Gastrointestinal Microbiota & Symptoms of Depression and Anxiety in Anorexia Nervosa-A Re-Analysis of the MICROBIAN Longitudinal Study.

The microbiota-gut-brain axis may play a role in the pathophysiology of anorexia nervosa (AN). Here, the relationship between the gastrointestinal microbiota and symptoms of depression, anxiety, and eating disorder pathology in patients with AN before (n = 55) and after weight restoration (n = 44) was investigated by reanalyzing the data of the MICROBIAN study. The gastrointestinal microbiota was analyzed using 16S rRNA amplicon sequencing. Symptoms of anxiety disorder, depression, and the severity of the eating disorder were measured by validated questionnaires. All analyses were adjusted for the body mass index (BMI). Several significant findings between psychological parameters and the gastrointestinal microbiota were not evident after controlling for the BMI. No differences in alpha and beta diversity between groups of higher and lower symptom severity levels for depression and anxiety were found. Positive associations between species of Blautia and Ruminococcus and depression symptoms, and between the phylum Firmicutes and anxiety symptoms were observed after rehabilitation, respectively. A positive correlation was found between propionate and acetate levels and the reduction of depression severity during inpatient treatment. Accounting for the weight status when analyzing the relationship between psychological parameters and the gastrointestinal microbiota in patients with underweight is important since the BMI may be the driver for many observed changes.

Liver epigenome changes in patients with hepatopulmonary syndrome: A pilot study.

The hepatopulmonary syndrome (HPS) is defined by the presence of pulmonary gas exchange abnormalities due to intrapulmonary vascular dilatations in patients with chronic liver disease. Changes in DNA methylation reflect the genomic variation. Since liver transplant (LT) reverts HPS we hypothesized that it may be associated with specific liver epigenetic changes. Thus, the aim of this study was to investigate the role of the liver epigenome in patients with HPS. We extracted DNA from paraffin embedded liver tissue samples from 10 patients with HPS and 10 age-, sex- and MELD (Model for End-stage Liver Disease)-matched controls. DNA methylation was determined using the 850K array (Illumina). Weighted Gene Co-expression Network Analysis (WGCNA) was used to identify modules related to defining physiologic characteristics of HPS. Only 12 out of the 20 liver biopsies (7 HPS and 5 controls) had sufficient quality to be analyzed. None of the 802,688 DNA probes analyzed in the case control comparison achieved a significant False Discovery Rate (FDR). WGCNA identified 5 co-methylated gene-modules associated to HPS markers, mainly related to nervous and neuroendocrine system, apoptotic processes, gut bacterial translocation, angiogenesis and vascular remodeling ontologies. To conclude, HPS is associated with nervous/neuroendocrine system and vascular remodeling related liver epigenetic changes.

Cyproterone acetate induces a wide spectrum of acute liver damage including corticosteroid-responsive hepatitis: report of 22 cases.

BACKGROUND & AIMS: Cyproterone acetate (CPA), an anti-androgenic drug for prostate cancer, has been associated with drug-induced liver injury (DILI). We aim to expand the knowledge on the spectrum of phenotypes and outcomes of CPA-induced DILI. METHODS: Twenty-two males (70 ± 8 years; range 54-83) developing liver damage as a result of CPA therapy (dose: 150 ± 50 mg/day; range 50-200) were included. Severity index and causality by RUCAM were assessed. RESULTS: From 1993 to 2013, 22 patients were retrieved. Latency was 163 ± 97 days. Most patients were symptomatic, showing hepatocellular injury (91%) and jaundice. Liver tests at onset were: ALT 18 ± 13 × ULN, ALP 0.7 ± 0.7 × ULN and total serum bilirubin 14 ± 10 mg/dl. International normalized ratio values higher than 1.5 were observed in 14 (66%) patients. Severity was mild in 1 case (4%), moderate in 7 (32%), severe in 11 (50%) and fatal in 3 (14%). Five patients developed ascitis, and four encephalopathy. One patient had a liver injury that resembled autoimmune hepatitis. Eleven (50%) were hospitalized. Nineteen patients recovered after CPA withdrawal, although three required steroid therapy (two of them had high ANA titres). Liver biopsy was performed in seven patients (two hepatocellular collapse, one submassive necrosis, two cholestatic hepatitis, one cirrhosis with iron overload and one autoimmune hepatitis). RUCAM category was 'highly probable' in 19 (86%), 'probable' in 1 (4%), and 'possible' in 2 (9%). CONCLUSIONS: CPA-induced liver injury is severe and can be fatal, and may occasionally resemble autoimmune DILI. The benefit/risk ratio of this drug should be thoroughly assessed in each patient.

Iron Deficiency Impairs Intra-Hepatic Lymphocyte Mediated Immune Response.

Hepatic expression of iron homeostasis genes and serum iron parameters predict the success of immunosuppression withdrawal following clinical liver transplantation, a phenomenon known as spontaneous operational tolerance. In experimental animal models, spontaneous liver allograft tolerance is established through a process that requires intra-hepatic lymphocyte activation and deletion. Our aim was to determine if changes in systemic iron status regulate intra-hepatic lymphocyte responses. We used a murine model of lymphocyte-mediated acute liver inflammation induced by Concanavalin A (ConA) injection employing mice fed with an iron-deficient (IrDef) or an iron-balanced diet (IrRepl). While the mild iron deficiency induced by the IrDef diet did not significantly modify the steady state immune cell repertoire and systemic cytokine levels, it significantly dampened inflammatory liver damage after ConA challenge. These findings were associated with a marked decrease in T cell and NKT cell activation following ConA injection in IrDef mice. The decreased liver injury observed in IrDef mice was independent from changes in the gut microflora, and was replicated employing an iron specific chelator that did not modify intra-hepatic hepcidin secretion. Furthermore, low-dose iron chelation markedly impaired the activation of isolated T cells in vitro. All together, these results suggest that small changes in iron homeostasis can have a major effect in the regulation of intra-hepatic lymphocyte mediated responses.

Functional consequences of transferrin receptor-2 mutations causing hereditary hemochromatosis type 3.

Hereditary hemochromatosis (HH) type 3 is an autosomal recessive disorder of iron metabolism characterized by excessive iron deposition in the liver and caused by mutations in the transferrin receptor 2 (TFR2) gene. Here, we describe three new HH type 3 Spanish families with four TFR2 mutations (p.Gly792Arg, c.1606-8A>G, Gln306*, and Gln672*). The missense variation p.Gly792Arg was found in homozygosity in two adult patients of the same family, and in compound heterozygosity in an adult proband that also carries a novel intronic change (c.1606-8A>G). Two new nonsense TFR2 mutations (Gln306* and Gln672*) were detected in a pediatric case. We examine the functional consequences of two TFR2 variants (p.Gly792Arg and c.1606-8A>G) using molecular and computational methods. Cellular protein localization studies using immunofluorescence demonstrated that the plasma membrane localization of p.Gly792Arg TFR2 is impaired. Splicing studies in vitro and in vivo reveal that the c.1606-8A>G mutation leads to the creation of a new acceptor splice site and an aberrant TFR2 mRNA. The reported mutations caused HH type 3 by protein truncation, altering TFR2 membrane localization or by mRNA splicing defect, producing a nonfunctional TFR2 protein and a defective signaling transduction for hepcidin regulation. TFR2 genotyping should be considered in adult but also in pediatric cases with early-onset of iron overload.

Hemocromatosis hereditaria. Problemas en el diagnóstico y tratamiento / Hereditary hemochromatosis. Problems in diagnosis and treatment

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Early periportal sinusoidal fibrosis is an accurate marker of accelerated HCV recurrence after liver transplantation.

BACKGROUND & AIMS: Significant liver fibrosis (F ⩾ 2) and portal hypertension (hepatic venous pressure gradient [HVPG] ⩾ 6 mmHg) 1 year after liver transplantation (LT) are predictors of severe hepatitis C recurrence. Periportal sinusoidal fibrosis (SF) is an early expression of the fibrogenic process in response to liver injury. We aimed to evaluate whether SF in early liver biopsies represents an early and accurate marker for identifying patients with severe HCV recurrence after LT. METHODS: A total of 101 HCV LT patients with early biopsy (<6 months), and HVPG measurement and/or liver biopsy one year after LT were included. Early biopsies were stained with Sirius Red and SF was graded semi-quantitatively. Results were compared between groups (significant SF vs. non-significant SF) and correlated with the development of severe HCV recurrence one year after LT. RESULTS: Patients with early significant SF had older donor age and higher necroinflammatory activity (NIA). The presence of early significant SF enabled identification of 78.9% and 90.6% of patients with F ⩾ 2 and HVPG ⩾ 6 mmHg, respectively, one year after LT. Donor age and NIA were independent predictors of significant fibrosis (F ⩾ 2) one year after LT, whereas donor age, ALT (3 months), NIA, and SF grade were independent predictors of portal hypertension (HVPG ⩾ 6). CONCLUSIONS: Significant SF in early biopsies is a good predictor of severe hepatitis C recurrence. This histological finding, when combined with simple variables, may be useful to select the best candidates for early antiviral therapy after LT.

A histologic scoring system for prognosis of patients with alcoholic hepatitis.

BACKGROUND & AIMS: There is no histologic classification system to determine prognoses of patients with alcoholic hepatitis (AH). We identified histologic features associated with disease severity and created a histologic scoring system to predict short-term (90-day) mortality. METHODS: We analyzed data from 121 patients admitted to the Liver Unit (Hospital Clinic, Barcelona, Spain) from January 2000 to January 2008 with features of AH and developed a histologic scoring system to determine the risk of death using logistic regression. The system was tested and updated in a test set of 96 patients from 5 academic centers in the United States and Europe, and a semiquantitative scoring system called the Alcoholic Hepatitis Histologic Score (AHHS) was developed. The system was validated in an independent set of 109 patients. Interobserver agreement was evaluated by weighted κ statistical analysis. RESULTS: The degree of fibrosis, degree of neutrophil infiltration, type of bilirubinostasis, and presence of megamitochondria were independently associated with 90-day mortality. We used these 4 parameters to develop the AHHS to identify patients with a low (0-3 points), moderate (4-5 points), or high (6-9 points) risk of death within 90 days (3%, 19%, and 51%, respectively; P < .0001). The AHHS estimated 90-day mortality in the training and test sets with an area under the receiver operating characteristic value of 0.77 (95% confidence interval, 0.71-0.83). Interrater agreement values were 0.65 for fibrosis, 0.86 for bilirubinostasis, 0.60 for neutrophil infiltration, and 0.46 for megamitochondria. Interestingly, the type of bilirubinostasis predicted the development of bacterial infections. CONCLUSIONS: We identified histologic features associated with the severity of AH and developed a patient classification system that might be used in clinical decision making.

Hepatitis autoinmune inducida por levofloxacino. Descripción de un caso / Levofloxacin-induced autoimmune hepatitis. Description of a case

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[Medicolegal analysis of legal claims in bariatric surgery]. / Análisis médico-legal de las reclamaciones judiciales en cirugía bariátrica.

OBJECTIVES: To analyse the causes for claims due to alleged malpractice in bariatric surgery and the results of the legal process. MATERIAL AND METHOD: A review was carried out on the case files of claims for damages as a result of bariatric surgery presented to the Professional Liability Department of the Catalonian Medical Colleges Council from 1992 to 2009. The claims rate was calculated using a survey of bariatric surgeons. RESULTS: A total of 49 cases were analysed, which represented 0.6% of the patients operated on. The patient died in 23 (47%) of the cases, 14% were left with serious after effects, 18% had mild after effects, and 21% made a complete recovery. The most frequent causes of death were peritonitis due to suture dehiscence (48%), and respiratory complications (17.4%). Retrospectively, malpractice was considered to have occurred in 10 (20%) of the sued cases due to lack of an adequate informed consent document, delay in recognising a complication, or an error in interpretation, or treatment of the complication. The doctor sued was convicted in 10 of the cases, 3 in a criminal court, and 7 in a civil court. There was acquittal in 19 cases, an out-of court settlement with payment of compensation in 4, withdrawal of the claim in 4, and judgement or sentence is still pending in 12 cases. CONCLUSION: The study showed a relatively low rate of claims for complications associated with bariatric surgery. The number of convictions was relatively high. The early detection of surgical complications is essential in order to reduce legal claims associated with bariatric surgery.

Análisis médico-legal de las reclamaciones judiciales en cirugía bariátrica / Medicolegal analysis of legal claims in bariatric surgery

Objetivos Analizar las causas de reclamación por presuntos defectos de praxis en cirugía bariátrica y los resultados del proceso judicial. Material y método Revisión de los expedientes de los casos de reclamación presentados al Servicio de Responsabilidad Profesional del Consejo de Colegios de Médicos de Cataluña desde 1992 hasta 2009 por daños como consecuencia de cirugía bariátrica. Se calculó la tasa de reclamaciones mediante una encuesta en los cirujanos bariátricos. Resultados Se analizaron 49 casos, que representan una tasa de reclamaciones del 0,6% de los pacientes operados. En 23 ocasiones (47%) tuvo lugar el fallecimiento del paciente, en el 14% quedaron secuelas graves, en el 18% secuelas leves y en el 21% hubo una recuperación completa. Las causas más frecuentes de muerte fueron peritonitis por dehiscencia de sutura (48%) y complicaciones respiratorias (17,4%). Se consideró retrospectivamente que habían existido defectos de praxis en 10 (20%) de los casos reclamados por falta de documento de consentimiento informado adecuado, retraso en el reconocimiento de la complicación, o error en la interpretación o tratamiento de la misma. En 10 casos hubo sentencia condenatoria para el médico reclamado, 3 en un juicio penal y 7 en juicio civil, hubo absolución en 19, acuerdo extrajudicial con pago de indemnización en 4, retirada de la reclamación en 4 y están todavía pendientes de juicio o de sentencia 12 casos. Conclusión Se demuestra una relativamente baja tasa de reclamaciones por complicaciones relacionadas con la cirugía bariátrica. La muerte del paciente fue la principal causa de reclamación. El número de sentencias condenatorias fue relativamente elevado. La detección precoz de las complicaciones quirúrgicas es indispensable para la reducción de la litigiosidad relacionada con cirugía bariátrica (AU)

Objectives To analyse the causes for claims due to alleged malpractice in bariatric surgery and the results of the legal process. Material and Method A review was carried out on the case files of claims for damages as a result of bariatric surgery presented to the Professional Liability Department of the Catalonian Medical Colleges Council from 1992 to 2009. The claims rate was calculated using a survey of bariatric surgeons. Results A total of 49 cases were analysed, which represented 0.6% of the patients operated on. The patient died in 23 (47%) of the cases, 14% were left with serious after effects, 18% had mild after effects, and 21% made a complete recovery. The most frequent causes of death were peritonitis due to suture dehiscence (48%), and respiratory complications (17.4%). Retrospectively, malpractice was considered to have occurred in 10 (20%) of the sued cases due to lack of an adequate informed consent document, delay in recognising a complication, or an error in interpretation, or treatment of the complication. The doctor sued was convicted in 10 of the cases, 3 in a criminal court, and 7 in a civil court. There was acquittal in 19 cases, an out-of court settlement with payment of compensation in 4, withdrawal of the claim in 4, and judgement or sentence is still pending in 12 cases. Conclusion The study showed a relatively low rate of claims for complications associated with bariatric surgery. The number of convictions was relatively high. The early detection of surgical complications is essential in order to reduce legal claims associated with bariatric surgery (AU)

Bone morphogenetic protein receptor 2 in patients with idiopathic portal hypertension.

In idiopathic portal hypertension (IPH) typical vascular lesions are present in the branches of the portal vein or in the perisinusoidal area of the liver. Similar histological alterations have been reported in the pulmonary vasculature of patients with idiopathic pulmonary artery hypertension (IPAH). As IPAH is associated with mutations of the bone morphogenetic protein receptor 2 (BMPR2) gene, the aim of this study was to investigate whether this association might also be found in patients with IPH. Twenty-three samples belonging to 21 unrelated caucasian patients with IPH followed in the hepatic haemodynamic laboratory of the Hospital Clinic in Barcelona were included in the study. All patients were studied for the entire open reading frame and splice site of the BMPR2 gene by direct sequencing and multiple ligation probe amplification (MLPA) in order to detect large deletions/duplications. None of the 23 patients had pulmonary artery hypertension. Four patients presented one single nucleotide polymorphism (SNP) in intron 5, four patients had a SNP in exon 12 and a SNP in exon 1 was found in two cases. Two patients had both intron 5 and exon 12 polymorphisms. All SNPs were previously described. Except for these three SNPs, neither mutations nor rearrangements have been identified in the BMPR2 gene in this population. We did not detect mutations or rearrangements in the coding region of the BMPR2 gene in our patients with IPH. These findings suggest that, in contrast to IPAH, mutations in BMPR2 are not involved in the pathogenesis of IPH.