自身免疫性肝病重叠综合征的诊断与治疗

近年来,自身免疫性肝病及其重叠综合征受到越来越多的关注。由于重叠综合征的发病率低,难以进行大规模的随机对照研究,导致该类疾病的诊断以及治疗方案没有统一标准,本文就该病的诊断及治疗做一综述     

自身免疫性肝病及其重叠综合征的诊断及治疗

自身免疫性肝病主要包括自身免疫性肝炎( 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 cholangitis,PSC)及其相互重叠的综合征,但就相互重叠关联而言尚没有明确的定义.在重叠综合征中,以AIH - PBC最为多见,在AIH或PBC患者中占10％[1].近年来由于相关临床经验的累积、实验室诊断技术的发展以及肝活检的普及,使得我国自身免疫性肝病检出率明显增高.     

中老年自身免疫性肝炎重叠综合征14例临床分析

目的探讨中老年自身免疫性肝炎(AIH)与慢性乙型病毒性肝炎重叠综合征患者的临床特征。方法采用国际自身免疫性肝炎小组新修订的描述性诊断标准,从确诊的50例中老年AIH患者中筛选出14例AIH/乙肝重叠综合征患者,分析比较中老年人AIH/乙肝重叠综合征和单纯AIH患者的生化和免疫学指标的特点。结果50例中老年AIH患者中,AIH/乙肝重叠综合征14例(占28%),单纯AIH36例(占72%)。AIH/乙肝重叠综合征患者丙氨酸氨基转氨酶(ALT)、天门冬氨酸氨基转氨酶(AST)、γ-球蛋白、ALT/ALP(碱性磷酸酶)、SMA、ANA效价明显高于单纯AIH患者;AIH/乙肝重叠综合症患者兼有AIH和乙肝的双重组织学特点。结论中老年人中单纯AIH与AIH/乙肝重叠综合征患者的生化检查、免疫学及肝组织病理学特征有差异,临床治疗选择药物时应区别对待。     

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应答。方法 对具有肝穿刺标本的16例PBC—AIH重叠综合征、26例Ⅰ型AIH和25例PBC（Scheuer分期Ⅰ、Ⅱ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 3组患者的性别、年龄、病程、症状无显著性差异；AIH—PBC重叠综合征患者血清碱性磷酸酶、γ-谷氨酰转肽酶、免疫球蛋白IgM以及抗线粒体抗体（AMA）、AMA—M2阳性率明显高于AIH组（P〈0．05）；而丙氨酸转氨酶、天冬氨酸转氨酶、7-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）。AIH—PBC重叠综合征患者肝组织学示界面炎／碎屑样坏死、小叶内炎症及胆管病变；重叠综合征患者接受熊去氧胆酸治疗可使肝功能改善。结论 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治疗有助于血生化学指标的改善。     

肝脏重叠综合征（上）

“重叠综合征”被引入肝脏是描述不同形式的自身免疫性肝病，包括自身免疫性肝炎（AIH）、原发性胆汁性肝硬化（PBC）和原发性硬化性胆管炎（PSC）。对于这些重叠综合征，是不同形式的实体或是自身免疫性肝病的多样表现还有争论。     

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。     

自身免疫性肝炎和原发性胆汁性肝硬化重叠综合征15例临床特点分析

自身免疫性肝病是一组具有自身免疫基础的炎症性肝病,包括自身免疫性肝炎(AIH)、原发性胆汁性肝硬化(PBC)和原发性硬化性胆管炎(PSC)等,临床上确有一部分患者可同时具有上述几种疾病的临床特点,即重叠综合症.对80例自身免疫性肝病患者临床资料进行回顾性分析,发现AIH/PBC重叠综合征15例,本文对其临床特点进行分析,报道如下.     

自身免疫性肝炎-原发性胆汁性肝硬化重叠综合征的诊治

自身免疫性肝炎（AI H）和原发性胆汁性肝硬化（PBC）是影响肝脏的两种自身免疫性疾病,每种疾病均具有各自的临床表现,免疫性和组织学特征,然而,某些患者同时具有两种疾病的特点,这种在同一时段或病程中具备PBC和AI H两种疾病特征的综合征称为AI H-PBC重叠综合征（AI H-PBC OS）。     

原发性胆汁性肝硬化／自身免疫性肝炎重叠综合征患者的临床和病理学研究

目的分析原发性胆汁性肝硬化（PBC）、自身免疫性肝炎（AIH）和PBC／AIH重叠综合征患者的临床和病理学特点。方法对105例自身免疫性肝病患者的临床资料进行分析,比较PBC／AIH重叠综合征和单纯PBC或AIH患者的临床表现和肝组织病理学变化。结果在105例患者中,包括11例PBC／AIH重叠综合征、60例PBC、33例AIH和1例原发性硬化性胆管炎（PSC）。PBC／AIH重叠综合征与PBC或AIH患者的性别、年龄、症状和并发症无明显差异（P〉0．05）,其实验室检查具有AIH的特点,如血清丙氨酸氨基转移酶、天冬氨酸氨基转移酶、免疫球蛋白IgG的明显升高,同时具有PBC的特点,如GGT、ALP、免疫球蛋白IgM的显著增高,但与PBC或AIH相比,无统计学差异（P〉0．05）;自身抗体检测可见抗核抗体、抗线粒体M2抗体和抗核心蛋白gP210抗体阳性,后两项抗体检出率明显高于AIH患者（P〈0．01）;肝组织病理学检查结果显示,PBC／AIH重叠综合征兼有PBC和AIH的特点,如界面炎和碎屑样坏死,汇管区浆细胞浸润,胆管不同程度的病变等。结论PBC／AIH重叠综合征的临床表现和肝组织病理学具有PBC和AIH的双重特征,应对此病充分认识,并探索有效的治疗方案。     

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.     

Overlap syndromes with autoimmune hepatitis in chronic cholestatic liver diseases

Conditions exhibiting features of two different autoimmune liver diseases are commonly designated overlap syndromes, although there is no current agreement on what constitutes an overlap syndrome or specific diagnostic criteria. As in the classic autoimmune liver diseases, such as autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC), the etiology is unknown but presumed to be related to alterations of immune regulation. Distinction of these clinical entities is important for management as outcomes may differ from outcomes of patients with diagnosis of classic autoimmune liver diseases. Due to their presumed rarity, no large therapeutic trials are available and treatment of overlap conditions is empirical and based upon extrapolation of data from the primary autoimmune liver diseases. PBC–AIH overlap is the most frequently described overlap syndrome and may be associated with a poor prognosis. This may represent an important and unrecognized cause of resistance to ursodeoxycholic acid in patients with PBC. PSC–AIH overlap is less commonly reported. Prognosis may be better than in patients with PSC alone; however, worse than in patients with AIH alone. Further studies are needed for determining diagnosis, natural history and optimal therapeutic strategies of overlap syndromes of autoimmune liver disease.     

Overlap syndromes of autoimmune hepatitis: what is known so far

The pattern of some autoimmune hepatitis can be difficult to classify, sometimes due to the overlap of these with primary biliary cirrhosis, primary sclerosing cholangitis and chronic viral hepatitis. The etiology of these variant forms remains unclear. The distinction among the overlap syndromes poses different problems both of prognosis and therapeutic approach. Presently, the utility of the scoring system devised and revised by the International Autoimmune Hepatitis Group regarding these cases is under discussion. Histological examination seems to be an important tool, but often the result does not help in defining a correct diagnosis. To date, the overlap syndromes can be classified at an intermediate level between cholestatic forms of autoimmune hepatitis or hepatic forms of cholestatic syndromes, but it cannot be excluded that the syndromes represent independent disorders.     

Overlap of primary biliary cirrhosis and autoimmune hepatitis: Characteristics,therapy, and long term outcomes

Background: Coexistence of primary biliary cirrhosis (PBC) and autoimmune hepatitis (AIH) is referred to as PBC‐AIH overlap. Pathogenesis of PBC‐AIH is not well understood and its diagnosis is challenging. We previously reported the clinical characteristics of 10 patients diagnosed with PBC‐AIH overlap. Aims: The aim of the study was extend the earlier series and evaluate the diagnostic criteria, biological characteristics, potential therapy, and long‐term outcomes of patients with PBC‐AIH overlap. Methods and Results: We retrospectively analyzed clinical, biochemical, and histological characteristics of 144 patients diagnosed with PBC and 73 diagnosed with AIH. We identified 16 cases of PBC‐AIH overlap, according to criteria established by Chazouillères et al. and other studies. PBC preceded AIH in 6 patients and both diseases occurred simultaneously in the remaining 10 patients. PBC‐AIH overlap has clinical, biochemical, and histological characteristics of both PBC and AIH. Thirteen patients treated with both ursodeoxycholic acid (UDCA) and immunosuppressive therapy responded well, with normal alanine aminotransferase (ALT) and alkaline phosphatase (ALP) levels. The remaining three patients treated with either prednisolone (PSL) or UDCA alone developed cirrhosis, varices, ascites, encephalopathy, or died of liver‐related causes at the 5, 12, and 14‐year follow up. Conclusions: PBC‐AIH overlap is not a rare entity; it was observed in 11% of PBC patients in this study. Further studies will be required to investigate whether PBC‐AIH overlap is distinct from the two individual diseases in terms of long‐term outcomes and therapeutic implications.     

Drug-induced autoimmune hepatitis: A minireview

Drug-induced autoimmune hepatitis (DIAIH) is a specific phenotype of drug-induced liver injury that may lead to the devastating outcome of acute liver failure requiring liver transplantation. Drugs implicated in DIAIH include antimicrobials such as nitrofurantoin and minocycline, non-steroidal anti-inflammatory drugs, statins as well as anti-tumor necrosis agents. The clinical features of drug-induced liver injury are indistinguishable from idiopathic autoimmune hepatitis (AIH) as both may have positive AIH-related autoantibodies, elevated immunoglobulin G, as well as similar histopathological findings. In patients who show no clinical improvement, or there is progressive liver injury despite cessation of the suspected drug, a liver biopsy should be considered, whereby the presence of advance fibrosis on histology favors the diagnosis of idiopathic AIH. Empirical treatment with corticosteroids may be required in patients with non-resolving liver injury. A typical clinical scenario supportive of DIAIH includes a history of drug exposure with spontaneous resolution of liver injury after drug withdrawal and the absence of relapse after rapid steroid taper. In this article we report two cases of DIAIH secondary to Sorafenib and Atorvastatin along with a review of currently available literature. Early identification and treatment often lead to a favorable outcome in DIAIH.     

Update on autoimmune hepatitis

Autoimmune hepatitis （AIH） is a necroinflammatory liver disease of unknown etiology that occurs in children and adults of all ages. Characteristics are its autoimmune features, hyperglobulinemia （IgG）, and the presence of circulating autoantibodies, as well as a response to immunosuppressant drugs. Current treatment consists of prednisone and azathioprine and in most patients this disease has become very treatable. Over the past 2 years, a couple of new insights into the genetic aspects, clinical course and treatment of AIH have been reported, which will be the focus of this review. In particular, we concentrate on genome-wide microsatellite analysis, a novel mouse model of AIH, the evaluation of a large AIH cohort for overlap syndromes, suggested novel criteria for the diagnosis of AIH, and the latest studies on treatment of AIH with budenoside and mycophenolate mofetil.     

Applicability of the IAIHG scoring system to the diagnosis of antimitochondrial/anti-M2 seropositive variant form of autoimmune hepatitis

BACKGROUND AND AIMS: According to the International Autoimmune Hepatitis Group (IAIHG) criteria, circulating antimitochondrial antibodies (AMA) do not support the diagnosis of autoimmune hepatitis (AIH). The aims of this study were to characterize a subset of patients with AIH who have AMA and antiM2 seropositivity, and to assess the applicability of the revised scoring system of the IAIHG in the diagnosis of this variant form of AIH. METHODS: Eighteen patients with AMA-AIH were enrolled and compared with 206 classical AIH and 85 primary biliary cirrhosis (PBC) controls. Human leukocyte antigen (HLA) class II alleles were determined by polymerase chain reaction (PCR) amplification with sequence-specific primers, and biopsies were blindly reevaluated. RESULTS: The patients with AMA-AIH were, on average, older than patients with classical AIH and had an hepatocellular pattern of elevated liver enzymes, hypergammaglobulinemia and lower levels of cholesterol, when compared with PBC controls. There were no histological signs of PBC or overlapping forms in any AMA-AIH biopsies. The majority of patients with AMA-AIH carried HLA antigens associated with classical AIH (DRB1*03, n = 5; DRB1*04, n = 7, and DRB1*13, n = 6). Pretreatment scores classified all AMA-AIH patients with probable (n = 17) or improbable (n = 1) AIH. After treatment, only 28% of AMA-AIH patients reached scores for definite diagnosis, compared with 90.1% of AIH-1 and 96.4 AIH-2. In the AMA-AIH group, only patients who relapsed after immunosuppressive drug withdrawal could be classified with definite AIH. CONCLUSIONS: AMA-AIH shares common features with classical AIH. The diagnosis of AMA-AIH may be swayed by the IAIHG criteria, rendering questionable the applicability of the revised scoring system to this variant form of AIH.     

A case of coexisting primary biliary cirrhosis and primary sclerosing cholangitis: a new overlap of autoimmune liver diseases

Although the etiology of AIH, PBC, and PSC remains unknown, it is apparent that these autoimmune liver diseases share many common features and can coexist in the same patient. Our patient had features of PBC and later clearly developed a picture of PSC. This case suggests that PBC, PSC, AIH, and autoimmune cholangitis are part of a spectrum of chronic autoimmune liver disease that develop in response to some yet unidentified antigen.