Clinical significance of therapy using branched‐chain amino acid granules in patients with liver cirrhosis and hepatocellular carcinoma

The liver is the major organ for the metabolism of protein, fat and carbohydrate. A nutritional approach is required in the treatment of cirrhosis, which is frequently complicated with protein–energy malnutrition. Several advanced treatment approaches for hepatocellular carcinoma (HCC) have been established in the past decade. HCC is often complicated by cirrhosis, so treatment of the underlying liver diseases is also necessary to improve the prognosis. Branched‐chain amino acid (BCAA) granules were developed originally for the treatment of hypoalbuminemia associated with decompensated cirrhosis. However, subsequent studies found various other pharmacological actions of this agent. We review the clinical significance of therapy using BCAA granules in patients receiving different treatment approaches for cirrhosis and HCC based on the published work as well as our own data.     

骨髓干细胞在大鼠肝再生环境中的分化

研究大鼠骨髓干细胞在部分肝切除后肝再生环境中的分化。从部分肝切除模型大鼠的胫骨中提取骨髓细胞,应用流式细胞仪富集骨髓干细胞,以PKH26-GL体外标记后通过门静脉进行自体移植,2周后行白蛋白和角蛋白8免疫组化检查。结果肝板肝细胞间PKH26-GL标记骨髓干细胞表达白蛋白、角蛋白8。提示骨髓干细胞在部分肝切除后肝再生环境中能分化为肝细胞,骨髓干细胞可能参与部分肝切除后的肝再生过程。     

Effects of late evening snack including branched‐chain amino acid on the function of hepatic parenchymal cells in patients with liver cirrhosis

Aim: A late evening snack (LES) improves protein‐energy malnutrition due to overnight starvation and the catabolic state in patients with liver cirrhosis. Our aim was to examine whether LES including a branched‐chain amino acid (BCAA) could maintain hepatic reserve and the function of hepatic parenchymal cells in patients with liver cirrhosis, including those in the early stage of disease. Methods: Seventeen patients with liver cirrhosis received LES with a BCAA‐enriched nutrient mixture. During the study period, each patient was instructed on energy and protein intake. Indicators of liver function measured at 6 months included maximum asialoscintigraphic removal (Rmax: indicator of total liver receptors), asialoscintigraphic imaging grade, serum albumin, ammonia, tyrosine and BTR (molar ratio of branched‐chain amino acids to tyrosine). Results: Serum albumin levels, BTR and tyrosine levels of the 17 patients were significantly improved after nutrient treatment. In patients with Rmax of 0.2 or higher, serum albumin level and tyrosine level were significantly improved. Conclusion: LES with BCAA‐enriched nutrient therapy can improve protein malnutrition in patients with liver cirrhosis, and is more useful in the early stages of liver cirrhosis in improving hepatic parenchymal cell mass.     

骨髓间充质干细胞移植在肝再生中的应用

随着当今医学的发展,干细胞的应用逐渐涉及到各个领域,并发挥着无限的潜能。干细胞以其自我更新及多向分化的能力可以对多种疾病进行替代治疗。肝病终末期肝细胞数量减少,肝功能衰竭,通过干细胞的替代治疗,肝功能能够得以改善,肝纤维化得到缓解甚至逆转。干细胞治疗成为有望替代肝移植的新技术。此文就干细胞在肝病治疗中的潜能作一综述,包括干细胞的来源、治疗机制、治疗途径,并对其临床应用进行探讨。     

Effects of branched‐chain amino acid‐enriched nutrient for patients with hepatocellular carcinoma following radiofrequency ablation: A one‐year prospective trial

Background and Aim: This prospective control study examined whether supplementation with branched‐chain amino acid (BCAA)‐enriched nutrients can help maintain and improve residual liver function and nutritional status in cirrhotic patients with hepatocellular carcinoma (HCC) after radiofrequency ablation (RFA). Methods: Subjects were 49 patients with hepatitis C‐related HCC who underwent RFA. Two groups were formed: BCAA group (BCAA‐enriched nutrient, aminoleban EN) and controls (standard diet only). Event‐free survival rate, liver function tests, and Short Form (SF)‐8 scores were evaluated in both groups before and one year after RFA. Energy metabolism using indirect calorimetry was measured before and after 3 months. Results: Complete data were obtained from 35 patients (BCAA group, n = 20; controls, n = 15). Six events (death, recurrence of HCC, rupture of esophageal varices and liver failure) occurred during the observation period, but frequencies of these events did not differ between groups. Event‐free survival rate tended to be higher in the BCA group than in controls. Among the parameters of liver function, serum albumin level was only significantly increased over 6 months, and remained at similar values for one year (P < 0.05). SF‐8 scores for general health, physical functioning, and social functioning were significantly elevated in the BCAA group (P < 0.05). Non‐protein respiratory quotient was significantly improved in the BCAA group (P < 0.01). Conclusion: Supplementation with BCAA‐enriched nutrients for one year in cirrhotic patients with HCC after RFA therapy can perform safety and improve both nutritional state and quality of life.     

Effect of an oral branched chain amino acid‐enriched snack in cirrhotic patients with sleep disturbance

Aim: Sleep is closely related to physical and mental health. Sleep disturbance is reported in patients without encephalopathy. We examined the relationship among cirrhotic symptoms, laboratory data and sleep disturbances. Next, we examined the influence of a branched chain amino acid (BCAA) supplement on sleep disturbance in cirrhotic patients. Methods: We investigated a total of 21 patients at Nagasaki University Hospital from January to June 2009. We constructed questionnaire items for the evaluation of cirrhotic symptoms. The items, as major symptoms of cirrhotic patients, were as follows: hand tremor, appetite loss, muscle cramp of foot, fatigue, decreased strength, anxiety, abdominal fullness, abdominal pain and a feeling of low energy. We used the Epworth Sleepiness Scale (ESS) for the evaluation of daytime hypersomnolence. Energy supplementation with a BCAA snack was performed as a late evening snack (LES). All patients were assessed at the time of entry into the study, and at 4 and 8 weeks. Results: It was found that BCAA snack, taken p.o. as an LES, improved the ESS for cirrhotic patients without encephalopathy. This beneficial result was recognized in the short term, 4 weeks after beginning of treatment. This study demonstrated the utility of BCAA supplementation for cirrhotic patients with sleep disturbance. However, the cirrhotic symptom‐related score was positively relation with the Child–Pugh score at the time of patient entry, and we were unable to identify the item that related to ESS. Conclusion: A BCAA snack is a useful drug for cirrhotic patients who do not have any overt encephalopathy, but who suffered from sleep disturbance.     

Effect of a late evening snack using branched‐chain amino acid‐enriched nutrients in patients undergoing hepatic arterial infusion chemotherapy for advanced hepatocellular carcinoma

Aim: A late evening snack (LES) is recommended for protein‐energy malnutrition in patients with liver cirrhosis. This study investigated energy metabolism in cirrhotic patients with hepatocellular carcinoma (HCC) and the effects of LES using a branched‐chain amino acid (BCAA)‐enriched nutrient in cirrhotic patients with advanced HCC undergoing hepatic arterial infusion chemotherapy (HAIC). Methods: Energy metabolism was measured using indirect calorimetry for 10 cirrhotic patients without HCC and 36 patients with various stages of HCC. Next, in 23 cirrhotic patients with advanced HCC undergoing HAIC, 13 patients received LES (LES group), and 10 patients received ordinary food (control group). Changes in energy metabolism and glucose tolerance were examined using indirect calorimetry and 75‐g oral glucose tolerance test (OGTT) before and after 1 cycle of treatment. Results: Non‐protein respiratory quotient (npRQ) was significantly lower in patients with advanced HCC than in cirrhotic patients without HCC, or in patients with early‐stage HCC. In cirrhotic patients with advanced HCC undergoing HAIC, npRQ, BCAA/tyrosine ratio (BTR), and prealbumin and ALT levels were significantly improved in the LES group, but not in controls. In addition, area under the concentration curve for glucose (AUC glucose) tended to be improved in the LES group. Conclusions: LES using BCAA‐enriched nutrients appears to improve energy metabolism and glucose tolerance in cirrhotic patients with advanced HCC undergoing HAIC.     

Expansion of haematopoietic stem cells from normal donors and bone marrow failure patients by recombinant hoxb4

In this study six versions of recombinant human hoxb4 proteins were produced and their effectiveness evaluated in expanding human haematopoietic stem and progenitor cells in vitro and in vivo . An N-terminal-tat and C-terminal histidine-tagged version of hoxb4 (T-hoxb4-H) showed the highest activity in expanding colony forming cells (CFCs) and long-term culture-initiating cells (LTC-ICs) when used at 50 nmol/l concentration in cell culture. Human cord blood CD34⁺ cells cultured with 50 nmol/l T-hoxb4-H showed a significant increase in severe-combined immunodeficient mouse-repopulating cells (SRCs). In a mouse model of immune-mediated bone marrow (BM) failure, T-hoxb4-H showed an additive effect with cyclosporine in alleviating pancytopenia. In addition, T-hoxb4-H expanded CFC and LTC-IC on BM samples from patients with refractory severe aplastic anaemia and myelodysplastic syndromes: after culturing with 50 nmol/l T-hoxb4-H for 4 d, BM cells from 10 of the 11 patients showed increases in CFC and LTC-IC, and the increase in LTC-IC was statistically significant in samples from four patients. Recombinant human hoxb4 could be a promising therapeutic agent for BM failure.     

Physiological variations of stem cell factor and stromal‐derived factor‐1 in murine models of liver injury and regeneration

Background/Aims: Stem cell factor (SCF) and stromal‐derived factor‐1 (SDF‐1) regulate the regenerative response to liver injury, possibly through activation of liver progenitor ‘oval’ cells and recruitment of circulating, marrow‐derived progenitors. Methods: We performed a detailed analysis of SCF, SDF‐1 and oval cell proliferation induced by tyrosinaemia, 3,5‐diethoxycarbonyl‐1,4‐dihydrocollidine (DDC) or liver irradiation in mice by ELISA and immunofluorescence. Results: Liver injury in the tyrosinaemia mouse is characterized by a dramatic decline in plasma SCF and absence of oval cell proliferation. In contrast, DDC induces bile duct (BD) and oval cell proliferation, and a modest decline in plasma SCF. Focal liver irradiation increases plasma SCF, but not oval cell density. In normal mouse liver, SCF is localized primarily to Kupffer cells, cholangiocytes and arterial smooth muscle, with little or no expression in hepatocytes. However, SCF appears in hepatocyte nuclei after injury, where its function is unknown. In all three models, SDF‐1 is expressed exclusively in BD epithelium, indicating that tissue SDF‐1 levels are proportional to the total mass of oval cells and cholangiocytes. However, increased plasma levels of SDF‐1 in fumaryl acetoacetate hydroxylase‐null mice were not accompanied by oval cell proliferation. Conclusion: Changes in SCF and SDF‐1 varied with the nature of liver injury and were not directly related to oval cell proliferation.