Dr Lee Yin Mei
Senior Consultant
Gastroenterology
NUHS

Simple steatosis (SS),
through steatohepatitis

Prevalence of NASH 325%
 Put
picture of
spectrum
NASH
Progression only occurs in
NASH: 27% develop fibrosis and
19% cirrhosis over a period of
nine years.
(Matteoni et al
Gastroent.1999;116:1413)
Fatty
Liver: Can we identify who
will progress
PL- referred for abnormal
LFT on health screening
50 year old female history of hypothyroidism. PMH
dyslipidemia (Simvastatin 10 mg ) and
hypothyroidism ( T4 75 mcg)
Lipid TC 4.89 mmol/l
HDL 1.09 mmol/l
LDL 2.96 mmol/l
TG1.89 mmmol/l
PL- referred for abnormal LFT
on health screening
ALB 40
ALT 30
AST 66
PLT 120
BMI 27.3
Fasting Glucose 4.5 mmol/l, 2
hour glucose (OGTT) 12
mmol/L
HBs AG negative anti-HCV
negative anti-HBS >1000, ANA
is 1/80 +, Ig G normal, US fatty
liver
Is this patient at risk for progression?
Does she have NASH?
Risk factors for progression
1. Obesity
2. High insulin levels
3. AST in pediatric patients with NAFLD
4. Fibrosis at first liver biopsy
Schwimmer J et al J of Pediatrics 2003;
143:500
Pagadala MR, Clin Liver Dis 2012:487
Mdm PL
Based on risk factors alone, she
has impaired glucose tolerance,
high AST, dyslipidemia and
obesity, the risk of NASH is high.
She is referred to NUH
(Wiliamson RM, Diabetes Care 2011;34:1139)
Liver biopsy is the gold standard
for diagnosis and staging of
NAFLD
Pros of liver biopsy
Gold standard for diagnosis of NASH and also
prognosis
Cons of liver biopsy
1. Cost
2. Risk of complications: pain, bleeding, mortality
(Rockey AASLD Hepat 2009:1017)
3. Risk of sampling error: Hepatol Res 2007:1002
Patient is not keen for liver
biopsy
Anxious and wants to know if
her condition is serious
Non invasive staging of NASH
A) FIBROSCAN
Liver stiffness measurement (LSM)
LSM good correlation to degree of
hepatic fibrosis in NAFLD
Stage 2 fibrosis AUROC 0.83
Stage 3 or more AUROC 0.93
Cirrhosis AUROC 0.95
Wong VW
Hepatology
2010;55;454
FIBROSCAN: Pros
FIBROSCAN: Cons
May be invalid for
lower grades of fibrosis, steatosis,
older >52,
and high BMI >35
falsely elevated in acute hepatitis
Wong GL Gastroenterol Rep 2013:1:19
Arena U Hep 2008;47:380
Castera:Hepatology 2013:51:828
Mdm PL
Fibroscan reading 10
KPa equivalent to F3-4
Non invasive staging of NASH
B) Blood tests: Can elevated ALT
predict fibrosis?
1/3 normal ALT had NASH or advanced
fibrosis AUROC= 0.62
50% of those with elevated ALT had no
fibrosis AUROC= 0.46
Verma S Liver Int 2013;33:1398
Francanzoni Hepatology 2008;48:792
Non invasive staging of NASH
C) Simple non invasive fibrosis scoring
systems
NAFLD-FS formula:
1.675 + 0.037 x age (years) + 0.094 x BMI + 1.13 x hyperglycemia or
diabetes (yes = 1, no = 0) + 0.99 AST/ALT ratio - 0.013x platelet (109/L)0.66x albumin (g/dL)
APRI:
AST (x ULN) /platelet x 100
FIB-4
[age (years) x AST (U/L) /platelet(109/L) x square root ALT (U/L)]
BARD score
scale 0-4: BMI > 28 =1 point, AST to ALT ratio >/ 0.8 = 2 points; diabetes
mellitus = 1 point.
Predicted those
with fibrosis
and also
excluded those
without
advanced
fibrosis
McPherson S Gut
2010; 59:1265
Correlation of NAFLD fibrosis
score, FIB4 APRI and BARD with
outcomes
Angulo P Gastro 2013;145; 782
NAFLD-FS
APRI
FIB4
BARD
LOW
1
1
1
1
MED
7.7*
8.8*
0.92
6.2*
HIGH
34*
20.9
14.6*
6.6*
LOW
1
1
1
1
MED
4.2*
1*
2.3
1.8
HIGH
58*
3*
6.9*
1.6
LIVER
MORTALITY
 Increasing
mortality with
increasing fibrosis according to
NAFLD FS FIB4 and APRI
 Deaths
were from cardiovascular
and non liver malignancy as only
3.2% had advanced fibrosis
Kim D, Hepatology 2013; 57:1057
Risk factor for HCC
Hazard Ratio
95% CI
AST >40 IU/L
8.2
2.56 – 26.26; P < 0.001
Platelet < 150 × 10 3
7.19
CI: 2.26 – 23.26; P =
0.001
Age ≥ 60 years
4.27
95 % CI: 1.30 – 14.01, P
=0.017
Diabetes
3.21
95 % CI: 1.09 – 9.50; P =
0.035
The annual rate of new HCC was 0.043 %
Yusuke K, AJG 2012:107:253
Simple non invasive fibrosis
scoring systems
Pros
Easy to use
Safe
cost effective
Good NPV
Cons
PPV only modest (27-79%) so that patients with
intermediate or high score need further
investigation to confirm advance fibrosis



Mdm PL’s Score
1.821
< -1.455: predictor of absence of significant fibrosis
(F0-F2 fibrosis)
≤ -1.455 to ≤ 0.675: indeterminate score
> 0.675: predictor of presence of significant fibrosis
(F3-F4 fibrosis)


Angulo P, Hui JM, Marchesini G et al. The NAFLD fibrosis score
A noninvasive system that identifies liver fibrosis in patients with
NAFLD
Hepatology 2007;45(4):846-854
1. Detect steatosis on ultrasound and have clinical
liver disease or abnormal LFT can do work up for
NAFLD
2. Screen for risk factors and other cause of steatosis
3. Screening for liver disease in patients with high risk
groups not advised at the moment as long term
benefits of screening and knowledge regarding
NAFLD not proven


Obesity
Weight reduction improves the liver
function tests in adult and pediatric
NAFLD patients (Ueno T, J Hepatol. 1997; Franzese A,
Dig Dis Sci 1997)

Fatty infiltration on liver histology also
decreases with weight loss (Andersen T , J of
Hep 1991) .
Low Carbohydrate Diet
(Samaha et al NEJM
2003;21:348:2074)
High
intensity and several
times/week

Warburton et al; Am J Cardiol 2005;95(9):1080
GREACE study Lancet 2010
 Metformin
has no significant effect on liver
histology and is not recommended
(Strength – 1, Evidence - A)
 Pioglitazone
can be used to treat
steatohepatitis
 Long term safety and efficacy of
pioglitazone in patients
 with NASH is not established. (Strength – 1,
Evidence
 - B)
 Vitamin
E 800 IU/day improves liver
histology in non-diabetic adults with
NASH and therefore it should be
considered as a first-line therapy
 (Strength - 1, Quality - B)
 UDCA
is not recommended for the
treatment of NAFLD (Strength – 1, Quality
– B)
 NASH
is progressive and should be
treated
 Establish diagnosis with evidence of
hepatic steatosis and inflammation and
no other causes for liver disease
 Treat the risk factors associated with the
metabolic syndrome
 Consider Vitamin E in non diabetics with
NASH