NAFLD as a Sexual Dimorphic Disease: Role of Gender and ......Alessandra Marrazzo. Dante Romagnoli....
Transcript of NAFLD as a Sexual Dimorphic Disease: Role of Gender and ......Alessandra Marrazzo. Dante Romagnoli....
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REVIEW
NAFLD as a Sexual Dimorphic Disease: Role of Genderand Reproductive Status in the Developmentand Progression of Nonalcoholic Fatty Liver Diseaseand Inherent Cardiovascular Risk
Stefano Ballestri . Fabio Nascimbeni . Enrica Baldelli .
Alessandra Marrazzo . Dante Romagnoli . Amedeo Lonardo
Received: November 28, 2016 / Published online: May 19, 2017� The Author(s) 2017. This article is an open access publication
ABSTRACT
Nonalcoholic fatty liver disease (NAFLD) spanssteatosis through nonalcoholic steatohepatis,cirrhosis, and hepatocellular carcinoma (HCC)associated with striking systemic features andexcess cardiovascular and liver-related mortal-ity. The pathogenesis of NAFLD is complex andmultifactorial. Endocrine derangements areclosely linked with dysmetabolic traits. Forexample, in animal and human studies, femalesex is protected from dysmetabolism thanks toyoung individuals’ ability to partition fattyacids towards ketone body production ratherthan very low density lipoprotein
(VLDL)-triacylglycerol, and to sex-specificbrowning of white adipose tissue. Ovariansenescence facilitates both the development ofmassive hepatic steatosis and the fibrotic pro-gression of liver disease in an experimentaloverfed zebrafish model. Consistently, estrogendeficiency, by potentiating hepatic inflamma-tory changes, hastens the progression of diseasein a dietary model of nonalcoholic steatohep-atitis (NASH) developing in ovariectomizedmice fed a high-fat diet. In humans, NAFLDmore often affects men; and premenopausalwomen are equally protected from developingNAFLD as they are from cardiovascular disease.It would be expected that early menarche, def-initely associated with estrogen activation,would produce protection against the risk ofNAFLD. Nevertheless, it has been suggested thatearly menarche may confer an increased risk ofNAFLD in adulthood, excess adiposity being theprimary culprit of this association. Fertile agemay be associated with more severe hepatocyteinjury and inflammation, but also with adecreased risk of liver fibrosis compared to menand postmenopausal status. Later in life, ovar-ian senescence is strongly associated with severesteatosis and fibrosing NASH, which may occurin postmenopausal women. Estrogen deficiencyis deemed to be responsible for these findingsvia the development of postmenopausal meta-bolic syndrome. Estrogen supplementation mayat least theoretically protect from NAFLDdevelopment and progression, as suggested by
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Stefano Ballestri and Fabio Nascimbeni contributedequally and are joint first authors.
S. BallestriAzienda USL di Modena, Pavullo Hospital, Pavullonel Frignano, Italy
F. Nascimbeni � D. Romagnoli � A. LonardoOspedale Civile di Baggiovara, AziendaOspedaliero-Universitaria di Modena, Modena, Italy
F. Nascimbeni (&) � E. Baldelli � A. MarrazzoDepartment of Biomedical, Metabolic and NeuralSciences, University of Modena and Reggio Emilia,Modena, Italye-mail: [email protected]
Adv Ther (2017) 34:1291–1326
DOI 10.1007/s12325-017-0556-1
http://www.medengine.com/Redeem/2128F060377C0C79http://www.medengine.com/Redeem/2128F060377C0C79http://crossmark.crossref.org/dialog/?doi=10.1007/s12325-017-0556-1&domain=pdfhttp://crossmark.crossref.org/dialog/?doi=10.1007/s12325-017-0556-1&domain=pdf
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some studies exploring the effect of hormonalreplacement therapy on postmenopausalwomen, but the variable impact of different sexhormones in NAFLD (i.e., the pro-inflammatoryeffect of progesterone) should be carefullyconsidered.
Keywords: Fibrosis; Hormones; Inflammation;Man; Menarche; Menopausal status; NASH;Physiopathology; Sex; Steatosis; Women
INTRODUCTION
Nonalcoholic fatty liver disease (NAFLD)encompasses the whole spectrum of (predomi-nantly) steatogenic liver disorders spanningsteatosis through nonalcoholic steatohepatitis(NASH), cirrhosis, and hepatocellular carci-noma (HCC) [1–3], associated with strikingsystemic features [4, 5] and excess cardiovascu-lar and liver-related mortality [6–9]. Histologi-cally indistinguishable from alcoholic liverdisease, and nevertheless observed in the non-alcoholic individual [10], NAFLD is closelylinked with insulin resistance (IR) [11] and,bidirectionally, with the metabolic syndrome(MetS) of which it may be both a cause and aconsequence [12, 13]. A leading cause ofchronic liver disease worldwide and affectingone out of four individuals in the European andnorth-American general populations [14],NAFLD is highly prevalent in certain groups ofindividuals carrying either the full-blown orindividual traits of the MetS [15]. Moreover,NAFLD carries an excess of health-relatedexpenditures owing to its close connectionswith progressive liver disease and car-dio-metabolic morbi-mortality [9, 16–19].
The pathogenesis of NAFLD has variablybeen conceptualized as two-hit [20], a one-hit[11], or a multistep process [21], and the last ispresently the most widely accepted pathogenicmodel. In its original definition, a first hit leadsto steatogenesis and a second one to fibrosis[22]. However, metabolic factors, and particu-larly IR, invariably account for most of the ele-mentary NAFLD histologic lesions in humans,indirectly supporting the outdated and yet
conceptually more parsimonious ‘‘one-hit’’theory [11, 12].
Evidence both in animals and humans sup-ports the notion that female sex is protectedfrom dysmetabolic traits thanks to young indi-viduals’ ability to partition fatty acids towardsketone body production rather than very lowdensity lipoprotein (VLDL)-triacylglycerol [23],and to sex-specific browning of white adiposetissue which contributes in protecting femalemice from experimental NAFLD associated withmethionine choline deficient diet [24].
In 1980, Ludwig reported that NASH wascommon among elderly women with metaboliccomorbidity [25]. However, we now know thatNAFLD more often affects men [15, 26] and thatpremenopausal women are equally protectedfrom NAFLD development as they are fromcardiovascular disease (CVD) [27, 28]. Recentstudies in the overnourished zebrafish modelhave shown that ovarian senescence, viahypoestrogenemia, facilitates both the devel-opment of massive hepatic steatosis and thefibrotic progression of liver disease [29]. Con-sistently, estrogen deficiency, by potentiatinghepatic inflammatory changes, hastens theprogression of disease in a dietary model ofNASH developing in ovariectomized mice fed acholesterol-rich hyperlipidic diet [30]. Collec-tively, these findings suggest that hormonalchanges, rather than those multiple physiologicderangements associated with aging per se [31],are a major determinant of progressive NAFLDin human menopause.
Obesity and obesity-related diseases, such astype 2 diabetes (T2D), MetS, and atherosclerosis,are complex conditions driven by genetic andenvironmental factors, in which a sexualdimorphism has been clearly established. Here,we have reviewed current evidence suggestingthat NAFLD is a sexually dimorphic condition,too. We hypothesized that the higher incidenceof disease in men and the worse outcome inpostmenopausal women, i.e., the ‘‘sexualdimorphism’’ of NAFLD, might offer clues use-ful in expanding our understanding of thepathogenesis and providing hints for preven-tion and treatment of NAFLD. Given thepotential research and clinical implications ofsexual dimorphism in NAFLD, we carried out a
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systematic review of the literature by using thefollowing keywords: steatosis OR fatty liverAND gender OR sex OR menopause. On thesegrounds, this narrative review is aimed tohighlight how sex modulates the developmentand progression of NAFLD and to pinpoint whatthe role of menarche and menopause is. Specialemphasis is conferred to CVD risk. The rela-tionship of polycystic ovary syndrome (PCOS)to NAFLD has recently been covered elsewhere[32] and is outside the scope of this review.
Compliance with Ethics Guidelines
This article is based on previously conductedstudies and does not involve any new studies ofhuman or animal subjects performed by any ofthe authors.
EPIDEMIOLOGY OF NAFLD
Gender and reproductive status modulate therisk of developing NAFLD and NASH with/without advanced fibrosis [15].
Risk of NAFLD
IncidenceEvidence from longitudinal studies suggeststhat the incidence of NAFLD is higher in themale as compared to the female gender(Table 1) [33–43]. One study investigating theincidence of NAFLD in women as a function ofreproductive status found incidence to behigher in menopausal (7.5%)/postmenopausal(6.1%) women as compared to premenopausal(3.5%) women. However, postmenopausal sta-tus was associated with an increased risk ofincident NAFLD at univariate but not at multi-variate analysis adjusted for age, metabolicsyndrome, and weight gain [37]. The incidenceof NAFLD in women taking hormonal replace-ment therapy (HRT) (5.3%) was higher than inpremenopausal (3.5%) women but lower thanin menopausal women (7.5%). HRT was notassociated with increased risk of incidentNAFLD either at univariate or at multivariateanalysis [37]. Indeed other longitudinal studies
suggest that estrogens are a protective factor forthe development of NAFLD. An Italian multi-centric study on 5408 healthy women who hadhad hysterectomies, randomly assigned toreceive tamoxifen (an estrogen inhibitor) orplacebo for 5 years, showed that tamoxifen wasassociated with higher risk of development ofNAFLD/NASH especially in overweight/obesewomen [44]. Finally a small double-blind, ran-domized placebo-controlled trial on 50 womenwith T2D showed that HRT containing low-doseestradiol and norethisterone significantlyreduced serum levels of liver function enzymes,potentially owing to a reduced liver fat accu-mulation [45].
Overall, data from epidemiological longitu-dinal studies have shown a key role of weightgain, presence of MetS and its single traits asindependent predictors of the development ofNAFLD [33–43]. Notably, some studies havefound that male sex was associated with inci-dent NAFLD independently of age and meta-bolic factors [33, 35, 41]. Moreover, two Asianstudies have reported a specific role of ageaccording to gender and reproductive status inmodulating the risk of incident NAFLD. Onestudy showed that age was an independentpredictor for developing NAFLD only in females[34] and the other one reported that ageincreased the risk for incident NAFLD in pre-menopausal but not in postmenopausal women[37].
PrevalenceDespite preliminary studies reporting a higherrisk of NAFLD in females, a large body of evi-dence now definitely supports the notion thatthe prevalence of NAFLD is higher in men thanin women and that gender-specific differencesexist in relation to age (Table 1)[33, 37, 41, 46–77]. Conflicting with the abovenotion, two large sample community Iranianstudies reported a higher prevalence of NAFLDin women than in men [70, 74]. However, thesefindings might, at least in part, be accounted forby women having markedly higher rates ofprevalence of obesity compared to men in thesestudies. Consistent with the view reportedabove, a higher prevalence of fatty liver has
Adv Ther (2017) 34:1291–1326 1293
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Table1
Genderim
pactson
incident
andprevalentNAFL
D.E
videncefrom
longitudinalandcross-sectionalstudies
Stud
yMetho
dFind
ings
Con
clusion
Stud
ypo
pulation
Diagnosis
ofFL
Incidence(lon
gitudinal
stud
ies)
Independ
ent
predictors
Kojim
a
etal.[33]
35,519
Japanese
subjects(health
check-up),65.2%M,m
eanage
45.8years,F-up
12years
US
14.3%
Msex(O
R1.7),
metabolicfactors
(BMIOR6.3)
Msexandmetabolicfactorsare
independ
entrisk
factorsforthe
incidenceof
NAFL
D
Ham
aguchi
etal.[34]
3147
healthyJapanese
(1694M),aged
21–8
0years,
meanF-up
414days
US
10%;in
M(14%
)[F(5%)
Age
(onlyin
F),w
eight
gain,and
MetS
NAFL
Dismoreincident
inmen
than
inwom
en
Suzuki
etal.
[35]
1537
Japanese
subjects
(1352M),meanage35
years,
meanF-up
60months
AST
,ALT
31/1000person-years
Msexoverallandin
subjects\40
years
(HR4.6);metabolic
factors
Msexandmetabolicfactorsare
independ
entrisk
factorsforthe
incidenceof
NAFL
D
Tsuneto
etal.[36]
1635
Nagasakiatom
icbomb
survivors(606
M),meanage
63years,F-up
11.6years
US
19.9/1000person-years(22.3in
M[
18.6in
F);M
(38%
)[F
(25%
)before
50years
Obesity,h
ypertension,
andhigh-TG
(gender
NS)
Genderisnotan
independ
entrisk
factor
forincident
NAFL
D
Ham
aguchi
etal.[37]
1603
Japanese
wom
en,aged
21–8
0years,meanF-up
414days
US
5%in
F;in
postmenopausal
(6.1–7
.5%)andun
derHRT
(5.3%)[
prem
enopausal
(3.5%)
Age
(onlyin
prem
enopausal),
weightgain,and
MetS
Thereisagradient
intheincidenceof
NAFL
Din
wom
en:
postmenopausal[
HRT[
prem
enopausal
Zhouet
al.
[38]
507Chinese
NAFL
D-free
participants,m
edianF-up
4years
US
9.1%
;in
M7.3%
[F9.7%
Age,m
etabolicfactors
(genderNS)
Genderisnotan
independ
entrisk
factor
forincident
NAFL
D
Zelber-Sagi
etal.[39]
147Israelisubjects,m
eanage
51.2years,F-up
7years
US
19.0%
(2.7%/year)
Weightgain
and
HOMA
(genderNS)
Genderisnotan
independ
entrisk
factor
forincident
NAFL
D
Sung
etal.
[40]
2589
Koreansubjects,m
ean
F-up
4.37
years
US
34.7/1000person-years;in
M
(23.4%
)[F(9.7%)
MetStraits(genderNS)
Genderwas
notan
independ
entrisk
factor
forincident
NAFL
D
Xuet
al.
[41]
5562
non-obeseChinese
subjects,m
eanage43
years,
F-up
5years
US
8.9%
Msex,youn
gerage,and
metabolicfactors
Msexisarisk
factor
fortheincidence
ofNAFL
Dat
multivariateanalysis
1294 Adv Ther (2017) 34:1291–1326
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Table1
continued
Stud
yMetho
dFind
ings
Con
clusion
Stud
ypo
pulation
Diagnosis
ofFL
Incidence(lon
gitudinal
stud
ies)
Independ
ent
predictors
Wonget
al.
[42]
565HongKongsubjects,m
ean
age48
years,medianF-up
47months
1 HNMR
3.4%
/year
MetS(M
sexpredictor
onlyat
univariate
analysis)
Msexisarisk
factor
fortheincidence
ofNAFL
Dat
univariate
analysis
Yun
etal.
[43]
37,130
Koreansubjects,m
ean
age(M
39.4,F
38.6years),
46%
M,F
-up2years
US
M(44.5/1000
person-years)[
F
(20.4/1000
person-years)
WC
gain
inboth
sexes
Visceralobesitystronglypredicts
NAFL
Din
either
gend
er
Stud
ypo
pulation
Diagnosisof
FLPrevalence
(cross-section
alstud
ies)
Independ
ent
predictors
Kojim
aet
al.[33]
39,151
Japanese
subjects(health
check-up),meanage45.8years,
61%
M
US
M(26%
)[F(12.7%
)NA
NAFL
Dismore
prevalentin
M
gend
er
Shen
etal.[46]
4009
Chinese
administrative
officersnon-drinkers,aged
20–8
1years,64%
M
US
M(13.3%
)[F
(2.7%)before
50years;similar
after50
years
Msex,age[
50years,
andmetabolictraits
Msexandmetabolic
factorsare
independ
entrisk
factorsforthe
prevalence
of
NAFL
D
Fanet
al.[47]
3175
Chinese
subjectsfrom
Shanghai,m
eanage52years,
38.4%
M
US
M(19.2%
)[F
(11.3%
)before
50years;F[
M
after50
years
Msex(O
R2.7)
and
metabolicfactors
Msexandmetabolic
factorsare
independ
entrisk
factorsforthe
prevalence
of
NAFL
D
Adv Ther (2017) 34:1291–1326 1295
-
Table1
continued
Stud
ypo
pulation
Diagnosisof
FLPrevalence
(cross-section
alstud
ies)
Independ
ent
predictors
Chenet
al.[48]
3245
adultsin
aTaiwan
rural
village,agedC18
years,45.3%
M
US
M(19.7%
)[F
(10.7%
)
Msexandmetabolic
factors;
ageC65
years
negative
predictor
Msexandmetabolic
factorsare
independ
entrisk
factorsforthe
prevalence
of
NAFL
D
Park
etal.[49]
6648
Koreansubjects,
aged
C20
years,53%
M
US
M(22.6%
)[F
(6.8%)before
50years;similar
after50
years
Menopausestatus
and
increasing
agein
F
Menopauseisastrong
risk
factor
for
prevalentNAFL
D
Zelber-Sagi
etal.[50]
352Israelisubjects,m
eanage
51years,53.4%
M
US
M(38%
)[F(21%
)M
sex(after
adjustmentfor
obesity)
Msexandmetabolic
factorsare
independ
entrisk
factorsforprevalent
NAFL
D
Zhouet
al.[51]
3543
inhabitantsof
6urbanand
ruralareasin
China,
aged[7years,37%
M
US
M(13.8%
)[F
(7.1%)before
50years;the
opposite
after
50years
Msexandmetabolic
factors
Msexandmetabolic
factorsare
independ
entrisk
factorsforprevalent
NAFL
D
Liet
al.[52]
9094
Chinese
subjects(m
edical
check-up),aged[18
years,52%
M
US
M(18.9%
)[F
(5.7%);increased
withagein
both
sexes\
50years
Msex,increasing
age,
BMI,andother
MetSfeatures
Msexandmetabolic
factorsare
independ
entrisk
factorsforprevalent
NAFL
D
1296 Adv Ther (2017) 34:1291–1326
-
Table1
continued
Stud
ypo
pulation
Diagnosisof
FLPrevalence
(cross-section
alstud
ies)
Independ
ent
predictors
Caballeriaet
al.[53]
766Spanishindividuals,aged
17–8
3years,33.4%
M
US
M(42.2%
)[F
(20.3%
)
Msex,increasing
age,
andmetabolic
factors
Msexandmetabolic
factorsare
independ
entrisk
factorsforprevalent
NAFL
D
Huet
al.[54]
7152
employeesof
Shanghai
work-un
its,aged
18–6
5years,
60.5%
M
US
M[
Fin
thesame
agegroup,
peaking
at50–6
5years;in
F[
50years
doubled
HighTG
levelwas
thestrongest
predictorin
M
whileobesitythe
strongestonein
F
Riskfactorsfor
prevalentNAFL
D
aregend
er-specific
Wonget
al.[55]
922individualsfrom
HongKong
population,aged19–7
2years,
58%
F
1 HMRS
M(36.8%
)[F
(22.7%
);in
M
peakingat
40years;
inFincreasing
after
menopause
Metabolicfactors(M
sexandolderage
NS)
Genderisnotan
independ
entrisk
factor
forprevalent
NAFL
D
Ham
aguchi
etal.[37]
4401
Japanese
subjects(health
check-up),aged
21-80years,
51.6%
men
US
M(24%
)and
postmenopausalF
(15%
)[remenopausalF
(6%);increased
withagein
Fonly
Postmenopause
and
HRT
NS(age
and
MetSadjusted);
agingin
prem
enopausalF
only(weightgain
andMetSadjusted)
MenopauseandHRT
arenot
independ
entrisk
factorsforprevalent
NAFL
D
Eguchiet
al.[56]
8352
Japanese
subjects(health
check-ups),aged21–8
6years,
51.8%
M
US
M[
Fat
allages
Metabolicfactors
(age[50
yearsin
F
only)
Genderisnotan
independ
entrisk
factor
forprevalent
NAFL
D
Adv Ther (2017) 34:1291–1326 1297
-
Table1
continued
Stud
ypo
pulation
Diagnosisof
FLPrevalence
(cross-section
alstud
ies)
Independ
ent
predictors
Younossiet
al.[57]
11,613
American
participants
(from
NHANESIII)
US
19%
Fsexandyoun
gerage
forlean
NAFL
D;
theopposite
for
NAFL
Dwith
BMIC25
Fsexisarisk
factor
forlean
NAFL
D
Lazoet
al.[58]
12,454
American
subjects(from
NHANESIII),aged
20–7
4years
US
M(20.2%
)[F
(15.8%
)
Prevalence
inM
(20.2%
)[F
(15.8%
)(adjusted
forage,race,B
MI,
T2D
)
Mgend
eris
associated
withan
increasedNAFL
D
prevalence
Wanget
al.[59]
4226
Chinese
subjects[60
years
vs3145
controls\60
yearsfrom
thesamecohort
US
M(32%
)[F(9%)
before
60years;
similarafter
60years
Msex(onlyin
those\
60years)
andmetabolic
factors
Msexandmetabolic
factorsare
independ
entrisk
factorsforprevalent
NAFL
D
Xuet
al.[41]
6905
non-obese(BMI\
25)
Chinese
subjects,6
3%M
US
7.3%
Msex,youn
gerage,
andmetabolic
factors
Msexandmetabolic
factorsare
independ
entrisk
factorsforprevalent
NAFL
D
Yan
etal.[60]
3762
Chinese
residents,aged
20–9
2years,61.9%
M
US
M(45%
)[F(30%
);
higher
before
50yearsbutsimilar
after
Metabolicfactors(M
sexpredictedonly
atun
ivariate
analysis)
Msexisarisk
factor
forprevalent
NAFL
Dat
univariate
analysis
only
1298 Adv Ther (2017) 34:1291–1326
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Table1
continued
Stud
ypo
pulation
Diagnosisof
FLPrevalence
(cross-section
alstud
ies)
Independ
ent
predictors
Chiloiroet
al.[61]
2974
SouthItaliansubjects,aged
30–8
9years,56.5%
M
US
M(37%
)[F(26%
)MetSanditsfeatures,
BMI,visceral,and
subcutaneous
fatin
both
MandF
Riskfactorsfor
prevalentNAFL
D
arenot
gend
er-specific
Foster
etal.[62]
3056
American
multiethn
ic
subjects,m
eanage63
years,55%
F
CT
NA
Fsexprotective
inall
andAAs;notin
Caucasiansand
Hispanics.Y
ounger
agein
all,
Caucasiansand
Hispanics;notin
AAs
Fsexisspared
from
prevalentNAFL
D
Yanget
al.[63]
2256
Chinese
subjects(health
check-up),meanage62.04years,
87.9%
M
US
M(28.4%
)[F
(20.3%
)
Younger
age,RDW
andmetabolic
factors(genderNS)
Genderisnotan
independ
entrisk
factor
forprevalent
NAFL
D
Saidaet
al.[64]
3110
Japanese
subjects(health
check-up),aged
C30
years,
59.5%
M
US
M(45%
)[F(23%
)Weightgain
C10
kg
sincetheageof
20yearsregardless
ofsex
Genderisnotan
independ
entrisk
factor
forprevalent
NAFL
D
Wanget
al.[65]
25,032
Chinese
subjects(health
check-up),aged
18–9
4years,
62%
M
US
M(32%
)[F(13%
);
similarin
both
sexes[
60years
Metabolicparameters
inboth
sexes;
increasing
age
(C60
years)onlyin
F
Riskfactorsfor
prevalentNAFL
D
arenot
gend
er-specific
Adv Ther (2017) 34:1291–1326 1299
-
Table1
continued
Stud
ypo
pulation
Diagnosisof
FLPrevalence
(cross-section
alstud
ies)
Independ
ent
predictors
Schn
eideret
al.[66]
4037
non-Hispanicwhite,2
746
non-Hispanicblack,
and2892
Mexican–A
merican
adultsin
theNHANESIII
US
M(15%
)[F(10%
)
among
non-Hispanic
whitesonly
(age-adjusted)
Genderdifference
still
significant
after
adjustmentfor
BMIandWC
Mgend
eris
associated
withan
increasedNAFL
D
prevalence
independ
entof
visceralobesity
Xiaoet
al.[67]
18,676
Chinesesubjects,m
eanage
40.6years,55.4%
M
US
M(33%
)[F(8%)
Msexandmetabolic
factors
Msexisan
independ
entrisk
factor
forprevalent
NAFL
D
Martı́nez-Alvaradoet
al.[68]
846Mexican
subjects,m
eanage
53years,49.3%
M
CT
M(36.5%
)[F
(28.4%
)
Metabolicfactors
(MetSin
Fonly)
Genderisnotan
independ
entrisk
factor
forprevalent
NAFL
D
Liu
etal.[69]
11,200
Chinese
gallstone-free
subjects,4
6.7%
M
US
M(31%
)[F(13%
)NA
NAFL
Dismore
prevalentin
M
gend
er
Amirkalaliet
al.[70]
5023
Iranianparticipants,m
ean
age45.35years,56.7%
M
US
F(46%
)[M
(42%
);
peakingin
M
40–6
0years,in
F[60
years
Age,M
etS,
andits
factors(higherORs
inF)
Genderisnotan
independ
entrisk
factor
forprevalent
NAFL
D
Nishiojiet
al.[71]
3271
Japanese
subjects(health
check-up),44.2%
M
US
M[
Fforallages,
except
in
obeseC70
years
Metabolicfactorsin
MandF
Riskfactorsfor
prevalentNAFL
D
arenot
gend
er-specific
Huang
etal.[72]
8626
Chinese
subjectsC40
years
US
M(28.7%
)*
F
(28.1%
)
NA
Nogend
erspecific
difference
in
prevalentNAFL
D
1300 Adv Ther (2017) 34:1291–1326
-
been also observed in male obese children andadolescents than in female ones [78].
Men commonly display an increasingprevalence of NAFLD during adulthood fromyoung to middle-age, describing an ‘‘invertedU-shaped curve’’ which starts declining after theage of 50–60 years [47, 56]. In women of fertileage, the prevalence of NAFLD is lower than inmen owing to the putative protective effect ofestrogens which, however, wanes after themenopause. Accordingly, the prevalence ofNAFLD in women rises after the age of 50 years,peaks at 60–69 years, and declines after 70 years[47, 54, 56]. As a result of this, after the fifthdecade, postmenopausal women compared tomen of the same age have a similar[46, 49, 60, 65] or even higher [47, 51] preva-lence of NAFLD. In agreement with these find-ings, a multicenter study from northern Italyfound that men with NAFLD were approxi-mately 10 years younger than women with thiscondition [79], a finding compatible with thehypothesis that premenopausal women are‘‘protected’’ from developing NAFLD. Con-versely, NAFLD is more prevalent in post-menopausal [37, 80–82] and PCOS-affectedwomen than premenopausal ones [80]. Consis-tently, a large cross-sectional population-basedsurvey in northeast Germany on 808 womenaged 40–59 years showed that menopause statuswas independently associated with hepaticsteatosis after adjustment for metabolic factors[83]. Interestingly, women with NAFLD exhibita significantly lower concentration of serumestradiol, which is the principal active estrogen,than NAFLD-free (premenopausal, post-menopausal, and PCOS) controls [80]. A lowerprevalence of NAFLD, as well as of MetS, hasbeen reported in postmenopausal womenreceiving HRT compared to those not receivingit, which suggests that HRT probably protectsfrom NAFLD. Moreover, in this study post-menopausal women with NAFLD who receivedHRT had lower frequency of insulin resistanceas well as MetS and showed reduced serumlevels of liver enzymes and ferritin [84].
Most studies using multivariate analysis haveshown that male sex is associated with anincreased prevalence of NAFLD independentlyof age and metabolic conditionsT
able1
continued
Stud
ypo
pulation
Diagnosisof
FLPrevalence
(cross-section
alstud
ies)
Independ
ent
predictors
Fattahiet
al.[73]
2980
Iraniansubjects,
aged
C18
years,31.3%
M
US
M(32.9%
)[F
(27.4%
)
NA
NAFL
Dismore
prevalentin
M
gend
er
Motam
edet
al.[74]
5052
Iraniansubjects,
aged
C18
years,56.6%
M
US
F(44.2%
)[M
(40.1%
)
Age,m
etabolic
factors;Fsex
protective
Fsexisspared
from
prevalentNAFL
D
AAsAfrican-Americans,BMIbody
massindex,Ffemale/s,FL
fattyliver,F
-upfollow-up,
1 HMRSproton
magneticresonancespectroscopy,H
OMAhomeostasis
modelassessment,HRThorm
onereplacem
enttherapy,M
male/s,MetSmetabolicsynd
rome,NAnotassessed,N
AFL
Dnonalcoholicfattyliverdisease,NHANES
IIINationalHealth
andNutrition
ExaminationSurvey
III,NSnotsignificant,O
Rodds
ratio,RDW
redbloodcelldistribution
width,T
2Dtype
2diabetes,T
Gtriglycerides,USultrasound
,WCwaistcircum
ference
Adv Ther (2017) 34:1291–1326 1301
-
[41, 46, 48, 50, 51, 53, 58, 62, 63, 66, 67, 74].Some studies have shown an independent,positive association between NAFLD andincreasing age in both sexes [46, 50–53, 70, 74]or in females only [65], while others reported aninverse association [41, 48, 62, 63]. At variance,other studies have shown that sex differences inthe prevalence of NAFLD were mostly accoun-ted for by metabolic factors [36, 37, 55, 56, 60,63, 64]. Finally, some studies failed to investi-gate the role of gender given that a separatemultivariate analysis according to sex was notperformed [34, 49, 54, 56, 61, 65, 68, 70, 71].
In addition to and independent of the role ofMetS and its components, menopausal status[49, 83, 85] and increasing age [49, 56, 82] haveall been consistently identified as strong riskfactors for NAFLD in women. Only in a fewstudies was the association between menopau-sal status and NAFLD no longer significant afteradjustment for age and metabolic factors[37, 81], indicating that menopause predisposesto developing NAFLD via incident dysmetabolictraits which typically appear in the post-menopausal age.
A recent cross-sectional study conducted in apopulation of postmenopausal women con-cluded that MetS, abdominal obesity, and IR arerisk factors for the development of NAFLD whilehigher adiponectin levels protect from devel-oping it [86]. These findings indicate thatNAFLD modifiers in this specific population ofwomen closely mirror those found in the gen-eral population.
In lean subjects [body mass index (BMI) lessthan 25 kg/m2)] NAFLD has been associatedwith younger age [41, 57] and either male [41]or female gender [57].
Risk of NASH and Fibrosis Progression
One large sample study based on an electronichealth file database reported that the risk of‘‘recorded’’ NAFLD/NASH diagnosis increasedlinearly with BMI, was higher in males thanfemales and in those with T2D [87]. However, theproportion of true NASH cases among the ‘‘recor-ded’’ diagnosis of NAFLD/NASH was unclear.
A longitudinal study in subjects with biop-sy-proven NAFLD found that sex was not anindependent risk factor for the progression offibrosis [88]. In agreement, a systematic reviewhas shown that age and hepatic necroinflam-mation are the only independent predictors ofthe development of advanced fibrosis in NASHpatients, while other parameters such as MetSfeatures and sex are not [89].
However, conflicting with the above studies,data from cross-sectional studies (Table 2)[29, 57, 65, 90–97], which are based, in themajority of cases, on a histological diagnosis ofNASH, tend to suggest that the risk of NASH andadvanced fibrosis is indeed higher in femalesthan males independent of metabolic factors[65, 90, 93, 94], and only a few studies conflictwith the above findings [91, 92, 95].
As is easily foreseeable, obese and post-menopausal women, compared to pre-menopausal and non-obese women, suffer froma remarkably higher prevalence of NAFLD andNASH as a result of a worse metabolic profile[82]. At variance, a recent study reported that,compared to men and postmenopausal women,the risk of lobular inflammation and hepatocyteinjury was significantly increased both in pre-menopausal women and in those taking syn-thetic hormones such as oral contraceptives andHRT [97]. Given the supposed effects of estro-gens on metabolic health and liver injury, thefindings of this study appear counterintuitive. Itis noteworthy that the study by Yang et al. hasseveral limitations, including some importantsources of potential bias, such as the restrictedenrollment at tertiary academic centers, meno-pausal category and synthetic hormone usewere self-reported, and information on cumu-lative estrogen and/or progesterone exposureand serum hormonal levels were lacking. Ofnote, the authors highlight that, despiteincreased liver injury and inflammation, pre-menopausal women were at decreased risk ofliver fibrosis compared with men and post-menopausal women. Moreover, sensitivityanalyses separately assessing the impact of pro-gesterone use and estrogen use clearly suggestedthat only the former was associated with liverdamage. Collectively these findings provide
1302 Adv Ther (2017) 34:1291–1326
-
Table2
Impact
ofgend
eron
NASH
/fibrosisprevalence
Stud
yMetho
dCross-section
alstud
ies
Find
ings
Con
clusion
Stud
ypo
pulation
Diagnosis
ofNASH
Prevalence
Independ
entpredictors
Singhet
al.
[90]
71consecutive
Asian-Ind
ianNASH
patients,aged9–
57years,
76.1%
M
Biopsy
NA
Fsexforfibrosisstage
Fsexisan
independ
ent
risk
factor
forfibrosis
Hossain
etal.[91]
432American
NAFL
D
patients,m
eanage
43.6years,22.9%
M
Biopsy
26.8%
NASH
and
17.4%
moderate-to
severe
fibrosis
MsexforNASH
andmoderate-to-severefibrosis
inaddition
toethn
icity,ALT,A
ST,m
etabolic
factors
Mgend
erisastrong
independ
entrisk
factor
forboth
NASH
and
fibrosis
Al-h
amoudi
etal.[92]
1312
SaudiArabian
inpatients,m
eanage
44.7years,51.0%
M
US
16.6%
NASH
(by
ALT[60
U/L)
Msex,youn
gageandlowtotalCH
predicted
high
ALT
inNAFL
D
Mgend
erisastrong
independ
entrisk
factor
for
hypertransam
inasem
ic
NAFL
D
Bam
bha
etal.[93]
1026
adults(N
ASH
CRN
Database),m
eanage
48.8years,37%
M
Biopsy
61%
NASH
and29%
advanced
fibrosis
FsexforNASH
andadvanced
fibrosis;increasing
ageforadvanced
fibrosis;plus
metabolicfactors
Fsexisan
independ
ent
risk
factor
forNASH
andfibrosis
Younossi
etal.[57]
11,613
American
participants(from
NHANESIII)
US
12%
NASH
(bygrade
2–3US-FL
?high
ALT,A
ST,and
/or
T2D
/IR)
Younger
ageandmetabolicfactors(genderNS)
Genderisnotan
independ
entrisk
factor
forNASH
Tapperet
al.
[94]
358NAFL
Dpatients,
62.9%
M
Biopsy
NASH
andadvanced
fibrosis[
inFvs
M
(45%
vs30%;23%
vs
14%)
Fsex,BMI,andALTforNASH
;age,AST
,and
APR
Iforadvanced
fibrosis
Fsexisan
independ
ent
risk
factor
forNASH
andfibrosis
Adv Ther (2017) 34:1291–1326 1303
-
Table2
continued
Stud
yMetho
dCross-section
alstud
ies
Find
ings
Con
clusion
Stud
ypo
pulation
Diagnosis
ofNASH
Prevalence
Independ
entpredictors
Wanget
al.
[65]
25,032
Chinese
subjects
(health
check-up),aged
18–9
4years,62%
M
US
NASH
withadvanced
fibrosis(byBAAT
score,AST
/ALT)[
Fvs
M
NA
Prevalence
ofNASH
with
advanced
fibrosisis
higher
inFsex
Yanget
al.
[95]
541American
patientswith
NASH
,meanage48
years,35.1%
M
Biopsy
100%
NASH
;22%
advanced
fibrosis
Msex,postmenopausalFstatus
(premenopausal
Freference;borderlin
eP),p
re-T2D
/T2D
for
fibrosis
Msexandpostmenopausal
status
areindepend
ent
risk
factorsforfibrosing
NASH
Turolaet
al.
[29]
244females
and244
age-matched
males
with
NAFL
D
Biopsy
F2–F
4fibrosis
Menopause,m
etabolicfactors,andNASH
for
F2–F
4fibrosisin
FwithNAFL
D
Menopause
isstrongly
associated
withfibrosing
NASH
Klairet
al.
[96]
488postmenopausal
NAFL
Dsubjects
Biopsy
Advancedfibrosis
38.4%
inprem
ature
menopause
Fvs
32.7%
inotherF
Prem
aturemenopause
andtimefrom
menopause
foradvanced
fibrosis(adjustedforage,race,
metabolicfactors)
The
longer
theduration
of
postmenopausalstatus
thehigher
therisk
of
NASH
Yanget
al.
[97]
1112
American
NAFL
D
patients(160
prem
enopausaland489
postmenopausalF;
463M)
Biopsy
NASH
[in
pre/postmenopausal
F(62%
)vs
M(50%
)
Lobular
inflammationrisk
increasedin
(1)
prem
enopausalF[
MandpostmenopausalF,
(2)oralcontraceptives
andHRT
users
(adjustedforcovariatesof
livermetabolicstress)
Fertile
ageandestrogen
use
may
predispose
tomore
necroinfl
ammatory
NASH
variants
ALTalanineam
inotransferase,A
STaspartateam
inotransferase,A
PRIAST
-to-plateletratioindex,BMIbody
massindex,Ffemale/s,FL
fattyliver,F-upfollow-up,
HRT
horm
onereplacem
enttherapy,
Mmale/s,MetSmetabolic
synd
rome,
NA
notassessed,NAFL
Dnonalcoholic
fattyliver
disease,
NASH
nonalcoholic
steatohepatitis,NHANESIIINationalHealth
andNutrition
ExaminationSurvey
III,NSnotsignificant,T2D
type
2diabetes,USultrasound
,WC
waist
circum
ference,yearsyears
1304 Adv Ther (2017) 34:1291–1326
-
novel hints regarding a potential multifacetedimpact of sex hormones in NAFLD.
Consistent with the hypothesis that estro-gens do exert a beneficial effect on NAFLD,menopause has been independently associatedwith significant fibrosis both in women withNAFLD and in an experimental zebrafishsteatosis model [29]. A recent study has shownthat men display a higher risk of advancedfibrosis compared to premenopausal women,while after menopause both sexes show a simi-lar severity of liver fibrosis, suggesting thatestrogens protect from the development offibrosis [95]. A subsequent study limited tonon-obese women with biopsy-proven NAFLDconfirmed that, even in non-obese NAFLDpatients, postmenopausal women still had moresevere fibrosis, when compared to pre-menopausal subjects [98]. Accordingly, a studyconducted in 488 postmenopausal women withbiopsy-proven NAFLD has shown that, inde-pendently of age and metabolic factors, thelonger the estrogen deficiency in post-menopausal status is (i.e., premature meno-pause and time from menopause), the higherthe risk of fibrosis is [96].
The role of gender in influencing liver-re-lated mortality in NAFLD is still uncertain,although some studies have reported that menare at an increased risk [99–101].
Risk of Hepatocellular Carcinoma
A universal feature of HCC is the striking maleprevalence, with a male/female ratio averaging2:1 to 7:1; the latter proportion is more oftenfound in HBV-related HCC [102]. Nevertheless,compared to viral etiologies of HCC,NAFLD-related HCC was found to be associatedwith the lowest male/female ratios in one study[103]. NAFLD-related HCC may also occur innon-cirrhotic livers, but this seems to be morelikely in men [104]. The sexual dimorphism inHCC is also maintained regarding prognosis,with women showing better survival rates[102, 105]. However, menopause seems toattenuate these advantages [102, 105].
In summary, the incidence of NAFLD ishigher in men than in women, and some
longitudinal studies indicate that male gender isan independent predictor of NAFLD develop-ment. The prevalence of NAFLD is globallyhigher in men than women, but after meno-pause women display a similar or even a higherprevalence compared to men, a finding sup-porting a protective effect of estrogens. Incross-sectional studies, male gender and meno-pausal status have often been associated withthe risk of NAFLD, independent of age andmetabolic factors. The prevalence of NASH andadvanced fibrosis has been found to be higherin postmenopausal women than in men; how-ever, longitudinal studies have failed to supporta role for gender in influencing the progressionof liver fibrosis. Finally, HCC is definitely morecommon in men than in women in cases due toviral etiology; NAFLD may probably lower themale/female ratio in the risk of developing HCCand it is possible that gender affects the prog-nosis of HCC.
NAFLD AND CVD
NAFLD is increasingly recognized as a multi-system disease [5]. A growing body of evidencesuggests that NAFLD (assessed by liver enzymes,imaging, or biopsy) is associated with increasedincidence and prevalence of subclinical andclinical CVD, mainly coronary heart disease(CHD), independently of age, gender, andmetabolic factors, as recently reviewed in detailelsewhere [106, 107]. In the general population,male sex is more prone to incident CHD underthe age of 50 years compared to women but,after menopause, the incidence in women dra-matically increases to approach that of men[108].
Gender-Specific Risk of CVD in Studieson NAFLD and CVD
Several longitudinal studies investigating theassociation between CVD and NAFLD havereported multivariate analysis models, whichhave been adjusted for multiple confounders,including sex; as a result of this, the influence ofgender in the risk of CVD cannot be evaluatedin such studies (reviewed in [106, 107]). A large
Adv Ther (2017) 34:1291–1326 1305
-
population-based American study (NHANES III)found that NAFLD assessed with ultrasound,together with male sex, age, race, and metabolicfactors independently predicted incident CVD[109]. Another study addressing CHD as a pre-specified outcome found that patients withNAFLD had a higher 10-year risk for CHD, ascalculated by the Framingham risk score, thanthe matched control population. This estimatedrisk was higher in men than in women andmore CVD events were reported among menthan women at the end of 10 year follow-up,although this finding was not statistically sig-nificant [110].
Many cross-sectional studies in which thediagnosis of NAFLD was based on liver imagingstudies (either ultrasound or CT scanning)showed an independent association of male sexwith coronary artery calcifications [111] as wellas significant CHD [112–115].
Gender Differences in the AssociationBetween NAFLD and CVD
Studies in which the diagnosis of NAFLD wasbased on surrogate indices, such as otherwiseunexplained raised liver enzymes, found thatsex modulates the association of NAFLD withincident CVD/mortality. For example, mostpopulation-based cohort and meta-analyticstudies reported an independent associationbetween raised GGT and incident CVD in bothsexes [116]; conversely, a population-basedcohort study from Germany found thatincreased GGT was associated with higher riskof all-cause and CVD mortality only in men butnot in women, and this association was strongerin men who also had ultrasound scanningfindings compatible with steatosis [101].Increased ALT has been variably associated withincident CVD either in both sexes [117, 118] orin men only [119]. A recent study found thatALT levels independently predicted insulinsensitivity only in women, suggesting that thisgender-specific association might explainthe sex difference in the predictive role ofincreased ALT for CVD [120]. Finally, a recentlarge Korean cross-sectional study reported thatmen had more prevalent ultrasonographic fatty
liver disease, carotid plaques, and increasedcarotid intima-media thickness (IMT) valuesthan women, but ultrasonographic fatty liverdisease independently predicted subclinicalcarotid atherosclerosis (IMT and plaques) inwomen only [121].
No gender difference has been reported inthe association between NAFLD assessed withliver ultrasound and incident CVD/mortality. Astudy based on a national Danish registryshowed that patients with a hospital dischargediagnosis of NAFLD had a higher all-causemortality, including liver and CVD related,which was similar among sexes [122]. A studyconducted in a community-based Japanesecohort of 1637 apparently healthy subjectsfound that the diagnosis of NAFLD based onultrasound findings was a predictor of CVD inboth men and women [123].
The only study carried out in post-menopausal women found a significant corre-lation between NAFLD (based on CT scanningfindings) and prevalence of coronary arterycalcification (CAC); however, NAFLD was notindependently associated with CAC in thesepostmenopausal women [124].
In summary, male patients carry anincreased risk of CVD; moreover, NAFLD seemsto be associated with CVD independently ofmetabolic factors in both sexes. Few data areavailable in postmenopausal women and stud-ies should specifically be conducted to ascertainwhether NAFLD is a specific/independent car-diovascular risk factor in this population ofpatients.
ROLE OF GENDER, REPRODUCTIVESTATUS, AND AGEIN THE HETEROGENEITY OF NAFLDPATHOBIOLOGY
Although NAFLD may be found in either genderfrom infancy to old adulthood, gender andreproductive status modulate the susceptibilityto development and progression of disease[125]. Indeed age, sex, and fertility exert avariable impact on those general pathogenicmechanisms which are involved in NAFLD.
1306 Adv Ther (2017) 34:1291–1326
-
Here we will specifically examine how body fatdistribution, obesity and local hypercorticolism,steatogenesis and lipidomics, oxidative stressand antioxidant mechanisms, endotoxins,immune response, and fibrogenesis are affectedby gender and sex hormones as a result ofreproductive status and age.
Factors Associated with NAFLD areDifferent in Men and in Women
A pioneering study supporting the notion thatgender-dimorphic risk factors are associatedwith NAFLD was published in 2000. This study,by evaluating 199 individuals, found that ele-vated BMI was an independent predictor of fattyliver in either sex. Glucose area under the curveand a central-type body fat distribution pre-dicted fatty liver only in women [126]. Simi-larly, insulin sensitivity has also been reportedto be strongly associated with gender-dimor-phic risk factors, i.e., fasting insulin and leptinlevels (but none of the liver enzymes) in menversus BMI and ALT in women [120]. Of note,Suzuki et al. demonstrated that the associationsbetween anthropometric measures (regionaladiposity) and degree of fibrosis clearly differbetween premenopausal women and post-menopausal women/men [127].
NAFLD Epidemiologyand Physiopathology are Modulatedby Age at Menarche and PostmenopausalStatus
In women, a complex interaction includinggenetic polymophisms, dietary habits, endoge-nous sex hormones, age at menarche, meno-pausal status, dysmetabolic traits, and HRTmodulates the risk of developing NAFLD, NASH,and fibrosis [84, 128–130].
Early menarche has been associated withhigher alanine aminotransferase, C-reactiveprotein, triglyceride levels, BMI, waist circum-ference, adult diabetes, cardiovascular morbid-ity and mortality, advanced liver disease, andHCC [131]. A recent Chinese study conductedin postmenopausal women has identified earlymenarche as a potential risk factor for NAFLD
later in life; consistently, late menarche protectsfrom NAFLD [130]. These associations weresignificantly attenuated after adjustment forcurrent BMI or HOMA-IR, suggesting that obe-sity and insulin resistance may partly mediatethe association between age at menarche andNAFLD [130]. The biological mechanism link-ing early menarche with increased risk ofNAFLD is far from being clearly elucidated. Ithas been suggested that early maturation maydetermine a longer duration of positive energybalance and a greater accumulation of body fat[132]. Consistently, a large cross-sectional studyamong middle-aged Korean women confirmedthat the inverse association between age atmenarche and NAFLD was partially mediated byadiposity [133]. Again, a recent study from theAmerican CARDIA cohort showed that earlymenarche was associated with NAFLD and vis-ceral and subcutaneous abdominal ectopic fatdepots in middle adulthood; these associationswere attenuated after adjustment for weightgain between young and middle adulthood[131]. Finally, a Chinese study suggested thatthe presence of central obesity and MetS, butnot NAFLD, after menopause was predicted bylonger duration of menstruation and earlymenarche [134].
Compared to the fertile age, menopauseincreases the risk of NAFLD and liver fibrosis[135] via long-standing estrogen deficiencyassociated with ovarian senescence and dys-metabolic features such as T2D, hypertriglyc-eridemia, and central obesity [29, 81].Consistently, HRT protects from NAFLD devel-opment [84], and oophorectomy in youngwomen with endometrial cancer independentlyincreases the risk of NAFLD together with thedevelopment of T2D and hypercholesterolemia[136]. These findings are in agreement with astudy suggesting that, in HCV infection,increasing severity of fibrosis is associated witha higher BMI, advanced steatosis, and themenopause and that, conversely, menopausalwomen receiving HRT exhibit a lower stage offibrosis [137]. Collectively, these data supportthe notion that estrogens have antifibrogenicproperties in humans. This antifibrotic activitymay occur by triggering anti-inflammatory,antioxidant, and antiapoptotic molecular
Adv Ther (2017) 34:1291–1326 1307
-
pathways [138], which are mimicked by exercisetraining [139].
Of concern, however, young women intheir reproductive age and those exposed tofemale synthetic hormones (oral contraceptiveor HRT) are not completely spared the risk ofdeveloping NAFLD and, indeed, they tend tohave more severe hepatocyte injury andinflammation. Notably, despite the possibilityof enhanced hepatocellular damage, pre-menopausal women have been consistentlyreported at decreased risk of liver fibrosiscompared to men and postmenopausalwomen. Moreover, sex hormones exert com-plex and variable effects on human NAFLD;indeed, the detrimental pro-inflammatoryimpact may be conveyed by progesterone, butnot estrogen [97].
Table 3 summarizes the physiological role ofestrogen, progesterone, and androgens accord-ing to gender, age, reproductive status, andobesity [140–157].
Obesity and Local Hypercortisolism
Obesity, which is closely linked with NAFLD,mimics hypercortisolism. It is of interest thatdespite the prevalence of obesity being higheramong women than men, the former aresomewhat protected from the associated car-diometabolic consequences; however, thiswanes after menopause, suggesting a role forestrogens. Mouse models suggest that sexuallydimorphic expression and activity of glucocor-ticoid metabolizing enzymes may have a role inthe differential metabolic responses to obesityin males and females [158].
Biochemical, genetic, and therapeutic stud-ies have provided robust evidence for 11b-hy-droxysteroid dehydrogenase type 1 (11b-HSD1)being key in the pathogenesis of NAFLD[159–161]. It is of interest, therefore, that11b-HSD1 gene expression is regulated in a tis-sue-specific and sexually dimorphic manner. Inparticular, intact rats exhibit hepatic 11b-HSD1mRNA levels 18-fold lower in the female thanthe male [162].
Body Fat Distribution
Regional adiposity displays a typical sexualdimorphism in humans. Women have a largercapacity to store fat in the subcutaneous com-partment [163]. Men generally have twice asmuch visceral fat compared to women for anygiven fat mass value [164]. This is relevant giventhat, compared to subcutaneous adipose tissuedepots, visceral adipose tissue depots in generaldisplay greater secretory capacity and a morepro-inflammatory profile [165]. Moreover, vis-ceral adipose depots release free fatty acids(FFAs) directly into the portal blood and thuspotentially overload the liver [166]. Not sur-prisingly, those phenotypes which occurwhenever, due to hormonal effect, peripheraladiposity is relatively restricted and visceraladiposity is expanded (i.e., male obesity andpostmenopausal women) have all been associ-ated with NASH, and fibrosing NASH[127, 167–169].
Steatogenesis and Lipidomics are Affectedby Sex Hormones
Steatosis will invariably occur as a result of animbalance among enhanced steatogenesis anddecreased capacity of oxidation of fatty acids[170]. Moreover, qualitative changes in thehepatic lipidomics may concur with lipotoxic-ity. Data suggest that all these mechanisms areunder the control of sex hormones. For exampleovariectomy in rats is associated with increasedintrahepatic steatogenesis which occursthrough a decreased synthesis of peroxisomeproliferator-activated receptor (PPAR), and anincreased transcription of genes encoding sterolregulatory element-binding protein 1[(SREBP-1), a nuclear transcription factor andmaster regulator of the endogenous synthesis ofcholesterol, fatty acids, triglycerides, and phos-pholipids] and stearoyl coenzyme A desaturase1 [(SCD1), the rate-limiting enzyme for gener-ating monounsaturated fatty acids (MUFA)from saturated fatty acids protects from hepa-tocyte lipotoxicity]; all these effects of
1308 Adv Ther (2017) 34:1291–1326
-
Table3
Physiologicalroleof
horm
ones
Men
Wom
enBothsexes
Obesity/type2diabetes
Estradiol
Estradiol
inmen
isessentialfor
modulatinglibido,
erectile
function,and
spermatogenesis
[140]
Astudycond
uctedin
healthymen
suggeststhat
estradiolprotects
from
NAFL
D[141]
End
ogenousestrogensaremaster
regulatorsof
lipid
metabolism
andinhibitinflammation,
vascular
cellgrow
th,and
plaque
progressionin
prem
enopausal
wom
en[142]
The
lossof
estrogenswhich
occurs
postmenopausally
isassociated
withamodestincrease
inLDL
cholesterolw
itheitherno
change
orasm
alldecrease
inHDL
cholesterol.Estrogen
administrationdecreasesLDL
cholesteroland
Lp(a)levelswhile
increasing
triglyceridesandHDL
cholesterollevels,
butthese
effectsaredepend
enton
thedose
androuteof
administration
[143]
Estrogens
improveinflammation
relatedto
metabolicdysfun
ction
(‘‘metaflam
mation’’).
Furtherto
adirect
downregulationof
inflammatorypathways,this
effect
isalso
mediatedby
metabolicam
elioration
[144]
Obesity
isassociated
with
hyperestrogenism
which,inturn,
increasestherisk
ofbreastcancer
inmen
[145]
Progesterone
Progesterone
hasim
portanteffects
inregulating
malefertility
by
affectingtheenergetic
homeostasisof
sperm
[146]
Progesterone
hasamajor
rolein
theovarianandmenstrualcycle;
moreoveritexertsan
immun
o
regulatory
function;regulates
thecontractionof
human
intestinalsm
ooth
musclecells
andthemotility
ofvarious
human
celltypes[147]
Progesterone
isan
independ
ent
predictorof
insulin
resistance
in
girls[148]
Progesterone
hasbeen
potentially
implicated
asatherapeutic
adjunctin
manyclinical
cond
itions
such
astraumatic
braininjury,A
lzheim
er’sdisease,
anddiabeticneuropathy
[147]
Increasing
levelsof
progesterone
have
been
associated
withthe
developm
entof
system
icinsulin
resistance
[149]
Little
isknow
nregardingtherole,if
any,of
serum
progesterone
in
NAFL
D
Adv Ther (2017) 34:1291–1326 1309
-
Table3
continued
Men
Wom
enBothsexes
Obesity/type2diabetes
And
rogens
The
synthesisof
testosterone
iskey
tomalefertility.A
negative
feedback
finelyregulatesthe
secretionof
horm
ones
atthe
levelsof
hypothalam
ic-pituitary–gonadal
axis.C
ongenitalor
acquired
disturbancesof
thisaxiswill
lead
tohypogonadism
andthus
impairmalefertility
[150].
Testosteronehasno
significant
correlationwithNAFL
Din
a
studyfrom
China
[141].
How
ever,itisan
independ
ent
predictorof
insulin
resistance
in
boys
[148]
And
rogens
have
important
biologicalrolesin
youn
gwom
en,
influencing
bone
andmuscle
mass,vascular
health,cognition,
mood,
well-b
eing,and
libido
[151]
How
ever,testosteronedeficiency
inyoun
gwom
enmay
pass
underdiagnosed
becauseof
generally
nonspecific
symptom
s
andinaccuracy
oftestosterone
measurement[152].The
prim
ary
indication
fortheprescription
of
testosterone
forwom
enislossof
libido[153]
Sarcopenia,n
amelythedeclinein
musclemassandstrength
which
occurswithageing,h
asbeen
associated
withadeficiencyin
both
17b-estradioland
testosterone,twosexhorm
ones
which
acto
nsatellitecells.T
hese
remainquiescentthroughout
life
andareactivatedin
response
to
stressfulevents,enablin
gthem
to
guiderepairandregeneration
of
theskeletalmuscle[154]
Obese
men
tend
tobe
hypogonadic
asaresultof
thefunctional
suppressionof
the
hypothalam
ic–p
ituitary–testicular
axis[155].How
ever,w
eightloss
obtained
witheither
alow-calorie
diet
orbariatricsurgeryis
associated
withthenorm
alization
ofsexhorm
onelevelsexhibiting
a
significant
increase
inboun
dand
unboun
dtestosterone
and
gonadotropin
levelsandadecrease
inestradiol[156].A
studyfrom
Japanreported
that
testosterone
levelswereinverselyassociated
withdiabetes
amongmen
butnot
amongwom
en[157]
1310 Adv Ther (2017) 34:1291–1326
-
ovariectomy are prevented by 177b-estradiolreplacement, indicating a role for estrogens inthe prevention of hepatic fat accumulation[171]. Consistently, hypoestrogenemia is asso-ciated with hepatic steatosis through changes ingene expression of molecules related to fat oxi-dation and lipogenesis; resistance and endur-ance training prevent this both in rats andhuman models [172–175]. Moreover, a normalactivity of stearoyl-CoA desaturase (SCD), therate-limiting enzyme for generating monoun-saturated fatty acids from saturated fatty acids,protects from hepatocyte lipotoxicity. Indeed,in mouse models of NAFLD, either geneticmanipulation or dietary changes that inhibitthe activity of SCD promote fibrosing NASH viahepatocyte lipotoxicity, despite inhibiting obe-sity and improving insulin resistance [176, 177].Interestingly, ovarian hormones are alsoinvolved in MUFA biosynthesis, via SCD1 [178].
Excess 16:0 fatty acids associated with denovo lipogenesis from high carbohydrate dietinhibits the synthesis of highly unsaturatedfatty acids; this may potentially account for theimproved metabolic profile which results fromsupplementing a hypercaloric diet with pre-formed eicosapentaenoic acid (EPA) anddocosahexaenoic acid (DHA) [179]. For exam-ple, findings from a genetically engineeredNASH mouse model fed a Western diet haveshown that dietary DHA was superior to EPA inattenuating Western diet-induced hyperlipi-demia and hepatic injury and at reversing thosedeleterious metabolic and histological effectsinduced in the liver by a Western diet [180].Interestingly, human (women using the con-traceptive pill or HRT and transsexual subjects)and experimental data in rats consistentlyindicate that sex hormones act to modifyplasma and tissue n-3 PUFA content, possibly byaltering the expression of desaturase and elon-gase enzymes in the liver [181]. Collectively,these findings suggest that enzyme activitieswhich are key in the development of a poten-tially hepatotoxic lipidomic signature are criti-cally controlled by sex hormones. Finally, it isof clinical importance that the therapeuticactivity of PPAR-a agonists in obesity and fattyacid oxidation is modulated by sex and estro-gens [182].
Oxidative Stress and AntioxidantMechanisms
Reactive oxygen species (ROS) result from theoxidation of fatty acids within mitochondriaand peroxisomes. The antioxidant defenseswhich physiologically constrain oxidative stressare hindered by nutritional deficiencies orchanges in the intestinal microbiome that limitavailability of choline [183]; by aging and thecontent of cysteine in diet, which, in turn, willaffect the intrahepatic synthesis of glutathione[184]; and by sex and menopause which bothaffect the normal metabolism of choline [185].
Endotoxin
Quali-quantitative changes in intestinal micro-biota (dysbiosis), which are often associatedwith dietary indiscretions, have consistentlybeen associated with increased gut permeabilitywhich could lead to increased translocation ofbacterial products from the intestinal lumeninto the portal circulation, thereby triggeringchronic inflammation [170]. It this context, it isrelevant that in an experimental model of liverfailure due to endotoxemia after hepatectomy,sexually mature female rats are more exposedthan males to endotoxin-induced liver injuryand that ovariectomy abrogates this sexualdimorphism [186]. Whether this also applies tohuman NAFLD, however, remains to be proven.
Interindividual Variation in ImmuneResponses is Another Key Liver DiseaseModifier in NAFLD
Whether metabolic inflammation is a gen-der-dimorphic phenomenon has not beenexplored in a systematic and organized manner.Obesity, however, will typically exhibit changesin the innate and adaptive immune mecha-nisms [187]. However, how mechanisticallysuch obesity-related dysregulation of immunedefenses will impact on the pathogenesis ofNASH is not fully elucidated. Experimental dataobtained in the ob/ob mouse model suggest arole for natural killer T cells (NKT cells) whichmay at least partly account for the
Adv Ther (2017) 34:1291–1326 1311
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interindividual variation in immune responsesbeing a key modifier in the development andprogression of NAFLD [125]. In this respect, itshould be highlighted that sex is a majordeterminant in the immune response. Sup-porting this notion, one study in young chil-dren reported that immune responses tovaccines were consistently higher or equivalentin girls compared with boys [188].
Liver Fibrosis
Liver fibrosis is the end-stage result of variousliver injuries. In recent times, importance hasbeen given to the Hedgehog signaling pathwayon the grounds that activation of this pathwaywill stimulate the proliferation and differentia-tion of hepatic stellate cells (HSCs) as myofi-broblasts (MF-HSCs), and, conversely,inhibiting Hedgehog activity in myofibroblastsderived from HSCs causes them to revert to amore quiescent (namely less fibrogenic) phe-notype [125]. Accordingly, Hedgehog ligandsand other factors that control fate decisions inHSCs are critical determinants of the develop-ment of cirrhosis due to various causes as well ofthe course of NASH [125]. For example, hepaticexpression of Hedgehog ligands and Hedgehogpathway activity progressively increase fromsimple steatosis, to NASH, and reach highestlevels in NASH-cirrhosis [189]. Of major signif-icance to the pathogenesis of NAFLD, theHedgehog pathway is strongly regulated bylipids [190], and conversely, Hedgehog signal-ing is a master regulator of body fat distributionand glucose metabolism [191, 192]. Thesefindings suggest that interindividual variationin Hedgehog signaling might contribute tovariability in both hepatic and extrahepaticoutcomes of the metabolic syndrome [125].
Experimental overexpression of Hedgehogligand in hepatocytes is able to induce a fibro-genic liver response and to promote hepato-carcinogenesis in a transgenic mouse model[193]. At least in part by modulating interme-diary metabolism [194, 195], Hedgehog alsointeracts with pathways which regulate growthand differentiation [194, 196–198], such asWnt/b-catenin signaling, which are of potential
significance for the development of hepatocel-lular carcinoma [199].
Treatment with compounds, e.g., vitamin E,that suppress Hedgehog ligand production andreduce the hepatic accumulation of Hedge-hog-responsive myofibroblasts has proven ben-eficial in human NASH [200].
Further studies are necessary to establishwhether and to what extent sex hormonesaffect Hedgehog signaling and how manipula-tion of cellular energy homeostasis might beexploited to prevent and manage fibrosingNASH, cirrhosis, and HCC in individuals withNAFLD.
CAN GENDER DIMORPHISMOF NAFLD BE EXPLOITEDFOR THERAPEUTIC PURPOSES?
In principle, sex differences found in NAFLDmay be accounted for by the effects of sexchromosomes; sex hormones; and by differ-ences in dietary and lifestyle habits [201, 202]. Abetter understanding of the physiopathologicalpeculiarities of NAFLD in women may con-tribute to developing tailored therapeuticinterventions [203]. Accordingly, the roles ofestrogen and HRT, the metabolism of choline,and the effect of weight reduction and exercis-ing in women are discussed in detail hereafter.
Estrogens
As detailed in Table 3, estrogens exert severalbeneficial metabolic effects. Experimental stud-ies suggest that estrogens promote the accu-mulation of peripheral gluteofemoralsubcutaneous adipose tissue and, within theliver, promote FFA beta-oxidation and preventthe accumulation of triglycerides; moreover,they regulate energy homeostasis, enhanceinsulin sensitivity, and exert a protective roleon the function of pancreatic beta-cells [201].Finally, estrogens seem to have antisteatotic,antioxidant, and antifibrogenic properties inthe liver [204, 205]. Estrogens may protect fromliver steatosis and fibrosis in female mice viaupregulation of miRNA-125b and miRNA-29,
1312 Adv Ther (2017) 34:1291–1326
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respectively [206, 207]. A recent experimentalstudy showed that the estrogen/estrogenreceptor alpha signaling plays essential roles inROS detoxification and in the reduction ofoxidative damage in the liver via partneringwith hepatic PPARG coactivator 1 alpha, thushalting the transition from simple steatosis tosteatohepatitis [205]. Estrogens are also knownto inhibit stellate cell activation and fibrogene-sis in experimental models [204]. Of note, astudy showed that the natural estrogen17b-estradiol prevents deoxycholic acid-in-duced hepatocellular damage in several celllines. This hepatoprotective effect of estrogenwas sustained by mechanisms which wereunlikely to be mediated by nuclear estrogenreceptor alpha [208]. Interestingly, it hasrecently been demonstrated that a non-nuclearestrogen receptor plays a key role in reducinghepatic steatosis in female mice [209]. Similarly,estrogen deficiency leads to fat redistributiontoward visceral fat accumulation and its inher-ently unfavorable metabolic derangements, andis thus able to induce the development andprogression of NAFLD/NASH both in mice andhumans. Of note, both aromatase knockoutmice, which are unable to synthesize endoge-nous estrogen, and estrogen receptor alphaknockout mice develop hepatic steatosis[210–212]. Patients with breast cancer treatedwith tamoxifen, a potent estrogen antagonist,develop progressive liver steatosis and NASH[213]. Surgical and physiological menopausalstatus have been invariably associated withexcess risk of NAFLD progression and liverfibrosis, and duration of estrogen deficiency hasbeen directly related to increased fibrosis risk inpostmenopausal women with NAFLD[95, 96, 98, 136].
Hormonal Replacement Therapy
Despite the above premises, the role of HRT inreverting the metabolic alterations associatedwith low levels of estrogens is a matter of dis-pute. In animal models, both estrogen andraloxifene, a second-generation selective estro-gen receptor modulator, have improvedinflammation and ballooning so halting the
progression of liver fibrosis in diet-inducedNASH in female ovariectomized mice [30, 214].However, the theoretical benefits of HRT in liverdisease remain to be proven in humans. Aseminal randomized placebo-controlled studysuggested that HRT containing low-dose estra-diol and norethisterone was able to reduce liverenzyme concentrations in women with T2D,potentially through the reduction of accumu-lation of fat in the liver [45]. Accordingly, anorth American study using data of theNHANES III survey showed that post-menopausal women who received HRT had asignificantly lower risk of NAFLD than post-menopausal women who did not (OR 0.69, 95%CI 0.48–0.99) [215]. However, whether HRTreduces the risk of NASH and/or fibrosis amongpostmenopausal women remains uncertain.Two studies showed no, or borderline, benefi-cial effects of HRT on fibrosis among post-menopausal women with NAFLD [95, 96].Worryingly, a recent study reported that syn-thetic hormone use was associated with moresevere hepatocellular injury and lobularinflammation. Further analysis showed thatprogesterone, but not estrogen use, was associ-ated with worse liver histological lesions, sug-gesting a multifaceted impact of sex hormoneson NASH features [97].
Choline
Several lines of evidence support a key role ofcholine as an essential nutrient and cellularcomponent. Choline is the major source ofmethyl groups in the diet and is a precursor ofphosphatidylcholine, which is an importantcomponent of cell membranes and VLDL,required for the export of lipids from the liverinto the bloodstream. Thus, depletion of cholineinhibits hepatic triglyceride export and inducesfatty liver in both experimental models andhumans [185, 203, 216, 217]. Of note, post-menopausal women are more prone than pre-menopausal women and men to develop NAFLDas a consequence of choline deficiency[128, 185, 217], and decreased dietary cholineintake has been significantly associated withincreased fibrosis in postmenopausal women
Adv Ther (2017) 34:1291–1326 1313
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with NAFLD [218]. Indeed, menopausal statusdetermines a differential susceptibility to cholinedeficiency arising from the estrogen-inducibleexpression and activity of phos-phatidylethanolamine-N-methyltransferase(PEMT), a key enzyme in de novo cholinebiosynthetic pathway. Following menopause,the endogenous supply of choline decreases as aresult of estrogen deficiency; consequently, thedietary requirement of choline is increased[185, 203, 216, 217]. Consistently, choline sup-plementation has been reported to improve orrevert liver steatosis in patients receivinglong-term total parenteral nutrition [219]. How-ever, no interventional studies have addressedwhether choline supplementation is able to pre-vent NAFLD or reduce NAFLD progression; more-over, future studies investigating the role ofpreventive or therapeutic choline supplementa-tion in postmenopausal women are eagerlyawaited.
Weight Reduction and Exercise
Lifestyle changes, i.e., physical activity and bal-anced diet, are the milestone of intervention forNAFLD treatment. In general, weight lossinduced by lifestyle changes improves IR andfeatures of the MetS, including NAFLD. Of note, amodest weight loss of as little as 2–3 kg is associ-ated with NAFLD reversal [39], and weight loss ofgreater than 7–10% significantly improves his-tological features of NASH, including fibrosis[220]. However, significant weight reductionachieved through dietary restrictions results innegative effects on lean muscle and bone mass inpostmenopausal women. Therefore, whileweight reduction in postmenopausal womenwith metabolic abnormalities and risk factors forNAFLD should be strongly recommended, spe-cial attention should be paid to how weight loss isobtained in older women to prevent the wors-ening of loss of lean mass [139, 203]. An inte-grated approach consisting of dietary changesalong with regular exercise is mandatory to pre-vent the untoward effect of losing lean mass.Both resistance training and aerobic exercise areeffective in preventing muscle and bone lossduring weight loss [203], and equally reduce liver
fat content [221, 222]. Postmenopausal womenwith higher levels of physical activity seem tohave lower total body and visceral fat and to beless likely to gain fat mass during menopause[139, 223]. However, only few studies havespecifically assessed the role of physical activityin NAFLD prevention/reversal in post-menopausal women. Data have shown thatexercise training effectively reduces liverenzymes in overweight postmenopausal women,probably as a reflection of liver fat content [224],and aerobic physical activity reduces cardiovas-cular risk factors in postmenopausal women withNAFLD [225]. Further studies are needed todefine the ideal structure and duration of exer-cise-based interventions in postmenopausalwomen with NAFLD or at risk of developing it.
In summary, there are no codified therapeuticinterventions approved for tackling NAFLD inwomen. Given the theoretical beneficial meta-bolic and hepatic effects of estrogens, it isintriguing to speculate that HRT might possiblyplay a role in the prevention and treatment ofmetabolic alterations associated with meno-pause, including NAFLD. However, studies inhumans are lacking and the potential metabolicbenefits should be weighed, in clinical practice,against the detrimental cardiovascular and neo-plastic risk associated with long-term HRT[226, 227]. Moreover, the multifaceted and vari-able impact of different sex hormones in NAFLDshould be carefully considered. Dietary changesassociated with either aerobic or resistancephysical exercise should be considered as themilestone of treatment of NAFLD. Future studieswill have to evaluate the effects on NAFLD pre-vention/treatment of supplementing choline toa balanced diet in postmenopausal women.Finally, the physiopathological peculiarities ofNAFLD in women and the gender-based differ-ences in the kinetics and dynamics of drugs andxenobiotics should be taken into account whendeveloping new treatment strategies andproposing interventional trials for NAFLD.
CONCLUSION
Consistent with the notion that NAFLD andNASH are strongly linked with hormonal
1314 Adv Ther (2017) 34:1291–1326
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influences [228], this narrative review article wasdriven by the hypothesis that what we called the‘‘sexualdimorphism’’ ofNAFLD might be useful inidentifying clues of pathogenic significance andproviding hints for prevention and treatment ofNAFLD. On these grounds, a systematic researchof the literature was conducted. What we foundwas that not only are men at an increased risk ofdeveloping NAFLD (Fig. 1) but also significantage-related changes in NAFLD epidemiology inwomen may potentially bear physiopathological,clinical, and therapeutic significance. NAFLDepidemiology and physiopathology are modu-lated by age at menarche and postmenopausalstatus (Fig. 2). It would be expected that earlymenarche, definitely associated with estrogen
activation, would produce protection against therisk of NAFLD. Nevertheless, it has been suggestedthat early menarche may confer an increased riskof NAFLD in adulthood, excess adiposity beingthe primary culprit of this association. Fertile agemay be associated with more severe hepatocyteinjury and inflammation, but also with adecreased risk of liver fibrosis compared to menandpostmenopausal status.Ovariansenescence isstrongly associated with severe steatosis andfibrosing NASH which may occur in post-menopausal women. Estrogen deficiency isdeemedtobe responsible for these findings via thedevelopment of postmenopausal metabolic syn-drome. Estrogen supplementation may at leasttheoretically protect from NAFLD development
NAFLD RISK HIGHLOW
PUTATIVE MECHANISMSNEMNEMOW
GLUTEOFEMORAL Distribu�on of adipose �ssue VISCERAL
KETONE BODY Fa�y acid par��oning VLDL-TAG
+ Browning of WAT -
Fig. 1 Physiopathological grounds accounting for male sexas a strong predictor of NAFLD. Male gender andmenopausal status have been associated with the risk ofNAFLD independently of age and metabolic factors incross-sectional studies. On the basis of human studies andextrapolation of notions from animal studies, it can bespeculated that female sex is protected from dysmetabolismthanks to young individuals’ ability to partition fatty acidstowards ketone body production rather than VLDL-TAG
[23], and to sex-specific browning of white adipose tissuewhich contributes in protecting female mice from exper-imental NAFLD associated with methionine cholinedeficient diet [24]. However, after menopause womendisplay a similar or even higher prevalence of NAFLDcompared to men, supporting a protective effect ofestrogens. Finally, risk factors associated with NAFLDdevelopment are different in men compared to women.TAG triacylglycerols, WAT white adipose tissue
Adv Ther (2017) 34:1291–1326 1315
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and progression, as suggested by some studiesexploring the effect of HRT on postmenopausalwomen, but the variable impact of different sexhormones in NAFLD (i.e., the pro-inflammatoryeffect of progesterone) should be carefully takeninto account when proposing treatment withsynthetic hormones.
Taken collectively, these data may generateinnovative hypotheses to be tested in appro-priate clinical and experimental studies onNAFLD physiopathology and treatment.
ACKNOWLEDGEMENTS
No funding or sponsorship was received for thisstudy or publication of this article.
All named authors meet the InternationalCommittee of Medical Journal Editors (ICMJE)criteria for authorship for this manuscript, takeresponsibility for the integrity of the work as awhole, and have given final approval for theversion to be published.
Stefano Ballestri, Fabio Nascimbeni, andAmedeo Lonardo conceived the idea of thisarticle and wrote its first draft. All the authorshave read, edited, and approved the variousversions of this article.
Disclosures. Stefano Ballestri and EnricaBaldelli have nothing to disclose. FabioNascimbeni is involved as a researcher in the‘‘Phase 3, Double Blind, Randomized,Long-Term, Placebo-controlled, Multicenter
STEATOFIBROSIS
Fig. 2 Hormonal changes are a major determinant ofprogressive NAFLD in human menopause. NAFLDepidemiology and physiopathology are modulated by ageat menarche and postmenopausal status. For example, earlymenarche may confer an increased risk of NAFLD inadulthood partly mediated by excess adiposity
[130, 131, 133]. Moreover, ovarian senescence, via estrogendeficiency, may eventually be conducive to both massiveliver steatosis and its fibrotic evolution via dysmetabolictraits including T2D, hypertriglyceridemia, and visceralobesity which are often found postmenopausally[29, 81, 135]
1316 Adv Ther (2017) 34:1291–1326
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study evaluating the Safety and Efficacy ofObethicolic Acid in Subjects with NASH’’ (Eu-draCT 2015-002560-16). Alessandra Marrazzo isinvolved as a researcher in the ‘‘Phase 3, DoubleBlind, Randomized, Long-Term, Placebo-con-trolled, Multicenter study evaluating the Safetyand Efficacy of Obethicolic Acid in Subjects withNASH’’ (EudraCT 2015-002560-16). AmedeoLonardo is involved as a researcher in the ‘‘Phase3, Double Blind, Randomized, Long-Term,Placebo-controlled, Multicenter study evaluatingthe Safety and Efficacy of ObethicolicAcid in Subjects with NASH’’ (EudraCT2015-002560-16). Dante Romagnoli serves as aconsultant for AbbVie.
Compliance with Ethics Guidelines. Thisarticle is based on previously conducted studiesand does not involve any new studies of humanor animal subjects performed by any of theauthors.
Data Availability. All data generated oranalyzed during this study are included in thispublished article.
Open Access. This article is distributedunder the terms of the Creative CommonsAttribution-NonCommercial 4.0 InternationalLicense (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommer-cial use, distribution, and reproduction in anymedium, provided you give appropriate creditto the original author(s) and the source, providea link to the Creative Commons license, andindicate if changes were made.
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