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liver fibrosis
A Historical Review and a SOTA Presentation
Robert G Gish MD
Senior Medical Director
St Joseph Hospital and Medical
Center
Relevant Disclosures
None
Who to treat:
a Focus on HCV
Fibrosis score
CRYOs
High HCC biomarkers
(baseline in all patients, then every 6 months in patients with F3 and F4)
AFPL3%, DCP, AFP (FDA approved as risk markers for HCC)
Levels : Correlate with advanced fibrosis
Liver Fibrosis
Choices
To Biopsy or not to Biopsy
that is the question!
Percent (%)
Arterial hypotension
various
0.056-83%
Hemorrhagic complications
Bacteremia
0.08%
Death
0.001-0.0001%
Bile peritonitis
0.03-0.22%
Pneumothorax, hemothorax
0.08-0.28%
Subcutaneous emphysema
0.014%
0.02%
Lungs-0.001%
Bile-0.003%
Colon-0.003%
Kidneys-0.09%
Liver biopsy
Serum markers
Elastography
Cost
2200$
Laboratory cost
Risks
Significant
Minimal, phlebotomy
None
Contraindications
Accuracy
80%
60-80%
60-95%
System requirements
Clinical laboratory,
phlebotomy, materials
Specimen adequacy
16 g needle
Length of liver fragment at
least 15mm with > 12 portal
tracts
Blood sample
Staff time
False positives
Interobserver variability
Sepsis, nonhepatic
inflammation, hemolysis,
trombocitopenia
False negatives
Interobserver variability
various
15-45 min
225
16% 25mm
150
75
0
10
15
20
25
30
35
40
45
50
Interferon
Interferon
Liver
Liver Transplantation
Transplantation
Popularized
Imaging
Imaging
Ultrasound
Ultrasound
CT
CT
All
All oral
oral therapies
therapies
HCV
HCV
ERCP
ERCP
1940s-1950s
1960s
1970s
1980s
1990s
2000s
>2010
2015
Iron work up
Autoimmune hepatitis
Primary biliary cholangitis
PSC
NASH
Cryptogenic
Infections: CMV, EBV, other
Liver masses not defined by CT/MR
Study
FibroTest
Fibrometer
ELF
Components
Bili GGT Hapto, A2m, ApoA1
PT, AST, A2M, HA, Urea
HA, PIIIP, TIMP1
FibroSpect
0.83-0.90
APRI
FIB4
Hepascore
AST, Platelets
AST, ALT, Platelets
Bili, GGT, HA, A2M
0.69-0.88
0.74-0.85
0.74-0.86
Forns
CT,GGT, Platelets
0.75-0.91
AUROC F>2
0.74-0.89
0.78-0.89
0.77-0.87
AUROC F4
0.82-0.92
0.94
0.87-0.90
0.61-0.94
0.8-0.93
0.8-0.94
22
50% of Biopsies
May Be Avoidable with FibroSure
Age, yrs
BMI, kg/m
AST/ALT ratio
APRI
Liver stiffness, kPa
F0F1 Fibrosis
F2F3F4 Fibrosis
P Value
50
29
0.68 0.4
0.72 1.17
6.92
57
30
0.92 0.5
0.84 0.26
18.52
.002
.07
.005
.5
.0001
Varices
Sensitivity, Specificity
PV size and cirrhosis
PV diameter>12mm
Sensitivity 76.7%, specificity 44.6%
Shen L et al. World J Gastroenterol. 2006 Feb 28;12(8):1292-5.
0.6
0.5
0.4
P<.0001
0.3
0.2
0.1
0
Place a Probe
PaP testing!
Ultrasound-based Elastography
FibroScan
Time
Ultrasound acquisitions
Time
FibroScan
The probe induces an
elastic wave through
the liver
2.5
cm
Explored
volume
1 cm
4 cm
8.75 kPa
Sensitivity: 81%; specificity: 78% Need
correction formula when using TE as
screening test for NASH
with > F2
Mean platelet counts (2A) and AST-to-platelet ratio index values (APRI: 2B) before HCV therapy (Pre-Tx) and at the time of
last follow-up evaluation in 100 patients with a sustained HCV virological response stratified by degree of hepatic fibrosis on
pre-treatment liver biopsy. Patients were categorized into three groups based upon pretreatment Ishak fibrosis scores of 0 to 2
(no fibrosis to portal fibrosis only), 3 to 4 (bridging hepatic fibrosis) and 5 to 6 (early and complete cirrhosis).
Table 4
Association of Initial Ishak Fibrosis Score from Initial, Pretreatment Liver Biopsy and
Transient Elastography Stiffness Score at the Time of Final Follow-up Evaluation
Analysis by McNemar's Test
Fibroscan on Follow-up
Baseline
Ishak
Score
Number
of
Patients
7.0
7.113.8
> 13.8
PValue
02
45
28 (62%)
16 (36%)
1 (2%)
0.0006
34
17
12 (71%)
4 (23%)
1 (6%)
56
1 (14%)
2 (29%)
Total
69
41 (59%)
22 (32%)
4 (57%)
6 Koh,
(9%)Aliment Pharm Ther
2013
F0
vs.
F1-4
Marcellin et al.
F0-2
vs.
F3-4
F0-3
vs.
F4
F0
vs.
F1-4
F0-2
vs.
F3-4
F0-3
vs.
F4
F0
vs.
F1-4
F0-2
vs.
F3-4
F0-3
vs.
F4
Cut-off
12
7.5
13.4
7.2
8.1
11
AUROC
0.88
0.90
0.96
0.76
0.87
0.94
0.81
0.93
0.93
Sensitivity
91
71
60
92
96
75
70
86
93
Specificity
75
100
95
17
59
93
83
85
87
PPV
98
100
82
94
68
78
80
66
38
NPV
38
79
87
13
94
92
73
95
99
Accuracy
90
86
86
88
77
89
76
85
87
Chan HL, et al. J Viral Hepat 2009. Marcellin P, et al. Liver Int 2009.
57
0.5-1.5
>1.5
FibroScan
<7.5
7.5
Liver BX
F0-F1
F2
Bergmann J, et al. EASL 2008
FibroScan: Advantages
Fibroscan has the most extensive data on
pubmed in HCV and HBV
The CPT code was written specifying the
technology (VCTE) that Fibroscan uses
Source: personal communication RGish
10
0
40
50
30
0
40
50
20
40
Time (ms)
60 %
-5
60
VS = F0
1.0 m/s
E = 3.0 kPa
F0
30
0
40
50
20
40
Time (ms)
60 %
-5
60
VS =F2
1.6 m/s
E = 7.7 kPa
F1
20
Depth (mm)
30
60
10
20
Depth (mm)
Depth (mm)
20
F2
20
40
Time (ms)
60 %
VS =F4
3.0 m/s
E = 27.0 kPa
F3
F4
-5
Ultrasound-based Elastography
Let us Contrast
Shearwave (Supersonic) and Transient Elastography (Fibroscan)
Elastography Studies
Magnetic-resonance elastography (MRE)
Continuous longitudinal vibrations at 60 Hz via the
driver
2D gradient-ECHO MRE sequence acquires images
Speakers notes: looks like something from the 1960s Jefferson Airplane concert?
Abstract#211
The Severity of Steatosis Influences Liver Stiffness
Measurement in Patients with Nonalcoholic Fatty Liver Disease
Noureddin
2.2 kPa
M, 59 yrs
4
5.9 kPa
Noureddin
M, 64 yrs
4
Noureddin
chronicliver diseaseinUnitedStates1
Spectrumof diseases (steatosis,steatohepatitis,brosis,HCC)
Goldstandarddiagnosis liver biopsy
Risks: infection,bleeding,perforation
Cons: samplingerror,subjectiveinterpretation
Utilityof noninvasiveimaging/diagnosticsemerging
Conventional ultrasound,CT,advancedMRI
Newquantitativeultrasoundtechnique(QUS) tissueparameter
backscatter coefcient (BSC)2
Several animal models, fewlargehumanstudies
Rawultrasonicsignalsfromliver andcalibrationphantom
capturedusingcurvedtransducer
Signals analyzedofineto calculateBSC(numeric
parameter representingenergyof ultrasonicsignals
scatteredbyliver)
Sametransducer placedonreferencephantom(Figure1)
Phantomsignalsusedtoeliminateoperator- and
instrument-dependent factorsincalculations
Makes BSCindependent of machinefactors
andthuspotentiallydeployabletoany
clinical USscanner
Datafor aeldof interest,or FOI (Figure2),is recorded
40
35
Figure1.Transducercapturingdataon
aparticipantandareference
phantom.
Transducer rst placedover the
participantsliver (left); datacaptured
for aeldof interest (FOI) fromwhich
BSCiscalculated.Transducer isthen
placedonphantom(right) tocorrect
for operator/machine-dependent
factors.
METHODS
IRB-approved,HIPAAcompliant,cross-sectional analysis
(participantsderivedconsecutivelyfromprospectivecohort
Inclusion: >18yearsold,informedconsent
Exclusion: pregnant/nursing,CIs toMRI,reasonsfor liver disease
alcohol,meds,infections,AI,metabolic,HCC
Participants screenedwithhistory/physicals, biochemical testing
Eligibleparticipants - samedayMRI/QUSof liver
Trainingor validationgroup(stratiedrandomization)
Spearmanscorrelation(PDFF vs QUSBSC)
AUCsand95%DeLongcondenceintervals
Optimal QUSBSCcut-offs obtained; secondaryAUC
analysis conductedat other MRI-PDFF thresholds
BSCcut-offs de
B riv
S C ed
a tfrom
3
FOI
Participants
Liver
Reference
Phantom
T r a in in g S e t
V a lid a tio n S e t
30
M R I P D F F (% )
AIMS
RESULTS
25
0 .0 0 3 8 1 /c
C u t-o ff fo r
20
15
10
5
0
0 .0 0 0 0 1
0 .0 0 0 1
Figure4.CorrelationbetweenBS
optimal BSCcut-off.
WhenBSCiscorrelatedwithMRIgroupsof 0.82and0.79,P <.0001
theoptimal BSCcut-offwas 0.003
MRI Protocol
Correlation between BSC
and
MRIProtondensity
fat fraction
(PDFF,standardizedMR-based
quantitativeimagingbiomarker of steatosis) of liver estimatedat 3T
PDFF in training/validation Ugroups
sedadvancedmulti-echoMRI techniquethat
minimizesT1bias,corrects for T2*decay
(n = 204), at optimal BSC cut-off.
Addressesspectral complexityof protons infats
MRI-PDFF maps(reconstructedofine) usedto draw1cmradius
circular ROIsfor four right liveNoureddin
r lobesegments (5-8) to obtainPDFF
values,whicharethenaveraged
Figure2.QUSBSCimageswithcorrespondingMRI-PDFFsegmentationmaps.
Aeldof interest (FOI) isselectedwithinahomogenouspart of theliver (top).
Thisareaissubdividedintosub-regionof interests(sub-ROIs) for whichBSCis
Table1.Secondaryanalysisofvario
andvalidationgroups,withoptimal
95%condenceintervals inparenthe
Liver Multi-Scan
The next wave in imaging
Perspectum System
T2*
Case
Super morbidly obese woman with
pre-and post-bariatric surgery scan
0346T
$628 (CPT code. 74183)
Payment:
CMS $54 outpatient, $154 hospital seeting
In Summary
Use multiple tests (7 or more) to stage your patients
PE, labs, US imaging, blood tests, endoscopy,
elastography, APRI, Fib-4
What Do I Do?
Always:
When to Biopsy
The obese patient who will not lose weight
Autoimmune hepatitis: all
Iron overload: meeting AASLD criteria with elevated
ferritin, and AST
Cryptogenic Liver Disease
FHF: to make a diagnosis or stage/grade disease
Other: granulomatous disease, infections, DILI,
Listservs:
rgish@robertgish.com
For weekly updates
Robertgish.com
For monthly newsletters HepaHealth
CLDF website
University of Washington HCV Project
Thank You To
Arizona GI Society