Diagnosticul bolii hepatice și al

Diagnosticul bolii hepatice și al complicațiilor acesteia

Coordonator național metodologie și monitorizare –prof.dr. Mariana JINGA

Titlul proiectului: „LIVE(RO) 1 - Formarea personalului medical din România pentru screeningul populațional al infecțiilor cronice cu virusuri hepatitice B/C/D”Contract de finanțare nr. POCU/308/4/9/120640

Diagnosticul bolii hepatice șial complicațiilor acesteia

DIAGNOSTICUL HEPATITEI CRONICE VIRALE

DIAGNOSTICUL SI STADIALIZAREA CIROZEI HEPATICE

DIAGNOSTICUL CANCERULUI HEPATIC

Diagnosticul hepatitei cronice virale: -anamneza-evidentierea persoanelor la risc

Calea de contaminare:

transfuzia de singe in antecedente

interventii chirurgicale in antecedente

tratamente stomatologice

contactul cu persoane contaminate cu virusuri hepatitice

antecedentelor familiale (mama),

utilizarea de droguri administrate parenteral,

utilizarea in comun de obiecte de igienapersonale

tatuaje,

dializa,

transplant,

hemofilie

mediul de lucru de risc: personal sanitar, moase, politist

Virsta de debut sau de depistare a bolii poate fi

oricare boala hepatica virala fiind intilnita la orice

virsta cu particularitati in functie de calea de

contaminare si reactivitatea imuna a subiectului.

Locul de provenienta sau domiciliul pacientului

poate sugera posibilitatea unui risc crescut: copii

institutionalizati, persoane incarcerate, persoane fara

locuinta.

Comportamentul social poate plasa persoana intr-un

grup de risc: dependenti de droguri, comportament

sexual.

Hepatita cronica HCV

VHC descoperit 1989 de catre CHOO

Hepatita post-transfuzionala nonA nonB

ARN virus hepatotrop din familia Flaviviridaelor

Afectiune hepatica caracterizata prin persistenta inflamatiei cronice timp de minimum 6 luni dupa expunerea la VHC

Cursul natural al infecţiei VHC50% vor dezvolta ciroza hepatica 1-5% anual fac HCC

Natural history/disease burden

Figure adapted from Asselah T, et al. J Hepatol 2014;61:193–51. van der Meer AJ, et al. J Hepatol 2016;65:S95–S108; 2. Butt AA, et al. JAMA Intern Med 2015;175:178–85; 3. Singh AG, et al. Clin Gastroenterol Hepatol 2010;8:280–8;EASL CPG HCV. J Hepatol 2018;69:461–511.

Long-term natural history of HCV infection is highly variable

Chronic HCV infection is accompanied by

Extrahepatic manifestations reported in up to 75% of patients, including:1

Mixed cryoglobulinaemia vasculitis, renal disease (elevated creatinine), type 2 diabetes, cardiovascular disease (vasculitis, arterial hypertension), porphyria cutanea tarda, lichen planus and lymphoproliferative disorders

Non-specific symptoms: fatigue, nausea, abdominal pain, weight loss

Rapid development of hepatic fibrosis and accelerated time to cirrhosis2

Increased risk for liver failure, HCC and liver-related mortality

Overall estimated annual risk for liver failure of 2.9%, HCC 3.2% andliver-related death 2.7% in patients with advanced fibrosis1,3

F0 F1 F2 F3F4

CTP A

F4

CTP B

F4

CTP CHCC

Hepatita cronica VHC -

diagnostic

1. Clinic

2. Biochimic

3. Serologic

4. Histopatologic

Hepatita cronica HCV

-Diagnostic clinic

• Clinic- majoritatea asimptomatici (90%)

• Manifestari clinice - nespecifice

• Astenie fizica, fatigabilitate – cel mai frecvent

• Durere hipocondrul dr

• Greata, inapetenta

• Artralgii, mialgii

• Prurit

• Ex obiectiv: normal / hepatomegalie moderata

• Manifestari extrahepatice 40-75%

Simptomele… sau

absenţa lor în HC VHC

Simptomatic37%

Ciroza7%

56%Asimptomatic

Unpublished data from MCV Hepatitis Program, 1995.

Diagnostic clinic HCV

Manifestari extrahepatice – mediate de complexe imune –pana la 75% din pacienti

Poliarterita nodoasa

Glomerulonefrita

Crioglobulinemie mixta esentiala

Anemie aplastica

Porfirie cutanata tardiva,

lichen plan

Artrite seronegative

Keratoconjunctivita sicca

Fibromialgie

Sdr. limfoproliferativ

Diagnostic biochimic HCV

• sindromul de colestaza: pigmenţi biliari (bilirubina, acizi biliari,

urobilinogen), enzime de colestază (GGT si fosfataza alcalina)

• sindromul de citoliză: TGP, TGO;

• sdr. de activitate mezenchimală: electroforeza proteinelor,

imunoglobulinele serice

• sindromul hepatopriv: tulburările metabolismului protidic

(serumalbuminele, factorii de coagulare, fibrinogenul, timpul de

protrombină), tulburările metabolismului lipidic (colesterolul,

lipidele totale, trigliceridele), tulburările metabolismului glucidic

• Biologic - 70% au transaminaze crescute

• Fara corelatie cu modificarile histologice sau cu nivelul ARN VHC

Diagnostic Hepatita

cronica HCV

• teste serologice

• teste moleculare pt detectia ARN-VHC

• examen histopatologic sau teste noninvazive de detectie a gradului de fibroza hepatica

Diagnosis of acute and

chronic hepatitis C

EASL Recommendations on Treatment of Hepatitis C 2018, Journal of Hepatology 2018 vol. xxx j xxx–xxx

Anti-HCV antibodies are detectable in serum or plasma by

enzyme immunoassay (EIA) in the vast majority of patients with

HCV infection,

EIA results may be negative in early acute hepatitis C and in

profoundly immunosuppressed patients

Following spontaneous or treatment-induced viral clearance,

anti-HCV antibodies persist in the absence of HCV RNA, but may

decline and finally disappear in some individuals

Diagnosis of acute and

chronic hepatitis C

All patients with suspected HCV infection should be tested for

anti-HCV antibodies in serum or plasma as first-line diagnostic

test.

In the case of suspected acute hepatitis C, in

immunocompromised patients and in patients on haemodialysis,

HCV RNA testing in serum or plasma should be part of the initial

evaluation.

If anti-HCV antibodies are detected, HCV RNA should be

determined by a sensitive molecular method with a lower limit of

detection ≤15 IU/ml .


Diagnosis of acute and chronic hepatitis C

In low- and middle-income countries, and in specific settings in

high-income countries, a qualitative HCV RNA assay with a lower

limit of detection ≤1,000 IU/ml can be used to provide broad

affordable access to HCV diagnosis and care .

Anti-HCV antibody-positive, HCV RNA-negative individuals should

be retested for HCV RNA 12 and 24 weeks later to confirm definitive

clearance .

HCV core antigen in serum or plasma is a marker of HCV replication

that can be used instead of HCV RNA to diagnose acute or chronic

HCV infection when HCV RNA assays are not available and/or not

affordable .

HCV genotype determination - With pan-genotypic HCV drug

regimens, it is possible to treat individuals without identifying their

HCV genotype and subtype.


Diagnosis of acute and chronic

HCV infection

EASL CPG HCV. J Hepatol 2018;69:461–511.

Recommendations

All patients with suspected HCV infection should be tested for anti-HCV Ab

in serum or plasma as first-line diagnostic testA 1

In cases of suspected acute hepatitis C, in immunocompromised patients

and patients on haemodialysis, serum or plasma HCV RNA testing should be

part of the initial evaluationA 1

If anti-HCV Ab detected, HCV RNA should be determined by a sensitive

molecular method (LLOD: ≤15 IU/mL)A 1

Anti-HCV Ab+, HCV RNA individuals should be retested for HCV RNA 12

and 24 weeks later to confirm definitive clearance A 1

In low- and middle-income countries, and specific high-income country

settings, a qualitative HCV RNA assay (LLOD: ≤1000 IU/mL) can be used to

provide broad affordable access to HCV diagnosis and care

B 2

Serum or plasma HCV core antigen (a marker of HCV replication) can be

used instead of HCV RNA to diagnose acute or chronic HCV infection when

HCV RNA assays are not available and/or not affordable

A 1

Grade of evidence Grade of recommendation


Screening for chronic HCV infection

*After shipment to a central laboratory where the EIA will be performed; †Using serum, plasma, fingerstick whole blood or saliva as matrices; ‡If HCV RNA assays are not available and/or not affordable; §If available and screening strategy is cost effective


Recommendations

Screening strategies

• Screening according to local epidemiology and within framework of

national plans

• May include at-risk populations, birth cohort testing and general

population testing in areas of intermediate to high seroprevalence (≥2–

5%)

• Based on detection of serum/plasma anti-HCV Abs using EIA

A

B

A

1

2

1

Anti-HCV Ab testing

• Should be offered with linkage to prevention, care and treatment

• Dried blood spots can be used as alternative to serum or plasma*

• Use RDTs† (as an alternative to classical EIA) at patient’s care site to

facilitate screening and improve access to care

A

A

A

1

2

2

HCV RNA testing

• If anti-HCV Ab detected, test for serum/plasma HCV RNA (or HCV core

antigen)‡ to identify patients with ongoing infection

• Dried blood spots can be used as alternative to serum or plasma*

• Reflex testing for HCV RNA in patients who are anti-HCV Ab+ should be

applied to increase linkage to care

Anti-HCV Ab screening can be replaced by a point-of-care HCV RNA assay

(LLOD: ≤1000 IU/mL) or HCV core antigen testing§

A

A

B

C

1

2

1

2



Dg morfologic -Ecografia abdominala, CT, RMN (elastografia IRM)

Metode de evaluare neinvaziva a gradului de fibroza hepatica:

1. Elastografia impulsionala (Fibroscan); valori > 13-15 kPa

=ciroza hepatica ; CAP (Controled Attenuation Parameter)

2. Fibromax, Fibrotest, Actitest,

3. APRI (recomandat de OMG): (TGO si Trombocite)

APRI<0,5 = lipsa fibrozei

APRI: 0,5-1,5 = fibroza<F2

APRI: >1,5 = fibroza severa (F3 sau F4)

4. Shear Wave Elastography:

ARFI (Acoustic radiation force impulse: Point SWE , 2D-SWE

Biopsia hepatica – stadiul fibrozei si gradul act necroinflamatorii

Non-invasive assessment of liver

disease severity

*Scales for liver stiffness cut-offs (in kPa) are different between FibroScan® and Aixplorer®;†Two cut-offs are provided for FIB-4 and for APRI, respectively, with their own sensitivities and specificities;

‡95%CI; §Median (range)EASL CPG HCV. J Hepatol 2018;69:461–511.

TestStage of fibrosis

Number of patients Cut-off(s) AUROC Sensitivity Specificity PPV NPV

FibroScan® F3 560 HCV+ 10 kPa* 0.83 72% 80% 62% 89%F4 1,855 HCV+ 13 kPa* 0.90–0.93 72–77% 85–90% 42–56% 95–98%

ARFI (VTQ®)

F32,691

(1,428 HCV+)1.60–2.17 m/sec

0.94(0.91–0.95)‡

84%(80–88%)‡

90%(86–92%)‡ NA NA

F42,691

(1,428 HCV+)2.19–2.67 m/sec

0.91(0.89–0.94)‡

86%(80–91%)‡

84%(80–88%)‡ NA NA

Aixplorer®F3 379 HCV+ 9 kPa* 0.91

90%(72–100%)‡

77%(78–92%)‡ NA NA

F4 379 HCV+ 13 kPa* 0.9386%

(74–95%)‡

88%(72–98%)‡ NA NA

FibroTest® F41,579

(1,295 HCV+)0.74 0.82–0.87 63–71% 81–84% 39–40 93–94

FIB-4 F4 2,297 HCV+1–45†

3.25†0.87§

(0.83–0.92)90%55%

58%92%

NA NA

APRI F4 16,694 HCV+ 1.0†

2.0†0.84§

(0.54–0.97)77%48%

75%94%

NA NA


5 biomarkeri serici specifici ajustati in raport cu sex, varsta, G, H:

-alfa-2 macroglobulina

-haptoglobina

-apolipoproteina A1

-GGT (gamma glutamyltranspeptidaza)

-bilirubina totala

Cut-off values: 0.00 to 0.21 for F0; 0.22 to 0.28 for F0-F1; 0.29 to 0.31 for F1: 0.32 to 0.48 for F1-

F2; 0.49 to 0.58 for F2; 0.59 to 0.72 for F3; 0.73 to 0.74 for F3-F4; and 0.75 to 1.00 for F4

Fibroscan

Pre-therapeutic assessment

*Alcoholism, cardiac disease, renal impairment, autoimmunity, genetic or metabolic liver diseases (e.g. genetic haemochromatosis, diabetes mellitus or obesity) and the possibility of drug-induced hepatotoxicity


Other causes of chronic liver disease, i.e. other blood-borne viruses, particularly HBV and HIV, should be investigated and ruled out

Recommendations

Evaluate contribution of comorbidities to progression of liver disease and

implement corrective measuresA 1

Liver disease severity must be assessed prior to therapy A 1

Identify patients with cirrhosis (F4): adjust treatment accordingly; mandatory

post-treatment surveillance for HCCA 1

Post-treatment surveillance for HCC must also be performed in patients with

advanced fibrosis (METAVIR score F3)B 1

Initially, assess fibrosis stage by non-invasive methods; reserve liver biopsy for

when there is uncertainty or potential additional aetiologiesA 1

Renal function (creatinine/eGFR) should be ascertained A 1

Identify extrahepatic manifestations of HCV infection in case of symptoms* A 1

HBV and HAV vaccination should be proposed to patients who are not

protectedA 1



1. van der Meer AJ, et al. J Hepatol 2016;65:S95–S108; 2. D’Ambrosio R, et al. Hepatology 2012;56:532–43; 3. Nahon P, et al. Gastroenterology 2017;152:142–56; 4. van der Meer AJ, et al. JAMA 2012;308:2584–93; 5. Bruno S, et al. J Hepatol

2016;64:1217–23; 6. Lee M-H, et al. J Infect Dis 2012;206:469–77; 7. Singh AG, et al. Clin Gastroenterol Hepatol 2010;8:280–8;

8. Hefferman A, et al. Lancet 2019; doi: 10.1016/S0140-6736(18)32277-3;EASL CPG HCV. J Hepatol 2018;69:461–511.

SVR corresponds to a definitive cure of HCV infection in nearly all

cases and is frequently associated with

Improvement in extrahepatic manifestations1

Improvement/disappearance of liver necroinflammation and

fibrosis1

Regression of advanced hepatic fibrosis (F3) or cirrhosis (F4)2

Reduced risk of HCC, hepatic decompensation, non-liver- and liver-

related mortality, and liver transplantation3–7

HCV therapy is one of the interventions necessary to reduce

global burden of disease8

Primary goal of therapy – cure HCV infection (SVR12 or SVR24)


Goals of therapy


Goal – to cure HCV infection (A1) in order to

Prevent the complications of HCV-related liver and

extrahepatic diseases, including:

Hepatic necroinflammation, fibrosis, cirrhosis, decompensation

of cirrhosis, HCC, severe extrahepatic manifestations and death

Improve quality of life and remove stigma

Prevent onward transmission of HCV

Indications for treatment of HCV: who

should be treated?

*Individuals who failed to achieve SVR after prior treatment; †Symptomatic vasculitis associated with HCV-related mixed cryoglobulinaemia, HCV immune complex-related nephropathy and non-Hodgkin B-cell lymphoma; ‡Non-liver solid organ or stem cell transplant recipients, HBV coinfection, diabetesEASL CPG HCV. J Hepatol 2018;69:461–511.

Recommendations

All patients with HCV infection must be considered for therapy, including

treatment-naïve and treatment-experienced* patientsA 1

Patients who should be treated without delay

• Significant fibrosis or cirrhosis (METAVIR score ≥F2): including compensated

(Child–Pugh A) and decompensated (Child–Pugh B or C) cirrhosis

• Clinically significant extra-hepatic manifestations†

• HCV recurrence after liver transplantation

• Patients at risk of rapid evolution of liver disease due to concurrent

comorbidities‡

• Individuals at risk of transmitting HCV

– PWID

– MSM with high-risk sexual practices

– Women of child-bearing age who wish to get pregnant

– Haemodialysis patients

– Incarcerated individuals

A 1

• In patients with decompensated cirrhosis and an indication for liver

transplantation (MELD score ≥18–20), transplant first and treat after

transplantation

• For waiting time >6 months, treat before transplant (clinical benefit not well

established)

B

B

1

2

• Treatment is generally not recommended in patients with limited life expectancy

due to non-liver-related comorbiditiesB 2


Endpoints of therapy


Recommendations

Main endpoint• Undetectable serum or plasma HCV RNA by sensitive assay

(LLOD ≤15 IU/mL) 12 weeks (SVR12) or 24 weeks (SVR24) after EOT

A 1

Alternative endpoint• Undetectable HCV core antigen in serum or plasma by EIA 24

weeks (SVR24) after EOT– In patients with detectable HCV core antigen prior to therapy, if

HCV RNA assays are not available and/or not affordable

A 1

Additional endpoint • Undetectable serum or plasma HCV RNA (SVR24) after EOT by

qualitative HCV RNA assay with LLOD ≤1000 IU/mL– In areas where sensitive assays are not available and/or not

affordable

B 1

• In patients with advanced fibrosis and cirrhosis, HCC surveillance must be continued: an SVR will reduce, but not abolish, the risk of HCC

A 1



Hepatita cronica HBV

Afectiune hepatica caracterizata prin persistenta inflamatiei cronice timp de minimum 6 luni dupa expunerea la VHB

Tablou clinic variabil in functie de stadiul infectiei si de severitatea bolii

Ex obiectiv poate fi normal

20% din pacienti – manifestari extrahepatice

Evaluarea activitatii si stadializarea bolii pentru a stabili severitatea sa si necesitatea tratamentului antiviral

Transaminazele pot fi sau nu crescute

HBV- Epidemiology and

public health burden

1. EASL CPG HBV. J Hepatol 2017;67:370–98; 2. Schweitzer A, et al. Lancet 2015;386:1546–55; 3. Ott JJ, et al. Vaccine 2012;30:2212–9; 4. GBD 2013 Mortality and Causes of Death Collaborators. Lancet 2015;385:117–71; 5. Coppola N, et al. Euro Surveill 2015;20:30009; 6. Hampel A, et al. Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 2016;59:578–83; 7. Chen C-L, et al. J Hepatol 2015;63:354–63.

Worldwide ≈250 million chronic HBsAg carriers2,3

686,000 deaths from HBV-related liver disease and HCC in 20134

Increasing prevalence in

some European countries:5,6

• Migration from high

endemic countries

HBsAg prevalence, adults (1949 years), 20053

<2%

24%

57%

≥8%

Not applicable

Decreasing

prevalence in some

endemic countries,

e.g. Taiwan7

Possible reasons:

• Improved

socioeconomic

status

• Vaccination

• Effective

treatments

Cursul natural al infecţiei VHB

Diagnosticul hepatitei

cronice VHB+

• Clinic

• Biochimic

• Serologic

• Histopatologic

Diagnostic clinic

Manifestari extrahepatice – 10-20%

Mediate de complexe imune

Poliarterita nodoasa

Glomerulonefrita

Crioglobulinemie mixta esentiala

Anemie aplastica

Diagnostic clinic Fara elemente semnificative

Astenie, fatigabilitate, scaderea capacitatii de efort

Durere hipocondrul drept

Subicter/icter in stadii avansate de boala

Hepato-splenomegalie

Anamneza poate decela momentul inocularii

Manifestarile clinice si evolutia depind de:

Varsta la momentul infectiei

Gradul de replicare virala

Capacitatea de aparare imuna a gazdei

Diagnostic biochimic Sindromul hepatocitolitic se traduce prin transaminaze ALAT,

ASAT crescute de câteva ori (în general 2-3xN), dar există şi

hepatite cronice cu transaminaze cvasinormale.

Sindromul inflamator se traduce prin creşterea gama

globulinelor, existând o oarecare corelaţie între nivelul lor şi

activitatea histologică a bolii.

Sindromul hepatopriv (coagulograma, albuminemia) este

puţin modificat.

Sindromul bilio-excretor, cu creşterea bilirubinei, GGT, FALC

este destul de rar.

Testele ce relevă insuficienţa functiei de sinteză hepatică

(albumina, testele de coagulare, bilirubina), scăderea

leucocitelor, trombocitelor, creşterea AFP – markează evoluţia

către ciroză


- evaluarea severitatii bolii

Ex clinic

Biochimic, bil, alb, GGT, FALC, coagulograma/INR, trombocitele

Alfafetoproteina

Ecografia abdominala

Teste de determinare a gradului de fibroza hepatica:

- teste non-invasive: elastografie, biomarkerii serici

- biopsia hepatica (in cazuri neconcludente)

Scop: detectia activitatii necroinflamatorii si a gradului de fibroza hepatica


- evaluarea severitatii bolii Elastografia tranzitorie cu Fibroscan (Echosens Paris, Franta)

≥ F2 7,9kPa

F4 11,7 kPa

Biomarkerii serici:

Directi (ac hyaluronic, TIMP1, PIIIPN),

Indirecti (FibroActiTest - Biopredictive, Paris, Franta)

Diagnostic serologic:

persistenta AgHBs la mai mult de 6 luni de la expunere

AgHBe/ac anti HBe

AND VHB cantitativ

Ac anti HVD (IgG, IgM si totali)

HBeAg

Anti-HBe

Phases of chronic HBV

infection

1. Lok A, et al. J Hepatol 2017;67:847–61;2. EASL CPG HBV. J Hepatol 2017;67:370–98

Phase 2 Phase 3Phase 1 Phase 4

HBeAg-positive

chronic hepatitis B

HBeAg-negative

chronic HBV infection

HBeAg-positive

chronic HBV infection

HBeAg-negative

chronic hepatitis B

New

nomenclature2

Diagnostic serologic –

markeri ‘clasici’

• Markeri serologici

• Markeri directi

• Ag HBs

• Ag HBe

• Markeri indirecti

• Ac anti HBs

• Ac anti HBc

• Ac anti HBc IgM

• Ac anti HBe

• Markeri moleculari

• HBV DNA

Diagnostic serologic Hep. Cr. VHB Ag HBs

Marker pentru infectie cronica

Persista > 6 luni = infectie cronica

Ac anti HBs

imunizare prin infectie sau vaccinare

- marcheaza eradicarea infectiei acute

- singurul Ac protector indus de vaccinurile disponibile

- persista toata viata conferind imunitate pe termen lung

Ag HBs + Ac anti HBs = infectie cronica

Ag HBc este un Ag intracelular, exprimat pe hepatocitele infectate

Ac anti HBc sunt detectati in ser in tot decursul infectiei VHB

- “Fereastra imunologica” (rolul Ac anti HBc IgM)

- Ac anti HBc IgM tip IgM apar in cursul infectiei acute (apare la o luna de la infectia

acuta si cu 1-2 sapt inainte de cresterea transaminazelor)

- e singurul marker imunologic detectat in cursul perioadei de “fereastra imunologica”

- titrul sau scade progresiv, pe masura ce se dezvolta raspunsul tip IgG - Conversie in Ac

anti HBc tip IgG

Diagnostic serologic Ag HBe

Codificat in regiunea precore

Se asociaza cu ADN VHB si AND polimeraza –

replicare

Ac anti HBe

Seroconversia Ag HBe – Ac anti HBe = stop

replicare

Markeri serologici - noi Markeri serologici

Ag HBs cantitativ

Markeri moleculari

Genotip HBV

Identificarea mutatiilor implicate in rezistenta antivirala

Markerii serologici ai hepatitei cu

virus VHB si importanta acestora

Diagnostic histopatologic Punctie biopsie hepatica

staging (fibroza)

grading (necroinflamatie)

Sisteme multiple de scorizare: Knodell, Ischak, Metavir

• Infiltrat inflamator cronic portal si periportal

• Infiltrat inflamator , fibroza de diferite grade, etc

• Hepatocite in “sticla mata”

HBeAg positive HBeAg negative

Phase 1 Phase 2 Phase 3 Phase 4 Phase 5

Chronic HBV

infection

Chronic

hepatitis B

Chronic HBV

infection

Chronic

hepatitis B

Resolved HBV

infection

HBsAg HighHigh/

intermediateLow Intermediate Negative

HBeAg Positive Positive Negative Negative Negative

HBV DNA >107 IU/mL 104–107 IU/mL <2,000 IU/mL* >2,000 IU/mL <10 IU/mL‡

ALT Normal Elevated Normal Elevated† Normal

Liver disease None/minimalModerate/

severeNone

Moderate/

severeNone§

Old

terminologyImmune tolerant

Immune reactive

HBeAg positiveInactive carrier

HBeAg negative

chronic hepatitis

HBsAg negative

/anti-HBc

positive

New nomenclature for chronic

phases in HVB

*HBV DNA levels can be between 2,000 and 20,000 IU/mL in some patients without signs of chronic hepatitis;†Persisitently or intermittently, based on traditional ULN (~40 IU/L). ‡cccDNA can frequently be detected in the liver;

§Residual HCC risk only if cirrhosis has developed before HBsAg loss. EASL CPG HBV. J Hepatol 2017;67:370–98

The natural history of chronic HBV infection has been schematically

divided into five phases

Chronic HBV

infection

Chronic

hepatitis B


Algorithm for the management of chronic HBV infection

EASL CPG HBV. J Hepatol 2017;67:370–98

Chronic HBV infection*

(no signs of chronic hepatitis)

Monitor

(includes HBsAg, HBeAg, HBV

DNA, ALT, fibrosis assessment)

Consider

Risk of HCC, risk of HBV

reactivation, extrahepatic

manifestations, risk of

HBV transmission

HBsAg positive

Chronic hepatitis B

± cirrhosis*

Start antiviral treatment

HBsAg negative, anti-HBc positive

No specialist follow-up

but inform patient and general

practitioner about the potential

risk of HBV reactivation

In case of immunosuppression,

start oral antiviral prophylaxis

or monitor

Suspected chronic HBV infection

NO

YES

Goals and endpoints of

therapy

*Often represents a partial immune control of the chronic HBV infection;†Achieved in most patients with long-term suppression of HBV replication;‡Indicates profound suppression of HBV replication and viral protein expression


Goals

Improve survival and quality of life by preventing disease

progression and HCC

Prevent mother-to-child transmission, hepatitis B reactivation,

and prevent and treat HBV-associated extrahepatic

manifestationsRecommendations

Main endpoint

• Induction of long-term suppression of HBV DNAI 1

Valuable endpoint

• Induction of HBeAg loss (± anti-HBe seroconversion)

in HBeAg-positive patients with chronic hepatitis B*

II-1 1

Additional endpoint

• ALT normalization (biochemical response)†II-1 1

Optimal endpoint

• HBsAg loss (± anti-HBs seroconversion)‡II-1 1


Special patient groups: patients with

extrahepatic manifestations


Some extrahepatic manifestations can be associated with

HBV infection

Vasculitis, skin manifestations (purpura), polyarteritis nodosa,

arthralgias, peripheral neuropathy and glomerulonephritis

HBsAg-positive patients with extrahepatic manifestations

and active HBV replication may respond to antiviral therapy

PegIFN can worsen some immune-mediated extrahepatic manifestations

Recommendations

Patients with replicative HBV infection and extrahepatic

manifestations should receive antiviral treatment with NAs II-2 1

PegIFN should not be administered in patients with

immune-related extrahepatic manifestations III 1


STAGES OF FIBROSIS

There are several histologic scoring systems for chronic liver

disease.

Many use five-point scales such as the METAVIR score:

●F0: No fibrosis

●F1: Portal fibrosis without septa

●F2: Few septa

●F3: Numerous septa without cirrhosis

●F4: Cirrhosis

Patients are typically considered to have significant fibrosis if

their fibrosis score is ≥F2.

Two prognostic stages of cirrhosis

Mild PH= hepatic venous pressure gradient >5 - <10 mmHg;

CSPH= hepatic venous pressure gradient ≥10 mmHg

Guadalupe García-Tsao, DDW 2018

D’Amico, Garcia-Tsao, Pagliaro. J Hepatol 2006;44:217

Ripoll et al. Gastroenterology 2007; 133:481.

Patients in different stages of cirrhosis have different risks of developing

complications and of dying

The natural history of cirrhosis

The natural history of cirrhosis is characterised by

A. asymptomatic , compensated phase

B. decompensated phase, marked by the development of

overt clinical signs, the most frequent of which are:

1. ascites,

2. bleeding,

3. encephalopathy,

4. jaundice.

The transition from compensated asymptomatic cirrhosis to

decompensated cirrhosis occurs at a rate of about 5% to 7% per

year

Diagnosticul clinic al cirozei

hepatice:

o tulburari variate ale starii de constienta: obnubilare, stupoare, coma

o Sangerari cutanate ( echimoze, purpura) HDS prinruptura varicelor esofagiene / gastrice exteriorizata prinhematemeza si melena

o marirea de volum a abdomenului prin ascita

o edeme hipoproteinemice

o icter sclerotegumentar

o astenie marcata cu adinamie

o dureri de hipocondru drept sau abdominale difuze

o flapping tremor

Examen obiectiv in CH

icter

ascita

hepatomegalie

splenomegalie,

circulatie venoasa colaterala,

tulburari ale starii de constienta,

Dg paraclinic al CH

Aceleasi teste ca si la hepatitele cronice

Pot avea frecvent:

Trombocitopenia

Hipoproteinemia cu hipoalbuminemie

Anomalii ale testelor coagulare

Suplimentare, investigatii pt a evalua complicatiile CH:

EDS,

Examenul ascitei

AFP

Diagnostic etiologic al CH

Diagnostic etiologic al CH

Markeri de infectare virala: Ag HBs si Ac anti HCV.

Odata depistat un marker de infectie virala se va face o

extensie a analizelor de laborator astfel:

o pentru AG HBs pozitiv: Ag HBe, Ac anti HBe, Ac anti HBs,

ADN-HBV, Ac anti VHD, si ARN-HDV in cazul pozitivitatii Ac

anti VHD)

o pentru Ac anti HCV: ARN-HCV

Complications of cirrhosis ascites, refractory ascites,

hyponatremia,

gastrointestinal bleeding,

bacterial infections,

acute kidney injury,

hepatorenal syndrome,

acute-on-chronic liver failure,

relative adrenal failure,

cirrhotic cardiomyopathy,

Hepatopulmonary syndrome,

porto-pulmonary hypertension

hepatocellular carcinoma

Spontaneous bacterial peritonitis

Hepatic encephalopathy

1. Overall management of DC

Suppression of aetiological factor(s)

Treatment of key pathogenic factors

2. Management of specific complications of DC

Ascites

Refractory ascites

Hepatic hydrothorax

Hyponatremia

Gastrointestinal bleeding

Bacterial infections

Renal impairment

Acute-on-chronic liver failure

Relative adrenal insufficiency

Cardiopulmonary complications

Management in CH

EASL CPG decompensated cirrhosis. J Hepatol 2018;doi: 10.1016/j.jhep.2018.03.024

Management strategies for DC

EASL CPG decompensated cirrhosis. J Hepatol 2018;doi: 10.1016/j.jhep.2018.03.024

Management of DC aims to improve outcomes of complications

Complications of DC

Ascites

Bacterial infections

GI bleeding

Increased understanding of DC pathophysiology permits the developmentof more comprehensive therapeutic and prophylactic approaches

to prevent or delay disease progression

Hyponatremia

Refractory

Hepatic

hydrothorax

Uncomplicated Renal impairment

AKI CKD

ACLF RAI Cardiopulmonary

PPHTCCM HPS

Scoruri prognostice in CH

MELD = 3.8*loge(serum bilirubin [mg/dL]) + 11.2*loge(INR) +

9.6*loge(serum creatinine [mg/dL]) + 6.4

MELD-Na = MELD + 1.32 * (137-Na) - [0.033*MELD * (137-Na)]

Stadializarea/clasificarea BAVENO: in 5 stadii evolutive cu

rol prognostic

Child-Pugh

Stadializarea CH

Scorul Child Pugh

Stadializarea/clasificarea BAVENO a CH:

5 stadii evolutive cu rol prognostic

Stadiul 1: CH compensata, fara varice si fara ascita

Stadiul 2: CH compensata, fara ascita, cu varice esofagiene

care nu au sangerat

Stadiul 3: CH decompensata cu sangerare variceala, cu sau

fara ascita

Stadiul 4: CH decompensata cu ascita, cu sau fara varice

esofagiene, dar care nu au sangerat

Stadiul 5: CH cu decompensare avansata, cu sindrom

hepato-renal/peritonita bacteriana

spontana/icter/hiponatremie/encefalopatie hepatica

Multi-stage model for the clinical course

of cirrhosis

D’Amico G, et al. J Hepatol 2018;68:56376;EASL CPG decompensated cirrhosis. J Hepatol 2018;doi: 10.1016/j.jhep.2018.03.024

Transition from compensated cirrhosis to DC occurs at a rate of ~5–7% per year

DC is a systemic disease, with multi-organ/system dysfunction

Decompensated

Stage 3: Bleeding

Stage 4:

First non-bleeding decompensation

Stage 5:

Second decompensating event

Compensated

Stage 0: no varices, mild PH

LSM >15 and <20 or HVPG >5 and <10

mmHg

Stage 1: no varices, CSPH

LSM ≥20 or HVPG ≥10 mmHg

Stage 2: varices (=CSPH)

End stage

Stage 6: late decompensation:

Refractory ascites, persistent PSE or

jaundice, infections, renal and other

organ dysfunction

ACLF

Death

Decompensated

Stage 3: Bleeding

Stage 4:

First non-bleeding decompensation

Stage 5:

Second decompensating event

Compensated

Stage 0: no varices, mild PH

LSM >15 and <20 or HVPG >5 and <10

mmHg

Stage 1: no varices, CSPH

LSM ≥20 or HVPG ≥10 mmHg

Stage 2: varices (=CSPH)

Multi-stage model for the clinical

course of cirrhosis

D’Amico G, et al. J Hepatol 2018;68:56376;EASL CPG decompensated cirrhosis. J Hepatol 2018;doi: 10.1016/j.jhep.2018.03.024

Transition from compensated cirrhosis to DC occurs at a rate of ~5–7%

per year

DC is a systemic disease, with multi-organ/system dysfunction

End stage

Stage 6: late decompensation:

Refractory ascites, persistent PSE or

jaundice, infections, renal and other

organ dysfunction

ACLF

Death

Asymptomatic

Median survival: 12 years

Symptomatic

Median survival: 2 years

HCCLiver cancer

• Fifth most common cancer

• Second most frequent cause of cancer-related death

globally

• 854,000 new cases and 810,000 deaths per year

• 7% of all cancers

HCC

• Accounts for approximately 90% of primary liver cancers

• Constitutes a major global health problem

• ~90% of HCCs are of known underlying aetiology1

• Most frequently HCV, HBV, alcohol and aflatoxin

exposure

EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma, Journal of Hepatology 2018 vol. 69 j 182–236

Surveillance for HCC

Utility of and applicability of surveillance is influenced by a

number of factors

Incidence of HCC in target populations

Availability of efficient diagnostic tests at acceptable costs

Availability and effectiveness of treatments

Definition of target populations must consider

Incidence of HCC in subsets of patients

Probability that effective therapies, particularly radical ones, are

suitable

EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma, Journal of Hepatology 2018 vol. 69 j 182–236

HCC incidence is higher in patients with more advanced cirrhosis

Probability of receiving effective therapy is lower*

Different incidence thresholds may apply to different target populations

Surveillance in patients at high risk of HCC

High rate of HCC in certain risk groups makes surveillance a cost-effective

route to reducing mortality

Interval should be dictated by rate of tumour growth and tumour

incidence in target population

6-month interval is reasonable and cost-effective

3 months: no clinical benefit

12 months: fewer early stage diagnoses and shorter survival

Recommendations

Cirrhotic patients, Child–Pugh stage A and B Low Strong

Cirrhotic patients, Child–Pugh stage C awaiting LT Low Strong

Non-cirrhotic HBV patients at intermediate or high risk of HCC*

(according to PAGE-B† classes for Caucasian subjects,

respectively 1017 and ≥18 score points)

Low Weak

Non-cirrhotic F3 patients, based on an individual risk assessment Low Weak

Cancerul hepatic

Diagnosticul clinic al HCC poate fi sugerat de:

• aparitia durerilor abdominale (de hipocondru drept) la un

pacient cunoscut cu hepatita sau ciroza

• scadere ponderala semnificativa pe interval de timp scurt

• decompensarea unei afectiuni hepatice in maniera rapida cu

icter, ascita, edeme

• aparitia unei tromboze portale

• febra

• hipoglicemia la un pacient hepatic cunoscut

• Scadere ponderala

• Hepatomegalie asimetrica

• Ascita, icter

Diagnosticul imagistic al HCC

Ecografia (US):

E folosita de prima intentie in screening sau in caz de suspiciune de

HCC;

un rezultat negativ nu exclude un HCC mic

identificarea unui nodul hepatic la un pacient cu risc nu inseamna

numaidecit ca acesta are HCC;

Dependenta de operator si de calitatea aparatului

CEUS (cu SonoVue) este utila in definirea sau descrierea unui nodul

anterior identificat prin procedeul US standard

Hipervascularizatie in faza arteriala si washout incomplet in faza tardiva

CT cu substanta de contrast este standardul de diagnostic pentru HCC șif. utila cand fondul suferintei hepatice este ciroza,

IRM cu contrast = cea mai mare acuratete pt diagnostic HCC ; diferite

subst de contrast (primovist): hipervascularizatie arteriala, hipocaptarea

in faza hepatobiliara, restrictia difuziei

Diagnosis of HCC

1. Diagnosis generally relies on pathology

2. Non-invasive criteria can be used in patients with cirrhosis

• Peculiar vascular derangement occurs during hepatic

carcinogenesis

• High pre-test probability of HCC

Recommendations

Diagnosis of HCC in cirrhotic patients should be based on

non-invasive criteria and/or pathology High Strong

In non-cirrhotic patients, diagnosis of HCC should be confirmed

by pathology

Moderat

eStrong

Pathological diagnosis of HCC should be based on

International Consensus recommendations1,2 using the required

histological and immunohistological analyses

High Strong

Non-invasive diagnosis of HCC

Non-invasive diagnostic criteria for patients with cirrhosis require

particular imaging techniques

Recommendations

Non-invasive criteria* can only be applied to cirrhotic patients

for nodule(s) ≥1 cm, in light of the high pre-test probability, and

are based on imaging techniques obtained by multiphasic CT,

dynamic contrast-enhanced MRI…

High Strong

…or CEUS Moderat

eWeak

Because of their higher sensitivity and the analysis of the whole

liver, CT or MRI should be used first High Strong

FDG PET scan is not recommended for early diagnosis of HCC

because of the high false-negative rate Low Strong

Non-invasive diagnosis of HCC

Serological tests that have been investigated or are under

investigation for early diagnosis of HCC include:

o alpha-fetoprotein (AFP) (>200 ng/ml),

o des-gamma-carboxy prothrombin (DCP) -also known as

prothrombin induced by vitamin K absence II (PIVKA II)

o the ratio of glycosylated AFP (L3 fraction) to total AFP,

o alpha-fucosidase,

o Glypican.

o AFP is the most widely tested biomarker in HCC.

Recall policy Appropriate recall policy is crucial for the success of

surveillance procedures

Defined algorithm followed when surveillance tests are abnormal

Recommendations

In patients at high risk of developing HCC:

• Nodule(s) <1 cm detected by US should be followed at ≤4-month intervals

in the first year

• If no increase in size or number of nodules, surveillance can be returned to

the usual 6-month interval

Low Weak

In cirrhotic patients, diagnosis of HCC for nodules of ≥1 cm can be achieved

with non-invasive criteria and/or biopsy-proven pathological confirmation High Strong

Repeated biopsy sampling is recommended in cases of:

• Inconclusive histological or discordant findings

• In cases of growth or change in enhancement pattern identified during

follow-up, but with imaging still not diagnostic for HCC

Low Strong

Algorithm for diagnosis of HCC and

recall in cirrhotic liver

*Using extracellular MRI contrast agents or gadobenate dimeglumine; †Diagnostic criteria: APHE and washout on the portal venous phase; ‡Lesion <1 cm stable for 12 months (three controls after 4 months) can be shifted back to regular 6-month surveillance;

§Diagnostic criteria: APHE and mild washout after 60 seconds; ‖Optional for centre-based programmes EASL CPG HCC. J Hepatol 2018; doi: 10.1016/j.jhep.2018.03.019

Mass/nodule at imaging

<1 cm >1 cm

Repeat US at 4 months Multiphasic contrast-enhanced CT or MRI,*

or gadoxetic-enhanced MRI†

1 positive technique:

HCC imaging hallmarks

No Yes

Stable‡ Growing/changing

pattern

Biopsy unclear:

Consider re-biopsyUse other modality: multiphasic contrast-enhanced

CT or MRI,* or gadoxetic-enhanced MRI,†

or contrast-enhanced ultrasound§

‖

1 positive technique: HCC imaging hallmarks

No Yes

Biopsy HCC

Non-HCC malignancy/

benign

Modified BCLC (Barcelona Clinic Liver Cancer)

staging system and treatment strategy

*Child–Pugh A without ascites. Applies to all treatment options apart from LT; †PS 1; tumour-induced modification of performance capacity; ‡Multiparametric evaluation: compensated Child–Pugh class A liver function with MELD score <10, matched with grade of portal hypertension,

acceptable amount of remaining parenchyma and possibility to adopt a laparoscopic/minimally invasive approach; §The stage migration strategy applies; ‖Sorafenib has been shown to be effective in first line, while regorafenib is effective in second line in case of radiological

progression under sorafenib. Lenvatinib has been shown to be non-inferior to sorafenib in first line, but no effective second-line option after lenvatinib has been explored. Cabozantinib has been demonstrated to be superior to placebo in 2nd or 3rd line with an improvement in OS.

Nivolumab has been approved in second line by FDA but not EMA based on uncontrolled Phase 2 data. Please see notes for full details.EASL CPG HCC. J Hepatol 2018; doi: 10.1016/j.jhep.2018.03.019

Very early stage (0)

Single <2 cm

Preserved liver

function*

PS 0

Early stage (A)

Solitary or

2–3 nodules <3 cm

Preserved liver

function*

PS 0

Intermediate stage (B)

Multinodular,

unresectable

Preserved liver

function*

PS 0

Advanced stage (C)

Portal invasion/

extrahepatic spread

Preserved liver

function*

PS1†–2

Terminal stage (D)

Not transferable HCC

End-stage

liver function

PS 3–4

Prognostic

stage

Solitary2–3 nodules

≤3 cm

Optimal surgical

candidate‡

Yes No

Yes No

Transplant

candidate

Treatment§

Survival >5 years >2.5 years ≥10 months 3 months

Chemoembolization Systemic therapy‖ BSCAblation Resection Transplant

HCC in cirrhotic liver

Ablation

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