EASL Clinical Practice Guidelines

PBC–AIH overlap syndrome

Primary biliary cirrhosis (PBC) and autoimmune hepatitis (AIH) are classically viewed as distinct liver diseases. However, patients presenting with clinical, biochemical, serological, and/or histological features reminiscent of both diseases, either simultaneously or consecutively have been repeatedly recognized. The ill-defined term “overlap syndrome” is used to describe these settings [[57], [58], [59], [60]]. The pathogenesis of PBC–AIH overlap syndrome is debated and it remains unclear whether this syndrome forms a distinct entity or a variant of PBC or AIH. Different pathophysiological mechanisms have been discussed: (i) a pure coincidence of two independent autoimmune diseases; (ii) a different genetic background which determines the clinical, biochemical and histological appearance of one autoimmune disease entity; and (iii) a representation of the middle of a continuous spectrum of two autoimmune diseases [[59], [60]].

Diagnosis

Standardization of diagnostic criteria for PBC–AIH overlap syndrome has not been achieved so far, and “overlap syndrome" is a much overused descriptive term in hepatology [61]. Diagnosis of PBC and AIH is based on the combination of biochemical, serological and histological features. However, no individual test shows absolute specificity and much depends on the relative weighting of individual diagnostic criteria, and the cut-off levels of continuous variables considered representative for one or another condition [59]. The 1999 scoring system, established by the International Autoimmune Hepatitis Group (IAIHG) for research purposes, comprises characteristic features of AIH and provides support for diagnosing AIH [62]. However, applicability of this scoring system remains questionable in this specific setting since a score of “definite" AIH can be only observed in the very few patients with characteristic overlap syndrome whereas nearly 20% of PBC subjects will be classified with “probable" AIH overlap [[61], [63], [64]]. The simplified diagnostic score recently proposed by the IAIHG has not been validated yet in patients with suspected PBC–AIH overlap syndrome [65]. To differentiate PBC from PBC–AIH overlap syndrome, another diagnostic score has been established but the usefulness of this rather complex score needs confirmation by cross-evaluation prior to introduction to the clinic [66]. Because of the limited applicability of the different diagnostic scores, another approach based on the major characteristics of PBC and AIH has been proposed and requires the presence of at least 2 of the 3 accepted criteria of both diseases for diagnosing PBC–AIH overlap syndrome (Table 4) [57] whereby histologic evidence of moderate to severe lymphocytic piecemeal necrosis (interface hepatitis) is mandatory.

Table 4
Diagnostic criteria of PBC–AIH overlap syndrome.

PBC criteria
1. AP >2× ULN or γGT >5× ULN
2. AMA ⩾1:40
3. Liver biopsy specimen showing florid bile duct lesions
AIH criteria
1. ALT >5× ULN
2. IgG >2× ULN or a positive test for anti-smooth muscle antibodies (ASMA)
3. Liver biopsy showing moderate or severe periportal or periseptal lymphocytic piecemeal necrosis

In addition to cases with simultaneous characteristics of PBC and AIH, which is the most frequent mode of presentation, transitions from PBC to AIH or vice-versa have been described and termed “sequential syndromes" or consecutive forms [67]. Occurrence of superimposed AIH cannot be predicted from baseline characteristics and initial response to UDCA therapy in PBC patients [67]. Lastly, overlap of AMA-negative PBC with AIH has also been reported [57].
Precise prevalence of PBC–AIH overlap syndrome is unknown but approximately 10% of adults with AIH or PBC may belong in this overlap category [[67], [68], [69]]. Patients with PBC–AIH overlap syndrome might have a more severe disease with worse clinical outcomes compared to patients with PBC alone [70]. This emphasizes the notion that overlap syndrome should always be considered once PBC has been diagnosed [68].

Treatment

The low prevalence of PBC–AIH overlap syndrome has made controlled therapeutic trials impossible in these patients. Thus, therapeutic recommendations rely on the experience in the treatment of either PBC or AIH, and on retrospective, non-randomized studies. Whether PBC–AIH overlap syndrome requires immunosuppressive therapy in addition to UDCA is a debated issue. Under UDCA therapy, biochemical response at 24 months and survival in one cohort of 12 strictly defined PBC–AIH overlap syndrome patients were similar to 159 patients with “pure” PBC [71]. However, adjunction of immunosuppressive therapy was required in most patients of other cohorts to obtain a complete biochemical response [[57], [58]]. In the largest long-term follow-up study, 17 strictly defined patients [64] received UDCA alone or UDCA in combination with immunosuppressors and were followed for 7.5 years. In the 11 patients treated with UDCA alone, biochemical response in terms of AIH features (ALT <2× ULN and IgG <16 g/L) was observed in only 3 patients whereas the 8 others were non-responders with increased fibrosis in 4. Overall, fibrosis progression in non-cirrhotic patients occurred more frequently under UDCA monotherapy (4/8) than under combined therapy (0/6) (p = 0.04). These results strongly suggest that combined therapy (UDCA and corticosteroids) is the best therapeutic option in most patients with strictly defined simultaneous PBC–AIH overlap syndrome. An alternative approach is to start with UDCA alone and to add corticosteroids if UDCA therapy does not induce an adequate biochemical response in an appropriate time span (e.g., 3 months) [69]. Prednisone has been used at an initial dose of 0.5 mg/kg/d and should be progressively tapered once ALT levels show a response [64]. Budesonide is a promising treatment option for patients with AIH and has also been used with success in some patients with PBC–AIH overlap syndrome [72]. The role of other immunosuppressants, e.g., azathioprine, in the long-term management of these patients is unclear, but its successful use in AIH makes azathioprine an attractive alternative to corticosteroids for long-term immunosuppressive therapy. Interestingly, by comparison with typical AIH, it has been suggested that doses of immunosuppressants could be lower and rate of successful withdrawal higher [64]. For corticosteroid-resistant patients, a beneficial effect of other immunosuppressants such as cyclosporine A has been reported [73].

In UDCA-treated PBC patients developing AIH (“sequential” overlap), use of immunosuppressive treatment is mandatory [67].

Recommendations

  1. Standardization of diagnostic criteria for PBC–AIH overlap syndrome has not been achieved. Strict diagnostic criteria as shown in Table 4 provide a useful diagnostic template (III/C2).
  2. PBC–AIH overlap syndrome should always be considered once PBC has been diagnosed because of potential implications for therapy (III/C2).
  3. Combined therapy with UDCA and corticosteroids is the recommended therapeutic option in patients with PBC–AIH overlap syndrome (III/C2). An alternative approach is to start with UDCA only and to add corticosteroids if UDCA therapy has not induced an adequate biochemical response in an appropriate time span (3 months) (III/C2). Steroid sparing agents should be considered in patients requiring long-term immunosuppression (III/C2).