In our study, the findings showed that compared to nonoverlapping AIH, those with AIH- PBC were at a higher risk of graft failure in the multivariate Cox models. Furthermore, upon evaluating the systems-specific causes of death, AIH-PSC were noted to have higher risks of graft infection-related deaths, whereas AIH-PBC were at a higher risk of death due to respiratory causes, ARDS, and recurrent liver disease. In general, the physiologic and the prognostic effects of AIH-overlap on AIH patients who undergo LT have been seldomly investigated, albeit a few single-center studies showed similar observations of non-difference in survival between the overlapping and non-overlapping AIH patients and a greater likelihood of disease recurrence among overlapping AIH patients (12, 13). However, both studies are lowly powered and hence were limited in their comparative abilities. When examining the pre-LT features of AIH-overlap, the prognosis is altered due to the copresence of PBC or PSC, with AIH-overlap patients featuring higher risk of morbidity and mortality (4–6, 14). The culprit for these differences in outcomes may be related to the substandard response to steroid therapy demonstrated by patients with AIH-overlap, whereby the induction of steroid therapy is often not sufficiently effective to control the disease flare prior to LT (15). For example, a number of studies showed that a combined therapy targeting both the PBC and AIH was more effective in attaining remission than monotherapy with steroids (15, 16). These types of differences presume that the post-LT prognosis may be altered by similar mechanisms of overlap affecting the host systems and the graft during and following LT.
In addition, prior studies have shown escalated rates of disease recurrence following LT among patients with autoimmune liver diseases (AIH, PBC, and PSC) (17–23), with recurrence rates of 16–43%, 10–50%, and about 20% respectively. The findings of a 6-fold increase in the rates of deaths due to disease recurrence suggests the concurrent presence of PBC as a comorbid diagnosis likely exacerbates the risk of recurrence, via mechanisms that are currently poorly defined. However, it is probable that the refractoriness of PBC-AIH overlap toward steroid therapy following LT may increase the recurrence risks (24–25). Furthermore, the histological changes may be pronounceably increased in the setting of simultaneous AIH- and PBC-related disease activity, which may escalate the risk of AIH-induced graft necroinflammation and disease recurrence (26). Similarly, PSC is thought to recur at an escalated rate (27, 28), resulting in biliary strictures and graft malfunction (27, 28). Furthermore, PSC are at a higher risk of steroid-resistant graft rejection (29, 30), which can debilitate the viability of the graft and result in graft failure. Combined, these features can exacerbate the rates of graft demise among AIH-PSC overlapping patients, as PSC and its phenotypic manifestations may exert these PSC-specific risks and curtail the survival of the graft. With steroid-resistant PSC, a stronger immunosuppressant regimen may be needed to achieve a therapeutic threshold; however, a downside of this would be the higher likelihood of infectious complications including graft infection observed among these patients. With disease recurrence, the stenotic trees in the biliary tract may serve as a nidus for infection in immunocompromised AIH-PSC patients. Furthermore, it is probable the coexisting bowel disease among AIH-PSC patients may serve as entry points for infectious pathogens. Currently, it is unclear why AIH-PBC patients experience higher rates of respiratory failure and ARDS-related deaths following LT. It can be presumed that while AIH-PBC patients necessitate higher immunosuppressant doses to maintain a rejection-free threshold, the AIH-PBC patients do not typically exhibit an infectious focus in the graft given the less frequent biliary involvement; hence, their manifestations of infective activity may include the commonly observed complications such as pneumonia and pneumonia-related ARDS, largely due to the immunocompromised state (31). Nonetheless, to identify the exact underlying causes, further studies are required.
Implications & limitations
Clinically, the post-LT care of AIH patients with PSC or PBC-overlap should be characterized by a general concern for the adverse outcomes observed in this study. For PSC-AIH patients, the graft function should be routinely monitored per the standard of care, but with greater clinical caution given the higher likelihood of graft infection and failure. Symptoms of infection should warrant a comprehensive workup that not only include the localized infections of native organs, but also the infection of the graft. PBC-overlap patients should be warranted to undergo routine liver function checks during the immediate to subacute post-LT period to ensure the laboratory markers of PBC-disease activity is not rising (ie alkaline phosphatase).
In the future, high-powered studies that concern the effects of histological overlap between AIH and PBC or AIH and PSC should be conducted. Currently, given the limitations of the UNOS database, we used the registry diagnoses to indicate the clinical overlap of AIH and autoimmune liver conditions. While this method precludes the disease-specific histological features from defining the different subtypes of AIH within the overlap spectrum (either AIH-PSC or AIH-PBC), we ensured the clinical diagnoses of AIH-overlap were present prior to comparing the prognostic risks. Nonetheless, the clinical diagnoses cannot ascertain the histological characteristics and hence requires further studies for validation purposes.