significant fibrosis predicts new-onset diabetes mellitus ......hbx pres2/s prec/pgrna pres1...
TRANSCRIPT
Significant fibrosis predicts new-onset diabetes mellitusand arterial hypertension in patients with NASH
Graphical abstract
NAFLD-related significant fibrosis as a determinant of metabolic outcomesin non-diabetic non-hypertensive patients
Cumulative incidence
1-year - 0.7%3-year - 2.1%5-year - 3.5%
1-year - 0.7%3-year - 2.8%5-year – 4.2%
1-year – 2.9%3-year – 11.4%5-year – 14.3%
1-year – 2.9%3-year – 14.3%5-year – 17.1%
Mild fibrosis (F0-F1)
Significant fibrosis (F2-F4)
Type 2 diabetes mellitus Arterial hypertension
N = 143
N = 35
Annual incidence
Significant fibrosis (F2-F4) Obesity (BMI >30)
7 cases/100 person-years 6.7 cases/100 person-years
Type 2 diabetes mellitus Arterial hypertension
Highlights� NAFLD-related significant fibrosis predicts the occurrence of
type 2 diabetes mellitus and arterial hypertension.
� The annual incidence of metabolic outcomes is four-timeshigher in the presence of significant fibrosis.
� Neither steatosis nor NASH predict the appearance of metabolicoutcomes.
� Hepamet fibrosis score >0.12 is associated with the risk ofdeveloping type 2 diabetes mellitus.
Authors
Javier Ampuero, Rocío Aller,Rocío Gallego-Durán, ., Javier Salmerón,Juan Turnes, Manuel Romero Gómez
[email protected] (J. Ampuero),[email protected] (M. RomeroGómez).
Lay summaryPatients with biopsy-proven non-alco-holic fatty liver disease and significantfibrosis were at risk of developing type 2diabetes mellitus and arterial hyper-tension. The risk of metabolic outcomesin patients with significant fibrosis wasincreased in the presence of obesity. Inaddition to liver biopsy, patients atintermediate-to-high risk of significantfibrosis by Hepamet fibrosis score wereat risk of type 2 diabetes mellitus.
Research ArticleNAFLD and Alcohol-Related Liver Diseases
July 2020
https://doi.org/10.1016/j.jhep.2020.02.028 e1© 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. J. Hepatol. 2020, 73, 17–25
Selonsertib for patients with bridging fibrosis orcompensated cirrhosis due to NASH: Results from
randomized phase III STELLAR trials
Graphical abstract
≥1-stage fibrosisimprovement
NASH resolutionwithout worsening
fibrosis
≥1-stage fibrosisimprovement
NASH resolutionwithout worsening
fibrosis
0
5
10
15
20
25
Prop
ortio
nof
patie
nts
(95%
CI)
SEL18 mg
SEL6 mg Placebo SEL
18 mgSEL6 mg Placebo
44/321 26/159 14/321 14/159
1314
16
54
9
p=0.56p=0.59
p=0.25p=0.14
SEL18 mg
SEL6 mg Placebo SEL
18 mgSEL6 mg Placebo
59/351 27/172 13/351 7/172
p=0.29p=0.67
p=0.37p=0.86
1917
16
44
2
STELLAR-3 STELLAR-4
41/322 16/322 67/354 8/354
Highlights� Selonsertib was safe and inhibited its target (ASK1) but did not
lead to fibrosis regression or reduce disease progression in NASH.
� Improvement in liver fibrosis on biopsy was associated withimprovement only in other histologic features.
� Improvements in ELF score and liver stiffness by transient elas-tography correlated with a variety of clinical parameters.
Authors
Stephen A. Harrison, Vincent Wai-Sun Wong, Takeshi Okanoue, .,Zachary Goodman, Eric J. Lawitz,Zobair Younossi
[email protected](S.A. Harrison).
Lay summaryPatients with non-alcoholic steatohe-patitis (NASH) can develop scarring ofthe liver (fibrosis), including cirrhosis,which increases the risks of liver fail-ure and liver cancer. We testedwhether 48 weeks of treatment withselonsertib reduced fibrosis in patientswith NASH and advanced liver scar-ring. We did not find that selonsertibreduced fibrosis in these patients.
Research ArticleNAFLD and Alcohol-Related Liver Diseases
https://doi.org/10.1016/j.jhep.2020.02.027 e2© 2020 Published by Elsevier B.V. on behalf of European Association for the Study of the Liver. J. Hepatol. 2020, 73, 26–39
Full-length 5’RACE identifies all major HBV transcripts inHBV-infected hepatocytes and patient serum
Graphical abstract
m7Gppp
pDephosphorylation of degraded mRNARemoval of 5'Cap
Anchor ligation
RT with first gene specific primer Gsp1
PCR with anchor primer andsecond gene specific primer Gsp2
Capped transcriptspecific amplicons
pAAAAA
pAAAAA
pAAAAA
HBx
preS2/S
preC/pgRNApreS1
Intracellularviral RNAs
Full length HBV 5'RACE
Encapsidatedviral RNAs
pgRNASpliced pgRNA
Different HBxtranscripts
Circulatingviral RNAs
321
pgRNASpliced pgRNA
Different HBxtranscripts
pAAAAA
preS
1
preS2S
HBx
preC/pg
cccDNA
Highlights� HBV full-length 5’RACE discriminates all viral transcripts
including HBx.
� Viral particles contain pgRNA, pgRNA splice variants anddifferent HBx RNAs.
� HBx RNAs in viral particles are both capped and uncapped.
� The composition of circulating viral RNA species can varyamong patients.
Authors
Bernd Stadelmayer, Audrey Diederichs,Fleur Chapus, ., Kara Carter,Barbara Testoni, Fabien Zoulim
[email protected](B. Stadelmayer), [email protected](F. Zoulim).
Lay summaryEspecially under infection conditions, ithas been difficult to study the differenthepatitis B virus transcripts in depth. Thisstudy introduces a new method that canbe used in any standard lab to discriminateall hepatitis B viral transcripts in cell cul-ture and in the serum of patients.
Research ArticleViral Hepatitis
https://doi.org/10.1016/j.jhep.2020.01.028 e3© 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. J. Hepatol. 2020, 73, 40–51
Hepatitis B core-specific memory B cell responsesassociate with clinical parameters in patients with
chronic HBV
Graphical abstract
0
6
9
3
IT IA IC ENEG
HBcAgHBsAg <<x 17.8 1.030.058
HBsAg Dylight650
HBs
Ag D
ylig
ht55
0
NUC
HBcAb (Serum)
HBcAb SFC (ELISPOT)
HBcAg+ B cells (FACS)
HBV DNA(log IU/ml)
ALT(ULN)
Blood CD19+ B cell Blood CD19+ B cellHBcAg Dylight650
HBc
Ag D
ylig
ht55
0
Highlights� B cell responses in chronic HBV are predominantly directed against
HBcAg, not HBsAg.
� HBcAg-specific memory B cells associate with HBV’s clinical phases.
� HBcAg-specific B cell responses are reduced during antiviral treatment.
Authors
Thomas Vanwolleghem, ZwierM.A. Groothuismink,Kim Kreefft, Magdeleine Hung,Nikolai Novikov, Andre Boonstra
[email protected](T. Vanwolleghem).
Lay summaryIn recent years, studies examin-ing the role of B cells duringchronic hepatitis B virus infec-tion have regained interest. Weshow that circulating B cellsmore often target the hepatitis Bcore antigen than the hepatitissurface antigen. Moreover, thesehepatitis B core-specific B cellsassociate with the natural his-tory of chronic HBV, and theirresponses decline during effec-tive antiviral treatment.
Research ArticleViral Hepatitis
https://doi.org/10.1016/j.jhep.2020.01.024 e4© 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. J. Hepatol. 2020, 73, 52–61
Hepatitis B-related outcomes following direct-actingantiviral therapy in Taiwanese patients with chronic
HBV/HCV co-infection
Graphical abstract
DAA
HCVXDAADAA
HBV
HCV
HBV±NUC
HBV
HBVHBVX
HCV/HBV dual infections
HCV SVR + HBsAg loss
HCV SVR + stable HBV
HCV SVR + HBV reactivation
10%
52%
38%20% (6/30) HBV
clinical flare
33% (2/6) death
Highlights� HBsAg levels decline during DAA therapy and rebound post-DAA
therapy in HBV/HCV coinfected patients.
� HBsAg loss can occur in HBV/HCV coinfected patients on DAAtherapy at a frequency seen in HBV monoinfection.
� HBV/HCV-coinfected patients are at risk of HBV reactivation afterDAA, especially in those with higher HBsAg levels.
� HBV/HCV coinfected cirrhotic patients on DAAs should undergoHBV prophylaxis to reduce risk of hepatic failure and death.
� Quantitative HBsAg measurement could guide decision-making inHBV/HCV coinfected patients on DAA therapy.
Authors
Ming-Lun Yeh, Chung-Feng Huang,Ching-I. Huang, ., Wan-Long Chuang,Raymond T. Chung, Ming-Lung Yu
[email protected] (M.-L. Yu).
Lay summaryWe studied outcomes relating to hep-atitis B virus (HBV) in patients coin-fected with both hepatitis B and C.Patients receiving direct-acting anti-viral treatment for hepatitis C weremore likely to experience seroclear-ance (or functional cure of HBV), butwere also more likely to experienceHBV reactivation, which can lead tohepatitis, liver failure and death. Incoinfected cirrhotic patients beingtreated for HCV, prophylactic treat-ment for HBV is mandatory.
Research ArticleViral Hepatitis
https://doi.org/10.1016/j.jhep.2020.01.027 e5© 2020 European Association for the Study of the Liver. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license(http://creativecommons.org/licenses/by-nc-nd/4.0/). J. Hepatol. 2020, 73, 62–71
IFNL3-adjuvanted HCV DNA vaccine reduces regulatory Tcell frequency and increases virus-specific T cell
responses
Graphical abstract
NS4B
NS5ANS3/4A
IFNL3 plasmid
Vaccination in chronicHCV patientsNCT02027116
CD4+ and CD8+ T cells
Regulatory T cells
Cytokine production (IFN-γ, TNF, and IL-2)
Total Treg frequency Activated Treg frequency
CTLA-4 expression
Vaccination inDAA-treated SVR subjects
NCT03674125
Prevention of HCV reinfection ?
HCV non-structural (NS) plasmids
HCV DNA vaccine(GLS-6150)
+
Highlights� DAAs successfully induce SVR in chronic HCV infection, but a
prophylactic HCV vaccine is still warranted.
� We report here the first-in-human study demonstrating safetyof an IFNL3-adjuvanted HCV DNA vaccine.
� IFNL3-adjuvanted HCV DNA vaccine reduces Treg cell frequencyand increases virus-specific T-cell responses.
� Ex vivo IFN-k3 treatment decreases Treg cell frequency in pre-vaccinated PBMCs, which might be an indirect effect by pDCs.
Authors
Ji Won Han, Pil Soo Sung, Seon-Hui Hong,., Jeong Heo, Sang Hoon Ahn, Eui-Cheol Shin
[email protected] (E.-C. Shin), [email protected] (S.H. Ahn), [email protected](J. Heo).
Lay summaryAlthough direct-acting antivirals(DAAs) are successfully used for thetreatment of chronic hepatitis C virus(HCV) infection, a prophylactic HCVvaccine needs to be developed, espe-cially for patients who achieve a sus-tained virologic response. In the currentstudy, we show that a DNA vaccine(GLS-6150) was safe and increasedHCV-specific T cell responses. A clinicaltrial is underway to test this vaccine inpatients with a sustained virologicresponse following DAA therapy.
Research ArticleViral Hepatitis
https://doi.org/10.1016/j.jhep.2020.02.009 e6© 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. J. Hepatol. 2020, 73, 72–83
Genotype correlates with the natural history of severebile salt export pump deficiency
Graphical abstract
0 5 10 150
20
40
60
80
100
% o
f pat
ient
sal
ive
with
nat
ive
liver
p <0.001
18
BSEP1At least one p.D482G or p.E297G mutation (residual function in BSEP)
BSEP2At least one missensemutation, yet not p.D482G or p.E297G
BSEP3Mutations leading to atruncated or non-functionalprotein
0 5 10 150
10
20
30
40
18Age (years)
% o
f pat
ient
s w
ithhe
pato
cellu
lar c
arci
nom
a
BSEP 3BSEP 2BSEP 1
p = 0.001
Highlights� NAPPED is the largest global database of genotyped patients
with BSEP deficiency.
� The genotype of patients with BSEP deficiency predictssurvival with native liver.
� Genotype predicts long-term benefit of interruption ofenterohepatic circulation.
� Serum bile acids can be a surrogate marker for long-termoutcome.
� Treatment of patients with BSEP deficiency should be basedon genotype.
Authors
Daan B.E. van Wessel, Richard J. Thompson,Emmanuel Gonzales, ., Ton M.G. Bunt,Bettina E. Hansen, Henkjan J. Verkade
[email protected] (H.J. Verkade).
Lay summaryThis study presents data from the largestgenetically defined cohort of patients withsevere bile salt export pump deficiency todate. The genotype of patients with severebile salt export pump deficiency is asso-ciated with clinical outcomes and the suc-cess of therapeutic interventions. Therefore,genotypic data should be used to guidepersonalized clinical care throughoutchildhood and adulthood in patients withthis disease.
Research ArticleDILI, Autoimmune, Cholestatic and Genetic Diseases
https://doi.org/10.1016/j.jhep.2020.02.007 e7© 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. J. Hepatol. 2020, 73, 84–93
A randomized, placebo-controlled, phase II study ofobeticholic acid for primary sclerosing cholangitis
Graphical abstract
Placebo
OCA 5-10 mgOCA 1.5-3.0 mg
-200
-150
-100
-50
0
50
Weeks
ALP
(U/L
) LS
mea
n (S
E) c
hang
e fro
m b
asel
ine
*
* p <0.05
***
0 2 6 12 14 18 24
Study design
Placebo
1.5 mg OCA
5 mg OCA
3.0 mg OCA
10 mg OCA
Screening≤30 days
from day 0
Randomization
12 weeks 12 weeks
2-Yearopen-labelLTSE
Titration visit
Highlights� Novel treatments for PSC are an urgent unmet need.
� This phase II study evaluated OCA in patients with PSC.
� OCA 5–10 mg significantly reduced serum ALP levels at 24weeks.
� The safety profile of OCA was consistent with previousstudies.
Authors
Kris V. Kowdley, Raj Vuppalanchi,Cynthia Levy, ., Leigh MacConell,David Shapiro, Christopher L. Bowlus
[email protected](K.V. Kowdley).
Lay summaryPrimary sclerosing cholangitis (PSC) is along-term disease that damages the bileducts in the liver over time. In the AESOPclinical study in patients with PSC, obe-ticholic acid reduced serum alkalinephosphatase (a potential marker of diseaseseverity) during an initial 24-week treat-ment period. The result was sustainedduring the 2-year, long-term extension ofthe study. The most common side effect ofobeticholic acid in the study was itchyskin, which is consistent with earlierclinical studies.
Research ArticleDILI, Autoimmune, Cholestatic and Genetic Diseases
https://doi.org/10.1016/j.jhep.2020.02.033 e8© 2020 European Association for the Study of the Liver. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license(http://creativecommons.org/licenses/by-nc-nd/4.0/). J. Hepatol. 2020, 73, 94–101
Toll-like receptor 4 is a therapeutic target for preventionand treatment of liver failure
Graphical abstract
Acute liverfailure
Acute-on-chronicliver failure
TLR4 TLR4
TLR4 signaling inhibitionTAK-242
Lipopolysaccharide (LPS)
Apoptotic cell deathsystemic inflammation
Necrotic cell deathsystemic inflammation
Highlights� Cirrhosis is associated with TLR4-related sensitization to
endotoxins and a switch from apoptotic to necroptotic celldeath.
� Inhibition of TLR4 signaling by TAK-242 reduces immune cellresponses and hepatocyte injury in response to LPS in vitro.
� In models of acute and acute-on-chronic liver failure, TAK-242 mitigated LPS-driven systemic inflammation and organinjury.
Authors
Cornelius Engelmann, Mohammed Sheikh,Shreya Sharma, ., Saurabh Gupta,Fausto Andreola, Rajiv Jalan
[email protected] (R. Jalan).
Lay summaryToll-like receptor 4 (or TLR4) mediatesendotoxin-induced tissue injury in liverfailure and cirrhosis. This receptor sensi-tizes cells to endotoxins, which are pro-duced by gram-negative bacteria. Thus,inhibiting TLR4 signaling with an inhibitor(TAK-242) ameliorates organ injury andsystemic inflammation in rodent models ofacute and acute-on-chronic liver failure.
Research ArticleCirrhosis and Liver Failure
https://doi.org/10.1016/j.jhep.2020.01.011 e9© 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. J. Hepatol. 2020, 73, 102–112
HDL-related biomarkers are robust predictors ofsurvival in patients with chronic liver failure
Graphical abstract
Stable cirrhosis228 patients
enrolled at Medical University of Graz
Acute decompensation280 patients
enrolled in CANONIC cohortincluding 107 patients with ACLF
Measurement ofHDL-relatedbiomarkers(HDL-C, apoA-I)
at baseline
Chr
onic
live
r fai
lure
Follo
w-u
p 12
mon
ths
HD
L-C
Apo
A-I
Cum
ulat
ive
surv
ival
Months
0.2
0.0
0.4
0.6
0.8
1.0
0 2 4 6 8 10 12
p <0.001
>17 mg/dl≤17 mg/dl
Cum
ulat
ive
surv
ival
Months
0.2
0.0
0.4
0.6
0.8
1.0
0 2 4 6 8 10 12
p <0.001
>50 mg/dl≤50 mg/dl
Exte
rnal
val
idat
ion
in98
5pa
tient
sen
rolle
dat
Med
ical
Uni
vers
ity o
fVie
nna
Highlights� HDL levels are profoundly decreased in chronic liver failure.
� HDL-related biomarkers (HDL-C, apoA-I) are robust predictors ofdisease progression and survival.
� The prognostic value of single HDL-related biomarkers is verysimilar to that of the composite scores.
� HDL-related biomarkers correlated inversely with markers ofinflammation.
Authors
Markus Trieb, Florian Rainer,Vanessa Stadlbauer, ., Joan Clària,Gunther Marsche, Rudolf E. Stauber
[email protected](G. Marsche), [email protected] (R.E. Stauber).
Lay summaryPeople who suffer from cirrhosis(scarring of the liver) have low levelsof cholesterol carried by high-densitylipoproteins (HDL-C). These alter-ations are connected to inflammation,which is a problem in severe liverdisease. Herein, we show that reducedlevels of HDL-C and apolipoprotein A-I(apoA-I, the main protein carried byHDL) are closely linked to the severityof liver failure, its complications andsurvival. Both HDL-C and apoA-I canbe easily measured in clinical labo-ratories and are as good as currentlyused prognostic scores calculatedfrom several laboratory values bycomplex formulas.
Research ArticleCirrhosis and Liver Failure
https://doi.org/10.1016/j.jhep.2020.01.026 e10© 2020 European Association for the Study of the Liver. Published by Elsevier B.V. This is an open access article under the CC BY-NC-NDlicense (http://creativecommons.org/licenses/by-nc-nd/4.0/). J. Hepatol. 2020, 73, 113–120
Stereotactic body radiation therapy vs. radiofrequencyablation in Asian patients with hepatocellular
carcinoma
Graphical abstract
Multinationalretrospective study
Propensity score matching
SBRT 496 tumorsRFA 1,568 tumors
SBRT 313 tumorsRFA 313 tumors
Cumulatvelocal recurrence
Gray's test, p<0.0010
20
40
60
80
100
0 12 24 36 48 60 72Time (Months)
Cum
ulat
ive
inci
denc
e of
loca
l pro
gres
sion
(%)
SBRTRFA
313 236 153 90 43 17 5313 197 134 84 49 26 14RFA
SBRTNo. at risk
Gray's test, p<0.0010
20
40
60
80
100
0 12 24 36 48 60 72Time (Months)
Cum
ulat
ive
inci
denc
e of
loca
l pro
gres
sion
(%)
SBRTRFA
496 315 200 121 64 28 101,568 1,086 771 501 294 155 62RFA
SBRTNo. at risk
1,568 1,086 771 501 22994 15RFAF
SBRT RFA
Highlights� SBRT provided better local control than RFA among patients with
HCC.
� Toxicity rates and survival outcomes were similar between thesetreatment modalities.
� SBRT is an effective alternative to RFA for larger tumors (>3 cm) ina subphrenic location (especially segment 8).
Authors
Nalee Kim, Jason Cheng, Inkyung Jung,., Seok Jae Heo, Jong Yoon Won,Jinsil Seong
[email protected] (J. Seong).
Lay summaryIt is currently not known what thebest treatment option is for patientswith unresectable hepatocellular car-cinoma. Here, we show that stereo-tactic body radiation therapy providesbetter local control than radio-frequency ablation, with comparabletoxicities. Stereotactic body radiationtherapy appears to be an effectivealternative to radiofrequency ablationthat should be considered when thereis a higher risk of local recurrence ortoxicity after radiofrequency ablation.
Research ArticleHepatic and Biliary Cancer
https://doi.org/10.1016/j.jhep.2020.03.005 e11© 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. J. Hepatol. 2020, 73, 121–129
Portopulmonary hypertension in the current era ofpulmonary hypertension management
Graphical abstract
60
40
20
Surv
ival
(%)
0
80
100
Months since PoPH diagnosis0 12 24 36 48 60
Transplanted patientsNo indication for LTIndication for LT but nottransplanted
Survival by liver transplant (LT) status
Overall survival
Cohort of 637 patients withportopulmonary hypertension
Initial PAH therapy in574 patients (90.1%)
Effect of oral PAH therapies on pulmonary vascular resistance
Endothelin receptor
antagonist
Phosphodiesterase-5inhibitors
Oral combination
therapy
-37%-40% -64%
Portopulmonary hypertension
Pulmonary vascular remodeling
Highlights� Portopulmonary hypertension is a severe complication of portal
hypertension.
� Therapies targeting pulmonary arterial hypertension improve car-diopulmonary haemodynamics.
� Combining these therapies and liver transplantation is associated withexcellent long-term outcomes.
Authors
Laurent Savale,Manuel Guimas,Nathan Ebstein, .,Marc Humbert, Pascal DeGroote, Olivier Sitbon
[email protected](L. Savale).
Lay summaryPortopulmonary hyperten-sion is defined by the pres-ence of pulmonary arterialhypertension in the contextof chronic liver disease and ischaracterized by progressiveshortness of breath andexercise limitation. The pres-ence of severe pulmonaryarterial hypertension in livertransplant candidates repre-sents a contraindication forsuch a surgery; however,treatments targeting pulmo-naryarterialhypertensionareefficacious, allowing for safetransplantation and confer-ring good survival outcomesin those who undergo livertransplantation.
Research ArticleLiver Transplantation
https://doi.org/10.1016/j.jhep.2020.02.021 e12© 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. J. Hepatol. 2020, 73, 130–139
Exercise retards hepatocarcinogenesis in obese miceindependently of weight control
Graphical abstract
Lean WT mice Obese diabeticfoz/foz mice
DEN injection
Sedentary mice
No HCC HCC in 7/11 mice
Lean WT mice Obese diabeticfoz/foz mice
DEN injection
Volountary exercise
HCC in 1/12 mice HCC in 2/13 mice
6 months
Highlights� Obesity and insulin resistance accelerate liver cancer onset in foz/foz mice.
� Mice with an in-cage exercise wheel engage in physical activity that abolishesthe effect of obesity on hepatocarcinogenesis.
� Pair-fed foz/foz mice exhibit similar weight gain but are not protected.
� Exercise decreases proliferation of dysplastic hepatocytes by activating p53 toinduce p27.
� A critical pathogenic role of JNK1 was also confirmed using Jnk1-/-.foz/foz mice.
Authors
Arfianti Arfianti,Sharon Pok, Vanessa Barn,., George N. Ioannou,Narci C-H. Teoh, GeoffreyC. Farrell
[email protected](G.C. Farrell).
Lay summaryFatty liver disease com-monly occurs alongsideobesity and diabetes, con-tributing to rapidlyincreasing rates of livercancer throughout theworld.Herein,weshowthatexercise reduces the inci-dence and progression ofhepatocellular carcinomainmousemodels.Theeffectof exercise on cancer riskwasshowntobeindepend-ent of changes in weight.Exercise could be a pro-tectivemechanismagainstliver cancer in at-riskindividuals.
Research ArticleExperimental and Translational Hepatology
https://doi.org/10.1016/j.jhep.2020.02.006 e13© 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. J. Hepatol. 2020, 73, 140–148
Hepatic stellate cell activation promotes alcohol-induced steatohepatitis through Igfbp3 and SerpinA12
Graphical abstract
Lipogenicgenes
↓SerpinA12NRP-1 ↓pAMPK
Hepatic stellate cell
Hepatocyte
↑pAkt
↑IGFBP3Integrin
Ethanol
Synectin
Highlights� HSCs regulate hepatocyte steatosis that precedes liver fib-
rosis in alcohol-related liver disease.
� HSC-derived Igfbp3 and SerpinA12 mediate lipid dropletformation in hepatocytes.
� These results are recapitulated in samples from patients withalcoholic hepatitis.
Authors
Juan P. Arab, Daniel Cabrera, TejasavS. Sehrawat, ., Marco Arrese, RobertC. Huebert, Vijay H. Shah
[email protected] (V.H. Shah).
Lay summaryHepatic stellate cells are known for theirrole in fibrosis (scarring of the liver). In thisstudy, we describe their role in the modu-lation of fat deposition and inflammation inthe liver, which occurs secondary to alcoholdamage.
Research ArticleExperimental and Translational Hepatology
https://doi.org/10.1016/j.jhep.2020.02.005 e14© 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. J. Hepatol. 2020, 73, 149–160
[18F]-Alfatide PET imaging of integrin avb3 for thenon-invasive quantification of liver fibrosis
Graphical abstract
Tail intravenous injection
Micro-PET/CT
PET/CT scan
[18F]-Alfatidebiodistribution
[18F]-Alfatideuptake
Hepatic integrinαvβ3 expression
Monitor liver fibrosis
18FAlfatide
18FAlfatide
Highlights� [18F]-Alfatide was demonstrated to bind specifically with integrin avb3
(mainly expressed on activated HSCs).
� [18F]-Alfatide can detect fibrosis progression both in animal liver fibroticmodels and human liver tissues.
� Imaging integrin avb3 with PET/[18F]-Alfatide offers a potential non-invasivemethod for monitoring fibrosis progression.
Authors
Tuo Shao, Zhen Chen,Vasily Belov, .,Xiaoyuan Chen, RaymondT. Chung, Steven H. Liang
[email protected] (S.H. Liang),[email protected](R.T. Chung), [email protected] (X. Chen).
Lay summaryIntegrinavb3expressiononactivated hepatic stellatecells (aHSCs) is associatedwith HSC proliferation dur-ing hepatic fibrogenesis.Herein, we show that aradioactive tracer, [18F]-Alfatide, binds to integrinavb3 with high affinity andspecificity. [18F]-Alfatidecould thusbeusedasanon-invasive imagingbiomarkerto track hepatic fibrosisprogression.
Research ArticleInnovative Diagnostics, Modelling and Digital Hepatology
https://doi.org/10.1016/j.jhep.2020.02.018 e15© 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. J. Hepatol. 2020, 73, 161–169