Hepatic encephalopathy as a complication of liver cirrhosis: an Asian perspective.

Hepatic encephalopathy is one of the most important clinical manifestations in decompensated liver cirrhosis. Accepted concepts regarding the pathophysiology of hepatic encephalopathy are that the endogenous neurotoxic substances, including ammonia: (i) escape from catabolism by the liver due both to the impaired function of the cirrhotic liver and also to the presence of portal systemic shunting; (ii) circulate at elevated concentrations in the systemic blood flow; (iii) reach the brain through the blood-brain barrier; and (iv) impair cerebral function leading to disturbances of consciousness. The majority of these toxic substances are produced in the intestine by the bacterial flora, and are absorbed into the portal venous flow. The epidemiology of liver cirrhosis depends particularly on its etiology, and shows a marked geographic difference worldwide between Western, and Asian countries. Hepatic encephalopathy developed at an annual rate of 8% in cirrhotics in Far Eastern studies. In Eastern and Far East countries, therapeutic options are similar to those in the western hemisphere, but pronounced application of dietary restriction, antimicrobial agents, disaccharides, shunt obliteration and branched chain amino acids is noted. In spite of improved therapeutic options for encephalopathy, the long-term survival is still low. Thus, hepatic encephalopathy remains a serious complication of liver cirrhosis. Establishment of truly effective prevention modalities and broader application of liver transplantation will help rescue patients suffering from this complication of liver cirrhosis in the near future.

Indirect calorimetry and anthropometry to estimate energy metabolism in patients with liver cirrhosis.

Energy malnutrition worsens survival in patients with liver cirrhosis, and is currently defined as non-protein respiratory quotient (npRQ) <0.85, as measured by indirect calorimetry. However, measurement of this npRQ is limited because of the high cost of indirect calorimetry. Therefore, we sought an alternative marker that can be used in the routine clinical setting. Forty-four inpatients with cirrhosis were recruited in this study. The last meal was served at 18:00 h on the previous day, and indirect calorimetry was performed between 07:00 and 09:00 h while the patients were still in bed. Fasting blood samples were collected in the early morning on the day of the test. Anthropometry was performed by an expert dietician. The correlations among npRQ, Child-Pugh score of disease severity, laboratory parameters, %AC (arm circumference), %TSF (triceps skinfold thickness), and %AMC (arm muscle circumference) were studied using simple linear regression analysis. ROC (Receiver operating characteristic) analysis was used to identify the cut-off values that would best predict npRQ=0.85. npRQ correlated significantly with %AC (r(2)=0.204, p=0.0021) and %AMC (r(2)=0.178, p=0.0043) but not with %TSF. npRQ was not significantly correlated with other laboratory or anthropometric measurements. The cut-off value for %AC that showed the largest AUC (area under the curve) by ROC analysis was 95, while that for %AMC was 92. Multiple regression analysis yielded an equation; npRQ=0.0019×(%AC)20.0134×(Child-Pugh score)+0.7791. Patient stratification by %AC=95 or by regression equation-based npRQ=0.85, but not by %AMC=92, produced significant difference in survival curves. %AC and regression equation could represent npRQ to some extent as parameters of energy nutrition in cirrhosis.

Dietary supplementation with branched-chain amino acids suppresses diethylnitrosamine-induced liver tumorigenesis in obese and diabetic C57BL/KsJ-db/db mice.

Obesity and related metabolic abnormalities, including insulin resistance, are risk factors for hepatocellular carcinoma in non-alcoholic steatohepatitis as well as in chronic viral hepatitis. Branched-chain amino acids (BCAA), which improve insulin resistance, inhibited obesity-related colon carcinogenesis in a rodent model, and also reduced the incidence of hepatocellular carcinoma in obese patients with liver cirrhosis. In the present study, we determined the effects of BCAA on the development of diethylnitrosamine (DEN)-induced liver tumorigenesis in obese C57BL/KsJ-db/db (db/db) mice with diabetes mellitus. Male db/db mice were given tap water containing 40 ppm DEN for an initial 2 weeks and thereafter they received a basal diet containing 3.0% of BCAA or casein, which served as a nitrogen content-matched control of BCAA, throughout the experiment. Supplementation with BCAA significantly reduced the total number of foci of cellular alteration, a premalignant lesion of the liver, and the expression of insulin-like growth factor (IGF)-1, IGF-2, and IGF-1 receptor in the liver when compared to the casein supplementation. BCAA supplementation for 34 weeks also significantly inhibited both the development of hepatocellular neoplasms and the proliferation of hepatocytes in comparison to the basal diet or casein-fed groups. Supplementation with BCAA improved liver steatosis and fibrosis and inhibited the expression of alpha-smooth muscle actin in the DEN-treated db/db mice. The serum levels of glucose and leptin decreased by dietary BCAA, whereas the value of the quantitative insulin sensitivity check index increased by this agent, indicating the improvement of insulin resistance and hyperleptinemia. In conclusion, oral BCAA supplementation improves insulin resistance and prevents the development of liver tumorigenesis in obese and diabetic mice.

Elevated serum tumor necrosis factor-alpha and soluble tumor necrosis factor receptors correlate with aberrant energy metabolism in liver cirrhosis.

OBJECTIVE: Protein-energy malnutrition is frequently observed in patients with liver cirrhosis and is associated with their poor prognosis. Tumor necrosis factor-alpha (TNF-alpha) is elevated in those patients and may contribute to the alterations of energy metabolism. Our aim was to characterize the aberrant energy metabolism in cirrhotic patients with regard to TNF-alpha. METHODS: Twenty-four patients (mean age 65 +/- 6 y) with viral liver cirrhosis who did not have hepatocellular carcinoma or acute infections were studied. Twelve healthy volunteers were recruited after matching for age, gender, and body mass index with the patients and served as controls (59 +/- 8 y). Serum levels of TNF-alpha, soluble 55-kDa TNF receptor (sTNF-R55), soluble 75-kDa TNF receptor (sTNF-R75), and leptin were determined by immunoassay. Substrate oxidation rates of carbohydrate and fat were estimated by indirect calorimetry after overnight bedrest and fasting. RESULTS: In cirrhotic patients, serum levels of TNF-alpha, sTNF-R55, and sTNF-R75 were significantly higher than those in the controls and correlated with the increasing grade of disease severity as defined by Child-Pugh classification. Serum leptin concentration was not different between cirrhotics and controls but correlated with their body mass index. The decrease in substrate oxidation rate of carbohydrate and the increase in substrate oxidation rate of fat significantly correlated with serum TNF-alpha, sTNF-R55, and sTNF-R75 concentrations. CONCLUSION: Tumor necrosis factor-alpha might be associated with the aberrant energy metabolism in patients with liver cirrhosis.