Cholestatic Phenotypes of Autoimmune Hepatitis

Accepted Manuscript Cholestatic Phenotypes of Autoimmune Hepatitis Albert J. Czaja, M.D

PII:

S1542-3565(13)01290-1

DOI:

10.1016/j.cgh.2013.08.039

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YJCGH 53483

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Clinical Gastroenterology and Hepatology

Received Date: 11 July 2013 Revised Date:

21 August 2013

Accepted Date: 21 August 2013

Please cite this article as: Czaja AJ, Cholestatic Phenotypes of Autoimmune Hepatitis, Clinical Gastroenterology and Hepatology (2013), doi: 10.1016/j.cgh.2013.08.039. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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CHOLESTATIC PHENOTYPES OF AUTOIMMUNE HEPATITIS Albert J. Czaja, M.D.

Running head: Cholestatic phenotypes of autoimmune hepatitis

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Manuscript number: CGH-D-13-00932.R1

Keywords: autoimmune hepatitis; cholestasis; atypical phenotypes; overlap

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Content: 4 tables; 2 figures; 81 references; 30 pages.

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Word count: abstract, 227; text, 5830 (including abstract, figure and table legends, and references)

From the Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, Minnesota USA.

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This review did not receive financial support from a funding agency or institution, and Albert J. Czaja, MD has no conflict of interests to declare. Albert J. Czaja, MD determined the theme of this manuscript, designed its format, reviewed the literature, selected the pertinent studies, drafted the manuscript, critically reviewed and revised its content, provided the photomicrographs from his own collection, typed the document, approved the final version, and submitted the manuscript for review. He received no writing or research assistance.

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Presented in part at the Annual Postgraduate Course of the American College of Gastroenterology, October 12, 2013, San Diego, California.

Address for Correspondence: Albert J. Czaja, M.D. Professor Emeritus of Medicine Mayo Clinic College of Medicine 200 First Street S.W. Rochester, Minnesota 55905 Telephone: 507-284-8118 Fax: 507-284-0538 e-mail: [email protected]

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ABSTRACT Autoimmune hepatitis can have cholestatic features that are outside the coded diagnostic

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criteria. These features have uncertain effects on the clinical presentation and progression of disease; popular designations that imply the overlap of diseases are presumptuous. Patients with autoimmune hepatitis can have anti-mitochondrial antibodies and coincidental bile duct injury or

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loss (2%–13% of patients), focal biliary strictures and dilations based on cholangiography (2%– 11%), or histologic changes of bile duct injury or loss in the absence of other features (5%–

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11%). These findings probably represent atypical manifestations of autoimmune hepatitis or variants of primary biliary cirrhosis or primary sclerosing cholangitis, depending on the predominant findings. Serum levels of alkaline phosphatase and γ-glutamyl transferase, histologic features of bile duct injury, and findings from cholangiography are associated with responsiveness to corticosteroid therapy and individualized, alternative treatments.

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Corticosteroid therapy, in combination with low-dose ursodeoxycholic acid, has been promulgated by international societies, but these recommendations are not based on strong

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evidence. The frequency, variable outcomes, and uncertainties in diagnosis and management of the cholestatic phenotypes must be addressed by a collaborative investigational network. This

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network should define the genetic and pathology features of these disorders, standardize their nomenclature, and establish a treatment algorithm. In this review, the different cholestatic phenotypes of autoimmune hepatitis, mechanisms of pathogenesis, current management strategies and outcomes, and opportunities for improving understanding and therapy are presented.

KEY WORDS: autoimmune hepatitis; cholestasis; overlap

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Autoimmune hepatitis (AIH) is defined by clinical, laboratory, and histological findings as a hepatitic rather than a cholestatic syndrome. (1) Indeed, the original codified diagnostic

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criteria for AIH were revised specifically to exclude cholestatic manifestations, (2) and the current comprehensive diagnostic scoring system protects the hepatitic phenotype of AIH by subtracting diagnostic points if the ratio of the serum alkaline phosphatase (AP) level to serum aspartate

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(AST) or alanine (ALT) aminotransferase level is too high, antimitochondrial antibodies (AMA) are present, or the histological examination discloses bile duct damage, destruction, or loss. (2)

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Cholestatic features in patients with otherwise typical AIH cannot be accommodated in conventional diagnostic categories, and they constitute variant syndromes. (3-5) Because the features frequently are reminiscent of primary biliary cirrhosis (PBC) (6) or primary sclerosing cholangtitis (PSC), (7) their clustering in AIH has generated the popular nomenclature of the overlap syndromes. (8-10) These overlap syndromes are clinical descriptions and not valid

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pathological entities. Their major clinical value is to identify individuals who may not respond to the conventional treatment regimens used for classical AIH. (4, 5) Inflammatory and destructive biliary changes have been described in the liver tissue of

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patients with AIH for more than four decades, (11, 12) and the association of cholestatic clinical

(13-15)

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and histological features with corticosteroid-refractory disease has long been recognized in AIH. The diversity of these manifestations and the uncertain effect of these changes on outcome

have warranted the exclusion of patients with a cholestatic phenotype from treatment trials. The goals of this review are to describe these cholestatic phenotypes, indicate current diagnostic criteria, suggest hypotheses for their occurrence, detail current management strategies and outcomes, and identify opportunities for improving classification, treatment, and understanding.

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Cholestatic Phenotypes of AIH There are three principal cholestatic phenotypes of AIH. (4, 5, 8-10) Patients may have

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AMA and histological findings of bile duct injury or loss that suggests PBC. They may have absence of AMA and endoscopic retrograde (ERC) or magnetic resonance (MRC)

cholangiograms that suggest PSC, or they may have a cholestatic syndrome characterized by the

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absence of AMA, normal ERC or MRC, and histological features of bile duct injury or loss. This latter category is probably heterogeneous and may include AMA-negative PBC and small

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duct PSC. (16, 17)

In each cholestatic phenotype, AIH is the predominant disease. (8-10) Patients in whom the cholestatic features of PBC or PSC are more pronounced than the hepatitic features of AIH should be considered separately as variants of PBC or PSC. (9, 10) These patients commonly have cirrhosis, portal hypertension, gastrointestinal bleeding, ascites, and esophageal varices (18) or

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reduced survival after corticosteroid treatment. (19) Patients with predominantly AIH and cholestatic phenotypes cannot be equated with patients with predominantly cholestatic liver

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disease and features of AIH. (8-10)

Cholestatic Findings Atypical in Classical AIH

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Essential to the concept of cholestatic AIH is an awareness of the cholestatic manifestations that are atypical in classical AIH. (9, 10) The serum AP level is more than two-fold the upper limit of the normal range (ULN) in only 21% of patients with classical AIH, and the level is greater than four-fold ULN in 0% (Table 1). (14) A serum AP level above two-fold ULN in an adult with AIH suggests the possibility of a cholestatic phenotype, and a level greater than four-fold ULN compels its consideration.

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The mean serum γ-glutamyl transferase (GGT) level is increased above ULN in patients with classical AIH, especially in males, and it is higher in patients with type 1 AIH than in

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patients with type 2 AIH. (20) The serum GGT abnormality typically improves during immunosuppressive therapy, and the abnormality is probably another laboratory manifestation of diffuse histological injury associated with liver inflammation. (20) Importantly, patients with

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typical AIH who have had limited responses to immunosuppressive therapy have had

significantly higher baseline serum GGT levels than patients who have responded completely to

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treatment. (21) These findings suggest that determinations of the serum GGT level at presentation and during treatment may be useful in suggesting a strong cholestatic component that is refractory to immunosuppressive treatment, especially if the level does not improve. Lymphoid and pleomorphic cholangitis are present in 7-9% of patients with classical AIH, (22) and isolated lesions of destructive cholangitis (florid duct lesions) can be identified in 0-

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5% (Table 1). (22, 23) Histological evidence of bile duct injury or loss is sufficiently unusual in classical AIH to signal the possibility of a cholestatic phenotype, and the finding should expand

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the diagnostic effort. (14, 24, 25)

Focal biliary strictures and dilations of the biliary tree suggest the presence of PSC, and

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the demonstration of these changes by ERC or MRC in patients with AIH establishes a cholestatic phenotype (Table 1). Typical biliary changes of PSC occur in less than 2% of adults with classical AIH (26) unless they have concurrent inflammatory bowel disease. (15) Forty-one percent of adults with AIH and chronic ulcerative colitis who undergo cholangiography have biliary changes of PSC, (15) and the frequency of this finding warrants biliary imaging in all such patients. (4, 15)

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Previous concern about the presence of unsuspected biliary changes by MRC in 10% of adults with AIH (27) was not corroborated in a study using a disease-control population, (26) and

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routine cholangiography has not been justified in adults with uncomplicated classical AIH. (26) The threshold for cholangiography may be lower in children with AIH because of the frequency of autoimmune sclerosing cholangitis. (28)

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Other clinical features suggestive of a cholestatic phenotype in AIH are the presence of AMA, including antibodies to the E2 subunit of the pyruvate dehydrogenase complex, (14, 29-31)

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abnormally increased serum immunoglobulin M level, (14) and positive rhodanine stain for hepatic copper content (Table 1). (14) Each finding warrants further investigation. Diagnostic Criteria for the Cholestatic Phenotypes of AIH

Diagnosis depends on a clinical judgment that incorporates laboratory, histological and radiological findings (Table 2). (8-10) The comprehensive and the simplified diagnostic scoring

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systems for AIH (2, 32) are not discriminative diagnostic indices, and they cannot be used to define cholestatic AIH or imply the presence of AIH in predominantly cholestatic liver diseases. (8-10)

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Each scoring system has been deficit in detecting cholestatic phenotypes of AIH, and liver tissue examination has been the most valuable diagnostic instrument when coupled with clinical

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judgment. (33, 34)

Serological tests may also be useful in clarifying the diagnosis, and enzyme immunoassays designed to detect antibodies against diverse PBC-specific antigens may characterize patients with AIH and otherwise unclassifiable cholestatic disease. (35) Furthermore, the presence of concomitant AMA and antibodies to double-stranded deoxyribonucleic acid (anti-dsDNA) has distinguished patients with features of AIH and PBC. (36)

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Cholestatic Phenotype of AIH with AMA and Histological Features of Cholangitis The “Paris criteria” have been endorsed (with one modification) by the European

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Association for the Study of the Liver (EASL) for the diagnosis of patients with features of AIH and PBC (Table 2). (37) According to the EASL criteria, all patients with this mixed phenotype must have interface hepatitis (the one modification of the “Paris citeria”). (8, 37) They must also

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have a serum ALT level ≥5-fold ULN, a serum immunoglobulin G (IgG) level ≥2-fold ULN, or smooth muscle antibodies (SMA). (37, 38) The PBC component must have two of three additional

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features, including serum AP level ≥2-fold ULN or GGT level ≥5-fold ULN, AMA, and florid duct lesions (destructive cholangitis) on histological examination. (37, 38) The “Paris criteria” have a diagnostic sensitivity of 92% and specificity of 97% when compared to clinical judgment, but they identify the most extreme form of the disease. (39) Application of these criteria to a large cohort of patients with PBC has indicated that only 1%

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satisfy “Paris criteria” for a mixed syndrome of PBC and AIH. (40) Furthermore, the “Paris criteria” have been derived from a cohort of patients with PBC rather than AIH, and they select

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patients with equally prominent manifestations of PBC and AIH. Patients with predominant features of AIH and ancillary features of AMA, serum AP level <2-fold ULN, and isolated

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features of bile duct injury or destruction, have a cholestatic phenotype that is not recognized by the “Paris criteria”. (4, 40)

Cholestatic Phenotype of AIH with Cholangiographic Abnormalities Focal strictures and dilatations of the biliary tree by ERC or MRC in patients with AIH define a cholestatic phenotype associated with features reminiscent of PSC (Table 2). (4, 8-10, 41, 42) Histological changes may disclose interface hepatitis with or without plasma cells, portal edema or fibrosis, ductopenia, ductal tortuosity, ductular proliferation, cholate stasis, or rarely

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obliterative fibrous cholangitis. (10, 24, 43) Inflammatory bowel disease is present in 16% of adults with AIH, and its presence compels the performance of cholangiography to exclude PSC. (15, 44)

(45)

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Serum AP levels are normal at presentation and during follow-up in 22% of patients with PSC, and the presence of inflammatory bowel disease may be the only basis for suspecting PSC in

individuals with otherwise classical AIH.

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Cholestatic Phenotype of AIH without AMA or Cholangiographic Abnormalities

Autoimmune hepatitis may have laboratory and histological manifestations reminiscent

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of PBC or PSC but lack AMA and an abnormal cholangiogram (Table 2). (9, 10) These patients were probably categorized previously as “autoimmune cholangitis”, (24, 46, 47) and they may constitute a heterogeneous category that includes patients with AMA-negative PBC (48, 49) and small duct PSC. (16, 17, 50) The serum AP level is typically greater than two-fold ULN, and histological findings may include portal fibrosis, portal edema, and ductopenia reminiscent of

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PSC (Figure 1) or a dense lymphoplasmacytic portal infiltrate with interface hepatitis and bile duct injury suggestive of PBC (Figure 2). (24, 43)

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Comprehensive serological assessments using enzyme immunoassays based on recombinant antigens for gp210, sp100, and mitochondrial components have demonstrated

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antibodies supporting the diagnosis of PBC in 35% of AMA-negative patients with cholestatic features. (35) These assays may be similarly useful in defining the nature of this cholestatic phenotype of AIH.

Frequency of the Cholestatic Phenotypes of AIH The estimated overall frequency of the cholestatic phenotypes of AIH is 14-20%, (4, 51, 52) and composites of reported experiences indicate that the frequencies of the phenotypes with features of PBC, features of PSC, and features of an indeterminant cholestatic nature are 2-13%,

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2-11%, and 5-11%, respectively. (9, 10, 26, 40, 52, 53) Of patients with AIH and abnormal serum AP and GGT levels, features of PSC have been demonstrated in 50% by MRC.(54) In patients with

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PSC, 30% have had features of AIH by the revised international scoring system for AIH. (53) The variability in frequencies probably reflects the nature of the cohort in which the mixed phenotype is sought and the method applied to discover them. The cholestatic phenotypes of AIH have

Greece,(56) India, (57) Malaysia, (58) and Japan. (59)

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been described in North America,(4) northern Europe, (41) Italy, (53) Romania, (52) Turkey,(55)

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Hypotheses for the Occurrence of the Cholestatic Phenotypes of AIH

The cholestatic phenotypes of AIH lack distinctive pathogenic mechanisms and a valid pathological designation. They may simply represent variant or atypical manifestations of classical disease (Table 3). (9, 10, 60) Outer boundaries between the diagnostic categories of autoimmune liver disease are not rigidly defined, and distinctions between the entities may be

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blurred at these outer margins. (60, 61) The cholestatic phenotypes of AIH could be at the fringe of classical disease, (60) or they could be hepatitic forms of PBC or PSC and misclassified as AIH. The possibility of misclassification is supported by the rarity that the highly disease-specific

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(62)

features of PBC (florid duct lesions) and PSC (cholangiographic changes of biliary strictures and

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dilations) occur together. (63, 64) Indeed, almost all the variant syndromes involving PBC and PSC are based on the coexistence of non-specific features attributable to AIH. (38, 41) The cholestatic phenotypes of AIH could represent a transition stage in the evolution of classical PBC or PSC in which there are mixed features in an early formative stage (Table 3). (6567)

The autoimmune liver diseases evolve through different stages, and they may have

diagnostically confusing features at early stages of development. Stage 2 PBC can be difficult to distinguish from AIH by histological examination, and similar difficulties may be encountered in

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early stage PSC. (43) Plasma cell infiltration can be a histological feature of AIH, PBC and PSC, (43)

and this finding in concert with incidental bile duct injury associated with an early exuberant

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inflammatory response (22, 68) may suggest concurrent PBC or PSC in AIH. Antimitochondrial antibodies may be low titer and transient in AIH and misdirect the diagnosis by favoring

concurrent PBC. (14, 29, 30) The observed transitions of AIH to PBC, (67) AIH to PSC, (65) PBC to

the non-specific nature of the features associated with AIH.

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AIH, (66) and PSC to AIH (69) may constitute these evolutionary pathways or further exemplify

(70)

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The cholestatic phenotypes of AIH could represent two diseases in the same individual, or they could constitute distinct yet unendorsed pathological entities. (9, 10) Patients with

classical AIH can have highly disease-specific findings of PBC (florid duct lesions) or PSC (characteristic cholangiographic or histological abnormalities), and these disease-specific features in a patient with otherwise classical AIH support the possibility of concurrent diseases

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(Table 3). (70) Furthermore, patients with autoimmune liver diseases can share genetic predispositions that favor their concurrence. (71) The rarity that PBC and PSC coexist challenges this hypothesis, and it supports the concept that the mixed syndromes are actually classical

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diseases with non-specific inflammatory features that resemble AIH. (62-64)

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The possibility that the various cholestatic phenotypes of AIH represent separate pathological entities must also be considered (Table 3). (61) Promiscuous immune responses could target hepatocytes, intrahepatic bile ducts, and the extrahepatic biliary system and result in a single complex disease with distinctive, yet undiscovered, immune regulatory defects and genetic predispositions. (9, 10, 72, 73)

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Treatments and Treatment Outcomes of the Cholestatic Phenotypes of AIH The strength of the cholestatic component determines in part the responsiveness to

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conventional corticosteroid therapy, and the serum AP and GGT levels, the histological findings of bile duct injury or loss, and the cholangiographic findings are important factors in developing the appropriate management strategy. (4, 5, 14, 15, 38) In patients with classical PSC, a normal serum

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AP level at presentation or an improvement during follow-up of an abnormal serum AP level to less than 40% of the level at presentation has been associated with a higher cumulative

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proportion of patients surviving 12 years. (45) Furthermore, the longest survival has been in patients who improved their serum AP level spontaneously without ursodeoxycholic acid. (45) These findings re-confirm the value of the serum AP level and its behavior in reflecting disease severity and outcome in classical PSC regardless of treatment. (74) They also underscore the importance of monitoring the serum AP level and its behavior in the cholestatic phenotypes of

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AIH, especially if there are cholangiographic changes of focal biliary strictures and dilations. Treatment and Outcome of the Cholestatic Phenotype of AIH with AMA and Cholangitis

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Patients with cholestatic AIH, AMA, and histological evidence of isolated lymphoid, pleomorphic, or destructive cholangitis who have a serum AP level ≤2-fold ULN respond as well

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to conventional corticosteroid therapy as patients with classical AIH (Table 4). (4, 5, 14) They enter remission as commonly (81% versus 86%), and they fail treatment as infrequently (14% versus 9%). (4, 30, 31, 62) The mild cholestatic manifestations do not impact on the response to conventional corticosteroid therapy, and these patients can be managed like classical AIH. In contrast, patients with AIH and AMA that satisfy “Paris criteria” by having serum AP levels ≥2-fold ULN and florid duct lesions on histological assessment have strong PBC features. (38, 70, 75)

This close resemblance to PBC has generated reluctance to treat such patients with

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conventional corticosteroid regimens, and it has justified management strategies that include the administration of corticosteroids in combination with low dose ursodeoxycholic acid (13-15

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mg/kg daily) (38, 75) or ursodeoxycholic acid (13-15 mg/kg daily) alone (Table 4). (76) The combination regimen of corticosteroids with low dose ursodeoxycholic acid has significantly improved the serum AP, GGT and ALT levels in 12 patients satisfying “Paris

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criteria” for PBC and AIH, and it has prevented progressive hepatic fibrosis in 6 patients who underwent follow-up histological examination. (9, 10, 38, 75) The combination regimen has also

ursodeoxycholic acid alone in 5 patients. (38)

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achieved more complete results than treatment with corticosteroids alone in 6 patients and

Budesonide (3 mg thrice daily) in combination with ursodeoxycholic acid can be considered in non-cirrhotic patients in an effort to reduce side effects associated with conventional corticosteroid regimens. (77) Combined therapy with immunosuppressive

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medications and ursodeoxycholic acid has been endorsed by EASL for patients satisfying the “Paris criteria”, but this recommendation is not strongly evidence-based. (8, 37)

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Treatment and Outcome of the Cholestatic Phenotype of AIH with Abnormal Cholangiogram Patients with the cholestatic phenotype of AIH that includes cholangiographic changes

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indicating focal bile duct strictures and dilations may respond to conventional corticosteroid therapy. (17, 19, 41) The experiences reporting corticosteroid responsiveness in patients with AIH and abnormal cholangiograms did not characterize the outcomes by serum AP level, (17, 19, 41) and it is unclear if the patients who responded to corticosteroid therapy had normal or decreasing serum AP levels. (45, 74) Typically, patients with AIH and an abnormal cholangiogram are less corticosteroidresponsive and have a poorer survival than patients with classical AIH. (4, 9, 10, 15, 19, 42, 56) They

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enter remission less commonly (20% versus 86%), fail treatment more often (80% versus 14%), and die of liver failure or require liver transplantation more frequently (33% versus 8%). (4)

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Differences in corticosteroid response may reflect the predominance of PSC over AIH, and many patients with this phenotype might be better classified as having atypical or hepatitic PSC.

Patients with AIH and cholangiographic changes of PSC do not respond to therapy with

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mycophenolate mofetil, (78, 79) and experiences with the calcineurin inhibitors have been

promising but meager. (8-10, 17) Treatment with immunosuppressive drugs in combination with

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low dose ursodeoxycholic acid (13-15 mg/kg daily) has had inconsistent results (response frequency, 22-100%), (17, 80) but combination therapy has been used most widely. EASL (37) and the AASLD (7) have each endorsed immunosuppressive therapy in combination with low dose ursodeoxycholic acid as treatment for AIH with cholangiographic changes of PSC (Table 4). This recommendation is not strongly evidence-based or detailed

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regarding the preferred regimen. Prednisone or prednisolone (0.5 mg/kg daily tapered to 10-15 mg daily) and azathioprine (50-75 mg daily) in combination with ursodeoxycholic acid (13-15

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mg/kg daily) has been associated with lower frequencies of liver transplantation, malignancy, and death in adults with this syndrome than in adults with classical PSC, and this schedule is an

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appropriate treatment option (Table 4). (9, 10, 80) Importantly, high dose ursodeoxycholic acid (2830 mg/kg daily) should not be used because of adverse outcomes probably associated with the hepatic toxicity of lithocholic acid. (81) Treatment and Outcome of the Cholestatic Phenotype of AIH of Uncertain Nature Treatment options for patients with the cholestatic phenotype of AIH of an uncertain nature are also limited. (9, 10) These patients respond as poorly to conventional corticosteroid therapy as patients with AIH and cholangiographic changes of PSC, (4) and 88-100% fail to

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improve to normal or near-normal liver tests. (4, 24) Furthermore, 17% experience disease progression, (4, 24) and 33% require liver transplantation. (4) Corticosteroid regimens have been

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generally ineffective, and therapies with low dose ursodeoxycholic acid alone has achieved laboratory and histological improvement in only 12%, whereas its combination with

corticosteroids has had variable results in small numbers. (24) Therapy usually involves

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corticosteroids alone, low dose ursodeoxycholic acid alone, or corticosteroids in combination with ursodeoxycholic acid depending on the intensity of the cholestatic features as reflected

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mainly by the serum AP level and the extent of bile duct injury or loss (Table 4). (5, 9, 10) Overview

The cholestatic phenotypes of AIH have clinical relevance that warrants their separation from classical AIH and compels their recognition as important clinical entities. (4, 13-15, 17, 19, 38, 80) The severity of cholestasis has been associated with diminished corticosteroid responsiveness, (4, and characterization of the cholestatic features that distinguish the phenotype is

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13-15, 17, 38)

essential to develop an appropriate management strategy. (8) The International Autoimmune Hepatitis Group (IAIHG) anticipated the possible proliferation of terms for mixed syndromes

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and proposed a moratorium on their use. (8) The designation of these mixed syndromes by their

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predominant disease and the restricted use of the diagnostic scoring system for AIH are the appropriate means to curtail the emergence of extraneous categories. The next steps are to acknowledge the clinical relevance of these cholestatic phenotypes, formalize their designations, and develop collaborative investigational networks that clarify genetic predispositions, pathogenic mechanisms, and management protocols. The cholestatic phenotypes have an estimated prevalence of 14-18% in patients with AIH, and this frequency should be sufficient to promote meaningful collaborative studies. Refinements in diagnosis and management must

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await a multicenter investigational impetus that is energized by the opportunity to define prognostic features, pathogenic mechanisms, and treatment strategies for clinically important but

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poorly understand and inadequately treated phenotypes of AIH.

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Table 1 Cholestatic Features in AIH Frequency in Classical AIH

Clinical Similarities

Abnormal serum AP or GGT level

Serum AP level>2-fold ULN in 21% of classical AIH and never >4-fold ULN (14) Serum GGT level never >5-fold ULN (38, 39)

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Cholestatic Features in AIH

PBC, PSC, small duct PSC, AMA-negative PBC

(4, 14, 16, 45)

Lymphoid or pleomorphic cholangitis in 7-9% of PBC, PSC (22) classical AIH (22) Florid duct lesions in 0-5% (23) Ductopenia, 0-7% (22, 23)

Abnormal ERC or MRC with biliary strictures and dilations

Abnormal ERC in 41% of adults with AIH and CUC (15) Abnormal ERC in 50% children with AIH (28) Abnormal MRC<2% of adults with classical AIH (26)

PSC (22) ASC in children (28)

AMA

AMA by IIF or ELISA, 7-34% (14, 30, 31) E2 subunit of pyruvate dehydrogenase, 8% (29)

PBC (6)

Predominant serum IgM abnormality

Predominant serum IgM elevation, 15% (14)

PBC, PSC (6, 7)

Increased hepatic copper concentration

Positive rhodanine stain, 9% (14)

PBC, PSC (6, 7)

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Concurrent inflammatory bowel disease

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Bile duct injury or loss

CUC in adults with classical AIH, 16% (15)

PSC (7)

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AIH, autoimmune hepatitis; AMA, antimitochondrial antibodies; AP, alkaline phosphatase; ASC, autoimmune sclerosing cholangitis; CUC, chronic ulcerative colitis; ELISA, enzyme-linked immunosorbent assay; ERC, endoscopic retrograde cholangiography; GGT; gamma glutamyl transferase; IgM, immunoglobulin M; IIF, indirect immunofluoresence; MRC, magnetic resonance cholangiography; PBC, primary biliary cirrhosis; PSC, primary sclerosing cholangitis; ULN, upper limit of normal range. Superscripted numbers are references.

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Table 2 Diagnostic Criteria for the Cholestatic Phenotypes of AIH

Paris Criteria modified by EASL (8, 37, 38) Interface hepatitis on histological examination and one of the following: serum ALT level ≥5-fold ULN, serum IgG level ≥2-fold ULN, or SMA positive, and two of the following: serum AP level greater than 2-fold ULN (or serum GGT level ≥5-fold ULN), AMA positive, or florid duct lesions on histological examination

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AMA positivity and histological features of cholangitis

Diagnostic Criteria

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Cholestatic Phenotypes of AIH

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Outliers to EASL-modified Paris criteria (4) Predominant AIH by clinical criteria and AMA, serum AP ≤2-fold ULN, pleomorphic, lymphocytic or isolated destructive cholangitis Predominant AIH by clinical criteria and focal strictures and dilations of biliary tree by ERC or MRC (15, 26-28, 41) Concurrent chronic ulceration colitis frequent (15) Serum AP level commonly ≥2-fold ULN (15)

Histological features of cholangitis with AMA negativity and normal cholangiography

Predominant AIH by clinical criteria (24) Histological features of bile duct injury or loss (24, 46, 47) AMA absent (24, 46, 47) Normal ERC or MRC (24) Serum AP level commonly ≥2-fold ULN (24)

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Focal strictures and dilations of biliary tree by cholangiography

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AIH, autoimmune hepatitis; ALT, alanine aminotransferase; AMA, antimitochondrial antibodies; AP, alkaline phosphatase; EASL, European Association for the Study of the Liver; ERC, endoscopic retrograde cholangiography; GGT, gamma glutamyl transferase; IgG, immunoglobulin G; MRC, magnetic resonance cholangiography; SMA, smooth muscle antibodies; ULN, upper limit of the normal range. Superscripted numbers are references.

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Table 3 Hypotheses for the Occurrence of the Cholestatic Phenotypes of AIH Supporting Evidence

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Hypothesis

Clinical, laboratory, serological and histological features of AIH not disease-specific (1) Features of AIH described in various chronic liver diseases with welldefined, non-autoimmune etiologies (1) Diagnostic scoring systems for AIH that suggest new syndromes in classical diseases are misapplied (2, 8, 32) Outer boundaries for diagnosing classical diseases with uncommon manifestations are unknown (60) No evidence of distinctive genetic predisposition or pathogenic mechanism for cholestatic forms (71) Cholestatic AIH may actually be atypical PBC or PSC since the features of AIH are not disease-specific and those features which are disease-specific (florid duct lesions and cholangiographic changes of PSC) rarely coexist (15, 60, 62-64)

Transition state in the emergence of classical disease

Mixed clinical and histological features can occur in early stage autoimmune diseases (25, 43, 62, 68) Evolutionary sequences in classical autoimmune disease may suggest transitions from one type of autoimmune disease to another (66, 67)

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Atypical phenotype of classical AIH

Highly disease-specific findings such as biliary strictures and dilations by cholangiography and florid duct lesions by histological examination occur in some patients with otherwise classical AIH (70)

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Concurrent diseases

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Conversely, these same highly disease-specific features rarely coexist suggesting that the concurrence mainly involves classical PBC or PSC with non-specific features that resemble AIH (63, 64)

Unrecognized new disease

Promiscuous immune-mediated responses that are directed against hepatocytes may include cholangiocytes and/or the biliary tree (72) Target antigens and defects in immune regulatory mechanisms are yet undiscovered (73)

AIH, autoimmune hepatitis; PBC, primary biliary cirrhosis; PSC, primary sclerosing cholangitis. Superscripted numbers are references.

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Table 4 Treatments and Treatment Outcomes for the Cholestatic Phenotypes AIH

AMA and florid duct lesions

Treatment Outcomes

Endorsed by EASL Prednisone or prednisolone, 30 mg daily tapered over 4 weeks to 10 mg daily as maintenance dose and azathioprine, 50 mg daily (1) combined with UDCA, 1315 mg/kg daily(37)

Serum AP ≤2-fold ULN (4) Corticosteroid response, 81% (4) Deterioration on treatment, 14% (4) Outcome similar to classical AIH (4) Serum AP >2-fold ULN Laboratory improvement, 100% (38) Prevents progressive hepatic fibrosis (38) Better results than steroids or UDCA alone (38)

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Unendorsed options Budesonide (3 mg thrice daily) as prednisone substitute in combination with azathioprine and UCDA (77)

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Treatments

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Cholestatic Phenotype

UDCA (13-15 mg/kg daily) only (76)

80)

Corticosteroids and UDCA Laboratory response, 22-100% (17, 80)

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Conventional corticosteroid therapy Lab and histological response, 20-100% (4, 41) Deterioration, 80% (4) Hepatic death or transplantation, 33% (4)

No endorsed treatment Serum AP ≤2-fold ULN Prednisone or prednisolone, 30 mg daily tapered over 4 weeks to 10 mg daily as maintenance dose and azathioprine, 50 mg daily(1)

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Bile duct injury or loss by histological examination, AMA negative, and normal cholangiogram

Endorsed by EASL and AASLD Prednisone or prednisolone, 0.5 mg/kg daily tapered to 10-15 mg daily, and azathioprine, 50-75 mg daily, combined with UDCA, 13-15 mg/kg daily (7, 8, 37,

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Biliary strictures and dilations by cholangiography

Serum AP>2-fold ULN UDCA alone (13-15 mg/kg daily) or combined with prednisone (5, 9)

Conventional corticosteroid therapy Little or no response, 88-100% (4, 24) Worsening, 17% (4) Liver transplantation, 33% (4) UDCA therapy Lab and histological improvement, 12% (24) Little or no response, 88% (24) Corticosteroids and UDCA Uncertain (5)

AASLD, American Association for the Study of Liver Diseases; AIH, autoimmune hepatitis; AMA, antimitochondrial antibodies; AP, alkaline phosphatase; EASL, European Association for the Study of the Liver; Lab, laboratory tests; UDCA, ursodeoxycholic acid; ULN, upper limit of the normal range. Superscripted numbers are references.

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LEGENDS Figure 1. Ductopenia. Portal tract with portal venule, portal fibrosis and edema, and portal

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arteriole without accompanying bile duct. Cholangioles proliferate at the periphery of the portal tract, and periportal hepatocytes are mildly swollen (cholate stasis). Hematoxylin-eosin, original magnification, x 200. Reproduced from HEPATOLOGY, Albert J. Czaja, et al, Autoimmune

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2000, with the permission of John Wiley and Sons, Inc.

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cholangitis within the spectrum of autoimmune liver disease, volume 31, figure 3, page 1234,

Figure 2. Destructive cholangitis. Dense lymphoplasmacytic portal inflammation with lymphocytic destructive cholangitis in patient with features of autoimmune hepatitis, negative antimitochondrial antibodies, and normal cholangiogram. Hematoxylin-eosin, original

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magnification, x 200.

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FIGURE 1.

Ductopenia. Portal tract with portal venule, portal fibrosis and edema, and portal arteriole

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without accompanying bile duct. Cholangioles proliferate at the periphery of the portal tract, and periportal hepatocytes are mildly swollen (cholate stasis). Hematoxylin-eosin, original magnification, x 200. Reproduced from HEPATOLOGY, Albert J. Czaja, et al, Autoimmune cholangitis within the spectrum of autoimmune liver disease, volume 31, figure 3, page 1234, 2000, with the permission of John Wiley and Sons, Inc.

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FIGURE 2

Destructive cholangitis. Dense lymphoplasmacytic portal inflammation with lymphocytic

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destructive cholangitis in patient with features of autoimmune hepatitis, negative antimitochondrial antibodies, and normal cholangiogram. Hematoxylin-eosin, original magnification, x 200.