Serum bile acid profiles distinguish severe alcoholic ... · • Severe alcoholic hepatitis has a serum bile acid profile distinct from patients with decompensated alcohol-related

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.

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.

Background (2)



• 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 (3)

Background (4)



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.

Background (5)



• 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

Aim



• 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)

Method (1)



• 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 (2)



• 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)



• 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 (3)



• 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 (4)



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 (5)



• Data analysed:

- Orthogonal projection to least squares discriminant analysis (OPLS-DA)

- Area under the receiver operating curve (AUROC) analysis

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)



• 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

Results (2)



Exploratory

Cohort

Validation

Cohort

AUROC (full bile

acid profile)0.93 0.93

95% CI 0.87-0.99 0.88-0.98

Results (3)



• 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

Results (4)



• 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

Results (5)



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

Results (6)



ROC curve:

Validation Cohort

• Validation cohort:

- TCA concentration ≥ 8300 nM

- 83% sensitivity for AH

- 85% specificity for AH

Conclusions



• 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

Limitations



• Controls with decompensated cirrhosis were diagnosed on clinical criteria

• Small sample sizes

• Need for further validation in independent, prospectively-biopsied cohorts

Acknowledgements



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

Questions?



[email protected]

Documents

Serum bile acid profiles distinguish severe alcoholic ... · • Severe alcoholic hepatitis has a serum bile acid profile distinct from patients with decompensated alcohol-related