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Introduction Prothrombin time is thought to be unreliable in cirrhotic patients to predict the risk of bleeding. We investigated whether prothrombin time ratio was an independent risk factor for bleeding alongside its clot waveform analysis. Methods We studied 307 consecutive cirrhotic patients and 115 healthy subjects. A coagulometer was used for detecting both prothrombin time and clot waveform analysis which included velocity (1st derivative) and acceleration (2nd derivative) of clot formation, and area of parabolic segment of the 1st and 2nd derivatives of prothrombin time (entire cycle of the clot formation). Results Logistic regression shows that prothrombin time ratio was the only variable significantly associated with the history of bleeding. Using a hemorrhagic score, the stepwise model included prothrombin time ratio and the area of parabolic segment of the 1st derivative of Prothrombin Time. Odds ratio was used to create a new score to be challenged against the hemorrhagic score in a ROC analysis. The AUC was 0.72, 95% CI: 0.67-0.77. Conclusion Prothrombin time ratio is associated to an increased bleeding risk. Its role may be further emphasized considering clot waveform analysis. The new score, if aggregated to prothrombin time ratio, could be useful to provide a single parameter immediately ready to assess the bleeding risk in the individual cirrhotic patient.

SummaryIntroduction Prothrombin time (PT) and activated partial thromboplastin time (aPTT) are abnormal but unreliable in cirrhotic patients to express their risk of bleeding. However, these patients may also suffer from thrombotic episodes. In order to investigate the dynamics of the formation of fibrin, the clot waveform analysis (CWA) of aPTT was studied together with a score for the evaluation of the thromboembolic risk. Methods CWA in terms of velocity (1st derivative), acceleration (2nd derivatives) and density (Delta) of aPTT and the Padua Prediction Score (PPS) for venous thromboembolism were studied in 191 cirrhotic patients. Results CWA values were lower in the cirrhotic patients when compared to the control groups. However, Delta, 1st and 2nd derivatives were higher in cirrhotic patients with elevated PPS in comparison to those with a low PPS. The 1st derivative was significantly associated with a high PPS score (>4): OR: 2.66, CI: 95% 1.23–5.78. Conclusions Two opposing tendencies seem to be present in cirrhotic disease: the first shows a weakness of clot formation while the second a predisposition towards thrombosis, identified by the PPS.

The purpose was to determine if brain damage in Wilson's disease (WD) is different in comorbid bipolar spectrum disorders (BDs), comorbid major depressive disorder (MDD) or without any mood disorders.An observational study was conducted on consecutive patients from a center for WD care. The study sample was divided by psychiatric assessment into WD without any mood disorders, WD with BDs and WD with MDD negative at Mood Disorder Questionnaire (MDQ).Thirty-eight WD patients were recruited (53.2% females): 21 without mood disorders (55.2%), 9 with comorbid BDs (26.7%) and 8 with MDD without MDQ+ (21.1%). The BDs showed a higher frequency of brain damage, reaching statistically significant differences in the basal ganglia (P.001), in the overall brain (P.003) and at the limit in the white matter (P.05).In WD, comorbidity with BDs is associated with earlier evidence of brain damage, especially in the basal ganglia. The results confirm the importance of screening and early diagnosis of BDs in WD. Future follow-up studies on large samples are required to confirm if detection of BDs may be an early marker of brain damage and if a good therapeutic response in BDs may improve the prognosis of WD.

Coeliac Disease (CD) is an autoimmune disease in which an environmental factor, gluten, triggers a pathological reaction. It results in intra- and entra-intestinal manifestations of disease, including, most frequently, diarrhoea, weight loss, and anaemia. CD occurs in ∼1% of the western population, being one of the most common autoimmune lifelong disorders, and may present with a variety of psychiatric comorbidities. Psychiatric comorbidity in CD often complicates the diagnosis, reduces the quality-of-life, and worsens the prognosis of affected patients. This review summarizes the epidemiological studies that underline this connection, and focuses on the potential mechanisms related to this comorbility, such as nutritional deficiencies, immune responses, interference in brain processes, and dysfunctions in the gut-brain axis. Factors that play a central role on patients' quality of life, psychological well-being and adherence are presented. Finally, evidence of regression in psychiatric symptoms following the introduction of a gluten-free diet is underlined as well.

Wilson's disease (WD) is a relatively rare autosomal recessive inherited disorder causing copper accumulation in different organs, mainly the liver and brain. Psychiatric disturbances represent a diagnostic and therapeutic issue in WD. A search for relevant articles was carried out on PubMed/Medline, Scopus, and Google Scholar, for papers focused on psychiatric disorders in WD published between 1985-2016. Ninety-two articles were included in this review, showing the findings from 35 observational and case-control studies and 57 case reports. This study discussed the findings on the prevalence of psychiatric symptoms in WD, their impact on the life of those diagnosed, and the efficacy of available treatments on the psychiatric outcomes of WD. Psychiatric disorders are confirmed frequent in WD, with a high prevalence of mood disorders, and contribute to worse Quality-of-Life and psychosocial outcomes. Because specific therapies for WD lead to a good life expectancy, adherence to medicaments and clinical monitoring should be warranted by a multidisciplinary approach, including a hepathologic, neurologic, and psychiatric careful evaluation and education of those affected and their relatives.

Non-alcoholic fatty liver disease (NAFLD) is a clinical-pathological syndrome that includes a wide spectrum of morphological alterations. In research, animal models are crucial in evaluating not only the pathogenesis of NAFLD and its progression, but also the therapeutic effects of various agents. Investigations on the ultrastructural features of NAFLD in humans are not copious, due to the difficulty to obtain human samples and to the long time of NAFLD to evolve. Translational comparative studies on the reliability of animal models in representing the histopathologic picture as seen in humans are missing. To overcome this lack of investigations, we compared the ultrastructural NAFLD features of an animal model versus human. Sprague-Dawley rats were fed with a high fat diet (HFD) for 1-4 weeks, while control rats were fed with a standard diet. Human specimens were collected from patients with diagnosed fatty liver disease, undergoing liver biopsies or surgery. Rat and human samples were examined by light microscopy and by transmission and high resolution scanning electron microscopy. The present work demonstrated that NAFLD in animal model and in human, share overlapping ultrastructural features. In conclusion, animal HFD represent an appropriate tool in studying the pathogenesis of NAFLD.

BACKGROUND AND AIMS. Determination of hepatic copper (Cu) concentration is important in Wilson's disease (WD) diagnosis. The aim of this study was to evaluate uneven distribution of liver Cu concentration and the utility of double-sample biopsy in WD diagnosis. METHODS. Thirty-five WD patients (20 male; mean age 41 ± 9 years) were enrolled in the study and double-liver samples for biopsy were obtained. A further 30 WD patients, in whom Cu determination was performed using single-liver samples, were also enrolled as controls. RESULTS. A marked difference in hepatic Cu concentration was observed between the two sample groups (p0.0001). This difference is statistically significant for all levels of liver fibrosis (p0.001) and for the comparison of hepatic and neurological phenotypes (p0.01). The sensitivity of the Cu concentrations obtained from the double-sample biopsies for the conventional cut-off value of 250 mg/g dry weight of tissue was 85.7% compared to 80% in the single-sample biopsies. By lowering the cut-off value from 250 to 50 µg/g of dry weight of tissue, the sensitivity of Cu content to diagnose WD increased to 97% for double-sample liver biopsy compared to 93% for single-sample liver biopsy. CONCLUSIONS. Liver Cu content was unevenly distributed in the WD subjects, irrespective of fibrosis levels and disease phenotypes; hence WD can be misdiagnosed using single-sample liver Cu measurement. Double-sample biopsy sensitivity is greater than that obtained with single-sample biopsy and should therefore be considered to evaluate liver Cu concentration at initial diagnosis in all patients.

The histological similarities seen in Wilson's disease (WD) and non-alcoholic steatohepatitis (NASH) led us to verify possible correlations between glucose and/or lipid and/or iron metabolism alterations and hepatic steatosis in WD patients.Thirty-five WD patients (20 females, 15 males, mean age 40.1 ± 5.4 years), and 44 NASH patients (25 females, 19 males, mean age 42.8 ± 6.7 years) were enrolled in the study. BMI, total/HDL/LDL-cholesterol, triglycerides and glucose serum levels were established in all subjects. HOMA index was calculated. Percutaneous liver biopsy with quantitative evaluation of steatosis and copper tissue content was performed in all WD patients and in NASH control group.Significant difference was seen in baseline serum levels of glucose, HOMA index, total cholesterol, triglycerides, and ferritin between the WD group and NASH group (P0.05) but steatosis scored was similar between two groups. No correlation between the level of steatosis and metabolic factors studied was highlighted. In WD, hepatic parenchymal copper concentration was 753 ± 65.3 mcg/g dry weight against 54.5 ± 16.9 mcg/g dry weight in NASH patients (P0.05). Higher liver copper concentrations were seen in patients with severe steatosis compared to those with mild (P=0.004) and moderate, (P=0.038) steatosis. Positive significant correlation between liver copper content and steatosis scores (r=0.87; r(2)=0.76) was observed.The hepatic steatosis in WD is not induced by metabolic comorbidities but by the accumulation of copper in the liver tissue. The hypothesise that the metabolic alterations could be co-factors in the pathogenesis of steatosis in these patients cannot be excluded.

Aims To evaluate Wilson's disease (WD) features in Sardinian patients with Kayser–Fleischer (KF) ring and to evaluate correlations between modifications in KF and anti-copper therapy and systemic WD evolution. Patients and methods Sixty-seven WD patients (35 m/32 f; mean age 41 years) were retrospectively studied. At diagnosis and during follow up comprehensive ophthalmologic and neurologic examinations, brain RMN and ECD SPECT, detailed objective laboratory studies and hepatic histological examination were performed on all patients for analysis. All patients were given anti-copper therapy with d -Penicillamine in mono-therapy or in combination with Zinc Salts. Results At diagnosis, KF was observed in 27% of patients with equal distribution in all age groups. Significant correlations between KF at diagnosis, neuro-psychiatric manifestations and pathologic features in brain RMN and in brain ECD SPECT were found at diagnosis. During follow up, a decrease in, or regression of KF was seen in 14% of patients. Anti-copper therapy leads to KF regression and prevents the appearance of KF. No significant correlations were observed between KF regression and clinical neurological or neuro-imaging improvement nor between KF modifications and clinical hepatic improvement. Conclusions Our study highlights the peculiar features of Sardinian WD patients: low representation of KF, its equal distribution in all age groups, significant correlation between KF at diagnosis and clinical neurological manifestations, pathologic brain RMN and brain ECD-SPECT are highlighted by our study. Anti-copper therapy induces KF regression and prevents its onset. Therefore, KF ring does appear to be a predictive factor in the neurological and hepatic evolution of WD.

Introduction: Wilson’s disease is an inherited disorder caused by a gene located on chromosome 13, which involved copper transportation across cell membranes. The disease can cause a reduced incorporation of copper into ceruloplasmin resulting in accumulation of this metal in the liver, central nervous system, kidneys and other organs. The objective is to define the frequencies of psychiatric disorders in WD, the amount of impairment of Quality of Life [QoL] in patients with WD and the relevance of the psychiatric disorders in the QoL of people suffering by WD. Methods: This is a systematic review. The search of the significant articles was carried out in PubMed using specific key words. Results: Such other neurological diseases, WD is characterized by chronic course and need of treatments, impairment of functional outcomes and high frequency of psychiatric symptoms, although a specific association between Bipolar Disorders and WD was recently found. Despite this, since today few studies are carried on WD patients’ quality of life related to psychiatric symptoms. Some new reports showed a link between presence of Bipolar Disorders diagnosis, cerebral damage and low Qol. Conclusion: Prospective studies on large cohorts are required to establish the effective impact of psychiatric disorders comorbidity, particularly Bipolar Disorders, on quality of life in WD and to clarify the causal link between brain damage, psychiatric disorders and worsening of QoL.

Considerable evidence suggests that iron could be a comorbid factor for liver injury in chronic hepatitis C (CHC). Elevated iron indices are frequently described in CHC and may impact negatively on the course of liver disease and on the response to interferon alfa therapy. The aim of this study was to evaluate the frequency of hemochromatosis gene mutations in Sardinian CHC patients, the association with iron overload and the impact on response to therapy.Sixty-nine CHC patients were enrolled. Iron indices, hepatic and viral parameters were detected. C282Y, H63D and S65C mutations were identified through a PCR. Liver biopsy was performed for hepatic fibrosis evaluation. All patients were treated for 6 months (viral genotype 2/3) or 12 months (viral genotype 1/4) with pegylated-interferon 180 mcg once weekly and ribavirin 1000-1200 mg/daily. Sustained virological response (SVR) was defined as undetectable HCV RNA 24 weeks after the end of treatment.HFE gene mutation was detected in 29 patients (42%). The presence of HFE mutations was significantly associated with elevated transferrin saturation (P 0.01). Hepatic fibrosis was more advanced in HFE mutation carriers (χ (2), P = 0.04). Among mutation carriers 27.5% achieved responses at the end of treatment compared with 60% of non-carriers (P = 0.005). Patients with HFE wildtype produced significant SVR compared with patients with HFE mutations (P = 0.03).The literature shows discordant results about the prevalence, hepatic distribution and possible therapeutic implications of iron overload in chronic hepatitis C. Our findings shows that HFE gene mutations could favor, synergically with CHC and other genetic or acquired factors, the development of liver damage and could influence the outcome of interferon treatment with higher rate of non-response.

Hypocaeruloplasminaemia can lead to tissue iron storage in Wilson's disease and the possibility of iron overload in long-term overtreated patients should be considered. The HFE gene encodes a protein that is intimately involved in intestinal iron absorption.The aim of this study was to determine the prevalence of the HFE gene mutation, its role in iron metabolism of Wilson's disease patients and the interplay of therapy in copper and iron homeostasis.The records of 32 patients with Wilson's disease were reviewed for iron and copper indices, HFE gene mutations and liver biopsy.Twenty-six patients were negative for HFE gene mutations and did not present significant alterations of iron metabolism. The HFE mutation was significantly associated with increased hepatic iron content (P0.02) and transferrin saturation index (P0.03). After treatment period, iron indices were significantly decreased only in HFE gene wild-type.The HFE gene mutations may be an addictional factor in iron overload in Wilson's disease. Our results showed that an adjustment of dosage of drugs could prevent further iron overload induced by overtreatment only in patients HFE wild-type.

From 1902 to 1983, 68 cases of hepatolenticular degeneration (HLD) were discovered in Sardinia, with a mean frequency, in reference to number of live births, of 27.7 and a sex ratio of 1.83. The prevalence of the disease was seen to be higher over the last few decades. With regard to the geographic distribution of the disease, 3 high-frequency areas were evident, in Barbagia, in Campidano, and in the area surrounding the city of Sassari. In 38.23% of cases, the clinical picture was of hepatoneurologic type; hepatic forms have become more frequent over the last decades. The first symptoms were observed at mean age of 15 years 8 months. The number of asymptomatic cases was fairly consistent (22.05%). The median survival rate in subjects who received inadequate therapy was 6 years 4 months. Only 3 patients of the 45 treated with adequate therapy died. The gene frequency, calculated by the application of Dahlberg's formula, was extremely high.

ObjectiveThe objective of this study was to compare the efficacy of anti-hepatitis C virus (anti-HCV) treatment schedules on the basis of an early virological response (EVR), defined as undetectable serum HCV-RNA (

Wilson's disease is a rare inherited disorder of copper metabolism, manifesting hepatic, neurological and psychiatric symptoms. Early diagnosis is often unfeasible and a unique diagnostic test is currently inapplicable. We performed the qualitative/quantitative characterization of the salivary proteome/peptidome of 32 Wilson's disease patients by an integrated top-down/bottom-up approach. Patients exhibited significant higher levels of S100A9 and S100A8 proteoforms, and their oxidized forms with respect to controls. Oxidation occurred on methionine and tryptophan residues, and on the unique cysteine residue, in position 42 in S100A8, and 3 in S100A9, that generated glutathionylated, cysteinylated, sulfinic, sulfonic, and disulfide dimeric forms. Wilson's disease patient saliva showed high levels of two new fragments of the polymeric immunoglobulin receptor, and of alpha-defensins 2 and 4. Overall, the salivary proteome of Wilson's disease patients reflected oxidative stress and inflammatory conditions characteristic of the pathology, highlighting differences that could be useful clues of disease exacerbation. (C) 2015 Elsevier B.V. All rights reserved.

Summary Background : An early virological response to interferon-α treatment is a strong predictor of sustained response, but it has never been exploited to stratify patients in clinical trials. Aim : To evaluate the efficacy of amantadine plus interferon-α compared with interferon-α alone in naive patients with chronic hepatitis C who were randomized on the basis of the early virological response to interferon-α. Methods : One hundred and eighty-one patients received recombinant interferon-α2a (3 MU three times weekly) for 2 months and 164 were evaluated for early (i.e. month 2) virological response. Hepatitis C virus (HCV) RNA-negative patients (n = 66) were randomized to receive 3 MU of interferon-α three times weekly, with or without amantadine (200 mg/day); HCV RNA-positive patients (n = 98) were randomized to receive 6 MU of interferon-α three times weekly, with or without amantadine (200 mg/day). HCV RNA-positive patients at 6 months discontinued treatment, and all others completed 12 months. Results : At month 6, HCV RNA-negative patients made up 54.2% of the interferon + amantadine group and 42.0% of the monotherapy group (P = 0.07). At month 12, HCV RNA-negative patients made up 38.5% of the interferon + amantadine group and 28.4% of the monotherapy group (N.S.). The sustained virological response rates were 21.6% and 20.9%, respectively (N.S.). Conclusion : The addition of amantadine does not enhance the sustained virological response to interferon-α in naive patients with chronic hepatitis C; however, an additive effect of amantadine occurs in the first 6 months, mainly in patients without an early response to monotherapy. Early response to interferon-α is a strong predictor of sustained virological response.

Non-alcoholic fatty liver disease (NAFLD) is a clinical-pathological syndrome that includes a wide spectrum of morphological alterations. In research, animal models are crucial in evaluating not only the pathogenesis of NAFLD and its progression, but also the therapeutic effects of various agents. Investigations on the ultrastructural features of NAFLD in humans are not copious, due to the difficulty to obtain human samples and to the long time of NAFLD to evolve. Translational comparative studies on the reliability of animal models in representing the histopathologic picture as seen in humans are missing. To overcome this lack of investigations, we compared the ultrastructural NAFLD features of an animal model versus human. Sprague-Dawley rats were fed with a high fat diet (HFD) for 1-4 weeks, while control rats were fed with a standard diet. Human specimens were collected from patients with diagnosed fatty liver disease, undergoing liver biopsies or surgery. Rat and human samples were examined by light microscopy and by transmission and high resolution scanning electron microscopy. The present work demonstrated that NAFLD in animal model and in human, share overlapping ultrastructural features. In conclusion, animal HFD represent an appropriate tool in studying the pathogenesis of NAFLD.

Objectives – The purpose of this study is to evaluate the efficiency of a few methodologies in detecting anatomo-functional brain abnormalities in patients with Wilson's disease. Materials and methods – Twenty-three patients with Wilson's disease underwent almost simultaneously brain magnetic resonance imaging (MRI), computerized electroencephalography (EEG), multimodal evoked potentials (EPs) and ECD single photon computerized tomography (SPECT) evaluation. The clinical picture was of the neurologic type in 8 patients and of the hepatic type in 15. Results – MRI was abnormal in 7 patients with neurological manifestations. The EPs proved pathologic in 7 neurologically symptomatic patients and in 4 cases with hepatic form. These results agree with those reported in other case studies. The EEG records were abnormal only in 3 cases. Nevertheless, the most interesting finding of this study is the particular frequency (86%) of diffuse or focal decrease of ECD uptake shown by brain SPECT. Conclusion – We highlight the use of this interesting procedure in the therapeutic monitoring of this disease.

Aims: The histochemical demonstration of hepatic copper is important in the diagnosis of Wilson's disease (WD). Conflicting results have been published with regard to the ability of different histochemical methods to demonstrate copper storage in the liver. Therefore, we evaluated the diagnostic value of three available histochemical methods in a large series of patients affected by WD. Methods and results Seventy-nine consecutive liver needle biopsies, from 74 patients, 39 males and 35 females, aged 4–60 years (mean age 28.5 years) were stained with orcein, rhodanine and using Timm's method. On the basis of the histological picture, liver biopsies were subdivided into three groups: group A, steatosis; group B, interface hepatitis; group C, chronic hepatitis with bridging fibrosis and/or cirrhosis. In group A, 30.4% of the cases were positive using Timm's method, vs 13.2% using the rhodanine and 17.5% using the orcein method. In group B, Timm's method was positive in 40.1% while rhodanine and orcein showed positivity in 26.7%. In group C, the Timm's method stained 58.6%, rhodanine 36.6% and orcein 29.3% positively. Conclusions Our data show that: (1) Timm's silver stain is the most sensitive method for the demonstration of copper in all cases of WD; (2) rhodanine and orcein have minor value in the diagnosis of WD, especially in the early stages of the disease; (3) to increase the diagnostic value of histochemistry for copper multiple histochemical stains in serial sections are required; and (4) although hepatic copper concentration is highest in the early stages of WD, the histochemical demonstration fails in a large number of cases.

Background/Aims: Determination of hepatic copper concentration is important in the diagnosis of Wilson's disease. We studied copper distribution in the cirrhotic liver of a patient who died of Wilson's disease. Methods: A liver slice extending from the left to the right lobe was divided into 38 samples. Each sample was analyzed for copper content by Induced Coupled Plasma Atomic Emission Spectroscopy. Results: The mean copper concentration in the liver was 1370 μg/g dt. A striking variability, up to 2–3-fold, in copper levels was observed between the samples: the copper concentration ranged from 880 to 2100 μg/g dt, with significant differences even between adjacent samples. Lobar differences were also observed, with a tendency of the right lobe to accumulate more copper than the left lobe. Histochemical analyses confirmed the uneven distribution of copper even at the acinar level. Copper was mainly stored in periportal hepatocytes (zone 1) and at the periphery of the regenerating nodules. Moreover, we observed some nodules with the majority of hepatocytes full of copper granules, adjacent to areas of parenchyma negative for copper stains. Conclusions: Our data show that: 1) copper is unevenly distributed in Wilson's disease in the cirrhotic stage; 2) a lobar pattern of copper distribution is evident in this case, characterized by a higher copper concentration in the right lobe; 3) the observed lobal pattern is different from that described in the newborn liver, characterized by a higher copper content in the left compartment of the liver; 4) copper content determined in a small liver sample cannot be considered as absolutely representative of the mean hepatic copper concentration. From a practical point of view, our data show that sampling variability deserves more consideration in the diagnosis and in the monitoring of Wilson's disease. The use of hepatic copper concentration in monitoring the efficacy of the copper-chelating therapy may be unreliable, particularly in the cirrhotic stage, because of the patchy distribution of copper, as demonstrated in this study.

Wilson's disease (WD) is a rare inborn disease related to copper storage, leading to liver cirrhosis and neuropsychological deterioration. The aim of this study was to determine the clinical presentation and long-term outcome, and to examine the progression of hepatic histopathology in serial liver biopsies from WD patients.We carried out a retrospective analysis of 60 patients with WD treated with zinc and/or penicillamine. Demographic, clinical, and laboratory data were gathered and 40 patients underwent an initial biopsy and at least one repeat biopsy. Patients were divided into two groups: progressors (patients who presented worsening of at least one unit of fibrosis) and nonprogressors (patients who presented stable or improved fibrosis scores).A total of 33/40 (83%) patients (nonprogressors) showed stable hepatic histology or improvement. Seven of 40 (17%) patients (progressors) showed worsening of fibrosis. There was no significant correlation between the histological findings and clinical parameters or initial presentation.In our study cohort, liver disease was stable or improving in most of the patients, and development of progressive hepatic symptoms while under treatment was a rare event. The development of new symptoms while under treatment or progression of pre-existing symptoms was more often recorded for neurological than for hepatic symptoms.

Background Short-term treatment for hepatitis B e antigen (HBeAg)-negative chronic hepatitis B remains unsatisfactory. The aim of our study was to compare the efficacy and safety of two sequential regimens of pegylated interferon (PEG-IFN)-α and telbivudine (LdT). Methods Adult patients with biopsy-proven HBeAg-negative chronic hepatitis B, elevated alanine aminotransferase (ALT) and serum HBV DNA≥2,000 IU/ml were randomized 1:1 at baseline to receive PEG-IFN 180 μg/week for 24 weeks followed by LdT 600 mg/day for 24 weeks (PEG-IFN first), or vice versa (LdT first), plus 24-week follow-up; individuals with HCV, HDV or HIV coinfections and lamivudine resistance were excluded. Primary end points were serum HBV DNAResults A total of 30 patients (86% male, median age 48 years) were enrolled: mean ±sdbaseline serum HBV DNA was 5.56 ±1.4 log IU/ml and ALT was 2.9 ±2.5x upper limit of normal. At end of follow-up (week 72), HBV DNAConclusions Sequential treatment with 24 weeks PEG-IFN followed or preceded by 24 weeks of LdT is safe. Virological response rate at week 72 was significantly higher in patients treated with LdT followed by PEG-IFN than vice versa. A sequential antiviral regimen of LdT followed by PEG-IFN, if confirmed in larger series, could improve response rates compared with standard PEG-IFN monotherapy.

Wilson's disease (WD), an autosomal recessive disorder of copper transport with a broad range of genotypic and phenotypic characteristics, results from mutations in the ATP7B gene. Herein we report the results of mutation analysis of the ATP7B gene in a group of 118 Wilson disease families (236 chromosomes) prevalently of Italian origin. Using DNA sequencing we identified 83 disease-causing mutations. Eleven were novel, while twenty one already described mutations were identified in new populations in this study. In particular, mutation analysis of 13 families of Romanian origin showed a high prevalence of the p.H1069Q mutation (50%). Detection of new mutations in the ATP7B gene in new populations increases our capability of molecular analysis that is essential for early diagnosis and treatment of WD.

Background/aims Liver biopsy has always represented the standard of reference in hepatic fibrosis assessment. Recently, blood markers and instrumental methods have been proposed for non-invasive assessment. The aim of this study was to validate transient elastography and other non-invasive tests compared to liver histology in Wilson's Disease. Methods Liver stiffness in 35 Wilson's Disease patients was evaluated by Fibroscan, serum fibrosis markers (AST-to-platelet-ratio index and FIB-4) and biopsy. Results Compared to liver histology, the FibroScan values increased proportionally with progression of the histological fibrosis stage. Significant fibrosis could be predicted with a Fibroscan cut-off value of 6.6 kPa. Advanced fibrosis could be predicted with a FibroScan cut-off value of 8.4 kPa. Serum fibrosis marker values gave good correlation with hepatic stage. Conclusions A FibroScan value of 6.6 kPa was found to be a significant separation limit for differentiating significant fibrosis stages from milder stages and a fibroscan value of 8.4 kPa was found to be a significant separation limit for differentiating advanced fibrosis stages from milder stages. FibroScan values are clinically useful for predicting fibrosis stages and helpful in managing chronic therapy in Wilson's Disease patients.

A psychiatric involvement is frequently present in Wilson’s disease. Psychiatric symptoms are sometimes the first and only manifestation of Wilson’s disease. More often a psychiatric involvement is present beside a neurologic or hepatic disease. We describe the case of a 18 years-old male patient who shows a clinic and laboratoristic pattern of cirrhosis and an history of subchronic hallucinatory psychosis, behavioral symptoms and mood disturbances with depressed mood. He hadn’t familiar history of liver or psychiatric disease. Laboratory and imaging tests confirmed the diagnosis of Wilson’s disease with psichiatric involvement. After liver transplantation copper metabolism and liver function normalised and we noticed no recurrency of the psichiatric illness. Very few cases of psychiatric improvement after orthotopic liver transplantation (OLT) has been described until now.

Background Pegylated interferon (PEG-IFN)-α monotherapy is the current standard of care for short-term antiviral treatment of hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB). We aimed to assess the safety and efficacy of PEG-IFN-α plus adefovir dipivoxil (ADV) versus PEG-IFN-α monotherapy for compensated HBeAg-negative CHB. Methods A multicentre randomized controlled trial was performed in eight outpatient hepatology/infectious disease clinics in central Italy. A total of 60 patients (67% male and median age 48 years) with biopsy-proven HBeAg-negative compensated CHB (mean alanine aminotranferase [ALT] levels 3.3 ±3x the upper normal limit and serum hepatitis B virus [HBV] DNA 5.8 ±0.9 log10 IU/ml) were randomized at baseline to receive PEG-IFN-α2a 180 μg/week plus ADV 10 mg/day or PEG-IFN-α2a monotherapy for 48 weeks. Post-treatment follow-up was for 24 additional weeks. The primary end point was sustained HBV DNA suppression defined as serum HBV DNAResults At week 48, HBV DNA was undetectable in 20/30 (67%) in the combination group versus 11/30 (37%) patients in the monotherapy group ( P=0.02). ALT normalization was achieved in 17/30 (57%) versus 10/30 (30%) patients, respectively ( P=0.03). At week 72, sustained virological response was achieved in 7/30 (23.3%) in the combination group versus 6/30 (20%) patients in the monotherapy group ( P=0.75); 5 (16%) patients in each group dropped out because of adverse events or non-compliance. Conclusions In HBeAg-negative CHB, combination PEG-IFN-α2a plus ADV for 48 weeks is safe and resulted in greater on-treatment efficacy than PEG-IFN-α2a monotherapy. No difference in sustained virological and biochemical response rates were observed between the two treatment regimens.

The paucity of the intrahepatic bile ducts, also known as ductopenia, is a well recognized disorder in pediatric patients. Recently, however, a similar disorder has been reported in adults and termed idiopathic adulthood ductopenia (IAD). We describe a 30-year-old patient with a 15 year history of episodes of jaundice. During icteric episodes, serum levels of bilirubin and alkaline phosphatase were markedly elevated. Between attacks, totalling more than 30, the patient was asymptomatic, but bilirubin and alkaline phosphatase levels were mildly elevated. No neonatal jaundice was present in the patient's history. PBC, PSC and drug-induced cholestasis were excluded. Two needle biopsies of the liver, taken within a 13 year interval, were available. The lobular architecture appeared progressively disturbed by porto-centro-portal bridging septa. In both biopsies, a destructive cholangitis was found. In the last biopsy, the majority of the septal and interlobular ducts appeared severely damaged and, in three out of seven portal tracts, the interlobular bile duct had disappeared. In the parenchyma, the main feature was a severe mainly canalicular bilirubinostasis. The patient described illustrates that IAD may have a clinical picture indistinguishable from benign recurrent intrahepatic cholestasis. The etiology of the disease, in this as in other patients, remains unknown.

To evaluate the impact of brain MRI and single-photon emission computed tomography (SPECT) in early detection of central nervous system abnormalities in patients affected by Wilson's disease (WD) with or without neurological involvement.Out of 25 consecutive WD patients, 13 showed hepatic involvement, ten hepatic and neurological manifestations, and twp hepatic, neurological, and psychiatric symptoms, including mainly movement disorders, major depression, and psychosis. Twenty-four healthy, age-gender matched subjects served as controls. All patients underwent brain MRI and (99m)Tc-ethyl-cysteinate dimer (ECD) SPECT before starting specific therapy. Voxel-by-voxel analyses were performed using statistical parametric mapping to compare differences in (99m)Tc-ECD brain uptake between the two groups.Brain MRI showed T2-weighted hyperintensities in seven patients (28%), six of whom were affected by hepatic and neurological forms. Brain perfusion SPECT showed pathological data in 19 patients (76%), revealing diffuse or focal hypoperfusion in superior frontal (Brodmann area (BA) 6), prefrontal (BA 9), parietal (BA 40), and occipital (BA 18, BA 39) cortices in temporal gyri (BA 37, BA 21) and in caudatus and putamen. Moreover, hepatic involvement was detected in nine subjects; eight presented both hepatic and neurological signs, while two exhibited WD-correlated hepatic, neurological, and psychiatric alterations. All but one patient with abnormal MRI matched with abnormal ECD SPECT. Pathologic MRI findings were obtained in six out of ten patients with hepatic and neurological involvement while abnormal ECD SPECT was revealed in eight patients. Both patients with hepatic, neurological, and psychiatric involvement displayed abnormal ECD SPECT and one displayed an altered MRI.These findings suggest that ECD SPECT might be useful in detecting early brain damage in WD, not only in the perspective of assessing and treating motor impairment but also in evaluating better the less investigated disorders in the cognitive domain.

S. Onali 1,5, S. Cappellini1,5, G. Serra1,5, T. Zolfino2,5, D. Murgia3,5, M.L. Ponti3,5, C. Balestrieri 1,5, M. Conti1,5, O. Sorbello4,5, A. Civolani4,5, M. Casale1,5, S. Casu1,5, F. Figorilli 1,5, M.C. Pasetto1,5, A. Gaspardini1,5, L. Secci1,5, C. Salustro1,5, R. Ganga3,5, M.R. Piras2,5, L. Demelia4,5, L. Chessa1,5 1 Center for the Study of Liver Diseases, Department of Medical Sciences “M.Aresu”, University of Cagliari, Italy 2 S.C. Gastroenterologia, AOB, Cagliari, Italy 3 S.C. Medicina Prima, AOB, Cagliari Italy 4 U.O. Gastroenterologia, AOU, Cagliari, Italy 5 Associazione Epatologi Sardi

AIM: To compare the efficacy and safety of recombinant human IFN β-1a alone or in combination with ribavirin in treatment-naive subjects with chronic hepatitis C. METHODS: Open, randomized trial was performed in 6 Italian tertiary centers: 102 of the 108 patients screened were randomized to receive 6 MIU of recombinant human IFN β-1a subcutaneously daily for 24 wk, alone (Group 1, n = 51) or in combination with ribavirin 1 000 to 1 200 mg/d (Group 2, n = 51). RESULTS: The end-of-treatment virologic response rate was 29.4% in Group 1 and 41.2% in Group 2 (non-significant). Twenty-four weeks after stopping therapy, sustained virologic response rate was 21.6% in Group 1 and 27.4% in Group 2 (non-significant). All subjects in Group 1 completed treatment, while two subjects in Group 2 stopped therapy due to treatment-related adverse events. CONCLUSION: Recombinant human IFN β-1a, alone or in combination with ribavirin, has an excellent safety profile and, may represent an alternative for chronic hepatitis C patients who are unable to tolerate pegylated α-interferon.

Background Although up to 90% of patients systemic sclerosis (SSc) have been estimated to have gastrointestinal involvement, liver disease (without any cause other than SSc itself) has been reported only rarely in this disease. Liver biopsy is considered the gold standard for an accurate assessment of liver fibrosis. However, it is an invasive and expensive tool, so there has been increasing interest in non-invasive assessment evaluation of liver stiffness (LS) by transient elastography (TE) which have been recently demonstrated to be useful for the diagnosis of various grades of fibrosis in the course of chronic liver diseases. Objectives To evaluate the presence of liver fibrosis in a series of SSc patients, without any functional sign of liver disease and any cause other than SSc itself, and to identify any possible associations with demographic data, disease duration and disease phenotype. Methods Thirty-nine SSc patients (33 females and 6 males) without liver diseases, mean age 63.4±13.2 years, disease duration 10.5±8,67 years, and a sex- and age-matched control group, were consecutively studied. LS was evaluated using TE (Fibroscan; Echosens, Paris, France) and measured in kPa. We adopted 5.3 kPa as the cutoff for abnormal LS values. Results Seventeen (43.5%) SSc patients had abnormal LS values when patients were classified into two groups according to the cutoff (group A 5.3 kPa); the median LS value was 4 kPa in group A and 7.1 kPa in group B. There were no significant differences between the two groups in disease duration, demographics, laboratory variables or disease characteristics. Among medications, a significant difference for patients on endothelin receptor antagonist therapy was seen in group B (P=0.02). Conclusions TE suggested, in a non-invasive fashion, liver fibrosis in 43.5% of our SSc patients, as a result of a primary hepatic involvement. LS measurement could be suggested for checking silent liver fibrosis in SSc, even in absence of abnormal liver function serological tests. However, further studies are required to investigate whether treatment regimens can influence the progression of liver fibrosis, or if they should be modified when abnormal LS values are identified. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.3523

This study was aimed to evaluate TT virus prevalence in subjects with hepatitis B virus (HBV), hepatitis C virus (HCV) and human immunodeficiency virus (HIV) infections in patients affected by hepatitis of unknown origin (non-A-non-E hepatitis) and in healthy subjects who had not been exposed to HBV, HCV and HIV. A total of 317 subjects were tested; 40 were HBsAg asymptomatic carriers, 57 subjects were anti-HCV positive (45 without chronic hepatitis and 12 with HCV-related chronic hepatitis), and 27 had chronic non-A-non-E hepatitis. Fifty-seven subjects were intravenous drug users (IVDUs) (52 with HCV or/and HIV infections), seven patients underwent a liver transplant for fulminant hepatitis and 137 were healthy subjects from the general population. Overall, TTV-DNA was detected in 62 subjects (19.6%): in 17.9% of the HBsAg carriers, in 14% of the anti-HCV-positive patients (in 8.3% and in 15.5% of patients with and without chronic hepatitis, respectively), in 22.2% of non-A-non-E hepatitis patients, in 22.8% of IVDUs, in 57.1% of fulminant hepatitis patients. TTV-DNA was also found in 20.4% healthy subjects. The prevalence in the different subgroups was not statistically different. The genotypes were identified in 40 of the 62 (64.5%) TTV-DNA positive samples: genotype 1a in 17.5%, 1b in 27.5%, genotype 2 in 27.5%, genotype 3 in 15.0%, genotype 4 in 5.0% and genotype 5 in 7.5%; the genotype distribution in the subsets of patients was not significantly different. In conclusion, this study showed that TTV infection is common in Italy; it is widespread throughout the entire population and five genotypes are present in Sardinia. Our results further dismiss the role of TTV as cofactor in influencing the clinical course of infections with other hepatitis viruses as well as the role of HIV in enhancing TTV transmission and replication.

To investigate the risk of sexual and intrafamilial transmission of HCV, 220 family members of 76 patients (index cases) with chronic type C viral liver disease were tested for serological markers of HCV Of the family members, 129 were offspring, 64 sexual partners, 15 parents and 12 siblings of the index cases. Anti-HCV was tested in all the household contacts; HCV-RNA was tested in antibody positive samples. The serologic markers of HCV were tested in a control group of 168 family members of 81 patients with chronic hepatitis unrelated to HCV. The overall prevalence of anti-HCV was 8.2% compared to 0.6% in the control group (p < 0.001). Sexual partners were anti-HCV positive more frequently than the other contacts (20% vs 2.2%; p < 0.001), without any difference in males or females. No correlation was observed between the occurrence of HCV infection in contacts and age, severity of liver disease or risk factor for the acquisition of HCV in the index cases. Seven of the 18 (39%) anti-HCV positive family contacts had biochemical evidence of chronic liver disease, histologically confirmed in the 6 patients who underwent a liver biopsy. Liver chemistry was normal in all the HCV-negative contacts. Ten of the 18 anti-HCV positive contacts (55%) were HCV-RNA positive. Genotypes were the same (lb) in 4 of the 7 viremic couples of subjects: in 3 of the 6 couples of sexual partners and in the only mother/son couple. These data suggest the occurrence of intraspousal transmission of HCV, while intrafamiliar acquisition of HCV in non-sexual contacts seems to be rare.

Background The aim of this study was to determine the risk for Bipolar Disorder (BD) in Wilson’s disease (WD) and to measure the impaired Quality of Life (QL) in BD with WD using standardized psychiatric diagnostic tools and a case control design. Methods This was a case control study. The cases were 23 consecutive patients with WD treated at the University Hospital in Cagliari, Italy, and the controls were 92 sex- and age-matched subjects with no diagnosis of WD who were randomly selected from a database used previously for an epidemiological study. Psychiatric diagnoses according to DSM-IV criteria were determined by physicians using structured interview tools (ANTAS-SCID). QL was measured by means of SF-12. Results Compared to controls, WD patients had lower scores on the SF-12 and higher lifetime prevalence of DSM-IV major depressive disorders (OR = 5.7, 95% CI 2.4–17.3) and bipolar disorders (OR = 12.9, 95% CI 3.6–46.3). BD was associated with lower SF-12 in WD patients. Conclusions This study was the first to show an association between BD and WD using standardized diagnostic tools and a case control design. Reports in the literature about increased schizophrenia-like psychosis in WD and a lack of association with bipolar disorders may thus have been based on a more inclusive diagnosis of schizophrenia in the past. Our findings may explain the frequent reports of loss of emotional control, hyperactivity, loss of sexual inhibition, and irritability in WD patients. This study was limited by a small sample size.

We studied DNA polymorphisms for five new chromosome 13 markers in 52 Wilson's disease (WD) families from Europe, North America, and the Middle East. There was significant evidence for linkage between the Wilson's disease locus (WND) and all the marker loci. Multilocus linkage analysis, using a genetic linkage map established from reference pedigrees, suggested that WND is most likely between D13S31 and D13S59, at distances of 0.4 and 1.2 centimorgans, respectively. Our results suggest that the chromosomal location of the Wilson's disease gene is the same in all families from the populations studied. This evidence and the availability of many close, flanking, and polymorphic DNA markers make possible accurate and informative testing of potential carriers and WD homozygotes in families with at least one previously affected child. An advantage of a genetic linkage test over other laboratory methods for prediction of genotype in WD is that a reliable diagnosis can be made at a much earlier stage in life, including prenatally. In addition, DNA testing can be used in place of an invasive liver biopsy procedure to confirm a diagnosis in patients with borderline serum ceruloplasmin levels. Presymptomatic identification will also allow therapeutic intervention to prevent symptoms before irreparable liver or neurologic damage occurs. We describe the implementation of prenatal and preclinical diagnosis for two families with WD.