Abstract
The liver is a unique organ that plays a vital role in the defense against pathogens and the maintenance of tolerance against autoantigens (Kubes and Jenne, Ann Rev Immunol 36:247–277, 2018). As the largest lymphoid organ, the liver is targeted by tissue-specific inflammatory response, observed in primary autoimmune liver diseases (AILD) including autoimmune hepatitis (AIH), primary biliary cholangitis (PBC, formerly known as primary biliary cirrhosis), and primary sclerosing cholangitis (PSC). AILD is characterized by peculiar histopathological change and chronic course, progressively developing into cirrhosis or even malignancy. The etiopathogenesis of AILD remains unclear, but it is believed to be multifactorial with genetic and environmental factors involved. The clinical presentations vary in individuals and are usually atypical. In some cases, liver biopsy is required for the definite diagnosis. Of note, overlap syndromes and liver involvement of systemic autoimmune diseases also account for part of liver dysfunction in an autoimmune setting.
AILD is a relatively rare disease with geographic variations and aggregation in family members. Although the prevalence is low, the health burden of these disorders to both individuals and society is substantial. The incidence and prevalence are reported to be increased in AIH, PBC, and PSC during the past few decades. More and more attention has been paid to the AILD these years, and several population-based researches fill the vacancy of epidemiology of AILD. In this chapter, we are going to describe the epidemiological features of AILD and to discuss the impact of genetic and environmental factors on the development of these complex diseases.
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Keywords
FormalPara Key Points-
The liver is a unique organ that plays a vital role in the defense against pathogens and the maintenance of tolerance against autoantigens.
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Despite its central role in immune tolerance, the liver, the largest lymphoid organ, is targeted by tissue-specific inflammatory responses in autoimmune liver diseases (AILD) including autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC).
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The etiopathogenesis of AILD remains unclear but is multifactorial with genetic and environmental factors.
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Overlap syndromes with liver involvement in systemic autoimmune diseases are common and poorly understood or defined.
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AILD are relatively rare with wide geographic variations and aggregation in family members.
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The prevalence of AILD is low, but the health burden of these disorders is substantial.
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Considerable work needs to be done on both the genetic and environmental contributors to these diseases.
Introduction
The liver is a unique organ that plays a vital role in the defense against pathogens and the maintenance of tolerance against autoantigens [1]. As the largest lymphoid organ, the liver is targeted by tissue-specific inflammatory response, observed in primary autoimmune liver diseases (AILD) including autoimmune hepatitis (AIH), primary biliary cholangitis (PBC, formerly known as primary biliary cirrhosis), and primary sclerosing cholangitis (PSC). AILD is characterized by peculiar histopathological change and chronic course, progressively developing into cirrhosis or even malignancy. The etiopathogenesis of AILD remains unclear, but it is believed to be multifactorial with genetic and environmental factors involved. The clinical presentations vary in individuals and are usually atypical. In some cases, liver biopsy is required for the definite diagnosis. Of note, overlap syndromes and liver involvement of systemic autoimmune diseases also account for part of liver dysfunction in an autoimmune setting.
AILD is a relatively rare disease with geographic variations and aggregation in family members. Although the prevalence is low, the health burden of these disorders to both individuals and society is substantial. The incidence and prevalence are reported to be increased in AIH, PBC, and PSC during the past few decades. More and more attention has been paid to the AILD these years, and several population-based researches fill the vacancy of epidemiology of AILD. In this chapter, we are going to describe the epidemiological features of AILD and to discuss the impact of genetic and environmental factors on the development of these complex diseases.
Autoimmune Hepatitis
AIH is a chronic progressive inflammatory liver disease, clinically manifested as elevated alanine aminotransferase (ALT)/aspartate aminotransferase (AST), hyperglobulinemia, and the presence of autoantibodies. If left untreated, AIH can lead to liver cirrhosis and hepatic failure, even hepatocellular carcinoma (HCC). The etiology of AIH is unclear, and it is hypothesized that unknown triggers result in autoimmune response to hepatocytes. Serologically, AIH can be divided into two subgroups: type 1 AIH which is characterized by antinuclear antibodies (ANAs) and/or anti-smooth muscle antibodies (ASMAs) and type 2 AIH which manifests anti-LKM-1 and anti-LC1. Exclusion of other liver disease and the correlation of clinical and histological presentations helps the diagnosis of AIH. The typical histologic features of AIH are interface hepatitis, emperipolesis, and hepatic rosette formation [2]. The treatment of AIH mainly depends on immunosuppressants, especially glucocorticoids and azathioprine.
AIH in the General Population
There is limited information regarding epidemiology on AIH. Previous population-based studies in Western countries revealed the annual incidence rates from 0.67 to 2.2/100,000 persons and a point prevalence from 11 to 26.9/100,000 persons [3,4,5,6,7,8]. The incidence and prevalence of AIH in Asia are relatively low, with an overall prevalence of 4–5.61 per 100,000 [9, 10]. AIH displays a female predominance (up to 95%), and most patients are middle-aged [4]. AIH may present at any age from childhood to elderly. Type 1 subtype of AIH mainly affects adults, while type 2 occurs frequently in younger patients. Type 1 AIH is more common than type 2 AIH, which is mostly a pediatric condition and more aggressive [11]. In Canada, the annual incidence of type 2 AIH is reported to be 0.23/100,000 children [12]. The 10-year cumulative mortality is estimated to be 26.4% in Northern Europe, at least twofold higher than the general population, especially patients with cirrhosis [5, 13]. Male gender and cirrhosis are associated with higher risk for HCC [14, 15]. Steroid treatment induces clinical, laboratory, and histological improvement in approximately 80% of patients [16], and the combination of steroids and azathioprine is associated with less side effects of steroids. However, a minority of patients will not respond to steroids and require alternative immunosuppressants such as mycophenolate mofetil.
Family Occurrence
Family occurrence has been rare. It has been reported that AIH accumulates in twins, siblings, parents, and children [17,18,19]. Recently, a Danish nationwide population-based study revealed that first-degree relatives of AIH patients have a fivefold increased likelihood to develop AIH, and the 10-year cumulative risk was 0.1% for the relatives [20]. Regarding the concordance of AIH in twins, no comprehensive studies have been reported previously. Nolte et al. described an acute hepatitis of unknown etiology, possibly with AIH origin in a monozygotic twin pair [18]. An epidemiological study in the Netherlands reported the concordance in monozygotic twins and discordance in dizygotic twins [17]. The Danish nationwide registry study also demonstrated a significantly higher risk of AIH in co-twins, and the probandwise concordance rate is higher in monozygotic than in dizygotic twins [20].
Risk Factors
Multiple factors contribute to the etiopathogenesis of AIH, including genetic predisposition (Table 11.1). Several genes have been reported to confer susceptibility to type 1 AIH, the strongest association of which is within the HLA-DRB1 locus, a class II MHC locus. In 2014, a genome-wide association study identified two relevant HLA alleles: HLA-DRB1*0301 as a primary susceptibility genotype and HLA-DRB1*0401 [21]. The study also demonstrated association between the AIH and variants of SH2B3 (rs3184504, 12q24) and CARD10 (rs6000782, 22q13.1) [21]. A number of other factors may trigger autoreactive response in AIH. The female predominance suggests a role for sexual hormones in AIH. Wei et al. demonstrated the dysbiosis in Chinese AIH population and identified several associated intestinal microbiota, suggesting the potential role of intestinal microbiome in the pathogenesis of AIH [22]. Administration of drugs could result in hepatic autoimmune responses. Drug-induced autoimmune hepatitis (DIAIH) is an increasingly recognized phenomenon, which has been reported to make up less than 10% of AIH case cohort in 2014 and increase to 18% in 2019 [8, 23, 24]. Notably, DIAIH differs from drug-induced liver injury by positive autoantibodies and response to immunosuppressants [24, 25]. Increasing usage of biological compound may contribute to the growing number of DIAIH.
Comorbidities
Some diseases have been reported to be associated with AIH, including systemic autoimmune diseases (i.e., systemic lupus syndrome, multiple sclerosis) [26], inflammatory bowel diseases (IBD) [27], celiac disease [28], and viral infections (i.e., hepatitis C virus (HCV), Epstein-Barr virus (EBV)) [29]. A subgroup of patients manifest signs of both AIH and PSC, named as autoimmune sclerosing cholangitis (ASC). Notably, IBD is a common comorbidity in ASC patients, the prevalence of which closely mirroring that in PSC patients in a population-based study [30]. The coexistence of AIH and IBD ranges from 4.5% to 18%, less common than that in ASC patients [31, 32]. AIH is also prevalent in HCV patients, in which the viral antigen is a mimicry of smooth muscle [33]. Thus, a mechanism of molecular mimicry is implicated in AIH patients with HCV infection. In addition, AIH patients have a higher risk to develop osteopenia secondary to prolonged usage of steroids as well as metabolic syndrome. Hematopoietic risks also increase as the side effects of azathioprine.
Primary Biliary Cholangitis
PBC is a chronic cholestatic liver disease characterized by nonsuppurative destructive inflammation of small and medium-sized bile ducts. Intrahepatic cholestasis and peribiliary fibrosis can culminate over time in an end-stage cirrhosis, eventually resulting in HCC. The majority of PBC cases arise insidiously, and the diagnosis is based on the presence of serum autoantibodies and the elevation of cholestatic enzymes (i.e., alkaline phosphatase, gamma-glutamyltransferase) [34]. Anti-mitochondrial antibody (AMA) reactive against the E2 subunit of the pyruvate dehydrogenase complex (PDC-E2) is a specific serum marker in PBC. Serum antinuclear antibodies (ANAs), such as anti-gp210 and anti-Sp100, are accepted as PBC-specific markers during diagnosis. Liver biopsy is unnecessary unless either serum autoantibodies or elevation of cholestatic enzymes is absent. The pathogenesis of PBC remains obscure, but the detection of autoreactive T cells and autoantibodies suggests autoimmune humoral responses against mitochondria [35, 36]. Ursodeoxycholic acid (UDCA) is the first-line therapy, and obeticholic acid (OCA) is optional for those UDCA-unresponsive or non-tolerant cases.
PBC in the General Population
The incidence and prevalence of PBC vary widely in different regions and seem to be increasing over time (Table 11.2). In 2012, systemic review of epidemiological studies worldwide reported that the incidence rate ranges between 0.9 and 5.8 per 100,000 inhabitants, with 92% of female patients, and the prevalence of PBC ranges from 1.91 to 40.2 per 100,000 inhabitants [37]. A recent meta-analysis of epidemiology of PBC in the Asia-Pacific region demonstrated a pooled overall incidence as 8.55 per 100,000 people. The pooled overall prevalence was estimated to be 118.75 per 100,000 people with a respective pooled prevalence of 36.24 and 146.47 cases per 100,000 during pre-UDCA era and post-UDCA era [38]. Of note, large population-based study reported the incidence and prevalence rates increase over time with a mean annual incidence of 1.1 between 2000 and 2007. It stated that the net growth of PBC patients in the Netherlands was attributed to increase in incidence instead of decrease in the number of deaths [39]. Another study in Sweden mentioned an increased prevalence of PBC during 30 years although incidence remained stable [40]. It is worth mentioning that countries, ethnicity, and variable criteria for case inclusions may explain the wide range of incidence and prevalence rates between different countries. However, the increase in prevalence may probably attribute to the increased recognition, better data capture, improved laboratory detection methods, and increased survival after UDCA treatment.
PBC has a female predominance with a female to male ratio of about 10 to 1 [34]. A cohort study in the USA estimated 12-year prevalence of PBC with a highest adjusted prevalence value among women (42.8 per 100,000) [41]. The symptoms are similar in men and women, but men may have a worse disease progression with a higher risk to develop HCC. PBC is closely associated with a higher risk of HCC [42]. Male sex and advanced liver stage are independent risk factors for the development of HCC in patients with PBC, suggested by the representative cohort in China and Japan [43, 44].
An international meta-analysis in Western countries reported that the 5-year, 10-year, and 15-year transplant-free survival rates were 90%, 77.5%, and 65.6%, respectively [45]. The 5-year death/liver transplantation in PBC patients is 4.02% in the Asia-Pacific region [38]. Before the availability of UDCA, PBC patients usually develop to an advanced stage with a subsequent median survival of 6–8 years [34]. In the UDCA era, the introduction of UDCA at early stage improves the survival rate of PBC patients [46,47,48]. The survival rate of patients who respond to UDCA treatment is similar to that of an age-matched and sex-matched healthy people [46]. The favorable effects of UDCA are probably attributed to the delay of histological progression and the development of esophageal varices.
Family Occurrence
The studies of familial PBC revealed a fundamental role played by genetic factors and environmental influences on the pathogenesis of PBC. The first-degree relatives of PBC patients have a higher risk of developing PBC [49]. A recent nationwide study with genealogical database has defined the relative risk of the first-, second-, and third-degree relatives of PBC patients as 9.13, 3.16, and 2.59, respectively. The fourth- and fifth-degree relatives also had a slight increase in the relative risk [50]. Apart from the familial aggregation of occurrence, the AMA aggregate among first-degree relatives as well, which recommends a close follow-up of these relatives for early diagnosis [51]. However, in AMA-negative first-degree relatives and AMA-positive first-degree relatives with normal alkaline phosphatase levels at initial assessment, the risk of developing PBC in the subsequent 8 years is low [52]. A recommendation for a standardized follow-up approach for family members of PBC patients requires further investigation. By comparing eight monozygotic and eight dizygotic twin pairs, concordance rate for PBC is estimated to be 63% in monozygotic twins and null in dizygotic twins [53]. Of note, the monozygotic concordance rate is the highest reported for autoimmune disease. However, the sibling relative risk, namely, the odds ratio for PBC of an individual with a sibling affected by PBC, is 10.5 among the lowest for autoimmune disease. Genome-wide analysis of epigenetics in monozygotic twins and sisters discordant for PBC has revealed particular differences in DNA methylation profiles, copy number variation, and gene expression which explains the different phenotypes in siblings [54].
Risk Factors
Although the etiopathogenesis of PBC remains to be determined, several risk factors have been identified (see Table 11.1). The familial occurrence suggests the genetic predisposition of PBC, like many other autoimmune diseases. HLA class II alleles are believed to be associated with the development of PBC, especially HLA-DRB1*08 allele family [55]. In recent years, high-throughput technologies such as genome-wide association studies (GWAS) have revealed more risk loci associated with PBC. Forty non-HLA alleles possibly contributing to PBC susceptibility are discovered according to the GWAS analyses from different countries. Even though it differs among different studies and populations, the identified genes participate in certain pathways including antigen presentation and production of interleukin (IL)-12 (i.e., IRF5, SOCS1, IL-12A, etc.), activation of T cells and interferon (IFN)-γ secretion (i.e., IL12R, TYK2, STAT4, etc.), and activation of B cells and production of immunoglobulins (i.e., ARID3a, POU2AF1, IKZF3, etc.) [56,57,58].
The environmental factors including urinary tract infections, cigarette smoking, and the use of hormone replacement therapies are associated with increased risk of PBC [59]. A strong relationship lies between smoking and PBC, demonstrated by studies from the UK and France [60, 61]. Molecular mimicry is considered to be the underlying mechanism by which pathogens and xenobiotics trigger autoimmune responses [62]. It is well established that humoral and cellular autoimmune responses in PBC are associated with pyruvate dehydrogenase complex (PDC-E2). The homozygous enzyme of PDC-E2 in microbiota or chemical xenobiotics can induce serological and histopathological changes in PBC [63]. Recent studies have revealed a correlation between the intestinal microbiome and PBC, suggesting the potential risk of dysbiosis in the pathogenesis of PBC [64].
Comorbidities
PBC frequently coexists with rheumatic disorders in up to 30% of cases. A monocentric study demonstrated the co-occurrence in 61.2% of cases of PBC patients, with the most common comorbidity as Sjögren’s syndrome, followed by Raynaud’s phenomenon and Hashimoto thyroiditis [65]. Other extrahepatic autoimmune diseases that might occur include Graves’ thyroiditis, systemic lupus erythematosus, scleroderma, rheumatoid arthritis, vasculitis, and celiac disease [65, 66]. Interestingly, extrahepatic autoimmune diseases commonly coexisted with PBC have a tendency to be less severe. For example, systemic sclerosis (SS) most commonly associated with PBC is limited to cutaneous tissue, and the disease progression is much slower compared with matched patients with PBC alone [67,68,69]. Similar to other chronic liver diseases, PBC is associated with a higher risk of HCC. The risk of HCC is reported higher in PBC, ranging from 6 to 18.8 times that of general population [42, 70, 71]. An internationally representative cohort study has reported that the incidence of PBC-HCC is significantly greater in male, patients with advanced disease, and 12-month UDCA non-responders [72]. Osteoporosis with an increased fracture risk is frequently encountered in PBC patients, largely driven by deficient bone formation [73,74,75]. Thus, vitamin D and calcium supplementation should be addressed in the clinical management of PBC patients.
Primary Sclerosing Cholangitis
PSC is a complex chronic cholestatic autoimmune disease with unknown causes. Unlike PBC, PSC is characterized by fibrotic obstructive cholangitis involving intra-/extrahepatic bile ducts and forms “onion-skin” fibrosis. Classically, PSC affects large bile duct while some may involve small ducts or overlap AIH. In a retraspective study, 89.9% patients had classical or large duct disease [76]. PSC is often associated with IBD, suggesting the important role of gut-liver axis in the pathogenesis of PSC. The recent guidelines for PSC suggest that all patients with IBD should receive an assessment for PSC [77]. The diagnosis is mainly based on abnormal cholestatic enzymes and distinctive radiological manifestations: segmental stenosis and dilation in magnetic resonance imaging (MRI). Liver biopsy is unnecessary unless in the case of small-duct PSC. There is no effective medical therapy for PSC, and many patients progress to end-stage liver disease that requires liver transplantation (LT) or even cholangiocarcinoma (CCA). PSC patients usually have a higher risk of developing CCA, and the annual incidence of developing CCA ranges between 0.5% and 1.5%, and the lifetime risk is between 6% and 12% [78].
PSC in the General Population
The epidemiological information of PSC is poorly described. The incidence rate of PSC ranges from 0.07 to 1.3 per 100,000 inhabitants per year, and the prevalence ranges from 0.22 to 16.2 (Table 11.3) [79]. A meta-analysis in 2011 reported a pooled incidence rate of 1.0 (0.82–1.17) per 100,000 person-years in six population-based studies in western countries. The pooled incidence rate ratio for males versus females was 1.7 (1.34–2.07), correlating with the susceptibility of males [80]. The incidence of PSC seems to be higher in Northern Europe and Northern America, but relatively low in Asia and Africa. The widely variable incidence and prevalence might be attributed to the ethnical diversity, and genetic background may play a role in the etiology and natural history of PSC [81]. Besides the genetic background, the study design and the inclusion criteria may partly explain the differences. A recent retrospective cohort study in the UK revealed an incidence of 0.68 per 100,000 person-years and a prevalence of 5.58 per 100,000 person-years, which is the highest incidence and prevalence reported ever in the UK [82]. It has been proposed that the incidence of PSC is increasing. Two cohort studies revealed a significant increase in incidence ratio of PSC over time with an average annual percent change of 3.06 in one study [83, 84]. A questionnaire-based survey conducted in Japan reported the point prevalence of PSC was 1.8 in 2016, indicating an increasing trend compared to the prevalence of 0.75 in 2007 [85]. Most patients with PSC have serum antibodies such as ANA, anti-SMA, and antineutrophil cytoplasmic antibody (ANCA) but are not specific. Recent studies identified zymogen granule glycoprotein 2 (GP2) as the first autoimmune mucosal target in PSC, the detection of antibody against which could be used for risk stratification [86]. Contrary to PBC, PSC has a male predominance, with a male/female ratio of 2/1 [87]. Female patients are usually associated with a lower risk of LT or death or malignancies [76]. The median transplant-free survival time of PSC is 14.5 according to an international retrospective study. The occurrence of hepatopancreatobiliary malignancies, mainly CCA, is associated with a significantly increased risk of patient mortality [76].
Family Occurrence
Unlike PBC, data on family occurrence of PSC is limited. A case report in 2005 described two brothers diagnosed with PSC who were positive for the susceptibility HLA haplotypes DR3-DQ2 and DR6-DQ6, suggesting a genetic origin of PSC [88]. In a monocentric study in Sweden, first-degree relatives of PSC patients have a PSC prevalence of 0.7%, nearly 100-fold increased risk compared to that of general population, indicating a potential role of genetic disposition [89]. Another study from Sweden also confirmed an increased risk of PSC in first-degree relatives of PSC patients. The offspring, siblings, and parents of PSC patient cohort had a significantly higher risk of cholangitis with the hazard ratios and 95% confidence intervals, 11.5 (1.6–84.4), 11.1 (3.3–37.8), and 2.3 (0.9–6.1), respectively [89].
Risk Factors
The etiology of PSC is unclear, but several genetic and nongenetic predispositions have been identified (see Table 11.1). Early serological studies documented the association between HLA complex and PSC. The following GWAS confirmed the importance of HLA as a risk locus. HLA-B*08 and DRB*03 have a strong association with PSC, with an odds ratio of 4.9 and 3.8, respectively [90]. Recently, the largest GWAS of PSC has identified a new significant locus which affects the expression of UBASH3A, a gene involved in the regulation of T cell signaling [91]. As for the genetic contribution to the disease severity and progression, genetic variant rs853974 outside the HLA complex is reported to be relevant to the disease progression of PSC [92]. In accordance with the strong association between PSC and IBD, PSC shares some susceptibility loci with PSC. However, most of these loci have failed to show a genetic link to PSC, suggesting that PSC-IBD might be a unique phenotype. As for environmental factors, smoking is considered to be a protective factor for PSC, independent of its protective effects on UC [93]. Like PBC and AIH, dysbiosis occurs in PSC patients, including bacteria and fungi [94, 95]. The identification of PSC marker genera either relevant to intestinal inflammation severity or biliary obstruction also suggests the association between PSC and microbiome [96].
Comorbidities
As mentioned above, PSC has a strong correlation with IBD, mostly ulcerative colitis (UC). The comorbidity of Crohn’s disease (CD) is less common than UC, and PSC patients usually show milder symptoms in the setting of CD than UC [76, 97]. Approximately 75% of PSC patients have concomitant IBD, while the prevalence of PSC is 8.1% in IBD patients [98, 99]. More and more studies demonstrated that IBD patients associated with PSC are identical to patients with IBD alone with a relatively mild clinical course but an increased risk of developing colorectal carcinoma [100, 101]. The presence of PSC symptoms at PSC diagnosis in IBD patients is the only factor related with this increased risk of colorectal carcinoma [102]. Whether PSC coexisting with IBD differs from PSC alone remains unclear and requires further investigation. CCA is another common comorbidity in PSC with a 398-fold increased risk of developing CCA in PSC patients compared to the general population in a population-based multicenter study [84]. And the risk of CCA is significantly higher in patients with concomitant IBD and PSC than general population in a clinical study with 20-year follow-up [103].
Overlap Syndromes
Coexistence of clinical features of at least two different AILDs is defined as overlap syndromes. In overlap syndromes, shared clinical, immunological, and histological features exist between AIH, PBC, and PSC. In most cases, overlap syndromes are between AIH and PBC or AIH and PSC, but a few cases have reported the overlap syndrome of PBC and PSC [104,105,106]. The epidemiological information of overlap syndromes is limited due to the diagnosis and publication bias.
AIH-PBC overlap syndrome is more common than AIH-PSC, largely due to the relative frequent occurrence of PBC and AIH in the spectrum of AILDs. The prevalence of AIH-PBC overlap syndrome is estimated to be 4.3–9.2% among patients with PBC and 2–19% among patients with AIH [107, 108]. The adjusted prevalence of AIH-PBC overlap syndrome by eliminating score for female gender or the presence of other autoimmune disorders is 4% [109]. AIH-PBC overlap syndrome seems to aggregate in Hispanic patients, with a significantly higher prevalence to develop overlap syndrome than that of non-Hispanic patients (31% vs. 13%, respectively) [110]. The frequency of cirrhosis and cirrhotic complications (i.e., gastrointestinal bleeding, portal hypertension, esophageal varices, etc.) are reported significantly higher in the overlap group than PBC alone [111]. A recent study compared the natural history of patients with PBC alone to those with overlap syndrome, and a decreased 5-year adverse event-free survival was observed in overlap patients [112]. The treatment of AIH-PBC overlap depends on the combination of steroids and UDCA, more effective than UDCA monotherapy according to a meta-analysis [113].
AIH-PSC overlap syndrome is a rare syndrome that has been described in both children and adults. AIH-PSC overlap is more common in children, adolescents, and young adults. The diagnosis is made upon the overt cholangiographic or histologic findings of PSC together with robust histologic features of AIH [108, 114]. The prevalence of characteristic cholangiographic appearance suggesting PSC found in adult AIH patients varies between different studies, ranging from 2% to 10% [115, 116]. The prevalence to develop PSC is much higher in children with AIH, up to 50% [31]. AIH is rarely diagnosed in patients with an original diagnosis of PSC, the prevalence of which ranges from 7% to 14% [117, 118]. The adverse outcome-free survival of patients with PSC/AIH overlap syndrome is reduced [119]. Interestingly, AIH-PSC overlap patients seem to have a better outcome than straightforward PSC patients with the combination treatment of UDCA and immunosuppressants [120, 121]. AIH-PSC overlap patients are still regarded to have a poorer prognosis than patients with classical AIH and AIH-PBC overlap [122].
Liver Involvement in Systemic Rheumatic Diseases
Liver involvement in systemic rheumatic diseases is common even though the liver is not a common target organ. The epidemiology of these liver autoimmune conditions is largely correlated to the prevalence of systemic rheumatic diseases and the susceptibility of liver involvement. Several common conditions will be discussed in detail in the following part.
IgG4-Related Diseases
IgG4-related disease is a systemic inflammatory condition that can affect multiple organs. Involvement of nearly every anatomic site has been reported, but the most commonly affected organs are pancreas, biliary tract, major salivary glands, lacrimal glands, retroperitoneum, and lymph nodes [123]. IgG4-related diseases share similar histological appearances: lymphoplasmacytic infiltration, storiform fibrosis, and obliterative phlebitis with variable presence of eosinophils [124, 125]. With regard to IgG4-related hepatobiliary disease, characteristic imaging features of segmental or diffuse biliary strictures with thickened bile duct walls are required to support the diagnosis apart from histopathological features [126]. The prevalence of IgG4-related hepatobiliary disease remains unclear. A nationwide survey in Japan identified 43 IgG4 sclerosing cholangitis (IgG4-SC) without autoimmune pancreatitis (AIP). The male to female ratio was 3.3 to 1 in IgG4-SC with an average age of onset of 69.3 years [127]. A novel concept of IgG4-realted AIH has been proposed [128, 129]. Patients who met the diagnostic criteria for AIH had a high serum IgG4 level, and abundant IgG4-positive plasma cells were reported to be diagnosed as IgG4-related AIH. The prevalence of IgG4-SC and IgG4-AIH is lacking due to the scarce reports.
Sarcoidosis
Sarcoidosis is a chronic granulomatous inflammatory disease that can affect any organ. Liver involvement is relatively common in sarcoidosis with prevalence ranging from 5% to 30% [130]. It has been found that 50–65% of sarcoid patients have hepatic involvement as per liver biopsy [131]. A population-based study reported a prevalence of 6%, and cholestatic enzymes are elevated in the majority of patients [132]. A close association has been demonstrated between sarcoidosis and hepatitis C virus infection [133]. It has also been reported that a link lies between sarcoidosis and PBC or AIH [32, 134]. The histological abnormalities of hepatic sarcoidosis include non-caseating granulomas, intrahepatic cholestasis, periportal fibrosis, etc. For patients with end-stage hepatic sarcoidosis who require liver transplantation, the 10-year survival rate is estimated to be 51.3%, lower than matched PSC/PBC group (61.5%) in a monocentric study [135].
Connective Tissue Diseases
Connective tissue diseases (CTDs) are composed of a large and heterogeneous group of immunological disorders with unknown etiology. Liver, as the largest lymphoid organ, is frequently involved in CTDs in the form of abnormal biochemical indexes.
Systemic lupus erythematosus (SLE) is a chronic systemic autoimmune disease that can cause damage to almost every organ. It has been reported that patients with SLE have a 9.3–59.7% chance to develop liver dysfunction during follow-up [136, 137]. With the criteria of liver disease as twofold elevation of liver enzymes, a monocentric study revealed 20.7% of SLE patients have liver disease and the prevalence to develop liver dysfunction is increased in males, indicating that male patients with SLE are more susceptible to liver involvement [138]. SLE-associated hepatitis, termed lupus hepatitis, occasionally occurs. It has been reported that 4.7% of SLE patients develop AIH and 19.4% of SLE patients have liver enzyme abnormalities [139].
Sjögren’s syndrome (SS) mainly affects salivary and lacrimal glands, manifested by keratoconjunctivitis sicca, xerostomia, and swelling of salivary glands. Liver involvement is commonly seen in SS. About 27–49% of SS patients have abnormal liver function with 11–21% found to develop hepatomegaly [140]. Of note, a group of SS patients have positive serum AMA [141]. AMA is considered to be associated with pathogenesis of SS. In both PBC and SS, the autoantibodies can target bile duct and salivary gland, partly explaining the presence of AMA in SS patients. SS patients have a higher risk of developing AILD with 9% PBC and 4% AIH [142, 143]. It is worth mentioning that liver function assessment should be conducted in SS patients regularly.
Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by joint involvement and extra-articular manifestations. Liver involvement is not a typical extra-articular manifestation in RA. The presentation of liver damage in RA is a cholestatic pattern with predominantly elevated ALkaline Phosphatase (ALP) and gamma-Glutamyl Transpeptidase (γGT). Abnormal liver function test results are present in between 18% and 50% of cases [144]. A recent cross-sectional study identified 44% liver involvement in RA patients with most of the cases asymptomatic [145]. Notably, the liver involvement in RA may be attributed to the hepatotoxicity of medications.
Besides the CTD mentioned above, systemic sclerosis, myopathies, antiphospholipid syndrome, and many other systemic autoimmune diseases can involve liver, characterized by abnormal liver enzymes or hepatomegaly. The prevalence of liver damage caused by systemic autoimmune disease varies between different diseases and ethnic groups. Liver function should be well-monitored once the diagnosis of CTD is made.
Conclusion
The increased annual incidence and prevalence have been drawing attention to the management of AILDs during the past decades. AIH, PBC, PSC, and overlap syndromes are the most recognized ones that affect liver in situ. Liver involvement of systemic rheumatic diseases usually does not display specific biochemical nor histological features. Although the prevalence is increasing, AILDs remains rare. The epidemiological features of these kinds of diseases are limited. Most AILDs have a female predominance with the exception of PSC and IgG4-related diseases. Ethnic and sexual factors usually play an important role in the occurrence and pathogenesis. Genetic predisposition is considered to have a strong association with the onset of AILDs. The management of these kinds of diseases usually relies on immunosuppressants, including glucocorticoids and immunosuppressive drugs. To sum up, AILDs should be considered in patients with liver dysfunction when the infectious and metabolic causes are ruled out.
References
Kubes P, Jenne C. Immune responses in the liver. Ann Rev Immunol. 2018;36(1):247–77.
de Boer YS, van Nieuwkerk CM, Witte BI, Mulder CJ, Bouma G, Bloemena E. Assessment of the histopathological key features in autoimmune hepatitis. Histopathology. 2015;66(3):351–62.
Ngu JH, Bechly K, Chapman BA, Burt MJ, Barclay ML, Gearry RB, et al. Population-based epidemiology study of autoimmune hepatitis: a disease of older women? J Gastroenterol Hepatol. 2010;25(10):1681–6.
Delgado JS, Vodonos A, Malnick S, Kriger O, Wilkof-Segev R, Delgado B, et al. Autoimmune hepatitis in southern Israel: a 15-year multicenter study. J Dig Dis. 2013;14(11):611–8.
Gronbaek L, Vilstrup H, Jepsen P. Autoimmune hepatitis in Denmark: incidence, prevalence, prognosis, and causes of death. A nationwide registry-based cohort study. J Hepatol. 2014;60(3):612–7.
Danielsson Borssen A, Marschall HU, Bergquist A, Rorsman F, Weiland O, Kechagias S, et al. Epidemiology and causes of death in a Swedish cohort of patients with autoimmune hepatitis. Scand J Gastroenterol. 2017;52(9):1022–8.
Puustinen L, Barner-Rasmussen N, Pukkala E, Färkkilä M. Incidence, prevalence, and causes of death of patients with autoimmune hepatitis: a nationwide register-based cohort study in Finland. Dig Liver Dis. 2019;51(9):1294–9.
Valgeirsson KB, Hreinsson JP, Bjornsson ES. Increased incidence of autoimmune hepatitis is associated with wider use of biological drugs. Liver Int. 2019;39(12):2341–9.
Jalihal A, Telisinghe PU, Chong VH. Profiles of autoimmune hepatitis in Brunei Darussalam. Hepatobiliary Pancreat Dis Int. 2009;8(6):602–7.
Lee YM, Teo EK, Ng TM, Khor C, Fock KM. Autoimmune hepatitis in Singapore: a rare syndrome affecting middle-aged women. J Gastroenterol Hepatol. 2001;16(12):1384–9.
Sokollik C, McLin VA, Vergani D, Terziroli Beretta-Piccoli B, Mieli-Vergani G. Juvenile autoimmune hepatitis: a comprehensive review. J Autoimmun. 2018;95:69–76.
Jiménez-Rivera C, Ling SC, Ahmed N, Yap J, Aglipay M, Barrowman N, et al. Incidence and characteristics of autoimmune hepatitis. Pediatrics. 2015;136(5):e1237.
van den Brand FF, van der Veen KS, de Boer YS, van Gerven NM, Lissenberg-Witte BI, Beuers U, et al. Increased mortality among patients with vs without cirrhosis and autoimmune hepatitis. Clin Gastroenterol Hepatol. 2019;17(5):940–947.e2.
Migita K, Watanabe Y, Jiuchi Y, Nakamura Y, Saito A, Yagura M, et al. Hepatocellular carcinoma and survival in patients with autoimmune hepatitis (Japanese National Hospital Organization-autoimmune hepatitis prospective study). Liver Int. 2012;32(5):837–44.
Montano-Loza AJ, Carpenter HA, Czaja AJ. Predictive factors for hepatocellular carcinoma in type 1 autoimmune hepatitis. Am J Gastroenterol. 2008;103(8):1944–51.
Lamers MM, van Oijen MG, Pronk M, Drenth JP. Treatment options for autoimmune hepatitis: a systematic review of randomized controlled trials. J Hepatol. 2010;53(1):191–8.
Van Gerven NMF, Verwer BJ, Witte BI, van Erpecum KJ, van Buuren HR, Maijers I, et al. Epidemiology and clinical characteristics of autoimmune hepatitis in the Netherlands. Scand J Gastroenterol. 2014;49(10):1245–54.
Nolte W, Polzien F, Sattler B, Ramadori G, Hartmann H. Recurrent episodes of acute hepatitis associated with LKM-1 (cytochrome P450 2D6) antibodies in identical twin brothers. J Hepatol. 1995;23(6):734–9.
Yoshida O, Abe M, Furukawa S, Murata Y, Hamada M, Hiasa Y, et al. A familial case of autoimmune hepatitis. Intern Med. 2009;48(5):315–9.
Grønbæk L, Vilstrup H, Pedersen L, Christensen K, Jepsen P. Family occurrence of autoimmune hepatitis: a Danish nationwide registry-based cohort study. J Hepatol. 2018;69(4):873–7.
De Boer YS, van Gerven NM, Zwiers A, Verwer BJ, van Hoek B, van Erpecum KJ, et al. Genome-wide association study identifies variants associated with autoimmune hepatitis type 1. Gastroenterology. 2014;147(2):443–452.e5.
Wei Y, Li Y, Yan L, Sun C, Miao Q, Wang Q, et al. Alterations of gut microbiome in autoimmune hepatitis. Gut. 2020;69(3):569–77.
Licata A, Maida M, Cabibi D, Butera G, Macaluso FS, Alessi N, et al. Clinical features and outcomes of patients with drug-induced autoimmune hepatitis: a retrospective cohort study. Dig Liver Dis. 2014;46(12):1116–20.
Bjornsson E, Talwalkar J, Treeprasertsuk S, Kamath PS, Takahashi N, Sanderson S, et al. Drug-induced autoimmune hepatitis: clinical characteristics and prognosis. Hepatology. 2010;51(6):2040–8.
Bjornsson ES, Bergmann OM, Björnsson HK, Kvaran RB, Olafsson S. Incidence, presentation, and outcomes in patients with drug-induced liver injury in the general population of Iceland. Gastroenterology. 2013;144(7):1419–25, 1425.e1-3; quiz e19-20.
Efe C, Wahlin S, Ozaslan E, Berlot AH, Purnak T, Muratori L, et al. Autoimmune hepatitis/primary biliary cirrhosis overlap syndrome and associated extrahepatic autoimmune diseases. Eur J Gastroenterol Hepatol. 2012;24(5):531–4.
Paolella G, Farallo M, Degrassi I, Agostoni C, Amoruso C, Nuti F, et al. Pediatric AILD and extra-hepatic immune-mediated comorbidities. Dig Liver Dis. 2019;51(2):281–5.
Vajro P, Paolella G, Maggiore G, Giordano G. Pediatric celiac disease, cryptogenic hypertransaminasemia, and autoimmune hepatitis. J Pediatr Gastroenterol Nutr. 2013;56(6):663–70.
Rigopoulou EI, Smyk DS, Matthews CE, Billinis C, Burroughs AK, Lenzi M, et al. Epstein-barr virus as a trigger of AILDs. Adv Virol. 2012;2012:987471.
Deneau M, El-Matary W, Valentino PL, Abdou R, Alqoaer K, Amin M, et al. Primary sclerosing cholangitis, autoimmune hepatitis, and overlap in Utah children: epidemiology and natural history. Hepatology. 2013;58(4):1392–400.
Gregorio GV, Portmann B, Karani J, Harrison P, Donaldson PT, Vergani D, et al. Autoimmune hepatitis/sclerosing cholangitis overlap syndrome in childhood: a 16-year prospective study. Hepatology. 2001;33(3):544–53.
Teufel A, Weinmann A, Kahaly GJ, Centner C, Piendl A, Wörns M, et al. Concurrent autoimmune diseases in patients with autoimmune hepatitis. J Clin Gastroenterol. 2010;44(3):208–13.
Nishiguchi S, Kuroki T, Ueda T, Fukuda K, Takeda T, Nakajima S, et al. Detection of hepatitis C virus antibody in the absence of viral RNA in patients with autoimmune hepatitis. Ann Intern Med. 1992;116(1):21–5.
Carey EJ, Ali AH, Lindor KD. Primary biliary cirrhosis. Lancet. 2015;386(10003):1565–75.
Kita H, Matsumura S, He XS, Ansari AA, Lian ZX, Van de Water J, et al. Quantitative and functional analysis of PDC-E2-specific autoreactive cytotoxic T lymphocytes in primary biliary cirrhosis. J Clin Invest. 2002;109(9):1231–40.
Zhang J, Zhang W, Leung PS, Bowlus CL, Dhaliwal S, Coppel RL, et al. Ongoing activation of autoantigen-specific B cells in primary biliary cirrhosis. Hepatology. 2014;60(5):1708–16.
Boonstra K, Beuers U, Ponsioen CY. Epidemiology of primary sclerosing cholangitis and primary biliary cirrhosis: a systematic review. J Hepatol. 2012;56(5):1181–8.
Zeng N, Duan W, Chen S, Wu S, Ma H, Ou X, et al. Epidemiology and clinical course of primary biliary cholangitis in the Asia–Pacific region: a systematic review and meta-analysis. Hepatol Int. 2019;13(6):788–99.
Boonstra K, Kunst AE, Stadhouders PH, Tuynman HA, Poen AC, van Nieuwkerk KM, et al. Rising incidence and prevalence of primary biliary cirrhosis: a large population-based study. Liver Int. 2014;34(6):e31–8.
Marschall HU, Henriksson I, Lindberg S, Söderdahl F, Thuresson M, Wahlin S, et al. Incidence, prevalence, and outcome of primary biliary cholangitis in a nationwide Swedish population-based cohort. Sci Rep. 2019;9(1):11525.
Lu M, Li J, Haller IV, Romanelli RJ, VanWormer JJ, Rodriguez CV, et al. Factors associated with prevalence and treatment of primary biliary cholangitis in United States health systems. Clin Gastroenterol Hepatol. 2018;16(8):1333–1341.e6.
Liang Y, Yang Z, Zhong R. Primary biliary cirrhosis and cancer risk: a systematic review and meta-analysis. Hepatology. 2012;56(4):1409–17.
Harada K, Hirohara J, Ueno Y, Nakano T, Kakuda Y, Tsubouchi H, et al. Incidence of and risk factors for hepatocellular carcinoma in primary biliary cirrhosis: national data from Japan. Hepatology. 2013;57(5):1942–9.
Rong G, Wang H, Bowlus CL, Wang C, Lu Y, Zeng Z, et al. Incidence and risk factors for hepatocellular carcinoma in primary biliary cirrhosis. Clin Rev Allergy Immunol. 2015;48(2):132–41.
Lammers WJ, Hirschfield GM, Corpechot C, Nevens F, Lindor KD, Janssen HL, et al. Development and validation of a scoring system to predict outcomes of patients with primary biliary cirrhosis receiving ursodeoxycholic acid therapy. Gastroenterology. 2015;149(7):1804–1812.e4.
Corpechot C, Carrat F, Bahr A, Chrétien Y, Poupon RE, Poupon R. The effect of ursodeoxycholic acid therapy on the natural course of primary biliary cirrhosis. Gastroenterology. 2005;128(2):297–303.
Pares A, Caballeria L, Rodes J. Excellent long-term survival in patients with primary biliary cirrhosis and biochemical response to ursodeoxycholic acid. Gastroenterology. 2006;130(3):715–20.
ter Borg PC, Schalm SW, Hansen BE, van Buuren HR, Dutch PBC Study Group. Prognosis of ursodeoxycholic acid-treated patients with primary biliary cirrhosis. Results of a 10-yr cohort study involving 297 patients. Am J Gastroenterol. 2006;101(9):2044–50.
Selmi C, Zuin M, Gershwin ME. The unfinished business of primary biliary cirrhosis. J Hepatol. 2008;49(3):451–60.
Örnolfsson KT, Olafsson S, Bergmann OM, Gershwin ME, Björnsson ES. Using the Icelandic genealogical database to define the familial risk of primary biliary cholangitis. Hepatology. 2018;68(1):166–71.
Lazaridis KN, Juran BD, Boe GM, Slusser JP, de Andrade M, Homburger HA, et al. Increased prevalence of antimitochondrial antibodies in first-degree relatives of patients with primary biliary cirrhosis. Hepatology. 2007;46(3):785–92.
Gulamhusein AF, Juran BD, Atkinson EJ, McCauley B, Schlicht E, Lazaridis KN. Low incidence of primary biliary cirrhosis (PBC) in the first-degree relatives of PBC probands after 8 years of follow-up. Liver Int. 2016;36(9):1378–82.
Selmi C, Mayo MJ, Bach N, Ishibashi H, Invernizzi P, Gish RG, et al. Primary biliary cirrhosis in monozygotic and dizygotic twins: genetics, epigenetics, and environment. Gastroenterology. 2004;127(2):485–92.
Selmi C, Cavaciocchi F, Lleo A, Cheroni C, De Francesco R, Lombardi SA, et al. Genome-wide analysis of DNA methylation, copy number variation, and gene expression in monozygotic twins discordant for primary biliary cirrhosis. Front Immunol. 2014;5:128.
Tanaka A, Leung PSC, Gershwin ME. The genetics and epigenetics of primary biliary cholangitis. Clin Liver Dis. 2018;22(3):443–55.
Cordell HJ, Han Y, Mells GF, Li Y, Hirschfield GM, Greene CS, et al. International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways. Nat Commun. 2015;6:8019.
Qiu F, Tang R, Zuo X, Shi X, Wei Y, Zheng X, et al. A genome-wide association study identifies six novel risk loci for primary biliary cholangitis. Nat Commun. 2017;8:14828.
Kawashima M, Hitomi Y, Aiba Y, Nishida N, Kojima K, Kawai Y, et al. Genome-wide association studies identify PRKCB as a novel genetic susceptibility locus for primary biliary cholangitis in the Japanese population. Hum Mol Genet. 2017;26(3):650–9.
Gershwin ME, Selmi C, Worman HJ, Gold EB, Watnik M, Utts J, et al. Risk factors and comorbidities in primary biliary cirrhosis: a controlled interview-based study of 1032 patients. Hepatology. 2005;42(5):1194–202.
Prince MI, Ducker SJ, James OF. Case-control studies of risk factors for primary biliary cirrhosis in two United Kingdom populations. Gut. 2010;59(4):508–12.
Corpechot C, Chrétien Y, Chazouillères O, Poupon R. Demographic, lifestyle, medical and familial factors associated with primary biliary cirrhosis. J Hepatol. 2010;53(1):162–9.
Selmi C, De Santis M, Cavaciocchi F, Gershwin ME. Infectious agents and xenobiotics in the etiology of primary biliary cirrhosis. Dis Markers. 2010;29(6):287–99.
Mattner J, Savage PB, Leung P, Oertelt SS, Wang V, Trivedi O, et al. Liver autoimmunity triggered by microbial activation of natural killer T cells. Cell Host Microbe. 2008;3(5):304–15.
Tang R, Wei Y, Li Y, Chen W, Chen H, Wang Q, et al. Gut microbial profile is altered in primary biliary cholangitis and partially restored after UDCA therapy. Gut. 2018;67(3):534–41.
Floreani A, De Martin S, Secchi MF, Cazzagon N. Extrahepatic autoimmune conditions associated with primary biliary cirrhosis. Clin Rev Allergy Immunol. 2015;48(2):192–7.
Feld JJ, Heathcote EJ. Epidemiology of AILD. J Gastroenterol Hepatol. 2003;18(10):1118–28.
Liberal R, Grant CR, Sakkas L, Bizzaro N, Bogdanos DP. Diagnostic and clinical significance of anti-centromere antibodies in primary biliary cirrhosis. Clin Res Hepatol Gastroenterol. 2013;37(6):572–85.
Rigamonti C, Bogdanos DP, Mytilinaiou MG, Smyk DS, Rigopoulou EI, Burroughs AK. Primary biliary cirrhosis associated with systemic sclerosis: diagnostic and clinical challenges. Int J Rheumatol. 2011;2011:976427.
Rigamonti C, Shand LM, Feudjo M, Bunn CC, Black CM, Denton CP, et al. Clinical features and prognosis of primary biliary cirrhosis associated with systemic sclerosis. Gut. 2006;55(3):388–94.
Boonstra K, Bokelaar R, Stadhouders PH, Tuynman HA, Poen AC, van Nieuwkerk KM, et al. Increased cancer risk in a large population-based cohort of patients with primary biliary cirrhosis: follow-up for up to 36 years. Hepatol Int. 2014;8(2):266–74.
Cavazza A, Caballería L, Floreani A, Farinati F, Bruguera M, Caroli D, et al. Incidence, risk factors, and survival of hepatocellular carcinoma in primary biliary cirrhosis: comparative analysis from two centers. Hepatology. 2009;50(4):1162–8.
Trivedi PJ, Lammers WJ, van Buuren HR, Parés A, Floreani A, Janssen HL, et al. Stratification of hepatocellular carcinoma risk in primary biliary cirrhosis: a multicentre international study. Gut. 2016;65(2):321–9.
Cuthbert JA, Pak CY, Zerwekh JE, Glass KD, Combes B. Bone disease in primary biliary cirrhosis: increased bone resorption and turnover in the absence of osteoporosis or osteomalacia. Hepatology. 1984;4(1):1–8.
Guañabens N, Cerdá D, Monegal A, Pons F, Caballería L, Peris P, et al. Low bone mass and severity of cholestasis affect fracture risk in patients with primary biliary cirrhosis. Gastroenterology. 2010;138(7):2348–56.
Fan J, Wang Q, Sun L. Association between primary biliary cholangitis and osteoporosis: meta-analysis. Clin Rheumatol. 2017;36(11):2565–71.
Weismuller TJ, Trivedi PJ, Bergquist A, Imam M, Lenzen H, Ponsioen CY, et al. Patient age, sex, and inflammatory bowel disease phenotype associate with course of primary sclerosing cholangitis. Gastroenterology. 2017;152(8):1975–1984.e8.
Role of endoscopy in primary sclerosing cholangitis: European Society of Gastrointestinal Endoscopy (ESGE) and European Association for the Study of the Liver (EASL) clinical guideline. J Hepatol. 2017;66(6):1265–81.
Chung BK, Karlsen TH, Folseraas T. Cholangiocytes in the pathogenesis of primary sclerosing cholangitis and development of cholangiocarcinoma. Biochim Biophys Acta. 2018;1864(4 Pt B):1390–400.
Tanaka A, Takikawa H. Geoepidemiology of primary sclerosing cholangitis: a critical review. J Autoimmun. 2013;46:35–40.
Molodecky NA, Kareemi H, Parab R, Barkema HW, Quan H, Myers RP, et al. Incidence of primary sclerosing cholangitis: a systematic review and meta-analysis. Hepatology. 2011;53(5):1590–9.
Toy E, Balasubramanian S, Selmi C, Li CS, Bowlus CL. The prevalence, incidence and natural history of primary sclerosing cholangitis in an ethnically diverse population. BMC Gastroenterol. 2011;11:83.
Liang H, Manne S, Shick J, Lissoos T, Dolin P. Incidence, prevalence, and natural history of primary sclerosing cholangitis in the United Kingdom. Medicine (Baltimore). 2017;96(24):e7116.
Lindkvist B, Benito de Valle M, Gullberg B, Björnsson E. Incidence and prevalence of primary sclerosing cholangitis in a defined adult population in Sweden. Hepatology. 2010;52(2):571–7.
Boonstra K, Weersma RK, van Erpecum KJ, Rauws EA, Spanier BW, Poen AC, et al. Population-based epidemiology, malignancy risk, and outcome of primary sclerosing cholangitis. Hepatology. 2013;58(6):2045–55.
Tanaka A, Mori M, Matsumoto K, Ohira H, Tazuma S, Takikawa H. Increase trend in the prevalence and male-to-female ratio of primary biliary cholangitis, autoimmune hepatitis, and primary sclerosing cholangitis in Japan. Hepatol Res. 2019;49(8):881–9.
Sowa M, Kolenda R, Baumgart DC, Pratschke J, Papp M, Tornai T, et al. Mucosal autoimmunity to cell-bound GP2 isoforms is a sensitive marker in PSC and associated with the clinical phenotype. Front Immunol. 2018;9:1959.
Bowlus CL. Cutting edge issues in primary sclerosing cholangitis. Clin Rev Allergy Immunol. 2011;41(2):139–50.
Van Steenbergen W, De Goede E, Emonds MP, Reinders J, Tilanus M, Fevery J. Primary sclerosing cholangitis in two brothers: report of a family with special emphasis on molecular HLA and MICA genotyping. Eur J Gastroenterol Hepatol. 2005;17(7):767–71.
Bergquist A, Lindberg G, Saarinen S, Broomé U. Increased prevalence of primary sclerosing cholangitis among first-degree relatives. J Hepatol. 2005;42(2):252–6.
Karlsen TH, et al. Genome-wide association analysis in primary sclerosing cholangitis. Gastroenterology. 2010;138(3):1102–11.
Ji SG, Juran BD, Mucha S, Folseraas T, Jostins L, Melum E, et al. Genome-wide association study of primary sclerosing cholangitis identifies new risk loci and quantifies the genetic relationship with inflammatory bowel disease. Nat Genet. 2017;49(2):269–73.
Alberts R, de Vries EMG, Goode EC, Jiang X, Sampaziotis F, Rombouts K, et al. Genetic association analysis identifies variants associated with disease progression in primary sclerosing cholangitis. Gut. 2018;67(8):1517–24.
Boonstra K, et al. Risk factors for primary sclerosing cholangitis. Liver Int. 2016;36(1):84–91.
Lemoinne S, Kemgang A, Ben Belkacem K, Straube M, Jegou S, Corpechot C, et al. Fungi participate in the dysbiosis of gut microbiota in patients with primary sclerosing cholangitis. Gut. 2020;69(1):92–102.
Torres J, Palmela C, Brito H, Bao X, Ruiqi H, Moura-Santos P, et al. The gut microbiota, bile acids and their correlation in primary sclerosing cholangitis associated with inflammatory bowel disease. United European Gastroenterol J. 2018;6(1):112–22.
Vieira-Silva S, Sabino J, Valles-Colomer M, Falony G, Kathagen G, Caenepeel C, et al. Quantitative microbiome profiling disentangles inflammation- and bile duct obstruction-associated microbiota alterations across PSC/IBD diagnoses. Nat Microbiol. 2019;4(11):1826–31.
Fevery J, Van Steenbergen W, Van Pelt J, Laleman W, Hoffman I, Geboes K, et al. Patients with large-duct primary sclerosing cholangitis and Crohn’s disease have a better outcome than those with ulcerative colitis, or without IBD. Aliment Pharmacol Ther. 2016;43(5):612–20.
Lunder AK, Hov JR, Borthne A, Gleditsch J, Johannesen G, Tveit K, et al. Prevalence of sclerosing cholangitis detected by magnetic resonance cholangiography in patients with long-term inflammatory bowel disease. Gastroenterology. 2016;151(4):660–669.e4.
Fausa O, Schrumpf E, Elgjo K. Relationship of inflammatory bowel disease and primary sclerosing cholangitis. Semin Liver Dis. 1991;11(1):31–9.
Jørgensen KK, Grzyb K, Lundin KE, Clausen OP, Aamodt G, Schrumpf E, et al. Inflammatory bowel disease in patients with primary sclerosing cholangitis: clinical characterization in liver transplanted and nontransplanted patients. Inflamm Bowel Dis. 2012;18(3):536–45.
Zheng HH, Jiang XL. Increased risk of colorectal neoplasia in patients with primary sclerosing cholangitis and inflammatory bowel disease: a meta-analysis of 16 observational studies. Eur J Gastroenterol Hepatol. 2016;28(4):383–90.
Guerra I, Bujanda L, Castro J, Merino O, Tosca J, Camps B, Gutiérrez A, et al. Clinical characteristics, associated malignancies and management of primary sclerosing cholangitis in inflammatory bowel disease patients: a multicentre retrospective cohort study. J Crohns Colitis. 2019;13(12):1492–1500.
Manninen P, Karvonen AL, Laukkarinen J, Aitola P, Huhtala H, Collin P. Colorectal cancer and cholangiocarcinoma in patients with primary sclerosing cholangitis and inflammatory bowel disease. Scand J Gastroenterol. 2015;50(4):423–8.
Oliveira EM, Oliveira PM, Becker V, Dellavance A, Andrade LE, Lanzoni V, et al. Overlapping of primary biliary cirrhosis and small duct primary sclerosing cholangitis: first case report. J Clin Med Res. 2012;4(6):429–33.
Mandolesi D, Lenzi M, D’Errico A, Festi D, Bazzoli F, Colecchia A. Primary biliary cholangitis-primary sclerosing cholangitis in an evolving overlap syndrome: a case report. Gastroenterol Hepatol. 2017;40(10):669–71.
Floreani A, Motta R, Cazzagon N, Franceschet I, Roncalli M, Del Ross T, et al. The overlap syndrome between primary biliary cirrhosis and primary sclerosing cholangitis. Dig Liver Dis. 2015;47(5):432–5.
Poupon R, Chazouilleres O, Corpechot C, Chrétien Y. Development of autoimmune hepatitis in patients with typical primary biliary cirrhosis. Hepatology. 2006;44(1):85–90.
Boberg KM, Chapman RW, Hirschfield GM, Lohse AW, Manns MP, Schrumpf E, et al. Overlap syndromes: the International Autoimmune Hepatitis Group (IAIHG) position statement on a controversial issue. J Hepatol. 2011;54(2):374–85.
Talwalkar JA, Keach JC, Angulo P, Lindor KD. Overlap of autoimmune hepatitis and primary biliary cirrhosis: an evaluation of a modified scoring system. Am J Gastroenterol. 2002;97(5):1191–7.
Levy C, Naik J, Giordano C, Mandalia A, O’Brien C, Bhamidimarri KR, et al. Hispanics with primary biliary cirrhosis are more likely to have features of autoimmune hepatitis and reduced response to ursodeoxycholic acid than non-hispanics. Clin Gastroenterol Hepatol. 2014;12(8):1398–405.
Neuhauser M, Bjornsson E, Treeprasertsuk S, Enders F, Silveira M, Talwalkar J, et al. Autoimmune hepatitis-PBC overlap syndrome: a simplified scoring system may assist in the diagnosis. Am J Gastroenterol. 2010;105(2):345–53.
Yang F, Wang Q, Wang Z, Miao Q, Xiao X, Tang R, et al. The natural history and prognosis of primary biliary cirrhosis with clinical features of autoimmune hepatitis. Clin Rev Allergy Immunol. 2016;50(1):114–23.
Zhang H, Yang J, Zhu R, Zheng Y, Zhou Y, Dai W, et al. Combination therapy of ursodeoxycholic acid and budesonide for PBC-AIH overlap syndrome: a meta-analysis. Drug Des Devel Ther. 2015;9:567–74.
Trivedi PJ, Hirschfield GM. Review article: overlap syndromes and AILD. Aliment Pharmacol Ther. 2012;36(6):517–33.
Abdalian R, Dhar P, Jhaveri K, Haider M, Guindi M, Heathcote EJ. Prevalence of sclerosing cholangitis in adults with autoimmune hepatitis: evaluating the role of routine magnetic resonance imaging. Hepatology. 2008;47(3):949–57.
Lewin M, Vilgrain V, Ozenne V, Lemoine M, Wendum D, Paradis V, et al. Prevalence of sclerosing cholangitis in adults with autoimmune hepatitis: a prospective magnetic resonance imaging and histological study. Hepatology. 2009;50(2):528–37.
van Buuren HR, van Hoogstraten HJE, Terkivatan T, Schalm SW, Vleggaar FP. High prevalence of autoimmune hepatitis among patients with primary sclerosing cholangitis. J Hepatol. 2000;33(4):543–8.
Kaya M, Angulo P, Lindor KD. Overlap of autoimmune hepatitis and primary sclerosing cholangitis: an evaluation of a modified scoring system. J Hepatol. 2000;33(4):537–42.
Lian M, Li B, Xiao X, Yang Y, Jiang P, Yan L, et al. Comparative clinical characteristics and natural history of three variants of sclerosing cholangitis: IgG4-related SC, PSC/AIH and PSC alone. Autoimmun Rev. 2017;16(8):875–82.
Zenouzi R, Lohse AW. Long-term outcome in PSC/AIH "overlap syndrome": does immunosuppression also treat the PSC component? J Hepatol. 2014;61(5):1189–91.
Floreani A, Rizzotto ER, Ferrara F, Carderi I, Caroli D, Blasone L, et al. Clinical course and outcome of autoimmune hepatitis/primary sclerosing cholangitis overlap syndrome. Am J Gastroenterol. 2005;100(7):1516–22.
Al-Chalabi T, Portmann BC, Bernal W, McFarlane IG, Heneghan MA. Autoimmune hepatitis overlap syndromes: an evaluation of treatment response, long-term outcome and survival. Aliment Pharmacol Ther. 2008;28(2):209–20.
Lee HE, Zhang L. Immunoglobulin G4-related hepatobiliary disease. Semin Diagn Pathol. 2019;36(6):423–33.
Kamisawa T, et al. IgG4-related disease. Lancet. 2015;385(9976):1460–71.
Deshpande V, Zen Y, Chan JK, Yi EE, Sato Y, Yoshino T, et al. Consensus statement on the pathology of IgG4-related disease. Mod Pathol. 2012;25:1181.
Culver EL, Chapman RW. IgG4-related hepatobiliary disease: an overview. Nat Rev Gastroenterol Hepatol. 2016;13(10):601–12.
Okazaki K, Uchida K, Koyabu M, Miyoshi H, Ikeura T, Takaoka M. IgG4 cholangiopathy – current concept, diagnosis, and pathogenesis. J Hepatol. 2014;61(3):690–5.
Umemura T, Zen Y, Hamano H, Ichijo T, Kawa S, Nakanuma Y, et al. IgG4 associated autoimmune hepatitis: a differential diagnosis for classical autoimmune hepatitis. Gut. 2007;56(10):1471.
Ishizu Y, Ishigami M, Kuzuya T, Honda T, Hayashi K, Nakano I, et al. Immunoglobulin G4-associated autoimmune hepatitis later complicated by autoimmune pancreatitis: a case report. Hepatol Res. 2016;46(6):601–6.
Coquart N, Cadelis G, Tressières B, Cordel N. Epidemiology of sarcoidosis in Afro-Caribbean people: a 7-year retrospective study in Guadeloupe. Int J Dermatol. 2015;54(2):188–92.
Holmes J, Lazarus A. Sarcoidosis: extrathoracic manifestations. Dis Mon. 2009;55(11):675–92.
Ungprasert P, Crowson CS, Simonetto DA, Matteson EL. Clinical characteristics and outcome of hepatic sarcoidosis: a population-based study 1976-2013. Am J Gastroenterol. 2017;112(10):1556–63.
Ramos-Casals M, Mañá J, Nardi N, Brito-Zerón P, Xaubet A, Sánchez-Tapias JM, et al. Sarcoidosis in patients with chronic hepatitis C virus infection: analysis of 68 cases. Medicine (Baltimore). 2005;84(2):69–80.
Kishor S, Turner ML, Borg BB, Kleiner DE, Cowen EW. Cutaneous sarcoidosis and primary biliary cirrhosis: a chance association or related diseases? J Am Acad Dermatol. 2008;58(2):326–35.
Bilal M, Satapathy SK, Ismail MK, Vanatta JM. Long-term outcomes of liver transplantation for hepatic sarcoidosis: a single center experience. J Clin Exp Hepatol. 2016;6(2):94–9.
Zheng RH, Wang JH, Wang SB, Chen J, Guan WM, Chen MH. Clinical and immunopathological features of patients with lupus hepatitis. Chin Med J. 2013;126(2):260–6.
Takahashi A, Abe K, Saito R, Iwadate H, Okai K, Katsushima F, et al. Liver dysfunction in patients with systemic lupus erythematosus. Intern Med. 2013;52(13):1461–5.
Liu Y, Yu J, Oaks Z, Marchena-Mendez I, Francis L, Bonilla E, et al. Liver injury correlates with biomarkers of autoimmunity and disease activity and represents an organ system involvement in patients with systemic lupus erythematosus. Clin Immunol. 2015;160(2):319–27.
Efe C, Purnak T, Ozaslan E, Ozbalkan Z, Karaaslan Y, Altiparmak E, et al. AILD in patients with systemic lupus erythematosus: a retrospective analysis of 147 cases. Scand J Gastroenterol. 2011;46(6):732–7.
Kaplan MJ, Ike RW. The liver is a common non-exocrine target in primary Sjögren’s syndrome: a retrospective review. BMC Gastroenterol. 2002;2:21.
Schlenker C, Halterman T, Kowdley KV. Rheumatologic disease and the liver. Clin Liver Dis. 2011;15(1):153–64.
Hatzis GS, Fragoulis GE, Karatzaferis A, Delladetsima I, Barbatis C, Moutsopoulos HM. Prevalence and longterm course of primary biliary cirrhosis in primary Sjögren’s syndrome. J Rheumatol. 2008;35(10):2012–6.
Lindgren S, Manthorpe R, Eriksson S. AILD in patients with primary Sjögren’s syndrome. J Hepatol. 1994;20(3):354–8.
Malnick S, Melzer E, Sokolowski N, Basevitz A. The involvement of the liver in systemic diseases. J Clin Gastroenterol. 2008;42(1):69–80.
Sellami M, Saidane O, Mahmoud I, Tekaya AB, Tekaya R, Abdelmoula L. Etiological features of liver involvement in rheumatoid arthritis. Curr Rheumatol Rev. 2019. [Epub ahead of print].
Isayama H, Tazuma S, Kokudo N, Tanaka A, Tsuyuguchi T, Nakazawa T, et al. Clinical guidelines for primary sclerosing cholangitis 2017. J Gastroenterol. 2018;53(9):1006–34.
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Lyu, Z., Gershwin, M.E., Ma, X. (2020). Geoepidemiology of Autoimmune Liver Diseases. In: Gershwin, M.E., M. Vierling, J., Tanaka, A., P. Manns, M. (eds) Liver Immunology . Springer, Cham. https://doi.org/10.1007/978-3-030-51709-0_11
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