Quantitative Assessment of the Liver: Breath...
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Quantitative Assessment of the Liver: Breath Tests
M. Shadab Siddiqui, M.D.
Virginia Commonwealth University
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Objectives
• Principles of breath tests
• Breath tests in NAFLD
• Potential applications of breath tests
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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 1994. Testa et al. Eur J Gastroenterol Hepatol 1999
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Examples of Breath Tests in Hepatology
• 13C-galactose breath test (GBT) predicts severity in cirrhosis
• 13C-Phenylalanine breath test (PheBT) can be used to monitor liver regeneration following partial hepatectomy
• 13C-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
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Principles of 13C-Breath Test
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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
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Potential Endpoints in Breath Tests
Time to peak
Height of Peak
Courtesy of Raffi Werner
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13C-Breath Tests in NAFLD
HEPATIC FUNCTION SUBSTRATE
MICROSOMAL
1. Aminopyrine2. Phenacetin3. Methacetin4. Caffeine
CYTOSOLIC1. Galactose2. Phenyalaine
MITOCHONDRIAL1. Methionine 2. Alpha-Ketoisocaproic Acid
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13C-Methacetin Breath Test for Quantitative Liver Function Test
Stravitz et al. J Hepatol 2015
75mg 13C-Methacetin
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Hepatic Metabolism of Methacetin
Stockmann et al. Ann Surg 2009DOB = delta over baseline
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13C-Methacetin Correlates with Liver Regeneration Post Partial Hepatectomy
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13C-MBT Differentiates NASH from Healthy Controls
Portincasa et al. Clin Sci. 2006
P=0.0006
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13C-MBT Differentiates between NASH vs. NAFL/Controls
Frierbinteanu-Braticevici et al. J Gastrointestin Liver Dis 2013
Dose at 10min
Cut-off %13C
AUROC(95% CI)
Sens Spec PPV NPV
NASH vs. NAFL
27.650.82
(0.72-0.92)95% 77% 67% 97%
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Patients with NASH have lower capacity to metabolize 13C-Methacetin
Frierbinteanu-Braticevici et al. J Gastrointestin Liver Dis 2013
Dose at 10min
Cut-off %13C
AUROC(95% CI)
Sens Spec PPV NPV
NASH vs. NAFL
17.150.82
(0.72-0.93)95% 74% 65% 97%
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Conflicting Findings?
Portincasa et al. Clin Sci. 2006Frierbinteanu-Braticevici et al. J Gastrointestin Liver Dis 2013
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Discriminative cut-off values of 13C-MBT for predicting fibrosis in NASH
Frierbinteanu-Braticevici et al. J Gastrointestin Liver Dis 2013
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13C-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 IndexCut-off: >1.0Sensitivity: 66.7%Specificity: 75.4%
AST:ALT RatioCut-off: >1.0Sensitivity: 63.0%Specificity: 59.4%
Dinesen et al. Dig Dis Sci 2008
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13C-MBT Can Identify Clinically Significant Portal Hypertension (HVPG≥10mmHg) in NASH
Cirrhosis
Ilan et al. EASL 2017
AUROC 95% CI
Platelets 0.76 0.68-83
APRI 0.71 0.63-0.80
Transient Elastography 0.71 0.61-0.80
13C-MBT 0.83 0.77-0.90
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13C-MBT as a Prognostic Biomarker in Cirrhosis
Stravitz et al. J Hepatol 2015
MELD≥15 MELD≥19 CPDR20≤0.55%
Not Significant5.49
(1.59-18.93)12.55
(1.60-98.25)
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13C-MBT as a Prognostic Biomarker in Cirrhosis
Liver Related Death Clinical Complications Ascites/Exacerbation
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13C-MBT is Better Predictor of Liver Related Death or Liver Transplantation
Shiffman et al. EASL 2017
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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
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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