Quantitative Assessment of the Liver: Breath Tests. M. Shadab Siddiqui, M.D. Virginia Commonwealth University

Transcription

1 Quantitative Assessment of the Liver: Breath Tests M. Shadab Siddiqui, M.D. Virginia Commonwealth University

2 Objectives Principles of breath tests Breath tests in NAFLD Potential applications of breath tests

3 Role for Quantitative Liver Tests Imaging & serum biomarkers do not always provide accurate measure of hepatic metabolic function Although liver biopsy can quantify hepatic fibrosis, it does not measure liver function or hepatic reserve Quantitative liver tests better predictor of outcomes Monoethylglycinexylidide (MEGX) more reliable and sensitive indicator of survival in cirrhosis Arrigoni et al. Hepatology Testa et al. Eur J Gastroenterol Hepatol 1999

4 Examples of Breath Tests in Hepatology 13 C-galactose breath test (GBT) predicts severity in cirrhosis 13 C-Phenylalanine breath test (PheBT) can be used to monitor liver regeneration following partial hepatectomy 13 C-caffeine breath test predicts improvement in liver function in HBV in response to therapy Hsieh et al. Eur J Surg Oncol 2006; Perr et al. Eur Rev Med Phamacol 2004; Park et al. Ailment Pharmacol Ther 2005

5 Principles of 13 C-Breath Test

6 Principles of Breath Tests Hepatic clearance: related to hepatic perfusion and extraction High extraction ratio: provide information of liver blood flow Low extraction ratio: hepatic metabolic capacity Location of rate-limiting metabolic step within liver may assess microsomal, cytosolic or mitochondrial liver functional capacity

7 Potential Endpoints in Breath Tests Time to peak Height of Peak Courtesy of Raffi Werner

8 13 C-Breath Tests in NAFLD HEPATIC FUNCTION SUBSTRATE MICROSOMAL 1. Aminopyrine 2. Phenacetin 3. Methacetin 4. Caffeine CYTOSOLIC MITOCHONDRIAL 1. Galactose 2. Phenyalaine 1. Methionine 2. Alpha-Ketoisocaproic Acid

9 13 C-Methacetin Breath Test for Quantitative Liver Function Test 75mg 13 C-Methacetin Stravitz et al. J Hepatol 2015

10 Hepatic Metabolism of Methacetin DOB = delta over baseline Stockmann et al. Ann Surg 2009

11 13 C-Methacetin Correlates with Liver Regeneration Post Partial Hepatectomy

12 13 C-MBT Differentiates NASH from Healthy Controls P= Portincasa et al. Clin Sci. 2006

13 13 C-MBT Differentiates between NASH vs. NAFL/Controls Dose at 10min Cut-off % 13 C AUROC (95% CI) Sens Spec PPV NPV NASH vs. NAFL ( ) 95% 77% 67% 97% Frierbinteanu-Braticevici et al. J Gastrointestin Liver Dis 2013

14 Patients with NASH have lower capacity to metabolize 13 C-Methacetin Dose at 10min Cut-off % 13 C AUROC (95% CI) Sens Spec PPV NPV NASH vs. NAFL ( ) 95% 74% 65% 97% Frierbinteanu-Braticevici et al. J Gastrointestin Liver Dis 2013

15 Conflicting Findings? Portincasa et al. Clin Sci Frierbinteanu-Braticevici et al. J Gastrointestin Liver Dis 2013

16 Discriminative cut-off values of 13 C-MBT for predicting fibrosis in NASH Frierbinteanu-Braticevici et al. J Gastrointestin Liver Dis 2013

17 13 C-MBT is an Accurate Predictor of Advanced Fibrosis 13C-MBT (delta/baseline) Cut-off: <14.6% Sensitivity: 92.6% Specificity: 84.1% AST:Platelet Ratio Index Cut-off: >1.0 Sensitivity: 66.7% Specificity: 75.4% AST:ALT Ratio Cut-off: >1.0 Sensitivity: 63.0% Specificity: 59.4% Dinesen et al. Dig Dis Sci 2008

18 13 C-MBT Can Identify Clinically Significant Portal Hypertension (HVPG 10mmHg) in NASH Cirrhosis AUROC 95% CI Platelets APRI Transient Elastography C-MBT Ilan et al. EASL 2017

19 13 C-MBT as a Prognostic Biomarker in Cirrhosis MELD 15 MELD 19 CPDR % Not Significant 5.49 ( ) ( ) Stravitz et al. J Hepatol 2015

20 13 C-MBT as a Prognostic Biomarker in Cirrhosis Liver Related Death Clinical Complications Ascites/Exacerbation

21 13C-MBT is Better Predictor of Liver Related Death or Liver Transplantation Shiffman et al. EASL 2017

22 State of Breath Tests in NAFLD Studies limited by: Sample size, histological distribution, heterogeneous population Non-standardized methodology Optimal endpoint is unknown Peak, Time to Peak, Cumulative Recovery, Composite Unclear accuracy: NAFL vs. NASH, Fibrosis stages Reproducibility Ability to detect change Bottom Line: NEED MORE DATA

23 Potential Applications of Breath Tests Clinical: 1. Identify at risk patients with cirrhosis 2. Acute liver failure Research: 1. Identify patients with clinically significant portal hypertension 2. Exclude cirrhosis patients at risk for decompensation unable to complete study