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INTRODUCTION AND OBJECTIVES: Autoimmune liver diseases (AILD) are rare causes hepatocellular carcinoma (HCC), and data on the efficacy and tolerability of anti-tumor therapies are scarce. This pan-European study aimed to assess outcomes in AILD-HCC patients treated with tyrosine kinase inhibitors (TKIs) or transarterial chemoembolization (TACE) compared with patients with more common HCC etiologies, including viral, alcoholic or non-alcoholic fatty liver disease. MATERIALS AND METHODS: 107 patients with HCC-AILD (AIH:55; PBC:52) treated at 13 European centres between 1996 and 2020 were included. 65 received TACE and 28 received TKI therapy. 43 (66 %) were female (median age 73 years) with HCC tumor stage BCLC A (34 %), B (46 %), C (9 %) or D (11 %). For each treatment type, propensity score matching was used to match AILD to non-AILD-HCC on a 1:1 basis, yielding in a final cohort of 130 TACE and 56 TKI patients for comparative analyses of median overall survival (mOS) and treatment tolerability. RESULTS: HCC-AILD patients showed comparable mOS to controls for both TACE (19.5 vs. 22.1 months, p = 0.9) and TKI (15.4 vs. 15.1 months, p = 0.5). Adverse events were less frequent in AILD-HCC patients than controls (33 % % vs. 62 %, p = 0.003). For TKIs, there were no significant differences in adverse events (73% vs. 86%, p = 0.2) or interruption rates (44% vs. 36 %, p = 0.7). CONCLUSIONS: In summary, this study demonstrates comparable mOS for AILD-HCC patients undergoing local and systemic treatments, with better tolerability than HCC of other causes. TKIs remain important therapeutic options for AILD-HCC patients, particularly given their exclusion from recent immunotherapy trials.
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Gyromitra esculenta, also known as "false morel" is one of the most poisonous mushrooms. This species is found all over the world, growing in coniferous forest in early spring time. Common manifestation of poisoning includes gastrointestinal symptoms which include varied degrees of liver impairment. We describe three cases: acute liver injury, acute liver failure and acute-on-chronic liver failure due to G. esculenta poisoning. At admission patients presented with encephalopathy and features of liver failure. Two of them recovered completely following supportive management while the remaining patient who also had preexisting liver disease developed multiorgan failure and subsequently died. Although a rare occurrence, G. esculenta poisoning should be considered in the differential diagnosis of acute liver failure.
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Insuficiência Hepática Crônica Agudizada/etiologia , Fígado/efeitos dos fármacos , Manihot/intoxicação , Intoxicação Alimentar por Cogumelos/complicações , Insuficiência Hepática Crônica Agudizada/diagnóstico , Idoso , Diagnóstico Diferencial , Evolução Fatal , Humanos , Fígado/diagnóstico por imagem , Falência Hepática Aguda/diagnóstico , Falência Hepática Aguda/etiologia , Masculino , Pessoa de Meia-Idade , Intoxicação Alimentar por Cogumelos/diagnósticoRESUMO
INTRODUCTION: Hyponatremia is associated with high mortality and predicts hepatic encephalopathy but its effect on health-related quality of life remains to be established. MATERIAL AND METHODS: In this study we prospectively analyzed the relationship between hyponatremia, clinical features and quality of life in a cohort of 116 patients with cirrhosis. Chronic Liver Disease Questionnaire and Medical Outcomes Study 36- Item Short Form Health Survey were performed to assess quality of life. Evaluation of hepatic encephalopathy included West-Haven criteria, Psychometric Hepatic Encephalopathy Score and Critical Flicker Frequency analysis. Severity of liver disease was assessed with Child-Pugh score and MELD. Univariate and multivariate analysis were implemented to evaluate the influence of analyzed factors on quality of life. RESULTS: Multivariate analysis has identified serum natremia, Psychometric Hepatic Encephalopathy Score, Critical Flicker Frequency and severity of liver disease measured with MELD and Child-Pugh score as independent factors affecting quality of life in patients with cirrhosis. West Heaven criteria failed to show the relationship with quality of life in analyzed subjects. Serum kalemia showed correlation with neither quality of life, hepatic encephalopathy nor severity of the disease. CONCLUSION: In patients with cirrhosis serum natremia along with severity of liver disease and hepatic encephalopathy exerts a significant effect on patients' quality of life.
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Encefalopatia Hepática/sangue , Hiponatremia/sangue , Cirrose Hepática/sangue , Qualidade de Vida , Sódio/sangue , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Distribuição de Qui-Quadrado , Feminino , Encefalopatia Hepática/diagnóstico , Encefalopatia Hepática/psicologia , Humanos , Hiponatremia/diagnóstico , Hiponatremia/psicologia , Cirrose Hepática/diagnóstico , Cirrose Hepática/psicologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Testes Neuropsicológicos , Polônia , Valor Preditivo dos Testes , Estudos Prospectivos , Psicometria , Fatores de Risco , Índice de Gravidade de Doença , Inquéritos e Questionários , Adulto JovemRESUMO
Oxidative stress elevates Ca2+ and, presumably, activates Ca2+ -dependent PKCs. We analyzed the participation of Ca2+ -dependent PKCs in actin disorganization and tight-junctional impairment induced by the pro-oxidant tert-butylhydroperoxide (tBOOH) in isolated rat hepatocyte couplets. tBOOH (100 microM) augmented radical oxygen species (ROS), as indicated by increased lipid peroxidation (+217%, p < 0.05) and intracellular production of 2',7'-dichlorofluorescein (+36%, p < 0.05). Cytosolic Ca2+ and PKCalpha translocation to membrane, an indicator of PKCalpha activation, were also elevated by tBOOH (+100 and +79%, respectively, p < 0.05). tBOOH increased the number of couplets displaying membrane blebs (+278%, p < 0.001) and caused redistribution of F-actin. tBOOH induced tight-junctional impairment, as indicated by a reduction in the percentage of couplets retaining presecreted cholyllysylfluorescein in their canalicular vacuoles (-54%, p < 0.001). tBOOH induced redistribution of the tight-junctional-associated protein ZO-1. All these events were prevented by the panspecific PKC inhibitors H7 and staurosporine, the Ca2+ -dependent PKC inhibitor Gö6976, the intracellular Ca2+ chelator BAPTA/AM, and the PKA activator dibutyryl-cyclic AMP. Furthermore, PKC inhibition and PKA activation not only prevented but also fully reversed tBOOH-induced blebbing. Conversely, tBOOH-induced ROS formation and Ca2+ elevation remained unchanged. We conclude that ROS induce hepatocellular actin-cytoskeleton rearrangement and tight-junctional impairment by a PKC-mediated, Ca2+ -dependent mechanism, which is counteracted by PKA.
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Actinas/metabolismo , Cálcio/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Citoesqueleto/metabolismo , Hepatócitos/metabolismo , Estresse Oxidativo , Proteína Quinase C/metabolismo , Junções Íntimas/metabolismo , Animais , Ativação Enzimática , Masculino , Proteína Quinase C/antagonistas & inibidores , Ratos , Ratos Wistar , terc-Butil Hidroperóxido/farmacologiaRESUMO
We have shown that Ca2+-mediated protein kinase C (PKC) activation induces impairment of bile salt secretory function and F-actin redistribution in hepatocyte couplets. Because oxidative stress induces Ca2+ elevation, we tested here whether PKC inhibition or protein kinase A (PKA) activation, which often counteracts PKC-dependent effects, can prevent and reverse these alterations. The pro-oxidant compounds tert-butylhydroperoxide (tBOOH, 100 microM) and 2,3-dimethoxy-1,4-naphthoquinone (30 microM), reduced by -41% and -29%, respectively, the percentage of couplets accumulating the fluorescent bile salt analog, cholyl-lysylfluorescein in their canalicular vacuoles (p < 0.01). tBOOH-induced bile salt secretory failure was accompanied by internalization of the canalicular bile salt export pump (Bsep), and disarrangement of cytoskeletal F-actin. All these deleterious effects were fully prevented by the intracellular Ca2+ chelator BAPTA/AM (20 microM), the pan-specific PKC inhibitors H7 (100 microM) and staurosporine (1 microM), the inhibitor of Ca2+-dependent PKCs, Gö6976 (2 microM), and the PKA activator dibutyryl-cAMP (500 microM). H7, Gö6976, and dibutyryl-cAMP not only prevented but also fully reversed the decrease in the cholyl-lysyl-fluorescein accumulation. In conclusion, these results suggest that low levels of oxidative stress impair bile salt secretion by internalizing Bsep through a Ca2+-dependent, PKC-mediated mechanism, and that inhibition of PKC, or activation of PKA, prevents and reverses these effects. Alterations in actin organization may be a causal factor.