Editorial: Autoimmune Hepatitis—Could It Be as Easy as Vitamin D?

Abstract

Despite increasing knowledge regarding pathogenesis and risk factors in autoimmune hepatitis (AIH), there is still significant morbidity and mortality associated with both the disease and its treatments.

Here, Kilani et al. [1] examine the impact of vitamin D levels on AIH outcomes, stratifying by deficiency, insufficiency and normal levels. This builds on previous work showing links between vitamin D deficiency and worse outcomes in AIH (treatment non-response, fibrosis progression, liver-related mortality and liver transplantation [LT] [2] and chronic liver disease [CLD]) [3, 4]. Crucially, there is also data in AIH to suggest that vitamin D may ameliorate disease progression and improve outcomes [5-7].

The powerful headline findings are that vitamin D deficient AIH patients have significantly increased all-cause mortality/hospitalizations, critical care admissions, decompensated cirrhosis, acute liver failure and LT at 1 year, as compared to those with normal levels (n = 1288 both groups). Those with vitamin D insufficiency had increased all-cause mortality/hospitalizations but no significant differences in liver-related outcomes.

Utilising the TriNetX research network for propensity score matching (PSM) enabled inclusion of 118 million patients with data about demographics, healthcare utilization and outcomes and adjustment for potential confounding factors (age, race, socio-economic factors, immunosuppressive (IS) therapy, comorbidities and other CLDs) [8]. However, while 39,426 patients were identified, only 7043 had documented vitamin D testing and treatment and a further 5401 were lost to keep similarity between records. The reason for exclusion depending on IS therapy is unclear. We, therefore, immediately introduce the risk of population bias. This, combined with the retrospective nature of the study, necessitates caution with interpretation of results.

Key limitations are the single vitamin D measurement performed throughout the analysis, patient inclusion only from the time of measurement and a short follow-up period of 1 year. We cannot, therefore, understand the dynamics of identified relationships.

The laboratory parameter findings are less striking than hard outcomes. By 1 year, only AST and bilirubin were statistically higher in vitamin D-deficient patients with no significant differences for insufficiency patients. We lack data on disease duration, IS changes during follow-up and are unable to assess disease activity (IgG levels unavailable).

The subgroup analyses about vitamin D replacement showed only that deficient patients who didn't receive replacement had increased all-cause mortality/ICU admissions. It is unclear whether patients were on replacement at time of vitamin D measurement (i.e. replacement was insufficient) or if treatment was commenced when low levels were found.

We are still to understand whether the relationship between vitamin D and AIH (and CLD more broadly) is cause, effect or simply association. Research has shown its immunomodulatory effects including regulatory T-cell promotion, genetic influences on disease susceptibility and broader anti-inflammatory and anti-fibrotic properties [5, 6, 9, 10]. Despite the study limitations, Kilani et al. [1] clearly demonstrate the need for prospective assessment of vitamin D replacement in AIH patients at time of diagnosis with longitudinal follow-up. We face the eternal challenge of rare disease research but existing international collaborative research networks make such a study a real possibility. If vitamin D, an easily modifiable risk factor, is found to improve outcomes in AIH it would be an extremely attractive option and easily incorporated into clinical care.