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Dec 17, 2022 203 likes •450 views

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,

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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.

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Background (1)

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
  • ngoing 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
  • utcomes1
  • 1. Spahr L et al. BMC Gastroenterol. 2011 Oct 28; 11:115.
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Background (2)

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.

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SLIDE 4

Serum bile acid profiles distinguish severe alcoholic hepatitis from decompensated alcohol-related cirrhosis

Background (3)

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Background (4)

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. mRNA expression data: Brandl K et al. J Hepatol. 2018 Aug;69(2):396-405.

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Background (5)

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

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Aim

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)

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Method (1)

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

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SLIDE 9

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

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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

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Method (3)

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
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Method (4)

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
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Method (5)

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
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1+1+0; N= 89; R2X(cum)= 0.506; R2Y(cum)= 0.474; Q2(cum)= 0.364 CV-ANOVA: P= 9.10E-08

Results (1)

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; R2Y(cum)= 0.535; Q2(cum)= 0.375 CV-ANOVA: P= 1.92E-08

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Results (2)

Serum bile acid profiles distinguish severe alcoholic hepatitis from decompensated alcohol-related cirrhosis

Exploratory Cohort Validation Cohort AUROC (full bile acid profile) 0.93 0.93 95% CI 0.87-0.99 0.88-0.98

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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 S-plot: Exploratory Cohort VIP scores: Exploratory Cohort

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Results (4)

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 S-plot: Validation Cohort VIP scores: Validation Cohort

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Results (5)

Serum bile acid profiles distinguish severe alcoholic hepatitis from decompensated alcohol-related cirrhosis

ROC curve: Exploratory Cohort ROC curve: Validation Cohort

Exploratory Cohort GCA TCA Bilirubin AUROC 0.90 0.87 0.79 95% CI

0.83- 0.97 0.77- 0.97 0.67- 0.91

Validation Cohort GCA TCA Bilirubin AUROC 0.85 0.83 0.65 95% CI 0.77- 0.92 0.74- 0.92 0.54- 0.76

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Results (6)

Serum bile acid profiles distinguish severe alcoholic hepatitis from decompensated alcohol-related cirrhosis

ROC curve: Validation Cohort

  • Validation cohort:
  • TCA concentration ≥ 8300 nM
  • 83% sensitivity for AH
  • 85% specificity for AH
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Conclusions

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

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Limitations

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
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Acknowledgements

Serum bile acid profiles distinguish severe alcoholic hepatitis from decompensated alcohol-related cirrhosis

Imperial College London:

  • Stephen Atkinson
  • Alex Pechlivanis
  • Elaine Holmes
  • Nikhil Vergis
  • Rooshi Nathwani
  • James Maurice
  • Simon Taylor-Robinson
  • Benjamin H Mullish
  • Mark Thursz
  • Thomas Barbera
  • Larry Koomson

The Institute of Hepatology (London):

  • Roger Williams
  • Vishal C Patel

King's College London and King’s College Hospital NHS Trust:

  • Mark JW McPhail
  • Ane Zamalloa
  • Ele Corcoran

STOPAH trial management group Funding:

  • 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

Alcoholic Hepatitis

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Questions?

Serum bile acid profiles distinguish severe alcoholic hepatitis from decompensated alcohol-related cirrhosis

luke.tyson@nhs.net