in
synthesis.
3.Two thirds of the amount of body
albumin
is
located
in
the
extravascular, extracellular space,
changes in distribution can alter the
serum concentration.
Patients with
Low serum albumin
No other
concentrations
FT abnormalities
Proteinuria
Acute inflammatory states: burns, trauma and sepsis.
Chronic inflammatory states: active rheumatic
disorders.
End-stage malnutrition.
Pregnancy.
Prothrombin time
Prothrombin time (PT) does not become
abnormal until more than 80 percent of liver
synthetic capacity is lost.
Abnormal PT prolongation may be a sign of
serious liver dysfunction.
Because factor VII has a short half-life of only
about six hours, it is sensitive to rapid changes in
liver synthetic function. Thus, PT is very useful
for following liver function in patients with acute
liver failure.
An elevated PT can result from a
vitamin K deficiency.
A trial of vitamin K injections (e.g., 5
mg
per
day
administered
subcutaneously for three days). The PT
should improve within a few days.
Blood Ammonia
Measurement of the blood ammonia
concentration is not always useful in
patients with known or suspected hepatic
encephalopathy:
Ammonia concentrations are much higher in the
brain than in the blood and therefore do not
correlate well.
Ammonia is not the only waste product
responsible for encephalopathy.
Blood ammonia levels are best measured
in arterial blood because venous
concentrations can be elevated as a result
of muscle metabolism of amino acids.
Blood ammonia concentrations are most
useful in evaluating patients with stupor or
coma of unknown origin.
It is not necessary to evaluate blood
ammonia levels routinely in patients with
known chronic liver disease who are
responding to therapy as expected.
Markers of Detoxication
Breath tests e.g. C14 aminopyrine, permits quantitative
measurement of drug metabolism, it consists of giving
C14 labelled aminopyrine by mouth. The labeled
methyle groups undergo demthylation after which they
are converted to Co2. Accordingly, expired Co2
becomes a measure of metabolic conversion of the drug,
and of the hepatic microsomal mass.
Aminopyrine be potentially toxic so:
* Caffiene clearance test ( 3.5 mg/kg max. 200 mg )
Lidocaine clearance (1.0 mg /kg), measurement of
MEGX.
Lodacaine:
It is an aminoethylamine that undergo de-ethylation in
the liver by cytochrome p450, the major metabolite is
monoethylglycine xylidide (ME GX).
Its clearance is decreased in direct relation to hepatic
injury and provides prognostic information regarding
hepatic metabolic function.
Lidocaine l mg/kg I.V. over 60 sec.
Serum samples at base line and 15 min.
Assess MEGX by automated fluorescence polarization
immunoassay.
Used to predict hepatic function in liver donors and in
candidates for liver transplantation.
Galactose clearance:
For cytosol galactokinase.
99Tc-labelled
sialoglycoprotein analogue.
For sinusoidal membrane receptor.
Tumour Markers
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AFP
AFP fraction
CEA
Serum Ferritin
Des gamma carboxyprothrombin
Grading Liver Function
by Child-Turcotte Class
This grading system can be used to:
Predict overall life expectancy.
Surgical mortality in patients with cirrhosis
and other liver diseases.
Transplantation.
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The presence of cirrhosis by itself is not an
indication for liver transplantation, and
transplantation is rarely performed in patients
who fall into Child class A. For example, the
10-year survival rate is as high as 80 percent in
patients with hepatitis C and cirrhosis who have
Child class A liver function and no variceal
bleeding. However, once patients with any type
of liver disease fall into the Child-Turcotte class
B or class C category, survival is significantly
reduced and transplantation should be
considered.
Liver Function Using the Child-Turcotte Class as
Modified by Pugh.
Criteria Assessed
•Encephalopathy
grade
•Ascites
•Bilirubin
(mg/dl)
•Bilirubin for primary
biliary cirrhosis (mg/dl)
•Albumin (g/dl)
•PT prolongation ( S )
Points Scored
1
2
3
None
Absent
1-2
1-4
None
Absent
1-2
1-4
3-4
Moderate
>3
>10
>3.5
>3.5
1-4
< 2.8
>6
1-4
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Patients with a score of 5 to 6 were given a
grade A and were considered to be good
candidates for sclerotherapy. A score from 7 to
9 was classifid as grade B and of moderate
surgical risk . Patients with a score of 10 to 15
were classified as grade C and were
considered poor surgical candidates. The
Child –Pugh grade has been equated with
survival rates for patients with liver disease.
Grade C patients have an overall mortality
near 80% at 5 years.
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The parameters described in the Child-Pugh
system are useful to monitor patients over
time to assess the severity and progression of
cirrhosis. In contrast, liver enzymes such as
ALT/AST and ALP are variable and to not
correlate with the degree of hepatic
dysfunction in patients with cirrhosis. A
falling albumin and an increasing bilirubin
and PT indicate progression of cirrhosis.
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Liver transplantation:
The presence of cirrhosis by itself is not an indication
for liver transplantation, and transplantation is rarely
performed in patients who fall into Child class A.
For example, the 10-year survival rate is as high as
80 percent in patients with hepatitis C and cirrhosis
who have Child class A liver function and no
variceal bleeding. However, once patients with any
type of liver disease fall into the Child-Turcotte class
B or class C category, survival is significantly
reduced and transplantation should be considered.