Hepatitele cronice

Hepatitele croniceBoal inflamatorie cronic a ficatului caracterizat prin necroz hepatocitar i inflamaie de intensitate variabil urmate, neobligatoriu, de fibroz i care dureaz peste 6 luni de la expunerea iniial i/sau o decelare iniial a bolii hepatice

Etiologia : - viral - autoimun - medicamentoas - alcoolic - af. congenitale (B. Wilson, alfa 1 AT) - necunoscut

I. H.C. ViraleVirusurile hepatice : H.C.V. = B, C, Dnu cronicizeaz: A, E, F, GB, TTVtropism hepatic : VCM, V E-B, febrei galbene (nu sunt cauz semnificativ de H.C.V)

VHB : hepadnavirusSer : particule Dane 42 nmparticule subvirale: spirale, filamente (Ag HBs fr potenial infectant) Structura VHB :nveli extern = Ag HBs :maremediumicnucleocapsida : exterior Ag HBc; Ag HBegenomul : ADN VHB dublu helix ADN - polimeraza

Adapted from Kann M and Gerlich WH. In: The Molecular Medicine of Hepatitis. 1997: 6377 The Structure of HBV

Genomul : 4 gene : S = proteina de S2 (S/pre S1/pre S2)C = Ag HBc i Ag HBeP = ADN polimerazaX = 2 proteine transactivatoare10 genotipuri : A - Jdistribuie geografic diferitseroconversie spontan HBe diferitnecroinflamaie/evol. CH (C > B, D>A)rspuns diferit la IFN (A, B > C,D)

Infecia VHB = 25% = HAcB (1% deces, restul vindecare)65% = infecie subclinic/tranzitorie autolimitat10% = HCB = 70% ( 10% Ag HBs+ fr afectare hepatic)10 - 30% = CH 5% = CHC

Ag. HBs :apariie precoce n infecie VHBlegare protein seric- invadare hepatocit = replicare viral : formare Ag HBs/Ag HBe/Ag HBc / ADN VHB/ ADN polimerazintegrarea n genomul gazdei = secreie Ag HBsmutaii = CHC

The Life Cycle of HBV in the HepatocyteAdapted from Lai CL and Yuen MF. J. Med. Virol. 2000; 61:36773Subviral particlesInfectious HBV virioncccDNAPartially dsDNAViral POL converts pgRNA to partially dsDNAEncapsidated pgRNAER/GolgiNucleusHBsAgHBcAgHBeAgPre-core/CoreRepair

Ag HBe : forma secretorie/solubil Ag HBcasociat n ser cu Ag HBsprezena = infectivitate max, - perpetuare infecieabsena = sistarea replicrii VHBAg HBc : numai n hepatocitinfectivitate max./replicare max.

Ac anti-HBs: 1 - 2% seroconversie naturalimunitate (Ag HBs-) risc CH/CHC supravieuirea20 - 40% sunt Ag HBs+:Ac heterotipiciformare CIC (GND sau PAN) Ag HBs subparticulefr semnificaie clinicAc anti- HBc : IgM titru = infecie acut VHBHCB activ ( citoliz)IgG = infecie cronic VHB (+ Ag HBs) vindecare ( + Ac anti HBs)

Ac anti HBe: seroconversia Ag HBe/anti HBereplicare VHB n HCBADN VHB : - replicare VHB /risc de progresie HCB

Evolutia naturala a infectiei cronice cu VHB: 4 faze

Variante VHB prin mutaii geneticeMutaii pre-core :Ag HBe-, anti HBe+, ADN VHB+ boal progresiv, N-I sever, fibroz progresiv, CH = 40%, replicare persistent rspuns alterat la IFNMutaii gena S : nu se formeaz Ag HBsabsena formrii Ac anti-HBseec vaccinare anti VHBMutaii gena P:tratament cu analogi nucleozidici

V.H. Delta (D)dimensiuni mici : nveli Ag HBsnucleocapsida ( ARN VHD incomplet + Ag HD: mic + mare)multiplicarea Ag HBs dependent3 genotipuri (cel mai frecvent 1)infecteaz numai hepatocitele (citopatogen)

Co-infecia : VHB + VHD (2% cronicizare)Ag HBs +Ac anti HBc/IgM+Ac anti HD/IgM+Suprainfecia : VHD la purttor VHBagravare HCB = CH Ag HBs +75% cronicizareAc anti HBc/totali +evoluie rapid CH (2-15a)Ag HD +15% deces la 1 - 2aAc anti HD/totali +

3. V.H.C.V. ARN = FlavivirideStructura : anvelop lipidicnucleocapsida (ARN VHC)6 genotipuri (variabilitate genetic)1b = virulen maxim, rezistenta terapeutica (60% - 1)3 4 milioane pacieni infectai/an

Virusul hepatitic C

Particulariti infecie VHC : 130 - 170 mil cazuriepisodul acut = evoluie subclinic (10% icter)20 - 30% clearance spontan al VHC dup infecie ac.cronicizare (85%) i CH (20%)risc de CHC (1 - 5%/an)evoluie lent, necunoscut frecventfibroz :10% < 10arapid = < 20aintermediar: > 20 anilent = fr CH

Factori prognostici de evoluie rapid : genotip 1 bviremie diversitate genetic transmitere transfuzional VHCimunodeficienVHB + VHC/ HIV + VHCalcool

II. HC medicamentoasATB = izoniazid, rifampicin, tetraciclinC V = alfa-metildopa, amiodaronG I = sulfasalazin, steroizi anabolizani, oxifenisatina

III. H.C. congenitaleBoala Wilson :alterare metabolism Cu ++/ a- acafectarea hepatic/neuro-psihica/oculara/an.hemoliticaCeruloplasmina < 10 mg% , Cu urina > 100g/24hTratament: penicilamina, trientina, Zn, tetramolibdat de NH4Deficit de alfa 1 AT = evoluie la CH

Explorarea pacientului cu H.CTestele funcionale hepaticeCitoliza : AST (GOT)ALT (GPT)LDHColestaza : B.T. peste 1 mg% urobilinogenului FAS = m. plasmatic hepatocit intestinal osoas G GT5` - nucleotidaza

Capacitate de sintez : albuminemia colestarolul esterificat factori ai coagulrii: fibrinogen, protrombin, V, VII, IX, XModificri imunologice : gamaglobuline IgG/IgA/IgM

Teste specifice dgs. etiologic : markeri infecie viralauto Ac ( ASMA, ANA, ATy etc.)determinri speciale : alfa 1 AT, ceruloplasmina, HLABilan hematologic : hemogram complet : anemie (feripriv/macro/hemol)hipersplenism/CIDhemostaza

P.B.H.(punctie-biopsie hepatica) : singura care permite aprecierea severitii leziunilor hepatice stabilete dgs+/alte leziuni oarb/ghidat: imagistic/transvenoas/laparoscopic D. Metode neinvazive: biomarkeri serici (Fibrotest)

Aspecte histologice1. H.C. periportal : piecemal necrosisII cu L, Plhepatocite edemaiate, necroz focal, apoptoz, corpi Malloryspaiu port lrgitanomalii ale epiteliului d. biliare/foliculi limfoizinecroz n puni/multilobular

H.C. portal : hepatita de interfaII cu L, Pl preponderent portalarhitectonica lobular pstratabsena proliferrii biliductelorH.C. lobular : afectare hepatocitar parcelarpredominana lobularII redus n spaiul port

Indexul de activitate histologic (HAI)Gradingul : severitatea/activitatea necroinflamatorie (minim-sever)Stagingul : fibroz (absen CH)Scor Knodell/Ishak/Metavir

Tipurile etiologice de H.C.A. HCBIncidena: peste 350 mil. infectai cronic (55% din HCV) prevalen Romnia 2 - 7% ( 15% din BCH )Transmisia infeciei de la om-om :orizontal : parenteral/percutansexualnonsexual (colectiviti/familie)verical : perinatal

Cronicizarea infeciei VHB:absena seroconversiei Ag HBe/Ac anti - HBepeste 90% infecie perinatal (sugarii mame infectate)- 50% l - 6 ani / 10% - 15% > 8 10 ani1% - 2% la adulii tineripeste 50% la imunodeficieni

Localizarea VHB : ficat, limfocite, splin, ggl. limfatici reinfecie posttransplant

Simptomatologiafrecvent asimptomatic la debut rar aspect de HBAcManifestri nespecifice apar n timpastenie accentuat de efortgrea, anorexiestadiu avansat : icter/urini hipercrome G/sindrom dispeptichepatalgii/epigastralgiiCH = ascit, edeme

Examen fizic :hepatomegalie moderat (sub 2 - 4cm) elastic-renitenticter fluctuantspenomegalie moderat (50%)tardiv : eritroz palmar, HTp

Form sever de HCB (10 - 20%)artralgii/artritmialgiierupii cutanate/urticariene/rash/eritem nodos femei G, grea, anorexie, dureri abdominale, pancreatit cronicvasculit :s. Raynaud (CME)GN (CIC-HBs+) copii predomin zona tropical b. hepatic mai uoar 30 - 60% remisie spontanneuropatie perifericpoliarterit nodoaspoliserozitamenoree/anemie aplasticaacrodermatit papuloas (< 4 ani)Complicaii : - CH, CHC, insuficien hepatocelular

Risc CH/CHC :ADN > 20.000 UI/mlALT/AST: - aproape de limita superiaor a N - 2 x NVHB genotip Cbrbat, vrstnicAHC(+) CHC, coinfecie HIV/VHCRisc redus CH/CHC:ALT/AST < limita superiaor a NADN sczut = mbuntire ALT/histo

Diagnosticul pozitiv

Markerii serologici

Ag HBs+ : persisten > 6 luni Ac anti HBc + :IgM = infecie acut/replicare viralIgG = infecie cronic (Ag HBs+)

Ag HBe : 25 - 50% din HCB, evoluie agresiv a boliiAc anti-HBe : seroconversie Ag/anti-HBe, replicare viral = prognostic bun, mutant pre-C (Ag HBe-/anti- HBe+/AND-VHB+)ADN VHB : cantitativ > 10.000 copii/ml (> 2.000 UI/ml)Purtator inactiv cu AgHBs > 1.00UI/ml + AND-VHB > 200 UI/ml = risc crescut de reactivare

T.F.H. ALT/AST = persisten/intensitate 5 8 xN (Ag HBe+) = replicare viral uoar G-GT, LDH, FAS (exacerbare)disfuncie hepatic = CH

Histologia (PBH) :anterior tratamentului antiviralspecificitate maxim severitate HCBsuperioar ALT/ASTleziuni HAI > 4 - Knodelllocalizare portal/periportal/lobularnecroinflamaie/fibrozhepatocite n sticl matdisplazieimunohistochimie (Ag HBc+/Ag HBs+)

Forme HCB :Ag HBe+: AST (VHB slbatic)Ag HBe- :AST , ADN VHB+ (mutant)AST , ADN- VHB- : VHC/VHD+alcool/droguri/paraziiCHC, alte complicaiiAg HBe- : AST = N, Ag HBs+, anti-HBe+, ADN- sub 200 UI/ml =purttor inactiv de Ag HBs (infecie VHB persistent fr boal necroinflamatorie hepatic)

Infecia ocult cu VHBCriterii: - Ag HBs (-), Ac anti-HBs(+/-) - ADN VHB (+) < 2.000 UI/ml - Ac anti HBc (+) secretor/(-) nonsecretor - ALT = Normal

Cauze : - VHB replicat extrahepatic - CIC = Ag + Ac VHB - mutani HBsConsecine: - risc transmisie infecie VHB - cauz de CH criptogenetic - reactivare sub citostatice

B. H.C.D15 20 mil. infectai croniczone geografice de infecie endemicSuprainfecie VHD : episod acut icteric pe fond de HCB, brusc evoluie sever din acel momentC-infecia v. infectia VHB: - mai sever - evoluie mai frecvent spre C.H. - risc mai mare de decompensare i de CHC

B. H.C.D.Ser : VHB + VHDPBH : necroze n puni, multifocaleafectare multilobularAg HD, ARN VHD n hepatocite

C. H.C.C.Simptomatologie frecvent asimptomatic6% nespecific (severitate): fatigabilitate, inapeten hepatalgii, mialgii grea, anorexie, disconfort abdominal capacitatea de concentrareStadiul avansat : icter, H-S megalie (79% v. 34%)Transmisie materno infantil (intrauterin, la natere)

Manifestri extrahepatice (mai ales n CH)CME (> 65 ani, F, CH)vasculit sistemic necrotizantneuropatie porfirie cutanat tardapurpur trombocitopenicGN membranoasS. Sjgren, Ty. autoimunulceraii corneeneartrit/artralgiilimfom nonhodgkinianfibroz pulmonar/afectare cardiac/DZII/SHNAAsocierii : CHC 50 - 75% VCH+, > 28 ani

Dgs +Anti VHC+ : ELISA gen 3/confirmare RIBA 3Ag VHC core: confirma infectia VHCARN VHC cantitativ = terapie/imunodeprimaiGenotipare (pretratament) Anti-VHC+TFH : Ag VHC coreALT/AST : + -N: 30 - 50% 25% (factori de risc) Tratament ARN VHCondulante/constant (anti TNF, VHB/D, VHA, VHE, CMV) + -alte teste modificate n stadiul avansat

PBH : foliculi limfoizi cu centrii germinativi sp. portafectarea biliductelor ( 10 - 15%)steatoz micro-/macroveziculara(50%, genotip 3)necroinflamaie , fibroz (PBH, AST/Nr.Tr, Fibrotest, Fibroscan)ECO : adenopatie hil

II. Hepatita autoimunCaracteristici generale:preponderen feminin (4:1)hipergamaglobulinemieauto - Acfenotip HLA DR3/DR4rspuns bun la imunosupresiveincidena : 2 24,5/100.000

Simptomatologie:Debut : 10% asimptomatic ( AST/ALT)insidios :nespecific/luni . Fatigabilitate progresiv, anorexiegrea, vrsturi, diaree, dureri abdominaleicter intermitent (25%), prurit/rash cutanatartralgii, mialgii, fenomene cushingoideCiroz hepatic: 25% sau boal cr. hepaticacut : . anorexie, gre, vrsturi, durei abd., icterocazional (25%, cu icter i I.H.ac 5%)asemntor HAc fulminante

APP/AHC + : DZ-I, Ty, CU, B. celiac, AR, LES poate apare la orice vrst :pubertate/decadele 4 - 6

Etiologia : necunoscutPatogeneza:Medicamente: nitrofurantoin, minociclina, atorvastatin, halotan; IFN (agravant)Susceptibilitate genetic: HLA DR-B1- 0301/0401Auto-antigene i mimetism molecular (CMV, HS,VHC)Imunoreglare alterat: deficit (nr./funcie) LTregNU virusuri hepatitice

Laborator :Hiper- globulinemie policlonal IgG 1,5 x NAST/ALT = 50 x N BTFAS = N, moderat FAS/AST = complement C4 i IgA (HAI tip II)cel. LE = 10 - 50%Ac anti VHC fals +

Histologia : PHB obligatoriu = hepatit de interfanecroinflamaie portal/septal, II dens cu L, Pl necroze n punte/panlobular/multilobularrozete hepatocitare/regenerare nodularNU leziuni : biliducte/granuloame/alte etiologii

Autoanticorpii : subtipuri de HAITip I :ASMA (100%)- Anti SLP/LP (30%)ANA > 1/80 (70 - 80%)ANCAp (90 %), anti-actin (AAA), anti-cromatinasociere : Ty, PR, an. Biermer, SS, vasculitpredomin la adult

Tipul II : Anti LKM -1 (CYP4502D6) (95 - 100%)Anti LC 1prepoderen la copil, F, evoluie CH (50%)Ac anti rceptor asialoglicoptrotein hepatic (88%) anti-ASGPR: comun ambelor tipuriDgs + : - creterea AST/ALT - creterea IgG - prezena auto-anticorpilor

Formele variant :HA + CBP :histologie CBP+ANA i/sau AMAhepatit de interfaHA + CSP + BII / HA + colangita autoimuna

III. H.C. medicamentoasToxicitate direct (intrinsec) :previzibildependent de dozapariie la scurt timp (paracetamol, iproniazid)Toxicitate indirect (idiosincrazie) : metabolic/imunoalergicimprevizibilnu depinde de dozapariie la expuneri repetate (halotan, alfa metildopa)

Leziuni induse medicamentos:acute : necroz, steatoz, colestazcronice : hep. cr., CH, B. venoocluzivCauze de H.C. medicamentoas:izoniazida, alfa metildopanitrofurantoinacetaminofen (Alc)MTX (PBH peste 3,5 4g)

Simptomatologia : asemntoare H. Vcr.apariie la continuarea administrrii dup primele semne de hepatotoxicitateremisiunea fenomenelor la sistarea produsuluiteren favorizant : F > 40 ani

Tratamentul hepatitelor croniceHCBProfixalia infeciei VHB :vaccin specific recombinat anti-hepatit Bimunoglobulin antihepatit B = 0,06mg/Kc + vaccin dup expunere acut/gravida infectat, imediat postpartum

Terapia antiviral : imunomodulatoareanalogi nucleozidici/-nucleotidiciObiective : eliminarea/supresia permanent a VHBreducerea/stoparea necroinflamaieipe termen lung prevenirea recidivelor - oprirea evoluie la CH/CHC

Indicaii/parametrii : virusologici : ser = Ag HBs+ADN VHB+ 20.000 UI/ml (Ag HBe+)ADN VHB+ 2.000 UI/ml (Ag HBe-/antiHBe+)IgG anti HVD-biologici : ALT 2 x N, peste 6 lunifibroza: PBH sau Fibromax: ALT < 2 x N si varsta > 40 ani 50 ani = entecavir, adefovir, Peg IFN (tineri cu ALT i AND-VHB moderate)> 50ani - < 65ani = analogi nucleozidici/-tidici; f) 65 ani = lamivudina

IFN alfa 2a/2b recombinatIFN = glicoprotein specific secretat v. stimuli virali/bacterieni/macromolecule nonselflegare de receptor specificForme :IFN : Mcf, PMN IFN : fibroblatiIFN : LThl (imun)

Posologie : Peg IFN 2a : 180 g/spt x 12 luniseroconversie Ag HBe/anti HBeseroconversie Ag HBs/anti HBs 15 - 20%normalizarea AST/ALT HAI 2 pct

Monitorizarea eficienei terapiei cu IFN ADN+VHB 24 i 48s postterapie (AND VHB nedetectabil n ser)Ag HBS cantitativ: 10% v.pretratament

Valoare predictiv pentru rspuns + (pretratement ) Ag HBe+ Ag HBe-vrsta sexul F FALT ser ADN VHB (A i B)

R.A. constituionale :pseudogripale G, grea, diareeparacetamol/algocalminhematologie : NL, NTr (Eltrombopag)autoimune : DZ, Ty, H autoimunAH, auto - Acneuropsihice Stop la 12s: - AgHBe+: nu Ag HBs i AgHBs < 20.000 UI/ml - Ag HBe-: nu Ag HBs i AND VHB < 2 log copii/ml

Analogi nucleozidici2. Lamivudina: 100 mg/zi > 12 luniYMDD = mutant gena PIndicaie : AST/ALT > 5 x N/absena rspunsului IFN/CH compensatTelbivudin, Entecavir (0,5 mg/zi)Adefovir (10 mg/zi), Tenofovir5. Telaprevir, Boceprevir/ inhibitorul polimerazei analogului uridin-nucleotidului

Ag HBe + = LamivudinAg HBe - = Lamivudin /Telbivudin + Tenofovir/Entecavir/Adefovir

Evaluare raspuns: la 6 luni (ALT + AND) i la 12 luni dup viremie nedetectabil (ALT, seroconversie HBs i HBe, AND-VHB)AgHBs cantitativ: in timpul terapiei = predictor pt. disparitia lui postterapie

II. HCDEradicare = Clearance-ul AgHBs. Persistena lui = VHD ramne infectant i capabil de reactivare a hepatitei . PEG-IFN alfa-2a = 9 mil UI x 3/s x 12 luni

IFN Analogi

Durat 16 - 48 s indefinit, termen lungRezisten -++Administrare s.c./sp.o./ziADN VHB +++RA ++ -Toxicitate - renal, miopatie +/- mitocondrial

Criterii de tratament VHCAc anti VHC (+) cu ARN VHC (+)ALT normale/crescuteFibroza: A/F/S>1 (PBH/Fibromax/Elastografie)Varsta < 65aniCH compensatCGM II, vasculit, GN

III. HCC . Peg IFN 2a = 180g/spt x 12 luniPeg IFN 2b = 0,5 1 g/kg/spt RVS = ALT N (40 - 54%)negativare ARN VHCmbuntire histologic

Terapie combinat : Peg IFN + Ribavirin 0,8 1,2 g/zi p. o. X 12 luni + Actiune directa + telaprevir/boceprevir (in fibroza mare: genotip 1) inhibitori de proteazTerapia orl, +/- IFN i Riba:Sofosbuvir (inhibitor analog nucleotidic) + simeprevir / ledipasvir / faldaprevir x 12 spt. (95% RVS) Predictori: polimorfism IFNL3 raspuns la terapie IFNR.A. Riba : anemie: < 10g% Hb = eritropoetina < 8,5g% Hb = stop Riba c. i. = la femeia gravid

Tratamentul HC-VHC+: genotip 1Factori predictivi n pretratament (IFN+Riba): - vrsta < 40 ani - ARN VHC < 600 000 UI/ml- absena CH/fibroz redus- absena rezistenei la insulin- polimorfismul cromozom 19 (IL28B)

Infecia VHC la femeieRol protector al estrogenilor: P.fertil MenopauzClearance VHC ++ +Fibroz + ++Raspuns terapie ++ +

Contraceptive pe perioada tratamentului cu Riba (fcut de partenerul cu HCC) + 6 luniFactori de risc: alcool, obezitate

Tratament paliativ : silimarin (1g p.o. anti VHB ?)/lagosaliv 52esseniale

IV. H. autoimunImunosupresoare forme severe: - ALT > 10xN/ALT > 5xN + IgG > 2N - necroze n puni/hep.interfa sever, manifestari extrahepatice P 30mg/s I, scdere treptat la 10-15mg/zi x 6-12 luni P +Aza (20mg) (50 100 mg) meninere rspuns 74% recderte la sistarea terapiei 30% rspuns incomplet la 3 ani de tratament

Alte imunosupresive :Ciclosporina ATacrolimus 3 mg x 2/zi x 3 luniBudesonid, deflazacortCiclofosfamid + PMycofenolat mofetilTransplant hepatic ortotopic (recdere 80%) la cei cu CH, fr rspuns terapeutic

V. Hepatita medicamentoas Sistarea medicamentului incriminat:ALT > 8 x NALT > 5 x N > 2 spt.ALT > 3 x N + BT > 2 x N sau INR 1,5

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