PowerPoint Presentation

Elastography and noninvasive testing for liver fibrosis

A Historical Review and a SOTA PresentationRobert G Gish MDSenior Medical Director St Joseph Hospital and Medical CenterArizona GI Society MeetingMarch 2015Relevant DisclosuresNone

Copy of these slides?: rgish@robertgish.com

Who to treat: a Focus on HCVFibrosis 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 FibrosisStart with a Physical Exam

Revista da Sociedade Brasileira de Medicina TropicalPrintversionISSN0037-8682Rev. Soc. Bras. Med. Trop.vol.43no.2UberabaMar./Apr.2010Clinical Exam and Abdominal UltrasoundChoicesTo Biopsy or not to Biopsythat is the question!

Complications of Liver BiopsyComplicationPercent (%)Arterial hypotensionvariousPain at the right hypochondrium, shoulder

0.056-83%

Hemorrhagic complicationsSubcapsular hematoma: 0.05%Intrahepatic hematoma: 0.05%Intraperitoneal bleeding: 0.03%Hemobilia: 0.05%Bacteremia0.08%Death0.001-0.0001%Bile peritonitis0.03-0.22%Pneumothorax, hemothorax 0.08-0.28%Subcutaneous emphysema0.014%Break of the biopsy needle 0.02%Biopsy of other organs Lungs-0.001%Bile-0.003%Colon-0.003%Kidneys-0.09%Modified from: Crockett et all 2006

Comparison of Liver Biopsy and Serum Markers of FibrosisFactorLiver biopsySerum markersElastographyCost2200$Laboratory costMachine investment $130,000, staff timeRisksSignificantMinimal, phlebotomyNoneContraindicationsMultiple: bleeding diathesis, morbid obesity, ascites, extrahepatic biliary obstructionConditions with high rate of false positivityPatient needs be able to lay still, ascites, volume overloadAccuracy80%60-80%60-95%System requirementsOperator, pathology laboratory, pathologistClinical laboratory, phlebotomy, materialsMachine, staff, timeSpecimen adequacy16 g needleLength of liver fragment at least 15mm with > 12 portal tractsBlood sampleStaff timeFalse positivesInterobserver variabilitySepsis, nonhepatic inflammation, hemolysis, trombocitopeniaObesity, narrow ribs, ascites, heart failure, volume overloadFalse negativesInterobserver variabilityVaries per testvariousTime for results24-72 hours minimum 1-2 hours minimum lab, 1-2 weeks for results15-45 minLiver Biopsy Stage of Fibrosis: 3 Samples

Accessed 9/21/14: http://www.meddean.luc.edu/lumen/MedEd/orfpath/cirhosis.htmF0 no fibrosis seen, no portal tractsF3? Fibrosis present,suggestion of a bridgeF4- bridging presentw/suggestion of nodule formationTrichrome stain will stain collagen present in fibrosis

10

Accessed 9/21/14: http://www.meddean.luc.edu/lumen/MedEd/orfpath/cirhosis.htmLiver Biopsy Stage of Fibrosis: One Patient% Of Correctly Classified Biopsies With The Converted METAVIR Score Of Fibrosis According To Length Of Biopsy Specimen All Stages Together

Bedossa P, et al. Hepatology 2003;38:14491457.Message: obtain at least 2 cm of tissue and use a 16 gauge needleQuality of Liver BiopsyPoynard T, et al. Clin Chem. 2004;50:1344-1355.Biopsy Length (mm)Pitie experience 1773 biopsies: 16% 25mm07515022530005101520253035404550Trends in Use of Liver BiopsyPopularized

1940s-1950s 1960s 1970s 1980s 1990s 2000s >2010 2015Viral Serology

ImagingUltrasound

CT

ERCPLiver Transplantation

HCV

Interferon

All oral therapiesHCV

Anesthesia for a patient undergoing a liver biopsyCourtesy of Nid Afdhal15...dabei werden 4 wesentliche Ursachen einer chron. Hepatitis unterschieden, die differentialdiagnostisch von anderen hepatobiliren Erkrankungen unterschieden werden, die das klinische Bild der chron. Hepatitis imitieren knnen.

Kryptogene Hepatitis: Ausschludiagnose !!Liver Biopsy: TodayIron work upAutoimmune hepatitisPrimary biliary cholangitisPSCNASHCryptogenicInfections: CMV, EBV, otherLiver masses not defined by CT/MR

Future: biopsy all hepatocellular carcinomas if patient has option for systemic/targeted therapyJust Draw BloodIs this sufficient?

Fibrosure in the United States

Poynard, Clin Chem 2004; 50: 1344-55.FibroSure: A Continuous Variable (n=1,270)Diagnostic performance of selected biomarkers22Marcellin P, et al. Lancet 2012;6736: 61425-1.StudyComponentsAUROC F>2AUROC F4FibroTestBili GGT Hapto, A2m, ApoA10.74-0.890.82-0.92FibrometerPT, AST, A2M, HA, Urea0.78-0.890.94ELFHA, PIIIP, TIMP10.77-0.870.87-0.90FibroSpectHA, A2M, TIMP10.83-0.90APRIAST, Platelets0.69-0.880.61-0.94FIB4AST, ALT, Platelets0.74-0.850.8-0.93HepascoreBili, GGT, HA, A2M0.74-0.860.8-0.94FornsCT,GGT, Platelets0.75-0.91

22

Imbert-Bismut. Lancet 2001; 357:1069-75. 50% of Biopsies May Be Avoidable with FibroSureAccuracy of APRI, FIB-4 and AST/ALT ratio

Holmberg CID 2013Factors Associated With Significant FibrosisF0F1 FibrosisF2F3F4 FibrosisP ValueAge, yrs5057.002BMI, kg/m2930.07AST/ALT ratio0.68 0.40.92 0.5.005APRI0.72 1.170.84 0.26.5Liver stiffness, kPa6.9218.52.0001AST/ALT ratio of over 0.8 is over 90% predictive of >= F3Just Use an UltrasoundPortal Vein Diameter /Size

Spleen Size

Liver configurationSmall right lobeLarge caudate/left lobeHeterogeneous

Varices

Revista da Sociedade Brasileira de Medicina TropicalPrintversionISSN0037-8682Rev. Soc. Bras. Med. Trop.vol.43no.2UberabaMar./Apr.2010Clinical Exam and Abdominal Ultrasound

How to do a Portal Vein MeasurementBroadest point just distal to the SPV/SMV confluence

Weinreb J et al. AJR 1982;139:497-49928Sensitivity, SpecificityPV size and cirrhosis324 patients w/chronic viral hepatitis (HCV/HBV)Liver biopsy and ultrasound Tested ability of diagnosing cirrhosisSpleen >12.1cm: Sensitivity of 60%, specificity 75.3% PV diameter>12mm Sensitivity 76.7%, specificity 44.6%

Shen L et al. World J Gastroenterol. 2006 Feb 28;12(8):1292-5.Helps to establish, as a composite, the presence of advanced fibrosis and portal HTN

29Portal Vein Size and Esophageal VaricesPV size 1.2cm on US could predict both presence and risk of variceal bleedingPV size on US is independently associated with bleeding esophageal varicesPV size >14mm: at a great risk of bleeding from esophageal varicesDevrajani BR et al. World J Med Sci 2009;4(1):50-53Prihatini JLA et al. Acta Med Indones 2005;37(3):126-131Plestina SR et al. Wien Klin Wochenschr 2005;20:711-71731Prognostic Value of Non-invasive Diagnostics forLiver Fibrosis in CHB and CHCPavlov C, et al. 60th AASLD; Boston, MA; October 30-November 3, 2009; Abst. 1660.All found to be accurate in diagnosing severe fibrosis (F2-F4) in pts withCHB and CHC

010.20.6Sensitivity0.80Specificity0.21Transient ElastographyAUROC=0.888 (pF2 Phase 1 Phase 2*81.9 (72.0-89.5)57.9 (52.7-63.0)79.0 (70.0-86.4)74.9 (68.0-80.9)>F3 Phase 1 Phase 288.3 (77.4-95.2)71.8 (64.2-77.6)81.9 (73.4-87.6)80.1 (76.0-84.3)F4 Phase 1 Phase 284.2 (68.7-94.0)75.9 (64.0-83.686.0 (79.4-91.1)85.1 (82.1-88.6)Diagnostic Accuracy Versus Biopsy(HCV and HBV)*P=0.043 versus phase 1.FSCAN: FibroScan.Slide: Diagnosis Accuracy of Liver Stiffness in Chronic Viral Hepatitis

Afdhal and colleagues conducted a US, multi-center, 2-phase study to validate the diagnostic accuracy of the assessment of liver stiffness by FibroScan LS compared to liver biopsy (reference assay) in patients with hepatitis B or C.1Phase 1 included 188/237 evaluable biopsy/FSCAN and phase 2 included 560/670 evaluable biopsy/FSCAN.The FSCAN/biopsy failure rates were 10.4% and 7.9%, respectively.

As shown in the table, the sensitivity and specificity results from both phases of the study indicate that liver stiffness has high accuracy for staging >F2 fibrosis. In addition, the AUC of 0.91 indicates that elastography is an excellent assay for excluding cirrhosis. However, it was found that a higher BMI can affect cutoffs, leading the authors to prefer the XL probe over the M probe .1

These data confirms that transient elastography very accurately assesses presence of cirrhosis in patients with chronic type B and C viral infection.1

ReferenceAfdhal NH, Bacon BR, Patel K, et al. Diagnostic accuracy of liver stiffness (FibroScan) in patients with chronic viral hepatitis: results of a large USA cohort. Hepatology. 2013;58(suppl 1):278A-279A. Abstract 141.

Cutoff of FibroScan for the diagnosis of significant fibrosis

Sensitivity: 81%; specificity: 78% Need correction formula when using TE as screening test for NASH with > F2Diagnosis of Significant Fibrosis With FibroScan8.75 kPa

TE compared to Liver Biopsy

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).Koh, Aliment Pharm Ther2013

Reproducibility of Transient Elastography Fraquelli et al, Gut 2007453 Subclinical Cirrhosis Diagnosed by Transient ElastographyDemonstrates Increased Risk of Severe Clinical Outcomes and HCC

Chen et al Montreal CanadaMethods: Patients with chronic liverdisease (CLD) and a valid Fibroscan were divided into: 1)SC (Fibroscan 13kPa and no thrombocytopenia, nor signsof advanced liver disease on ultrasound or endoscopy); 2)non-cirrhotic CLD (Fibroscan 13.8024528 (62%)16 (36%)1 (2%)0.0006341712 (71%)4 (23%)1 (6%)5671 (14%)2 (29%)4 (57%)Total6941 (59%)22 (32%)6 (9%)Table 4Association of Initial Ishak Fibrosis Score from Initial, Pretreatment Liver Biopsy and Transient Elastography Stiffness Score at the Time of Final Follow-up EvaluationAnalysis by McNemar's TestChan HL, et al. J Viral Hepat 2009..HBV: what to do with ALT and kPA elastography?57Transient Elastography in CHB 57Chan HL, et al. J Viral Hepat 2009. Marcellin P, et al. Liver Int 2009.Chan et al. Normal ALTChan et al. Elevated ALTMarcellin et al. F0 vs. F1-4F0-2 vs. F3-4F0-3 vs. F4F0 vs. F1-4F0-2 vs. F3-4F0-3 vs.F4F0 vs. F1-4F0-2 vs. F3-4F0-3 vs. F4Cut-off591257.513.47.28.111AUROC0.880.900.960.760.870.940.810.930.93Sensitivity917160929675708693Specificity7510095175993838587PPV9810082946878806638NPV387987139492739599Accuracy908686887789768587Data of Fibroscan in HBV mainly derived from 2 trials (Chan and Marcellin)

57FibroScan and APRI forFibrosis in CHBN=175 Dutch cohort CHB (n=93), CHC (n=82) Original study cutoffs (F2=7.1 and F3=9.5kPa)For CHB pts. AUROC F2-4 (FS=0.84, APRI=0.73); APRI + FS=0.85Reduced need for liver biopsy by 48% in CHB, 38% for CHC

Bergmann J, et al. EASL 2008APRIFibroScanLiver BXF0-F1F20.5-1.5>1.5 x10ULN, FS at baseline during flare and at 3-6 monthsBaseline stiffness=18.5 kPa (6.9-73.5), peak ALT 15433-6 months=8.4 kPa (4.4-25.1); median ALT 31Good correlation FS and ALT r=0.64

Fung J et al. EASL 20083rd Generation: Ultrasound-based Elastography

Muller et al. UMB 2009; 35: 219-29Bavu et al. UMB 2011;37: 1361-73AixplorerSupersonic shear imaging (ShearWave) Multiple wave fronts with frequencies ranging from 60-600 HzReal-time imaging available to target area of interestBuilt in Doppler US130,000$Does the CPT code apply ?

Advantages of the SW with US and DopplerThe technician can guide the device to a larger sampling area to include regions of the liver directly avoiding the central vessels, gallbladder, kidneys, surroungdng blood vessels, lung, ribs and liver defectsSource: personal communication RGishUltrasound-based Elastography

Cassinotto C, et al. J Hepatol. 2014;61:550-7.

Let us Contrast Shearwave (Supersonic) and Transient Elastography (Fibroscan) Why would you want to do sequential fibrosis exams (biopsy vs elastography?)

Parenchymal extinction nodule PENHepatology.1995 May;21(5):1238-47.Hepatic and portal vein thrombosis in cirrhosis: possible role in development of parenchymal extinction and portal hypertension.Wanless IR1,Wong F,Blendis LM,Greig P,Heathcote EJ,Levy G.

X

Just Add the Elastography Test to Your Magnetic Resonance ExamBenefit: you can also calculate fat %Iron

Device advise? (Rgish)GE bestSiemens second bestPhillips has not matured their technologyNew 2nd or 3rd Gen: 1.5t scanner probably bestNew 3t scanner second best1st Gen 1.5t should not be usedElastograhy Device cost is $60,000 + software cost Elastography Studies

Talwalker JA, et al. AJR. 2009;193:122-7.Magnetic-resonance elastography (MRE)Continuous longitudinal vibrations at 60 Hz via the driver2D gradient-ECHO MRE sequence acquires images

Magnetic Resonance ElastographySpeakers notes: looks like something from the 1960s Jefferson Airplane concert?

Talwalker JA, et al. AJR. 2009;193:122-7.

Slides Courtesy of S PettaPetta, M Maida, FS Macaluso, V Di Marco, C Camm, D Cabibi, A Crax.

Sezione di Gastroenterologia, Di.Bi.M.I.S., University of Palermo, Italysalvatore.petta@unipa.it

Abstract#211The Severity of Steatosis Influences Liver Stiffness Measurement in Patients with Nonalcoholic Fatty Liver DiseaseNoureddin73MethodsPatients: 306 consecutive patients with biopsy-proven NAFLDHistology: Scoring according to Kleiners classification; LSM measurement: FibroScan (Echosens, Paris, France), using the M probe*. Test acceptable if 10 successful acquisitions with a success rate of at least 60%, and with an interquartile range lower than 30%.

*When the study was started the XL probe and the Controlled Attenuated Parameter (CAP) software were not available.

Noureddin7474Biopsy-proven NAFLD + Reliable Liver StiffnessN=253LSM8.4*N=164 (65%) LSM>8.4*N=89 (35%) VCTE 0.899 vs. 0.829, p= 0.0092*3D-MRE > 2D-MRE 0.914 vs. 0.902, p=0.5018

2DMRE 3DMRE VCTE VCTE-reliable0.70.80.91.00.0217*0.0092*2DMRE: 0.9023DMRE: 0.914VCTE: 0.829VCTE-reliable: 0.899NoureddinConclusions: In this head-to-head study, the diagnostic performance (AUROC) for detecting clinically significant hepatic fibrosis (F2-F4) was:0.902 for 2D-MRE0.914 for 3D-MRE0.829 for VCTE The diagnostic accuracy of 3D-MRE is greater than that of VCTE (p = 0.0217). If exams with unreliable VCTE results are excluded, then the AUROC of VCTE is improved to 0.899, but at the expense of more technical failures and unreliable results (18/97).

NoureddinImportance and ImplicationsMRE has performed better in detecting fibrosis than fibroscan.Further studies are needed.

Noureddin

Correlation between BSC and MRI-PDFF in training/validation groups (n = 204), at optimal BSC cut-off.Abstract # 1084 AASLD 2014 Noninvasive Diagnosis of Nonalcoholic Fatty Liver Disease and Quantification of Liver Fat by New Quantitative Ultrasound NoureddinLiver Multi-ScanThe next wave in imaging

Reference: Seattle Radiology PDF

Reference: Seattle Radiology PDF

Pavlides et al; J Hepatology 2014Perspectum System

Predicting outcomes from LIF (Liver Imaging Fibrosis) score

Reference: Seattle Radiology PDFT2*

CaseSuper morbidly obese woman with pre-and post-bariatric surgery scan

FibroCT

MR SpectroscopyWhat about genetic testing ?Evaluate for polymorphismsCreating a Cirrhosis Risk ScoreCeleraProbability score to reflect the combined risk of 7 SNPs

Calculated using a Nave Bayes algorithmEach SNP is weighted differently based on their risk estimates

Ranges from 0-1 (0% to 100%)The higher the CRS, the higher the risk for cirrhosis01Cirrhosis Risk Score (CRS)Illustrative Example:

CRS: Prognostic ValueIdentifies Patients at High RiskHigh risk010.70Physicians may use CRS in combination with other diagnostic tests and clinical information to identify patients at an early stage of disease to aid in treatment candidacy

CPT Code for Elastography?Yes for MRE since 20090346T$628 (CPT code. 74183)

Yes for TE 2013Specifies the methodology for Fibroscan (0346T, 91299) The FibroScan 502 Touch device utilizes Vibration Controlled Transient Elastography (VCTE) to aid in the clinical management of chronic liver disease.

Payment:CMS $54 outpatient, $154 hospital seetingIn SummaryUse multiple tests (7 or more) to stage your patientsPE, labs, US imaging, blood tests, endoscopy, elastography, APRI, Fib-4If you are using these tests to obtain HCV approval: use the best test to prove advanced fibrosisDo not let the insurance companies bully you into doing a liver biopsy

For the Obese Patient Where TE or SSI and US are Not UsableDo MRE and fat % analysisWhat Do I Do?Always: look at the platelet countAST to ALT ratioSpleen Size, PV diameter, liver texture, liver configurationAPRI scoreFIB-4 score

HCV patients: where availableElastography, Phoenix, San Jose GI and Stanford practices

Complex patients: MR with elastography, fat and iron assessment When to BiopsyThe obese patient who will not lose weightAutoimmune hepatitis: allIron overload: meeting AASLD criteria with elevated ferritin, and ASTCryptogenic Liver DiseaseFHF: to make a diagnosis or stage/grade diseaseOther: granulomatous disease, infections, DILI, Listservs:rgish@robertgish.comFor weekly updates

Robertgish.comFor monthly newsletters HepaHealth

CLDF website

University of Washington HCV Project

Thank You ToArizona GI Society