Edi o ial
Hepa ocellula ca cinoma sc eening in NAFLD: The pa adox o nea ly hal
he cases a ising in non-ci ho ic low isk pa ien s
Li e cance is in he op h ee leading causes o dea h om cance
wo ldwide. Hepa ocellula ca cinoma (HCC) accoun s o 85% o p i-
ma y li e cance s and de elops in pa ien s wi h ch onic li e disease
(CLD). The p og essi e inc ease in he p e alence o nonalcoholic
a y li e disease (NAFLD), which ecen ly eached up o 30% o he
global popula ion [1], and he ecen e ec i e ea men o hepa i is
C, esul s in NAFLD being he mos apidly inc easing e iology o
HCC. Since he beginning o he millennium, he p opo ion o
NAFLD-a ibu able HCC inc eased up o 8- old, cu en ly accoun ing
o 15% o HCC cases [2].
NAFLD-associa ed HCC has he pa icula i y o being 5 imes mo e
equen in he p e-ci ho ic phase o he disease, as compa ed wi h
o he e iologies o CLD [3]. Ac ually, 2 ou o 5 pa ien s wi h NAFLD-
associa ed HCC do no ha e ci hosis [3]. Impo an ly, he absence o
ci hosis does no seem o independen ly impac su i al, which
a he is dependen on he cance s age and ea men p o ided.
F om ano he pe spec i e, conside ing he isk o NAFLD pa ien s
de eloping HCC, hose wi hou ci hosis ha e 100 imes lowe isk:
he HCC annual incidence a e is a ound 3.8% in pa ien s wi h ci ho-
sis (simila o o he e iologies) and 0.03% in pa ien s in he p e-ci -
ho ic s a e [4].
NAFLD-associa ed HCC, compa ed o o he e iologies, ends o
occu la e in li e, in pa ien s wi h me abolic and ca dio ascula
como bidi ies [2]. This may help explain why, in pa ien s wi h HCC
and li e ci hosis, NAFLD pa ien s, as compa ed o o he e iologies,
p esen a wo se p ognosis [2]. The ea men o hose pa ien s is no
only jeopa dized by olde age and como bidi ies, NAFLD-associa ed
HCC seems o be less esponsi e o immuno he apy [5].
Impo an ly, we a e ailing o sc een hese pa ien s, since mo e e-
quen ly han in o he e iologies, NAFLD-associa ed HCC is de ec ed ou -
side specific su eillance [2]. This canno be jus ified only by non-
ci ho ic HCC, which would all ou o sc eening p og ams because i
also happens in he con ex o ci hosis. Indeed, pa ien s wi h hepa i is C
i us-associa ed ci hosis a e 2 imes mo e likely o be en olled in HCC
sc eening p og ams han pa ien s wi h NAFLD-associa ed ci hosis [6].
Cu en sc eening ools pe o m wo se in pa ien s wi h NAFLD.
Fo example, ul asound, he basis o he biannual p oposed HCC
sc eening p o ocol, seems o be 3 imes mo e inaccu a e o de ec
HCC in pa ien s wi h NAFLD-associa ed ci hosis compa ed o o he
o ms o li e ci hosis [7], as s ea osis inc eases ul asound a enua-
ion impai ing he de ec ion o deep li e nodules. Also, he e is a
dose-dependen dec ease in ul asound accu acy wi h inc easing
BMI [7]. Ul asound epo s should illus a e he possible limi a ions
o isualiza ion acco ding o he US LI-RADS algo i hm, which s a i-
fies in o minimal, mode a e, and se e e limi a ions. Pa ien s wi h
low ul asound sco es would p obably benefi om o he imaging
echniques such as CT and MRI, o he mos ecen ly p oposed abb e-
ia ed MRI p o ocols. The combina ion o he ul asound wi h alpha-
e op o ein (AFP) seems o inc ease by 20% he sensi i i y o HCC
sc eening. Howe e , in non-hepa i is C i us ci hosis, a cu o o
11ng/mL may ou pe o m he classic 20ng/mL cu o [8]. Clinical-lab-
o a o y sco es may ou pe o m AFP. One such sco e, al eady e alu-
a ed in phase 2 s udies in NAFLD-associa ed ci hosis, is he GALAD
ha inco po a es sex, age, and umo ma ke s, wi h an AUROC o
0.90. GALAD sco e may also be use ul o iden i y pa ien s a isk o
de eloping HCC ha would benefi om being en olled in sc eening
p og ams since high sco es ha e been de ec ed e en 1.5 yea s be o e
he de elopmen o HCC [9].
Taking all in o conside a ion, when deciding o sc een pa ien s
wi h HCC, we ace he pa adox o up o 40% o pa ien s wi h NAFLD-
associa ed HCC no p esen ing li e ci hosis, while, he de elopmen
o HCC in a pa ien wi h NAFLD wi hou ci hosis is a e y a e e en .
Pa ien s wi h NAFLD-associa ed ci hosis, ha is, wi h li e s i ness
measu emen (LSM) highe han 15kPa, should undoub edly be con-
side ed o HCC sc eening, since i s annual incidence is highe han
he 1.5% cu o o HCC sc eening cos -e ec i eness in pa ien s wi h
ci hosis. No iceably, o he ac o s mus be aken in o conside a ion
when en olling pa ien s in HCC sc eening p og ams, such as unc-
ional s a us, o e all heal h and app op ia eness o HCC ea men i
HCC is ound. Sc eening may be mo e expensi e in NAFLD-associa ed
ci hosis, wi h a highe need o mo e sensi i e echniques such as
abb e ia ed MRI due o less accu acy o ul asound in his se . As
such, isk-s a ifica ion models such as he hcc isk [10] ha in eg a-
es age, gende , BMI, diabe es-melli us, pla ele s coun , amino ans-
e ases, and se um albumin, may help iden i y low isk pa ien s ha
would no benefi om sc eening and high- isk pa ien s ha would
benefi om mo e in ensi e sc eening s a egies.
Rega ding p e-ci ho ic HCC, uni e sal sc eening is no cos -e ec-
i e, he challenge being he iden ifica ion o high- isk popula ions.
Indeed, non-ci ho ic NAFLD-a ibu ed HCC co esponds o 6% o HCC
[2], and conside ing an es ima ed global incidence o o e 1 million
cases by 2025, excluding non-ci ho ic NAFLD pa ien s om sc eening,
would esul in 60000 HCC cases pe yea being missed om sc eening
p og ams. The mos impo an isk ac o o HCC de elopmen in
pa ien s wi h non-ci ho ic NAFLD is he p esence and se e i y o li e
fib osis (assessed by his ology, non-in asi e sco es o LSM) [11].Indeed,
cu en guidelines by Eu opean, Ame ican and Japanese socie ies o he
s udy o he li e , al eady ecommend sc eening in pa ien s wi h F3
fib osis. O he isk ac o s a e olde age (being exceedingly a e in hose
younge han 65 yea s old), he p esence o diabe es-melli us, pa icu-
la ly hose wi h e hinopa hy [12], and inc eased amino ans e ase le -
els [3]. Alcohol in ake, e en in he social ange, is a s ong isk ac o in
h ps://doi.o g/10.1016/j.aohep.2023.101101
1665-2681/© 2023 Fundación Clínica Médica Su , A.C. Published by Else ie España, S.L.U. This is an open access a icle unde he CC BY-NC-ND license
(h p://c ea i ecommons.o g/licenses/by-nc-nd/4.0/)
Annals o Hepa ology 28 (2023) 101101
Con en s lis s a ailable a ScienceDi ec
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ci ho ic pa ien s, whe eas in non-ci ho ic is con o e sial, albei he e
is a known syne gism be ween alcohol and inc easing BMI [13].As
such, p obably pa ien s sui ed o sc eening would be olde han 65 yea s
old, wi h diabe ic e inopa hy, inc eased amino ans e ases, and some
li e fib osis.
Polygenic [14] and ansc i p ome [15] isk sco es ha e shown
p omising esul s in s a i ying NAFLD pa ien s o HCC isk, e en in
he p e-ci ho ic s a e, wi h he o me showing high pe o mance
o selec ing pa ien s o sc eening, and he la e o excluding hem.
In conclusion, HCC sc eening in NAFLD pa ien s is ailing o 3 main
easons: 1) as onishingly unde -diagnosis o NAFLD-associa ed ci hosis
o ad anced fib osis in he gene al popula ion, 2) imp essi e unde -
sc eening o HCC in pa ien s al eady known o ha e NAFLD-associa ed
ci hosis, and 3) a high p opo ion o HCC diagnosed in p e-ci ho ic
pa ien s. The fi s p emise could be o e come wi h an ac i e sea ch o
ad anced li e fib osis in high- isk popula ions such as obese and
pa ien s wi h diabe es-melli us, as al eady p oposed in AASLD guide-
lines. The second p emise wa an s highe awa eness om physicians
ha ake ca e o hese pa ien s. Rega ding non-ci ho ic NAFLD
pa ien s, he e is s ill a need o be e s a ifica ion ools such as clinical
and polygenic sco es ha accu a ely iden i y pa ien s a isk o HCC, so
we do no miss 1 in e e y 20 HCC cases wo ldwide.
Decla a ion o in e es
None.
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Ma iana Ve delho Machado*
Se i¸co de Gas en e ologia, Hospi al de Vila F anca de Xi a,
Lisboa, Po ugal
Faculdade de Medicina, Uni e sidade de Lisboa, Lisboa, Po ugal
*Co esponding au ho .
E-mail add ess: [email p o ec ed]
M.V. Machado Annals o Hepa ology 28 (2023) 101101
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