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HEPATITE CRONICE

Definitie, cadru nosologic Morfopatologie leziuni caracteristice Gradare/stadializare Etiologie Tablou clinic Diagnostic etape Tipuri etiologice Particularitati, evolutie, complicatii Tratament
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HEPATITA CRONICA CU VIRUS B


DEFINITIE boala inflamatorie hepatica determinata de virusul B cu potential evolutiv spre ciroza sau asociata cu ciroza pt. visusul B
este posibila si infectia cronica inactiva (viremie joasa) - starea de purtator 2

HEPATITA CRONICA CU VIRUS B

TRANSMITEREA VIRUSULUI B (EPIDEMIOLOGIE) perinatal parenteral


transfuzii, injectii, grefe, transplant

sexual (frecvent !)
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How Do You Acquire The Infection In The West?


Transfusion and transplant recipients Newborns of long-term carriers

Individuals with multiple sexual partners

Intravenous drug users

Healthcare workers

Prisoners and other institutionalised people

Hepatitis - Disease Terminology


Acute hepatitis Short-term hepatitis, during which the bodys immune system clears the virus from the body within 6 months

Chronic hepatitis Long-term hepatitis, in which the infection persists beyond 6 months because the bodys immune system cannot clear the virus from the body

HEPATITA CRONICA CU VIRUS B


PATOGENEZA
virusul B nu are un efect citopat major, dar ini ierea si ntre inerea leziunilor necesit persisten a HBV !

RASPUNSUL LA INFECTIA CU HBV


R. antiviral precoce, adecvat = vindecare R. imunitar indecvat (toleranta imuna par ial ) = cronicizare, purt tor
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HEPATITA CRONICA CU VIRUS B


1. RASPUNSUL ANTIVIRAL ADECVAT limitarea infectiei (IFN, Ac anti-pre S) eliminarea hepatocitelor infectate (limfocite NK si T citotoxice) = necroz hepatocitara ! => sunt oprite: integrarea ADN viral in ADN cromozomial hepatocitar declansarea agresiunii autoimune/hepatocite
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HEPATITA CRONICA CU VIRUS B


2. RASPUNSUL IMUNITAR INADECVAT (mediat prin deficit de interferon IFN = toleran imun )
eliminare incompleta sau prelungita a HBV integrarea HBV in genomul hepatocitar persistenta leziunilor inflamatorii (cronice) autointretinere
reactie (auto)imuna fata de proteine normale ale membranei hepatocitare
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HEPATITA CRONICA CU VIRUS B


RASP IMUNITAR INADECVAT - consecinte: LEZIUNI HEPATOCITARE
raspuns imunitar celular (T) fata de hepatocitele care exprima la suprafata Ag virale + molecule HLA

LEZIUNI SISTEMICE
raspuns imunitar umoral (AC) prin complexe imune circulante (CIC) + complement (artrita, rash, GNA)

RISC PT. HEPATOCARCINOM


legat de integrarea HBV in genomul hepatocitar (HBV este oncogen !)
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HEPATITA CRONICA CU VIRUS B

HISTOPATOLOGIE (variabil) necroza (piece-meal, bridging, spotty) infiltrat inflamator (portal, periportal) fibroza

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HEPATITA CRONICA CU VIRUS B


TABLOU CLINIC sd. asteno-adinamic + icter = activitate sd. dispeptic, subfebrilitati, prurit stelute vasculare, sd.hemoragipar hepatomegalie splenomegalie ff. rar: ascita tranzitorie
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Signs and Symptoms Of HBV Infection


The majority of patients with chronic hepatitis B have no symptoms

Short-Term Infection


Long-Term Infection
   

     

Tiredness or flu-like symptoms Nausea or stomach ache Diarrhoea Skin rash Yellow eyes/skin (jaundice) Light-coloured stools Dark yellow urine

Same symptoms as acute Muscles and joints ache Weakness Signs and symptoms of cirrhosis Signs and symptoms of liver cancer

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HEPATITA CRONICA CU VIRUS B


EXPLORARI COMPLEMENTARE biochimice hepatice (variabil) hematologice (leucopenie, trombocitopenie) imunologice (IgG, CIC) MK infectiei virale (persistenta HBV) US (utila pentru dg. cirozei si diferential!) biopsie (gradare, stadializare)
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HEPATITA CRONICA CU VIRUS B


DIAGNOSTIC epidemiologie
conditii de infectie cu HBV

manifestari clinice
astenie + icter + HSM

laborator
citoliza + MK infectiei HBV + viremie

biopsie hepatica (PBH)


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HEPATITA CRONICA CU VIRUS B


DIAGNOSTIC DIFERENTIAL toate bolile hepatice parenchimatoase cronice, inclusiv cirozele hepatice toate bolile hepatice parenchimatoase acute (forme prelungite) boli de sistem (colagenoze), ICC, septicemii, (care pot evolua cu afectare hepatica)
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HEPATITA CRONICA CU VIRUS B

EVOLUTIE SI PROGNOSTIC inactivitate (purtator - aparent sanatos) ciroza hepatica carcinom hepatocelular (HCC)

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Progression Of Hepatitis B Infection


Silent Cirrhosis

Resolution

Resolution

Short-term Infection

Long-term Hepatitis

Cirrhosis

Liver Cancer

Death

Long-term Carrier

Cirrhosis

Death

30 - 50 Years
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HEPATITA CRONICA CU VIRUS B TRATAMENT


SCOP supresia permanenta sau eliminarea virusului clearance-ul AgHbs scaderea infectiozitatii normalizarea parametrilor biochimici rezolutia procesului inflamator hepatic prevenirea HCC
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HEPATITA CRONICA CU VIRUS B TRATAMENT


TRATAMENT interferon (IFN) - ef.antiviral/imunomodulator chimioterapice antivirale interferon + subst. antivirale (?)

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HEPATITA CRONICA CU VIRUS B TRATAMENT

Factori predictivi ai raspunsului pozitiv


infectie recenta, adult, sex feminin stare de imunocompetenta pastrata virus salbatic (raspunsul este mai slab pt. varianta mutanta pre-core)

Criterii de selectie (Romania)


Biochimic
citoliza inalta (> 2 x N)

Virusologic
Ag HBs pozitiv, AgHBe poz sau neg, AcHBe neg sau poz, ADN HBV 100.000 copii / ml

Histologic
Scor Ishack: indice necro-inflamator = 6, fibroza < 6

Varsta < 65 ani

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HEPATITA CRONICA CU VIRUS B TRATAMENT

MIJLOACE 1. INTERFERON (Intron, Roferon) Scheme de tratament:


5 MU/zi, subcutan, 4 - 6 luni 10 MU de 3 ori pe sapt, 4 - 6 luni

Rata de raspuns:
AgHBe pozitiv
30-40% pierd MK replicare, dintre acestia = raspuns durabil -80-90%

AgHBe negativ
raspuns durabil 20-25%
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HEPATITA CRONICA CU VIRUS B TRATAMENT


MIJLOACE 2. LAMIVUDINA (Epivir, Zeffix - Glaxo) inhiba replicarea virala - activitatea polimerazei VHB-ARN dependente (indiferent de raspunsul imun al gazdei) indicatii
practic - orice pacient (inclusiv cu ciroza) pacienti cu contraindicatii pt. IFN pacienti cu virus mutant pre-core (rezistent la IFN)

schema de tratament: 100 mg / zi, in prezent, cel putin 2 ani ! rata de raspuns: 17-20% (1 an), 33% (3 ani) defecte: selectare mutanti, durata scurta a raspunsului

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HEPATITA CRONICA CU VIRUS B TRATAMENT

Alte resurse terapeutice actuale


PEG-IFN interferon pegylat (Pegasys) IFN pegylat + medicatie antivirala (lamivudina) medicatie antivirala recenta:
adefovir, tenofovir, entecavir (Baraclude)
eficienta crescuta efecte secundare mai mici selectare mai rara a formelor mutante rezistente

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Prevention Of Hepatitis B
HBV infection can be prevented in non-infected individuals by vaccination with HBV vaccine. However the millions of infected people will not benefit Series of 3 injections at 0, 1 and 6 months Vaccination is effective in over 90% of recipients By 1998, 80 countries had introduced vaccination programmes
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HEPATITA CRONICA CU VIRUS C


DEFINITIE
boala inflamatorie hepatica determinata de virusul C cu potential evolutiv spre ciroza sau asociata cu ciroza

EPIDEMIOLOGIE
~ 3-5% din populatie prezinta AcHCV! dintre cei infectati, peste 80 % vor ramane purtatori ai virusului C (de fapt = HC !!)
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HEPATITA CRONICA CU VIRUS C


TRANSMITEREA VIRUSULUI C (EPIDEMIOLOGIE)
transfuzii, factor VIII (hemofilie) injectii (toxicomani), hemodializa, interventii chirurgicale transplant organe perinatal sexual (homo-, heterosexualitate comportament dezordonat)
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HEPATITA CRONICA CU VIRUS C


PATOGENEZA - persistenta HCV este obligatorie
=> leziuni hepatocitare prin: efect citopatic direct (HCV = virus ARN) citotoxicitate limfocitara (CD4, CD8) ~ FACTORI VIRALI marimea inoculului, nivel viremie (replicare rapida), genotip viral (1b), grad de diversitate genetica virala (mare) HCV = inta mobila pt.sist. imun (epitopi ff.rapid variabili) ~ FACTORI GAZDA varsta, sex, coinfectie HBV/HIV, etilism, deficite imune (celulare/umorale)
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HEPATITA CRONICA CU VIRUS C


HISTOPATOLOGIE necroza infiltrat inflamator (agregate limfoide) steatoza macroveziculara leziuni ale ductelor biliare fibroza
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HEPATITA CRONICA CU VIRUS C


MANIFESTARI CLINICE sd.asteno-adinamic, fatigabilitate icter, hepatosplenomegalie + hipersplenism manifestari extrahepatice:
crioglobulinemie mixta, glomerulonefrita membranoproliferativa poliarterita nodoasa Sindrom Sjogren, tiroidita Hashimoto, hipotiroidism, DZ hematologic: anemie aplastica, limfome, purpura trombocitopenica
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HEPATITA CRONICA CU VIRUS C


EXPLORARI COMPLEMENTARE teste functional-biochimice hepatice teste imunologice
Ig , CIC , auto Ac, crioglobuline

imagistice - US MK infectiei virale


Atc antiHCV, HCV-ARN + coinfectie (B, HIV)

biopsie hepatica (diagnostic, grad, stadiu)


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HEPATITE CRONICE
GRADAREA evalueaza activitatea necro-inflamatorie scor) => HC minima / usoara / moderata / severa caracterizeaza prognosticul imediat STADIALIZAREA evalueaza amploarea fibrozei (scor) si, prin aceasta, progresiunea bolii si dezvoltarea cirozei caracterizeaza prognosticul la distanta
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HEPATITA CRONICA CU VIRUS C


DIAGNOSTIC conditii de infectie C (anamneza) manifestari clinice (astenie, icter, HSM + manifestari extrahepatice) laborator (citoliza + MK virali + viremie + autoAc) biopsie hepatica (histopatologie)
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HEPATITA CRONICA CU VIRUS C

DIAGNOSTIC DIFERENTIAL toate bolile parenchimatoase hepatice cronice, inclusiv cirozele hepatice boli de sistem si autoimune (dg.dificil !)

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HEPATITA CRONICA CU VIRUS C


EVOLUTIE SI PROGNOSTIC Dintre pacientii infectati cu HCV: ~ 80% dezvolta hepatita cronica (10 ani) 25% dezvolta ciroza hepatica (20 ani) 3,5 5% dezvolta HCC (peste 30 ani) in functie de:
nivelul viremiei, genotip 1b, varsta > 40 ani, sex (barbati), substrat histologic, asocierea etilismului sau altor boli

TRATAMENT -interferon + subst. antivirale


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HEPATITA CRONICA CU VIRUS C TRATAMENT SCOP


Ideal - eradicarea ARN-HCV din toate compartimentele terapie de eradicare: in stadiul precoce al bolii terapie supresiva: in stadiul precirotic/cirotic criterii de selectie - hepatita activa (ideal), fibroza (relativ) redusa factori predictivi ai raspunsului pozitiv (virus, gazda)
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HEPATITA CRONICA CU VIRUS C TRATAMENT 1. INTERFERON (monoterapie) - depasit !


3 MU de 3 ori / saptamana, 12 luni raspuns: 30-40%, dar numai 10-20% la 6 luni de la intreruperea tratamentului

2. INTERFERON + RIBAVIRINA
IFN 3 MU de 3 ori/sapt. + Ribavirina 800 -1000 -1200 mg/zi, 12 luni raspuns: ~ 50% la terminarea tratamentului rasp. sustinut (1b): 33% (IFN + Riba) la 6 luni de la oprirea trat.

Astazi = PEG-IFN + Ribavirina pt. 12 luni!


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HEPATITA CRONICA CU VIRUS C TRATAMENT


3. PEG -INTERFERON (Pegasys sau Peg-Intron) + RIBAVIRINA 800-1200 mg la start determinare viremie (incarcare virala) la 12 sapt. de terapie - determinare viremie (EVR)
negativare VHC sau scadere cu cel putin 2 log (100 x) continua terapia (raspuns precoce) scadere viremie mai putin de 2 log stop terapie

continuare terapie pana la 48 saptamani


la final viremie=incarcare virala raspuns viral (ETR) la 6 luni de la terminarea tratamentului incarcare virala raspuns sustinut (SVR) (vindecare)

efecte secundare (hematologice, tiroida, psihice) rata de succes (genotip 1b) : SVR ~ 60-66% ! 37