Case 3 -

Overlap Syndrome of Primary Biliary Cirrhosis and Autoimmune Hepatitis Julia C. Iezzoni

Clinical History The patient, a 52-year-old Caucasian female, presented with complaints of pruritis. Laboratory studies demonstrated markedly elevated aminotransferases and moderately elevated alkaline phosphatase and gamma-glutamyltranspeptidase (GGT). Viral serologies were negative, but anti-nuclear antibodies and anti-smooth muscle antibodies were present at titers of 1:640 and 1:160, respectively. Anti-mitochondrial antibodies also were detected. A liver biopsy was performed. Diagnosis: Overlap Syndrome of Primary Biliary Cirrhosis and Autoimmune Hepatitis Case 3 - Figure 1 - H&E Case 3 - Figure 2 - H&E Case 3 - Figure 3 - H&E Case 3 - Figure 4 - H&E Pathologic findings: The liver biopsy demonstrates a prominent portal lymphoplasmacytic inflammatory infiltrate, with associated bile duct damage, and a portal-base nonnecrotizing epithelioid granuloma. In other portal tracts, there is significant interface hepatitis. Discussion It is generally accepted that primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), and autoimmune hepatitis (AIH) each have an autoimmune basis. Conceptually, these autoimmune liver diseases can be divided into two main categories, hepatitic and cholestatic, based on the putative target - the hepatocyte (in AIH) or the bile duct (in PBC and PSC). This likely cellular site of attack is reflected in the pattern of the serum liver enzyme and function tests abnormalities and the histologic features, as discussed below. PBC and PSC on one hand, and AIH on the other hand, are generally differentiated easily on the basis of clinical, biochemical, serological, radiological, and histological findings. However, occasionally there are cases in which the findings are an admixture of those typical of PBC or PSC and those typical of AIH, and the classification of such cases of chronic liver disease is difficult. These so-called "overlap syndromes" are a heterogeneous group of disorders, and the specific criteria for their diagnosis are not uniformly defined. The correct identification of the AIH in the setting of either PBC or PSC has important therapeutic implications, however, as this autoimmune hepatitic component may respond to immunosuppressive therapy. The histologic examination of the liver biopsy is a key part of the evaluation of a patient with possible overlap syndrome. Primary biliary cirrhosis is a form of chronic cholestatic liver disease in which there is progressive destruction of the small and medium-sized intrahepatic bile ducts by a non-suppurative inflammatory process. It is a disease primarily of middle-aged women, with a female:male ratio of 10:1. The pattern of liver biochemistry is cholestatic, with elevated ALP and GGT. Most cases of PBC are associated with high titers of circulating antimitochondrial antibodies (AMA), and a positive AMA is now considered the major diagnostic hallmark of the disease. Approximately 5% - 10% of cases, however, are AMA-negative. In the published literature these AMA-negative cases have been referred to as "autoimmune cholangitis", "autoimmune cholangiopathy", and "AMA-negative PBC". As the histological features and natural history of the AMA-positive and AMA-negative cases generally are indistinguishable, these are considered to be essentially one entity for the purpose of most discussion. Early in its course, PBC is characterized histologically by a portal mixed inflammatory infiltrate, composed of lymphocytes, plasma cells, and eosinophils, that is centered around the bile ducts. Lymphocytes infiltrate the biliary epithelium focally, with evidence of damage (so-called florid duct lesions), and non-necrotizing epithelioid granulomas may be present in the portal tracts. At this stage, the inflammation is confined to the portal tracts, and the limiting plates are intact. Injury of the bile ducts leads to proliferation of bile ductules, and as the disease progresses, the inflammatory infiltrate extends from the portal tracts, through the limiting plate, and into the surrounding hepatic parenchyma. As a result of the ongoing injury, fibrosis develops, and eventually progresses to cirrhosis. While there is no cure for PBC, ursodeoxycholic acid (UDCA) therapy has led to an increase in the survival of patients with PBC. Primary sclerosing cholangitis also is a form of chronic cholestatic liver disease, and it is characterized by progressive fibro-obliterative destruction of segments of the biliary tree. The disease typically affects the extrahepatic and large intrahepatic ducts. The small intrahepatic ducts also may be involved, and in about 5% of the cases of PSC, the small ducts are affected exclusively - so-called "small duct PSC". Most patients with PSC are male, and the onset generally is before age 45 years. The disease also occurs in children. Approximately 70% of patients with PSC have ulcerative colitis, and there is a strong association of PSC with other autoimmune diseases. The pattern of liver biochemistry is cholestatic, with elevated ALP and GGT. The "gold standard" for the diagnosis of PSC is the pattern of abnormality observed with endoscopic retrograde cholangiography (ERCP), specifically stricturing and proximal dilatation of the bile ducts, giving them a "beaded" appearance. While the histologic findings of the extrahepatic bile ducts are characterisitic (i.e. progressive concentric fibrosis and eventual obliterative sclerosis), these large bile ducts rarely can be demonstrated by a percutaneous liver biopsy. The histologic appearance of the hepatic parenchyma is that of chronic large duct obstruction, with bile ductular prolferation and portal and periportal lymphocytic inflammation. With ongoing injury, there is progressive fibrosis and eventual cirrhosis. The severity of symptoms and rate of progression to cirrhosis in PSC are highly variable. Currently, there is no effective therapy for PSC. Autoimmune hepatitis is a form of chronic hepatitis characterized by a predominence in females, polyclonal hypergammaglobulinemia, a variety of defined autoantibodies (e.g. ANA, SMA, or LKM-1), and an immunogenetic predisposition (HLA DR3 or DR4), in the absence of hepatitic viral infection. The pattern of liver biochemistry is hepatitic, with AST or ALT > ALP. There are no morphologic features that are pathognomonic of AIH, but the characteristic histologic picture is that of an interface (periportal or periseptal) hepatitis with a predominantly lymphoplasmacytic necroinflammatory infiltrate, with or without lobular (intra-acinar) involvement. In cases of more severe disease or during disease "flares", there may be portal-portal or central-portal bridging necrosis, often with the formation of liver cell rosettes and nodular regeneration. If left untreated, patients with AIH generally progress from periportal and lobular damage to bridging fibrosis and cirrhosis; at any stage, fulminant acute "flares" of disease may intervene. Most cases of AIH respond significantly to immunosuppressive therapy, and in some patients, there is evidence of reversal of fibrosis and cirrhosis with this treatment. While the hallmarks of PBC and PSC are the presence of AMA and cholangiographic abnormalities, respectively, unfortunately, there is no analogous diagnostic marker that is specific for AIH. While AIH is characterized by the constellation of findings described above, many of these features occur with variable frequency and magnitude of severity in a wide range of other liver diseases. Since AIH is devoid of specific, pathognomonic features, historically, the criteria used to diagnosis AIH varied greatly between institutions. To establish a consensus, in 1992 the International AIH Group agreed upon criteria for the diagnosis of AIH. This included a descriptive set of criteria, which was recommended for diagnostic use in routine clinical practice, and a numerical scoring system, which could be used in conjunction with the descriptive criteria for diagnostically difficult cases or for research purposes. The descriptive criteria and the numerical scoring system each classify patients as having either "definite" or "probable" AIH, depending on the strength of the clinical and histologic data. While subsequent studies documented that these criteria imparted a high sensitivity for the diagnosis of AIH, they suffered from a lack of specificity, especially in the numerical scoring of "probable" AIH. As such, in 1998, these criteria were modified, among other things, to exclude cholestatic liver disease. The resultant descriptive and numercial scoring systems are shown in Table 1 and 2, respectively. While these criteria currently are used in clinical practice and research studies, it is acknowledged that they should be re-evaluated periodically to assess their diagnostic accuracy and clinical relevance. An overlap syndrome between PBC and AIH has been described, and in this disorder, there is an admixture of some (but not necessarily all) of the biochemical and histological characteristics of each separate disease. PBC and AIH may occur either simultaneously or consecutively in this syndrome. While the establishment of diagnostic criteria awaits a consensus, one of the major studies of the PBC-AIH overlap syndrome required the following: for the diagnosis of each disease (namely PBC and AIH), the presence of at least two of the three following criteria was required. The PBC criteria were: 1) serum ALP levels at least two times the upper limit of normal values; 2) a positive test for AMA; 3) liver histology that had florid bile duct lesions. The AIH criteria were: 1) serum ALT levels at least five times the upper limit of normal values; 2) serum immunoglobulin G levels at least two times the upper limit of normal values; 3) liver histology that had moderate to severe periportal or periseptal hepatocellular lymphocytic piecemeal necrosis. With these criteria, the study found that 9% of patients with PBC additionally had features of AIH; as such, the presence of overlap with AIH is not rare among patients with PBC. In these patients, the presence of interface hepatitis, of moderate or severe degree, and lobular inflammatory activity, key features of AIH, appeared to identify a subset of PBC patients in whom immunosuppressive agents may be of therapeutic benefit. It was recommended that patients with PBC-AIH overlap syndrome be treated with a combination of UDCA and corticosteroids. An overlap syndrome of PSC and AIH has been described and consists of a combination of features of PSC and AIH. The disease mainly occurs in younger adults, but children also may be affected. In investigations of cases of possible PSC-AIH overlap syndrome, the presence of PSC was documented by ERCP, and these patients then were evaluated for features of AIH. In the reported studies, the prevalence of AIH in patients with PSC varied from 1.4% - 8% for "definite" AIH and 6% - 22% for "probable" AIH. The criteria used for the diagnosis of an AIH component, however, varied between studies, and this difference likely accounts for the conflicting reports of the prevalence of AIH in patients with PSC. Specifically, a higher prevalence of AIH in PSC cases was found when the diagnosis of AIH was based on conventional descriptive criteria, whereas a lower prevalence was determined when the revised numerical scoring system for AIH was applied. Of note, regardless of the diagnostic criteria used, most of the reported cases of PSC-AIH overlap syndrome histologically demonstrated interface hepatitis and a prominent lymphoplasmacytic inflammatory infiltrate. Additionally, there are reports of response to immunosuppressive therapy in these patients. As is apparent from the above discussion, the identification of an autoimmune overlap syndrome is highly dependent on the criteria used for the diagnosis, especially those used for the identification of an AIH component. While the specific diagnostic criteria for overlap syndromes require further studies for clarification and validation, it is apparent that overlap syndromes do exist. To this end, it has been hypothesized that autoimmune liver disease is a spectrum, with a continuum from one disease to the next. PSC/PBC and AIH are extreme points on the opposite ends of this spectrum, and the various overlap syndromes fall somewhere inbetween. The correct identification of an overlap syndrome has important therapeutic implications, as the AIH component may respond to immunosuppressive therapy. The liver histology therefore has an important diagnostic and therapy-defining role. As such, the recommendation issued by the International AIH Group regarding the diagnosis of AIH may be applied aptly to the diagnosis of overlap syndromes - "a diagnosis…should not be made without liver histology - and consultation with a hepatopathologist is strongly recommended." References Chazouilleres O, Wendum D, Serfaty L, Montembault S, Rosmorduc O, Poupon R. Primary biliary cirrhosis-autoimmune hepatitis overlap syndrome: clinical features and response to therapy. Hepatol 1998;28:296-301. Chazouilleres O. Diagnosis of primary sclerosing cholangitis-autoimmune hepatitis overlap syndrome: to score or not to score? J Hepatol 2000;33:661-3. International Autoimmune Hepatitis Group Report. Review of criteria for diagnosis of autoimmune hepatitis. J Hepatol 1999;31:929-38. Johnson PJ, McFarlane IG. Meeting report: International autoimmune hepatitis group. Hepatol 1993;18:998-1005. Kaya M, Angulo P, Linder KD. Overlap of autoimmune hepatitis and primary sclerosing cholangitis: an evaluation of a modified scoring system. 2000;33:537-42. Lohse AW, zum Buschenfelde K-HM, Franz B, Kansler S, Gerken G, Dienes H-P. Characterization of the overlap syndrome of primary biliary cirrhosis (PBC) and autoimmune hepatitis: evidence of it being a hepatitic form of PBC in genetically susceptible individuals. Hepatol 1999;29:1078-84. Poupon R, Chazouilleres O, Poupon RE. Chronic cholestatic diseases. J Hepatol 2000;32(suppl 1):129- 40. van Buuren HR, van Hoogstraten HJF, Terkivatan T, Schalm SW, Vleggaar FP. High prevalance of autoimmune hepatitis among patients with primary sclerosing cholangitis. J Hepatol 2000;33:543-8. Table 1: Revised descriptive criteria for diagnosis of autoimmune hepatitis Features Definitive Probable Liver histology Interface hepatitis (as defined in text) of moderate or severe activity with or without lobular hepatitis or central-portal bridging necrosis, but without biliary lesions or well-defined granulomas or other prominent changes suggestive of a different etiology. Same as for "definite". Serum biochemistry Any abnormality in serum aminotransferases, especially (but not exclusively) if the serum alkaline phosphatase is not markedly elevated. Normal serum concentrations of a1-anti-trypsin, copper, and ceruloplasmin. Same as for "definite" but patients with abnormal concentrations of copper or ceruloplasmin may be included, provided that Wilson's disease has been excluded by appropriate measures. Serum immunoglobulins Total serum globulin or g-globulin or IgG concentrations greater than 1.5 times the upper normal limit. Any elevation of serum globulin or g-globulin or IgG concentrations above the upper normal limit. Serum autoantibodies Seropositivity for ANA, SMA, or anti-LKM-1 antibodies at titres greater than 1:80. Lower titres (particularly titres of anti-LKM-1) may be significant in children. Seronegativity for AMA. Same as for "definite" but at titres of 1:40 or greater. Patients who are seronegative for these antibodies but who are seropositive for other antibodies specified in the text may be included. Viral markers Seronegativity for makers of current infection with hepatitis A, B, and C viruses Same as for "definite". Other etiologic factors Average alcohol consumption less than 25g/day. No history of recent use of known hepatotoxic drugs. Alcohol consumption less than 50g/day and no recent use of known hepatotoxic drugs. Patients who have consumed larger amount of alcohol or who have recently taken potentially hepatotoxic drugs may be included,if there is clear evidence of continuing liver damage after abstinence from alcohol or withdrawal of the drug. Tables 2A-C: Revised scoring system for diagnosis of autoimmune hepatitis Table 2A: Revised scoring system for diagnosis Parameter/Features Score Notes* Female gender +2 ALP:AST (or ALT) ratio: 1 <1.5 +2 1.5-3.0 0 >3.0 -2 Serum globulins or IgG above nomal >2.0 +3 1.5-2.0 +2 1.0-1.5 +1 <1.0 0 ANA, SMA, LKM-1 2 >1:80 +3 1:80 +2 1:40 +1 <1:40 0 AMA positive -4 Hepatitis viral markers: 3 Positive -3 Negative +3 Drug history: 4 Positive -4 Negative +1 Average alcohol intake <25g/day +2 >60g/day -2 Liver histology: Interface hepatitis 3+ Predominantly lymphoplasmacytic infiltrate 1+ Rosetting of liver cells 1+ None of the above -5 Biliary changes -3 5 Other changes -3 6 Other autoimmune disease(s) +2 7 Optional additional parameters: 8 Seropositivity for other defined autoantibodies 2+ 9 HLA DR3 or DR4 1+ 10 Response to therapy: 11 Complete +2 Relapse +3 Interpretation of aggregate scores: Score Notes* Pre-treatment: Definite AIH >15 Probable AIH 10-15 Post-treatment Definite AIH >17 12 Probable AIH 12-17 * See explanatory notes in Table 2B Table 2B: Explanatory notes for Table 2A The ALP:AST (or ALT) ratio relates to the degree of elevation above the upper normal limits (unl) of these enzymes, i.e.=(IU/l ALP unl ALP) )IU/l AST unl AST). Titres determined by indirect immunofluorescence on rodent tissue or, for ANA, on Hep-2 cells. Lower titres (especially of LKM-1) are significant in children and should be scored at least +1. Score for markers of hepatitis A, B and C viruses (i.e. positive/negative for IgM anti-HAV, HbsAg, IgM anti-Hbc, anti-HCV and HCV-RNA). If a viral etiology is suspected despite seronegativity for these markers, test for other potentially hepatotropic viruses such as CMV and EBV may be relevant. History of recent or current use of known or suspected hepatotoxic drugs. "Biliary changes" refers to bile duct changes typical of PBC or PSC (i.e. granulomatous cholangitis, or severe concentric periductal fibrosis, with ductopenia, established in an adequate biopsy specimen) and/or a substantial periportal ductular reaction (so-called marginal bile duct proliferation with cholangiolitis) with copper/copper-associated protein accumulation. Any other prominent feature or combination of features suggestive of a different etiology. Score for history of any other autoimmune disorder(s) in patient or first-degree relative. The additional points for other defined autoantibodies and HLA DR3 or DR4 (if results for these parameters are available) should be allocated only in patients who are seronegative for ANA, SMA, and LKM-1. Other "defined" autoantibodies are those for which there are published data relating to methodology of detection and relevance to AIH. These include pANCA, anti-LC1, anti-SLA, anti-ASGPR, anti-LP and anti-sulfatide (see text). HLA DR3 and DR4 are mainly of relevance to North European caucasoid and Japanese populations. One point may be allocated for other HLA Class II antigens for which there is published evidence of their associations with AIH in other populations. Assessment of response to therapy (as defined in Table 2C) may be made at any time. Points should be added to those accrued for features at initial presentation. Response and relapse as defined in Table 2C. Table 2C: Definitions of response to therapy Response Definition Complete Either or both of the following: marked improvement of symptoms and return of serum AST or ALT, billirubin and immunoglobulins values completely to normal within 1 year and sustained for at least a further 6 months on maintenance therapy, or a liver biopsy specimen at some time during this period showing at most minimal activity. or Either or both of the following: marked improvement of symptoms together with at least 50% improvement of all liver results during the first month of treatment, with AST or ALT levels continuing to fall to less than twice the upper normal limit within 6 months during any reductions towards maintenance therapy, or a liver biopsy with 1 year showing only minimal activity Relapse Either or both of the following: an increase in seurm AST or ALT levels of greater than twice the upper normal limit or a liver biopsy showing active disease with or without reappearance of symptoms, after a "complete" response as defined above. or Reappearance of symptoms of sufficient severity to require increased (or reintroduction of) immunosuppression, accompanied by an increase in serum AST or ALT levels after a "complete" response as defined above.