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Chronic immunosuppression is associated with increased and more severe viral infections. However, little is known about the association between immunosuppression and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Our aim was to describe the clinical course of patients with immunosuppressed autoimmune hepatitis (AIH) during coronavirus disease 2019 (COVID-19) infection in Italy. Our study is a case series of patients with AIH treated with immunosuppression, who tested positive for SARS-CoV-2 in March 2020 during the outbreak of COVID-19. Ten patients from seven different hospitals in Italy were diagnosed with COVID-19 during the outbreak of SARS-CoV-2 in March 2020. Seven subjects were female (70%), and age ranged from 27 to 73 years. Before the onset of SARS-CoV-2 infection, all patients were taking immunosuppressive therapy for AIH, and eight of them were on biochemical remission. Two other patients had recent acute onset of their AIH, and consequently started high-dose steroids, as per induction protocol. All patients had a respiratory syndrome and a positive nasal swab for SARS-CoV-2. Five patients developed a computed tomography-confirmed COVID-19 pneumonia. Six subjects received a combination of antiretroviral and antimalarial drugs. In seven patients, the dosage of immunosuppressive medication was changed. Liver enzymes were repeated during SARS-CoV-2 infection in all hospitalized cases; they remained within the normal range in all cases, and improved in the two acute cases treated with high-dose steroids. The clinical outcome was comparable to the reported cases occurring in non-immunosuppressed subjects. Conclusion: Patients under immunosuppressive therapy for AIH developing COVID-19 show a disease course presumptively similar to that reported in the non-immunosuppressed population. These data might aid in medical decisions when dealing with SARS-CoV-2 infection in immunocompromised patients., (© 2020 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of the American Association for the Study of Liver Diseases.)

Background & Aims: Primary sclerosing cholangitis (PSC) has a variable, often progressive, course. Magnetic resonance cholangiography (MRC) is used in the diagnosis of PSC. Magnetic resonance risk scoring systems, called Anali without and with gadolinium, are used to predict disease progression, determined by radiologic factors. We aimed to assess the prognostic value of Anali scores in patients with PSC and validate our findings in a separate cohort., Methods: We performed a retrospective study of patients with large-duct PSC (internal cohort, 119 patients in France; external cohort, 119 patients in Canada, Italy, and the United Kingdom). All the first-available MRC results were reviewed by 2 radiologists and the Anali scores were calculated as follows: Anali without gadolinium = (1× dilatation of intrahepatic bile ducts) + (2× dysmorphy) + (1× portal hypertension); Anali with gadolinium = (1× dysmorphy) + (1× parenchymal enhancement heterogeneity). The primary end point was survival without liver transplantation or cirrhosis decompensation. The prognostic value of Anali scores was assessed by Cox regression modeling., Results: During a total of 549 patient-years for the internal cohort and 497 patient-years for the external cohort, we recorded 2 and 8 liver transplantations, 4 and 3 liver-related deaths, and 26 and 25 cirrhosis decompensations, respectively. In the univariate analysis, factors associated with survival without liver transplantation or cirrhosis decompensation in the internal cohort were as follows: serum levels of bilirubin, aspartate aminotransferase, alanine aminotransferase, γ-glutamyl transferase, alkaline phosphatase, albumin, and Anali scores. Anali scores without and with gadolinium identified patients' survival without liver transplantation or cirrhosis decompensation with a c-statistic of 0.89 (95% CI, 0.84-0.95) and 0.75 (95% CI, 0.64-0.87), respectively. Independent prognostic factors identified by multivariate analysis were Anali scores and bilirubinemia. The prognostic value of Anali scores was confirmed in the external cohort., Conclusions: In internal and external cohorts, we found that Anali scores, determined from MRC, were associated with outcomes of patients with PSC. These scores might be used as prognostic factors., (Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Objectives: Magnetic resonance (MR) risk scores and liver stiffness (LS) have individually been shown to predict clinical outcomes in primary sclerosing cholangitis (PSC). The aim of this study was to assess their complementary prognostic value., Methods: Patients with PSC from 3 European centers with a 3-dimensional MR cholangiography available for central reviewing and a valid LS measurement assessed by vibration-controlled transient elastography by FibroScan performed within a 6-month interval were included in a longitudinal retrospective study. The MR score (Anali) without gadolinium (Gd) was calculated according to the formula: (1 × dilatation of intrahepatic bile ducts) + (2 × dysmorphy) + (1 × portal hypertension). The primary end point was survival without liver transplantation or cirrhosis decompensation. The prognostic values of LS and Anali score without Gd were assessed using Cox proportional hazard models., Results: One hundred sixty-two patients were included. Over a total follow-up of 753 patient-years, 40 patients experienced an adverse outcome (4 liver transplantations, 6 liver-related deaths, and 30 cirrhosis decompensations). LS and Anali score without Gd were significantly correlated (ρ = 0.51, P < 0.001) and were independently associated with the occurrence of an adverse outcome. Optimal prognostic thresholds were 10.5 kPa for LS and 2 for the Anali score without Gd. Hazard ratios (95% confidence interval) were 2.07 (1.06-4.06) and 3.78 (1.67-8.59), respectively. The use in combination of these 2 thresholds allowed us to separate patients into low-, medium-, and high-risk groups for developing adverse outcomes. The 5-year cumulative rates of adverse outcome in these 3 groups were 8%, 16%, and 38% (P < 0.001), respectively., Discussion: The combined use of MRI and vibration-controlled transient elastography permits easy risk stratification of patients with PSC.

Background & Aims: Recently the Amsterdam-Oxford model (AOM) was introduced as a prognostic model to assess the risk of death and/or liver transplantation (LT) in primary sclerosing cholangitis (PSC). We aimed to validate and assess the utility of the AOM., Methods: Clinical and laboratory data were collected from the time of PSC diagnosis until the last visit or time of LT or death. The AOM was calculated at yearly intervals following PSC diagnosis. Discriminatory performance was assessed by calculation of the C-statistic and prediction accuracy by comparing the predicted survival with the observed survival in Kaplan-Meier estimates. A grid search was performed to identify the most discriminatory AOM threshold., Results: A total of 534 patients with PSC and a mean (SD) age of 39.2 (13.1) years were included. The diagnosis was large duct PSC in 466 (87%), PSC with features of autoimmune hepatitis in 52 (10%) and small-duct PSC in 16 (3%). During the median (IQR) follow-up of 7.8 (4.0-12.6) years, 167 patients underwent LT and 65 died. The median LT-free survival was 13.2 (11.8-14.7) years. The C-statistic of the AOM ranged from 0.67 at baseline to 0.75 at 5 years of follow-up. The difference between the predicted and observed survival ranged from -1.6% at 1 year to + 3.9% at 5 years of follow-up. Patients that developed AOM scores >2.0 were at significant risk of LT or death (time-dependent hazard ratio 4.09; 95% CI 2.99-5.61)., Conclusions: In this large cohort of patients with PSC, the AOM showed an adequate discriminative performance and good prediction accuracy at PSC diagnosis and during follow-up. This study further validates the AOM as a valuable risk stratification tool in PSC and extends its utility., Lay Summary: In our study we assessed whether the Amsterdam-Oxford model (AOM) is able to correctly estimate the risk of liver transplantation or death in patients with primary sclerosing cholangitis (PSC). This model uses 7 objective and readily available variables to estimate prognosis for individual patients at the time of PSC diagnosis. The AOM may aid in patient counselling and timing of diagnostic procedures or therapeutic interventions for complications of liver disease. We confirm that the model works well at PSC diagnosis, but also when the AOM is recalculated at different timepoints during follow-up, greatly improving the applicability of the model in clinical practice and for individual patients., (Copyright © 2019 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Patients with primary sclerosing cholangitis (PSC) tend to develop progressive liver fibrosis and end-stage liver disease within 10-20 years. 1 The International PSC Study Group declared research on surrogate endpoints a high-priority task not least for ongoing clinical trials on novel treatment options. 2 The spleen in patients with PSC often enlarges even before cirrhosis develops. Transient elastography (TE) has been investigated as a dynamic and prognostic marker in PSC. 3,4 However, TE is not generally accessible, measures only a small part of the right liver, and is prone to errors in obese patients, and liver stiffness is related to postprandial status, liver inflammation, and biliary obstruction. 5 We have recently demonstrated that single-point spleen length (SL) measurement has a prognostic performance similar to liver stiffness measured by TE. 3,4,6 SL measurement is a fast, simple, and ubiquitously available method. However, absolute spleen size depends on body height and sex, 7 and single-point measurement of SL cannot be used to assess the effects of therapeutic interventions. To overcome these issues, we assessed the intra-individual development of spleen size over time (delta spleen length: dSL = SL 2 - SL 1 ) to evaluate its role as a novel surrogate marker, which accounts for the dynamic nature of PSC progression., (Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.)

This review shows the images obtained with non-contrast MR lymphography in different pathologic conditions affecting the liver. Non-contrast MR lymphography is obtained with a free-breathing 3D high spatial resolution fast-recovery fast spin-echo sequence similar to that used for 3D MR cholangiopancreatography. The liver is the largest lymph-producing organ generating approximately half of the body's lymphatic fluid and is the most important part of the lymphatic system from a functional point of view. Therefore, understanding the anatomy, physiology, and physiopathology of the lymphatics of the liver is important. However, its anatomy and pathology are relatively unknown because of the absence of commonly used imaging techniques. We describe the anatomy, the physiology, and the pathophysiology of the lymphatic system of the liver and the possibility of identifying dilated lymphatic vessels in various liver diseases and conditions. Disruption of normal lymphatic structure and function is observed in various disease conditions. Liver lymph flow is directly correlated with portal venous pressure. Therefore, a dilatation of liver lymphatics is observed in portal hypertension as well as in increased pressure in hepatic veins. After liver transplantation, ligation of lymphatic vessels at the hilum reduces chylous ascites and results in lymphatic dilatation which is easily observed. In severe long-standing biliary stenosis, dilated lymphatic vessels are commonly demonstrated with non-contrast MR lymphography. In hepatocellular carcinoma, intrahepatic cholangiocarcinoma, and some metastases, lymphatic vessels are abundant in the immediate vicinity of the tumour. These various lymphatic abnormalities can be demonstrated with non-contrast MR lymphography.Key Points • Anatomy and pathology of the lymphatics of the liver are relatively unknown, partly because of lack of current imaging technique. • Non-contrast MR lymphography is obtained with a free-breathing 3D high spatial resolution fast spin-echo sequence similar to that used for 3D MR cholangiopancreatography. • Non-contrast MR lymphography may participate to the understanding of several abnormal liver conditions including portal hypertension, biliary diseases, and malignant hepatic tumours.

Background: The aim of this study was to identify predictive criteria of improvement after endoscopic treatment (ET) for severe strictures of extrahepatic bile ducts in patients with primary sclerosing cholangitis (PSC)., Methods: PSC patients who had at least one ET for severe stricture were included. Features of magnetic resonance cholangiography (MRC), performed before ET, were evaluated according to a standard model of interpretation, and a radiologic qualitative score of probability of improvement after ET was built. Score 3 (likely) was given in case of severe common bile duct (CBD) stricture with marked dilatation without severe strictures of upstream ducts, Score 1 (unlikely) was given in case of severe multiple strictures of secondary ducts without biliary dilatation and Score 2 (undeterminate) was given to an intermediate pattern. The response to ET was assessed at 2 months (T2-response) from the last ET and at 12 months (T12-response) from inclusion., Results: Thirty-one patients were included. All had severe stricture (reduction ≥ 75% of the diameter) of CBD and 50% had severe stricture of right and/or left hepatic duct (LHD) at MRC before ET. According to the qualitative score, 16 patients had Score 3, 7 had Score 1 and 9 had Score 2. T12-response was obtained in 50% of patients. In univariate analysis, short LHD strictures, bilirubin, transaminases, pruritus and Score 3 were associated with T12-response. Increased bilirubin and transaminases were independent predictive factors of T12-response (HR 24, 95% CI: 3.4-170.4, P = 0.001 and 23.8, 95% CI: 3.4-169.4, P = 0.002, respectively)., Conclusion: MRC, together with biochemical features, may contribute to identify the PSC patients who are likely to be improved after ET for severe strictures of extrahepatic bile ducts., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Background: It is still not clear whether primary biliary cholangitis (PBC) is associated with abnormalities of the cardiovascular system. We aimed to assess the relationship between PBC and coronary flow reserve (CFR)., Methods: Our inclusion criterion was a diagnosis of PBC with no clinical evidence of heart disease or metabolic syndrome. Coronary flow velocity in the left anterior descending coronary artery was measured using transthoracic Doppler echocardiography at rest (DFVr), and during adenosine infusion (DFVh). The corrected CFR (cCFR) was defined as the ratio of DFVh to DFVr corrected for cardiac workload (cDFVr). Microvascular resistance was also assessed in baseline (BMR) and hyperemic conditions (HMR)., Results: 37 PBC patients and 37 sex- and age-matched controls were considered. The cCFR was significantly lower in PBC patients (2.8 ± 0.7 vs. 3.7 ± 0.7, p < 0.0001), and abnormal (≤2.5) in 13 (35%) of them, but in none of the controls (p < 0.0001). The cDFVr was higher in patients with abnormal cCFR (29.0 ± 6.0 vs. 20.4 ± 4.5 cm/sec, p < 0.0001). The CFR and cCFR did not correlate with any characteristics of PBC, comorbidities or Framingham risk scores. The BMR and HMR correlated with time since PBC diagnosis and duration of symptoms., Conclusion: The CFR is reduced in PBC, apparently due to mechanisms correlating with the time since diagnosis. In particular, the higher cDFVr with a lower basal resistance in patients with cCFR ≤ 2.5 suggests a compensatory mechanism against any cardiomyocyte bioenergetics impairment., (Copyright © 2018 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Aims: To evaluate the prognostic value of cystic dilatation (CD) of the intrahepatic biliary ducts in patients with primary sclerosing cholangitis (PSC)., Methods: A single-center cohort of 205 patients with PSC from 2003 to 2016 was analysed. CD was defined by quantitative and qualitative criteria. Radiological and clinical courses were assessed. A Kaplan-Meier analysis was used to estimate cumulative survival without liver transplantation (LT) from the date of PSC diagnosis. A log-rank test was performed to compare survival time of PSC patients with and without CD., Results: A total of 15 (7.3%) PSC patients (12 males) with a median age of 23 years at diagnosis had CD. Five patients had one CD; seven patients had two or three CDs; and three patients had diffuse CD. CDs ranged in small diameter size from 12 to 32 mm. Radiological evolution of CD was markedly variable. However, a radiological worsening of PSC over time was observed in all patients. The clinical course was characterized by the occurrence of complications in most patients. Half of the patients with CD underwent LT at a median time of 40 months from diagnosis of CD and the median survival time from PSC diagnosis was significantly lower than in PSC without CD (10.7 vs. 23.4 years; HR 3.8, 95% confidence interval: 1.7-8.3, p = 0.001)., Conclusions: CD in PSC is an unusual condition that mostly affects young patients. It is characterized by a rapid, unfavorable course and constitutes a significant prognostic factor., Key Points: • Cystic dilatation of the intrahepatic biliary ducts affects young patients with primary sclerosing cholangitis and is characterized by a markedly variable radiological evolution. • Biliary wall inflammation, found in explanted livers, could be a key feature in the pathogenesis of cystic dilatation. • Cystic dilatation of the intrahepatic biliary ducts is characterized by an unfavorable course and constitutes a significant prognostic factor of primary sclerosing cholangitis.

The most important autoimmune liver disease include: autoimmune hepatitis, primary biliary cholangitis and primary sclerosing cholangitis. In general, about one in three patients with an autoimmune liver disease have a concomitant extrahepatic autoimmune disease, which may include rheumatological, endocrinological, gastrointestinal, pulmonary or dermatological conditions. The pathogenesis of these conditions includes the production of both innate and adaptive immune responses targeting cholangiocytes as well as different extrahepatic tissues. In this sense, extrahepatic autoimmunity represent a continuous spectrum of autoimmunity involving liver and extrahepatic tissues. This review aims to focus the clinical and pathophysiological aspects of extrahepatic autoimmunity associated to autoimmune liver diseases., (Copyright © 2018 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.)

Patients with Primary Biliary Cholangitis (PBC) exhibit delayed sleep-wake habits, disturbed night sleep and daytime sleepiness/fatigue. Such combination of symptoms is reminiscent of delayed sleep-wake phase disorder (DSPD), which benefits from morning light treatment. The aim of the present pilot study was to test the effect of morning light treatment in a group of 13 well-characterized patients with PBC [all females; (mean ± SD) 53 ± 10 years]. Six healthy individuals (4 females, 57 ± 14 years) and 7 patients with cirrhosis (1 female, 57 ± 12 years) served as controls and diseased controls, respectively. At baseline, all participants underwent an assessment of quality of life, diurnal preference, sleep quality/timing (subjective plus actigraphy), daytime sleepiness, and urinary 6-sulphatoxymelatonin (aMT6s) rhythmicity. Then they underwent a 15-day course of morning bright light treatment, immediately after getting up (light box, 10,000 lux, 45 min) whilst monitoring sleep-wake patterns and aMT6s rhythmicity. At baseline, both patients with PBC and patients with cirrhosis had significantly worse subjective sleep quality compared to controls. In patients with PBC, light treatment resulted in an improvement in subjective sleep quality and a reduction in daytime sleepiness. In addition, both their sleep onset and get-up time were significantly advanced. Finally, the robustness of aMT6s rhythmicity (i.e., strength of the cosinor fit) increased after light administration but post-hoc comparisons were not significant in any of the groups. In conclusion, a brief course of morning bright light treatment had positive effects on subjective sleep quality, daytime sleepiness, and sleep timing in patients with PBC. This unobtrusive, side-effect free, non-pharmacological treatment is worthy of further study.

Autoimmune Hepatitis (AIH) can present under clinical profile as acute hepatitis of unexplained cause. We analyzed clinical, therapeutical and prognostic implications of AIH presenting as acute hepatitis in a cohort of patients admitted to 3 referral Centres in Italy. AIH onset was considered acute when transaminases were higher than 10 times the normal limit and/or bilirubin higher than 5 mg/ml (irrespectively from the histology, available only in 62% of cases). Among 479 patients diagnosed as AIH, 202 (43%) met the criteria of acute onset. This former group of patients on the basis of the histology has been subdivided in the "genuine" acute onset (83 pts) and acute "on chronic" onset (45 pts) At onset, clinical acute AIH showed significantly higher ALT, bilirubin and INR levels (p < 0.001 for all), lower albumin values (p = 0.001), similar IgG levels; Response to treatment was similar between the two groups. The progression to liver cirrhosis or its complications was significantly less frequent in acute onset AIH (13% vs. 22%, p = 0.02). The "genuine" acute patients showed a higher albumin serum levels (40 vs. 36, p = 0.001), lower INR levels (1.12 vs. 1.26, p = 0.002) and less tendency to the progression of liver disease (7% vs. 12%, p = NS) with respect to acute "on chronic" onset patients. Clinical acute hepatitis represents a common presentation of AIH, responds to standard immunosuppression regimen and would seem to be correlated with a better long-term prognosis., (Copyright © 2018 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Patients with PBC have at least 60% of probability to have an autoimmune extrahepatic condition. The pathogenesis of these conditions includes a common mechanism involving both innate and adaptive immune responses targeting cholangiocytes and different extrahepatic tissues. The recent EASL guidelines recommend the management of these conditions, although detailed practical treatments have not been indicated. Autoimmune extrahepatic conditions may include: rheumatologic, endocrine, pulmonary, gastrointestinal, dermatologic diseases. This review aims to focus the most important extrahepatic autoimmune conditions associated to PBC with practical recommendation regarding diagnostic approach and management., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC) are human primary cholangiopathies characterized by the damage of mature cholangiocytes and by the appearance of ductular reaction (DR) as the results of hepatic progenitor cell activation. This study evaluated the differences in progenitor cell niche activation between these two cholangiopathies. Liver tissue was obtained from healthy liver donors (n = 5) and from patients with PSC (n = 20) or PBC (n = 20). DR, progenitor cell phenotype, and signaling pathways were investigated by IHC analysis and immunofluorescence. Our results indicated that DR was more extended, appeared earlier, and had a higher proliferation index in PBC compared with PSC. In PBC, DR was strongly correlated with clinical prognostic scores. A higher percentage of sex determining region Y-box (SOX)9 + and cytokeratin 19 + cells but fewer features of hepatocyte fate characterized progenitor cell activation in PBC versus PSC. Lower levels of laminin and neurogenic locus notch homolog protein 1 but higher expression of wingless-related integration site (WNT) family pathway components characterize progenitor cell niche in PSC compared with PBC. In conclusion, progenitor cell activation differs between PSC and PBC and is characterized by a divergent fate commitment and different signaling pathway predominance. In PBC, DR represents a relevant histologic prognostic marker., (Copyright © 2018 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Objectives: Primary biliary cholangitis (PBC) is often associated with other autoimmune diseases, but little is known about the influence of thyroid disease (TD) on the natural history of PBC. Our aim is to analyze the association between PBC and TD, and the latter's impact on the natural history of PBC at two European centers., Methods: The study involved 921 PBC patients enrolled between 1975 and 2015 in Padova (376 patients) and Barcelona (545 patients), with a mean follow-up of 126.9±91.7 months. Data were recorded on patients' histological stage at diagnosis, biochemical data, associated extrahepatic autoimmune conditions, and clinical events, including hepatic decompensation., Results: A total of 150 patients (16.3%) had TD, including 94 patients (10.2%) with Hashimoto's thyroiditis; 15 (1.6%) with Graves' disease; 22 (2.4%) with multinodular goiter; 7 (0.8%) with thyroid cancer; and 12 (1.3%) with other thyroid conditions. The prevalence of different types of TD was similar in Padova and Barcelona, except for Graves' disease and thyroid cancer, which were more frequent in the Padova cohort (15.7 vs. 5.0%, and 8.6 vs. 1.3%, respectively, P<0.05). Overall, there were no differences between PBC patients with and without TD in terms of their histological stage at diagnosis, hepatic decompensation events, occurrence of HCC, or liver transplantation rate. The presence of associated TD was not associated with lower survival for PBC patients in either cohort., Conclusions: TDs, and autoimmune TD like Hashimoto's thyroiditis in particular, are often associated with PBC, but the presence of TD does not influence the rate of hepatic complications or the natural history of PBC.

Background: Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease with a strong association with inflammatory bowel disease (IBD). Medical treatment for PSC is still disappointing, whereas immunomodulators and biologics have been proven to be effective in IBD., Aims: This study aimed to analyze (i) the natural history of patients with PSC with or without IBD and (ii) the long-term efficacy of biologics in patients with PSC and concomitant IBD or rheumatological disorders., Patients and Methods: This study included 92 consecutive PSC patients, 50 (54.3%) men and 42 (45.7%) women, with a mean age of 32.0±14.3 years at diagnosis and a mean follow-up duration of 103.8±86 months. Forty-nine (53.3%) patients had associated IBD (38 ulcerative colitis, 10 Crohn's disease, one indeterminate colitis)., Results: No significant differences were found between PSC patients with and without associated IBD in terms of liver transplantation, cancer, and death rates. Cholangiocarcinoma was only identified among patients with PSC alone, whereas other cancers (hepatocellular carcinoma, colorectal, and gallbladder cancer) were found only in the group with associated IBD. Five PSC patients were treated with biologic agents: three with adalimumab and one with infliximab for IBD or for rheumatoid arthritis, and one patient with rituximab for rheumatoid arthritis. Adalimumab decreased alkaline phosphatase in two of three patients after 6 and 12 months, infliximab reduced γ-glutamyltransferase after 6 and 12 months, but liver function tests tended to deteriorate thereafter. Cholangiography changes remained stable in all patients., Conclusion: Biologic agents may improve liver function tests in PSC patients, but may be associated with adverse events including deterioration of liver function.

Primary biliary cholangitis (PBC), previously known as primary biliary cirrhosis, is a model autoimmune disease with chronic cholestasis characterized by the hallmark of anti-mitochondrial antibodies and treated with ursodeoxycholic acid (UDCA). However, approximately 20-40% of patients incompletely respond to UDCA and have an increased risk of disease progression. Although there have been significant advances in the immunobiology of PBC, these have yet to be translated into newer therapeutic modalities. Current approaches to controlling the immune response include broad immunosuppression with corticosteroids as well as targeted therapies directed against T and B cells. In contrast, ameliorating cholestasis is the focus of other therapies in development, including obeticholic acid. In this article the authors will discuss ongoing clinical trials and, in particular, the rationale for choosing agents that may effectively target the aberrant immune response.

A very critical feature in women's health is the identification of risk factors for pregnancy and adverse fetal outcome. Primary biliary cirrhosis is an autoimmune disease of the liver that predominantly affects older women. However, the serologic onset of this disease appears to precede clinical manifestations by many years. The goal of this case controlled study was to analyze fertility in primary biliary cirrhosis (PBC) and investigate the outcome of pregnancy, and the influence of pregnancy on the course of the disease. The study included 233 consecutive female patients with PBC seen between 1987 and 2012. Among them, 186 had at least one conception and were matched for age with a 1:2 group of controls (367 healthy women with at least one conception in their life). PBC patients experienced 507 pregnancies as opposed to 700 pregnancies among controls (mean 1.91 vs 2.73, p < 0.05). The two groups' life history was similar in terms of miscarriages, voluntary interruptions of pregnancy, and term and preterm deliveries. The rates for one or more cesarean deliveries were lower for PBC patients (5.7 vs 11.7 %, p < 0.05). Pruritus during pregnancy was recorded in 15 pregnancies involving 13 PBC patients (3.0 %) and none of the controls. Perinatal and postnatal deaths and complications at childbirth were only recorded in the PBC patients, involving a total of 11 babies (2.7 %, p < 0.05). Eight pregnancies occurred after PBC was diagnosed in six patients, all of which had a favorable course at term, with no complications at childbirth. Ursodeoxycholic acid was continued during pregnancy and no exacerbation of the disease was observed. In conclusion, successful completion of pregnancy is a realistic expectation for PBC patients, though pregnancy and delivery must be monitored for the potentially higher than normal risk of childbirth complications.

Primary biliary cirrhosis (PBC) is a rare inflammatory liver disease for which ursodeoxycholic acid (UDCA) is the only therapy approved by the U.S. Food and Drug Administration. Patients with a biochemical response to UDCA therapy have a similar survival rate compared to the general population. However, up to 40% of PBC patients do not achieve a complete response to UDCA, have an increased risk of liver-related death and liver transplantation, and represent a persistent medical need for new therapies. Several novel drugs have recently been studied and show potential efficacy in PBC. Obeticholic acid, a farnesoid X receptor agonist, has been tested in phase II trials and initial results after 1 year in a phase III international trial suggest that it may be effective in achieving a biochemical response in approximately 40% of patients who do not completely respond to UDCA. Several small studies on fibrates have suggested that they may have efficacy, but larger studies are needed. Surprisingly, results of immunomodulators and biologics have not yet been able to demonstrate efficacy, but new approaches have shown promise in animal models and their translation to human clinical trials are awaited.

Limited information and divergent results are available on the prevalence/incidence, survival, and risk factors for developing extrahepatic malignancies (EMs) in primary biliary cirrhosis (PBC). The aim of the study was to analyze the epidemiology and survival rates for EM in PBC patients. The study was conducted on two series of patients followed up at two European centers (361 in Padova, Italy, and 397 in Barcelona, Spain) for a mean 7.7 ± 7 and 12.2 ± 7 years, respectively. The cancer incidence was compared with the standardized incidence ratios (SIRs) calculated using the Cancer Registry of the Veneto Region (Italy) and the Cancer Registry of Tarragona (Spain). Seventy-two patients developed EM. The prevalence of cases was similar in Padova (9.7 %) and Barcelona (9.4 %). The overall cancer incidence was similar to the expected incidence for the general population in the same geographical area (SIR = 1.2), and so was the crude EM rate (855.01 vs 652.86 per 100,000 patient-years, respectively, RR = 1.3). Logistic regression analysis showed that advanced histological stage and extrahepatic autoimmune diseases were significantly associated with the onset of EM. Survival was similar for PBC patients with and without EM (p = n.s.), and actual survival was similar to the one predicted by the Mayo model. The incidence of EM in PBC patients was found similar in Italy and Spain and no different from that of the general population. Advanced histological stage and extrahepatic autoimmune disease were risk factors significantly associated with EM developing in PBC. The onset of cancer in PBC patients does not influence the natural history of their liver disease.

There is a paucity of information on extrahepatic autoimmune (EHA) conditions associated with primary biliary cirrhosis (PBC) and on the impact of EHA conditions on PBC patients' survival. Our goal was to assess the association between PBC and other autoimmune diseases and the impact of EHA conditions on the natural history of PBC. We took advantage of 361 consecutive PBC patients enrolled between 1975 and 2012 (22 males, 339 females; mean follow-up 8 ± 6.9 years). Any associated EHA conditions, PBC histological stage at diagnosis, biochemical data, physiological history, and extrahepatic malignancies developing during the follow-up were recorded. Survival was analyzed by means of Kaplan-Meier curves. Importantly, 221 patients (61.2 %) had at least one EHA conditions: 45 patients (20.4 %) had Hashimoto thyroiditis; 7 (3.2 %) had Graves' thyroiditis; 65 (29.4 %) had Raynaud's phenomenon; 124 (56.1 %) had Sjogren's syndrome; 8 (3.6 %) had systemic lupus erythematosus; 22 (9.9 %) had scleroderma; 22 (9.9 %) had rheumatoid arthritis; 18 (8.1 %) had cutaneous autoimmune diseases; 8 (3.6 %) had vasculitis; 5 (1.4 %) had celiac disease; and 25 (13.1 %) had other EHA conditions. The proportion of patients with associated EHA conditions enrolled during representative periods (1975-1980, 1981-1990, 1991-2000, 2001-2010, 2011-2012) remained stable. No differences emerged between patients with versus without EHA conditions in terms of mean age at PBC diagnosis, antimitochondrial antibody (AMA), or antinuclear antibody (ANA) positivity, histological stage at diagnosis, smoking habits, alcohol consumption, or BMI >25. Multiple logistic regression analysis showed that only female gender was significantly associated with positivity for EHA conditions (OR 4.8; 95 % CI 1.6-13.7, p = 0.004). The mean survival after the diagnosis of PBC was much the same in patients with and without EHA conditions. In conclusion, EHA conditions are often associated with PBC, especially in female patients, but they do not reduce patient survival.

Background: The overlap syndrome between primary biliary cirrhosis and primary sclerosing cholangitis is an extremely rare condition that has been reported in only six published cases so far., Methods: Here we report two cases showing the clinical manifestations of both primary biliary cirrhosis and primary sclerosing cholangitis., Results: In one case the overlap condition was associated with psoriatric arthritis, and the patient successfully underwent dual treatment with ursodeoxycholic acid and the anti-tumour necrosis factor-alpha agent adalimumab. In the second case, the predominant condition was, initially, an antimitochondrial antibody-negative primary biliary cirrhosis with progressive course towards end-stage liver disease; the patient then developed either antimitochondrial antibody positivity or changes in the biliary tree compatible with primary sclerosing cholangitis., Conclusions: These two cases add information on a controversial issue in the literature, and indicate the importance of recognizing a possible overlap syndrome to optimize treatment., (Copyright © 2015 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Introduction: Primary biliary cirrhosis (PBC) is characterized by a long natural history and a low incidence of cardiovascular events despite high serum cholesterol levels. The role of any metabolic conditions (obesity, hypertension, diabetes) in association with PBC has not been analyzed, however., Aim: : To assess the influence of metabolic syndrome (MS) on response to ursodeoxycholic acid (UDCA) and the survival in PBC patients., Methods: The historical database (1975 to 2011) comprising consecutively enrolled PBC patients with a mean follow-up of 123 months (range, 12 to 425 mo) was used. All patients were treated with UDCA (15 mg/kg/d). Responders to UDCA were defined as patients achieving at least a 40% drop in their alkaline phosphatase levels after 1 year. MS was defined according to the American Heart Association criteria. Survival was analyzed by means of Kaplan-Meier curves., Results: A total of 171 PBC patients were eligible for the study; 55 of them (32.1%) fulfilled the criteria for MS at presentation. Liver function tests and Mayo score were found comparable in PBC patients with and without MS. Histologic stages were similar in the 2 groups at the baseline. Significantly more cardiovascular events occurred in patients with MS during the follow-up (P<0.0001). Response to UDCA was greater in the group without MS, but the difference was not statistically significant. The Kaplan-Meier curves were similar in the 2 groups., Conclusions: When associated with MS, PBC should be monitored carefully due to the risk of cardiovascular events.

Background & Aims: Noninvasive surrogate end points of long-term outcomes of patients with primary biliary cirrhosis (PBC) are needed to monitor disease progression and evaluate potential treatments. We performed a meta-analysis of individual patient data from cohort studies to evaluate whether patients' levels of alkaline phosphatase and bilirubin correlate with their outcomes and can be used as surrogate end points., Methods: We performed a meta-analysis of data from 4845 patients included in 15 North American and European long-term follow-up cohort studies. Levels of alkaline phosphatase and bilirubin were analyzed in different settings and subpopulations at different time points relative to the clinical end point (liver transplantation or death)., Results: Of the 4845 patients, 1118 reached a clinical end point. The median follow-up period was 7.3 years; 77% survived for 10 years after study enrollment. Levels of alkaline phosphatase and bilirubin measured at study enrollment (baseline) and each year for 5 years were strongly associated with clinical outcomes (lower levels were associated with longer transplant-free survival). At 1 year after study enrollment, levels of alkaline phosphatase that were 2.0 times the upper limit of normal (ULN) best predicted patient outcome (C statistic, 0.71) but not significantly better than other thresholds. Of patients with alkaline phosphatase levels ≤ 2.0 times the ULN, 84% survived for 10 years compared with 62% of those with levels >2.0 times the ULN (P < .0001). Absolute levels of alkaline phosphatase 1 year after study enrollment predicted patient outcomes better than percentage change in level. One year after study enrollment, a bilirubin level 1.0 times the ULN best predicted patient transplant-free survival (C statistic, 0.79). Of patients with bilirubin levels ≤ 1.0 times the ULN, 86% survived for 10 years after study enrollment compared with 41% of those with levels >1.0 times the ULN (P < .0001). Combining levels of alkaline phosphatase and bilirubin increased the ability to predict patient survival times. We confirmed the predictive value of alkaline phosphatase and bilirubin levels in multiple subgroups, such as patients who had not received treatment with ursodeoxycholic acid, and at different time points after study enrollment., Conclusions: Levels of alkaline phosphatase and bilirubin can predict outcomes (liver transplantation or death) of patients with PBC and might be used as surrogate end points in therapy trials., (Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background and Aim: The serpin squamous cell carcinoma antigen complexed with IgM (SCCA-IgM) has been reported as a promising serological marker for hepatocellular carcinoma (HCC). We aimed to further evaluate SCCA-IgM diagnostic accuracy and to determine its prognostic role., Methods: SCCA-IgM levels were determined in 327 sera obtained from 81 HCC patients, 206 cirrhotics and 40 healthy blood donors (controls). Sensitivity, specificity, correlation with clinical and tumor parameters and with survival were evaluated., Results: HCC patients had SCCA-IgM levels significantly higher than controls and cirrhotics (P < 0.0001). Sensitivity, specificity, positive and negative predictive values for HCC were 89%, 50%, 41% and 92%, respectively. In comparison, sensitivity and specificity for alphafetoprotein were 48% and 85%. SCCA-IgM levels were not significantly correlated with clinical or biological variables. With a cut-off of 130 AU/mL (receiver operating characteristic curves), SCCA-IgM proved efficient in the prediction of prognosis, identifying the patients with long overall survival (efficiency validated in the homogenous subgroup of patients with intermediate-stage HCC undergoing transarterial chemoembolization) and predicting progression-free survival. A Cox multivariate analysis confirmed SCCA-IgM predictive value, identifying tumor size and SCCA-IgM levels as independent predictors of survival. A reduction in SCCA-IgM levels correlated with response to treatment., Conclusions: SCCA-IgM is a sensitive marker of HCC in patients with cirrhosis even though lacking in specificity. The determination of the levels of the marker in HCC patients is highly efficient in predicting the patients' prognosis, identifying those with long overall and progression-free survival and the responders and should be introduced in the clinical practice., (© 2014 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.)

In this article, the authors use the term "overlaps" to refer to the coexistence of primary biliary cirrhosis (PBC) with another autoimmune condition that involves the liver or extrahepatic organs. Diagnosing PBC-autoimmune hepatitis (PBC-AIH) overlap syndrome remains a challenge, especially because there is still no consensus on the most appropriate diagnostic criteria. The prevalence of this condition varies considerably among series of PBC patients, and its treatment demands a combination of ursodeoxycholic acid and immunosuppressive drugs. Overlap syndrome between PBC and primary sclerosing cholangitis is described in exceptional cases. About one in three PBC patients have a concomitant extrahepatic autoimmune disease, which may include rheumatological, endocrinological, gastrointestinal, pulmonary, or dermatological conditions. Overlaps raise several questions, about whether they share much the same genetic susceptibility, as is generally assumed. The pathogenesis of these conditions includes the production of both innate and adaptive immune responses targeting cholangiocytes as well as different extrahepatic tissues. In this sense, overlaps in PBC represent a continuous spectrum of autoimmunity involving liver and extrahepatic tissues., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Background: Impaired sleep quality and daytime sleepiness have been described in patients with primary biliary cirrhosis (PBC). However, no information is available on their sleep timing/diurnal preference., Aims: To evaluate such variables and determine their relationship with sleep quality, fatigue, pruritus and quality of life., Methods: Seventy-four patients with PBC (58 ± 12 years), 79 healthy volunteers (56 ± 8 years) and 60 patients with cirrhosis (58 ± 12 years) underwent formal assessment of sleep quality/timing, diurnal preference and daytime sleepiness. Patients with PBC also underwent assessment of fatigue, quality of life and the daytime course of sleepiness/pruritus., Results: Sleep timing was significantly delayed in both patients with PBC and with cirrhosis, compared to healthy volunteers (sleep onset time: 23:18 ± 01:00 vs. 23:30 ± 01:00 vs. 22:54 ± 00:54 hours, respectively; P < 0.05). In patients with PBC, delayed sleep timing was associated with impaired sleep quality (P < 0.05). Sleepiness showed a physiological daily rhythm, with early afternoon/evening peaks. Pruritus was absent in the morning and increased over the afternoon/evening hours. Both the daytime course of pruritus and sleepiness changed in relation to diurnal preference. Patients with PBC and significant pruritus (upper quartile) had prolonged sleep latency (39 ± 37 vs. 21 ± 23 min, P = 0.05) and earlier wake-up times (5.9 ± 0.8 vs. 6.7 ± 0.9 min, P < 0.05). Significant correlations were observed between sleep timing and quality of life., Conclusions: Patients with PBC exhibited a delay in sleep timing that was associated with impaired sleep quality/quality of life. In addition, an interplay was observed between diurnal preference and the daytime course of pruritus/sleepiness., (© 2012 John Wiley & Sons A/S.)

Introduction: Hepatocellular carcinoma (HCC) is an established indication for liver transplantation (LT), but the selection criteria and priority are still debated., Aims: To ascertain the number and features of patients with HCC who undergo transplantation in a Western country, the number of patients eligible for LT according to the American Association for the Study of Liver Diseases (AASLD) guidelines, the number of patients who actually undergo transplantation and whether adherence affects survival., Methods: This is a retrospective analysis from a multicentre Italian database of 2042 cases of HCC, recruited prospectively and consecutively. Kaplan-Meier (log rank) and Cox multivariate analysis estimated survival., Results: Patients who had undergone transplantation (50, 2.5%, with no change over time) had a median survival of 133 months, significantly influenced by the number of lesions and alpha-fetoprotein levels, which were found to be independent predictors of survival on multivariate analysis. Milan criteria were fulfilled in 68%, impacting on survival, whereas 48% fulfilled AASLD guidelines, without such an impact. Two hundred and twenty-eight (11%) patients were eligible for LT according to AASLD; in this group, alpha-fetoprotein levels and Child-Pugh class were independent predictors of survival., Conclusion: Among patients with HCC, those undergoing LT represent a small minority; even fewer (1%) are those who undergo transplantation according to AASLD guidelines, adherence to which only marginally affects survival. Overall, LT impact on HCC patients' treatment is very limited.

Therapeutic options in advanced stage hepatocellular carcinoma have been very poor until the discovery of new therapeutic agents that target the molecular pathways involved in hepatocarcinogenesis. In this paper we try to review the most important molecular agents in development, with a specific focus on sorafenib's role and safety profile, especially in the treatment of patients with suboptimal liver function., (Copyright © 2012 S. Karger AG, Basel.)

Background: Patients with chronic hepatitis C and persistently normal alanine transaminase levels have recently been included in the guidelines for antiviral treatment., Aim: To evaluate the efficacy of PEG-interferon α-2a and weight-based ribavirin doses in patients with these characteristics in a single Italian centre., Materials and Methods: Patients with chronic hepatitis C and at least three normal alanine transaminase values over a 12-month period were offered a treatment with PEG-interferon α-2a 180 mg/week and ribavirin (800 mg/day for weight <60 kg; 1000 mg/day for weight >60 and <75 kg; 1200 mg/day for weight >75 kg) for 24 weeks (according to genotype 2 or 3) or for 48 weeks (according to genotype 1 or 4). Each patient at baseline underwent liver stiffness (LS) examination using Fibroscan. Data were analysed according to the intention-to-treat criteria., Results: A total of 227 patients (55 men, 172 women) were enrolled into the study: 65 (28.6%) had genotype 1, 144 (63.4%) genotype 2, nine (4.0%) genotype 3 and nine (4.0%) genotype 4. Patients with genotype 2 or 3 (N=153 with easy genotypes) were allocated in group 1 and those with genotype 1 or 4 (N=74 with difficult genotypes) in group 2. According to the LS measurement, patients were classified as follows: 159 (70.0%) presented absent or mild fibrosis (LS=2.5-7.0 kPa), 61 (26.9%) patients had significant fibrosis (LS=7.1-9.5) and seven (3.1%) patients had severe fibrosis (LS >9.6). Twelve patients (5.3%) dropped out within 4 months because of side-effects, whereas 215 patients completed the study. Overall, 13 patients were considered nonresponders (5.7%) and six patients (2.6%) were relapsers to the therapy. The sustained virological response (SVR) rate was 85.4% and it was higher in 'easy' genotypes (2 or 3) compared with 'difficult' genotypes (1 or 4) (92.2 vs. 74.3%, P<0.001). No statistical difference was found in the SVR rate between patients presenting absent or mild fibrosis as against those with significant fibrosis. Multivariate analysis, including factors correlated with SVR, showed that easy genotype and female sex are significantly associated with a SVR., Conclusion: Patients with chronic hepatitis C and persistently normal transaminases have an 85.4% chance to clear the virus with conventional antiviral treatment. Female patients in fertile age with easy genotypes have a 100% chance to reach a SVR.

Background: The performance of transient elastography in primary biliary cirrhosis has yet to be fully established., Aim: To assess: (1) the performance of transient elastography in identifying significant fibrosis in primary biliary cirrhosis by comparison with surrogate markers (AST platelet ratio index (APRI), FIB-4, Fibroindex, Forns, aspartate aminotransferase/alanine aminotransferase ratio); (2) the correlation between liver stiffness and Mayo score prognostic index., Methods: One hundred and twenty patients with primary biliary cirrhosis were consecutively enrolled. The performance of each marker and of liver stiffness was compared with histological staging and METAVIR at time of liver biopsy., Results: The area under receiver operating characteristic (ROC) of liver stiffness were 0.87, 0.88, 0.99 for histological stage ≥II, ≥III and =IV and 0.89, 0.92, 0.99 for METAVIR ≥2, ≥3 and =4. Transient elastography alone proved better able in identifying any grade of fibrosis or cirrhosis than noninvasive markers. Combining each surrogate marker with transient elastography did not improve the area under ROC. Transient elastography correlated positively with the Mayo score (P<0.001). Logistic regression analysis showed that transient elastography was associated with an advanced fibrosis (P<0.001)., Conclusions: Transient elastography proved a simple, reliable and useful method for assessing liver fibrosis in primary biliary cirrhosis, whereas noninvasive surrogate markers proved unsatisfactory in predicting significant fibrosis., (Copyright © 2011 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

With respect to hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), primary, secondary, and tertiary prevention measures have been or should be adopted. In primary prevention, behavioral patterns represent an important risk factor for HBV infection and should be controlled, discouraging those favoring infection. Interferon treatment shows a modest effect in reducing HCC risk in treated patients, but the data obtained cannot be converted in clinical practice. Nucleoside analogs significantly reduce, but do not abolish, HCC risk in patients with cirrhosis, and should therefore be used in patients with cirrhosis and also to diminish the risk of the other potential complications. With respect to secondary prevention, surveillance with semiannual ultrasound examination is indicated in patients with HBV-related cirrhosis as well as in other subgroups of patients, depending on racial and geographical pattern. Finally, the role of interferon in tertiary prevention of HCC relapse after radical treatment is still under debate; some evidence in favor of the treatment is present, but side effects due to toxicity are frequent and severe enough to limit patients' compliance substantially. As there is definitely no agreement on the efficacy and cost-effectiveness of antiviral treatment in HCC prevention, there is still a need for well-constructed, large size, and randomized prospective trials to confirm what is still required based on expert opinion rather than on sound scientific evidence.

Background: The efficacy of retreatment with pegylated interferon (PEG-IFN) plus ribavirin for patients relapsing after a previous treatment remains to be fully elucidated, although extended treatment seems to be the best option in such cases., Aim: To evaluate the efficacy of two extended protocols in patients with genotypes 1 or 4, or those with genotypes 2 or 3., Methods: A total of 181 patients who had relapsed after a previous antiviral treatment with PEG-IFNα2a plus weight-based ribavirin were offered retreatment with the same dose of both PEG-IFN plus ribavirin, to be continued for 48 weeks in those with genotypes 2 or 3 (group 1), and for 72 weeks in those with genotypes 1 or 4 (group 2)., Results: A total of 59 patients (32.5%) refused the retreatment, while 122 (78 men, 44 women) patients were enrolled in the study: 41 were allocated in group 1 and 81 in group 2. Cirrhosis at baseline (staging 5/6 according to Ishak's score was recorded in 11 patients, six in group 1 and five in group 2). Nine patients (7.3%) in group 2 discontinued the treatment (due to lack of response). The remaining patients completed the treatment and were followed-up for at least 12 months after the treatment. Sustained virological response (SVR) rate was 82.9% in group 1 and 50.6% in group 2., Conclusion: Patients with chronic hepatitis C with 'easy genotypes' relapsers to a previous antiviral treatment have more than 80% probability of achieving a SVR with a 48-week retreatment. Patients with 'difficult genotypes' have more than 50% chance of a SVR after a 72-week extended treatment.

Context: Gastric type I carcinoid is a rare neoplasm, deriving from enterochromaffin-like cells (ECL), mainly affecting women with autoimmune gastritis. The approach to treatment, either endoscopic, medical or surgical, is not well defined, particularly in multifocal tumours or carcinoids with rapid growth/frequent recurrence., Objective: To determine whether an anti-G17 vaccination might interfere on the natural history of gastric type I carcinoid., Setting: Padua teaching Hospital, outpatient clinic., Design and Patients: Three patients with type I gastric carcinoid in autoimmune gastritis were administered, after informed consent and ethic committee approval, with a vaccine against gastrin 17 (G17), a synthetic peptide that stimulates specific and high-affinity anti-G17 antibodies, and followed up endoscopically and clinically for a mean of 36 months., Main Outcome Measures: Gastric histology and specifically carcinoid growth/recurrence and trend in time in gastrin, G17, pepsinogens, chromogranin A and clinical parameters., Results: Following vaccination, carcinoid regression was observed in 2/3 patients and, in one of the patients, even the disappearance of ECL hyperplasia, with a reduced ECL cells stimulation, confirmed by a significant reduction in chromogranin A levels. Regression was observed in the two patients that showed a more clear local response to the vaccine. Increased autoantibody titre was observed, but no appearance of new autoimmune diseases., Conclusions: Anti-G17 vaccination induced regression of type I gastric carcinoid and could be considered for the treatment of this tumour, when endoscopic removal is not indicated.

Background: The natural history of primary biliary cirrhosis (PBC) is still debated., Aims: To evaluate: (i) long-term survival in a large cohort of PBC patients observed prospectively at a single centre and (ii) mortality in relation to baseline characteristics and ursodeoxycholic acid (UDCA) treatment., Methods: We considered all consecutive patients between 1973 and 2007 (327 subjects; 310 females, 17 males)., Results: The mean follow-up was 9.1±7.7 years. The patients' age at diagnosis for representative periods (1973-1980, 1981-1990, 1991-2000, 2001-2007) increased progressively from 47.7±1.5 to 53.2±1.2, to 65.2±2.1 and then 63.6±2.9 years. The proportion of asymptomatic patients at diagnosis increased from 30 to 48% in the last decade, while associated symptoms of extrahepatic autoimmunity remained unchanged. Eighty patients (24.4%) died, 74 of them because of liver failure (12 patients developed hepatocellular carcinoma); nine patients underwent liver transplantation. From 1988 onwards, all patients were treated with UDCA (n=288). The mean age at death for the sample as a whole was 67.2±1.3 years. The survival probability at 20 years was 82% for patients with histological stages I-II at entry, 64% for those with stage III and 42% for those with stage IV (P=0.0007). Mortality was significantly reduced in patients treated with UDCA (P=0.012), whereas it was independently associated with oesophageal varices (P=0.015). Patients treated with UDCA had a better prognosis than those untreated, irrespective of the histological stage. Early treated subjects with a good response to UDCA have an 85% chance of survival at 20 years., Conclusions: The clinical presentation of PBC has been changing over the years. Its early detection and early treatment improve the related survival rates., (© 2010 John Wiley & Sons A/S.)

Background: Hepcidin has emerged as the primary regulator of iron homeostasis. Previous studies on assessing urinary hepcidin are limited. We developed a method for quantifying hepcidin-25 (Hep-25) in plasma using surface-enhanced laser-desorption-ionization time-of-flight mass spectrometry (SELDI-TOF/MS) and a 25-AA peptide as reference standard. The aims of the study were 1) to assess the performance of this method in different conditions of iron metabolism disorders; 2) to assess the diagnostic validity of non-invasive serum biomarkers in the identification of iron overload., Methods: Validation of the method was performed in 10 patients with type I hemochromatosis (HE) and in 177 subjects previously enrolled in a general population epidemiological study. Among the latter group, 17 had non-alcoholic fatty liver disease, 10 had chronic hepatitis C, and 150 subjects had normal ultrasound, normal liver function tests (LFTs), an alcohol intake < 20 g ethanol/day and were negative for the C282Y mutation. The following biomarkers were assayed in each case: plasma Hep-25, C282Y and H63D mutations of the HFE gene; serum iron, ferritin (SF), transferrin saturation, transaminases, γ-glutamyltransferase (GGT), glucose, insulin, total cholesterol, high-density lipoprotein (HDL)-cholesterol, low-density lipoprotein (LDL)-cholesterol and triglycerides., Results: Plasma Hep-25 concentrations were higher in HCV+ patients (26.3 ± 7.2 nmol/L) than in controls, and correlated positively with SF (p < 0.001). H63D heterozygous subjects revealed a pattern of iron overload that was significantly higher than H63D wild type subjects. Analyzing the data with the Biomarker Pattern 5.0.2. software to identify the most significant biomarkers for discriminating between HE cases and controls allowed us to produce an algorithm with four terminal nodes, which included glucose > 4.8 mmol/L and Hep-25/SF ratio ≤ 6.6 as the main splitters. These variables enabled the correct diagnosis of HE with 100% sensitivity, 93% specificity and an area under the receiver operating characteristic (ROC) curve of 0.993., Conclusions: Our plasma Hep-25 mass spectrometry method yields measurements that reflect pathological and genetic influences; simple non-invasive biomarkers (Hep-25/SF ratio and glucose) can predict the presence of HE.