RESUMEN
Hepatic encephalopathy (HE) is a serious neuropsychiatric complication of cirrhosis and/or porto-systemic shunting. The clinical symptoms are widely variable, extending from subtle impairment in mental state to coma. The utility of categorizing the severity of HE accurately and efficiently serves not only to provide practical functional information about the current clinical status of the patient but also gives valuable prognostic information. In the past 20-30 years, there has been rapid progress in understanding the pathophysiological basis of HE; however, the lack of direct correlation between pathogenic factors and the severity of HE make it difficult to select appropriate therapy for HE patients. In this review, we will discuss the classification system and its limitations, the neuropsychometric assessments and their challenges, as well as the present knowledge on the pathophysiological mechanisms. Despite the many prevalent hypotheses around the pathogenesis of the disease, most treatments focus on targeting and lowering the accumulation of ammonia as well as inflammation. However, treatment of minimal HE remains a huge unmet need and a big concerted effort is needed to better define this condition to allow the development of new therapies. We review the currently available therapies and future approaches to treat HE as well as the scientific and clinical data that support their effectiveness.
Asunto(s)
Amoníaco/sangre , Edema Encefálico/complicaciones , Encefalopatía Hepática/clasificación , Encefalopatía Hepática/fisiopatología , Cirrosis Hepática/complicaciones , Cirrosis Hepática/fisiopatología , Albúminas/administración & dosificación , Albúminas/uso terapéutico , Amoníaco/metabolismo , Antibacterianos/uso terapéutico , Ácidos y Sales Biliares/líquido cefalorraquídeo , Encéfalo/metabolismo , Encéfalo/fisiopatología , Edema Encefálico/metabolismo , Disfunción Cognitiva/complicaciones , Dipéptidos/uso terapéutico , Metabolismo Energético/fisiología , Fármacos Gastrointestinales/uso terapéutico , Encefalopatía Hepática/psicología , Encefalopatía Hepática/terapia , Humanos , Lactulosa/normas , Lactulosa/uso terapéutico , Cirrosis Hepática/sangre , Cirrosis Hepática/líquido cefalorraquídeo , Ornitina/análogos & derivados , Ornitina/uso terapéutico , Derivación Portosistémica Quirúrgica/métodos , Pronóstico , Psicometría/métodos , Índice de Severidad de la Enfermedad , Transmisión Sináptica/fisiologíaRESUMEN
Although hepatic encephalopathy (HE) on the background of acute on chronic liver failure (ACLF) is associated with high mortality rates, it is unknown whether this is due to increased blood-brain barrier permeability. Specific gravity of cerebrospinal fluid measured by CT is able to estimate blood-cerebrospinal fluid-barrier permeability. This study aimed to assess cerebrospinal fluid specific gravity in acutely decompensated cirrhosis and to compare it in patients with or without ACLF and with or without hepatic encephalopathy. We identified all the patients admitted for acute decompensation of cirrhosis who underwent a brain CT-scan. Those patients could present acute decompensation with or without ACLF. The presence of hepatic encephalopathy was noted. They were compared to a group of stable cirrhotic patients and healthy controls. Quantitative brain CT analysis used the Brainview software that gives the weight, the volume and the specific gravity of each determined brain regions. Results are given as median and interquartile ranges and as relative variation compared to the control/baseline group. 36 patients presented an acute decompensation of cirrhosis. Among them, 25 presented with ACLF and 11 without ACLF; 20 presented with hepatic encephalopathy grade ≥ 2. They were compared to 31 stable cirrhosis patients and 61 healthy controls. Cirrhotic patients had increased cerebrospinal fluid specific gravity (CSF-SG) compared to healthy controls (+0.4 %, p < 0.0001). Cirrhotic patients with ACLF have decreased CSF-SG as compared to cirrhotic patients without ACLF (-0.2 %, p = 0.0030) that remained higher than in healthy controls. The presence of hepatic encephalopathy did not modify CSF-SG (-0.09 %, p = 0.1757). Specific gravity did not differ between different brain regions according to the presence or absence of either ACLF or HE. In patients with acute decompensation of cirrhosis, and those with ACLF, CSF specific gravity is modified compared to both stable cirrhotic patients and healthy controls. This pattern is observed even in the absence of hepatic encephalopathy suggesting that blood-CSF barrier impairment is manifest even in absence of overt hepatic encephalopathy.
Asunto(s)
Insuficiencia Hepática Crónica Agudizada/líquido cefalorraquídeo , Insuficiencia Hepática Crónica Agudizada/fisiopatología , Barrera Hematoencefálica/fisiopatología , Líquido Cefalorraquídeo/química , Cirrosis Hepática/líquido cefalorraquídeo , Cirrosis Hepática/fisiopatología , Insuficiencia Hepática Crónica Agudizada/diagnóstico por imagen , Anciano , Química Encefálica , Enfermedad Crónica , Femenino , Encefalopatía Hepática/líquido cefalorraquídeo , Humanos , Cirrosis Hepática/diagnóstico por imagen , Pruebas de Función Hepática , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Gravedad Específica , Tomografía Computarizada por Rayos XRESUMEN
Increased plasma and CSF concentrations of substances which bind to brain benzodiazepine receptors have previously been reported in cirrhotic patients with hepatic encephalopathy (HE). However, their relationship to previous intake of pharmaceutical benzodiazepines has not been clearly established. In the present study, plasma levels of benzodiazepine receptor ligands (BZRLs) were measured using a sensitive radioreceptor assay in 12 control subjects with no evidence of hepatic, neurological or psychiatric illness, 11 cirrhotic patients without HE, 24 cirrhotic patients with moderate (grade I-II) HE and in 45 cirrhotic patients with severe (grade II-IV) HE. In addition, CSF concentrations of BZRLs were measured in 8 cirrhotic patients with HE and an equal number of age-matched controls. Recent intake (within 10 days) of pharmaceutical benzodiazepines was assessed by detailed review of medical files, and interviews with the patient, at least one family member as well as the pharmacist. Significantly increased plasma concentrations of BZRLs were observed in cirrhotic patients with severe encephalopathy (p < 0.02) compared to controls and to cirrhotic patients without (or with mild) neurological impairment. Increased plasma BZRLs could be accounted for by prior exposure to benzodiazepine medication in all cases. CSF concentrations of BZRLs in cirrhotic patients were not significantly different from control values. These findings do not support a role for "endogenous" benzodiazepines in the pathogenesis of HE in chronic liver disease but suggest that pharmaceutic benzodiazepines administered to cirrhotic patients as sedatives or as part of endoscopic work-up could have contributed to the neurological impairment in some patients.
Asunto(s)
Benzodiazepinas/farmacología , Encefalopatía Hepática/sangre , Encefalopatía Hepática/líquido cefalorraquídeo , Receptores de GABA-A/metabolismo , Animales , Benzodiazepinas/sangre , Benzodiazepinas/líquido cefalorraquídeo , Unión Competitiva/efectos de los fármacos , Fraccionamiento Celular , Cerebelo , Enfermedad Crónica , Clonazepam/farmacología , Diazepam/farmacología , Flumazenil/farmacología , Moduladores del GABA/farmacología , Humanos , Isoquinolinas/farmacología , Cirrosis Hepática/sangre , Cirrosis Hepática/líquido cefalorraquídeo , Oxazepam/farmacología , Ensayo de Unión Radioligante , Ratas , TritioRESUMEN
To study the effect of ammonia administration on amino acids and indoleamines in cerebrospinal fluid (CSF) and on amino acids, insulin, and glucagon in plasma in humans with liver cirrhosis, we performed seven ammonia tolerance tests on six patients with stable liver cirrhosis. The grade of encephalopathy was determined by psychometric tests. Only one of the patients had pronounced encephalopathy. The other patients had no or only slight encephalopathy. The plasma concentrations of valine, leucine, isoleucine, phenylalanine, tyrosine, and methionine decreased after the ammonia load, whereas no changes were found in the plasma concentrations of glucagon and insulin. In CSF the concentrations of glutamine, aromatic amino acids, and indoleamines increased only in the patient who had pronounced encephalopathy, whereas no changes were found in the other patients. The effect of an ammonia load on the concentrations of neutral amino acids in CSF in patients with pronounced encephalopathy remains to be demonstrated.
Asunto(s)
Aminoácidos/líquido cefalorraquídeo , Cloruro de Amonio/farmacología , Cirrosis Hepática/líquido cefalorraquídeo , 5-Hidroxitriptófano/líquido cefalorraquídeo , Adulto , Anciano , Aminoácidos/sangre , Cloruro de Amonio/administración & dosificación , Tolerancia a Medicamentos , Humanos , Ácido Hidroxiindolacético/líquido cefalorraquídeo , Masculino , Persona de Mediana Edad , Serotonina/líquido cefalorraquídeoAsunto(s)
Trastornos del Conocimiento/líquido cefalorraquídeo , Trastornos de la Conciencia/líquido cefalorraquídeo , Glutamina/líquido cefalorraquídeo , Hepatopatías/líquido cefalorraquídeo , Adolescente , Adulto , Anciano , Trastornos de la Conciencia/diagnóstico , Trastornos de la Conciencia/etiología , Femenino , Encefalopatía Hepática/líquido cefalorraquídeo , Encefalopatía Hepática/diagnóstico , Hepatitis/líquido cefalorraquídeo , Humanos , Cirrosis Hepática/líquido cefalorraquídeo , Hepatopatías/complicaciones , Masculino , Persona de Mediana EdadRESUMEN
Plasma and cerebrospinal fluid amino acid levels wee measured in 12 cirrhotic patients in grade 0 hepatic encephalopathy and 17 in grade 3-4 hepatic encephalopathy. In 5 of these patients amino acid determinations were performed during the evolution of the encephalopathy. No correlation was found between the degree of hepatic encephalopathy and the plasma amino acid imbalance. In the CSF of cirrhotic patients without encephalopathy, a significant increase was found in nearly all amino acids, including those known to not easily cross the blood-brain barrier; this suggests the presence of a nonspecific modification of the blood-brain barrier permeability. In patients with severe hepatic encephalopathy, the further increase only in cerebrospinal fluid aromatic amino acids and methionine levels suggests the presence of a selective stimulation of the neutral amino acid transport system across the blood-brain barrier. Finally, the good correlation between glutamine and the sum of neutral amino acids found in the cerebrospinal fluid only in the presence of encephalopathy supports the hypothesis that brain glutamine may stimulate neutral amino acid transport across the blood-brain barrier.
Asunto(s)
Aminoácidos/análisis , Encefalopatía Hepática/metabolismo , Adulto , Anciano , Aminoácidos/sangre , Aminoácidos/líquido cefalorraquídeo , Femenino , Encefalopatía Hepática/sangre , Encefalopatía Hepática/líquido cefalorraquídeo , Humanos , Cirrosis Hepática/sangre , Cirrosis Hepática/líquido cefalorraquídeo , Cirrosis Hepática/metabolismo , Masculino , Persona de Mediana EdadRESUMEN
Lumbar CSF indoleacetic acid (IAA) was higher in patients with cirrhosis of the liver than in controls. It was also higher in CSF of patients in coma than in those with hepatic cirrhosis but not in coma. There was a strong correlation (r = 0.89, p less than 0.01) between the grade of hepatic coma and CSF IAA. These data indicate that there is an association between elevated CNS tryptamine metabolism and hepatic coma. How far changes in the metabolism of tryptamine and other trace amines are relevant to the induction of hepatic coma or are simply a reflection of advanced liver dysfunction is unclear.
Asunto(s)
Encefalopatía Hepática/líquido cefalorraquídeo , Triptaminas/líquido cefalorraquídeo , Adulto , Anciano , Femenino , Humanos , Ácidos Indolacéticos/líquido cefalorraquídeo , Cirrosis Hepática/líquido cefalorraquídeo , Masculino , Persona de Mediana Edad , Probenecid/uso terapéuticoRESUMEN
The concentrations of tryptophan in serum and CSF, as well as that of 5-HIAA in CSF were investigated in various group of patients. Those with hepatic cirrhosis have normal total serum tryptophan. However, because of the low concentration of serum albumin the percentage of nonalbumin-bound tryptophan is elevated about 50 percent above the mean control value. By contrast tryptophan in the CSF was increased by 50 to over 800 percent. This suggests that there is also an increase in brain tryptophan and serotonin in the cirrhotic patients. No significant difference was found for the concentrations of tryptophan in CSF of patients in coma and those not in coma. Patients with hepatic coma had an elevated concentration of 5-HIAA in the lumbar CSF which may reflect the increase in this compound and in serotonin reported by Jellinger and Riederer (1977). However, following treatment with probenecid in order to block the egress of 5-HIAA from the CSF, the concentration of 5-HIAA in relation to that of probenecid was not significantly different for the group with hepatic coma as compared with the control group.
Asunto(s)
Encefalopatía Hepática/líquido cefalorraquídeo , Triptófano/líquido cefalorraquídeo , Encefalopatía Hepática/sangre , Encefalopatía Hepática/complicaciones , Humanos , Ácido Hidroxiindolacético/líquido cefalorraquídeo , Cirrosis Hepática/líquido cefalorraquídeo , Cirrosis Hepática/complicaciones , Triptófano/sangreAsunto(s)
Dopamina/biosíntesis , Encefalopatía Hepática/líquido cefalorraquídeo , Ácido Homovanílico/líquido cefalorraquídeo , Ácido Hidroxiindolacético/líquido cefalorraquídeo , Lactatos/líquido cefalorraquídeo , Cirrosis Hepática/líquido cefalorraquídeo , Manifestaciones Neurológicas/metabolismo , Fenilacetatos/líquido cefalorraquídeo , Probenecid , Serotonina/biosíntesis , Equilibrio Ácido-Base , Adulto , Anciano , Humanos , Concentración de Iones de Hidrógeno , Hígado/metabolismo , Persona de Mediana Edad , Manifestaciones Neurológicas/líquido cefalorraquídeo , Probenecid/líquido cefalorraquídeoRESUMEN
A possible relationship between blood acid-base state and the concentration of cerebrospinal fluid potassium has been examined in patients with systemic disturbances of acid-base metabolism. Over the range of values studied it was not possible to demonstrate any significant correlation between these parameters.
Asunto(s)
Equilibrio Ácido-Base , Potasio/líquido cefalorraquídeo , Síndrome de Cushing/líquido cefalorraquídeo , Síndrome de Cushing/fisiopatología , Humanos , Concentración de Iones de Hidrógeno , Hiperaldosteronismo/líquido cefalorraquídeo , Hiperaldosteronismo/fisiopatología , Fallo Renal Crónico/líquido cefalorraquídeo , Fallo Renal Crónico/fisiopatología , Cirrosis Hepática/líquido cefalorraquídeo , Cirrosis Hepática/fisiopatologíaRESUMEN
CSF from neurological and other patients was analyzed for its content of tryptophan, 5-HIAA and homovanilic acid (HVA). The gradients of concentration of these substances from ventricular spaces to lumbar sac indicate that tryptophan and 5-HIAA probably enter the CSF from all levels of the nervous system, but that HVA originates entirely in the brain. A study of CSF tryptophan in patients with hepatic cirrhosis provided no support for theories which implicate abnormal tryptophan metabolism as a cause of hepatic coma.