factors affecting the sedimentation rate
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Factors Affecting the Sedimentation Rate. Elevating the ESR: Inflammatory Diseases Cytokine driven processes that elevate fibrinogen ie TB, Pneumonia, rheumatoid arthritis - PowerPoint PPT PresentationTRANSCRIPT
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Factors Affecting the Sedimentation Rate
Elevating the ESR: Inflammatory Diseases
Cytokine driven processes that elevate fibrinogen ie TB, Pneumonia, rheumatoid arthritis • Relative/Absolute Increase in Globulin Proteins
Loss of albumin ie nephrotic syndrome or increase in globulins ie multiple myeloma • Extensive Tissue Necrosis
Myocardial infarction, trauma, tumors • Other Causes
Pregnancy (increase in fibrinogen, anemia), anemia, age, heparinized blood
• Lowering the ESR: • Increased Plasma Viscosity
Waldenstrom's macroglobulinemia • Red Cell Number or Shape
Polycythemia vera, sickle cell disease • Decreased Plasma Proteins
Hepatic necrosis, hypofibrinogenemia • Others Causes
Trichinosis
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• Range - The range of normal SRE is 0-15 mm/hr for men and 0-20 mm/hr for women. Many articles have detailed the elevation of the ESR with age and some have suggested the formula of age divided by 2 for men and age plus 10 divided by 2 for women although this has not been universally adopted.
• Utility - Although still widely used, the sedimentation rate has limited use as a diagnostic test. It is useful for predicting prognosis in diseases such as rheumatoid arthritis and Hodgkin's disease and it has utility as a marker of treatment efficacy in many diseases such as rheumatoid arthritis, the vasculitides, collagen vascular diseases, and septic arthritis.
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CRP (Proteina C reattiva)• The C-reactive protein owes its name to the ability of this protein to
precipitate pneumococcal C-polysaccharide in the presence of calcium. It was first discovered in 1930 by Tillet and Frances.
• a positive CRP may indicate any of a number of things: • Rheumatoid arthritis • Rheumatic fever • Cancer • Tubercolosis • Pneumococcal pneumonia • Myocardial infartion • Systemic Lupus Erithematosus • Positive CRP results also occur during the last half of pregnancy or
with the use of oral contraceptives.
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Utility - Because the CRP is a direct measure of inflammation and it is becoming easier and cheaper to do, there may be a time the CRP supersedes the ESR (although the same was said for the measure of plasma viscosity 10 years ago). It is as useful as the ESR in most cases and more accurately reflects the current level of inflammation.
CRP
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PRINCIPALI MALATTIE AUTOIMMUNI
SISTEMICHE INTERMEDIE ORGANO-SPECIFICHE
LES S. GOODPASTURE T. HASHIMOTO
AR UVEITE FACOGENICAADDISON IDIOPATICO
LUPUS DISCOIDE CIRROSI B. PRIM. GASTRITE ATROFICA
SCLERODERMIA OFTALMIA SIMPATICA DIABETE GIOVANILE
D. MIOSITESCLEROSI MULTIPLA IFERTILITA' MASCH.
CONNETTIVITEMISTA
M. DI SJOGREN S. PLURIENDOCRINEAUTOIMMUNIMIASTENIA GRAVE
COLITE ULCEROSA ANEMIA PERNICIOSA
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Lupus eritematoso sistematico Appare nelle donne tra 13 e 40 anni. Rapporto maschio-
femmina 1:10 Caratterizzato da febbre, debolezza, artriti, disfunsioni
renali I pazienti producono autoanticorpi verso il DNA, istoni,
eritrociti, piastrine, leucociti, e fattori di coagulazione del sangue
Gli immunocomplessi depositati lungo le pareti dei vasi sanguigni causano una ipersensibilità di tipo III, originano danno endoteliale che da luogo alle reazioni infiammatorie che generano vasculuiti e glomerulonefriti
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Esami di Routine e Lupus
Incremento della VES e dei livelli di PCR
Emocromo:Anemia (Sintomo Costante)
Leucopenia (Linfocitopenia)
Trombocitopenia
Alterazioni della coagulazione (Lupus Anticoagulante)
Esame Urine: Albuminuria (Microalbuminuria)
Ematuria
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Allo stato attuale la dimostrazione della positività della ricerca di autoanticorpi anti-
nucleo (ANA) o la presenza di anticorpi anti-dsDNA o anti-Sm (uno degli antigeni nucleari estraibili, ENA) costituiscono 2 degli 11 criteri utilizzati da anni per la
diagnosi di lupus eritematoso sistemico
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In generale il protocollo diagnostico iniziale, in pazienti sintomatici prevede
la rilevazione degli anticorpi anti-nucleo in IFI; il pattern di fluorescenza nucleare o citoplasmatico determina la scelta successiva, rappresentata dalla ricerca di autoanticorpi diretti verso
uno o più specifici autoantigeni intracellulari
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UV light
Autoimmunity
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Determinazione degli ANA: Tecnica IFI
Standardizzata con linee cellulari epiteliali (HEp-2) (esprimono antigeni umani presenti in tutte le fasi del ciclo cellulare)
Ai fini diagnostici I titoli di 1:40 e di 1:160 sono considerati come livelli decisionali: Titolo soglia 1:40 (alta sensibilità/bassa specificità)
<1:40 negativo. (Anticorpi antinucleo a basso titolo 1:40 - 1:80 possono essere presenti in soggetti sani, nelle gravide, in donne sopra i 40 anni, negli anziani)
>1:40 e <1:160 basso positivo (in assenza di sintomi specifici, il protocollo diagnostico deve prevedere un monitoraggio in tempi successivi)
>/=1:160 sono da considerare comunque suggestivi di patologia autoimmune.
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Pattern periferico Forte fluorescenza alla periferia del nucleo debole al centro. Dovuta alla presenza di autoanticorpi diretti contro ds DNA o contro desossiribonucleoproteine
Pattern omogeneo Fluorescenza omogeneamente diffusa a tutto il nucleo con colorazione dei cromosomi delle cellule in mitosi. Gli Ab sono diretti contro desossiribonucleoproteine, istoni, dsDNA.
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IL test IFI viene utilizzato anche per la valutazione degli anticorpi anti ds DNA questo test si fonda su una reazione a carico del DNA mitocondriale a doppia elica contenuto nel cinetoplasto di un emoflagellato non patogeno per l’uomo (Crithidia luciliae)
NegativoPositivo
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Limitazioni di quest’approccio:
Alcuni ENA (anti-Ro/SSA ed anti-Jo1) possono dare risultati falsamente negativi (ridotta espressione degli antigeni-bersaglio nelle cellule HEp-2; perdita e/o denaturazione degli antigeni in fase di allestimento dei vetrini
Non univocità della modalità di refertazione
Dipendenza dell’affidabilità del dato dall’esperienza del microscopista
Difficoltà di reperimento di sieri standard di riferimento
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Gli anticorpi anti-DNA
Test EIA DNA a singola elica (denaturato, ssDNA; determinanti
antigenici: zone ricche di G-C e A-T) DNA nativo a doppia elica (dsDNA, epitopi localizzati
lungo lo scheletro glico-fosfato)
Metodica IFI (Crithidia luciliae),DNA nativo a doppia elica
Gli anticorpi anti-ssDNA non hanno una buona associazione con precisi quadri patologici. Gli anticorpi anti-dsDNA sono
altamente specifici per il LES (10° criterio diagnostico del LES)
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AutoantigeniENA: Ro/SS-ALa/SS-BSmRNPTopoisomerasi I (Scl-70)Istidil-tRNA sintetasi (Jo-1)Proteina B centromerica (CENP-B)rRNPNucleosomi (cromatina)
In presenza di segni clinici di S. di Sjogren o di Dermatomiosite/polimiosite possono
rappresentare il principale dato di laboratorio.
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Protocolli diagnostici in alcune malattie Autoimmuni
LUPUS
ANA Pattern omogeneo o periferico ad
alto titoloAnti dsDNA PositivoENA anti-Sm (altri inutili)AnticorpiAntifosfolipidi Incostantemente presenti e lupus Anticoagulante
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Protocolli diagnostici di base in alcune malattie Autoimmuni
Sindrome di Sjogren
•IgG Incremento policlonale•ANA 20% dei casi negativi
80% dei casi positivi 80% granulare20% omogeneoRaramente Nucleolare
•Anti dsDNA (Inutili)
•ENA 80% Ssa/Ro70% SSb/La
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Protocolli diagnostici di base in alcune malattie Autoimmuni
Polimiosite/Dermatomiosite
VES Molto Elevata
Emocromo Lieve anemia, Eosinofilia
ANA Pattern granulare
Anti dsDNA (Inutili)
ENA 15% dei casi positivo Jo1
CPK, LDH Generalmente aumentate
Fattore Reumatoide 30% dei casi positivo
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Antiphospholipid antibodies:
• Can be present in 30% 0f SLE patients.
• Antibodies directed against phosphorylated polysaccharide esters of fatty acids
• Include: lupus anticoagulant, 2-glycoprotein-I, anti-prothrombin Abs, and anticardiolipin Ab.
• False positive VDRL can be seen in 50% of patients
• aPL production can also be associated with:MedicationsInfectionsNeoplasms (lymphoma)
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ANCAAnti-Neutrophil Cytoplasmic
Antibodies
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ANCA:• Abs directed against several proteins in
cytoplasm of neutrophils in sera of patients with different Vascular Autoimmune disease and Systemic Autoimmune Disease .
• Measured by indirect immunofluorescence.
• ELISA is used to detect specific Abs to proteinase-3 , and myeloperoxidase (MPO)
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ANCA Patterns:1. Cytoplasmic ANCA (C-ANCA):
anti-proteinase -3
2. Perinuclear ANCA (p-ANCA): anti- myeloperoxidase (MPO), but also elastase and other proteins in the neutrophil granules
3. Atypical Patterns: Ab to elastase, cathepsin G, lactoferrin, etc.
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Gli ANCA: patologie associateGli ANCA: patologie associate Sono considerati i principali markers sierologici specifici delle Sono considerati i principali markers sierologici specifici delle
vasculiti e delle malattie infiammatorie croniche,con un’incidenza vasculiti e delle malattie infiammatorie croniche,con un’incidenza dell’85-90% nelle prime e 20-70% nelle seconde ;dell’85-90% nelle prime e 20-70% nelle seconde ;
Vasculite :Vasculite : infiammazione e infiammazione e Malattie infiammatorie Malattie infiammatorie cronichecroniche
necrosi dei vasi con conseguentenecrosi dei vasi con conseguente intestinali (MICI):intestinali (MICI):modificazione del lume vasale ed modificazione del lume vasale ed con questo termine si con questo termine si
indicano : indicano : alterazioni ischemiche dei tessutialterazioni ischemiche dei tessuti - - Rettocolice ulcerosa:Rettocolice ulcerosa:irrorati;irrorati; infiammazione del colon; infiammazione del colon;quella maggiormentequella maggiormente - - Morbo di CrohnMorbo di Crohn : :
distruzionedistruzionerappresentata è il rappresentata è il Morbo di Wegener.Morbo di Wegener. continua della parete continua della parete
dell’intestino,specialmente dell’intestino,specialmente a carico del tenue.a carico del tenue.
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ClassificazioneClassificazione p-ANCA o ANCA perinucleari : p-ANCA o ANCA perinucleari : reagiscono principalmente reagiscono principalmente
con la mieloperossidasi (MPO) presente nei granuli con la mieloperossidasi (MPO) presente nei granuli αα--azzurrofili, dando una fluorescenza di tipo perinucleare ;azzurrofili, dando una fluorescenza di tipo perinucleare ;
c-ANCA o ANCA citoplasmatici :c-ANCA o ANCA citoplasmatici : diretti contro la diretti contro la proteinasi3 (PR3), dando una fluorescenza finemente proteinasi3 (PR3), dando una fluorescenza finemente granulare e diffusa per il citoplasma ;granulare e diffusa per il citoplasma ;
x-ANCA o ANCA atipici : x-ANCA o ANCA atipici : - danno una fluorescenza sia citoplasmatica che - danno una fluorescenza sia citoplasmatica che nucleare nucleare - si osservano nei soggetti affetti da MICI,ma hanno una - si osservano nei soggetti affetti da MICI,ma hanno una sensibilità sconosciuta e una specificità bassa.sensibilità sconosciuta e una specificità bassa.
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C-ANCA (cytoplamsic-ANCA):– Diffuse staining of neutrophil cytoplasm in
immunofluorescene.– Recognizes PR3(Proteinase –3), a serine protease
in primary granules of neutrophils.– Is seen in 85% (range 30-90%) of patients
with Wegeners Granulomatosis.– Highly specific for WG (98%)– Titer correlates with disease activity (in 60%
of cases) and severity.
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P-ANCA:• P-ANCA in the setting of vasculitis is Ab
against MPO.• Vasculitidies associated with MPO include:
– Microscopic Polyangiitis (45-80%)– Idiopathic Crescentic GN: (65%)– Churg Strauss: (60%)– PAN: (15%)
• Anti- MPO can also be due to medications:PTU, hydralazine, minocycline, D-penicillamine.
• Atypical P-ANCA can be seen with: RA, SLE, IBD, Chronic liver diseases.
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Rheumatoid Arthritis
Laboratory Testing, Principals and Guidelines
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Rheumatoid Factor (RF)Introduction:• RF is an antibody directed against the FC
portion of IgG.
• RF was originally described by Waaler and Rose in 1940
• The RF measured in laboratories is IgM RF, but IgG & IgA RF have been described.
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Conditions Associated with Positive RF:I. Healthy Individuals: RF can be positive in up to 4% of young
and healthy individuals. RF positivity is higher in elderly people
without rheumatic diseases (ranging from 3-25% in different studies).
RF titer in this setting is usually < 1:160
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Conditions Associated with Positive RF: …cont.
II. Rheumatic Disorders: Rheumatoid Arthritis: 26-90%* Sjogren’s syndrome: 75-95% SLE: 15-35% Polymyositis/Dermatomyositis: 5-
10%* Variable in different studies, depending on
severity of disease in the study population
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Non-Rheumatic Diseases associated with Positive RF
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Anti-Cyclic Citrullinated Peptide:• Target amino acid is citrulline, in filaggrin molecule
derived from human skin.
• Citrulline is a post-translationally modified arginine residue.
• ELISA assay for anti-CCP may be useful in early stages of polyarthritis. [1]
Sensitivity SpecificityAnti-CCP 56% 90%IgM RF 73% 82%RF & anti-CCP 48% 96%
[1] Bas et al. Rheumatoloy (Oxford) 2003; 62: 870
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Serum Electrophoresis
• Gel electrophoresis shows an increase in the globulins especially gamma (antibodies) and alpha-2-globulin
• There is often a decrease in albumin (7)
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Complete Blood Count (CBC)
• WBC in the peripheral blood often remained undisturbed
• RBC’s show a moderate normocytic hypochromic anemia of chronic disease
• A decrease in serum iron is common, Total Iron Binding Capacity (TIBC) and normal iron stores (ferritin) are essentially normal
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Creatinine Kinase (CK)
• Serum CK is decreased below normal in >60% of RA patients. This is not to be confused with the CKMB (Myocardial) portion or CKMM (skeletal muscle) enzymes that are often measured during a MI or chronic muscular diseases (7)
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Synovial Biopsy
• Synovial fluid has high WBC and low viscosity, glucose is greatly diminished in the synovium
• RF usually present• Characteristic rheumatoid nodules to aide
in diagnosis• Positive biopsy of subcutaneous
rheumatoid nodule and synovia
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American Rheumatism Association Diagnosis Criteria
Positive biopsy within diagnostic guidelines: criteria consists of:– Poor mucin clotting of synovial fluid (4)– Characteristic histological changes in
synovium: mesothelial, macrophage, LE cells
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Testing non-indicative of RA
• Other routine serological quantitative testing is normal. This group includes Calcium, Uric Acid, Alkaline Phosphorus, Phosphorus, and Antistreptolysin O titers
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Diagnostica di laboratorio nello
studio delle patologie immunoallergiche
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La diagnostica dell’ asma bronchiale è costituita da:
• Anamnesi ed esame obiettivo
• Test specifici in vivo e in vitro
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VALUTAZIONE ANAMNESTICA
• Predisposizione familiare (atopia) o altre patologie immunologiche;
• Attività lavorativa • Abitudini di vita (sport, fumo, ambiente)
• Terapie in atto
• Stagionalità degli eventi allergici e modalità di insorgenza
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Le reazioni di ipersensibilità IgE mediate determinano diversi tipi
sintomatologie
L’allergia costituisce l’aspetto patologico, che si traduce in danno,con quadri clinici diversi secondo gli organi interessati:
• Rino-congiuntivite• Asma• Orticaria• Allergie intestinali• Shock anafilattico
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I TEST UTILIZZATI SONO:
IN VIVOTest cutanei PRICK E PATCH TEST
IN VITRO PRIST o IgE totali RAST o IgE specifiche
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IL RISCONTRO DI ELEVATI LIVELLI DI IgE TOTALI NON AUTORIZZA UNA DIAGNOSI DI ALLERGIA, POICHE’ POSSONO ESSERE ANCHE PRESENTI IN:
Soggetti normali, Patologie Parassitarie Connettiviti, Infezioni batteriche cronicheMalattie Linfoproliferative
DOSAGGIO IgE TOTALI
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Sistema di classificazione e cut-off relativi alla classe di IgE Specifiche
• Elaborati in base alla curva standard e alla calibrazione, forniti in kU/L
Classe kU/L 0 <0,35 Assente o non rilevabile
I 0,35-0,69 Basso
II 0,70-3,49 Moderato III 3,50- 17,49 Elevato IV 17,5-52,49 Molto elevato V 52,5-99,99 Molto elevato VI >100 Molto elevato
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DOSAGGIO MEDIATORI E CITOCHINE
EOS
EOSINOFILI
ECP
PBM
T
T-LINFOCITI
IL-x
Basophil
BASOFILO
CHEMOCHINE
- Mast cellule
ISTAMINA
PGs - LTs
TRIPTASI
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ANA: If the ANA is positive, the laboratory automatically performs Extractable Nuclear Antigens (ENA) and Double Stranded DNA Antibody (dsDNA) tests.
If the ANA is negative, one may still request the Autoimmune Screen Panel II (Advanced) depending on the working diagnosis.
Once the ANA has tested positive there is no diagnostic benefit in repeating this test.
Please remember that an ANA may also be positive in up to 5% of normal young females and decisions to proceed with further testing should always take into account overall clinical and laboratory features.
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Rheumatoid Factor (RF): This test can be used alone or along with other diagnostic tests to identify specific autoimmune/rheumatologic or even infectious and malignant diseases.
The test identifies the presence of a RF (an antibody {G,A,or M}) directed specifically against the CH2/3 domain of IgG.
The titre may be relevant in some but not all conditions for disease monitoring (eg infections such as Tb), but a positive test is significant.
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Serum electrophor
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aPTT: This test is used to measure how well the patient’s blood is clotting. It may be prolonged in association with autoimmune/rheumatologic disease and coagulopathies.
C3, C4, CH50: These tests measure the levels of complement proteins in a patient’s blood. The C4(classical pathway) and C3 (alternate) are static measures of the serum levels of these proteins, whereas the CH50 is a functional assay that correlates with the complement cascade activity. If the measured values are not within the reference range, this may be indicative of an autoimmune/rheumatologic disease with immune complex deposition.
SPEP (Serum protein electrophoresis): This test is used to monitor albumin and globulin protein levels in a patient’s blood. If an autoimmune/rheumatologic disease is affecting these levels, the test results may be out of the reference range. Lower albumin levels may reflect chronic illness, elevated acute phase reactants infection or inflammation, elevated gammaglobulins inflammation and if a spike present, possible gammopathy.
Coombs (direct): If an autoimmune/rheumatologic disease is suspected to be causing hemolytic anemia this test can check whether antibodies are indeed bound to red blood cells. This would indicate an autoimmune condition as the cause of the RBC destruction.
Autoimmune Screen Panel II
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Serum Iron, TIBC: These tests are ordered together to test for iron levels and saturation in the patient’s blood. Serum iron tests the amount of iron in the patient’s serum while TIBC tests how much iron the patient’s transferrin plasma proteins can bind. An elevated serum iron and increased saturation will be seen in Hemochromatosis, which can be a cause of CPPD arthopathy (pseudogout).
Crystal Screen Panel
Ca, Phos, Mg: These tests measure the amount of these minerals in the patient’s blood. Several crystal arthropathies may be associated with abnormal levels of these minerals.
Serum Uric Acid: This test is used to detect the level of uric acid in the patient’s blood. High levels of uric acid can lead to monosodium urate crystal build up in joints which causes gout.
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ImmunodeficitPATOLOGIA MECCANISMI
IMMUNODEFICIENZECongeniteAcquisite
IMMUNITA' UMORALE
IMMUNITA' CELLULARE
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L'immunodeficienza può essere secondaria perdita di proteine come si verifica nel caso di gravi ustioni, nelle enteropatie
proteino-disperdenti, nella sindrome nefrosica. Le malattie da virus e batteri sono spesso accompagnate da immunodeficienza
riguardante soprattutto i linfociti T.
L’esempio più tipico è l’infezione da HIV
Anche virus diversi dall’HIV alterano la responsività immunologica come il virus del morbillo e l’HTLV-1.
lebbra lepromatosa
Infezione da Mycobacterium tubercolosis
Funghi o di parassiti come il plasmodio della malaria.
L'immunodeficienza secondaria al morbillo può durare oltre due mesi e causare riattivazione tubercolare.
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ALTRE IMMUNODEFICIENZE ACQUISITE
1. l’immunodeficit può essere la complicanza di un processo morboso
2. l’immunodeficit può essere la conseguenza di una terapia, in tal caso si parla di immunodeficienza iatrogena.
la senescenza La malnutrizione proteica e calorica La carenza di oligo elementi Le neoplasie,
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L’immunodepressione iatrogena è dovuta nella maggior parte dei casi a terapie farmacologiche che uccidono o inattivano funzionalmente i linfociti
Corticosteroidi, Ciclosporina ARadiazioni e farmaci inibitori della
proliferazione cellulare
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METODI DIAGNOSTICI IN CASO DI SOSPETTO IMMUNODEFICIT – PRIMO LIVELLO
•ESAME EMOCROMOCITOMETRICO CON FORMULA (VALORI RELATIVI ED ASSOLUTI DELLE SINGOLE CELLULE)•ELETTROFORESI SIERICA•DOSAGGIO DELLE IMMUNOGLOBULINE (IgG, IgA E IgM)•DOSAGGIO DEL COMPLEMENTO•RICERCA DI AUTOANTICORPI NON-ORGANO SPECIFICI
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Deficit Ig: What do we measure?
• Protein levels• Immunoglobulin levels • Immunoglobulin subclasses• Specific functional antibody levels• Complement levels
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Evaluating Lymphocyte Functionality by Immunoglobulin and Antibody Levels
• Ig levels (preferably relative to serum albumen as a marker for loss)– by RID, ELISA; low or elevated
• Existing titers– Isohemagglutinins, anti A and B isoagglutinins, T independent B
cell response– heteroagglutinins/heterolysins (srbc)– bactericidal (E. coli).
• IgG responses to vaccines (Never live ones!)– T-dependent: DTP (tetanus), poliomyelitis, Hib-conjugate– T-independent (over 5 years of age): Pneumococcal or Hib
polysaccharide, typhoid Vi
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What tests can we perform in cell mediated immunodeficiences?
• Lymphocyte subset measurement
• Tests of cellular function
• Cytokine assays
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By Presence/Absence/Counting• Complete blood count and differential
– totals and distribution of types of cells
• Fluorescent activated cell sorter (FACS) for subpopulation counts– B lymphocytes: CD19 or CD20– T cells: CD3 (T and NK); CD4 and CD8– Phagocytic functional deficit
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Flow cytometry results
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In vitro Mitogenesis
• Leukocytes are collected from blood.
• White cells are cultured in wells of microplates with appropriate stimulants.
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In Vitro Proliferation Tests Compared
St im u l a t o r s X - I r r a d i a t e d
Re sp o nd e rs
H3-T hymidine
+
+
M L R
M itoge n
+
Re sp o nd e rs+
H3-T hymidine
B l a s t o g e n e s i s
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Nitroblue Tetrazolium Test
• neutrophils• tests phagocytosis, and dye reduction during superoxide
production
+
Cel l s w i t hIn t r ac e l l u l a rRed u c ed D ye