Clinical �

Hepato-Gastroenterology 2010; 57:285-289© H.G.E. Update Medical Publishing S.A., Athens-Stuttgart

Therapy Response and Outcome of Overlap Syndromes: Autoimmune Hepatitis and Primary Biliary Cirrhosis Compared to

Autoimmune Hepatitis and Autoimmune Cholangitis

Ersan Ozaslan1, Cumali Efe1, Sabiye Akbulut1, Tugrul Purnak1, Berna Savas2, Esra Erden2, Emin Altiparmak1

1Numune Education and Research Hospital, Department Of Gastroenterology, 2Ankara Medical Faculty, İbni Sina Hospital, Department of Pathology, Ankara, Turkey

Corresponding Author: Ersan Ozaslan, Cukurambar Mah. 40. Cad. 5/13, Cankaya Ankara, Turkey

Tel: +903122873882, Fax: +903123125026, E-mail: er72@hotmail.com

KEY WORDS: Autoimmune hepatitis; Primary Biliary cirrhosis; Autoimmune cholangitis; AMA-negative primary biliary cirrhosis; Therapy

Background/Aims: We have assessed two dif-ferent overlap syndrome groups in patients with AIH-PBC and AIH-AIC, with respect to therapy response and outcome.Methodology: In this retrospective, non-ran-domized study, a total of 22 overlap cases were collected, 12 of those had a simultaneous form of AIH-PBC and 10 of those with AIH-AIC. Two groups were compared in terms of clinical, bio-chemical, immunological, histological features and response to treatment. The mean follow-up time was 31.7±11.0mo in AIH-PBC and 41.1±29.6mo in AIH-AIC, respectively.Results: The clinical and laboratory characteris-tics at presentation were not significantly differ-ent between the two groups, except a higher se-rum IgM level and lower AIH score in AIH-PBC group compared to AIH-AIC group (p<0.05). First-line treatment was UDCA alone in 3 of AIH-PBC

group and combination of UDCA and immunsup-pressives in the remaining AIH-PBC (n=9) and in all of the AIH-AIC (n=10). During follow-up, only one of 10 patients in AIH-AIC group, but six of 12 patients in AIH-PBC group progressed to liver failure. So, complete remission was significant-ly higher in the AIH-AIC than in the AIH-PBC group (%90 vs %50, p=0.045).Conclusion: To our results, in cases of AIH-PBC/AIC overlap, patients with high AIH score and negative AMA should be treated with combined therapy of corticosteroids and UDCA. However, patients with low AIH score and positive AMA should use UDCA firstly, if no response, the ad-dition of corticosteroids should be considered with close monitoring. In this cohort, the prognosis of AIH-PBC overlap was much worse than that of AIH-AIC.

ABSTRACT

INTRODUCTION

Autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) are the three important autoimmune diseas-es involving the liver. The term “overlap syndrome” describes variant forms of AIH which present with characteristics of AIH and PBC or PSC. AIH-PBC overlap syndrome is the most common type, in al-most 10% of adults with AIH or PBC (1-3).

It has been shown that ursodeoxycholic acid (UDCA) is effective in PBC (4) whereas immuno-suppressive therapy using corticosteroids alone or in association with azathioprine is the gold standart for AIH (5). Outcome and treatment results are less reported issues of overlap syndromes and whether AIH-PBC overlap syndrome requires immunosup-pressive therapy in addition to UDCA remains

controversial (2, 3). Some authors (6, 7) demonstra-ted a clear superiority of combination therapy, while others (8) found the response to UDCA therapy was enough.

Autoimmune cholangitis (AIC) was first report-ed as ‘immunocholangitis’ in 1987 (9) when three women were described who presented with signs and symptoms of PBC, but were AMA-negative and ANA-positive, and responded to immunosuppres-sive therapy. It is considered a disease of unknown cause that typically has serum ANA with or without SMA in serum and cholestatic clinical, laboratory, and/or histologic changes in the absence of AMA. This definition was coined to include PBC with non-typical presentation, small-duct primary sclerosing cholangitis, idiopathic adulthood ductopenia, and transitional stages of the classic diseases (10). Al-though a consensus is still awaited, recent studies

� Hepato-Gastroenterology 57 (�0�0) E Ozaslan, C Efe, S Akbulut, et al.

support the view that PBC and AIC are variants of one single disease only differing in serum autoan-tibody pattern, and named AIC as “AMA-negative PBC” (11-13). Concomitant features of AIH and AIC have been reported very rarely. In a case report, an AMA-negative woman with mixed biochemical and histological features of AIH and AIC responded to combined treatment with UDCA, prednisone, and azathioprine (14). Alric et al. (15) described seven patients with AIH-AMA negative PBC overlap who showed a favorable response to combined therapy.

Therefore, more studies are worthwhile in these rare patient groups of overlap syndrome to define the outcomes and optimal therapeutic strategies.

In the present study, we have assessed two differ-ent overlap syndrome groups in patients with AIH-PBC and AIH-AIC. In this retrospective non-rand-omized study, two groups were compared in terms of clinical, biochemical, immunological, histological features and response to treatment.

METHODOLOGY

Patients and diagnostic criteriaRecords of the patients with autoimmune liver

disease who were followed up at our Gastroenter-ology Unit from 2001 to 2007 were reviewed. The patients with AIH-PBC and AIH-AIC overlap syn-dromes were included in the study. In all patients, metabolic causes of liver disease had been ruled out, and hepatitis B and C virus serological tests were negative. No patient had history of alcohol abuse, hepatotoxic agent or inflammatory bowel disease. Extrahepatic biliary lesions had been excluded in all patients by abdominal ultrasound, and also by endoscopic retrograde cholangio-pancreatography (ERCP) in four patients of the AIH-PBC group and by magnetic resonance cholangiopancreatography (MRCP) in two patients of AIH-AIC group. The study groups included only simultaneous forms of overlap syndrome and each patient had a minimum follow-up of 1 year. According to these criteria, 22 patients were collected, 12 of those had a simultane-ous form of AIH-PBC and 10 of those with AIH-AIC overlap syndrome. Clinical and laboratory param-eters were obtained at the initial and at follow-up visits (every 3 to 6 months) after the initiation of therapy.

AIH-PBC overlap syndrome was defined by the simultaneous occurrence of AIH and PBC. For di-agnosis of each disease, presence of at least 2 of the 3 accepted criteria was required (16). AIH criteria were the following: (I) alanine aminotransferase (ALT) levels at least five times the upper limit of normal values (ULN), (II) serum immunoglobulin G (IgG) levels at least two times the ULN or a positive test for smooth muscle antibodies (ASMA), (III) a liver biopsy showing moderate or severe periportal or periseptal lymphocytic piecemeal necrosis. In ad-dition, AIH score was determined for each patient (17). PBC criteria were the following: (I) alkaline phosphatase (ALP) levels at least two times the ULN or γ glutamyltranspeptidase (GGT) levels at least five times the ULN, (II) a positive test for AMA by immunoflourescence, (III) a liver biopsy specimen showing florid bile duct lesions.

AIH-AIC overlap syndrome was defined by the simultaneous occurrence of AIH and AIC. AIH cri-teria were described above, and moreover AIH score was determined for each patient. AIC criteria were the following: (I) serum ANA and/or smooth muscle (SMA) positivity and/or hypergammaglobulinemia, (II) serum AMA negativity by IF, (III) biochemical and/or histologic features of cholestatic and hepato-cellular injury, and (IV) exclusion of chronic viral, metabolic, or toxic liver disease (10).

TABLE � Clinical Features in two Groups of Overlap Syndrome

Group 1 AIH-PBC

(n: 12)

Group 2 AIH-AIC

(n: 10)p

Age 43.9±16.5 45.1±15.2 >0.05Sex, F/M 11/1 10/- >0.05Other autoimmune diseases 2 (%16.7) 2 (%20) >0.05Symptoms >0.05

Asymptomatic 3 (%25) 4 (%33.3)Pruritis 8 (%66.7) 5 (%41.3)Fatigue 6 (%50) 5 (%41.3)Jaundice 6 (%50) 6 (%50)Weight loss 2 (%16.7) 3 (%25)Arthritis 2 (%16.7) 3 (%25)Myalgia 4 (%33.3) 2 (%16.7)

AIH: autoimmune hepatitis, PBC: primary biliary cirrhosis, AIC: autoimmune cholangitis

TABLE � Biochemical and Serological Features in two Groups of Overlap Syndrome

InitialGroup 1 AIH-PBC

(n: 12)

Group 2 AIH-AIC

(n: 10)p

ALT 211.5±248.7 423.8±403.7 >0.05AST 204.1±295.5 564.3±548.2 >0.05ALP 490.3±216.5 566.8±492.2 >0.05GGT 405.8±274.9 414.2±334.0 >0.05Total bilirubin 4.1±7.0 3.5±3.0 >0.05IgG 22.9±5.2 26.9±9.5 >0.05IgM 5.5±0.9 3.7±1.6 <0.05Albumin 37.7±4.1 40.4±3.9 >0.05ANA positive 11 (%91.7) 9 (%90) >0.05LKM-1 positive 2 (%16.7) 1 (%10) >0.05Anti-M2 positive 12 (%100) 0 <0.05ds-DNA positive 2 (%16.7) 2 (%20) >0.05p-ANCA positive 2 (%16.7) 1 (%10) >0.05IAHG score 10.5±1.3 14.7±2.7 <0.05

AIH: autoimmune hepatitis, PBC: primary biliary cirrhosis, AIC: autoimmune cholangitis IAHG: International Autoimmune Hepatitis Group

�Hepato-Gastroenterology 57 (�0�0)Running Title?????

Follow-up analysis included clinical and labora-tory data. Laboratory investigations were serum ALT, AST, ALP, GGT, total bilirubin, albumin, IgG, IgM; if indicated hepatitis B and C serology, PTZ, abdominal USG and endoscopy. The AMA and anti-M2 fraction were measured by immunoblotting technique. The other auto-antibodies were meas-ured by immunofluorescence; viral markers were measured by ELISA.

Histopathological assessmentAll of 22 patients included in the study under-

went liver biopsy before treatment, repeated bi-opsies were available only for two patients. Liver biopsy specimens were fixed in formaline and embedded in paraffin, and sections were stained with hematoxylin-eosin and Masson’s trichrome. All specimens were reviewed by two pathologists, and biopsies were evaluated according to Metavir, Knodell and Ishak scoring systems (17). Activity of chronic hepatitis was assessed by the intensity of periportal and lobular necroinflammatory lesions whereas stage of fibrosis was evaluated according to the scoring outlines. Biliary changes were evalu-ated by Ludwig stage (18).

Response to treatment and follow-upThe patients in both groups were treated with

UDCA or combined therapy including UDCA plus immunsuppresives (prednisolone, azathioprine, and/or cyclosporine). Treatment decisions had been based on clinical judgment rather than a fixed study design. Patients were categorized to the main treat-ment outcomes (19): Complete remission is defined as the disappearance of symptoms (fatigue, weight loss, pruritis, arthritis and arthralgia), improve-ment of serum aminotransferase less than twice normal or normal level, normal serum bilirubin and gamma globulin levels and normal hepatic tissue or minimal inflammation and piecemeal necrosis. Incomplete remission considered same or no im-provement in clinical, biochemical and histological features after 6 months therapy, no worsening of the condition and failure to achieve remission after 3 years. Treatment failure is defined as worsening clinical, biochemical and histological features in spite of therapy; increase of serum aminotrans-ferase by %67, development of ascites, jaundice and hepatic encephalopathy.

StatisticsStatistical analysis was performed using SPSS

13.0 for windows. Quantitative data were expressed as median-SD. Comparisons were made by using non-parametric tests: the Mann–Whitney rank sum test. Ratios were compared by using the chi-square (χ2) test. Differences with a p value <0.05 were considered significant.

RESULTS

Clinical, biochemical and histological features

Group 1 and group 2 were similar for age, sex and main presenting symptoms (Table 1). The re-sults of laboratory tests are summarized in Table 2. The AIH-AIC group showed higher levels of ALT, AST and IgG than AIH-PBC group, but these dif-ferences were not statistically significant. The level of total bilirubin was higher in AIH-PBC group but also this difference was not statistically significant. The number of patients positive for ANA, ASMA, LKM-1, p-ANCA, and anti-ds-DNA were similar in both groups. However, the IgM levels and the inci-dence of AMA were significantly different in both groups. The plasma IgM level were higher in the AIH-PBC group (p<0,05). In addition, the M2 frac-tion of AMA was positive in 12 patients of AIH-PBC

TABLE � Histological Features in two Groups of Overlap Syndrome

InitialGroup 1 AIH-PBC

(n: 12)

Group 2 AIH-AIC

(n: 10)p

Piecemeal necrosis 11 (%91.7) 10 (%100) >0.05Lymphoplasmocytic infiltration 9 (%75) 8 (%80) >0.05

Rosette formation 6 (%50) 4 (%40) >0.05Biliary changes >0.05

Ductal proliferation 6 (%50) 4 (%40)Ductopenia 4 (%33.3) 5 (%50)Florid duct lesion 5 (%41.3) 3 (%30)Cholangitis 3 (%25) 5 (%50)Granulomatosis 5 (%41.3) 6 (%60)

Histological stage >0.05Stage 0 - (%0) 1 (%10)Stage 1 3 (%25) 3 (%30)Stage 2 4 (%33.3) 1 (%10)Stage 3 3 (%25) 5 (%50)Stage 4 2 (%16.7) - (%0)

HAI score 10.75±2.3 11.1±2.5 >0.05

AIH: autoimmune hepatitis, PBC: primary biliary cirrhosis, AIC: autoimmune cholangitis, HAI: histological activity index

TABLE 4 Therapy Response in two Groups of Overlap Syndrome

Group 1 AIH-PBC

(n: 12)

Group 2 AIH-AIC

(n: 10)p

Follow-up (months) 31.7±11.0 41.1±29.6 >0.05Therapy response 6 (%50) 9 (%90) <0.05Treatment UDCA and/or IS UDCA and IS >0.05

AIH: autoimmune hepatitis, PBC: primary biliary cirrhosis, AIC: autoimmune cholangitis, IS: immunsupresive therapy

4 Hepato-Gastroenterology 57 (�0�0) E Ozaslan, C Efe, S Akbulut, et al.

group but in none of the AIH-AIC group (p<0,001). According to revised International Autoimmune Hepatitis Group (IAHG) scoring system, the mean AIH score was 10.5±1.3 for patients with AIH-PBC and 14.7±2.7 for patients with AIH-AIC (p<0.05). Only 3 of the subjects in AIH-AIC group, were ob-served to fulfill the criteria for “definite” AIH (score >15), while the remaining 7 in AIH-AIC and all of the 12 cases of AIH-PBC were designed as “proba-ble” AIH (score: 10-15). Detailed data about scoring were as follows: AIH-PBC group (12 points in one patient, 11 points in four, and 10 points in seven) and AIH-AIC group (20 points in one patient, 16 points in two, and 15 points in two, 14 points in one, 13 points in three, and 12 points in one).

Two patients had scleroderma and Sjögren’s syndrome in AIH-PBC group; while one patient had systemic lupus erythematosus, and one patient had both celiac and autoimmune thyroiditis in AIH-AIC group. Both groups showed no significant differenc-es in histological findings (p>0.05) (Table 3).

Response to treatment and outcomeThe incidence of response to therapy was sig-

nificantly higher in the AIH-AIC than in the AIH-PBC (%90 vs %50, p=0.045) (Table 4). The mean follow-up time was 31.7±11.0 mo in AIH-PBC and 41.1±29.6 mo in AIH-AIC respectively.

In AIH-PBC group, six patients achieved com-plete remission (50%), three with only UDCA and three with UDCA associated to prednisone (Table 5). The remaining six patients in group AIH-PBC had liver failure after 10, 13, 14, 20, 26 and 38 months of diagnosis, respectively. At the diagnosis, two of these patients were at stage 4, two of patients were at stage 2, and the others were at stage 3 and 1, liver disease. Two patient in stage 4 had liver failure after 8, 10 months, one of this patient died of upper gastrointestinal bleeding after 6 months, the other patient died of spontaneous bacterial perito-nitis after 2 months. Of the remaining 4 patients, one had liver transplantation after decompanseted cirrhosis, one was followed-up with decompansated cirrhosis, and two with treatment failure without cirrhosis. In AIH-AIC group, nine patients achieved complete remission (90%), all of with UDCA asso-ciated to prednisone with azathioprine (Table 5). In AIH-AIC group, only one patient progressed to liver failure after 26 months of follow up. She had stage 3 liver disease at the time of diagnosis, and liver transplantation was performed 6 month after diagnosis. Steroids could be able to be stopped in all three responder patients of AIH-PBC group, and in six of AIH-AIC group (Table 5). Azathioprine was stopped in two patients of AIH-AIC group, due to nausea and pregnancy, and these were put on low dose steroids.

DISCUSSIONOverlap syndromes do not have codified defini-

tions. Despite ongoing controversies with regards to the diagnostic criteria, the term of overlap syn-

TABLE 5 Detailed Therapy Features and Outcome in two Groups of Overlap Syndrome

Group 1 (AIH-PBC)

Case Initial therapy Follow-up Current

therapy Comment

1 UDCA UDCA UDCA remission2 UDCA UDCA UDCA remission

3 UDCA+ prednisolon UDCA UDCA remission

4 UDCA+ prednisolon UDCA UDCA

5 UDCA+ prednisolon UDCA UDCA remission

6 UDCA+ prednisolon

UDCA+ prednisolon -

7 UDCA+AZT UDCA UDCAtreatment failure

cirrhosis, transplantation

8 UDCA UDCA UDCA remission

9 UDCA+ prednisolon

UDCA+ prednisolon*

UDCA+ prednisolon* treatment failure

10 UDCA+ prednisolon UDCA UDCA treatment failure

cirrhosis

11 UDCA+ prednisolon UDCA UDCA remission

12 UDCA+ prednisolon

UDCA+ prednisolon - treatment failure

cirrhosis, exitus

Group 2 (AIH-AIC)

Case Initial therapy Follow-up Current

therapy Comment

1 UDCA+ prednisolon

UDCA+AZT >Cyc

UDCA+ colchicin

treatment failure transplantation

2 UDCA+ prednisolon UDCA UDCA+AZT remission

3 UDCA+ prednisolon UDCA - remission

4 UDCA+ prednisolon UDCA UDCA remission

5 UDCA+ prednisolon

UDCA+ prednisolon** UDCA+AZT remission

6 UDCA+ prednisolon

UDCA+ prednisolon** UDCA+AZT remission

7 UDCA+ prednisolon UDCA UDCA remission

8UDCA+

prednisolon+ AZT

UDCA+ prednisolon*”

UDCA+ prednisolon*” remission

9 UDCA+ prednisolon UDCA UDCA remission

10UDCA+

prednisolon+ AZT

UDCA+ prednisolon*!

UDCA+ prednisolon*! remission

*low dose, 10 mg; ** steroid was stopped due to osteoporosis, diabetes; “AZT was stopped due to pregnancy; !AZT was stopped due to nausea. AIH: autoimmune hepatitis, PBC: primary biliary cirrhosis, AIC: autoimmune cholangitis Remission indicates symptomatic and biochemical normalization in all cases, repeated liver biopsy were also available for two cases.

5Hepato-Gastroenterology 57 (�0�0)Running Title?????

drome actually includes a heterogeneous group of patients with mixed features of PBC and AIH. (1-3). In this study, for the diagnosis of PBC-AIH overlap, we used the strict diagnostic criteria proposed by Chazouillères et al. in 1998 (16). Diagnostic crite-ria for AIH-AIC are still unclear. In this study, for the diagnosis of AIH-AIC overlap, we used the di-agnostic criteria proposed by Czaja et al. (10) and calculated the IAHG score for each patient. Czaja et al. (10) have described autoimmune cholangitis as a variant syndrome on following criteria (1) se-rum ANA and/or smooth muscle (SMA) positivity and/or hypergammaglobulinemia, (2) serum AMA negativity by IF, (3) biochemical and/or histologic features of cholestatic and hepatocellular injury, and (4) exclusion of chronic viral, metabolic, or toxic liver disease. This definition was coined to include PBC with atypical presentation, small-duct pri-mary sclerosing cholangitis, idiopathic adulthood ductopenia, and transitional stages of the classic diseases. In recent years, the term of “AMA-nega-tive PBC” has gained popularity to describe au-toimmune cholangitis (11, 12). Consensus is still awaited on this issue. So, in a broader definition, our study groups, AIH-PBC and AIH-AIC, may also be regarded as “PBC with hepatitic features” and “AIH with cholestatic features”, respectively. In support of this assumption, our study disclosed higher levels of serum IgM and AMA positivity and lower IAHG score in AIH-PBC overlap compared to AIH-AIC. Although serum levels of ALT, AST and IgG were higher in the latter group, it was not statistically significant. Only 3 out of 10 patients in AIH-AIC group were classified as ‘definite’ AIH according to the international AIH scoring system (5). All of 12 patients in AIH-PBC and remaining 7 patients in AIH-AIC group were classified as “probable” (mean IAHG score 10.5 vs 14.7). This is not surprising since biliary features have a strong negative impact in this scoring system and a score of ‘definite’ AIH can be only observed in only rare patients, like previously reported (7, 20). Chazouil-lères et al. (7) and Silveira et al. (19), reported 15 out of 17 and all of 26 AIH-PBC patients as ‘prob-able’ AIH, respectively. We could not find any his-tological feature that could differentiate AIH-PBC from AIH-AIC. Biliary lesions were very similar in both groups, for ductal proliferation, ductopenia, destructive cholangitis and granuloma.

It has been shown that UDCA is effective in PBC (4), whereas immunosuppressive therapy us-ing corticosteroids alone or in association with aza-thioprine is the gold standart for AIH (5).

However, therapy of AIH-PBC overlap syndrome is still controversial and whether overlap syndrome requires immunosuppressive therapy in addition to UDCA remains an unresolved issue despite ac-cumulated literature. Some authors (6,7) demon-strated a clear superiority of combination therapy, while the others (8) found the response to UDCA therapy enough. Joshi et al. (8) found that, under UDCA therapy, biochemical response at 24 months

and survival of PBC-AIH overlap patients (n=12) were similar to patients with pure PBC (n=159) and, upon these results, did not recommend cor-ticosteroids for PBC patients with laboratory fea-tures of AIH. Chazouillères et al. (7) reported the therapy responses of 17 patients with PBC and AIH with either UDCA or UDCA and immunosup-pressive agents, such as prednisolone, azathioprine and mycophenolate mofetil. The combination of UDCA and immunosuppressive therapy was able to induce biochemical response and to stop fibrosis progression in all patients (6/6), while UDCA alone achieved these only in 3 cases (3/11). Furthermore, the patients who did not respond to UDCA (n=7) had laboratory improvement and stabilization of their fibrosis after treatment with the combination regimen.

The results of therapy response in our patients with AIH-PBC overlap are much more disappoint-ing. Although UDCA alone (3/12) or with immu-nosuppresives (3/12) were able induce complete remission, half of the group had an accelerated course under combination therapy and progres-sion occurred in a relatively short period of time (10 months to 3 years). Predictive factors of non-response to therapy were not identified in our study presumably because of small number of patients but it must be stated that three of six non-respond-ers had more severe histological stage (two in stage 4, one in stage 3).

At present, there is no consensus regarding the optimal therapy for AIC because, due to the low prevalence of this disease, no controlled therapeu-tic trials have been undertaken. Gisbert et al. (21) reviewed 106 patients of AIC from 30 uncontrolled studies, where favourable effect of ursodeoxycholic acid on the serum biochemical markers of patients with AIC has been demonstrated in most studies (approximately 80% of patients). Additionally, a favourable effect of immunosuppressive treatment has also been demonstrated in approximately one-half of AIC patients. In cases of AIC that exhibit overlapping features with AIH, corticosteroids alone or in combination with azathioprine may be particularly effective. Ben-Ari et al. (22), Sánchez-Pobre et al. (23), Masumoto et al. (24), and Sherlock (25), described four, four, three and five patients respectively, with features of overlap between AMA-negative primary biliary cirrhosis and AIH. Improvements in clinical and biochemical features in addition to hepatic inflammation occurred in all patients but bile duct lesions persisted. On the other hand, the reports about therapy response of patients with AIH-AIC to combination of ursode-oxycholic acid and immunosuppressive therapy, are very rare. Li et al. (14) reported a patient with autoimmune cholangitis and autoimmune hepa-titis, treated with combination therapy. On treat-ment, serum aminotransferases and cholestasis markers improved. A follow-up liver biopsy revealed improvement of both hepatic necro-inflammation and bile duct lesions. Alric et al. (15) described

� Hepato-Gastroenterology 57 (�0�0) E Ozaslan, C Efe, S Akbulut, et al.

seven patients with AIH+AMA negative PBC overlap who were treated with standardized treatment by UDCA associated to prednisone with azathioprine, a complete biochemical response was observed in four (57%) of the cases and a partial response with a decrease of at least a half of biochemical values was achieved in five (71.4%) of patients. Histologi-cal evaluation on a second liver biopsy was not per-formed. Our study illustrates that a combination of corticosteroids and ursodeoxycholic acid are very effective in patients with features of both AIH-AIC, with a figure of 90% complete remission.

The most impressive finding of our study is a marked difference between AIH-AIC vs. AIH-PBC overlap syndromes, with regard to therapy response and prognosis. The complete response to therapy was much better in the AIH-AIC cases than those of AIH-PBC (%90 vs. %50). The mean follow-up time was 41.1±29.6 mo in AIH-AIC and 31.7±11.0 mo in AIH-PBC, respectively. During this period, only one patient in AIH-AIC group (%10), but four patients in AIH-PBC group (%33) developed into cirrhosis, with two deaths in the latter group. Although a firm con-clusion can not be drawn, predominant hepatic fea-

tures of AIH-AIC cases demonstrated with relatively high transaminases and IAHG score compared to AIH-PBC cases, may be an explanation for favorable therapy response. But similar histological findings in both two groups weakens this possibility. Further studies with larger groups may clarify this issue.

In conclusion, treatment must be individual-ized for AIH-PBC (including AMA positive “true PBC” or AMA negative “AIC”) overlap cases, until the era of codified diagnostic criteria and validat-ed treatment strategies. We propose that patients with high AIH score and negative AMA should be treated with combined therapy of corticosteroids and UDCA, however, patients with low AIH score and positive AMA should use UDCA firstly, if no response, the addition of corticosteroids should be considered with close monitoring. The prognosis of AIH-PBC overlap (or PBC with hepatitic features) is much worse than that of AIH-AIC (or AIH with cholestatic features).

ACKNOWLEDGEMENTS:We are grateful to Osman Yuksel MD for ana-

lyzing the statistical data of the study.

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