Are Antibodies to Carbonic Anhydrase II Specific for Anti-Mitochondrial Antibody-Negative Primary Biliary Cirrhosis?

Antibodies to carbonic anhydrase II (CAII) have been reported to be specific to anti-mitochondrial antibody (AMA) -negative primary biliary cirrhosis (PBC). We examined whether antibodies to CAII are specific for AMA-negative PBC or a nonspecific response in autoimmune liver disease. Antibody assays to CAII, by western immunoblot (dilution 1:200), were performed on sera from 16 AMA-negative PBC patients, 21 AMA-positive PBC patients, 21 autoimmune hepatitis type 1 (AIH) patients, and 18 alcoholic liver disease (ALD) patients. CAII antibody activity was found in 8 of 16 (50%) of the AMA-negative PBC patients, 9 of 21 (43%) of the AMA-positive PBC group, 10 of 21 (48%) of the AIH group, and in 3 of 18 (17%) of the ALD control group. There was no difference in the prevalence of CAII antibody reactivity between the AMA-negative PBC, AMA-positive PBC, and AIH groups. In conclusion, we determined that CAII antibodies are detected with equal frequency in AMA-positive PBC and AIH. Given that CAII antibodies have been reported in other nonhepatic autoimmune diseases, we conclude that CAII antibodies are likely a nonspecific marker of autoimmunity rather than specific for AMA-negative PBC.     

Long-term follow-up of antimitochondrial antibody-positive autoimmune hepatitis

Antimitochondrial antibodies (AMAs) are the serological hallmark for primary biliary cirrhosis (PBC). When AMAs are detected in patients with chronic hepatitis, they negatively impact on the autoimmune hepatitis (AIH) scoring system. The purpose of this study was to determine if AMAs detected in the sera of patients with overt AIH have clinical or pathological significance. All patients with a clinicopathologic diagnosis of AIH from one center were reviewed. Only those meeting the criteria for probable or definite AIH according to the International Autoimmune Hepatitis Group were included. Patients found to be consistently AMA-positive via enzyme-linked immunosorbent assay (ELISA) for pyruvate dehydrogenase complex E2 subunit were reviewed in detail. Fifteen of 126 patients with typical features of AIH (pretreatment AIH score >10) had detectable AMAs in serum. None had any histologic features suggestive of PBC. None had detectable anti-liver-kidney-microsomal antibodies. Of these 15 patients, all have remained persistently AMA-positive via ELISA. All 15 patients have been followed long-term, and their clinical course remained typical for AIH. No bile duct damage typical of PBC was seen on initial or follow-up liver biopsies. CONCLUSION: Patients with overt AIH who test positive for AMAs at initial presentation and are treated with corticosteroid therapy have shown no clinical or histologic evidence of PBC despite the continued detection of AMAs over a follow-up of up to 27 years.     

Transitions between variant forms of primary biliary cirrhosis during long-term follow-up

BackgroundConditions exhibiting features of two different autoimmune liver diseases are designated overlap syndromes. Variant forms display some, but not all, characteristics of a distinct autoimmune liver disease. We describe transitions over time between variant forms of PBC, i.e. AMA-negative PBC, autoimmune hepatitis (AIH)–PBC overlap and autoimmune cholangitis (AIC) in a large cohort of PBC patients in Sweden.MethodsWe retrieved all patients with variant forms of PBC in six university hospitals in Sweden, covering 60% of the Swedish population. The diagnosis of PBC and its variants was based on laboratory findings and compatible histological features. The revised autoimmune hepatitis scoring system proposed by the International Autoimmune Hepatitis Group was used to establish the diagnosis of AIH.ResultsIn a population of 800 patients with PBC, we identified 35 (5%) variant forms; 25 patients with AIH–PBC overlap, 8 with AIC and 2 with AMA-negative PBC at the time of our study. The initial diagnoses were PBC (3 patients), AIH (3), AIH–PBC overlap (16), AIC (8) and AMA-negative PBC with (1) or without (4) concomitant AIH. The median follow-up was 125 (41–360) months. Immunosuppression and ursodeoxycholic acid induced a complete or good regression of increased aminotransferases in about half of the patients who were given one or both of these treatments.ConclusionsVariant forms of PBC are seen in approximately 5% of PBC patients in Sweden. Transition between different forms may occur, emphasizing the value of repeat biopsies, but established overlapping AIH–PBC seems to be stable over time.     

Autoimmune cholangitis

Autoimmune cholangitis is the term that has been used to describe patients who have the clinical, biochemical, and histologic characteristics of primary biliary cirrhosis (PBC), but who are antinuclear antibody positive rather than anti-mitochondrial antibody (AMA) positive in their sera. The course of their disease is similar to AMA positive cases, and the associated nonhepatic autoimmune diseases are the same in both AMA-positive and AMA-negative PBC. Serial testing for AMA using highly sensitive and specific techniques over time suggests that in subjects with autoimmune cholangitis, their AMA negative status remains negative. The beneficial response to treatment with ursodeoxycholic acid is the same as for AMA-positive PBC. It may be preferable to use the term autoimmune cholangitis, further stratified by AMA status, instead of the somewhat innapropriate term primary biliary cirrhosis.     

Antimitochondrial antibody-negative primary biliary cirrhosis

There is a subset of patients who have biochemical and histologic features consistent with primary biliary cirrhosis (PBC) who lack antimitochondrial antibodies (AMA). This entity is usually referred to as AMA-negative PBC or alternatively autoimmune cholangitis. Patients who have AMA-negative PBC are believed to have a similar clinical course, response to treatment, and prognosis as their AMA-positive counterparts. As more sensitive and specific serologic tests are developed to detect serum AMA, it is possible we may find that these patients initially believed to be AMA-negative are indeed AMA-positive, suggesting a single disease process.     

Fas polymorphisms influence susceptibility to autoimmune hepatitis

BACKGROUND AND AIMS: Genetic factors associated with autoimmune hepatitis (AIH) and primary biliary cirrhosis (PBC), immune-mediated chronic inflammatory liver diseases of unknown etiology, remain to be elucidated. Polymorphisms of the gene encoding Fas have been linked to a variety of autoimmune diseases. We hypothesized that Fas gene polymorphisms might be genetic markers for AIH and PBC. METHODS: To determine the frequency and significance of Fas polymorphisms in patients with AIH and PBC, 74 Japanese AIH patients, 98 Japanese PBC patients, and 132 ethnically matched control subjects were investigated by the use of the Taqman assay. RESULTS: We found significant differences between AIH patients and controls in allele frequencies of Fas-670 (p=0.009), Fas IVS (intervening sequence) 2nt176 (p=0.018), Fas IVS3nt46 (p=0.031), and Fas IVS5nt82 (p=0.013) polymorphisms. Haplotype analysis revealed that one of the haplotypes, GATGC, was associated with increased AIH prevalence. On the other hand, we found no statistically significant differences between PBC patients and controls in allele frequencies of the Fas polymorphisms genotyped in this study. CONCLUSIONS: These results indicate a genetic link of Fas polymorphisms to the development of AIH. Further studies are needed to determine the genetic factors contributing to the development of AIH.     

Clinical significance of autoantibodies to p53 protein in patients with autoimmune liver diseases

BACKGROUND:Autoantibodies to p53 (anti-p53) are rarely present in the sera of patients with autoimmune diseases or the sera of patients with malignancies.OBJECTIVE:To examine the prevalence of anti-p53 in patients with autoimmune liver disease including autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), AIH/PBC overlap syndrome (AIH/PBC OS) and primary sclerosing cholangitis (PSC), and to determine the clinical significance of anti-p53 in autoimmune liver diseases.METHODS:Forty patients with AIH, 41 patients with PBC, eight patients with AIH/PBC OS and five patients with PSC were enrolled. Anti-p53 and antibodies to double-stranded DNA (anti-ds-DNA) were analyzed using commercially available ELISA kits. Demographic, laboratory and histological data were compared between the AIH groups seropositive and seronegative for anti-p53.RESULTS:Six of 40 (15.0%) patients with AIH and four of eight (50.0%) patients with AIH/PBC OS were positive for anti-p53. One of 41 (2.4%) patients with PBC was also positive for anti-p53, but all five patients with PSC were negative, indicating a significantly higher prevalence of anti-p53 in patients with AIH or AIH/PBC OS compared with patients with PBC. None of the AIH patients positive for anti-p53 progressed to hepatic failure or relapsed after immunosuppressive treatment. Titres of anti-ds-DNA in patients with AIH and AIH/PBC OS significantly correlated with titres of anti-p53 (r=0.511; P=0.0213).CONCLUSION:The emergence of anti-p53 is likely to be useful for discriminating AIH or AIH/PBC OS from PBC and helpful for predicting favourable prognoses in patients with AIH. DNA damage may trigger the production of anti-p53 in patients with AIH or AIH/PBC OS.     

自身免疫性肝炎和原发性胆汁性肝硬化重叠综合征患者的临床特点

目的 了解自身免疫性肝炎(AIH)、原发性胆汁性肝硬化(PBC)重叠综合征的临床特点。方法 对129例自身免疫性肝病患者的临床资料进行回顾分析,按国际评分标准,诊断AIH/PBC重叠综合征,并将其生物化学、自身抗体、肝穿刺结果与单纯的AIH、PBC患者病例资料比较。 结果 129例自身免疫性肝病患者中35例为AIH/PBC重叠综合征患者,占27.1％,以女性患者为主,男女比例为1:10,平均年龄(50.79±11.27)岁,其实验室检查具有AIH患者的特点,如:氨基转移酶、γ 球蛋白、免疫球蛋白G的明显升高,同时也具有PBC的特点,如:碱性磷酸酶、免疫球蛋白M的显著增高,自身抗体检测可见抗核抗体(74.3％)、抗线粒体抗体(68.6％)、M2抗体(45.7％)阳性;肝穿刺结果有界面坏死、浆细胞浸润及胆管不同程度的损害。 结论 AIH/PBC重叠综合征为独立于AIH、PBC存在的疾病,有必要对此及早诊断,寻找有效的治疗方法。     

Development of autoimmune hepatitis in patients with typical primary biliary cirrhosis

Primary biliary cirrhosis (PBC)-autoimmune hepatitis (AIH) overlap syndrome is a clinical entity characterized by the occurrence of both conditions at the same time in the same patient. In addition to PBC-AIH overlap syndrome, transitions from one autoimmune disease to another have been reported, but no systematic series have been published. We report a series of 12 patients with consecutive occurrence of PBC and AIH (i.e., PBC followed by AIH). Among 282 PBC patients, 39 were identified who fulfilled criteria for probable or definitive AIH. AIH developed in 12 patients (4.3%). The baseline characteristics of the patients were similar to those of patients with classical PBC. Time elapsed between the diagnosis of PBC and the diagnosis of AIH varied from 6 months to 13 years. Patients with multiple flares of hepatitis at the time of diagnosis of AIH had cirrhosis on liver biopsy. Ten patients were given prednisone +/- azathioprine; short-term as well as sustained remissions were obtained in 8 of these, while two had multiple relapses and eventually died 8 and 7 years after diagnosis of AIH. In conclusion, the development of superimposed AIH could not be predicted from baseline characteristics and initial response to UDCA therapy. If not detected early, superimposed AIH can result in rapid progression toward cirrhosis and liver failure in PBC patients.     

A scoring system for primary biliary cirrhosis and its application for variant forms of autoimmune liver disease

Background: Although primary biliary cirrhosis (PBC) and autoimmune hepatitis (AIH) are two independent autoimmune liver diseases, it is sometimes difficult to characterize the variant forms of autoimmune liver disease. A PBC scoring system, in combination with the AIH scoring system may be helpful to characterize such patients. Methods: A PBC scoring system was introduced that selected 14 categories characteristic of PBC. One hundred and thirty-four patients with PBC, 31 patients with autoimmune cholangitis (AIC), 22 patients with overlap syndrome, and 48 patients with AIH were included in the study. The AIC patients fulfilled the PBC criteria but were negative for anti-mitochondrial antibody and positive for anti-nuclear antibody. Overlap syndrome patients fulfilled both the PBC and AIH criteria. Results: The total scores (means ± SD) for the PBC, AIC, overlap syndrome, and AIH patients were 23.3 ± 4.7, 9.3 ± 4.4, 18.0 ± 5.9, and 3.6 ± 3.3, respectively. When definite and probable PBC patients were defined as those with a total score of over 17 and 9–17, respectively, all except for 1 patient could be classified as definite or probable PBC. Four of the 48 AIH patients were classified as probable PBC. PBC scores for the variant autoimmune liver diseases showed a wide deviation. Plotting both PBC and AIH scores in a rectangular coordinate enabled us to locate each patient with variant forms according to the deviation from classical PBC or AIH. Conclusions: The PBC scoring system might be useful in characterizing the features of variant forms of autoimmune liver disease. Received: March 6, 2002 / Accepted: June 14, 2002 Reprint requests to: K. Yamamoto Editorial on page 106     

A 38-year-old African-American woman with an unusually rapid progression of "Primary Biliary Cirrhosis": a missed opportunity!

The case discussed is of a 38-year-old African-American woman who developed upper abdominal symptoms and liver test abnormalities. She underwent cholecystectomy for presumed gallstone disease. This was followed by a worsening of her condition, with the development of jaundice in the next 2 weeks. Results of reevaluation included transaminases around 1000 IU/L with minimal elevation of alkaline phosphatase (ALP), an antimitochondrial antibody (AMA) titer of 1:320, and an elevated immunoglobulin M (IgM). The antinuclear antibodies (ANA) level was positive, but titers were not obtained. There was no suggestion of bile duct obstruction. Liver biopsy findings were believed to be consistent with primary biliary cirrhosis (PBC). She was therefore started on, but failed treatment with, ursodeoxycholic acid. She was transferred to a transplant center 8 weeks later after a brief episode of encephalopathy and hypoglycemia. The clinical findings were consistent with subfulminant hepatic failure secondary to autoimmune hepatitis (AIH) with an ANA titer of 1:1280, an anti-smooth muscle antibody (SMA) titer of 1:40, and an elevated IgG. Review of the biopsy showed panlobular inflammation and bridging necrosis consistent with severe AIH. On imaging, she had ascites and a nodular appearance of the liver. An immediate drop in transaminases followed corticosteroid therapy, but her disease was already irreversible, and she underwent successful liver transplantation. The explanted liver was shrunken and noncirrhotic with massive hepatocellular collapse and contained multiple regenerating nodules, explaining the ultrasonographic appearances. The inflammatory component had greatly diminished compared with the earlier biopsy. The case illustrates the importance of knowledge of the natural course of a specific disease and the careful interpretation of clinical data, including autoimmune markers. PBC would rarely cause liver failure in a young woman; it is not a rapidly progressive disease. The original clinical diagnosis was unduly swayed by a positive AMA, which can be seen in up to 20% of patients with AIH. Markedly elevated transaminases with minimal elevation of ALP and positive ANA in a young woman should have pointed toward AIH at an earlier stage. The academic discussion of AMA-positive AIH versus PBC/AIH overlap syndrome remains intriguing, but prompt institution of aggressive immunosuppressive therapy aimed at the AIH component should not be deferred. In retrospect, an opportunity was missed.     

自身免疫性肝炎、原发性胆汁性胆管炎及其重叠综合征患者临床特征比较*

目的 比较自身免疫性肝炎(AIH)、原发性胆汁性胆管炎(PBC)和AIH/PBC重叠综合征(AIH/PBC OS)患者临床特征的异同。方法 2017年12月～2019年2月南通市第三人民医院收治的92例自身免疫性肝病患者中包括AIH 35例、PBC 30例和AIH/PBC OS 27例,记录临床表现和血液化验资料并比较三组的异同。结果 AIH、PBC和AIH/PBC OS患者年龄、性别、体质指数和病程比较,无显著性差异(P>0.05);三组乏力、腹胀、纳差、发热和皮肤瘙痒发生率无显著性差异(P>0.05);PBC和AIH/PBC OS患者黄疸更深,血清ALP和GGT水平更高,而AIH患者血清ALT和AST水平更高 (P<0.05);AIH患者凝血功能指标TT显著长于其他两组(P<0.05);AIH患者外周血Hb水平显著低于其他两组(P<0.05);AIH患者血清ASMA阳性率为14.3%,显著高于其他两组的0.0%和0.0%(P<0.05),PBC和AIH/PBC OS患者血清AMA/AMA-M2阳性率分别为93.3%和92.6%,而AIH患者为0.0%(P<0.05);三组血清免疫球蛋白水平差异无统计学意义(P>0.05),三组合并甲状腺功能亢进、系统性红斑狼疮、干燥综合征、类风湿性关节炎、2型糖尿病和慢性肾小球肾炎方面差异,也无统计学意义(P>0.05)。结论 AIH、PBC和AIH/PBC OS患者具有相似的临床症状和体征,但血生化指标、自身抗体表现各有特征,了解这些特征对临床提高诊断和治疗水平将有很大的帮助。     

Body mass index in Japanese patients with autoimmune liver disease: overweight patients with primary biliary cirrhosis tend to be asymptomatic

BACKGROUND/AIMS: The aim of this study was to investigate the effects of being overweight on autoimmune hepatitis (AIH) and primary biliary cirrhosis (PBC) patients. METHODOLOGY/RESULTS: 44 AIH and 95 PBC patients were enrolled in this study. Body weight and body mass index (BMI) of AIH (57.6 +/- 10.4 kg and 23.8 +/- 2.9 kgm(-2), respectively) were higher than those of PBC (51.6 +/- 7.0 kg and 22.0 +/- 2.6 kgm(-2), respectively) (P < 0.001). The prevalence of overweight patients in AIH was also higher than those in PBC (P < 0.005). Being overweight and having 25 < or = BMI < 30 did not affect the progression of hepatic fibrosis in AIH and PBC. In comparison with the non-overweight with PBC, overweight patients with PBC tended not to be symptomatic, such as having itching or fatigue (P = 0.027). CONCLUSIONS: Clinicians should be aware that not only non-alcoholic fatty liver disease but also PBC patients might be included among the overweight hepatic disease patients with unknown etiology.     

164例自身免疫性肝病临床分析

目的 分析比较自身免疫性肝炎（autoimmune hepatitis，AIH）、原发性胆汁性肝硬化（primary biliary cirrhosis，PBC）、原发性硬化性胆管炎（primary sclerosing cholangltis）及其重叠综合征的临床特点、生化特征和治疗反应，提高对自身免疫性肝病的认识。方法对77例AIH患者、46例PBC患者、11例PSC患者和30例PBC-AIH重叠综合征患者的临床及实验室检查资料进行回顾性分析。结果除PSC外，大多数自身免疫性肝病多发于中年女性，从出现症状到明确诊断平均需要2．5年。AIH、PBC-AIH重叠患者具有较高的转氨酶，PBC、PSC具有较明显的GGT、ALP升高。临床表现上AIH、PBC、PSC、AIH-PBC黄疸发生率分别为84％、78％、90％和67％，皮肤瘙痒的发生率分别为43％、56％、81％和60％。PSC和AIH-PBC具有较高的AIH评分，27％的PSC患者和33％AIH-PBC的评分达到可能的AIH。合理应用UDCA和免疫抑制剂可使90％的PBC和AIH患者症状在六个月内得到缓解、肝功能恢复明显改善。结论 AIH、PBC-AIH的肝功能异常以转氨酶升高为主，PBC、PSC以胆汁淤积为主。应用AIH评分系统诊断可能的AIH时应注意鉴别PSC及其它自身免疫性肝病。UDCA和免疫抑制剂可改善绝大多数患者的症状和肝功能异常。     

自身免疫性肝病临床与病理研究

目的分析自身免疫性肝病临床、病理特点,探讨早期诊断、治疗方法。方法１９９６—１９９８年收治６２例自身免疫性肝病,比较原发性胆汁性肝硬化（ＰＢＣ）、自身免疫性肝炎（ＡＩＨ）的临床症状、体征、生物化学指标及病理特征。结果自身免疫性肝病中ＰＢＣ占５９．６８％, ＡＩＨ ４０．３２％。自身免疫性肝病中８３．８％是中老年女性,男女之比１∶１０,而ＡＩＨ　１∶５,发病年龄平均３５岁。ＰＢＣ中血循环自身免疫抗体阳性率８５．２９％,ＡＩＨ　７８．９５％。在阳性病例中 ＡＭＡ, ＡＭＡ－Ｍ２阳性率 １００％, ＡＮＡ阳性率 ８０％,血清免疫球蛋白异常, ＰＢＣ　ＩｇＭ增高占８０％, ＡＩＨＩｇＧ增高占８２．２５％, Ｐ值＜０．０５和Ｐ值＜ ０．０２５。 ＰＢＣ肝脏活组织病理显示,胆管炎和胆管增生、炎症、损伤或三者共存的特征。ＡＩＨ显示门静脉区炎症、淋巴细胞、单核细胞、浆细胞浸润、坏死、纤维化。结论ＰＢＣ和ＡＩＨ是自身免疫性肝病临床上两个常见类型,其中ＡＩＨ以Ⅰ型为主;而血中ＡＭＡ－Ｍ２是ＰＢＣ特征抗体,强的松龙治疗效果ＡＩＨ优于ＰＢＣ。     

Overlap syndromes

In hepatology, the term overlap syndrome describes variant forms of the major hepatobiliary autoimmune diseases, autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), and primary sclerosing cholangitis (PSC). Patients with overlap syndromes present with both hepatitic and cholestatic biochemical and histological features of AIH, PBC, and/or PSC, and usually show a progressive course toward liver cirrhosis and liver failure without adequate treatment. AIH-PBC overlap syndromes have been reported in almost 10% of adults with AIH or PBC, whereas AIH-PSC overlap syndromes were found in 6 to 8% of children, adolescents, and young adults with AIH or PSC. A minority of patients may also show transition from stable PBC to AIH, AIH to PBC, or AIH to PSC, as documented by single case reports and small case series. Single cases of AIH and autoimmune cholangitis (antimitochondrial antibody-negative PBC) overlap have also been reported. Empiric medical treatment of AIH-PBC and AIH-PSC overlap syndromes includes anticholestatic therapy with ursodeoxycholic acid and immunosuppressive therapy with corticosteroids and azathioprine. In end-stage disease, liver transplantation is the treatment of choice.     

Spectrum of autoimmune liver diseases in western India

BACKGROUND AND AIM: The prevalence and spectrum of autoimmune liver diseases (AILDs) in India are rarely reported in comparison to the West. METHOD: During a study period of 7 years, all patients with chronic liver diseases (CLDs) were evaluated for the presence of AILDs on the basis of clinical, biochemical, imaging, serological, and histological characteristics. RESULTS: Of a total of 1760 CLD patients (38.1% females), 102 patients (5.7%) had an AILD. A total of 75 (11.2%) female patients had an AILD. Among males, 27 (2.4%) had an AILD. The prevalence of AILDs in women increased from 11.2% to 45.7% and in men from 2.4% to 10.3%, after excluding alcohol, hepatitis B virus, and hepatitis C virus as a cause of CLD. Of the AILDs, autoimmune hepatitis (AIH) was present in 79 patients (77.4%), followed in descending order by primary biliary cirrhosis (PBC) in 10 patients (9.8%), PBC/AIH true overlap syndrome in six patients (5.8%), primary sclerosing cholangitis (PSC) in five patients (4.9%), and PBC/AIH switchover syndrome in two patients (1.9%). None had PSC/AIH or PBC/PSC overlap syndrome. Associated known autoimmune diseases were found in 40 (39.2%) patients. CONCLUSIONS: AILDs are not uncommon in India. They should be suspected in all cases of CLDs, especially in middle-aged women who do not have problems with alcoholism and who are without viral etiology, as well as in all patients with known autoimmune diseases.     

Primary biliary cirrhosis with features of autoimmune hepatitis

The diagnosis of primary biliary cirrhosis (PBC) is made via a composite of clinical, laboratory, serologic, and histologic assessments, but within each parameter there exists a wide spectrum, so that the features of PBC are not always uniform. PBC is just one of several liver diseases thought to have an autoimmune basis. Therefore, it is not surprising, given the complexity of the immune response, that some patients thought to have PBC may have features of autoimmune hepatitis (AIH). Whether such patients have PBC with features of AIH, or antimitochondrial antibody-negative PBC, or another disease altogether, remains unclear.     

Characterization of the overlap syndrome of primary biliary cirrhosis (PBC) and autoimmune hepatitis: evidence for it being a hepatitic form of PBC in genetically susceptible individuals

Some patients with autoimmune liver disease present with a clinical and/or histological picture showing characteristic findings of both autoimmune hepatitis (AIH) and primary biliary cirrhosis (PBC). Various names, mostly overlap syndrome, have been used to describe these cases, which have thus far not been more closely characterized. The aim of this study was the comparison of 20 patients with overlapping features to representative patients considered suffering from typical AIH or typical PBC (20 patients in each group). We found these patients to indeed show a very mixed picture of both conditions biochemically, serologically, and histologically. However, closer analysis suggested that all of these patients were primarily suffering from PBC as all of them had at least either bile duct destruction on histology or anti-M2 positive antimitochondrial antibodies (AMA). We suggest that these PBC patients because of their genetic susceptibility, evidenced by the AIH-characteristic histocompatibility leukocyte antigen (HLA) type B8, DR3, or DR4, developed a more hepatitic picture. Response to immunosuppressive therapy was excellent. We propose that the name "overlap syndrome" be abandoned for "PBC, hepatitic form." These observations not only have pathophysiological implications, but also suggest that therapy of PBC should be guided by the degree of biochemical and histological hepatic involvement.     

Overlap syndromes: the International Autoimmune Hepatitis Group (IAIHG) position statement on a controversial issue

Some patients present with overlapping features between disorders within the spectrum of autoimmune liver diseases (i.e. autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), and primary sclerosing cholangitis (PSC)) and are commonly classified as having an "overlap syndrome". Standardized definitions of "overlap syndromes" are lacking. The aim of this report by the International Autoimmune Hepatitis Group (IAIHG) is to evaluate if there are important reasons to classify conditions with overlapping features between autoimmune liver diseases as separate diagnostic entities. Definition of diagnostic criteria for overlap conditions can only be arbitrary. The IAIHG scoring system for diagnosis of AIH has been widely used to diagnose "overlap syndromes", but was not intended for such use and has not proven to be an efficient tool for this purpose. Some patients with overlapping features between a cholestatic and hepatitic disorder appear to benefit from treatment with a combination of ursodeoxycholic acid and immunosuppressants, but this strategy is not evidence-based, and it seems unjustified to define new diagnostic groups in this regard. The IAIHG suggests that patients with autoimmune liver disease should be categorized according to the predominating feature(s) as AIH, PBC, and PSC/small duct PSC, respectively, and that those with overlapping features are not considered as being distinct diagnostic entities. The IAIHG scoring system should not be used to establish subgroups of patients. Patients with PBC and PSC with features of AIH should be considered for immunosuppressive treatment. Due to the low prevalence of such "overlap syndromes", prospective interventional therapeutic trials cannot be expected in the foreseeable future.