PLASMA PROTEINS The amount of protein in the vascular compartment - PowerPoint Presentation

1. PLASMA PROTEINSThe amount of protein in the vascular compartmentdepends on the balance between the rates of synthesis andcatabolism or loss. However, also important is the relativedistribution between the intravascular and extravascularcompartments, as the concentration depends on therelative amounts of protein and water in the vascularcompartment. Therefore, abnormal concentrations donot necessarily reflect defects in protein metabolism

2. Protein synthesisHepatocytes synthesize many plasma proteins; those ofthe complement system are also made by macrophages.Immunoglobulins are mainly derived from the Blymphocytes of the immune system.Protein catabolism and lossMost plasma proteins are taken up by pinocytosis intocapillary endothelial cells or mononuclear phagocytes,where they are catabolized. Small-molecular-weightproteins are lost passively through the renal glomeruliand intestinal wall. Some are reabsorbed, either directlyby renal tubular cells or after digestion in the intestinallumen; others are catabolized by renal tubular cells

3. Function of plasma protein1-Control of extracellular fluid distributionThe distribution of water between the intravascular andextravascular compartments is influenced by the colloidosmotic effect of plasma proteins, predominantly albumin2-Transport function Albumin and specific binding proteins transporthormones, vitamins, lipids, bilirubin, calcium, tracemetals and drugs. Combination with protein allowspoorly water-soluble substances to be transportedin plasma. The protein-bound fraction of many ofthese substances is physiologically inactive, unlike theunbound fraction.

4. Qualitative methods for studying plasmaand urinary proteinsElectrophoresisElectrophoresis is a technique that separatescompounds such as proteins according to theirdifferent electrical charges. It is usually performed byapplying a small amount of serum to a strip of celluloseacetate or agarose and passing a current across it for astandard time. In this way, five main groups of proteins– namely albumin and the α1, α2, β and g globulins –may be distinguished after protein staining and maybe visually compared with those in a normal controlserum. The following description applies to the normalappearance, in adults, of the principal bands seen afterelectrophoresis on cellulose acetate:

5. Albumin, usually a single protein, makes up the most obvious band. alpha1-globulins consist almost entirely of alpha1-antitrypsin and alpha1-antichymotrypsin.alpha2-globulins consist mainly of alpha2-macroglobulin and and haptoglobinβ-globulins often separate into two; β1 consistsmainly of transferrin and lipoprotein (LDL), and β2 consists of the C3(component of complement.)g-globulins are immunoglobulins; some immunoglobulinsare also found in the alpha2 and β regions.If plasma rather than serum is used, fibrinogen appears as a distinct band in the β–g region.

6. Electrophoretic patterns in diseaseParallel changes in all protein fractionsReduction may occur in severe undernutrition,sometimes due to malabsorption, unless accompaniedby infection and haemodilution. An increase may occurin haemoconcentration.The acute-phase patternTissue damage usually triggers the sequence ofbiochemical and cellular events associated withinflammation. The biochemical changes include thestimulation of synthesis of the so-called acute-phaseproteins, with a rise in the alpha1-globulin and alpha2-globulinfractions. The plasma concentrations of these proteinsreflect the activity of the inflammatory response,and their presence is responsible for the rise in theerythrocyte sedimentation rate (ESR) and increasedplasma viscosity characteristic of such a response.

7. Chronic inflammatory statesIn chronic inflammation, the usual increase inimmunoglobulin synthesis may be visible as a diffuserise in g-globulin. If there is an active inflammatory reaction, the increased density in the g-globulin regionis associated with an increase in the alpha1 and alpha2 fractions of the acute-phase responseCirrhosis of the liverThe changes in the concentrations of plasma proteins usually are‘non-specific’, but in cirrhosis a characteristicpattern is sometimes seen. Albumin and often alpha1-globulin concentrations are reduced and the g-globulinconcentration is markedly raised, with apparent fusionor ‘bridging’ of the b and g bands because of an increasein plasma IgA concentrations

8. Nephrotic syndromePlasma protein changes depend on the severity ofthe renal lesion. In early cases, a low plasma albuminconcentration may be the only abnormality, but thetypical pattern in established cases is reduced albumin,alpha1-globulin and sometimes g-globulin bands and anincrease in alpha2-globulin concentration due to a relativeor absolute increase in the high-molecular-weight a2-macroglobulin. If the syndrome is due to conditionssuch as systemic lupus erythematosus (SLE), theg-globulin concentration may be normal or raised.a1-Antitrypsin deficiencyThe alpha1 band consists almost entirely of a1-antitrypsinand its absence or an obvious reduction in its densitysuggests a1-antitrypsin deficiency

9. AlbuminAlbumin, with a molecular weight of about 65 kDa, issynthesized by the liver. It has a normal plasma biologicalhalf-life of about 20 days. About 60 per cent in theextracellular fluid is in the interstitial compartment.However, the concentration of albumin in the smallerintravascular compartment is much higher because ofthe relative impermeability of the blood vessel wall. Thisconcentration gradient across the capillary membrane isimportant in maintaining plasma volume

10. Cuases of hypoalbuminaemiaDilutional hypoalbuminaemia1-Dilutional hypoalbuminaemia may, as in the case oftotal protein, result from artefactual changes due totaking blood from the arm into which an infusion isflowing, administration of an excess of protein-freefluid or fluid retention, usually in oedematous states orduring late pregnancy.2-Redistribution of albuminRedistribution of albumin from plasma into theinterstitial fluid space results from:1-Recumbency: plasma albumin concentrations may be5–10 g/L lower in the recumbent than in the uprightposition because of the redistribution of fluid.2-Increased capillary membrane permeability: this is theusual cause of the rapid fall in plasma concentrationfound in many circumstances, for example postoperativelyand in most illnesses.

11. Decreased synthesis of albumin1-undernutrition, resulting in an inadequate supply ofdietary nitrogen,2- malabsorption, resulting in impaired absorption ofdietary peptides and amino acids,3- impairment of synthesis, due to chronic liverdysfunction, for example cirrhosisIncreased loss of albumin from the body1-the skin, because of extensive burns or skin diseasessuch as psoriasis; a large part of the interstitial fluidis subcutaneous,2-the intestinal wall, in protein-losing enteropathy,3-the glomeruli, in the nephrotic syndrome.Increased catabolism of albuminCatabolism (and therefore nitrogen loss) is increased inmany illnesses, including sepsis and hyperthyroidism.

12. Consequences of hypoalbuminaemiaThe following may occur.Fluid distribution Albumin is quantitatively themost important protein contributing to the plasma colloid osmotic pressure Oedema may occur in severe hypoalbuminaemia Binding functions Albumin binds calcium, bilirubinand free fatty acids.drugs

13. ParaproteinaemiaThe term paraprotein (or also called M protein) refersto the appearance of an abnormal, narrow, dense bandon the electrophoretic strip. It is found most commonlyin the g region, but may be anywhere from the alpha2 tothe g region. Paraproteins can often be shown to be monoclonal.Causes of paraproteinaemiamyelomatosis, which accounts for most of the cases of malignant paraproteinaemiamacroglobulinaemia (Waldenström’smacroglobulinemia)B-cell lymphomas, including chronic lymphatic leukemia,,sometimes in SLE, chronic inflammation or infections and cryoglobulinaemia

14. The consequences of malignant B-cell proliferation1-increased plasma viscosity2-A high plasma total protein concentration3-Hyponatraemia4-Bence Jones protein5-normochromic normocytic anaemia, a commonpresenting feature of any malignant disease,6- haemorrhages, perhaps due to complexing ofcoagulation factors by the paraprotein,7- Raynaud’s phenomenon, which may occur if theparaprotein is a cryoglobulin,8-hypercalcaemia may also be present

15. Myelomatosis (multiple myeloma; plasma-cell myeloma)Myelomatosis is caused by the malignant proliferation of plasma cells throughout the the bone marrow.The condition becomes increasingly frequent after the age of 50; it can occur before the age of 30, but is rare.The sex incidence is about equal. The clinical features are due to malignant proliferation of plasma cells and disordered immunoglobulin synthesis and/or secretion from the cell.Bone pain may be severe and is due to pressure from the proliferating cells. Radiographs may show discrete punched-out areas of radiotranslucency in the skull, vertebrae, ribs and pelvis.

16. There may be generalized osteoporosis. Pathological fractures mayoccur. Histologically there is little osteoblastic activityaround the lesion, which arises in the marrow ratherthan in the bone itself; consequently, the plasma alkalinephosphatase activity is normal unless there is liverinvolvement, in which case the raised level is of hepatic,not bony, origin. A normal plasma alkaline phosphataseactivity, in cases with bone lesions, suggests myelomatosisrather than bony metastases. Hypercalcaemia may occurand also renal failure. The latter may occur as a result ofBence Jones proteinuria as well as the hypercalcaemia.Amyloidosis is also associated.

17. CryoglobulinaemiaCryoglobulins are proteins that precipitate when cooledbelow body temperature. They may be associated withdiseases known to produce paraproteins. About halfof them can be shown to consist of a monoclonalimmunoglobulin (usually IgM or IgG). The patientusually presents with other symptoms of the underlyingdisease and the cryoglobulin is found duringinvestigation. Occasionally, intravascular precipitationmay occur at temperatures above 22°C and, if theconcentration of protein is high, presenting symptomsand signs may be skin lesions such as purpura andRaynaud’s phenomenon. In some cases the proteinis polyclonal

18. AmyloidAmyloid diseases are secondary protein structurediseases in which insoluble protein fibrils accumulateextracellularly. At least 20 different types of fibrilshave been described in human amyloidosis, each witha different clinical picture. All types of tissue amyloidconsist of a major fibrillar protein that defines their type are:1-soluble in water and in buffers of low ionic strength,2- amorphous eosinophilic appearance on lightmicroscopy after haematoxylin and eosin staining,3-green fluorescence seen under polarized light afterCongo red staining,4- regular fibrillar structure as observed by electronmicroscopy,5- X-ray diffraction shows b-pleated sheet structure.

19. PROTEINS IN URINEThe loss of most plasma proteins through theglomeruli is restricted by the size of the pores in, andby a negative charge on, the basement membrane thatrepel negatively charged protein molecules. Alterationof either of these factors by glomerular disease mayallow albumin and larger proteins to enter the filtrate.Low-molecular-weight proteins are filtered even undernormal conditions; most are absorbed and metabolizedby tubular cells. Normal subjects excrete up to 0.08 gof protein a day in the urine, amounts undetectable byusual screening tests. Proteinuria of more than 0.15 g aday almost always indicates disease.

20. Renal proteinuria1-Glomerular proteinuria is due to increased glomerularpermeability, as in nephrotic syndrome. Albumin isusually the predominant protein in the urine.2-Transient proteinuriaTransient proteinuria may be associated with physicalexertion, trauma, cardiac failure, fever and other acute illness.3-‘Orthostatic’ (‘postural’) proteinuriaProteinuria is usually more severe in the uprightthan in the prone position. The term ‘orthostatic’ or‘postural’ has been applied to proteinuria, often severe,which disappears at night. Overnight urine collectionshows normal albumin excretion (i.e. less than 50 mgduring the 8-h period). It appears to be glomerularin origin and is most common in adolescents andyoung adults, typically those who are tall and thin. Itmay be associated with severe lordosis. Renal functionis normal and proteinuria is usually less than 1g/day

21. 4-MicroalbuminuriaSensitive immunological assays have shown the normaldaily excretion of albumin to be less than 0.05 g.Patients with diabetes mellitus who excrete morethan this, but whose total urinary protein excretion is‘normal’, are said to have microalbuminuria and to beat greater risk of developing progressive renal diseasethan those whose albumin excretion is normal. Thiscan be assessed from the urinary albumin to creatinineratio (ACR) The incidence of this complication may bereduced by optimization of glycaemic control and alsoblood pressure using angiotensin-converting enzyme. Microalbuminuriacan also occur in other diseases, such as inflammatorybowel disease or rheumatoid arthritis.5-Tubular proteinuriaTubular proteinuria may be due to renal tubular damagefrom any cause, especially pyelonephritis. If glomerularpermeability is normal, proteinuria is usually less than1 g/day and consists mainly of low-molecular-weightglobulins and not albumin.

22. alpha-globulins and β-globulins are sensitive markersof renal tubular damage. Tubular proteinuria can bediagnosed by measuring certain low-molecular-weightproteins in urine, such as retinol-binding protein (RBP),N-acetyl-b-D-glucosaminidase or a lpha1-microglobulin.However, because the β2-microglobulins in urineare unstable, other proteins, such as RBP, may be betterindicators of tubular damage6-Overflow proteinuriaThis occurs when proteins of low molecular weight arefiltered normally by the glomerulus and reabsorbed atthe proximal tubule but are produced in amounts greaterthan the reabsorptive capacity of the proximal tubule.Overflow proteinuria can be due to the productionof BJP, to severe haemolysis with haemoglobinuria,or to severe muscle damage

23. 7-Nephrotic syndromeAn established case of the nephrotic syndrome ischaracterized by proteinuria, hypoalbuminaemia,oedema and hyperlipidaemia. The clinical condition iscaused by increased glomerular permeability, resultingin a daily urinary protein loss of, by definition, morethan 3 g