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Journal of Digestive Diseases 2014; 15; 660–668
doi: 10.1111/1751-2980.12196
Original article
Primary biliary cirrhosis–autoimmune hepatitis overlap syndrome: Simplified criteria may be effective in the diagnosis in Chinese patients Fang LIU,* Zhen Guo PAN,† Jin YE,‡ Dong XU,§ Hui GUO,¶ Gang Ping LI,‡ Ke Shu XU,‡ Xiao Hua HOU‡ & Yu Hu SONG‡ *Institute of Hematology, ‡Department of Gastroenterology, Union Hospital, §Department of Infectious Diseases, ¶Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, and †Department of Gastroenterology, Huai’an First People’s Hospital, Nanjing Medical University, Huai’an, Jiangsu Province, China
OBJECTIVE: To evaluate the Paris criteria, the revised diagnostic criteria and the simplified diagnostic scoring system in the diagnosis of primary biliary cirrhosis (PBC)–autoimmune hepatitis (AIH) overlap syndrome in Chinese patients. METHODS: Medical records of the patients who were diagnosed with PBC at the Union Hospital and Tongji Hospital, Tongji Medical University, Huazhong University of Science and Technology (Wuhan, Hubei Province, China) from 2003 to 2012 were retrospectively reviewed. The overlap syndrome was diagnosed based on the Paris criteria, the revised criteria and the simplified criteria, respectively. Patients’ clinical characteristics, laboratory examination results and histological findings were collected. The sensitivity and specificity of the three criteria for diagnosing PBC– AIH overlap syndrome were calculated.
RESULTS: PBC–AIH overlap syndrome was diagnosed in 2, 13 and 10 patients with PBC based on the Paris, the revised and the simplified criteria, respectively. The sensitivity and specificity of the simplified criteria in diagnosing the overlap syndrome was 90.0% and 98.2%, which were the highest among the three criteria, followed by the revised criteria. The Paris criteria showed a high specificity (100%) but a relatively low sensitivity (20.0%). In addition, some patients who did not fulfil the Paris criteria still benefited from the immunosuppressive agents. CONCLUSIONS: For Chinese patients with the PBC–AIH overlap syndrome, the simplified criteria appear to be the most efficacious compared with the Paris criteria and the revised criteria. Further studies should be performed to confirm these observations with respect to long-term outcomes and therapeutic implications.
KEY WORDS: autoimmune hepatitis, biliary liver cirrhosis, diagnosis, immunosuppresion, overlap syndrome, patient selection.
Correspondence to: Yu Hu SONG, Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, Hubei Province 430022, China. Email: [email protected] Conflict of interest: None. The abstract has been presented as a poster in Gastro 2013 APDW/WCOG Shanghai, Asian Pacific Digestive Week 2013/
660
World Congress of Gastroenterology, 21–24 September 2013 (J Gastroenterol Hepatol 2013; 28 Suppl 3: 166). © 2014 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd
Journal of Digestive Diseases 2014; 15; 660–668 INTRODUCTION Primary biliary cirrhosis (PBC) is a slowly progressive autoimmune liver disease that mainly occurs in middle-aged women. Histologically, this disease is characterized by granulomatous destruction of interlobular bile ducts and progressive ductopenia, leading to liver damage, fibrosis and even cirrhosis.1,2 Some patients with PBC also manifest with biological and histological features of autoimmune hepatitis (AIH), including elevated serum levels of immunoglobulin G (IgG), positive anti-smooth muscle antibody (ASMA) test and histologically confirmed interface hepatitis.3–6 Patients presenting with the features of both PBC and AIH are described as having PBC–AIH overlap syndrome, in which PBC and AIH can occur either consecutively or simultaneously.7–9 Although some developments have been achieved in the diagnosis and treatment of patients with PBC– AIH overlap syndrome, it remains challenging to diagnose the disease due to a lack of the consensus on the diagnostic and treatment criteria for this disease. Since their first proposal by Chazouillères et al. in 1998, the Paris criteria have been commonly applied for diagnosing the PBC–AIH overlap syndrome.7–16 The efficacy of the Paris criteria for diagnosing the PBC–AIH overlap syndrome has been validated in a Dutch population, although with a limited sample size, resulted in a sensitivity of 92% and a specificity of 97%.17 However, its efficacy needs to be further evaluated because the degree of elevated alanine aminotransferase (ALT) or IgG levels required for the diagnosis of overlap syndrome is not quite clear. Although patients with typical AIH can be diagnosed easily in clinical practice, atypical AIH appearances might be difficult to be distinguished from other diseases. The most common diagnostic scoring systems for AIH include the revised and the simplified criteria.18,19 Researchers at the Mayo Clinic use both criteria to diagnose the PBC–AIH overlap syndrome,9,20 in which the simplified criteria appeared to be more specific for overlap syndrome and could help in the clinical assessment of the patients compared with the revised criteria. It is a challenge for hepatologists in China to standardize the diagnostic criteria for the PBC–AIH overlap syndrome due to the insufficient data on the diagnostic values of the Paris criteria, the revised scoring system and the simplified criteria for PBC–AIH overlap syndrome in Chinese patients. In this study, we aimed to assess the performances of these criteria in diagnosing the PBC–AIH overlap syn-
Criteria for PBC–AIH overlap syndrome
661
drome and to determine suitable diagnostic criteria for Chinese patients with this overlap syndrome. PATIENTS AND METHODS Patients Medical records of patients who were diagnosed with PBC at the Union Hospital and Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology (Wuhan, Hubei Province, China) from 2003 to 2012 were retrospectively reviewed. Exclusion criteria were: (i) patients aged 70 years; (ii) patients with features suggestive of coexisting liver diseases, such as primary sclerosing cholangitis or extrahepatic bile duct diseases; (iii) those with decompensated cirrhosis; (iv) those with severe systematic diseases; and (v) pregnancy or lactation. The characteristics of the patients including their age, gender, liver function test results, the titers of serum autoantibodies such as antinuclear antibodies (ANA), ASMA, antimitochondrial antibodies (AMA), liver kidney microsomes type 1 (LKM-1) antibodies and anti-soluble liver antigen/liver–pancreas (SLA/LP) as well as the histological evidence based on liver biopsy (if available) were collected and analyzed. All liver tissue specimens were blindly assessed by two hepatopathologists (Hui GUO and Ling YANG) according to the grades for necroinflammation (G0, no necroinflammation; G1, mild piecemeal necrosis; G2, moderate piecemeal necrosis [involves 50% of the circumference of most portal tracts]) and fibrosis stage (F0, no fibrosis; F1, portal fibrosis without septa; F2, portal fibrosis with rare septa; F3, numerous septa without cirrhosis; F4, cirrhosis) (Fig. 1). The follow-up period of the enrolled patients ranged from 9 months to 4 years. The study was approved by the Ethnic Committees of both hospitals. Diagnostic criteria
PBC PBC was diagnosed when two of the following three criteria were met: (i) alkaline phosphatase (ALP) level at least twice the upper limit of normal (ULN) or γ-glutamyl transpeptidase (γ-GT) level at least five times the ULN; (ii) positive result of AMA test; and (iii) histological evidence of nonsuppurative destructive cholangitis and destruction of interlobular bile ducts.1,21
© 2014 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd
662
(a)
F Liu et al.
Journal of Digestive Diseases 2014; 15; 660–668
(b)
Figure 1. Histological appearance of typical primary biliary cirrhosis–autoimmune hepatitis overlap syndrome showing (a) lymphoplasmacytic infiltration, severe interface hepatitis, lymphocytic cholangitis and significant bile duct loss (HE stain, ×100); (b) the same liver biopsy specimen shows severe interface hepatitis and lymphoplasmacytic infiltration (HE stain, ×400).
AIH AIH was defined based on the Paris criteria,16 the revised scoring system18 and the simplified scoring system,19 respectively, which will be described below. Paris criteria. The Paris criteria for the diagnosis of AIH were: (i) ALT ≥ 5 × ULN; (ii) IgG ≥ 2 × ULN or positive serum ASMA; and (iii) histologically confirmed moderate or severe hepatic peri-portal or periseptal lymphocytic piecemeal necrosis. For the diagnosis of AIH, the presence of at least two of the three specific criteria of each disorder was required. PBC and AIH occurred synchronously or sequentially. Histological evidence of moderate or severe interface hepatitis was mandatory for the diagnosis of the PBC– AIH overlap syndrome.4,22 Revised scoring system for the diagnosis of AIH. In the revised AIH scoring system proposed by the International Autoimmune Hepatitis Group, scores that included 12 clinical parameters such as female gender, serum globulins or IgG level and autoantibody titers were calculated.18 Probable AIH was defined as a sum of scores of 10–15 prior to therapy, while a sum of score >15 led to a diagnosis of definite AIH. Simplified criteria for the diagnosis of AIH. The simplified criteria for the diagnosis of AIH consist of only four clinical parameters, and the scores are as follows: (i) serum titers of ANA or ASMA ≥ 1:40 (1 point); (ii) ANA or ASMA ≥ 1:80, or LKM ≥ 1:40 or positive soluble liver antibody (SLA) (2 points, additional points for all autoantibodies with a maximum of 2 points); (iii) IgG over ULN (1 point) or > 1.10 × ULN (2 points); (iv) histological evidence that is compat-
ible with AIH (1 point) or typical AIH (2 points), which is a necessary condition; and (v) the absence of viral hepatitis (2 points).19 A score sum of ≥7 is defined as definite AIH, and ≥6 is defined as probable AIH. In our study, serum titers of ANA and ASMA were detected through indirect immunofluorescence with the lowest dilution turning out to be 1:100. Therefore, an ANA or ASMA titer ≥1:100 was scored as 1 point and that of ≥1:320 was scored as 2 points.11 Interface hepatitis, lymphocytic/lymphoplasmacytic infiltration in portal tracts and extending into the lobule, emperipolesis and hepatic rosette formation are regarded as typical appearances for the diagnosis of AIH, while compatible features are chronic hepatitis with lymphocytic infiltration in the absence of all the typical features. Each of the three typical histological features should be present in typical AIH. When there were signs of other diseases such as steatohepatitis, liver histology was considered atypical.19 In patients with PBC whose serum IgG levels were lacking, γ-GT was used for the calculation.18,20 Diagnostic criteria for PBC–AIH overlap syndrome. The diagnosis of the PBC–AIH overlap syndrome was established by the synchronous or subsequent presence of both PBC and AIH, based on the Paris criteria. In addition, the patients were also diagnosed with the PBC–AIH overlap syndrome if the following criteria were met: (i) ALT levels higher than the ULN; (ii) IgG levels higher than the ULN; (iii) histologically confirmed moderate or severe interface hepatitis; and (iv) patients with a therapeutic response to immunosuppressive treatments. Statistical analysis Statistical analyses were performed using SPSS 16.0 (SPSS Inc., Chicago, IL, USA). Continuous variables were presented as mean ± standard deviation, whereas discrete parameters were expressed as numbers and percentages. The differences in the parameters between patients with the PBC–AIH overlap syndrome and those with PBC alone diagnosed based on different criteria were compared using Student’s t-test and the χ2 test, when appropriate. A two-tailed P value of ≤0.05 was regarded as statistically significant. RESULTS Patients’ characteristics A total of 107 patients who were diagnosed with PBC from 2003 to 2012 were enrolled in the study,
© 2014 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd
Journal of Digestive Diseases 2014; 15; 660–668
Criteria for PBC–AIH overlap syndrome
including 10 men and 97 women. Liver biopsy specimens were available in 65 (60.7%) of all cases. The remaining 42 patients had refused or had contraindications to liver biopsy. The PBC patients with or without liver biopsy shared similar clinical, biochemical and serological characteristics (Table 1). The proportion of patients with serum ALT level ≥ 5 × ULN was 11.2% (12/107), and that of the patients with IgG >2 × ULN was 4.2% (4/95). Of all patients, 10.9% (10/92) were found to be seropositive for ASMA. Among the PBC patients who received liver biopsy, 10 were diagnosed with the PBC–AIH overlap syndrome according to the simplified diagnostic criteria.
Diagnosis of the PBC–AIH overlap syndrome
Paris criteria Among the 65 patients with PBC who received liver biopsy, only 2 (3.1%) were diagnosed with the PBC– AIH overlap syndrome according to the Paris criteria, based on ASMA seropositivity and the presence of histological features (moderate to severe piecemeal necrosis); however, IgG level (>1.45 × ULN) and serum liver aminotransferase (>2.4 × ULN) did not fulfill the Paris criteria (Table 2). The Paris criteria
Table 1.
663
showed a low sensitivity of 20% but a high specificity of 100% for diagnosing the PBC–AIH overlap syndrome.
Revised scoring system A total of 13 (20.0%) of the 65 patients who received liver biopsy were identified with the PBC–AIH overlap syndrome based on the revised diagnostic scoring system. The sum of their scores ranged from 10 to 15 points, most of the points being gained from female gender, low levels of ALP and aspartate aminotransferase (AST), the absence of drug use or viral hepatitis antigens and antibodies, a modest average daily alcohol intake and the presence of ANA seropositivity. IgG level in patients with the PBC–AIH overlap syndrome was slightly higher than that in those with PBC alone (P < 0.05, Table 2). We assessed the pathological changes in the liver in all patients with PBC who received liver biopsy; 15 patients presented with moderate to severe piecemeal necrosis. Among the cases with the PBC–AIH overlap syndrome, five presented with mild or no piecemeal necrosis. The sensitivity and specificity of the revised criteria in the diagnosis of the PBC–AIH overlap syndrome was 60.0% and 87.3%, respectively.
Characteristics of the patients having primary biliary cirrhosis (PBC) with or without liver biopsy
Characteristics Age, years (mean ± SD) Gender, n (M/F) Peripheral blood parameters ALT, U/L (mean ± SD) ALT ≥ 5× ULN, n (%) ALP, U/L (mean ± SD) γ-GT, U/L (mean ± SD) Total bilirubin, μmol/L (mean ± SD) Albumin, g/L (mean ± SD) IgM, g/L (mean ± SD) IgG, g/L (mean ± SD)# >2 × ULN, n (%) 1–2 × ULN, n (%)
Journal of Digestive Diseases 2014; 15; 660–668
doi: 10.1111/1751-2980.12196
Original article
Primary biliary cirrhosis–autoimmune hepatitis overlap syndrome: Simplified criteria may be effective in the diagnosis in Chinese patients Fang LIU,* Zhen Guo PAN,† Jin YE,‡ Dong XU,§ Hui GUO,¶ Gang Ping LI,‡ Ke Shu XU,‡ Xiao Hua HOU‡ & Yu Hu SONG‡ *Institute of Hematology, ‡Department of Gastroenterology, Union Hospital, §Department of Infectious Diseases, ¶Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, and †Department of Gastroenterology, Huai’an First People’s Hospital, Nanjing Medical University, Huai’an, Jiangsu Province, China
OBJECTIVE: To evaluate the Paris criteria, the revised diagnostic criteria and the simplified diagnostic scoring system in the diagnosis of primary biliary cirrhosis (PBC)–autoimmune hepatitis (AIH) overlap syndrome in Chinese patients. METHODS: Medical records of the patients who were diagnosed with PBC at the Union Hospital and Tongji Hospital, Tongji Medical University, Huazhong University of Science and Technology (Wuhan, Hubei Province, China) from 2003 to 2012 were retrospectively reviewed. The overlap syndrome was diagnosed based on the Paris criteria, the revised criteria and the simplified criteria, respectively. Patients’ clinical characteristics, laboratory examination results and histological findings were collected. The sensitivity and specificity of the three criteria for diagnosing PBC– AIH overlap syndrome were calculated.
RESULTS: PBC–AIH overlap syndrome was diagnosed in 2, 13 and 10 patients with PBC based on the Paris, the revised and the simplified criteria, respectively. The sensitivity and specificity of the simplified criteria in diagnosing the overlap syndrome was 90.0% and 98.2%, which were the highest among the three criteria, followed by the revised criteria. The Paris criteria showed a high specificity (100%) but a relatively low sensitivity (20.0%). In addition, some patients who did not fulfil the Paris criteria still benefited from the immunosuppressive agents. CONCLUSIONS: For Chinese patients with the PBC–AIH overlap syndrome, the simplified criteria appear to be the most efficacious compared with the Paris criteria and the revised criteria. Further studies should be performed to confirm these observations with respect to long-term outcomes and therapeutic implications.
KEY WORDS: autoimmune hepatitis, biliary liver cirrhosis, diagnosis, immunosuppresion, overlap syndrome, patient selection.
Correspondence to: Yu Hu SONG, Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, Hubei Province 430022, China. Email: [email protected] Conflict of interest: None. The abstract has been presented as a poster in Gastro 2013 APDW/WCOG Shanghai, Asian Pacific Digestive Week 2013/
660
World Congress of Gastroenterology, 21–24 September 2013 (J Gastroenterol Hepatol 2013; 28 Suppl 3: 166). © 2014 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd
Journal of Digestive Diseases 2014; 15; 660–668 INTRODUCTION Primary biliary cirrhosis (PBC) is a slowly progressive autoimmune liver disease that mainly occurs in middle-aged women. Histologically, this disease is characterized by granulomatous destruction of interlobular bile ducts and progressive ductopenia, leading to liver damage, fibrosis and even cirrhosis.1,2 Some patients with PBC also manifest with biological and histological features of autoimmune hepatitis (AIH), including elevated serum levels of immunoglobulin G (IgG), positive anti-smooth muscle antibody (ASMA) test and histologically confirmed interface hepatitis.3–6 Patients presenting with the features of both PBC and AIH are described as having PBC–AIH overlap syndrome, in which PBC and AIH can occur either consecutively or simultaneously.7–9 Although some developments have been achieved in the diagnosis and treatment of patients with PBC– AIH overlap syndrome, it remains challenging to diagnose the disease due to a lack of the consensus on the diagnostic and treatment criteria for this disease. Since their first proposal by Chazouillères et al. in 1998, the Paris criteria have been commonly applied for diagnosing the PBC–AIH overlap syndrome.7–16 The efficacy of the Paris criteria for diagnosing the PBC–AIH overlap syndrome has been validated in a Dutch population, although with a limited sample size, resulted in a sensitivity of 92% and a specificity of 97%.17 However, its efficacy needs to be further evaluated because the degree of elevated alanine aminotransferase (ALT) or IgG levels required for the diagnosis of overlap syndrome is not quite clear. Although patients with typical AIH can be diagnosed easily in clinical practice, atypical AIH appearances might be difficult to be distinguished from other diseases. The most common diagnostic scoring systems for AIH include the revised and the simplified criteria.18,19 Researchers at the Mayo Clinic use both criteria to diagnose the PBC–AIH overlap syndrome,9,20 in which the simplified criteria appeared to be more specific for overlap syndrome and could help in the clinical assessment of the patients compared with the revised criteria. It is a challenge for hepatologists in China to standardize the diagnostic criteria for the PBC–AIH overlap syndrome due to the insufficient data on the diagnostic values of the Paris criteria, the revised scoring system and the simplified criteria for PBC–AIH overlap syndrome in Chinese patients. In this study, we aimed to assess the performances of these criteria in diagnosing the PBC–AIH overlap syn-
Criteria for PBC–AIH overlap syndrome
661
drome and to determine suitable diagnostic criteria for Chinese patients with this overlap syndrome. PATIENTS AND METHODS Patients Medical records of patients who were diagnosed with PBC at the Union Hospital and Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology (Wuhan, Hubei Province, China) from 2003 to 2012 were retrospectively reviewed. Exclusion criteria were: (i) patients aged 70 years; (ii) patients with features suggestive of coexisting liver diseases, such as primary sclerosing cholangitis or extrahepatic bile duct diseases; (iii) those with decompensated cirrhosis; (iv) those with severe systematic diseases; and (v) pregnancy or lactation. The characteristics of the patients including their age, gender, liver function test results, the titers of serum autoantibodies such as antinuclear antibodies (ANA), ASMA, antimitochondrial antibodies (AMA), liver kidney microsomes type 1 (LKM-1) antibodies and anti-soluble liver antigen/liver–pancreas (SLA/LP) as well as the histological evidence based on liver biopsy (if available) were collected and analyzed. All liver tissue specimens were blindly assessed by two hepatopathologists (Hui GUO and Ling YANG) according to the grades for necroinflammation (G0, no necroinflammation; G1, mild piecemeal necrosis; G2, moderate piecemeal necrosis [involves 50% of the circumference of most portal tracts]) and fibrosis stage (F0, no fibrosis; F1, portal fibrosis without septa; F2, portal fibrosis with rare septa; F3, numerous septa without cirrhosis; F4, cirrhosis) (Fig. 1). The follow-up period of the enrolled patients ranged from 9 months to 4 years. The study was approved by the Ethnic Committees of both hospitals. Diagnostic criteria
PBC PBC was diagnosed when two of the following three criteria were met: (i) alkaline phosphatase (ALP) level at least twice the upper limit of normal (ULN) or γ-glutamyl transpeptidase (γ-GT) level at least five times the ULN; (ii) positive result of AMA test; and (iii) histological evidence of nonsuppurative destructive cholangitis and destruction of interlobular bile ducts.1,21
© 2014 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd
662
(a)
F Liu et al.
Journal of Digestive Diseases 2014; 15; 660–668
(b)
Figure 1. Histological appearance of typical primary biliary cirrhosis–autoimmune hepatitis overlap syndrome showing (a) lymphoplasmacytic infiltration, severe interface hepatitis, lymphocytic cholangitis and significant bile duct loss (HE stain, ×100); (b) the same liver biopsy specimen shows severe interface hepatitis and lymphoplasmacytic infiltration (HE stain, ×400).
AIH AIH was defined based on the Paris criteria,16 the revised scoring system18 and the simplified scoring system,19 respectively, which will be described below. Paris criteria. The Paris criteria for the diagnosis of AIH were: (i) ALT ≥ 5 × ULN; (ii) IgG ≥ 2 × ULN or positive serum ASMA; and (iii) histologically confirmed moderate or severe hepatic peri-portal or periseptal lymphocytic piecemeal necrosis. For the diagnosis of AIH, the presence of at least two of the three specific criteria of each disorder was required. PBC and AIH occurred synchronously or sequentially. Histological evidence of moderate or severe interface hepatitis was mandatory for the diagnosis of the PBC– AIH overlap syndrome.4,22 Revised scoring system for the diagnosis of AIH. In the revised AIH scoring system proposed by the International Autoimmune Hepatitis Group, scores that included 12 clinical parameters such as female gender, serum globulins or IgG level and autoantibody titers were calculated.18 Probable AIH was defined as a sum of scores of 10–15 prior to therapy, while a sum of score >15 led to a diagnosis of definite AIH. Simplified criteria for the diagnosis of AIH. The simplified criteria for the diagnosis of AIH consist of only four clinical parameters, and the scores are as follows: (i) serum titers of ANA or ASMA ≥ 1:40 (1 point); (ii) ANA or ASMA ≥ 1:80, or LKM ≥ 1:40 or positive soluble liver antibody (SLA) (2 points, additional points for all autoantibodies with a maximum of 2 points); (iii) IgG over ULN (1 point) or > 1.10 × ULN (2 points); (iv) histological evidence that is compat-
ible with AIH (1 point) or typical AIH (2 points), which is a necessary condition; and (v) the absence of viral hepatitis (2 points).19 A score sum of ≥7 is defined as definite AIH, and ≥6 is defined as probable AIH. In our study, serum titers of ANA and ASMA were detected through indirect immunofluorescence with the lowest dilution turning out to be 1:100. Therefore, an ANA or ASMA titer ≥1:100 was scored as 1 point and that of ≥1:320 was scored as 2 points.11 Interface hepatitis, lymphocytic/lymphoplasmacytic infiltration in portal tracts and extending into the lobule, emperipolesis and hepatic rosette formation are regarded as typical appearances for the diagnosis of AIH, while compatible features are chronic hepatitis with lymphocytic infiltration in the absence of all the typical features. Each of the three typical histological features should be present in typical AIH. When there were signs of other diseases such as steatohepatitis, liver histology was considered atypical.19 In patients with PBC whose serum IgG levels were lacking, γ-GT was used for the calculation.18,20 Diagnostic criteria for PBC–AIH overlap syndrome. The diagnosis of the PBC–AIH overlap syndrome was established by the synchronous or subsequent presence of both PBC and AIH, based on the Paris criteria. In addition, the patients were also diagnosed with the PBC–AIH overlap syndrome if the following criteria were met: (i) ALT levels higher than the ULN; (ii) IgG levels higher than the ULN; (iii) histologically confirmed moderate or severe interface hepatitis; and (iv) patients with a therapeutic response to immunosuppressive treatments. Statistical analysis Statistical analyses were performed using SPSS 16.0 (SPSS Inc., Chicago, IL, USA). Continuous variables were presented as mean ± standard deviation, whereas discrete parameters were expressed as numbers and percentages. The differences in the parameters between patients with the PBC–AIH overlap syndrome and those with PBC alone diagnosed based on different criteria were compared using Student’s t-test and the χ2 test, when appropriate. A two-tailed P value of ≤0.05 was regarded as statistically significant. RESULTS Patients’ characteristics A total of 107 patients who were diagnosed with PBC from 2003 to 2012 were enrolled in the study,
© 2014 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd
Journal of Digestive Diseases 2014; 15; 660–668
Criteria for PBC–AIH overlap syndrome
including 10 men and 97 women. Liver biopsy specimens were available in 65 (60.7%) of all cases. The remaining 42 patients had refused or had contraindications to liver biopsy. The PBC patients with or without liver biopsy shared similar clinical, biochemical and serological characteristics (Table 1). The proportion of patients with serum ALT level ≥ 5 × ULN was 11.2% (12/107), and that of the patients with IgG >2 × ULN was 4.2% (4/95). Of all patients, 10.9% (10/92) were found to be seropositive for ASMA. Among the PBC patients who received liver biopsy, 10 were diagnosed with the PBC–AIH overlap syndrome according to the simplified diagnostic criteria.
Diagnosis of the PBC–AIH overlap syndrome
Paris criteria Among the 65 patients with PBC who received liver biopsy, only 2 (3.1%) were diagnosed with the PBC– AIH overlap syndrome according to the Paris criteria, based on ASMA seropositivity and the presence of histological features (moderate to severe piecemeal necrosis); however, IgG level (>1.45 × ULN) and serum liver aminotransferase (>2.4 × ULN) did not fulfill the Paris criteria (Table 2). The Paris criteria
Table 1.
663
showed a low sensitivity of 20% but a high specificity of 100% for diagnosing the PBC–AIH overlap syndrome.
Revised scoring system A total of 13 (20.0%) of the 65 patients who received liver biopsy were identified with the PBC–AIH overlap syndrome based on the revised diagnostic scoring system. The sum of their scores ranged from 10 to 15 points, most of the points being gained from female gender, low levels of ALP and aspartate aminotransferase (AST), the absence of drug use or viral hepatitis antigens and antibodies, a modest average daily alcohol intake and the presence of ANA seropositivity. IgG level in patients with the PBC–AIH overlap syndrome was slightly higher than that in those with PBC alone (P < 0.05, Table 2). We assessed the pathological changes in the liver in all patients with PBC who received liver biopsy; 15 patients presented with moderate to severe piecemeal necrosis. Among the cases with the PBC–AIH overlap syndrome, five presented with mild or no piecemeal necrosis. The sensitivity and specificity of the revised criteria in the diagnosis of the PBC–AIH overlap syndrome was 60.0% and 87.3%, respectively.
Characteristics of the patients having primary biliary cirrhosis (PBC) with or without liver biopsy
Characteristics Age, years (mean ± SD) Gender, n (M/F) Peripheral blood parameters ALT, U/L (mean ± SD) ALT ≥ 5× ULN, n (%) ALP, U/L (mean ± SD) γ-GT, U/L (mean ± SD) Total bilirubin, μmol/L (mean ± SD) Albumin, g/L (mean ± SD) IgM, g/L (mean ± SD) IgG, g/L (mean ± SD)# >2 × ULN, n (%) 1–2 × ULN, n (%)
