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Neutrophil-to-Lymphocyte Ratio and Corticosteroid Response in Alcoholic Hepatitis

| Hepatology
Authors:
*Ewan Forrest,1,a,b,c Natasha Storey,1,a,b Rohit Sinha,2,a,b Stephen R. Atkinson,3,a,b Nikhil Vergis,3,a,b Paul Richardson,4,a,b Steven Masson,5,a,b Mark R Thursz,3,a,b Michael Allison,6,a,b Anne McCune,7,c Ashwin Dhanda,8,c Dev Katarey,9,c Jonathan Potts,9,c Sumita Verma,9,c Richard Parker,10,c Peter C. Hayes2,a,b,c
Disclosure:

The authors have declared no conflicts of interest.

Acknowledgements:

These studies were performed by the members of the STOPAH NLR Group, which includes the named authors plus Dr Debbie Shawcross, Liver Unit, King’s College Hospital, London, UK; Dr Dermot Gleeson, Liver Unit, Sheffield Teaching Hospitals, Sheffield, UK; Dr Steve Hood, Liver Unit, Aintree Hospital, Aintree, UK; Dr Mark Wright, Liver Unit, University Hospital Southampton, Southampton, UK; Dr John Dillon, Ninewells Hospital, Dundee; Dr David Patch, Liver Unit, Royal Free Hospital, London, UK; Dr Jennifer Ryan, Liver Unit, King’s College Hospital, London, UK; Dr Graham Foster, Queen Mary University of London, London, UK; Dr Toby Delahooke, University Hospitals of Leicester, Leicester, UK; Dr Sulleman Moreea, Bradford Teaching Hospitals, Bradford, UK; Dr Andrew Fraser, formerly of Aberdeen Royal Infirmary, Aberdeen, UK; Dr Stephen Ryder, Queen’s Medical Centre, Nottingham, UK; and Dr Andrew Austin, Derby Teaching Hospitals, Derby, UK.

Citation
EMJ Hepatol. ;7[1]:51-53.

Each article is made available under the terms of the Creative Commons Attribution-Non Commercial 4.0 License.

INTRODUCTION

Treatment of alcoholic hepatitis with corticosteroids remains controversial, with  recent studies indicating only a 28-day survival benefit.1 The neutrophil-to-lymphocyte ratio (NLR) may reflect the systemic inflammatory response, and the authors have previously shown that the NLR can affect the outcome of corticosteroid response in alcoholic hepatitis patients.2 These abstracts aimed to determine the associations of baseline NLR with acute kidney injury (AKI), infection, and Lille response, as well as to externally validate the NLR as a means of identifying patients for corticosteroid therapy.

A) BASELINE NEUTROPHIL-TO-LYMPHOCYTE RATIO INDICATES BOTH PREVALENT AND INCIDENT INFECTION AND ACUTE KIDNEY INJURY, AND PREDICTS LILLE CORTICOSTEROID RESPONSE IN ALCOHOLIC HEPATITIS

The NLR was calculated from 789 patients who participated in the STOPAH trial, with patients randomised to receiving or not receiving prednisolone. Prevalent AKI was defined by an initial creatinine level ≥133.0 μmol/L and incident AKI was defined as either an increase of serum creatinine by 26.5 µmol/L or by 50% by Day 7 in those without baseline AKI. Patients presenting with infections (prevalent infection) were treated prior to randomisation; incident infections were determined after inclusion in the trial.

Those with prevalent AKI had a higher NLR than those without (11.1 versus 6.0; p=0.001; 95% confidence interval [CI]: 2.6–7.6), as did those with prevalent infection compared to those without (7.8 versus 6.3; p=0.02; 95% CI: 0.2–2.8).

A favourable Lille score with prednisolone treatment was more likely if NLR ≥5 versus <5 (56.5% versus 41.1%: p=0.01; overall response [OR]: 1.86; 95% CI: 1.16–2.99). The risk of developing infection after prednisolone treatment was greater if NLR >8 versus <8 after 7 days (17.3% versus 7.4%: p=0.006; OR: 2.60; 95% CI: 1.32–5.14) and 28 days (30.6% versus 20.0%: p=0.031; OR: 1.76; 95% CI: 1.05–2.96). The risk of incident AKI after prednisolone treatment was greater for those with NLR >8 versus <8 (20.8% versus 7.0%: p=0.008; OR: 3.46; 95% CI: 1.39–8.62).

The finding reaffirmed previous observations that prednisolone does not improve outcomes for those with NLR <5 or >8 but does improve outcome beyond 28 days for those with NLR 5–8 (Table 1).

Table 1: Mortality relative to neutrophil-to-lymphocyte ratio category and prednisolone treatment in all patients.

HR: hazard ratio; NLR: neutrophil-to-lymphocyte ratio.

This may be explained by the greater likelihood of achieving a Lille response if NLR <5, but only achieving a reduction in AKI and  infection if NLR ≤8.

B) A MODIFIED GLASGOW ALCOHOLIC HEPATITIS SCORE INCORPORATING THE NEUTROPHIL-TO-LYMPHOCYTE RATIO IS SUPERIOR TO OTHER BASELINE SCORES OF PROGNOSIS IN ALCOHOLIC HEPATITIS

In the same cohort of patients, there was a strong correlation between the total white blood cell count (WCC) and NLR: r=0.564; 95% CI: 0.52–0.60; p<0.0001. In view of this, the NLR was incorporated into the Glasgow Alcoholic Hepatitis Score (GAHS)3 with an NLR threshold of 5 replacing the total WCC threshold of 15, creating a modified GAHS (mGAHS). The areas under the curve for mGAHS for 28-day and 90-day outcomes were 0.783 (95% CI: 0.752–0.812) and 0.739 (95% CI: 0.706–0.770), respectively. For 28-day outcome, the mGAHS area under the curve was superior to that of the Maddrey’s discriminant function (0.684: p<0.0001; 95% CI: 0.05–0.14), the original GAHS (0.763: p=0.027; 95% CI: 0.002–0.040), and the model for end-stage liver disease (0.739: p=0.0014; 95% CI: 0.009–0.080).

C) VALIDATION OF THE PRE-TREATMENT NEUTROPHIL-TO-LYMPHOCYTE RATIO TO PREDICT RESPONSE TO CORTICOSTEROIDS IN SEVERE ALCOHOLIC HEPATITIS

The observations from the previous abstract were then tested in an independent validation group of 237 patients. Again, no improvement in outcome with corticosteroids was seen at either 28 days or 90 days for NLR <5 (28-day mortality 10.0% versus 5.1%; p=0.416; 90-day mortality 16.3% versus 18.4% p=0.843) or NLR >8 (28-day mortality 23.5% versus 28.0%; p=0.469; 90-day mortality 39.2% versus 48.0%; p=0.362). In total, 28-day mortality for NLR 5–8 was reduced by corticosteroid treatment (2.7% versus 28.6%; p=0.0023) with a trend to reduced mortality at Day 90: 21.6% versus 37.4%; p=0.097. Those with a mGAHS ≥9 and NLR 5–8 had a significant reduction in 90-day mortality with prednisolone treatment: 23.3% versus 46.4%; p=0.036; hazard ratio: 0.268; 95% CI: 0.10–0.71.

CONCLUSIONS

These abstracts indicate the association of NLR with risk of infection and AKI in alcoholic hepatitis, as well as the chance of a Lille response to  alcoholic hepatitis. Incorporation of the NLR in place of WCC improves prognostic accuracy. These results reaffirm and externally validate the observation that corticosteroid treatment for those with NLR <5 or >8 is ineffective but improves outcomes for those with NLR 5–8 beyond 28 days.

References
Thursz MR et al. Prednisolone or pentoxifylline for alcoholic hepatitis. N Engl J Med. 2015;372:1619-28. Forrest E et al. Baseline neutrophil to lymphocyte ratio can identify favourable corticosteroid response in alcoholic hepatitis. J Hepatol. 2017;66(1):S99. Forrest EH et al. Analysis of factors related to mortality in alcoholic hepatitis and the derivation and validation of the Glasgow Alcoholic Hepatitis Score. Gut. 2005;54(8):1174-9.