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BACKGROUND & AIMS: Obeticholic acid (OCA) is the only licensed second-line therapy for primary biliary cholangitis (PBC). With novel therapeutics in advanced development, clinical tools are needed to tailor the treatment algorithm. We aimed to derive and externally validate the OCA response score (ORS) for predicting the response probability of individuals with PBC to OCA. METHODS: We used data from the Italian RECAPITULATE (N = 441) and the IBER-PBC (N = 244) OCA real-world prospective cohorts to derive/validate a score including widely available variables obtained either pre-treatment (ORS) or also after 6 months of treatment (ORS+). Multivariable Cox regressions with backward selection were applied to obtain parsimonious predictive models. The predicted outcomes were biochemical response according to POISE (alkaline phosphatase [ALP]/upper limit of normal [ULN]<1.67 with a reduction of at least 15%, and normal bilirubin), or ALP/ULN<1.67, or normal range criteria (NR: normal ALP, alanine aminotransferase [ALT], and bilirubin) up to 24 months. RESULTS: Depending on the response criteria, ORS included age, pruritus, cirrhosis, ALP/ULN, ALT/ULN, GGT/ULN, and bilirubin. ORS+ also included ALP/ULN and bilirubin after 6 months of OCA therapy. Internally validated c-statistics for ORS were 0.75, 0.78, and 0.72 for POISE, ALP/ULN<1.67, and NR response, which raised to 0.83, 0.88, and 0.81 with ORS+, respectively. The respective performances in validation were 0.70, 0.72, and 0.71 for ORS and 0.80, 0.84, and 0.78 for ORS+. Results were consistent across groups with mild/severe disease. CONCLUSIONS: We developed and externally validated a scoring system capable to predict OCA response according to different criteria. This tool will enhance a stratified second-line therapy model to streamline standard care and trial delivery in PBC.
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Iron overload caused by hereditary hemochromatosis (HH) increases free reactive oxygen species that, in turn, induce lipid peroxidation. Its 4-hydroxynonenal (HNE) by-product is a well-established marker of lipid peroxidation since it reacts with accessible proteins with deleterious consequences. Indeed, elevated levels of HNE are often detected in a wide variety of human diseases related to oxidative stress. Here, we evaluated HNE-modified proteins in the membrane of erythrocytes from HH patients and in organs of Hfe-/- male and female mice, a mouse model of HH. For this purpose, we used one- and two-dimensional gel electrophoresis, immunoblotting and MALDI-TOF/TOF analysis. We identified cytoskeletal membrane proteins and membrane receptors of erythrocytes bound to HNE exclusively in HH patients. Furthermore, kidney and brain of Hfe-/- mice contained more HNE-adducted protein than healthy controls. Our results identified main HNE-modified proteins suggesting that HH favours preferred protein targets for oxidation by HNE.
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Hemocromatose , Sobrecarga de Ferro , Humanos , Masculino , Camundongos , Feminino , Animais , Hemocromatose/genética , Aldeídos/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Peroxidação de Lipídeos , Proteína da Hemocromatose/genética , Proteína da Hemocromatose/metabolismoRESUMO
Less than 5% of patients with liver cirrhosis (LC) with portal hypertension (PH) develop atypical shunt (in regions other than the esophagus or the stomach). Within this group are varices associated with a stoma, for example the ones associated with an uretero-ileostomy which are infrequent. They are a diagnostic and therapeutic challenge, as they can cause hemorrhages due to PH. We present a clinical case about stoma varicose bleeding as the latest guidelines for the management of PH do not mention them or their treatment due to their low incidence.
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Hipertensão Portal , Derivação Portossistêmica Transjugular Intra-Hepática , Trombose , Varizes , Humanos , Derivação Portossistêmica Transjugular Intra-Hepática/efeitos adversos , Recidiva Local de Neoplasia , Hemorragia/complicações , Hipertensão Portal/complicações , Hipertensão Portal/cirurgia , Varizes/cirurgia , Trombose/complicações , Cirrose Hepática/complicações , Hemorragia Gastrointestinal/etiologia , Hemorragia Gastrointestinal/cirurgia , Veia Porta , Resultado do TratamentoRESUMO
A 93-year-old woman with a history of endometrial adenocarcinoma treated with surgery and pelvic radiotherapy that led to radicular stenosis in the sigma and acute biliary pancreatitis, without subsequent cholecystectomy. She attended the emergency department for abdominal pain, vomiting and abdominal distension, with metallic noises. An abdominal CT scan showed a gallbladder with cholelithiasis, in wide contact with the colonic framework and dilation of the colonic loops with hydro-aerial levels with a partially calcified image embedded in the known sigmoid stenosis, compatible with intestinal obstruction. Given the high surgical risk, colonoscopy was performed, which identified an impassable punctate stricture with a fibrous appearance. Pneumatic dilatation and subsequent removal of gallstones with biopsy forceps was performed, with an adequate evolution. While gallstone ileus is a rare condition that accounts for 5% of episodes of intestinal obstruction, its location in the colon is even rarer. It is usually managed surgically, with a significant impact on morbidity. This case is of interest because of the infrequent occurrence of obstruction secondary to these two concomitant causes and the possible usefulness of endoscopic treatment in patients at high surgical risk.
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Cálculos Biliares , Íleus , Obstrução Intestinal , Doenças do Colo Sigmoide , Feminino , Humanos , Idoso de 80 Anos ou mais , Cálculos Biliares/complicações , Constrição Patológica , Íleus/etiologia , Doenças do Colo Sigmoide/complicações , Obstrução Intestinal/etiologia , Colo SigmoideRESUMO
Pembrolizumab, a programmed cell death receptor (PD-1) inhibitor, have improved the prognosis in several types of cancer. Despite the important clinical benefits, checkpoint inhibition have been associated with inflammatory and immune-related side effects (irAE).
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Colite , Doenças do Sistema Imunitário , Anticorpos Monoclonais Humanizados , Colite/induzido quimicamente , Colite/tratamento farmacológico , Humanos , Fígado , Receptor de Morte Celular Programada 1 , Ustekinumab/efeitos adversosRESUMO
SARS-CoV2 infection and vaccination against this virus have been related to the development of autoimmune diseases. We report a case of autoimmune hepatitis (AIH) after SARS-COV2 vaccine. Male, 76 years old, with a history of hepatic cirrhosis secondary to primary biliary cholangitis (PBC), compensated, treated with ursodeoxycholic acid and obeticholic acid. The patient received the third dose of the SARS-CoV2 vaccine (BioNTech/Pfizer) in December 2021. In subsequent analytical control, the patient presented altered liver test, with elevation of ALT and AST. Ultrasound was performed, without alterations, and viral causes were ruled out. IgG elevation and positive antinuclear antibodies were observed. A liver biopsy was performed, with findings of intense interface and lobular hepatitis and areas of centrilobular necrosis. The inflammation was predominantly lymphoplasmacytic. The patient was diagnosed with AIH and initiated therapy with steroids and azathioprine, currently with an adequate response. AIH is an immune-mediated disease of uncertain etiology. Cases of AIH with SARS-CoV2 vaccination as a possible trigger have recently been published, with characteristics similar to ours. Some of them had a history of autoimmune pathology, such as this case (PBC). Therefore, it is suggested that vaccination can induce the development of autoimmune pathology in patients at risk. Our reported case reinforces the hypothesis of an association between AIH and the SARS-CoV2 vaccine.
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Vacinas contra COVID-19 , COVID-19 , Hepatite Autoimune , Cirrose Hepática Biliar , Idoso , Vacinas contra COVID-19/efeitos adversos , Hepatite Autoimune/tratamento farmacológico , Hepatite Autoimune/etiologia , Humanos , Cirrose Hepática Biliar/tratamento farmacológico , Masculino , RNA Viral/uso terapêutico , SARS-CoV-2RESUMO
INTRODUCTION: Obeticholic acid (OCA) and fibrates therapy results in biochemical improvement in placebo-controlled trials in patients with primary biliary cholangitis and insufficient response to ursodeoxycholic acid. There is scarce information outside of clinical trials. Therefore, we have assessed the effectiveness and adverse events of these treatments. METHODS: Data from patients included in the ColHai registry treated with OCA, fibrates, or both were recorded during a year, as well as adverse events and treatment discontinuation. RESULTS: Eighty-six patients were treated with OCA, 250 with fibrates (81% bezafibrate; 19% fenofibrate), and 15 with OCA plus fibrates. OCA group had baseline significantly higher alkaline phosphatase (ALP) (P = 0.01) and lower platelets (P = 0.03) than fibrates. Both treatments significantly decreased ALP, gamma-glutamyl transferase (GGT), and transaminases and improved Globe score. Albumin and immunoglobulin type M improved in the fibrates group. ALP decrease was higher under fibrates, whereas alanine aminotransferase decline was higher under OCA. Although baseline transaminases and GGT were higher in patients with OCA plus fibrates, significant ALP, GGT, alanine aminotransferase, and Globe score improvement were observed during triple therapy. Adverse events were reported in 14.7% of patients (21.3% OCA; 17.6% fenofibrate; 10.7% bezafibrate), mainly pruritus (10.1% with OCA). Discontinuation was more frequent in fenofibrate treatment mainly because of intolerance or adverse events. DISCUSSION: Second-line therapy with OCA or fibrates improves hepatic biochemistry and the GLOBE score in primary biliary cholangitis patients with suboptimal response to ursodeoxycholic acid. Simultaneous treatment with OCA and fibrates improved ALP as well.
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Bezafibrato/uso terapêutico , Ácido Quenodesoxicólico/análogos & derivados , Fenofibrato/uso terapêutico , Cirrose Hepática Biliar/tratamento farmacológico , Ácido Quenodesoxicólico/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Autoimmune hepatitis (AIH) frequently affects women of childbearing age in whom the desire to have a family raises the question regarding the potential risks for the fetus and the mother. The information on AIH in pregnant patients is scarce.1 The aims of this study were (1) to identify the risk factors associated with flares in pregnant patients diagnosed with AIH, (2) to determine the course of AIH in patients with pregnancy-related flares, and (3) to describe the outcome of AIH diagnosed in the postpartum period.
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Glucocorticoides/uso terapêutico , Hepatite Autoimune/tratamento farmacológico , Imunossupressores/uso terapêutico , Complicações na Gravidez/tratamento farmacológico , Exacerbação dos Sintomas , Aborto Espontâneo/epidemiologia , Adulto , Alanina Transaminase/sangue , Aspartato Aminotransferases/sangue , Azatioprina/uso terapêutico , Estudos de Coortes , Diabetes Gestacional/epidemiologia , Quimioterapia Combinada , Feminino , Hepatite Autoimune/sangue , Humanos , Hipertensão Induzida pela Gravidez/epidemiologia , Período Pós-Parto , Prednisona/uso terapêutico , Gravidez , Complicações na Gravidez/sangue , Resultado da Gravidez , Estudos RetrospectivosRESUMO
The use of direct-acting antivirals (DAA) for the hepatitis C virus (HCV) has yielded a significant improvement in the treatment of autoimmune hepatitis (AIH) associated with HCV infection. Interferon was the cornerstone of HCV therapy before the introduction of these agents into the clinical practice. Herein, we report the case of an HCV-infected patient who developed an interferon-induced AIH and since then, has received immunosuppressive therapy. Administration of DAA resulted in a sustained virologic response (SVR) and clinical AIH remission which allowed a discontinuation of immunosuppressive treatment.
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Antivirais/uso terapêutico , Hepatite C Crônica/tratamento farmacológico , Hepatite Autoimune/tratamento farmacológico , Antivirais/efeitos adversos , Azatioprina/uso terapêutico , Benzimidazóis/uso terapêutico , Feminino , Fluorenos/uso terapêutico , Hepatite C Crônica/complicações , Hepatite Autoimune/etiologia , Humanos , Imunossupressores/uso terapêutico , Interferons/efeitos adversos , Pessoa de Meia-Idade , Prednisona/uso terapêutico , Sofosbuvir , Resposta Viral Sustentada , Uridina Monofosfato/análogos & derivados , Uridina Monofosfato/uso terapêuticoRESUMO
BACKGROUND: Diagnosis of de novo immune hepatitis (dnIH) after liver transplantation relies on biopsy findings, with an abundance of plasma cells (PCs) in the inflammatory infiltrates a hallmark of the disease. Very little is known about what other types of immune cells exist in the infiltrates mainly located in the portal areas of the liver tissue. METHODS: We analyzed the composition of T cells, B cells, PCs, and macrophages in the liver biopsies of 12 patients with dnIH, 9 of them obtained at the time of diagnosis. For comparison, biopsies from 9 patients with chronic rejection (CR) were included in the study. The results were analyzed by a computer-assisted stereology quantification method. RESULTS: The major components of the infiltrates in the portal areas were CD3+ T lymphocytes in both groups, with 36.6% in the dnIH group versus 49.4% in the CR group. CD20+ B lymphocytes represented 14.9% in the dnIH group and 29.1% in the CR group. Macrophage levels were very similar in the dnIH and CR group (19.7% versus 16.8%, respectively). PCs were much less represented in CR biopsies than those from the dnIH group (mean value of 4.7% versus 28.8%). CONCLUSION: In conclusion, the determination of a characteristic cellular profile could be an important tool for a more reliable diagnosis of dnIH, in support of the histological evaluation made by the pathologist, which in most cases is challenging. Recognition of this condition is crucial because it leads to graft failure if left untreated.
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Hepatite Autoimune/imunologia , Hepatite Autoimune/patologia , Imuno-Histoquímica/métodos , Biópsia , Contagem de Células , Doença Crônica , Progressão da Doença , Feminino , Rejeição de Enxerto/imunologia , Hepatite Autoimune/tratamento farmacológico , Humanos , Processamento de Imagem Assistida por Computador , Inflamação/patologia , Masculino , Plasmócitos/patologia , Esteroides/uso terapêuticoRESUMO
We present the case of a patient with primary sclerosing cholangitis who presented a rapidly evolving cholestatic syndrome, with severe hyperbilirubinemia after placing a TIPS. It was resolved with a biliary prosthesis inserted by ERCP. To date, no similar cases have been described in the literature, as it is a rare complication and, on the other hand, the experience with TIPS in patients with PSC is limited. The causes of hyperbilirubinemia after TIPS placement are very varied and it is crucial to perform a differential diagnosis to establish an early treatment.
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Colangite Esclerosante/complicações , Colangite Esclerosante/cirurgia , Colestase/etiologia , Derivação Portossistêmica Transjugular Intra-Hepática/efeitos adversos , Adulto , Colangiopancreatografia Retrógrada Endoscópica , Colestase/diagnóstico por imagem , Colestase/cirurgia , Humanos , Masculino , Complicações Pós-Operatórias/sangue , Próteses e ImplantesRESUMO
The translocation of nanomaterials or complex delivery systems into the cytosol is a major challenge in nanobiotechnology. After receptor-mediated endocytosis, most nanomaterials are sequestered and undergo degradation, therapy inactivation, or exocytosis. Herein we explore a novel surface particle coating made of adsorbed carbon nanotubes that provides coated materials with new properties that reproduce the viral cell-invasive mechanisms, namely, receptor-mediated endocytosis, endolysosomal escape, and cytosolic particle release preserving cell viability. This novel biomimetic coating design will enable the intracytoplasmic delivery of many different functional materials endowed with therapeutic, magnetic, optical, or catalytic functionalities, thus opening the door to a wide array of chemical and physical processes within the cytosolic or nuclear domains, and supporting new developments in the biotechnological, pharmaceutical, and biomedical industries.
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Materiais Biomiméticos/metabolismo , Materiais Revestidos Biocompatíveis/metabolismo , Citoplasma/metabolismo , Endocitose , Nanopartículas/metabolismo , Dióxido de Silício/metabolismo , Materiais Biomiméticos/química , Biomimética , Sobrevivência Celular , Materiais Revestidos Biocompatíveis/química , Células HeLa , Humanos , Nanopartículas/química , Nanotubos de Carbono/química , Dióxido de Silício/química , Propriedades de SuperfícieRESUMO
BACKGROUND & AIMS: Chronic outcome following acute idiosyncratic drug-induced liver injury (DILI) is not yet defined. This prospective, long-term follow-up study aimed to analyze time to liver enzyme resolutions to establish the best definition and risk factors of DILI chronicity. METHODS: 298 out of 850 patients in the Spanish DILI registry with no pre-existing disease affecting the liver and follow-up to resolution or ⩾1year were analyzed. Chronicity was defined as abnormal liver biochemistry, imaging test or histology one year after DILI recognition. RESULTS: Out of 298 patients enrolled 273 (92%) resolved ⩽1year from DILI recognition and 25 patients (8%) were chronic. Independent risk factors for chronicity were older age [OR: 1.06, p=0.011], dyslipidemia [OR: 4.26, p=0.04] and severe DILI [OR: 14.22, p=0.005]. Alanine aminotransferase (ALT), alkaline phosphatase (ALP) and total bilirubin (TB) median values were higher in the chronic group during follow-up. Values of ALP and TB >1.1 x upper limit of normal (xULN) and 2.8 xULN respectively, in the second month from DILI onset, were found to predict chronic DILI (p<0.001). Main drug classes involved in chronicity were statins (24%) and anti-infectives (24%). Histological examination in chronic patients demonstrated two cases with ductal lesion and seven with cirrhosis. CONCLUSIONS: One year is the best cut-off point to define chronic DILI or prolonged recovery, with risk factors being older age, dyslipidemia and severity of the acute episode. Statins are distinctly related to chronicity. ALP and TB values in the second month could help predict chronicity or very prolonged recovery. LAY SUMMARY: Drug-induced liver injury (DILI) patients who do not resolve their liver damage during the first year should be considered chronic DILI patients. Risk factors for DILI chronicity are older age, dyslipidemia and severity of the acute episode. Chronic DILI is not a very common condition; normally featuring mild liver profile abnormalities and not being an important clinical problem, with the exception of a small number of cases of early onset cirrhosis.
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Doença Hepática Induzida por Substâncias e Drogas , Alanina Transaminase , Seguimentos , Humanos , Estudos Prospectivos , Fatores de RiscoRESUMO
Successful cognitive aging is often thought to result from resistance to the accumulation of pathology, resilience to the effects of pathological accumulation, or some combination of the two. While evidence for resilience has been found in typical aging populations, the oldest-old provide us with a unique window into the role of pathological accumulation in impacting cognition. Here, we aimed to assess group differences in measures of amyloid and tau across older age groups using data from the Alzheimer's Disease Neuroimaging Initiative (ADNI age: 60-89) and The 90+ Study (age: 90-101). Additionally, using the ADNI dataset, we performed exploratory analyses of regional cingulate AV-45 SUVRs to assess if amyloid load in particular areas was associated with Top Cognitive Performance (TCP). Consistent with the literature, results showed no group differences in amyloid SUVRs both regionally and in the whole cortex. For tau with AV-1451, we also observed no differences in Braak composite SUVRs. Interestingly, these relationships persisted in the oldest-old. This indicates that Top Cognitive Performance throughout aging does not reflect resistance to amyloid and tau burden, but that other mechanisms may be associated with protection against amyloid and tau related neurodegeneration.
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An interlaboratory collaborative study to validate a colorimetric phosphatase inhibition assay for quantitative determination of the okadaic acid (OA) toxins group in molluscs, OkaTest, was conducted. Eight test materials, including mussels, scallops, clams, and cockles, were analyzed as blind duplicates. Blank samples and materials containing different OA toxin levels ranging from 98 to 275 microg/kg OA equivalents were included. The study was carried out by a total of 16 laboratories from 11 different countries. Values obtained for repeatability relative standard deviations (RSDr) ranged from 5.4 to 11.2% (mean 7.5%). Reproducibility RSD (RSD(R)) values were between 7.6 and 13.2% (mean 9.9%). The Horwitz ratio (HorRat) values ranged between 0.4 and 0.6. A recovery assay was also carried out using a sample spiked with OA. A mean recovery of 98.0% and an RSD of 14.5% were obtained. The results obtained in this validation study indicate that the colorimetric phosphatase inhibition assay, OkaTest, is suitable for quantitative determination of the OA toxins group. OkaTest could be used as a test that is complementary to the reference method for monitoring the OA toxins group.
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Colorimetria/métodos , Inibidores Enzimáticos/análise , Ácido Okadáico/análise , Fosfoproteínas Fosfatases/antagonistas & inibidores , Reprodutibilidade dos TestesAssuntos
Hemangioma/complicações , Hipertensão Portal/etiologia , Neoplasias Hepáticas/complicações , Neoplasias Primárias Múltiplas/complicações , Circulação Colateral , Emergências , Hemangioma/diagnóstico por imagem , Hepatomegalia/etiologia , Humanos , Falência Hepática/etiologia , Neoplasias Hepáticas/diagnóstico por imagem , Transplante de Fígado , Masculino , Pessoa de Meia-Idade , Neoplasias Primárias Múltiplas/diagnóstico por imagem , Peritonite/etiologiaRESUMO
Epithelial basement membrane corneal dystrophy is a rare entity, characterized by recurrent corneal erosions secondary to a disorder in the attachment of the corneal epithelium to the basement membrane. To date, mainly the ophthalmological aspect of cases has been reported, with little emphasis on the pathology of this lesion. Here we aim to describe the microscopy and discuss the clinical and therapeutic aspects of a case.
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Síndrome de Cogan , Distrofias Hereditárias da Córnea , Epitélio Corneano , Humanos , Epitélio Corneano/patologia , Distrofias Hereditárias da Córnea/complicações , Distrofias Hereditárias da Córnea/patologia , Síndrome de Cogan/complicações , Síndrome de Cogan/patologia , Membrana Basal/patologiaRESUMO
INTRODUCTION: Surgical delay is one of the risk factors for mortality and morbidity in patients with HF. One of the causes of delay is due to admission on Thursday-Friday, weekends, holidays or previous periods. The final objective of this study is to analyze administrative-organizational delay in complication and mortality rates. MATERIAL AND METHODS: A total of 607 cases of surgically operated hip fractures were analyzed. Two groups were established, one of them operated on in < 48 h (ND group) and the other surgically delayed for administrative organizational reasons (AA group). Demographic variables related to treatment and fracture were analyzed in both groups, as well as the rates of surgical wound complications, general complications and mortality rate in the first 30 days, in the first year and more than one year after surgery. RESULTS: We observed a surgical wound seroma and staining rate of 15.7% in the AA group and 9.6% in the ND group; and a surgical wound surface infection rate of 1.9% in the AA group and 0.8% in the ND group (p = 0.275). General complications occurred in 34.4% (AA group) and 29% (ND group). The 30-day mortality rate was 4.8% in the AA group and 1.9% in the ND group (p = 0.081). CONCLUSION: We found no statistically significant differences in patients delayed for administrative reasons in terms of mortality and surgical wound and general complication rates. Although the proportion of surgical wound complications and 30-day mortality was higher in the AA group versus the ND group.