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Is Liver Biopsy the Gold Standard? Mamta K. Jain, MD, MPH

Is Liver Biopsy the Gold Standard? Mamta K. Jain, MD, MPH. What are the indications for a liver biopsy?. Diagnosis of liver disease Assess severity of liver disease Assess response to treatment. Hepatitis B.

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Is Liver Biopsy the Gold Standard? Mamta K. Jain, MD, MPH

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  1. Is Liver Biopsy the Gold Standard? Mamta K. Jain, MD, MPH

  2. What are the indications for a liver biopsy? • Diagnosis of liver disease • Assess severity of liver disease • Assess response to treatment

  3. Hepatitis B • Initial trials used pre-treatment and post-treatment biopsy to assess response to nucleoside therapy • Knodell index grades histological activity from 0-22 • Periportal bridging necrosis (0-10) • Focal necrosis (0-4) • Portal inflammation (0-4) • Fibrosis (0-4) • Treatment response based on 2 point decrease in necroinflammatory activity • composed of the first three parameters • measured (0-18) Lai et al. New Engl J Med 1998;339:61-8

  4. Hepatitis C • Clinical trials have used viral response as primary endpoint • Liver biopsies pre- and post- treatment were done for • Confirmation of chronic hepatitis, r/o other causes, identify cirrhosis (staging) • Change in histological activity • Knodell HAI • METAVIR McHutchison et al. New Engl J Med 1998;339:1485-92 Poynard et al. Lancet 1998;352:1426-32

  5. Relationship Between Liver disease Stage and Fibrosis • Fibrosis– excess collagen • Collagen proportion of liver fibrosis correlates with hepatic venous pressure gradient (HVPG) • Increasing fibrosis has prognostic value • Histological assessment of fibrosis is by trichrome or reticulin stains but does not correlate with quantitative amount of hepatic collagen • Fibrosis is part of histologic staging of disease severity Germani et al. Histopathology 2010; 57:773-784

  6. Relationship Between Liver Disease Stage and Fibrosis • Staging describes features that depend on architectural changes, not just degree of fibrosis • Histopathologic assignment of liver disease stage is a different process from measurement of liver fibrosis • Both measurements are complementary but are imperfectly correlated Germani et al. Histopathology 2010; 57:773-784

  7. Size of Liver Biopsy • Smaller biopsy is associated with greater sampling error • Error reduced by increasing sample size and number of biopsies performed • Study found 25 mm biopsy had error rate of 25% • Optimal size 40 mm • But only 16% of samples are >20 mm Bedossa et al. Hepatology 2003;38:1449-1457

  8. Sampling Error • Studies have shown 10-30% of cirrhosis was understaged by percutaneous liver biopsy • Study of biopsy of the left and right lobe of the liver found discrepancy in 50% of the samples • Inaccurate by 1 stage • Underestimation of inflammation Maharaj et al. Lancet 1986; 1:523-25 Poniachik et al. Gastrointest endosc 1996; 43:568-571 Regev et al. Am J Gastroenterol 2002; 97:2614-2618.

  9. 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 consistent Regev et al. Am J Gastroenterol 2002; 97:2614-2618.

  10. Complications • HALT-C reported complications of liver biopsy in HCV patients with advanced liver disease • 1.1 % serious adverse events • 0.6% due to bleeding (most common) • More common if platelet <60,000 • INR>1.3 Seeff et al. Clin Gastroentrol Hepatol 2010; 8:877--83.

  11. Pro and Cons for Liver Biopsy Pros Cons Invasive Risk of complications 1-5% Mortality .01% to 0.1% Limitations Sampling error Intra-observer variability • Steatosis assessment and quantification • Fibrosis assessment and architectural distortion • Iron level measurement • Diagnose other pathology • Using special stains • other liver disease (viral hepatitis + NAFLD, EtOH, etc)

  12. What are the alternatives? • Radiology • CT • MRI • US • Hepatic elastography • Serum markers of fibrosis • Indirect • Direct

  13. Pros and Cons for Radiology Pros Cons Insufficient resolution to detect earlier stages of fibrosis • Non-invasive • US with Doppler can be used to support diagnosis of cirrhosis • Accuracy 82-88% Aube et al. J Hepatol 1999; 30:472-478 Gaiani et al. J Hepatol 1997;27:979-985

  14. 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 shear • velocity of the shear wave is related to tissue stiffness • more rigid, the faster the wave travels • Increased rigidity is marker of progressive fibrosis Sandrin et al. Ultrasound Med Biol 2003;29:1705-1713.

  15. Liver Fibrosis Measurement of Stiffness in Patients with HCV Pt distribution for METAVIR fibrosis stage, activity grade, and steatosis AUROC curve 0.97-0.99 0.91-0.95 0.79-0.81 Ziol et al. Hepatology 2005; 41:48-54.

  16. Liver Stiffness and HVPG • HVPG– predictor of survival and decompensation in cirrhotic patients • Liver stiffness measurement (LSM) predicted severe portal hypertension in HCV patients • AUROC curves for prediction of HVPG • >10mmHg was 0.99 • >12mmHg was 0.92 • LSM Cut-off values 13.6kPa sensitivity 97% • LSM Cut-off values 17.6kPa sensitivity 94% Vizzutti et al. Hepatology 2007; 45:1290-97.

  17. Pro and Cons for FibroScan Pros Cons Poor performance in mild to moderate disease Cannot be used in Patients with ascites Morbid obesity (BMI>40) Cost Cannot distinguish between stage 0-II or III-IV • Non-invasive • Able to assess a much larger proportion of the liver • Serial measurements to evaluate fibrosis progression

  18. Serum Markers of Fibrosis • Ideal biomarker • Liver specific • Independent of metabolic alterations • Detect fibrosis regardless of cause • Sensitive enough to distinguish between fibrosis stages • Reflective of dynamic changes Friedman. J Hepatol. 2003; 38 (Suppl 1); S38-S53.

  19. Indirect Markers of Fibrosis • FibroTest/FibroSure • Alpha-2 globulin • Alpha-2 macroglobulin • Gamma globulin • Apoliprotein A1 • Gamma-glutamyltransferase (GGT) • Total bilirubin • ActiTest • Fibrotest +ALT • Forns index • APRI • Fib-4 • AST/ALT ratio • AST/ALT with plts Afdhal and Shiffman 2006 www.CCO hepatitis.

  20. FibroTest • Classifies fibrosis into 1 of 3 categories • Mild (METAVIR F0-F1) • Significant (METAVIR F2-F4) • Indeterminate • HCV • Detect F2 or higher stage • 75% sensitivity • 85% specificity • Accuracy 46% Imbert-Bismut Lancet. 2001;357:1069-1075.

  21. ActiTest • FibroTest + ALT • Reflects necro-inflammation and fibrosis • Better at identifying more advanced fibrosis associated with histological inflammation • Meta-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;101:547-555

  22. Forns Test • Uses 4 common clinical measurements • Patient age • Cholesterol level • Platelet count • Gamma-glutamyltranspeptidase • Studies HCV patients to • 96% NPV in mild fibrosis • 66% PPV in F2-F4 • Able to accurately exclude mild fibrosis • Inferior to FibroTest Forns et al. Hepatology. 2003; 34 (4 pt 1): 986-992. Thabut et al. Hepatology. 2003:37:1220-1221

  23. APRI • Uses clinical variables • ALT and platelet count • NPV • Significant fibrosis 86% • Cirrhosis 98% • PPV • Significant fibrosis 88% • Cirrhosis 57% • Able to exclude cirrhosis Wai et al. Hepatology. 2003; 38: 518-526.

  24. Fib-4 Index • Uses clinical variables • Platelets • ALT • AST • Age • <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: 32-36.

  25. Indirect Methods Pros Cons Not sensitive enough to distinguish between stages Degree of fibrosis does not linearly correlate with biopsy stage May be better to evaluate for inflammation (i.e., FibroTest) • Non-invasive • Less expensive • Useful in HCV for determining significant fibrosis (METAVIR stage F2-F4) when HCV treatment is recommended • May be most useful in fibrosis that is unevenly distributed

  26. Direct Markers • Measure qualitative and quantitative changes in extracellular matrix markers • Markers matrix deposition • Procollagen type I carboxy-terminal peptide • Procollagen type III amino-terminal peptide • Tissue inhibitor of metalloproteinase • Transforming growth factor-beta • Collagen type IV • Markers of matrix removal • Procollagen Type IV C peptide • Procollagen Type IV N peptide • Matrix metalloproteinase • Other markers • Hyaluronic acid • YkL-40 • Combination biomarker assay • FibroSpect • ELF • SHASTA None of these markers are liver specific and are influenced by metabolism Afdhal and Shiffman 2006 www.CCO hepatitis.

  27. Is Liver Biopsy a Gold Standard? • Perhaps it depends on why biopsy is being done • Yes, if it is : • To diagnose a disease (excluding viral hepatitis) • To exclude other concomitant disease • To measure iron stores • To quantify steatosis • To get special stains for diagnosis • To stage liver disease if fibrosis is evenly distributed

  28. Is Liver Biopsy a Gold Standard? • No, if it is: • To determine cirrhosis • To evaluate for significant fibrosis • To determine stage if fibrosis is unevenly distributed • To follow longitudinally

  29. Future • Hepatitis C • With 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 treated • If 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 biopsy • Non-invasive tests need to be validated as predictors of poor outcomes and not just on correlation to liver biopsy stage • Hepatitis B • Will 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)

  30. Conclusions • Liver biopsy still plays an important role in • Diagnosis of some types of liver disease • Quantification of steatosis • Measurement of iron stores • To distinguish between earlier stages of disease • Fibrosis can be determined by other means such as elastography or other non-invasive tests

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