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Amino Acids

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Title: Amino Acids


1
  • Amino Acids
  • Dietary proteins are the primary source of a.a.s
    for endogenous protein synthesis.
  • - a.a.s in blood are filtered through the
    glomerular membranes then reabsorbed in the renal
    tubules by saturable transport systems. When the
    transport mechanism becomes saturated or is
    defective, a.a.s spill into the urine resulting
    in aminoaciduria.
  • Two types of aminoaciduria have been identified
  • 1. Overflow aminoaciduria which occurs when the
    plasma level of one or more a.a.s exceeds that of
    renal threshold (tubular capacity for
    reabsorption).
  • 2. Renal aminoaciduria which occurs when plasma
    levels are normal but the renal transport system
    has a congenital or acquired defect.

2
The aminoaciduria - Aminoaciduria may be primary
or secondary. Primary disease due to an
inherited enzyme defect, also called inborn error
of metabolism. -The defect is located either in
the pathway by which a specific a.a. is
metabolized or in the specific renal tubular
transport system by which the a.a. is
reabsorbed. -The defect in the enzyme results in
substrate accumulation or its diversion into
alternative paths. Products of the normal path
are not formed at all or formed in smaller
amounts.
3
Secondary aminoaciduria - Secondary
aminoaciduria could be due to either to disease
of an organ such as the liver, which is an active
site of a.a. metabolism, or a generalized renal
tubular dysfunction. - It can affect many a.a.
simultaneously Examples of disorders that result
in secondary overflow amnioaciduria are acute
viral hepatitis and acetaminophen poisoning.
Generalized secondary renal aminoaciduria is due
to progressive damage to the renal tubules It
can be caused by poisons (especially heavy
metal), or disease, or by congenital conditions
such as Wilsons disease.
4
Amino acid disorders
  • Phenylketonuria (PKU)
  • Urea cycle disorders
  • Tyrosinaemia type 1
  • Homocystinuria
  • Maple syrup urine disease (MSUD)
  • Renal transport disorders
  • Cystinuria

5
Amino acid disorders
6
Selected disorders of a.a. metabolism Hyperphenyla
laninemias these are a group of disorders
resulting from impaired conversion of
phenylalanine to tyrosine due to the defect in
phenyalanine hydroxylase that found only in the
liver and kidneys.
Defects in this enzyme ? Hyperphenylalaninemia ?
phenylalanine accumulates in blood, urine and CSF
? phenylketonuria (PKU) Untreated PKU results in
severe mental retardation. Affected children
appear normal at birth, and the earliest symptoms
are usually nonspecific-delayed development,
feeding difficulties and vomiting. Children
with PKU elicit an unusual but characteristic
musty odor in urine or sweat, owing to increased
production of phenylpyruvate. Early diagnosis
is essential to avoid the adverse effects of PKU
and consequently neonatal screening has become
widespread.
7
Phenylketonuria (PKU)
Elevated blood-phenylalanine activates the normal
minor metabolic pathways of phenylalanine ?
increased production of phenylketones (e.g.,
phenylpyruvate) and other metabolites that
excreted into the urine.
Treatment of PKU consists of restricting dietary
phenyalanine before the onset of brain damage
8
Tyrosinemia Tyrosinemia has several forms,
each of which is accompanied by high level of
tyrosine and phenolic aciduria. Tyrosine is
essential for protein synthesis and serves as a
precursor for thyroxine, melanin and
catecholamines. The pigment melanin is derived
from tyrosine by the activity of tyrosinase.
Clinical syndromes resulting from inherited
defects in melanin synthesis are collectively
known as albinism.
9
Albinism refers to a group of conditions in which a defect in tyrosine metabolism results in a deficiency in the production of melanin. These defects result in the partial or full absence of pigment from the skin, hair, and eyes. Albinism appears in different forms, and it may be inherited by one of several modes. Complete albinism (also called tyrosinase-negative oculocutaneous albinism) results from a deficiency of tyrosinase activity, causing a total absence of pigment from the hair, eyes, and skin It is the most severe form of the condition.
Albinism
10
  • Cystinuria
  • Classic cystinuria is the most frequently inborn
    error of a.a. transport. This disease is
    characterized by massive excretion of cystine,
    lysine, arginine and ornithine.
  • Normally these a.a.s are filtered by the
    glomerulus and reabsorbed in the proximal renal
    tubule.
  • In cystinuria re-absorption fails because a
    carrier system that transports all a.a.s is
    defective.
  • Because cystine is the least soluble of all the
    naturally occurring a.a.s, its overexertion often
    leads to the formation of cystine caliculi in the
    renal pelvis, ureters, and bladder obstruction,
    infection, and renal insufficiency occasionally
    result.
  • Treatment involves reducing the concentration of
    cystine in urine by drinking large amounts of
    water, increasing cystine solubility by
    maintaining the urine alkaline and, if necessary,
    reducing cystine excretion by using pencillamine

11
  • Maple syrup urine disease
  • Maple syrup urine disease (MSUD) takes its name
    from the characteristic maple syrup or burnt
    sugar odour of the urine of affected persons
    which is due to high concentrations of aliphatic
    keto acids.
  • a.a. analysis of blood and urine show high levels
    of leucine, isoleucine and valine.
  • These branched-chain a.a.s are normally converted
    by transamination to their corresponding ?-keto
    acids, by the enzyme branched-chain amino
    transfersae then oxidized into acyl-coenzyme A
    (CoA) derivatives by branched-chain ?-keto acid
    dehydroghenase
  • An inherited defect in the enzyme branched-chain
    ?-keto acid dehydroghenase results in
    accumulation of the branched-chain a.a.s and
    their corresponding ?-keto acids in blood, urine
    and CSF.

12
Maple syrup urine disease
13
Amino acid disorders
14
  • PLASMA ENZYMES
  • Measurements of the activity of enzymes in
    plasma are of value in the diagnosis and
    management of a wide variety of diseases.
  • Most enzymes measured in plasma are primarily
    intracellular, being released into the blood when
    there is damage to cell membranes,
  • Small amounts of intracellular enzymes are
    present in the blood as a result of normal cell
    turnover.
  • When damage to cells occurs, increased amounts
    of enzymes will be released and their
    concentrations in the blood will rise.
  • However, such increases are not always due to
    tissue damage.
  • Other possible causes include increased cell
    turnover, cellular proliferation (e.g.
    neoplasia), increased enzyme synthesis (enzyme
    induction), obstruction to secretion, decreased
    clearance.
  • Many other enzymes, for example renin,
    complement factors and coagulation factors, are
    actively secreted into the blood, where they
    fulfill their physiological function.

15
A major disadvantage in the use of enzymes for
the diagnosis of tissue damage is their lack of
specificity to a particular tissue or cell type.
Many of these enzyme are not used as diagnostic
tool but used for monitoring the diseases Many
enzymes are common to more than one tissue This
problem may be overcome to some extent in two
ways A) First, different tissues may contain
(and thus release when they are damaged) two or
more enzymes in different proportions e.g.
alanine and aspartate aminotransferase are both
present in cardiac muscle and hepatocytes, but
there is relatively more alanine transaminase in
the liver B) Second, some enzymes exist in
different forms (isoforms), termed isoenzymes.
Individual isoforms are often characteristic of
a particular tissue. So the pattern of increase
of different enzymes can indicate the site of
problem, e.g. high GGT and high ALP or AST
indicates a problem in the liver While high ALT
and CK-MB indicates MI
16
Factors Affecting Results of Plasma Enzyme
Assays Analytical factors affecting results.
Results of enzyme assays are not usually
expressed as concentrations, but as activities.
So the results of such measurements depend on
many analytical factors including the
concentrations of the substrate and product, the
pH and temperature at which the reaction is
carried out, the type of buffer, and the presence
of activators or inhibitors. Physiological
factors affecting enzyme activities, include for
example age plasma aspartate transaminase
activity is moderately higher during the neonatal
period than in adults plasma alkaline
phosphatase activity of bony origin is higher in
children than in adults. sex plasma
gama-glutamyltransferase activity is higher in
men than in women physiological conditions
plasma alkaline phosphatase activity rises during
the last trimester d pregnancy because of the
presence of the placental isoenzyme several
enzymes, such as the transaminases and creatine
kinase, rise moderately in plasma during and
immediately after labour or strenuous exercise.
17
Two important transferases Alanine
aminotransferas (ALT) called also Glutamate
Pyruvate transferase (GPT) or Serum ALT SGPT,
found in many tissues catalyzes the transfer of
amino gp of alanine to produce pyruvate and
glutamate. Aspartate aminotransferase (AST)
called also GlutamateOxaloacetate transferase
(GOT) or Serum AST SGOT, - During the
catabolism of amino acids AST takes amino group
from glutamate to oxaloacetate forming aspartate.
Which used as source of NH4 group in Urea
synthesis Aspartate ? source of amino group of
the urea in the urea cycle.
18
Aspartate Transaminase (AST) 10-45 U/L AST
(glutamate oxaloacetate transaminase GOT) is
present in high concentrations in cells of
cardiac and skeletal muscle, liver, kidney and
erythrocytes. Damage to any of these tissues may
increase plasma AST levels. AST can be used as
indicator of muscle damage. Causes of Raised
Plasma AST Activities Artifact due to in-vitro
release from erythrocytes if there is haemolysis
or if separation of plasma from cells is
delayed. Physiological during the neonatal
period (about 1.5 times the upper adult reference
limit). Marked increase (10 to 100 times the
upper adult reference limit) circulatory failure
with 'shock' and hypoxia myocardial infarction
acute viral or toxic hepatitis.
19
Aspartate Transaminase (AST) Moderate
increase Cirrhosis (may be normal, but may rise
to twice the upper adult reference limit)
infectious mononucleosis (due to liver
involvement (type of viral infection
mononucleosis refers to an increase in a
special type of white blood cells (lymphocytes)
cholestatic jaundice (up to 10 times the upper
adult reference limit) malignant infiltration of
the liver skeletal muscle disease after trauma
or surgery (especially after cardiac surgery)
severe hemolytic episodes (of erythrocyte origin).
20
Alanin Transaminase (ALT) 10-50 U/L ALT
(glutamate pyruvate transaminase, GPT) is present
in high concentrations in liver and, to a lesser
extent, in skeletal muscle, kidney and heart ALT
is more specific for liver than muscle Causes of
Raised Plasma ALT Activities Marked increase (10
to 100 times the upper limit of normal (ULN))
- acute viral or toxic hepatitis. - circulatory
failure with 'shock' and hypoxia Moderate
increase -cirrhosis (may be normal or up to
twiceULN) -infectious mononucleosis (due to
liver involvement) -liver congestion secondary
to congestive cardiac failure -cholestatic
jaundice (up to 10 times the upper reference
limit in adults) -surgery or extensive trauma
and skeletal muscle disease (much less affected
than AST).
21
  • Gamma-glutamyl-transferase (GGT)
  • GGT occurs mainly in the cells of liver, kidneys,
    pancreas and prostate.
  • Plasma GGT activity is higher men lt50 U/L) than
    in women lt30 U/L.
  • It is very sensitive but unspecific indicator for
    liver dysfunction
  • Sensitive ? anything wrong in the liver will
    elevate its activity but non-specific ? cant
    indicate the reason of liver disease
  • Causes of raised plasma GGT activity
  • -Induction of enzyme synthesis, without cell
    damage, by drugs or alcohol. Many drugs most
    commonly the anticonvulsant phenobarbitone and
    phenytoin, and alcohol induce proliferation of
    the endoplasmic reticulum.
  • Cholestatic liver disease, (cholestasis is a
    condition where bile cannot flow from the liver
    to the duodenum) changes in GGT activity usually
    parallel those of alkaline phosphatase.
  • In biliary obstruction, plasma GGT activity may
    increase before that of alkaline phosphatase.
  • Hepatocellular damage, such as that due to
    infectious hepatitis measurement a plasma
    transaminase activities is a more sensitive
    indicator of such conditions.
  • Plasma GGT activity is frequently very high in
    patients with alcoholic liver disease and can be
    elevated, due to enzyme induction, the absence of
    of liver damage

22
Alkaline Phosphatase (ALP) -The alkaline
phosphatases are a group of enzymes that
hydrolyze organic phosphates at high pH. -They
are present in most tissues but are in
particularly high concentration in the
osteoblasts of bone and the cells of the
hepatobiliary tract, intestinal wall, renal
tubules and placenta. -The exact metabolic
function of ALP is unknown but it is probably
important for calcification of bone. - In adults
plasma ALP is derived mainly from bone and liver
in approximately equal proportions the
proportion due to the bone fraction is increased
when there is increased osteoblastic activity
that may be physiological.
23
Causes of raised plasma ALP activity Physiological
during the last trimester of pregnancy the
plasma total ALP activity rises due to the
contribution of the placental isoenzyme Bone
disease Rickets and osteomalacia Rickets is
an abnormal bone formation in children resulting
from inadequate calcium in their bones
Osteomalacia softening of the bones, resulting
from defective bone mineralization in adults
Paget's disease and (ALP may be very high)
Paget's disease is a chronic bone disorder that
is due to irregular breakdown and formation of
bone tissue. Primary hyperparathyroidism with
extensive bone disease Liver disease intra- or
extrahepatic cholestasis, lesions, tumor,
granulomas, and other causes of hepatic
infiltration. Malignancy bone or liver
involvement or direct tumor production.
24
Lactate dehydrogenase
Homolactic fermentation conversion of pyruvate
to lactate
  • Reduction of pyruvate to lactate
  • Lactate is formed by the action of Lactate
    dehydrogenase
  • It is the final product of anaerobic glycolysis
    in eukaryotic cells
  • It is also formed in RBC, lens and cornea of the
    eye, kidney medulla, testes and leukocytes

25
  • Lactate Dehydrogenase (LD) 110-230 U/L
  • - The enzyme is widely distributed in the body,
    with high concentrations in cells of cardiac and
    skeletal muscle, liver, kidney, brain and
    erythrocytes
  • Measurement of plasma total LD activity is
    therefore a nonspecific marker of cell damage.
  • Causes of Raised Plasma Total LD Activity.
  • Artifact
  • due to in vitro haemolysis or delayed separation
    of plasma from whole blood.
  • Marked increase (more than 5 times ULN)
  • -Circulatory failure with 'shock' and hypoxia
  • - Myocardial infarction
  • Some hematological disordersas megaloblastic
    anaemia, acute leukaemias and lymphomas,

26
Creatine Kinase (CK) CK is most abundant in cells
of cardiac and skeletal muscle and in brain, but
also occurs in other tissues such as smooth
muscle. Causes of raised plasma CK
activities Artifact due to in vitro
haemolysis Physiological neonatal period
(slightly raised above the adult reference
range). Marked increase Circulatory failure and
shock myocardial infarction Muscular
dystrophies and high breakdown of skeletal
muscle. The muscular dystrophies are the
most-known group of hereditary muscle diseases
characterized by progressive skeletal muscle
weakness, defects in muscle proteins, and the
death of muscle cells and tissue.
27
Creatine Kinase (CK) Moderate increase Muscle
injury after surgery (for about a week)
physical effort, moderate exercise and muscle
cramp an intramuscular injection hypothyroidism
(thyroxine may influence the catabolism of the
enzyme) alcoholism (due to alcoholic myositis
(inflammation of the muscle)
ISOENZYMES OF CK CK has 3 isoenzymes CK-MM
(CK-3) is the predominant isoenzyme in skeletal
and cardiac muscle and is detectable in the
plasma of normal subjects. CK-MB (CK-2) accounts
for about 35 the total CK activity in cardiac
muscle and less than 5 in skeletal muscle Its
plasma activity is always high after myocardial
infarction. CK-BB (CK-1) is present in high
concentrations in the brain and in the smooth
muscle of the gastrointestinal and genital
tracts. Raised plasma activities may occur during
labour and child birth.
28
Non-specific Causes of Raised Plasma Enzyme
Activities Change in plasma enzyme activity could
be due to nonspecific causes -Slight rises in
plasma aspartate transaminase activities are
common in non-specific findings in many
illnesses. - Moderate exercise, or a large
intramuscular injection, may lead to a rise in
plasma creatine kinase activity - Some drugs,
such as the anticonvulsants phenytoin and
phenobarbitone, may induce synthesis of the
microsomal enzyme, gammaglutamyltransferase, and
so increase its plasma activity in the absence of
disease. - Plasma enzyme activities may be raised
if the rate of clearance from the circulation is
reduced.
29
Plasma Proteins Proteins are polymers of a.a.s
that are covalently linked through peptide bonds.
The different R groups found in a.a.s influence
the structure, functionality and properties of
the individual proteins. Proteins may be
classified as fibrous (mainly structural) or
globular. Nearly all other proteins of clinical
interest are soluble globular proteins such as
haemoglobin, enzymes and plasma proteins. The
complex bending and folding of polypeptide chains
is a result of numerous interactions of their R
groups. Globular proteins are compact and have
little or no space of water in the interior of
the molecule, where most of the hydrophobic R
groups are located. Most polar R groups are
located on the surface of the protein where
influence on protein solubility, acid-base
behaviour and electrophoretic mobility Most
globular proteins are affected with temperature
and pH.
30
  • Plasma proteins
  • Over 100 individual proteins have a
    physiological function in the plasma.
    Quantitatively, the single most important protein
    is albumin. The other proteins are known
    collectively as globulins.

31
Protein Properties - Many of the properties of
proteins are used for their separation,
identification and assay 1-Molecular size Most
proteins are macromolecules, so can be separated
from smaller molecules by dialysis or
ultrafiltration, chromatography and by
density-gradient ultracentrifugation 2.
Differential solubility Protein solubility is
affected by the pH, ionic strength, temperature
and dielectric constant of the solvent. 3.
Electrical charge Separation by electrophoresis,
this is based on the capability of a mixture of
proteins with various species of different
charge/mass ratios to migrate at different rates
in an electrical field. 4. Adsorption on finely
divided inert materials These materials offer a
large surface area for interaction with protein,
such as charcoal, silica or alumina. 5. Specific
binding to antibodies, coenzymes, or hormone
receptors The unique properties of protein to
recognize and bind to a complementary compound
with high specificity is the basis for
immunoassays.
32
  • Analysis of proteins
  • Methods for the analysis of proteins in body
    fluids can be grouped as follows
  • Quantitative measurements of total protein and
    albumin.
  • Separation by electrophoresis, which provides
    semiquantitative estimations of the main classes
    of proteins present in fairly high
    concentrations.
  • Specific quantitative assays of particular
    proteins by immunoassays using specific antisera
    and measurement of antigen-antibody complexes.
  • Detection and identification of abnormal proteins.

33
Serum Protein Electrophoresis
Electrophoresis separates proteins according to
their different electrical charges It is usually
performed by applying a small amount of serum to
a strip of cellulose acetate or agarose and
passing a current across it for standard time.
34
Serum Protein Electrophoresis
Electrophoresis separates proteins into five main
groups of proteins, albumin and the ?1-,?2-,?-
and ?-globulins,
Anode
Cathode
Anode
Cathode
35
Principal bands seen after electrophoresis on
cellulose acetate of normal adult serum 1.
Albumin, usually a single protein, makes up the
most obvious band. 2. ?1-Globulins consists
almost entirely of ?1-antitrypsin. 3.
?2-Globulins consists mainly of
?2-macro-globulin and haptoglobin. 4. ?-Globulins
often separate into two ?1 consists mainly of
transferrin with a contribution from LDL and ?2
consists of C3 complement. 5. ?-Globulins are
immunoglobulins. Some immunoglobulins are found
also in the ?2 and ? regions. - If plasma rather
than serum is used, fibrinogen appears as a
distinct band in the ?-? region. This may make
interpretation difficult blood should be allowed
to clot and serum used if electrophoresis is to
be performed.
36
Principal plasma proteins Principal plasma proteins Principal plasma proteins
Class Protein Approximate mean serum concentration (g/L)
prealbumin 0.25
albumin albumin 40
?1-globulin ?1-antitrypsin ?1-acid glycoprotein 2.9 1.0
?2-globulin haptoglobins ?2-macroglobulin caeruloplasmin 2.0 2.6 0.35
?-globulin transferrin low density lipoprotein complement components (C3) 3.0 1.0 1.0
?-globulins IgG IgA IgM IgD IgE 14.0 3.5 1.5 0.03 trace
Many other important proteins are present in only
very low concentration
37
Serum protein electrophoresis applied to the
serum not plasma Electrophoresis separates
proteins into five main groups of proteins,
albumin and the ?1-,?2-,?- and ?-globulins, may
be distinguished after staining and may be
visually compared with those in a normal control
serum. Each of the globulin fractions contain
several proteins. Changes in electrophoretic
patterns are most obvious when 1. The
concentrations of protein, such as albumin, which
is usually in high concentration, are
abnormal. 2. There are parallel changes in
several proteins in the same fraction. 3. New
band that is not seen in normal serum.
38
  • Electrophoretic patterns in disease
  • Some abnormal electrophoretic patterns are
    characteristic of a particular disorder or while
    others indicate non-specific pathological
    processes.
  • For example, the ?2 band which contains
    haptoglobin may be reduced if there is in vivo
    haemolysis and split into two if in vitro
    haemolysis has occurred.
  • ? Parallel changes in all fractions. Reduction
    may occur in sever malnutrition, unless
    accompanied by infection or haemodilution.
  • ? The acute-phase pattern. Tissue damage of any
    kind triggers the sequence of biochemical and
    cellular events associated with inflammation. The
    biochemical changes include stimulation of
    synthesis of the so-called acute-phase proteins,
    with a rise in the ?1- and ?2-globulin fractions
    ? increase the erythrocyte sedimentation rate
    (ESR).
  • Chronic inflammatory state usual increase in
    immunoglobulin synthesis may be visible as a
    diffuse rise in ?-globulin.
  • Nephrotic syndrome. Plasma protein changes depend
    on the severity of the renal lesion.

39
  • Plasma proteins
  • Proteins are present in all body fluids including
    blood plasma. These proteins are examined
    frequently for diagnostic purposes.
  • The amount of protein in the vascular compartment
    depends on the balance among
  • The rate of synthesis
  • The rate of catabolism or loss
  • The relative distribution between the intra- and
    extravascular compartments ? the concentration
    depends on the relative amounts of protein and
    water in the vascular compartment.
  • Many plasma proteins are synthesized in the
    liver. Some proteins are synthesized both in
    cells and macrophages. Immunoglobulins are mainly
    derived from the B cells of the immune system.
  • Most plasma proteins are taken up by pinocytosis
    into the capillary endothelial cells or
    mononuclear phagocytes where they are
    catabolized. Some are catabolized by renal
    tubular cells.
  • Small proteins are lost passively through the
    renal glomeruli and intestinal wall. Some are
    reabsorbed, either directly by renal tubular
    cells or after digestion in the intestinal lumen

40
Total plasma protein (62-80 gm/L) - Alterations
in plasma protein can be due to A) Change in the
concentration of a specific protein in plasma
(due to changes in the rate of synthesis or
removal) B) Change in the volume of distribution
(plasma water). Decrease in the volume of
plasma water (haemoconcentration) ? as relative
hyperproteinaemia ? concentrations of all plasma
proteins are increased to the same
degree Hyperproteinaemia is caused by 1)
dehydration (haemoconcentration) due to
inadequate water intake or excessive water loss,
as in sever vomiting, diarrhoea, diabetic
acidosis. 2) an increase in the concentration of
specific protein normally present in relatively
low concentration, as, for example, increases in
APRs and polyclonal or monoclonal immunoglobulins
as a result of infection. Hypoproteinaemia
caused by a) decreased synthesis, b)
Haemodilution and c) protein redistribution.
Haemodilution (increase in plasma water volume)
? hypoproteinaemia concentrations of all the
individual plasma proteins are decreased to the
same degree. Haemodilution occurs with water
intoxication or salt retention syndromes, during
massive intravenous infusions.
41
  • Total plasma protein
  • A rapid decrease in protein concentration is
    most frequently due to
  • 1) An increase in plasma volume.
  • 2) Capillary permeability increases in patients
    with septicaemia or generalised inflammatory
    conditions since proteins will diffuse out into
    the interstitial space.
  • The concentration of plasma proteins is
    affected by posture
  • Albumin is present in such high concentrations
    that low levels of this protein alone may cause
    hypoproteinaemia
  • Plasma total protein concentrations may be
    misleading They may be normal in the presence of
    quite marked changes in the constituent proteins.
  • a fall in plasma albumin concentration may be
    balanced by a rise in immunoglobulin
    concentrations, it is quite common.
  • Most individual proteins except albumin
    contribute little to the total protein
    concentration quite a large percentage change in
    the concentration of one may not cause a
    detectable change in the total protein
    concentration.

42
Plasma protein can be divided into 1) Acute
phase reactants (APR) ? these proteins have
specific role in inflammatory response so they
will increase in inflammatory conditions 2)
Negative acute phase reactants ? these proteins
have no role in in inflammation but number of
these proteins decrease in inflammatory
conditions. Like albumin, prealbumin, transferrin
.
43
  • Specific plasma proteins
  • Albumin (35-47 gm/L)
  • The most abundant plasma protein representing
    40-60 of the total protein.
  • It is synthesised in the liver at a rate that
    is dependent on protein intake but subject to
    feedback regulation by the plasma albumin level.
  • Contributes largely to the oncotic pressure of
    plasma. Oncotic pressure is the osmotic pressure
    due to the presence of proteins and is an
    important determinant of the distribution of
    extracellular fluid (ECF) between the
    intravascular and extravascular compartments.
  • The chief biological functions of albumin are
    to
  • Transport and store wide variety of ligands.
  • Maintain the plasma oncotic pressure.
  • Serve as a source of endogenous a.a.s.

44
Hypoalbuminaemia Low albumin concentration may
be due to dilution or redistribution. True
albumin deficiency may be caused by a decreased
rate of synthesis, or by an increased rate of
catabolism or loss from the body.
Causes of hypoalbuminaemia
Decreased synthesis Malnutrition resulting in an inadequate supply of dietary nitrogen Malabsorption resulting in impaired absorption of dietary peptides and a.a. Liver disease Increased volume of distribution Overhydration Increased capillary permeability septicaemia Increased excretion/degradation Nephrotic syndrome Burns Haemorrhage Catabolic states severe sepsis, fever, trauma, Malignant disease
45
Consequences of hypoalbuminaemia 1. Fluid
distribution. The decreased plasma oncotic
pressure disturbs the equilibrium between plasma
and interstitial fluid ? there will be a decrease
in the movement of the interstitial fluids back
into the blood ? accumulation of interstitial
fluid (edema) ? relative decrease in plasma
volume ? fall in renal blood flow ? stimulates
the secretion of renin, and aldosterone through
the formation of angiotensin ? sodium retention
and thus an increase in ECF volume which
potentiates the edema. 2. Binding functions.
Albumin is a high capacity, low affinity
transport protein for many substances, such as
thyroid hormones, calcium, bilirubin and fatty
acids. Many drugs are bound to albumin in the
blood stream as salicylates, penicillin and
sulphonamides. The drug fraction that is bound
to albumin is physiologically and
pharmacologically inactive ? A reduction in
plasma albumin, may increase the plasma free
concentration of those drugs ? cause toxic effects
46
  • Hyperalbuminaemia
  • Hyperalbuminaemia may be due to
  • An artefact, a result of venous stasis during
    blood collection (a sample that was taken from
    an arm at an excessively long cuffing period)
  • Over-infusion of albumin
  • Dehydration high level of plasma
    albumin-greater than 50 g/l is usually indicative
    of severe dehydration.
  • Albumin synthesis is increased in some
    pathological states but never causes
    hyperalbuminaemia.
  • The plasma albumin concentration is used as a
    test of liver function. Because of its relatively
    long half-life (approximately 20 days) in the
    plasma,
  • Albumin concentration is usually normal in acute
    hepatitis.
  • Albumin test is not useful marker for short term
    acute function of the liver
  • Low Albumin concentrations are characteristic of
    chronic liver disease, due to both decreased
    synthesis and an increase in the volume of
    distribution as a result of fluid retention and
    the formation of ascites (free fluid in the
    peritoneal cavity).

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  • ?2-Macroglobulin (a2M)
  • The largest plasma protein.
  • ?2-Macroglobulin inhibits proteases that
    released in inflammatory conditions and destroy
    the tissues and cells ? its main function to
    protect tissues from proteases and it is not
    released during acute inflammation.
  • It is not APR.
  • Because of its large size, it tends to remain in
    the intravascular compartment.
  • It is synthesised in the liver and in the
    reticuloendothelial system.
  • It increases in nephrotic syndrome, because it
    is retained and will not be lost because of its
    large size.
  • Its hepatic synthesis increases in order to
    compensate partially for the decrease in albumin
    normally active in maintaining the oncotic
    pressure.

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  • Transferrin (TRF) B-globulin protein (2.1-3.6
    g/L)
  • It is synthesized mainly in the liver, and in
    the endocrine glands as ovaries and tests.
  • TRF is a ?-globulin which is the major
    iron-transporting protein in the plasma.
  • It reversibly binds numerous cations iron,
    copper, zinc, cobalt and calcium-although only
    iron binding appear to have physiological
    significance.
  • TRF is normally about 30-40 saturated with
    iron and its half life 7 days.
  • Its concentration correlates with the total
    iron-binding capacity of serum.
  • Measurements of plasma transferrin level is
    useful for the differential diagnosis of anaemia
    and for monitoring its treatment.

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Transferrin (TRF) (2.1-3.6 g/L) TRF Plasma
levels are regulated by availability of iron ?
iron deficiency, TRF rise and, upon successful
treatment with iron, it returns to normal level.
In common iron deficiency, the TRF level is
increased due to increases in synthesis ? this
guarantee that any amount of iron absorbed will
be transported and bound to TRF directly and in
this case the of saturation will be less than
30 ? the protein is less saturated with iron
because plasma iron levels are low If the anemia
is due to failure to incorporate iron into
erythrocytes, Vit B12 or folic acid deficiency
the TFR level is normal or low but the protein is
highly saturated with iron. High levels of TRF
occur in pregnancy and oestrogen administration.
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  • ?1-Fetoprotein (AFP)
  • - It is the principal foetal protein.
  • - Appears in infantile urine ? it presents in
    amniotic fluid and maternal blood
  • It is determined in amniotic fluid and in
    maternal serum for the antenatal diagnosis (tests
    before the birth) of neural tube defects.
  • Neural tube defect (NTD) A major birth defect
    caused by abnormal development of the neural
    tube, the structure present during embryonic life
    which gives rise to the central nervous system
    the brain and spinal cord. Neural tube defects
    (NTDs) are among the most common birth defects
    that cause infant mortality (death) and serious
    disability. There are a number of different types
    of NTDs
  • During the foetus growth ? the CNS starts with
    the spinal cord then the nervous system ?
    ?1-Fetoprotein test is done in the 4th months of
    pregnancy to make sure that CNS of the foetus is
    developing normally. High level of this protein
    due the leakage to the amniotic fluid and to
    mother serum indicates defect in CNS development
  • - Detection of higher AFP than the normal in
    early pregnancy can suggest CNS defects
  • Gross elevations of AFP serum levels are found
    in approximately 80 of patients with
    hepatocellular carcinoma,
  • Sequential assays are particularly useful for
    prognosis and for monitoring treatment.

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Neural tube defect (NTD)
Anencephaly congenital absence of all or a major
part of the brain
Spina bifida
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Acute phase reactants (APR) Are protein
synthesized in the liver in response to
inflammatory mediators cause the non-specific
changes in plasma protein concentrations, in
response to acute or chronic tissue damage and
other inflammatory responses The acute-phase
reactants include 1) Activators of other
inflammatory pathways such as C-reactive protein,
so called because it reacts with the
C-polysaccharide of bacteria. During this
response, the concentrations of C-reactive
protein may increase as much as thirty-fold. 2)
Inhibitors for enzymes released in inflammation
such as ?1-antitrypsin, so they will protect body
cells from the attack from these enzymes. 3)
Scavengers such as haptoglobin which binds
haemoglobin released by local in vivo haemolysis
during the inflammatory response.
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C-reactive protein - It is a substance in the
sera of acutely ill patients. - It binds and
complexes with the polysaccharides present in
many bacteria, fungi and protozoal parasites and
becomes an activator of the classic complement
pathway. C-reactive protein, dramatically
increases following myocardial infarction,
trauma, infections, surgery or neoplastic
proliferation. C-reactive protein is test of
choice in monitoring the acute phase response, in
monitoring patients with inflammatory joint
disease such as rheumatoid arthritis. - The most
widely used parameters in inflammation monitoring
are C-reactive protein and ESR (erythrocyte
sedimentation Rate) both will increase in
inflammation.
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Acute phase proteins 1. ?1-Antitrypsin (AAT) -
It is an acute phase reactant with antiprotease
activity. - Plasma concentrations rise two to
three days after trauma or acute infection. - Its
deficiency is associated with lung and liver
disease. - As a protease inhibitor, AAT acts
against chymotrypsin, renin, urokinase, plasmin
and possibly thrombin, but the inhibition of
greatest clinical significance is directed
against neutrophil elastase and collagenase. -
The function of AAT is to neutralise lysosomal
elastase released on phagocytosis of particles by
polymophonuclear leukocytes. -AAT, being a
relatively small molecule, can pass from
capillaries into tissue fluid, bind protease, and
pass back into the intravascular fluid.
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  • -low levels of AAT are found in
  • (1) neonatal respiratory distress syndrome,
  • (2) in sever protein-losing disorders and
  • (3) in congenital deficiency.
  • -Increased levels are more common because AAT is
    an APR.
  • The clinical consequences of inherited disorders
    of ?1-antitrypsin synthesis.
  • - Inhaled particles and bacteria are continuously
    removed from the lungs by leukocytes. This
    phagocytosis gives rise to the release of
    elastase.
  • -When there is deficiency of AAT, the uninhibited
    enzyme attacks and destroys the elastin of the
    alveolar wall.
  • The loss of elasticity of the lung tissue results
    in emphysema with impaired ventilation and
    susceptibility to serious respiratory infections.
    The liver is also affected
  • The condition may be aggravated by cigarette
    smoking, air pollution or infection.

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2. Haptoglobin acute phase protein - Its
function is to bind free haemoglobin released
into the plasma during intravascular haemolysis.
- The haemoglobin-haptoglobin complexes formed
are removed by the reticuloendothelial system -
Its components are metabolised to free a.a.s and
iron - Haptoglobin thus prevents loss of
haemoglobin to urine and conserves iron. - Thus
a low plasma haptoglobin concentration can be
indicative of intravascular haemolysis, or
haemoglobin turnover, as occur in haemolytic
anaemias, transfusion reactions and malaria. -
Low concentrations due to decreased synthesis are
seen in chronic liver disease, metastatic disease
and severe sepsis. - Haptoglobin is an acute
phase protein and its concentration also
increases in burns, nephrotic syndrome
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3. Caeruloplasmin - Caeruloplasmin is a late
APR - It is the principal copper-containing
protein in plasma. It is a copper donor, another
possible role of CER is as an antioxidant - Once
CER is synthesised, it neither gains nor loses
copper unless metabolised. -Plasma copper
consists of a non-dialysable fraction (95)
attached to CER and of dialyzable (free) fraction
(5) loosely bound to albumin and histidine.
-Copper is transported in the dialysable form
from the gut to the liver it is incorporated
into the CER apoprotein, which is released into
the bloodstream. - Increased absorption of
copper leads to increased synthesis of CER and
increased excretion of copper-protein complexes
in the bile. -Synthesis of CER thereby provides
a first-line reaction to potential copper
toxicity.
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Wilsons disease CER deficiency It is rare
condition where the plasma CER is typically
reduced ? free copper concentration is increased.
Unless treated with copper chelators such as
penicillamine, the disease is always progressive
and fatal and causes liver dysfunction. The two
fundamental disturbances could occur I) a gross
decrease in the rate of incorporation of copper
into apoprotein II) a marked reduction in the
biliary excretion of copper. - Copper is
deposited in the kidneys, in the liver (where it
causes cirrhosis) and in brain (where it damages
the basal ganglia). - Low plasma levels of CER
are also found in malnutrition, malabsorption,
nephrosis and sever liver disease. Exercise,
pregnancy and by oestrogen-containing oral
contraceptives increase CER concentration.
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  • Immunoglobulins
  • Immunoglobulins are unique in their
    heterogenisity, in their sites of synthesis and
    in the fact their synthesis is an adaptive
    response to antigenic stimulation.
  • -The immunoglobulins are a group of plasma
    proteins that function as antibodies, recognising
    and binding foreign antigens.
  • This facilitates the destruction of these
    antigens by elements of the cellular immune
    system.
  • Since every immunoglobulin molecule is specific
    for one antigenic determinant, or epitope, there
    are vast numbers of different immunoglobulins.

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Immunoglobulins Most plasma proteins are
synthesised in the liver. Immunoglobulins are
synthesised and secreted by plasma cells (mature
B-lymphocyte, immunoglobulin producing cells),
-These cells develop numerous receptor
immunoglobulins on their surface membranes. Upon
encountering antigen, these B-lymphocytes
proliferate and develop into plasma cells, each
of which secretes into the blood a highly
specific antibody capable of binding additional
antigen. The stimulating antigen are normally
foreign but may be on host cell surfaces and
cause autoimmune disease
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All Immunoglobulins share similar basic
structure, consisting of two identical heavy
polypeptide chains and two identical light
chains, linked by disulphide bridges. There
are five types of heavy chain (? Gamma, ? Alpha,
? Mu, ? Delta, ? Epsilon) and two types of light
chain (? Kappa, ? Lambda),
The immunoglobulin class is determined by the
type of heavy chains. Light chains, are
produced independently and in slight excess of
their incorporation into immunoglobulins, their
constant regions have different structures.
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There are five types of heavy chain (? Gamma, ?
Alpha, ? Mu, ? Delta, ? Epsilon) and two types of
light chain (? Kappa, ? Lambda), The
immunoglobulin class is determined by the type of
heavy chains.
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  • IgG
  • Is the most abundant immunoglobulin.
  • It forms 65 of immunoglobulin in extravascular
    liquids and 70-75 of serum Antibodies of the IgG
    class are produced in response to most bacteria
    and viruses they aggregate and coat small
    soluble foreign proteins such as bacterial
    toxins.
  • IgGs that are slightly different in the
    structure of their variable regions
  • IgA
  • Approximately 10-15 of serum immunoglobulins is
    IgA
  • Secretary IgA is found in tears, sweat, saliva,
    milk, colostrum (is the first milk that breasts
    produce in the early days of breast feeding) and
    GI and bronchial secretions.
  • It is synthesised mainly by plasma cells in the
    mucous membranes of the gut and bronchi and in
    the lactating breast.
  • The secretary component makes IgA more resistant
    to enzymes and protects the mucosa from bacteria
    and viruses.
  • Its presence in colostrum and milk probably
    protects neonates from intestinal infections.

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  • IgD
  • Accounts for less than 1 of serum
    immunoglobulins.
  • Like IgD and IgM are surface receptors for
    antigen in B-lymphocytes, but its primary
    function is unknown.
  • IgM
  • Is the most ancient and least specialised
    immunoglobulin
  • The only immunoglobulin that produced by neonate
  • In adult serum, it is the third most abundant
    immunoglobulin and accounts for 5-10 of the
    total circulating immunoglobulins.
  • Most of IgM is a pentamer of five IgM monomers.
  • Its high molecular weight prevents its passage
    into extravascular spaces.
  • B-lymphocytes at first have IgM surface
    receptors and secrete IgM in the first or
    primary response to an antigen.

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  • IgE
  • Is rapidly and firmly bound to mast cells and
    only trace amounts of it are normally present in
    serum.
  • Each molecule may be a different antibody
    produced by a different variable region.
  • When antigen (allergen) cross-links two of the
    attached IgE molecules, the mast cell is
    stimulated to release histamine and other
    vasoactive amines.
  • These amines are responsible for the vascular
    permeability and smooth muscle contraction
    occurring in such allergic reactions as hay
    fever, asthma, urticaria and eczema.

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  • Immunoglobulins disorders
  • Increases and decreases of plasma immunoglobulin
    concentrations can be either physiological or
    pathological in origin.
  • Hypogammaglobulinaemia
  • Physiological causes
  • At birth IgA and IgM concentrations are low and
    rise steadily,
  • IgA may not reach the normal adult concentration
    until after the end of the first decade.
  • IgG is transported across the placenta during
    the last trimester of pregnancy and levels are
    high at birth (except in premature infants).
  • The IgG concentration then declines, as maternal
    IgG is cleared from the body, before rising again
    as it is slowly replaced by the infants own IgG.
  • Physiological hypogammaglobulinaemia is one of
    the reasons for the susceptibility of infants
    (especially the premature) to infection.

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  • Pathological causes
  • Various inherited disorders of immunoglobulin
    synthesis are known ? defect or partial defect of
    only one or two immunoglobulins.
  • Complete absence of immunoglobulins (Brutons
    disease) and affected children develop recurrent
    bacterial infections,
  • Acquired Hypogammaglobulinaemia resulted form
    haematological malignancies, such as chronic
    lymphatic leukaemia, multiple myeloma and
    Hodgkins disease.
  • Hypogammaglobulinaemia can be a complication of
    the use of cytotoxic drugs and is a feature of
    severe protein-losing states, for example, the
    nephrotic syndrome and increased catabolism
  • Measurements of the specific class of
    immunoglobulin is essential for the diagnosis of
    hypogammaglobulinaemia.

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  • Hypergammaglobulinaemia
  • physiological causes
  • Increased serum immunoglobulins can be seen in
    both acute and chronic infections.
  • IgG tends to increase in most bacterial and
    viral infections
  • IgA in skin, gut, respiratory and renal
    infections
  • IgM in primary viral infections and bloodstream
    infections such as malaria.
  • Chronic bacterial infections cause an increase
    in serum levels of all immunoglobulins.
  • Pathological causes
  • IgG tends to predominate in autoimmune
    responses
  • IgG and other plasma immunoglobulin
    concentrations are increased in autoimmune
    diseases, for example, rheumatoid disease and
    systemic lupus erythromatosus (SLE), and in
    chronic liver diseases which have an autoimmune
    basis.
  • The measurement of an specific immunoglobulin is
    important for diagnosis of some infectious
    diseases e.g., in chronic active hepatitis, IgG
    and sometimes IgM are increased.
  • Estimations of IgE are used in the management of
    asthma and other allergic conditions, especially
    in children.

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  • Monoclonal immunoglobulins (paraproteins)
  • A single clone of plasma cells produces
    immunoglobulin molecules with identical
    structures. If the clone is permitted to
    multiply, the concentration of its particular
    protein in the patients serum becomes so great.
  • These monoclonal immunoglobulins, which are also
    called paraproteins, may be polymers, monomers,
    or fragments of immunoglobulin molecules if
    fragments they are usually light chains (Bence
    Jones proteins) or, rarely, heavy chains or
    half-molecules.
  • Paraproteins (usually IgG or IgA) occur most
    frequently in multiple myeloma (malignant
    proliferation of plasma cells).
  • Since all molecules are identical, the
    paraprotein is seen on electrophoresis as a
    separated band, usually in the ?-region. The
    urine also must be examined because these
    proteins rapidly cleared into urine
  • Detection of paraproteins (Bence Jones proteins)
    indicates the presence of neoplastic plasma cells
  • Paraproteins can also be benign, that is, not
    associated with malignant disease. The incidence
    of benign paraproteinaemia increases with age.

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  • The liver
  • The liver is the largest organ in the human body
    it weighs approximately 1.2 to 1.5 kg in the
    adult.
  • The liver has a dual blood supply the portal
    vein, which carries nutrient-rich blood from the
    capillary bed of the alimentary tract, and the
    hepatic artery, which carries well-oxygenated
    blood to the liver.
  • Venous drainage from the liver occurs via the
    right and left hepatic veins.
  • The liver is of vital importance in intermediary
    metabolism and in the detoxification and
    elimination of toxic substances.
  • Major functions of the liver
  • Carbohydrate metabolism gluconeogenesis,
    glycogen synthesis glycogenolysis
  • Fat metabolism fatty acid synthesis, cholesterol
    synthesis excretion, lipoprotein synthesis,
    ketogenesis and bile synthesis 25-hydroxylation
    of vitamin D
  • Protein metabolism synthesis of plasma proteins
    (including some coagulation factors but not
    immunoglobulins, urea synthesis
  • Hormone metabolism metabolism and excretion of
    steroid hormones, metabolism of polypeptide
    hormones
  • Drugs and foreign compounds metabolism and
    excretion
  • Storage glycogen vitamin A vitamin B12 iron
  • Metabolism and excretion of bilirubin

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Excretion and detoxification function of the
liver 1. Bilirubin 2. Amino acids, which are
deaminated in the liver. Amino groups, and the
ammonia produced by intestinal bacterial action
and absorbed into the portal vein are converted
to urea. 3. Cholesterol, which is excreted in the
bile either unchanged or after conversion to bile
acids. 4. Steroidal hormones, which are
metabolised and inactivated by conjugation with
glucuronate or sulphate and excreted in the urine
in these water-soluble forms. 5. Many drugs. 6.
Toxins, the reticuloendothelial Kupffer cells in
the hepatic sinusoids are well placed to extract
toxic substances which have been absorbed from
the GIT. Efficient excretion of the end-products
of metabolism and of bilirubin depends on 1.
Normally functioning liver cells. 2. Normal blood
flow through the liver. 3. Normal biliary ducts.
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  • Simple damage to the liver may not obviously
    affects its activity since the liver has
    considerable functional reserve.
  • So simple tests of liver function (e.g., plasma
    bilirubin and albumin concentrations) are
    insensitive indicators of liver disease, a fall
    in plasma albumin concentration could be
    attributed to advanced liver disease.
  • Tests reflecting liver damage (measurements of
    the activities of hepatic enzymes in plasma) are
    used.
  • The most common disease processes affecting the
    liver are
  • ? Hepatitis, with damage to liver cells.
  • ? Cirrhosis, in which increased fibrous tissue
    formation leads to shrinkage of the liver,
    decreased hepatocellular function and obstruction
    of bile flow.
  • ? Tumours, most frequently secondary for
    example, metastases from cancers of the large
    bowel, stomach and bronchus.
  • Patients with liver disease often present with
    characteristic symptoms and signs, but the
    clinical features may be non-specific and in some
    patients, liver disease is discovered
    incidentally.
  • Extrahepatic biliary disease may present with
    clinical features suggestive of liver disease ?
    may have secondary effects on the liver for
    instance, obstruction to the common bile duct may
    cause jaundice and, if prolonged, a form of
    cirrhosis.

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Bilirubin metabolism - Bilirubin is derived from
the haem moiety of the haemoglobin, myglobin and
cytochrome molecules Haem Pophyrins Porphyrins
are cyclic compounds that bind metal ions usually
Fe2,Fe3. -Heme one ferrous ion coordinated in
the center of porphyrins. -Heme is highly
turned over 67 gm is synthesized and destroyed
daily Structure of porphorins -Ring structure of
4 pyrrole rings linked with methylenyl
bridge. -Side chains different porphyrins vary
of the side chain that are attached to pyrrole
rings.
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  • Bilirubin metabolism
  • - Bilirubin is derived from the haem moiety of
    the haemoglobin, myglobin and cytochrome
    molecules
  • - Iron is reutilized
  • RBC are taken up by liver and spleen and
    macrophages, and
  • degraded by reticulo-endothelial system (RE)
  • Formation of bilirubin
  • -Degradation is catalyzed by microsomal heme
    oxygenase enzyme of the ER cells.
  • -The enzyme add the OH to the methylen bridge
    oxidation? CO and Fe3 is released and the
    product is Billiverdin then it is reduced into
    Billirubin.
  • Uptake of Billirubin by liver
  • - Billirubin is slightly soluble in water
    ?transported in the blood through complexion to
    albumin, then taken by hepatocytes.
  • Formation of Billirubin diglucuronide
  • - In hepatocytes, the solubility of Billirubin is
    increased by addition of two molecules of
    Glucuronic acid catalyzed by Billirubin
    glucuronyl transferase using UDP-glucuronic
    acid.

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Heme Degradation
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Excretion of Billirubin into bile - Conjugated
bilirubin is water-soluble and is secreted
actively into the biliary canaliculi, eventually
reaching the small intestine via the ducts of the
biliary system. Secretion into the biliary
canaliculi is the rate limiting step in bilirubin
metabolism -Billirubin diglucuronide is
hydrolyzed and reduced by bacteria in the gut to
yield urobillinogen.
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  • Jaundice
  • Jaundice The yellow staining of tissues skin
    and sclera due to bilirubin deposition, is a
    frequent feature of liver disease.
  • High level Bilirubin is toxic to CNS
  • The bilirubin normally present in plasma is
    mainly (approximately 95) unconjugated since it
    is protein bound, it is not filtered by the renal
    glomeruli and, in health, bilirubin is not
    detectable in the urine.
  • Bilirubinuria appearance of bilirubin in urine
    ? reflects an increase in the plasma
    concentration of conjugated bilirubin, and is
    always pathological.
  • Clinical jaundice may not be seen unless the
    plasma bilirubin concentration is more than two
    and half times the upper limit of normal.
  • Hyperbilirubinaemia can be caused by increased
    production of bilirubin, impaired metabolism,
    decreased excretion or even combination.

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Jaundice can be classified to ? An increased
rate of bilirubin production exceeds normal
excretory capacity of the liver (prehepatic
jaundice)(Hemolytic jaundice sickle cell anemia,
or malaria). ? The normal load of bilirubin
cannot be conjugated and/or excreted by damaged
liver cells (hepatic jaundice). Hepatocellular
Jaundice liver damage, cirrhosis, hepatitis. ?
The biliary flow is obstructed, so that
conjugated bilirubin cannot be excreted into the
intestine and is returned into the systemic
circulation (posthepatic jaundice) Obstructive
jaundice bile duct obstruction.
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  • Biochemical assessment of liver function
  • Bilirubin ( total bilirobin 0.3-1.2 mg/dl)
  • Unconjugated hyperbilirubinaemia
  • -Unconjugated hyperbilirubinaemia occurs if there
    is
  • A marked increase in the bilirubin load as a
    result of haemolysis, or of the breakdown of
    large amounts of blood after haemorrhage into the
    GIT. In haemolysis, hyperbilirubinaemia is due to
    increased production of bilirubin, which exceeds
    the capacity of the liver to remove and conjugate
    the pigment.
  • Unconjugated hyperbilirubinaemia is also can be
    associated to high urobilinogen. Haemolytic
    disease ? more bilirubin is excreted in the bile
    ? the amount of urobilinogen entering the hepatic
    circulation ? increased and urinary urobilinogen
    is increased.
  • As a result of haemolytic disease, the plasma
    concentration of unconjugated bilirubin may be as
    high as 500 ?mol/L (30 mg/dl) and exceeds the
    plasma protein-binding capacity.
  • Impaired binding of bilirubin to ligand or
    impaired conjugation with glucuronate in the
    liver. Like in some liver disease.
  • It could be due to an inherited abnormality of
    bilirubin metabolism (defect in the conjugating
    enzyme) Gilberts syndrome,
  • Unconjugated bilirubin is normally totally bound
    to albumin. It not water soluble and therefore
    cannot be excreted in the urine.
  • Patients with unconjugated hyperbilirubinaemia
    do not have bilirubinuria.

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  • Conjugated hyperbilirubinaemia
  • Due to leakage of bilirubin from either
    hepatocytes or the biliary system into the
    bloodstream when its normal route of excretion is
    blocked.
  • The water-soluble conjugated bilirubin entering
    the systemic circulation is excreted in the
    urine, giving it a deep orange-brown colour.
  • In complete biliary obstruction, no bilirubin
    reaches the gut, no urobilin is formed and the
    stools are pale in colour.
  • Hyperbilirubinaemia can be due to an excess of
    both conjugated and unconjugated bilirubin.
  • Bilirubinuria is always pathological.

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  • Jaundice in
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