EDITORIAL The Liver Breath! Breath Volatile Organic Compounds for the Diagnosis of Liver Disease lcohol is a major factor leading to an increased burden of chronic liver disease morbidity and mortality throughout Europe and the United States.1,2 There has also been a significant rise in alcohol-related health costs; for example, a recent UK report from the Royal College of Physicians estimated the annual cost of alcohol-related health care at £2.9 billion.2 Alcoholic hepatitis (AH) is a severe manifestation of alcohol-related liver disease and is an inflammatory disorder on the background of heavy alcohol use. The dominant pathophysiology is alcohol-related increased gut permeability promoting translocation of bacterial products into the portal venous system and liver sinusoids with release of pro-inflammatory cytokines, mainly tumor necrosis factor–a resulting in liver inflammation.3 As a consequence of this inflammatory cascade, patients present with jaundice, hepatic tenderness, coagulopathy, and, often, evidence of established chronic liver disease, with signs of portal hypertension, including ascites and hepatic encephalopathy. Histologic findings demonstrate macrovesicular steatosis, neutrophilic infiltration, ballooning of hepatocytes, and the presence of Mallory bodies. The degree of hepatic fibrosis is variable, with cirrhosis being present in 60%–70% with AH. Targeting the inflammatory process has, to date, been the cornerstone of medical management of AH.4 Prognostic scoring systems have been developed to define the severity and predict short-term survival, in patients with AH. The characteristics and utility of these scoring tools have been reviewed.4 One-month mortality is 30%–40% in patients with a Maddrey’s Discriminant Function >32 and w60% in those with a Glasgow Alcoholic Hepatitis Score >9.5,6 These models have also been used to identify patients who may benefit from corticosteroid therapy. In a further refining of prognostic tools, the Lille model incorporates a dynamic element, namely, the change in bilirubin at day 7 of steroid therapy to identify nonresponders to medical therapy7; this model has recently been used to identify medical nonresponders to therapy who may benefit from early liver transplantation.8 Despite the availability of these prognostic tools, the appropriate medical management of AH remains unclear. There is a lack of consensus surrounding the use of corticosteroids because of the risk of sepsis and gastrointestinal bleeding, despite data showing improvement in short- and medium-term survival.4 Pentoxifylline has antitumor necrosis factor–a activity and in a recent randomized controlled trial has demonstrated a reduction in short-term mortality in patients with AH

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primarily from the prevention of hepatorenal syndrome.9 However, this has yet to be confirmed in other studies. A multicenter UK study (Steroids or Pentoxifylline for Alcoholic Hepatitis [STOPAH]; EudraCT 2009-01389742), currently under way, is aiming to recruit 1200 patients; this well-powered study will, it is hoped, resolve the current controversies around optimal medical management.10 The utility of histologic findings in confirming the diagnosis of AH and, possibly, guide management remains controversial on a number of levels. Coagulopathy, thrombocytopenia, and ascites are common and a percutaneous liver biopsy is often contraindicated. Transjugular liver biopsy is not universally available outside tertiary care centers. The relatively large volume of AH patients makes tertiary care management and histologic confirmation of all patients unachievable. In centers where transjugular liver biopsy is available, issues arise with the size of tissue obtained for analysis, the time delay in performing biopsy and subsequently reporting on the specimen, and the potential delay in clinical intervention. Histology enables differentiation of AH from decompensated, alcohol-related cirrhosis and sepsis-related cholestasis. This distinction informs subsequent medical management. In addition, histology allows grading of the severity of AH and may predict outcome.11 Whether this is of clinical use given the array of prognostic models available is unclear.12 A compelling argument against the mandatory use of histology is the high level of accuracy in diagnosing AH with clinical criteria alone. Recent data have demonstrated that a minimal level of bilirubin (>80 mmol/L or 4.68 mg/dL) allied to a clinical diagnosis in histologically confirmed AH was accurate in 96% of cases.13 The STOPAH trial has relied on clinical inclusion criteria alone, but a subset of patients will have histology performed to confirm the accuracy of clinical criteria and further clarify the place of histology. Noninvasive diagnostics in the management of AH, including transient elastography and Doppler studies of hepatic artery blood flow, have to date been disappointing.14,15 There is a need for well-validated tools in this setting to confirm AH without recourse to a biopsy and possibly as a treatment guide to gauge response to therapy. Clearly, there is a need for more reliable, minimally invasive tests for the assessment of liver disease. In this issue, Hanouneh et al16 explore the use of breath biomarkers to diagnose AH. Breath analysis offers a noninvasive means to study the composition of volatile organic compounds (VOCs) present in the blood and is an attractive means to evaluate health and disease in a patient-friendly manner. Breath can be collected repeatedly without any risk to patients, and its analysis offers a potentially valuable screening tool for clinical diagnosis and monitoring the efficacy of therapy.

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Hanouneh et al report a model based on breath levels of trimethylamine and pentane, distinguishing patients with AH from those with acute liver decompensation from causes other than alcohol, or controls without liver disease, with up to 90% sensitivity and 80% specificity. Trimethylamine is produced from food by gut microflora, and its conversion to trimethylamine N-oxide is impaired in patients with liver disease. It is unclear why significantly elevated levels of trimethylamine were detected in cirrhotic patients with AH compared with patients with acute decompensation from causes other than alcohol. One explanation may be the influence of recent alcohol intake on the gut and liver and the increased severity of liver damage, as depicted by the higher Model for EndStage Liver Disease scores in the AH group. Nevertheless, this is an exciting observation as it may provide clues to means of accessing liver damage. Elevated breath pentane levels are associated with oxidative stress in patients with cancer, infection, and hypoxia. Pentane is a by-product of lipid peroxidation, a process that degrades fatty acids in cell membranes, causing damage to cells. The raised levels of this compound in those with AH may be the result of alcoholinduced liver injury; however, this compound lacks sensitivity and specificity as a biomarker of specific diseases and is better described as a marker of oxidative stress associated with a range of diseases. In the current study, the authors combined 2 VOCs in the model, strengthening the test for AH and improving its sensitivity and specificity—the pentane showing oxidative stress, and the trimethylamine, perhaps, localizing the disease to the liver. Van den Velde et al sampled the breath of patients with cirrhosis and healthy individuals with the aim of identifying compounds to aid the diagnosis of cirrhosis.17 Four compounds, dimethyl sulfide, acetone, 2-pentanone, and 2-butanone, facilitated the differentiation of liver patients from healthy volunteers with a sensitivity and specificity of 100% and 70%, respectively. However, this study only reported odorous compounds that may be responsible for halitosis in the context of liver cirrhosis; nonodorous compounds may be equally important. In a later study, the same group studied a wider range of compounds and were able to differentiate between healthy controls and patients with cirrhosis with 83% sensitivity and 100% specificity.18 Verdam et al studied breath VOC profiles of overweight and obese subjects (body mass index, 24.8–64.3) and related these to plasma aminotransferase levels and liver histology.19 The presence of 3 breath compounds (n-tridecane, 3-methyl-butanonitrile, and 1-propanol) differentiated subjects with and without nonalcoholic steatohepatitis with 90% sensitivity and 69% specificity. The diagnostic ability of the breath test compared favorably with that of plasma transaminases, with a misdiagnosis rate of 18%, compared with 50% based on serum aminotransferases. The analysis of VOCs therefore provides a useful discriminatory test. Fecal VOCs may

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also be used to distinguish obese patients with nonalcoholic fatty liver disease from healthy controls; however, fecal samples are less readily acquired than breath samples.20 Our group has studied breath VOC profiles of patients with various liver disorders and, based on the presence or absence of particular VOCs, alcoholic patients with and without cirrhosis could be differentiated with a sensitivity of 100% and a specificity of 85.7%.21 The presence of hepatic encephalopathy was correctly identified in 90.9% of the alcoholic cirrhosis cohort. Furthermore, nonalcoholic cirrhosis, alcoholic cirrhosis, and harmful drinking (with no evidence of chronic liver disease) could be differentiated from healthy controls with a sensitivity of 92.3%, 97.1%, and 100%, respectively. The results reported by Hanouneh et al are promising and give further proof of concept for breath-based assessment of liver injury. Studies like this are a driving force for the development of novel electronic nose technologies based on sensors that can provide point-of-care breath tests to give results in real time. Breath testing is, potentially, a new tool that can complement currently used diagnostic tests for liver diseases in clinical practice to help reduce the number of invasive procedures performed and to increase the sensitivity and specificity of current clinical tools. Breath VOC testing is an emerging area with a potential to revolutionize patient care in the future. TANZEELA KHALID, PhD Department of Gastroenterology University of Liverpool Liverpool, United Kingdom PAUL RICHARDSON, FRCP Department of Gastroenterology Royal Liverpool University Hospital NHS Trust Liverpool, United Kingdom CHRIS S. PROBERT, FRCP Department of Gastroenterology University of Liverpool Liverpool, United Kingdom

References 1. Alcohol Misuse. Can the NHS afford it? Recommendations for a coherent alcohol strategy for hospitals: a report. The Working Party of the Royal College of Physicians, 2001. 2. Singal AK, Kamath PS, Gores GJ, et al. Alcoholic hepatitis: current challenges and future directions. Clin Gastroenterol Hepatol 2013 Jun 27. 3. Gao B, Bataller R. Alcoholic liver disease, pathogenesis and new therapeutic targets. Gastroenterology 2011;141:1527–1585. 4. Lucey M, Mathurin P, Morgan TR. Alcoholic hepatitis. N Engl J Med 2009;360:2758–2769. 5. Maddrey WC, Boitnott JK, Bedine MS, et al. Corticosteroid therapy of alcoholic hepatitis. Gastroenterology 1978;75:193–199.

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6. Forrest EH, Evans CD, Stewart S, et al. Analysis of factors predictive of mortality in alcoholic hepatitis and derivation and validation of the Glasgow Alcoholic Hepatitis Score. Gut 2005; 54:1174–1179.

Clinical Gastroenterology and Hepatology Vol. 12, No. 3 15. Han SH, Rice S, Cohen SM, et al. Duplex Doppler ultra sound of the hepatic artery in patients with acute alcoholic hepatitis. J Clin Gastroenterol 2002;34:573–577.

7. Louvet A, Naveau S, Abdelnour M, et al. The Lille model, a new tool for therapeutic strategy in patients with severe alcoholic hepatitis treated with steroids. Hepatology 2007;45:1348–1354.

16. Hanouneh IA, Zein NN, Cikach F, et al. The breathprints in patients with liver disease identify novel breath biomarkers in alcoholic hepatitis. Clin Gastroenterol Hepatol 2014;12: 516–523.

8. Mathurin P, Moreno C, Samuel D, et al. Early liver transplantation for severe alcoholic hepatitis. N Engl J Med 2011; 365:1790–1800.

17. Van den Velde S, Nevens F, Van Hee P, et al. GC-MS analysis of breath odor compounds in liver patients. J Chromatogr B Analyt Technol Biomed Life Sci 2008;875:344–348.

9. Akriviadis E, Botla R, Briggs W, Han S, Reynolds T, Shakil O. Pentoxifylline improves short-term survival in severe acute alcoholic hepatitis: a double-blind, placebo-controlled trial. Gastroenterology 2000;119:1637–1648.

18. Dadamio J, Van den Velde S, Laleman W, et al. Breath biomarkers of liver cirrhosis. J Chromatogr B 2012;905:17–22.

10. Forrest E, Mellor J, Stanton L, et al. Steroids or pentoxifylline for alcoholic hepatitis (STOPAH), study protocol for a randomised controlled trial. Trials 2013;14:262. 11. Mookerjee RP, Lackner C, Stauber R, et al. The role of liver biopsy in the diagnosis and prognosis of patients with acute deterioration of alcoholic cirrhosis. J Hepatol 2011;55:1103–1111. 12. Forrest EH, Gleeson D. Is liver biopsy necessary in alcoholic hepatitis? J Hepatol 2012;56:1428–1429. 13. Hamid R, Forrest EW. Is histology required for the diagnosis of alcoholic hepatitis? A review of published randomised controlled trials. Gut 2011;60(Suppl 1):A233. 14. Valle SD, Massironi S, Pozzi R, et al. Transient elastography in acute alcoholic hepatitis and during follow up, a single centre experience. Hepatology 2012;56:S538.

19. Verdam FJ, Dallinga JW, Driessen A, et al. Non-alcoholic steatohepatitis: a non-invasive diagnosis by analysis of exhaled breath. J Hepatol 2013;58:543–548. 20. Raman M, Ahmed I, Gillevet PM, et al. Fecal microbiome and volatile organic compound metabolome in obese humans with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol 2013;11:868–875. 21. Khalid TY, De Lacy Costello B, Ewen R, et al. Breath volatile analysis from patients diagnosed with harmful drinking, cirrhosis and hepatic encephalopathy: a pilot study. Metabolomics 2013; 9:938–948.

Conflicts of interest The authors disclose no conflicts. http://dx.doi.org/10.1016/j.cgh.2013.10.032

The liver breath! Breath volatile organic compounds for the diagnosis of liver disease.

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