When to Treat: Staging Liver Disease David L. Thomas, MD, MPH Professor of Medicine Johns Hopkins School of Medicine
Disclosures Received royalties from UpToDate, Inc.
Staging refers to the assessment of liver fibrosis
Stages of liver fibrosis Portal Periportal 1 2 3 4 Septal Cirrhosis
Staging refers to the assessment of liver fibrosis Snapshot Different from inflammation Useful for many forms of liver disease HCV HBV Alcohol NAFL/NASH
Staging refers to the assessment of liver fibrosis Snapshot Different from inflammation Useful for many forms of liver disease Goals may vary Focus Treat Need surveillance HCV F3-4 +/- (DURATION) YES HBV Necroinflammation (F2-4) + (INDICATION) A FACTOR ETOH F2-4 + (INDICATION) YES NAFL NASH AND F2-4? (INDICATION) YES
Staging refers to the assessment of liver fibrosis Snapshot Different from inflammation Useful for many forms of liver disease Goals may vary Insurance approvals Focus Treat Need surveillance HCV ++++++ Variable +/- (DURATION) YES HBV Necroinflammation (F2-4) + (INDICATION) A FACTOR ETOH F2-4 + (INDICATION) YES NAFL NASH AND F2-4? (INDICATION) YES
There are at least 3 staging methods Accepted staging methods 1. Liver biopsy 2. Blood markers 3. Elastography 4. Combinations of 1-3 Not for staging 1. Viral load 2. HCV genotype 3. Ultrasound 4. CT scan or MRI
Sampling error of liver biopsy Fibrosis area: 65% Courtesy of M. Pinzani, Florence Fibrosis area: 15%
Liver Biopsy Readings Can Underestimate Fibrosis Sampling error (significant fibrosis) 161 > 3 cm biopsies reduced 1.5 cm and 1 cm and rescored 1 % mild : 3 cm, 59%; 1.5 cm, 68%; 1 cm, 80% 41 of 124 patients (33.1%) had > 1 stage difference in R and L lobes 2 1 Colloredo J Hepatol 2003; 2 Regev Am J Gastro 2002
FIB4 is inexpensive and widely available FIB 4 = Age (yrs) x AST (U/L) Platelet count (10 9 /L) x ALT (U/L) 1/2 Sterling Hepatology 2006; Vallet-Pichard Hepatology 2007
FIB4 is inexpensive and widely available FIB 4 = Age (yrs) x AST (U/L) Platelet count (10 9 /L) x ALT (U/L) 1/2 847 liver biopsies with chronic HCV FIB -4 Metavir Number 0 73 1 470 2 158 3 85 4 61 Sterling Hepatology 2006; Vallet-Pichard Hepatology 2007
FIB4 is inexpensive and widely available FIB 4 = Age (yrs) x AST (U/L) Platelet count (10 9 /L) x ALT (U/L) 1/2 FIB -4 Metavir Number 0 73 1 470 2 158 3 85 4 61 Sterling Hepatology 2006; Vallet-Pichard Hepatology 2007
FIB4 is inexpensive and widely available FIB 4 = Age (yrs) x AST (U/L) Platelet count (10 9 /L) x ALT (U/L) 1/2 45 yrs, AST 110, PLT 99, ALT 100 FIB -4 35 yrs, AST 75, PLT 263, ALT 100 Metavir Number 0 73 1 47 0 2 158 3 85 4 61 Sterling Hepatology 2006; Vallet-Pichard Hepatology 2007
FIB4 is inexpensive and widely available FIB 4 = Age (yrs) x AST (U/L) Platelet count (10 9 /L) x ALT (U/L) 1/2 FIB -4 >1.45: 89% sensitive for F4; 58% specific 57-86% sensitive for F2-4; 28-85% specific Sterling Hepatology 2006; Vallet-Pichard Hepatology 2007; Chou USPSTF review online Metavir Number 0 73 1 47 0 2 158 3 85 4 61
FIB4 is inexpensive and widely available FIB 4 = Age (yrs) x AST (U/L) Platelet count (10 9 /L) x ALT (U/L) 1/2 FIB -4 >3.25: 40-55% sensitive for F4; 91-95% specific Metavir Number 0 73 1 47 0 2 158 3 85 4 61 Sterling Hepatology 2006; Vallet-Pichard Hepatology 2007; Chou USPSTF review online
Commercial algorithms like FibroSure/FibroTest are preferred to FIB4 by some insurance companies Fibrotest 1 : α2-macroglobulin, apolipoprotein A 1, GGT, haptoglobin, total bilirubin f5=4.467 Log[α2-macroglobulin (g/l)]-1.357 Log[Haptoglobin (g/l)] 1.017 Log[GGT (IU/l)] 0.0281 [Age(in years)] 1.737 Log[Bilirubin (umol/l)]-1.184 [ApoA1 (g/l)] 0.301 Sex (female=0, male=1)-5.540 U.S. patent 6,631,330 1 Imbert Bismut Lancet 2001; Myers AIDS 2003
Commercial algorithms like FibroSure/FibroTest are preferred to FIB4 by some insurance companies but give similar information FibroSure (LabCorp) = FibroTest (Quest) 1 Imbert Bismut Lancet 2001; Myers AIDS 2003; Vallet-Pinchard Hepatology 2007
Transient elastography has high sensitivity for cirrhosis de Ledinghen et al. JAIDS 2006
Elastography to detect complications of cirrhosis among 144 with F3-4 Vizzutti Hepatology 2007
The risk of HCC increases with liver stiffness Incidence of HCC in 866 patients by elastography Zhang J Cancer Res Clin Oncol 2004; Masuzaki, Hepatol 2009
There are limitations of elastography Stability of measurements Operator dependent Invalid result Food effect Obesity Complications of cirrhosis Castera Hepatology 2010
Noninvasive testing can change the likelihood of cirrhosis* Test % Sens % Spec AUROC Pos LR Neg LR Fibrotest >.56 85 74.86 3.3 0.2 Fibrotest >.73 56 81-2.9 0.54 FIB4, >1.45 90 58.87 2.1 0.17 APRI, >1.0 77 75 0.84 3.1 0.31 Elastography, 12.5 87 91 0.95 9.7 0.14 Chou Ann Intern Med 2013; Castera Gastro 2012
Elastography can be combined with serum fibrosis tests Bordeaux algorithm for cirrhosis Attribute accuracy 94.2 sensitivity 86.5 specificity 95.4 NPV 97.7 PPV 76.1 Neg likelihood ratio Bordeaux 0.14 biopsy 24.6% Boursier Hepatology 2012
Repeating elastography after treatment: low baseline stage and SVR have good survival Vergniol Hepatology 2014
Which staging test is best for HCV?
Staging tests predict mortality similarly 297 HIV/HCV coinfected patients with LSM and biopsy within 12 months Dec 2005-Dec 2011. LSM-based models performed 8.4% better than liver biopsy Macias AIDS 2013
Which staging test is best for HCV? The one the insurance company accepts for preapproval Cirrhosis: elastography F0-1: serum markers F2: none
Noninvasive tests can be used for other forms of disease Diagnostic accuracy of transient elastography used for detection of F3-4 in alcohol-related liver disease Pavlov Cochrane Review 2015
Noninvasive tests can be used for other forms of disease Diagnostic accuracy of transient elastography is similar to shear wave elastography for detection of F3-4 in alcohol-related liver disease Thiele Gastro 2016
Diagnostic accuracy of transient elastography and MR elastography used for detection of NASH Imajo Gastro 2016
Diagnostic accuracy of elastography for HBV related liver cancer mreach-b adds liver stiffness measure (LSM) instead of HBV DNA level (REACH B) 5 year risk of HCC according to various algorithms in HBV patients in ETV Jung Hepatology 2015
Future directions with liver staging Nuanced management of cirrhosis?no need for HCC or variceal screen?more frequent Monitoring after treatment
Conclusions Stage with what you have to rule out cirrhosis (and get insurance approvals) Combine elastography and blood tests when possible Use noninvasive staging first for other forms of liver disease Repeat staging if questions remain
Multiparametric MR Banerjee J Hepatol 2014
Multiparametric MR Banerjee J Hepatol 2014