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Background & Aims: Calprotectin reflects neutrophil activation and is increased in various inflammatory conditions including severe COVID-19. However, serial serum calprotectin measurements in COVID-19 patients are limited. We assessed prospectively, calprotectin levels as biomarker of severity/outcome of the disease and a COVID-19 monitoring parameter in a large cohort of consecutive COVID-19 patients., Methods: Calprotectin serum levels were measured in 736 patients (58.2 % males; median age 63-years; moderate disease, n = 292; severe, n = 444, intubated and/or died, n = 50). Patients were treated with combined immunotherapies according to our published local algorithm. The endpoint was the composite event of intubation due to severe respiratory failure (SRF)/COVID-19-related mortality., Results: Median (interquartile range) calprotectin levels were significantly higher in patients with severe disease [7(8.2) vs. 6.1(8.1)μg/mL, p = 0.015]. Calprotectin on admission was the only independent risk factor for intubation/death (HR=1.473, 95 %CI=1.003-2.165, p = 0.048) even after adjustment for age, sex, body mass index, comorbidities, neutrophils, lymphocytes, neutrophil to lymphocytes ratio, ferritin, and CRP. The area under the curve (AUC, 95 %CI) of calprotectin for prediction of intubation/death was 0.619 (0.531-0.708), with an optimal cut-off at 13 μg/mL (sensitivity: 44 %, specificity: 79 %, positive and negative predictive values: 13 % and 95 %, respectively). For intubated/died patients, paired comparisons from baseline to middle of hospitalization and subsequently to intubation/death showed significant increase of calprotectin (p = 0.009 and p < 0.001, respectively). Calprotectin alteration had the higher predictive ability for intubation/death [AUC (95 %CI):0.803 (0.664-0.943), p < 0.001]., Conclusions: Calprotectin levels on admission and their subsequent dynamic alterations could serve as indicator of COVID-19 severity and predict the occurrence of SRF and mortality., Competing Interests: Declaration of Competing Interest G.L. Norman is an employee of Werfen. All other authors have no relevant financial or non-financial interests to disclose., (Copyright © 2023. Published by Elsevier B.V.)

Background: FibroMeter and FibroMeter vibration-controlled transient elastography (FibroMeter VCTE) were assessed in a Greek cohort of patients with chronic viral hepatitis (CVH) B and C or metabolic dysfunction-associated steatotic liver disease (MASLD) to evaluate their accuracy in predicting advanced liver fibrosis against other well-validated noninvasive markers., Methods: Group 1: n=83 CVH and group 2: n=38 MASLD patients underwent liver biopsy and transient elastography (TE) on the same day as sera collection. FibroMeter scores APRI and FIB-4 were calculated in all 121 patients, while MASLD fibrosis score (MFS) was also calculated in group 2., Results: In CVH, FibroMeter VCTE performed equivalently to TE and better than the other markers in predicting advanced (≥F3) and significant (≥F2) fibrosis (area under the receiver operating characteristic curve [AUC] 0.887, P<0.001 for F3; AUC 0.766 P<0.001 for F2). FibroMeter Virus (cutoff 0.61) had lower sensitivity (20%) but performed equivalently to APRI and FIB-4. In MASLD, all markers but APRI performed equivalently in predicting advanced fibrosis. FibroMeter VCTE >0.2154 had the same sensitivity (100%) and specificity (81%) as TE (cutoff >7.1 kPa). FibroMeter MASLD >0.25 performed equivalently to MFS and FIB4, but with higher specificity (100%). Both FibroMeter and FibroMeter VCTE correlated with liver histology but not with liver enzymes., Conclusions: FibroMeter VCTE predicts accurately advanced fibrosis in CVH and MASLD, irrespectively of transaminase levels. FibroMeter Virus can be applied only as an alternative marker in CVH, while FibroMeter MASLD performs equally to TE and calculated scores (MFS, FIB-4) in predicting advanced fibrosis in MASLD patients., Competing Interests: Conflict of Interest: None, (Copyright: © Hellenic Society of Gastroenterology.)

Background & Aims: 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., Methods: 123 AMA-positive AIH-patients were investigated and compared with 711 age-matched AMA-negative AIH-patients and 69 patients with AIH/PBC variant., Results: 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)., Conclusions: 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., Competing Interests: Declaration of Competing Interest The following authors have no relevant financial or non-financial interests to disclose: N.K. Gatselis, K. Zachou, E.L.R. Cançado, T. Arinaga-Hino, P. Muratori, C. Efe, A. Floreani, A. Takahashi, A. Takaki, B. Terziloli Beretta-Piccoli, B. van Hoek, E. Lytvyak, L. Vilar Guedes, T. Purnak, N. Cazzagon, V. Lygoura, P. Arvaniti, E.I. Rigopoulou, L. Muratori, G.N. Dalekos. A.J. Montano Loza has received funding from the University of Alberta Hospital Foundation (UHF) and the Canadian Liver Foundation (CLF). P. Invernizzi has received research, and implementation grants by Abbvie, Intercept, Gilead., (Copyright © 2023. Published by Elsevier B.V.)

Background: Primary biliary cholangitis (PBC) has been long associated with impairment of various aspects of health-related quality of life (HRQoL) with substantial differences among populations. This study evaluated for the first-time the HRQoL in Greek PBC patients in conjunction with clinical and laboratory parameters of patients., Methods: We analyzed prospectively collected data regarding the HRQoL by using the PBC-40 and SF-36 questionnaires in 374 Greek PBC patients and 131 age- and sex-matched non-PBC controls., Results: The PBC-40 questionnaire is a reliable tool for HRQoL assessment in Greek PBC patients (Cronbach's α > 0.7 for all domains). Implementation of PBC-40 and SF-36 demonstrated significant impairment of HRQoL in Greek PBC patients compared to controls ( P < 0.001 for all comparisons). Emotional dysfunction, social impairment, and fatigue (100%, 80.5% and 78%, respectively) were amongst those with the highest, while cognitive dysfunction (32%) with the least impact on quality of life. Fatigue was associated with female sex ( P = 0.02), longer disease duration ( P = 0.01), presence of cirrhosis ( P = 0.02) and positivity for PBC-specific ANA ( P < 0.05), while social dysfunction with increased age ( P < 0.001), longer disease duration ( P < 0.001) and presence of cirrhosis ( P = 0.004). Living in urban areas was linked to impaired social function ( P = 0.04), cognition ( P = 0.02), fatigue ( P = 0.04) and increased total PBC-40 score ( P = 0.01)., Conclusions: Implementation of PBC-40 and SF-36 revealed impaired HRQoL in Greek PBC patients with fatigue, social and emotional dysfunction exerting the highest impact. However, total, and individual PBC-40 scores were lower than that reported in studies from Northern/Central Europe and Canada. Deranged HRQoL was associated with severity of liver disease and presence of PBC-specific ANA., Competing Interests: Conflicts of Interest Dalekos GN is the Editor Board Member of the journal. The article was subject to the journal’s standard procedures, with peer review handled independently of this editor and his research groups., (© 2023 Eirini I. Rigopoulou, Marianna Bakarozi, Ioannis Dimas, Konstantinos Galanis, Vasiliki Lygoura, Nikolaos K. Gatselis, Mairi Koulentaki, George N. Dalekos, published by De Gruyter on behalf of Scholar Media Publishing.)

COVID-19 is characterized by a heterogeneous clinical presentation and prognosis. Risk factors contributing to the development of severe disease include old age and the presence of comorbidities. However, the genetic background of the host has also been recognized as an important determinant of disease prognosis. Considering the pivotal role of innate immunity in the control of SARS-CoV-2 infection, we analyzed the possible contribution of several innate immune gene polymorphisms (including TLR2 -rs5743708, TLR4 -rs4986790, TLR4 -rs4986791, CD14 -rs2569190, CARD8 -rs1834481, IL18 -rs2043211, and CD40 -rs1883832) in disease severity and prognosis. A total of 249 individuals were enrolled and further divided into five (5) groups, according to the clinical progression scale provided by the World Health Organization (WHO) (asymptomatic, mild, moderate, severe, and critical). We identified that elderly patients with obesity and/or diabetes mellitus were more susceptible to developing pneumonia and respiratory distress syndrome after SARS-CoV-2 infection, while the IL18 -rs1834481 polymorphism was an independent risk factor for developing pneumonia. Moreover, individuals carrying either the TLR2 -rs5743708 or the TLR4 -rs4986791 polymorphisms exhibited a 3.6- and 2.5-fold increased probability for developing pneumonia and a more severe disease, respectively. Our data support the notion that the host's genetic background can significantly affect COVID-19 clinical phenotype, also suggesting that the IL18 -rs1834481, TLR2 -rs5743708, and TLR4 -rs4986791 polymorphisms may be used as molecular predictors of COVID-19 clinical phenotype.

Hepcidin regulates iron metabolism by inhibiting intestinal iron absorption and iron release from iron stores. In addition to iron overload, inflammatory conditions also up-regulate hepcidin synthesis, which may serve as an antimicrobial defense by reducing iron availability to the invading microbes. The purpose of this study is to test this hypothesis in human patients by determining serum hepcidin concentration by enzyme linked immunosorbent assay (ELISA) in healthy blood donors ( n = 60) and patients hospitalized because of bacteremia ( n = 50), before (day 0) and after seven days (day 7) of appropriate antibiotic treatment. Serum hepcidin was significantly increased in patients with bacteremia, both at day 0 and at day 7, compared to healthy controls. However, there was significant reduction of serum hepcidin after 7-day treatment, in concert with changes in serum C-reactive protein (CRP). The hepcidin changes were similar for both Gram-negative and Gram-positive single infection cases, while CRP was significantly reduced only in the former. In contrast to hepcidin, the levels of serum ferritin in the patients remained high after treatment, irrespective of infection type. These data confirm the stimulation of hepcidin secretion in human subjects upon different types of systemic microbial infection and suggest that hepcidin is a more sensitive and treatment-responsive acute-phase marker than ferritin in bacteremia, which needs to be explored with bigger-sized and better-matched patient cohorts.

Risk stratification of coronavirus disease-19 (COVID-19) patients by simple markers is critical to guide treatment. We studied the predictive value of soluble interleukin-2 receptor (sIL-2R) for the early identification of patients at risk of developing severe clinical outcomes. sIL-2R levels were measured in 197 patients (60.9% males; median age 61 years; moderate disease, n = 65; severe, n = 132, intubated and/or died, n = 42). All patients received combined immunotherapies (anakinra ± corticosteroids ± intravenous immunoglobulin ± tocilizumab) according to our local treatment algorithm. The endpoint was the composite event of intubation due to severe respiratory failure (SRF) or mortality. Median (interquartile range) sIL-2R levels were significantly higher in patients with severe disease, compared with those with moderate disease (6 (6.2) vs. 5.2 (3.4) ng/mL, p = 0.017). sIL-2R was the strongest laboratory predictive factor for intubation/death (hazard ratio 1.749, 95%CI 1.041-2.939, p = 0.035) after adjustment for other known risk factors. Youden's index revealed optimal sIL-2R cut-off for predicting intubation/death at 9 ng/mL (sensitivity: 67%; specificity: 86%; positive and negative predictive value: 57% and 91%, respectively). Delta sIL-2R between the day of event or discharge minus admission date was higher in patients that intubated/died than in those who did not experience an event (2.91 (10.42) vs. 0.44 (2.88) ng/mL; p = 0.08)). sIL-2R on admission and its dynamic changes during follow-up may reflect disease severity and predict the development of SRF and mortality.

Background & Aims: Autoimmune hepatitis (AIH) affects both sexes and all age groups. However, very few studies have focused specifically on the characteristics and outcome of AIH in patients aged 70 y or older., Methods: 25/234 patients with well-established AIH and disease onset at ≥70-y (median: 73-y) were analysed and compared to the rest patients (median: 47 y). Treatment response was assessed in all patients from both groups who were eligible for treatment (n = 202)., Results: Disease presentation was mainly insidious in both groups (19/25, 76% vs. 134/209, 64.1%; P = .313). At diagnosis, older patients had lower alaninoaminotrasferase (101[433] vs. 199[441] IU/L, P < .05) but were more frequently cirrhotic (12/25, 48% vs. 57/209, 27.3%; P = .03). Importantly, similar rates of on-treatment response (16/18, 89% vs. 154/184, 84%; P = .565), corticosteroid withdrawal (10/16, 62.5% vs. 113/154, 73.4%; P = .355) and complete withdrawal of immunosuppression (1/16, 6.3% vs. 40/154, 26%; P = .122) were achieved in both groups. Treatment-related adverse events were evenly observed between groups (6/18, 33% vs. 54/184, 29%; P = .724). In treated patients, the age ≥70 y was only associated with the overall mortality (HR 8.3 [95% CI: 2.1-36.4], P = .003), but not with the liver-related mortality (HR 3.4 [95% CI: 0.4-30.0], P = .268)., Conclusion: AIH should be seriously considered in patients ≥70 y with unexplained impaired liver function tests as the disease is not infrequent in this group and seems to bear an increased risk for advanced disease stage at diagnosis. However, if immunosuppression is started promptly, it seems as safe and effective as in younger patients., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background & Aims: In autoimmune hepatitis (AIH), normal levels of transaminases and IgG define biochemical remission and are considered the best surrogate markers for histological remission. This study assessed whether this also applies to patients with AIH cirrhosis., Methods: In this European multicentric study, we included 125 biopsies from 113 patients with AIH and histologically proven cirrhosis; 105 biopsies from 104 patients with AIH without cirrhosis served as controls. Biochemical parameters were available within 4 weeks of biopsy. AIH activity was graded according to the modified Hepatitis Activity Index (mHAI), with mHAI ≥4/18 considered to indicate risk of disease progression., Results: In total, 47 out of 125 liver biopsies were obtained from patients with AIH cirrhosis and normal ALT levels at time of biopsy. Only 26% (12/47) of those livers showed histological remission (mHAI <4/18), whereas 36% (17/47) showed moderate to high histological activity (mHAI ≥6/18). In patients with noncirrhotic AIH, 88% (46/52 biopsies) of cases with normal ALT levels had histological remission and only 4% (2/52) had an mHAI ≥6/18 ( p <0.001). The addition of IgG to define complete biochemical remission only slightly improved the association with histological remission in the limited number of patients with AIH cirrhosis available for analysis [29% (5/17) of biopsies with mHAI <4/18]. ALT correlated closely with mHAI in AIH without cirrhosis but poorly in AIH with cirrhosis., Conclusions: In contrast to patients with noncirrhotic AIH, in patients with AIH cirrhosis, who are at risk of disease progression, normal ALT levels and potentially also complete biochemical remission are poor surrogate markers of histological remission. Thus, new biomarkers are needed to monitor disease activity and progression in patients with AIH cirrhosis., Lay Summary: Autoimmune hepatitis (AIH) is an inflammatory disease of the liver that usually responds to immunosuppressive therapy. Serum transaminases and IgG levels within the normal ranges define complete biochemical remission and are considered as surrogate markers for histological disease activity. Here, we show that those biochemical markers are not sufficient to indicate low disease activity in patients with AIH and already established cirrhosis. Consequently, until better biomarkers for disease activity are found, only liver biopsy can reliably indicate disease activity in the presence of cirrhosis. Additional investigations, such as measurements of liver stiffness, should be undertaken to monitor non-invasively for disease progression in patients with AIH and established cirrhosis., Competing Interests: The authors have declared no conflicts of interest., (© 2021 The Authors.)

Aims Infection by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) may lead to the development of severe respiratory failure. In hospitalized-patients, prompt interruption of the virus-driven inflammatory process by using combination treatments seems theoretically of outmost importance. Our aim was to investigate the hypothesis of multifaceted management of these patients. Methods A treatment algorithm based on ferritin was applied in 311 patients (67.2% males; median age 63-years; moderate disease, n=101; severe, n=210). Patients with ferritin <500ng/ml received anakinra 2-4mg/kg/day ± corticosteroids (Arm A, n=142) while those with ≥500ng/ml received anakinra 5-8mg/kg/day with corticosteroids and γ-globulins (Arm B, n=169). In case of no improvement a single dose of tocilizumab (8mg/kg; maximum 800mg) was administered with the potential of additional second and/or third pulses. Treatment endpoints were the rate of the development of respiratory failure necessitating intubation and the SARS-CoV-2-related mortality. The proposed algorithm was also validated in matched hospitalized-patients treated with standard-of-care during the same period. Results In overall, intubation and mortality rates were 5.8% and 5.1% (0% in moderate; 8.6% and 7.6% in severe). Low baseline pO 2 /FiO 2 and older age were independent risk factors. Comparators had significantly higher intubation (HR=7.4; 95%CI: 4.1-13.4; p<0.001) and death rates (HR=4.5, 95%CI: 2.1-9.4, p<0.001). Significant adverse events were rare, including severe secondary infections in only 7/311 (2.3%). Conclusions Early administration of personalized combinations of immunomodulatory agents may be life-saving in hospitalized-patients with COVID-19. An immediate intervention (the sooner the better) could be helpful to avoid development of full-blown acute respiratory distress syndrome and improve survival., (Copyright © 2021. Published by Elsevier B.V.)

Introduction and Objectives: We assessed FibroMeter virus (FMvirus) and FibroMeter vibration-controlled transient elastography (FMVCTE) in 134 patients with autoimmune liver diseases [ALD, autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC)], in order to assess new potential non-invasive biomarkers of liver fibrosis in patients with ALD, as similar data are missing., Patients and Methods: The following groups were included: group 1: n = 78 AIH; group 2: n = 56 PBC. FMvirus and FMVCTE were determined in all 134 patients who underwent liver biopsy and TE the same day with sera collection. In addition, APRI and FIB-4 scores were calculated., Results: The AUCs for TE and FMVCTE were significantly better (0.809; p < 0.001 and 0.772; p = 0.001, respectively for AIH and 0.997; p < 0.001 and 1; p < 0.001, for PBC) than the other three markers in predicting ≥ F3 fibrosis irrespective of the biochemical activity. FMVCTE and TE had good diagnostic accuracy (75.6% and 73%, respectively) for predicting severe fibrosis in AIH and performed even better in PBC (94.6% and 96.4%, respectively). The cut-offs of TE and FMVCTE had the best sensitivity and specificity in predicting ≥ F3 fibrosis in both AIH and PBC., Conclusions: FMVCTE seems to detect severe fibrosis equally to TE in patients with ALD but with better specificity. Biochemical disease activity did not seem to affect their diagnostic accuracy in ALD and therefore, could be helpful for the assessment of fibrosis, especially if they are performed sequentially (first TE with the best sensitivity and then FMVCTE with the best specificity)., (Copyright © 2020 Fundación Clínica Médica Sur, A.C. Published by Elsevier España, S.L.U. All rights reserved.)

Background: It was studied if early suPAR-guided anakinra treatment can prevent severe respiratory failure (SRF) of COVID-19., Methods: A total of 130 patients with suPAR ≥6 ng/ml were assigned to subcutaneous anakinra 100 mg once daily for 10 days. Primary outcome was SRF incidence by day 14 defined as any respiratory ratio below 150 mmHg necessitating mechanical or non-invasive ventilation. Main secondary outcomes were 30-day mortality and inflammatory mediators; 28-day WHO-CPS was explored. Propensity-matched standard-of care comparators were studied., Results: 22.3% with anakinra treatment and 59.2% comparators (hazard ratio, 0.30; 95% CI, 0.20-0.46) progressed into SRF; 30-day mortality was 11.5% and 22.3% respectively (hazard ratio 0.49; 95% CI 0.25-0.97). Anakinra was associated with decrease in circulating interleukin (IL)-6, sCD163 and sIL2-R; IL-10/IL-6 ratio on day 7 was inversely associated with SOFA score; patients were allocated to less severe WHO-CPS strata., Conclusions: Early suPAR-guided anakinra decreased SRF and restored the pro-/anti-inflammatory balance., Funding: This study was funded by the Hellenic Institute for the Study of Sepsis, Technomar Shipping Inc, Swedish Orphan Biovitrum, and the Horizon 2020 Framework Programme., Clinical Trial Number: NCT04357366., Competing Interests: EK, SM, NG, EK, MS, GL, AS, DP, SG, OT, VP, KT, MK, VL, MD, IP, KA, DM, AG, AS, TG, KK, TM, IT, KS, LC, SC, NV, CA, SC, MK No competing interests declared, PP honoraria from GILEAD Sciences, Janssen, and MSD, GD Advisor/Lecturer for Abbvie, Bristol-Myers Squibb, Gilead, Novartis, Roche, Amgen, MSD, Janssen, Ipsen and Pfizer, has received Grant support from Bristol-Myers Squib, Gilead, Roche, Janssen, Abbvie and Bayer and was or is currently PI in National & International Protocols sponsored by Abbvie, Bristol-Myers Squibb, Novartis, Gilead, Novo Nordisk, Genkyotex, Regulus Therapeutics Inc, Tiziana Life Sciences, Bayer, Astellas, Ipsen, Pfizer and Roche, GP independent educational grants from Pfizer, MSD, Angelini, and Biorad, HM honoraria, consulting fees and non-financial support from healthcare companies, including Amgen, Angelini, Bayer, Mylan, MSD, Pfizer, and Servier, Jv Senior editor, eLife, JE cofounder, shareholder and CSO of ViroGates A7S, Denmark and is named inventor on patents on suPAR owned by Copenhagen University Hospital Hvidovre, Denmark, MN supported by an ERC Advanced Grant (#833247) and a Spinoza grant of the Netherlands Organization for Scientific Research. He has also received independent educational grants from TTxD, GSK and ViiV HealthCare, EG Reviewing editor, eLife, (© 2021, Kyriazopoulou et al.)

Background: The epidemiology of hepatitis B virus (HBV) infection has changed in recent years as a result of various factors. Our aim was to assess the epidemiological characteristics and the evolution of the HBV infection in a well-defined area of Greece., Method: Prospectively collected data from 1910 consecutive patients (60.8% male, age: 50.1 years) with chronic hepatitis B (CHB) followed from 1999-2016 were analyzed., Results: Of the patients evaluated, 90.6% were of Greek and 8% of Albanian origin. Vertical/intrafamilial transmission during early childhood (56.8%) and traditional practices (17.2%) were the most common infection sources. Several areas with higher rates of CHB were identified. At first evaluation, 68.8% had chronic infection, 21.7% chronic hepatitis, 6.1% cirrhosis and 3.4% hepatocellular carcinoma (HCC). Comparison between 2 periods (1999-2010 and 2011-2016) revealed older age and longer disease duration at first presentation (P<0.001 for both) to be more common during 2011-2016, while patients of foreign nationality doubled during this period. There was a trend towards more advanced disease stage at first assessment during 2011-2016. Patients after 2011 had lower rates of virological and biochemical breakthrough (P<0.001 for both) during treatment with new antivirals. In addition, fewer patients progressed to cirrhosis (P=0.02) and HCC (P=0.04)., Conclusions: CHB continues to be a major health problem in Central Greece, as highlighted by the preservation of high prevalence areas and a tendency towards an increase of chronic liver disease burden longitudinally. Our data highlight the need for scaling-up prevention and treatment strategies, especially in at-risk populations., Competing Interests: Conflict of Interest: None, (Copyright: © 2021 Hellenic Society of Gastroenterology.)

Objective: Interleukin 12 receptor beta 1 (IL-12Rβ1) deficiency is a primary immunodeficiency that exposes affected individuals to an augmented risk of intracellular pathogen-mediated infections. The paradoxical presence of autoimmune manifestations in immune-deficient patients has been recognized, but the basis of this phenomenon is unclear, with the role of frequent infections being a possible trigger to break tolerance. Our study aimed to analyze extensively a profile of autoantibodies in a clinically well-defined case series of patients with IL-12Rβ1 deficiency., Methods: Eight patients with IL-12Rβ1 deficiency referred to Children's Medical Center in Tunis, Tunisia, during 1995-2012 were enrolled in the study. Sixteen age- and gender-matched blood donors served as controls. Serum, liver-related autoantibodies immunoglobulin (Ig)G, IgM, IgA were tested by ELISA and by standard indirect immunofluorescence on Hep-2 cells., Results: We found a significant prevalence of liver autoantibodies in the study group. Regarding primary biliary cholangitis (PBC), two of eight patients were positive for MIT3 autoantibodies, both confirmed by immunofluorescence, and one patient was positive for PBC-specific antinuclear antibodies, sp100. Moreover, two patients had significantly increased gamma-glutamyltransferase levels and one had IgM levels twice the upper limit of normal. Intriguingly two patients were positive for anti-actin antibodies; a typical feature of autoimmune hepatitis type 1, along with a significant increase in IgG levels., Conclusions: This is the first report of a serological analysis in patients with an IL-12Rβ1 deficiency. Despite the difficulty in interpreting the role of the IL-12, the evidence of liver-specific autoantibodies confirms the importance its signal in liver autoimmunity., (© 2019 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.)

Several hepatobiliary disorders have been reported in ulcerative colitis (UC) patients with primary sclerosing cholangitis (PSC) being the most specific. Primary biliary cholangitis (PBC), previously known as primary biliary cirrhosis, rarely occurs in UC. We present two PBC cases of 67 and 71 years who suffered from long-standing UC. Both patients were asymptomatic but they had increased cholestatic enzymes and high titres of antimitochondrial antibodies (AMA)-the laboratory hallmark of PBC. After careful exclusion of other causes of cholestasis by MRI/magnetic resonance cholangiopancreatography (MRCP), virological and microbiological investigations, a diagnosis of PBC associated with UC was established. The patients started ursodeoxycholic acid (13 mg/kg/day) with complete response. During follow-up, both patients remained asymptomatic with normal blood biochemistry. Although PSC is the most common hepatobiliary manifestation among patients with UC, physicians must keep also PBC in mind in those with unexplained cholestasis and repeatedly normal MRCP. In these cases, a reliable AMA testing can help for an accurate diagnosis., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background & Aims: Primary biliary cholangitis (PBC) is a disease with rising prevalence and considerable geographical variation. To describe the prevalence, spatial and time distribution, baseline characteristics, response to treatment, outcome and the validity of GLOBE score in a large cohort of Greek PBC patients as an independent validation of this score has not been done so far., Methods: The last 16years, 482 PBC patients (86.5% females) were evaluated and analysed retrospectively, using a prospectively collected database. Special attention was paid to the assessment of treatment response according to GLOBE score., Results: Age at initial evaluation was 56.3±13.7years. Among 432 Thessaly residents, prevalence was 582/million (non-homogeneous distribution). Nineteen districts showed a prevalence >800/million. Symptomatic disease onset could be identified in 91 patients, with a significant peak during spring (P=0.03). At diagnosis, 43.6% were asymptomatic and 16.2% cirrhotic. Male sex (P=0.02), older age (P<0.001), alcohol consumption (P<0.01) and concomitant liver disease (P<0.001) were negative prognostic factors for cirrhosis. During a median [interquartile range, range] follow-up of 5.1 (7.8, 15.7) years, 62 patients died or underwent liver transplantation. Patients with GLOBE score>0.30 had significantly worse prognosis (P<0.001) with 5-, 10-, and 15-year survival rates of 84%, 50% and 42%., Conclusions: There is increased PBC prevalence in Thessaly with remarkable geographic clustering and seasonal variability. PBC is diagnosed at early stages although males had a more advanced disease. GLOBE score applies perfectly in Greek patients and this will likely help detecting patients that may benefit from new therapies., (Copyright © 2017 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.)