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
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.
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
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
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."
- 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. |
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. |
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.