Presentation on theme: "Is Liver Biopsy the Gold Standard?"— Presentation transcript:
1 Is Liver Biopsy the Gold Standard? I want to thank the organizers of this conference for inviting me to speak. Today, I am going to discuss if liver biopsy is the gold standard.Is Liver Biopsy the Gold Standard?Mamta K. Jain, MD, MPH
2 What are the indications for a liver biopsy? Diagnosis of liver diseaseAssess severity of liver diseaseAssess response to treatmentIn order to understand why the liver biopsy may be considered we need to examine why a liver biopsy may be done. One reason is the diagnoses liver disease. Second, a biopsy may be done to assess severity of liver disease, and finally, a bx is done to assess response to treatment.Add slide that liver bx is not needed in everyoneWhat are the indications for doing a liver bx in HBV and HCV?
3 Hepatitis BInitial trials used pre-treatment and post-treatment biopsy to assess response to nucleoside therapyKnodell index grades histological activity from 0-22Periportal bridging necrosis (0-10)Focal necrosis (0-4)Portal inflammation (0-4)Fibrosis (0-4)Treatment response based on 2 point decrease in necroinflammatory activitycomposed of the first three parametersmeasured (0-18)Historically, liver biopsies have been used in clinical trials. In HBV, a pre- and post bx was done to assess response to nucleoside therapy. Now we use virologic markers to assess response to therapy.So when lamivudine was in clinical trials for HBV, the knodell index was used to assess response. It was a grade from The components of the histological activity isPeriportal briding necorosis, forcal necrosis, portal inflammation, and fibroiss.Treatment response was based on 2 point decrease in necroinflammation which was composed of the first three parameters and is measured on scale of 0-18.Lai et al. New Engl J Med 1998;339:61-8
4 Hepatitis CClinical trials have used viral response as primary endpointLiver biopsies pre- and post- treatment were done forConfirmation of chronic hepatitis, r/o other causes, identify cirrhosis (staging)Change in histological activityKnodell HAIMETAVIRIn HCV, the clinical trials have always used viral response as primary endpoint. However pre-and post liver biopsies were done for1. Confirmation of chronic hepatitis and to rule out other causes like alcohol, fatty liver, and the identify cirrhosis (staging). A secondary endpoint of efficacy was change in HAI score mMcHutchison et al. New Engl J Med 1998;339:Poynard et al. Lancet 1998;352:
5 Relationship Between Liver disease Stage and Fibrosis Fibrosis– excess collagenCollagen proportion of liver fibrosis correlates with hepatic venous pressure gradient (HVPG)Increasing fibrosis has prognostic valueHistological assessment of fibrosis is by trichrome or reticulin stains but does not correlate with quantitative amount of hepatic collagenFibrosis is part of histologic staging of disease severityGermani et al. Histopathology 2010; 57:
6 Relationship Between Liver Disease Stage and Fibrosis Staging describes features that depend on architectural changes, not just degree of fibrosisHistopathologic assignment of liver disease stage is a different process from measurement of liver fibrosisBoth measurements are complementary but are imperfectly correlatedI want to take a moment to talk about the difference of fibrosis vs. stagingStaging describes the features that depend on architectural changes. It is not just the degree of fibrosis that is present on the biopsy.Histopathologic assignment of liver disease stage is a different process from measurement of liver fibrosisBoth processes are complementary but are imperfectly correlated.Thus measurement of fibrosis is not the same as measurement of cirrhosisGermani et al. Histopathology 2010; 57:
7 This is a biopsy specimen of a normal liver. Normal architrecture.
8 Now in contrast, you can see on this biopsy that there are nodules characteristic of cirhosis.
9 Size of Liver BiopsySmaller biopsy is associated with greater sampling errorError reduced by increasing sample size and number of biopsies performedStudy found 25 mm biopsy had error rate of 25%Optimal size 40 mmBut only 16% of samples are >20 mmNow let talk a little about the limitations of the liver bxSize of liver bx affects identification of staging. Error can be reduced…In one study 25 mm bx had an error rate of 25%Optimal size if 4 mm but only 16% fo the samples are >20 mmBedossa et al. Hepatology 2003;38:
10 Sampling ErrorStudies have shown 10-30% of cirrhosis was understaged by percutaneous liver biopsyStudy of biopsy of the left and right lobe of the liver found discrepancy in 50% of the samplesInaccurate by 1 stageUnderestimation of inflammationIn addition to size of the bx, there is some inherent problems with sampling error especially in disease which may have hetrogenous pattern. Studies have shown that 10-30% of cirrhosis is missed by liver bxOne study in which both the left and right lobe of the liver was biopsied, there was as much to 50% discrepancy in the read in 50% of the samplesMaharaj et al. Lancet 1986; 1:523-25Poniachik et al. Gastrointest endosc 1996; 43:Regev et al. Am J Gastroenterol 2002; 97:
11 Intra-observer Variability Intra-observer variability seen in up to 10% of samples and was 1 stage or 1 grade.Use of scoring system has made staging more consistentAnother problem is variability of characterizing the stage and grade on liver bx which was seen in 10%Use of a scoring system has made staging more consistentRegev et al. Am J Gastroenterol 2002; 97:
12 ComplicationsHALT-C reported complications of liver biopsy in HCV patients with advanced liver disease1.1 % serious adverse events0.6% due to bleeding (most common)More common if platelet <60,000INR>1.3Finally, liver bx are invasive procedures and have complications.In the HALT-C study reported complications of liver bx in HCV patients with advanced liver diseaseThey had complication rate of 1.1% SAEAnd .6% was due to bleeding, which was also the most commonUsually the bleeding was more likely to occur if plt <60K or INR>1.3Seeff et al. Clin Gastroentrol Hepatol 2010; 8:
13 Pro and Cons for Liver Biopsy ProsConsSteatosis assessment and quantificationFibrosis assessment and architectural distortionIron level measurementDiagnose other pathologyUsing special stainsother liver disease (viral hepatitis + NAFLD, EtOH, etc)InvasiveRisk of complications 1-5%Mortality .01% to 0.1%LimitationsSampling errorIntra-observer variabilityTo summarizePros including assessment and quantification of steatosis, assessment of fibrosis and architectural distoration,Measure iron levels, stains can also be used to dignoase other pathologyAnd also bx can allow you to dx other disease which may not have serolgical markersThe cons include invasiveness which has been reported between 1-5%If bx is obtained there are issues with inadequate staging and grading due to sample size, inherent differences sampling, and variability among pathologist with regard to reading.
14 What are the alternatives? RadiologyCTMRIUSHepatic elastographySerum markers of fibrosisIndirectDirectNow what are the alternativesRadiographic techniques include , such as CT, MRI, Ultrasound. Hepatic elastography has been used to assess fibrosis. And then there are serum markers of fibrosis which use indirect and direct markers
15 Pros and Cons for Radiology Non-invasiveUS with Doppler can be used to support diagnosis of cirrhosisAccuracy 82-88%Insufficient resolution to detect earlier stages of fibrosisAube et al. J Hepatol 1999; 30:Gaiani et al. J Hepatol 1997;27:
16 Hepatic Elastography Emerging technology to stage hepatic fibrosis Elastography technique measures liver stiffness of hepatic tissue (FibroScan; Echosens, Paris, France)Ultrasound wave that produces elastic shearvelocity of the shear wave is related to tissue stiffnessmore rigid, the faster the wave travelsIncreased rigidity is marker of progressive fibrosisSandrin et al. Ultrasound Med Biol 2003;29:
17 Liver Fibrosis Measurement of Stiffness in Patients with HCV Pt distribution for METAVIR fibrosis stage, activity grade, and steatosisAUROC curveLiver fibrosis measurmeent of stiffnessZiol et al. Hepatology 2005; 41:48-54.
19 Liver Stiffness and HVPG HVPG– predictor of survival and decompensation in cirrhotic patientsLiver stiffness measurement (LSM) predicted severe portal hypertension in HCV patientsAUROC curves for prediction of HVPG>10mmHg was 0.99>12mmHg was 0.92LSM Cut-off values 13.6kPa sensitivity 97%LSM Cut-off values 17.6kPa sensitivity 94%Vizzutti et al. Hepatology 2007; 45:
20 Pro and Cons for FibroScan ProsConsNon-invasiveAble to assess a much larger proportion of the liverSerial measurements to evaluate fibrosis progressionPoor performance in mild to moderate diseaseCannot be used inPatients with ascitesMorbid obesity (BMI>40)CostCannot distinguish between stage 0-II or III-IV
21 Serum Markers of Fibrosis Ideal biomarkerLiver specificIndependent of metabolic alterationsDetect fibrosis regardless of causeSensitive enough to distinguish between fibrosis stagesReflective of dynamic changesFriedman. J Hepatol. 2003; 38 (Suppl 1); S38-S53.
22 Indirect Markers of Fibrosis FibroTest/FibroSureAlpha-2 globulinAlpha-2 macroglobulinGamma globulinApoliprotein A1Gamma-glutamyl transferase (GGT)Total bilirubinActiTestFibrotest +ALTForns indexAPRIFib-4AST/ALT ratioAST/ALT with pltsAfdhal and Shiffman hepatitis.
23 FibroTest Classifies fibrosis into 1 of 3 categories Mild (METAVIR F0-F1)Significant (METAVIR F2-F4)IndeterminateHCVDetect F2 or higher stage75% sensitivity85% specificityAccuracy 46%Imbert-Bismut Lancet. 2001;357:
24 ActiTest FibroTest + ALT Reflects necro-inflammation and fibrosis Better at identifying more advanced fibrosis associated with histological inflammationMeta-analysis of HCV patients found both FibroTest and ActiTest reliable alternatives for liver biopsy.Poynard et al. Comp Hepatol 2004;3:8.Halfon et al. Am J Gastroenterol. 2006;101:
25 Forns Test Uses 4 common clinical measurements Patient age Cholesterol levelPlatelet countGamma-glutamyl transpeptidaseStudies HCV patients to96% NPV in mild fibrosis66% PPV in F2-F4Able to accurately exclude mild fibrosisInferior to FibroTestForns et al. Hepatology. 2003; 34 (4 pt 1):Thabut et al. Hepatology. 2003:37:
26 APRI Uses clinical variables ALT and platelet count NPV PPV Significant fibrosis 86%Cirrhosis 98%PPVSignificant fibrosis 88%Cirrhosis 57%Able to exclude cirrhosisWai et al. Hepatology. 2003; 38:
27 Fib-4 Index Uses clinical variables PlateletsALTASTAge<1.45 NPV 94.7% to exclude severe fibrosis (F3-F4) with sensitivity 74.3%>3.25 PPV significant fibrosis 82% with specificity of 98%Fib-4 <1.45 or >3.25 (62% of all cases) was highly correlated to FibroTest in 92% and 76%Vallet-Pichard et al. Hepatology. 2007; 46:
28 Indirect Methods Pros Cons Non-invasive Less expensive Useful in HCV for determining significant fibrosis (METAVIR stage F2-F4) when HCV treatment is recommendedMay be most useful in fibrosis that is unevenly distributedNot sensitive enough to distinguish between stagesDegree of fibrosis does not linearly correlate with biopsy stageMay be better to evaluate for inflammation (i.e., FibroTest)
29 Direct MarkersMeasure qualitative and quantitative changes in extracellular matrix markersMarkers matrix depositionProcollagen type I carboxy-terminal peptideProcollagen type III amino-terminal peptideTissue inhibitor of metalloproteinaseTransforming growth factor-betaCollagen type IVMarkers of matrix removalProcollagen Type IV C peptideProcollagen Type IV N peptideMatrix metalloproteinaseOther markersHyaluronic acidYkL-40Combination biomarker assayFibroSpectELFSHASTANone of these markers are liver specific and are influenced by metabolismAfdhal and Shiffman hepatitis.
30 Is Liver Biopsy a Gold Standard? Perhaps it depends on why biopsy is being doneYes, if it is :To diagnose a disease (excluding viral hepatitis)To exclude other concomitant diseaseTo measure iron storesTo quantify steatosisTo get special stains for diagnosisTo stage liver disease if fibrosis is evenly distributed
31 Is Liver Biopsy a Gold Standard? No, if it is:To determine cirrhosisTo evaluate for significant fibrosisTo determine stage if fibrosis is unevenly distributedTo follow longitudinally
32 FutureHepatitis CWith new DAA with high SVR rates, perhaps a liver biopsy is not needed?Biopsy is not typically performed in genotype 2 and 3 if patient willing to be treatedIf liver biopsy and elastography are not equivalent, then what impact does this have on patient characterization in clinical trials?Clinical trials are using FibroScan in Europe instead of liver biopsyNon-invasive tests need to be validated as predictors of poor outcomes and not just on correlation to liver biopsy stageHepatitis BWill we still need biopsy to determine disease activity to assess for treatment?May not need biopsy in HIV/HBV who were started on ART with Truvada (treatment based on viral load and not on biopsy)
33 Conclusions Liver biopsy still plays an important role in Diagnosis of some types of liver diseaseQuantification of steatosisMeasurement of iron storesTo distinguish between earlier stages of diseaseFibrosis can be determined by other means such as elastography or other non-invasive tests