Jurnal Ricky 2
Jurnal Ricky 2
Jurnal Ricky 2
OF HEPATOLOGY
Antiviral therapies
Anti-inflammation therapies
Potential
chemoprevention Anti-fibrotic therapies
strategies
Metabolic disease treatment
Fig. 1. HCC-preventive interventions in the natural history of HCC development in progressive fibrotic liver diseases.
HCC-preventive strategy targeting each specific clinical context (i.e., aetiology-specific or independent primary, secondary, and
tertiary prevention) should be developed to ensure its clinically meaningful impact on the course of fibrotic liver disease
progression towards HCC. IEN, intraepithelial neoplasia; HCC, hepatocellular carcinoma.
HCV-related cirrhosis) and results in often harmful at work 2.44).47 Association of metabolic HCC risk
over- or under-estimation of HCC risk for each factors is affected by smoking (interaction p =
patient.34,35 Thus, prediction of individual HCC 0.004).48 Alcohol exposure may also enhance risk,
risk is critical for implementing effective and fea- as suggested by characteristic somatic DNA
sible HCC screening. aberrations.12
REACH-B Prospective-retrospective, HCC (3/5/10 yr) HBV 3,584 + 1,505* Asian 0% + 18%* Sex, age, ALT, HBeAg, HBV DNA External 263
cohort
CU-HCC Prospective-retrospective, HCC (5yr) HBV 1,005 + 424* Asian 38% + 16%* Age, albumin, bilirubin, HBV DNA, External 264
cohort cirrhosis
Yang, et al. Prospective-retrospective, HCC (5/10 yr) HBV 2,435 + 1,218* Asian n.a. Sex, age, HCC family history, alcohol, Internal 265
Sohn, et al. Retrospective, cohort HCC (5yr) HBV 990 + 1,071* Asian 39% + 35%* Age, sex, cirrhosis Internal 268
269
FIB-4 Retrospective, cohort HCC HBV 986 Asian 9.9% AST, ALT, platelet, age No
270
GAG-HCC Retrospective, cohort HCC (5/10 yr) HBV 820 Asian 15% Age, sex, HBV DNA, core promoter No
mutations, cirrhosis
43
Shin, et al. Retrospective, cohort HCC (5yr) HBV 227 Asian 50.3% LSM, spleen diameter, platelet No
271
Kim, et al. Retrospective, cohort HCC HBV 2,878 Asian 10% LSM No
Singal, et al. Prospective-retrospective, HCC (3/5yr) HCV 442 + 1,050* White, black, 100% + 41%* 23 clinical variables External 272
cohort Hispanic
REVEAL-HCV Prospective-retrospective, HCC (5yr) HCV 1,095 + 572* Asian 1.4% + 7.0%* Age, ALT, AST/ALT, HCV RNA, cirrhosis, External 273
38
Huang, et al. Retrospective, cohort HCC HCC 533 n.a. 7% CPA No
Motosugi, et al. Retrospective, case-control HCC HCV 66:66§ Asian n.a. LSM by MRE No 41
Chang, et al. Retrospective, cohort HCC (5yr) HCV after IFN 1,252 + 627* Asian 45% (F3/4) Age, sex, platelet, AFP, advanced fibrosis, Internal 277
280
ADRESS-HCC Retrospective, cohort HCC (1yr) HCV, alcohol, 17,124 + White, Hispanic 100% Age, diabetes, race, etiology, sex, Child- External
NASH/cryptogenic 17,808* Pugh score
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Velázquez, et al. Prospective, cohort HCC (4yr) Alcohol, HCV 295 + 168* n.a. 100% Age, HCV, prothrombin time, platelet Internal 281
282
VFMAP Retrospective, cohort HCC (5yr) Non-viral, HCV 1,808 Asian 13% LSM, fast plasma glucose, sex, age, AFP No
155
Wen, et al. Retrospective, cohort HCC (10 yr) General population 428,584 Asian n.a. Smoking, alcohol, physical activity, Internal
diabetes, AST, ALT, AFP, HBV, HCV
42
Singh, et al. Meta-analysis of 9, HCC, fibrosis HCV, HBV, alcohol, 4,038, 2,410 n.a. n.a. LSM by TE, MRE n.a.
6 studies (decompensation) NASH
283
Konerman, et al. Prospective-retrospective, Fibrosis (>2 Ishak HCV 184 White 0% 25 clinical variables Internal
cohort score, 1.5/3.5 yr)
(continued on next page)
529
Review
ADRESS-HCC, age, diabetes, race, aetiology of cirrhosis, sex and severity of liver dysfunction-HCC; AFP, a-fetoprotein; ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CPA, collagen
proportionate area; ELF, enhanced liver fibrosis; FILI, fibrosis improvement after lifestyle interventions; GGT, c-glutamyltransferase; HbA1c, glycated haemoglobin, type A1c; HBeAg, hepatitis B e antigen; HBV, hepatitis B virus; HCC,
hepatocellular carcinoma; HCV, hepatitis C virus; IFN, interferon; LSM, liver stiffness measurement; MRE, magnetic resonance elastography; NASH, non-alocoholic steatohepatitis; PIIINP, propeptide of type III procollagen; REACH-B,
Risk estimation for hepatocellular carcinoma in chronic hepatitis B; REVEAL-HCV, Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer in HCV; SVR, sustained virologic response; TIMP1, tissue inhibitor of
Validation Refs.
284
285
286
37
Abundance of serum/plasma proteins such as
insulin-like growth factor 1 (IGF1) and osteopon-
Internal
No
No
tern of total serum protein (GlycoHCCRiskScore)
has identified a subset of patients with compen-
sated cirrhosis at risk of HCC.64 Body fluid (e.g.
blood, urine)-based biomarkers will enable less
Advanced fibrosis, age, AST, GGT,
25% (F3/4)
Case:control. n.a., not available/applicable. ‘‘Prospective-retrospective” indicates retrospective analysis of prospectively collected cohort in the past.287
100%
(F3)*
0%
n.a.
n.a.
n.a.
300
69
Fibrosis
Prospective-retrospective,
Prospective-retrospective,
cohort
cohort
Training + validation.
FILI score
ELF score
Review
Table 2. Molecular feature-based HCC/fibrosis risk indicators.
Risk indicator Study design Endpoint Major No. Major race/ Cirrhosis Combined clinical Validation Refs.
aetiology subjects ethnicity variables
288
Circulating microRNA Prospective-retrospective, HCC HBV 373 Asian 34.6% n.a. No
signature cohort
63
IGF 1 (serum protein) Prospective, cohort HCC HCV 104 White 100% n.a. External
289
EGF 61*G (SNP, rs4444903) Prospective-retrospective, HCC HCV 816 White, black 15.4% Age, sex, smoking history, External
cohort ALP, platelet
50
MPO -463*G (SNP, rs2333227) Prospective-retrospective, HCC HCV 205 White 100% n.a. No
cohort
64
Journal of Hepatology 2018 vol. 68 j 526–549
nested case-control
10,292–294
186/32-gene signature (liver Prospective-retrospective, HCC, HCC HCV, HBV, 82 + 25/ Asian + n.a./ 52.4% + n.a./ AFP, vascular invasion, External
tissue transcriptome) cohort recurrence Alcohol, NASH 216/145/ white/white/ 100%/100%/43%* bilirubin, platelet, Child-
263* Asian* Pugh class, AJCC stage
295
HSC signature (liver tissue Experiment + HCC, HCC HCV, HBV Mouse + White/Asian 100%/100% Bilirubin, platelet No
transcriptome) retrospective, cohort recurrence 216/82
296
Activated HSC signature (liver Retrospective, cohort HCC HBV 247+ 226/ Asian 90.7% n.a. External
tissue transcriptome) recurrence 72*
297
HIR signature (liver tissue Retrospective, cohort Late HCC HBV 72 + 96/ Asian 50% + 62.5%/ n.a. External
transcriptome) recurrence 228* 92.5%*
297
65-gene signature (HCC tissue Retrospective, cohort Early HCC HBV 72 + 96/ Asian 50% + 62.5%/ n.a. External
transcriptome) recurrence 228* 92.5%*
Cirrhosis risk score (serum Retrospective, case- Fibrosis HCV 205:66§ n.a. 21.8% (F2) n.a. No 298
AFP-L3 Meta-analysis (8 studies) HCV n.a. Asian 21–49% 93–100% 0.69 n.a.
299
DCP Meta-analysis (16 studies) HCV n.a. Asian 7–56% 72–100% 0.70 n.a.
Integrative score
GALAD model Prospective, case-control Alcohol, HCV, HBV 25% + 22%* n.a. 94% 83% 0.95 External 73
Doylestown Prospective-retrospective, nested HBV/HCV + HCV/HBV/HCV* 54%/79% + 48%/100%/33%* n.a. 53/58/63% Fixed to 95% 0.84/0.89/0.88 External 72
algorithm case-control
Experimental biomarker
300
GPC3 Meta-analysis (19 studies) HBV, HCV n.a. n.a. 55% 84% 0.76 n.a.
microRNA panel Retrospective, case-control HBV 78% + 75% (BCLC 0/A)* Asian 81% 84% 0.89 External 301
DKK1 Retrospective, case-control HBV 67.2% + 31.1% (BCLC 0/A)* Asian 71% 87% 0.86 External 302
MDK Retrospective, case-control HBV 49.2% + 100% (BCLC 0/A)* Asian 86% 90% n.a. External 303
304
Annexin A2 Retrospective, case-control HBV 81.7% (AJCC I/II) Asian 83% 68% 0.79 No
305
GlycoHCCTest Retrospective, case-control HBV 34.7% (AJCC I/II) Asian 57% 88% 0.81 No
Osteopontin Prospective-retrospective, case-control HCV + HBV* 60% (BCLC 0/A) + n.a.* n.a. + Asian* 93% 61% 0.93 External 306
307
GP73 Prospective-retrospective, case-control HCV 48% (UNOS TNM 1/2) White 69% 86% 0.79 No
64
GlycoHCCRiskTest Prospective-retrospective, case-control HCV n.a. n.a. n.a. n.a. 0.73 No
308
Fucosylated Prospective-retrospective, case-control HCV 60% (UNOS TNM 1/2) n.a. n.a. n.a. 0.88 No
kininogen
Diagnostic performance measures (sensitivity, specificity, AUROC) were derived from meta-analysis or validation studies.
AFP, a-fetoprotein;AFP-L3, lens culinaris agglutinin-reactive fraction of AFP ; AJCC, American Joint Committee on Cancer; AUROC, area under the receiver operating characteristic curve; BCLC, Barcelona Clinic Liver Cancer ; DCP, des-
gamma-carboxy prothrombin ; DKK1, Dickkopf-1 ; GALAD, gender, age, AFP-L3, AFP, des-carboxy prothrombin ; GP73, Golgi protein-73; GPC3, glypican 3 ; HBV, hepatitis B virus ; HCC, hepatocellular carcinoma ; HCV, hepatitis C
virus ; MDK, midkine ; UNOS, United Network of Organ Sharing.
*
Training + validation. ‘‘Prospective-retrospective” indicates retrospective analysis of prospectively collected cohort in the past.287
OF HEPATOLOGY
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533
Review
AM063 Perindopril
Lysophospholipids Ang I
ATX ACE
Gut microbial Viral infection
Metformin Erlotinib components,
LPA metabolites DAMPs Ang II
Cytoplasm
Fig. 3. Molecular targets of potential HCC chemoprevention therapies. Intra- and extracellular targets of potential HCC chemopreventive therapies are
summarised. Solid line with arrowhead or bar indicates activation or inhibition, respectively. Dotted line with arrowhead indicates translocation between
intracellular compartments. ACE, angiotensin-converting enzyme; AMPK, adenosine monophosphate-activated protein kinase; Ang, angiotensin; AT1,
angiotensin type 1 receptor; BCAA, branched-chain amino acid; COX2, cyclooxygenase 2; DAMPs, damage-associated molecular pattern; EGFR, epidermal
growth factor receptor; ER, endoplasmic reticulum; ERK, extracellular signal–regulated kinase; FGF21, fibroblast growth factor 21; GSK3, glycogen synthase
kinase 3; HIF, hypoxia inducible factor; HMG-CoA, 3-hydroxy-3nethyl-glutaryl-coenzyme A; IFNR, interferon receptor; IGFR, insulin-like growth factor 1
receptor; JAK, Janus kinase; JNK, c-Jun N-terminal kinase; LKB1, liver kinase B1; LPAR, lysophosphatidic acid receptor; MDM, mouse double minute; mTOR,
mammalian target of rapamycin;NF-jB, nuclear factor-kappa B; PDGFR, platelet-derived growth factor receptor; PGE2, prostaglandin E2; PI3K,
phosphoinositide 3-kinase; RAR, retinoic acid receptor; ROS, reactive oxygen species; RXR, retinoid X receptor; STAT, signal transducers and activator of
transcription; TLR, Toll-like receptor; TNFR, tumour necrosis factor receptor; TSC, tuberous sclerosis complex; VEGFR, vascular endothelial growth factor
receptor; YAP, Yes-associated protein.
rapamycin (mTOR) pathway via activation of suppresses progenitor/stem cell activation and
AMPK and its upstream regulator, LKB1;180 it reduces HCC burden in a rat model of
inhibits angiogenesis via suppression of hypoxia cirrhosis-driven carcinogenesis, although the
inducible factor 1 a (HIF1A) and vascular HCC-preventive effect is observed only when
endothelial growth factor (VEGF);181 it blocks cell metformin treatment is started before develop-
cycle progression by decreasing cyclin D1 expres- ment of cirrhosis.185
sion;182 it suppresses cell survival by upregulating A meta-analysis of 19 studies involving
IjBa, which inhibits NF-Κb;180 whilst it 550,882 patients with diabetes suggested that
induces apoptosis via a p53-independent mecha- metformin use reduced HCC incidence (OR 0.52)
nism183 and CCAAT/enhancer-binding protein d compared to non-users.186 In exploratory sub-
(CEBPD)-induced autophagy184 (Fig. 3). Metformin group analysis, metformin remained protective in
NCT02273362 Erlotinib Kinase inhibitor I Secondary Cirrhosis Safety, pEGFR, 186- 45 1/2018
gene signature
NCT03024684 Atorvastatin Statin IV Tertiary HCC (BCLC 0/A) after curative HCC recurrence 240 1/2022
ablation or hepatectomy
NCT03184493 Metformin, celecoxib Anti-inflammation, Anti-diabetic III Tertiary HCC after hepatectomy HCC recurrence 200 6/2021
NCT02281266 Thymalfasin Immune modulator IV Tertiary HBV-HCC after hepatectomy DFS 360 10/2018
NCT02686372 HBV antigen specific TCR Immune modulator I Tertiary CHB after transplantation Safety 10 11/2020
redirected T cell
NCT01924624 Thalidomide Immune modulator, anti- IV Tertiary HCC after hepatectomy DFS 140 12/2019
angiogenesis
NCT02447679 Thalidomide, tegafur- Immune modulator, anti- II Tertiary HCC after hepatectomy HCC recurrence 40 Completed, not
uracil angiogenesis, cytotoxic agent reported
NCT03178929 SAMe Nutritional supplement n.a. Tertiary HCC (BCLC 0/A) after radical HCC recurrence 207 8/2020
treatment
NCT01770431 Huaier granule Traditional herbal medicine IV Tertiary HCC (BCLC A/B) after hepatectomy HCC recurrence, 1,080 Completed*
metastasis
NCT02399033 Xihuang Capsules Traditional herbal medicine IV Tertiary HCC (BCLC 0-B) after hepatectomy HCC recurrence 1,000 12/2019
NCT01717066 Ginsenoside Rg Chemo-sensitiser, anti- III Tertiary HCC (BCLC A) after hepatectomy HCC recurrence 480 Completed, not
angiogenesis reported
NCT00116454 131 I-lipiodol Cytotoxic agent III Tertiary Viral/alcohol-HCC after hepatectomy HCC recurrence 73 Completed, not
or ablation (≤2 tumors) reported
NCT02767375 Hepatic arterial infusion Cytotoxic agent II Tertiary HCC after hepatectomy DFS 192 12/2018
chemotherapy III
AFP-L3, lens culinaris agglutinin-reactive fraction of a-fetoprotein; BCLC, Barcelona clinic liver cancer; CHB, chronic hepatitis B; CHC, chronic hepatitis C; DFS, disease-free survival; HBV, hepatitis B virus; HCC, hepatocellular
carcinoma; LSM, liver stiffness measurement; SAMe, S-adenosylmethionine; TCR, T cell receptor; VAP-1, vascular adhesion protein 1; 25(OH)D, 25-hydroxy vitamin D.
OF HEPATOLOGY
JOURNAL
*
Presented in J Hepatol 2017;66:S622.
537
Review
patients with HBV/HCV infection (OR 0.50), cirrho- neoplastic cells in the liver, which can be inhibited
sis (OR 0.49), and obesity (OR 0.42). However, by gut sterilisation in mice.196 Overexpression of
pooled results of two randomised controlled trials cyclooxygenase 2 (COX2) has been implicated in
enrolling 8,798 patients found no significant dif- hepatocarcinogenesis in experimental models.197
ference in HCC risk according to metformin use COX2 expression in hepatocytes is sufficient to
(OR 0.84; p = 0.87). A phase III trial was initiated induce HCC through induction of promoter hyper-
to evaluate the secondary HCC chemopreventive methylation by reducing tet methylcytosine
effect of metformin in compensated HCV-related dioxygenase 1 (TET1) expression, silencing tumour
cirrhosis and insulin resistance in France, however suppressor genes and activating oncogenic path-
the trial was terminated based on the decision of ways.198 Hepatic translocation of lipoteichoic and
the investigator (NCT02319200). A phase II trial deoxycholic acids from gut microbiota enhances
is planned to evaluate change in liver fibrosis by SASP of hepatic stellate cells to upregulate COX2-
metformin in patients infected with HCV, with or mediated PGE2 production via TLR2, and sup-
without HIV coinfection (NCT02306070). presses antitumour immunity in a mouse model
of obesity/NAFLD-associated HCC.150 HCC upregu-
Fibroblast growth factor 21 (FGF21) lated long non-coding RNA (HULC) stabilises COX2
FGF21 is a pleiotropic hormone with various ben- protein and promotes HCC cell growth.199 Acti-
eficial effects on glucose metabolism and sugar vated hepatic stellate cells enhance immunosup-
intake and preference, which can be regulated by pressive cell populations, including myeloid-
a variety of mechanisms including adipose- derived suppressor cells and regulatory T cells
derived circulating miRNAs and genetic polymor- (Tregs) via COX2-PGE2-EP4 signalling.200 Co-
phism (rs838133).187–189 Lack of FGF21 acceler- administration of a COX2 inhibitor, NS398, and
ates the development of NASH and HCC in simvastatin synergistically reduces proliferation
diabetic mice.190 FGF21 inhibits mTOR and and enhances apoptosis of HCC cell lines.201
improves insulin resistance, making it a candidate In a clinical trial enrolling 232 patients who
treatment for type 2 diabetes.191 A synthetic underwent curative HCC resection or ablation
FGF21 protein, LY2405319, reduces transforming (i.e. tertiary prevention), a COX2 inhibitor, meloxi-
growth factor b1 (TGFb1) and collagen I expres- cam, did not improve overall and disease-free sur-
sion as well as NF-jB, p65, c-Jun N-terminal vival, although subgroup analyses suggested a
kinase 1/2 (JNK1/2), and p38 phosphorylation, possible chemopreventive effect in non-viral
and inhibits NASH progression in leptin-deficient HCC.202 A phase III trial of another COX2 inhibitor,
ob/ob mice fed methionine- and choline-deficient celecoxib, with or without metformin for tertiary
diet, suggesting that FGF21 may have a role in prevention in patients who underwent curative
chemoprevention of NAFLD cirrhosis and/or HCC resection is now recruiting participants
HCC.192 (NCT03184493). In a phase III trial conducted in
Korea, adjuvant immunotherapy with activated
cytokine-induced killer cells (an NK cell subset
Generic chemoprevention strategies incubated with patient-derived peripheral blood
Anti-inflammatory and immunomodulatory mononuclear cells, IL2, and CD3 antibody) reduced
therapies recurrence-free survival (HR 0.63) and overall
Chronic hepatic inflammation is a well- death (HR 0.21) in patients with HCC treated with
established driver of hepatocarcinogenesis.14 The resection or ablation.203 Thymalfasin, an immune
HCC-preventive effect of low-dose maintenance modulator with pleiotropic activities towards T
interferon therapy in patients with HCV cirrho- cells, NK cells, and dendritic cells, prolonged the
sis20,21 is likely due to reduced hepatic inflamma- time to HCC recurrence and increased survival,
tion, so called ‘‘biochemical response”, instead of when used as an adjuvant therapy for patients
viral clearance, although the drug’s intolerability with HBV-related HCC, in several pilot studies.204
hampers its wider use.24 Hepatic expression of A multicentre clinical trial is planned to evaluate
an interferon-stimulated gene, retinoic acid- the effect of thymalfasin on two-year recurrence-
inducible gene-I (RIG-I), and downstream STAT1 free survival rate and the tumour immune
signalling are suppressed in association with microenvironment in patients with curatively
increased HCC risk, which possibly contributes to treated HBV-related HCC (NCT02281266).
the higher HCC incidence in men than women.193
There is somewhat conflicting epidemiological Anti-fibrotic therapies
evidence about the HCC-preventive effect of non- Anti-fibrotic therapies may serve as HCC chemo-
steroidal anti-inflammatory drugs (NSAIDs), prevention by halting progression of fibrotic liver
including aspirin.194 A pooled analysis of 10 US- diseases towards carcinogenesis, as suggested by
based cohorts (679 HCC cases in 1,084,133 indi- experimental studies and recent clinical trials.5
viduals) suggested a protective effect of aspirin Hepatocyte apoptosis caused by chronic injury
use (HR 0.68).195 Intestinal microbiota can induce leads to the release of inflammation-mediating
innate immune signalling via Toll-like receptor 4 damage-associated molecular patterns (DAMPs),
(TLR4) and support promotion of transformed including TNF, IL6, IL1b, reactive oxygen species
(VAP-1), which is linked to hepatic inflammation cellular signals via G-protein-coupled receptors,
and fibrosis in NASH5 (NCT02098785). and regulate cell survival, differentiation, prolifer-
Dietary phytochemicals such as curcumin (tur- ation, and migration.239 In the liver, expression of
meric extract), resveratrol (polyphenol in grapes, autotaxin (ATX), which converts lysophos-
red wine, and berries), silymarin (herbal flavo- phatidylcholine into LPA, increases HCV replica-
noid), and carotenoids have been evaluated as tion and is elevated in the serum of patients
potential HCC chemoprevention agents because infected with HCV, in association with hepatic
of their ability to activate cytoprotective mecha- fibrosis and HCC.240 In NAFLD, lipotoxic lipids,
nisms such as the Keap1/Nrf2 pathway in including LPA, are generated from excess dietary
carcinogen-induced rodent models, although sup- fat and sugars, and induce phenotypic manifesta-
porting clinical evidence is lacking.14 This class of tions of NASH, fibrosis, and HCC in the Substrate
compounds may need careful assessment given Overload Lipotoxic Liver Injury model of NAFLD
the recent classification of curcumin as a pan- pathogenesis.142 In a transcriptome-based meta-
assay interference compound that likely shows analysis of 523 human fibrotic livers, LPA receptor
false experimental activity.231 A reduction of 1 (LPAR1) signalling was identified as a pan-
DNA damage biomarkers including urine 8- aetiology HCC risk driver, and Rho kinase and
hydroxydeoxyguanosine (8-OHdG) was observed Ras/MAPK/ERK, but not PI3K/AKT/mTOR sig-
for epigallocatechin gallate (EGCG, green tea nalling, were identified as its downstream effector
polyphenol) and broccoli sprout in human, pathways in cirrhotic livers.10 Genetic knockout of
although their HCC-preventive effect is undeter- ATX, as well as pharmacological inhibition of ATX
mined.14 The liquorice root extract glycyrrhizin or LPAR1, ameliorates liver fibrosis and HCC in
reduced HCC incidence when ALT was normalised multiple rodent models,10,241 reinforcing the LPA
(HR 0.39).232 S-adenosylmethionine (SAMe), a pathway as a promising chemoprevention target.
ubiquitous major methyl donor, is reduced in The renin-angiotensin system is involved in
rodent HCC models, and SAMe treatment sup- liver fibrosis and carcinogenesis.14 Angiotensin II-
presses HCC development.14 In a phase II trial, mediated NF-kB activation promotes fibrogenic
24 weeks of SAMe treatment did not alter AFP myofibroblast survival, which can be inhibited by
levels or biomarkers of liver injury and oxidative an angiotensin-converting enzyme (ACE) inhibitor,
stress, in 87 patients with HCV-related captopril.242 Hepatic stellate cell-targeted delivery
cirrhosis.233 of an angiotensin II type 1 receptor blocker (ARB),
losartan, reduced liver fibrosis by inhibiting
Molecular targeted therapies expression of NADPH oxidase and collagen type
The PI3K/AKT/mTOR pathway is involved in cell I.243 An ARB, telmisartan, prevents hepatic carci-
cycle progression and proliferation, and is an noma in CDAA-induced NASH fibrosis and HCC in
appealing target for HCC chemoprevention.14 rats.244 In a retrospective single centre clinical
AKT was indeed identified as a key HCC risk driver study, the use of ARBs was associated with longer
in a meta-analysis of the human liver transcrip- time to HCC recurrence and increased survival
tome.10 Retrospective studies and their meta- after radiofrequency ablation.245 An ACE inhibitor,
analysis suggest that mTOR inhibitor-based perindopril, combined with vitamin K2 reduced
immunosuppression reduces post-transplant HCC HCC recurrence after curative therapy.246 A
recurrence,234 but adverse effects, including hep- clinical trial of perindopril in combination with
atic artery thrombosis and decreased patient and BCAA reduced serum VEGF level and post-
graft survival, have been noted in patients receiv- ablation HCC recurrence in 54 patients with insu-
ing the mTOR inhibitor sirolimus.235 In animal lin resistance.247
models of chemical- and obesity-driven HCC A synthetic acyclic retinoid (vitamin A ana-
development, sirolimus activates IL6/STAT3 and logue), peretinoin, inhibits multiple cellular sig-
enhances HCC development, despite a transient nalling pathways, including Wnt and platelet-
reduction in steatosis.236 To determine the benefit derived growth factor; it also induces differentia-
or harm of mTOR inhibition, sirolimus and evero- tion and apoptosis of hepatic stem cells, and is
limus have been tested in prospective trials for assumed to suppress neoplastic clones.248–250 Per-
prevention of post-transplantation HCC recur- etinoin also inhibits HCV replication and infec-
rence.237 In a phase III trial of 525 patients (viral tious virus release in cultured cells.251 In
hepatitis, 48%; alcoholic, 31%) sirolimus after atherogenic high-fat diet-fed mice, peretinoin
transplantation did not improve recurrence-free activates autophagy and suppresses NASH and
survival beyond five years (HR 0.84), although HCC development.252 In a phase III trial of pereti-
subgroup analyses suggested that patients with noin in 377 patients with curatively treated
less advanced HCC tumours, within Milan criteria HCV-related HCC, a lower trend of HCC recurrence
or younger age, may benefit from the therapy (SiL- was observed for the entire study period (HR
VER trial).238 0.73), and also after two years of randomisation
Bioactive lipids, e.g. lysophosphatidic acid (LPA) (HR 0.27).23 A follow-up survey reported a longer
and sphingosine-1-phosphate (S1P), transmit overall survival in patients treated with a higher
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