Overlap syndrome
Diagnostic features
AIH > PBC
Serum IgG level above ULN [61]
AIH = PBC
2 of 3 features of AIH [35]:
Serum ALT ≥5-fold ULN
IgG level ≥2-fold ULN or presence of SMA
Moderate-severe interface hepatitis
2 of 3 features of PBC [35]:
Serum AP level ≥2-fold ULN or GGT level ≥5-fold ULN
AMA p resent
Florid duct lesions (destructive cholangitis)
Sensitivity, 92 %; specificity, 97 % (against clinical judgment) [62]
PBC > AIH
Predominant features of PBC [41]
Mild or transient inflammatory features of AIH [41]
Outside Paris criteria [63]
AIH − PSC
Features of autoimmune hepatitis [16]
AMA absent [16]
Bile duct injury or loss by histological examination [66]
AIH − Cholestasis
The “Paris criteria” provide a uniform diagnostic approach, and they define an overlap syndrome in which the features of autoimmune hepatitis and PBC are equally weighted [35, 49, 62] (Table 18.1). Three hallmark features of autoimmune hepatitis (serum ALT level ≥5 times the upper limit of the normal range [ULN], IgG level ≥twice ULN or positive test for SMA, and histological findings of moderate to severe interface hepatitis) must be present with three hallmark features of PBC (serum alkaline phosphatase level ≥twice ULN or GGT ≥5 times ULN, positive test for AMA, and histological evidence of florid duct lesions) [35, 49]. The sensitivity and specificity of the “Paris criteria” for the overlap syndrome of autoimmune hepatitis and PBC are 92 % and 97 %, respectively, using clinical judgment as the gold standard for diagnosis [62]. EASL has supported these diagnostic recommendations with the stipulation that interface hepatitis must be present in all patients with this overlap syndrome [11, 49].
Not captured by the “Paris criteria” are patients with predominant features of autoimmune hepatitis who have AMA and histological findings of bile duct injury or loss but less pronounced manifestations of cholestasis (serum alkaline phosphatase level <twice ULN and GGT level <5-fold ULN) [16] (Table 18.1). Similarly, patients with predominant features of PBC who have less-pronounced manifestations of liver inflammation (serum ALT level <5-fold ULN and IgG level <twice ULN) can be overlooked [41, 63]. Clinical judgment remains the gold standard for the diagnosis of the overlap syndromes, and patients with mixed features cannot be excluded from the diagnosis by arbitrarily set criteria [24, 26]. In one study, the “Paris criteria” identified the overlap syndrome in only 1 % of patients with PBC, whereas criteria that included patients with less-pronounced mixed features and responsiveness to corticosteroids increased the yield almost threefold [63].
Autoimmune Hepatitis and PSC
The diagnosis of an overlap syndrome between autoimmune hepatitis and PSC requires predominant features of autoimmune hepatitis, absence of AMA, and cholangiographic evidence of focal bile duct strictures and dilations [24–26, 57] (Table 18.1). Concurrent ulcerative colitis is commonly present [16, 56]; serum alkaline phosphatase and GGT levels are usually increased [64, 65]; and histological examination frequently discloses bile duct injury or loss [66]. Children with autoimmune hepatitis and cholangiographic changes of bile duct injury have been designated as having “autoimmune sclerosing cholangitis” [65, 67]. Female gender (55–74 %) and concurrent inflammatory bowel disease (44–75 %) are common in children with the overlap syndrome between autoimmune hepatitis and PSC [68], but these features are not requisites for the diagnosis [65]. Patients with predominant features of PSC and secondary findings of autoimmune hepatitis should be distinguished from those mainly with features of autoimmune hepatitis as they may respond differently to treatment [36, 42, 56].
Autoimmune Hepatitis and Cholestasis
Patients with predominant features of autoimmune hepatitis, elevated serum alkaline phosphatase and GGT levels, histological findings of bile duct injury or loss , absence of AMA, and normal cholangiograms have a cholestatic syndrome which is unclassifiable [24, 26]. These patients have been designated as having “autoimmune cholangitis” [69–77], but they probably constitute an overlap syndrome with AMA-negative PBC or small duct PSC [77–82] (Table 18.1). This category is still poorly defined, and patients with unclassified cholestasis should be separated from the overlap syndromes with mixed features compatible with classical diseases [24].
PBC and PSC
Patients with classical laboratory and histological features of PBC may have cholangiographic changes of PSC, and these mixed features have justified the designation of an overlap syndrome between PBC and PSC [83–85] (Table 18.1). Eight patients with the overlap syndrome of PSC and PBC have been reported in 6 clinical studies [83–88]. The frequency of this syndrome is estimated to be 0.7 % in a cohort of 261 patients with autoimmune liver disease followed for as long as 20 years [84]. The inflammatory manifestations of autoimmune hepatitis are not disease-specific [4, 7], whereas the serological (AMA) and histological (destructive cholangitis) features of PBC [9, 89] and the cholangiographic changes of PSC (focal biliary strictures and dilations) [10] are disease-specific. The low frequency of concurrent disease-specific findings for PBC and PSC suggests that these overlap syndromes are mainly inflammatory variants of PBC and PSC rather than two superimposed diseases [24].
Frequency
The frequency of the overlap syndromes varies in accordance with the diagnostic criteria that are applied and the patient cohort that is investigated [24]. The frequency of patients with predominantly autoimmune hepatitis, AMA, and histological features of bile duct injury or loss is 7 % [16]. The frequency of patients with predominantly PBC and features of autoimmune hepatitis is 3–13 % [16, 35, 63, 90, 91]. Cholangiographic changes of PSC occur in 2–11 % of patients with classical autoimmune hepatitis [16, 56, 58, 59, 92], and findings compatible with autoimmune hepatitis are present in 2–33 % of patients with classical PSC [3, 17, 40, 42, 51]. The wide range of occurrence and the occasionally high reported frequencies of this overlap syndrome probably reflect the frequency that nonspecific inflammatory changes reminiscent of autoimmune hepatitis can occur in PSC. Autoimmune hepatitis has unclassifiable cholestatic changes in 5–11 % [16, 26, 82]. The overall frequency of the overlap syndromes in cohorts of patients with autoimmune liver disease is estimated to be 14–20 % [16, 25, 40, 45, 90, 93].
Pathogenic Possibilities
The overlap syndromes have not been validated as distinct pathological entities, and they may simply be clinical descriptors that accommodate variant presentations of the classical diseases [18, 49]. The serum levels of AST, ALT, and IgG that are truly incompatible with the diagnosis of PBC, and the serum levels of alkaline phosphatase and GGT that are truly incompatible with the diagnosis of autoimmune hepatitis are uncertain [14, 94]. Similarly, the degrees of interface hepatitis and bile duct injury that confidently differentiate autoimmune hepatitis from PBC or PSC are unclear [76, 95–97]. The boundary between hepatitic PBC or PSC and cholestatic autoimmune hepatitis is poorly drawn [14, 37], and the overlap syndromes may constitute a diagnostic category that accommodates these uncertainties [24, 26].
The overlap syndromes could be transitional stages in the evolution of the classical disease [24, 26]. Early stages of PBC or PSC may lack disease-specific laboratory and histological findings [92], and the histological findings of early stage PBC and PSC may resemble those of autoimmune hepatitis [66]. Features of autoimmune hepatitis may coexist with features of PBC and small duct PSC during the evolution of each cholestatic disease [74, 76], and these transitions may explain the reported sequences of autoimmune hepatitis transitioning to PBC [55, 98], PBC transitioning to autoimmune hepatitis [53, 54, 98], and PSC emerging in autoimmune hepatitis [52]. Alternatively, each classical autoimmune liver disease may have shared pathogenic mechanisms that can produce similar manifestations or unmask neo-antigens that redirect the autoreactive response to secondary antigenic targets that are less typical of the primary disease [99, 100]. In this context, the overlap syndromes could be part of a continuous spectrum of immune-mediated injury involving liver and non-liver tissues [101]. The emergence of features of autoimmune hepatitis in 2.5 % of patients with PBC and the development of PBC in 1.2 % of patients with autoimmune hepatitis after a mean observation interval of 6.5 years (range, 1–14 years) support this hypothesis [98].
The overlap syndromes could be two autoimmune liver diseases that occur simultaneously in the same individual [18, 24]. HLA DRB1*04 is a genetic susceptibility factor for autoimmune hepatitis, and it occurs more frequently in patients with autoimmune hepatitis or PBC than in patients with PSC [99]. In contrast, patients with autoimmune hepatitis or PSC have a higher frequency of HLA DRB1*03 than patients with PBC [99]. These findings suggest that genetic factors may be shared and contribute to the clustering of certain autoimmune liver diseases. Furthermore, the concurrence of certain highly specific features of one disease (destructive cholangitis or focal biliary strictures and dilations) in another disease is difficult to accept as within a single diagnostic boundary [18, 95]. Certain protective genetic factors might also contribute to the rarity of an overlap syndrome between PBC and PSC [99].
The overlap syndromes could be independent pathological entities with their own distinctive pathogenic mechanisms and clinical phenotype [24]. This highly theoretical possibility is based on the presumption that diverse antigens can trigger autoreactive responses in genetically predisposed individuals that have targets within the liver and biliary system [102–104]. Patients with autoimmune hepatitis and mixed connective tissue disease are characterized by a high proportion of T cells that are positive for interferon-gamma (IFN-γ) and by a severe impairment of immune suppressor function [105]. These findings suggest that patients with overlap syndromes have immune reactivity that is poorly regulated and shewed along a cytokine pathway that favors the emergence of tissue-infiltrating cytotoxic T cells [105]. This mechanism may promote the emergence of multiple immune-mediated diseases or define a separate pathological entity. The possibility of a separate disease entity characterized by its own antigenic trigger, genetic predisposition, immunological defects, clinical presentation, and outcome are justifications for the continued separation and study of these diseases.
Management Strategies and Results
The overlap syndromes do not have therapies that have been rigorously evaluated by clinical trial [22, 24] (Fig. 18.1). The treatment regimens that have been promulgated have been based on weak clinical evidence [9–11], and management strategies must be individualized and directed by the predominant manifestations of the disease [38, 49]. The degree of cholestasis as reflected in the laboratory findings (serum alkaline phosphatase and GGT levels), histological features (destructive cholangitis and bile duct loss), and radiographic images (focal biliary strictures and dilations) is probably the principal factor associated with outcome [16, 35, 56, 94, 106].
Fig. 18.1
Treatment algorithm for the overlap syndromes. All treatments are empiric and directed by the predominant features of the mixed syndrome. Patients with predominant features of autoimmune hepatitis (AIH) and secondary features of primary biliary cholangitis (PBC) that are outside the Paris criteria (AIH > PBC) are characterized by antimitochondrial antibodies (AMA) and serum alkaline phosphatase (AP) levels less than (<) twofold the upper limit of the normal range (ULN). These patients are frequently corticosteroid responsive, especially if serum immunoglobulin G (IgG) levels are 1.3-fold ULN or greater, and they can be managed with conventional corticosteroid regimens with or without (±) azathioprine. Patients that satisfy the Paris criteria have equally weighted features of AIH and PBC (AIH = PBC), and therapy with low-dose ursodeoxycholic acid (UDCA) in combination with corticosteroids has been recommended. Patients with predominant features of PBC and mild or transient inflammatory changes reminiscent of AIH (PBC > AIH) can be treated with UDCA alone or in combination with corticosteroids. Patients with AIH and cholangiographic features of focal biliary strictures and dilations (AIH-PSC) warrant a treatment trial with UDCA in combination with corticosteroids. Patients with AIH and a cholestatic syndrome that could be associated with AMA-negative PBC or small duct PSC are characterized by the absence of AMA and normal endoscopic retrograde cholangiography (ERC) or magnetic resonance cholangiography (MRC). These patients are also candidates for combination therapy with UDCA and corticosteroids. Salvage therapies with calcineurin inhibitors and mycophenolate mofetil have not been rigorously evaluated, and the emergence of features of liver failure warrant liver transplantation
Autoimmune Hepatitis-PBC Overlap
Patients with predominant features of autoimmune hepatitis and secondary features of PBC manifested mainly by AMA, serum alkaline phosphatase level <twice ULN, and histological findings of isolated bile duct injury or loss respond as well to corticosteroid therapy as patients with classical autoimmune hepatitis [16, 38] (Fig. 18.1). Eighty-one percent improve to normal or near-normal liver tests and liver tissue with conventional corticosteroid treatment, and the frequency of treatment failure is similar to that of treated patients with classical autoimmune hepatitis (14 % versus 9 %) [16]. The frequency of improvement during corticosteroid therapy is 72–77 % in patients with serum IgG levels ≥1.3-fold ULN [61], definite autoimmune hepatitis by the simplified scoring system of the IAIHG [61], or histological activity scores that exceed activity scores for cholangitis [60]. These experiences indicate that the degree of inflammatory activity typical of autoimmune hepatitis is a key consideration when deciding to treat with corticosteroids in patients with PBC. Prednisone in combination with azathioprine is the preferred treatment of classical autoimmune hepatitis [107], and it is the regimen that can be applied to those patients with strong features of autoimmune hepatitis and weak manifestations of PBC (Table 18.2).
Table 18.2
Management strategies for overlap syndromes
Overlap syndrome | Management strategy |
|---|---|
AIH > PBC (outside Paris criteria) | |
Induction phase: prednisone or prednisolone, 30 mg daily × 1 week, 20 mg daily × 1 week, 15 mg daily × 2 weeks, and azathioprine, 50 mg daily | |
Maintenance phase: prednisone or prednisolone, 10 mg daily, and azathioprine, 50 mg daily. Treatment until resolution of laboratory tests and liver tissue | |
European preference is to administer prednisolone (up to 1 mg/kg daily) in combination with azathioprine (1–2 mg/kg daily) with gradual reduction in prednisolone dose over 2–3 months to 10 mg daily [8] | |
AIH = PBC (Paris criteria satisfied) | |
Salvage therapies (limited experience): | |
Cyclosporine, 5–6 mg/kg daily; tacrolimus, 4–8 mg daily; mycophenolate mofetil, 2 g daily [108] | |
Liver transplantation [122] | |
PBC > AIH (outside Paris criteria) | |
AIH − PSC | |
AIH − Cholestasis | Combination therapy (preferred): UDCA, 13–15 mg daily, prednisone or prednisolone, 10 mg daily, and azathioprine, 50 mg daily [32] |
Patients that satisfy the “Paris criteria” with equally weighted features of autoimmune hepatitis and PBC uniformly experience statistically significant improvements in serum alkaline phosphatase, GGT, and ALT levels when treated with corticosteroids in combination with UDCA, and the frequencies of response have been superior to those of patients treated with UDCA or corticosteroids alone [35] (Fig. 18.1). These findings have been supported by a retrospective analysis involving 88 patients who satisfied the “Paris criteria” from seven centers in five countries [108]. Therapy with UDCA (13–15 mg/kg daily) was ineffective in 37 %, and the lack of response was associated with severe interface hepatitis on histological examination. In contrast, 73 % of patients who were previously untreated or unresponsive to UDCA improved on combination therapy with UDCA and prednisone (30–60 mg daily) alone or in combination with azathioprine (50–150 mg daily) [108] (Table 18.2). Combination therapy has also been effective in another study involving eight patients who had initially failed monotherapy with UDCA. Laboratory tests improved in six patients and fibrosis did not progress during a mean observation interval of 7.5 years [43]. The combination regimen of corticosteroids and UDCA has been endorsed by EASL for the overlap syndrome of autoimmune hepatitis and PBC, and this recommendation has been based mainly on experiences with patients satisfying the Paris criteria [11, 49].
Patients with PBC who were identified retrospectively as having features of autoimmune hepatitis have also responded to UDCA alone (13–15 mg/kg daily), and the frequency of response has been similar to that of patients without these features [41] (Fig. 18.1). Furthermore, the manifestations of autoimmune hepatitis have been transient in some placebo-treated individuals [41]. The autoimmune hepatitis component in these patients may have constituted a self-limited inflammatory response rather than a sustained and important driver of disease activity . UDCA (13–15 mg/kg daily) is a treatment option in those patients with predominant features of PBC and mild inflammatory or transient changes reminiscent of autoimmune hepatitis [41] (Table 18.2). In these patients, the severity of interface hepatitis on histological examination may be the critical determinant of when to add corticosteroids to the regimen with UDCA [108].
Salvage therapies with cyclosporine (5–6 mg/kg daily), tacrolimus (4–8 mg daily), mycophenolate mofetil (2 g daily) have been administered to 13 patients who failed to improve during initial therapy (Table 18.2), and 54 % responded by attaining complete or partial responses, including 3 of 5 patients treated with cyclosporine, one patient treated with cyclosporine and mycophenolate mofetil, 3 of 4 patients treated with tacrolimus , and three patients treated with mycophenolate mofetil [108]. Nonsteroidal immunosuppressive medications are considerations in the refractory patient, recognizing the empiric and limited nature of this rescue strategy.
Budesonide (3 mg thrice daily) has been used successfully in combination with UDCA in some patients with classical PBC [109, 110], but its use in the overlap syndrome between PBC and autoimmune hepatitis has been sparse and disappointing [48] (Table 18.2). Corticosteroid-induced side effects are possible in patients with cirrhosis probably because of decreased first-pass hepatic clearance of the drug and increased systemic bio-availability [48, 109, 111]. Therapy with budesonide has not been formally endorsed in the management of the overlap syndromes.
Autoimmune Hepatitis-PSC Overlap
Corticosteroids alone [16, 36, 51, 112] or in combination with UDCA [42, 47] have been the principal treatments of the overlap syndrome between autoimmune hepatitis and PSC [49]. Conventional corticosteroid regimens have induced laboratory and histological improvement in 20–100 % of patients, albeit the number of individuals in these reports has ranged from 5 to 16 [16, 36, 46, 51, 56, 112] (Table 18.2). Corticosteroid therapy has also had uncertain effects on survival. Death from liver failure or requirement for liver transplantation has occurred more frequently in patients with overlapping features of autoimmune hepatitis and PSC than in similarly treated patients with classical autoimmune hepatitis (33 % versus 8 %) [16]. Survival has also been lower in patients treated mainly with corticosteroids than in patients with classical autoimmune hepatitis (hazard ratio, 2.08) and patients with autoimmune hepatitis and PBC (hazard ratio, 2.14) [46]. The principal factors contributing to the variable corticosteroid responses are unclear, but they may relate to the degree of cholestasis and the intensity of the histological features of interface hepatitis. Patients with PSC who have responded to corticosteroid therapy have been characterized by higher serum levels of ALT and bilirubin and lower serum levels of alkaline phosphatase than nonresponders [112].
Prednisolone (or prednisone) in combination with UDCA has been the treatment recommended in the guidelines developed by EASL and AASLD [10, 11, 49], and currently this combination regimen is the preferred management strategy (Fig. 18.1). Prednisolone (initial dose, 0.5 mg/kg daily, tapered to 10–15 mg daily) in conjunction with azathioprine (50–75 mg daily) and UDCA (15–20 mg/kg daily) improved laboratory tests and survival in seven patients compared to 34 patients with classical PSC who were treated with UDCA alone [42, 49] (Table 18.2). Corticosteroid regimens that commonly included UDCA also decreased laboratory abnormalities in 23 of 27 children with autoimmune hepatitis and autoimmune sclerosing cholangitis (83 %) and improved histological findings in 17 (63 %) [49, 65, 113].
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