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