Minimal Hepatic Encephalopathy in Cirrhosis- How Long to Treat?

Abstract: Introduction. Minimal hepatic encephalopathy (MHE) can reverse after short-term treatment. However, relapse rate of MHE after stopping treatment has not been studied so far. We aimed to evaluate long-term (9 months) efficacy of a short-term (3 months) treatment of MHE with lactulose/rifaximin, for maintenance of remission from MHE. Material and methods. In this prospective study, consecutive patients with cirrhosis and MHE were treated with lactulose/rifaximin for 3 months. After treatment, they were followed up for 6 months. Psychometric testing for diagnosis of MHE was performed at baseline, 3 months and 9 months. Results. Of the 527 patients screened, 351 were found eligible and tested for MHE. Out of these, 112 (31.9%) patients had MHE (mean age 55.3 years; 75% males). They were randomized to receive Rifaximin (n = 57; 1,200 mg/day) or Lactulose (n = 55; 30-120 mL/day) for three months. At 3 months, 73.7% (42/57) patients in Rifaximin group experienced MHE reversal compared to 69.1% (38/55) in Lactulose group (p = 0.677). Six months after stopping treatment, 47.6% (20/42) in rifaximin group and 42.1% (16/38) patients in lactulose group experienced MHE relapse (p = 0.274). The overt hepatic encephalopathy development rate (7.1% vs. 7.9%) and mortality rate (0.23% vs. 0%) were similar in both groups. The Child-Turcotte-Pugh score and model for end stage liver disease (MELD) scores of patients who had MHE relapse were higher compared to those who didn’t. On multivariate regression analysis, MELD score was an independent predictor of MHE relapse. Conclusion. Of the patients who became MHE negative after short-term (3 months) treatment with rifaximin/lactulose, almost 50% had a relapse of MHE at 6 months follow-up.

Eficacia y seguridad de rifaximina alfa en pacientes con encefalopatia hepatica refractaria al uso de lactulosa / Efficacy and safety of rifaximin alfa in patients with hepatic encephalopathy refractory to the use of lactulose

INTRODUCCIÓN: Antecedentes: El presente dictamen responde a la solicitud de evaluación del uso del petitorio de Rifaximina alfa en pacientes con encefalopatia hepática refractaria al uso de lactulosa. Aspectos Generales: Se estima que aproximadamente 5.5 millones de personas en los Estados Unidos sufren de cirrosis hepática, una causa de movilidad y mortalidad tanto en este país como en el mundo. La encefalopatia hepática o encefalopatía portosistemica constituye una complicación de la cirrosis hepática y falla de la función neuropsiquiátrica asociada con falla en la función hepática. A pesar que la condición es frecuentemente diagnosticada aún no existe un claro entendimiento de la patogénesis. Sin embargo, se estipula que se puede deber a un incremiento en las concentraciones de amoniaco en vista que el higado ya no es capaz de eliminar las toxinas de la sangre causando así toxicidad en el cerebro. Puede presentarse como episodios agudos o crónicamente a largo plazo. Tecnología Sanitaria de Interés: La Rifaximina alfa es un agente antimicrobiano con un amplio espectro de acción sobre Bacterias Gram-positivas y Gram- negativas, tanto aerobias como anaerobais. La característica de Rifaximina alfa es su forma polimorfa alfa y su escasa absorción en el tracto gastrointestinal (inferior a 1%), lo cual favorece la concentración del fármaco en el intestino y sobre todo, en las heces en forma activa. METODOLOGÍA: Estrategia de Búsqueda: Se llevó a cabo una búsqueda sistemática de la literatura con respecto a la eficacia y seguridad de Rifaximina alfa para el tratamiento de pacientes con encefalopatía hepática con resistencia (falla) al tratamiento estándar con lactulosa. La búsqueda se inicio revisando la información sobre el uso del medicamento de acuerdo con entidades reguladoras com la Food and Drug Administration (FDA), la European Medicines Agency (EMA) y la Dirección General de Medicamentos y Drogas (DIGEMID). Posteriomente se buscaron Guías de Práctica Clínica a través de los metabuscadores: Translating Research into Practice (TRIPDATABASE), National Library of Medicine (Pubmed-Medline), The National Guuideline of Clearinghouse, y Health Systems Evidence. Finalmente. se realizó una búsqueda dentro de la información generada por grupos internacionales que realizan revisiones sistemáticas, evaluación de tecnologías sanitarias y guías de práctica clínica. RESULTADOS: Sinopsis de la Evidencia: En la presente sinopsis se describe la evidencia disponible que sustenta la eficacia y seguridad de Rifaximina alfa para el tratamiento de pacientes con encefalopatia hgepática refractarios al tratamiento estándar con lactulosa. CONCLUSIONES: A la fecha, no se ha evaluado la eficacia y seguridad de Rifazimina alfa como monoterapia ni en pacientes refractarios a lactulosa, por lo que la evidencia encontrada responde la pregunta PICO de manera indirecta. Actualmente no existe alternativa de tratamiento a lactulosa en el Petitorio Farmacológico de EsSalud, por lo que es necesario contar con una alternativa de tratamiento para así evitar el deterioro de la calidad de vida del paciente, dadas las limitaciones en las funciones cognitiva y psicomotriz a la que la enfermedad conlleva. El Instituto de Evaluacioón de Tecnologías en Salud e Investigación-IETSI, aprueba el uso de Rifaximina alfa en pacientes con encefalopatía hepática refractaria al uso de lactulosa. El presente Dicatamen Preliminar tiene una vigencia de dos años a partir de su fecha de publicación.

Rifaximina para encefalopatía hepática en niños: Caso clínico / Rifaximin for hepatic encephalopathy in children: Case report

La rifaximina es un antibiótico recientemente aprobado para el tratamiento de la encefalopatía hepática en adultos. En niños mayores de 12 años se aprobó su uso en la diarrea del viajero y se lo emplea ampliamente en la enfermedad infamatoria intestinal. Comunicamos el primer caso del que tenemos conocimiento, de un paciente en edad pediátrica que recibió rifaximina para tratar la encefalopatía hepática, con buena respuesta clínica.

Rifaximin is an antibiotic recently approved for the treatment of hepatic encephalopathy in adults. In children more than 12 year-old, it has been approved for travelers' diarrhea and it is also widely used in infammatory bowel disease. We report, to our knowledge, the frst case of a pediatric patient who received rifaximin for hepatic encephalopathy with good clinical outcome.

Acquired hepatocerebral degeneration and hepatic encephalopathy: correlations and variety of clinical presentations in overt and subclinical liver disease / Degeneração hepatocerebral adquirida e encefalopatia hepática: correlações e variedade de apresentações clínicas na doença hepática evidente e subclínica

Acquired hepatocerebral degeneration (AHD) and hepatolenticular degeneration can have similar clinical presentations, but when a chronic liver disease and atypical motor findings coexist, the distinction between AHD and hepatic encephalopathy (HE) can be even more complicated. We describe three cases of AHD (two having HE) with different neuroimaging findings, distinct hepatic diseases and similar motor presentations, all presenting chronic arterial hypertension and weight loss before the disease manifestations. The diagnosis and physiopathology are commented upon and compared with previous reports. In conclusion, there are many correlations among HE, hepatolenticular degeneration and AHD, but the overlapping of AHD and HE could be more common depending on the clinical knowledge and diagnostic criteria adopted for each condition. Since AHD is not considered a priority that affects the liver transplant list, the prognosis in AHD patients remains poor, and flow interruption in portosystemic shunts must always be taken into account.

A degeneração hepatocerebral adquirida (AHD) e a degeneração hepatolenticular podem ter apresentações clínicas semelhantes, mas quando uma doença hepática crônica e achados motores atípicos coexistem, a distinção entre AHD e encefalopatia hepática (HE) pode ser ainda mais complicada. Descrevemos três casos de AHD (dois tendo HE) com diferentes achados em neuroimagem, doenças hepáticas distintas e apresentações motoras semelhantes, todos com hipertensão arterial e perda de peso antes das manifestações motoras. O diagnóstico e a fisiopatologia são comentados e comparados com relatos prévios. Concluímos que existem muitas correlações entre HE, degeneração hepatolenticular e AHD, mas a sobreposição de HE e AHD pode ser mais comum dependendo do conhecimento clínico e da acurácia dos critérios diagnósticos adotados para cada enfermidade. Como a AHD não é considerada prioridade na lista de transplante hepático, o prognóstico dos pacientes com AHD permanece ruim, e a interrupção do fluxo nos shunts portossistêmicos deve ser sempre considerada.

Metronidazole-induced encephalopathy in a patient with liver cirrhosis / 대한간학회지

Encephalopathy is a disorder characterized by altered brain function, which can be attributed to various causes. Encephalopathy associated with metronidazole administration occurs rarely and depends on the cumulative metronidazole dose, and most patients with this condition recover rapidly after discontinuation of therapy. Because metronidazole is metabolized in the liver and can be transported by the cerebrospinal fluid and cross the blood-brain barrier, it may induce encephalopathy even at a low cumulative dose in patients with hepatic dysfunction. We experienced a patient who showed ataxic gait and dysarthric speech after receiving metronidazole for the treatment of hepatic encephalopathy that was not controlled by the administration of lactulose. The patient was diagnosed as metronidazole-induced encephalopathy, and stopping drug administration resulted in a complete recovery from encephalopathy. This case shows that caution should be exercised when administering metronidazole because even a low dose can induce encephalopathy in patients with liver cirrhosis.

A critical analysis of studies assessing L-ornithine-L-aspartate (LOLA) in hepatic encephalopathy treatment / Uma análise crítica dos estudos de avaliação do L-ornitina-L-aspartato (LOLA) no tratamento da encefalopatia hepática

CONTEXT: Experimental and clinical studies suggest that LOLA may have a favorable influence on hepatic encephalopathy due to the effect on the reduction of ammonia, and improvement of the symptoms and laboratory findings. OBJECTIVES: To evaluate and to critically analyze the efficacy and/or effectiveness results of the use of LOLA when compared to placebo in the treatment of hepatic encephalopathy. DATA SOURCES: LILACS, SciELO, MEDLINE, PubMed database and Cochrane Collaboration Register of Controlled Trials were searched from 1966 to September of 2006. The review has included all the randomized controlled double-blind clinical trials performed in humans in English language. RESULTS: Four studies published between 1993 and 2000 were selected and reviewed. LOLA was showed as being able to reduce hyperammonemia in patients with hepatic encephalopathy, when compared to patients in the placebo group. CONCLUSIONS: Although the trials have shown efficacy of LOLA in reducing hyperammonemia of hepatic encephalopathy, sufficient evidence of a significant beneficial effect of LOLA on patients with hepatic encephalopathy was not found. The studies performed in this area were small, with short follow-up periods and half of them showed low methodological quality.

CONTEXTO: Estudos experimentais e clínicos sugerem que a L-ornitina-L-aspartato pode ter uma influência favorável na encefalopatia hepática em virtude do seu efeito na redução da amônia, e melhora dos sintomas e achados laboratoriais. OBJETIVOS: Avaliar e analisar criticamente os estudos de eficácia e/ou efetividade do uso de L-ornitina-L-aspartato quando comparado com placebo no tratamento da encefalopatia hepática. FONTES DE INFORMAÇÃO: Foram pesquisadas as bases de dados LILACS, SciELO, MEDLINE, PubMed e o Registro de Ensaios Controlados da Colaboração Cochrane no período de 1966 até setembro de 2006. A revisão incluiu todos os ensaios clínicos controlados randomizados, duplo-cego, em seres humanos, no idioma inglês. RESULTADOS: Foram selecionados e revisados quatro estudos publicados entre 1993 e 2000, que mostraram que a L-ornitina-L-aspartato foi capaz de reduzir a hiperamonemia em portadores de encefalopatia hepática, quando comparados ao grupo que utilizou placebo. CONCLUSÕES: Embora os estudos tenham demonstrado eficácia da L-ornitina-L-aspartato em reduzir a hiperamonemia da encefalopatia hepática, não foi encontrada evidência suficiente que a L-ornitina-L-aspartato tenha um efeito clínico benéfico significativo em pacientes com encefalopatia hepática. Os ensaios realizados neste campo foram pequenos com períodos curtos de acompanhamento e a metade deles com baixa qualidade metodológica.

Hypertonic saline solution increases cerebral perfusion pressure during clinical orthotopic liver transplantation for fulminant hepatic failure: preliminary results

Neste estudo testamos a hipótese de que os efeitos benéficos decorrentes da administração da solução salina hipertônica (NaCl 7,5%, 4 mL/kg) sobre a hemodinâmica sistêmica e cerebral na hipertensão intracraniana e no choque hemorrágico, possam atenuar a diminuição da pressão de perfusão cerebral que freqüentemente acompanha o transplante do fígado para hepatite fulminante.MÉTODO: Foram estudados 10 pacientes com hepatite fulminante em encefalopatia grau IV e monitorização de pressão intracraniana submetidos ao transplante do fígado. A hemodinâmica sistêmica e cerebral de 3 pacientes que receberam solução salina hipertônica durante a fase anepática (Grupo SSH) foi analisada comparando com os dados obtidos de 7 pacientes transplantados anteriormente nas mesmas condições (Grupo Controle). Os valores de pressão intracraniana máxima e a correspondente pressão arterial média foram coletados em quatro tempos: (T1) nos últimos 10 min da fase de disseccão, (T2) nos primeiros 10 minutos da fase anepática, (T3) no final da fase anepática e (T4) nos primeiros 5 min da reperfusão.RESULTADO: Imediatamente após a infusão da solução salina hipertônica a pressão intracraniana diminuiu 50,4%. Nos primeiros 5 min da reperfusão a pressão intracraniana no Grupo SSH se manteve estável e todos os pacientes apresentavam pressão intracraniana menor que 20 mmHg enquanto no Grupo Controle a pressão intracraniana aumentou 46,5% (p<0,001). O Grupo SSH apresentou maior estabilidade hemodinâmica, nos primeiros 5 min da reperfusão hepática, a pressão arterial média no Grupo SSH aumentou 21,1% e no Grupo Controle diminuiu 11,1% (p<0,001). Nos primeiros 5 min da reperfusão a pressão de perfusão cerebral no Grupo SSH aumentou 28,3% e no Grupo Controle diminuiu 28,5% (p< 0,001). A natremia no final da fase anepáica e após 3 horas da reperfusão foi significativamente maior no Grupo SSH (153.00 ± 2.66 and 149.00 ± 1.73 mEq/L) que no Grupo Controle (143.71 ± 3.30 and 142.43 ± 1.72 mEq/L), p=0.003 e p< 0.001 respectivamente.CONCLUSÃO: Estes resultados sugerem que a solução salina hipertônica pode ser utilizada com sucesso como medida neuroprotetora no transplante de fígado para hepatite fulminante, promovendo diminuição efetiva da pressão intracraniana e estabilidade cardiocirculatória, proporcionando aumento sustentado da PPC durante a cirurgia.

Comparison of Rifaximin and Lactulose for the Treatment of Hepatic Encephalopathy: A Prospective Randomized Study

Rifaximin has been reported to be effective for the treatment of hepatic encephalopathy (HE) in Europe. However, it is unknown whether Rifaximin is effective for the treatment of HE in Koreans, therefore we conducted a open-label prospective randomized study to evaluate the efficacy of rifaximin versus lactulose in Korean patients. Fifty-four patients with liver cirrhosis and hepatic encephalopathy were enrolled. Thirty-two patients were randomized to receive rifaximin and 22 to receive lactulose both over a 7-day periods. Before and at the end of treatment, gradation of blood ammonia, flapping tremor, mental status, number connection test (NCT) were performed and estimation of HE indexes determined. Both rifaximin and lactulose were effective in the majority of patients (84.4% and 95.4%, respectively, p=0.315). Blood NH3, flapping tremor, mental status, and NCT was significantly improved by rifaximin and lactulose, and the post- treatment levels of these measures were similar for the rifaximin and lactulose-treated groups, as was the HE index (rifaximin group (10.0-->> 4.2, p=0.000) ; lactulose group (11.3-->> 5.0, p=0.000) ). One patient treated with rifaximin complained of abdominal pain, which was easily controlled. There was no episode of renal function impairment in either treatment group. Rifaximin proved to be as safe and as effective as lactulose for the treatment of Korean patients with hepatic encephalopathy.

Role of gut bacteria in the therapy of hepatic encephalopathy with lactulose and antibiotics.

The pathogenesis of hepatic encephalopathy is mediated to a large extent by ammonia, mainly derived from the gut. Both bacterial and nonbacterial mechanisms of ammoniagenesis have been shown, but ammoniagenesis mediated by colonic bacteria is probably of clinical significance. The therapy of hepatic encephalopathy is based on the putative etiological agents, including ammonia. Non-absorbable disaccharides and antibiotics have been shown to modify gut flora and decrease blood ammonia levels, but these are not necessarily related (indicating nonbacterial sources of ammonia, which may also be decreased by these compounds). A combination of these has been suggested but not consistently demonstrated to be beneficial in hepatic encephalopathy. Sodium benzoate is an alternate method of nonbacterial, non-hepatic metabolic binding pathway for ammonia disposal. Other mechanisms of gut bacterial modification may be achieved albeit transiently by the use of resistant bacteria like Enterococcus faecium.

Perinephric abscess mimicking fulminant hepatic failure

We describe a female diabetic patient who presented with features suggestive of hepatobiliary disease and who exhibited clinical signs of fulminant hepatic failure. Identification and drainage of a right perinephric abscess resulted in prompt resolution of both the physical signs and biochemical indices of liver disease. Infection remote from the hepatobiliary tree can mimic fulminant hepatic failure, and recognition of this unusual presentation of infection is important if dangerous delay in diagnosis and treatment is to avioded.

Encefalopatía hepática

Mental deterioration in patients with fulminant hepatitis is a poor prognosis sign. Patients in stages III or IV with stupor or coma have cerebral edema. The increase in cerebral fluid eventually leads to endocraneal hypertension. Brain edema is not the cause of encephalopathy, only when the structures are displaced or intracraneal pressure increases, pupilary abnormalities, abnormal caloric reflexes and myoclonic seizures appears. Significant elevation of intracraneal pressure can be asymptomatic leading to temporal lobe herniation and death. Liver transplantation has changed the prognosis, and subdural and epidural monitoring has been developed in order to evaluate this problem optimally. Monitoring of cerebral perfusion pressure (mean arterial pressure - endocraneal pressure) to assess brain flow is essential. Values of less than 40mmHg imply cerebral ischemia. In patients with cirrhosis encephalopathy has several stages, and sleep disturbances can present very early. Asterixis is a sensible but not specific sign and the classic "faetor hepaticus" is not frequent. Most of the time a precipitating factor can be identified: gastrointestinal bleeding, sedatives, iuremia, infections, constipation, high protein intake and hypokalemia, chronic porto-systemic encephalopathy is mainly related to spontaneous porto-systemic collaterals or surgically created shunts. The most important pathogenetic factors are: ammonia, glutamate, increase cerebral serotonine, increase GABA tone and recently the presence of endogenous benzodiazepines. New therapeutic modalities included the administration of flumazenil, vegetable protein, lactulose and sodium benzoate...

Management of fulminant hepatic failure with Mannitol. [short communication]

Eight patients with fulminant hepatic were managed conservatively using intermittent infusion of 20 percent mannitol. All but one case regained consciousness within seven days of commencement of the mannitol infusion. All have maintained normal hepatic function over a period of twelve to eighteen months. Mannitol still remains an effective treatment modality in centres where newer and sophisticated methods of therapy are now available