control of replication of hepatitis b and c virus improves...

Control of replication of hepatitis B and C virusimproves patient and graft survival in kidney

transplantation

Graphical abstract Authors

10-year graft survival according tovirological status

10-year patient survival according tovirological status

100

80

60

40

20

01,8001,080 1,4407203600

Time (d)

%

10

30

90

50

2,160 2,520 2,880 3,240 3600

70

82.7% ± 0.3%81.2% ± 2.1%

71.3% ± 2%p <0.0001

Non-infected group

HBV infected group

HCV infected group

Non-infected group

HBV infected group

100

80

60

40

20

01,8001,080 1,4407203600

Time (d)

10

30

90

50

2,160 2,520 2,880 3,240 3,600

70

HCV infected group

64.7% ± 0.3%62.3% ± 2.4%

50.6% ± 1.9%p <0.0001

%

Highlights� Chronic HBV infection no longer influences 10-year patient

or graft survival in kidney transplant recipients.

� Chronic HCV infection still negatively impacts 10-yearpatient and graft survival.

� The negative effect of chronic HCV infection is removed bysustained viral suppression.

� Antiviral therapy should be systematically proposed forHBV- and/or HCV-infected kidney transplant recipients/can-didates.

Hélène Fontaine, Laurent Alric,Julien Labreuche, ..., Stanislas Pol,Alain Duhamel, Philippe Mathurin

[email protected](P. Mathurin)

Lay summaryPreviously, infections with hepatitis B orhepatitis C virus led to poor outcomes inkidney transplant recipients. However,the outcomes of kidney transplants inpatients with viral suppression are asgood as those for kidney transplants innon-infected patients. Antiviral therapyshould be systematically proposed tohepatitis B and/or hepatitis C-infectedkidney transplant recipients or candidatesto prevent the deleterious hepatic andextrahepatic impact of chronic viral repli-cation. Recent access to direct-actingantivirals in patients with hepatitis Cvirus and renal dysfunction providesexciting new opportunities.

https://doi.org/10.1016/j.jhep.2018.12.036 e49� 2019 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. J. Hepatol. 2019, 70, 831–838

Research ArticleMay 2019

Viral Hepatitis

JOURNAL OF HEPATOLOGY

Outcomes of treatment for hepatitis C in prisonersusing a nurse-led, statewide model of care


Highlights� Nurse-led care was associated with SVR12 rates of >95% in

large numbers of prisoners.

� <20% of prisoners required specialist input.

� >80% of prisoner had never pursued specialist hepatitis Ccare in the community.

Timothy Papaluca, Lucy McDonald, AnneCraigie, ..., Margaret Hellard, David Iser,Alexander Thompson

[email protected](A. Thompson)

Lay summaryThere is a high burden of hepatitis Cinfection among prisoners worldwide.Prisoners who continue to inject drugsare also at risk of developing new infec-tions. For this reason, the prison settingprovides an opportunity to treat thosepeople at greatest risk of infection and tostop transmission to others. We devel-oped a new method of providing hepatitisC treatment to prisoners, in which nursesrather than doctors assessed prisonerslocally at each prison site. Treatmentwas safe and most prisoners were cured.Such programs will contribute greatly toachieving the World Health Organiza-tion’s hepatitis C elimination goals.


Research ArticleViral Hepatitis

https://doi.org/10.1016/j.jhep.2019.01.012 e50Crown Copyright � 2019 Published by Elsevier B.V. on behalf of European Association for the Study of the Liver. All rights reserved.J. Hepatol. 2019, 70, 839–846

Estimation of renal function in patients with livercirrhosis: Impact of muscle mass and sex


Cirrhosis

Creatinine based-eGFRcompared with mGFR

Renal functionoverestimation

Male Female

51.6% 79.1%

Sex

All patients

58.4%

Decreasedmuscle mass

Related factors

OR 0.87(95% CI 0.80-0.93; p <0.001)

OR 1.02(95% CI 0.83-1.25; p = 0.862)

Different impact of muscle mass on overestimation per sex

Highlights� Renal function overestimation occurs frequently in patients

with liver cirrhosis when using serum creatinine.

� Decreased muscle mass impacts on overestimation of kidneyfunction especially in male patients with cirrhosis.

� Compared to creatinine, cystatin C correlated better withmGFR and had a higher predictive ability for clinicaloutcomes.

� Cystatin C might be a promising marker to accurately assessrenal function in cirrhotic patients.

Jeong-Ju Yoo, Sang Gyune Kim, Young SeokKim, ...,Hong Soo Kim,Young DonKim,GabJin Cheon

[email protected](S.G. Kim)

Lay summaryOverestimation of renal function fre-quently occurs in patients with livercirrhosis when using serum creatinine.Decreased muscle mass has a great im-pact on overestimation of kidney functionespecially in male patients with cirrhosis.Compared with creatinine, cystatin C wasmore closely correlated with measuredglomerular filtration rate and had a high-er predictive ability for renal complica-tions and survival than creatinine.


Research ArticleCirrhosis


Survival advantage for patients accepting the offer of acirculatory death liver transplant


Although outcomes from DCD is inferior to DBD liver transplantation (A), the survival benefit of accepting an early offer of a DCD liver transplant is significant over waiting for a “better” DBD liver (B).

0

20

40

60

80

100

% T

rans

plan

t sur

viva

l

0 1 2 3 5Years post-transplant

4

DBDDCD

0

20

40

60

80

100

% P

atie

nt s

urvi

val

0 1 2 3 5Years post-transplant

4

Wait for a potential DBD donor

Accept a DCD donor (current practice)

A B

Highlights� Outcomes for DCD are inferior to DBD liver transplantation

in the UK experience.

� There is a survival advantage in accepting a DCD offer ratherthan waiting for a ‘‘better DBD liver.

� This survival advantage is most pronounced in patients withmore advanced disease.

� This study provides strong support for the use of DCD liversin all patients.

� This should facilitate discussions with individuals aboutaccepting or declining a DCD liver offer.

Rhiannon Taylor, Elisa Allen,James A. Richards, ..., James Neuberger,David Collett, Gavin J. Pettigrew

[email protected](G.J. Pettigrew)

Lay summaryThis study looks at patients who require aliver transplant to save their lives; thisliver can be donated by a person who hasdied either after their heart has stopped(donation after cardiac death [DCD]) orafter the brain has been injured and canno longer support life (donation afterbrainstem death [DBD]). We know thatlivers donated after brainstem deathfunction better than those after cardiacdeath, but there are not enough of theselivers for everyone, so we wished to helppatients decide whether it was better forthem to accept an early offer of a DCDliver than waiting longer to receive a‘‘better liver from a DBD donor. We foundthat patients were more likely to surviveif they accepted the offer of a livertransplant as soon as possible (DCD orDBD), especially if their liver disease wasvery severe.


Research ArticleTransplantation


Outcomes of radiofrequency ablation as first-linetherapy for hepatocellular carcinoma less than 3cm

in potentially transplantable patients


N° at risk

Log-rank test p <0.001

Cum

ulat

ive

haza

rd

167 157 131 102 65 53HCC ≤2 cm134 112 84 63 39 26HCC >2 cm

0 1 2 3 4 5Years after ablation

HCC >2cmHCC ≤2cm

0.00

0.40

0.60

0.80

1.00

0.20

HCC 2-3 cm

HCC <2 cm

Highlights� Most patients with single HCC �3 cm treated by RFA will

eventually develop recurrent HCC distant to the ablationsite.

� Many patients treated with HCC will recur beyond the Milancriteria despite close post-RFA surveillance.

� Patients with tumors >2 cm and higher serum alpha-fetoprotein are at greater risk of recurrence beyond Milancriteria.

AdamDoyle, Andre Gorgen, Hala Muaddi, ...,Eberhard L. Renner, Morris Sherman, Gon-zaloSapisochin

[email protected](Gonzalo Sapisochi)

Lay summaryRadiofrequency ablation and liver trans-plantation are treatment options for earlystages of hepatocellular carcinoma (HCC).After ablation some patients will experi-ence recurrence or metastatic spread ofthe initial tumor or may develop newtumors within the liver. Despite closefollow-up, these recurrences can progressrapidly and exceed transplant criteria,preventing the patient from receiving atransplant. We identified that patientswith HCC >2 cm and higher serumalpha-fetoprotein are at greater risk ofrecurrence beyond the transplant criteria.These data suggest that liver transplanta-tion should be considered immediatelyafter the first HCC recurrence for thesepatients.


Research ArticleCancer


Time association between hepatitis C therapy andhepatocellular carcinoma emergence in cirrhosis:

Relevance of non-characterized nodules


15

10

5

20

0Global Nodule free Non

characterizedBenign

Inci

denc

e (H

CC

/100

PY

)

Relative risk by Nodules

RR 0.36 (95% Cl 0.05; 2.62)

RR 2.83 (95% Cl 1.55; 5.16)

Nodules

Highlights� The risk of HCC in patients with HCV cirrhosis treated with

DAAs persists despite viral cure.

� The presence of indeterminate nodules before starting DAAis associated with a 3 times greater risk of HCC.

� A time association between DAA therapy and developingHCC reflects increased short-term HCC risk.

� DAA therapy elicits a mechanism that primes the emergenceof HCC early during follow-up.

Zoe Mariño, Anna Darnell, Sabela Lens, ...,Xavier Forns, Jordi Bruix, María Reig

[email protected](M. Reig)

Lay summaryIn this cohort of cirrhotic patients,interferon-free therapies achieved a highrate of sustained virologic response(>95%); however, we reported a risk ofde novo hepatocellular carcinoma of 3.73per 100 person-years and a clear-cut timeassociation with antiviral therapy. Thetime association between starting direct-acting antivirals and developing hepato-cellular carcinoma, together with theassociation with the presence of non-characterized nodules at baseline ultra-sound, suggests that antiviral therapyelicits a mechanism (probably immune-related) that primes the growth andclinical recognition of hepatocellular car-cinoma early during follow-up. As aresult, short-term liver cancer risk issignificantly increased.



https://doi.org/10.1016/j.jhep.2019.01.005 e54� 2019 Published by Elsevier B.V. on behalf of European Association for the Study of the Liver. J. Hepatol. 2019, 70, 874–884

Association between physical activity and risk ofhepatobiliary cancers: A multinational cohort study


0

0.0002

0.0004

0.0006

Cum

ulat

ive

inci

denc

e of

HC

C

0 5 10 15Years of follow-up

Inactive

Moderately inactive

Moderately active

Active

Total physical activity

0

0.0002

0.0004

0.0006

Cum

ulat

ive

inci

denc

e of

HC

C

0 5 10 15

None

≤2 hours/week

>2 hours/week

Vigorous physical activity

Years of follow-up

Highlights� Liver cancer rates are increasing in Western countries,

possibly due to increases in obesity, diabetes, and physicalinactivity.

� Previous evidence was not convincing to support an effect ofphysical activity on liver cancer.

� We found that physical activity reduced the risk of hepato-cellular carcinoma by about 45%.

Sebastian E. Baumeister,Sabrina Schlesinger,Krasimira Aleksandrova, ..., Elio Riboli,Elisabete Weiderpass, Michael F. Leitzmann

[email protected](S.E. Baumeister)

Lay summaryIn a pan-European study of 467,336 menand women, we found that physicalactivity is associated with a reduced riskof developing liver cancers over the nextdecade. This risk was independent ofother liver cancer risk factors, and didnot vary by age, gender, smoking status,body weight, and alcohol consumption.




Development of a prognostic score for recommendedTACE candidates with hepatocellular carcinoma:

A multicentre observational study


Largest tumour diameter (cm)

Tum

our n

umbe

r

2

3

4

5

6

7

8

9

2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 181

10

0.700.65

0.600.55

0.500.45

0.40

0.35

0.30

0.25

0.20

0.15 (3 yr survival estimates)

Nomogram for predicting survival with tumour burden n recommended TACE candidates

A

B

2 4 6 8 10 12 14 16 18 20 22 24 26 28 30

0.20.30.40.50.60.70.80.9

0.10.20.30.40.50.60.70.8

0.10.20.30.40.50.60.7

Median survival (months)102030405080

Largest tumour diameter (cm)+

tumour number

60

1-yr survival probability



Goodoutcome

Moderateoutcome

Poor outcome

Contour plot of 3-year survival probability and tumour burden

Highlights� First prognostic model specifically developed for ideal TACE

candidates.

� The individualized prediction score is presented as the sumof tumour size (cm) and number.

� With cut-offs of 6 and 12, the score can stratify thesepatients into 3 prognostic strata.

� The score outperformed other available models in perfor-mance and discrimination.

� The score is advantageous for easy-to-use and individualizedprediction.

Qiuhe Wang, Dongdong Xia, Wei Bai, ...,Jielai Xia, Daiming Fan, Guohong Han

[email protected](G. Han)

Lay summaryThere is currently no prognostic modelspecifically developed for recommendedor ideal transarterial chemoembolization(TACE) candidates with hepatocellularcarcinoma, despite these patients beingfrequently identified as the best targetpopulation in pivotal randomized con-trolled trials. The six-and-twelve scoreprovides patient survival prediction,especially in ideal candidates of TACE,outperforming other currently availablemodels in both training and validationsets, as well as different subgroups. Withcut-off values of 6 and 12, the score canstratify ideal TACE candidates into 3strata with significantly different out-comes and may shed light on risk strat-ification of these patients in clinicalpractice as well as in clinical trials.




A novel HBx genotype serves as a preoperative predictorand fails to activate the JAK1/STATs pathway in

hepatocellular carcinoma


ProliferationGood prognosis

HBx-WT

HBx-WT

HBx-WT

JAK1

STAT3

STA

T3

STAT5

STA

T5

ProliferationPoor prognosis

P P

PP

STAT3

P

STAT3

STAT5STAT5

JAK1 JAK1

HBx-E2

HBx-E2

ProliferationGood prognosis

HBx-WT

HBx-WT

HBx-WT

JAK1

STAT3

STA

T3

STAT5

STA

T5

ProliferationPoor prognosis

P P

PP

STAT3

P

STAT3

STAT5STAT5

JAK1 JAK1

HBx-E2

HBx-E2

Highlights� Three HBx genotypes were identified in tumor and non-

tumor tissues from patients with HBV-related HCC.

� HBx-E2 indicated better recurrence-free survival and overallsurvival for patients with HBV-related HCC.

� HBx-E2 preoperatively predicted the prognosis of patientswith BCLC stage B HCC after resection.

� HBx-E2 and HBx-E2-N lost the ability to promote theproliferation of HCC cells and normal hepatocytes.

� HBx-E2 and HBx-E2-N failed to interact with JAK1 andactivate the JAK1/STAT3/STAT5 signaling pathway.

Qing-guoXu, Sheng-xianYuan,Qi-fei Tao, ...,Hui Liu, Fu Yang, Wei-ping Zhou

[email protected](H. Liu) [email protected](F. Yang) [email protected](W.-p. Zhou)

Lay summaryWe classified a novel genotype of the full-length hepatitis B virus X gene (HBx),HBx-E2. This genotype was identified intumor and nontumor tissues from pa-tients with hepatitis B virus-related hep-atocellular carcinoma. HBx-E2 couldpreoperatively predict the prognosis ofpatients with intermediate stage hepato-cellular carcinoma, after resection.




The long non-coding RNA LncHDAC2 drives the self-renewal of liver cancer stem cells via activation of

Hedgehog signaling


Liver CSCs

CytoplasmNucleus

lncHDAC2 NuRD complex

Liver CSCself-renewal

PTCH1 Hh signaling

TSSPTCH1promoter

Highlights� Long non-coding RNA lncHDAC2 is highly expressed in liver

cancer stem cells.

� LncHDAC2 promotes the self-renewal of liver cancer stemcells.

� LncHDAC2 associates with HDAC2 in liver cancer stem cells.

� LncHDAC2-mediated PTCH1 downregulation promotes Hhsignaling, driving self-renewal of liver cancer stem cells.

JiayiWu,PingpingZhu,TiankunLu, ...,YajingHao,Lei He,Zusen Fan

[email protected](Z. Fan)

Lay summaryLiver cancer stem cells harbor hightumor-initiating potential and conferresistance to typical therapies, but themechanism underlying their self-renewalremains elusive. LncHDAC2 augments theself-renewal of these cells, promotingtumor propagation. In liver cancer stemcells, lncHDAC2 activates Hedgehog sig-naling to initiate liver tumorigenesis.Therefore, lncHDAC2 and the Hedgehogsignaling pathway may serve as biomark-ers and potential drug targets for hepato-cellular carcinoma.


Research ArticleMolecular and Cell Biology


Non-nucleoside reverse transcriptase inhibitorefavirenz activates PXR to induce

hypercholesterolemia and hepatic steatosis


Efavirenz

PXRRXR

CD36SQLE

SR-BI

Cholesterol

Squalene

HMG-CoA

AcetoacetylCoA AcetylCoA

SQLE

HDL-C

Fatty acids

CD36

Steatosis

Highlights� Efavirenz is widely prescribed for patients with HIV.

� Efavirenz increases the risk of dyslipidemia and hepaticsteatosis in patients.

� Efavirenz is a potent agonist of the nuclear receptor PXR.

� Efavirenz activates PXR to elicit the adverse effects on lipidhomeostasis in mice.

� PXR regulates the expression of several key lipogenic genesin the liver.

Taesik Gwag, Zhaojie Meng, Yipeng Sui, ...,Shuxia Wang, Richard N. Greenberg,Changcheng Zhou

[email protected](C. Zhou)

Lay summaryEfavirenz is widely prescribed for HIV-infected patients but has some sideeffects. It can increase lipid levels inpatients’ blood and liver. Here we showthat efavirenz can activate a unique liverprotein called PXR which mediates theadverse effects of efavirenz on lipid levelsin mouse models.


Research ArticleMolecular and Cell Biology


Th17 cell frequency is associated with low bone massin primary sclerosing cholangitis


PSC

Damagedbile ducts

Osteoclasts

PSC patientsAbcb4-/- mice

Bone loss

Bone resorption

IL-17 productionby Th17 cells

IL-17 antibodypreventsbone loss

(i.e. Dpd)-

+

Highlights� Decreased bone mass in patients with PSC is associated with

increased bone resorption.

� Th17 cell frequency correlates with bone resorption indicesin patients with PSC.

� Increased osteoclastogenesis is corrected by IL-17 inactiva-tion in Abcb4�/� mice.

Tobias Schmidt, Dorothee Schwinge, TimRolvien, ..., Christoph Schramm, ThorstenSchinke, Michael Amling

[email protected](M. Amling)

Lay summaryPrimary sclerosing cholangitis (PSC) is acholestatic liver disease characterized byprogressive bile duct destruction. Oneserious complication of PSC is reducedbone mass resulting in increased fracturerisk. Herein, we demonstrate that Th17cells mediate bone loss in PSC by inducingbone resorption, which suggests thatantibody-based IL-17 blockade might bebeneficial for the treatment of bone lossin affected patients.


Research ArticleCholestasis and Autoimmune Diseases


Central role of the b-cell in driving regression ofdiabetes after liver transplantation in cirrhotic patients


Diabetic before OLT

(DM; n = 36)

Regressorsafter OLT

(REG; n = 23)

Non-regressorsafter OLT

(NON-REG; n = 13)

Non-diabeticbefore OLT

(Non-DM; n = 44)

Progressorsafter OLT

(PROG; n = 4)

Non-progressorsafter OLT

(NON-PROG; n = 40)

Net

bal

ance

and

rela

tive

role

s of

cha

nges

in th

e 3

dete

rmin

ants

of g

luco

se re

gula

tion

Vect

or p

lots

of i

nsul

in b

ioav

aila

bilit

y in

resp

onse

to g

luco

se (d

eter

min

ed b

y β-

cell

func

tion

and

insu

lin c

lear

ance

, PC

adj)

vs in

sulin

sen

sitiv

ity (O

GIS

-2h)

normal feedback loop

normal feedback loop

0255075

100125150175200225250275300

340 350 360 370 380 390 400 410 420 430 440 450 460

OGIS-2h (µmol/min1/m2 BSA)

PCad

j [(p

mol

/L)/(

mm

ol/L

)]

0255075

100125150175200225250275300

340 350 360 370 380 390 400 410 420 430 440 450 460

PCad

j(pm

ol/L

)/(m

mo l

/L)]

OGIS-2h (µmol/min1/m2 BSA)

Highlights� The mechanisms underlying diabetes regression after liver

transplantation are unclear.

� Diabetes regressed in �2/3 of diabetic patients and devel-oped in <10% of non-diabetic individuals.

� Only baseline HbA1c and a family history of diabetesindependently predicted regression.

� b-cell function governed changes in glucose regulation afterliver transplantation.

� A sustained improvement of insulin sensitivity accompaniedrescue of b-cell function.

Valeria Grancini, Maddalena Trombetta,Maria Elena Lunati, ...,Giuseppe Pugliese,Riccardo C. Bonadonna, Emanuela Orsi

[email protected](E. Orsi)

Lay summaryDiabetes occurring in cirrhosis as a directconsequence of loss of liver functionshould regress after transplantation of anew functioning liver, though the patho-physiological mechanisms are unclear.This is the first study evaluating thecontribution of all 3 direct determinantsof insulin-dependent glucose regulationusing a sophisticated mathematical mod-el. Results show that b-cell function is thekey process governing favourable ordetrimental changes in glucose regulationin cirrhotic patients undergoing trans-plantation, pointing to the need to devel-op therapies to sustain b-cell function inthese individuals.


Research ArticleGenetic and Metabolic Diseases


Hepatic PPARa is critical in the metabolicadaptation to sepsis


PPARα Immunecells

Liver

Bacterialinfection

InflammationMetabolicadaptation

Ketone bodies Cytokines

Survival

PPARα Immunecells

Liver

Bacterialinfection

InflammationMetabolicadaptation

Ketone bodies Cytokines

Survival

Highlights� Sepsis activates hepatic PPARa.

� PPARa plays a protective role in sepsis.

� Ppara-deficiency impairs FA utilization in the liver duringsepsis.

� Hepatocyte Ppara-deficiency worsens the outcome of bacte-rial infection.

� PPARa activity is lower in livers of non-surviving critically illpatients.

Réjane Paumelle, Joel T. Haas,Nathalie Hennuyer, ..., Hervé Guillou,David Dombrowicz, Bart Staels

[email protected](B. Staels)

Lay summaryAs the main cause of death in critically illpatients, sepsis remains a major healthissue lacking efficacious therapies. Whilecurrent clinical literature suggests animportant role for inflammation, meta-bolic aspects of sepsis have mostly beenoverlooked. Here, we show that mice withan impaired metabolic response, due todeficiency of the nuclear receptor PPARain the liver, exhibit enhanced mortalityupon bacterial infection despite a similarinflammatory response, suggesting thatmetabolic interventions may be a viablestrategy for improving sepsis outcomes.




The non-transcriptional activity of IRF3 modulateshepatic immune cell populations in acute-on-chronic

ethanol administration in mice


Highlights� Interferon regulatory factor 3 (IRF3) has both transcriptional

and non-transcriptional activity.

� Gao-binge ethanol exposure increases both the phosphory-lation and ubiquitination of IRF3.

� Irf3�/� are protected from ethanol-induced liver injury butmice expressing non-transcriptional IRF3 activity are not.

� The non-transcriptional activity of IRF3 modulates the innateimmune environment of the liver.

Carlos Sanz-Garcia, Kyle L. Poulsen, DamienBellos, ..., Saurabh Chattopadhyay, GanesSen, Laura E. Nagy

[email protected] (L.E. Nagy).

Lay summaryActivation of the innate immune systemcontributes to inflammation in the pro-gression of alcohol-related liver disease,as well as to the resolution of injury. Herewe show that the protein IRF3 modulatesthe innate immune environment of theliver in a mouse model of alcoholic hep-atitis. It does this by increasing the apop-totic cell death of immune cells thatpromote the resolution of injury.




control of replication of hepatitis b and c virus improves...

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