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• Occasionally, AMA -the specific marker of PBC- can be detected in AIH patients. • The clinical significance of this finding remains obscure. • AIH severity and response to therapy were similar in AMA(+) and AMA(-) AIH patients. • AMA(+) AIH patients had higher risk to develop histological bile duct injury. • AMA(+) AIH patients with non-specific bile duct injury had higher risk to progress. Antimitochondrial antibodies (AMA) are specific markers for the diagnosis of primary biliary cholangitis (PBC) but can also be found occasionally in patients with autoimmune hepatitis (AIH). The present large multicentre cohort study assessed the prevalence and significance of AMA in AIH-patients. 123 AMA-positive AIH-patients were investigated and compared with 711 age-matched AMA-negative AIH-patients and 69 patients with AIH/PBC variant. AMA prevalence in AIH-patients was 5.1% (range: 1.2%-11.8%). AMA-positivity was associated with female sex (p = 0.031) in AMA-positive AIH-patients but not with liver biochemistry, bile duct injury on liver biopsy, disease severity at baseline and response to treatment compared to AMA-negative AIH-patients. Comparing AMA-positive AIH-patients to those with AIH/PBC variant, there was no difference in disease severity. Regarding liver histology, AIH/PBC variant patients were characterized by the presence of at least one feature of bile duct damage (p <0.001). Response to immunosuppressive treatment was similar among groups. From AMA-positive AIH patients only those with evidence of non-specific bile duct injury had higher risk to progress to cirrhosis (HR=4.314, 95%CI: 2.348–7.928; p <0.001). During follow-up, AMA-positive AIH-patients had higher risk to develop histological bile duct injury (HR 4.654, 95%CI 1.829–11.840; p = 0.001). AMA presence is relatively common among AIH-patients, but their clinical significance seems important only when they co-exist with non-specific bile duct injury at the histological level. Therefore, a careful evaluation of liver biopsy seems of utmost importance in these patients. [Display omitted] [ABSTRACT FROM AUTHOR]

Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease characterized by the immune-mediated destruction of small and medium intrahepatic bile ducts, involving predominantly females. PBC has long been described as an autoimmune liver disease, also because it is very often associated with many autoimmune conditions. More recently, another pathogenic mechanism exploring the damage of cholangiocytes has been hypothesized, i.e. a defect in the biliary umbrella which is physiologically responsible for the exchange of the ions Cl− and HCO3− and maintains the integrity of glycocalyx. To provide a state-of-the-art analysis of this topic, a systematic review of literature in PubMed, Scopus, and Science Direct was conducted (inclusive dates: 1986–2023). Although the etiology remains unknown, pathogenesis consists of a complex immune-mediated process resulting from a genetic susceptibility. PBC can be triggered by an immune-mediated response to an autoantigen, which leads to a progressive destruction of bile ducts and eventually to a progressive fibrosis with cirrhosis. The defect in the 'bicarbonate umbrella' acts as a protection against the toxic hydrophobic bile acids, leading to a toxic composition of bile. This review offers a summary of the current knowledge about the pathogenesis of PBC, indicating that this is probably based on the mutual relationship between the immune insult and the unbalanced secretory mechanisms. [ABSTRACT FROM AUTHOR]

Primary biliary cholangitis (PBC) is a chronic autoimmune cholestatic liver disease characterized by T-lymphocyte-mediated damage to intrahepatic biliary epithelial cells and the presence of a specific serological marker, antimitochondrial antibodies, and which, if left untreated, leads to end-stage biliary cirrhosis. PBC remains a major public health problem. Until recently, PBC was referred to as "primary biliary cirrhosis", but the disease is often diagnosed in the pre-cirrhotic phase, when there is no formed cirrhosis yet, but there is only a threat of its development. The change in the definition of the disease harmoniously fits into the framework of the concept of preventive medicine, since with timely diagnosis and adequate therapy, this phase of the disease can be extended for years and decades, but all these years the patient is “traumatized” by a prediagnosed liver cirrhosis. At the end of the previous decade, a large number of international clinical recommendations and guidelines on PBC were published. As part of the review of the current state of the PBC problem, publications from various international databases were used, with an emphasis on publications of the current decade, which note the importance of early diagnosis of the disease with an emphasis on biochemical markers of cholestasis (primarily alkaline phosphatase) and immunological markers (primarily turn antimitochondrial antibodies) and early initiation of treatment with the first-line drug – ursodeoxycholic acid.

This document discusses the diagnostic and prognostic value of quantitative detection of antimitochondrial antibodies subtype M2 (AMA-M2) using chemiluminescence immunoassay in primary biliary cholangitis (PBC). PBC is an autoimmune liver disease that can lead to liver cirrhosis and failure if left untreated. AMA-M2 is the most specific autoantibody used for diagnosing PBC. The study conducted involved 158 PBC patients and 20 negative controls, and the results showed that the chemiluminescence immunoassay had good diagnostic efficacy and consistency with other detection methods. Additionally, there was a significant correlation between AMA-M2 and the occurrence of liver cirrhosis in PBC patients. [Extracted from the article]

Primary biliary cholangitis (PBC) is an autoimmune hepatobiliary disease characterized by immune mediated destruction of the intrahepatic small bile ducts and the presence of antimitochondrial antibodies (AMAs). The mitochondrial autoantigens have been identified as the E2 subunits of the 2-oxo-acid dehydrogenase complex, including the E2 subunits of pyruvate dehydrogenase, branched-chain 2-oxo acid dehydrogenase complex, oxoglutarate dehydrogenase complex, E3 binding protein and PDC E1 alpha subunit. The AMA epitope is mapped within the E2 lipoic acid binding domain, which is particularly important for oxidative phosphorylation. In addition, lipoic acid, which serves as a swinging arm to capture electrons, is particularly susceptible to an electrophilic attack and may provide clues to the etiology of PBC. This review emphasizes the molecular characteristics of AMAs, including detection, immunochemistry and the putative role in disease. These data have significance not only specifically for PBC, but generically for autoimmunity.

Primary biliary cirrhosis (PBC) is an inflammatory disease or chronic liver inflammation, with slow progressive characteristic and is an unknown cholestatic liver disease and commonly happen in middle-aged women. The incidence of PBC is 0.03 – 5.8 per 100,000 people per year, prevalence of 1.91-40.2 per 100,000 people and continues to increase. Based on the American Association for Study of Liver Disease criteria, the diagnosis of PBC is made in the presence of two out of three criteria, which are increase of alkaline phosphatase, positive antimitochondrial antibodies (AMA), and histopathology examination. We reported a case which is very rarely found; a 47-year-old women with the chief complaints of decrease consciousness and jaundice. In physical examination, there were anaemic conjunctiva, icteric sclera, hepatosplenomegaly, palmar erythema, and liver nails. In the patient, there was no evidence of obstruction in imaging with two-fold increase of alkaline phosphatase and positive AMA test. Patient was hospitalised to slow down the progression of the disease and to overcome the signs (e.g. pruritus, osteoporosis and sicca syndrome).

Background: The natural history of patients with anti‐mitochondrial antibody (AMA)‐negative Primary Biliary Cholangitis (PBC) cirrhosis has not been well defined, with prior studies showing discordant results. Furthermore, most studies of AMA‐negative PBC have limited numbers of patients with cirrhosis and liver‐related outcomes. Methods: We investigated the association of AMA‐negative PBC and the development of death, liver‐related death, decompensation and hepatocellular carcinoma (HCC), in a large cohort of predominantly male patients with PBC cirrhosis assembled from the Veterans Health Administration. Results: In a cohort of 521 patients with PBC cirrhosis (65 AMA‐negative) with a total follow‐up of 2504.3 person‐years (PY) from cirrhosis diagnosis, patients with AMA‐negative PBC were younger and more likely to be black but had similar rates of UDCA response. AMA‐negative PBC cirrhosis was associated with similar unadjusted rates of liver‐related death (4.6 vs 5.9 per 100 PY, P =.44), overall death (7.7 vs 9.6 per 100 PY, P =.31), decompensation (7.3 vs 5.1 per 100 PY, P =.12) and HCC (0.6 vs 1.0 per 100 PY, P =.63) to AMA‐positive PBC. After adjusting for confounders, AMA‐negative PBC cirrhosis was associated with similar rates of liver‐related death (sub‐Hazard Ratio [sHR] 1.27, 95% CI 0.71‐2.28, P =.42, death [sHR] 1.24, 95% CI 0.81‐1.90, P =.32), decompensation (sHR 1.05, 95% CI 0.56‐1.98, P =.87) and HCC (sHR 0.48, 95% CI 0.11‐2.10, P =.33) to AMA‐positive patients. Conclusion: In a cohort of predominantly male patients, AMA‐negative PBC cirrhosis was associated with similar rates of overall or liver‐related death, HCC or decompensation compared with AMA‐positive disease. [ABSTRACT FROM AUTHOR]

Introduction: A proportion of patients with drug-induced liver injury (DILI) present with autoantibodies, which has led to the current concept of autoimmune-like DILI. However, no standardized definition exists and the clinical relevance has not been studied in detail yet. Methods: 143 patients with DILI enrolled in a prospective study were analyzed. DILI diagnosis was based on the monocyte-derived hepatocyte-like cell test and supported by Roussel Uclaf Causality Assessment Method (RUCAM) and expert adjudication. Testing for antinuclear antibodies (ANA) and antimitochondrial antibodies (AMA) was performed using immunofluorescence. ANA titers ≥1:100 were considered positive and ≥1:400 clinically relevant; AMA positivity was considered at titers ≥1:100. Results: 67% exhibited ANA ≥1:100 and 29% ANA ≥1:400; 10% were AMA positive. There was no significant correlation between the ANA titers and the causative drug, while AMA positive patients had taken nonsteroidal anti-inflammatory drugs more frequently. No difference was seen regarding clinical characteristics or laboratory parameters in patients with ANA ≥1:400, while patients with positive AMA presented with higher aminotransferases, bilirubin, and international normalized ratio. Significantly higher proportions of patients with ANA ≥1:400 or AMA positivity exhibited elevated immunoglobulin G levels. AMA positivity but not elevated ANA titers correlated with a higher proportion of Hy's law positivity. Conclusion: A closer look in a causality proven DILI cohort provided no evidence that presence of ANA titers is specific for DILI by a certain medication. AMA rather than ANA positivity was related to a more pronounced liver injury. [ABSTRACT FROM AUTHOR]

Background: Systemic sclerosis (SSc) and primary biliary cholangitis (PBC) are autoimmune diseases that may occur concomitantly and are both strongly associated with disease-specific autoantibodies. This study investigated the prevalence and fine specificity of PBC-specific serology (PBC-Ab) and associations with the SSc-subtypes and SSc-specific antibodies as well as the association with cholestatic liver enzymes. Furthermore, three different techniques for the detection of PBC-Ab were compared. Methods: Serum of 184 Belgian SSc patients with a known SSc-antibody profile, was analyzed for PBC-Ab (antimitochondrial antibodies [AMA], anti-Gp210, anti-Sp100 and anti-PML) using indirect immunofluorescence (IIF) analysis on human epithelioma-2000 (HEp-2000) cells (ANA-IIF, Immunoconcepts) and liver-kidney-stomach tissue sections (IIF-LKS) (Menarini), and a line immunoblot (LB) (EuroImmun). Alkaline phosphatase/γ-glutamyl transferase (ALP/GGT) were evaluated at time of first sampling (t0) and after 3 years of follow-up (t3). Results: PBC-Ab were present in 13% of patients and significantly correlated with centromere antibodies (anti-CENP-B), but not correlated with the limited cutaneous SSc subgroup (lcSSc). The most frequent reactivities were AMA (11%, with 9% AMA-M2) and Sp-100 antibodies (5%), showing a major overlap. There was no relevant association between the presence of PBC-Ab and ALP or GGT elevation at t0 nor at t3. Detection of AMA with IIF-LKS is comparable to LB. ANA-IIF screening was less sensitive compared to LB. Conclusions: A wide range of PBC-Ab is detectable in SSc in the absence of cholestatic liver enzyme elevations, even after 3 years of follow-up. However, as these antibodies may precede PBC-disease up to 10 years further prospective follow-up of our cohort will be necessary. [ABSTRACT FROM AUTHOR]

Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are the main autoimmune cholestatic liver diseases. IgG4-associated sclerosing cholangitis is another distinct immune-mediated cholestatic disorder of unknown aetiology that is frequently associated with autoimmune pancreatitis or other IgG4-related diseases. Although the majority of PBC and PSC patients have a typical presentation, there are common and uncommon important variants or specific subgroups that observed in everyday routine clinical practice. In this updated review, we summarize the published data giving also our own experience on the variants and specific groups of autoimmune cholestatic liver diseases. Actually, we give in detail the underlining difficulties and the rising dilemmas concerning the diagnosis and management of these special conditions in the clinical spectrum of autoimmune cholestatic liver diseases including the IgG4-associated sclerosing cholangitis highlighting also the uncertainties and the potential new eras of the research agenda. [ABSTRACT FROM AUTHOR]

Anti-mitochondrial antibody (AMA) is a typical serum marker for primary biliary cholangitis (PBC), and the diagnosis of AMA-negative PBC may easily be neglected in clinical practice. This article analyzes the differences in epidemiology, clinical and pathological features, and treatment outcome between AMA-negative and AMA-positive PBC and points out that there are significant differences between them in the symptom of pruritus, immunoglobulin M, and severity of bile duct injury. For patients with a clinical diagnosis of AMA-negative PBC, immunofluorescence assay combined with immunological detection should be performed to exclude the false-negative result of AMA, and a confirmed diagnosis can be made with reference to the manifestation of cholestasis, positive results of anti-sp100, anti-gp210, and anti-ANA antibodies, and typical hyperactive cholangitis based on pathological examination. Differential diagnosis of this disease with other types of bile duct injury or absence of bile duct should be taken seriously in clinical practice. [ABSTRACT FROM AUTHOR]

Background and Objectives: Laboratory liver abnormalities can be observed in patients affected with polymyalgia rheumatica (PMR) and/or giant cell arteritis (GCA), especially with a cholestatic pattern. The first objective of our review article is to discuss the potential link between antimitochondrial antibodies (AMA) and/or primary biliary cholangitis (PBC) and PMR/GCA, according to the evidences of literature. The second objective is to discuss the association of PMR/GCA with the other rheumatic diseases having PBC as a common manifestation. Materials and Methods: A literature search was performed on PubMed and Medline (OVID interface) using these terms: polymyalgia rheumatica, giant cell arteritis, antimitochondrial antibodies, primary biliary cholangitis, primary Sjogren’s syndrome, systemic sclerosis, and systemic lupus erythematosus. The search was restricted to all studies and case reports published in any language. Reviews, conference abstracts, comments, and non-original articles were excluded; however, each review’s reference list was scanned for additional publications meeting this study’s aim. When papers reported data partially presented in previous articles, we referred to the most recent published data. Results and Conclusions: Our literature search highlighted that cases reporting an association between AMA, PBC and PMR/GCA were very uncommon; AMA antigenic specificity had never been detected and biopsy-proven PBC was reported only in one patient with PMR/GCA. Finally, the association of PMR/GCA with autoimmune rheumatic diseases in which PBC is relatively common was anecdotal.

Testing for liver-related autoantibodies should be included in the workup of patients with hepatitis or cholestasis of unknown origin. Although most of these autoantibodies are not disease specific, their determination is a prerequisite to diagnose autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC), and they are components of the diagnostic scoring system in these diseases. In primary sclerosing cholangitis (PSC), on the other hand, autoantibodies are frequently present but play a minor role in establishing the diagnosis. In PSC, however, data on antibodies suggest a link between disease pathogenesis and the intestinal microbiota. This review will focus on practical aspects of antibody testing in the three major autoimmune liver diseases AIH, PBC, and PSC.

Primary biliary cholangitis (PBC), which is the commonest autoimmune cholestatic liver disease in adults, may lead to increasingly severe ductopenia and liver fibrosis. The cause of PBC is unknown, but a genetic predisposition in synergy with an environmental factor(s) is probably implicated. Biochemical criteria for expected non-response to treatment with ursodeoxycholic acid (UDCA), after 6 to 24 months, have been proposed in the last decade and the value of prognostic indicators in PBC has been assessed, including the patient's age, blood levels of bilirubin, albu Ursomin and alkaline phosphatase, and platelet count (Globe score). Despite better understanding of prognostic indicators and the response criteria to UDCA therapy in PBC, upward trends are being noted in the mortality rate and the need for liver transplantation. Patients who fail to achieve a satisfactory biochemical response to UDCA, who constitute about one third, are in need of second line therapies, either alone or in combination with UDCA, because this population shows a distinct risk of progression to cirrhosis and the complications of end-stage liver disease, including liver failure, portal hypertension, and hepatocellular carcinoma. A currently licensed, second-line therapeutic agent for PBC is obeticholic acid (OCA), which has been approved by EMA and FDA. Other novel therapies under development aim not only at preventing the onset of end-stage liver disease, but also at ameliorating the symptoms of PBC. [ABSTRACT FROM AUTHOR]

We describe a 53-year-old woman with primary Sjögren's syndrome and tubulointerstitial nephritis showing distal renal tubular acidosis and Fanconi syndrome. The patient showed high serum IgM levels and positivity for antimitochondrial antibodies, although her liver function was in normal range. According to our literature review, 75% of patients with tubulointerstitial nephritis who were positive for antimitochondrial antibodies showed Fanconi syndrome, suggesting that these antibodies may directly be associated with the pathophysiology of Fanconi syndrome. [ABSTRACT FROM AUTHOR]

Testing for liver-related autoantibodies should be included in the workup of patients with hepatitis or cholestasis of unknown origin. Although most of these autoantibodies are not disease specific, their determination is a prerequisite to diagnose autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC), and they are components of the diagnostic scoring system in these diseases. In primary sclerosing cholangitis (PSC), on the other hand, autoantibodies are frequently present but play a minor role in establishing the diagnosis. In PSC, however, data on antibodies suggest a link between disease pathogenesis and the intestinal microbiota. This review will focus on practical aspects of antibody testing in the three major autoimmune liver diseases AIH, PBC, and PSC. [ABSTRACT FROM AUTHOR]

Autoimmune Hepatitis (AIH) and Primary Biliary Cirrhosis (PBC) are important immune mediated liver diseases. They are usually differentiated based on clinical, biochemical, serological and histological parameters. The presence of autoantibodies, clinical and serological findings can sometimes occur in different combinations leading to overlap syndromes, which is rare. Early recognition of such overlap syndromes is clinically significant from treatment point of view. Here, we report a case of AIH-PBC overlap syndrome with a brief review of literature on overlap syndromes.

Primary biliary cholangitis (PBC) is an autoimmune liver disease characterized by biliary destruction, progressive cholestasis, and potentially liver cirrhosis. Patients develop a well-orchestrated immune reaction, both innate and adaptive, against mitochondrial antigens that specifically targets intrahepatic biliary cells. A puzzling feature of PBC is that the immune attack is predominantly organ specific, although the mitochondrial autoantigens are found in all nucleated cells. The disease results from a combination of genetic and environmental risk factors; however, the exact pathogenesis remains unclear. Serologically, PBC is characterized by presence of antimitochondrial antibodies, which are present in 90-95 % of patients and are often detectable years before clinical signs appear. Like other complex disorders, PBC is heterogeneous in its presentation, symptomatology, disease progression, and response to therapy. A significant number of patients develop end-stage liver disease and eventually require liver transplantation. Recent studies from large international cohorts have better identified prognostic factors, suggesting a change in patient management based on risk stratification. Therapeutic options are changing. In this review we discuss data on the autoimmune responses and treatment of the disease. [ABSTRACT FROM AUTHOR]

The aim of review. Primary biliary cirrhosis (PBC) is related to the group of autoimmune cholestasisassociated liver diseases. In the last years prevalence of PBC increased considerably, especially – in Northern European countries. Despite of sufficient progress in studying of main pathophysiological mechanisms of PBC, etiology of disease remains obscure. There was a task to fill these gaps to some extent.Key points. Etiological factors increasing risk of PBC development include genetic factors, immunologic disorders, and environmental features. Thus the contribution of each of the mentioned groups of factors, at least, partly is determined by demographic, ethnic and geographical features.Conclusion. Detection of risk factors and the possible PBC causes allows to develop additional treatment approaches, and define new PBC markers, increase rate of early stage diagnostics.

Introduction: A reliable liver autoimmune serology for the diagnosis of primary biliary cholangitis (PBC) is of particular importance. Recognition of patients at early stages and prompt treatment initiation may alter the outcome, slow progression, delays liver failure, and improves survival. Areas covered: In this review, we summarize and discuss the published data obtained from literature searches from PubMed and The National Library of Medicine (USA) and our own experience on the current and potential molecular based approaches to the diagnosis of PBC. Expert commentary: Standardization of liver diagnostic serology and clinical governance are two major points as antimitochondrial antibodies are the diagnostic hallmark of the disease and PBC-specific antinuclear antibodies could assist in the diagnosis and estimation of prognosis. New biomarkers such as novel autoantibodies, genetic polymorphisms, metabolomic profiling, micro-RNA and epigenetics may assist to the understanding, diagnosis and management of the disease. [ABSTRACT FROM PUBLISHER]

Primary biliary cirrhosis (PBC) is an organ-specific autoimmune disease that predominantly affects women and is characterized by chronic, progressive destruction of small intrahepatic bile duct with portal inflammation and ultimately fibrosis, leading to liver failure in the absence of treatment. The serologic hallmark of PBC is the presence of autoantibodies to mitochondria, especially to the E2 component of the pyruvate dehydrogenase complex (PDC). Current theories on the pathogenesis of PBC favor the hypothesis that the disease develops as a result of an inappropriate immune response following stimulation by an environmental or infectious agent. Like other better characterized autoimmune diseases, there appears to be a genetic susceptibility and a triggering event that initiates the autoimmune attack on bile duct cells. DRB1*0801 and DRB1*0803 are the major susceptibility alleles among Northern European and Japanese populations, respectively. The generation of immune responsiveness to self-antigen can result in pathogenic autoimmune damage of the intrahepatic biliary epithelial cells mediated by both humoral and cellular immune responses. The pathogenetic mechanism is believed to be caused by a defect in immunologic tolerance, resulting in the activation and expansion of self-antigen specific T and B lymphocyte clones and the production of circulating autoantibodies in addition to a myriad of cytokines and other inflammatory mediators. Human and animal studies have suggested that the induction of an antibody response reactive with self-antigen may result from a number of different priming events. Among the events demonstrated to induce an antibody response cross-reactive with self-PDC are exposures to bacterial PDC or retroviral proteins or xenobiotics or microchimerism. The diversity of the potential events giving rise to antibody responses cross-reactive with PDC, which could promote subsequent T-cell tolerance breakdown, suggests the intriguing possibility that PBC could represent a condition with a common final pathway but with multiple triggers able to induce a B-cell response cross-reactive with self-PDC. There are important questions about the pathogenesis of PBC which remain unanswered.

Aim. To ascertain initial signs of primary biliary cirrhosis (PBC), criteria of its early diagnosis, variants of the course, clinical picture and life quality of PBC patients. Material and methods. 128 PBC patients were examined in the Central Research Institute of Gastroenterology from 1991 to 2002. Quality of life was assessed by SF-36 questionnaire adapted for patients with chronic cholestatic diseases of the liver. Results. The patients complained of skin pruritus (80%), jaundice (66%), fatigue (68.8%), weight loss (24.6%o). The disease manifested with skin pruritis in 75.8%, jaundice - in 12.5% patients. Decompensated hepatic cirrhosis (Child-Pugh C) at first hospitalisation was diagnosed in 11.7% cases. The earlest and most significant biochemical markers of PBS were high activity of gammaglutamiltranspeptidase (GGTP) and alkaline phosphatase (AP). IgM level was high in 70.5% cases. Anfimitochondrial antibodies were detected in 83.6% examinees. Overlapping with autoimmune hepatitis was seen in 9.4%. One-third of the patients had systemic symptoms. Quality of life deteriorated. Conclusion. PBC may be long asymptomatic. The absence of skin pruritus is not a sure sign of the disease absence. To detect PBC early, young and middle-aged women with unexplained weakness or skin pruritus should undergo a comprehensive examination including measurements of GGTP, AP, AM A, IgM, morphological investigation of liver tissue. PBC patients had low quality of life. This should be accounted for when treating patients, in determination of their working ability and for early referral for liver transplantation.

Chronic non-suppurative destructive cholangitis, the so-called primary biliary cirrhosis, is characterised by changes, which occur in intrahepatic bile ducts in early stages and in hepatic parenchyma as the disease progresses. The disease gradually evolves into the full-blown picture of biliary cirrhosis. Primary biliary cirrhosis predominantly affects women between 35 and 60 years of age in all social classes and in all races. Our patient was a woman, old 78 years old who admitted for treatment of hypertrophie cardiomyopathy. During the routine laboratory exploration signs of cholestasis were noted: higher values of alkaline phosphatase and gamma glutamyl transferase, combined with low level of platelets, probably of autoimmune origin. Hypercholesterolaemia (7.8 mmol/L) associated with normal values of triglycerides was observed. The main criterion for establishing the diagnosis of primary biliary cirrhosis was the titer of antimito-chondrial antibodies in the serum, which was 1:640. At the same time, she had a urinary infection, caused by Escherichia coli, which confirmed possible relationship between primary biliary cirrhosis and occurence of some Gramm negative bacteria, reported elsewhere. On the other hand, biopsy of the liver was just an auxiliary method, serving for the confirmation of diagnosis. Ursodeoxycholic acid was used as the main drug in the therapy of primary biliary cirrhosis. This case of primary biliary cirrhosis is a worth report because of the comorbidity with cardiac symptoms, which were covering symptoms of hepatic disorder.

Objective To explore the serological characteristics of viral hepatitis patients with positive anti-mitochondrial antihody (AMA)-M2 and its clinical implications. Methods Serum was collected from viral hepatitis patients who were admitted to Beijing Youan Hospital, Capital Medical University, fromjanuary 2011 to Decemher 2013. SerumAMA-M2 was measured hy ELISA. A total of 102 viral hepatitis patients with positive AMA-M2 were screened out, including 53 patients with chronic hepatitis B (CHB), 27 patients with chronic hepatitis C (CHC), 5 patients with hepatitis E (HE), 9 patients with CHB accompanied hy primary hiliary cirrhosis (PBC), and 7 patients with CHC accompanied hy PBC. We also collected serum from 60 PBC patients as controls. Patients were grouped hy the clinical diagnosis and analyzed retrospectively considering their serological characteristics. Comparison of continuous data was made hy one-way ANO-VA. Results Level of serum AMA-M2 was low and medium in the CHB, CHC, and HE groups and was significantly lower than those of the PBC group and CHB/PBC and CHC/PBC groups ( all P < 0.0001). Serum ALT and AST in the HE group were significantly higher than that in the PBC group (P<0.01). Serum gamma-glutamyl transpeptidase (GGT) levels in the CHB and CHC groups were significantly lower than that in the PBC group (hoth P <0.001), hut did not show significant difference when compared with the CHB/PBC or CHC/PBC group (P > 0.05). Serum alkaline phosphatase (ALP) and IgM in the CHB group were significantly lower than those in the PBC group (P < 0.0001). Serum ALP and IgM in the CHC group were significantly lower than those in the PBC group and CHC/PBC group (all P < 0.05). Serum IgM in the HE group was significantly lower that that in the PBC group (P <0.01). Serum C3 level in the CHB group was significantly lower than those in the PBC group and CHB/PBC group (both P<0.05). Conclusion AMA-M2 is not restricted to PBC pa'tients alone, and medium or low level of AMA-M2 can be seen in patients with viral hepatitis, which is not an autoimmune disease. Other serological markers such as ALP, GGT, IgM, and C3 are helpful in diagnosing and differentiating PBC [ABSTRACT FROM AUTHOR]

Objective: Autism is a neurodevelopmental disorder characterized by impairment in verbal and nonverbal communication, repetitive and stereotypic behavior. Dysregulated immune system has a role in the pathogenesis of Autism. This study was designed to measure the prevalence of antimitochondrial (AM) antibodies in a group of autistic children. Methods: AM antibodies subtype 2 (AMA-M2) were evaluated by indirect solid phase enzyme immunoassay in 62 autistic children and 14 age-matched healthy controls. Autistic activity was assessed by using the Childhood Autism Rating Scale. Results: Significantly elevated levels of AMA-M2 were observed in the sera of autistic children (n = 54, 0.221 ± 0.029 IU/ml [mean ± SEM]) compared with healthy controls (n = 14, 0.111 ± 0.010 IU/ml [mean ± SEM], p = 0.0008) and there was no significant difference in patients with moderate to severe autism (p = 0.49). AM antibodies in autistic patients have no correlation with Childhood Autism Rating Scale score. Conclusion: The current study demonstrated significantly high levels of AMA-M2 in autistic subjects when compared with healthy controls. Further large-scale studies are required to dissect any pathogenic role of these antibodies in the development of autism. [ABSTRACT FROM AUTHOR]

Background & Aims In recent years, primary biliary cirrhosis is mostly diagnosed in patients who are asymptomatic; however, a proportion of cases still present with typical complaints such as fatigue and/or pruritus. We compared biochemical, histological and immunological features of patients with or without fatigue and/or pruritus at onset to see whether the different clinical presentation may eventually impact on disease progression. Methods We analysed the Bologna cohort of 216 patients with primary biliary cirrhosis referred to our Centre between 1997 and 2007, according to symptomatic (fatigue and/or pruritus) or asymptomatic presentation. Clinical, biochemical, histological and immunological feature at diagnosis, response to ursodeoxycholic acid and progression of the disorder were compared after a mean follow-up of 81 ± 75 months. Results At diagnosis, symptomatic patients were significantly more often women (98.6% vs. 87.2%, P = 0.004), younger (mean age 49 ± 12 vs. 55 ± 12 years, P = 0.003) and with more pronounced biochemical activity, as indicated by higher alkaline phosphatase (mean 2.93 ± 2 vs. 2.12, P = 0.002) and aminotransferase (mean 1.92 ± 1 vs. 1.47 ± 1.27, P = 0.014) levels, whereas histological stage and autoantibody profile were similar. Symptomatic patients were less likely to respond to ursodeoxycholic acid therapy (63% vs. 81%, P = 0.006) and developed more often cirrhosis and its complications (31% vs. 13%, P = 0.004). Conclusions Fatigue and/or pruritus at onset identify a subset of patients with primary biliary cirrhosis who preferentially are women, younger, with a particularly active disease, less responsive to ursodeoxycholic acid treatment, and more inclined to evolve to cirrhosis and its complications. [ABSTRACT FROM AUTHOR]

Antimitochondrial, anti-gp210, anti-sp100, and anticentromere antibodies are specifically detected in primary biliary cirrhosis (PBC). In clinical practice, they are useful for the diagnosis of PBC or for evaluating disease severity, clinical phenotype, and long-term outcome. In the typical or classical form of PBC which shows slow progressive loss of small bile ducts with a parallel increase in liver fibrosis, anti-gp210 antibodies are a strong risk factor for progression to jaundice and hepatic failure, whereas the presence of anticentromere antibodies is a risk factor for progression to cirrhosis and portal hypertension. Of note, the autoimmune repertoire, which is established during the early stage of the disease process, can influence the clinical phenotype and the long-term prognosis of PBC. Because the natural course of PBC is being altered by treatment with ursodeoxycholic acid, the clinical significance of these PBC-specific autoantibodies awaits re-evaluation in various ethnicities. [ABSTRACT FROM AUTHOR]

In primary biliary cirrhosis (PBC), the breach of tolerance that leads to active disease involves a disruption in several layers of control, including central tolerance, peripheral anergy, a "liver tolerance effect," and the action of T regulatory cells and their related cytokines. Each of these control mechanisms plays a role in preventing an immune response against self, but all of them act in concert to generate effective protection against autoimmunity without compromising the ability of the host immune system to mount an effective response to pathogens. At the same time, genetic susceptibility, environmental factors, including infection agents and xenobiotics, play important roles in breach of tolerance in the development of PBC. [ABSTRACT FROM AUTHOR]

Within the last decade, several mouse models that manifest characteristic features of primary biliary cirrhosis (PBC) with antimitochondrial antibodies (AMAs) and immune-mediated biliary duct pathology have been reported. Here, the authors discuss the current findings on two spontaneous (nonobese diabetic autoimmune biliary disease [NOD.ABD] and dominant negative transforming growth factor-β receptor II [dnTGFβRII]) and two induced (chemical xenobiotics and microbial immunization) models of PBC. These models exhibit the serological, immunological, and histopathological features of human PBC. From these animal models, it is evident that the etiology of PBC is multifactorial and requires both specific genetic predispositions and environmental insults (either xenobiotic chemicals or microbial), which lead to the breaking of tolerance and eventually liver pathology. Human PBC is likely orchestrated by multiple factors and hence no single model can fully mimic the immunopathophysiology of human PBC. Nevertheless, knowledge gained from these models has greatly advanced our understanding of the major immunological pathways as well as the etiology of PBC. [ABSTRACT FROM AUTHOR]

Primary biliary cirrhosis (PBC) is a chronic cholestatic disease characterized by the presence of antimitochondrial antibodies (AMA). PBC-specific antinuclear antibodies (ANA) have been characterized and associated with disease progression and outcome. We evaluated the clinical significance of the presence and serial changes in titers of AMA, PBC-specific ANA (anti-gp210, anti-sp100) and anti-chromatin antibodies. Over a median (IQR) period of 35 (36) months, 512 specimens were collected from 110 patients. Autoantibodies were detected by commercial ELISAs (INOVA Diagnostics). Biochemical, clinical, and histological status were included at initial presentation and during follow-up visits. The Mayo risk score was calculated as a prognostic index at each time point. Liver biopsy findings were classified according to Ludwig's classification and biochemical response to ursodeoxycholic acid was evaluated according to Pares. At baseline, AMA IgG and IgA, anti-gp210 IgG, anti-sp100 IgG and anti-chromatin IgG were detected in 92/110 (83.6%), 57/110 (51.8%), 5/110 (4.5%), 14/110 (12.7%), and 0/110 (0%) patients, respectively. Positivity for all autoantibodies apart from anti-chromatin, at baseline visit ( n = 110 patients), in all tested sera ( n = 512) as well as increased autoantibodies titers during follow-up were associated with biochemically and/or histologically advanced disease. A decrease of anti-sp100 titers but not of anti-gp210 titers during follow-up was associated with improvement of Mayo risk score ( p = 0.025) and response to ursodeoxycholic acid ( p = 0.016). These results suggest that detection of AMA and PBC-specific ANA was correlated with disease severity. Serial changes of anti-sp100 titers and not of anti-gp210 titers might prove useful for monitoring the disease course and treatment outcome. [ABSTRACT FROM AUTHOR]

Autoantibodies in hepatitis C virus-infected patients may indicate autoimmune hepatitis or other immune-mediated diseases. This may impact safety and efficacy of interferon-based therapy of chronic hepatitis C. We investigated the association between a positive test result for a variety of autoantibodies and the initiation and efficacy of therapy for chronic hepatitis C. We analysed an observational cohort of 24 306 patients for an association between autoantibodies and treatment outcome. 8241 patients were tested simultaneously for antinuclear antibodies ( ANA), liver kidney microsomal antibodies ( LKM), smooth muscle antibodies ( SMA) and antimitochondrial antibodies ( AMA). Matched-pair analysis was performed matching one autoantibody-positive patient to three controls. Control patients had negative tests for all four antibodies. Analyses were performed for patients with a single positive autoantibody test and for patients with multiple positive autoantibody tests. A positive test result for ANA, LKM, SMA or AMA did not affect the physician's decision to initiate therapy with pegylated interferon and ribavirin. In addition, a positive test for one or multiple autoantibodies did not adversely affect sustained virologic response. There was no difference in fibrosis stage or alanine transaminase at baseline or during therapy irrespective of antibody status. Thyroid dysfunction was more frequent in patients with positive LKM antibodies ( P = 0.004). Initiation of therapy for chronic hepatitis C and outcome were not affected by the presence of ANA, LKM, SMA or AMA. Routine testing of these autoantibodies seems not warranted. Determination of autoantibodies should be guided by individualized clinical decisions. [ABSTRACT FROM AUTHOR]

The association between celiac disease and primary biliary cirrhosis is well established. The breakdown of gut-liver axis equilibrium plays a central role in the development of immune disorders involving the small bowel and liver. In celiac disease, immunologically active molecules generated from the cross-linking between tissue transglutaminase and food/bacterial antigens reach the liver through the portal circulation owing to the increased intestinal permeability. A molecular mimicry between bacterial antigens and the pyruvate dehydrogenase E2 component, recognized by antimitochondrial autoantibodies, may have a role in primary biliary cirrhosis pathogenesis. An aberrant intestinal T lymphocyte homing to the liver may contribute to trigger immune hepatic damage. Both celiac disease and primary biliary cirrhosis share several features, including a higher prevalence in females, autoimmune comorbidities and specific autoantibodies. Reciprocal screening for both diseases is recommended, as an early diagnosis with the appropriate treatment can improve the outcome of these patients. [ABSTRACT FROM AUTHOR]

Abstract: Environmental stimulation is a major factor in the initiation and perpetuation of autoimmune diseases. We have addressed this issue and focused on primary biliary cirrhosis (PBC), an autoimmune disease of the liver. Immunologically, PBC is distinguished by immune mediated destruction of the intra hepatic bile ducts and the presence of high titer antimitochondrial autoantibodies (AMA) directed against a highly specific epitope within the lipoic acid binding domain of the pyruvate dehydrogenase E2 subunit (PDC-E2). We submit that the uniqueness of AMA epitope specificity and the conformational changes of the PDC-E2 lipoyl domain during physiological acyl transfer could be the lynchpin to the etiology of PBC and postulate that chemical xenobiotics modification of the lipoyl domain of PDC-E2 is sufficient to break self-tolerance, with subsequent production of AMA in patients with PBC. Indeed, using quantitative structure activity relationship (QSAR) analysis on a peptide-xenobiotic conjugate microarray platform, we have demonstrated that when the lipoyl domain of PDC-E2 was modified with specific synthetic small molecule lipoyl mimics, the ensuing structures displayed highly specific reactivity to PBC sera, at levels often higher than the native PDC-E2 molecule. Hereby, we discuss our recent QSAR analysis data on specific AMA reactivity against a focused panel of lipoic acid mimic in which the lipoyl di-sulfide bond are modified. Furthermore, data on the immunological characterization of antigen and Ig isotype specificities against one such lipoic acid mimic; 6,8-bis(acetylthio)octanoic acid (SAc), when compared with rPDC-E2, strongly support a xenobiotic etiology in PBC. This observation is of particular significance in that approximately one third of patients who have taken excessive acetaminophen (APAP) developed AMA with same specificity as patients with PBC, suggesting that the lipoic domain are a target of APAP electrophilic metabolites such as NAPQI. We submit that in genetically susceptible hosts, electrophilic modification of lipoic acid in PDC-E2 by acetaminophen or similar drugs can facilitate loss of tolerance and lead to the development of PBC. [Copyright &y& Elsevier]

Primary biliary cholangitis (PBC) is a chronic immune-mediated liver disease characterized by a lymphocytic cholangitis, with subsequent cholestasis, progressive liver fibrosis, and ultimately complications arising from end-stage liver disease. Testing for autoantibodies is important in the diagnosis of PBC, as well as stratifying prognosis. This review focuses on the role of autoantibodies in the diagnosis of PBC, as well as the relationship between autoantibodies with pathophysiology and prognostication, along with a discussion regarding novel and other related disease autoantibodies., Competing Interests: Disclosure No relevant disclosures for all authors., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: This study describes the clinical, histological, and genetic profile of AMA-M2 positive liver disease in north India. Methods: Over 13.5 years, 11,221 patients suspected of AiLD (autoimmune liver disease) and negative for viral markers were screened for autoantibodies, ANA, ASMA, AMA, and LKM, by indirect immunofluorescence. Of these patients, 135 were AMA positive and 132 AMA-M2 positive. Clinical presentation of most of these patients was neither typical of AIH nor PBC. Sera of these patients were further tested for gp 210 and Sp 100. Fifty consecutive consenting patients were typed for HLA class II alleles DR and DQ and their clinical, biochemical, histology and genetic profiles were reviewed to characterize the disease spectrum in north India. Results: Only 22 of 50 patients had liver histology reports, and could be categorized on the basis of the criteria by Chazouillers et al. Of these 22, 13 had overlap syndrome, eight had classical PBC, whereas one had probable PBC. The remaining 28 could not be suitably categorized due to lack of liver histology. HLA DRB1*03 was found to be significantly associated with the disease in North Indian population. Conclusion: This 13.5-year study demonstrates a definite rising annual incidence of AMA-M2-positive liver disease in north India. Complete evaluation of 50 patients indicated that a hepatitic variant of PBC (PBC-AIH), which is significantly associated with DRB1*03, predominates in north India. [ABSTRACT FROM AUTHOR]

Primary biliary cirrhosis (PBC) is a chronic inflammatory disease that affects small intrahepatic biliary ducts leading to liver cirrhosis. PBC primarily affects middle-aged women. The most typical symptoms are pruritus and fatigue. PBC is diagnosed on the basis of appearance of antimitochondrial autoantibodies, raised activity of alkaline phosphatase in serum and characteristic histopatologic features of liver biopsy. Treatment with ursodeoxycholic acid is a basic therapy of the disease but in some cases inefficient. Knowledge about genetic and environmental factors that cause PBC should allow to prevent the development of the disease and introduce an effective targeted treatment. [ABSTRACT FROM AUTHOR]

Background: In a recent study we showed that in patients with primary biliary cirrhosis (PBC) being positive or negative for anti-M2 antibodies reacting with the 2-oxoacid-dehydrogenase complex (ODC) also antibodies to the beta- and gamma-subunits of F1F0-ATPase (anti-β, anti-γ) occur. This is a mitochondrial enzyme but parts are also expressed on plasma membranes of endothelial cells. Here we wanted to analyse in more detail their clinical relevance. Methods: Fifty-nine untreated and histologically defined PBC patients who had been followed for at least five years were included into the study (51 anti-M2 positive, 8 anti-M2 negative). Twenty-three of them were treated in the follow up with ursodeoxycholic acid (UDCA), eight received during a trial methotrexate (MTX). In 13 patients orthotopic liver transplantation (OLT) had to be performed. Serum samples before and during therapy were available. Patients were analysed with respect to laboratory parameters, disease activity and histological stages. Patients' sera were tested by ELISA for IgG- and IgM-antibodies against the beta- and gamma-subunits which had been recombinant expressed in E.coli and highly purified by electro-elution from SDS-gels after electrophoresis. Results: Fifty-nine percent of the anti-M2 positive and 50% of the anti-M2 negative PBC patients had anti-β- and/or anti-γ-antibodies. There were no differences between anti-β- and/or anti-γ-antibody positive or negative patients with respect to biochemical parameters, immunoglobulins, histological stages or disease activity. Antibody reactivity significantly decreased during UDCA and MTX-treatment and also after OLT. Conclusions: Antibodies to the β- and γ-subunits of F1F0-ATPase occur in anti-M2 positive and -negative PBC but do not have any relevance with respect to clinical activity or prognosis. However, in contrast to the anti-M2 antibodies they decrease during UDCA and immunosuppressive therapy. [ABSTRACT FROM AUTHOR]

Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease in which an immune-mediated injury targets the small intrahepatic bile ducts. PBC is further characterized by highly specific serum antimitochondrial autoantibodies (AMAs) and autoreactive T cells, a striking female predominance, a strong genetic susceptibility and a plethora of candidate environmental factors to trigger the disease onset. For these reasons, PBC appears ideal to represent the developments of the clonal selection theory over the past decades. First, a sufficiently potent autoimmunogenic stimulus in PBC would require the coexistence of numerous pre-existing conditions (mostly genetic, as recently illustrated by genome-wide association studies and animal models) to perpetuate the destruction of the biliary epithelium by the immune system via the persistence of forbidden clones. Second, the proposed modifications of mitochondrial autoantigens caused by infectious agents and/or xenobiotics well illustrate the possibility that peculiar changes in the antigen structure and flexibility may contribute to tolerance breakdown. Third, the unique apoptotic features shown for cholangiocytes are the ideal setting for the development of mitochondrial autoantigen presentation to the immune system through macrophages and AMA; thus, turning the non-traditional mitochondrial antigen into a traditional one. This article will review the current knowledge on PBC etiology and pathogenesis in light of the clonal selection theory developments. [ABSTRACT FROM AUTHOR]

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

To describe the clinical and immunologic patterns of disease expression of patients with chronic hepatitis C virus (HCV) infection and positive antimitochondrial antibodies (AMA). We investigated the presence of AMA in 237 consecutive HCV patients with extrahepatic manifestations from an International Registry. AMA were detected by indirect immunofluorescence in triple rat tissue (liver, stomach and kidney), aceton-fixed criosections and FITC-conjugated rabbit anti-human immunoglobulins. We found positive AMA in 18 (8%) out of 237 HCV patients. All patients were female with a mean age at protocol inclusion of 65.8 years (ranging from 37 to 87 years). Twelve (67%) patients fulfilled classification criteria for systemic autoimmune diseases (SAD), including Sjögren's syndrome ( n = 7), systemic sclerosis ( n = 3) and systemic lupus erythematosus ( n = 2). Fourteen (78%) of the HCV-AMA patients presented at least one of the highly suggestive characteristics of primary biliary cirrhosis (PBC): 9 (50%) had a specific M2 pattern, 6 (33%) had more than twice normal levels of alkaline phosphatase, 5 (28%) had raised IgM levels and 4 (22%) a histological pattern compatible with PBC. Five (28%) patients developed neoplasia after detection of AMA. Seven (39%) patients died, due to neoplasia ( n = 4), cirrhotic complications ( n = 2) and hepatopulmonary syndrome ( n = 1). We describe a subset of HCV patients with positive AMA who presented a broad spectrum of clinical features, including liver, autoimmune and neoplasic manifestations. Two-thirds of these patients presented an associated SAD, mainly Sjögren's syndrome or systemic sclerosis, together with a high frequency of multiple autoantibodies and an increased prevalence of cirrhosis and neoplasia. [ABSTRACT FROM AUTHOR]