Cerebral hemodynamic and metabolic changes in fulminant hepatic failure / Modificações da hemodinâmica e metabolismo cerebral na insuficiência hepatica fulminante

ABSTRACT Intracranial hypertension and brain swelling are a major cause of morbidity and mortality of patients suffering from fulminant hepatic failure (FHF). The pathogenesis of these complications has been investigated in man, in experimental models and in isolated cell systems. Currently, the mechanism underlying cerebral edema and intracranial hypertension in the presence of FHF is multi-factorial in etiology and only partially understood. The aim of this paper is to review the pathophysiology of cerebral hemodynamic and metabolism changes in FHF in order to improve understanding of intracranial dynamics complication in FHF.

RESUMO O edema cerebral e a hipertensão intracraniana (HIC) são as principais causas de morbidade e mortalidade de pacientes com insuficiência hepática fulminante (IHF). A patogênese dessas complicações tem sido investigada no homem, em modelos experimentais e em sistemas celulares isolados. Atualmente, o mecanismo subjacente ao edema cerebral e HIC na presença de IHF é multifatorial em etiologia e pouco compreendido na literatura. O objetivo deste trabalho é revisar a fisiopatologia das alterações hemodinâmicas e metabólicas cerebrais na IHF, visando melhorar a compreensão da complicação da hemodinâmica encefálica na IHF.

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.

Encefalopatía hepática en el 2011 / Hepatic encephalopaty in 2011

Hepatic encephalopathy (HE) is a neuropsychiatric and motor disorder, resulting from hepatic failure. It is one of the main manifestations of chronic liver disease and the cardinal presentation of acute liver failure. Its presence and severity are the main prognostic determinants among these patients. It is frequent in advanced chronic liver disease (30-45 percent) and in patients with TIPS (transjugular intrahepatic portosystemic shunt) (10-50 percent). Its pathogenesis is complex and it has multiple components, including ammonia, inflammatory cytokines, benzodiazepine- and manganese-like components, which alter the function of the neuronal cell. Its management requires identification and treatment of the precipitating factors, and ruling out other causes of mental status alteration. The majority of the therapies are aimed at reducing ammonia load in the intestine, such as non absorbable disaccharides (lactulose), antibiotics (neomycin, metronidazole and currently, rifaximin) and other, whose role has yet to be established. Severe encephalopathy is considered an indicator for liver transplantation. This article will analyze mainly hepatic encephalopathy in cirrhotic patients, its classification, etiopathogeny and current management.

La encefalopatía hepática (EH) es un síndrome neuropsiquiátrico y motor, que resulta de una disfunción hepática. Es una de las manifestaciones principales de la enfermedad hepática crónica y la presentación cardinal en la falla hepática aguda. Su presencia y gravedad son uno de los mayores determinantes pronósticos en estos pacientes. Es frecuente en enfermedad hepática crónica avanzada (30-45 por ciento)y en portadores de shunt postosistémico transyugular intrahepático (TIPS) (10-50 por ciento). Su patogénesis es compleja y tiene múltiples componentes, incluyendo el amonio, citoquinas inflamatorias, compuestos que semejan a benzodiacepinas y manganeso, que causan alteración funcional de la célula neuronal. El manejo requiere identificar y tratar los factores precipitantes, además de excluir otras causas de alteración del estado mental. La mayoría de las terapias están dirigidas a reducir la carga de amonio en el intestino, tales como los disacáridos no absorbibles (lactulosa), antibióticos (neomicina, metronidazol y actualmente rifaximina) y otros cuyo rol está por establecerse. La encefalopatía grave es considerada un indicador para trasplante hepático. En este artículo analizaremos principalmente la encefalopatía hepática en pacientes con cirrosis, su clasificación, etiopatogenia y manejo actual.

Espectroscopia cerebral em candidatos a transplante hepático / Cerebral magnetic resonance spectroscopy in patients with hepatic encephalopathy: analysis before and after liver transplantation

OBJETIVOS: Determinar os níveis dos metabólitos (mio-inositol [MI], colina [Cho], glutamina [Glx], creatina [Cr] e N-acetilaspartato [NAA]) por meio da espectroscopia por ressonância magnética em portadores de hepatopatia crônica, antes e após o transplante hepático, correlacionando com a avaliação clínica. MÉTODOS: Foram estudados prospectivamente 25 pacientes portadores de hepatopatia crônica do Serviço de Transplante Hepático da Universidade Federal do Paraná por meio de avaliação clínica e espectroscópica. Trinta voluntários sadios formaram o grupo controle, sendo submetidos às mesmas avaliações. Dezesseis dos 25 pacientes também foram avaliados após o transplante. RESULTADOS: Antes do transplante hepático reduções significativas nos índices de MI/Cr e Cho/Cr e aumento significativo no índice de Glx/Cr foram observadas nos pacientes portadores de encefalopatia hepática comparados ao grupo controle. Os critérios quantitativos de Ross para diagnóstico espectroscópico da encefalopatia hepática (MI/Cr e Cho/Cr < média + 2 desvios padrão do grupo controle) demonstraram uma sensibilidade de 61,54 por cento, especificidade de 91,67 por cento e precisão de 76 por cento, sendo que a Cho/Cr foi o melhor parâmetro isolado. A espectroscopia após o transplante mostrou mudanças nos índices metabólicos comparados com o status pré-transplante. CONCLUSÃO: A espectroscopia permite um diagnóstico preciso da encefalopatia hepática. A melhora dos níveis metabólicos após o transplante hepático sugere um importante papel do MI e da Cho no desenvolvimento da encefalopatia hepática.

OBJECTIVES: To determine the metabolite levels (myo-inositol [MI], choline [Cho], glutamate [Glx], creatine [Cr] and N-acetylaspartate [NAA]) visible on magnetic resonance spectroscopy in patients with chronic hepatic failure, before and after liver transplantation and to correlate these data with results of neuropsychiatric tests and clinical findings. METHODS: Twenty five patients with chronic hepatic failure from the Liver Transplantation Unit of the Federal University of Parana were prospectively studied. Patients were submitted to clinical evaluation and magnetic resonance spectroscopy. Thirty healthy volunteers also submitted to the same evaluations. Sixteen of the 25 patients were evaluated after liver transplantation. RESULTS: Before liver transplantation, significant reductions in MI/Cr and Cho/Cr and a significant increase in Glx/Cr were observed in patients with hepatic encephalopathy compared with healthy subjects. The Ross's criteria for spectroscopic diagnosis of the hepatic encephalopathy (MI/Cr and Cho/Cr lower than 2 SD of controls) demonstrated a sensitivity of 61.54 percent, specificity of 91.67 percent and accuracy of 76 percent, further Cho/Cr was the best parameter. Spectroscopy after liver transplantation showed changes in the metabolite ratios compared with the pretransplantation status. CONCLUSION: Magnetic resonance spectroscopy permits an accurate diagnosis of hepatic encephalopathy. Improvement of metabolic ratios after liver transplantation suggests an important role of MI and Cho in the development of hepatic encephalopathy.

Role of trace elements in hepatic encephalopathy: zinc and manganese.

Apart from increased blood ammonia, alterations in various other substances have been implicated in the pathogenesis of hepatic encephalopathy (HE). The role of trace elements like zinc and manganese has been described recently. Zinc is an essential trace element and functions as an antioxidant. Low zinc concentrations have been reported in patients with cirrhosis of the liver, particularly those with HE. Patients with fulminant hepatic failure and subacute hepatic failure have also been shown to have low serum zinc levels. In animal experiments, zinc supplementation leads to a reduction in blood ammonia. Zinc deficiency also leads to alteration of neurotransmitters like gamma aminobutyric acid and norepinephrine. Zinc supplementation has been tried in HE. It may have a role in mild chronic HE, though further trials are necessary. Increased serum manganese levels have been shown in acute and chronic hepatitis, cirrhosis and congenital disorders like Alagille's syndrome. High manganese content has been reported in the globus pallidus in animals as well as brain tissues of patients dying of HE. Miners with chronic manganese exposure have encephalopathy and extra-pyramidal features similar to HE. It has been postulated that manganese impairs neuronal oxidative metabolism. The role of manganese in the pathogenesis of HE and the possibility of its chelation as treatment need further study.

Magnetic resonance imaging and spectroscopy in hepatic encephalopathy.

Hepatic encephalopathy (HE) is a potentially reversible neuropsychiatric syndrome secondary to cirrhosis and other severe liver diseases. Magnetic resonance imaging (MRI) and MR spectroscopy (MRS) have been explored to provide new insight into the pathophysiology, diagnosis and treatment of HE. MRI shows brain atrophy especially in the frontal region. Globus pallidus, putamen and portions of the internal capsule appear hyperintense on T1-weighted images; this is likely to be due to deposition of manganese as a result of portosystemic shunting and liver dysfunction. MRS permits the detection and quantification of certain brain metabolites in vivo. There is decrease in myoinositol and choline concentrations and increase in glutamine concentrations. There is no change in n-acetyl-aspartate. Depletion of myoinositol is the most sensitive and specific spectroscopic marker in HE. Its loss is most likely a compensatory mechanism for the accumulation of glutamine. In conclusion, MRI and MRS examine different aspects of hepatocerebral disease.

A long-term intake of a protein hydrolysate seems to increase the risk of encephalopathy in mice infected with Schistosoma mansoni

Previous investigations showed that Schistosoma mansoni infection aggravates protein malabsorption in undernourished mice and this can be reverted by administration of casein hydrolysate. The present study was undertaken to evaluate the effects of ingestion of casein hydrolysate for long periods. Albino Swiss mice were divided into eight groups. Diets contained 5 per cent (undernourished) or 20 per cent (controls) casein levels. For each group there were sub-groups ingesting whole or hydrolysed casein for 12 weeks. Infections with S. mansoni developed in half of the animals under each diet. All undernourished mice developed malabsorption. Low albuminemia was detected in infected animals independently of the protein level in the diet. However, albuminemia was lower in infected controls than in undernourished non-infected mice, suggesting a deficient liver protein synthesis. Infected mice fed on a 20 per cent protein hydrolysed diet exhibited low weight gain and high mortality rates. On the other hand, non-infected mice ingesting the same diet had the highest body weights. We are investigating the hypothesis that infected mice, even when fed normal diets, are unable to metabolise large amounts of amino acids due to the liver lesions related to schistosomiasis and as a result die of hepatic coma. In some of them, the excessive accumulation of ammonia in the blood enhances the outcome of an encephalopathy.

Effect of three antibacterial drugs in lowering blood & stool ammonia production in hepatic encephalopathy.

Neomycin (700 mg/8 h), ampicillin (500/6 h) and metronidazole (400 mg/8 h), were compared for their effect, on oral administration for 4 days, in reducing blood ammonia in 27 patients with stable chronic liver disease. It was found that there was 38.2, 38.5 and 8.7 m mol/litre mean reduction in blood ammonia in the neomycin, ampicillin and metronidazole treated groups respectively. The difference in blood ammonia was statistically significant for both neomycin (P = 0.01) and ampicillin (P = 0.03) but there was no significant change after metronidazole treatment (P = 0.6). The total stool enzyme activity at optimum pH was maximally reduced by ampicillin and minimally with metronidazole. The reduction was noted to be 3.51 m mol/1 (P = 0.01), 3.87 m mol/1 (P = 0.08) and 2.8 m mol/1 (P = 0.02) of NH3/g dry weight of stool for neomycin, ampicillin and metronidazole respectively. The main bacterial gut enzymes responsible for ammonia production, urease and protease, were found to be very sensitive to stool pH. At pH 6 their activity was around 20 per cent of what was found in optimum pH of 7.4 and at pH 5 it is only about 8 per cent of optimum activity. None of the three antibacterial agents changed the stool pH significantly. It can be concluded that oral neomycin and ampicillin are superior to oral metronidazole in lowering blood ammonia.

Biogenic amine status in acute fulminant hepatocellular failure in children.

This study involved pediatric cases with Acute fulminant hepatocellular failure (AFHF) put on conventional therapy at the Hospital for children, Madras. In these cases, the biogenic amine status was studied at the time of admission, during therapy and at the time of recovery in responders. The CSF 5-HT, 5-hydroxyindoleacetic acid (5-HIAA) and Homovanillic acid (HVA), blood 5-HT and 5-HIAA, and urinary 5-HIAA followed almost a similar pattern of changes during the course of AFHF: increase at precoma, further increase at coma, return towards control at recovery. In striking contrast, urinary 3-methoxy-4-hydroxyphenyl glycol (MHPG) and 3-methoxy-4-hydroxymandelic acid (VMA) registered a decrease at precoma, a further fall at coma and a value closer to control at recovery. The results suggest the usefulness of assay of these parameters in monitoring cases of AFHF during therapy and in offering prognosis for these cases.