AIH-PBC Overlap Syndrome Research Articles

Spontaneous development of an autoimmune hepatitis - primary biliary cholangitis overlap syndrome in dnTGFβRII Aire-/- mice.

Autoimmune regulator (Aire) and TGF-β signaling play important roles in central tolerance and peripheral tolerance, respectively, by eliminating or suppressing the activity of autoreactive T cells. We previously demonstrated that dnTGFβRII mice develop a defect in peripheral tolerance and a primary biliary cholangitis (PBC)-like disease. We hypothesized that by introducing the Aire gene to this model, we would observe a more severe PBC phenotype. Interestingly, however, we demonstrated that, while dnTGFβRII Aire-/- mice do manifest key histological and serological features of autoimmune cholangitis, they also develop mild to moderate interface hepatitis and show high levels of alanine transaminase (ALT) and antinuclear antibodies (ANA), characteristics of autoimmune hepatitis (AIH). To further understand this unique phenotype, we performed RNA sequencing (RNA-seq) and flow cytometry to explore the functional pathways and immune cell pathways in the liver of dnTGFβRII Aire-/- mice. Our data revealed enrichments of programmed cell death pathways and predominant CD8+ T cell infiltrates. Depleting CD8+ T cells using an anti-CD8α antibody significantly alleviated hepatic inflammation and prolonged the life span of these mice. Finally, RNA-seq data indicated the clonal expansion of hepatic CD8+ T cells. In conclusion, these mice developed an autoreactive CD8+ T-cell-mediated autoimmune cholangitis with concurrent hepatitis that exhibited key histological and serological features of the AIH-PBC overlap syndrome, representing a novel model for the study of tolerance and autoimmune liver disease. © 2023 The Pathological Society of Great Britain and Ireland.

Metabolomic profiling and discrimination of autoimmune hepatitis, primary biliary cholangitis, and overlap syndrome

<p indent="0mm">Autoimmune liver disease (AILD) is a kind of liver disease caused by immune dysfunction, including autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and overlap syndrome (OS). In AILD patients, the immune system attacks the liver, and elevated autoantibodies can be found in serum. AIH and PBC are two kinds of AILD with high incidence, and their pathogenesis is different. AIH is characterized by interfacial hepatitis caused by the autoimmune system attacking hepatocytes. The clinical features of PBC are non-suppurative, destructive cholestasis resulting from immune damage affecting the interlobular bile ducts. Due to the complex and promiscuous pathogenesis of autoimmune diseases and the low specificity of clinical features, challenges remain in the clinical diagnosis of AILD. Liver biopsy results are necessary for the accurate diagnosis of AILD, but biopsy is not conducive to the prognosis of patients, and the pathological changes of patients may be non-specific. Therefore, the need of finding serological metabolites with low high specificity and invasive features becomes urgent. Metabolomics has unique advantages in reflecting the overall pathophysiological changes of the body by analyzing the metabolites. Untargeted metabolomics has been widely used in the study of liver-related diseases and has good application value for clinical diagnosis. In this study, we attempted to characterize the metabolic signatures of autoimmune liver diseases by serum metabolomics. A mass spectrometry-based untargeted metabolomics study was performed on the serum of AIH (<italic>n</italic>=42), PBC (<italic>n</italic>=103), and AIH-PBC OS (<italic>n</italic>=57) patients. The differentiable metabolites for PBC and AIH samples were obtained by principal component analysis and orthogonal partial least-squares-discriminant analysis, which consisted of the metabolomic signatures. Among the metabolomic signatures, the fingerprint metabolites were further extracted by clustering analysis using the values of area under the curve (AUC) of each differentiable metabolite, binary logistic regression model, and variable importance projection scores. 101 signature metabolites from all metabolite variables were identified, and 29 fingerprint metabolites were further screened out and enriched in bile, phospholipids, and amino acids metabolisms pathway, with most classification ability to distinguish PBC and AIH. The eigenmetabolite compressed from the fingerprint metabolites visualized the significant difference between PBC and AIH (<italic>P</italic>&lt;0.0001) and achieved a good potential for classification (AUC=0.797). Based on fingerprint metabolites, AIH and PBC samples could be separated into three zones, the “pure zone” of PBC, the “pure zone” of AIH, and the mixture zone of PBC and AIH. We put OS samples into the model and found that samples showed different distribution characteristics in three zones, indicating that OS patients according to the current diagnostic criteria have different metabolic characteristics and etiological tendencies, requiring a more accurate diagnosis. This study revealed a metabolic outlook for AIH, PBC, and their overlap syndrome, and the diagnostic model based on fingerprint metabolites with the potential ability to facilitate precise diagnosis and management of patients with autoimmune liver diseases.

The Spectrum of Autoimmune Liver Disorders, Clinical Presentation, and Autoantibodies in Patients From a Tertiary Care Center in Pakistan.

BackgroundThe autoimmune illnesses that affect the liver include autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), and overlap syndrome. In our patients, we aimed to address the complete spectrum of autoimmune liver disorders, clinical presentation, and autoantibodies.MethodsThe study included all the patients diagnosed with autoimmune liver disorder irrespective of age, gender, and ethnic background presented at the liver clinic of the hospital in the last two years. The diagnosis was based on characteristic clinical and laboratory findings, the presence of one or more characteristic autoantibodies, and/or histological abnormalities. The diagnosis of AIH was further validated by revised International AIH Group criteria using a scoring calculator. The diagnostic criteria for PBC required the presence of chronic elevation of alkaline phosphatase (ALP) with positive antimitochondrial antibody (AMA) or positive PBC-specific anti-nuclear antibodies (ANA) (sp-100, gp-210) tests and/or compatible histology. The patients of AIH-PBC overlap syndrome fulfilled the criteria for AIH in the setting of PBC. Patients having liver involvement in other autoimmune disorders were included in the study.ResultsThe total number of patients was 124; 83 (67%) were females; mean age ± standard error of mean (SEM) was 44.97 ± 1.47 years with a range of 09-84 years. Type-1 AIH was seen in 68 (54.8%) patients, type-2 AIH in 10 (8.1%) patients, PBC in 22 (17.7%) patients, overlap of PBC with AIH in 10 (8.1%) patients, IgG4 disease in four (3.2%) patients, psoriasis-specific immune hepatitis in four (3.2%) patients, celiac disease-related hepatitis in three (2.4%) patients, sarcoidosis in two (1.6%) patients, and ichthyosis-associated hepatitis in one (0.8%) patient. There was a high prevalence of cirrhosis (50%) at the time of presentation; 19% of patients had decompensated liver disease. ANA was positive in 52/68 cases of AIH type-1, but anti-smooth muscle antibody (ASMA) was reactive only in nine cases and anti-soluble liver antigen (SLA) in five cases. There was no female preponderance in type-2 AIH (M:F = 6:4). AMA was reactive in 25 (78%) cases of PBC and overlap syndrome. Antibodies prevalent in PBC (AMA-M2, AMA-M2-3E, sp-100, gp-210, anti-Ro52) were also seen in some cases of AIH, though they did not fulfill the criteria of the overlap syndrome.ConclusionThere is an unmet need for the early diagnosis of autoimmune liver diseases and the initiation of appropriate management to prevent complications.

Evaluation of controlled attenuation parameter in assessing hepatic steatosis in patients with autoimmune liver diseases.

BACKGROUNDHepatic steatosis commonly occurs in some chronic liver diseases and may affect disease progression.AIMTo investigate the performance of controlled attenuation parameter (CAP) for the diagnosis of hepatic steatosis in patients with autoimmune liver diseases (AILDs).METHODSPatients who were suspected of having AILDs and underwent liver biopsy were consistently enrolled. Liver stiffness measurement (LSM) and CAP were performed by transient elastography. The area under the receiver operating characteristic (AUROC) curve was used to evaluate the performance of CAP for diagnosing hepatic steatosis compared with biopsy.RESULTSAmong 190 patients with biopsy-proven hepatic steatosis, 69 were diagnosed with autoimmune hepatitis (AIH), 18 with primary biliary cholangitis (PBC), and 27 with AIH-PBC overlap syndrome. The AUROCs of CAP for the diagnosis of steatosis in AILDS were 0.878 (0.791-0.965) for S1, 0.764 (0.676-0.853) for S2, and 0.821 (0.716-0.926) for S3. The CAP value was significantly related to hepatic steatosis grade (P < 0.001). Among 69 patients with AIH, the median CAP score was 205.63 ± 47.36 dB/m for S0, 258.41 ± 42.83 dB/m for S1, 293.00 ± 37.18 dB/m for S2, and 313.60 ± 27.89 dB/m for S3. Compared with patients with nonalcoholic fatty liver disease (NAFLD) presenting with autoimmune markers, patients with AIH concomitant with NAFLD were much older and had higher serum IgG levels and LSM values.CONCLUSIONCAP can be used as a noninvasive diagnostic method to evaluate hepatic steatosis in patients with AILDs. Determination of LSM combined with CAP may help to identify patients with AIH concomitant with NAFLD from those with NAFLD with autoimmune phenomena.

S2617 Autoimmune Hepatitis vs Primary Biliary Cholangitis: A Case of Overlap Syndrome

INTRODUCTION: Immune-mediated liver diseases including autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) are rare. Overlap between these entities comprises an even smaller group with AIH-PBC being the most common. We present the case of a woman complaining of pruritus and elevated liver enzymes leading to diagnosis of AIH-PBC overlap syndrome. CASE DESCRIPTION/METHODS: A 43 year woman with history of hyperlipidemia presented with diffuse pruritus and bruising for 2 weeks. On presentation, the patient was hemodynamically stable. Her physical exam showed mild abdominal tenderness and excoriations on her extremities. Laboratory analysis demonstrated an elevated Alkaline phosphatase 1334, AST 243 and ALT 310. Total bilirubin was mildly elevated at 1.4, direct bilirubin 0.6 and GGT 1145. Hepatitis panel was non reactive. ANA screen was positive with titer 1:1280 in a dense fine speckled pattern. Anti-mitochondrial and anti-smooth muscle antibodies were negative. A liver biopsy denoted absence of interlobular bile ducts, portal lymphoplasmacytic infiltrates with interface hepatitis, mild portal fibrosis with no bridging fibrosis or cirrhosis and collections of histiocytes appearing as poorly formed granulomas. Upper endoscopy was unremarkable. Based on these findings, the diagnosis of AIH-PBC overlap was made. She was referred to transplant hepatology and was treated with ursodeoxycholic acid (UDCA), corticosteroids and mycophenylate mofetil. Subsequent testing showed significant improvement in liver function tests with normalization of bilirubin levels. DISCUSSION: AIH-PBC is the most common type of overlap syndrome found in approximately 8–10% in patients. Overlapping features include symptoms, clinical findings, biochemical tests, a variety of immunological findings and histology. These criteria were supported in our patient with findings of portal lymphoplasmacytic infiltrates with interface hepatitis, absence of interlobular bile ducts and collections of histiocytes appearing as granulomas on liver biopsy. More specifically our patient fell into the sub-entity, often named autoimmune cholangitis or AMA negative PBC which typically presents with elevated antinuclear antibodies with or without smooth muscle antibodies. Since most patients of AIH-PBC overlap syndrome required additional treatment with an immunosuppressive regimen in addition to UDCA, the distinction of this overlap condition should neither be delayed nor missed.Figure 1.: Lymphoplasmacytic infiltrates.

Primary biliary cholangitis (PBC) - autoimmune hepatitis (HAI) overlap syndrome (OS)

The AIH-PBC overlap syndrome is the most common form of OS. The aim: to study the clinical and paraclinical characteristics of the overlap syndrome and to specify the therapeutic and evolutionary characteristics. Methods: The medical data of 42 PBC patients were evaluated for associated autoimmune hepatitis. Results: Among the 42 cases of PBC, we retained 16 cases of OS (37%). All female the association of diagnostic criteria for PBC and HAI was simultaneous in 80%. Treatment with AUDC, corticosteroid and Azathioprine was started in the majority of our patients. The course was marked by a complete (10 cases) or incomplete (n = 6) response. Conclusion: OS should be considered in the presence of any mixed cytolytic and cholestatic liver disease. Its recognition is essential in order to adapt treatment and prevent progression to cirrhosis and its complications.

2487 Primary Biliary Cholangitis With Autoimmune Hepatitis Overlap in Twin Males: A Unique Case of Related Autoimmune Diseases

INTRODUCTION: Primary biliary cholangitis (PBC) and autoimmune hepatitis (AIH) are immune-mediated liver diseases with female predominance. Combined features of both, termed AIH-PBC overlap syndrome, occurs in rare instances. We present a unique case of AIH-PBC overlap syndrome in twin males. CASE DESCRIPTION/METHODS: Twin #1 was a 36-year-old man when he presented in 2012 with asymptomatic liver enzyme elevation. No new medications, herbals, alcohol or illicit drug use. No known family history of liver disease. Labs showed total bilirubin (TB) 0.5, alkaline phosphatase (ALP) 478, aspartate aminotransferase (AST) 81, alanine aminotransferase (ALT) 111, gamma-glutamyl transferase (GGT) 625, positive anti-mitochondrial antibody (AMA) &gt;1:640, and hypergammaglobulinemia (2128 mg/dL). Liver biopsy showed moderate plasma rich cell infiltrate with bile duct damage and mild fibrosis, consistent with AIH-PBC overlap. Patient was treated with steroids, azathioprine (AZA), and ursodeoxycholic acid (UDCA), later switched to obeticholic acid due to refractory PBC. He subsequently experienced marked biochemical improvement without disease progression. Twin #2 presented in 2017 with elevated liver enzymes and pruritus. Labs showed TB 1.1, ALP 755, AST 81, ALT 116, GGT 838, positive ANA &gt;1:2560, positive AMA &gt;100, and positive ASMA &gt;100. Liver biopsy showed moderate bile duct epithelial injury with lymphoplasmacytic infiltrate, consistent with AIH-PBC overlap, and stage II/IV hepatic fibrosis. He was treated with steroids, AZA, and UDCA. He also experienced marked biochemical improvement without disease progression. DISCUSSION: PBC, a rare autoimmune disorder with female preponderance, can lead to cirrhosis and liver failure. PBC-AIH overlap syndrome, described in 4.8-9.2% patients with PBC, is more likely to have rapid disease progression and hepatic decompensation. Combination of steroids, AZA and UDCA has been variably effective and can delay disease progression. To the best of our knowledge, this is the first case of AIH-PBC overlap syndrome reported in twin males and highlights the importance of inherited factors in immune mediated liver disorders. Although it is known that PBC and AIH are associated with human leukocyte antigen genes on chromosome 6, further study of the association between these disorders is limited by the paucity of patients. Early diagnosis of this condition is essential to prevent liver related complications with medical management.

3195 Autoimmune Hepatitis With Primary Biliary Cirrhosis: An Overlapping Syndrome of the Liver

INTRODUCTION: Autoimmune liver diseases consist of Primary Biliary Cirrhosis (PBC), Autoimmune Hepatitis (AIH) and Primary Sclerosing Cholangitis (PSC). Overlap syndromes are defined when there are characteristic features of AIH along with PBC and PSC. We report the presentation and management of an AIH-PBC overlap syndrome. CASE DESCRIPTION/METHODS: A 60-year-old Asian female with a past history of hypertension, presented with fatigue, myalgia, nausea, vomiting, and icterus for ten days. She denied the use of illicit drugs, alcohol consumption or family history of liver disease. On arrival, she had a temperature of 38.2°C, a pulse of 110 beats/minute, blood pressure of 100/70 mm Hg, and oxygen saturation of 97% on room air. Physical exam revealed icterus 1+, and mild tenderness in the right hypochondriac area. Laboratory investigations revealed leukocyte count of 15.2 K/ul, alanine transaminase of 1107 U/l, aspartate aminotransferase of 1010 U/l, alkaline phosphatase of 685 U/l, total bilirubin of 10 mg/dl with the direct component of 9 mg/dl, and gamma-glutamyl transferase of 666 U/l. Further workup revealed anti-nuclear antibody titer of 1:1000, antimitochondrial antibody (AMA) titer of 1:80 with negative peripheral antineutrophil cytoplasmic antibody and hepatitis serology. Ultrasound of the abdomen showed common-bile duct (CBD) stricture formation. The patient underwent endoscopic retrograde cholangiopancreatography with sphincterotomy and stenting. Liver biopsy showed interface hepatitis with portal tract inflammation. Brush border sampling from the CBD revealed lymphocytic and neutrophilic infiltrate. A diagnosis of AIH-PBC overlap syndrome was made. She was started on piperacillin/tazobactam 4.5 gm and metronidazole 400 mg along with with ursodeoxycholic acid (UDCA) 300 mg, thrice a day. After a month, the stent was removed and there was a resolution of symptoms with normalization of liver enzymes. DISCUSSION: The minimum criteria required for the diagnosis of AIH-PBC overlap syndrome include positive AMA and histology showing bile duct abnormality in an otherwise classical AIH (Table 1). Management is usually with UDCA, immunosuppressants, and corticosteroids. It is prudent to maintain a modest index of suspicion of overlap syndromes in patients such as ours. Early diagnosis and appropriate management are of paramount importance.

Autoimmune hepatitis — Primary biliary cholangitis overlap syndrome. Long-term outcomes of a retrospective cohort in a university hospital

Abstract Background Autoimmune hepatitis (AIH) with characteristics of primary biliary cholangitis (PBC) is known as overlap syndrome. Its prevalence and prognosis have not yet been determined comparatively with AIH. Methods A retrospective cohort study was conducted comparing patients diagnosed with AIH and AIH-PBC overlap syndrome, followed-up for seven years in a university hospital in Colombia, until 31 December 2016. Results A total of 210 patients were included (195 women, mean age 48.5 years). Of these, 32 (15.2%) had AIH-PBC overlap syndrome. At diagnosis, no significant differences were found by demographic profile, positive autoantibodies (ANA, ASMA), except AMA (81.2% vs 3.9%, p Conclusions AIH-PBC overlap syndrome accounts for a significant proportion of patients with AIH, with greater progression to cirrhosis, indication of liver transplantation and possibly retransplantation. This higher risk of adverse outcomes suggests closer monitoring, probably with follow-up until confirmed histopathological remission.

Síndrome de superposición: hepatitis autoinmune y colangitis biliar primaria. Resultados a largo plazo de una cohorte retrospectiva en un hospital universitario

BackgroundAutoimmune hepatitis (AIH) with characteristics of primary biliary cholangitis (PBC) is known as overlap syndrome. Its prevalence and prognosis have not yet been determined comparatively with AIH. MethodsA retrospective cohort study was conducted comparing patients diagnosed with AIH and AIH-PBC overlap syndrome, followed-up for seven years in a university hospital in Colombia, until 31 December 2016. ResultsA total of 210 patients were included (195 women, mean age 48.5years). Of these, 32 (15.2%) had AIH-PBC overlap syndrome. At diagnosis, no significant differences were found by demographic profile, positive autoantibodies (ANA, ASMA), except AMA (81.2% vs 3.9%, P<.001), and histological grade of fibrosis. The most frequent clinical presentations were nonspecific symptoms in AIH-PBC and acute hepatitis in AIH. Although there were no significant differences, AIH showed a greater biochemical response to immunosuppressive management (87.3% vs 74.2%, P=.061) and a greater number of relapses in those who achieved partial or complete remission during treatment (12.4% vs 7.63%; P=.727). Patients with AIH-PBC had greater progression to cirrhosis (22.2% vs 13.1%, P=.038), even in those who achieved partial or complete biochemical remission without relapse, with greater indication of orthotopic liver transplantation (P=.009), but not retransplantation (P=.183); there were no differences in mortality. ConclusionsAIH-PBC overlap syndrome accounts for a significant proportion of patients with AIH, with greater progression to cirrhosis, indication of liver transplantation and possibly retransplantation. This higher risk of adverse outcomes suggests closer monitoring, probably with follow-up until confirmed histopathological remission.

Overlap Syndrome of Autoimmune Hepatitis and Primary Biliary Cirrhosis: A Clinical Enigma

“Overlap syndrome” is a term used to describe variant forms of autoimmune hepatitis (AIH) which present with characteristics of AIH and primary biliary cirrhosis (PBC) or primary sclerosing cholangitis (PSC). Patients with overlap syndrome present with both hepatitic and cholestatic serum liver test and the clinical, biochemical, and histological features of these autoimmune diseases are overlapped. Thus, it is difficult to appreciate overlap syndrome as an actual diagnostic entity. AIH-PBC is the most common form of overlap syndrome, affecting almost 10% of adults with AIH or PBC. Transitions from PBC to AIH-PBC overlap syndrome have also been reported. Ursodeoxycholic acid is usually combined with immunosuppressive therapy but end-stage disease requires liver transplantation. We present a case of Overlap Syndrome (AIHPBC) in a 16 year old girl who presented to us with features of obstructive jaundice. She had six months history of generalised itching, yellow discoloration of skin and urine, decreased appetite and intermittent abdominal pain. Liver function test revealed conjugated hyperbilirubinemia, with moderate elevation of liver enzymes. Antinuclear, anti-muscle M2 and anti-glycoprotein 210 antibodies were positive. Liver biopsy showed features of primary biliary cirrhosis. The patient responded to ursodeoxycholic acid and immunosuppression.

Overlap Syndrome of Autoimmune Hepatitis, Primary Biliary Cholangitis, and Primary Sclerosing Cholangitis in a Patient with Systemic Lupus Erythematosus: A Case Report of Complex Autoimmune Liver Disease

Introduction: Overlap syndrome is a spectrum of clinical manifestations between Autoimmune hepatitis (AIH), Primary Biliary Cholangitis (PBC), and Primary Sclerosing Cholangitis (PSC). Overlap syndromes between AIH-PBC and AIH-PSC are well recognized. Overlap between PBC-PSC has only been reported in a few patients. To our knowledge, it is extremely rare for PBC, PSC and probable AIH overlap syndrome to occur in the same patient.Figure 1Figure 2Case report: The patient is a 48-year old Hispanic male with liver cirrhosis and SLE. His cirrhosis was complicated by esophageal varices, thrombocytopenia, coagulopathy, hypoalbuminemia, and chronic portal vein thrombosis. His biochemical profile revealed elevated ALT (2X upper limit of normal (ULN)) and AST (4X ULN), persistently elevated alkaline phosphatase (3X ULN) and elevated bilirubin (2X ULN). Investigations for etiology of cirrhosis included a detailed social history were done. Viral hepatitis serology, iron studies, celiac panel, ceruloplasmin and alpha-1 antitrypsin level were unremarkable. Anti-nuclear antibody (ANA) was positive with a titer of 1:320, anti-smooth muscle antibody (ASMA) was positive with a serum level of 20 (Normally < 20) and P-ANCA was positive. Anti-Soluble liver antigen (anti-SLA) and anti-liver kidney microsomal 1 antigen (Anti-LKM1) were negative. Gamma globulin level was elevated at 2501 mg/dL (normal range 694-1617). Anti-mitochondrial antibody (AMA) was positive with a level of 71.9 units (Normally < 20). The more specific antibody for PBC, AMA-M2, was also positive as well. He also had a positive anti-dsDNA. The patient met criteria for AIH-PBC overlap syndrome based on Paris Criteria. He was on prednisone for autoimmune thrombocytopenia and was started on oral Ursodeoxycholic acid. We also performed an ERCP with cholangiography which showed segmental irregularities of intrahepatic bile ducts with beaded appearance suggestive of sclerosing cholangitis. Based on patient's liver enzymes profile, autoimmune markers, and ERCP findings; he was diagnosed with AIH-PBC-PSC overlap syndrome. We wanted to obtain a liver biopsy, however it could not be done as patient deceased due to septic shock. Conclusion: We are presenting a case with complex clinical spectrum of autoimmune liver diseases which include AIH, PBC, and PSC. To our knowledge, this is only the second reported case of all these diseases overlapping in the same patient; and the first reported case in a patient with SLE.

Retrospective analysis of autoimmune hepatitis-primary biliary cirrhosis overlap syndrome in Korea: characteristics, treatments, and outcomes.

Background/AimsOverlap syndrome of autoimmune hepatitis (AIH) and primary biliary cirrhosis (PBC) (AIH-PBC overlap syndrome) is a rare disease that has not been clearly characterized in Korean patients. This study investigated the clinical features of AIH-PBC overlap syndrome compared with those of AIH and PBC alone.MethodsThis retrospective cohort study included 158 consecutive patients who were diagnosed as AIH (n=61), PBC (n=81), or AIH-PBC overlap syndrome (n=9) based on the Paris and the International Autoimmune Hepatitis Group (IAIHG) criteria from 2001 to 2011 in Korea. We compared the clinical features of these three groups retrospectively, including their biochemical characteristics, treatments, responses, and clinical outcomes.ResultsThe AIH-PBC overlap syndrome patients exhibited biochemical characteristics of both AIH and PBC, and showed a similar response to ursodeoxycholic acid (UDCA) monotherapy as for the PBC patients. However, the response of AIH-PBC overlap syndrome patients to UDCA and steroid combination therapy was worse than the response of AIH patients to steroid-based therapy (P=0.024). Liver cirrhosis developed more rapidly in AIH-PBC overlap syndrome patients than in AIH patients group (P=0.013), but there was no difference between AIH-PBC overlap syndrome patients and PBC patients. The rates of developing hepatic decompensation did not differ significantly between the groups.ConclusionsThe AIH-PBC overlap syndrome patients exhibited a worse response to UDCA and steroid combination therapy and a faster cirrhotic progression compared with AIH patients.

Changes of IL-12 and IL-17 levels in patients with autoimmune liver disease and its clinical significance

Objective To investigate the expression of interleukin(ID-12 and IL-17 in the serum and liver tissues of patients with autoimmune liver disease(AILD) and to discuss the relevant significance.Methods The peripheral blood and liver tissues were collected from 21 patients with autoimmune hepatitis(AIH),21 with primary biliary cirrhosis(PBC),and 9 with AIH-PBC overlap syndrome(AIH-PBC OS).The serum IL-12 and IL-17 levels were assayed by ELISA,and the expression and location of IL-12 and IL-17 in the liver tissues were detected by immunohistochemistry method.Alamine transaminaseC ALT) andγ-glutamyltransferase(GGT) were measured by automatic biochemical analyzer.The correlation of serum IL-12 and IL-17 expressions with ALT and GGT levels was analyzed.Ten healthy participants taking a physical examination and 10 normal liver tissues were used as controls.Results The serum levels of IL-12 in AIH,PBC,and AIH-PBC OS groups were significantly lower than that in the control group(P0.01),and the serum levels of IL-17 in the three groups were significantly higher than that in the control group(P0.01).A negative correlation was found between serum IL-12 and IL-17 in AIH and PBC groups(AIH:r=-0.752,P0.05;PBC:r=-0.436,P0.05),and serum IL-17 was positively correlated with ALT and GGT(AIH:r=0.825,P0.05;PBC:r=0.571,P0.05).IL-12 was mainly expressed in bile duct epithelium and Kupffer cells,and the expression rates in the 3 experimental groups were significantly lower than that in the control group(AIH:19.05%[4/21],PBC:9.52%[2/21],AIH-PBC OS:11.11%[1/9],control:90.00%[9/10];P 0.01).IL-17 was mainly expressed in lymphocytes and monocytes,and the expression rates in the 3 experimental groups were significantly higher than that in control group(AIH:71.43%[15/21],PBC:76.19%[16/21],AIH-PBC OS:77.78%[7/ 9],control:10.00%[1/10];P0.01).IL-12 expression in the liver tissues was negatively correlated with IL-17 expression in AIH and PBC groups(AIH:r=-0.499,P=0.021;PBC:r=-0.580,P = 0.006).Conclusion IL-12 expression is reduced in AILD patients,decreasing the inhibition against Th17 cell differentiation,leading to IL-17 increase and mediating inflammatory injury,which indicates that IL-12/IL-17 inflammatory pathway may participate in the development and progression of AILD.

Autoimmune hepatitis-primary biliary cirrhosis overlap syndrome concomitant with immune hemolytic anemia and immune thrombocytopenic purpura (Evans syndrome)

Autoimmune hepatitis (AIH) and primary biliary cirrhosis (PBC) associated with Evans syndrome; combination of autoimmune hemolytic anemia (AIHA) and immune thrombocytopenic purpura (ITP) has rarely been reported. We report the case of a 53-year-old patient who presented with weakness, myalgia, arthralgia, shortness of breath and purpura. Initial laboratory investigations revealed liver dysfunction, anemia and thrombocytopenia. Anti-nuclear (ANA) and antimitochondrial M2 (AMA M2) antibodies were positive. Diagnose of PBC-AIH overlap was made by clinical, serological and histological investigations. AIHA and ITP was identified with clinical-laboratory findings and bone marrow puncture. She was treated with IVIG followed by prednisolone and ursodeoxycholic acid. Hemoglobin-thrombocytes increased rapidly and transaminases improved at day 8. We have reported the first case in the literature with AIH-PBC overlap syndrome concurrent by ITP and AIHA which suggest the presence of shared genetic susceptibility factors in multiple autoimmune conditions including AIH, PBC, ITP and AIHA.

Validation of the simplified criteria for diagnosis of autoimmune hepatitis in Chinese patients

In 1999, the International Autoimmune Hepatitis Group (IAIHG) revised the diagnostic criteria for autoimmune hepatitis (AIH). It subsequently developed the simplified criteria in 2008 to enhance clinical applicability and practicability. In this study, we validated the simplified diagnostic criteria in Chinese patients with AIH or other chronic liver diseases in comparison with the revised original criteria. Diagnostic scores were determined using the revised original criteria and the simplified criteria in 405 patients with diverse liver diseases. The sample included 127 patients with AIH type I diagnosed by the descriptive criteria, 77 patients with primary biliary cirrhosis (PBC), 6 patients with AIH-PBC overlap syndrome, 47 patients with drug-induced liver injury (DILI), 36 patients with non-alcoholic steatohepatitis (NASH), 82 patients with chronic hepatitis B (CHB), and 30 patients with chronic hepatitis C (CHC). The simplified criteria were compared to the revised original criteria based on sensitivity, specificity, and predictability for the pre-treatment diagnosis of AIH. The simplified criteria had sensitivity and specificity of 90% and 95%, respectively, for the diagnosis of probable AIH in the Chinese patients. This compares well with the more rigorous revised original criteria, which had sensitivity and specificity of 100% and 93%, respectively, for probable AIH. On definite AIH, the simplified criteria had sensitivity and specificity of 62% and 99%, respectively, compared to 64% and 100% for definite AIH by the revised original criteria. In addition, the predictabilities of the revised original criteria and simplified criteria were 96% and 94% for probable AIH, and 88% and 87% for definite AIH, respectively, in our groups. Using the revised original criteria, 84 patients were diagnosed with definite AIH. On the other hand, among these 84 patients, the simplified criteria diagnosed only 61 patients with definite AIH (accordant diagnosis) and provided the 23 other patients with downgraded diagnosis. Comparison of the clinical and laboratory features of these two groups (accordant diagnosis vs. downgraded/excluded diagnosis) showed that the patients with downgraded diagnosis had significantly higher histological scores than the patients with accordant diagnosis. The simplified criteria are comparable to the revised original criteria and have high sensitivity and specificity for the diagnosis of AIH in Chinese patients. Liver histology is critical for the diagnosis of AIH especially when using the simplified criteria. Further study or prospective evaluation is needed to confirm these observations, however, due to the small group of CHC patients as well as the absence of primary sclerosing cholangitis (PSC) patients in our study.

Analysis of clinical features and liver histopathology of autoimmune liver diseases: an analysis of 109cases

Objective To analyze the clinical characteristics of autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC) and AIH/PSC or/PBC overlap syndrome in order to further understand the autoimmune liver diseases (AILD). Methods One hundred and nine patients with AILDs confirmed pathologically were collected between Jan. 2004 and June 2006. Of 109 patients, AIH was found in 27 eases, PBC in 67 cases, PSC in 4 eases, AIH-PSC overlap syndrome in 1 case and AIH-PBC overlap syndrome in 10 cases. The clinical and laboratory data of all patients were assessed retrospectively. Results The AILD was predominantly found in middle-aged women (73.3% ,80/109), and the main clinical manifestations were jaundice, malaise, anorexia and pruritus. The age distribution of patients with AIH showed a single peak at 50 years. Elevated serum gamma globulin and IgG were found in patients with AIH, of whom 62.9% (17/27) were positive for anti-nuclear antibody (ANA) and 3 were positive for liver-kidney microsomes type 1 antibody. The main histological changes in severe AIH cases included interface hepatitis (77.7 %) and bridging necrosis. Most of the PBC patients were presented with elevated serum alkaline phosphatase, glutamyl transpeptidase and IgM. Fifty patients (74.6%) were positive for anti-mitochondrial antibody (AMA) and AMA-M2. The pathological examination showed that 28. 3% of the cases were in Ⅰ or Ⅱ stage and 71.7% in Ⅲ or Ⅳ stage in patients with PBC who received liver biopsy. The pathologic change of reduction or even disappearing of bile ducts was found in 62. 6% patients with PBC. The clinical and pathological manifestations in patients with AIH-PBC overlap syndrome had both characteristics of PBC and AIH. Three out of 10 patients with AIH-PBC overlap syndrome were positive for ANA and AMA/AMA-M2. Conclusion Since AILD is not rare in Chinese, its diagnosis should be based on the clinical presentation, biochemical, immunological and histologic changes. Key words: Hepatitis, autoimmune; Liver cirrhosis, biliary; Cholangitis, sclerosing

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.

Cholestatische Hepatitis bei Situs inversus abdominalis

A 75 year old patient was admitted to hospital due to painless jaundice and fatigue. Patient's history was not remarkable for chronic viral hepatitis, autoimmune hepatitis, hereditary metabolic disorders or a hepatotoxic damage. Laboratory tests revealed significant elevation of the parameters of cholestasis and aminotransferase activity, a significantly elevated titer of both antinuclear (ANA) and antimitochondrial (AMA) antibodies. Abdominal ultrasound and computertomography showed no mechanic cholestasis nor tumorous process but a situs inversus abdominalis of the abdominal parenchymatous organs. Portal and periportal inflammation, consistent with autoimmune hepatitis, was diagnosed histologically after performing laparoscopic liver biopsy. Regarding the significantly elevated cholestatic parameters and the positive AMA-autoantibodies AIH-PBC overlap syndrome was highly probable so medical treatment including both ursodeoxycholic acid and immunosuppressive therapy with corticosteroids and azathioprine was started resulting in a continous downward tendency of liver enzymes and an improvement of the patient's clinical condition. Finding the correct diagnosis and therapy of autoimmune liver disease is not always easy and unproblematic. Regarding its sometimes fatal progression and good response towards medical treatment prompt diagnosis and institution of autoimmune hepatitis--alone or combined as PBC/AIH overlap syndrome--should not be deferred. Laparoscopic liver biopsy should be the method of choice in patients's with situs inversus abdominalis regading the variable anatomy.

Post‐liver transplantation de novo hepatitis with overlap features

The development of de novo autoimmune liver disease after liver transplantation (LT) has been described in both children and adults. Reported herein is a case that is best characterized as post-LT de novo hepatitis with features of autoimmune hepatitis (AIH)-primary biliary cirrhosis (PBC) overlap. A 56-year-old man underwent LT for decompensated liver disease secondary to non-alcoholic steatohepatitis. His liver function tests became markedly abnormal 8 months after LT. Sequential liver transplant biopsy findings were confusing and shared findings seen with both AIH and PBC. Although standard autoimmune serological tests were negative, a dramatic biochemical response was observed to a regimen consisting of prednisone, mycophenolate mofetil, and ursodeoxycholic acid added to maintainance tacrolimus. The donor was histocompatibility leukocyte antigen, DR4, positive, a haplotype associated with the development of AIH-PBC overlap syndrome. In conclusion the authors believe that this may be a case of post-LT de novo overlap syndrome of AIH-PBC, a novel 'autoimmune-type' response.