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University of Groningen
Fatty liver diseaseEdens, Mireille Angélique
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Chapter 8.1: General discussion - part 1
Evidence on screening for fatty liver disease: Future perspectives
Submitted/ under review _ Review Paper
Mireille A. Edens
Ronald P. Stolk
Department of Epidemiology
University Medical Center Groningen University of Groningen
Groningen, the Netherlands
Chapter 8.1: General discussion - part 1.
166
ABSTRACT
Background and Aim Fatty liver disease (FLD) is currently (one of) the most prevalent
hepatic condition(s) worldwide and likely increasing. Since FLD initially gives no clinical
symptoms, but does increase morbidity risk, screening could be useful. The aim of this
paper is to discuss if screening for FLD would be effective.
Methods The world health organisation screening criteria, organised into the categories:
‘condition’, ‘diagnosis’, ‘treatment’, and ‘cost’ & ‘screening program’, are discussed.
Results FLD is associated with increased risk for severe liver pathology (cirrhosis and
hepatocellular carcinoma) and cardiovascular pathology (components of the metabolic
syndrome). Compared to reference populations, survival of both patients with non-alcoholic
FLD (NAFLD; including both steatosis and steatohepatitis) and patients with non-alcoholic
steatohepatitis (NASH) is reduced. Moreover, both liver-related mortality and
cardiovascular-related mortality are increased. An estimated 8.3% of patients with NAS
will develop fibrosis, and an estimated 37.6% of patients with NASH will progress in
fibrosis stage. Ultrasonography is an acceptable method for assessing FLD. Most FLD
cases have a behaviour-related etiology, which provides opportunity for treatment. Studies
on cost-effectiveness of screening for FLD lack, but prospects are promising given the
increased costs (both financial and quality of life) of patients with FLD.
Conclusion Based on the evidence presented in this paper, we conclude that screening for
FLD is advisable. However, cost effectiveness studies on screening for fatty liver disease
are yet to be performed.
Screening for fatty liver disease
167
PREFACE
In CHAPTERS 2 and 3 we found that fatty liver disease is highly prevalent, and associated
with an increased cardiovascular disease risk. Therefore, in this chapter, we investigated
whether screening for fatty liver disease would be beneficial.
INTRODUCTION
Excess fat should be stored in adipocytes (subcutaneous fat), where it functions as an
‘adipose organ’ 1. In the case of dietary overflow, lipids can be stored in the peritoneal
cavity (visceral fat), retro-peritoneal (peri-renal fat), or ectopically, i.e. inside myocytes and
organs (e.g. the liver) as well 2. Hepatic free fatty acids (HFFAs), i.e. not oxidated, secreted
as very low density lipoprotein, or excreted as phospholipids into bile, are stored as neutral
triglycerides (TGs) within lipid vesicles [CHAPTER 4] 3. Continuous accumulation of intra-
hepatocellular TGs will result in fatty liver disease (FLD).
FLD, which includes both alcoholic FLD (AFLD) and non-alcoholic FLD (NAFLD; by
≤20g ethanol a day 4), refers to a broad spectrum. Repeated biopsies have revealed that non-
alcoholic steatosis (NAS; fat, with or without non-specific inflammation) can progress to
non-alcoholic steatohepatitis (NASH; fat + inflammation, without of with fibrosis) 5.
Fibrosis progression in the case of NASH, delineating loss of liver fat and inflammation 6,
results in cirrhosis (fibrosis stage 4 7), also referred to as ‘burned out NASH’ 8. It has been
known for many years that cryptogenic cirrhosis can be associated with hepatocellular
carcinoma (HCC) 6, but it only recently discovered that active NASH without cirrhosis can
be accompanied by HCC as well 9, 10. In the case of a NASH background, HCC can be
multi-focal 10. Besides a hepatic risk, NAFLD may also increase cardiovascular disease
(CVD) risk, as a (non-alcoholic) fatty liver overproduces several CVD risk markers
[CHAPTER 3] 11. NAFLD is usually asymptomatic. Non-specific complaints of weakness
and fatigue 12, 13, and a vague right upper abdominal discomfort or epigastric pain are
reported by some patients 6, 13-15. Clinical signs of chronic liver disease are absent, apart
from hepatomegaly in some patients 12, 14, 15. NASH is generally discovered incidentally
during investigation of other (unrelated) medical conditions 12, 15 or after health screening 15.
Chapter 8.1: General discussion - part 1.
168
These risks, may warrant aggressive screening on steatosis 10, 16, in order to prevent
progression to NASH and symptomatic disease.
FLD and NAFLD are highly prevalent worldwide. The estimated current prevalence of
NAFLD by imaging in the Asia-Pacific region was recently reviewed by Amarapurkar ea.
(2007) and ranges from 16% to 42% 17. Two studies in Japan have revealed an incidence of
FLD as well, i.e. from 12.6% in 1989 to 30.3% in 2000 18, and from 33.3% in 2000 to
38.5% in 2005 in men, while the prevalence remained similar in women 19. The estimated
prevalence of FLD and NAFLD by imaging in the Western population varies from 27.4%
to 31% 20-22 and 27% 20, respectively.
However, despite currently being the most common hepatic condition worldwide and likely
increasing, screening on FLD has not been recommended. The World Health Organisation
(WHO) has published screening criteria, originally introduced by Wilson and Jungner 23
and expanded later 24. The aim of this paper is to discuss if screening for FLD would be
effective, by discussing the WHO screening criteria, organised into the following
categories: ‘condition’, ‘diagnosis’, ‘treatment’, ‘cost’ & ‘screening program’ (table І).
Table І. O
rgan
isat
ion o
f sc
reen
ing c
rite
ria
CATEGORY 25
NR
WIL
SON &
JUNGNER CRIT
ERIA
23, 24
EXPANSIO
N 24
Conditio
n
1a
The
conditio
n so
ught
should
be
an im
port
ant
hea
lth pro
ble
m fo
r th
e in
div
idual
and c
om
munity
1b
The
nat
ura
l his
tory
of
the
conditio
n,
incl
udin
g d
evel
opm
ent
from
lat
ent
to
dec
lare
d d
isea
se, sh
ould
be
adeq
uat
ely u
nder
stood
1c
Ther
e sh
ould
be
a re
cogniz
able
lat
ent or
earl
y s
ym
pto
mat
ic s
tage
1d
T
her
e sh
ould
be
a def
ined
tar
get
popula
tion.
Dia
gnosi
s
2a
The
test
should
be
acce
pta
ble
to the
popula
tion
2b
Ther
e sh
ould
be
a su
itab
le tes
t or
exam
inat
ion
2c
Fac
ilitie
s fo
r dia
gnosi
s (a
nd tre
atm
ent)
should
be
avai
lable
Tre
atm
ent
3a
Ther
e sh
ould
be
an a
ccep
ted tre
atm
ent fo
r pat
ients
with r
ecognis
ed d
isea
se
3b
Ther
e sh
ould
be
an a
gre
ed p
olicy
on w
hom
to tre
at a
s pat
ients
3c
Fac
ilitie
s fo
r (d
iagnosi
s an
d)
trea
tmen
t sh
ould
be
avai
lable
Cost
4
The
cost
of
case
-fin
din
g (
incl
udin
g d
iagnosi
s an
d t
reat
men
t of
pat
ients
dia
gnose
d)
should
be
econom
ical
ly
bal
ance
d
in
rela
tion
to
poss
ible
ex
pen
diture
on m
edic
al c
are
as a
whole
Scr
eenin
g
pro
gra
m
5a
Cas
e-fi
ndin
g s
hould
be
a co
ntinuin
g p
roce
ss a
nd n
ot
a ‘o
nce
and f
or
all’
pro
ject
5b
Should
res
pond to a
rec
ognis
ed n
eed
5c
T
he
obje
ctiv
es o
f sc
reen
ing s
hould
be
def
ined
at th
e outs
et
5d
T
he
over
all ben
efits
of
scre
enin
g s
hould
outw
eigh the
har
m
5e
T
her
e sh
ould
be
scie
ntifi
c ev
iden
ce
of
scre
enin
g
pro
gra
m
effe
ctiv
enes
s
5f
T
he
pro
gra
m
should
in
tegra
te
educa
tion,
test
ing,
clin
ical
se
rvic
es, an
d p
rogra
m m
anag
emen
t
5g
T
her
e sh
ould
be
qual
ity
ensu
rance
, w
ith
mec
han
ism
s to
m
inim
ize
pote
ntial
ris
ks
of
scre
enin
g
5h
T
he
pro
gra
m sh
ould
en
sure
in
form
ed ch
oic
e, co
nfi
den
tial
ly,
and r
espec
t fo
r au
tonom
y
5i
T
he
pro
gra
m s
hould
pro
mote
equity a
nd a
cces
s to
scr
eenin
g f
or
the
entire
tar
get
popula
tion
5j
Pro
gra
m e
val
uat
ion s
hould
be
pla
nned
fro
m the
outs
et
Screening for fatty liver disease
169
190
Chapter 8.1: General discussion - part 1.
170
THE CONDITION
FATTY LIVER DISEASE-ASSOCIATED HEALTH PROBLEMS?
Besides occasional non-specific vague complaints 6, 12-15 and hepatomegaly 12, 14, 15, FLD is
associated with various health problems. Physical problems include liver failure caused by
cirrhosis 6, 26 and/or HCC 6, 9, 10, and increased CVD risk [CHAPTER 3] 4, 11. Additionally,
decreased quality of life has been reported 27.
Overall survival compared to reference populations
A meta-analysis on survival of patients with NAFLD has recently been published 16.
Because of its relevance for screening (detection of an early latent stage), this section
focuses specifically on histological-determined FLD subtypes and age (table ІІ). Compared
to reference populations, overall survival of patients with NAS is non-significantly reduced
28-30, whereas survival of both patients with NAFLD 13, 29 and NASH 29, 30 are significantly
reduced. Additionally, survival of patients with AFLD is significantly reduced as well 30.
Causes of death
The primary cause of death in patients with NAFLD is CVD-related death 13, 29-31. CVD-
related death was 7.5% in a reference population, slightly increased to 8.6% in patients with
NAS (p=ns compared to the reference population) and significantly increased to 15.5% in
patients with NASH (p<.05 compared to the reference population) 29. Compared to
reference populations, patients with NASH 29, 32 have a increased risk for liver-related
death. In severe NASH, i.e. half of the population with cirrhosis, infection is the primary
cause of death 33.
Table ІІ.
Longit
udin
al s
tudie
s on s
urv
ival
of
fatt
y liv
er d
isea
se s
ubty
pes
ALIV
E AT BASELIN
E
FOLLOW
-UP PERIO
D
DECEASED
FLD subtypes, i.e. n and age
mean (±sd) & m
edian (range)
N (N%)
Cause of death
NA
S
NA
SH
A
FL
D
E
xtr
a-hep
atic
H
epat
ic
U
Car
dio
vas
cula
r dis
ease
M
O
LB
D
HC
C
Car
dia
c O
V
IHD
O
C
Mat
teoni ea
. (1
999)
32
Unit
ed S
tate
s of
Am
eric
a
N=
59 (
2C
) A
ge
T1: 53 (
±15)
Age
T2: 46 (
±12)
8.9
(±5.5
) &
NR (
0.4
–17.8
)
48 (
36%
) 9
2
2
10
10
11
1
3
N
=73 (
18C
) A
ge
T3: 49 (
±15)
Age
T4: 56 (
±11)
7.8
(±5.3
) &
NR (
0.1
–18.2
)
Dam
-Lar
sen e
a.
(2004)
34
Den
mar
k
N=
109
Age:
39 (
19–80)
16.7
(0.2
–21.9
) 27 (
25%
)
1
N=
106
§
Age:
50 (
26–72)*
**
9.2
(0.6
–23.1
) 79 (
75%
)
22
Dam
-Lar
sen e
a.
(2005)
28†
Den
mar
k
N=
170
Age:
39 (
19–84)
19 (
0.2
–27.1
) N
R
1
N=
247
§
Age:
50 (
26–76)*
**
12.8
(0.1
–27.1
) N
R
54
Ekst
edt ea
. (2
006)
29
Sw
eden
N=
58
Age:
47 (
±12)
13.7
(±1.3
) &
NR (
10.3
–16.3
)
7 (
12%
) 5
1
1
N
=71 (
4C
) A
ge:
55 (
±12)*
**
19 (
27%
) 11
4
2
1
1
San
yal
ea.
(2006)
33
Unit
ed S
tate
s of
Am
eric
a
N=
152
‡ (
74C
) A
ge
CT
P-A
: 55 (
±N
R)
Age
CT
P-B
: 52 (
±N
R)
Age
CT
P-C
: 60 (
±N
R)
10
29 (
19%
) 2
6
5
14
2
Raf
iq e
a. (
2009)
31
Unit
ed S
tate
s of
Am
eric
a
N=
101
Age:
49 (
±15)
18.5
(≥
5–28.5
) 78 (
49%
) 22
14
2
2
7
N
=57
Age:
52 (
±13)
10
Soder
ber
g e
a.
(2010)
30
Sw
eden
N=
67 (
4C
) A
ge:
45 (
±12)
21 (
±7.7
) &
24 (
0.5
–28)
23 (
34%
) 7
5
4
4
2
1
N
=51 (
5C
) A
ge:
49 (
±N
R)
24 (
47%
) 7
8
6
3
N=
25 (
2C
) ¶
Age:
NR
20 (
80%
) 8
1
4
5
2
***,
p<
.001;
†,
enla
rgem
ent
of
thei
r st
udy f
rom
2004;
‡,
n=
74 C
TP
_A
, n=
43 C
TP
_B
, n=
35 C
TP
_C
); §
, al
coholic
stea
tosi
s; ¶
, al
coholic
fatty l
iver
dis
ease
; C
, ci
rrhotics
; C
TP
, C
hild-T
urc
otte-
Pugh s
core
; H
CC
, hep
atoce
llula
r ca
rcin
om
a; L
BD
, liver
and b
ilia
ry d
isea
se (
excl
udin
g H
CC
); M
, ex
tra-
hep
atic
mal
ignan
cy;
NA
FL
D,
non-a
lcoholic
fatty l
iver
dis
ease
; N
AS,
non-a
lcoholic
stea
tosi
s; N
ASH
, non-a
lcoholic
stea
tohep
atit
is;
NR,
not
report
ed;
OC
, oth
er c
ardia
c ca
use
; O
, oth
er e
xtr
a-hep
atic
cau
se; O
V, oth
er v
ascu
lar
even
ts; U
, unknow
n c
ause
.
Screening for fatty liver disease
171
Table ІІІ. L
ongitudin
al s
tudie
s on f
ibro
sis
pro
gre
ssio
n o
f non-a
lcoholic
fatt
y liv
er d
isea
se, by s
eria
l his
tolo
gic
al a
nal
ysi
s
Country of
origin
First biopsy
Follow up period
Last biopsy
NAS
NAFLD
NASH
mean (±sd) & m
edian (range)
Fibrosis
regression
Fibrosis
stable
Fibrosis progression
↑F
→C
Lee
(1989)
12
US
A
N=
8
2.8
(±1.6
) &
2.4
(1.2
–6.1
)
N=
3
N=
3
N=
2
Pow
ell ea
. (1
990)
6
AU
S
N=
13
4.5
(±1.8
) &
4 (
1–8)
N=
1
N=
8
N=
3
N=
1 &
→H
CC
Bac
on e
a. (
1994)
14
US
A
N=
2
5.5
(±2.1
) &
5.5
(4–7)
N
=1
N
=1
Tel
i ea
. (1
995)
15
UK
N
=12
NR (
7.6
–16)
NR
NR
N=
1
Evan
s ea
. (2
002)
35
UK
N
=7
8.2
(±2.6
) &
7 (
5.5
–11.9
)
N=
3
N=
4
Har
riso
n e
a. (
2003)
5
US
A
N
=22 (
3 N
AS
, 19 N
AS
H)
5.7
(N
R)
& N
R (
1.4
–15.7
) N
=4
N=
11
N=
6
N=
1
Fas
sio e
a. (
2004)
36
AR
G
N=
22
5.3
(±2.7
) &
4.3
(3–14.3
) N
=4
N=
11
N=
7
Hui ea
. (2
005)
37
CH
INA
N=
17 (
3 N
AS
, 14 N
AS
H)
5.8
(±1.4
) &
6.1
(3.8
–8)
N
=8
N=
8
N=
1
Adam
s ea
. (2
005)
38†
US
A
N
=103 (
7 N
AS
, 96 N
AS
H)
3.2
(±3)
& N
R (
0.7
–21.3
) N
=30
N=
35
N=
29
N=
9
†, th
is s
tudy is
a cl
inic
al tri
al b
ut th
e ‘i
nte
rven
tion’
had
no e
ffec
t on h
isto
logy; ↑, in
crea
se to h
igher
sta
ge;
→, pro
gre
ssio
n to.
AR
G, A
rgen
tina;
C, ci
rrhosi
s; F
, fi
bro
sis;
HC
C, hep
atoce
llula
r ca
rcin
om
a; N
AF
LD
, non-a
lcoholic
fatt
y liv
er d
isea
se; N
AS, non-a
lcoholi
c
stea
tosi
s; N
AS
H, non-a
lcoholic
stea
tohep
atitis
; N
R, not re
port
ed; U
K, U
nit
ed K
ingdom
; U
SA
, U
nit
ed S
tate
s of
Am
eric
a; A
US, A
ust
ralia
Chapter 8.1: General discussion - part 1.
172
Screening for fatty liver disease
173
NATURAL HISTORY OF FATTY LIVER DISEASE?
Several studies on fibrosis progression in the case of (non-alcoholic) fatty liver disease have
been performed 5, 6, 12, 14, 15, 35-38 and summarised in table ІІІ. NAS could be considered a
latent stage of FLD as it is relatively non-progressive 15, 28, 29. An estimated one-twelfth
(8.3%) of patients with NAS will develop fibrosis 15. Fibrosis progression in patients with
NASH has recently been systematically reviewed by Argo ea. (2009) 39. Of all NASH
patients (n=221 in total) having a second biopsy after 5.3 (±4.2) year, 37.6% progressed to
a higher fibrosis stage, 41.6% had no change, and 20.8% regressed to a lower fibrosis stage
39.
Fibrosis progression
Mean fibrosis progression rate was 0.03 (±0.53) stages/year 39. However, when cirrhotics
are excluded (as they cannot progress further), mean fibrosis progression will be higher 13.
Importantly, fibrosis progression delineates regression of both fat 6, 36, 38 and inflammation 5
,
6, 38. Figure І shows a theoretical model on the FLD spectrum.
Associates of fibrosis progression
Multivariate analysis, with advanced fibrosis (stage 3 and 4) as dependent variables,
revealed that both age and inflammation on initial biopsy are independent predictors of
progression to advanced fibrosis 39. Although this implies important prognostic value these
results are not surprising, as injury yields an inflammatory response 40 resulting in repair of
the injury by means of fibrosis [CHAPTER 4] 3. If inflammation on initial biopsy (and
cirrhotics) is excluded, low initial fibrosis stage, BMI, and diabetes are predictors of
fibrosis progression 38.
DEFINED TARGET POPULATION?
The aim of screening for FLD would be to detect an increased CVD risk and/or hepatic
risk, thereby increasing opportunity for intervention, in order to prevent progression of
CVD risk and hepatic risk, i.e. secondary prevention. The most efficient/effective approach
would be to screen people with an already increased hepatic risk and/or CVD risk, e.g.
diabetes. Patients with type 2 diabetes and NAFLD (by ultrasonography) have a
significantly higher incidence of CVD events compared to patients with type 2 diabetes
without NAFLD 41. Diabetes predisposes to hormone sensitive lipase-induced breakdown
Chapter 8.1: General discussion - part 1.
174
of TG vesicles, releasing more toxic HFFAs [CHAPTER 4] 3, and is a predictor of fibrosis
progression 38.
Screening high risk groups does raise the question of population screening, i.e. primary
prevention 42. Epidemiological studies have revealed that NAFLD is most common at
middle age and decreases at higher ages 43-45.
Fat
Inflammation
Fibrosis
Infiltration:
INFILTRATION
PROGRESSION OF THE FATTY LIVER DISEASE SPECTRUM (SPEED OF PROGRESSION DEPENDS ON THE AMOUNT OF DETERMINANTS, PER INDIVIDUAL)
Normal NASS NASni NASH-f NASH+f/c Cirrhosis
Increased HCC risk
Figure 1. Schematic model on the natural history of fatty liver disease
The scale of natural progression was estimated from progression throughout the various FLD stages is based on long-term follow up studies (appendix
ІІb). The starting stage may vary between individuals.HCC, hepatocellular carcinoma; NASH-f, non-alcoholic steatohepatitis without fibrosis; NASH+f,
non-alcoholic steatohepatitis with fibrosis, NASni, non-alcoholic steatosis with non-specific inflammation; NASS, non-alcoholic simple steatosis.
Screening for fatty liver disease
175
DIAGNOSIS
METHOD ACCEPTABLE TO THE POPULATION?
A diagnosis modality for screening should firstly be non-invasive, which excludes liver
biopsy and computed tomography (harmful radiation). Secondly, a diagnosis method
should be low-cost, which excludes magnetic resonance spectroscopy and magnetic
resonance imaging. Additionally, a diagnosis method should be liver-specific, which
excludes aminotransferases as aminotransferases are produced and present in numerous
tissues 46, 47. An elevation of aminotransferases can therefore be attributed to other diseases
as well 48, 49. The remaining diagnosis method is ultrasonography.
IS ULTRASONOGRAPHY SUITABLE FOR FATTY LIVER DISEASE?
Within the FLD spectrum, fat can both occur separately and coexist with inflammation
and/or fibrosis (figure І). Therefore, in order to estimate the place within the FLD spectrum,
fat, inflammation, and fibrosis are to be determined ideally.
Fat A selection of ultrasound validation studies is shown in table ΙV. Qualitative
ultrasonography is a valid and reliable method for diagnosing FLD, i.e. an abundance of
liver fat 50-52. Validity is decreased in (morbidly) obese people 53, 54. A quantitative
ultrasonography method has recently been developed as well [CHAPTER 5] 55.
Inflammation Ultrasonography is (currently) unable to determine hepatic inflammation,
which means that it is unable to distinguish steatosis and steatohepatitis. Perhaps it might
be of value to estimate splenomegaly 56, but validation studies using ultrasonography-
determined splenomegaly have not been published.
Fibrosis Ultrasonography can estimate hepatic fibrosis. Two meta-analysis on transient
ultrasonographic elastography (FibroScan), i.e. in all liver diseases 57 and in FLD
specifically 16 have recently been published and show acceptable results (table ΙV). The
success rate (applicability) of ultrasonographic elastography is not perfect, which is mostly
attributed to obesity 16, 57. This suggests that for obese patients an extra large transducer
may be required 58. Additionally, it should theoretically be able to estimate fibrosis using
ultrasonographic texture analysis [CHAPTER 5] 55, but more validation work is needed.
Table ΙV. V
alid
ity o
f ultra
sonogra
phy f
or
asse
ssin
g f
atty
liv
er d
isea
se, se
lect
ion o
f th
e lite
ratu
re
Country of
origin
Gold
Standard
Population
Hepatic fat
Hepatic fibrosis
SE (%)
SP (%)
AUC
r SE (%)
SP (%)
AUC
Qualitative ultrasonography
Sav
erym
utt
u e
a. (
1986)
50,
and J
ose
ph e
a. (
1991)
51
Unit
ed K
ingdom
H
(ql.)
(S)L
D
89–94
84–93
- -
NA
N
A
NA
Ham
aguch
i ea
. (2
007)
52
Japan
H
(ql.)
Excl
. A
s an
d v
H
91.2
–92.6
100
0.9
8
- N
A
NA
NA
Quantitative ultrasonography
Eden
s ea
. (2
009)
[C
HAPTER 5
] 55
The
Net
her
lands
1H
MR
S (
qnt.)
Gen
. (n
o k
now
n
LD
excl
. F
LD
) 66.7
100
- .7
89*
- -
-
Transien
t ultrasonographic elastography †
‡
Met
a-an
alysi
s:
Fri
edri
ch-R
ust
ea.
(2008)
57
All
countr
ies
(n=
50 s
tudie
s)
H (
ql.)
F≥2
NA
N
A
NA
N
A
56 –
100
18 –
100
0.6
8 –
1.0
0
F≥3
NA
N
A
NA
N
A
58 –
95
78 –
97
0.7
2 –
0.9
7
F=
4 (
i.e.
C)
NA
N
A
NA
N
A
73 –
100
78 –
98
0.8
1 –
0.9
9
Wes
tern
reg
ion
(n=
46 s
tudie
s)
F≥2
NA
N
A
NA
N
A
56 –
100
18 –
100
0.6
8 –
1.0
0
F≥3
NA
N
A
NA
N
A
58 –
95
85 –
97
0.7
2 –
0.9
7
F=
4 (
i.e.
C)
NA
N
A
NA
N
A
73 –
100
81 –
98
0.8
7 –
0.9
9
Asi
a-P
acif
ic
regio
n
(n=
4 s
tudie
s)
F≥2
NA
N
A
NA
N
A
79 –
90
78 –
88
0.7
7 –
0.8
1
F≥3
NA
N
A
NA
N
A
86 –
95
78 –
92
0.7
9 –
0.9
3
F=
4 (
i.e.
C)
NA
N
A
NA
N
A
80 –
86
78
0.8
1 –
0.8
8
Met
a-an
alysi
s:
Muss
o e
a. (
2010)
16
All
countr
ies
(n=
6 s
tudie
s)
H (
ql.)
F≥2
NA
N
A
NA
N
A
79 –
100
74 –
93
0.8
4 –
0.9
9
F≥3
NA
N
A
NA
N
A
75 –
100
81 –
100
0.9
0 –
1.0
0
Wes
tern
reg
ion
(n=
2 s
tudie
s)
F≥2
NA
N
A
NA
N
A
81 –
100
78 –
92
0.8
6 –
0.9
9
F≥3
NA
N
A
NA
N
A
100
100
1.0
0
Asi
a-P
acif
ic
regio
n
(n=
4 s
tudie
s)
F≥2
NA
N
A
NA
N
A
79 –
100
74 –
93
0.8
4 –
0.9
9
F≥3
NA
N
A
NA
N
A
75 –
100
81 –
93
0.9
0 –
0.9
9
*, p<
.001;
†, cu
t-off
val
ues
dif
fer
per
stu
dy;
‡, su
cces
s-ra
tes
dif
fer
per
stu
dy.
As,
alc
oholics
; A
UC
, ar
ea u
nder
the
curv
e ra
nge;
C,
cirr
hosi
s; D
VS,
theo
reti
cally p
oss
ible
, but
in n
eed o
f fu
rther
dev
elopm
ent
and
val
idat
ion s
tudie
s; E
xcl
., e
xcl
udin
g; F, fi
bro
sis
stag
e as
det
erm
ined
by M
ET
AV
IR a
nd o
ther
sco
ring s
yst
ems;
FL
D, fa
tty liv
er d
isea
se; G
en.,
gen
eral
popula
tion; H
, his
tolo
gy;
1H
MR
S; M
agnet
ic R
esonan
ce S
pec
trosc
opy; L
D, li
ver
dis
ease
; N
A, not ap
pli
cable
; ql., qual
itat
ive;
qnt.,
quan
tita
tive;
r, co
rrel
atio
n c
oef
fici
ent
by P
ears
on;
SE
, se
nsi
tivity r
ange;
(S)L
D, (s
usp
ecte
d)
liver
dis
ease
; SP, sp
ecif
icity r
ange;
vH
, vir
al
hep
atit
is.
Chapter 8.1: General discussion - part 1.
176
Screening for fatty liver disease
177
TREATMENT
ACCEPTED TREATMENT?
When discussing treatment, it is relevant to distinguish cases with a behavioural etiology
and cases with a non-behavioural etiology. Patients with a behaviour-related etiology can
potentially be treated (‘is controllable’), in contrast to patients with a more complicated
etiology like genetic, drug-related, and/or environment-related (‘partially controllable’). In
order to determine a suitable treatment for the individual patient, etiologic factors per
individual patient should be determined. Risk factors for FLD can be arranged in the
following three categories: 1] risk factors for hepatic lipid content, 2] risk factors for
inhibited hepatic metabolism, and 3] risk factors for hepatic inflammation [CHAPTER 4] 3.
Behavioural etiology, i.e. controllable
Given the link with overnutrition & low physical activity, and alcohol (AFLD) [CHAPTER
4] 3, it is to be expected that most of the FLD cases have a behaviour-related etiology.
These behaviour-related cases may be naturally resolved by breaking off etiologic
behaviour. Weight loss interventions resulting in weight loss of ≥2.6 body mass index-
points, were effective in improving NAFLD [CHAPTER 3] 4, 11. This can be achieved
through diet 59, exercise alone 60, diet & exercise 59, 60, or bariatric surgery 59. Weight loss
should not go too fast, given the risk of accentuation or development of focal fatty change
in liver segment ІV 61. A part of the patients may be able to achieve and maintain weight
loss themselves 62. If needed, general practitioners, nutritionists 63, and cognitive behaviour
therapists 64, 65, may be able to assist people with their weight loss.
Non-behavioural etiology, i.e. partially controllable
In the case of a non-behaviour-related etiology, etiologic factors should be abolished, e.g.
use of hepatotoxic drugs if possible 66, 67 and protection for or change of the environment 68.
Otherwise, the non-natural cases may be in need of pharmacological treatment to either
resolve FLD itself [CHAPTER 3] 11, 59, 69 or to resolve FLD associated pathology [CHAPTER
3] 4, 11, 70. A systematic clinical review has recently been published, which describes the
actions and effects of potential pharmacological treatment modalities for FLD 59. It should
be noted that effects of pharmacological approaches are often confounded by weight loss
[CHAPTER 3] 11. If pharmacological treatment coincides with weight loss, it is difficult to
determine the independent effect of the pharmacological intervention. A meta-analysis on
Chapter 8.1: General discussion - part 1.
178
randomised clinical trials for FLD was recently published as well, reporting that
randomised trials of adequate size and duration using histological endpoints are needed, to
assess long-term safety and efficacy 69.
AGREED POLICY WHO TO TREAT?
Policy decision guidelines are based on increased absolute risks 42. This likely means that
people with known hepatic and/or CVD risk factors should be offered screening and
treatment for FLD.
Screening for fatty liver disease
179
COST AND SCREENING PROGRAM
COST OF FLD?
It has been shown that patients with FLD (by ultrasonography and alanine
aminotransferase) have more consults from specialists and use more medication compared
to subjects without FLD 70, suggesting that screening and treatment might potentially cut
down health care expenditure 70. The increased medication use in FLD was largely
attributable to diabetes and lipid lowering medication 70.
COST OF A SCREENING PROGRAM FOR FLD?
To the best of our knowledge, there are no published studies on the cost-effectiveness of
ultrasonographic screening for FLD. It is important to realise, that with ultrasonographic
screening for FLD, screening for other (un)expected hepatic lesions, e.g. HCC, will
automatically be included as well. Screening for HCC has been reported to be effective, at
least in a high risk group 71. Cost-effectiveness was not studied, but the authors did report
that the estimated costs of the screening program were similar to their national breast
cancer screening program 71.
AFTER FLD DIAGNOSIS?
After having diagnosed FLD it may be wise to determine etiology and/or comorbidity of
FLD. The design of a potential screening program, including potential management and
treatment of discovered cases, is shown in appendix І.
Etiology
As described in the treatment section, it may be relevant to determine etiology for each
individual patient in order to determine the most appropriate action(s). A behavioural
etiology could simply be determined by questionnaires on behaviour, anthropometry, and
ultrasonography. A non-behavioural etiology could be identified by questionnaires on
behaviour, (familiar) diseases, and environment.
Comorbidity
Given the strong association of FLD with components of the MetS [CHAPTER 3] 4, 11,
components of the MetS should be assessed as well.
Chapter 8.1: General discussion - part 1.
180
DISCUSSION
Taken together, the screening criteria regarding ‘condition’, ‘treatment’, ‘diagnosis’, and
‘screening program’ (table І) seem to be reasonable met or possible to meet. Currently cost-
effectiveness studies on screening for FLD lack, but prospects are promising given the
increased cost (both financial 70 and quality of life 27) of patients with FLD. Before
screening prime time, general practioners and specialists should bear FLD in mind and
stimulate weight loss.
STUDIES USED IN THIS PAPER
Histological analysis
Most studies used in this paper used histology as diagnosis modality. It should be noted that
the first histological scoring protocol for internationally uniform scoring of FLD, was
published in 1999 72 and updated in 2005 7. Despite currently being the only modality that
can stage FLD (i.e. distinguish steatosis and steatohepatitis), it has some diagnostic
disadvantages as well. Liver biopsy is subject to sampling bias 73, 74 and histological
analysis is subject to scoring variability (particularly of inflammation) 7, 72, 75.
Risks in the general population
Many studies used in this paper were studies on ‘natural’ NAFLD, which means that,
besides obesity and diabetes, many known etiologic factors were excluded. Obviously,
all/many etiologic factors for FLD [CHAPTER 4] 3 are present in the general population,
which may suggest a (much) faster fibrosis progression rate in the general population.
CONCLUSION
Based on the evidence presented in this paper, we conclude that screening for FLD is
advisable. However, cost effectiveness studies on screening for FLD are yet to be
performed.
Screening for fatty liver disease
181
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Screening for fatty liver disease
189
USG outcome:
Determ
ineFLD pathogenesisand
pathophysiology[ A]:
Action(s):
Action(s) to beconsidered:
Re-screen:
Norm
alliver
FLD
Fat +
F0-F1
Fat +
F1-F2
Abnorm
al
liver
HCC orotherlesion
Continu lifestyle
Questionnaire onbehaviour&lifestyle:
•Nutrition
•Alcohol and other drugs (current & recent history)
•Energy expenditure
(Fat +)
F3-F4
Questionnaire on complaints and (potential) diseases:
•Knowndiseases
•Known family disease history (e.g. HH)
Questionnaire on drugs/medicine:
•All drugs used currently
•All drugs used in recent history
Change lifestyle:
•Limit calorie intake [E]
•Limit alcohol and usedrugs
•Exersice[F]
Weightloss [G]:
•2.6 BMI-points[ C]
•Gradual, to prevent worsening [H]
These are likelyalreadybeingtreated
Questionnaire on Environment:
Known exposure to toxins at work or elsewhere
Protect for the environment [L]
Changelifestyle:
•Nutritional counselling[M]
•Rehabilitationprogram
•(Cognitive) behavioural therapy [N]
Weight loss:
•Drugs for weight loss [E]
•Bariatric surgery [E]
Screeningfor(family) disease
Examination of obesity, particularly VAT:
•APM for BMI and waist-to-hip ratio
•USG for VAT/SAT ratio [B]
Blood tests for assessment CVD [C] and/or hepatic risk:
•Glucose
•Lipids
•Blood pressure
•Inflammation
•Coagulation
Treatment for insulin resistance [E]
Examination of small intestinal bacterial overload:
Breath test [D]
Treat infection
Examination of lipodystrophy:
•APM/USG for SAT
•Questionnaire/blood tests on menopausal state
•Angiotensinreceptor blockade [E]
•Anti-TNFα[E]*
Examination of liver disease (other than FLD):
•Autoimmunehepatitis
•Viralhepatitis
Take into account genotype [O]
Correct unfavourable fat distribution:
•via Thiazolidinediones[E]
•via horm
ones(HRT)
t = 5
t = 3
t = 2
Appropriate treatm
ent
Refer to a specialist
Refer to a specialist
Fat +
F2-F3
•Eliminate/minimise drug use if possible[I]
•Use drugs without hepatic metabolism [J]
and/or without immunogeneity[K]
•Change nutrition
•Limit alcohol use
Change the environment [L]
Appen
dix І. P
ote
ntial
des
ign o
f a
scre
enin
g p
rogra
m f
or
fatt
y liv
er d
isea
se, w
hic
h is
not ev
aluat
ed y
et, th
us
pure
ly h
ypoth
etic
al
[A],
[CHAPTER 4
] 3; [B],
76-7
8; [C
], [CHAPTER 3
] 11; [D
], 7
9, 80; [E], 5
9; [F], 6
0; [G
], [CHAPTER 3
] 4, 11, 59, 62; [H
], 6
1; [I],
66, 67; [J], 8
1; [K
], 8
2; [L], 6
8; [M
], 6
3; [N
], 6
4, 65; [O
], 8
3.
AP
M,
anth
ropom
etry
; B
MI,
body m
ass
index
; C
VD
, ca
rdio
vas
cula
r dis
ease
; F
, fi
bro
sis
stag
e; F
LD
, fa
tty l
iver
dis
ease
; H
CC
, hep
atoce
llula
r ca
rcin
om
a; H
H,
her
edit
ary h
aem
och
rom
atosi
s; H
RT
, horm
one
repla
cem
ent
ther
apy;
SA
T,
subcu
taneo
us
adip
ose
ti
ssue;
t,
tim
e in
yea
rs;
TN
Fα,
tum
our
nec
rosi
s fa
ctor
alpha;
U
SG
, ult
raso
nogra
phy;
VA
T,
vis
cera
l ad
ipose
ti
ssue.
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