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.

Detecção de encefalopatia hepática mínima através de testes neuropsicológicos e neurofisiológicos e o papel da amônia no seu diagnóstico / Minimal hepatic encephalopathy detection by neuropsychological and neurophysiological methods and the role of ammonia for its diagnosis

CONTEXTO: A encefalopatia hepática mínima vem sendo sistematicamente investigada em pacientes com cirrose hepática. Entretanto, existem controvérsias quanto aos melhores métodos, bem como o papel da amônia para seu diagnóstico. OBJETIVO: Avaliar a frequência de encefalopatia hepática mínima diagnosticada através de testes neuropsicológicos e neurofisiológicos em cirróticos, bem como os possíveis fatores de risco para esta condição, incluindo o papel da concentração arterial de amônia em seu diagnóstico. MÉTODOS: Indivíduos com cirrose hepática foram avaliados através do teste de conexão numérica partes A e B (TCN-A e TCN-B) e potencial evocado relacionado a eventos (P300). O diagnóstico de encefalopatia hepática mínima foi feito quando da presença de anormalidade no P300 e em, pelo menos, um dos testes neuropsicológicos. As concentrações arteriais de amônia, a escolaridade e a gravidade da cirrose hepática também foram avaliadas em todos. RESULTADOS: Foram avaliados 48 pacientes cirróticos, com média de idade 50 ± 8 anos, sendo 79 por cento do sexo masculino. As principais causas foram a alcoólica e a viral. O P300 foi anormal em 75 por cento dos casos e o TCN-A e TCN-B anormais em 58 por cento e 65 por cento dos casos, respectivamente. Os resultados do TCN-B foram influenciados pela escolaridade. A frequência de encefalopatia hepática mínima foi de 50 por cento. A concentração arterial de amônia não foi significantemente maior em pacientes com diagnóstico de encefalopatia hepática mínima (195 ± 152 mmol/L versus 148 ± 146 mmol/L; P>0,05). Não houve diferença significante entre os grupos com e sem encefalopatia hepática mínima quanto às demais variáveis estudadas. CONCLUSÃO:A encefalopatia hepática mínima é condição frequente em pacientes com cirrose hepática. A concentração arterial de amônia não parece ter papel importante no seu diagnóstico.

CONTEXT: Minimal hepatic encephalopathy has been systematically investigated in cirrhotic patients. Although, there are controversies regarding the best methods as well as the role of ammonia for its diagnosis. OBJECTIVE: To evaluate the frequency of minimal hepatic encephalopathy diagnosed by neuropsychological and neurophysiological methods in cirrhotic patients, as well as possible associated risk factors for this condition, including the role of arterial ammonia concentrations for its diagnosis. METHODS: Cirrhotic patients were evaluated by the number connection test parts A and B (NCT-A and NCT-B), and auditory evoked-related potentials (P300). Minimal hepatic encephalopathy was diagnosed by the presence of abnormal P300 and in unless one of the performed neuropsychologic tests. Arterial ammonia concentration, scholarity and cirrhosis severity accessed by Child-Pugh classification were evaluated in all. RESULTS: Forty-eight cirrhotic patients were evaluated, with median age 50 ± 8 years old, 79 percent male. The main etiologies were alcoholic and viral. The P300 was abnormal in 75 percent of cases, while NCT-A and NCT-B were abnormal in 58 percent and 65 percent, respectively. The NCT-B results were influenced by scholarity. The minimal hepatic encephalopathy frequency was 50 percent. Arterial ammonia concentration was not significantly increased in minimal hepatic encephalopathy diagnosed patients (195 ± 152 mmol/L versus 148 ± 146 mmol/L; P>0,05). There was no difference between groups with or without minimal hepatic encephalopathy in the other studied variables. CONCLUSION: Minimal hepatic encephalopathy is a frequent condition in cirrhotic patients. The arterial ammonia concentration does not play a major role in its diagnosis.

The Association Between the Serum Sodium Level and the Severity of Complications in Liver Cirrhosis

BACKGROUND/AIMS: Dilutional hyponatremia associated with liver cirrhosis is caused by impaired free water clearance. Several studies have shown that serum sodium levels correlate with survival in cirrhotic patients. Little is known, however, regarding the relationship between the degree of dilutional hyponatremia and development of cirrhotic complications. The aim of this study was to evaluate the association between the serum sodium level and the severity of complications in liver cirrhosis. METHODS: Data of inpatients with cirrhotic complications were collected retrospectively. The serum sodium levels and severity of complications of 188 inpatients were analyzed. RESULTS: The prevalence of dilutional hyponatremia, classified as serum sodium concentrations of < or =135 mmol/L, < or =130 mmol/L, and < or =125 mmol/L, were 20.8%, 14.9%, and 12.2%, respectively. The serum sodium level was strongly associated with the severity of liver function impairment as assessed by Child-Pugh and MELD scores (p<0.0001). Even a mild hyponatremia with a serum sodium concentration of 131-135 mmol/L was associated with severe complications. Sodium levels less than 130 mmol/L indicated the existence of massive ascites (OR, 2.685; CI, 1.316-5.477; p=0.007), grade III or higher hepatic encephalopathy (OR, 5.891; CI, 1.490-23.300; p=0.011), spontaneous bacterial peritonitis (OR, 2.562; CI, 1.162-5.653; p=0.020), and hepatic hydrothorax (OR, 5.723; CI, 1.889-17.336; p=0.002). CONCLUSIONS: Hyponatremia, especially serum levels < or =130 mmol/L, may indicate the existence of severe complications associated with liver cirrhosis

Clinical and Biochemical Parameters of Nutrition to Predict Hepatic Encephalopathy in Cirrhotic Patients / 대한소화기학회지

BACKGROUND/AIMS: Protein-calorie malnutrition is a common complication in cirrhosis. Protein restriction for the treatment of hepatic encephalopathy (HE) may cause disease progression and poor prognosis. Therefore, we evaluated important clinical parameters for nutritional state in cirrhotic patients with or without HE to predict the development of HE. METHODS: Twenty-two cirrhotic patients were divided into two groups; group A-13 patients without HE and group B-9 patients with HE. Clinical and biochemical parameters, serum proteins {serum albumin, insulin-like growth factor-1 (IGF-1), transferrin, leptin, etc}, immunologic parameters and anthropometry were measured. RESULTS: Child-Pugh score and Model for End-stage Liver Disease (MELD) scale were higher in group B (p<0.01). After correction of various factors affecting nutritional assessment, especially of Child-Pugh score and MELD scale, leptin was higher in group B (p<0.05). There was no difference in anthropometric measurements. Transferrin correlated inversely with MELD scale in group A (p<0.01). IGF-1 correlated inversely with total lymphocyte count in group B (p<0.05). Leptin correlated with Child-Pugh scores, total lymphocyte count and mid-arm muscle cirumference in group A (p<0.05, p<0.05 and p<0.05, respectively), and correlated inversely with CD8 in group B (p<0.05). CONCLUSIONS: Leptin level is higher in patients with HE, and further studies for parameters of nutrition to predict HE in many cirrhotic patients will be needed.

Study of serum prealbumin and serum alpha fetoprotein in cases of fulminant hepatic failure.

We studied serum prealbumin (SPA) and serum alpha fetoprotein (AFP) to assess liver cell injury and prognosis in patients with fulminant hepatic failure (FHF). We studied 21 patients of FHF of viral etiology, 10 acute viral hepatitis (AVH) and 10 healthy controls. Initial (on the day of admission) AFP levels were significantly elevated in FHF group (30.28 +/- 63.58 ng/ml, p < 0.01 compared to AVH and control group in whom it was undetectable. Serum AFP correlated well with deranged Liver Functions (LFT). In the Survivors (n = 4) of FHF, serial estimations (on Day 5 and Day 10 of admission) revealed declining AFP Levels, correlating with clinical recovery. SPA on admission was significantly reduced in FHF group (15.10 +/- 9 mg/dl p < 0.05) compared to AVH (37.0 +/- 9.34 mg/dl) and control group (40.25 +/- 5.92 mg/dl). Low SPA also correlated with deranged LFT. Serial estimations in the survivors (Day 5, Day 10) revealed rising SPA which correlated with clinical recovery.

Serum zinc levels in hepatic encephalopathy.

BACKGROUND: Zinc is essential for various metabolic processes of the body. Since serum zinc levels are lowered in liver diseases, it has been postulated to be a precipitating factor for hepatic encephalopathy. METHODS: We prospectively studied serum zinc levels in consecutive patients with fulminant hepatic failure, subacute hepatic failure and chronic liver disease with encephalopathy. Serum zinc levels were correlated with various clinical and biochemical parameters and final outcome of patients. Serum zinc levels were estimated by atomic absorption spectrometry at admission and also 24 hours after recovery in survivors. RESULTS: Of the 55 patients (age 17-65 years, 35 men) studied, 30 had acute, 5 subacute and 20 chronic liver disease. Patients with hepatic encephalopathy had significantly lower serum zinc levels as compared to 20 age and sex matched controls. High serum bilirubin levels and prothrombin time showed inverse relationship with serum zinc levels. There was no relationship of serum zinc levels with age, sex, grade and duration of encephalopathy, liver size, ascites or splenomegaly. CONCLUSIONS: Hepatic encephalopathy is associated with low serum zinc levels. Recovery occurred in 17 patients despite persisting low serum zinc levels. Serum bilirubin > 23 mg/dL and prothrombin time prolongation > 12 seconds above control have inverse correlation with serum zinc level.

Observation of lipid profile and lipoproteins in viral hepatitis and hepatic coma.

Lipid profile and lipoprotein levels were estimated in 35 patients of viral hepatitis, 15 patients of viral hepatitis with coma and in age and sex match 35 healthy controls. The values were compared in different groups. Levels of triglycerides were significantly raised (145.00 +/- 30.70 mg/dl) in viral hepatitis as compared to viral hepatitis with coma (111.40 +/- 16.80 mg/dl) which were similar to controls (110.8 +/- 20.6 mg/dl). Patients who recovered had higher levels of triglycerides (136.0 +/- 30.8 mg/dl) as compared to those who expired (110 +/- 15.72 mg/dl). Total serum cholesterol remained statistically unaltered in both groups. HDLc was significantly decreased in both groups, viral hepatitis (2.23 +/- 6.7 mg/dl) and viral hepatitis with coma (16.52 +/- 2.27 mg/dl) in comparison to controls (62.21 +/- 18.04 mg/dl). The levels were much lower in patients with coma than without coma. Furthermore the values were still lower in patients who expired (15.82 +/- 2.27 mg/dl) than in patients who recovered (24.13 +/- 7 mg/dl). The levels of LDLc were significantly raised in both groups, as compared with each other and in relation to mortality. VLDLc levels were significantly decreased in patients of viral hepatitis (22.13 +/- 5.8 mg/dl) as well as on viral hepatitis with coma (21.89 +/- 4.3 mg/dl). However, no significant difference was observed when compared with each other and in relation to mortality. Thus it may be concluded that isolated low value of HDLc in viral hepatitis may be used as a prognostic indicator.

Fulminant hepatitis in dengue infection.

Eight cases of liver failure and encephalopathy were observed among twenty cases of grade 3 and grade 4 dengue hemorrhagic fever/dengue shock syndrome admitted to the Department of Pediatrics, University Hospital, Kuala Lumpur from January 1990 to December 1991. All patients with deterioriation in mental status showed a marked increase in liver enzymes (aspartate and alanine aminotransaminases) and severe coagulopathy. Six patients needed cerebral protection, including ventilation, intravenous sedation and muscle relaxants. There was one death during the period of study and one case of residual hemiparesis in a boy who had, in addition, intracerebral hemorrhage. All other survivors had complete recovery of liver and neurological function.

Observation on serum prolactin in hepatic cirrhosis.

Serum prolactin assays in patients of hepatic cirrhosis were analysed. Patients with cirrhosis had higher values of serum prolactin (27.2 +/- 5.1 ng/ml in males and 38.4 +/- 4.1 ng/ml in females) as compared to control subjects (p less than 0.05). Majority of patients of cirrhosis with suspected portal-systemic encephalopathy had significantly higher serum prolactin than those without encephalopathy (p less than 0.05). Significantly higher values of serum prolactin on admission had positive correlation with mortality (p less than 0.01). Clinico-biochemical severity of hepatic dysfunction was directly correlated with level of serum prolactin. The present study reveals the possibility of diagnostic and prognostic values of serum prolactin in cirrhosis, specially in clinical/sub-clinical subsets of portal-systemic encephalopathy.

Antithrombin III in liver disorders.

Biological and immunological antithrombin III was studied in 26 patients of viral hepatitis including 6 with encephalopathy, and in 11 patients with cirrhosis of liver. There was a significant reduction in both biological and immunological activity of antithrombin III in all the groups of liver disorders studied. There was a good correlation between biological and immunological activity of antithrombin III (P less than 0.05). Further, there was a significant inverse correlation between immunological activity of antithrombin III and SGOT/SGPT (P less than 0.01) as well as serum bilirubin (P less than 0.001), signifying the prognostic value of antithrombin III in hepatitis. Biological activity on the other hand did not show any relation with the hepatic enzymes or bilirubin elevation. The antithrombin III levels appeared to decline in direct proportion to the degree of hepatic necrosis, probably due to reduced synthesis.

Serum magnesium levels in chronic renal failure. Clinical significance and correlation with sodium potassium and calcium.

Fifty cases with chronic renal failure and 25 age and sex matched normal healthy controls were studied. The mean serum magnesium level was significantly higher (4.10 +/- 0.85 mg/dl) in the patients as compared to controls (2.40 +/- 0.14 mg/dl; p less than 0.001) and levels rose progressively with deterioration in renal function. Significantly higher serum magnesium levels were observed in patients of chronic renal failure with encephalopathy than in those without. Greater the impairment in level of consciousness, higher was the magnesium level. Improvement in neurological status correlated well with fall in serum magnesium level. The fall was significantly higher in patients on dialysis as compared to non-dialysed patients. Serum magnesium is a worthwhile tool in assessing duration of disease, morbidity and mortality in patients with chronic renal failure. Its estimation may help in evaluating conservative treatment and dialysis in chronic renal failure.

Serum and urinary copper in acute hepatic encephalopathy.

Serum and 24 hours' urinary copper levels were studied in 71 patients with acute viral hepatitis including 35 with encephalopathy. Thirty age and sex matched healthy controls were also studied. Copper estimation was done by atomic absorption spectrophotometry. Serum and 24 hours' urinary copper levels (164.85 +/- 29.31 micrograms/dl and 123.54 +/- 7.87 micrograms/24 h respectively) were significantly (P less than 0.001) increased in acute viral hepatitis patients. There was no significant difference in levels between patients with and without encephalopathy.

Exchange transfusion in cerebral malaria complicated by disseminated intravascular coagulation.

A patient with cerebral malaria complicated by full-blown DIC, after failing to respond to other forms of treatment, was successfully treated by exchange transfusion. To the best of the authors' knowledge, this may be first reported case of full-blown DIC in malaria successfully treated by exchange transfusion.