Serum bile acid profiles distinguish severe alcoholic hepatitis from decompensated alcohol-related cirrhosis Luke D Tyson , Stephen Atkinson, Alex Pechlivanis, Elaine Holmes, Nikhil Vergis, Rooshi Nathwani, James Maurice, Simon Taylor-Robinson, Benjamin H Mullish, Roger Williams, Mark JW McPhail, Vishal C Patel, Mark Thursz on behalf of the STOPAH trial management group.
Serum bile acid profiles distinguish severe alcoholic hepatitis from decompensated alcohol-related cirrhosis • Alcoholic hepatitis (AH) is characterised by the acute onset of jaundice in patients with ongoing alcohol misuse • Severe AH (mDF ≥ 32) has a high mortality (>50% at one year) • Patients with severe AH have marked cholestasis: this is associated with poor outcomes 1 Background (1) 1. Spahr L et al . BMC Gastroenterol. 2011 Oct 28; 11:115.
Serum bile acid profiles distinguish severe alcoholic hepatitis from decompensated alcohol-related cirrhosis • Differences in the serum bile acid (BA) profiles of patients with AH have been reported compared to alcohol-dependent and healthy controls Figure: Brandl K et al. Dysregulation of serum bile acids and FGF19 in alcoholic hepatitis. J Hepatol . 2018 Aug;69(2):396-405. Background (2)
Serum bile acid profiles distinguish severe alcoholic hepatitis from decompensated alcohol-related cirrhosis Background (3)
Serum bile acid profiles distinguish severe alcoholic hepatitis from decompensated alcohol-related cirrhosis Hepatocyte diagram: Halilbasic E et al. J Hepatol. 2013 Jan;58(1):155-68 . Background (4) mRNA expression data: Brandl K et al. J Hepatol . 2018 Aug;69(2):396-405.
Serum bile acid profiles distinguish severe alcoholic hepatitis from decompensated alcohol-related cirrhosis • Accurate diagnosis of severe AH is important to guide therapy • Existing clinical criteria are imperfect • Steatohepatitis on liver biopsy is the gold standard but high cost and potential complications Background (5)
Serum bile acid profiles distinguish severe alcoholic hepatitis from decompensated alcohol-related cirrhosis • The aim of this study was to assess if bile acid profiles can be used to distinguish severe AH from its most common differential: decompensated alcohol-related cirrhosis (DC) Aim
Serum bile acid profiles distinguish severe alcoholic hepatitis from decompensated alcohol-related cirrhosis • Serum bile acids measured by mass spectrometry • Profiled in an initial exploratory cohort • Quantified in a confirmatory validation cohort • All inpatients with alcohol-related liver disease recruited to a number of clinical trials and biobanks Method (1)
Serum bile acid profiles distinguish severe alcoholic hepatitis from decompensated alcohol-related cirrhosis • Patients with severe AH: - 18 years or older - Average alcohol consumption >80g/day for men; >60g/day for women Serum bilirubin >80 μmol /L (4.7 mg/dL) - mDF ≥32 - - Diagnosis confirmed by liver biopsy showing steatohepatitis - Excluded if: jaundiced >3 months; cessation of alcohol >2 months; other cause of cholestasis; AST >500 IU/L; ALT >300 IU/L Method (2)
Serum bile acid profiles distinguish severe alcoholic hepatitis from decompensated alcohol-related cirrhosis • Patients with severe AH: - 18 years or older - Average alcohol consumption >80g/day for men; >60g/day for women Serum bilirubin >80 μmol /L (4.7 mg/dL) - mDF ≥32 - - Diagnosis confirmed by liver biopsy showing steatohepatitis - Excluded if: jaundiced >3 months; cessation of alcohol >2 months; other cause of cholestasis; AST >500 IU/L; ALT >300 IU/L Method (2)
Serum bile acid profiles distinguish severe alcoholic hepatitis from decompensated alcohol-related cirrhosis • Patients with DC (exploratory cohort): - Cirrhosis due to alcohol-related liver disease - Decompensated - Did not meet clinical criteria for AH - MELD >18 • Patients with DC (validation cohort): - Cirrhosis due to alcohol-related liver disease - Decompensated - Did not meet clinical criteria for AH - Bilirubin >80 µmol/L Would have had a mDF ≥32 if they did have AH - Method (3)
Serum bile acid profiles distinguish severe alcoholic hepatitis from decompensated alcohol-related cirrhosis Exploratory Cohort Validation Cohort AH DC AH DC N= 68 21 65 40 Male (%) 71 76 60 78 Mean age (years) 49 54 47 51 Median MELD 23 26 25 30 Mean bilirubin (µmol/L) 378 246 323 261 Median mDF 54 - 56 - Method (4)
Serum bile acid profiles distinguish severe alcoholic hepatitis from decompensated alcohol-related cirrhosis • Data analysed: - Orthogonal projection to least squares discriminant analysis (OPLS-DA) - Area under the receiver operating curve (AUROC) analysis Method (5)
Serum bile acid profiles distinguish severe alcoholic hepatitis from decompensated alcohol-related cirrhosis • OPLS-DA accurately discriminated AH from DC in both exploratory and validation cohorts 1+2+0; N= 105; R2X(cum)= 0.511; 1+1+0; N= 89; R2X(cum)= 0.506; R2Y(cum)= 0.535; Q2(cum)= 0.375 R2Y(cum)= 0.474; Q2(cum)= 0.364 CV-ANOVA: P= 1.92E-08 CV-ANOVA: P= 9.10E-08 Results (1)
Serum bile acid profiles distinguish severe alcoholic hepatitis from decompensated alcohol-related cirrhosis Exploratory Validation Cohort Cohort AUROC (full bile 0.93 0.93 acid profile) 95% CI 0.87-0.99 0.88-0.98 Results (2)
Serum bile acid profiles distinguish severe alcoholic hepatitis from decompensated alcohol-related cirrhosis • Model diagnostics identified glycocholic (GCA) and taurocholic (TCA) acid as the dominant metabolites in the multivariate models VIP scores: Exploratory Cohort S-plot: Exploratory Cohort Results (3)
Serum bile acid profiles distinguish severe alcoholic hepatitis from decompensated alcohol-related cirrhosis • Model diagnostics identified glycocholic (GCA) and taurocholic (TCA) acid as the dominant metabolites in the multivariate models VIP scores: Validation Cohort S-plot: Validation Cohort Results (4)
Serum bile acid profiles distinguish severe alcoholic hepatitis from decompensated alcohol-related cirrhosis Exploratory Cohort GCA TCA Bilirubin AUROC 0.90 0.87 0.79 0.83- 0.77- 0.67- 95% CI 0.97 0.97 0.91 Validation Cohort GCA TCA Bilirubin AUROC 0.85 0.83 0.65 ROC curve: ROC curve: 0.77- 0.74- 0.54- Exploratory Cohort 95% CI Validation Cohort 0.92 0.92 0.76 Results (5)
Serum bile acid profiles distinguish severe alcoholic hepatitis from decompensated alcohol-related cirrhosis • Validation cohort: - TCA concentration ≥ 8300 nM - 83% sensitivity for AH - 85% specificity for AH ROC curve: Validation Cohort Results (6)
Serum bile acid profiles distinguish severe alcoholic hepatitis from decompensated alcohol-related cirrhosis • Severe alcoholic hepatitis has a serum bile acid profile distinct from patients with decompensated alcohol-related cirrhosis and similar liver dysfunction • The entire bile acid profile and the individual bile acids GCA and TCA are promising non- invasive biomarkers for severe alcoholic hepatitis and may reduce the need for liver biopsy Conclusions
Serum bile acid profiles distinguish severe alcoholic hepatitis from decompensated alcohol-related cirrhosis • Controls with decompensated cirrhosis were diagnosed on clinical criteria • Small sample sizes • Need for further validation in independent, prospectively-biopsied cohorts Limitations
Serum bile acid profiles distinguish severe alcoholic hepatitis from decompensated alcohol-related cirrhosis The Institute of Hepatology (London): Imperial College London: • • Roger Williams Stephen Atkinson • • Vishal C Patel Alex Pechlivanis • Elaine Holmes King's College London and King’s College Hospital NHS Trust: • Nikhil Vergis • Mark JW McPhail • Rooshi Nathwani • James Maurice • Ane Zamalloa • Simon Taylor-Robinson • Ele Corcoran • Benjamin H Mullish • Mark Thursz STOPAH trial management group • Thomas Barbera Funding: • • Larry Koomson NIHR Academic Clinical Fellowship (LD Tyson) • NIHR Imperial College Biomedical Research Centre • MRC Clinical Research Training Fellowship (S Atkinson) • MRC Stratified Medicine Consortium: Minimising Mortality from Acknowledgements Alcoholic Hepatitis
Serum bile acid profiles distinguish severe alcoholic hepatitis from decompensated alcohol-related cirrhosis Questions? luke.tyson@nhs.net
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