THE CLINICAL EVALUATION OF DISEASE …...DIAGNOSTIC ACCURACY ROC and AUROC curves: show the trade...

MASSIMO PINZANI, M.D., Ph.D.MASSIMO PINZANI, M.D., Ph.D.DIPARTIMENTO DI MEDICINA INTERNA DIPARTIMENTO DI MEDICINA INTERNA CENTER FOR RESEARCH, HIGH EDUCATION AND CENTER FOR RESEARCH, HIGH EDUCATION AND TRANSFER TRANSFER ““DENOTheDENOThe””UNIVERSITAUNIVERSITA’’ DI FIRENZE, FIRENZE, ITALYDI FIRENZE, FIRENZE, ITALY

THE CLINICAL EVALUATION OF DISEASE THE CLINICAL EVALUATION OF DISEASE PROGRESSION IN CLD: TOWARDS AN PROGRESSION IN CLD: TOWARDS AN INTEGRATED SYSTEM?INTEGRATED SYSTEM?

I DO NOT HAVE ANY CONFLICT OF INTEREST IN THE I DO NOT HAVE ANY CONFLICT OF INTEREST IN THE COMMERCIAL DEVELOPMENT OF PRODUCTS OR DEVICES COMMERCIAL DEVELOPMENT OF PRODUCTS OR DEVICES

MENTIONED IN THIS PRESENTATIONMENTIONED IN THIS PRESENTATION

1.1.-- DIAGNOSTIC ACCURACY: ARE THERE GOLD STANDARDS ?DIAGNOSTIC ACCURACY: ARE THERE GOLD STANDARDS ?

4.4.-- NONNON--INVASIVE METHODS: GOOD FOR ANY STAGE OF INVASIVE METHODS: GOOD FOR ANY STAGE OF FIBROTIC EVOLUTION?FIBROTIC EVOLUTION?

2.2.-- BIOCHEMICAL MARKERS: THE WAY TO GO ?BIOCHEMICAL MARKERS: THE WAY TO GO ?

3.3.-- TRANSIENT ELASTOGRAPHY: MORE DIAGNOSTIC TRANSIENT ELASTOGRAPHY: MORE DIAGNOSTIC FLEXIBILITY?FLEXIBILITY?

THE CLINICAL EVALUATION OF DISEASE PROGRESSION THE CLINICAL EVALUATION OF DISEASE PROGRESSION IN CLD: TOWARDS AN INTEGRATED SYSTEM?IN CLD: TOWARDS AN INTEGRATED SYSTEM?

5.5.-- WHAT SHOULD WE DO NOW?WHAT SHOULD WE DO NOW?

6.6.-- WHAT SHOULD WE EXPECT WITHIN TEN YEARS?WHAT SHOULD WE EXPECT WITHIN TEN YEARS?

DDIAGNOSTICIAGNOSTIC AACCURACYCCURACY

ROC and AUROC curvesROC and AUROC curves: show the trade off between : show the trade off between sensitivity sensitivity and and specificityspecificity (any increase in sensitivity will be accompanied by a decrease (any increase in sensitivity will be accompanied by a decrease in in specificity).specificity).

SENSITIVITYSENSITIVITY:: the proportion of truly diseased persons, as measured the proportion of truly diseased persons, as measured by the by the gold standardgold standard, who are identified as diseased by the test under , who are identified as diseased by the test under study.study.

SPECIFICITYSPECIFICITY: the proportion of truly non diseased persons, as : the proportion of truly non diseased persons, as measured by the measured by the gold standardgold standard, who are so identified by the diagnostic test , who are so identified by the diagnostic test under study.under study.

NEGATIVE/POSITIVE PREDICTIVE VALUESNEGATIVE/POSITIVE PREDICTIVE VALUES: the probability : the probability that a person with a positive test is a true positive, or that athat a person with a positive test is a true positive, or that a person with person with a negative test truly does not have the disease. They are determa negative test truly does not have the disease. They are determined by ined by the the sensitivitysensitivity and and specificityspecificity of the test, and by the prevalence of the of the test, and by the prevalence of the condition for which the test is used.condition for which the test is used.

GOLD STANDARD ?GOLD STANDARD ?

NONNON--INVASIVE TESTINVASIVE TEST

Established and Candidate Biomarkers of Established and Candidate Biomarkers of FibrosisFibrosis

•• ““IndirectIndirect””: : Not related to Fibrogenesis Not related to Fibrogenesis –– AST, ALT, AST, ALT, γγGT, Apolipoprotein A1, bilirubin, GT, Apolipoprotein A1, bilirubin,

αα22--macroglobulin, haptoglobin, cholesterolmacroglobulin, haptoglobin, cholesterol–– HOMAHOMA--IR, HOGISIR, HOGIS–– Platelets, INR/PTPlatelets, INR/PT

•• ““DirectDirect””: : ECM components and enzymesECM components and enzymes–– HA, PIIINP, Collagen IV, Collagen VI, TIMPHA, PIIINP, Collagen IV, Collagen VI, TIMP--1, 1,

LamininLaminin, YKL, YKL--40, 40, TenascinTenascin, , UndulinUndulin, MMP, MMP--1, MMP1, MMP--22

COMPLICATIONS OF COMPLICATIONS OF PORTAL PORTAL

HYPERTENSIONHYPERTENSION

HEPATOCELLULAR HEPATOCELLULAR FAILUREFAILURE

FIBROGENESISFIBROGENESISINFLAMMATION AND INFLAMMATION AND ECM DEGRADATIONECM DEGRADATION

HEPATOCELLULAR HEPATOCELLULAR AND BILIARY AND BILIARY

DAMAGEDAMAGE

HAHATYPE IV COLLTYPE IV COLL

MMP2MMP2alpha2alpha2--MGMG

γγ--GLOBULINGLOBULINFERRITINFERRITIN

ALTALTASTASTGGTGGT

PIII NPPIII NPMMP1MMP1TIMP1TIMP1

CHOLESTEROLCHOLESTEROLHAPTOGLOBINHAPTOGLOBIN

APOAPO--A1A1BILIRUBINBILIRUBIN

INR/PIINR/PIALBUMINALBUMIN

PLATELET PLATELET COUNTCOUNT

TTHEHE OORIGINRIGIN OFOF BBIOCHEMICALIOCHEMICAL MMARKERSARKERS

AGE & GENDERAGE & GENDERINSULIN RESISTANCEINSULIN RESISTANCEBMI & VISCERAL OBESITYBMI & VISCERAL OBESITY

BBIOCHEMICAL IOCHEMICAL MMARKERS: ARKERS: OOVERALL VERALL PPERFORMANCEERFORMANCE

1.1.-- MILD/NO FIBROSIS vs. SIGNIFICANT FIBROSIS: MILD/NO FIBROSIS vs. SIGNIFICANT FIBROSIS: MEDIAN AUC = MEDIAN AUC = 0.770.77

2.2.-- CIRRHOSIS vs. NON CIRRHOSIS: MEDIAN CIRRHOSIS vs. NON CIRRHOSIS: MEDIAN AUC = AUC = 0.870.87

COMPLICATIONS OF COMPLICATIONS OF PORTAL PORTAL

HYPERTENSIONHYPERTENSION

HEPATOCELLULAR HEPATOCELLULAR FAILUREFAILURE

FIBROGENESISFIBROGENESISINFLAMMATION AND INFLAMMATION AND ECM DEGRADATIONECM DEGRADATION

HEPATOCELLULAR HEPATOCELLULAR AND BILIARY AND BILIARY

DAMAGEDAMAGE

PIII NPPIII NPMMP1MMP1TIMP1TIMP1

HAHATYPE IV COLLTYPE IV COLL

MMP2MMP2alpha2alpha2--MGMG

PLATELET PLATELET COUNTCOUNT

CHOLESTEROLCHOLESTEROLHAPTOGLOBINHAPTOGLOBIN

APOAPO--A1A1BILIRUBINBILIRUBIN

INR/PIINR/PIALBUMINALBUMIN

γγ--GLOBULINGLOBULINFERRITINFERRITIN

ALTALTASTASTγγGTGT

F0 F1 F2 F3 F4

GRAY AREAGRAY AREA

FIBROTESTFIBROTESTFORNS, APRI, FIBROINDEX, BONACINI, POHLFORNS, APRI, FIBROINDEX, BONACINI, POHL

ELFELF

MP3MP3

FIBROMETERFIBROMETER

IIMPLEMENTATION OF MPLEMENTATION OF BBIOCHEMICAL IOCHEMICAL MMARKERSARKERS

1.1.-- IMPROVE THE QUALITYIMPROVE THE QUALITY OF OF ““GOLDGOLD--STANDARDSSTANDARDS””

2.2.-- TEST THE DIAGNOSTIC ACCURACY IN TEST THE DIAGNOSTIC ACCURACY IN LONGITUDINAL AND LONGITUDINAL AND PROGNOSTICPROGNOSTIC STUDIESSTUDIES

3.3.-- WORK ON AN OPTIMAL WORK ON AN OPTIMAL ““RERE--SHUFFLESHUFFLE”” OF OF THE AVAILABLE MARKERS THE AVAILABLE MARKERS

4.4.-- EVALUATE THE EVALUATE THE CUMULATIVE POTENTIALCUMULATIVE POTENTIALOF DIFFERENT NON INVASIVE METHODSOF DIFFERENT NON INVASIVE METHODS

AUC

GRAY AREAGRAY AREA

TTRANSIENT RANSIENT EELASTOGRAPHY LASTOGRAPHY (LSM)(LSM): : PPROBLEMS & ROBLEMS & LLIMITATIONSIMITATIONS

1.1.-- LSM WORKS WELL ONLY WHEN THE AMOUNT OF LSM WORKS WELL ONLY WHEN THE AMOUNT OF FIBROSIS BECOMES SIGNIFICANT: I.E. FIBROSIS BECOMES SIGNIFICANT: I.E. >> F2. F2.

2.2.-- THE HIGH CUTTHE HIGH CUT--OFF VARIABILITY FOR OFF VARIABILITY FOR >> F4F4 IS LIKELY IS LIKELY DUE TO AN DUE TO AN INSUFFICIENT DEFINITIONINSUFFICIENT DEFINITION OF THE OF THE CIRRHOTIC STAGECIRRHOTIC STAGE

3.3.-- INTERINTER-- AND INTRAAND INTRA--OBSERVER AGREEMENTS ARE OBSERVER AGREEMENTS ARE EXCELLENT BUT SIGNIFICANTLY INFLUENCED BY BMI EXCELLENT BUT SIGNIFICANTLY INFLUENCED BY BMI AND DEGREE OF STEATOSIS AND DEGREE OF STEATOSIS 4.4.--THE THE ““NORMAL RANGENORMAL RANGE”” OF LSM VALUES STILL RELIES OF LSM VALUES STILL RELIES ON VALUES OF PTS CLASSIFIED AS ON VALUES OF PTS CLASSIFIED AS ““F0F0””

5.5.-- INCIDENCE AND RELEVANCE OF CONFOUNDING INCIDENCE AND RELEVANCE OF CONFOUNDING FACTORS, I.E. INFLAMMATION AND TISSUE EDEMAFACTORS, I.E. INFLAMMATION AND TISSUE EDEMA


1.1.-- LSM WORKS WELL ONLY WHEN THE AMOUNT OF LSM WORKS WELL ONLY WHEN THE AMOUNT OF FIBROSIS BECOMES SIGNIFICANT: I.E. FIBROSIS BECOMES SIGNIFICANT: I.E. >> F2. F2.

2.2.-- THE HIGH CUTTHE HIGH CUT--OFF VARIABILITY FOR OFF VARIABILITY FOR >> F4F4 IS LIKELY IS LIKELY DUE TO AN INSUFFICIENT DEFINITION OF THE DUE TO AN INSUFFICIENT DEFINITION OF THE CIRRHOTIC STAGECIRRHOTIC STAGE

3.3.-- INTERINTER-- AND INTRAAND INTRA--OBSERVER AGREEMENTS ARE OBSERVER AGREEMENTS ARE EXCELLENT BUT SIGNIFICANTLY INFLUENCED BY BMI EXCELLENT BUT SIGNIFICANTLY INFLUENCED BY BMI AND DEGREE OF STEATOSIS AND DEGREE OF STEATOSIS 4.4.--THE THE ““NORMAL RANGENORMAL RANGE”” OF LSM VALUES STILL RELIES OF LSM VALUES STILL RELIES ON VALUES OF PTS CLASSIFIED AS ON VALUES OF PTS CLASSIFIED AS ““F0F0””

5.5.-- INCIDENCE AND RELEVANCE OF CONFOUNDING INCIDENCE AND RELEVANCE OF CONFOUNDING FACTORS, FACTORS, I.E. INFLAMMATION AND TISSUE EDEMAI.E. INFLAMMATION AND TISSUE EDEMA


DOES LSM REFLECT ONLY THE FIBROTIC DOES LSM REFLECT ONLY THE FIBROTIC TRANSFORMATION OF LIVER TISSUE?TRANSFORMATION OF LIVER TISSUE?

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I II III I II III HEPATOLOGY 2007; 46:IN PRESSHEPATOLOGY 2007; 46:IN PRESS

Beyond Beyond ““F4F4””: A Clinical Limbo: A Clinical Limbo

F0/F1F0/F1 F4F4

HVPG > 5HVPG > 5 HVPG > 10HVPG > 10

Clinical Signs of Clinical Signs of DecompensatedDecompensatedCirrhosis/HCC Cirrhosis/HCC

HVPG > 12HVPG > 12

Significant Risk of Significant Risk of VaricealVariceal Bleeding Bleeding

PROGRESSION OF PROGRESSION OF CIRRHOSIS CIRRHOSIS (F4 A(F4 A--BB--C ???)C ???)

Patient FOLLOWPatient FOLLOW--UP: routine UP: routine lab test, US, AFPlab test, US, AFP

Liver Stiffness Value (Liver Stiffness Value (KPaKPa))

27.527.5 49.149.1 53.753.737.537.5 62.762.7

No Esophageal No Esophageal VaricesVaricesStage 2 or 3Stage 2 or 3

No ChildNo Child--Pugh B or CPugh B or C

No past history of No past history of ascitesascites

No Hepatocellular Carcinoma

No past history of variceal bleeding

HV

PG

(mm

Hg)

TransientTransient ElastographyElastography forfor DiagnosisDiagnosis of of AdvancedAdvanced FibrosisFibrosisand and PortalPortal HypertensionHypertension in in PatientsPatients WithWith HepatitisHepatitis C C

RecurrenceRecurrence After After LiverLiver TransplantationTransplantationCarrionCarrion etet al.al. LiverLiver TrasplantationTrasplantation 20062006

PearsonPearson’’s s correlationcorrelation 0.84; 0.84; P P < 0.001< 0.001

Hepatic Stiffness as a Predictor of HVPGHepatic Stiffness as a Predictor of HVPG

VIZZUTTI F. et AL, HEPATOLOGY 2007; 45:1290VIZZUTTI F. et AL, HEPATOLOGY 2007; 45:1290--12971297

●13.6 kPa

Hepatic Stiffness as a Predictor of HVPGHepatic Stiffness as a Predictor of HVPG

●

17.6 kPa


Varices

Hepatic Stiffness is a Poor Predictor of Hepatic Stiffness is a Poor Predictor of Upper GI Upper GI VaricesVarices

●

17.6 kPa


““A LITTLE KITCHEN MAKES A A LITTLE KITCHEN MAKES A LARGE HOUSELARGE HOUSE””

NNoo ssiiggnniiffiiccaanntt ffiibbrroossiiss

((ii..ee.. FF00--FF11))

NNoo bbiiooppssyy

CCiirrrrhhoossiiss ((ii..ee.. FF44))

FFoollllooww oorr ttrreeaatt

GGrraayy aarreeaa ((ii..ee.. FF22--FF33))

NNoo bbiiooppssyy

HHCCCC aanndd vvaarriicceess ssccrreeeenniinngg

BBiiooppssyy iiff rreessuullttss iinnfflluueennccee

mmaannaaggeemmeenntt

BBiiooppssyy iiff rreessuullttss iinnfflluueennccee

mmaannaaggeemmeenntt

SSuussppeecctteedd CChhrroonniicc LLiivveerr DDiisseeaassee

AAppppllyy ttwwoo uunnrreellaatteedd NNIITTss

CCoonnccoorrddaanntt NNIITTssDDiissccoorrddaanntt NNIITTss

A PA POSSIBLEOSSIBLE FFLOWLOW--CCHARTHART

RRELATIVE ELATIVE PPORTAL ORTAL HHYPOPERFUSION OF YPOPERFUSION OF FFIBROTIC IBROTIC DDISTAL ISTAL PPARENCHYMAL WITH ARENCHYMAL WITH AARTERIAL RTERIAL

CCOMPENSATION AT OMPENSATION AT TCTC

METAVIR F4METAVIR F4

BIOLOGICAL EQUIVALENTBIOLOGICAL EQUIVALENT: PARENCHYMAL ARTERIALIZATION AND : PARENCHYMAL ARTERIALIZATION AND NEOANGIOGENESISNEOANGIOGENESIS

FFUTURE AND UTURE AND HHOPESOPES

1.1.-- TECHNOLOGICAL IMPROVEMENT OF TECHNOLOGICAL IMPROVEMENT OF STANDARD IMAGING METHODS (STANDARD IMAGING METHODS (CTCT--MRMR) WITH ) WITH DEDICATION TO THE STUDY OF DIFFUSE DEDICATION TO THE STUDY OF DIFFUSE (RATHER THAN FOCAL) TISSUE ALTERATIONS (RATHER THAN FOCAL) TISSUE ALTERATIONS (INCLUDING (INCLUDING ANGIOGENESISANGIOGENESIS))

2.2.-- DEVELOPMENT OF IMAGING METHODS DEVELOPMENT OF IMAGING METHODS EMPLOYING EMPLOYING BIOMARKERSBIOMARKERS: I.E. A MOLECULES : I.E. A MOLECULES THAT ASSOCIATED WITH A FLUOROCHROME THAT ASSOCIATED WITH A FLUOROCHROME ARE ABLE TO IDENTIFY RECEPTORS OR TO ARE ABLE TO IDENTIFY RECEPTORS OR TO DYNAMICALLY INTERACT WITH OTHER DYNAMICALLY INTERACT WITH OTHER MOLECULS ACTIVELY INVOLVED IN THE MOLECULS ACTIVELY INVOLVED IN THE PATHOGENIC PROCESSPATHOGENIC PROCESS ((PET SCANPET SCAN))


F0F0 F4F4

HVPG HVPG > > 5 mmHg5 mmHgHVPG HVPG < < 10 mmHg10 mmHg

TOD

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TOM

OR

RO

WTO

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RR

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LSM + BIOCHEMICAL LSM + BIOCHEMICAL MARKER(S) MARKER(S) w/wow/wo LIVER LIVER BIOPSYBIOPSY

LSMLSMHVPG HVPG w/wow/wo TJLB (+CM)TJLB (+CM)BIOCHEMICAL MARKERS ?BIOCHEMICAL MARKERS ?

ororF1F1 F2F2 F3F3

PET + BMKPET + BMK

CT, MRCT, MR

DOPPLER US WITH CMDOPPLER US WITH CM

AKNOWLEDGMENTSAKNOWLEDGMENTS

FRANCESCO VIZZUTTIFRANCESCO VIZZUTTI

UMBERTO ARENAUMBERTO ARENA

FABIO MARRAFABIO MARRA

ANTONIO PETRARCAANTONIO PETRARCA

STEFANO COLAGRANDESTEFANO COLAGRANDE

THE CLINICAL EVALUATION OF DISEASE …...DIAGNOSTIC ACCURACY ROC and AUROC curves: show the trade...

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