AMA-negative Primary Biliary Cholangitis Research Articles

Diagnostic value of anti-hexokinase 1 and anti-kelch-like 12 antibodies in primary biliary cholangitis patients

Abstract Objectives Anti-mitochondrial antibody (AMA) is not always present in patients with primary biliary cholangitis (PBC). We aimed to determine the additional value of anti-hexokinase 1 (anti-HK1) and anti-kelch-like 12 (anti-KLHL12) antibody in PBC and analyzed the biochemical and immunological parameters of 212 subjects, including PBC patients and healthy controls. Methods Serum anti-gp210 and sp100 antibodies were determined by an immunoblotting test (IBT). Enzyme-linked immunosorbent assay (ELISA) was employed to evaluate anti-HK1 and anti-KLHL12. The diagnostic value of anti-HK1 and anti-KLHL12 to PBC was analyzed by constructing a receiver operating characteristic (ROC) curve. Results ROC analyses didn’t show a very good performance of serum anti-HK1 for PBC diagnosis; the AUC was 0.664 with a sensitivity of 53.3 % and a specificity of 79.2 %. Regarding anti-KLHL12, ROC analysis yielded an AUC of 0.626, with a sensitivity of 45.7 % and a specificity of 93.8 %. For AMA-negative PBC patients, the AUC increased to 0.790 for KLHL12, and 0.708 for HK1. AMA combined with anti-HK1 or anti-KLHL12 antibody significantly improved the diagnostic sensitivity of PBC from 82 to about 95 %, respectively. In AMA-negative PBC patients, the sensitivities for anti-HK1 (62.50 %) and anti-KLHL12 (75 %) antibodies were higher than for anti-gp210 (37.5 %) and anti-sp100 antibody (43.75 %). When these four antibodies were combined, the overall sensitivity increased to 87.5 %. Conclusions The determination of anti-HK1 and anti-KLHL12 facilitates the diagnosis of PBC, particularly in AMA-negative patients. Adding anti-HK1 and anti-KLHL12 antibodies to clinical detection enables early diagnosis and timely treatment, potentially improving patient prognosis.

Antimitochondrial antibody-negative primary biliary cirrhosis with secondary Sjogren syndrome: a case report

Introduction and importance: Primary biliary cholangitis (PBC) is a rare immune-mediated liver disease characterized by the destruction of intrahepatic bile ducts and a positive antimitochondrial antibody (AMA), which is considered a serological hallmark for the diagnosis. Rarely, AMA can be absent/nondetectable in a few cases and is referred to as ‘AMA-negative’. Case presentation: The authors present such an uncommon case of AMA-negative PBC in a 39-year-female with Sjogren’s syndrome who presented with fatigue, pruritus, and dry eyes. Clinical discussion: Previously published studies state that approximately only about 5% of patients with PBC are ‘AMA-negative’. For patients negative for AMA, the diagnosis has to be based on typical pathological features of this disease. Once a diagnosis of PBC is established, regardless of whether it is positive or negative for AMAs, ursodeoxycholic acid is a widely accepted treatment. Conclusion: The presence/absence of AMAs is associated with similar clinical, biochemical, and histopathological characteristics in PBC. The identification of AMAs alone should not impact the diagnosis or treatment of PBC.

Prevalence of Primary Biliary Cholangitis in a Cohort of Primary Sjögren's Syndrome Patients.

ObjectiveTo analyze the prevalence and clinical progression of primary biliary cholangitis (PBC) in patients with primary Sjögren's syndrome (pSS) and possible associations between biochemical and immunological features and the development of PBC.MethodsWe retrospectively reviewed a cohort of 115 pSS patients followed up in an outpatient clinic from 1987 to 2020, without a history of liver disease, and looked for the presence of PBC through analysis of several biochemical, immunological, and histologic characteristics.ResultsTwenty patients (17.4%) had chronic cholestatic liver biochemistry. After exclusion of extrahepatic liver disease by abdominal ultrasound, 13 of them were tested for antimitochondrial autoantibodies (AMA) detected by indirect immunofluorescence (IF), of which five tested positive, fulfilling the diagnostic criteria for PBC. Three of the five PBC patients and three of the eight chronic cholestasis AMA-negative patients were further investigated with liver biopsy, which showed features of PBC in all three PBC patients and in one of the chronic cholestasis AMA-negative patients, allowing for the diagnosis of AMA-negative PBC in the latter. The remaining two AMA-negative patients had liver histology compatible with autoimmune hepatitis and unspecific findings, respectively. Overall, six (5.2%) patients with pSS had AMA-positive PBC (n=5) or AMA-negative PBC (n=1). Comparing immunological characteristics between PBC and non-PBC patients, we found that PBC patients had a higher mean maximum erythrocyte sedimentation rate (ESR) during follow-up than patients without PBC. All PBC patients were treated with ursodeoxycholic acid (UDCA) and after treatment with UDCA, only one patient showed biochemical and clinical progression of PBC, with increasing alkaline phosphatase and total bilirubin levels, eventually progressing to cirrhosis.ConclusionsAmong patients with pSS, PBC had an overall prevalence of six of 115 (5.2%). Higher ESR was a feature associated with PBC patients. In our cohort, after initiation of UDCA treatment, PBC showed predominantly slow progress, with only one patient progressing to cirrhosis during follow-up.

Rates of decompensation, hepatocellular carcinoma and mortality in AMA-negative primary biliary cholangitis cirrhosis.

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. 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. 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. 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.

Anti-mitochondrial Antibody-Negative Primary Biliary Cholangitis Is Part of the Same Spectrum of Classical Primary Biliary Cholangitis

Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease in which anti-mitochondrial antibodies (AMA) are the diagnostic hallmark. Whether AMA-negative PBC patients represent a different phenotype of disease is highly debated. The purpose of our study was to compare AMA-positive and AMA-negative PBC patients in a large non-white admixed Brazilian cohort. The Brazilian Cholestasis Study Group multicentre database was reviewed to assess demographics, clinical features and treatment outcomes of Brazilian PBC patients, stratifying data according to AMA status. A total of 464 subjects (95.4% females, mean age 56 ± 5years) with PBC were included. Three hundred and eighty-four (83%) subjects were AMA-positive, whereas 80 (17%) had AMA-negative PBC. Subjects with AMA-negative PBC were significantly younger (52.2 ± 14 vs. 59.6 ± 11years, p = 0.001) and had their first symptom at an earlier age (43.2 ± 13 vs. 49.5 ± 12years, p = 0.005). Frequency of type 2 diabetes was significantly increased in subjects with AMA-negative PBC (22.5% vs. 12.2%, p = 0.03). Lower IgM (272.2 ± 183 vs. 383.2 ± 378mg/dL, p = 0.01) and triglycerides (107.6 ± 59.8 vs.129.3 ± 75.7mg/dL, p = 0.025) and higher bilirubin (3.8 ± 13.5 vs. 1.8 ± 3.4mg/dL, p = 0.02) levels were also observed in this subgroup. Response to ursodeoxycholic acid varied from 40.5 to 63.3% in AMA-positive and 34to62.3% in AMA-negative individuals, according to different response criteria. Outcomes such as development of liver-related complications, death and requirement for liver transplantation were similar in both groups. AMA-negative PBC patients are similar to their AMA-positive counterparts with subtle differences observed in clinical and laboratory features.

Autoimmune liver damage in patients with primary Sjogren's syndrome associated with anticentromeric antibodies

Objective: to determine the frequency, spectrum and severity of liver affection in anti-centromere antibodies (ACA) positive patients with primary Sjogren's syndrome (pSS).Patients and methods. 119 ACA-positive patients with pSS were included in the study, 37 (31%) of them had signs of liver damage, 3 of these patients were excluded from the study (2 had cholelithiasis, 1 had viral hepatitis B). Signs of autoimmune liver damage were found in 34 (28.6%) patients, most of them were seropositive for antimitochondrial antibodies (AMA). The diagnosis of primary biliary cholangitis (PBC) and autoimmune hepatitis (AIH) was established according to the recommendations of the American Association for the Study of Liver Diseases, the Russian Gastroenterological Association and the Russian Society for the Study of the Liver. In 5 (14.7%) patients the cause of cholestasis remained unspecified.Results and discussion. AMA were found in 73.5% of patients, elevated serum IgM levels – in 57.6%. Clinically liver damage in most cases was characterized by an asymptomatic, slowly progressive course without a dramatic increase of symptoms over time. Liver cirrhosis was found in 14.7% of patients. According to clinical, laboratory and morphological manifestations, PBC was diagnosed in 21 patients, 4 of them also had a cross syndrome with AIH. AMA-negative PBC was found in 3 patients and isolated AIH – in 1. In most cases, histological stage I of PBC was detected. During follow-up, median of 7 years (range from 2 to 15 years), in 7 patients with stage I PBC and in 7 AMA-positive patients without functional liver disorders no clinical, laboratory or instrumental progression of liver damage was noted. In this regard, it was suggested that these patients have epitheliitis of the biliary ducts as manifestation of glandular affection in pSS, and not true PBC.Conclusion. Autoimmune liver lesions are detected in 28.6% of ACA-positive patients with pSS, most (41.2%) of them develop epitheliitis of the biliary ducts as pSS manifestation or a combination of pSS with PBC (with the same frequency), less often PBC / AIH cross syndrome is diagnosed. PBC / pSS-related epitheliitis of the biliary ducts in ACA-positive patients is characterized by a slowly progressive asymptomatic course in most cases and rarely leads to the development of liver cirrhosis.

Promyelocytic Leukemia Antigen Expression: a Histological Marker for Primary Biliary Cholangitis Diagnosis?

Background and ObjectivesDistinguishing primary biliary cholangitis (PBC) from other cholestatic diseases at the histological level could be assisted by new methods, such as immunohistochemical staining of specific antigens.MethodsWe evaluated whether the detection of promyelocytic leukemia protein (PML) can serve as a specific and sensitive marker for PBC diagnosis. Liver biopsies from 26 PBC patients, 20 primary sclerosing cholangitis (PSC), 37 viral hepatitis, 11 non-alcoholic steatohepatitis (NASH) and 5 normal patients were investigated after immunostaining with the anti-PML monoclonal PG-M3, IgG1 antibody.ResultsImmunoreactivity in bile ducts was expressed by the PML-score (quotient of positive ducts to the total number of portal tracts multiplied by 2). PML-score was higher in PBC as compared to controls (P < 0.001). Using a cutoff of 0.18, PML-score proved highly sensitive (84.6%) and specific (89.7%) for confirming PBC as compared to only 5% of PSC, 9.1% of NASH and 13.5% of viral hepatitis patients (P < 0.001). Irrespective of the underlying disease, patients with PML-score > 0.18 were older (P = 0.007), more often females (P < 0.001) with higher ALP (P < 0.001), γ-GT (P = 0.001) and IgM (P < 0.001) compared to the patients with PML-score < 0.18.ConclusionsWe postulate that a simple PML immunohistochemical test could be sufficient for histopathological discrimination of PBC in problematic cases of undefined cholestatic disorders, including small-duct PSC and AMA-negative PBC cases.

A woman with anti-mitochondrial antibody-negative primary biliary cholangitis for a long-term intermittent elevated hepatic enzymes: a case report

: Primary biliary cholangitis (PBC) is a chronic progressive cholestatic liver and autoimmune disease. It characterizes the anti-mitochondrial antibody (AMA) positive and detectable in nearly all patients, acting as a major diagnostic and etiological marker. Here, we reported a patient who was diagnosed with PBC while her AMA was negative. It was a rare subtype of PBC with specific characteristics. This patient suffered long-term elevated hepatic enzyme and cirrhosis while without any other hepatic damage symptoms. Strangely, none of the classic serum markers of cirrhotic etiology was positive, including the hepatic virus antigen, AMA, anti-liver/kidney microsome (LKM) antibody, ceruloplasmin. Whereas some systemic immune parameters like erythrocyte sedimentation rate (ESR) and antinuclear antibody (ANA) appeared unnormal. Moreover, the result of hepatic histology appeared representative PBC. All in all, her test results were unusual and prone to misdiagnosed. After considering all these results carefully and completely. The patient was confirmed diagnosed with AMA negative PBC. With the therapy of ursodeoxycholic acid and polyene phosphatidylcholine, the liver function profile has been increasingly improved. It reminded us in spite that AMA played an important role in PBC diagnose, we should pay attention to the AMA-negative, which usually acts as a puzzle and complicated case prone to misdiagnosis. Besides, we also reviewed the studies till date which containing etiology, characteries and prognosis of AMA-negative PBC, in order to learn more about this novel subtype.

S3525 Primary Biliary Cholangitis: A Not so Primary Suspect

INTRODUCTION: Primary biliary cholangitis (PBC) is an increasingly prevalent autoimmune (AI) chronic cholestatic disease with specific bile duct pathology. The anti-mitochondrial antibody (AMA) is found in 95% of cases and is highly specific for PBC. It is most commonly seen in females (90–95%), Caucasians, and age of diagnosis usually ranges from 30 to 65 years old. The most common symptoms include fatigue and pruritus. We present a case of an adult African male presenting with jaundice who was AMA negative and found to have PBC. CASE DESCRIPTION/METHODS: A 60-year-old African male with a past medical history of diabetes mellitus, hypertension and sickle cell trait presented with jaundice, fatigue, diffuse itching, and a 14 lb unintentional weight loss over 6 months. He had no risk factors for viral hepatitis, did not consume alcohol, and had no personal or family history of AI disorders. Physical exam was notable for scleral icterus and excoriations on extremities. Labs revealed a total bilirubin of 10.1 mg/dL, alkaline phosphatase 840 IU/L, AST/ALT 78/54 IU/L, INR 1.2 and normal iron studies. Viral hepatitis panel was negative for hepatitis A, B and C with negative AMA, ANA, and anti actin antibody. A MRCP revealed early cirrhosis vs. hepatitis, mild ascites and suboptimal visualization of the pancreatic duct but no evidence of biliary duct dilatation. EGD and colonoscopy findings were normal. EUS was done in which a prominent pancreatic head was seen; biopsies were negative. An ERCP revealing ductopenia and small intrahepatic ducts. A liver biopsy revealed pericholangitis and bridging fibrosis consistent with PBC. He was started on ursodeoxycholic acid. One month later he was seen in clinic with resolution of fatigue and pruritus. Labs revealed a total bilirubin of 5 mg/dL down from 10 mg/dL and an alkaline phosphatase of 470 IU/L down from 840 IU/L with AST/ALT 85/38 IU/L. DISCUSSION: Although PBC is commonly diagnosed in women and AMA is positive 95% of time, this case identifies an African male with negative AMA found to have PBC based on liver histology. It is important to note there have been increased cases of males diagnosed with PBC. It is unclear how many of these males are AMA negative. AMA-negative PBC has been shown to have greater bile duct damage and loss compared with AMA-positive PBC. However whether there are differences in clinical outcomes has not been determined and more studies are needed.

Autoimmune liver diseases

Autoimmune liver diseases comprise aspectrum of progredient idiopathic inflammatory diseases. Typical histological features of autoimmune hepatitis (AIH) include the pattern of chronic hepatitis with predominant plasma cell-rich interface activity, rosetting of hepatocytes, and emperipolesis. Florid bile duct lesions are the key feature of primary biliary cholangitis (PBC); onion-like periductal fibrosis characterizes the primary sclerosing cholangitis (PSC). Variants of AIH, or overlap syndromes, show intersecting histomorphologic findings with PBC or PSC. The diagnosis of the different autoimmune inflammatory liver diseases is based on clinical presentation, a hepatitic or cholestatic pattern of liver enzymes, immuno-serological findings, image analysis in PSC, and liver biopsy as afacultative or obligatory adjunct. Liver biopsy plays amajor role in the diagnosis of AIH, small-duct PSC, AMA-negative PBC, IgG4-related diseases, overlap syndrome, and in the recognition of concurrent liver diseases, especially drug-induced liver diseases. Herewith pathologists can help clinicians find adequate therapy for different autoimmune inflammatory liver diseases.

Implication of Increased Serum IL-31 for Primary Biliary Cholangitis

ABSTRACT Interleukin-31 (IL-31) has diverse biological functions. Increased IL-31 has been found in some skin and autoimmune diseases. There has been no study reporting the association between IL-31 and primary biliary cholangitis (PBC). This study was designed to determine serum IL-31 level and to explore its diagnostic value for PBC as well as the association of IL-31 with inflammatory and fibrotic progression. 60 PBC patients, 32 age- and sex-matched patients with chronic hepatitis B (CHB) and 30 age- and sex-matched healthy controls (HC) were recruited. The sera were detected for IL-31, IL-4, interferon gamma (IFN-γ), IL-17 and other laboratory indicators. Serum IL-31 levels were significantly higher in PBC patients (median, IQR, 20.6, 16.7–26.2, pg/ml) than CHB patients (median, IQR, 11.3, 8.0–13.0, pg/ml) and HC (median, IQR, 11.0, 10.0–12.2 pg/ml) (P < .001). Serum IL-31 performed well for identifying PBC, especially for antimitochondrial antibodies (AMA)-negative PBC with AUC of 0.900, optimal cutoff value of 13.6 pg/ml, sensitivity of 87.5% and specificity of 83.9%. Serum IL-31 was positively correlated with platelet count (r = 0.368, P = .004), but negatively with FIB4 (r = −0.307, P = .017) and histological stages (r = −0.364, P = .004) in PBC patients. It was also significantly correlated with IFN-γ (r = 0.404, P = .001) and IL-4 (r = 0.291, P = .026), but not with IL-17 (r = 0.151, P = .259) in PBC patients. Serum IL-31 is increased in and may be a useful marker for PBC, in particular, for AMA-negative PBC. Furthermore, it is inversely associated with fibrotic progression of PBC.

Novel Biomarkers for AMA-Negative Primary Biliary Cholangitis

Antimitochondrial antibodies (AMAs) diagnose primary biliary cholangitis (PBC) in about 90% of cases. In their absence, two novel biomarkers —

Evaluation of a novel extended automated particle-based multi-analyte assay for the detection of autoantibodies in the diagnosis of primary biliary cholangitis.

Anti-mitochondrial autoantibodies (AMA) detected by indirect immunofluorescence (IIF) on rodent tissues are the diagnostic marker of primary biliary cholangitis (PBC). However, up to 15% of patients with PBC are AMA-negative by IIF. In the effort to close the serological gap and improve the diagnostic sensitivity of PBC testing, recently, novel autoantibodies specific for PBC, such as kelch-like 12 (KLHL12, KLp epitope) and hexokinase 1 (HK1) have been described. In this study, we evaluated the autoantibody profile in a large cohort of PBC patients and in patients with other liver disease, including anti-HK1 and anti-KLp autoantibodies. Sera of 194 PBC patients (126 AMA-IIF-positive and 68 AMA-IIF-negative) and 138 disease controls were tested for a panel of PBC-specific antibodies (MIT3, sp100, gp210, HK1, KLp) using a new automated particle-based multi-analyte technology (PMAT) assay on the Aptiva instrument (Inova). Selecting a cutoff yielding a specificity of >95% for all the markers, the sensitivity for anti-MIT3, anti-sp100, anti-gp210, anti-HK1 and anti-KLp in the PBC AMA-IIF-negative cohort was 20.6%, 16.2%, 23.5%, 22.0%, 17.6 and 13.2%, respectively. Six out of the 68 (8.8%) AMA-IIF negative sera were positive for anti-HK1 or anti-KLp alone. Using these new markers in addition to anti-MIT3, anti-sp100 and anti-gp210, the overall sensitivity in this cohort of AMA-IIF-negative patients increased from 53% to 61.8%, reducing the serological gap in AMA-negative PBC patients. PBC antibody profiling, made possible by the new Aptiva-PMAT technology, allows recognition of a higher number of AMA-negative PBC patients than conventional immunoassays and may represent a useful tool to evaluate the prognostic significance of autoantibody association in PBC patients.

Enhanced expression of miR-21 and miR-150 is a feature of anti-mitochondrial antibody-negative primary biliary cholangitis

Background & AimsAnti-mitochondrial-autoantibodies (AMA) remain a hallmark of Primary Biliary Cholangitis (PBC) however approximately 10% of patients test negative for these antibodies. They do not differ in terms of biochemistry or clinical presentation from AMA positive ones. Epigenetics play a key role in immune signalling. Two microRNAs (miRs), namely, miR-21 and miR-150 are known to be involved in liver inflammation and fibrosis. The expression of those two microRNAs and their downstream targets were analyze in the context of AMA-status and the stage of liver fibrosis.MethodsThe relative levels of miR-21 and miR-150 and their target genes: cMyb, RAS-guanyl-releasing protein-1(RASGRP1), and DNA-methyltransferase-1(DNMT1) were determined by Real-Time PCR in serum, liver tissue and peripheral blood mononuclear cells (PBMCs) of patients with PBC.ResultsSerum expressions of miR-21 and miR-150 were significantly enhanced in AMA-negative patients, and they inversely correlated with disease-specific AMA titers in PBS patients. In PBMCs, an increased expression of miR-21 correlated with decreased levels of RASGRP1 and DNMT1 mRNAs whereas, the level of miR-150 remained comparable to controls; and cMyb mRNA was downregulated. In cirrhotic livers, the level of miR-21 was unchanged while miR-150 expression was increased.ConclusionThis study convincingly report, that AMA-negative PBC is characterized by notable alternations of miR-21 and miR-150 and their downstream targets compared to AMA-positive patients underlining their possible importance in the induction of the disease and its progression to fibrosis.

Detection of anti-kelch-like 12 and anti-hexokinase 1 antibodies in primary biliary cholangitis patients in China.

primary biliary cholangitis (PBC) is a chronic cholestatic disease, characterized by positive anti-mitochondrial autoantibodies (AMA) in 90-95 % patients. Anti-kelch-like 12 (anti-KLHL12) and anti-hexokinase1 (anti-HK1) antibodies have been identified as the two new serum markers in recent years, which are used in the diagnosis of AMA-negative PBC patients. The objective of the study was to examine the performance of these two new biomarkers in China. a total of 192 patients were enrolled and screened for anti-KLHL12 and anti-HK1 antibodies and AMA by ELISA. Receiver operating characteristic (ROC curve) analysis was applied to examine the diagnostic importance of AMA, anti-KLHL12 and anti-HK1 antibodies. Furthermore, correlation analysis between some important biochemical indexes (alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase [ALP], bilirubin, gamma-glutamil transferasa [γ-GT]), staging of pathological changes of the liver and the expression of novel antibodies in PBC patients were also examined. the positivity of the anti-HK1 antibody in AMA-positive PBC patients and AMA-negative patients was 44.7 % and 33.3 %, respectively. The specificity, proportion of positive patients (PPV) and proportion of negative patients (NPV) were 93 %, 89 % and 53 %, respectively. In contrast, the positivity to the anti-KLHL12 antibody in AMA-positive and negative PBC patients was 41.2 % and 22.2 %, respectively. Specificity, PPV and NPV were 98 %, 95 % and 52 %, respectively. The area under the curve (AUC) with anti-HK1 and anti-KLHL12 antibodies were 0.720 and 0.703. With the combination with anti-HK1 and anti-KLHL12 antibodies, the AUC of AMA increased from 0.889 to 0.891, increasing the sensitivity from 0.764 to 0.836. Anti-KLHL12 and anti-HK1-positive patients had higher serum levels of ALP, γ-GT and bilirubin, with statistically significant differences (p < 0.01) compared with anti-KLHL12 or anti-HK1-negative patients. Notably, correlation analysis showed a significant positive correlation between antibody expression and ALP, γ-GT and bilirubin serum levels (r = 0.735, 0.491, 0.466; p < 0.01). anti-HK1 and anti-KLHL12 antibodies have been identified as two significant biomarkers in PBC patients. Furthermore, the presence of these antibodies is likely to correlate with the severity of PBC.

2793 Primary Biliary Cholangitis (PBC): Any Differences Between Males and Females?

INTRODUCTION: PBC (primary biliary cholangitis) is a cholestatic autoimmune liver disease characterized by destruction of small intrahepatic bile ducts. PBC predominantly affects females but has also been reported in males. Characteristics of PBC in males have not been well described. We aimed to determine the incidence, characteristics, and prognosis of male patients with PBC as compared to females. METHODS: We performed a retrospective chart review of all patients with biopsy proven PBC seen at our large tertiary care hospital. We collected data on demographics, clinical and laboratory variables, mortality, and liver transplantation if any. Kaplan-Meier analysis was used to determine time to development of hepatic decompensation in patients with PBC, stratified by gender. RESULTS: We included 290 patients with biopsy-proven PBC, 254 (88%) were females and 36 (12%) were males. Mean age at diagnosis of PBC in males versus females was 50 ± 17 vs 54 ± 12 years, respectively (P = 0.09). Body mass index (P = 0.3) and presence of Diabetes (P = 0.06) were comparable between males and females. Mean alkaline phosphatase was similar between both groups at diagnosis, 334 U/L vs 320 U/L (P = 0.61). At the time of diagnosis, 31% of Males had advanced hepatic fibrosis (F3-F4) as compared to 16% of females (P = 0.09) (Table). AMA negative PBC was noted in 16% of females versus 0% of males. Disease progression was higher in males; portal hypertension developed in 42% of males vs 16% in females (P &lt; 0.001), and decompensated cirrhosis was noted in 33% of males versus 10% of females (P &lt; 0.001). Kaplan Meier time to hepatic decompensation showed increased risk of development of hepatic decompensation in males as compared to females (P &lt; 0.001) (see figure). Bone disease was higher in females (osteopenia 22.5% and 6% osteoporosis) than males (12.5% and 3%, respectively). CONCLUSION: Male patients with PBC may have advanced fibrosis at diagnosis as compared to females. Additionally, male PBC patients seem to have a more aggressive course as they are more likely to develop portal hypertension and hepatic decompensation as compared to female patients with PBC, despite comparable age, and alkaline phosphatase level at the time of diagnosis. Bone disease was more common in the females as compared to males.

Hepatic Langerhans Cell Histiocytosis (LCH) Mimicking Antimitochondrial Antibody (AMA)–Negative Primary Biliary Cholangitis (PBC), Presenting as a Harbinger of Multisystem LCH

Abstract Objectives LCH is a rare systemic disorder characterized by an infiltration of CD1a+/Langerin+ histiocytes. LCH commonly involves bone, skin, and lymph nodes in children. Hepatic involvement is rarely observed in multisystem LCH. We describe an exceptional case of hepatic LCH in an adult, mimicking AMA-negative PBC, preceding the diagnosis of multisystem LCH. Methods A 65-year-old man presented with intermittent pruritus, weakness, dyspnea, fever, and chills that have been progressive for 4 years. Physical examination was unremarkable. Laboratory work revealed elevated alkaline phosphatase (471 U/L; ref 40-120 U/L), GGT (271 U/L; ref 0-41 U/L), total bilirubin (2.0 mg/dL; ref 0.0-1.2 mg/dL), and direct bilirubin (1.1 mg/dL; ref 0.0-0.3 mg/dL). Indirect bilirubin, AST, and ALT were within normal limits. Liver biopsy was performed. Results Liver biopsy showed lobular and portal nonnecrotizing granulomas with one “florid duct lesion” with duct injury, suggestive of PBC. Tests for autoimmune diseases including AMA were negative. ERCP was negative for biliary obstruction. One month after the liver biopsy, he developed flaking, red, and burning rash on the right scalp, forehead, and epigastric skin. A skin biopsy at an outside institution revealed dermal and epidermal infiltration of CD1a-positive histiocytes with indented nuclei and pale eosinophilic cytoplasm, consistent with LCH. Subsequent reexamination of the liver biopsy showed that the histiocytes within the florid duct lesion were positive for CD1a and S-100, while the remaining granulomas were negative. The following day, a small focus of LCH was noted in his gastric biopsy performed for gastritis symptoms. Conclusion Hepatic LCH may mimic AMA-negative PBC histologically and clinically, and may present as a harbinger of multisystem LCH. While rendering the diagnosis would be challenging without prior history of LCH and with focal involvement, awareness of such presentation and communication with clinical colleagues may be helpful.

Is autoimmune cholangitis-anti-mitochondrial antibody-negative primary biliary cholangitis still an independent disease?

Autoimmune cholangitis (AIC) was first reported in 1987 as a chronic cholestatic disease that occurs predominantly in middle-aged women and has a common clinical manifestations, biochemical abnormalities and pathological changes with primary biliary cholangitis (PBC). However, serum anti-mitochondrial antibodies (AMA) are negative, and ANA and/or smooth muscle antibody positive rates are higher. The treatment response and prognosis with ursodeoxycholic acid and steroids is poor, thus it needs to be treated with immunosuppressive agents. Presently, the exact pathological mechanism of AIC is still unclear, and there is no unified assertion that classifies it as a new autoimmune liver disease or AMA-negative PBC. This article reviews the worldwide published work on AIC and compares them with PBC.

Implication of increased serum stromal cell-derived factor-1 for primary biliary cholangitis

BackgroundStromal cell-derived factor-1 (SDF-1), also called chemokine (C-X-C motif) ligand 12 (CXCL12), as a chemokine for premature B cells, T cells and monocytes, is detected in liver, pancreas, spleen and heart. However, its diagnostic value for primary biliary cholangitis (PBC) as well as the association of SDF-1 with inflammatory and fibrotic progression is unclear. The aim of this study was to determine serum stromal cell-derived factor-1 (SDF-1) level and to explore its diagnostic value for primary biliary cholangitis (PBC) as well as the association of SDF-1 with inflammatory and fibrotic progression of PBC. MethodsA total of 60 PBC patients who received liver biopsy, 32 age- and sex-matched patients with chronic hepatitis B (CHB) and 30 age- and sex-matched healthy controls (HC) were recruited. The sera were measured for SDF-1, interleukin-4 (IL-4), interferon gamma (IFN-γ) and IL-17 using multiplex immunoassay. PBC was divided into four histologic stages according to Scheuer's classification. ResultsThe results showed significantly higher median level of serum SDF-1 (median, interquartile (IQR), 1186.96, 1002.05–1471.33 pg/mL) in PBC patients than those with CHB (median, IQR, 740.69,600.30–1239.27 pg/mL) and HC (median, IQR, 738.44, 687.65–879.33 pg/mL) (P < 0.001). There was no significant difference between CHB patients and HC (P = 0.526). The receiver operating characteristic curves (ROC) showed good diagnostic performance of serum SDF-1 for PBC, AMA-positive and -negative PBC. In particular for AMA-negative PBC, the area under ROC was 0.817, with optimal cutoff value of 802.64 pg/mL and the sensitivity of 100%. Serum SDF-1 level was not associated with other immune, inflammatory and fibrotic indicators, including AMA, ANA, anti-gp210, sp100 and centromere antibodies, bilirubin, ALT, AST, ALP, GGT, WBC, neutrophil, lymphocyte, platelet, Neutrophil- (NLR) and platelet-lymphocyte (PLR), AST to ALT ratio, AST to platelet ratio index (APRI) and FIB-4 index (P > 0.05). Also, there was no significant difference for serum SDF-1 among histological stages (P = 0.091). However, Serum SDF-1 level was significantly correlated with serum IL-17 (r = 0.373, P = 0.004), but not with IL-4 (r = 0.110, P = 0.407) and IFN-γ (r = 0.215, P = 0.098) in those with PBC. ConclusionSerum SDF-1 is increased in and may be a potential useful marker for PBC. Moreover, it may be associated with Th17 recruitment and differentiation in PBC. However, serum SDF-1 may not be associated with the progression of PBC.

Exploring pathogenesis of primary biliary cholangitis by proteomics: A pilot study.

AIMTo explore the pathogenesis of primary biliary cholangitis (PBC) by identifying candidate autoantibodies in serum samples by proteomics and bioinformatics.METHODSNine antimitochondrial antibody (AMA)-positive PBC patients and nine age- and sex-matched AMA-negative PBC patients were recruited. Antigen enrichment technology was applied to capture autoantigens of human intrahepatic biliary epithelial cells (HiBECs) that are recognized by autoantibodies from the sera of PBC patients. Candidate autoantigens were identified by label-free mass spectrometry. Bioinformatics analysis with MaxQuant software (version 1.5.2.8), DAVID platform, and Cytoscape v.3.0 allowed illustration of pathways potentially involved in the pathogenesis of PBC.RESULTSIn total, 1081 candidate autoantigen proteins were identified from the PBC patient pool. Among them, 371 were determined to be significantly differentially expressed between AMA-positive and -negative PBC patients (P < 0.05). Fisher’s exact test was performed for enrichment analysis of Gene Ontology protein annotations (biological processes, cellular components, and molecular functions) and the Kyoto Encyclopedia of Genes and Genomes pathways. Significantly different protein categories were revealed between AMA-positive and -negative PBC patients. As expected, autoantigens related to mitochondria were highly enriched in AMA-positive PBC patients. However, lower levels of AMA were also detected in AMA-negative PBC patients. In addition, autoantigens of AMA-negative PBC patients were mainly involved in B-cell activation, recognition of phagocytosis, and complement activation.CONCLUSIONAMA-negative PBC individuals may not exist, but rather, those patients exhibit pathogenesis pathways different from those of AMA-positive PBC. Comprehensive research is needed to confirm these observations.