new tools for assessing disease sererity, progression and...
TRANSCRIPT
Jidong Jia, MD, PhD
Beijing Friendship Hospital,
Capital Medical University
2016-3-14
New Tools for Assessing Disease Sererity,
progression and regression in HBV and HCV
Liver fibrosis is a common pathway to advanced liver disease
Pellicoro A,et al. Nat Rev Immunol 2014;14:181-94
Liver Histopathology
• Semi-quantitative scoring
systems:
Metavir
Ishak
Knodell
• Quantitative
morphometry :
Collagen proportionate area
(CPA)
Fibro-C-index
qFibrosis
Invasive method
Liver biopsy
- Semi-quantitative (histological)
scoring systems
- Quantitative computer-
assisted morphometric studies:
o Collagen proportionate
area (CPA)
o Fibro-C-index
o qFibrosis
Invasive method
Liver biopsy
- Semi-quantitative (histological)
scoring systems
- Quantitative computer-
assisted morphometric studies:
o Collagen proportionate
area (CPA)
o Fibro-C-index
o qFibrosis
• Limitations
Invasive
Expensive
Sampling error
Inter- and intra-observer
variation
Noninvasive Assessment for Liver Fibrosis
• Currently available tests
Biological (serum biomarker algorithms)
Physical (imaging assessment of tissue stiffness)
Physiological (breath test)
• Emerging novel tests
– Functional genomic, microparticle, protein-profiling and
bioimaging tools
– Assessment of dynamic nature of fibrogenesis
– Key to evaluation of efficacy of antifibrotic compounds
Semin Liver Dis 2015;35:166–183
Serum Biomarkers for Liver Fibrosis
Direct serum markers
• Glycoproteins/proteoglycan:
laminin, hyaluronate….
• collagens: Procollagen III, type
IV collagen….
• collagenases and their
inhibitors: MMP, TIMP-1…
• Reflect ECM turnover ( matrix
synthesis or degradation )
• Not routinely available
• Not specific to liver
Indirect serum markers
• Platelet count, PT, AST/ALT ratio
• FibroTest: α2-MG, ApoA1,
haptoglobin, γGT, and bilirubin
• APRI: AST to Platelet Ratio Idex
• FIB-4: Age, ALT, AST, Platelet
• Reflect alterations in hepatic function (more on diagnosis of cirrhosis)
• Routinely available
• Usually no extra cost
The predictive ability of APRI, FIB-4 and AST/ALT,
for ≥F3 fibrosis in 2372 US patients with CHC
Holmberg SD, et al. CID 2013
FibroTest /Fibrosure for significant fibrosis (F2-4)
or cirrhosis (METAVIR F4)in CHB
Significant fibrosis (F2-F4) Cirrhosis (F4)
Salkic NN, et al. AJG 2014
AUROC=0.84 (95 % CI: 0.78 – 0.88)
AUROC=0.87
(95 % CI: 0.85 – 0.90)
Meta-analysis of FibroTest for significant
fibrosis and cirrhosis in CHB
Xu XY, et al. PlosOne 2014
F≥2 F4
AUROCs for ELF and TE diagnosis of significant
fibrosis (F≥2) (A) and cirrhosis (F4) in CHC
F≥2 F=4
(ELF: HA+PIIIP+TIMP-1)
Fernandes FF, et al. JCG 2015
Imaging Assessments For Liver Fibrosis
• Ultrasound elastography Transient elastography (TE)
Fibroscan- EchoSense
Real-time elastography (RTE)
HI Vision-Hitachi
Shear Wave Elastography(SWE)
VTTQ(ARFI)- Siemens system
Shear Wave Elastography-SuperSonic system
ElastQP-Phillips system
• Magnetic Resonance Elastography (MRE)
Ferraioli G, et al. J Ultrasound Med 2014
Meta-analysis of AUROCs TE for significant fibrosis
and cirrhosis in CHB
Cho YE, et al. PloS ONE 2012
AUROC of TE, FIB-4 and APRI for the diagnosis of F ≥ 2
and F4 METAVIR stages in 469 CHB patients
F ≥ 2 F4
Jia JD, et al. JGH 2015
AUROC for 10 models, according to METAVIR Fibrosis
Stages in 259 CHB patients
Cheng J, et al. PLoS ONE 2015
AUROC for LFI from RTE (Hitachi) and LSM from TE (Fibroscan) for
diagnoses of fibrosis ≥F2 and cirrhosis (F4) in CHB
F=4 F≥2
Meng F, et al. J Ultrasound Med 2015
3 major techiques for Sear Wave Elastography (SWE)
Super-Sonic system (Sear Wave Elastography)
Siemens system (ARFI, VTTQ=Virtual
Touch Tissue Quantification)
Phillips System (ElastPQ)
Ferraioli G, et al.
J Ultrasound Med 2014
ROC for SWE (ARFI, Siemens) and TE for diagnosis
of significant fibrosis (F≥2) in CHB
Friedrich-Rust M, et al. JVH 2013
AUROC for SWE (SuperSonic) for identifying ≥F2 and
F4 in patients with CHC
F≥2 F=4
Samir AE, et al. Radiology 2015
Correlations between MRE and Metavir score
in 32 patients with CHB.
Venkatesh SK, et al. Magn Reson Med 2014; 72:1123–1129
Meta-analysis: Composite box plot graph showing MRE
values for various stages (METAVIR) of fibrosis
Singh S, et al. CGH 2014
Meta-analysis: Diagnostic Performance of MRE
for Fibrosis of Different Etiology
Singh S, et al. CGH 2014
Changes of LSM in CHB after NA therapy
The mean interval between two LSMs was 411.5 ±149.5 (180-1,062) days
Kim JK, et al. J Korean Med Sci 2014
Changes of LSM after ETV therapy
P<0.01
P<0.01
n-=233 n-=13
( with mean interval of 52.8 and 61.9 weeks in the 2 groups)
Kuo YH, et al. PloS ONE 2014
Changes of Ishak score and APRI and FIB-4
in CHB patients on TDF therapy
Kim WR, et al. J Hepatol 2015
APRI FIB-4
Multivariate analysis of negative prognostics
of sustained virologic response in CHC
on dual or triple therapy
N=65 N=20
Stasi C, et al. WJG 2015
LSM by TE and LFI by RTE correlates treatment
response by antiviral therapy in CHC patients
• LSM and LFI correlated well before and after therapy
(r = 0.567, p = 0.003 and r = 0.576, p = 0.002,
respectively).
• In the group without a sustained virological
response (SVR), LSM increased in 4 of 5 patients.
• In the SVR group, both LSM and LFI decreased in all
patients except 1 (18/19, 94.7%)
• In the patient with an increase in LSM despite
achieving SVR, LSM decreased quickly after alcohol
cessation.
Yada N, et al. Oncology 2014
MALDI-TOF MS Identified Serum Peptide Pattern for Prediction of HBV-Cirrhosis
Complete mass spectrum of
serum samples between
HBV-cirrhosis and non-LC groups
in the 800–10,000 m/z range.
Red line=HBV-cirrhosis group
Blue line=non-LC group.
Cao Y, et al. BioMed Research International
High Throughput LC-IMS-MS Identified relative log2 intensity proteins with
significant differential abundance in CHC
Baker ES, et al. Molecular & Cellular Proteomics 2014