Neuron-derived CCL2 contributes to microglia activation and neurological decline in hepatic encephalopathy

BACKGROUND: CCL2 was up-regulated in neurons and involved in microglia activation and neurological decline in mice suffering from hepatic encephalopathy (HE). However, no data exist concerning the effect of neuron-derived CCL2 on microglia activation in vitro. METHODS: The rats were pretreated with CCL2 receptor inhibitors (INCB or C021, 1 mg/kg/day i.p.) for 3 days prior to thioacetamide (TAA) administration (300 mg/kg/day i.p.) for inducing HE model. At 8 h following the last injection (and every 4 h after), the grade of encephalopathy was assessed. Blood and whole brains were collected at coma for measuring CCL2 and Iba1 expression. In vitro, primary neurons were stimulated with TNF-α, and then the medium were collected for addition to microglia cultures with or without INCB or C021 pretreatment. The effect of the medium on microglia proliferation and activation was evaluated after 24 h. RESULTS: CCL2 expression and microglia activation were elevated in the cerebral cortex of rats received TAA alone. CCL2 receptors inhibition improved neurological score and reduced cortical microglia activation. In vitro, TNF-α treatment induced CCL2 release by neurons. Medium from TNF-α stimulated neurons caused microglia proliferation and M1 markers expression, including iNOS, COX2, IL-6 and IL-1ß, which could be suppressed by INCB or C021 pretreatment. The medium could also facilitate p65 nuclear translocation and IκBα phosphorylation, and NF-κB inhibition reduced the increased IL-6 and IL-1ß expression induced by the medium. CONCLUSION: Neuron-derived CCL2 contributed to microglia activation and neurological decline in HE. Blocking CCL2 or inhibiting microglia excessive activation may be potential strategies for HE.

Is propofol safe when administered to cirrhotic patients during sedative endoscopy?

BACKGROUND/AIMS: In patients with liver cirrhosis, drugs acting on the central nervous system can lead to hepatic encephalopathy and the effects may be prolonged. Recently, misuse of propofol has been reported and the associated risk of death have become an issue. Propofol is commonly used during sedative endoscopy; therefore, its safety in high-risk groups must be further investigated. We performed a pilot study of the safety and efficacy of propofol during endoscopy in Korean patients with cirrhosis. METHODS: Upper gastrointestinal endoscopy was performed under sedation with propofol along with careful monitoring in 20 patients with liver cirrhosis and 20 control subjects. The presence or development of hepatic encephalopathy was assessed using the number connection test and neurologic examination. RESULTS: Neither respiratory depression nor clinically significant hypotension were observed. Immediate postanesthetic recovery at 5 and 10 minutes after the procedure was delayed in the cirrhotic patients compared with the control group; however, at 30 minutes, the postanesthetic recovery was similar in both groups. Baseline psychomotor performance was more impaired in cirrhotic patients, but propofol was not associated with deteriorated psychomotor function even in cirrhotic patients with a minimal hepatic encephalopathy. CONCLUSIONS: Sedation with propofol was well tolerated in cirrhotic patients. No newly developed hepatic encephalopathy was observed.

A thioacetamide-induced hepatic encephalopathy model in C57BL/6 mice: a behavioral and neurochemical study / Modelo de encefalopatia hepática induzida por tioacetamida em camundongos C57BL/6: estudo comportamental e neuroquímico

OBJECTIVE: Hepatic encephalopathy (HE) is a neuropsychiatric syndrome resulting from liver failure. In the present study, we aimed to standardize an animal model of HE induced by thioacetamide (TAA) in C57BL/6 mice evaluating behavioral symptoms in association with liver damage and alterations in neurotransmitter release. METHOD: HE was induced by an intraperitoneal single dose of TAA (200 mg/kg, 600 mg/kg or 1,200 mg/kg). Behavioral symptoms were evaluated using the SHIRPA battery. Liver damage was confirmed by histopathological analysis. The glutamate release was measured using fluorimetric assay. RESULTS: The neuropsychiatric state, motor behavior and reflex and sensory functions were significantly altered in the group receiving 600 mg/kg of TAA. Biochemical analysis revealed an increase in the glutamate release in the cerebral cortex of HE mice. CONCLUSION: HE induced by 600mg/kg TAA injection in C57BL/6 mice seems to be a suitable model to investigate the pathogenesis and clinical disorders of HE.

OBJETIVO: A encefalopatia hepática (EH) é uma síndrome neuropsiquiátrica resultante da falência hepática. O objetivo do presente estudo foi estabelecer um modelo de EH induzida por tioacetamida (TAA) em camundongos C57BL/6 avaliando transtornos comportamentais, falência hepática e alterações na liberação de neurotransmissores. MÉTODO: A EH foi induzida por meio de uma única dose intraperitoneal de TAA (200 mg/kg, 600 mg/kg, 1.200 mg/kg). As alterações comportamentais foram avaliadas utilizando a bateria SHIRPA. A falência hepática foi confirmada através de análises histopatológicas e a liberação de glutamato medida, por ensaio fluorimétrico. RESULTADOS: Foram encontradas alterações significativas no estado neuropsiquiátrico, comportamento motor e função reflexa e sensorial no grupo que recebeu 600 mg/kg de TAA. Análises bioquímicas revelaram aumento na liberação de glutamato no córtex cerebral dos camundongos com EH. CONCLUSÃO: A EH induzida por 600 mg/kg de TAA em camundongos C57BL/6 parece ser um modelo apropriado para a investigação da patogênese e dos transtornos clínicos da EH.

Hepatitis fulminante por halotano: informe de dos casos clinicopatológicos / Fulminant hepatitis by halothane: report of two clinicopathological cases

El halotano fue introducido por primera vez en la práctica clínica en 1956 y desde entonces se ha informado sobre muchos casos de daño hepático posterior a la exposición a este halogenado. Su incidencia es de uno por cada 10,000 anestesias con halotano, pero después de múltiples exposiciones la frecuencia aumenta a siete por cada 10,000 anestesias. No obstante, la hepatitis fulminante asociada a halotano es baja, a pesar de su gran uso (uno por cada 35,000 anestesias). Los hallazgos histológicos en hígado son: presencia de necrosis submasiva a masiva de predominio centrolobulillar e infiltración grasa (esteatosis). El primer caso registrado en el Hospital General de México fue en el año de 1972. En el presente informe se presenta dos casos clinicopatológicos de hepatitis fulminante por halotano, posterior a la primera exposición a este agente anestésico

Halothane-induced fulminant hepatic failure.

Fulminant hepatic failure developed in the early post-operative period in a patient after third exposure to halothane. Exclusion of other causes of post-operative jaundice and temporal relationship of jaundice to anesthesia suggested halothane as the etiologic agent for the submassive necrosis, which was documented at postmortem liver biopsy.

Ascite: tratamento clínico e complicaçöes / Ascitis: clinical treatment and complications

A causa mais freqüente de ascite em nosso meio é a cirrose hepática. O tratamento desta complicaçäo, tem como modificar a evoluçäo da doença básica que continuará progressiva e fatal. A melhor forma de tratar esta cimplicaçäo é internar o paciente. Inicialmente deve-se efetuar uma punçäo abdominal para estudo do líquido. A dieta deve ser pobre em sal (40 mEq de sódio), avaliando-se o pêso e diurese diárias. Os doentes com boa funçäo renal têm excelente resposta a esta abordagem. Quando näo há resposta à restriçäo dietética, é instituída a terapêutica com diuréticos, dando-se preferência a espironolactona. A resposta deve acontecer entre três e seis dias. Este diurético deve ter a preferência no uso, ao invés da furosemide que causa perda excessiva de potássio e surgimento de encefalopatia. As complicaçöes mais comuns no tratamento säo a encefalopatia hepática em geral por desequilíbrio hidro-eletrolítico e a síndrome hépato-renal

Isoniazid-rifampicin-induced submassive hepatic necrosis.

A 58-year-old woman with tuberculosis received antituberculous drugs which included isoniazid, rifampicin, and ethambutol. Nausea and anorexia were initial symptoms while jaundice and abdominal pain were late manifestations. She became comatose and died 7 weeks after therapy. Autopsy revealed submassive necrosis of the liver and active advanced pulmonary tuberculosis. It is, thus, necessary for the physician to be alert for this serious complication in prescribing a combination of these antituberculous drugs.