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Acute cholecystitis (AC), generally associated with the presence of gallstones, is a relatively frequent disease that can lead to serious complications. For these reasons, AC warrants prompt clinical diagnosis and management. There is general agreement in terms of considering early laparoscopic cholecystectomy (ELC) to be the best treatment for AC. The optimal timeframe to perform ELC is within 72 h from diagnosis, with a possible extension of up to 7-10 days from symptom onset. In the first hours or days after hospital admission, before an ELC procedure, the patient's medical management comprises fasting, intravenous fluid infusion, antimicrobial therapy, and possible administration of analgesics. Additionally, concomitant conditions such as choledocholithiasis, cholangitis, biliary pancreatitis, or systemic complications must be recognized and adequately treated. The importance of ELC is related to the frequent recurrence of symptoms and complications of gallstone disease in the interval period between the onset of AC and surgical intervention. In patients who are not eligible for ELC, it is suggested to delay surgery at least 6 weeks after the clinical presentation. Critically ill patients, who are unfit for surgery, may require rescue treatments, such as percutaneous or endoscopic gallbladder drainage (GBD). A particular treatment approach should be applied to special populations such as pregnant women, cirrhotic, and elderly patients. In this review, we provide a practical diagnostic and therapeutic approach to AC, even in specific clinical situations, based on evidence from the literature.
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Grayscale abdomen ultrasound (US) is routinely performed in pregnant women with suspected pregnancy-related liver dysfunction, but its diagnostic yield is very low. We aimed to investigate the association between Doppler-US findings, liver stiffness measurement (LSM) and different causes of pregnancy-related liver dysfunction. This is a prospective cohort study of pregnant women referred to our tertiary center for any suspected gastrointestinal disease between 2017 and 2019 and undergoing Doppler-US and liver elastography. Patients with previous liver disease were excluded from the analysis. For group comparisons of categorical and continuous variables, the chi-square test or Mann-Whitney test, and the McNemar test were used, as appropriate. A total of 112 patients were included in the final analysis, of whom 41 (36.6%) presented with suspected liver disease: 23 intrahepatic cholestasis of pregnancy (ICP), six with gestational hypertensive disorders and 12 cases with undetermined causes of elevated liver enzymes. Values of LSM were higher and significantly associated with a diagnosis of gestational hypertensive disorder (AUROC = 0.815). No significant differences at Doppler-US or LSM were found between ICP patients and controls. Patients with undetermined causes of hypertransaminasemia showed higher hepatic and splenic resistive indexes than controls, suggesting splanchnic congestion. The evaluation of Doppler-US and liver elastography is clinically useful in patients with suspected liver dysfunction during pregnancy. Liver stiffness represents a promising non-invasive tool for the assessment of patients with gestational hypertensive disorders.
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PURPOSE: The role of liver stiffness (LS) on ultrasound elastography in the prediction of hepatocellular carcinoma (HCC) recurrence after treatment with radiofrequency ablation (RFA) is still unclear. Our aim was to perform a systematic review and meta-analysis to assess whether LS can predict the recurrence of HCC after RFA. MATERIALS AND METHODS: Medline via PubMed, Embase, Scopus, and Cochrane Library databases, and abstracts of international conference proceedings were searched up to June 30, 2020. Cohort studies were included if they assessed the association between LS values measured by ultrasound elastography before RFA and HCC recurrence. RESULTS: 9 studies including 1373 patients with HCC treated by RFA, 643 of whom developed HCC recurrence, were identified. The mean value of LS before RFA was significantly higher in patients who developed HCC recurrence than in those who did not (weighted mean difference=11.98 kPa, 95%CI: 7.60-16.35, I2=63.8%). There was a significant positive association between LS value and HCC recurrence both at univariate (unadjusted HR=1.03, 95%CI: 1.00-1.07, I2=72.7%) and multivariate analysis (adjusted HR=1.03, 95%CI: 1.02-1.04, I2=0). Patients with LS value ≥13-14 kPa or >1.5 m/s have a higher risk of both HCC recurrence (unadjusted HR=2.18, 95%CI: 1.46-3.25, I2=49.7%; adjusted HR=2.41, 95%CI: 1.53-3.79, I2=0) and overall mortality (adjusted HR=4.38; 95%CI: 2.33-8.25, I2=0) in comparison with those with LS below these cutoffs. CONCLUSION: Liver ultrasound elastography appears to be a reliable tool to predict HCC recurrence and overall survival after RFA. This technique may be useful for the management of patients with HCC treated by RFA.
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Carcinoma Hepatocelular , Ablação por Cateter , Técnicas de Imagem por Elasticidade , Neoplasias Hepáticas , Ablação por Radiofrequência , Humanos , Carcinoma Hepatocelular/diagnóstico por imagem , Carcinoma Hepatocelular/cirurgia , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/cirurgia , Técnicas de Imagem por Elasticidade/métodos , Ablação por Cateter/efeitos adversos , Ablação por Cateter/métodos , Recidiva Local de Neoplasia/diagnóstico por imagem , Recidiva Local de Neoplasia/etiologia , Recidiva Local de Neoplasia/cirurgia , Resultado do TratamentoRESUMO
Contrary to humans, candidiasis is a rare infection in animals. However, in reptiles, candidiasis can cause gastrointestinal, cutaneous, or rarely systemic infections in stressed animals. The infections due to Yarrowia lipolytica have been increasingly described in human medicine, and hundreds of cases are reported, comprised of granulomatous lung lesions. Herein, granulomatous pneumonia of a spectacled caiman, Caiman crocodilus, was described, and the presence of Y. lipolytica in the lesion was confirmed through histopathology, microbiologic cultures, and molecular methods. The cause of death of the spectacled caiman was ascribed to bacterial shock septicemia consequentially to a traumatic lesion. However, in the right lung, several nodules containing white exudate were evidenced. At mycological and molecular analyses, Y. lipolytica was evidenced, and the histological finding confirmed the presence of a Candida infection in the lung granulomatous lesions. The comparison of ITS sequences with 11 Yarrowia spp. isolates, recently described in green sea turtles, and with a human strain was conducted, and the whole genome of a strain isolated in the spectacled caiman was sequenced. Even though Y. lipolytica is considered a non-pathogenic yeast and has been rarely described in animals, it seems to cause granulomatous lesions in reptiles as in humans.
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INTRODUCTION: Coeliac disease and dermatitis herpetiformis are immune-mediated diseases triggered by the consumption of gluten in genetically predisposed individuals. These guidelines were developed to provide general practitioners, paediatricians, gastroenterologists, and other clinicians with an overview on the diagnosis, management and follow-up of coeliac patients and those with dermatitis herpetiformis. METHODS: Guidelines were developed by the Italian Societies of Gastroenterology. Following a systematic literature review, the Grading of Recommendations Assessment, Development and Evaluation methodology was used to assess the certainty of the evidence. Statements and recommendations were developed by working groups consisting of gastroenterologists and a paediatrician with expertise in this field. RESULTS: These guidelines provide a practical guidance for the diagnosis, management and follow-up of coeliac patients and dermatitis herpetiformis in children and adults, both in primary care and in specialist settings. We developed four sections on diagnosis, gluten-free diet, follow-up and risk of complications in adults, one section focused on diagnosis and follow-up in children and one on the diagnosis and management of dermatitis herpetiformis. CONCLUSIONS: These guidelines may support clinicians to improve the diagnosis and management of patients with coeliac disease.
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Doença Celíaca , Dermatite Herpetiforme , Gastroenterologia , Adulto , Doença Celíaca/complicações , Doença Celíaca/diagnóstico , Doença Celíaca/terapia , Criança , Dermatite Herpetiforme/diagnóstico , Dermatite Herpetiforme/terapia , Dieta Livre de Glúten , Glutens/efeitos adversos , Humanos , Revisões Sistemáticas como AssuntoRESUMO
(1) Introduction: Liver resection (LR) for hepatocellular carcinoma (HCC) is often burdened by life-threatening complications, such as post-hepatectomy liver failure (PHLF). The albumin-bilirubin (ALBI) score can accurately evaluate liver function and the long-term prognosis of HCC patients, including PHLF. We aimed to evaluate the diagnostic value of the ALBI grade in predicting PHLF in HCC patients undergoing LR. (2) Methods: MEDLINE, Embase, and Scopus were searched through January 17th, 2021. Studies reporting the ALBI grade and PHLF occurrence in HCC patients undergoing LR were included. The Odds Ratio (OR) prevalence with 95% confidence intervals (CI) was pooled, and the heterogeneity was expressed as I2. The quality of the studies was assessed using QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies). (3) Results: Seven studies met the inclusion criteria and were included in the analysis. A total of 5377 patients who underwent LR for HCC were considered, of whom 718 (13.4%) developed PHLF. Patients with ALBI grades 2 and 3 before LR showed increased rates of PHLF compared to ALBI grade 1 patients. The pooled OR was 2.572 (95% CI, 1.825 to 3.626, p < 0.001), with substantial heterogeneity between the studies (I2 = 69.6%) and no publication bias (Begg's p = 0.764 and Egger's p = 0.851 tests). All studies were at a 'low risk' or 'unclear risk' of bias. Univariate meta-regression analysis showed that heterogeneity was not dependent on the country of study, the age and sex of the participants, the definition of PHLF used, the rate of patients in Child-Pugh class A or undergoing major hepatectomy. (4) Conclusions: In this meta-analysis of published studies, individuals with ALBI grades of 2 and 3 showed increased rates of PHLF compared to ALBI grade 1 patients.
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Portal hypertension is the main driver of complications in patients with advanced chronic liver disease (ACLD) and is defined by values of hepatic venous pressure gradient measurement (HVPG) >5 mmHg. Values of HVPG ≥10 mmHg determine the presence of clinically significant portal hypertension (CSPH), the main predictor of the risk of variceal bleeding, hepatic decompensation, and mortality. However, its measurement is invasive and requires high expertise, so its routine use outside third level centers or clinical trials is limited. In the last decades, several non-invasive tests (NITs) have been developed and validated for the diagnosis of portal hypertension. Among these, liver (LSM) and spleen stiffness measurement (SSM) are the most promising tools available, as they have been proven accurate to predict CSPH, high-risk esophageal varices, decompensation, and mortality in patients with ACLD. In the last Baveno VI Consensus proceedings, LSM evaluation was recommended for the first time for diagnosis of CSPH (LSM >20-25 kPa) and the screening of patients with a low probability of having high-risk varices (LSM <20 kPa and platelet count >150.000/mm3). In this review, we aimed to summarize the growing evidence supporting the use of non-invasive tests for the evaluation of portal hypertension in patients with chronic liver disease.
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The assessment of portal hypertension is a relevant step in the evaluation of newly diagnosed advanced chronic liver disease (ACLD). The current gold standard includes the invasive evaluation of hepatic venous pressure gradient (HVPG) and endoscopy. However, noninvasive or minimally invasive techniques to assess portal hypertension have been proposed and well established. In the present manuscript, we review clinical studies on the use of noninvasive or minimally invasive techniques to assess portal hypertension in ACLD patients.
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BACKGROUND: Data concerning patients originates from a variety of sources on social media. OBJECTIVE: The aim of this study was to show how methodologies borrowed from different areas including computer science, econometrics, statistics, data mining, and sociology may be used to analyze Facebook data to investigate the patients' perspectives on a given medical prescription. METHODS: To shed light on patients' behavior and concerns, we focused on Crohn's disease, a chronic inflammatory bowel disease, and the specific therapy with the biological drug Infliximab. To gain information from the basin of big data, we analyzed Facebook posts in the time frame from October 2011 to August 2015. We selected posts from patients affected by Crohn's disease who were experiencing or had previously been treated with the monoclonal antibody drug Infliximab. The selected posts underwent further characterization and sentiment analysis. Finally, an ethnographic review was carried out by experts from different scientific research fields (eg, computer science vs gastroenterology) and by a software system running a sentiment analysis tool. The patient feeling toward the Infliximab treatment was classified as positive, neutral, or negative, and the results from computer science, gastroenterologist, and software tool were compared using the square weighted Cohen's kappa coefficient method. RESULTS: The first automatic selection process returned 56,000 Facebook posts, 261 of which exhibited a patient opinion concerning Infliximab. The ethnographic analysis of these 261 selected posts gave similar results, with an interrater agreement between the computer science and gastroenterology experts amounting to 87.3% (228/261), a substantial agreement according to the square weighted Cohen's kappa coefficient method (w2K=0.6470). A positive, neutral, and negative feeling was attributed to 36%, 27%, and 37% of posts by the computer science expert and 38%, 30%, and 32% by the gastroenterologist, respectively. Only a slight agreement was found between the experts' opinion and the software tool. CONCLUSIONS: We show how data posted on Facebook by Crohn's disease patients are a useful dataset to understand the patient's perspective on the specific treatment with Infliximab. The genuine, nonmedically influenced patients' opinion obtained from Facebook pages can be easily reviewed by experts from different research backgrounds, with a substantial agreement on the classification of patients' sentiment. The described method allows a fast collection of big amounts of data, which can be easily analyzed to gain insight into the patients' perspective on a specific medical therapy.
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Proton pump inhibitors are among the most commonly prescribed classes of drugs, and their use is increasing, in particular for long-term treatment, often being over-prescribed and used for inappropriate conditions. In recent years, considerable attention has been directed towards a wide range of adverse effects, and even when a potential underlying biological mechanism is plausible, the clinical evidence of the adverse effect is often weak. Several long-term side effects have been investigated ranging from interaction with other drugs, increased risk of infection, reduced intestinal absorption of vitamins and minerals, and more recently kidney damage and dementia. The most recent literature regarding these adverse effects and their association with long-term proton pump inhibitor treatment is reviewed, and the mechanisms through which these possible complications might develop are discussed.
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Inibidores da Bomba de Prótons/administração & dosagem , Inibidores da Bomba de Prótons/efeitos adversos , Cálcio/metabolismo , Doenças Cardiovasculares/etiologia , Clopidogrel , Demência/induzido quimicamente , Interações Medicamentosas , Fraturas Ósseas/etiologia , Neoplasias Gastrointestinais/etiologia , Humanos , Absorção Intestinal/efeitos dos fármacos , Nefropatias/induzido quimicamente , Pneumonia/etiologia , Risco , Ticlopidina/análogos & derivados , Ticlopidina/farmacocinética , Fatores de Tempo , Vitaminas/metabolismoRESUMO
BACKGROUND & AIMS: Indocyanine green retention test (ICG-r15) is a non-invasive marker of functional hepatic reserve. Among patients with compensated cirrhosis, ICG-r15 correlates to the degree of portal hypertension (PH); however, its prognostic relationship with the occurrence of decompensation events still requires clarification. METHODS: ICG-r15 was prospectively measured in 154 patients with compensated cirrhosis. Patients with hepatocellular carcinoma (HCC), Child-Pugh B-C, MELD>15, bilirubin > 2 mg/dl, INR > 1.5 or portal vein thrombosis were excluded. All patients underwent laboratory tests, upper endoscopy and hepatic venous pressure gradient (HVPG). Decompensation, development of HCC, liver transplant and death were recorded and analysed through competing-risk analysis. RESULTS: The study group was composed of 134 patients who were followed for a median of 39 months. During follow-up, 46 patients (34.3%) developed liver decompensation. Hepatocellular carcinoma occurred in 18 patients and two patients died from non-liver-related causes. The 1-, 2- and 3-year cumulative incidences of decompensation were 9.7%, 28.4% and 33.4% respectively. Patients with ICG-r15 < 10% did not experience any decompensation events during follow-up, while the 3-year cumulative incidence of decompensation of patients with ICG-r15 between 10% and 22.9% was 29.2% and that of patients with ICG-r15 ≥ 23% was 70.0% (P < 0.001). ICG-r15 gave the lowest pseudo-log-likelihood value, in comparison to oesophageal varices present, MELD, low platelet count and HVPG. CONCLUSIONS: ICG-r15 appears to be strictly related to liver decompensation, longitudinally confirming the preliminary findings of its correlation with PH among patients with compensated cirrhosis, and can be used for patient prognostication.
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Hipertensão Portal/diagnóstico , Verde de Indocianina/metabolismo , Cirrose Hepática/complicações , Idoso , Biomarcadores/metabolismo , Carcinoma Hepatocelular/complicações , Endoscopia Gastrointestinal , Varizes Esofágicas e Gástricas/complicações , Feminino , Humanos , Hipertensão Portal/complicações , Incidência , Estimativa de Kaplan-Meier , Cirrose Hepática/fisiopatologia , Testes de Função Hepática , Neoplasias Hepáticas/complicações , Masculino , Pessoa de Meia-Idade , Pressão na Veia Porta , Prognóstico , Estudos Prospectivos , Análise de Regressão , Medição de RiscoRESUMO
Mild to moderate autoimmune thrombocytopenia (AITP) is a common finding in patients receiving interferon-based antiviral treatment, due to bone marrow suppression. Here we report the case of a patient with chronic genotype 1b hepatitis C virus (HCV) infection treated with pegylated-interferon alpha-2a, ribavirin and telaprevir for 24 wk; the patient developed severe AITP three weeks after treatment withdrawal. We performed a systematic literature search in order to review all published cases of AITP related to HCV antiviral treatment. To our knowledge, this is the second case of AITP observed after antiviral treatment withdrawal. In most published cases AITP occurred during treatment; in fact, among 24 cases of AITP related to interferon-based antiviral treatment, only one occurred after discontinuation. Early diagnosis of AITP is a key factor in order to achieve an early interferon discontinuation; in the era of new direct antiviral agents those patients have to be considered for interferon-free treatment regimens. Prompt prescription of immuno-suppressant treatment (i.e., corticosteroids, immunoglobulin infusion and even rituximab for unresponsive cases) leads to favourable prognosis in most of cases. Physicians using interferon-based treatments should be aware that AITP can occur both during and after treatment, specially in the new era of interferon-free antiviral treatment. Finally, in the case of suspected AITP, presence of anti-platelet antibodies should be checked not only during treatment but also after discontinuation.
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OBJECTIVE: Chlamydia pneumoniae has been linked to atherosclerosis, strictly associated with hyperlipidemia. The liver plays a central role in the regulation of lipid metabolism. Since in animal models C. pneumoniae can be found at hepatic level, this study aims to elucidate whether C. pneumoniae infection accelerates atherosclerosis by affecting lipid metabolism. METHODS: Thirty Balb/c mice were challenged intra-peritoneally with C. pneumoniae elementary bodies and thirty with Chlamydia trachomatis, serovar D. Thirty mice were injected with sucrose-phosphate-glutamate buffer, as negative controls. Seven days after infection, liver samples were examined both for presence of chlamydia and expression of genes involved in inflammation and lipid metabolism. RESULTS: C. pneumoniae was isolated from 26 liver homogenates, whereas C. trachomatis was never re-cultivated (P < 0.001). C. pneumoniae infected mice showed significantly increased serum cholesterol and triglycerides levels compared both with negative controls (P < 0.001 and P = 0.0197, respectively) and C. trachomatis infected mice (P < 0.001). Liver bile acids were significantly reduced in C. pneumoniae compared to controls and C. trachomatis infected mice. In C. pneumoniae infected livers, cholesterol 7α-hydroxylase (Cyp7a1) and low-density lipoprotein receptor (Ldlr) mRNA levels were reduced, while inducible degrader of the low-density lipoprotein receptor (Idol) expression was increased. Hypertriglyceridemia was associated to reduced expression of hepatic carnitine palmitoyltransferase-1a (Cpt1a) and medium chain acyl-Coenzyme A dehydrogenase (Acadm). Pro-inflammatory cytokines gene expression was increased compared to negative controls. Conversely, in C. trachomatis infected animals, normal serum lipid levels were associated with elevated pro-inflammatory cytokines gene expression, linked to only a mild disturbance of lipid regulatory genes. CONCLUSION: Our results indicate that C. pneumoniae mouse liver infection induces dyslipidemic effects with significant modifications of genes involved in lipid metabolism.
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Infecções por Chlamydia/microbiologia , Colesterol/metabolismo , Falência Hepática Aguda/microbiologia , Fígado/metabolismo , Triglicerídeos/metabolismo , Acil-CoA Desidrogenase/metabolismo , Animais , Aterosclerose/complicações , Aterosclerose/microbiologia , Ácidos e Sais Biliares/metabolismo , Carnitina O-Palmitoiltransferase/metabolismo , Infecções por Chlamydia/complicações , Chlamydia trachomatis , Chlamydophila pneumoniae , Citocinas/metabolismo , Regulação da Expressão Gênica , Ácido Glutâmico/química , Inflamação , Infusões Parenterais , Metabolismo dos Lipídeos , Lipídeos/sangue , Fígado/microbiologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Fosfatos/química , Sacarose/químicaRESUMO
BACKGROUND: Fitz-Hugh-Curtis syndrome is a rare extra-pelvic complication of genital infection involving the perihepatic capsule. Most cases have been described in women in association with pelvic inflammatory disease; in rare cases it has been reported in men. Because the main symptom is acute abdominal pain, and laboratory and imaging findings are frequently nonspecific, the differential diagnosis, considering other gastrointestinal or renal diseases, can be difficult in the early stage of the syndrome, leading to frequent misdiagnosis and mismanagement. CASE REPORT: We report a case of Fitz-Hugh-Curtis syndrome in a 26-year-old man who first presented to the emergency department with acute abdominal pain, vomiting, and fever. Diagnosis was possible on the basis of clinical signs of orchiepididymitis, abnormal ultrasound findings, and specialist consultation with the Sexually Transmitted Infection Clinic. An acute gonoccocal infection was revealed, which was complicated by a collection of free perihepatic fluid and a subcapsular hypoechoic focal lesion. Prompt antibiotic therapy was established, with complete resolution of the symptoms within a few days. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Awareness of the clinical presentation, imaging, and laboratory findings during the acute phase of Fitz-Hugh-Curtis syndrome could help emergency physicians to make an early diagnosis and to correctly manage such patients. Improved diagnostic skills could prevent chronic complications that are especially a risk in the case of delayed or minor genitourinary symptoms.
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Infecções por Chlamydia/diagnóstico , Infecções por Chlamydia/microbiologia , Gonorreia/complicações , Hepatite/diagnóstico , Hepatite/microbiologia , Doença Inflamatória Pélvica/diagnóstico , Doença Inflamatória Pélvica/microbiologia , Peritonite/diagnóstico , Peritonite/microbiologia , Dor Abdominal/microbiologia , Doença Aguda , Adulto , Diagnóstico Diferencial , Febre/microbiologia , Humanos , Masculino , Vômito/microbiologiaRESUMO
Phytosterols, besides hypocholesterolemic effect, present anti-inflammatory properties. Little information is available about their efficacy in Inflammatory Bowel Disease (IBD). Therefore, we have evaluated the effect of a mixture of phytosterols on prevention/induction/remission in a murine experimental model of colitis. Phytosterols were administered x os before, during and after colitis induction with Dextran Sodium Sulfate (DSS) in mice. Disease Activity Index (DAI), colon length, histopathology score, 18F-FDG microPET, oxidative stress in the intestinal tissue (ileum and colon) and gallbladder ileum and colon spontaneous and carbachol (CCh) induced motility, plasma lipids and plasma, liver and biliary bile acids (BA) were evaluated. A similar longitudinal study was performed in a DSS colitis control group. Mice treated with DSS developed severe colitis as shown by DAI, colon length, histopathology score, 18F-FDG microPET, oxidative stress. Both spontaneous and induced ileal and colonic motility were severely disturbed. The same was observed with gallbladder. DSS colitis resulted in an increase in plasma cholesterol, and a modification of the BA pattern. Phytosterols feeding did not prevent colitis onset but significantly reduced the severity of the disease and improved clinical and histological remission. It had strong antioxidant effects, almost restored colon, ileal and gallbladder motility. Plasmatic levels of cholesterol were also reduced. DSS induced a modification in the BA pattern consistent with an increase in the intestinal BA deconjugating bacteria, prevented by phytosterols. Phytosterols seem a potential nutraceutical tool for gastrointestinal inflammatory diseases, combining metabolic systematic and local anti-inflammatory effects.
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Anti-Inflamatórios/farmacologia , Colite/tratamento farmacológico , Colo/efeitos dos fármacos , Fitosteróis/farmacologia , Animais , Ácidos e Sais Biliares/metabolismo , Colesterol/sangue , Colite/induzido quimicamente , Colite/metabolismo , Colite/patologia , Colo/patologia , Sulfato de Dextrana , Modelos Animais de Doenças , Vesícula Biliar/efeitos dos fármacos , Vesícula Biliar/patologia , Íleo/efeitos dos fármacos , Íleo/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Estresse Oxidativo , Peristaltismo/efeitos dos fármacos , Indução de Remissão , Índice de Gravidade de DoençaRESUMO
We report on the relationship between the structure-pharmacokinetics, metabolism, and therapeutic activity of semisynthetic bile acid analogs, including 6α-ethyl-3α,7α-dihydroxy-5ß-cholan-24-oic acid (a selective farnesoid X receptor [FXR] receptor agonist), 6α-ethyl-23(S)-methyl-3α,7α,12α-trihydroxy-5ß-cholan-24-oic acid (a specific Takeda G protein-coupled receptor 5 [TGR5] receptor agonist), and 6α-ethyl-3α,7α-dihydroxy-24-nor-5ß-cholan-23-sulfate (a dual FXR/TGR5 agonist). We measured the main physicochemical properties of these molecules, including ionization constants, water solubility, lipophilicity, detergency, and protein binding. Biliary secretion and metabolism and plasma and hepatic concentrations were evaluated by high-pressure liquid chromatography-electrospray-mass spectrometry/mass spectrometry in bile fistula rat and compared with natural analogs chenodeoxycholic, cholic acid, and taurochenodexycholic acid and intestinal bacteria metabolism was evaluated in terms of 7α-dehydroxylase substrate-specificity in anaerobic human stool culture. The semisynthetic derivatives detergency, measured in terms of their critical micellar concentration, was quite similar to the natural analogs. They were slightly more lipophilic than the corresponding natural analogs, evaluated by their 1-octanol water partition coefficient (log P), because of the ethyl group in 6 position, which makes these molecules very stable toward bacterial 7-dehydroxylation. The hepatic metabolism and biliary secretion were different: 6α-ethyl-3α,7α-dihydroxy-5ß-cholan-24-oic acid, as chenodeoxycholic acid, was efficiently conjugated with taurine in the liver and, only in this form, promptly and efficiently secreted in bile. 6α-Ethyl-23(S)-methyl-3α,7α,12α-trihydroxy-5ß-cholan-24-oic acid was poorly conjugated with taurine because of the steric hindrance of the methyl at C23(S) position metabolized to the C23(R) isomer and partly conjugated with taurine. Conversely, 6α-ethyl-3α,7α-dihydroxy-24-nor-5ß-cholan-23-sulfate was secreted in bile unmodified and as 3-glucuronide. Therefore, minor structural modifications profoundly influence the metabolism and biodistribution in the target organs where these analogs exert therapeutic effects by interacting with FXR and/or TGR5 receptors.
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Ácidos e Sais Biliares/farmacocinética , Receptores Citoplasmáticos e Nucleares/agonistas , Receptores Acoplados a Proteínas G/agonistas , Animais , Bactérias/metabolismo , Bile/química , Ácidos e Sais Biliares/análise , Ácidos e Sais Biliares/sangue , Fenômenos Químicos , Humanos , Fígado/metabolismo , RatosRESUMO
UNLABELLED: Noninvasive markers would be useful for the assessment of portal hypertension (PH) and esophageal varices (EV) in patients with cirrhosis. The aim of our study was to evaluate the performance of the indocyanine green (ICG) retention test as a noninvasive marker of PH and EV, measured against the gold standards (hepatic venous pressure gradient [HVPG] measurement and upper endoscopy). We prospectively enrolled patients with compensated cirrhosis referral to our unit. All patients underwent laboratory tests, abdominal ultrasound, upper gastrointestinal endoscopy, HVPG measurement, and the ICG 15-minute retention (ICG-r15) test. We evaluated the sensitivity and specificity of the ICG retention test and other noninvasive tools for the diagnosis of PH and EV. Ninety-six consecutive Child-Pugh A patients (67 male and 29 female; 60.3 ± 11.8 years of age) were enrolled. Seventy-four patients had clinically significant portal hypertension (CSPH), of whom 59 had severe portal hypertension (SPH). ICG-r15 and Lok index were independently related to the presence of both CSPH and SPH, whereas ICG-r15 and INR were related to EV. ICG-r15 values (<6.7% and <6.9%, respectively) were able to rule out the presence of CSPH and SPH (LR(-) 0.15 and 0.14); ICG-r15 <10% provided a 97.8% sensitivity (LR(-) 0.042) for the exclusion of EV and a 100% sensitivity (LR(-) 0.0) for large EV. CONCLUSION: The ICG-r15 test is an effective tool for assessment of PH in patients with compensated cirrhosis. Although this would not replace endoscopy, the ICG-r15 appears able to identify patients with advanced liver disease in which endoscopy is mandatory as well as rule out the presence of EV in patients with compensated cirrhosis.