Quantitative Assessment of the Liver: Breath Tests

M. Shadab Siddiqui, M.D.

Virginia Commonwealth University

Objectives

• Principles of breath tests

• Breath tests in NAFLD

• Potential applications of breath tests

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

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

Principles of 13C-Breath Test

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

Potential Endpoints in Breath Tests

Time to peak

Height of Peak

Courtesy of Raffi Werner

13C-Breath Tests in NAFLD

HEPATIC FUNCTION SUBSTRATE

MICROSOMAL

1. Aminopyrine2. Phenacetin3. Methacetin4. Caffeine

CYTOSOLIC1. Galactose2. Phenyalaine

MITOCHONDRIAL1. Methionine 2. Alpha-Ketoisocaproic Acid

13C-Methacetin Breath Test for Quantitative Liver Function Test

Stravitz et al. J Hepatol 2015

75mg 13C-Methacetin

Hepatic Metabolism of Methacetin

Stockmann et al. Ann Surg 2009DOB = delta over baseline

13C-Methacetin Correlates with Liver Regeneration Post Partial Hepatectomy

13C-MBT Differentiates NASH from Healthy Controls

Portincasa et al. Clin Sci. 2006

P=0.0006

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%

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%

Conflicting Findings?

Portincasa et al. Clin Sci. 2006Frierbinteanu-Braticevici et al. J Gastrointestin Liver Dis 2013

Discriminative cut-off values of 13C-MBT for predicting fibrosis in NASH

Frierbinteanu-Braticevici et al. J Gastrointestin Liver Dis 2013

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

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

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)

13C-MBT as a Prognostic Biomarker in Cirrhosis

Liver Related Death Clinical Complications Ascites/Exacerbation

13C-MBT is Better Predictor of Liver Related Death or Liver Transplantation

Shiffman et al. EASL 2017

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

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