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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.


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


169


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

.


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


172


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


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.


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.


176


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


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.


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.


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.


181

Reference List (1) Avram MM, Avram AS, James WD. Subcutaneous fat in normal and diseased

states: 1. Introduction. J Am Acad Dermatol 2005 October;53(4):663-70.

(2) Snijder MB, van Dam RM, Visser M, Seidell JC. What aspects of body fat are particularly hazardous and how do we measure them? Int J Epidemiol 2006 February;35(1):83-92.

(3) Edens MA, Groen AK, Stolk RP. Pathogenesis of fatty liver disease: A theory on 'lipid content', 'inhibited metabolism', and 'inflammation'. Submitted 2010.

(4) Kotronen A, Yki-Jarvinen H. Fatty liver: a novel component of the metabolic syndrome. Arterioscler Thromb Vasc Biol 2008 January;28(1):27-38.

(5) Harrison SA, Torgerson S, Hayashi PH. The natural history of nonalcoholic fatty liver disease: a clinical histopathological study. Am J Gastroenterol 2003 September;98(9):2042-7.

(6) Powell EE, Cooksley WG, Hanson R, Searle J, Halliday JW, Powell LW. The natural history of nonalcoholic steatohepatitis: a follow-up study of forty-two patients for up to 21 years. Hepatology 1990 January;11(1):74-80.

(7) Kleiner DE, Brunt EM, Van NM, Behling C, Contos MJ, Cummings OW, Ferrell LD, Liu YC, Torbenson MS, Unalp-Arida A, Yeh M, McCullough AJ, Sanyal AJ. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology 2005 June;41(6):1313-21.

(8) Ong J, Younossi ZM, Reddy V, Price LL, Gramlich T, Mayes J, Boparai N. Cryptogenic cirrhosis and posttransplantation nonalcoholic fatty liver disease. Liver Transpl 2001 September;7(9):797-801.

(9) Cuadrado A, Orive A, Garcia-Suarez C, Dominguez A, Fernandez-Escalante JC, Crespo J, Pons-Romero F. Non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma. Obes Surg 2005 March;15(3):442-6.

(10) Chagas AL, Kikuchi LO, Oliveira CP, Vezozzo DC, Mello ES, Oliveira AC, Cella LC, Herman P, Bachella T, Caldwell SH, Alves VA, Carrilho FJ. Does hepatocellular carcinoma in non-alcoholic steatohepatitis exist in cirrhotic and non-cirrhotic patients? Braz J Med Biol Res 2009 October;42(10):958-62.

(11) Edens MA, Kuipers F, Stolk RP. Non-alcoholic fatty liver disease is associated with cardiovascular disease risk markers. Obes Rev 2009 July;10(4):412-9.

(12) Lee RG. Nonalcoholic steatohepatitis: a study of 49 patients. Hum Pathol 1989 June;20(6):594-8.


182

(13) Adams LA, Lymp JF, St Sauver J, Sanderson SO, Lindor KD, Feldstein A, Angulo P. The natural history of nonalcoholic fatty liver disease: a population-based cohort study. Gastroenterology 2005 July;129(1):113-21.

(14) Bacon BR, Farahvash MJ, Janney CG, Neuschwander-Tetri BA. Nonalcoholic steatohepatitis: an expanded clinical entity. Gastroenterology 1994 October;107(4):1103-9.

(15) Teli MR, James OF, Burt AD, Bennett MK, Day CP. The natural history of nonalcoholic fatty liver: a follow-up study. Hepatology 1995 December;22(6):1714-9.

(16) Musso G, Gambino R, Cassader M, Pagano G. Meta-analysis: Natural history of non-alcoholic fatty liver disease (NAFLD) and diagnostic accuracy of non-invasive tests for liver disease severity. Ann Med 2010 November 2.

(17) Amarapurkar DN, Hashimoto E, Lesmana LA, Sollano JD, Chen PJ, Goh KL. How common is non-alcoholic fatty liver disease in the Asia-Pacific region and are there local differences? J Gastroenterol Hepatol 2007 June;22(6):788-93.

(18) Kojima S, Watanabe N, Numata M, Ogawa T, Matsuzaki S. Increase in the prevalence of fatty liver in Japan over the past 12 years: analysis of clinical background. J Gastroenterol 2003;38(10):954-61.

(19) Imamura Y, Uto H, Oketani M, Hiramine Y, Hosoyamada K, Sho Y, Hiwaki T, Baba Y, Tahara K, Kubozono O, Kusano K, Tsubouchi H. Association between changes in body composition and the increasing prevalence of fatty liver in Japanese men. Hepatol Res 2008 November;38(11):1083-6.

(20) Volzke H, Robinson DM, Kleine V, Deutscher R, Hoffmann W, Ludemann J, Schminke U, Kessler C, John U. Hepatic steatosis is associated with an increased risk of carotid atherosclerosis. World J Gastroenterol 2005 March 28;11(12):1848-53.

(21) Szczepaniak LS, Nurenberg P, Leonard D, Browning JD, Reingold JS, Grundy S, Hobbs HH, Dobbins RL. Magnetic resonance spectroscopy to measure hepatic triglyceride content: prevalence of hepatic steatosis in the general population. Am

J Physiol Endocrinol Metab 2005 February;288(2):E462-E468.

(22) Haenle MM, Brockmann SO, Kron M, Bertling U, Mason RA, Steinbach G, Boehm BO, Koenig W, Kern P, Piechotowski I, Kratzer W. Overweight, physical activity, tobacco and alcohol consumption in a cross-sectional random sample of German adults. BMC Public Health 2006;6:233.

(23) Wilson JM, Jungner YG. [Principles and practice of mass screening for disease]. Bol Oficina Sanit Panam 1968 October;65(4):281-393.


183

(24) Andermann A, Blancquaert I, Beauchamp S, Dery V. Revisiting Wilson and Jungner in the genomic age: a review of screening criteria over the past 40 years. Bull World Health Organ 2008 April;86(4):317-9.

(25) Grootendorst DC, Jager KJ, Zoccali C, Dekker FW. Screening: why, when, and how. Kidney Int 2009 October;76(7):694-9.

(26) Clark JM, Diehl AM. Nonalcoholic fatty liver disease: an underrecognized cause of cryptogenic cirrhosis. JAMA 2003 June 11;289(22):3000-4.

(27) David K, Kowdley KV, Unalp A, Kanwal F, Brunt EM, Schwimmer JB. Quality of life in adults with nonalcoholic fatty liver disease: baseline data from the nonalcoholic steatohepatitis clinical research network. Hepatology 2009 June;49(6):1904-12.

(28) Dam-Larsen S, Franzmann MB, Christoffersen P, Larsen K, Becker U, Bendtsen F. Histological characteristics and prognosis in patients with fatty liver. Scand J

Gastroenterol 2005 April;40(4):460-7.

(29) Ekstedt M, Franzen LE, Mathiesen UL, Thorelius L, Holmqvist M, Bodemar G, Kechagias S. Long-term follow-up of patients with NAFLD and elevated liver enzymes. Hepatology 2006 October;44(4):865-73.

(30) Soderberg C, Stal P, Askling J, Glaumann H, Lindberg G, Marmur J, Hultcrantz R. Decreased survival of subjects with elevated liver function tests during a 28-year follow-up. Hepatology 2010 February;51(2):595-602.

(31) Rafiq N, Bai C, Fang Y, Srishord M, McCullough A, Gramlich T, Younossi ZM. Long-term follow-up of patients with nonalcoholic fatty liver. Clin Gastroenterol

Hepatol 2009 February;7(2):234-8.

(32) Matteoni CA, Younossi ZM, Gramlich T, Boparai N, Liu YC, McCullough AJ. Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity. Gastroenterology 1999 June;116(6):1413-9.

(33) Sanyal AJ, Banas C, Sargeant C, Luketic VA, Sterling RK, Stravitz RT, Shiffman ML, Heuman D, Coterrell A, Fisher RA, Contos MJ, Mills AS. Similarities and differences in outcomes of cirrhosis due to nonalcoholic steatohepatitis and hepatitis C. Hepatology 2006 April;43(4):682-9.

(34) Dam-Larsen S, Franzmann M, Andersen IB, Christoffersen P, Jensen LB, Sorensen TI, Becker U, Bendtsen F. Long term prognosis of fatty liver: risk of chronic liver disease and death. Gut 2004 May;53(5):750-5.

(35) Evans CD, Oien KA, MacSween RN, Mills PR. Non-alcoholic steatohepatitis: a common cause of progressive chronic liver injury? J Clin Pathol 2002 September;55(9):689-92.


184

(36) Fassio E, Alvarez E, Dominguez N, Landeira G, Longo C. Natural history of nonalcoholic steatohepatitis: a longitudinal study of repeat liver biopsies. Hepatology 2004 October;40(4):820-6.

(37) Hui AY, Wong VW, Chan HL, Liew CT, Chan JL, Chan FK, Sung JJ. Histological progression of non-alcoholic fatty liver disease in Chinese patients. Aliment Pharmacol Ther 2005 February 15;21(4):407-13.

(38) Adams LA, Sanderson S, Lindor KD, Angulo P. The histological course of nonalcoholic fatty liver disease: a longitudinal study of 103 patients with sequential liver biopsies. J Hepatol 2005 January;42(1):132-8.

(39) Argo CK, Northup PG, Al Osaimi AM, Caldwell SH. Systematic review of risk factors for fibrosis progression in non-alcoholic steatohepatitis. J Hepatol 2009 August;51(2):371-9.

(40) Hotamisligil GS. Inflammation and metabolic disorders. Nature 2006 December 14;444(7121):860-7.

(41) Targher G, Bertolini L, Poli F, Rodella S, Scala L, Tessari R, Zenari L, Falezza G. Nonalcoholic Fatty liver disease and risk of future cardiovascular events among type 2 diabetic patients. Diabetes 2005 December;54(12):3541-6.

(42) Jackson R. Guidelines on preventing cardiovascular disease in clinical practice. BMJ 2000 March 11;320(7236):659-61.

(43) Nomura H, Kashiwagi S, Hayashi J, Kajiyama W, Tani S, Goto M. Prevalence of fatty liver in a general population of Okinawa, Japan. Jpn J Med 1988 May;27(2):142-9.

(44) Bedogni G, Miglioli L, Masutti F, Tiribelli C, Marchesini G, Bellentani S. Prevalence of and risk factors for nonalcoholic fatty liver disease: the Dionysos nutrition and liver study. Hepatology 2005 July;42(1):44-52.

(45) Chen CH, Huang MH, Yang JC, Nien CK, Yang CC, Yeh YH, Yueh SK. Prevalence and risk factors of nonalcoholic fatty liver disease in an adult population of taiwan: metabolic significance of nonalcoholic fatty liver disease in nonobese adults. J Clin Gastroenterol 2006 September;40(8):745-52.

(46) Leh H, Courtay C, Gerardin P, Wellman M, Siest G, Visvikis A. Cloning and expression of a novel type (III) of human gamma-glutamyltransferase truncated mRNA. FEBS Lett 1996 October 7;394(3):258-62.

(47) Lindblom P, Rafter I, Copley C, Andersson U, Hedberg JJ, Berg AL, Samuelsson A, Hellmold H, Cotgreave I, Glinghammar B. Isoforms of alanine aminotransferases in human tissues and serum--differential tissue expression using novel antibodies. Arch Biochem Biophys 2007 October 1;466(1):66-77.


185

(48) Zamora S, Adams C, Butzner JD, Machida H, Scott RB. Elevated aminotransferase activity as an indication of muscular dystrophy: case reports and review of the literature. Can J Gastroenterol 1996 October;10(6):389-93.

(49) Pettersen I, Andersen JH, Bjornland K, Mathisen O, Bremnes R, Wellman M, Visvikis A, Huseby NE. Heterogeneity in gamma-glutamyltransferase mRNA expression and glycan structures. Search for tumor-specific variants in human liver metastases and colon carcinoma cells. Biochim Biophys Acta 2003 May 30;1648(1-2):210-8.

(50) Saverymuttu SH, Joseph AE, Maxwell JD. Ultrasound scanning in the detection of hepatic fibrosis and steatosis. Br Med J (Clin Res Ed) 1986 January 4;292(6512):13-5.

(51) Joseph AE, Saverymuttu SH, al Sam S, Cook MG, Maxwell JD. Comparison of liver histology with ultrasonography in assessing diffuse parenchymal liver disease. Clin Radiol 1991 January;43(1):26-31.

(52) Hamaguchi M, Kojima T, Itoh Y, Harano Y, Fujii K, Nakajima T, Kato T, Takeda N, Okuda J, Ida K, Kawahito Y, Yoshikawa T, Okanoue T. The severity of ultrasonographic findings in nonalcoholic fatty liver disease reflects the metabolic syndrome and visceral fat accumulation. Am J Gastroenterol 2007 December;102(12):2708-15.

(53) Mottin CC, Moretto M, Padoin AV, Swarowsky AM, Toneto MG, Glock L, Repetto G. The role of ultrasound in the diagnosis of hepatic steatosis in morbidly obese patients. Obes Surg 2004 May;14(5):635-7.

(54) Moura Almeida A, Cotrim HP, Barbosa DB, de Athayde LG, Santos AS, Bitencourt AG, De Freitas LA, Rios A, Alves E. Fatty liver disease in severe obese patients: diagnostic value of abdominal ultrasound. World J Gastroenterol 2008 March 7;14(9):1415-8.

(55) Edens MA, van Ooijen PM, Post WJ, Haagmans MJ, Kristanto W, Sijens PE, van der Jagt EJ, Stolk RP. Ultrasonography to quantify hepatic fat content: validation by 1H magnetic resonance spectroscopy. Obesity (Silver Spring) 2009 December;17(12):2239-44.

(56) Suzuki K, Kirikoshi H, Yoneda M, Mawatari H, Fujita K, Nozaki Y, Takahashi H, Abe Y, Inamori M, Shimamura T, Kobayashi N, Kubota K, Saito S, Nakajima A. Measurement of spleen volume is useful for distinguishing between simple steatosis and early-stage non-alcoholic steatohepatitis. Hepatol Res 2010 July 1;40(7):693-700.

(57) Friedrich-Rust M, Ong MF, Martens S, Sarrazin C, Bojunga J, Zeuzem S, Herrmann E. Performance of transient elastography for the staging of liver fibrosis: a meta-analysis. Gastroenterology 2008 April;134(4):960-74.


186

(58) Friedrich-Rust M, Hadji-Hosseini H, Kriener S, Herrmann E, Sircar I, Kau A, Zeuzem S, Bojunga J. Transient elastography with a new probe for obese patients for non-invasive staging of non-alcoholic steatohepatitis. Eur Radiol 2010 June 6.

(59) Kaser S, Ebenbichler CF, Tilg H. Pharmacological and non-pharmacological treatment of non-alcoholic fatty liver disease. Int J Clin Pract 2010 June;64(7):968-83.

(60) Caldwell S, Lazo M. Is exercise an effective treatment for NASH? Knowns and unknowns. Ann Hepatol 2009;8 Suppl 1:S60-S66.

(61) Yoshimitsu K, Irie H, Kakihara D, Tajima T, Asayama Y, Hirakawa M, Ishigami K, Noshiro H, Kakeji Y, Honda H. Postgastrectomy development or accentuation of focal fatty change in segment IV of the liver: correlation with the presence of aberrant venous branches of the parabiliary venous plexus. J Clin Gastroenterol 2007 May;41(5):507-12.

(62) Wing RR, Tate DF, Gorin AA, Raynor HA, Fava JL. A self-regulation program for maintenance of weight loss. N Engl J Med 2006 October 12;355(15):1563-71.

(63) Thomas EL, Brynes AE, Hamilton G, Patel N, Spong A, Goldin RD, Frost G, Bell JD, Taylor-Robinson SD. Effect of nutritional counselling on hepatic, muscle and adipose tissue fat content and distribution in non-alcoholic fatty liver disease. World J Gastroenterol 2006 September 28;12(36):5813-9.

(64) Marchesini G, Suppini A, Forlani G. NAFLD treatment: cognitive-behavioral therapy has entered the arena. J Hepatol 2005 December;43(6):926-8.

(65) Bellentani S, Dalle Grave R, Suppini A, Marchesini G. Behavior therapy for nonalcoholic fatty liver disease: The need for a multidisciplinary approach. Hepatology 2008 February;47(2):746-54.

(66) Huet PM, Villeneuve JP, Fenyves D. Drug elimination in chronic liver diseases. J Hepatol 1997;26 Suppl 2:63-72.

(67) Navarro VJ, Senior JR. Drug-related hepatotoxicity. N Engl J Med 2006 February 16;354(7):731-9.

(68) Cotrim HP, De Freitas LA, Freitas C, Braga L, Sousa R, Carvalho F, Parana R, Santos-Jesus R, Andrade Z. Clinical and histopathological features of NASH in workers exposed to chemicals with or without associated metabolic conditions. Liver Int 2004 April;24(2):131-5.

(69) Musso G, Gambino R, Cassader M, Pagano G. A meta-analysis of randomized trials for the treatment of nonalcoholic fatty liver disease. Hepatology 2010 July;52(1):79-104.


187

(70) Baumeister SE, Volzke H, Marschall P, John U, Schmidt CO, Flessa S, Alte D. Impact of fatty liver disease on health care utilization and costs in a general population: a 5-year observation. Gastroenterology 2008 January;134(1):85-94.

(71) Qian MY, Yuwei JR, Angus P, Schelleman T, Johnson L, Gow P. Efficacy and cost of a hepatocellular carcinoma screening program at an Australian teaching hospital. J Gastroenterol Hepatol 2010 May;25(5):951-6.

(72) Brunt EM, Janney CG, Di Bisceglie AM, Neuschwander-Tetri BA, Bacon BR. Nonalcoholic steatohepatitis: a proposal for grading and staging the histological lesions. Am J Gastroenterol 1999 September;94(9):2467-74.

(73) Ratziu V, Charlotte F, Heurtier A, Gombert S, Giral P, Bruckert E, Grimaldi A, Capron F, Poynard T. Sampling variability of liver biopsy in nonalcoholic fatty liver disease. Gastroenterology 2005 June;128(7):1898-906.

(74) Ratziu V, Bugianesi E, Dixon J, Fassio E, Ekstedt M, Charlotte F, Kechagias S, Poynard T, Olsson R. Histological progression of non-alcoholic fatty liver disease: a critical reassessment based on liver sampling variability. Aliment Pharmacol

Ther 2007 September 15;26(6):821-30.

(75) Younossi ZM, Gramlich T, Liu YC, Matteoni C, Petrelli M, Goldblum J, Rybicki L, McCullough AJ. Nonalcoholic fatty liver disease: assessment of variability in pathologic interpretations. Mod Pathol 1998 June;11(6):560-5.

(76) Stolk RP, Wink O, Zelissen PM, Meijer R, van Gils AP, Grobbee DE. Validity and reproducibility of ultrasonography for the measurement of intra-abdominal adipose tissue. Int J Obes Relat Metab Disord 2001 September;25(9):1346-51.

(77) Stolk RP, Meijer R, Mali WP, Grobbee DE, van der Graaf Y. Ultrasound measurements of intraabdominal fat estimate the metabolic syndrome better than do measurements of waist circumference. Am J Clin Nutr 2003 April;77(4):857-60.

(78) Lucia Rolfe E, Sleigh A, Finucane FM, Brage S, Stolk RP, Cooper C, Sharp SJ, Wareham NJ, Ong KK. Ultrasound measurements of visceral and subcutaneous abdominal thickness to predict abdominal adiposity among older men and women. Obesity (Silver Spring) 2010 March;18(3):625-31.

(79) Wigg AJ, Roberts-Thomson IC, Dymock RB, McCarthy PJ, Grose RH, Cummins AG. The role of small intestinal bacterial overgrowth, intestinal permeability, endotoxaemia, and tumour necrosis factor alpha in the pathogenesis of non-alcoholic steatohepatitis. Gut 2001 February;48(2):206-11.

(80) Miele L, Valenza V, La Torre G, Montalto M, Cammarota G, Ricci R, Masciana R, Forgione A, Gabrieli ML, Perotti G, Vecchio FM, Rapaccini G, Gasbarrini G,


188

Day CP, Grieco A. Increased intestinal permeability and tight junction alterations in nonalcoholic fatty liver disease. Hepatology 2009 June;49(6):1877-87.

(81) Lammert C, Bjornsson E, Niklasson A, Chalasani N. Oral medications with significant hepatic metabolism at higher risk for hepatic adverse events. Hepatology 2009 September 14.

(82) Pichler WJ. Pharmacological interaction of drugs with antigen-specific immune receptors: the p-i concept. Curr Opin Allergy Clin Immunol 2002 August;2(4):301-5.

(83) Larrey D, Pageaux GP. Genetic predisposition to drug-induced hepatotoxicity. J Hepatol 1997;26 Suppl 2:12-21.


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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