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
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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 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
• 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 .
EASL Recommendations on Treatment of Hepatitis C 2018, Journal of Hepatology 2018 vol. xxx j xxx–xxx
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.
EASL Recommendations on Treatment of Hepatitis C 2018, Journal of Hepatology 2018 vol. xxx j xxx–xxx
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
EASL Recommendations on Treatment of Hepatitis C 2018, Journal of Hepatology 2018 vol. xxx j xxx–xxx
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
EASL CPG HCV. J Hepatol 2018;69:461–511.
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
Grade of evidence Grade of recommendation
EASL Recommendations on Treatment of Hepatitis C 2018, Journal of Hepatology 2018 vol. xxx j xxx–xxx
=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;
EASL Recommendations on Treatment of Hepatitis C 2018, Journal of Hepatology 2018 vol. xxx j xxx–xxx
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
EASL CPG HCV. J Hepatol 2018;69:461–511.
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
Grade of evidence Grade of recommendation
EASL Recommendations on Treatment of Hepatitis C 2018, Journal of Hepatology 2018 vol. xxx j xxx–xxx
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)
EASL Recommendations on Treatment of Hepatitis C 2018, Journal of Hepatology 2018 vol. xxx j xxx–xxx
Goals of therapy
EASL CPG HCV. J Hepatol 2018;69:461–511.
Goal – to cure HCV infection (A1) in order to
Prevent the complications of HCV-related liver and
• 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
Grade of evidence Grade of recommendation
Endpoints of therapy
EASL CPG HCV. J Hepatol 2018;69:461–511.
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
Grade of evidence Grade of recommendation
EASL Recommendations on Treatment of Hepatitis C 2018, Journal of Hepatology 2018 vol. xxx j xxx–xxx
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
*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
EASL Recommendations on Treatment of Hepatitis C 2018, Journal of Hepatology 2018 vol. xxx j xxx–xxx
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
EASL CPG HBV. J Hepatol 2017;67:370–98
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
Grade of evidence Grade of recommendation
Special patient groups: patients with
extrahepatic manifestations
EASL CPG HBV. J Hepatol 2017;67:370–98
Some extrahepatic manifestations can be associated with
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