Overlap syndromes among autoimmune liver diseases

The three major immune disorders of the liver are autoimmune hepatitis（AIH）,primary biliary cirrhosis（PBC） and primary sclerosing cholangitis（PSC）.Variant forms of these diseases are generally called overlap syndromes,although there has been no standardised definition.Patients with overlap syndromes present with both hepatitic and cholestatic serum liver tests and have histological features of AIH and PBC or PSC.The AIH-PBC overlap syndrome is the most common form,affecting almost 10% of adults with AIH or PBC.Single cases of AIH and autoimmune cholangitis（AMA-negative PBC） overlap syndrome have also been reported.The AIH-PSC overlap syndrome is predominantly found in children,adolescents and young adults with AIH or PSC.Interestingly,transitions from one autoimmune to another have also been reported in a minority of patients,especially transitions from PBC to AIH-PBC overlap syndrome.Overlap syndromes show a progressive course towards liver cirrhosis and liver failure without treatment.Therapy for overlap syndromes is empiric,since controlled trials are not available in these rare disorders.Anticholestatic therapy with ursodeoxycholic acid is usually combined with immunosuppressive therapy with corticosteroids and/or azathioprine in both AIH-PBC and AIH-PSC overlap syndromes.In end-stage disease,liver transplantation is the treatment of choice.     

107例自身免疫性肝炎及其重叠综合征患者的临床分析

目的 分析自身免疫性肝炎(AIH)77例及其重叠综合征患者30例的临床表现、免疫学及生物化学特点及其治疗方案.方法 164例自身免疫性肝病患者中,AIH患者77例和AIH胆汁性肝硬化(PBC)重叠综合征患者30例,分析患者的临床特点、生物化学及组织学变化和治疗应答反应等. 结果 AIH患者的发病年龄高峰在50岁左右,肝功能生物化学检查结果显示为肝炎样异常,丙种球蛋白和免疫球蛋白G均明显高于正常.74%的患者抗核抗体阳性,32%的患者抗平滑肌抗体阳性,52%的患者伴发了肝外自身免疫性疾病.肝组织病理变化以界面性肝炎为主(65%),在中、重度患者则出现小叶性肝炎、玫瑰花结样改变、桥接样坏死等.AIH-PBC重叠综合征患者血清ALT、AST、γ谷氨酰转移酶、碱性磷酸酶和抗核抗体、抗线粒体抗体(AMA)/AMA-M2阳性率较高,组织学检查往往还伴有胆管的病变.60例AIH患者接受免疫抑制剂强的松龙联合硫唑嘌呤治疗第1年时,AIH治疗患者达完全缓解者42例(70%),其中26例持续缓解,16例复发(激素减量至≤10 mg/d或停药后),10例部分缓解,8例无应答.持续缓解者的AST、ALT、免疫球蛋白G、丙种球蛋白及血总胆红素水平均显著低于非持续缓解者(34例,JD值均＜0.05),此类患者撤除了硫唑嘌呤,单用激素的剂量均可维持在5～10 mg/d.AIH-PBC重叠综合征组经联合熊去氧胆酸治疗后除碱性磷酸酶和γ谷氨酰转移酶外,其余肝功能指标(ALT、AST、总胆红素)亦明显改善(P值均＜0.01).结论 AIH及AIH-PBC重叠综合征在临床上并不少见,诊断需综合临床、生物化学、免疫学和病理学等检测结果.AIH患者联合应用糖皮质激素、硫唑嘌呤达持续缓解者,可改为单用小剂量激素治疗.AIH-PBC患者加用熊去氧胆酸治疗,亦可获得较好的疗效.     

中晚期自身免疫性肝炎-原发性胆汁性肝硬化重叠综合征的临床病理研究

目的探讨中晚期自身免疫性肝炎-原发性胆汁性肝硬化（AIH-PBC）重叠综合征的临床病理特征及治疗直答。方法对具有肝穿刺标本的11例PBC-AIH重叠综合征和13例PBC（Seheuer分期3、4期）患者进行比较，重点分析AIH-PBC重叠综合征的临床、病理特点及治疗应答。结果两组患者的性别、年龄、病程、症状无显著差异；AIH-PBC重叠综合征患者的丙氨酸氨基转移酶、天冬氨酸氨基转移酶、γ-球蛋白、免疫球蛋白IgG以及抗核抗体或抗平滑肌抗体阳性率明显高于PBC（P〈0．05）。肝组织学见汇管区与肝腺泡内以单个核细胞为主的较多炎细胞浸润，其中易见浆细胞的聚积性浸润。可见不同时期小胆管损伤或毛细胆管反应性增生并侵蚀肝界板；重叠综合征患者经熊去氧胆酸治疗可使肝功能改善，与PBC患者无明显差异。结论中晚期AIH-PBC重叠综合征临床、血清学及组织病理学表现出AIH和PBC双重特征，UDCA治疗有助于血生化指标的改善。     

进行性家族性肝内胆汁淤积症3型合并AIH-PBC重叠综合征1例

背景自身免疫性肝炎(autoimmune hepatitis,AIH)和原发性胆汁性胆管炎(primary biliary cholangitis,PBC)的AIH-PBC重叠综合征在肝病中并非少见,同时合并进行性家族性肝内胆汁淤积症则较为罕见,通常容易造成漏诊.病例简介本例患者因为肝功能异常伴黄疸11年均未能明确诊断.在本院住院期间,AIH-PBC重叠综合征获得确诊.在接受正规治疗后,效果欠佳.给与遗传性肝病基因检测,发现ABCB4基因突变,提示患者同时合并进行性家族性肝内胆汁淤积症3型(progressive familial intrahepatic cholestasis type 3,PFIC3).2020年和2021年,患者先后因为“上消化道出血”又2次入住我院,病情呈现不断加重的趋势.结论对于1例久未获得确诊的肝病患者,通过生化学、血清学、影像学、组织学等检查,明确了AIH-PBC重叠综合征的诊断.但本病例由于脾脏明显肿大,似不能完全以AIH-PBC重叠综合征加以解释,因此对患者进行了遗传性肝病相关的基因检测,发现了ABCB4基因突变,避免了PFIC3的漏诊.     

自身免疫性肝病重叠综合征的诊断和治疗

自身免疫性肝病（AILD）是一组以肝脏病理损害和肝功能异常为主要表现的自身免疫性疾病,可分为自身免疫性肝炎（AIH）、原发性胆汁性肝硬化（PBC）和原发性硬化性胆管炎（PSC）,重叠综合征指同时具有其中两种疾病的临床和病理表现。重叠综合征相对少见,主要包括AIH—PBC和AIH—PSC。由于重叠综合征在临床表现、血清学和组织学方面综合了两种AILD的特点,其诊断和治疗有一定难度并存在争议。对其临床表现以及诊断和治疗方案进行深入研究有助于对该病的认识和防治。     

自身免疫性肝炎和原发性胆汁性肝硬化重叠综合征的临床特征及疗效观察

目的观察自身免疫性肝炎和原发性胆汁性肝硬化(AIH-PBC)重叠综合征的临床特征及治疗效果。方法研究1:回顾分析124例PBC、57例AIH、39例AIH-PBC重叠综合征患者的临床特征;研究2:根据不同治疗方案对39例AIH-PBC重叠综合征患者进行分组疗效分析。结果在220例自身免疫性肝病患者中,AIH-PBC重叠综合征占17.73%。3组患者的性别组成差异无统计学意义,但发病年龄AIH组相似文献   

自身免疫性肝病活检组织病理学特征分析109例

目的:分析比较自身免疫性肝炎(AIH)、原发性胆汁性肝硬化(PBC)、原发性硬化性胆管炎(PSC)及其重叠综合征的组织病理学变化,提高对自身免疫性肝病(AILD)的认识.方法:对27例AIH、67例PBC、4例PSC、1例AIH-PSC重叠综合征和10例AIH-PBC重叠综合征患者的肝穿组织病理资料进行回顾性分析.结果:AILD患者多发于中年女性(73.3%),肝组织病理变化以界面性肝炎为主(77.7%),在重度患者则出现重度界面性肝炎、桥样坏死等.PBC患者早期(Ⅰ、Ⅱ)占28.3%,而晚期(Ⅲ、Ⅳ)占71.7%,肝组织病理变化以小胆管减少甚至消失为主(62.6%).AIH-PBC重叠综合征患者并非罕见,他的肝组织病理学具有AIH和PBC的双重特征.结论:AILD是非病毒性肝病的重要组成部分,其诊断需综合临床表现、生化、免疫指标和组织学变化.     

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。     

自身免疫性肝炎-原发性胆汗性肝硬化重叠综合征的临床特点及诊断分析

目的：分析自身免疫性肝炎（AIH）-原发性胆汁性肝硬化（PBC）重叠综合征患者临床特点、实验室结果、诊断正确率及时长。方法选取2009年1月至2013年6月经过肝活组织病理检查明确诊断为AIH-PBC重叠综合征的患者53例,对照组为AIH及PBC患者各53例。对患者的临床表现、实验室结果及入院后诊断情况进行回顾分析。正态分布的定量资料采用单因素方差分析对各组间进行比较,两两比较采用SNK-q检验。定性资料采用R ×C列联表法进行各组间比较,两两比较采用Scheffe可信区间法。结果53例AIH-PBC重叠综合征患者ALT为（173．65±52．08）U/L,血清TBil为（38．07±6．82）μmol/L,ALP为（293．81±28．89）U/L,GGT为（57．57±78．84）U/L。其中ALP较两个对照组差异有统计学意义;血清免疫球蛋白IgM为（3．33±2．12） g/L,较两个对照组差异具有统计学意义。自身抗体中抗线粒体抗体M2亚型（AMA-M2）（27/53）较两对照组差异具有统计学意义;未经肝活组织检查诊断正确率（52．83％）最低、入院后明确诊断需要时间最长[（8±7．7）d]。结论 AIH-PBC 重叠综合征临床表现更类似于PBC,但生化检查结果更类似于AIH,AIH-PBC 重叠综合征兼有AIH和PBC的双重特点。     

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.     

Overlap syndrome of primary biliary cirrhosis and autoimmune hepatitis with unusual initial presentation as fulminant hepatic failure

Autoimmune hepatitis and primary biliary cirrhosis are generally easy to discriminate on the basis of clinical, laboratory, and histological findings. The presence of anti-mitocondrial antibodies seropositivity and cholestatic clinical, laboratory, and/or histological features in patients with autoimmune hepatitis indicates the overlap syndrome of autoimmune hepatitis and primary biliary cirrhosis. Fulminant hepatic failure is an unusual initial form of presentation of autoimmune hepatitis and primary biliary cirrhosis overlap syndrome. We report the case of a 50-year-old woman with autoimmune hepatitis and primary biliary cirrhosis overlap syndrome who presented with fulminant hepatic failure. Fulminant hepatic failure has a high mortality rate and may require liver transplant. Our patient revealed a good response to corticosteroid and ursodeoxycholic acid therapy. It is important to identify and distinguish autoimmune hepatitis and variant syndromes from other forms of liver disease because of response to corticosteroid therapy.     

Overlap syndrome of autoimmune hepatitis and primary biliary cirrhosis triggered by fluvastatin

Although statins are generally well-tolerated drugs, recent cases of autoimmune hepatitis (AIH) associated with their use have been reported. A 59-year-old Japanese man reported with liver damage, which appeared one month after beginning treatment with fluvastatin and continued after discontinuation of the drug. Although drug-induced liver injury was possible, positive autoantibody tests (antinuclear antibodies >1/1280, anti-mitochondrial M2 antibodies 21 index value) also suggested autoimmune liver disease. Liver biopsy findings were consistent with an overlap of autoimmune hepatitis and primary biliary cirrhosis. Treatment with prednisone and ursodeoxycholic acid led to a good response. In this patient, manifestation of AIH and primary biliary cirrhosis overlap syndrome was possibly triggered by statin use. Autoimmune liver disease should be considered as a possible diagnosis in patients with evidence of prolonged liver damage after discontinuation of statins.     

De novo autoimmune hepatitis after liver transplantation

Allograft dysfunction with clinical, serologic, and histologic features resembling autoimmune hepatitis (AIH) may develop in pediatric and adult patients who have received a liver transplant (LT) for end-stage diseases other than AIH. This condition is now known as de novo AIH, although its pathophysiology is still uncertain and whether it represents a specific type of rejection or a genuine form of AIH is under debate. The occurrence of de novo AIH seems to be unrelated to the etiology of the disease necessitating liver transplantation, but it has been correlated with antiviral treatment in cases of hepatitis C virus (HCV) infection recurring after LT. Several investigators have reported adverse outcome of de novo AIH, including graft failure, particularly in cases with late diagnosis. Prompt treatment with prednisone, with or without azathioprine (in addition to the basic immunosuppressive regimen), seems to be the best option. The histology of de novo AIH is characterized by an infiltrate rich in plasma cells with significant interface hepatitis and perivenular necro-inflammatory activity. These features are not specific for autoimmune damage; therefore, other causes of graft dysfunction must be excluded. The final diagnosis may be a challenge in patients with recurrent hepatitis C, and requires careful clinical and pathologic assessment.     

Primary biliary cirrhosis and autoimmune hepatitis overlap syndrome: therapeutic features in 5 patients

Autoimmune hepatitis (AIH) and primary biliary cirrhosis (PBC) are two different liver diseases, however diagnosis criteria of these two affections can be found in a same patient. The aim of this study is to relate the clinical, serologic and histologic features of patients presenting the overlap syndrome, AIH-PBC, defined by the presence of at least of two main criteria of each disease and to evaluate their response to therapy. PATIENTS AND METHODS: This was a retrospective study concerning patients presenting overlap syndrome diagnosed between January 1998 and December 2001. These patients had been treated with ursodesoxycholic acid (AUDC) or prednisone and azathioprine or a combination of these three products. Clinical and biological criteria were used to assess response to therapy. RESULTS: Five patients fulfilled the diagnostic criteria of overlap syndrome. All patients were females, the median age was 38 years (range: 19-65 years). Three patients were treated by UDCA, a clinical and biological response was noted in only one patient. Two patients were treated by prednisone and azathioprine without any remission. Three patients were treated by a combination of these three products with a good response in two cases. CONCLUSION: Optimal treatment for overlap AIH-PBC syndrome remains to be determined. Treatment with UDCA or immunosuppressor alone is not efficient. A combination of these drugs should be evaluated in further studies.     

Concordancia entre el resultado de la biopsia hepática y el índice APRI (Ast to Platelet Ratio Index) en el diagnóstico de cirrosis en pacientes con enfermedad hepática autoinmune

Introduction and objectivesIt has been proposed that non-invasive methods may replace liver biopsy for the diagnosis of tissue damage in patients with autoimmune liver disease (ALD). The aim of this study was to determine diagnostic performance and degree of concordance between the APRI index and liver biopsy for diagnosing cirrhosis in these patients.Material and methodsIn a cohort of patients with ALD, the value of the APRI index and liver biopsy results were determined according to the METAVIR score. The AUC and the degree of concordance between an APRI value >2 and a METAVIR score of F4 were evaluated as markers of liver cirrhosis, through a kappa statistic.ResultsIn total, 70 patients (age 51 ± 13 years) were included. The most common autoimmune liver diseases were primary biliary cirrhosis (PBC) (40%), autoimmune hepatitis (AIH) (24.3%) and AIH-PBC overlap syndrome (32.9%). Cirrhosis was confirmed by biopsy in 16 patients (22.9%). 15 patients (21.4%) had an APRI index >2 (Cirrhosis) and only six met both criteria. The AUC of the APRI was 0.77 (95% CI 0.65-0.88). The degree of concordance between the tests was low for an APRI cut-off point >2 (kappa 0.213; 95% CI 0.094-0.332), as well as for cut-off points >1.5, >1 and >0.5 (kappa 0.213, 0.255, 0.257, respectively)ConclusionOur results suggest that there is little concordance between APRI and liver biopsy for the diagnosis of cirrhosis in patients with ALD. It should therefore not be used as a single diagnostic method to determine cirrhosis.     

Diagnosis of Liver Involvement in Primary Sj?gren Syndrome

Liver involvement was one of the first extraglandular manifestations to be reported in patients with primary Sjögren syndrome (SS). In the 1990s, a study of liver involvement in patients with primary SS integrated the evaluation of clinical signs of liver disease, liver function and a complete panel of autoantibodies. Recent developments in the field of hepatic and viral diseases have significantly changed the diagnostic approach to liver involvement in SS. The most recent studies have shown that, after eliminating hepatotoxic drugs and fatty liver disease, the two main causes of liver disease in primary SS are chronic viral infections and autoimmune liver diseases. The differential diagnosis of liver disease in primary SS (viral vs autoimmune) is clinically important, since the two processes require different therapeutic approaches and have different prognoses. With respect to viral infections, chronic HCV infection is the main cause of liver involvement in SS patients from the Mediterranean area, while chronic HBV infection may be the main cause of liver involvement in SS patients from Asian countries. After eliminating viral hepatitis, primary biliary cirrhosis (PBC) should be considered the main cause of liver disease in primary SS. PBC-related SS patients may have a broad spectrum of abnormalities of the liver, including having no clinical or analytical data suggestive of liver disease. Autoimmune hepatitis (AIH) is the second most frequently found autoimmune liver disease to be associated with SS (all reported cases are type I), and nearly 10% of these patients have an AIH-PBC overlap. Finally, IgG4-related disease must be investigated in patients with SS presenting with sclerosing cholangitis, especially when autoimmune pancreatitis or retroperitoneal fibrosis are also present.     

自身免疫性肝病重叠综合征的临床治疗探讨

目的探讨自身免疫性肝病重叠综合征的治疗方法,提高治疗的有效性与安全性。方法 32例自身免疫性肝炎（AIH）-原发性胆汁性肝硬化（PBC）重叠综合征患者,均给予强的松（0.5mg.kg-1.d-1）联合熊去氧胆酸（UDCA,15 mg.kg-1.d-1）治疗,回顾性分析治疗前、后不同时段患者疾病状态的变化,评价临床疗效。结果所有患者症状、体征明显减轻,生化指标、肝脏病理损害均明显改善,与入院前比较差异有统计学意义（P〈0.01或P〈0.05）。IgG、IgM、抗平滑肌抗体（SMA）、抗线粒体抗体（AMA）治疗前后无明显变化,差异无统计学意义（P〉0.05）。结论强的松联合UDCA短期内能明显减轻AIH-PBC患者的临床症状、体征,改善生化学和肝组织学指标,提高患者生存质量,治疗安全有效。     

Autoimmune liver diseases in children - what is different from adulthood?

Autoimmune liver disorders in childhood include autoimmune hepatitis, autoimmune sclerosing cholangitis and de novo autoimmune hepatitis after liver transplant. These inflammatory liver disorders are characterised histologically by interface hepatitis, biochemically by elevated transaminase levels and serologically by autoantibodies and increased levels of immunoglobulin G. Autoimmune hepatitis is particularly aggressive in children and progresses rapidly unless immunosuppressive treatment is started promptly. With appropriate treatment 80% of patients achieve remission and long-term survival. Autoimmune sclerosing cholangitis responds to the same treatment used for autoimmune hepatitis in regards to parenchymal inflammation, but bile duct disease progresses in about 50% of cases, leading to a worse prognosis and higher transplantation requirement; it has a high recurrence rate post-liver transplant. De novo autoimmune hepatitis after liver transplant affects children transplanted for non-autoimmune conditions and responds well to the same treatment schedule used for autoimmune hepatitis, but not to the schedule used for acute rejection.     

Nodular regenerative hyperplasia of the liver,CREST syndrome and primary biliary cirrhosis: an overlap syndrome?

Nodular regenerative hyperplasia of the liver (NRHL) has been found in association with collagen vascular diseases, after drug therapy, with autoimmune disease, and with a variety of haematological disorders. The association of NRHL with the syndrome of Calcinosis cutis, Raynaud's phenomenon, oesophageal dysfunction, sclerodactyly and telangiectasia (CREST syndrome) has only been reported on two previous occasions. The liver disease usually associated with CREST syndrome is primary biliary cirrhosis (PBC) and recently nodular hyperplasia of the liver has been reported in patients with early stage PBC. We present a case of NRHL with CREST syndrome and serological and biochemical features of PBC, a newly recognised overlap syndrome.     

自身免疫性肝病患者外周血淋巴细胞亚群的频率变化及临床意义

目的调查原发性胆汁性肝硬化(PBC)、自身免疫性肝炎(AIH)及AIH-PBC重叠综合征患者外周血淋巴细胞亚群频率变化及其临床意义。方法本中心2001年6月-2010年12月期间,对41例AIH-PBC、37例AIH和36例PBC患者,以及50例健康人群外周血进行淋巴细胞亚群频率检测。分析患者年龄、性别、肝功能、是否肝硬化及淋巴细胞亚群频率的变化。结果与健康组相比,AIH-PBC重叠综合征组、PBC组和AIH组的CD3+CD4+T细胞频率显著升高,而CD3-CD16+CD56+NK细胞频率显著降低;PBC组和AIH-PBC重叠综合征中CD4+/CD8+比值、CD3-CD19+B细胞频率偏高,CD3+CD8+%T细胞频率降低。在疾病发展的不同阶段,AIH-PBC重叠综合征组和PBC组中,肝硬化组CD3+%T细胞频率、CD3+CD8+%T细胞频率较非肝硬化组偏低。结论通过回顾性分析健康人群和AIH、PBC及AIH-PBC重叠综合征患者淋巴细胞亚群的分布特点及其与疾病进展的关系,为临床科学评价上述自身免疫性肝病人群的免疫状态提供重要的免疫指标。