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NASH : Diagnosis and investigation
VII Workshop international, Curitiba, Brazil 29/08/2014
Vlad Ratziu, Université Pierre et Marie Curie, Hôpital Pitié Salpêtrière, Paris, France
Usual diagnostic circumstances for NAFLD
LFTs + Ultrasound
LFTs + Metabolic RF
Increased ferritin
Cirrhosis X
Metabolic RF + Normal ALT
NASH
Key points : presence of steatosis (ultrasound, markers) presence of metabolic risk factors
NASH : when to think about it ?
Metabolic risk factors
• BMI > 25 kg/m²
• Waist circ 94/80 ou 102/88
• Arterial HTN 135/85 mmHg
• Glycemia >6.1 mmol/l
• TG > 1.7 mmol/l
• HDLc < 1/1.3 mmol/l
• Ferritin 350 µg/ml
• Atheromatosis
• 1st degree family history
Altered LFTs
Steatosis on ultrasound
Cirrhosis diagnosis
Work-up in patients with NAFLD: a multiorgan approach
NAFLD
Extrahepatic comorbidities
Liver condition
•Type 2 diabetes •Sleep apnea •Hypertension, arterial •Dyslipidemia
•Cofactors of fibrosis •Pathological form •Stage •Prognosis
?
Obstructive sleep apnea aggravating
NASH
Severity of chronic intermittent hypoxia
Seve
rity
of
his
tolo
gic
inju
ry
Diurnal asthenia Sleepiness Attention problems Frequent waking-up Snoring
Courtesy Aron-Wisnewsky, J Hepatol 2011
NAFLD
Coexistence other CLDs Positive definition Alcohol
Secondary
PRIMARY Metabolic
Risk Factors
• Alcohol • Drugs (amiodarone, metothrexate, tamoxifen, corticosteroids) • A/hypo betalipoprotéinémia • Chronic HCV (genotype 3) • Maladie de Wilson • Toxiques industriels • Lipodystrophies • Cholesteryl ester storage disease • Microvesicular steatosis
NAFLD and ALD can coexist
and HCV
and HBV
and … - NAFLD SHOULD NO LONGER BE
A DIAGNOSIS OF EXCLUSION
Screening strategies I – Diagnostic tools
LFTs Metabolic RF
Steatosis
IR surrogates : HOMA Dynamic tests Waist circumference Adipose tissue IR Lipid metabolism IR
US, CT, MRI : if >20-30% not quantifiable
ULN IU/L Lab variablity
Screening strategies IV
Chronic liver disease
Metabolic risk factors IR Stéatose
Liver biopsy
Bariatric surgery, cholecystectomy Liver biopsy
General population - NO
Patients with IR (metabolic RF, PCOS, lipodystrophia) :
What to do... in clinical practice ?
Metabolic Risk Factors
LFTs
Ultrasound
Abnormal LFTs
Steatosis
Liver specialist referral
Eliminate other causes of CLD Assess potential for progression &
fibrotic severity (decide LB) Initiate monitoring +/- therapy
STEATOHEPATITIS Hepatic cell injury
+ Inflammation
NAFL
NAFLD
Different clinical outcome
Steatosis alone or non-specific inflammation
Histological diagnosis of NASH
A TRIAD
-Steatosis -Hepatic cell injury (ballooning) -Inflammation (lobular, portal)
Preferential ZONE 3 distribution
• Mallory bodies and PMN infiltrate not necessary for diagnosis • NAS score not diagnostic • Fibrosis not part of the diagnosis
TO REMEMBER :
Steatosis : 0, 1, 2, 3
Ballooning : 0, 1, 2
Inflammation : 0, 1, 2
Agreement for diagnosis before and after the use of FLIP algorithm
Κ score
Biopsy with full
agreement
between
pathologists (%)
Biopsy with
agreement with
reference
diagnosis (%)
1st group
Baseline
classification 0.54 26/40 (65%) 31/40 (77%)
Algorithmic
classification 0.66 34/40 (85%) 39/40 (97%)
2nd group
Baseline
classification 0.35 18/40 (45%) 17/40 (42%)
Algorithmic
classification 0.61 28/40 (70%) 30/40 (75%)
FLIP algorithm for NAFLD classification
SAF score S(0,1,2,3) A (bal+lob inflam 0,1,2,3,4) F (0,1,2,3,4)
S3A2F1 S1A3F4
Clinical validation of the FLIP algorithm and of the SAF score
Nascimbeni F, ILC 2014
Bed-Side Risk Factors for Severe
Fibrosis in NASH
• Age > 45-50 yrs
• Diabetes
• BMI > 27 kg/m²
• Arterial HTN
• Hypertriglyceridemia (TG > 1.7 mmol/L)
• ALT>2N
• AST/ALT > 1
Ratziu, Gastroenterology 2000
Angulo, Hepatology 1999
Dixon, Gastroenterology 2001
Screening strategies – II non invasive prediction
WHAT HOW WHY
Fibrosis
Steatohepatitis
Steatosis
Prognosis Cirrhosis surveillance Pharmacol treatment
Prognosis Intensive counselling Pharmacol treatment
Diagnosis (if > sensitive US) Early changes therapy
Risk of metabolic complications
Serum markers (FibroTest, FibroMeter,
ELF, Angulo*)
Elastometry*
Serum markers (CK18*, NASHDiagnostics,
NASHTest)
Serum markers (SteatoTest*, FLI*,
Kotronen index) Elastometry- CAP
attenuation
Staging fibrosis with NFS, FIB-4, and others …
High (>92%) NPV for advanced fibrosis Useful in clinical practice for excluding advanced fibrosis ELF performed only marginally better than NFS Modest PPV – liver biopsy still neessary
McPherson, Gut 2010
Guha, Hepatology 2008
Non-invasive measurement of hepatic fibrosis
• FibroTest
• ELF Panel
• Fibromètre
• NAFLD fibrosis score
biopredictive.com Biols.fr
Fibrometer
SERUM MARKERS TRANSIENT ELASTOMETRY
33
Prediction of advanced fibrosis by Fibroscan
Wong, Hepatology 2010
Fibroscan M or XL ?
M XL
Failure
Unreliable
10-16%
33-50%
1-2%
25%
1.7 Kpa (+/-2.3) lower for XL Similar diagnostic performance
M XL
F 2
F4
7
8.7
6.2
7.2 F 3
10.3 7.9
XL probe second line if M fails ? Wong, Am J Gastro 2012
Myers, Hepatology 2012
Short-term variability of elastometry measurements
531 paired liver stiffness measurements in 432 patients > 1 day and <1 year apart
Nascimbeni F, Clin Gastro Hepatol in press
Short-term variability of elastometry measurements
531 paired liver stiffness measurements in 432 patients > 1 day and <1 year apart
Nascimbeni F, Clin Gastro Hepatol in press
6.5-7 kPa
New Imaging Methods for Fibrosis Assessment
• Fibroscan M and XL
• Real-time shear-wave elastography
• Acoustic radiation force imaging
• MR-Elastography
Recent progress in non-invasive assesment of liver injury
• Combination of techniques
• Prognostic value
• New markers
Castera, Angulo Nat Rev Gastro Hepatol 2013
Crespo, J Hepatol 2012
Fibroscan + ELF Algorithm
TE and FibroTest predicts overall mortality
Vergniol, Gastroenterology 2011
HCV, N=1457
NFS predicts mortality
Angulo, Gastroenterology in press
NAFLD, N=320
• Most interesting in predicting progression to NAFLD
• Baseline FGF21 and BMI independent predictors of NAFLD
Li, J Hepatol 2013
FGF-21 in NAFLD
P3NP as a marker of both NASH and fibrosis
N=172 NAFLD patients
Tanwar, Hepatology 2013
Serum CK-18 for the diagnosis of NASH
335
194 200 145
Feldstein, Hepatology 2009
AUROC of Plasma CK-18 Fragment Concentration
for NASH or Fibrosis
Courtesy K Cusi , J Hepatol 2013 in press
Limited sensitivity (58%) and NPV (49%) for the diagnosis of NASH Inadequate screening test for NASH
N=424 obese/overweight US subjects
When to perform liver biopsy on an individual basis ?
• Metabolically stable ?
• Attempt diet and lifestyle change
Failure (s) previous attempts ?
Never tried
Improvement weight, IR, ALT N
No change
Fibrosis risk
Comorbidities
Patient motivation
Trials
FT/FS (or clinical)
+/+ +/- -/-
MONITORING
LB
Monitoring
• LFTs
• Fibrosis :
– Serum markers (FibroTest, ELF panel, Fibrometer)
– Elastometry
• Metabolic condition :
– Serum glucose, lipids, HBA1c
– HOMA
• Repeat liver biopsy ?
Ongoing challenges
• Identification of the disease in patients exposed to NASH risk-factors
• Confident identification of NASH without biopsy
• Validation of non-invasive long-term follow-up
• Large mass-screening test for idetification of mild, non progressive disease
• Reproducible histological classification with prognostic value