serum bile acid profiles distinguish severe alcoholic ... · • severe alcoholic hepatitis has a...
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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
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
outcomes1
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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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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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 CohortROC curve:
Validation Cohort
Exploratory Cohort
GCA TCA Bilirubin
AUROC 0.90 0.87 0.79
95% CI0.83-
0.97
0.77-
0.97
0.67-
0.91
Validation Cohort
GCA TCA Bilirubin
AUROC 0.85 0.83 0.65
95% CI0.77-
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