Introduction
Autoimmune hepatitis (AIH) is a rare, chronic liver disease characterized by chronic inflammation targeting hepatocytes with a prevalence ranging from 16 to 18 cases per 100,000 inhabitants in Europe [
1]. If left untreated, AIH can progress to end stage liver disease or acute liver failure with liver transplantation being required [
2,
3]. Immunosuppressive therapy has significantly improved the prognosis of patients with AIH [
4]. The combination of corticosteroids with azathioprine is recommended for first line treatment. Frequently, tapering of immunosuppressive therapy over time can be successfully performed without losing remission [
5,
6]. By preventing recurrent flares, disease progression can be halted in most patients, although long-term mortality still remains higher compared to the general population [
7]. In the management of AIH, biochemical remission defined by normalization of ALT, AST and immunoglobulin G (IgG) is considered a complete response to treatment [
8,
9].
Beyond biochemical remission, reported or perceived health is critical for the management of patients with AIH, and health-related quality of life (HRQL) is an integral part of the general concept of being healthful. HRQL—the determination of how a patient feels and functions—can be measured by different instruments in defined domains that include general health or disease-specific health aspects. HRQL is potentially influenced by disease activity, but also adverse effects from treatment or comorbidities. In patients with AIH, an increased prevalence of anxiety and major depressive symptoms have been observed [
10]. While an effect of these comorbidities on HRQL appears obvious, depression and anxiety are also associated with a greater degree of non-adherence to immunosuppressive therapy [
11] and thus can accelerate disease progression and the burden of disease. Adverse effects from the use of corticosteroids can also potentially impair HRQL in AIH [
12]. In a Japanese study exploring 265 patients with AIH, a negative impact of corticosteroid use on the subdomain ‘worry’—but not overall HRQL scores—was detected [
13]. Studies that explored budesonide did not find a difference for the use of budesonide over corticosteroids with regards to HRQL [
14].
Currently, there is only limited data available related to the impact of biochemical remission on HRQL in AIH. Yet, no study has focussed on correlating clinical and biochemical parameters with HRQL. Hence, the aim of this study was to analyse HRQL using a liver disease-specific tool, compare these to generic measures of quality of life and determine the effects of biochemical remission and identify surrogate markers of HRQL.
Discussion
In this study, we assessed HRQL using two validated questionnaires—the liver-specific CLDQ and the generic EQ-5D-5L—in patients with AIH. Each questionnaire is validated in German and carries several subdomains to address different aspects of a patients’ well-being. The central finding of the current analysis is that patients with a complete biochemical remission have a higher HRQL in comparison to an incomplete remission in this cohort, when using a liver disease-specific tool. While the CLDQ overall score as well as several subdomains exhibited a positive correlation with biochemical remission, no correlation with the general HRQL tool—EQ-5D-5L—was detectable. One important aspect is that the CLDQ was designed to capture liver-specific aspects of the quality of life, which are not assessed by the generic/general questionnaires [
16]. Additionally, we observed a significant correlation of several liver related blood and clinical parameters with the total value of CLDQ, but not the UI-value of EQ-5D-5L.
The CLDQ overall score was 5.31 among all AIH patients. Interestingly, this overall score was comparable to patients with compensated cirrhosis and covert hepatic encephalopathy that were assessed in the same outpatient setting [
19] and also comparable to a Japanese study that compared AIH with healthy controls [
13]. Furthermore, fatigue is a prominent symptom in chronic liver disease and occurs in a variety of aetiologies including viral hepatitis, cholestatic liver disease or non-alcoholic fatty liver disease [
20,
21]. In the current study, the employed questionnaires captured fatigue as the most relevant and burdening symptom in AIH and the CLDQ subdomain fatigue exhibited the lowest score. Similar findings were replicated in a study that employed the modified fatigue impact score (MFIS) and observed a strong impact of AIH on fatigue [
14]. A recent study highlighted that fatigue in patients with decompensated liver cirrhosis was associated with anaemia [
19]. In the present study, we did not enrol patients with decompensated cirrhosis and no correlation between haemoglobin, haematocrit or erythrocytes and HRQL was detectable (data not shown). More intriguingly, the subscale fatigue was independently affected by the status of biochemical remission. Yet, the mechanisms underlying fatigue in AIH remain poorly understood [
22], and further investigations are needed to unveil the underlying pathophysiology. Another aspect is the comparison of mental vs. physical health and a recent study in AIH reported that mental well-being is more severely impaired compared to physical well-being [
10].
The EQ-5D-5L was employed to assess general/generic HRQL and the corresponding UI-value can be used to compare it to other disease states. In the EQ-5D-5L, females reported a significantly lower UI-value, as well as a lower score in the subdomain pain/discomfort compared to males indicating that women perceive and experience HRQL impairment stronger than men. Similar findings have been reported previously in other chronic liver diseases [
21] and cirrhosis [
19] and this is likely related to a different self-perception of the body and general health [
23].
Next, we explored surrogate markers of disease activity, as well as clinical parameters and their impact on CLDQ total value and EQ-5D-5L UI-value. On univariable analyses, AST was inversely correlated with CLDQ total value. Elevated AST blood levels have been linked to a progression of disease and treatment failure [
24,
25]. Furthermore, patients exhibiting an incomplete biochemical remission had an overall worse CLDQ total value. More notably, using a multivariable approach, AST and incomplete remission were the only independent predictors of an impaired HRQL in this cohort as captured by CLDQ. This could be in parts related to disease progression and its liver-related complications. In fact, a German study previously showed that the severity of depression and anxiety are associated with concerns about disease progression in AIH, consequently leading to a lower HRQL [
10]. Furthermore, age did not significantly correlated with CLDQ total value which is in line with findings of a Polish study that did not describe an impact of age using generic HRQL tools [
14]. Interestingly, the EQ-5D-5L was more likely to detect non liver related aspects to be associated with a lower HRQL.
Although previous studies have observed a negative impact of corticosteroids on HRQL [
12], we did not observe a significant difference between patients receiving corticosteroids vs. no corticosteroids in the current analysis. This is interesting and is most likely related to differences between baseline characteristics and treatment intensity of the two cohorts. Importantly, most of the patients in the current analysis were treated with azathioprine and low dose of corticosteroids or even corticosteroid free, thus providing potential insight on these different findings. However, patients with a complete biochemical remission were lower on steroids, and mostly received an azathioprine monotherapy in comparison to patients with an incomplete remission. Therefore, a lower use of steroids in the complete remission group could likely contribute to an overall lower disease burden due to lower drug-related side effects.
We included a small cohort of 19 patients that were diagnosed with an AIH-overlap syndrome. In this subgroup, HRQL was not significantly different compared to non-overlap patients. These findings differed from observations in the larger analysis in the UK-AIH cohort, when patients with AIH and PBC or PSC overlap exhibited a lower EQ-5D-5L UI-value [
12]. These differences can be multifactorial and we have previously observed a country-specific impact between the UK and Germany when exploring HRQL in NAFLD [
23].
The current study has several limitations. Most importantly, the two HRQL tools were not specifically validated for AIH. Therefore, the cause for the differences that are captured between the liver-specific tool (CLDQ) and the generic tool (EQ-5D-5L) can only be speculated on. Nevertheless, CLDQ has been widely adopted to study HRQL in different aetiologies of chronic liver disease [
26]. In a Japanese study, EQ-5D-5L scores were significantly impaired in AIH patients and were highly associated with corticosteroid use [
12]. Importantly and as detailed above, the current analysis was performed in patients that received combined therapy with low-dose steroids. The generalizability of the current study is limited as it constitutes a single-centre analysis and thus the results have to be interpreted with caution. The findings are specific for the outpatient setting at the study centre. Also, HRQL can be impacted by country and culture-specific differences [
21] and thus it is difficult to merge data from independent study centres. Yet, one strength of the analysis is the large cohort of 116 AIH patients and the standardized use of two different HRQL questionnaires with one focussing on liver disease and one on general HRQL.
In conclusion, the current study provides evidence that a complete biochemical remission is corresponding to a higher HRQL. The current study identified surrogate markers that correlated with HRQL and can therefore help physicians identify potential HRQL aspects in their patients. However, future studies are warranted to verify these results.
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