, ,

: %
.
5%

: , ,
( & )
Hippokratia 2009; 13: 9-19
Hepatology 2005; 41: 1313-1321

Histopathology 2006; 49: 450-465

Aliment Pharmacol Ther 2007;25:883-889

M
HCV- ( 3)
X

O
M/ ,

Wilson

, , , -HIV, .


60 Thaler H.

Thaler H. et al. Dtsch Med Wochenschr 1962; 87: 1049-1055

Thaler H. et al. Virchows Arch Pathol Anat Physiol Klin Med 1962; 335: 180-210

1980 Ludwig J et al.

Ludwig J. et al. Mayo Clinic Proc 1980; 55:434-438

NAFLD:
>5%

.
Farrell GC. et al. Hepatology 2006; 43: S99-S112

2012

Am J Gastroenterol 2012; 107: 811-26

Gastroenterology 2012; 142: 1592-609

Hepatology 2012; 55: 2005-23

 NAFLD
1.
1.
2.

2. 2
1.
2.

NAFL

NASH

Cirrhosis


NAFLD
, LF, Kcal-

Exp Diabetes Res. 2012;2012:404632

Arq Gastroenterol 2012;49:89-96


NAFLD CVD
Arterioscler Thromb Vasc Biol. 2008;28:27-38

20-80% NAFLD Chol / Tg

Obes Rev. 2005;6:5-7
Nat Rev Gastroenterol Hepatol. 2009;6:236-47.

Tg > 200mg/dL x3 P NAFLD vs

HDL< 35mg/dL x2 P NAFLD vs
Clark JM et al. Gastroenterology 2002; 122; 1649-1657

Tg > 500mg/dL Tg 250-500mg/dL & LDL>130mg/dL x5-6 P

Assy N et al. Dig Dis Sci 2000; 45: 1929-1934

..
: NAFLD
Arq Bras Cardiol. 2005;84:3-28
Ann Hepatol. 2011;10:33-37.

, Glu, Tg +
Ann Hepatol. 2011;10:33-37.


IR+ NAFLD
NGT
Diabetes Care. 2004;27:824-30
J Gastroenterol Hepatol. 2004;19:854-8
Diabetes. 2001;50:1844-50

IGT
43%
- 62%

NAFLD

IR NAFLD
Digestive and Liver Disease 2010;42:320330

NAFLD 1 CVD
J Hepatol. 2010;53:713-8.

AGES , ,
Pathophysiology. 2008;15:109-14

NAFLD <> MS

MS 2637% >x3 ..
MS NAFLD > control

NAFLD
56-63% >3x ..
(18%)

NAFLD

Non- NAFLD

437

1957

IDF

161 (36.84%)

105 (5.37%)

NCEP/ATP III

114 (26.09%)

89 (4.55%)

NAFLD MS > control

Journal of Digestive Diseases 2011; 12; 125130

NAFLD MS, DM
NAFLD : ALT (>40 IU/l),
Follow up 11ys , DM, MS.

DM

MS

NAFLD -DM

Non- NAFLD - DM

20/106, 18.9%

15/246, 6.1%;

<0.001

NAFLD -MS

Non- NAFLD - MS

27/81, 33.3%

51/226, 22.6%

0.056

WC, A.Y, IR NAFLD

MS, DM.
NAFLD p DM, MS,

Am J Gastroenterol. 2009;104:861-867

NAFLD -
/

stress


85 NAFLD
160 ,

Diabetes Care 2006;29:1325-30

NAFLD CVD
,

Hepatology. 2005;42:473-80.
World J Gastroenterol. 2005;11:1848-53.


2.839
2
69,5%
NAFLD

NAFLD

Diabetes Care 2007;30:1212-8


420 NAFLD &
7,6

&

(33%)
(28%)
(13%)

Gastroenterology 2005;129:113-21


1.
2.

3.
4.

5.
6.

1.

Nature Reviews Endocrinology 2011;7:456465

Digestive Diseases and Sciences 2010; 55:560578

-
,

-
,
(, )
NASH -
,
, ,
,

2.
1
: ALT, AST
Usu <4 x
78% NAFLD ..

Hepatology 2004:40:13871395
Gastroenterology 2008:134;16821698

AST/ALT<1 : AST/ALT>1
Hepatology 1999:30;13561362

GT ,
Hepatology 2009; 50:14031411

Gastroenterology 2009;136:477485

GT>96.5 U/L
83%
69%

Hepato-Gastroenterology 2008;55:1433-8

ALP
Fe:50% NASH

Hepatology 1999:30;1356-62

..,
, , , PT

3.


vs +

Stress

Exp Diabetes Res. 2012;2012:145754

3.1

TNF-a + NASH
Hepatology 2004:40;4654
Hepatology 2003;37:343350
Diabetes 2002;51:18761883

TNF-a ,
Liver International 2006;26:3945

NASH vs
4.0g//mL : 68%, : 79%
American Journal of Gastroenterology 2007; 102:19311938

+-IR (3.0)+ IV 7S (5.0 ng/mL)

NASH : 94%, : 77%
American Journal of Gastroenterology 2007;102:19311938

CRP
hs-CRP

3.2

IV 7S 84% NPV
() 78% NPV
World Journal of Gastroenterology 2005;11:255259

NASH vs
IV 7S 86% PPV
HA 92% PPV
World Journal of Gastroenterology 2005;11:255259

NAFLD
IV 7S
HA:46.1 ug/l : 85%, : 80%
Liver International 2005;25:779786

() : 87%, : 89%,
PPV:82% NPV:89%
Brazilian Journal of Medical and Biological Research 2005;38:747753

3.3
3.4
,

Vit E, , ,
(GSH-Px)
Experimental Diabetes Research;2012:2012:145754

============================================
CK-18 (caspase-generated cytokeratin-18)
CK-18

NASH >
PPV:77%, NPV:71%

: 78% & :87%
, cut-off
Annals of Medicine 2011;43:61749
J Gastroenterol Hepatol. 2011;26:1536-1543
J Hepatol 2012;56:1363-70
Journal of Clinical Gastroenterology 2010;44:440447

4.


NASH

1.
2. NASH
3.

4.1 ()
NAFLD liver fat score
MS, T2DM, Ins , AST, AST/ALT

Cut-off point : -0.640 : 86% , : 71%
Gastroenterology 2009;137:865-872

Low cut-off point: -1.413

(95% accuracy)
High cut-off point: 1.257

(95% accuracy)

4.1 ()
Fatty Liver Index (FLI) : 0-100

WC> BMI> Tg >-GT

FLI < 30 NAFLD

FLI 60 NAFLD

BMC Gastroenterology 2006;6:33

4.2 NASH (I)

HAIR (Hypertension, ALT, Insulin Resistance)
HAIR= (0-3) :
Hypertension =1
ALT >40
=1
+ IR index >5.0 =1

HAIR: 2
:0.8
:0.89
Gastroenterology 2001;121:91100

4.2 NASH (II)

NASH-test

Tg
Chol
AST
ALT
2-

-GT
-1

NASH
: 94%
PPV: 66%
: 33%
NPV : 81%

BMC Gastroenterol;2006:10;6:34

4.3 (I)
FibroTest

-GT
ALT
-1

2-

F0=
F2= /

F1=
F4=
BMC Gastroenterology 2006;6:6
J Gastroenterol Hepatol. 2011;26:1536-1543

4.3 (II)
NFS (NAFLD Fibrosis Score)

Plts

AST/ALT

NASH

NAFLD fibrosis score =

1.675 + 0.037 x age (yrs) + 0.094 x BMI (kg/m2) + 1.13 x
IFG/diabetes (yes=1, no=0) + 0.99 x AST/ALT ratio + 0.013 x
platelet (X109/l) - 0.66 x albumin (g/dl).
Hepatology 2007;45:846-854
Ann Med. 2011;43:617-49

NFS (NAFLD Fibrosis Score)

http://nafldscore.com/

-
(13 3.064)

<-1.455
: 0.90
: 0.60

> 0.675
: 0.67
: 0.97
Annals of Medicine 2011;43:61749.

4.3 (III)
FIB-4

Plt, ALT, AST

:
:

85%

65%

NPV:

95%
Hepatology 2007; 46:3236
Gut 2010;59:12651269

4.3 (IV)
BARD (0-4)
BMI

AST/ALT

DM

NAFLD
BMI 28 = 1
AST/ALT 0.8 = 2
DM = 1

Score 0-1: NPV .

:
:
PPV:
NPV:

77%
51%
45%
81%
Gut 2008; 57 14411447
Journal of Hepatology 2011; 54:160163

4.3 (V)
APRI (AST to Platelet Ratio Index)
HCV

<0.3
0.5
1.5 .

Journal of Hepatology 2009;50:165173

AGA 2012
MS
NAFLD,

(1)

NAFLD Fibrosis Score:

NAFLD &
/
(1)

CK18


(1)

5.1 U/S ()
screening
, NAFLD

> ,
U/S



RadioGraphics 2006; 26:16371653

Normal

NAFLD

5.1 U/S ()
: 91%

: 93%

PPV: 89%

NPV:94%

NASH,
Digestive and Liver Disease 2006; 38:485489
NASH vs

5.1 U/S (I)

Levovist
( , , )

vs NASH/

Hepatology Research 2007; 37: 722730

5.2 CT
Hounsfield
(vs )
<

10 Hus

<40HUs ( )
>30% :95-100% & :73-100%

Normal
Radiology 2009;237:159 169

Gastroenterology and Hepatology 2009; 7:135140

NAFLD
Radiology 2005; 237:159169

5.3 MRI

vs U/S, CT
<3%
,

Journal of Clinical Gastroenterology 2005;39:619625

 - Fibroscan
,
(stiffness)
.

Fibroscan
NASH

: 0.94
: 0.95
Ann Med. 2011;43:617-49

 - Fibroscan
K- &



.
() u (kPa).

6. ()
NAFLD vs NASH gold standard

6. ()
NAS: score

(03)
(03)
-hepatocyte
ballooning- (02)

score .
score >5 NASH
<3 NASH .

6. ()

NASH

NASH
>5%10%

T Masson
Cs +

Mallory
( )

(ballooned)

6. (V)

()
, ,

1/50.000

,

Gastroenterology 2005;128:18981906

Hepatology 2005;41:13131321

Obesity Surgery 2005;15:497501

 AGA 2012
NAFLD

.
(1)

+ NAFLD Fibrosis Score

NAFLD
.
(1)

NAFLD


.
(1)

Aliment Pharmacol Ther 2011; 33: 525540

Eur J Clin Invest. 2012;42:411-8

Eur J Clin Invest. 2012;42:411-8

Eur J Clin Invest. 2012;42:411-8

LF

, ,

(-500) - (-1000) kcal/d

<30%
NASH

60min, 3d/w 5d/w

Frontiers in Bioscience 2012; 17:2259-2268

Diabetologia.201255:885-904


,
.

ALT + (U/S)

Clin Gastroenterol Hepatol. 2006;4:63944.

Hepatology 2009;49: 8086.

Diabetologia meta-analysis -
78 RT
(38 NASH, 40 NAFLD)
LF, TZD, Met, antioxidants

Diabetologia 2012; 55:885904

LF (AGA 2012)
(+/- )
.
(1)

3-5% .
( 10%)
/.
(1)

NAFLD
.
.
(1)



IR,
?

Exp Diabetes Res. 2012; 2012: 716404

 (AGA 2012)



NASH

(1)


78 RT (38 NASH, 40 NAFLD)

-
LF, TZD, Met, antioxidants

&
vs

(:4.8%)
Diabetologia.2012;55:885-904

NEJM 2006;355:2297-307

 (AGA 2012)

NASH
.

SOS: (
NASH)

NASH .

(1)

 GLP-1 ???

GLP-1 .

(NCT00529204 NCT00650546).

(LEAD)-2,
( CT-).

Vit - E
PIVENS
247 NASH
Vit-E (800 mg/d) 96

placebo:

- 26 (n=105.065),

4% (95% CI 1,01-1,07)
N Engl J Med 2010;362:1675-85

Vit - E (AGA 2012)

(-)
vit- 800 IU/d
NASH
1
(1)

:
NASH
NAFLD
NASH

(800 IU = 360 mg)

(1C)


NAFLD

CVD

The Greek Atorvastatin and

Coronary Heart Disease
Evaluation (GREACE)
CHD, <75ys, Tg<400mg/dL, LDL>100mg/dL

437 <3
( NAFLD)

vs placebo 3ys

10% VS 30% (p<0.0001)

<1% (n=7): >3*

Lancet. 2010 ;376:1916-22


Dallas Heart Study

ALT

Hepatology 2006;44:466-471

J Hepatol 2007:47:135-141
Hepatology 2007;46:1453-63

Atherosclerosis 2004;174:193-6

J Gastrointest Liv Dis 2007;16:39-46

J Gastroenterol 2010;45:750-7

16 NASH 12

J Clin Gastroenterol 2009;43:990-4

Diabetologia.2012;55:885-904

 (AGA 2012)

( )
NAFLD
NASH.
(1)

RCTs

NASH.
(1)


TNF-

TNF-
.

NASH
TNF-

 , -3
UDCA NAFLD, NASH
(1B)

-3 .
NAFLD, NASH
1
NAFLD.
(1B)



NAFLD NASH, .
(1)

,

.
(1B)

NAFLD.
(1B)

 NAFLD
Pioglitazone
Vit. E

Dyson JK, et al. Frontline Gastroenterology 2014;0:110

Dyson JK, et al. Frontline Gastroenterology 2014;0:110

Dyson JK, et al. Frontline Gastroenterology 2014;0:110

In Mediterranean
countries, alcohol
consumption and the
obesity epidemic
threaten to halt the
recently improving trend
in liver cirrhosis
prevalence, or even to
reverse it.

Dyson JK, et al. Frontline Gastroenterology 2014;5:211218

Dyson JK, et al. Frontline Gastroenterology 2014;5:211218

Dyson JK, et al. Frontline Gastroenterology 2014;5:211218

J Clin Gastroenterol. 2014 Jul;48(6):467-73

J Clin Gastroenterol. 2014 Jul;48(6):467-73

J Clin Gastroenterol. 2014 Jul;48(6):467-73

J Clin Gastroenterol. 2014 Jul;48(6):467-73

Hallsworth K, et al. Frontline Gastroenterology 2015;6:4451

Physical activity and energy

expenditure were assessed objectively using a
multisensor array (SenseWear Pro3 ,
Bodymedia, Pennsylvania, USA) previously
validated in healthy adults.

Total sedentary duration was classed as total time spent in

activities 2.9 METs, excluding sleep. Patterns of sedentary
behaviour were assessed by power law analyses of the lengths of
sedentary bouts fitted from raw sedentary data, as described in more
detail previously.29

The following matrices of physical activity were derived from the multisensor array as units per
day: total energy expenditure (TEE); active energy expenditure (AEE); average metabolic
equivalents (MET); duration of physical activity (>3.0 METs); duration of moderate physical
activity (3.0 5.9 METs); duration of vigorous activity (6.0 9.0 METs); duration of very vigorous
activity ( 9.0 METs); number of steps; and duration of monitor worn.

Hallsworth K, et al. Frontline Gastroenterology 2015;6:4451

Objectively measured physical activity levels were lower in non-alcoholic fatty liver
disease (NAFLD) compared with healthy Controls.
(A) Steps. (B) Total energy expenditure. (C) Physical activity duration. (D) Average MET levels.
Hallsworth K, et al. Frontline Gastroenterology 2015;6:4451

(A) Sedentary time

(B) Sedentary to active transitions

Sedentary time was higher in non-alcoholic fatty liver disease (NAFLD)

than healthy controls with fewer sedentary to active transitions.

Hallsworth K, et al. Frontline Gastroenterology 2015;6:4451

NAFLD: &

NASH

NAFLD % LDL


!!!