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Essential phospholipids in fatty liver: a scientific update
Karl-Josef Gundermann1
Simon Gundermann2
Marek Drozdzik1
VG Mohan Prasad3
1Department of Pharmacology, Pomeranian Medical University, Szczecin, Poland; 2Department of Radiology, Hospital Hohenlind, Cologne, Germany; 3VGM Hospital Institute of Gastroenterology, Coimbatore, India
Correspondence: VG Mohan Prasad VGM Hospital Institute of Gastroenterology, Trichy Road, Rajalakshmi Mills Stop, Singanallur 641005, Coimbatore, India Tel +91 98 4220 4995 Email [email protected]
Aim: Although essential phospholipids (EPL) from soybean are often used in membrane-associated disorders and diseases, their high quality of purification and effects on prevalent liver
diseases, especially on fatty liver diseases (FLDs) of different origin, are still widely unknown
and a matter of continuous active research. The aim of this article is to review, discuss, and
summarize the available results of EPL in the treatment of FLD.
Methods: Database research was carried out on Medline, Embase, Cochrane Library, country-specific journals, and follow-up literature citations for relevant hepatogastroenterological articles
published between 1988 and 2014. We searched for and reviewed only those papers that indi-
cated minimum extraction amount of 72% (3-sn-phosphatidyl)choline from soybean as being
necessary to treat patients with a considerable amount of 1,2-dilinoleoylphosphatidylcholine
as a key component in EPL.
Results: EPL has a well-established mode of action, therapeutic effectiveness, and lack of toxicity, which ensures clinically relevant efficacy-to-safety ratio. It influences membrane- dependent
cellular functions and shows anti-inflammatory, antioxidant, antifibrogenic, anti apoptotic,
membrane-protective, and lipid-regulating effects. Due to its positive effects on membrane com-
position and functions, it accelerates the improvement or normalization of subjective symptoms;
pathological, clinical, and biochemical findings; hepatic imaging; and liver histology. It is justified
to administer EPL together with other therapeutic measurements in the liver.
Conclusion: Pharmacological and clinical results confirm the efficacy of EPL in the treatment of FLD.
Keywords: fatty liver disease, essential phospholipids, dilinoleoylphosphatidylcholine, membrane
IntroductionNonalcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD) are one
and the same fatty liver disease (FLD) with an underlying multicausal origin, such as
obesity, alcohol drinking, and diabetes mellitus,1 which are important public health
problems, for which an established therapy is not yet available. This is a medical
challenge as progressive course from simple steatosis to steatohepatitis and possible
cirrhosis with development of liver cancer is known.1–3 Therapy of NAFLD is currently
mainly directed at treating components of the metabolic syndrome. Diet and physi-
cal exercise are recommended as a basic universal approach. Some pharmacological
agents show promising results, although on the basis of recent clinical trials no firm
conclusions can yet be drawn.4 The situation is comparable with ALD.3 The nontoxic
essential phospholipids (EPL) have been already widely accepted to be effective in
Clinical and Experimental Gastroenterology
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C
linic
al a
nd E
xper
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astr
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or p
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nal u
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various liver diseases.5,6 However, as a clinical overview
of available results specifically in FLDs of different origin
has not yet been published since 1988, it is the purpose of
this article to evaluate the clinical efficacy and safety of
EPL in these frequent liver diseases. The term EPL with its
polyenylphosphatidylcholine (also called polyene phosphati-
dylcholine [PPC]) molecules indicates a well-defined, highly
purified extract of the semen of soybeans (glycine max) with
standardized contents of 72%–96% (3-sn-phosphatidyl)
choline. The quantitatively and qualitatively dominating
molecule in EPL is 1,2-dilinoleoylphosphatidylcholine
(DLPC) (Figure 1), with up to 52% of the administered
PCs.6 This high level of DLPC is the main difference
between EPL/PPC and the typical phospholipids as well
as PC consumed through diet and synthesized within the
body. With a share of ∼1.3%, highly unsaturated PCs with an additional, unsaturated fatty acid in the first position of
the PC molecule are rare.7 By administering EPL, the amount
of hepatic DLPC significantly increased.8
Phospholipids are known to form the double layer of
cellular and subcellular membranes and precondition their
fluidity and biological activity. The efficacy of EPL in the
therapy of liver diseases is confirmed not only by the ability
of DLPC to be incorporated into damaged sections of mem-
branes, which improves hepatic regeneration and replaces
endogenous, less unsaturated PC molecules but also by its
ability to increase membrane fluidity and functioning. With
regard to in vitro and animal investigations, EPL influences
membrane-dependent cellular functions and shows antioxi-
dant, anti-inflammatory, antifibrotic, apoptosis-modulating,
regenerative, membrane-repairing and -protective, cell-
signaling and receptor-influencing, and lipid-regulating
effects.6
Materials and methodsDatabase research was carried out on Medline, Embase,
Cochrane Library, country-specific journals, and follow-up
literature citations for relevant hepatogastroenterological
articles published between 1988 and 2014. In a two-step
process, we first used combinations of keywords including
NAFLD, ALD, essentiale, ESLs, polyenylphosphatidylcho-
line, polyene phosphatidylcholine, dilinoleoylphosphatidyl-
choline, phosphatidylcholine, and therapy. In the second step,
we reviewed those papers that indicated minimum extraction
amount of 72% PC from soybean as being necessary to treat
patients with a considerable amount of DLPC as a key com-
ponent in EPL (for details see later), or that were based on the
trade name Essentiale®. Studies with less purified PC from
soybean or with PC from other provenience were excluded.
All papers that were reported in different languages other
than English were completely translated into English. Of the
83 clinical studies in total, 25 representative ones regarding
the causes of FLD, study design, and investigated variables
were selected, including one case report study and seven
double-blind studies (Table 1).
ResultsClinical efficacy of EPL in NAFLDFifty-three clinical studies about EPL and NAFLD have
been published since 1988, of which 45 were published
since 2000. Twenty-eight, mostly randomized studies, were
open controlled and three double-blind. Dosage of EPL
and treatment duration varied as a rule between 1.05 g/d
and 1.8 g/d per os and lasted from 4 weeks to .24 months,
in most studies 3–6 months with 1.8 g of EPL/d. Therapy
started in some studies with 500–1,000 mg EPL iv over
10 days to 4 weeks, before continuing with oral EPL
C O C H
O
O
O HH
H2C P O C C
H HO
N CH2
CH2
Lipophilicnonpolar head
Hydrophilicpolar head
1-position
2-position
3-position
O C
O
−
+
CH2
H2C
Figure 1 1,2-Dilinoleoylphosphatidylcholine (DLPC), the main active ingredient in EPL.Abbreviation: EPL, essential phospholipids.
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Tab
le 1
Ove
rvie
w o
f rev
iew
ed c
linic
al s
tudi
es r
egar
ding
the
influ
ence
of a
dmin
istr
atio
n of
EPL
on
FLD
Clin
ical
stu
dyA
ge/s
ex (
n)St
udy
popu
lati
on a
nd d
esig
nE
ffect
sR
emar
ks
wat
anab
e et
al9
Mea
n 46
yr/
4 m
and
8
fO
pen
cont
rolle
d st
udy:
of 1
2 pa
tient
s w
ith o
besi
ty w
ith F
L, s
ix r
ecei
ved
0.5
g EP
L po
tid
vs
six
0.5
g ni
cotin
ic a
cid
(nic
erito
l) tid
for
2 m
onth
s.
EPL:
TC
and
TG
↓ (
P,0.
05);
fat
in t
he li
ver
↓ as
see
n fr
om C
T
(P,
0.02
). N
o A
DR
. N
icer
itol:
TC a
nd T
G ↓
, fat
in t
he li
ver
and
CH
E (P
,0.
05);
1× fl
ush.
A
LT, o
ral g
luco
se t
oler
ance
tes
t, ob
esity
inde
x, a
nd s
kin-
fold
th
ickn
ess
impr
oved
in b
oth
grou
ps, t
oo.
BT: d
iet
and
phys
ical
exe
rcis
e.
Com
para
ble
effic
acy
in b
oth
grou
ps.
Gon
ciar
z et
al13
EPL:
mea
n 54
yr/
4 m
an
d 11
f Pl
aceb
o: m
ean
49 y
r/
8 m
and
7 f
Ran
dom
ized
dou
ble-
blin
d st
udy:
of
30 p
atie
nts
with
dia
bete
s w
ith F
L,
15 r
ecei
ved
0.6
g EP
L po
tid
vs
15
corr
espo
ndin
g pl
aceb
o fo
r 6
mon
ths.
EPL:
live
r si
ze a
nd y
-GT
↓ (
P,0.
05);
gluc
ose
↓ (P
,0.
01).
His
tolo
gy: m
arke
d im
prov
emen
ts in
four
cas
es.
Fina
l pat
ient
s’ e
valu
atio
n: e
ight
impr
ovem
ents
. Pl
aceb
o: g
luco
se ↓
(P,
0.05
). H
isto
logy
: mar
ked
impr
ovem
ent
in o
ne c
ase
(no
fatt
y in
filtr
atio
n bu
t ci
rrho
sis
deve
lope
d).
Fina
l pat
ient
s’ e
valu
atio
n: o
ne p
atie
nt im
prov
emen
t. N
o A
DR
.
2 w
eeks
pre
trea
tmen
t ph
ase:
no
hep
atop
rote
ctor
s. O
besi
ty
allo
wed
. Die
t in
cas
e of
obe
sity
. 1.
0–1.
5 g
tolb
utam
ide
in fi
ve
plac
ebo
and
seve
n EP
L pa
tient
s.
Stat
istic
s: U
-tes
t an
d w
ilcox
on
mat
ch-p
aire
d si
gned
tes
t.
Cai
rella
et
al10
46.1
±12.
2 yr
/15
m
and
25 f
Ope
n co
ntro
lled
stud
y:
of 4
0 pa
tient
s w
ith o
besi
ty w
ith F
L,
20 r
ecei
ved
0.6
g EP
L po
tid
vs
20 d
iet
only
for
3 m
onth
s.
EPL:
14
of 1
9 pa
tient
s im
prov
ed U
S, o
ut o
f whi
ch s
ix n
orm
aliz
ed.
Con
trol
: thr
ee o
f 20
patie
nts
impr
oved
US.
EP
L vs
con
trol
: mor
e fr
eque
nt n
orm
aliz
atio
n of
AST
, AP,
y-G
T, a
nd
seru
m a
nd u
rine
bili
rubi
n (P
,0.
001)
.
BT: d
iet.
Add
ition
ally
, sin
gle
case
s pr
esen
tatio
n.
Kog
a et
al11
42.6
±11.
4 yr
/29
m
and
22 f
Ope
n st
udy:
51
patie
nts
(39
obes
e,
six
diab
etic
, five
alc
ohol
ic, a
nd o
ne
unkn
own)
with
FL
rece
ived
0.5
g E
PL
po t
id fo
r 6
mon
ths.
All
case
s in
clud
ed: U
S im
prov
ed o
r no
rmal
ized
in 5
1% o
f pat
ient
s (P
,0.
001)
; AST
(P
ns),
ALT
, and
y-G
T ↓
in m
ales
(P,
0.01
). Im
prov
emen
t in
LFT
in 7
2% o
f pat
ient
s.
Alc
ohol
-exc
lude
d ev
alua
tion:
US
impr
oved
or
norm
aliz
ed (P
,0.
01);
AST
, ALT
, and
y-G
T im
prov
ed o
r no
rmal
ized
(P,
0.01
, P,
0.00
1,
and
P,0.
05, r
espe
ctiv
ely)
. N
o fu
rthe
r im
prov
emen
t af
ter
16 w
eeks
. Su
bjec
tive
sym
ptom
s im
prov
ed o
r di
sapp
eare
d.
No
diet
or
alco
hol
cons
umpt
ion.
St
atis
tics:
wilc
oxon
tes
t. G
reat
er e
ffica
cy in
cas
es o
f m
ore
dist
urbe
d liv
er fu
nctio
n an
d in
cas
es w
ith d
ecre
asin
g di
stur
bed
lipid
leve
ls.
Li e
t al
12EP
L: 4
4.1±
8.2
yr/1
5 m
an
d 9
f Pl
aceb
o: 4
6.2±
7.5
yr/
5 m
and
7 f
Ran
dom
ized
dou
ble-
blin
d st
udy:
of
36 p
atie
nts
with
obe
sity
with
FL,
24
rece
ived
0.6
g E
PL p
o tid
+ o
ne t
able
t of
vita
min
s/d
vs 1
2 co
rres
pond
ing
plac
ebo
and
vita
min
s fo
r 3
mon
ths.
EPL:
incr
ease
d T
C ↓
by
10%
, TG
↓ b
y 9%
(P,
0.05
). A
LT a
nd A
ST
norm
aliz
ed in
87.
5%. F
LD im
prov
ed a
s se
en fr
om C
T (P
,0.
05).
Plac
ebo:
no
sign
ifica
nt c
hang
e of
TC
, TG
, AST
, and
ALT
. No
chan
ge in
CT
. M
ean
redu
ctio
n be
twee
n gr
oups
P,
0.01
. EPL
sig
nific
antly
effe
ctiv
e in
21
and
effe
ctiv
e in
thre
e pa
tient
s. N
o A
DR
.
2 w
eeks
pre
trea
tmen
t ph
ase:
no
live
r pr
otec
tive
agen
ts.
No
alco
hol o
r an
imal
fat.
Stat
istic
s: t-
test
for
com
pari
son.
Yin
and
Kon
g14
EPL:
mea
n 56
yr/
73 m
an
d 52
f C
ontr
ol: m
ean
55 y
r/
33 m
and
27
f
Ope
n co
ntro
lled
stud
y: o
f 185
pat
ient
s w
ith d
iabe
tes
with
FL,
125
rec
eive
d BT
+ 0
.6 g
EPL
po
tid v
s 60
BT
alo
ne
for
3 m
onth
s.
EPL:
cur
ativ
e ef
fect
in 7
8 pa
tient
s sig
nific
ant,
in 3
5 ef
fect
ive,
and
in 1
2 no
t effe
ctiv
e. T
otal
effe
ctiv
e ra
te 9
0.2%
(P,
0.05
com
pare
d to
con
trol
). A
LT ↓
(P,
0.01
). T
C, T
G, a
nd L
DL-
C ↓
and
HD
L-C
↑ (
P,0.
05).
Diff
eren
ces
sign
ifica
nt c
ompa
red
to c
ontr
ol (P
,0.
05).
Con
trol
: cur
ativ
e ef
fect
in th
ree
patie
nts
signi
fican
t, in
28
effe
ctiv
e, a
nd
in 2
9 no
t effe
ctiv
e. T
otal
effe
ctiv
e ra
te 5
1.0%
. A
LT, T
C, T
G, L
DL-
C, a
nd H
DL-
C (
P ns
). N
o si
gnifi
cant
diff
eren
ce fo
r fa
stin
g bl
ood
gluc
ose
betw
een
grou
ps.
Dis
ease
sin
ce 1
–28
yr (
mea
n 9.
6 yr
). BT
: die
t, or
al a
ntid
iabe
tics,
and
ph
ysic
al e
xerc
ise.
N
o bl
ood
lipid
met
abol
ism
af
fect
ing
drug
s. A
t th
e ni
ght
befo
re t
reat
men
t, hi
gh-fa
t di
et
and
alco
hol f
orbi
dden
. (Con
tinue
d)
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EPL in fatty liver disease
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Tab
le 1
(Co
ntin
ued)
Clin
ical
stu
dyA
ge/s
exSt
udy
popu
lati
on a
nd d
esig
nE
ffect
sR
emar
ks
Ohb
ayas
hi20
51.6
±13.
9 yr
/16
m
and
9 f
Ope
n st
udy:
25
patie
nts
(18
NA
SH,
7 w
ith a
lcoh
olic
FLD
) re
ceiv
ed 0
.5 g
EP
L po
tid
for
12 m
onth
s.
NA
SH: A
ST a
nd A
LT ↓
, alre
ady
signi
fican
t afte
r 4
wee
ks th
erap
y (P
=0.0
04 a
nd P
=0.0
05).
y-G
T re
mai
ned
norm
al. I
mpr
ovem
ent
sust
aine
d th
roug
hout
the
stud
y.
ASH
: AST
, ALT
, and
y-G
T ↓
, alr
eady
sig
nific
ant
afte
r 8/
4 w
eeks
(P
=0.0
33, P
=0.0
21, t
rend
). Im
prov
emen
t su
stai
ned
(ALT
and
y-G
T)
or c
ontin
ued
to n
orm
al (
AST
). A
DR
: one
pat
ient
mild
gas
tric
dis
com
fort
and
one
pat
ient
mild
di
arrh
ea a
nd lo
ose
stoo
ls.
Lipi
d le
vels
rem
aine
d un
alte
red.
Poon
goth
ai
et a
l1541
±8 y
r/14
m a
nd 1
4 f
Ope
n st
udy:
of 2
8 pa
tient
s w
ith
diab
etes
with
NA
FLD
, 22
wer
e av
aila
ble
for
follo
w-u
p an
d re
ceiv
ed
0.7
g EP
L po
tid
for
6 m
onth
s.
US:
two
of fo
ur o
f gra
de 1
of N
AFL
impr
oved
, one
sho
wed
no
chan
ge, a
nd o
ne w
orse
ned.
In c
ase
of g
rade
2 a
nd 3
, five
of 1
2 an
d fiv
e of
six
impr
oved
. Ove
rall,
54.
5% im
prov
ed, 4
0.9%
did
not
cha
nge,
an
d on
e ca
se w
orse
ned.
80
% o
f pat
ient
s w
ith g
rade
3 im
prov
ed in
hep
atic
ech
otex
ture
, w
hile
onl
y 50
% o
f gra
de 1
pat
ient
s.
LFT:
AST
, ALT
, and
y-G
T ↓
(P=0
.004
, P=0
.007
, and
P=0
.024
, re
spec
tivel
y). E
ven
amon
g pa
tient
s w
ithou
t US
chan
ges,
decr
ease
in a
ll en
zym
es. A
ST a
nd A
LT s
tart
ed to
impr
ove
with
in 2
mon
ths
of th
erap
y,
y-G
T af
ter
6 m
onth
s. FP
G, H
bA1c, a
nd T
C ↓
(P=0
.007
, P=0
.001
, and
P=0
.046
, res
pect
ivel
y).
No
AD
R.
BT: d
iet
and
antid
iabe
tics;
ad
ditio
nally
, 16.
6% o
n a
stat
in
and
8.3%
on
a fib
rate
. SP
SS s
tatis
tical
pac
kage
10.
0.
Ohb
ayas
hi e
t al
2130
–62
yr/5
m a
nd 3
fO
pen
stud
y: e
ight
pat
ient
s w
ith
NA
SH r
ecei
ved
0.5
g EP
L po
tid
for
12 m
onth
s.
AST
, ALT
, and
y-G
T ↓
(P=
0.01
2, P
=0.0
05, t
rend
) af
ter
4 w
eeks
, la
stin
g du
ring
the
12-
mon
th t
reat
men
t (P
,0.
05, P
,0.
01, t
rend
). H
isto
logy
of p
atie
nts
afte
r 6
mon
ths:
one
of s
even
impr
oved
from
st
age
2 to
1 (B
runt
cla
ssifi
catio
n); a
dditi
onal
ly, f
atty
live
r, b
allo
onin
g,
and/
or in
flam
mat
ion
of li
ver
lobu
le a
nd p
erip
orta
l are
a im
prov
ed in
fiv
e ca
ses.
One
no
chan
ge a
nd o
ne s
light
agg
rava
tion.
N
o A
DR
.
Stat
istic
ana
lysi
s w
ith JM
P Ed
ition
5.1
.1a
(SA
S In
stitu
te In
c.,
Car
y, N
C, U
SA).
Lian
g22
EPL:
mea
n 54
yr/
18 m
an
d 12
f G
P: m
ean
52 y
r/12
m
and
8 f
Ope
n co
ntro
lled
stud
y: o
f 50
patie
nts
with
FL,
30
rece
ived
0.6
g E
PL p
o tid
fo
r 2
wee
ks a
nd 0
.3 g
EPL
po
tid fo
r 2
wee
ks v
s 20
pat
ient
s 40
mg
GP
tid
for
4 w
eeks
.
EPL:
AST
, ALT
, TC
, and
TG
↓ (
P,0.
01).
28 p
atie
nts
effe
ctiv
e (c
ombi
natio
n of
sym
ptom
s, U
S, li
pid
leve
ls, a
nd
LFT
) an
d tw
o in
effe
ctiv
e: o
vera
ll 93
.3%
. G
P: A
ST a
nd A
LT ↓
(P,
0.05
). T
en p
atie
nts
effe
ctiv
e an
d te
n in
effe
ctiv
e: o
vera
ll 50
%.
Diff
eren
ces
betw
een
grou
ps P
,0.
01.
No
AD
R.
BT: 0
.2 g
inos
in t
id a
nd 0
.1 g
vi
tam
in C
tid
; die
t ad
just
men
t an
d ph
ysic
al e
xerc
ise.
A
dditi
onal
ly, d
rugs
to
trea
t th
e ca
uses
of t
he c
ondi
tion.
t-
test
for
com
pari
son.
Arv
ind
et a
l2618
–60
yrR
ando
miz
ed d
oubl
e-bl
ind
stud
y: o
f 40
pat
ient
s w
ith N
AFL
D, 2
0 re
ceiv
ed
0.35
mg
EPL
po t
id v
s 20
UD
CA
(7
–10
mg/
kg 1
× da
ily)
for
3 m
onth
s.
In e
ach
grou
p, t
en p
atie
nts
with
N
AFL
D a
nd t
en o
bese
.
EPL:
in 4
5% n
ause
a, m
alai
se, a
nd a
bdom
inal
dis
tens
ion
sign
ifica
ntly
de
crea
sed.
AST
, ALT
, and
AP
↓ (P
=0.0
87, P
=0.0
05, a
nd P
=0.0
02,
resp
ectiv
ely)
. US:
impr
ovem
ent n
ot n
otew
orth
y af
ter
1 m
onth
but
in
20%
afte
r 3
mon
ths.
GLY
: in
30%
nau
sea,
mal
aise
, and
abd
omin
al d
iste
nsio
n si
gnifi
cant
ly
decr
ease
d. A
LT ↓
(P=
0.03
8), A
ST a
nd A
P ns
US
impr
ovem
ent
not
note
wor
thy
afte
r 1
mon
th b
ut in
10%
afte
r 3
mon
ths.
N
o A
DR
.
Inta
ke o
f all
othe
r m
edic
atio
ns
stop
ped
duri
ng s
tudy
. N
o m
ajor
diff
eren
ces
in
resp
onse
in s
ubgr
oups
.
Ohb
ayas
hi e
t al
1646
yr/
1 f
Cas
e re
port
: one
pat
ient
with
N
ASH
rec
eive
d 7
mon
ths
270
mg/
d na
tegl
inid
e, fo
llow
ed b
y ad
ditio
nal
0.5
g EP
L po
tid
for
2 yr
.
Stea
tosi
s de
crea
sed
from
sco
re 2
to
1; b
allo
onin
g, in
tra-
acin
ar,
and
port
al in
flam
mat
ion
disa
ppea
red
afte
r 9
mon
ths
trea
tmen
t, co
rres
pond
ing
to d
ecre
ase
of s
tagi
ng fr
om 2
to
0 (B
runt
cl
assi
ficat
ion)
. A
fter
9 m
onth
s, U
S im
prov
emen
t of
dee
p ec
ho a
tten
uatio
n w
ith
hepa
tore
nal e
cho
cont
rast
. H
OM
A-R
, AST
, ALT
, y-G
T, a
nd fe
rriti
n no
rmal
ized
.
No
diet
, exe
rcis
e, a
lcoh
ol
cons
umpt
ion,
or
vira
l hep
atiti
s.
Mar
ked
labo
rato
ry e
ffect
s af
ter
4 w
eeks
.
Shen
25EP
L: 2
7–60
yr/
72 m
an
d 28
f G
LY: 2
5–60
yr/
68 m
an
d 32
f
Ran
dom
ized
ope
n co
ntro
lled
stud
y:
of 2
00 p
atie
nts
with
NA
FLD
, 100
re
ceiv
ed 0
.25
g EP
L iv
qd
as in
fusi
on
for
1 m
onth
, fol
low
ed b
y 0.
6 g
EPL
po
tid v
s 10
0 pa
tient
s 60
ml G
LY iv
/d q
d as
infu
sion
, fol
low
ed b
y 15
0 m
g G
LY
po t
id fo
r 1
mon
th.
EPL:
AST
, ALT
, and
TG
impr
oved
to
norm
al (P
,0.
01).
U
S: 2
5 m
arke
d ef
fect
iven
ess
and
66 e
ffect
ive
(91%
). G
LY: A
ST a
nd A
LT im
prov
ed t
o no
rmal
(P,
0.01
), T
G n
s.
US:
14
mar
ked
effe
ctiv
enes
s an
d 54
effe
ctiv
e (6
8%).
Tot
al e
ffica
cy s
igni
fican
tly d
iffer
ent
betw
een
grou
ps (P
,0.
05).
NA
FLD
ass
ocia
ted
in 2
2 (E
PL)
and
20 (
GLY
) pa
tient
s w
ith
chro
nic
hepa
titis
B a
nd in
13
(EPL
) an
d 16
(G
LY)
with
typ
e II
diab
etes
. SP
SS s
tatis
tical
pac
kage
.
Buye
vero
v et
al17
$18
yr
Ope
n co
ntro
lled
stud
y: o
f 40
patie
nts
with
mix
ed s
teat
ohep
atiti
s, 2
5 re
ceiv
ed 1
.7 g
/d m
etfo
rmin
+ 0
.6 g
EP
L po
tid
vs
15 m
etfo
rmin
onl
y fo
r 6
mon
ths.
AST
, ALT
, and
y-G
T ↓
; P,
0.05
vs
cont
rol g
roup
.D
iet,
exer
cise
, and
alc
ohol
ab
stin
ence
.
Sun
et a
l1842
±3 y
r/40
m a
nd 3
4 f
Ran
dom
ized
ope
n co
ntro
lled
stud
y:
of 7
4 pa
tient
s w
ith d
iabe
tes
with
N
AFL
D, 3
4 re
ceiv
ed 0
.5 g
met
form
in
tid +
0.6
g E
PL p
o tid
vs
34 m
etfo
rmin
on
ly fo
r 3
mon
ths.
EPL:
TC
, TG
, and
US
appe
aran
ce im
prov
ed (P
,0.
05).
Tot
al
effe
ctiv
e ra
te 7
8.4%
. C
ontr
ol: T
C, T
G, a
nd U
S ap
pear
ance
impr
oved
(P,
0.05
). T
otal
ef
fect
ive
rate
54.
1%.
Diff
eren
ces
betw
een
grou
ps s
igni
fican
t (T
C a
nd T
G, P
,0.
01;
US
appe
aran
ce a
nd t
otal
effe
ctiv
e ra
te, P
,0.
05).
BT: d
iet
and
phys
ical
exe
rcis
e.
SPSS
sta
tistic
al p
acka
ge 1
1.0.
Zhu
ang
and
Z
hang
27
Mea
n 41
.5 y
r/48
m
and
34 f
Ran
dom
ized
ope
n co
ntro
lled
stud
y:
of 8
2 pa
tient
s w
ith N
ASH
, 40
rece
ived
0.
6 g
EPL
po t
id +
0.2
5 g
UD
CA
vs
42 o
nly
0.6
g EP
L po
tid
for
6 m
onth
s.
EPL
+ U
DC
A: s
ympt
oms
disa
ppea
red
com
plet
ely.
AST
, ALT
, TC
, an
d T
G d
ecre
ased
or
norm
aliz
ed (P
,0.
05).
US:
65%
impr
oved
. 20
pat
ient
s re
cove
red,
nin
e m
arke
dly
impr
oved
, and
sev
en s
how
ed
effe
ctiv
enes
s (9
0%).
EPL:
sym
ptom
s di
sapp
eare
d co
mpl
etel
y. A
ST, A
LT, T
C, a
nd T
G ↓
(P
,0.
05).
40.5
% im
prov
ed.
US:
40.
5% im
prov
ed. 1
2 pa
tient
s re
cove
red,
sev
en m
arke
dly
impr
oved
, and
ten
sho
wed
effe
ctiv
enes
s (6
9%).
Com
bina
tion
mor
e ef
fect
ive
than
EPL
alo
ne (P
,0.
05).
BT: a
o di
et, a
lcoh
ol a
bstin
ence
, ph
ysic
al e
xerc
ise.
SP
SS s
tatis
tical
pac
kage
13.
0.
Zho
u an
d Su
n28
BT +
EPL
: 17–
56
yr/3
7 m
and
17
f BT
: 16–
60 y
r/34
m
and
14 f
Ran
dom
ized
ope
n co
ntro
lled
stud
y: o
f 10
2 pa
tient
s w
ith F
LD, 5
4 re
ceiv
ed B
T
+ 0.
5 g
EPL
iv/d
in 2
50 m
L 5%
glu
cose
fo
r 1
mon
th, f
ollo
wed
by
5 m
onth
s BT
+ 0
.6 g
EPL
po
tid v
s 48
pat
ient
s BT
alo
ne.
Sign
ifica
nt d
iffer
ence
s in
favo
r of
BT
+ E
PL fo
r A
LT, A
ST, a
nd T
G
↓; P
ns
for
y-G
T, T
BA, T
C, H
DL,
and
LD
L.
Sign
ifica
nt d
iffer
ence
of l
iver
his
tolo
gica
l im
prov
emen
t (P
,0.
05).
BT
+ E
PL h
ad a
rat
e of
20.
4% (
11 o
f 54)
and
EPL
of 1
0.4%
(5
of 4
8).
BT: s
ilybi
n (4
tbl
) +
gluc
uron
olac
tone
(2
tbl)
+ vi
tam
in B
com
plex
(2
tbl)
po t
id.
SPSS
sta
tistic
al p
acka
ge 1
3.0.
(Con
tinue
d)
Clinical and Experimental Gastroenterology 2016:9submit your manuscript | www.dovepress.comDovepress
Dovepress
108
Gundermann et al
Clin
ical
and
Exp
erim
enta
l Gas
troe
nter
olog
y do
wnl
oade
d fr
om h
ttps:
//ww
w.d
ovep
ress
.com
/ by
137.
108.
70.1
4 on
23-
Jan-
2020
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per
sona
l use
onl
y.
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-
Tab
le 1
(Co
ntin
ued)
Clin
ical
stu
dyA
ge/s
exSt
udy
popu
lati
on a
nd d
esig
nE
ffect
sR
emar
ks
Ohb
ayas
hi20
51.6
±13.
9 yr
/16
m
and
9 f
Ope
n st
udy:
25
patie
nts
(18
NA
SH,
7 w
ith a
lcoh
olic
FLD
) re
ceiv
ed 0
.5 g
EP
L po
tid
for
12 m
onth
s.
NA
SH: A
ST a
nd A
LT ↓
, alre
ady
signi
fican
t afte
r 4
wee
ks th
erap
y (P
=0.0
04 a
nd P
=0.0
05).
y-G
T re
mai
ned
norm
al. I
mpr
ovem
ent
sust
aine
d th
roug
hout
the
stud
y.
ASH
: AST
, ALT
, and
y-G
T ↓
, alr
eady
sig
nific
ant
afte
r 8/
4 w
eeks
(P
=0.0
33, P
=0.0
21, t
rend
). Im
prov
emen
t su
stai
ned
(ALT
and
y-G
T)
or c
ontin
ued
to n
orm
al (
AST
). A
DR
: one
pat
ient
mild
gas
tric
dis
com
fort
and
one
pat
ient
mild
di
arrh
ea a
nd lo
ose
stoo
ls.
Lipi
d le
vels
rem
aine
d un
alte
red.
Poon
goth
ai
et a
l1541
±8 y
r/14
m a
nd 1
4 f
Ope
n st
udy:
of 2
8 pa
tient
s w
ith
diab
etes
with
NA
FLD
, 22
wer
e av
aila
ble
for
follo
w-u
p an
d re
ceiv
ed
0.7
g EP
L po
tid
for
6 m
onth
s.
US:
two
of fo
ur o
f gra
de 1
of N
AFL
impr
oved
, one
sho
wed
no
chan
ge, a
nd o
ne w
orse
ned.
In c
ase
of g
rade
2 a
nd 3
, five
of 1
2 an
d fiv
e of
six
impr
oved
. Ove
rall,
54.
5% im
prov
ed, 4
0.9%
did
not
cha
nge,
an
d on
e ca
se w
orse
ned.
80
% o
f pat
ient
s w
ith g
rade
3 im
prov
ed in
hep
atic
ech
otex
ture
, w
hile
onl
y 50
% o
f gra
de 1
pat
ient
s.
LFT:
AST
, ALT
, and
y-G
T ↓
(P=0
.004
, P=0
.007
, and
P=0
.024
, re
spec
tivel
y). E
ven
amon
g pa
tient
s w
ithou
t US
chan
ges,
decr
ease
in a
ll en
zym
es. A
ST a
nd A
LT s
tart
ed to
impr
ove
with
in 2
mon
ths
of th
erap
y,
y-G
T af
ter
6 m
onth
s. FP
G, H
bA1c, a
nd T
C ↓
(P=0
.007
, P=0
.001
, and
P=0
.046
, res
pect
ivel
y).
No
AD
R.
BT: d
iet
and
antid
iabe
tics;
ad
ditio
nally
, 16.
6% o
n a
stat
in
and
8.3%
on
a fib
rate
. SP
SS s
tatis
tical
pac
kage
10.
0.
Ohb
ayas
hi e
t al
2130
–62
yr/5
m a
nd 3
fO
pen
stud
y: e
ight
pat
ient
s w
ith
NA
SH r
ecei
ved
0.5
g EP
L po
tid
for
12 m
onth
s.
AST
, ALT
, and
y-G
T ↓
(P=
0.01
2, P
=0.0
05, t
rend
) af
ter
4 w
eeks
, la
stin
g du
ring
the
12-
mon
th t
reat
men
t (P
,0.
05, P
,0.
01, t
rend
). H
isto
logy
of p
atie
nts
afte
r 6
mon
ths:
one
of s
even
impr
oved
from
st
age
2 to
1 (B
runt
cla
ssifi
catio
n); a
dditi
onal
ly, f
atty
live
r, b
allo
onin
g,
and/
or in
flam
mat
ion
of li
ver
lobu
le a
nd p
erip
orta
l are
a im
prov
ed in
fiv
e ca
ses.
One
no
chan
ge a
nd o
ne s
light
agg
rava
tion.
N
o A
DR
.
Stat
istic
ana
lysi
s w
ith JM
P Ed
ition
5.1
.1a
(SA
S In
stitu
te In
c.,
Car
y, N
C, U
SA).
Lian
g22
EPL:
mea
n 54
yr/
18 m
an
d 12
f G
P: m
ean
52 y
r/12
m
and
8 f
Ope
n co
ntro
lled
stud
y: o
f 50
patie
nts
with
FL,
30
rece
ived
0.6
g E
PL p
o tid
fo
r 2
wee
ks a
nd 0
.3 g
EPL
po
tid fo
r 2
wee
ks v
s 20
pat
ient
s 40
mg
GP
tid
for
4 w
eeks
.
EPL:
AST
, ALT
, TC
, and
TG
↓ (
P,0.
01).
28 p
atie
nts
effe
ctiv
e (c
ombi
natio
n of
sym
ptom
s, U
S, li
pid
leve
ls, a
nd
LFT
) an
d tw
o in
effe
ctiv
e: o
vera
ll 93
.3%
. G
P: A
ST a
nd A
LT ↓
(P,
0.05
). T
en p
atie
nts
effe
ctiv
e an
d te
n in
effe
ctiv
e: o
vera
ll 50
%.
Diff
eren
ces
betw
een
grou
ps P
,0.
01.
No
AD
R.
BT: 0
.2 g
inos
in t
id a
nd 0
.1 g
vi
tam
in C
tid
; die
t ad
just
men
t an
d ph
ysic
al e
xerc
ise.
A
dditi
onal
ly, d
rugs
to
trea
t th
e ca
uses
of t
he c
ondi
tion.
t-
test
for
com
pari
son.
Arv
ind
et a
l2618
–60
yrR
ando
miz
ed d
oubl
e-bl
ind
stud
y: o
f 40
pat
ient
s w
ith N
AFL
D, 2
0 re
ceiv
ed
0.35
mg
EPL
po t
id v
s 20
UD
CA
(7
–10
mg/
kg 1
× da
ily)
for
3 m
onth
s.
In e
ach
grou
p, t
en p
atie
nts
with
N
AFL
D a
nd t
en o
bese
.
EPL:
in 4
5% n
ause
a, m
alai
se, a
nd a
bdom
inal
dis
tens
ion
sign
ifica
ntly
de
crea
sed.
AST
, ALT
, and
AP
↓ (P
=0.0
87, P
=0.0
05, a
nd P
=0.0
02,
resp
ectiv
ely)
. US:
impr
ovem
ent n
ot n
otew
orth
y af
ter
1 m
onth
but
in
20%
afte
r 3
mon
ths.
GLY
: in
30%
nau
sea,
mal
aise
, and
abd
omin
al d
iste
nsio
n si
gnifi
cant
ly
decr
ease
d. A
LT ↓
(P=
0.03
8), A
ST a
nd A
P ns
US
impr
ovem
ent
not
note
wor
thy
afte
r 1
mon
th b
ut in
10%
afte
r 3
mon
ths.
N
o A
DR
.
Inta
ke o
f all
othe
r m
edic
atio
ns
stop
ped
duri
ng s
tudy
. N
o m
ajor
diff
eren
ces
in
resp
onse
in s
ubgr
oups
.
Ohb
ayas
hi e
t al
1646
yr/
1 f
Cas
e re
port
: one
pat
ient
with
N
ASH
rec
eive
d 7
mon
ths
270
mg/
d na
tegl
inid
e, fo
llow
ed b
y ad
ditio
nal
0.5
g EP
L po
tid
for
2 yr
.
Stea
tosi
s de
crea
sed
from
sco
re 2
to
1; b
allo
onin
g, in
tra-
acin
ar,
and
port
al in
flam
mat
ion
disa
ppea
red
afte
r 9
mon
ths
trea
tmen
t, co
rres
pond
ing
to d
ecre
ase
of s
tagi
ng fr
om 2
to
0 (B
runt
cl
assi
ficat
ion)
. A
fter
9 m
onth
s, U
S im
prov
emen
t of
dee
p ec
ho a
tten
uatio
n w
ith
hepa
tore
nal e
cho
cont
rast
. H
OM
A-R
, AST
, ALT
, y-G
T, a
nd fe
rriti
n no
rmal
ized
.
No
diet
, exe
rcis
e, a
lcoh
ol
cons
umpt
ion,
or
vira
l hep
atiti
s.
Mar
ked
labo
rato
ry e
ffect
s af
ter
4 w
eeks
.
Shen
25EP
L: 2
7–60
yr/
72 m
an
d 28
f G
LY: 2
5–60
yr/
68 m
an
d 32
f
Ran
dom
ized
ope
n co
ntro
lled
stud
y:
of 2
00 p
atie
nts
with
NA
FLD
, 100
re
ceiv
ed 0
.25
g EP
L iv
qd
as in
fusi
on
for
1 m
onth
, fol
low
ed b
y 0.
6 g
EPL
po
tid v
s 10
0 pa
tient
s 60
ml G
LY iv
/d q
d as
infu
sion
, fol
low
ed b
y 15
0 m
g G
LY
po t
id fo
r 1
mon
th.
EPL:
AST
, ALT
, and
TG
impr
oved
to
norm
al (P
,0.
01).
U
S: 2
5 m
arke
d ef
fect
iven
ess
and
66 e
ffect
ive
(91%
). G
LY: A
ST a
nd A
LT im
prov
ed t
o no
rmal
(P,
0.01
), T
G n
s.
US:
14
mar
ked
effe
ctiv
enes
s an
d 54
effe
ctiv
e (6
8%).
Tot
al e
ffica
cy s
igni
fican
tly d
iffer
ent
betw
een
grou
ps (P
,0.
05).
NA
FLD
ass
ocia
ted
in 2
2 (E
PL)
and
20 (
GLY
) pa
tient
s w
ith
chro
nic
hepa
titis
B a
nd in
13
(EPL
) an
d 16
(G
LY)
with
typ
e II
diab
etes
. SP
SS s
tatis
tical
pac
kage
.
Buye
vero
v et
al17
$18
yr
Ope
n co
ntro
lled
stud
y: o
f 40
patie
nts
with
mix
ed s
teat
ohep
atiti
s, 2
5 re
ceiv
ed 1
.7 g
/d m
etfo
rmin
+ 0
.6 g
EP
L po
tid
vs
15 m
etfo
rmin
onl
y fo
r 6
mon
ths.
AST
, ALT
, and
y-G
T ↓
; P,
0.05
vs
cont
rol g
roup
.D
iet,
exer
cise
, and
alc
ohol
ab
stin
ence
.
Sun
et a
l1842
±3 y
r/40
m a
nd 3
4 f
Ran
dom
ized
ope
n co
ntro
lled
stud
y:
of 7
4 pa
tient
s w
ith d
iabe
tes
with
N
AFL
D, 3
4 re
ceiv
ed 0
.5 g
met
form
in
tid +
0.6
g E
PL p
o tid
vs
34 m
etfo
rmin
on
ly fo
r 3
mon
ths.
EPL:
TC
, TG
, and
US
appe
aran
ce im
prov
ed (P
,0.
05).
Tot
al
effe
ctiv
e ra
te 7
8.4%
. C
ontr
ol: T
C, T
G, a
nd U
S ap
pear
ance
impr
oved
(P,
0.05
). T
otal
ef
fect
ive
rate
54.
1%.
Diff
eren
ces
betw
een
grou
ps s
igni
fican
t (T
C a
nd T
G, P
,0.
01;
US
appe
aran
ce a
nd t
otal
effe
ctiv
e ra
te, P
,0.
05).
BT: d
iet
and
phys
ical
exe
rcis
e.
SPSS
sta
tistic
al p
acka
ge 1
1.0.
Zhu
ang
and
Z
hang
27
Mea
n 41
.5 y
r/48
m
and
34 f
Ran
dom
ized
ope
n co
ntro
lled
stud
y:
of 8
2 pa
tient
s w
ith N
ASH
, 40
rece
ived
0.
6 g
EPL
po t
id +
0.2
5 g
UD
CA
vs
42 o
nly
0.6
g EP
L po
tid
for
6 m
onth
s.
EPL
+ U
DC
A: s
ympt
oms
disa
ppea
red
com
plet
ely.
AST
, ALT
, TC
, an
d T
G d
ecre
ased
or
norm
aliz
ed (P
,0.
05).
US:
65%
impr
oved
. 20
pat
ient
s re
cove
red,
nin
e m
arke
dly
impr
oved
, and
sev
en s
how
ed
effe
ctiv
enes
s (9
0%).
EPL:
sym
ptom
s di
sapp
eare
d co
mpl
etel
y. A
ST, A
LT, T
C, a
nd T
G ↓
(P
,0.
05).
40.5
% im
prov
ed.
US:
40.
5% im
prov
ed. 1
2 pa
tient
s re
cove
red,
sev
en m
arke
dly
impr
oved
, and
ten
sho
wed
effe
ctiv
enes
s (6
9%).
Com
bina
tion
mor
e ef
fect
ive
than
EPL
alo
ne (P
,0.
05).
BT: a
o di
et, a
lcoh
ol a
bstin
ence
, ph
ysic
al e
xerc
ise.
SP
SS s
tatis
tical
pac
kage
13.
0.
Zho
u an
d Su
n28
BT +
EPL
: 17–
56
yr/3
7 m
and
17
f BT
: 16–
60 y
r/34
m
and
14 f
Ran
dom
ized
ope
n co
ntro
lled
stud
y: o
f 10
2 pa
tient
s w
ith F
LD, 5
4 re
ceiv
ed B
T
+ 0.
5 g
EPL
iv/d
in 2
50 m
L 5%
glu
cose
fo
r 1
mon
th, f
ollo
wed
by
5 m
onth
s BT
+ 0
.6 g
EPL
po
tid v
s 48
pat
ient
s BT
alo
ne.
Sign
ifica
nt d
iffer
ence
s in
favo
r of
BT
+ E
PL fo
r A
LT, A
ST, a
nd T
G
↓; P
ns
for
y-G
T, T
BA, T
C, H
DL,
and
LD
L.
Sign
ifica
nt d
iffer
ence
of l
iver
his
tolo
gica
l im
prov
emen
t (P
,0.
05).
BT
+ E
PL h
ad a
rat
e of
20.
4% (
11 o
f 54)
and
EPL
of 1
0.4%
(5
of 4
8).
BT: s
ilybi
n (4
tbl
) +
gluc
uron
olac
tone
(2
tbl)
+ vi
tam
in B
com
plex
(2
tbl)
po t
id.
SPSS
sta
tistic
al p
acka
ge 1
3.0.
(Con
tinue
d)
Clinical and Experimental Gastroenterology 2016:9 submit your manuscript | www.dovepress.comDovepress
Dovepress
109
EPL in fatty liver disease
Clin
ical
and
Exp
erim
enta
l Gas
troe
nter
olog
y do
wnl
oade
d fr
om h
ttps:
//ww
w.d
ovep
ress
.com
/ by
137.
108.
70.1
4 on
23-
Jan-
2020
For
per
sona
l use
onl
y.
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-
Tab
le 1
(Co
ntin
ued)
Clin
ical
stu
dyA
ge/s
exSt
udy
popu
lati
on a
nd d
esig
nE
ffect
sR
emar
ks
Fan
et a
l23EP
L: 5
4.29
±10.
11/2
1 m
an
d 21
f X
C: 5
4.62
±9.6
7/20
m
and
22 f
Ran
dom
ized
ope
n co
ntro
lled
stud
y:
of 8
4 pa
tient
s w
ith N
AFL
D a
nd
hype
rlip
idem
ia, 4
2 re
ceiv
ed 0
.6 g
EPL
po
tid
vs
42 p
atie
nts
0.6
g X
C +
5 m
g lo
vast
atin
2×
daily
for
6 m
onth
s.
EPL:
AST
, ALT
, y-G
T, C
HE,
TC
, TG
, HD
L-C
, LD
L-C
, FPG
, TN
F-α,
an
d IL
-6 ↓
(P,
0.01
). X
C: A
ST, A
LT, y
-GT
, CH
E, T
C, T
G, H
DL-
C, L
DL-
C, F
PG, T
NF-
α,
and
IL-6
↓ (
P,0.
01).
No
sign
ifica
nt d
iffer
ence
s be
twee
n th
e gr
oups
. O
ne A
DR
und
er X
C (
diar
rhea
), no
AD
R u
nder
EPL
.
Oth
er d
rugs
with
sam
e ef
fect
no
t al
low
ed.
SPSS
sta
tistic
al p
acka
ge 1
0.0.
Guo
et
al24
EPL:
42.
3±12
.1 y
r/36
m
and
30 f
GLY
: 41.
2±15
.5 y
r/
30 m
and
24
f
Ran
dom
ized
ope
n co
ntro
lled
stud
y: o
f 12
0 pa
tient
s w
ith N
ASH
, 58
rece
ived
2×
0.2
5 g
EPL
iv/d
in 2
50 m
L 5%
gl
ucos
e fo
r 2
wee
ks, f
ollo
wed
by
0.6
g EP
L po
tid
for
4 w
eeks
vs
42 p
atie
nts
150
mg
GLY
(ga
mlix
in)
iv/d
in 5
%
gluc
ose,
follo
wed
by
150
mg
GLY
po
tid fo
r 4
wee
ks.
EPL:
Inci
denc
e of
hep
atic
pai
n, a
bdom
inal
dis
tens
ion,
fatig
ue, a
nd
cons
tipat
ion
↓; A
ST, A
LT, y
-GT
, TB,
TC
, TG
↓, L
DL
and
HD
L ns
. Im
prov
emen
t of
fatt
y liv
er in
tens
ity: P
,0.
001.
G
LY: I
ncid
ence
of h
epat
ic p
ain,
abd
omin
al d
iste
nsio
n, fa
tigue
, and
co
nstip
atio
n ↓;
AST
, ALT
, y-G
T, T
B ↓,
TC
, TG
, LD
L, a
nd H
DL
ns.
Impr
ovem
ent
of fa
tty
liver
inte
nsity
: P=0
.017
. Si
gnifi
cant
diff
eren
ces
betw
een
grou
ps fo
r fa
tty
liver
(fr
om 2
3 to
ni
ne p
atie
nts
unde
r EP
L an
d fr
om 1
5 to
12
unde
r G
LY),
and
for
TC
an
d T
G.
Tw
o A
DR
und
er E
PL (
tran
sien
t di
arrh
ea),
five
unde
r G
LY: 2
× tr
ansi
ent
BP ↑
and
3×
mild
hyp
o-K
+ .
BT: d
iet
and
phys
ical
exe
rcis
e.
SPSS
sta
tistic
al p
acka
ge 1
3.0.
Sas
et a
l19–
Ran
dom
ized
blin
ded
stud
y: o
f 215
pa
tient
s w
ith d
iabe
tes
with
NA
SH,
189
wer
e av
aila
ble
for
follo
w-u
p; 1
52
patie
nts
rece
ived
BT
+ 0
.6 g
EPL
po
tid v
s 37
onl
y BT
for
6 m
onth
s.
114
patie
nts
wer
e tr
eate
d fo
r 7
yr.
ALT
, AST
, and
y-G
T ↓
(P=
0.02
, P=0
.04,
P=0
.03,
bas
elin
e vs
6
mon
ths
trea
tmen
t).
US
impr
oved
dur
ing
the
sam
e tim
e in
101
of 1
52 p
atie
nts
and
rem
aine
d un
chan
ged
in s
even
of 1
52 p
atie
nts
(P=0
.02)
. Se
ven
year
s tr
eatm
ent
led
to s
igni
fican
t de
crea
se in
US
in 9
3 of
11
4 pa
tient
s an
d a
mor
e ef
fect
ive
cont
rol o
f dia
bete
s in
98
of
114
patie
nts
(sig
nific
ant
redu
ctio
n in
HBA
1c).
Prog
ress
of h
epat
ic fi
bros
is s
low
ed v
s co
ntro
l (P=
0.03
), an
d st
eato
sis
incr
ease
d in
the
con
trol
gro
up a
nd d
ecre
ased
und
er E
PL
(P=0
.02)
.
BT: d
iet,
phys
ical
exe
rcis
e an
d 1
g/d
met
form
in.
Knü
chel
32M
ean
49 y
r/49
mR
ando
miz
ed d
oubl
e-bl
ind
stud
y: o
f 40
pat
ient
s w
ith A
FLD
, 20
rece
ived
1.
0 g
EPL
po t
id v
s 20
cor
resp
ondi
ng
plac
ebo
for
2 m
onth
s.
Und
er E
PL A
ST, A
LT, L
AP,
GLD
H, A
P, T
C, L
DL-
C, T
G, T
B,
IgA
, IgG
, IgM
↓ (
P,0.
01).
Satu
rate
d fa
tty
acid
s an
d ol
eic
acid
de
crea
sed,
lino
leic
, lin
olen
ic, a
nd a
rach
idon
ic a
cid
incr
ease
d.
Patie
nts’
eva
luat
ion
of t
hera
peut
ic o
utco
me
unde
r EP
L ve
ry g
ood
(6)
or g
ood
(14)
vs
good
(7)
, mod
erat
e (8
), an
d no
effe
ct (
5) u
nder
pl
aceb
o.
Exce
pt C
18:3, s
igni
fican
t di
ffere
nces
bet
wee
n EP
L an
d pl
aceb
o (P
,0.
01).
BT: u
sual
die
t. N
o sp
ecia
l die
t. N
o tr
eatm
ent
with
any
oth
er
liver
dru
gs 2
wee
ks b
efor
e st
udy.
St
atis
tics:
t-te
st, U
-tes
ts.
Schü
ller
Pére
z an
d G
onzá
les
San
Mar
tin33
EPL:
46.
0±2.
4 yr
/18
m
and
2 f
Plac
ebo:
49.
6±2.
9 yr
/19
m a
nd 1
f
Ran
dom
ized
dou
ble-
blin
d st
udy:
Of
40 p
atie
nts
with
AFL
D, 2
0 re
ceiv
ed
1.0
g EP
L po
tid
vs
20 c
orre
spon
ding
pl
aceb
o fo
r 3
mon
ths.
AP
↓ (P
,0.
05)
unde
r EP
L on
ly. B
etw
een
grou
ps s
igni
fican
t di
ffere
nces
of y
-GT
and
TB
(P,
0.05
). A
ll ot
her
labo
rato
ry v
aria
bles
w
ithin
nor
mal
or
norm
aliz
ed in
bot
h gr
oups
. Phy
sici
ans’
eva
luat
ion
of t
hera
peut
ic o
utco
me
unde
r EP
L go
od (
3), m
oder
ate
(14)
, or
no
effe
ct (
3) v
s m
oder
ate
(9)
or n
o ef
fect
(11
) un
der
plac
ebo.
N
o A
DR
.
Stat
istic
s: s
ign
test
afte
r D
ixon
an
d M
ood,
wilc
oxon
sig
ned-
rank
tes
t, M
ann–
whi
tney
U
-tes
t.
Pano
s et
al30
EPL:
45.
8±1.
4 yr
/25
m
and
28 f
Plac
ebo:
49.
3±1.
6 yr
/22
m a
nd 2
9 f
Ran
dom
ized
dou
ble-
blin
d st
udy:
of
104
patie
nts
with
ASH
, 53
rece
ived
2.
0 g
EPL
po t
id. v
s 51
cor
resp
ondi
ng
plac
ebo
for
up t
o 24
mon
ths.
32 p
atie
nts
died
(12
EPL
, 20
plac
ebo)
and
26
(14
EPL,
12
plac
ebo)
de
faul
ted
or w
ere
with
draw
n.
Impr
oved
sur
viva
l und
er E
PL v
s pl
aceb
o (6
9 vs
49%
(P=0
.11)
). G
reat
est
tend
ency
for
impr
oved
sur
viva
l in
Pugh
’s B
sta
tus
with
tw
o of
12
unde
r EP
L (1
7%)
vs s
even
of 1
6 un
der
plac
ebo
(44%
) (P
ns)
. Mea
n su
rviv
al t
ime
76 w
eeks
und
er E
PL v
s 58
.5 w
eeks
und
er
plac
ebo,
res
pect
ivel
y (P
=0.0
94),
in P
ugh’
s gr
oup
B 83
.9 w
eeks
and
56
.6 w
eeks
. N
o A
DR
.
Tre
atm
ent
with
any
oth
er li
ver
drug
s st
oppe
d 2
wee
ks b
efor
e tr
ial.
Stat
istic
s: χ
2 -te
st (
Yat
e’s
mod
ifica
tion)
or
t-te
st a
s ap
prop
riat
e. S
urvi
val:
Kap
lan–
Mei
er m
etho
d. T
wo-
taile
d te
sts
of s
igni
fican
ce.
Lieb
er e
t al
31EP
L: 4
8.8±
8.2
yr/3
85
m
Plac
ebo:
48.
8±9.
1 yr
/379
m
Ran
dom
ized
dou
ble-
blin
d st
udy:
of
789
patie
nts
with
per
iven
ular
/sep
tal
fibro
sis
or in
com
plet
e ci
rrho
sis,
396
re
ceiv
ed 1
.5 g
EPL
po
tid v
s 39
3 co
rres
pond
ing
plac
ebo
for
24 m
onth
s.
2-yr
bio
psy
in 2
02 E
PL a
nd 2
10 p
lace
bo p
atie
nts.
EP
L no
t si
gnifi
cant
ly d
iffer
ed fr
om p
lace
bo o
n th
e st
age
of fi
bros
is
as a
lcoh
ol w
as r
educ
ed in
bot
h gr
oups
to
∼2.5
dri
nks/
d.
In a
sub
grou
p of
52
patie
nts
cont
inui
ng t
o dr
ink
$84
g/d
cha
nges
in
the
his
tolo
gica
l sem
iqua
ntita
tive
scor
ing
syst
em fa
vore
d EP
L (P
=0.1
84).
Impr
ovem
ent
in t
rans
amin
ase
and
bilir
ubin
favo
ring
EPL
se
en a
t so
me
time
poin
ts in
hep
atiti
s C
vir
us-p
ositi
ve d
rink
ers
or
heav
y dr
inke
rs. P
ositi
ve t
rend
in fa
vor
of E
PL fo
r as
cite
s, b
oth
on
phys
ical
exa
min
atio
n (P
,0.
059)
and
at
follo
w-u
p re
port
(P,
0.05
7).
No
AD
R.
His
tory
of a
t le
ast
80 g
alc
ohol
/d
for
$19
yr.
St
atis
tics:
incl
uded
ana
lysi
s of
var
ianc
e pr
oced
ures
fo
r co
ntin
uous
dat
a an
d χ2
pr
oced
ures
for
cate
gori
cal d
ata.
H
aybi
ttle
–Pet
o m
etho
d fo
r da
ta
safe
ty m
onito
ring
. Dat
abas
e an
d st
atis
tical
ana
lyse
s w
ith S
AS.
Sas
et a
l3541
.1±4
.9 y
rR
ando
miz
ed b
linde
d st
udy:
of 8
6 pa
tient
s w
ith n
ot c
ompl
icat
ed A
LD,
56 p
atie
nts
rece
ived
0.6
g E
PL p
o tid
vs
30
case
s 0.
4 g/
d vi
tam
in E
for
6 m
onth
s.
Betw
een
grou
ps s
igni
fican
t di
ffere
nces
of A
ST, A
LT, a
nd y
-GT
(P
,0.
02, P
,0.
04, a
nd P
,0.
03, r
espe
ctiv
ely)
; mea
n va
lue
of d
isea
se
activ
ity b
y M
etav
ir s
cale
A1
unde
r EP
L an
d A
3 un
der
vita
min
E.
His
tolo
gy a
nd F
ibro
max
sho
wed
tha
t pr
ogre
ss o
f hep
atic
fibr
osis
si
gnifi
cant
ly s
low
ed (
Fibr
omax
: F1
vs F
3) (
P,0.
05),
and
stea
tosi
s in
crea
sed
unde
r vi
tam
in E
and
dec
reas
ed u
nder
EPL
(P,
0.05
). U
S im
prov
ed u
nder
EPL
in 4
9 of
56
patie
nts,
and
glu
cose
, ins
ulin
le
vels
, and
HO
MA
dec
reas
ed s
igni
fican
tly, t
oo.
BT: i
nclu
ded
diet
, phy
sica
l ex
erci
se, a
nd n
o al
coho
l.
Abb
revi
atio
ns: A
DR
, adv
erse
dru
g re
actio
n; A
FLD
, alc
ohol
ic fa
tty
liver
dis
ease
; ALD
, alc
ohol
ic li
ver
dise
ase;
ALT
, ala
nine
am
inot
rans
fera
se; A
P, a
lkal
ine
phos
phat
ase;
ASH
, alc
ohol
ic s
teat
ohep
atiti
s; A
ST, a
spar
tate
am
inot
rans
fera
se;
BT, b
asic
tre
atm
ent;
C, c
hole
ster
ol; C
HE,
cho
lines
tera
se; C
T, c
ompu
ted
tom
ogra
phy;
d, d
ays;
EPL
, ess
entia
l pho
spho
lipid
s; f,
fem
ale;
FL,
fatt
y liv
er; F
LD, f
atty
live
r di
seas
e; F
PG, f
astin
g pl
asm
a gl
ucos
e; γ
-GT
, gam
ma-
glut
amyl
tra
nsfe
rase
; G
LDH
, gl
utam
ate
dehy
drog
enas
e; G
LY,
diam
mon
ium
gly
cyrr
hici
nate
; G
P, g
ynos
tem
ma
pent
aphy
llum
gyp
enos
ides
; H
bA1c
, he
mog
lobi
n A
1c;
HD
L, h
igh-
dens
ity l
ipop
rote
in;
HO
MA
, H
omeo
stas
is M
odel
Ass
essm
ent;
iv,
intr
aven
ous;
Ig
, im
mun
oglo
bulin
; IL,
inte
rleu
kin;
LA
P, le
ucin
e am
ino
pept
idas
e; L
DL,
low
-den
sity
lipo
prot
ein;
LFT
, liv
er fu
nctio
n te
sts;
m, m
ale;
NA
FLD
, non
alco
holic
fatt
y liv
er d
isea
se; N
ASH
, non
alco
holic
ste
atoh
epat
itis;
ns,
not
sig
nific
ant;
tid, t
hree
tim
es d
aily
; po,
ora
lly; q
d, d
aily
; TB,
tot
al b
iliru
bin;
tbl
, tab
let;
TC
, ser
um t
otal
cho
lest
erol
; TG
, ser
um t
rigl
ycer
ides
; TN
F-α,
tum
or n
ecro
sis
fact
or-a
lpha
; UD
CA
, urs
odeo
xych
olic
aci
d; U
S, u
ltras
onog
raph
y; X
C, x
uezh
ikan
g ca
psul
e;
yr, y
ear.
Clinical and Experimental Gastroenterology 2016:9submit your manuscript | www.dovepress.comDovepress
Dovepress
110
Gundermann et al
Clin
ical
and
Exp
erim
enta
l Gas
troe
nter
olog
y do
wnl
oade
d fr
om h
ttps:
//ww
w.d
ovep
ress
.com
/ by
137.
108.
70.1
4 on
23-
Jan-
2020
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per
sona
l use
onl
y.
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-
Tab
le 1
(Co
ntin
ued)
Clin
ical
stu
dyA
ge/s
exSt
udy
popu
lati
on a
nd d
esig
nE
ffect
sR
emar
ks
Fan
et a
l23EP
L: 5
4.29
±10.
11/2
1 m
an
d 21
f X
C: 5
4.62
±9.6
7/20
m
and
22 f
Ran
dom
ized
ope
n co
ntro
lled
stud
y:
of 8
4 pa
tient
s w
ith N
AFL
D a
nd
hype
rlip
idem
ia, 4
2 re
ceiv
ed 0
.6 g
EPL
po
tid
vs
42 p
atie
nts
0.6
g X
C +
5 m
g lo
vast
atin
2×
daily
for
6 m
onth
s.
EPL:
AST
, ALT
, y-G
T, C
HE,
TC
, TG
, HD
L-C
, LD
L-C
, FPG
, TN
F-α,
an
d IL
-6 ↓
(P,
0.01
). X
C: A
ST, A
LT, y
-GT
, CH
E, T
C, T
G, H
DL-
C, L
DL-
C, F
PG, T
NF-
α,
and
IL-6
↓ (
P,0.
01).
No
sign
ifica
nt d
iffer
ence
s be
twee
n th
e gr
oups
. O
ne A
DR
und
er X
C (
diar
rhea
), no
AD
R u
nder
EPL
.
Oth
er d
rugs
with
sam
e ef
fect
no
t al
low
ed.
SPSS
sta
tistic
al p
acka
ge 1
0.0.
Guo
et
al24
EPL:
42.
3±12
.1 y
r/36
m
and
30 f
GLY
: 41.
2±15
.5 y
r/
30 m
and
24
f
Ran
dom
ized
ope
n co
ntro
lled
stud
y: o
f 12
0 pa
tient
s w
ith N
ASH
, 58
rece
ived
2×
0.2
5 g
EPL
iv/d
in 2
50 m
L 5%
gl
ucos
e fo
r 2
wee
ks, f
ollo
wed
by
0.6
g EP
L po
tid
for
4 w
eeks
vs
42 p
atie
nts
150
mg
GLY
(ga
mlix
in)
iv/d
in 5
%
gluc
ose,
follo
wed
by
150
mg
GLY
po
tid fo
r 4
wee
ks.
EPL:
Inci
denc
e of
hep
atic
pai
n, a
bdom
inal
dis
tens
ion,
fatig
ue, a
nd
cons
tipat
ion
↓; A
ST, A
LT, y
-GT
, TB,
TC
, TG
↓, L
DL
and
HD
L ns
. Im
prov
emen
t of
fatt
y liv
er in
tens
ity: P
,0.
001.
G
LY: I
ncid
ence
of h
epat
ic p
ain,
abd
omin
al d
iste
nsio
n, fa
tigue
, and
co
nstip
atio
n ↓;
AST
, ALT
, y-G
T, T
B ↓,
TC
, TG
, LD
L, a
nd H
DL
ns.
Impr
ovem
ent
of fa
tty
liver
inte
nsity
: P=0
.017
. Si
gnifi
cant
diff
eren
ces
betw
een
grou
ps fo
r fa
tty
liver
(fr
om 2
3 to
ni
ne p
atie
nts
unde
r EP
L an
d fr
om 1
5 to
12
unde
r G
LY),
and
for
TC
an
d T
G.
Tw
o A
DR
und
er E
PL (
tran
sien
t di
arrh
ea),
five
unde
r G
LY: 2
× tr
ansi
ent
BP ↑
and
3×
mild
hyp
o-K
+ .
BT: d
iet
and
phys
ical
exe
rcis
e.
SPSS
sta
tistic
al p
acka
ge 1
3.0.
Sas
et a
l19–
Ran
dom
ized
blin
ded
stud
y: o
f 215
pa
tient
s w
ith d
iabe
tes
with
NA
SH,
189
wer
e av
aila
ble
for
follo
w-u
p; 1
52
patie
nts
rece
ived
BT
+ 0
.6 g
EPL
po
tid v
s 37
onl
y BT
for
6 m
onth
s.
114
patie
nts
wer
e tr
eate
d fo
r 7
yr.
ALT
, AST
, and
y-G
T ↓
(P=
0.02
, P=0
.04,
P=0
.03,
bas
elin
e vs
6
mon
ths
trea
tmen
t).
US
impr
oved
dur
ing
the
sam
e tim
e in
101
of 1
52 p
atie
nts
and
rem
aine
d un
chan
ged
in s
even
of 1
52 p
atie
nts
(P=0
.02)
. Se
ven
year
s tr
eatm
ent
led
to s
igni
fican
t de
crea
se in
US
in 9
3 of
11
4 pa
tient
s an
d a
mor
e ef
fect
ive
cont
rol o
f dia
bete