Extending the Baveno VII definition of recompensation to autoimmune hepatitis: Considerations regarding treatment timing and response criteria

To the Editor:

With great interest, we read the recent study by Chen, Wen, Li et al.¹ exploring the concept of hepatic recompensation in decompensated cirrhosis due to autoimmune hepatitis (AIH), which advanced our understanding of liver disease regression across all cirrhosis aetiologies.

Combining prior evidence of recompensation in other rare immune-mediated liver diseases (e.g. primary biliary cholangitis²), with reports that immunosuppressive therapy (IS) in AIH can improve prognosis even in decompensated cirrhosis,³ the authors extend the Baveno VII concept of recompensation⁴ to AIH and explore its incidence and implications. Although the current Baveno VII⁴ definition is limited to alcohol-related or viral liver disease, for which effective (or even curative) aetiological treatments exist, the authors propose a complete biochemical response (CBR) to IS as a surrogate marker of disease control for recompensation in AIH. Simultaneously, the authors adhere to the remaining Baveno VII recompensation criteria, including the absence of ascites and hepatic encephalopathy off therapy, no variceal bleeding for at least 1 year, and a sustained improvement in hepatic function, thereby strengthening the validity of their findings.

By applying the authors’ proposed concept to our cohort of 21 patients with decompensated AIH (n = 18 ascites, n = 3 variceal bleeding; all with an established AIH diagnosis according to the simplified IAIHG score) receiving IS, we found that recompensation according to Baveno VII criteria following CBR was achieved in 4 patients (19%) over a median follow-up of 6.7 years – a rate lower than the 31% observed by our colleagues, which may reflect more pronounced disease severity at the time of decompensation in our cohort (median MELD of 15 [IQR 11-18] vs. 12 in their study). Furthermore, the authors defined cirrhosis not only by liver biopsy, but also by clinical or imaging criteria, which may have led to the inclusion of some cases who actually presented with acute-severe AIH. Acute-severe presentation may involve mild ascites or hepatic encephalopathy in the context of severe hepatocellular inflammation.⁵ Importantly, 50% of the patients with AIH included in their study who eventually recompensated only had mild ascites (≤3 cm ascites on imaging).¹ Thus, although liver biopsy in AIH cirrhosis has considerable pitfalls (e.g. sampling error) and requires expert pathological assessment,⁶ a subgroup analysis limited to patients with a multimodal diagnosis of AIH-related cirrhosis, integrating histological, biochemical and imaging findings, for diagnostic and prognostic assessment would be recommended.

Nevertheless, in both cohorts, recompensation significantly improved the prognosis and all 4 recompensated patients in our cohort showed excellent long-term outcomes and remained alive at last follow-up, with observation times ranging from 5.2 to 16.9 years. In accordance with the low rate of re-decompensation after recompensation reported by our colleagues, none of the recompensated patients in our cohort required liver transplantation. In contrast, 6 of the 17 patients without recompensation in our cohort died and 4 required liver transplantation.

Despite these promising findings, several treatment-related aspects merit attention when implementing the concept of recompensation in AIH. Specifically, in the study by Chen, Wen, Li et al., decompensation occurred either prior to initiation of IS or despite ongoing IS, with no significant difference in the likelihood of recompensation between the two groups. In contrast, none of our patients who decompensated on IS achieved recompensation, and their mortality was higher than in those who initiated IS only after decompensation (Fig. 1). Thus, close monitoring of treatment response and strategies to maximize adherence to IS in (re-)compensated patients are pivotal to avoid development of decompensation.

Fig. 1.

Individual outcomes of patients with autoimmune hepatitis-related decompensated cirrhosis stratified by the timepoint of initiation of immunosuppressive therapy.

CBR, complete biochemical response; IS, immunosuppression.

Regarding patients initiating IS after decompensation, both our data and that of the current study suggest that shorter intervals between decompensation and treatment initiation increase the likelihood of recompensation. A similar phenomenon has also been observed in decompensated alcohol-related cirrhosis, where a shorter interval from decompensation to abstinence significantly increased the probability of recompensation.⁷

Regarding the use of CBR as a surrogate for disease control in AIH, we agree that a clear criterion would be desirable when extending the strict Baveno recompensation definition to AIH. However, although the authors demonstrate that achieving CBR increases the likelihood of resolving clinical decompensation, resolution can also occur in patients receiving IS without CBR, albeit at a lower rate. Notably, while 55% of patients on IS achieved clinical resolution of decompensating events, only 31% achieved recompensation. Furthermore, among patients with resolved decompensation, achieving CBR did not yield an independent prognostic value for predicting transplant-free survival. This raises the question of whether CBR is a reliable surrogate for defining recompensation in AIH, given that persistently elevated immunoglobulins are a common phenomenon in cirrhosis due to systemic inflammation.⁸ Similarly, while transaminases are well-established markers of inflammatory activity, their value is limited in cirrhosis, as they have been shown to correlate only poorly with the histological degree of hepatocellular inflammation in decompensated AIH cirrhosis.⁹ Along the same lines, the role of CBR as a surrogate marker may be further limited by the potential occurrence of disease flares despite an initial treatment response. Thus, histologic remission on liver biopsy (modified histologic activity index ≤3)¹⁰ may be preferable to CBR in proving true aetiological control in AIH,⁴ and could support the development of more appropriate non-invasive indicators of disease control for recompensation.

In conclusion, we congratulate Chen, Wen, Li et al. for their efforts in shedding light on recompensation in decompensated AIH. While open questions remain, such as the impact of combined aetiologies including AIH variant syndromes or superimposed steatotic liver disease, the study clearly highlights the prognostic benefit of recompensation in AIH – key insights for the upcoming Baveno VIII consensus meeting and a ray of hope for our patients.

Financial support

No dedicated funding was received.

Authors' contributions

All authors contributed either to study concept and design (BSH, LB, TR, AFS) and/or data acquisition (all authors), analysis (BSH, LB) or interpretation (all authors). BSH, LB, TR and AFS drafted the manuscript, which was critically revised by all other authors. All authors read and approved the final manuscript.

Data availability

The data that support the findings of this study are available upon reasonable request from the corresponding author.

Conflicts of interest

BSH received travel support from Falk and Ipsen. LB received travel support from Gilead and Ipsen, research grant support from Gilead and speaker honoraria from Ipsen. ST declares no conflict of interest. EH declares no conflict of interest. MM served as a speaker and/or consultant and/or advisory board member for AbbVie, Collective Acumen, Gilead, and W. L. Gore & Associates and received travel support from AbbVie and Gilead. MT has received research grants from Albireo, Alnylam, Cymabay, Falk, Gilead, Intercept, MSD, Takeda and Ultragenyx and travel grants from Abbvie, Falk, Gilead, Intercept and Jannsen. He has advised for Abbvie, Albireo, BiomX, Boehringer Ingelheim, Falk Pharma GmbH, Genfit, Gilead, Hightide, Intercept, Janssen, MSD, Novartis, Phenex, Pliant, Regulus, Siemens and Shire and has served as speaker for BMS, Falk, Gilead, Intercept, Madrigal and MSD. He is a co-inventor of patents for the medical use of norUDCA (nor-ursodeoxycholic acid/norucholic acid) filed by the Medical Universities of Graz and Vienna. TR received grant support from AbbVie, Boehringer-Ingelheim, Gilead, MSD, Philips Healthcare, Gore; speaking honoraria from AbbVie, Gilead, Gore, Intercept, Roche, MSD; consulting/advisory board fee from AbbVie, Bayer, Boehringer-Ingelheim, Gilead, Intercept, MSD, Siemens; and travel support from Boehringer-Ingelheim, Gilead and Roche. AFS received speaker honorary from Gilead, Boehringer-Ingelheim, Orphalan, Triogen, consulting/advisory board fees from Abacus Medicine, Gilead, Ipsen, Triogen, and travel support from Gilead, Boehringer-Ingelheim, Roche, MSD, and AbbVie.

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Supplementary data

The following are the Supplementary data to this article: