Breath Analysis Using an Electronic Nose in Non Alcoholic Fatty Liver Disease (BEN)

Breath Analysis Using an Electronic Nose in Non Alcoholic Fatty Liver Disease (BEN) Study

The purpose of this is to analyse human exhaled breath by means of a device called electronic nose(eNose) in patients with non-alcoholic fatty liver disease (NAFLD) as a way to non-invasive assessment of liver disease.This device is medically adapted and clinically validated in patients with lung conditions.

Study Overview

• Status: Completed
• Conditions: Non-alcoholic Fatty Liver Disease
• Intervention / Treatment: Device: Breath analysis - electronic signature "Breath-print"

Detailed Description

Human exhaled breath contains over 3000 volatile organic compounds (VOCs) that vary in relative concentration in health and disease. Metabolic disorders affecting the liver, such as NAFLD, produce disproportionate organic compounds produced as a by-product of metabolism and thus expired in exhaled breath, excreted in urine and detectable in blood. NAFLD prevalence is increasing and has reached epidemic proportions affecting 90% of obese adults and 22%-53% of obese children.Liver biopsy is the gold standard in diagnosing NAFLD, but it is unpleasant and can lead to complications. There is an unmet need to develop a non-invasive method of assessing liver disease. Comon Invent (Delft, Netherlands) together with the respiratory department at the Amsterdam Medical Centre (AMC), University of Amsterdam, have adapted the electronic nose known as SpiroNose as a prototype device for clinical use. Sensitive electronic sensors detect molecules in breath and generate signals. Complex algorithms and analytical technics allow pattern recognition of breath samples from different subjects. Well charaterised patients will be selected into clinical categories of non-alcoholic fatty liver disease with and without cirrhosis and be compared with healthy individuals.

Edinburgh will be the only site conducting this study. In addition to exhaled breath analysis, blood and urine will be collected to study the end products of metabolism.Furthermore, stool and urine collected from some subjects will be analysed to understand the role of gut bacteria in fermentation, metabolic products as a result cause VOC production.

• Study Type: Observational
• Enrollment (Actual): 90

Contacts and Locations

Study Locations

• United Kingdom
  • Midlothian
    • Edinburgh, Midlothian, United Kingdom, EH16 4SA
      • Clinical Research Facility - Wellcome Trust, Royal Infirmary Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

All eligible patients will have to consent to the study. The study population will consist of participants aged between 18 and 75 years old in the following cohorts (Healthy individuals, Non-alcoholic steatohepatitis (non-cirrhotic) and compensated Non-alcoholic liver cirrhosis). Each cohort will have 30 patients. There will be an equal number of participants for the healthy control group. In summary, the investigators aim to recruit 30 subject in the patient cohorts and 30 in healthy, totaling a number of 90 in the study

Description

Inclusion Criteria:

• Healthy individuals with no known or self declared medical illness with BMI (body mass index) within normal range (18.5-25)
• Non alcoholic fatty liver disease without cirrhosis
• Compensated (no evidence of ascites, encephalopathy) NAFLD cirrhosis; assessed by scoring system - Child's Pugh

Exclusion Criteria:

• Ongoing or recent (within last 6months) alcohol consumption more than 21 units per week for males and 14 units per week for females.
• BMI > 40
• Chronic respiratory disease e.g. Chronic obstructive pulmonary disease (COPD), asthma, interstitial fibrosis
• Use of antibiotics within last 4 weeks of sample collection and inflammatory bowel disease, irritable bowel syndrome, celiac sprue, or other chronic inflammatory diseases of the intestines (for intestinal microbiome analysis)
• Other known liver disease e.g. Primary Biliary Cholangitis/cirrhosis (PBC), Alcoholic liver disease (ALD), Autoimmune and hepatitis
• Inability to provide informed consent.
• Participation in other clinical intervention/drug trial

Study Plan

How is the study designed?

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Healthy; Healthy volunteer: self-declared healthy individual (no known illness or medications) with Normal BMI	Device: Breath analysis - electronic signature "Breath-print"; Patients and Healthy volunteers ( as defined in 3 cohorts) will breath into disposable, once-use only bacterial filter channeled into electronic device comprising on sensors capable to reacting to organic compounds. Breathing manoeuvre will be simple, non-exertional and relaxed. 2 breathing manoeuvres will be performed and sensor responses will be captured.
Nonalcoholic steatohepatitis; NAFLD without cirrhosis: Metabolic syndrome with known liver disease (NAFLD, excluding other coexisting liver condition) without cirrhosis	Device: Breath analysis - electronic signature "Breath-print"; Patients and Healthy volunteers ( as defined in 3 cohorts) will breath into disposable, once-use only bacterial filter channeled into electronic device comprising on sensors capable to reacting to organic compounds. Breathing manoeuvre will be simple, non-exertional and relaxed. 2 breathing manoeuvres will be performed and sensor responses will be captured.
NAFLD Cirrhosis; NAFLD cirrhosis: well characterised NAFLD compensated cirrhosis (Child's A-B)	Device: Breath analysis - electronic signature "Breath-print"; Patients and Healthy volunteers ( as defined in 3 cohorts) will breath into disposable, once-use only bacterial filter channeled into electronic device comprising on sensors capable to reacting to organic compounds. Breathing manoeuvre will be simple, non-exertional and relaxed. 2 breathing manoeuvres will be performed and sensor responses will be captured.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Characterise the electronic signature "breath-print" in pre-defined cohorts	Identify disease specific electronic nose wave pattern	12 months
Characterisation of exhaled breath composition	Molecular characterisation of breath volatile organic compounds through Gas Chromatography and Mass Spectrometry	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Profiling intestinal microbiome and assessing end-metabolic products in urine	Demonstrate dysbiosis in stool microbial and characterise metabolic products in urine of cohorts studied	12 months

Collaborators and Investigators

• Sponsor: University of Edinburgh
• Collaborators: University of Amsterdam; University of Strathclyde
• Investigators: Principal Investigator: Peter C Hayes, MD,PhD,FRCPE, Centre for liver and digestive disorder, Royal Infirmary of Edinburgh, Edinburgh, EH16 4SA

Publications and helpful links

General Publications

• Wlodzimirow KA, Abu-Hanna A, Schultz MJ, Maas MA, Bos LD, Sterk PJ, Knobel HH, Soers RJ, Chamuleau RA. Exhaled breath analysis with electronic nose technology for detection of acute liver failure in rats. Biosens Bioelectron. 2014 Mar 15;53:129-34. doi: 10.1016/j.bios.2013.09.047. Epub 2013 Sep 30.
• de Vries R, Brinkman P, van der Schee MP, Fens N, Dijkers E, Bootsma SK, de Jongh FH, Sterk PJ. Integration of electronic nose technology with spirometry: validation of a new approach for exhaled breath analysis. J Breath Res. 2015 Oct 15;9(4):046001. doi: 10.1088/1752-7155/9/4/046001.
• Probert CS, Ahmed I, Khalid T, Johnson E, Smith S, Ratcliffe N. Volatile organic compounds as diagnostic biomarkers in gastrointestinal and liver diseases. J Gastrointestin Liver Dis. 2009 Sep;18(3):337-43.
• Wu GD, Lewis JD, Hoffmann C, Chen YY, Knight R, Bittinger K, Hwang J, Chen J, Berkowsky R, Nessel L, Li H, Bushman FD. Sampling and pyrosequencing methods for characterizing bacterial communities in the human gut using 16S sequence tags. BMC Microbiol. 2010 Jul 30;10:206. doi: 10.1186/1471-2180-10-206.
• Sinha R, Lockman KA, Homer NZM, Bower E, Brinkman P, Knobel HH, Fallowfield JA, Jaap AJ, Hayes PC, Plevris JN. Volatomic analysis identifies compounds that can stratify non-alcoholic fatty liver disease. JHEP Rep. 2020 Jun 15;2(5):100137. doi: 10.1016/j.jhepr.2020.100137. eCollection 2020 Oct.

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2016
• Primary Completion (Actual): August 1, 2017
• Study Completion (Actual): May 1, 2018

Study Registration Dates

• First Submitted: January 13, 2016
• First Submitted That Met QC Criteria: October 27, 2016
• First Posted (Estimate): November 1, 2016

Study Record Updates

• Last Update Posted (Actual): June 26, 2018
• Last Update Submitted That Met QC Criteria: June 21, 2018
• Last Verified: October 1, 2016

More Information

Terms related to this study

• Keywords: NAFLD; Volatile organic compounds; Electronic nose; Non invasive diagnosis of NAFLD; exhaled breath analysis
• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease
• Other Study ID Numbers: 165914

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Individual participant data will not shared. Participants will be identified as a part of pre-defined cohort as categorised clinically.