Autoimmune hepatitis overlap syndrome: Clinical presentation, treatment response, and disease evolution: Tertiary centre experience

First-Degree Living-Related Donor Liver Transplantation in Autoimmune Liver Diseases.

Long-term outcome in PSC/AIH “overlap syndrome”: Does immunosuppression also treat the PSC component?

See article on page 95 Autoimmune diseases aggregate in the one patient and/or family members: such clustering was an early defining marker for an autoimmune disease. 1 Examples are provided by the clustering of autoimmune thyroiditis with gastritis and insulitis (diabetes), Sjögren's disease with rheumatoid arthritis, primary biliary cirrhosis (PBC) with the CREST syndrome, and autoimmune hepatitis (AIH) with haemolytic blood diseases, thyroiditis, ulcerative colitis and others. 2 These clustered diseases are independent entities, but there is an underlying pathogenetic determinant in common: this is a defect in the establishment and maintenance of self tolerance, that is, autoimmunity and/or an aberrant inflammatory response. The independent existence within a cluster of two or even more autoimmune or inflammatory diseases poses less of a problem than when there is coexpression of two usually distinct disease entities within a single organ, in which case the term 'overlap' is used. One early example was the overlap of Hashimoto's thyroiditis and thyrotoxicosis, dubbed 'Hashitoxicosis'. In the case of the liver, several such coexistences or overlaps are recognized, and there is much uncertainty as to how they should be defined, named and classified. As background, Table 1 summarizes features of the known or suspected autoimmune diseases of the liver. Historically, in 1969, there was a viewpoint that chronic active hepatitis (the predecessor of autoimmune hepatitis of today) and PBC could be linked in the unified concept of autoimmune liver disease. 4 An early study revealed that in 11% of cases of chronic active hepatitis (CAH) there was a positive test for antimitochondrial antibody (AMA) together with clinical and histological features of both CAH and PBC, 5 and MacSween, in a personal experience covering both diseases, noted that histopathologIcal differentiation was difficult in some 15% of cases. 6 The concept of 'overlap' or 'mixed form' disease, with features of both CAH and PBC, was formally introduced in 1977 by Klöppel et al.7 In 1980, the CAH–PBC overlap syndrome was given a serological basis, together with yet another descriptive term of chronic cholestatic hepatitis by Berg et al. who reported 17 cases of which all were positive for auto-antibodies usually associated with CAH, and also for the AMA typical of PBC, together with a new antimitochondrial reactant designated M4. 8 In 1992, Davis et al. reported on the CAH–PBC overlap syndrome, citing 11 cases that were clinically typical, although not studied for the auto-antibodies characteristic of AIH: their cases were seropositive for anti-M2 but an anti-M4 type of reactivity was not demonstrable. The report of the International Autoimmune Hepatitis Group (IAIHG), 10 convened in Brighton in 1992 to generate diagnostic criteria for AIH, stated that the overlap of AIH and PBC was well recognized, but such cases comprised only a 'small proportion' of the total case-load in most centres and, hence, elected to defer preparation of diagnostic criteria. Intrafamilial occurrence of single or multiple autoimmune diseases is well recognized. Among the liver diseases, this applies more to PBC 11 than to AIH despite the weaker human leucocyte antigen (HLA) associations in PBC than AIH. Hence, it is surprising that reports are so scarce on the intrafamilial overlap of AIH with PBC. There is one published example, that of two elderly sisters of whom one had PBC and the other had AIH with concurrent myxoedema, with various tissue auto-antibodies being demonstrable among the relatives. 12 The perceived frequency of overlap may well depend on the standpoint of the observer, whether from a primary interest in AIH or PBC. From an AIH standpoint, Kenny et al. described 187 Mayo Clinic patients with severe, chronic, active (presumably autoimmune) hepatitis among whom they identified 37 (20%) with a positive test for AMA. 13 These 37 patients also had higher serum levels of alkaline phosphatase (ALP) and an increased frequency in liver biopsies of stainable hepatic copper (features suggestive of PBC), but 91% of the 37 cases could be allocated to a CAH category; only four (2.1%) of the 37 had titres of AMA > 1/40, and only two (1.1%) had histological features typical of PBC. From a PBC standpoint, Chazouillères et al. assessed clinical features and response to therapy in 12 patients (10 females, two males, median age 50 years), selected from 130 consecutive patients with a primary diagnosis of PBC, and for whom diagnostic criteria for both diseases were fulfilled. 14 For 11, there were histological features of both diseases at the time of clinical presentation and, for one, an initial presentation of 'pure' PBC was followed by a typical flare of AIH. The authors concluded that the frequency of the AIH–PBC overlap syndrome among patients with PBC was 9%, there was usually a coexistence ab initio of both diseases, and that treatment should be directed to both diseases (i.e. a combination of ursodeoxycholic acid (UDCA) and a corticosteroid drug). In a further Mayo Clinic study, Czaja analysed overlap or 'variant' syndromes based on 223 patients with primary diagnoses of AIH (162), PBC (37) or primary sclerosing cholangitis (PSC; 26). 15 Of the 162 cases with AIH, there were eight (5%) with coexisting PBC as judged simply by a positive test for AMA, and of 37 with PBC there were seven (19%) with coexisting AIH as judged by the IAIHG scoring system. 10 Detailed histological or immunoserological comparisons for overlap cases in the various groups were not given in any of the studies cited above. The second report from the IAIHG, prepared in 1999, discussed the overlap of AIH with various cholestatic syndromes, and concluded that 'all of these disparate disorders (if, indeed, they are distinct) are still in need of a universally agreed definition and classification', and suggested that advice be obtained from an international working party. 16 Meanwhile overlaps could be dealt with either by nominating the independent occurrence of two diseases, given that criteria for both are fulfilled, or by defining criteria for each overlap syndrome as such. The latter seems preferable, given a likely shared immunopathological basis for both conditions, and the known tendency for escalation among autoimmune diseases. More detailed serological investigation should help. Apart from the conventional auto-antibodies described above, diagnostic pointers may be provided by the perinuclear type of anti-neutrophil cytoplasmic antibody (pANCA) which occurs frequently in AIH 16,17 but seldom in PBC, and perhaps also by other AIH-related auto-antibodies (e.g. to soluble liver antigen (anti-SLA), or to liver cytosol antigen type 1 (anti-LC1). 18 The entity known as autoimmune cholangitis/cholangiopathy (AIC) has itself been thought to represent an overlap disease. This was first described in 1987 as a chronic obstructive intrahepatic inflammatory cholangitis in which the biochemical features were those of PBC, but the serological features differed in that the test for AMA was negative and that for antinuclear antibody (ANA) was positive, and there was a response to corticosteroid drugs. 19 This entity subsequently attracted a number of case studies and commentaries, recently summarized and reviewed in a conjoint study on 24 cases of AIC from Japanese colleagues and this laboratory. 20 This study compared clinical, biochemical, histological and serological features of AIC with those of AIH and PBC. The results refuted the idea that AIC is a cholangiopathic variant of AIH and indicated that so-called AMA-negative PBC 21 may be too simplistic, yet were consistent with the current viewpoint that AIC aligns closely with PBC, clinically and histologically. 20 Also, in AIC, the expressions of ANA by immunofluorescence and immunoblot are those that occur in the 50% of ANA-positive cases of PBC, namely auto-antibodies to centromere, the Sp-100 antigen, and anti-nuclear pore proteins including gp210, its aminoterminal fragment and/or p62 nucleoporin. 20 Studies by immunoblot on our 24 cases of AIC disclosed that, whereas AMA was negative by immunofluorescence, there was often serological reactivity demonstrable by immunoblot with components of the M2 autoantigen family, the E2 subunits of the 2-oxo-acid dehydrogenase complex (2-OADC) enzymes: this is in accord with positivity by immunoblot in cases of AMA-negative PBC. 22 Thus, we concluded that AIC is part of PBC but, by reason of the distinctive serological features, it should be regarded as a nosological entity, at least until the actual pathogenesis of PBC itself is revealed. 20 The above having been said, might AIC in fact coexist with AIH? Some reports indicate this to be the case. Ben-Ari et al. recorded the shared histological features of periportal and introlobular inflammation and bile duct damage, and biochemical remission with prednisolone, 23 and Czaja stated that 11 of 162 cases (17%) of AIH had features of AIC. 15 Li and co-authors, in this issue of the Journal, report the case of a 42-year-old Chinese female who expressed 'characteristic features of both diseases'. 24 The biochemical features included highly raised serum levels of ALP and γ-glutamyl transpeptidase, increased serum cholesterol and normal immunoglobulin (Ig)G but an increased IgM: all are more suggestive of PBC or AIC than of AIH. Serologically, AMA was negative but immunoblot to confirm non-reactivity to 2-OADC-E2 enzymes was not performed. The test for smooth muscle antibody (SMA) was negative and ANA was positive, but the specificity of the ANA was that of anticentromere, which is one of the particular trio of ANA reactivities (see above) that mark ANA-positive cases of PBC. Histologically, there was an AIH-PBC overlap, but the presence of periductular granulomas points more particularly to PBC. There was an initial response to prednisolone, and prednisolone dependence, in addition to benefit from UDCA. Thus, the case of Li et al.24 shows sufficient features to justify being styled an overlap, but the bias seems much more towards AIC than AIH. Autoimmune hepatitis–primary sclerosing cholangitis is an interesting overlap because PSC can be questioned as a 'qualified' autoimmune disease. Taking data from a recent review, 25 the sex bias is towards men (70%); the usual accompanying disease, ulcerative colitis, which coexists in some 75% of cases, is itself questionable as an autoimmune expression; the characteristic histopathology with biliary periductular 'onion-skin' fibrosis is not typical for an autoimmune process; there is neither a disease-specific nor tissue-specific auto-antigen; there is a muted, if any, response to corticosteroids or immunosuppressive drugs; and, finally, the miscellaneous immune aberrations that are described 25,26 cannot be readily assembled into a concept of autoimmune pathogenesis. The evidence for autoimmunity that does exist for PSC comprises a high frequency of pANCA 27 and an association with HLA alleles that includes the autoimmune haplotype HLA B8,DR3, and DRw52a. 28 Thus, PSC may well be viewed as immunologically mediated but is, like its partner disease ulcerative colitis, the outcome of an aberrant immune response directed primarily to intestinal luminal antigens, presumably of bacterial origin. The frequency of overlap of AIH and PSC is hard to estimate. Roberts et al. from the Mayo Clinic reported eight patients (four males, four females) fulfilling criteria for both diseases, with five developing PSC after the clinical onset of AIH, seven having an accompanying ulcerative colitis and all giving a poorer response to corticosteroid therapy. 29 The analysis of overlaps by Czaja included 26 cases of PSC, with a positive IAIHG score for AIH in as many as 14 (54%) of the cases; 15 this may reflect the recognized low specificity of the scoring system in the setting of cholestatic syndromes. 16 Boberg et al. reported on 114 adults with PSC among whom criteria for AIH were met by 40, two definite and 38 probable; 30 however, using a revised scoring system, only 10 of the 38 retained a score for probable AIH. 16 Although cases with the primary diagnosis of AIH seldom show concordant features of PSC, an obstructive pattern of tests of liver function may develop in the later stages of AIH. McNair et al., in 1998, commented on the scarcity of overlap between AIH and PSC in their report of five examples, claiming that of cases reported in the literature, only 11 were sufficiently well documented for comparison with their five cases. 31 Of these five, four were male (a PSC bias), four had a marked elevation of ALP (a PSC bias), all had hyperglobulinaemia (an AIH bias), and two had ulcerative colitis. Immunoserological tests (performed in the hospital laboratory) revealed that ANA was positive in two (titres 1:2560 and 1:320, pattern not specified), SMA in four (an AIH bias) and pANCA in all five. Radiography showed strictured ducts with beading (a PSC bias); histology showed changes of pericholangitis in three cases; and there was a response to prednisolone in all cases (an AIH bias). While the frequency of overlap of AIH and PSC is low in adults, this may not pertain in children, according to the description by Wilschanski et al.32 although this overlap was not emphasized in the report by Gregorio et al. on 47 cases of AIH in children. 33 Roberts commented on the difficulties in distinguishing between the two conditions on clinical, histological or even serological data and called for further studies to elucidate whether the overlap represented a single disease process with combined features of AIH and PSC, or the concurrence of two 'mechanistically distinct' but clinically similar entities. 34 There can be apparent overlaps between AIH and other diseases within the immunoinflammatory spectrum of histological CAH. First, in reference to chronic viral hepatitis, an autoimmune overlay appears to be much more frequent in infection with hepatitis C than hepatitis B. In fact, in chronic hepatitis C infection, there are various immune aberrations including the mixed cryoglobulinaemia syndrome which is due to deposition of immune complexes that include components of HCV, as well as autoimmune serological expressions similar to those seen in either type 1, or type 2, AIH. These are probably provoked by virus infection in the liver. 35 Wilsonian CAH may resemble the necroinflammatory features of AIH histologically 36 but, according to the literature review of Milkiewicz et al. (submitted for publication, 1999), autoimmune serological expressions are rare. Similarly, CAH in alcoholic patients is more a histological than a serological diagnosis. 37 Perhaps in these various examples, autoimmunization is consequential to hepatocellular damage from a primary cause but serves as an additional pathogenetic component. There may be insights to be gained from immune-mediated liver diseases that do not overlap. One example is type 2 AIH, for which reports of overlap with other diseases are lacking, even with the type 1 variant. Another claimed example of non-overlap among inflammatory liver diseases is PBC and PSC. 26 There remain substantial gaps in knowledge on how autoimmune diseases are initiated and sustained: a provisional outline is presented in Table 2. Consideration of overlap syndromes has conceptional connotations for at least three areas. First, for nosologists, overlap syndromes pose uncertainty whether there should be separate nomination of the two diseases contributing to the overlap, or whether the overlap should be defined as a single entity. If the latter were the case, nomenclature groups will need to develop appropriate criteria, equivalent to those established or in de facto use for AIH, PBC and PSC. A recognized handicap is that a defining serological marker (or markers) for the common type 1 AIH, equivalent to the anti-CY-P450-2D6 that characterizes type 2 AIH, is still not yet available. For the most-discussed of the overlaps, AIH and PBC, it seems that PBC is the more dominant of the partners onto which features of AIH become added, as judged from observations that this overlap is more frequent from the PBC perspective than the AIH perspective. 13,14 Second, for therapists, medication appropriate to each partner of the overlap should be prescribed. This applies particularly to AIH–PBC and AIH–PSC overlaps, and to AIC, in which a combination of immunosuppression (prednisolone, azathioprine) and UDCA would be logical, and preliminary indications of benefit are already available. 24,38 Third, for theorists, the study of overlaps may be informative for an understanding of the general pathogenesis of autoimmune liver diseases (see Table 2). The recognized genetic elements in autoimmune disease are estimated to comprise 30–60% of the overall risk and, of this, genes of the major histocompatibility complex (AIH) are the main contributor. These HLA alleles, and genes that influence the specificity of B and T cell antigen receptors, determine the direction of responses to specific auto-antigenic molecules and, thus, confer disease individuality. Other immune-response genes will have a general influence, either by effects on tolerogenesis overall, or on apoptosis, on the balance of cytokines produced by T helper -l or -2 cells, or on expression of other inflammatory mediators. The combined effects of such general immune response genes would explain autoimmune escalation in which there is cumulative organ or tissue involvement to produce a complex multisystem disease phenotype. The process of epitope-spreading is described as either intramolecular, which implies spread to different epitopes on the one auto-antigen, or intermolecular, which implies spread to different auto-antigens in the one cell or tissue. 39 This process would be facilitated by a permissive genotype and an inflammatory milieu and ambient cytokines, and also could contribute to disease overlaps and diversification and serological responses to multiple auto-antigens. In the context of genetics, Lohse et al. suggest, as indicated above, that the PBC–AIH overlap syndrome is, in fact, primarily PBC with hepatic expressions conferred by HLA susceptibility alleles B8, DR3 or DR4. 40 In conclusion, overlap syndromes, are a reality among the hepatic autoimmune diseases. These are a nuisance for nosologists, but careful study of clinical, laboratory and particularly the serological features of these syndromes and their outcome, should provide interesting insights for autoimmunity. Moreover, their recognition should prompt the use of novel combined therapies. A clarion call can, therefore, be made for increased international collaborations among hepatologists, including exchanges of histological material, serum samples and DNA for immunogenetic analysis, as no single clinic would have sufficient cases or access to sufficient technological resources, to provide a solution to these 'double disease' occurrences. The outcome would be an overlap of benefits for both hepatology and clinical immunology.

Content available: Audio Recording.

Primary sclerosing cholangitis (PSC) is a chronic progressive inflammatory disease of the bile ducts that is surrounded by much uncertainty. First of all, it is a rare disease, with reported prevalence between 0 and 31.7 per 100,000 individuals,1Boonstra K. Beuers U. Ponsioen C.Y. Epidemiology of primary sclerosing cholangitis and primary biliary cirrhosis: a systematic review.J Hepatol. 2012; 56: 1181-1188Abstract Full Text Full Text PDF PubMed Scopus (457) Google Scholar,2Barner-Rasmussen N. Pukkala E. Jussila A. et al.Epidemiology, risk of malignancy and patient survival in primary sclerosing cholangitis: a population-based study in Finland.Scand J Gastroenterol. 2020; 55: 74-81Crossref PubMed Scopus (31) Google Scholar and establishing a diagnosis can be difficult. The primary pathology is hidden deep in the liver, and there is no specific and easy noninvasive diagnostic test for PSC. Histologic features of fibrosing cholangiopathy are present in <20% of liver biopsy specimens obtained from patients with PSC and can also be seen in cases of secondary sclerosing cholangitis. Current US and European guidelines do not recommend liver biopsy for making a diagnosis of PSC except for suspected cases of small duct PSC and pediatric cases.3Lindor K.D. Kowdley K.V. Harrison M.E. ACG clinical guideline: primary sclerosing cholangitis.Am J Gastroenterol. 2015; 110: 646-659Crossref PubMed Scopus (358) Google Scholar,4European Association for the Study of the LiverEASL clinical practice guidelines: management of cholestatic liver diseases.J Hepatol. 2009; 51: 237-267Abstract Full Text Full Text PDF PubMed Scopus (1433) Google Scholar In addition, biliary tract abnormalities can be found on magnetic resonance cholangiopancreatography (MRCP) or endoscopic retrograde cholangiography (ERC) in a wide array of conditions (see Supplementary Table 1). Furthermore, the course of PSC can be variable. Liver transplant–free survival ranges between 14.5 and 21.3 years in large cohorts.5Weismüller T.J. Trivedi P.J. Bergquist A. et al.Patient age, sex, and inflammatory bowel disease phenotype associate with course of primary sclerosing cholangitis.Gastroenterology. 2017; 152: 1975-1984Abstract Full Text Full Text PDF PubMed Scopus (313) Google Scholar,6Boonstra K. Weersma R.K. van Erpecum K.J. et al.Population-based epidemiology, malignancy risk, and outcome of primary sclerosing cholangitis.Hepatology. 2013; 58: 2045-2055Crossref PubMed Scopus (460) Google Scholar An important risk factor affecting survival is the development of cholangiocarcinoma (CCA). This has a cumulative incidence of approximately 20% at 20 years after diagnosis, but one third of CCA cases become manifest within 1 year after the diagnosis of PSC.5Weismüller T.J. Trivedi P.J. Bergquist A. et al.Patient age, sex, and inflammatory bowel disease phenotype associate with course of primary sclerosing cholangitis.Gastroenterology. 2017; 152: 1975-1984Abstract Full Text Full Text PDF PubMed Scopus (313) Google Scholar,6Boonstra K. Weersma R.K. van Erpecum K.J. et al.Population-based epidemiology, malignancy risk, and outcome of primary sclerosing cholangitis.Hepatology. 2013; 58: 2045-2055Crossref PubMed Scopus (460) Google Scholar Last but not least, the cause of PSC is still enigmatic, and consequently, there is no therapy that has been proven to modify disease progression. In recent years, there has been an upsurge of pilot studies and phase 2 clinical trials. Phase 2 and 3 trials are hampered by the lack of established surrogate endpoints for clinical outcome, the heterogeneity of the disease course, and the lack of clear definitions for many key clinical disease characteristics.7Ponsioen C.Y. Chapman R.W. Chazouillères O. et al.Surrogate endpoints for clinical trials in primary sclerosing cholangitis: review and results from an International PSC Study Group consensus process.Hepatology. 2016; 63: 1357-1367Crossref PubMed Scopus (124) Google Scholar While the available national and international clinical practice guidelines predominantly focus on clinical management, the International PSC Study Group (IPSCSG) has recognized that there is a vital need for clinical trials to use uniform definitions for the diagnosis of PSC and for assessing disease severity and outcomes.3Lindor K.D. Kowdley K.V. Harrison M.E. ACG clinical guideline: primary sclerosing cholangitis.Am J Gastroenterol. 2015; 110: 646-659Crossref PubMed Scopus (358) Google Scholar,4European Association for the Study of the LiverEASL clinical practice guidelines: management of cholestatic liver diseases.J Hepatol. 2009; 51: 237-267Abstract Full Text Full Text PDF PubMed Scopus (1433) Google Scholar,8Chapman M.H. Thorburn D. Hirschfield G.M. et al.British Society of Gastroenterology and UK-PSC guidelines for the diagnosis and management of primary sclerosing cholangitis.Gut. 2019; 68: 1356-1378Crossref PubMed Scopus (135) Google Scholar Therefore, the IPSCSG has commissioned a consensus process among its experts to issue a set of definitions to aid clinical trialists designing much needed clinical trials. To this end, an extensive consensus process was initiated, applying a hybrid between a Delphi process and a nominal group process, as was previously used by the IPSCSG and the European Crohn's and Colitis Organization.7Ponsioen C.Y. Chapman R.W. Chazouillères O. et al.Surrogate endpoints for clinical trials in primary sclerosing cholangitis: review and results from an International PSC Study Group consensus process.Hepatology. 2016; 63: 1357-1367Crossref PubMed Scopus (124) Google Scholar,9Dignass A. Eliakim R. Magro F. et al.Second European evidence-based consensus on the diagnosis and management of ulcerative colitis part 1: definitions and diagnosis.J Crohns Colitis. 2012; 6: 965-990Abstract Full Text Full Text PDF PubMed Scopus (675) Google Scholar Where necessary, an additional survey was conducted among all IPSCSG members (see the Supplementary Methods for details). Results are presented as a comprehensive set of consensus statements (CSs) and diagnostic criteria for PSC. Although patients with PSC are increasingly diagnosed at earlier stages of disease based on asymptomatic serum liver enzyme abnormalities, at least 45% of patients PSC present with symptoms on either a constant or intermittent basis, which significantly reduces quality of life.10Broome U. Olsson R. Lööf L. et al.Natural history and prognostic factors in 305 Swedish patients with primary sclerosing cholangitis.Gut. 1996; 38: 610-615Crossref PubMed Google Scholar Furthermore, more than 22% of asymptomatic patients may develop symptoms within 5 years. The most common clinical symptoms associated with PSC are fatigue; pruritus; right upper quadrant (RUQ) abdominal pain; and emotional distress, which may include anxiety and depression symptoms. Pruritus and abdominal pain can fluctuate dramatically, and this may be suddenly worsened because of the development of a biliary obstruction or acute bacterial cholangitis. Therefore, clinical evaluation with laboratory testing and imaging may be necessary in the event of the sudden appearance or worsening of symptoms. Emotional distress for many patients is attributable to chronic anxiety about the uncertain etiology of the disease, the lack of effective therapy, and the risk of malignancy, among others.11Ranieri V. Kennedy E. Walmsley M. et al.The Primary Sclerosing Cholangitis (PSC) Wellbeing study: understanding psychological distress in those living with PSC and those who support them.PLoS One. 2020; 15e0234624Crossref PubMed Scopus (10) Google Scholar The incorporation of clearly defined patient-reported symptoms into the design of clinical trials is both desirable from a patient-centered perspective and highly encouraged by regulatory agencies12Ponsioen C.Y. Lindor K.D. Mehta R. et al.Design and endpoints for clinical trials in primary sclerosing cholangitis.Hepatology. 2018; 68: 1174-1188Crossref PubMed Scopus (43) Google Scholar (Box 1, CS 1.1). Recently, 2 such tools have emerged. One patient-reported outcome (PRO) dedicated to PSC showed excellent reliability and was able to discern patients with cirrhosis and those with a history of depression.13Younossi Z.M. Afendy A. Stepanova M. et al.Development and validation of a primary sclerosing cholangitis-specific patient-reported outcomes instrument: the PSC PRO.Hepatology. 2018; 68: 155-165Crossref PubMed Scopus (21) Google Scholar A more recently developed tool to assess patient-reported symptoms, the Simple Cholestatic Complaints Score, was developed through digital surveys of patients and showed good criterion and construct validity and a very high test-retest reproducibility.14Munster K.N. Dijkgraaf M.G.W. Gennep S. et al.The Simple Cholestatic Complaints Score is a valid and quick patient-reported outcome measure in primary sclerosing cholangitis.Liver Int. 2020; 40: 2758-2766Crossref PubMed Scopus (0) Google Scholar Further validation of these tools in larger and more diverse cohorts is needed.Box 1Consensus StatementsTabled 11.Clinical symptoms1.1.Assessment of symptoms in patients with PSC for clinical trial purposes should be performed through disease-specific and validated quantitative tools.1.2.Assessment of symptoms in patients with PSC should take into consideration and be distinguished from symptoms attributable to active inflammatory bowel disease and other coexistent conditions.2.Laboratory markers2.1.The presence of significant elevations of serum aminotransferase activity (>5 × ULN) and/or IgG (>2 × ULN) can be indicative of features of coexisting autoimmune hepatitis and should trigger consideration of liver biopsy for diagnostic and stratification purposes when considering enrolling a subject in a clinical trial.2.2.Serum IgG4 concentrations can be elevated in patients with PSC, in the absence of classical features of IgG4-related disease, but IgG4 elevations are not validated markers of disease diagnosis, severity, prognosis, or treatment.3.Imaging3.1.The pattern of PSC can be defined according to the appearances of cholangiography using high-quality magnetic resonance cholangiography (MRC) (at least 1.5 T):3.1.1.Small duct when a recent cholangiogram (not older than 1 year) is normal3.1.2.Intrahepatic when there are intrahepatic changes but the common ducts and first-order ducts are normal3.1.3.Extrahepatic disease when the common ducts and/or the first-order ducts are involved4.Histology4.1.Histologic findings in a liver biopsy sample from patient suspected to have PSC can be defined (classified) as follows:4.1.1.Typical of PSC: features of fibrosing cholangiopathy present (periductal fibrosis, fibro-obliterative duct lesions)4.1.2.Compatible with PSC: features of chronic biliary disease present (see text for further details) without typical bile duct lesions4.1.3.Atypical for PSC: features atypical for PSC present. Examples include•unusually prominent inflammatory activity suggesting the possibility of PSC-AIH overlap syndrome•features suggesting an alternative diagnosis, such as fatty liver disease, or IgG4-associated cholangitis.4.2.A liver biopsy specimen showing typical or compatible histologic features is required to establish a diagnosis of small duct PSC.4.3.In a person with PSC, a liver biopsy specimen showing at least moderate interface hepatitis in addition to features compatible with or diagnostic of PSC is required to establish a diagnosis of PSC with features of AIH or PSC-AIH overlap syndrome.4.4.The histologic features that indicate disease progression (staging) in PSC include fibrosis, bile duct loss, and evidence of chronic cholestasis (demonstrated by deposition of copper-associated protein in periportal hepatocytes).5.Concurrent IBD5.1.The definition and description of IBD in PSC should follow the European Crohn's and Colitis Organization (ECCO) guidelines and Montreal classification. Any patient with established PSC should undergo a full ileocolonoscopy with histology before concurrent IBD may be excluded.5.2.When assessing the existence of backwash ileitis, it is recommended that the ECCO definition be followed. This defines backwash ileitis as continuous extension of macroscopic or histologic inflammation from the cecum into the most distal ileum.6.Staging6.1.Disease staging of PSC is defined as the histologic progression from initial disease onset to cirrhosis.6.2.A clinically significant change in disease stage is defined by a 1-point change in the Ludwig or Nakanuma system or a 2-point change in the Ishak system.6.3.Histologic cirrhosis is a clinically significant endpoint.6.4.Cirrhosis (stage 5–6 by Ishak) in PSC can be defined by an LS of >14.4 kPa measured by VCTE.6.5.Cirrhosis (stage 5–6 or greater by Ishak) in PSC can be defined by an ELF score of >9.8 or FibroTest of >7.3.7.Clinical endpoints7.1.Liver transplant:Liver transplant is an appropriate endpoint in PSC clinical trials. However, divergent indications for transplant listing (end-stage disease, dysplasia, CCA, symptoms, intractable cholangitis) and method of transplantation (deceased vs living donation) should not be grouped into a single endpoint because of the wide heterogeneity of clinical practice.7.2.Liver-related death:Liver-related death in the setting of PSC is defined as death from clinically significant portal hypertension, synthetic liver dysfunction, or specific complications from biliary disease such as hepatobiliary infections.8.Cancer development8.1.Cholangiocarcinoma:8.1.1.CCA in PSC requires pathologic confirmation and is classified according to CCA in general.8.1.2.Dysplastic changes considered precursors to CCA in PSC are defined by standard criteria.8.2.Colorectal carcinoma:8.2.1.CRC in the setting of PSC is defined according to standard criteria.9.Pediatric PSC9.1.Pediatric PSC is not a specific disease phenotype. PSC in children should be described in terms of small vs large duct involvement, whether features of overlap with AIH are present or absent, and whether IBD is present or absent, as in adult patients.9.2.Terms such as juvenile sclerosing cholangitis and autoimmune sclerosing cholangitis should be avoided.9.3.When gGT is substituted for ALP, the consensus definitions in this document are applicable to children.10.Recurrent PSC10.1.The diagnosis of rPSC is based on the presence of compatible radiologic changes (using high-quality MR) with/or without histologic findings, along with the exclusion of other causes of similar findings. Open table in a new tab Tabled 11.Clinical symptoms1.1.Assessment of symptoms in patients with PSC for clinical trial purposes should be performed through disease-specific and validated quantitative tools.1.2.Assessment of symptoms in patients with PSC should take into consideration and be distinguished from symptoms attributable to active inflammatory bowel disease and other coexistent conditions.2.Laboratory markers2.1.The presence of significant elevations of serum aminotransferase activity (>5 × ULN) and/or IgG (>2 × ULN) can be indicative of features of coexisting autoimmune hepatitis and should trigger consideration of liver biopsy for diagnostic and stratification purposes when considering enrolling a subject in a clinical trial.2.2.Serum IgG4 concentrations can be elevated in patients with PSC, in the absence of classical features of IgG4-related disease, but IgG4 elevations are not validated markers of disease diagnosis, severity, prognosis, or treatment.3.Imaging3.1.The pattern of PSC can be defined according to the appearances of cholangiography using high-quality magnetic resonance cholangiography (MRC) (at least 1.5 T):3.1.1.Small duct when a recent cholangiogram (not older than 1 year) is normal3.1.2.Intrahepatic when there are intrahepatic changes but the common ducts and first-order ducts are normal3.1.3.Extrahepatic disease when the common ducts and/or the first-order ducts are involved4.Histology4.1.Histologic findings in a liver biopsy sample from patient suspected to have PSC can be defined (classified) as follows:4.1.1.Typical of PSC: features of fibrosing cholangiopathy present (periductal fibrosis, fibro-obliterative duct lesions)4.1.2.Compatible with PSC: features of chronic biliary disease present (see text for further details) without typical bile duct lesions4.1.3.Atypical for PSC: features atypical for PSC present. Examples include•unusually prominent inflammatory activity suggesting the possibility of PSC-AIH overlap syndrome•features suggesting an alternative diagnosis, such as fatty liver disease, or IgG4-associated cholangitis.4.2.A liver biopsy specimen showing typical or compatible histologic features is required to establish a diagnosis of small duct PSC.4.3.In a person with PSC, a liver biopsy specimen showing at least moderate interface hepatitis in addition to features compatible with or diagnostic of PSC is required to establish a diagnosis of PSC with features of AIH or PSC-AIH overlap syndrome.4.4.The histologic features that indicate disease progression (staging) in PSC include fibrosis, bile duct loss, and evidence of chronic cholestasis (demonstrated by deposition of copper-associated protein in periportal hepatocytes).5.Concurrent IBD5.1.The definition and description of IBD in PSC should follow the European Crohn's and Colitis Organization (ECCO) guidelines and Montreal classification. Any patient with established PSC should undergo a full ileocolonoscopy with histology before concurrent IBD may be excluded.5.2.When assessing the existence of backwash ileitis, it is recommended that the ECCO definition be followed. This defines backwash ileitis as continuous extension of macroscopic or histologic inflammation from the cecum into the most distal ileum.6.Staging6.1.Disease staging of PSC is defined as the histologic progression from initial disease onset to cirrhosis.6.2.A clinically significant change in disease stage is defined by a 1-point change in the Ludwig or Nakanuma system or a 2-point change in the Ishak system.6.3.Histologic cirrhosis is a clinically significant endpoint.6.4.Cirrhosis (stage 5–6 by Ishak) in PSC can be defined by an LS of >14.4 kPa measured by VCTE.6.5.Cirrhosis (stage 5–6 or greater by Ishak) in PSC can be defined by an ELF score of >9.8 or FibroTest of >7.3.7.Clinical endpoints7.1.Liver transplant:Liver transplant is an appropriate endpoint in PSC clinical trials. However, divergent indications for transplant listing (end-stage disease, dysplasia, CCA, symptoms, intractable cholangitis) and method of transplantation (deceased vs living donation) should not be grouped into a single endpoint because of the wide heterogeneity of clinical practice.7.2.Liver-related death:Liver-related death in the setting of PSC is defined as death from clinically significant portal hypertension, synthetic liver dysfunction, or specific complications from biliary disease such as hepatobiliary infections.8.Cancer development8.1.Cholangiocarcinoma:8.1.1.CCA in PSC requires pathologic confirmation and is classified according to CCA in general.8.1.2.Dysplastic changes considered precursors to CCA in PSC are defined by standard criteria.8.2.Colorectal carcinoma:8.2.1.CRC in the setting of PSC is defined according to standard criteria.9.Pediatric PSC9.1.Pediatric PSC is not a specific disease phenotype. PSC in children should be described in terms of small vs large duct involvement, whether features of overlap with AIH are present or absent, and whether IBD is present or absent, as in adult patients.9.2.Terms such as juvenile sclerosing cholangitis and autoimmune sclerosing cholangitis should be avoided.9.3.When gGT is substituted for ALP, the consensus definitions in this document are applicable to children.10.Recurrent PSC10.1.The diagnosis of rPSC is based on the presence of compatible radiologic changes (using high-quality MR) with/or without histologic findings, along with the exclusion of other causes of similar findings. Open table in a new tab A particular challenge in assessing clinical symptoms in patients with PSC is the frequent concurrence of inflammatory bowel disease (IBD), which itself can influence the clinical course of PSC and may also account for a significant proportion of symptoms, especially during periods of IBD exacerbations.15Cheung A.C. Patel H. Meza-Cardona J. et al.Factors that influence health-related quality of life in patients with primary sclerosing cholangitis.Dig Dis Sci. 2016; 61: 1692-1699Crossref PubMed Scopus (1) Google Scholar Existing tools, including the PSC PRO, do not specifically account for symptoms attributable to IBD. Although the Simple Cholestatic Complaints Score did not show a difference in PSC patient symptoms according to the presence or absence of IBD, a systematic evaluation of IBD symptoms in patients with PSC has not been performed, which can result in confounding findings. Therefore, assessment of PSC symptoms should be performed alongside specifically designed tools to detect symptoms from IBD in those with PSC-IBD or other relevant coexistent conditions (Box 1, CS 1.2) This is critically important for clinical trials that aim to use PRO measures as endpoints in PSC. Cholestatic serum liver tests are a characteristic, but nonspecific, feature of biliary disease irrespective of the nature of biliary involvement. Alkaline phosphatase (ALP) as the hallmark of cholestasis is elevated in the vast majority of patients with PSC.16Poupon R. Liver alkaline phosphatase: a missing link between choleresis and biliary inflammation.Hepatology. 2015; 61: 2080-2090Crossref PubMed Scopus (75) Google Scholar Previously, it was thought that to make a diagnosis of PSC, elevation of ALP, or gamma-glutamyl transpeptidase (gGT) in children (see the "Pediatric Primary Sclerosing Cholangitis" section) was a prerequisite. Recent studies have shown that elevated cholestatic serum parameters need not always be present. For more background, see the Supplementary Material. Aminotransferases are often moderately elevated, whereas at diagnosis, serum bilirubin and albumin levels are usually normal.3Lindor K.D. Kowdley K.V. Harrison M.E. ACG clinical guideline: primary sclerosing cholangitis.Am J Gastroenterol. 2015; 110: 646-659Crossref PubMed Scopus (358) Google Scholar Aminotransferase activity of more than 5 times the upper limit of normal (ULN) and a serum IgG of >2 × ULN should raise the suspicion of coexisting autoimmune hepatitis (AIH) and should trigger consideration of liver biopsy to identify histologic features that would support a diagnosis of AIH or PSC/AIH overlap, also called variant syndrome (Box 1, CS 2.1). This has management consequences, because patients with PSC/AIH commonly respond favorably to immunosuppressive medication such as corticoids and thiopurines, although not as well as patients with isolated AIH.17Boberg K.M. Chapman R.W. Hirschfield G.M. et al.Overlap syndromes: the International Autoimmune Hepatitis Group (IAIHG) position statement on a controversial issue.J Hepatology. 2011; 54: 374-385Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar In contrast to primary biliary cholangitis (PBC) and AIH, there is no pattern of autoantibody reactivity in patients with PSC of relevance to diagnosis or treatment. Positive titers of autoantibodies are common in PSC, including antinuclear antibody (8%–77%), smooth muscle antibody (0%–83%), and atypical perinuclear antibody (26%–94%).18Prideaux L. De Cruz P. Ng S.C. et al.Serological antibodies in inflammatory bowel disease: a systematic review.Inflamm Bowel Dis. 2012; 18: 1340-1355Crossref PubMed Scopus (139) Google Scholar,19Moiseev S. Cohen Tervaert J.W. Arimura Y. et al.2020 International consensus on ANCA testing beyond systemic vasculitis.Autoimmun Rev. 2020; 19: 102618Crossref PubMed Scopus (18) Google Scholar However, these are also frequently present in AIH, and perinuclear antineutrophil cytoplasmic antibodies can be found in ulcerative colitis (UC) in 41%–73% and in Crohn's disease in 6%–38%.17Boberg K.M. Chapman R.W. Hirschfield G.M. et al.Overlap syndromes: the International Autoimmune Hepatitis Group (IAIHG) position statement on a controversial issue.J Hepatology. 2011; 54: 374-385Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 18Prideaux L. De Cruz P. Ng S.C. et al.Serological antibodies in inflammatory bowel disease: a systematic review.Inflamm Bowel Dis. 2012; 18: 1340-1355Crossref PubMed Scopus (139) Google Scholar, 19Moiseev S. Cohen Tervaert J.W. Arimura Y. et al.2020 International consensus on ANCA testing beyond systemic vasculitis.Autoimmun Rev. 2020; 19: 102618Crossref PubMed Scopus (18) Google Scholar Serum IgG4 levels can be elevated in patients with PSC, but this has no validated bearing on diagnosis or disease severity (Box 1, CS 2.2). For distinction from IgG4-sclerosing cholangitis, see the Supplementary Material. Biliary imaging is integral to the diagnosis and classification of PSC. MRCP has been established as the noninvasive imaging of choice.3Lindor K.D. Kowdley K.V. Harrison M.E. ACG clinical guideline: primary sclerosing cholangitis.Am J Gastroenterol. 2015; 110: 646-659Crossref PubMed Scopus (358) Google Scholar,4European Association for the Study of the LiverEASL clinical practice guidelines: management of cholestatic liver diseases.J Hepatol. 2009; 51: 237-267Abstract Full Text Full Text PDF PubMed Scopus (1433) Google Scholar Regarding the utility of magnetic resonance imaging (MRI) in PSC, the reader is referred to a recent publication from the IPSCSG Working Group on MRI in PSC.20Schramm C. Eaton J. Ringe K.I. et al.Recommendations on the use of magnetic resonance imaging in PSC-A position statement from the International PSC Study Group.Hepatology. 2017; 66: 1675-1688Crossref PubMed Scopus Google Scholar A of features are described in large duct PSC, including or within the and/or biliary of the intrahepatic ducts with of the biliary of the and changes not of PSC, and from causes of secondary sclerosing cholangitis in the absence of can be difficult. in the bile ducts on cholangiography are thought to be highly specific for PSC. in the common and common bile the are usually seen in disease and are reported in of cases in a large of C.Y. et al.Natural history of primary sclerosing cholangitis and prognostic of cholangiography in a 51: PubMed Scopus (0) Google Scholar small duct PSC cholangiography is normal is an in PSC. recent have reported on the history of small cohorts of small duct PSC patients to large duct PSC was described in and after a of years of in K. Eaton et resonance imaging features of primary sclerosing 2020; PubMed Scopus Google K.I. Bergquist A. H. et features and MRI progression of small duct primary sclerosing cholangitis J 2020; Full Text Full Text PDF PubMed Scopus (0) Google Scholar (Box 1, CS was no with MRI findings and progression to large duct PSC in either in the bile ducts are a common and clinically relevant of the chronic inflammatory process that in the biliary in PSC. a of large duct PSC patients with the incidence of the development of can be to to approximately in patients with large duct A. P. et al.Development of bile duct in patients with primary sclerosing cholangitis with outcome after endoscopic Hepatol. Full Text Full Text PDF PubMed Scopus Google Scholar extensive in the Supplementary the a of criteria that into the definition of a as in of is called a when it the criteria before MRCP or with of in or first-order intrahepatic not and worsening of cholestatic symptoms within 2 biliary or and/or of × ULN and recent for × P. et of in primary sclerosing cholangitis: outcome after Full Text Full Text PDF PubMed Scopus Google and/or within for × or of >2 × ULN no within is

Diagnosis and Management of Primary Sclerosing Cholangitis

Diagnosing AIH in Children: Is the International AIH Group Scoring System Useful?Ebbeson RL, Schreiber RA. Clin Gastroenterol Hepatol 2004;2:935-940. Summary: In 1992, the International Autoimmune Hepatitis Group developed a scoring system for adults to differentiate autoimmune hepatitis from other causes of chronic liver disease (1). In the present study, Ebbeson and Schreiber investigated the possibility that a modification of this system could be applied to children both to diagnose autoimmune hepatitis and to distinguish them from children with biliary features or “overlap syndrome.” The authors retrospectively applied the International Autoimmune Hepatitis Group scoring system to 28 children with a diagnosis of chronic immune liver disease (21 with autoimmune hepatitis, 4 with isolated sclerosing cholangitis and 3 with overlap syndrome). A diagnosis of overlap syndrome was made when the patient had not only the clinical and histologic findings of autoimmune hepatitis but also findings of sclerosing cholangitis on cholangiography. The authors found that 18 of 21 patients with autoimmune hepatitis scored were identified as “definite” autoimmune hepatitis (>15 points) and the other three as “probable” (10 to 15 points). Four patients with primary sclerosing cholangitis were identified as “other” (<10 points) and three with overlap syndrome were identified as “definite” autoimmune hepatitis. It was noted that removing the two points allocated for <25 g daily alcohol intake did not alter the classification of the patients either before or after treatment in any way. The authors state that in growing children, gamma-glutamyl transaminase is a more specific marker of cholestatic liver disease than alkaline phosphatase, as the latter may reflect bone activity. When gamma-glutamyl transaminase was substituted for alkaline phosphatase in the item of the scoring system comparing the ratio of alkaline phosphatase to aspartate aminotransferase, five patients who scored “definite” for autoimmune hepatitis by the original system were reclassified as “probable” autoimmune hepatitis. Four of these five patients had incomplete response to treatment. Of the five reclassified as “probable” autoimmune hepatitis, two had sclerosing cholangitis confirmed by endoscopic retrograde cholangiopancreatography and a diagnosis of overlap syndrome, one had biliary changes on ultrasound and was awaiting cholangiography, one had inconclusive changes on endoscopic retrograde cholangiopancreatography because of incomplete filling of the biliary tree (follow-up liver biopsy showed biliary changes) and the last did not have cholangiographic studies performed (young age and complete response to treatment). Ebbeson and Schreiber concluded this paper by endorsing the modified International Autoimmune Hepatitis Group scoring system in the diagnosis of autoimmune hepatitis in children. Comments: The scoring system for autoimmune hepatitis studied in this paper was first proposed in 1992 by an international panel of experts (the International Autoimmune Hepatitis Group) (1). The need for clear diagnostic criteria for what was then known as chronic active hepatitis was heightened by the identification of the hepatitis C virus in 1989 (2). The scoring system was constructed on clinical and biochemical parameters characteristic of autoimmune hepatitis. In the original scoring system, points were assigned for “minimal” parameters of (i) female gender, (ii) hepatitic biochemical profile, (iii) hyperglobulinemia, (iv) increased autoantibody titers, (v) absence of viral hepatitis markers, (vi) family history of autoimmunity and (vii) absence of drug or alcohol ingestion. Additional parameters included (i) characteristic histology, (ii) genetic factors and (iii) response to immunosuppressive therapy. A pretreatment aggregate score of >15 was designated “definite” and scores between 10-15 “probable” autoimmune hepatitis. Post-treatment scores >17 were designated “definite” and scores of 12 to 17 “probable” autoimmune hepatitis, respectively (1). Several groups (2,3) have attempted to validate the International Autoimmune Hepatitis Group scoring system. In one pediatric study, when the original scoring system was applied retrospectively to 52 children with a diagnosis of untreated autoimmune hepatitis, 35 (67%) scored as definite autoimmune hepatitis and the remaining 17 as probable autoimmune hepatitis (4). While on treatment, 10 more patients fulfilled criteria for definite autoimmune hepatitis. As 86% of 52 children could be designated as definite autoimmune hepatitis and the remaining probable autoimmune hepatitis, the authors felt that the scoring system could be applied to the pediatric age group. The diagnostic criteria were reviewed and modified in 1999 (5). The principal changes related to the alkaline phosphatase:aspartate aminotransferase ratio, drug history, liver histology and response to treatment. To increase weighting against biliary disease, the negative score for anti-mitochondrial antibody epositivity was increased from −2 to −4 and the score for histologic evidence of bile duct damage was increased from −1 to −3. Because interface hepatitis is particularly characteristic of autoimmune hepatitis, a score of −5 was allocated to those who did not have this feature. As classic autoimmune hepatitis does not always respond to treatment, it was decided to remove points for “no response,” “treatment failure” or “partial response.” It was also noted that because low titers of antibodies may be significant in children, the previous specification for autoantibody titers was not a significant factor in childhood scoring. In consideration of the importance of correct identification of autoantibodies both in diagnosis and in monitoring disease activity, a committee was formed to work towards standardization of methodology and data collection on the sensitivity and specificity of various assay systems (6). The overlap between sclerosing cholangitis and autoimmune hepatitis has been a matter of controversy, and several groups have used the scoring system to better delineate this group of patients. Boberg et al. used the original scoring system to evaluate 114 primary sclerosing cholangitis patients in Norway and reported that two primary sclerosing cholangitis patients (1.8%) fulfilled criteria for “definite” and 38 (33%) fulfilled criteria for “probable” autoimmune hepatitis (7). After the criteria were modified, the modified scoring system was applied to the same group of primary sclerosing cholangitis patients. Reanalysis showed that of the 38 (33.3%) originally classified as probable, only 10 (8.8%) remained in this category, giving an overall specificity of 89.5% for exclusion of autoimmune hepatitis in this group of primary sclerosing cholangitis patients (1). Chazouilleres and colleagues evaluated four groups (7-10) using the scoring system and reported that the modified system was more specific in diagnosing the overlap syndrome (11). In pediatrics, Gregorio et al. investigated whether sclerosing cholangitis with an autoimmune serology and autoimmune hepatitis are distinct entities (12). Overall, 25 (89%) patients with autoimmune hepatitis and 15 of 23 (65%) with autoimmune sclerosing cholangitis would have been diagnosed as definite autoimmune hepatitis post-treatment (P = 0.041) by using the scoring criteria (12). The difference in the adult studies and the pediatric study could be explained by the inclusion criteria. In the adult studies, any patient with cholangiographic changes of sclerosing cholangitis was included, whereas in the pediatric study only those with both autoantibodies and characteristic changes on cholangiography were included. The International Autoimmune Hepatitis Group scoring system is not used commonly in pediatric clinical practice. The study of Ebbeson and Schreiber may persuade some readers to do so in children with a complicated presentation. The studies discussed above demonstrate that the International Autoimmune Hepatitis Group scoring system can effectively separate autoimmune hepatitis from isolated sclerosing cholangitis while highlighting the difficulty in identifying those with overlap between autoimmune hepatitis and sclerosing cholangitis. The current study, though retrospective and with small sample size, is novel in that by substituting gamma-glutamyl transferase for alkaline phosphatase, Ebbeson and Schreiber have tried to identify the overlap group. The basis for making this change appears appropriate given that alkaline phosphatase is affected by bone activity especially in a growing child (13). In routine clinical practice, the majority of children with autoimmune hepatitis are likely to be assigned to the “definite” group. Those who are designated as ‘probable’™ are more likely to have biliary features and comprise the overlap group. Problems with sedation for imaging studies in small children and the technical expertise required to perform endoscopic retrograde cholangiopancreatography have limited the use of this diagnostic test. The scoring system may help limit biliary imaging studies to those with overlap features whose scores indicate “probable” autoimmune hepatitis. This group of children might benefit from addition of ursodeoxycholic acid to the immunosuppressive regimen. The usefulness of the International Autoimmune Hepatitis Group scoring system has also been recently illustrated by Bridoux-Henno et al. in diagnosing autoimmune hepatitis when the sole antibody present was anti-liver cytosol antibody (14). In conclusion, the international scoring system has a place in confirming the diagnosis of autoimmune hepatitis in cases with a complicated clinical presentation. The scoring system also provides a means of comparison between different centers in different parts of the world. Nanda Kerkar Assistant Professor Division of Pediatric Hepatology Recanati Miller Transplant Institute, Mount Sinai Medical Center New York, New York

Patients With Autoimmune Hepatitis Who Have Antimitochondrial Antibodies Need Long-term Follow-up to Detect Late Development of Primary Biliary Cirrhosis

Overlap syndromes: The International Autoimmune Hepatitis Group (IAIHG) position statement on a controversial issue

Background: Outcomes on the liver transplant waitlist can vary by etiology. Our aim is to investigate differences in waitlist mortality of autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC) using the United Network for Organ Sharing (UNOS) database. Methods: We identified patients who were listed for liver transplantation from 1987 to 2016 with a primary diagnosis of AIH, PBC, or PSC. We excluded patients with overlap syndromes, acute hepatic necrosis, missing data, and those who were children. The primary outcome was death or removal from the waitlist due to clinical deterioration. We compared waitlist survival using competing risk analysis. Results: Between 1987 and 2016, there were 7412 patients listed for liver transplant due to AIH, 8119 for PBC, and 10,901 for PSC. Patients with AIH were younger, more likely to be diabetic, and had higher listing model for end-stage liver disease (MELD) scores compared to PBC and PSC patients. Patients with PBC and AIH were more likely to be removed from the waitlist due to death or clinical deterioration. On competing risk analysis, AIH patients had a similar risk of being removed from the waitlist compared to those with PBC (subdistribution hazard ratio (SHR) 0.94, 95% CI 0.85–1.03) and higher risk of removal compared to those with PSC (SHR 0.8, 95% CI 0.72 to 0.89). Conclusion: Autoimmune hepatitis carries a similar risk of waitlist removal to PBC and a higher risk than PSC. The etiology of this disparity is not entirely clear and deserves further investigation.

Overlap syndrome is a spectrum of clinical manifestations of autoimmune hepatitis (AIH), Primary Biliary Cholangitis (PBC), and Primary Sclerosing Cholangitis (PSC). It is extremely rare for PBC, PSC, and AIH to occur in the same patient. We present a 48-year-old Hispanic man with a history of SLE who presented with elevated liver enzyme. He was found to have liver cirrhosis and diagnosed with PBC, PSC, and probable AIH overlap syndrome. To our knowledge, this is only the second reported case of all these diseases overlapping in the same patient; and the first reported case in a patient with SLE.

{"href":"Single Video Player","role":"media-player-id","content-type":"play-in-place","position":"float","orientation":"portrait","label":"","caption":"","object-id":[{"pub-id-type":"doi","id":""},{"pub-id-type":"other","content-type":"media-stream-id","id":"1_cdq2peg7"},{"pub-id-type":"other","content-type":"media-source","id":"Kaltura"}]}

Multiple Choice Questions

To evaluate the frequency of cholestatic pattern in patients with autoimmune hepatitis (AIH) and to identify predictive factors associated with the development of the overlap syndrome. Eighty-two consecutive patients diagnosed with AIH at the referral centre between January 1998 and June 2002 were included in the study. The new scoring system modified by the International Autoimmune Hepatitis Group was used to classify patients as definite/probable. Overlap syndrome was considered when the patient had clinical, serological and histological characteristics of two conditions: AIH and primary biliary cirrhosis (PBC) or AIH and primary sclerosing cholangitis (PSC). From the 82 AIH patients (76 female and six male), 84.1% presented definite AIH (> 15 points) and 15.9% probable AIH (10 - 15 points). The frequency of the overlap syndrome was 20%: 13% with PBC and 7% with PSC. In the univariate analysis the overlap syndrome was associated with male gender (P = 0.01), age < 35 years (P < 0.0001), histopathological aspect of cholestasis (P < 0.0001), suboptimal response to treatment (P < 0.0001) and probable AIH (P < 0.0001). Age < 35 years, probable AIH and the absence of anti-nuclear antibody (ANA) have been identified as independent indicators of the overlap diagnosis by the logistic regression analysis. Patients with overlap syndrome between AIH and primary cholestatic liver disease are frequently diagnosed in clinical practice, representing 20% of AIH cases in our study. The independent predictive factors associated with the diagnosis of overlap syndrome are young age, ANA(-) profile, and probable diagnosis according with the scoring system for AIH.

Overlap syndrome of primary biliary cirrhosis and autoimmune hepatitis with unusual initial presentation as fulminant hepatic failure