Makoto Shiraki

Sarcopenia impairs prognosis of patients with liver cirrhosis.

OBJECTIVE Sarcopenia is characterized by the loss of skeletal muscle mass, and is reported to appear in patients with liver cirrhosis (LC). The aim of this study was to investigate the prevalence of sarcopenia in patients with LC, and to test the association between sarcopenia and patient outcomes. We also analyzed the effect of branched-chain amino acid (BCAA) supplementation on sarcopenic LC. METHODS Clinical and blood biochemical data of 130 patients with LC who underwent abdominal computed tomography scan were analyzed in this retrospective study. The cross-sectional area of skeletal muscles was measured at the level of the third lumbar vertebra on the scan. The skeletal muscle index was calculated to identify sarcopenia. Cirrhotic patients who were treated with BCAA supplementation of 12 g/d for ≥ 1 y were defined as the BCAA group, and the effect of BCAA on sarcopenic LC was evaluated. RESULTS Sixty-eight percent of all patients (82% of men and 50% of women) were diagnosed with sarcopenia. Male sex (P = 0.01) and body mass index (P < 0.0001) were predictors of sarcopenia. The multivariate Cox proportional hazards model found BCAA supplementation (hazard ratio [HR], 0.38; P = 0.01), sarcopenia (HR, 3.03; P < 0.01), and Child-Pugh classes B (HR, 2.39; P = 0.03) and C (HR, 5.49; P < 0.001) to be independently associated with mortality. The mortality of sarcopenic LC was significantly higher than that of non-sarcopenic LC (P = 0.01). Moreover, BCAA supplementation improved the survival of sarcopenic patients in subgroup analysis (P < 0.01). CONCLUSIONS Sarcopenia is significantly associated with mortality in patients with LC. BCAA supplementation might be associated with improved survival of such patients.

Improvement of fuel metabolism by nocturnal energy supplementation in patients with liver cirrhosis.

Aims: patients with liver cirrhosis exhibit abnormal fuel metabolism, including increased fat and decreased glucose oxidation. Such altered energy metabolism is similar to that observed after starvation and could lead to malnutrition. We therefore studied whether nocturnal energy supplementation might improve the fuel metabolism in cirrhotic patients. Methods: 12 cirrhotic patients and 14 healthy controls participated in this study. Subjects in the two groups ate isonitrogenous (1.2 g/kg/day) and isocaloric (35 kcal/day) diets for 1 week before and during the study. On day 1 of the study, indirect calorimetry was carried out in the morning after an overnight fast. The next morning, the same measurement was performed after the patients took a liquid nutrient (Ensure Liquid(R), 250 kcal) at 23:00 on day 1. Respiratory quotient (RQ), resting energy expenditure (REE), and substrate oxidation rates of glucose (% CHO), fat (% FAT) and protein were estimated from measured VO(2), VCO(2) and urinary nitrogen. Results: Significant decreases in RQ, and % CHO and a significant increase in % FAT were observed at baseline in cirrhotic patients as compared with controls. After the nocturnal energy supplementation, RQ, % CHO and % FAT in cirrhotic patients were significantly recovered, ending at levels close to normal. Conclusions: These results suggest that nocturnal energy supplementation could be useful to correct abnormal fuel metabolism and to prevent malnutrition 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 α‐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. (Cancer Sci 2009)

Estrogen and α-Fetoprotein Levels in Maternal and Umbilical Cord Blood Samples in Relation to Birth Weight

Birth weight has been associated with a subsequent risk of breast cancer. The present study examined associations between birth weight and pregnancy estrogens and α-fetoprotein (AFP). The concentrations of estradiol, estriol, and AFP were measured in maternal and umbilical cord blood samples from 194 women during pregnancy and at birth. Birth weight was significantly positively correlated with maternal serum estradiol and estriol levels in the 29th week (estradiol: r = 0.16, P = 0.03; estriol: r = 0.29, P = 0.001) and at delivery (estradiol: r = 0.20, P = 0.01; estriol: r = 0.41, P < 0.0001) after controlling for covariates. The umbilical cord estriol level was moderately but significantly correlated with birth weight (r = 0.15, P = 0.049). There was no significant association between umbilical cord serum estradiol and birth weight. There was no significant association between birth weight and maternal serum AFP in any gestational week. Umbilical cord AFP was significantly inversely correlated with birth weight (r = −0.16, P = 0.04). Umbilical cord AFP was unrelated to cord levels of estradiol and estriol. The data suggested a greater exposure to estriol and a lower exposure to AFP among high birth weight babies. (Cancer Epidemiol Biomarkers Prev 2006;15(8):1469–72)

Oral branched‐chain amino acid supplementation improves the oxidized/reduced albumin ratio in patients with liver cirrhosis

Aim:  Branched‐chain amino acid (BCAA) supplementation improves hypoalbuminemia in decompensated cirrhotics. Recently, it was clarified that the ratio of oxidized albumin within total albumin rises with progression of liver cirrhosis. We conducted a feasibility study to investigate whether BCAA supplementation might improve this ratio.

Supplementation with Branched-chain Amino Acids Inhibits Azoxymethane-induced Colonic Preneoplastic Lesions in Male C57BL/KsJ-db/db Mice

Purpose: Obesity and related metabolic abnormalities, including insulin resistance and activation of the insulin-like growth factor (IGF)/IGF-I receptor (IGF-IR) axis, are risk factors for colon cancer. Supplementation with branched-chain amino acids (BCAA) reduces the risk of liver cancer in cirrhotic patients who are obese, and this has been associated with an improvement of insulin resistance. The present study examined the effects of BCAA on the development of azoxymethane (AOM)-initiated colonic premalignant lesions in C57BL/KsJ-db/db (db/db) mice that were obese and had hyperinsulinemia. Experimental Design: Male db/db mice were given 4 weekly s.c. injections of AOM (15 mg/kg of body weight) and then they were fed a diet containing 3.0% BCAA or casein, a nitrogenc content–matched control diet, for 7 weeks. Results: Feeding with BCAA caused a significant reduction in the number of total aberrant crypt foci and β-catenin accumulated crypts, both of which are premalignant lesions of the colon, compared with the control diet–fed groups. BCAA supplementation caused a marked decrease in the expression of IGF-IR, the phosphorylated form of IGF-IR, phosphorylated glycogen synthase kinase 3β, phosphorylated Akt, and cyclooxygenase-2 proteins on the colonic mucosa of AOM-treated mice. The serum levels of insulin, IGF-I, IGF-II, triglyceride, total cholesterol, and leptin were also decreased by supplementation with BCAA. Conclusion: BCAA supplementation in diet improves insulin resistance and inhibits the activation of the IGF/IGF-IR axis, thereby preventing the development of colonic premalignancies in an obesity-related colon cancer model that was also associated with hyperlipidemia and hyperinsulinemia. BCAA, therefore, may be a useful chemoprevention modality for colon cancer in obese people.

Japan Society of Hepatology guidelines for sarcopenia in liver disease (1st edition): Recommendation from the working group for creation of sarcopenia assessment criteria

Sarcopenia is defined by muscle loss and muscle dysfunction. Sarcopenia is classified into primary and secondary types, based on the cause. Primary sarcopenia is mainly aging‐related sarcopenia, whereas secondary sarcopenia is the reduced muscle mass and strength that accompanies an underlying disease. Given the essential role of the liver in metabolism, secondary sarcopenia due to nutritional disorders or other factors can frequently occur in liver disease. In 2015, the Japan Society of Hepatology (JSH) decided to establish its own assessment criteria for sarcopenia in liver disease because the number of liver disease patients with sarcopenia is expected to increase and there is cumulative evidence to indicate sarcopenic patients have poor clinical outcomes. A working group to create assessment criteria for sarcopenia has thus been established by the JSH. In this article, we summarize the current knowledge with regard to sarcopenia and present the assessment criteria for sarcopenia in liver disease proposed by the JSH (1st edition). To the best of our knowledge, this is globally the first proposed assessment criteria for sarcopenia specializing in liver disease.

JSH guidelines for sarcopenia in liver disease (first edition): Recommendation from the working group for creation of sarcopenia assessment criteria in the JSH

Sarcopenia is defined by muscle loss and muscle dysfunction. Sarcopenia is classified into primary and secondary types, based on the cause. Primary sarcopenia is mainly aging‐related sarcopenia, whereas secondary sarcopenia is the reduced muscle mass and strength that accompanies an underlying disease. Given the essential role of the liver in metabolism, secondary sarcopenia due to nutritional disorders or other factors can frequently occur in liver disease. In 2015, the Japan Society of Hepatology (JSH) decided to establish its own assessment criteria for sarcopenia in liver disease because the number of liver disease patients with sarcopenia is expected to increase and there is cumulative evidence to indicate sarcopenic patients have poor clinical outcomes. A working group to create assessment criteria for sarcopenia has thus been established by the JSH. In this article, we summarize the current knowledge with regard to sarcopenia and present the assessment criteria for sarcopenia in liver disease proposed by the JSH (1st edition). To the best of our knowledge, this is globally the first proposed assessment criteria for sarcopenia specializing in liver disease.

Nutritional status and quality of life in current patients with liver cirrhosis as assessed in 2007-2011.

Current guidelines recommended adequate nutritional support for patients with liver cirrhosis to improve clinical outcome and quality of life (QOL). However, these evidences were obtained more than 10 years ago when malnutrition prevailed. In recent years, the impact of obesity on liver damage and carcinogenesis has grown. We attempted to elucidate the nutritional state and QOL in present cirrhotics.

Long-term outcome of branched-chain amino acid treatment in patients with liver cirrhosis

Clinical impact of protein‐energy malnutrition (PEM) on the outcome of liver cirrhosis is well documented. As a candidate interventional modality to improve PEM in cirrhosis, effects of branched‐chain amino acid (BCAA) supplementation on event‐free survival and quality of life (QOL) was first reported by Yoshida et al. in 1989. Although critical arguments still continue regarding the effects of BCAA, several randomized trials in the last 5 years have brought positive results, and seem to have settled the discussion in a favorable direction for the efficacy of BCAA in liver cirrhosis. Actually, The European Society for Clinical Nutrition and Metabolism (ESPEN) upgraded the recommendation of BCAA supplementation in decompensated liver cirrhosis in the latest revision of its guidelines in 2006, by referring to the literatures from Italy and Japan. Particularly in these two long‐term randomized studies with 1–2 years‐supplementation, event‐free survival was estimated by employing composite endpoints such as aggravation of hepatic failure (ascites, peripheral edema, hepatic encephalopathy, and jaundice), rupture of esophageal or gastric varices, development of liver cancer, and death from any cause. Both trials agreed on the effect of BCAA to reduce the incidence of hepatic failure, thus contributing to the rise in the event‐free survival. Quality of life is another essential marker of outcome survey. Marchesini, Muto, and Nakaya reported the improved QOL in cirrhotics with BCAA supplementation. In particular, quantitative analysis of QOL measured by Short Form 36 (SF‐36) questionnaire demonstrated a significant recovery of general heath perception score in BCAA supplemented patients in a randomized trial. In this article, the long‐term outcome of BCAA treatment in liver cirrhosis will be reviewed with its action mechanisms. In addition, the effects of BCAA treatment on the incidence of liver cancer in obese patients with type C liver cirrhosis, significance of obesity as a risk factor for type C liver cancer, and a possible role of Body Mass Index to estimate the histological grade of fat deposition in the liver will be briefly discussed.