HEPATITE CRONICE

• Definitie : Reactie inflamatorie cronica

evoluand fara ameliorare timp de minimum 6
luni. Acest termen asigura cronicitatea
• Nu este o boala, ci un sindrom caracterizat
prin:
• 1. Manifestari clinice
• 2. Anomalii biochimice
• 3. Modificari histologice comune
• Se exclud din start
HEPATITELE GRANULOMATOASE
CLINIC :
1. Febra
2. Manifestari sistemice
3. Hepatomegalie
4. Hipertensiune portala
5. Anomalii ale testelor hepatice
 ETIOLOGIE

• 1. Infectioase : a. Bruceloza
b.Tuberculoza
c. Histoplasmoza
d. Candidioza
e. Schistosomiaza
f. Febra Q
2. Imunologice a. Sarcoidoza
b. Ciroza biliara primitiva

3. Medicamentoase a. Difenilhidantoina
b. allopurinolul

4. Neoplasme a. limfoame
b. carcinoame
 Hepatite medicamentoase

Normal Troglitazone

Biseptol La 2 luni

Didanozona
Acetaminofen
Lobul hepatic normal Sulfasalazina

Estradiol Metildopa
Amiodarona Metotrexat

Toxicitate vit A Ciclofosfamida

 CLASIFICAREA
GRANULOAMELOR
CAZEOASE tuberculoza

NONCAZEOASE sarcoidoza, C.B.P.

LIPOGRANULOAME ingestia de uleiuri

minerale

NECROZA arterita cu celule gigante

FIBRINOIDA INELARA
 HEPATITE CRONICE DIFUZE

• Istoric
• 1948 Wood Hepatita Cronica Infectioasa
• 1950 Waldenstrom noteaza predispozitia feminina
• 1951 Kunkel hepatita cu hiperglobulinemie
• 1955 Mackay le denumeste “Lupoida”
• 1957 Rezultatele Corticoterapiei
• 1968 Clasificarea histologica
• 1969 Mistilis si Blackburn introduc Imunosupresa
• 1974 Modificarea clasificarii histologice
• 1994 Clasificarea etiologica
 HEPATITE CRONICE DIFUZE

• Prioritati romanesti :

• Bruckner - Moga 1963 Medicina interna

• Fodor 1967 Hepatita cronica

 HEPATITE CRONICE DIFUZE

Clinica :

1. Astenie fizica
2. Icter
3. Hepatomegalie
 Anomalii Biochimice
• 1. Cresterea aminotransferazelor este
anomalia princeps
• 2. Raportul
ASAT/ALAT > 2 - leziune
alcool indusa
ASAT/ALAT < 1 - leziune
viral indusa
Anomalii biochimice tipice in boli
Hepatobiliare
•
 Aspecte Morfologice

• Scopurile examenului histologic

• 1.Determinarea etiologiei : Stabilirea diagnosticului
• 2. Explicarea anomaliilor biochimice
• 3. Gradarea activitatii necroinflamatorii ( HAI )
• 4. Stadializarea fibrozei
• 5. Evaluarea terapiei
• 6. Detectia / Excluderea altor boli ( Leziuni )
 Inflamatia Portala

• 1. Limfocite
• 2. Plasmocite
• 3. Macrofage
 Inflamatia Periportala

• 1. Contine acelasi tip de celule

• 2. Produce lezare hepatocitara
• 3. Consecutiv apare colagenul
• 4. Defineste activitatea bolii si poate fi gradata
 Inflamatia lobulara

• 1. Se insoteste de necroza
• 2. Este variabila
• 3. Are anomalii nucleare
• 4. Determina grading - ul
 Fibroza

• 1. Incepe in spatiul port

• 2. Se extinde periportal
• 3. Produce septuri portoportale
• 4. In faze severe apar septuri
porto – centrale
• 5. Determina staging-ul
 Grading HAI ISHAK

• 1-3 hepatita cronica minima

• 4-8 hepatita cronica blanda
• 9-12 hepatita cronica moderata
• 13-18 hepatita cronica severa
 STAGING

• 0 absenta
• 1 blanda periportala
• 2 moderata portoportala
• 3 severa portocentrala
• 4 ciroza
HEPATITE CRONICE DIFUZE
• Clasificare etiologica
• 1. AUTOIMUNA
• 2. VIRALA B
• 3. VIRALA B cu D
• 4. VIRALA C
• 5. MEDICAMENTOASA
• 6. BOALA WILSON
• 7. DEFICIT A1AT
• 8. CRIPTOGENETICE
Hepatite
cronice
 Causes of viral hepatitis
Hepatitis Common Transmission routes Infection
virus name
A Infectious hepatitis Enteral Acute only

B Serum hepatitis Parenteral, vertical, sexual Acute

Chronic (5 - 10%)

C Non-A Parenteral, vertical, sexual, Acute

Non-B hepatitis other routes undefined Chronic(50 - 70%)

D Delta virus Parenteral; Acute

HBV an essential co-factor Chronic (5 - 10%)

E Enteral Acute only

G Parenteral, other routes undefined Acute and chronic

TTV Parenteral Acute

 Burden of chronic
hepatitis B
• Around 350 million people are
chronically infected with HBV
• >75% of these are of Asian origin
• 25-40% of chronically infected
individuals will die prematurely from the
disease
• 9th leading cause of death worldwide
Prevalence of chronic HBV carriers

Percentage chronic HBsAg carriers:

< 2% - Low
2-7% - Intermediate
Margolis et al, 1991
> 8% - High
 Transmission of HBV infection
Transfusion
(unscreened blood, Mother to baby
blood products)

Body fluids Contaminated needles

(blood, semen, HEPATITIS B and syringes
secretions)

Organs and Child to child

tissue transplantation
Structure of HBV

Envelope
containin
g
HBsAg
DNA polymerase
Double-stranded
DNA

Single-stranded
DNA

HBcAg
(HBeAg)
 Hepatitis B Antigens
Hepatitis B surface antigen (HBsAg)
• First serological marker to appear
• Persistence for >6 months = chronic infection

Hepatitis B e antigen (HBeAg)

• Marker of viral replication
• Present in acute and chronic infection
• Absence does not necessarily indicate absence of
viral replication
 Hepatitis B Antibodies
Anti-HBs • Marker of recovery after loss of HBsAg
• Marker of immunity after Hep B
vaccine

• Coupled to loss of HBeAg suggests a

Anti-HBe favourable outcome
• In presence of HBV DNA may indicate
precore mutant infection
 Hepatitis B Antibodies
• Marker of recovery after loss of HBsAg
Anti-HBs
• Marker of immunity after Hep B vaccine

• Coupled to loss of HBeAg suggests a favourable

Anti-HBe outcome
• In presence of HBV DNA may indicate precore
mutant infection

• Indicates current or previous infection

• Not associated with recovery or immunity
Anti-HBc
 Hepatitis B Antibodies
Anti-HBs • Marker of recovery after loss of HBsAg
• Marker of immunity after Hep B vaccine
• Coupled to loss of HBeAg suggests a
favourable outcome
Anti-HBe
• In presence of HBV DNA may indicate
precore mutant infection
• Indicates current or previous infection
Anti-HBc • Not associated with recovery or immunity

• Indicates acute infection

IgM anti-HBc
 Never Been Exposed to
Hepatitis B
No viral markers
No immune response to the
– HBsAg - virus
– HBeAg -  Anti-HBc -
– HBV DNA -  Anti-HBs -
 Anti-HBe -
 Acute Hepatitis B

Full complement of viral Some immune response

markers, all present for to the virus
< 6 months
– HBsAg
– Anti-HBc +
+
– HBeAg + – Anti-HBs -
– HBV DNA + – Anti-HBe -

• Evidence of acute infection

• Anti-HBc IgM +
 Chronic Hepatitis B with
Evidence of Viral Replication
Some immune response
Full complement of viral to the virus
markers, present for > 6
months
– HBsAg + – Anti-HBc +
– HBeAg + – Anti-HBs -
– HBV DNA +
– Anti-HBe -

• No evidence of acute infection

• Anti-HBc IgM -
 Chronic Hepatitis B with
Evidence of Viral Replication
Some immune response
Only one viral marker to the virus

 HBsAg +
– Anti-HBc +
for  6 months
– Anti-HBs -
 HBeAg -
– Anti-HBe +
 HBV DNA -

• No evidence of acute infection

• Anti-HBc IgM -
Value of serum HBV DNA
assessment
• Prognosis

• Identification of viraemia irrespective of

HBeAg status

• Therapy selection

• Monitoring
– virological response to therapy
– disease progression
– HBV replication after liver transplantation
 HBV DNA Assays

• Liquid phase hybridisation - Abbott

• Branched chain DNA assay - Chiron

• RNA-DNA hybrid assay - Digene

• Polymerase chain reaction (PCR)

 Progression to Chronic Hepatitis B Virus Infection
Typical Serologic Course
Acute Chronic
(6 months) (Years)
HBeAg anti-HBe
HBsAg
Total anti-HBc
Titer

IgM anti-HBc

0 4 8 12 16 20 24 28 32 36 52 Years
Weeks after Exposure
 IMUNOPATOGENEZA
Boli extrahepatice:

• 1. Poliarterita nodoasa
• 2. GN Membranoasa / Membranoproliferativa
• 3. Vasculita Leucocitoclazica
• 4. Crioglobulinemie
Possible outcomes of infection
with hepatitis B virus
Transient
Subclinical 65%
100% Infection
Acute
HBV
Recovery Infection

Adapted from Feitelson, 1994

Possible outcomes of infection
with hepatitis B virus
Transient
Subclinical 65%
100% Infection
Acute
HBV
Recovery Infection

99% 25%
Acute
Hepatitis

Adapted from Feitelson, 1994

Possible outcomes of infection
with hepatitis B virus
Transient
Subclinical 65%
100% Infection
Acute
HBV
Recovery Infection

99% 25%
Acute
Hepatitis
1%
Fulminant
Hepatitis

Adapted from Feitelson, 1994

Death
Possible outcomes of infection
with hepatitis B virus
Transient
Subclinical 65%
100% Infection
Chronic
Acute
10% Infection
HBV
Recovery Infection

99% 25%
Acute
Hepatitis
1%
Fulminant
Hepatitis

Adapted from Feitelson, 1994

Death
Natural history of chronic HBV infection

Resolution

Chronic
Infection
70-90%

Asymptomatic
Chronic Carrier

Adapted from Feitelson, 1994

 Natural history of chronic HBV infection

Inactive
Resolution Resolution Resolution
Cirrhosis

10-30%
Chronic Chronic HCC
Cirrhosis Dysplasia
Infection Hepatitis

70-90%

Asymptomatic Death Death Death

Chronic Carrier

Adapted from Feitelson, 1994

 Hepatita B
Stadiile infectiei cu virus B
• Marker Faza replicativa Faza integrativa

STADIUL 1 2 3 4

AgHBs + + + -
Anti HBs - - - +
HBV DNA ++ + - -
Anti HBc + + + +
Ag HBe + + - -
Anti HBe - - + +
ALAT N crescut N N
 Hepatitis B - Clinical Features

 Incubation period: Average 60-90 days

Range 45-180 days

 Clinical illness (jaundice): <5 yrs, <10%

>5 yrs, 30%-50%

 Acute case-fatality rate: 0.5%-1%

 Hepatitis B - Clinical Features

 Incubation period: Average 60-90 days

Range 45-180 days
 Clinical illness (jaundice): <5 yrs, <10%
>5 yrs, 30%-50%
 Acute case-fatality rate: 0.5%-1%
 Chronic infection: <5 yrs, 30%-90%
>5 yrs, 2%-10%
 Premature mortality from
chronic liver disease: 15%-25%
Clinical Features of Liver
Disease
• Early/mild disease - no symptoms
• Fatigue, weakness
• Abdominal pain
• Nausea, vomiting, anorexia
• Jaundice
• Hepatomegaly
 Jaundice
• Due to excess bilirubin
in tissues

• Yellow discolouration
of:

– Skin
– Mucous membranes
– Sclera of the eyes
 Assessing Severity of Liver
Disease in Hepatitis B
• Mild
Raised ALT and/or AST only

• More severe
Raised ALT/AST and raised bilirubin

• Severe, impending liver failure

Reduced albumin
Prolonged prothrombin time
Currently Used or Approved Antiviral Therapies for HBeAg-Positive Chronic HBV Infection in
Patients Who Have Not Received Treatment

Dienstag J. N Engl J Med 2008;359:1486-1500

 Hepatita D

• 1987 Rizzeto
• Virus ARN
• Necesita HBV care furnizeaza :
1. Nucleocapsida
2. Anvelopa
Survine :
1. Coinfectie
2. Suprainfectie
Important de cautat la:
1. Bolnavii ce se agraveaza
2. Bolnavii AgHBe negativi
Infectare :
1. Parenterala
2. Intrafamiliara
 HEPATITA C

1. Virus ARN din familia Flaviridae

- 9400 nucleotide codand un
polipeptid de 3000 aa.
 The HCV Genome and Expressed Polyprotein

Lauer G and Walker B. N Engl J Med 2001;345:41-52

GENOTIPURI SIMMONDS

• Clasificarea in 6 tipuri:
 1a
 1b (90% in Romania)
 2a
 2b
 3a
 4a
 Produce cvasispecii-impiedicand realizarea unui
vaccin .
Distributia geografica: 1a,b SUA, Euroa
1b,2a,2b Japonia
3 Thailanda, Australia,
Europa de nord
4.Asia
5.Africa de Sud
6. Hong Kong
• Epidemiologie:
• 1,4 % din populatia generala
• 0,1-0,7 %donatori
• 4-6 % Africa, Orientul Mijlociu
• Creste cu varsta 0,2-3,9 %
• Dializati 20 %
• Hemofilicii 65 %
• Narcomanii 70 %
• Personalul medical 0-10 %
• TRANSMISIE:
• 40-50% droguri intravenoase
• 5-25% transfuzii
• CAI DE TRANSMISIE:
• ace - droguri
• - personal medical
• hemodializa 2-3%
• tatuaje
• transfuzie – sange
• - produse 0,1%
• sexual
• intrafamilial
• 50% cai necunoscute
 Manifestari clinice
1. Simptome mai blande
2. Multi asimptomatici
3. 25 % icter
DIAGNOSTIC
I NESPECIFIC 1. Anamneza  factori de risc
2. ALAT

II SPECIFIC 1. IMUNOLOGIC a) ELISA

b) RIBA
c) WESTERN BLOT
2. MOLECULAR a) PCR
b) DNA

III HISTOLOGIC
COINFECTIA B cu C

Se caracterizeaza prin : 1. nivele reduse ale viremiei

2. nivele foarte mari ALAT
3. evolutie grava
4. rezistenta la tratament
5. experienta redusa
ALTE AFECTIUNI PRIN VIRUS C

1. S. Sjögren
2. Crioglobulinemie
3. Porfiria acuta tarda
4. Limfoame non - hodgkiniene
DECIZIA DE TRATAMENT
ESTE DEPENDENTA DE:
I. GRADUL DE ACTIVITATE AL BOLII

DA ! cand I.A.H.  6 KNODELL

ALAT  1.5-2 N

NU ! cand I.A.H.  6 KNODELL

ALAT - N
 Diagnosticul de leziune:
HEPATITA
1. Criteriul biologic
- nivele crescute ALAT, ASAT
2. Criteriul histologic
- infiltrat inflamator
- necroza
- steatoza (virus C)
 Nu sunt eligibili:
a). Alcoolicii - complianta redusa
- efecte sinergice
- incarcare cu Fier
- replicare virala mare
- depresie imuna
b). Toxicomanii - risc de reinfectie
c). Ciroticii decompensati
 II. VARSTA

- copii, adulti  65 ani,

Varsta biologica mai importanta decat cea cronologica

Varstele inaintate asociaza boli ce pot fi contraindicatii

III. SANSA DE VINDECARE

- absenta cirozei

- fibroza redusa
 IV. RISCURI

- legate de terapie
boli autoimune
rezistenta la tratament

- legate de teren
transplantatii
 V. CONTRAINDICATII
(in principal pentru IFN)
1. Epilepsie
2. Psihoze
3. Citopenii
4. Ciroze
5. Graviditate
6. Comorbiditati grave - a). Insuficienta cardiaca
b). Insuficienta renala
c). Diabet
d). Poliartrita reumatoida
 SCOPUL TRATAMENTELOR

1. Diminuarea necroinflamatiei

2. Reducerea fibrozei

determinanti esentiali ai prognosticului

 RASPUNSUL VIROLOGIC

1. Clearence-ul viral este telul ideal,

irealizabil in prezent
2. Locuri de replicare extrahepatice
mononucleare, SNC (virus C)

3. Seroconversia Ag HBe nu inseamna neaparat

eradicarea virusului

4. Limita de detectie a AND - HVB depinde de

metoda
HEPATITA CRONICA B
INDICATII

1. Varsta  65 ani
2. ALAT > 2 N, peste 6 luni
3. Semne de replicare virala
4. IAH  6 KNODELL
FACTORII PREDICTIVI DE
BUN AUGUR

1. ADN viral  200 pg/mL

2. ALAT > 5 N
3. Sex feminin
4. Varsta < 40 ani
5. Absenta cirozei
FACTORII PREDICTIVI DE
RAU AUGUR

1. ADN viral > 200 pg/mL

2. Ag HBe negativ

3. Coinfectie HIV, HDV

4. ALAT normal
 HEPATITA CRONICA C
1. ALAT > 1.5 - 2 N, mai mult de 6 luni
2. ARN VIRAL, ANTI HVC de generatia a III

NU sunt contraindicatii
1. Prezenta anti LKM1 (5%)

2. Coinfectia cu virus G
FACTORII FAVORABILI DE
EVOLUTIE
1. Durata scurta a bolii
2. Genotipurile 2, 3
3. Viremie redusa < 2x106 copii/mL
4. Complexitate redusa a HVR 1
5. Absenta fibrozei
6. Sex feminin
7. Varsta < 40 ani
8. Sistem imun - T/B crescut
- CD11-, CD8+ reduse
FACTORII PREDICTIVI CU
INFLUENTA NEGATIVA
1. Genotipul 1
2. Sarcina virala mare
3. Variabilitate mare
4. Sex masculin
5. Varsta > 40 ani
6. Coinfectia HIV, HVB
7. Obezitate
8. Incarcare cu fier (hepatocitara, serica)
 HEPATITA CRONICA D
Se supune criteriilor hepatitei B, la care
se adauga:

- anti HVD

- ARN viral
 INTERFERONII

Proteine membranare Limfocit B

Limfocit T
 HLA I, II monocit
2 microglobulina
Fe fibroblasti
IFN  IFN ,

R R

mesager
Efecte antitumorale

ARN
proteina

Imunomodulatoare
- citokine
- C2
- activare celulara
 MOD DE ACTIUNE

I Antiviral 1. Inhiba ARN -ul viral

2. Activeaza enzimele antivirale
a ) 2’, 5’ oligoadenilat sintetaza
b ) proteinkinaza
II Imunomodulator Amelioreaza actiunea TH , NK

EFECTE ADVERSE

1. Constitutionale
2. Hematologice
3. Neuropsihiatrice
4. Autoimune - ANA
- SMA
- Antitiroidieni
ANALOGI NUCLEOZIDICI

1. LAMIVUDINA
2. RIBAVIRINA
3. ACICLOVIR
4. FAMCICLOVIR
5. ADENINARABINOZID
6. GANCICLOVIR
 HEPATITE AUTOIMUNE
Hepatita cronica, predominent periportala cu hiper  globulinemie si autoanticorpi tisulari
care raspunde la tratamentul imunosupresor, cel mai frecvent.

I II III

Anticorpi ANA, SMA Anti LKM1 Anti SLA

Alti anticorpi Antiactina Anti P450 Anti LP
Antitiroida Anti c. parietale SMA
Antihistone Antitiroida AMA
p ANCA Anti I. Langerhans
Antigen posibil Asialoglicoproteina P450 Citokeratina 8 / 18
Alti termeni lupoida 2a criptogenetice
Varsta 16 - 30 2 - 14 20 - 40
Sex F F F
Boli imune tiroidita diabet ?
sinovita vitiligo ?
colita tiroidita ?
Laborator   globuline  IgA ?
Tratament corticoizi corticoizi corticoizi
Criterii de diagnostic ( Los Angeles ’ 94 )

SIGUR 1AT PROBABIL – excludere Wilson

Ceruloplasmina N anti HVC
Cupremie

Absenta markerilor virus B si C

VCM, E - B
Absenta drogurilor hepato-toxice

Ingestie alcool < 35 g/zi M < 50 g/zi M

< 25 g/zi F < 40 g/zi F
 globuline IgG > 150 % N 1/40 adulti, 1/10 copii
SMA, AMA, anti LKM1 > 1 / 80
Biopsie

Transaminaze mult crescute fata de fosfataza

DIAGNOSTIC DIFERENTIAL

1. B. WILSON - ceruloplasmina
- excretia urinara de cupru
- examen oftalmologic
- cupru hepatic

2. Hemocromatoza - sideremie
- transferina
- depozite de fier hepatic

3. Ciroza fibroasa preliminara - anti M2

- biopsie
- lipsa de raspuns la costicoizi

4. Colangita sclerozanta primitaiva ERCP

 PATOGENIE

I predispozitie genetica HCA - B8

- DR3 , DR52

II agent trigger - virusul rujeolic

- virusul Ebstein Barr
- virusurile hepatitice
III autoantigene - nu sunt organ specifice
- cauza sau efect ?
 ANOMALII ALE SISTEMULUI IMUN

1. HLA – DR  loci codeaza : - proteine din sistemul complementului

- Ig
- receptori T

2. Deficit functional TS - date in vitro

- efectul corticoizilor
- primar ? secundar ?
PROBLEMA AUTOIMUNITATII IN Hepatita virala C

10 % din pacientii cu Hepatita C au anticorpi

Decizia de tratament trebuie sa se bazeze pe :

1. Titrul anticorpilor

2. PCR HVC
 Scorul diagnostic
ITEM PUNCTE
1. Sex F 2
2.F.A./ALT <1,5 = +2; >3 = -2
3.IgG >2N=3 ; <1N = 0
4.Autoanticorpi >1/80 = 3pct
5.AMA - 3 pct
6.Markeri virali +/- 3 pct
7.Medicamente - = 3 / + =4 pct
8.Alcool < 25g/zi = +2 pct
9.Histologie Piece-meal = 3 pct
10.Boli autoimune +2 pcte
11.Raspuns la tratament +2 pcte
 SEMNIFICATIE
PRETRATAMENT PUNCTEH

H.A.I. DEFINITA > 15 pct

H.A.I. PROBABILA 10- 15 pct

POSTTRATAMENT

H.A.I. DEFINITA > 17 pct

H.A.I PROBABILA 12 -17 PCT

INDICATII DE TRATAMENT

I ABSOLUTE 1. ALAT > 10 N

2. ALAT > 5 N +  globuline 2N
3. Bridging necrosis
4. simptome incapacitante
5. boala evolutiva

II RELATIVE 1. ALAT < 10 N

2. ALAT < 5 N +  globuline < 2N
3. hepatita periportala
4. astenie
TRATAMENT MONOTERAPIE TERAPIE COMBINATA

ATAC PREDNISON 20- 30 mg PREDNISON 20- 30 mg

AZATIOPRINA 50 – 100 mg

MENTINERE PREDNISON 5 – 15 mg PREDNISON 5 - 10 mg

AZATIOPRINA 2 mg / kcorp si
AZATIOPRINA 50 – 150 mg
 Alte tratamente
• Ciclosporina 5-6 mg/kgcorp/zi
recaderi la oprire

• Tacrolimus 4 mg x 2/zi

• Budesonid 6-8 mg/zi - 10 sapt.

• Ac. Ursodezoxicolic 250-750 mg/zi - 2 luni

• Imunoglobuline
ALTI AGENTI :

1. CICLOSPORINA 5 mg / kcorp
2. TACROLIMUS 4 mg / zi
3. AC URSODESOXICOLIC 250 – 750  nesigur
4. TIMOZINA descurajant
5. FOSFATIDILCOLINA + CORTICOIZI