1. HEPATITELE CRONICE Cuprinde boli cu : Manifestari clinice asemanatoare
Leziuni necroinflamatorii cronice
Evolutie catre ciroza si CHC
dr cora pop hepatite cronice
dr cora pop hepatite cronice

2. HEPATITELE CRONICE Hepatitele cronice virale-B,C Hepatita autoimuna
Hepatita cronica indusa de medicamente
Boala Wilson
dr cora pop hepatite cronice
dr cora pop hepatite cronice

3. HEPATITELE CRONICE VIRALEB
Hepatita cronica cu virus C D
Inflamatia persistenta a ficatului cel putin 6 luni dupa expunerea initiala/detectia bolii
Sunt diferente importante de virusologie/ epidemiologie/metode de dg/patogeneza intre virusuri
dr cora pop hepatite cronice
dr cora pop hepatite cronice

4. HEPATITA CRONICA CU VIRUS B
Hepadnavirus ADN care foloseste pentru replicare ARN- reverstranscriptaza(ca un retrovirus)
Asemanari multiple cu virusul HIV (Oncogenit/transmit/integr in genomul gazdei)
genomul viral cuprinde
- gena S -antigenul de suprafata-HBsAg
- gena C-antigen core-HBcAg
-gena P- cea mai mare parte din genom-
proteina P- ADNpolimeraza/ revers transcriptasa/ RNasa
dr cora pop hepatite cronice
dr cora pop hepatite cronice

5. Anvelopa este antigenica(AgHBs) Nucleocapsida este antigenica(AgHBc)
Format din ADN dublu catenar inconj de un miez-nucleocapsida inconj de o anvelopa
Anvelopa este antigenica(AgHBs) Nucleocapsida este antigenica(AgHBc)
Imunitatea la AgHBs este protectoare(natural sau vaccinal)
AgHBe deriva din gena de miez
dr cora pop hepatite cronice
dr cora pop hepatite cronice

6. dr cora pop hepatite cronice

7. PATOGENEZA: HBV puternic hepatotrop
leziunile apar prin raspunsul imun al gazdei
limfocitele T citotoxice- anti HBs
-distrug hepatocitele infectate
- det clearance viral/hepatita cr
un raspuns redus imun al gazdei creste riscul infectiei cronice
dr cora pop hepatite cronice
dr cora pop hepatite cronice

8. EPIDEMIOLOGIE
prevalenta milioane de oameni in lume sunt purtatori
Prevalenta crescuta in Africa/Asia
Factori de risc -activit sexuala cu risc
-droguri iv
-dializa
-zone cu risc
-profesia
dr cora pop hepatite cronice
dr cora pop hepatite cronice

9. ANATOMOPATOLOGIE infiltrat inflamator limfocitar portal
hepatocite ground-glass (citoplasma vazuta cu H-E- AgHBBs)
necroza hepatocitara
-piecemeal necrosis
inflamatie lobulara si necroza lobulara 
AgHBc:Nc hepatocitari/Citoplasma
dr cora pop hepatite cronice
dr cora pop hepatite cronice

10. MANIFESTARI CLINICE Boala acuta usoara/asimptomatica
Boala cronica* -asimptomatica
-manifestari nespec astenie
-artralgii
-durere in hip dr
-manifest cirozei
-manifest cancerului hepatic
dr cora pop hepatite cronice
dr cora pop hepatite cronice

11. *HEPATITA CRONICA CU VIRUS B Istoria Naturala
risc de cronicizare
varsta in mom infectarii
90%
NOU NASCUT
>50%
ADULTI IMUNODEPRIMATI
<5%
ADULTI IMUNOCOMPETENTI
dr cora pop hepatite cronice
dr cora pop hepatite cronice

12. MANIFESTARI CLINICE MANIFESTARI EXTRAHEPATICE -artralgii
-glomerulonefrita
-poliarterita nodoasa
-vasculita
-crioglobulinemie
dr cora pop hepatite cronice
dr cora pop hepatite cronice

13. EXAMEN CLINIC sarac/normal/manifest cirozei/cancerului +/-Stelute
+/-Eritem palmar
Ficat
Splenomegalie
dr cora pop hepatite cronice
dr cora pop hepatite cronice

14. COMPLICATII CIROZA -20% in 5 ani CANCERUL HEPATOCELULAR
-creste riscul de 10 ori
Relatia HVB-ciroza-cancer
dr cora pop hepatite cronice
dr cora pop hepatite cronice

15. DIAGNOSTIC AgHBs AgHBc/AgHBe/PCR TGP/TGO/1-5 ori N, TGP>TGO FA
Bilirubina/albumina/timp protrombina N
Ecografia
biopsia hepatica
dr cora pop hepatite cronice
dr cora pop hepatite cronice

16. HEPATITA CRONICA CU VIRUS B
Markeri serologici
Stadiul bolii
HBsAg
Infectie in desfasurare
IgM antiHBc
Infectie recenta
IgG antiHBc/ cu AntiHBs
Infectie in antecedente
Ac anti HBs
vaccinare
Ag HBe
Replicare virala activa
Ac HBe
Replicare /infectivitate scazuta
AND HVB
boala activa/replicare activa
*interpretarea testelor serologice in infectia cu virus B
dr cora pop hepatite cronice
dr cora pop hepatite cronice

17. EVOLUTIA MARKERILOR SEROLOGICI
IN INFECTIA CU VIRUS B
dr cora pop hepatite cronice
dr cora pop hepatite cronice

18. TRATAMENT Obiectivele tratamentului
-preventia complicatiilor pe termen lung
-reducerea mortalitatii
-ameliorarea simptomatologiei
-oprirea replicarii virale/normalizarea TGP
-reducerea inflamatiei hepatice
-preventia infectarii altor persoane
dr cora pop hepatite cronice
dr cora pop hepatite cronice

19. TRATAMENT Indicatiile terapiei: · TGP crescut
·        HBV ADN >105 copii/ml
dr cora pop hepatite cronice
dr cora pop hepatite cronice

20. TRATAMENT
INTERFERON
-scaderea ADN HVB si disparitia AgHBe la 1/3 din pacienti det scaderea mortalitatii si reducerea complic
-interferon pegylat-1/sapt sc/ Alfa Ifn 5 MU/zi
-ALT scade
-  HBV ADN scade <200pg/ml
dr cora pop hepatite cronice
dr cora pop hepatite cronice

21. TRATAMENT LAMIVUDINA Oral-ANALOG DE NUCLEOTIDE
Inhibitor de revers transcriptaza(prot P)
Scaderea viremiei duce la ameliorarea histologiei
ADEFOVIR dipivoxil
·        Oral-analog si activ NK cel si IFN
·        Supresia virala determina ameliorarea hist hepatica
·        Nici o rezistenta genotipica la 48 saptamani de
terapie
·        Eficace la HBV rezistent la lamivudina
dr cora pop hepatite cronice
dr cora pop hepatite cronice

22. TRATAMENT TRANSPLANT HEPATIC -tratam pt cei cu boala hep avansata
-recurenta dupa transplant frecventa
dr cora pop hepatite cronice
dr cora pop hepatite cronice

23. HEPATITA CRONICA CU VIRUS C
VHC virus ARN din familia flavivirusurilor
 Replicarea in hepatocit
 6 genotipuri 1b europa/ 1a america-corelat cu rasp la tratam/ nu cu evol bolii
Peste 50 de subtipuri
La acelasi individ variatii in secventa genotipurilor infectante
dr cora pop hepatite cronice
dr cora pop hepatite cronice

24. EPIDEMIOLOGIE Prevalenta 1% 170 mil de oameni
Variatii geografice-Africa-13%
Factori de risc-transfuzii
-droguri iv
-hemodializa
-profesia
-contact sexual<5%
Singura infectie hepatitica care are potential de vindecare cu tratam antiviral
dr cora pop hepatite cronice
dr cora pop hepatite cronice

25. PATOGENEZA 3 mecanisme patogenice propuse: Direct citopatic
Inflam si distructie mediata imun-cel mai probabil LT
Autoimunitate mediata viral
dr cora pop hepatite cronice
dr cora pop hepatite cronice

26. ANATOMOPATOLOGIE inflam limfocitara periportala
hepatita activa cu bridging fibrosis,
necroza hepatocitara
steatoza
agregate limfoide
lezarea canalelor biliare
ciroza
dr cora pop hepatite cronice
dr cora pop hepatite cronice

27. MANIFESTARI CLINICE Particularitati clinice:
Infectia acuta este asimptomatica 20%/
rar icter10%
Infectie persistenta la peste 80% cazuri-
Croniciz dep de-asoc cu HIV/ sex/virsta/inoculare
Progresia silentioasa-descoperire intamplatoare
Infectia cronica-astenie
-depresie
-dispepsie
-discomfort abd
Manifestarile complicatiilor
dr cora pop hepatite cronice
dr cora pop hepatite cronice

28. MANIFESTARI CLINICE MANIFESTARI EXTRAHEPATICE
Secundare CI formate la contact cu virusul
Tiroidita autoimuna
Limfom B nonH
Diabet
Crioglobulinemie
Porfirie CT
Lichen plan
GNMP (rar)
dr cora pop hepatite cronice
dr cora pop hepatite cronice

29. COMPLICATII CIROZA CANCER HEPATIC (15% din cei cu ciroza) IH –rar
20-30 ani boala clinica semnificativa
dr cora pop hepatite cronice
dr cora pop hepatite cronice

30. DIAGNOSTICUL Teste serologice
-detectarea Ac la virus la 2sapt pina la 3 luni de la inf
-pt screening
-exista 3 generatii de evaluari serologiceRIBA/EIA
-ele folosesc antigene recombinate
-nu diferentiaza intre acut/ cronic/ vindecare
Valoarea TGP-creste la 1luna/ pina la 1000U/L/ fluctueaza-50% N la un mom dat
dr cora pop hepatite cronice
dr cora pop hepatite cronice

31. DIAGNOSTICUL ARN viral- PCR –HCV-ARN la 2-3sapt de la infectie
-Confirmarea infectiei
-inainte de terapie
-monitorizarea terapiei
Genotiparea
Biopsia hepatica-scorul METAVIR
dr cora pop hepatite cronice

32. BIOPSIA HEPATICA
dr cora pop hepatite cronice

33. BIOPSIA HEPATICĂ
dr cora pop hepatite cronice

34. DIAGNOSTIC Test negativ pt Ac anti HCV- exclude infectia
Test pozitiv pt Ac anti HCV+ALT crescut- dg pozitiv
Test pozitiv pt Ac anti HCV+ALT normal-se face HCV-RNA
Imediat dupa expunere HCV-RNA si tratament
dr cora pop hepatite cronice

35. Liang TJ, Ghany MG. N Engl J Med 2013;368:1907-1917.
Life Cycle of the Hepatitis C Virus (HCV) and Targets of Therapy.
Figure 1. Life Cycle of the Hepatitis C Virus (HCV) and Targets of Therapy. The sequential steps of HCV propagation in a hepatocyte are shown in Panel A. The virus forms complexes with lipoproteins and circulates in the blood. HCV entry factors include scavenger receptor B1 (SCARB1), CD81, claudin 1 (CLDN1), occludin, epidermal growth factor receptor (EGFR), and Niemann-Pick C1-like protein 1 (NPC1L1).4 Panel B shows the virus-encoded gene products displayed topologically on the endoplasmic reticulum membrane, as well as the major viral and host targets that are the focus of agents in advanced clinical development. Other targets in the HCV life cycle, such as viral proteins p7 and NS4B (Panel B), and host targets, including HCV entry factors, lipid metabolism, and membrane signaling pathway involved in replication (Panel A), are also being targeted for HCV therapeutic development. Inhibitors against some of the entry factors have already been developed for other purposes and are currently being tested as treatment for HCV infection. 5– 7 The symbols (+) and (−) refer to the positive and negative strand, respectively, of the viral genome. CypA denotes cyclophilin A, E envelope glycoprotein, GAG glycosaminoglycan, LDLR low-density lipoprotein receptor, NI nucleoside analogue inhibitor, NNI non-nucleoside analogue inhibitor, and NS nonstructural protein.
Liang TJ, Ghany MG. N Engl J Med 2013;368:

36. TRATAMENT combinatie IFNα-PEG + RIBAVIRINA
IFNα-PEG + RIBAVIRINA+BOCEPREVIR/TELAPREVIR genotipul 1
Ribavirina analog guanozinic
Boce/tela inhibitori de proteaze
determina un raspuns viral sustinut la 40-80%
Raspunsul la terapie:
-ALT N si HCV-RNA absent la 6 luni de la oprirea terapiei
The creation of the new standard 'triple therapy' with the DAA medications has led to significant improvements in the response rates for patients with genotype 1 HCV, with SVR rates as high as 63–75% and reduction in duration of therapy by half for many patients based on response-guided therapy (RGT). The first Food and Drug Administration (FDA)-approved protease inhibitors, telaprevir and boceprevir, are designed to mimic the natural NS3/NS4A protease substrate in genotype 1 HCV, therefore inhibiting the onset of the replication process. The successes, failures, and new challenges of triple therapy have become well known. Although the advent of triple therapy has dramatically improved outcomes for many, therapeutic options for HCV are still far from optimal. Many new side effects have been encountered with creative management strategies developed, drug interactions have taken on new importance and issues with resistance and intolerance persist. With the explosion of research and development of newer DAA and additional therapeutic targets, we are at the very beginning of a new era in HCV therapy. A review of the lessons learned from the beginning will be important as we move forward.
dr cora pop hepatite cronice
dr cora pop hepatite cronice

37. TRATAMENT RIBAVIRINA Agent antiviral pentru virus ADN/ARN
Monoterapia cu RBV:NU
ALT seric scazut
Ameliorari minore in histologia hepatica
Nu modifica HCV-RNA seric
Direct inhibition of HCV RNA-dependent RNA polymerase ?
dr cora pop hepatite cronice
dr cora pop hepatite cronice

38. TRATAMENT Boceprevir -tablete -la 4 sapt de la initierea Ifn+Ribav
-ef adverse: oboseala/ anemie/ greata/ cefalee/ insomnie/ neutropenie/ rash/ dermatita exfoliativa/disgeuzie
dr cora pop hepatite cronice

39. Liang TJ, Ghany MG. N Engl J Med 2013;368:1907-1917.
Boceprevir- and Telaprevir-Based Regimens for Treatment of HCV Infection.
Figure 2. Boceprevir- and Telaprevir-Based Regimens for Treatment of HCV Infection. The boceprevir-based regimen and the telaprevir-based regimen differ in several aspects: first, with respect to the specific therapeutic regimen for each type of patient (those who have not received prior therapy vs. those who have received prior therapy, including patients with a relapse after an initial response, those with a partial response, and those with no response); second, with respect to the schedule and duration of the combination therapy; and third, with respect to the points at which therapy is changed, depending on the patient's response, and the points at which therapy is stopped. Typically, telaprevir is given together with peginterferon and ribavirin (peginterferon alfa-2a, 180 μg per week, or peginterferon alfa-2b, 1.5 μg per kilogram of body weight per week, in combination with ribavirin, 1000 mg daily for a patient with a body weight of less than or equal to 75 kg and 1200 mg daily for a patient with a body weight of >75 kg) during the first 12 weeks of therapy; peginterferon and ribavirin are then continued without the protease inhibitor for a total of either 24 or 48 weeks, depending on the virologic response to the triple therapy (response-guided therapy). In contrast, boceprevir is administered starting 4 weeks after the initiation of peginterferon and ribavirin (at the same doses as above) and is continued for a total of 28 or 48 weeks, again depending on the virologic response. In general, with both regimens, patients with cirrhosis should receive the same treatment as patients who have not had a response to previous therapy. The stopping rules were as follows: for the telaprevir-based regimen, patients with an HCV RNA level greater than 1000 IU/ml at week 4 or week 12 should discontinue all three drugs; for the boceprevir-based regimen, patients with an HCV RNA level greater than or equal to 100 IU/ml at week 12 should discontinue all three drugs. For both regimens, patients with detectable HCV RNA at week 24 should discontinue therapy. Boc denotes boceprevir, PIFN peginterferon alfa, R ribavirin, and Tpv telaprevir.
Liang TJ, Ghany MG. N Engl J Med 2013;368:

40. TRATAMENT sofosbuvir (400 mg) si RBV plus PEG 12 sapt HCV genotip 1
sofosbuvir (400 mg) plus simeprevir (150 mg), +/- RBV 12 sapt fără IFN
dr cora pop hepatite cronice

41. TRATAMENT TRANSPLANT HEPATIC - indicaţia cea mai frecventă
recidiva este universală
Imunoprofilaxia-nu
Retratament
Genotype 3 responses less well than genotype 2
RVR important predictor of SVR
Consider shorter duration Rx (e.g. 16 wks) only if RVR and other favorable baseline factors
Consider longer duration Rx (>24 weeks) and weight-based ribavirin if no RVR
Effect of partial versus complete EVR not assessed, but effect likely to be similar to G1 patients
If no RVR and no complete EVR, consider longer Rx (48 weeks) and higher ribavirin doses
dr cora pop hepatite cronice
dr cora pop hepatite cronice

42. COMPLICAŢIILE TERAPIEI
IFN
- Simptome gripale
- Oboseală
- Agravarea starii generale
- Supresie medulară
 RIBAVIRINĂ                   
- Anemie hemolitica -boala coronariană/art. periferica
- Insuficienţa cardiacă
Long-term virological response after SVR: 98-99%
Clinical relevance of detection of small amounts of HCV RNA uncertain
Fibrosis progression rate: slowed
Especially responders, including reversal of cirrhosis
Incidence of HCC: reduced
Especially patients with SVR
Life expectancy and survival: improved
Decreased risk of liver-related death
dr cora pop hepatite cronice
dr cora pop hepatite cronice

43. COMPLICAŢIILE TERAPIEI
CI terapiei cu IFN + RIBAVIRINA
Boli psihice prost controlate
Sarcina
Ciroza decompensată
Insuficienţa renala
Pancreatită
dr cora pop hepatite cronice
dr cora pop hepatite cronice

44. COMPLICAŢIILE TERAPIEI
CI relative ale terapiei cu IFN+RIBAVIRINA
o       Boli CV
o       DZ
o       Convulsii
o       Boli pulmonare
o       L<1500/mm
o       Trombocite<75000/mm
o       Varsta>65 ani
dr cora pop hepatite cronice
dr cora pop hepatite cronice

45. HEPATITA CRONICA CU VIRUS D
Molecula ARN unicatenara
AgHBs este folos ca proteina de anvelopa
HDV se reactiveaza in prezenta HBV
HDV infecteaza numai hepatocitele
dr cora pop hepatite cronice
dr cora pop hepatite cronice

46. EPIDEMIOLOGIE: numai in prezenta HBV:
·        coinfectie-ambele virusuri simultan
·        suprainfectia la o HBV cronica
persoane infectate
droguri iv f de risc cel mai important
dr cora pop hepatite cronice
dr cora pop hepatite cronice

47. MANIFESTARI CLINICE simptome nespecifice infectia trebuie suspectata:
·        infectie HBV fulminanta
·        infectie HBV acuta care se amelioreaza dar recidiveaza ulterior
·        coinfectia HBV-HDV:
boala acuta mai severa decat HBV singura
risc crescut de IHF
dr cora pop hepatite cronice
dr cora pop hepatite cronice

48. TRATAMENT Alfa Ifn raspuns la 50% Raspuns viral/biochimic rar sustinut
9MU de 3 ori/saptaman
Lamivudina si AF-?
Transplant hepatic
dr cora pop hepatite cronice
dr cora pop hepatite cronice