HEPATITE CRONICE Definitie, cadru nosologic Morfopatologie leziuni caracteristice Gradare/stadializare Etiologie Tablou clinic Diagnostic etape Tipuri etiologice Particularitati, evolutie, complicatii Tratament1

HEPATITA CRONICA CU VIRUS BDEFINITIE 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 !)3

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

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Hepatitis - Disease TerminologyAcute 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

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HEPATITA CRONICA CU VIRUS BPATOGENEZA 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 tor6

HEPATITA CRONICA CU VIRUS B1. 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/hepatocite7

HEPATITA CRONICA CU VIRUS B2. 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 hepatocitare8

HEPATITA CRONICA CU VIRUS BRASP 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 !)9

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 BTABLOU CLINIC sd. asteno-adinamic + icter = activitate sd. dispeptic, subfebrilitati, prurit stelute vasculare, sd.hemoragipar hepatomegalie splenomegalie ff. rar: ascita tranzitorie11

Signs and Symptoms Of HBV InfectionThe 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 BEXPLORARI 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)13

HEPATITA CRONICA CU VIRUS BDIAGNOSTIC epidemiologie conditii de infectie cu HBV

manifestari clinice astenie + icter + HSM

laborator citoliza + MK infectiei HBV + viremie

biopsie hepatica (PBH)14

HEPATITA CRONICA CU VIRUS BDIAGNOSTIC 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)15

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 InfectionSilent Cirrhosis

Resolution

Resolution

Short-term Infection

Long-term Hepatitis

Cirrhosis

Liver Cancer

Death

Long-term Carrier

Cirrhosis

Death

30 - 50 Years17

HEPATITA CRONICA CU VIRUS B TRATAMENTSCOP supresia permanenta sau eliminarea virusului clearance-ul AgHbs scaderea infectiozitatii normalizarea parametrilor biochimici rezolutia procesului inflamator hepatic prevenirea HCC18

HEPATITA CRONICA CU VIRUS B TRATAMENTTRATAMENT 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%21

HEPATITA CRONICA CU VIRUS B TRATAMENTMIJLOACE 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 BHBV 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 programmes24

HEPATITA CRONICA CU VIRUS CDEFINITIE 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 !!)25

HEPATITA CRONICA CU VIRUS CTRANSMITEREA VIRUSULUI C (EPIDEMIOLOGIE) transfuzii, factor VIII (hemofilie) injectii (toxicomani), hemodializa, interventii chirurgicale transplant organe perinatal sexual (homo-, heterosexualitate comportament dezordonat)26

HEPATITA CRONICA CU VIRUS CPATOGENEZA - 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)27

HEPATITA CRONICA CU VIRUS CHISTOPATOLOGIE necroza infiltrat inflamator (agregate limfoide) steatoza macroveziculara leziuni ale ductelor biliare fibroza28

HEPATITA CRONICA CU VIRUS CMANIFESTARI 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 trombocitopenica29

HEPATITA CRONICA CU VIRUS CEXPLORARI 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)30

HEPATITE CRONICEGRADAREA 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 distanta31

HEPATITA CRONICA CU VIRUS CDIAGNOSTIC conditii de infectie C (anamneza) manifestari clinice (astenie, icter, HSM + manifestari extrahepatice) laborator (citoliza + MK virali + viremie + autoAc) biopsie hepatica (histopatologie)32

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 CEVOLUTIE 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. antivirale34

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)35

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!36

HEPATITA CRONICA CU VIRUS C TRATAMENT3. 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