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 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 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.     

原发性胆汁性胆管炎-自身免疫性肝炎重叠综合征的诊治

自身免疫性肝病(AILD)包括原发性胆汁性胆管炎(PBC)、自身免疫性肝炎(AIH)、原发性硬化性胆管炎(PSC)。患者可在初诊时或随访的过程中出现2种AILD的特征,通常将这种情况称为“重叠综合征”,其中以PBC重叠AIH最为常见。与单纯PBC或AIH相比,PBC-AIH重叠综合征门静脉高压、消化道出血、腹水、死亡及肝移植发生率明显升高,病情进展也更迅速,因此,其早诊早治显得尤为重要。对近年PBC-AIH重叠综合征的诊治进展进行综述。     

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.     

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.     

Hepatobiliary associations with inflammatory bowel disease

Hepatobiliary disease is not uncommon in patients with inflammatory bowel disease (IBD). The most common autoimmune hepatic associations are primary sclerosing cholangitis (PSC) and autoimmune hepatitis (AIH). The immunosuppressant medications used in the treatment of IBD also have potential hepatotoxicity. PSC is most commonly associated with IBD, specifically ulcerative colitis. AIH, a more classic autoimmune disease diagnosed commonly in isolation of other conditions in the same individual, is less commonly associated with IBD. Additionally, a subgroup of patients have features of both PSC and AIH, termed overlap syndrome, that is also sometimes seen in IBD patients. This review will discuss the most common liver disease associations seen in patients with IBD: PSC, AIH and overlap syndrome. Additionally, the most common drug-related hepatotoxicities encountered when treating IBD will be reviewed.     

The future of autoimmune liver diseases – Understanding pathogenesis and improving morbidity and mortality

Autoimmune liver diseases (AILD), namely autoimmune hepatitis (AIH), primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), are rare diseases. These days, patients with PBC almost never require liver transplantation. When treated early with ursodeoxycholic acid patients have a normal life expectancy if the disease is diagnosed at an early stage and the patients respond to treatment. Patients with AIH often go into remission with first‐line therapy including corticosteroids alone or in combination with azathioprine. Nevertheless, about one quarter of patients already developed cirrhosis at diagnosis. Those who do not respond to first line standard of care (SOC) have significant liver‐related morbidity and mortality. No approved second‐ or third‐line treatments are available and the drugs are selected based on limited case series and personal experience. Larger trials are needed to develop efficient therapies for difficult‐to‐treat AIH patients. No treatment has been found to alter the natural course of disease in patients with PSC except for liver transplantation. Identifying PSC patients at risk of developing cholangiocarcinoma (CCA) is another unmet need. Current research in all AILD including AIH, PBC and PSC, focuses on improving our understanding of the underlying disease process and identifying new therapeutic targets to decrease morbidity and mortality.     

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.     

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     

Autoimmune liver diseases and diabetes: A propensity score matched analysis and a proportional meta-analysis

Background and Aims

Patients with some chronic liver diseases have increased risk of diabetes. Whether this is also the case for patients with autoimmune liver diseases is unknown. The study aimed to calculate risk and worldwide prevalence of diabetes in patients with autoimmune hepatitis (AIH), primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC).

Methods

We performed a case–control study using data from the United Kingdom Biobank (UKB) and compared frequency of type 1 diabetes (T1D) and type 2 diabetes (T2D) in AIH and PBC with age-, sex-, BMI- and ethnicity-matched controls. Next, we performed a systematic review and proportional meta-analysis searching PubMed, Embase, Cochrane Library and Web of Science (inception to 1 May 2022 [AIH]; 20 August 2022 [PBC]; 11 November 2022 [PSC]). The pooled prevalence of diabetes was calculated using an inverse method random effects model.

Results

Three hundred twenty-eight AIH patients and 345 PBC patients were identified in UKB and risk of T1D and T2D significantly increased compared with matched controls. Our systematic search identified 6914 records including the UKB study. Of these, 77 studies were eligible for inclusion comprising 36 467, 39 924 and 4877 individuals with AIH, PBC and PSC, respectively. The pooled prevalence of T1D was 3.8% (2.6%–5.7%), 1.7% (0.9%–3.1%), 3.1% (1.9%–4.8%) and of T2D 14.8% (11.1%–19.5%), 18.1% (14.6%–22.2%), 6.3% (2.8%–13.3%) in patients with AIH, PBC and PSC, respectively.

Conclusions

Patients with autoimmune liver diseases have increased risk of diabetes. Increased awareness of diabetes risk in patients with autoimmune liver diseases is warranted.     

自身免疫性肝病109例的临床与病理特征分析

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AIH重叠综合征的临床特点、生化特征和组织学变化,以提高对自身免疫性肝病(AILD)的认识.方法 收集2004年1月-2008年6月肝穿刺病理学检查确诊的AILD患者共109例,其中AIH 27例、PBC 67例、PSC 4例、AIH-PSC重叠综合征1例和AIH-PBC重叠综合征10例,对患者的临床及实验室检查资料进行回顾性分析.结果 AILD患者多发于中年女性(73.3%,80/109),常见症状为黄疸、乏力、纳差和皮肤瘙痒.AIH患者的发病年龄高峰在50岁左右,肝功能检查结果显示为肝炎样异常,丙种球蛋白和免疫球蛋白G均明显高于正常值,62.9%的患者(17/27)抗核抗体(ANA)阳性.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件肝炎、桥样坏死等.PBC患者主要表现为碱性磷酸酶、γ-谷氨酰转肽酶和胆红素明显升高,伴免疫球蛋白M升高,74.6%的患者(50/67)线粒体抗体(AMA)和(或)AMA-M2亚型阳性.所有PBC患者行肝脏病理学检查,早期(Ⅰ、Ⅱ)占28.3%,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 0A).AIH-PBC重叠综合征患者的临床表现和肝组织病理学具有AlH和PBC的双重特征,其中有3例患者同时检测到ANA和AMA/AMA-M2阳性.结论 AILD在中国人中并非少见,其诊断需综合临床表现、生化、免疫指标和组织学变化.     

Recurrence of autoimmune liver diseases after liver transplantation

Liver transplantation(LT) is the most effective treatment modality for end stage liver disease caused by many etiologies including autoimmune processes. That said, the need for transplantation for autoimmune hepatitis(AIH) and primary biliary cirrhosis(PBC), but not for primary sclerosing cholangitis(PSC), has decreased over the years due to the availability of effective medical treatment. Autoimmune liver diseases have superior transplant outcomes than those of other etiologies. While AIH and PBC can recur after LT, recurrence is of limited clinical significance in most, but not all cases. Recurrent PSC, however, often progresses over years to a stage requiring re-transplantation. The exact incidence and the predisposing factors of disease recurrence remain debated. Better understanding of the pathogenesis and the risk factors of recurrent autoimmune liver diseases is required to develop preventive measures. In this review, we discuss the current knowledge of incidence, diagnosis, risk factors, clinical course, and treatment of recurrent autoimmune liver disease(AIH, PBC, PSC) following LT.     

Epidemiology of autoimmune liver disease

Primary biliary cirrhosis (PBC), autoimmune hepatitis (AIH) and primary sclerosing cholangitis (PSC) are chronic liver diseases that likely have an autoimmune basis to their pathogenesis. Although significant strides have been made in the clinical management of these conditions, their pathogenesis remains obscure. Understanding of various epidemiological factors may shed light on predisposing or causative factors for these diseases. Most is known about the epidemiology of PBC, with only minimal information on that of PSC and AIH. In this review, the current data on the epidemiology of PBC, AIH and PSC are summarized and suggestions are made for future work in this important area.     

Autoimmune hepatitis and overlap syndromes

Autoimmune hepatitis (AIH) is an immune-mediated, autodestructive liver disease with hepatocytes as target cells, mostly affecting young women. Primary biliary cirrhosis (PBC) is also regarded as an autoimmune liver disease with bile duct epithelia as the target cells, resulting in a continuous loss of bile ducts. Both diseases may occur simultaneously in their full manifestations in about 10% to 20% of cases, thus constituting an overlap syndrome with PBC directing the course of the disease. AIH may also occur simultaneously with primary sclerosing cholangitis (PSC), with a frequency of between 2% and 8% of patients with PSC. In most cases, AIH precedes manifestation of PSC. In children, the overlap syndrome of AIH and PSC seems to make up an entity of its own: autoimmune sclerosing cholangitis.     

Diagnostic and therapeutic questions in overlap syndromes of autoimmune hepatitis

The term 'overlap syndromes of liver diseases' includes coexistence of autoimmune hepatitis (AIH), primary sclerosing cholangitis (PSC), primary biliary cirrhosis (PBC). Due to their unknown etiology, as well as their variable presentation with mixed clinical and biochemical features, these overlap syndromes are often a diagnostic and therapeutic challenge for hepatologists. The most frequent association reported occurs between AIH and PBC. More rare is the overlap between AIH and PSC, typical in young age and often concomitant with an inflammatory bowel disease as ulcerative colitis. The treatment of choice is based on ursodeoxycholic acid and immunosoppressive drugs, used at the same time or consecutively, according to the course of disease. Histological examination seems an important tool, but often does not help for a correct diagnosis due to lack of specificity. Two particular forms of variant syndrome are the so called outlier syndromes, without clear characteristics of overlap: the autoimmune cholangitis, probably a form of PBC anti-mitochondrial antibodies negative, and the hepatitis C virus related with stigmata of autoimmunity, such as nonspecific autoantibodies at low titer. The diagnostic score system elaborated in 1999 by the International AIH Group can help for diagnosis, even if its definite validity is lacking.     

Autoimmune liver disease: diagnosis and therapy

Autoimmune Hepatitis (AIH), primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC) and overlap syndromes of these three disease entities are regarded as autoimmune liver diseases. These conditions are important differential diagnoses of elevated liver function tests as about 10 % of liver transplantations in Europe and North America are for these indications. The diagnosis is often difficult but can be facilitated by sequential measurement of relevant autoantibodies, exclusion of other liver disease, ultrasound, ERCP and liver histology. In AIH immunosuppressive therapy has been shown to prevent or stop the development of cirrhosis and improve the prognosis of the patients decisively. In other autoimmune liver diseases this evidence is missing making individual therapeutic decisions necessary. Ursodesoxycholic acid (UDCA) seems to slow disease progression in particular in early stages of PBC.     

Clinical and pathological characteristics of the autoimmune hepatitis and primary biliary cirrhosis overlap syndrome

BACKGROUND AND AIMS: The defining of the autoimmune hepatitis (AIH) and primary biliary cirrhosis (PBC) overlap syndrome as a separate clinicopathological entity has been controversial and temporally and geographically subjective. METHODS: From 1979 until 2000, 227 patients diagnosed with AIH, PBC or the overlap thereof were treated. Cases with genuine AIH/PBC overlap syndrome were sorted out using close clinical follow up and serial liver biopsies. RESULTS: Of the 227 patients, 19 (8.4%) were diagnosed with the AIH/PBC overlap syndrome. They all cleared a score >10 for the diagnosis of AIH, and tested positive for antimitochondrial antibodies during their courses. Long-term follow up with frequent histological examinations, however, established the diagnosis of AIH/PBC overlap syndrome in only two (0.8%) patients. The most powerful factor distinguishing AIH from PBC was acidophilic bodies in lobules that were detected significantly more frequently in patients with AIH than PBC or spurious overlap syndrome (39/46 [85%]vs 3/85 [4%], P < 0.001). It was more reliable than bile-duct lesions for the distinction of PBC from AIH. CONCLUSIONS: Although AIH/PBC overlap syndrome does exist, it is infrequent and needs to be diagnosed carefully using close clinical and histological follow up to enable timely and effective treatment.     

Overlap syndromes from pediatrics to adulthood

Abstract   Overlap syndromes are autoimmune conditions with mixed immunological, clinical and histological features. The most frequent overlaps are between primary biliary cirrhosis (PBC) and autoimmune hepatitis (AIH), and between AIH and sclerosing cholangitis (SC). True AIH/PBC overlap syndrome is rare and characterized by elevation of transaminases and immunoglobulin G (IgG), positive anti-smooth muscle antibodies and a liver biopsy showing interface hepatitis as well as changes typical of PBC. These patients respond to immunosuppressive treatment that must be given promptly, to avoid progression to liver failure. The so-called 'autoimmune cholangitis' defines a small group of patients with cholestatic and histological features of PBC but negative for anti-mitochondrial antibody (AMA) and positive for PBC-specific anti-nuclear antibody (ANA). The positivity for ANA in these patients is a consequence of the AMA negativity, since AMA masks ANA on immunofluorescence. These patients' clinical course and response to treatment resemble that of classical PBC. AIH/ASC overlap syndrome is characterised by elevated levels of IgG and circulating autoantibodies, including ANA, SMA and atypical perinuclear anti-neutrophil cytoplasmic antibody, in association with cholangiographic changes typical of SC. This condition affects in particular children and young adults and may represent the early stage of adult primary SC. The parenchymal liver inflammation responds satisfactorily to immunosuppression, while the bile duct damage may progress despite treatment.     

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。