The Diagnostic and Prognostic Significance of Liver Histology in Alcoholic Hepatitis

Ewan Forrest; Gemma Petts; Andrew Austin; Kirsty Lloyd; Mark Wright; Nikhil Vergis; Stephen Atkinson; Steven Masson; David Patch; Alberto Quaglia; Mark Thursz; Robert Goldin

Disclosures

Aliment Pharmacol Ther. 2021;53(3):426-431. 

In This Article

Discussion

A clear set of clinical criteria were used to define patients with severe AH for inclusion in STOPAH, a multicentre double-blinded randomised control trial.[9] These criteria are similar to those proposed by the National Institute on Alcohol Abuse and Alcoholism to identify "probable" AH, although the threshold for bilirubin was higher in STOPAH at 80 μmol/L as opposed to just over 50 μmol/L.[14] When liver biopsy was undertaken in STOPAH it confirmed the presence of ASH in 87% of all patients biopsied, although 98% of biopsies were compatible with alcohol-related liver injury. In the STOPAH trial, liver biopsy did not form part of the trial protocol but participating centres were encouraged to carry out biopsies in cases especially where there was clinical uncertainty. Therefore there may be a bias towards alternative diagnoses compared with a policy of obtaining a biopsy from all suspected alcoholic hepatitis patients. Despite this potential bias, a high proportion of biopsies showed ASH. An interesting observation is the lower mortality in biopsied patients compared with the remainder of the non-biopsied STOPAH patients. The difference in mortality was reflected in hospital sites with a high rate of biopsy. This indicates that the favourable outcome of biopsied patients is not a factor of the experience or expertise of the recruiting site but is more likely to reflect a degree of selection bias in the biopsied population. It may be that a biopsy is less likely to be undertaken when patients are unwell in ways not clearly reflected in standard prognostic scores.

Liver biopsies were performed at different times during the course of the trial. The timing of biopsy relative to randomisation, the exposure to prednisolone and the severity of clinical AH scores all affected the rate of liver biopsy histological confirmation with ASH. Patients biopsied early (before randomisation), not exposed to prednisolone and with severe clinical disease (high GAHS or MELD scores) had a higher rate of diagnostic features of ASH (100%) compared to biopsies obtained with none of these features (81%). However only 2% of the biopsies studied did not show features of alcohol-related liver injury.

A clinical diagnosis of AH may be less accurate in patients with less clinically severe disease given the lower rate of ASH confirmation in those with MELD <25. This could even apply to those with a MELD >20, the threshold for severe disease suggested by the American College of Gastroenterology[2] and the American Association for the Study of Liver Disease.[3] Similarly, this may be particularly relevant for those patients who fulfil the National Institute on Alcohol Abuse and Alcoholism criteria but whose serum bilirubin is less than 80 μmol/L.

By the nature of the recruitment criteria to the STOPAH trial, those with bilirubin 50–80 μmol/L were not addressed in this study but it can be assumed that their clinical prognostic scores would be lower as serum bilirubin is integral to both GAHS and MELD. Therefore the role of biopsy in these patients requires further investigation and inclusion of liver biopsy as part of clinical trials involving this cohort might be required to address this.

When considering the clinical significance of these findings it is important to consider the issue of sampling error as a reason for negative biopsies. Milder disease may be associated with patchy or less volume of active disease (such as hepatocyte ballooning), thereby reducing the chance of a biopsy being taken from a portion of affected liver. Again, this may be of particular significance if patients with bilirubin just over 50 μmol/L but less than 80 μmol/L are to be considered as probable alcoholic hepatitis using the National Institute on Alcohol Abuse and Alcoholism criteria. Taking these factors into account, if a liver biopsy is to be taken for diagnostic or clinical trial purposes in the setting of suspected AH, it should be considered more so for those with clinically mild disease and should be taken early before corticosteroid treatment is initiated to give the best chance of identifying histological features of ASH.

The AHHS is a prognostic scoring system for liver biopsies in AH. Whilst the survival rate of the severe disease group was less than moderate or mild disease groups, the difference did not reach significance. In the STOPAH cohort, the survival of the severe group was also higher than reported in the original description of the AHHS.[6] Comparison of the AHHS with established clinical AH prognostic scores showed no difference in discriminatory ability. Therefore the AHHS did not provide any additional prognostic information to that available from scores based upon clinical and laboratory variables.

Only 17% of patients enrolled in STOPAH underwent liver biopsy but this low rate of biopsy in AH patients reflects the published literature on the clinical practice in the United Kingdom and United States of America, where biopsy rates as low as 11% and 15% of AH cases have been reported.[15,16]

Nevertheless, this study still represents a substantial collection of liver biopsies in patients with clinically severe alcoholic hepatitis and is similar in number to that of the original AHHS description.

It is notable that of the 182 biopsies, 12% were deemed inadequate for histological assessment. The pathologists chose to use five portal tracts as a cut-off to define adequacy, but in the liver distorted by severe fibrosis, this may not be the ideal parameter. However this high rate of inadequate biopsies raises further questions as to the necessity or desirability of biopsy prior to specific treatment of AH. In this patient cohort, which also showed a high percentage of significant liver fibrosis on liver biopsy, if an adequate biopsy is a pre-requisite for histological assessment then either some patients will never achieve this level of diagnostic clarity, or they will have to undergo repeated biopsies until adequate tissue is obtained, thereby delaying their intervention.

In summary, this study demonstrates that there is a high level of concordance between liver biopsy histological features of ASH and a clinical diagnosis of severe AH when the biopsy is taken early on in clinical assessment and ideally prior to the start of corticosteroid treatment. Biopsies taken later, after the administration of corticosteroid therapy, are less likely to satisfy the histological criteria of ASH. The study has also demonstrated that the AHHS, a histological prognostic tool for ASH performed comparably but no better than existing clinical prognostic tools. Therefore the role of liver biopsy is best reserved for cases of diagnostic uncertainty when taken early in the assessment of clinically severe AH.

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