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Amino acids dietary proteins are the primary source of a a s for endogenous protein synthesis

  • 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.


Amino acids dietary proteins are the primary source of a a s for endogenous protein synthesis

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.


Amino acids dietary proteins are the primary source of a a s for endogenous protein synthesis

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 Wilson’s disease.


Amino acids dietary proteins are the primary source of a a s for endogenous protein synthesis

Amino acid disorders

  • Phenylketonuria (PKU)

  • Urea cycle disorders

  • Tyrosinaemia type 1

  • Homocystinuria

  • Maple syrup urine disease (MSUD)

  • Renal transport disorders

    • Cystinuria


Amino acids dietary proteins are the primary source of a a s for endogenous protein synthesis

Amino acid disorders


Amino acids dietary proteins are the primary source of a a s for endogenous protein synthesis

Selected disorders of a.a. metabolism

Hyperphenylalaninemias: 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.


Amino acids dietary proteins are the primary source of a a s for endogenous protein synthesis

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


Amino acids dietary proteins are the primary source of a a s for endogenous protein synthesis

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.


Amino acids dietary proteins are the primary source of a a s for endogenous protein synthesis

Albinism


Amino acids dietary proteins are the primary source of a a s for endogenous protein synthesis

  • 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


Amino acids dietary proteins are the primary source of a a s for endogenous protein synthesis

  • 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.


Amino acids dietary proteins are the primary source of a a s for endogenous protein synthesis

Maple syrup urine disease:


Amino acids dietary proteins are the primary source of a a s for endogenous protein synthesis

Amino acid disorders


Amino acids dietary proteins are the primary source of a a s for endogenous protein synthesis

  • 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.


Amino acids dietary proteins are the primary source of a a s for endogenous protein synthesis

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


Amino acids dietary proteins are the primary source of a a s for endogenous protein synthesis

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.


Amino acids dietary proteins are the primary source of a a s for endogenous protein synthesis

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 Glutamate–Oxaloacetate 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.


Amino acids dietary proteins are the primary source of a a s for endogenous protein synthesis

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.


Amino acids dietary proteins are the primary source of a a s for endogenous protein synthesis

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).


Amino acids dietary proteins are the primary source of a a s for endogenous protein synthesis

  • 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 twice*ULN);

    • -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).


Amino acids dietary proteins are the primary source of a a s for endogenous protein synthesis

  • Gamma-glutamyl-transferase (GGT)

  • GGT occurs mainly in the cells of liver, kidneys, pancreas and prostate.

  • Plasma GGT activity is higher men <50 U/L) than in women <30 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  can’t 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


Amino acids dietary proteins are the primary source of a a s for endogenous protein synthesis

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 boneand 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.


Amino acids dietary proteins are the primary source of a a s for endogenous protein synthesis

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.


Amino acids dietary proteins are the primary source of a a s for endogenous protein synthesis

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


Amino acids dietary proteins are the primary source of a a s for endogenous protein synthesis

  • 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,


Amino acids dietary proteins are the primary source of a a s for endogenous protein synthesis

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.


Amino acids dietary proteins are the primary source of a a s for endogenous protein synthesis

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.


Amino acids dietary proteins are the primary source of a a s for endogenous protein synthesis

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.


Amino acids dietary proteins are the primary source of a a s for endogenous protein synthesis

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.


Amino acids dietary proteins are the primary source of a a s for endogenous protein synthesis

  • 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.


Amino acids dietary proteins are the primary source of a a s for endogenous protein synthesis

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 ratiosto 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.


Amino acids dietary proteins are the primary source of a a s for endogenous protein synthesis

  • 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.


Amino acids dietary proteins are the primary source of a a s for endogenous protein synthesis

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.


Amino acids dietary proteins are the primary source of a a s for endogenous protein synthesis

Serum Protein Electrophoresis

Electrophoresis separates proteins into five main groups of proteins, albumin and the 1-,2-,- and -globulins,

Anode

Cathode

Anode

Cathode


Amino acids dietary proteins are the primary source of a a s for endogenous protein synthesis

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.


Amino acids dietary proteins are the primary source of a a s for endogenous protein synthesis

Many other important proteins are present in only very low concentration


Amino acids dietary proteins are the primary source of a a s for endogenous protein synthesis

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.


Amino acids dietary proteins are the primary source of a a s for endogenous protein synthesis

  • 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.


Amino acids dietary proteins are the primary source of a a s for endogenous protein synthesis

  • 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


Amino acids dietary proteins are the primary source of a a s for endogenous protein synthesis

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.


Amino acids dietary proteins are the primary source of a a s for endogenous protein synthesis

  • 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 proteinconcentrations 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.


Amino acids dietary proteins are the primary source of a a s for endogenous protein synthesis

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 ….


Amino acids dietary proteins are the primary source of a a s for endogenous protein synthesis

  • 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.


Amino acids dietary proteins are the primary source of a a s for endogenous protein synthesis

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.


Amino acids dietary proteins are the primary source of a a s for endogenous protein synthesis

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


Amino acids dietary proteins are the primary source of a a s for endogenous protein synthesis

  • 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 isnot 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).


Amino acids dietary proteins are the primary source of a a s for endogenous protein synthesis

  • 2-Macroglobulin (α2M)

  • 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.


Amino acids dietary proteins are the primary source of a a s for endogenous protein synthesis

  • 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.


Amino acids dietary proteins are the primary source of a a s for endogenous protein synthesis

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.


Amino acids dietary proteins are the primary source of a a s for endogenous protein synthesis

  • 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 theleakage 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.


Amino acids dietary proteins are the primary source of a a s for endogenous protein synthesis

Neural tube defect (NTD):

Anencephaly: congenital absence of all or a major part of the brain

Spina bifida


Amino acids dietary proteins are the primary source of a a s for endogenous protein synthesis

Acute phase reactants (APR)

Are protein synthesized in the liver in response to inflammatory mediators causethe 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.


Amino acids dietary proteins are the primary source of a a s for endogenous protein synthesis

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.


Amino acids dietary proteins are the primary source of a a s for endogenous protein synthesis

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.


Amino acids dietary proteins are the primary source of a a s for endogenous protein synthesis

  • -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.


Amino acids dietary proteins are the primary source of a a s for endogenous protein synthesis

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


Amino acids dietary proteins are the primary source of a a s for endogenous protein synthesis

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.


Amino acids dietary proteins are the primary source of a a s for endogenous protein synthesis

Wilson’s 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.


Amino acids dietary proteins are the primary source of a a s for endogenous protein synthesis

  • 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.


Amino acids dietary proteins are the primary source of a a s for endogenous protein synthesis

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


Amino acids dietary proteins are the primary source of a a s for endogenous protein synthesis

* 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.


Amino acids dietary proteins are the primary source of a a s for endogenous protein synthesis

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.


Amino acids dietary proteins are the primary source of a a s for endogenous protein synthesis

  • 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.


Amino acids dietary proteins are the primary source of a a s for endogenous protein synthesis

  • 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.


Amino acids dietary proteins are the primary source of a a s for endogenous protein synthesis

  • 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.


Amino acids dietary proteins are the primary source of a a s for endogenous protein synthesis

  • 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 infant’s own IgG.

  • Physiological hypogammaglobulinaemia is one of the reasons for the susceptibility of infants (especially the premature) to infection.


Amino acids dietary proteins are the primary source of a a s for endogenous protein synthesis

  • Pathological causes

  • Various inherited disorders of immunoglobulin synthesis are known  defect or partial defect of only one or two immunoglobulins.

  • Complete absence of immunoglobulins (Bruton’s disease) and affected children develop recurrent bacterial infections,

  • Acquired Hypogammaglobulinaemia resulted form haematological malignancies, such as chronic lymphatic leukaemia, multiple myeloma and Hodgkin’s 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.


Amino acids dietary proteins are the primary source of a a s for endogenous protein synthesis

  • Hypergammaglobulinaemia

  • physiological causes

  • Increased serum immunoglobulins can be seen in both acute and chronic infections.

  • IgGtends to increase in most bacterial and viral infections

  • IgAin 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.


Amino acids dietary proteins are the primary source of a a s for endogenous protein synthesis

  • 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 patient’s 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.


Amino acids dietary proteins are the primary source of a a s for endogenous protein synthesis

  • 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


Amino acids dietary proteins are the primary source of a a s for endogenous protein synthesis

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.


Amino acids dietary proteins are the primary source of a a s for endogenous protein synthesis

  • 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.


Amino acids dietary proteins are the primary source of a a s for endogenous protein synthesis

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 Fe+2,Fe+3.

-Heme: one ferrous ion coordinated in the center of porphyrins.

-Heme is highly turned over: 6–7 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.


Amino acids dietary proteins are the primary source of a a s for endogenous protein synthesis

  • 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 Fe+3 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.


Amino acids dietary proteins are the primary source of a a s for endogenous protein synthesis

Heme Degradation


Amino acids dietary proteins are the primary source of a a s for endogenous protein synthesis

Reabsorbed,go to kidneys and converted excreted as urobillinogen & urobillin (yellow color)

Most are oxidizedby bacteria to stercobillin (brown color)

Urobillinogen

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.


Amino acids dietary proteins are the primary source of a a s for endogenous protein synthesis

  • 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.


Amino acids dietary proteins are the primary source of a a s for endogenous protein synthesis

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.


Amino acids dietary proteins are the primary source of a a s for endogenous protein synthesis

  • 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 aninherited abnormality of bilirubin metabolism (defect in the conjugating enzyme) ’Gilbert’s 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.


Amino acids dietary proteins are the primary source of a a s for endogenous protein synthesis

  • 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.


Amino acids dietary proteins are the primary source of a a s for endogenous protein synthesis

Jaundice in newborns

  • It is physiological jaundice is defined as mild jaundice not present at birth, which develops during the first few days and continues during the first week of life, and for which there is no obvious pathological reason.

  • The transient ‘physiological’ jaundice of the new-borns reflects decrease in the activity of Billirubin glucuronyl transferase

  • The activity increases rapidly.

  • Jaundice during the first 24 hours of life is more likely to be pathological than physiological.

  • Proportionally more unconjugated bilirubin reaches the liver in the newborn infant than in the adult because:

  • 1. The red cell half-life is shorter; the blood haemoglobin concentration falls rapidly during the first week of life, even in normal infants.

  • 2. Delayed clamping of the umbilical cord may significantly increase red cell mass.

  • 3.Damages may occur during birth  haemoglobin breakdown increases the plasma bilirubin concentration.


Amino acids dietary proteins are the primary source of a a s for endogenous protein synthesis

  • Newborns pathological Jaundice that diagnosed in during the first 24 hours of life could occur due:

  • With excessive haemolysis, as in Rhesus incompatibility,

  • a lack of enzyme activity, as occurs in prematurity and in Crigler-Najjar syndrome (the conjugating enzyme is severely reduced).

  • The high plasma level of unconjugated bilirubin leads to jaundice and kernicterus (bilirubin encephalopathy)

  • Bilirubin is destroyed by ultraviolet light and lesser degrees of unconjugated hyperbilirubinaemia can be treated by phototherapy. Water loss from the skin may be high and fluid balance must be carefully monitored.


Amino acids dietary proteins are the primary source of a a s for endogenous protein synthesis

  • Methods for the determination of bilirubin

  • The most widely used routine methods for bilirubin measurements are photometric methods based on diazo reaction.

  • The diazo reagent reacts with bilirubin to produce colorimetric dye.

  • The fraction of bilirubin that reacted with the diazo reagent in the absence of alcohol is called the direct bilirubin fraction (conjugated).

  • Theindirect bilirubin (for Un-Conjugated) is used for the difference between total bilirubin (found after the addition of alcohol to the reaction mixture) and the direct bilirubin fraction.

  • Bilirubin levels in an adult in serum 0.3-1.2 mg/dl (5-21 mol/L), urine negative

  • Conjugated bilirubin (direct) in serum 0- 0.2 mg/dl (0-3.4 mol/L)


Amino acids dietary proteins are the primary source of a a s for endogenous protein synthesis

  • Diseases of the Liver

  • Cholestasis: is any condition in which bile excretion from the liver is blocked, which can occur either in the liver or in the bile ducts.

  • Cholestasis may be either:

  • * Intrahepatic, in which bile secretion from the hepatocytes into the canaliculi is impaired, due to: viral hepatitis; drugs such as chlorpromazine or toxins such as alcohol; inflammation of the biliary tract; autoimmune disease (primary biliary cirrhosis); cystic fibrosis.

  • * Extrahepatic: due to obstruction to the flow of preformed bile through the biliary tract by: biliary stones; inflammation of the biliary tract; pressure on the tract from outside by malignant tissue, usually of the head of the pancreas.


Amino acids dietary proteins are the primary source of a a s for endogenous protein synthesis

Diseases of the Liver

-Alkaline phosphatase activity is the most sensitive test for cholestasis.

*Increased synthesis of ALP in the affected ducts increases the activity of this enzyme in plasma.

* Patients with prolonged, cholestasis may present with severe jaundice and itching due to deposition of retained bile salts in the skin;

* Rarely there is bleeding due to malabsorption of vitamin K, with consequent prothrombin deficiency.

* Cholesterol retention may cause hypercholesterolaemia.

* Dark urine and pale stools suggest biliary retention of conjugated bilirubin,


Amino acids dietary proteins are the primary source of a a s for endogenous protein synthesis

  • 2. Hepatitis:

  • Acute Hepatitis

  • Hepatitis is the Latin word for liver inflammation.

  • * It is characterized by the destruction of a number of liver cells and the presence of inflammatory cells in the liver tissue.

  • * Acute hepatitis is most frequently caused by infectious agents, particularly viruses, and toxins.

  • * Some drugs and chemicals can cause acute hepatitis, including alcohol, paracetamol and carbon tetrachloride.

  • * The viruses primarily associated with hepatitis are hepatitis A, B and ‘non-A, non-B’ (principally hepatitis C virus)

  • -Most cases of viral hepatitis resolve completely.


Amino acids dietary proteins are the primary source of a a s for endogenous protein synthesis

  • Acute Hepatitis

  • -In severe cases, hepatic failure may develop, but most patients who survive the acute illness eventually recover completely, and transaminase activities return normal in ten to twelve weeks.

  • Patients may present with jaundice but this is often not apparent early in the course of the disease.

  • The biochemical findings in acute hepatitis are associated with those of cell membrane damage with an increase in plasma ALT activity greater than that of AST.

  • Hepatitis A (infectious hepatitis), an RNA enterovirus, spread by contact with faecal matter, most often through ingestion of contaminated food.

  • Rarely fatal, it cannot be treated except by bed rest for 1–4 weeks, during which time no alcohol should be consumed.

  • Infection with hepatitis A never leads to chronic disease.

  • It may recur after 3 months.


Amino acids dietary proteins are the primary source of a a s for endogenous protein synthesis

  • Hepatitis B (serum hepatitis): Hepatitis B ranks as the ninth leading killer in the world

  • * is spread through blood, semen, vaginal secretions, and saliva the virus

  • * may take up to 6 months to incubate, and people may also become asymptomatic carriers.

  • Hepatitis B may heal slowly, and is a leading cause of chronic liver disease and cirrhosis.

  • Effective vaccines exist

  • Hepatitis C: remains in the blood for years and accounts for a large percentage of cirrhosis, liver failure, and liver cancer cases.

  • Its main mode of transmission is through blood transfusion, and possibly sexual intercourse


Amino acids dietary proteins are the primary source of a a s for endogenous protein synthesis

  • b. Chronic hepatitis

  • Chronic hepatitis is defined as hepatic inflammation persisting without improvement for six months.

  • Causes include autoimmune liver damage, chronic infection with hepatitis B or C, alcohol and drugs.

  • *Chronic active hepatitis (is caused by active hepatocellular destruction and usually progresses to cirrhosis, which may be present at the time of diagnosis.

  • chronic active hepatitis may respond to treatment with immunosuppresive or antiviral agents, according to its etiology,

  • *Chronic persistent hepatitis (a form of chronic hepatitis that is usually benign, has good prognosis, not progressing to cirrhosis, and usually asymptomatic without physical findings but with continuing abnormalities of tests of liver status).

  • Plasma transaminase activities are elevated in all types, reflecting the continuing hepatocellular damage.

  • ALP activity is usually normal.

  • Indices of synthetic function (albumin, prothrombin time) are often abnormal in chronic active hepatitis but not in chronic persistent hepatitis.


Amino acids dietary proteins are the primary source of a a s for endogenous protein synthesis

  • 3. Cirrhosis

  • - Progressive disease of the liver characterised by diffuse damage to hepatic parenchymal cells, with nodular regeneration, fibrosis, and disturbance of normal architecture;

  • -Associated with failure in the function of hepatic cells and interference with blood flow in the liver, frequently resulting in jaundice, portal hypertension, ascites, and ultimately hepatic failure.

  • - Cirrhosis is the end result of many inflammatory and metabolic diseases involving the liver, including prolonged toxic damage due to alcohol.

  • Causes of cirrhosis include chronic excessive alcohol intake, autoimmune disease, persistence of hepatitis B or C virus and various inherited metabolic diseases, such as Wilson’s disease, haemochromatosis and 1-antitrypsin deficiency.


Amino acids dietary proteins are the primary source of a a s for endogenous protein synthesis

* Cirrhosis can be the cause of biochemical abnormalities decreased albumin synthesis, decreased cholesterol synthesis, insulin resistance and increased prothrombin time,

Prothrombin time (PT) is a blood test that measures how long it takes blood to clot. It can be used to check for bleeding problems and for monitoring the anticoagulant activities.

Prothrombin time, clotting time  acute diseases

* Most of clotting factors are synthesized in the liver (Factor VII is an important one)  if there is any liver problem  clotting time will be increased

Factor VII is vit K dependent so in certain cases, the high prothrombine time is not due to liver diseases but due to vit K deficiency

* Due to the great functional capacity of the liver, metabolic and clinical abnormalities may not become apparent until late in the course of the disease;

There are no reliable, simple biochemical tests to diagnose subclinical liver disease.


Amino acids dietary proteins are the primary source of a a s for endogenous protein synthesis

Cirrhosis


Amino acids dietary proteins are the primary source of a a s for endogenous protein synthesis

  • 3. Tumors

  • The liver is a common site for tumor metastasis.

  • Primary liver tumors are rare and are associated with cirrhosis, persistence of serological markers for hepatitis B and C, and various carcinogens, including aflatoxins.

  • Plasma -fetoprotein is elevated at diagnosis in approximately 70% of patients with primary hepatocellular carcinomas and is a valuable marker for this tumor although it can be increased, usually to a lesser extent, in acute and chronic hepatitis and in cirrhosis.


Amino acids dietary proteins are the primary source of a a s for endogenous protein synthesis

  • Liver Function Tests and Diseases

  • Liver function Tests

  • 1) Testing of Bilirubin which indicates the excretory capacity of the liver: prehepatic, hepatic, posthepatic jaundice

  • 2) Testing of enzymes (ALT, AST, ALP and GGT)

  • ALT is more specific for liver, ALP can indicate the Cholestasis, GGT is sensitive to liver diseases but non-specific

  • 3) Testing of plasma proteins, which indicates the synthetic capacity of the liver

  • Measurement of albumin conc chronic diseases

  • Prothrombin time, clotting time  acute diseases

  • Polyclonal response in the Ig mainly IgG. When there is liver cirrhosis of autoimmune origin  high level of IgG


The end

The End


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