Long-term Branched-chain Amino Acid Supplementation Improves Glucose Tolerance in Patients with Nonalcoholic Steatohepatitis-related Cirrhosis

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1 CASE REPORT Long-term Branched-chain Amino Acid Supplementation Improves Glucose Tolerance in Patients with Nonalcoholic Steatohepatitis-related Cirrhosis Teruki Miyake 1, Masanori Abe 1, Shinya Furukawa 1, Yoshio Tokumoto 1, Kumiko Toshimitsu 2, Teruhisa Ueda 1, Shin Yamamoto 1, Masashi Hirooka 1, Teru Kumagi 1, Yoichi Hiasa 1, Bunzo Matsuura 1 and Morikazu Onji 1 Abstract Branched-chain amino acid (BCAA) supplements have mainly been administered as a nutritional intervention for decompensated liver cirrhosis. Several studies have shown that short-term BCAA supplementation improves insulin and glucose tolerance in patients with liver cirrhosis. However, the long-term effects of BCAA supplementation on glucose tolerance and in patients with nonalcoholic steatohepatitis (NASH)- related liver cirrhosis are unknown. Herein, we report 2 cases of NASH-related liver cirrhosis in which longterm BCAA supplementation improved glycemic control. We conclude that in the absence of an effective conventional therapy for NASH-related liver cirrhosis, BCAA supplementation should be considered as an alternative treatment. Key words: nonalcoholic steatohepatitis, cirrhosis, branched-chain amino acid, glycemic control (Intern Med 51: , 2012) () Introduction Nonalcoholic steatohepatitis (NASH) was first described in 1980 (1) and has since been recognized with increasing frequency. Nonalcoholic fatty liver diseases (NAFLDs), including NASH, are emerging as some of the most common liver diseases, and NAFLDs progress from simple steatosis to steatohepatitis and cirrhosis (2, 3). Obesity, metabolic syndrome, type 2 diabetes, and hyperlipidemia are frequently associated with NAFLD (2). Insulin resistance is an underlying factor in these metabolic disorders (4, 5), and it could play a critical role in the pathogenesis of NAFLDs (6, 7). In Japan, branched-chain amino acid (BCAA) supplementation has mainly been administered as a nutritional intervention for decompensated liver cirrhosis (8-10). In addition, several clinical studies have shown that BCAA supplementation improves insulin and glucose tolerance in patients with liver cirrhosis (11, 12). However, these short-term studies evaluated the effect of BCAA for less than 3 months. The effect of BCAA administration on glucose tolerance in patients with NASH-induced liver cirrhosis has not been investigated. Herein, we report 2 cases of long-term BCAA treatment to evaluate the potential benefits of improved glycemic control in individuals with NASH-induced liver cirrhosis. Case 1 Case Reports A 62-year-old Japanese woman was referred to Ehime University Hospital for examination and treatment of cryptogenic liver cirrhosis. She was diagnosed as having type 2 diabetes mellitus and esophageal varices when she was 59 years old; she subsequently underwent an endoscopic Department of Gastroenterology and Metabiology, Ehime University Graduate School of Medicine, Japan and Nutrition Division, Ehime University Hospital, Japan Received for publication February 20, 2012; Accepted for publication May 8, 2012 Correspondence to Dr. Masanori Abe, masaben@m.ehime-u.ac.jp 2151

2 Table. Laboratory Data of Case 1 and Case 2 at Admission Case 1 Case 2 Reference range WBC (/ L) 2,400 4,400 (3,900 9,800) RBC ( 10 4 / L) ( ) Hb (g/dl) ( ) HCT (%) ( ) PLT ( 10 4 / L) ( ) PT (%) (80 120) T. Bil (mg/dl) ( ) CHE (IU/L) ( ) AST (IU/L) (9 37) ALT (IU/L) (3 49) ALP (IU/L) ( ) -GTP (IU/L) (6 71) TP (g/dl) ( ) ALB (g/dl) ( ) T.cho (mg/dl) ( ) TG (mg/dl) (66 213) HDL-C (mg/dl) (45 55) NEFA (mg/dl) ( ) FPG (mg/dl) (70 110) (%) ( ) GA (%) ( ) C-peptide (ng/ml) 2 2 ( ) Insulin ( U/mL) 14.4 NE ( ) Ferritin (ng/ml) (27 211) Type IV collagen (0 6) (ng/ml) Hyaluronic acid (ng/ml) (0 50) ANA (-) (-) AMA (-) (-) HBsAg (-) (-) anti-hbc (-) (-) anti-hcv (-) (-) WBC: white blood cells, RBC: red blood cells, Hb: hemoglobin, HCT: hematocrit, PLT: platelets, PT: prothrombin time, T. Bil: total bilirubin, CHE: cholinesterase, AST: aspartate aminotransferase, ALT: alanine aminotransferase, ALP: alkaline phosphatase, -GTP: -glutamyl transpeptidase, TP: total protein, ALB: albumin, T. cho: total cholesterol, TG: triglycerides, HDL-C: high-density lipoprotein cholesterol, NEFA: nonesterified fatty acid, FPG: fasting plasma glucose, : hemoglobin A1c, GA: glycoalbumin, NE: not examined, ANA: antinuclear antibody, AMA: antimitochondrial antibody, HBsAg: hepatitis B surface antigen, anti-hcv: antibody against Hepatitis C Virus variceal ligation procedure. On physical examination, her height was 155 cm, weight was 53.4 kg, and body mass index (BMI) was 22.2 kg/m 2. She did not have a habit of alcohol consumption or a family history of diabetes mellitus or liver disease. The laboratory data on admission are shown in Table. Ultrasonography revealed irregularities in internal echogenicity and slight steatosis in the liver. Computed tomography (CT) revealed mild splenomegaly and ascites. Laparoscopy identified diffuse small nodules on the liver surface, which displayed dark red coloration with patchy yellowness (Fig. 1A). The left lobe of the liver was enlarged (Fig. 1B). Liver biopsy confirmed the presence of micronodules. Large vacuoles of lipid and ballooned hepatocytes were present throughout acini, predominantly in zone 3. Neither Mallory-Denk bodies nor megamitochondria were observed. The patient was diagnosed as having NASHinduced liver cirrhosis. Diet therapy based on the European Society for Parenteral and Enteral Nutrition guidelines (13), was initiated. The daily caloric intake was 1,900 kcal (36 kcal/kg standard body weight) and protein intake was 64 g (1.2 g/kg). We also prescribed glimepiride (1 mg/day). Yet, there was no improvement in glycemic control at 10 months. and glycoalbumin (GA) levels, which were approximately 7.6% and 27.2%, respectively, during this period, remained unaltered (Fig. 3). The patient s serum albumin concentration and BCAA/tyrosine ratio (BTR) were low at 3.7 g/dl and 3.41, respectively. In order to improve glycemic control, we prescribed 3 daily oral sachets of BCAA granules (L-isoleucine, g; L-leucine, g; L- valine, g per sachet; Livact granules; Ajinomoto Co., Inc., Tokyo, Japan) to be taken postprandially. Following 12 months of BCAA therapy, no measureable alterations were seen in serum albumin or transaminase levels; markers of hepatic fibrosis, such as type IV collagen and hyaluronic acid; liver fats; body weight or body composition including muscle and fat (InBody720, Biospace, Tokyo, Japan); or respiratory quotient (AE-300S, Minato Medical Science, Osaka, Japan) (data not shown). In contrast, levels of and GA gradually decreased to 6.8% and 20.9%, respectively. Levels of fasting plasma glucose, insulin, and C- peptide were also decreased (Fig. 2). Case 2 A 71-year-old Japanese man was admitted to Ehime University Hospital for glycemic control and examination of cryptogenic chronic liver injury. He was diagnosed with type 2 diabetes mellitus at 59 years of age, and had been receiving insulin treatment for the 6 years prior to admission. On physical examination, his height was 158 cm, weight was 65.4 kg, and BMI was 26.2 kg/m 2. He did not have a habit of alcohol consumption or a family history of diabetes mellitus or liver disease. His laboratory data on admission are shown in Table. Abdominal ultrasonography and CT showed mild ascites. Liver biopsy revealed multiple nodules that were mostly micronodules (Fig. 3A). In addition, pericellular fibrosis was apparent (Fig. 3A). Large vacuoles of lipid, necroinflammation, and ballooned hepatocytes were present throughout acini, predominantly in zone 3 (Fig. 3B). Neither Mallory-Denk bodies nor megamitochondria was observed. The patient was diagnosed as having NASHinduced liver cirrhosis. The patient received insulin (102 units/day) and underwent diet therapy: total energy, 1,600 kcal/day (29.1 kcal/kg standard body weight) and protein intake, 66 g (1.2 g/kg standard body weight). This treatment regimen had little effect on glycemic control but levels were higher than approximately 8.7% for 8 months (Fig. 4). The patient s serum albumin concentration and BCAA/tyrosine ratio (BTR) were relatively low at 3.7 g/dl 2152

3 A B Figure 1. Images from laparoscopy. Laparoscopy identified diffuse small nodules on the liver surface, which displayed dark red coloration with patchy yellowness (A). The left lobe of the liver was enlarged (B). BCAA mg/day (%) 7.6 Glimepiride 1 mg/day Body weight (kg) Body Weight pre (month) FPG 140 mg/dl Insulin C-peptide 3.5 ng/ml FPG 69 mg/dl Insulin 11.9 C-peptide 2.5 ng/ml Figure 2. Clinical course. level gradually decreased over 12 months after initiating the administration of BCAA. : hemoglobin A1c, BCAA: branched-chain amino acid, FPG: fasting plasma glucose and 4.88, respectively. In order to improve malnutrition and control the level of glucose, we prescribed 3 daily sachets of BCAA granules to be taken orally and postprandially. His laboratory data such as serum transaminase levels, markers of hepatic fibrosis, liver fats, body weight, body composition, and respiratory quotient did not change for 12 months. However, level was gradually decreased to 6.4%. In addition, the dose of insulin was also decreased to 84 units/ day. Discussion The increasing prevalence of obesity and type 2 diabetes in society is likely responsible for the increasing number of patients with NAFLD (14, 15). Recently, it has been proposed that NAFLD should be included as a component of the metabolic syndrome (6, 7). Insulin resistance causes hepatic steatosis, which results in increased oxidative stress, and leads to steatohepatitis and cirrhosis (2, 3). In general, the majority of patients with liver cirrhosis also present with other complications such as glucose intolerance, which leads to a poor prognosis (16). The characteristics of glucose intolerance in patients with cirrhosis are unusual and difficult to control (17, 18). Liver dysfunction deteriorates insulin clearance from the blood, and induces insulin resistance. Insulin resistance induced by chronic hyperinsulinemia causes postprandial hyperglycemia. On the other hand, energy depletion is observed in the early morning fasting state in patients with liver cirrhosis (17, 18). Therefore, both cirrhosis and NASH are presumed to be as- 2153

4 A B Figure 3. Microphotograph of the liver specimen. (A) Reticulin stain. Regenerating micro nodules were observed. Pericellular fibrosis was also seen ( 40). (B) Hematoxylin and Eosin staining. Moderate fatty changes and ballooning of hepatocytes were observed. Mild infiltration of inflammatory cells was seen, but Mallory-Denk bodies were not observed ( 100). BCAA mg/day (%) Insulin 102 units/day Insulin 84 units/day Body weigt (kg) 69 Body Weight pre (month) Figure 4. Clinical course. level gradually decreased over 12 months after initiating the administration of BCAA. In addition, the dose of insulin was also decreased to 84 units/day. : hemoglobin A1c, BCAA: branched-chain amino acid sociated with glucose intolerance. In Japan, pharmacological supplementation of BCAA is used widely to recover hypoalbuminemia in patients with decompensated liver cirrhosis, and consequently the clinical evidence on the efficacy of this therapy has accumulated (8-10). The available data indicates that BCAA supplementation raises the serum albumin level and improves the quality of life and survival of patients with decompensated liver cirrhosis. BCAA supplementation has been reported to improve glucose metabolism (11, 12). However, mechanisms underlying the efficacy of BCAA supplementation on glucose intolerance in patients with liver cirrhosis have not been completely clarified. Nishitani et al. reported that BCAAs improve glucose uptake in isolated skeletal muscle in an in vitro rat model of liver cirrhosis, presumably by its ability to promote translocation of glucose transporter proteins to the plasma membrane in the absence of additional insulin release (19, 20). The present patient with NASHrelated cirrhosis complicated with diabetes received BCAA supplementation for more than 1 year, demonstrating improved glucose tolerance but no change in liver function or markers of fibrosis. Furthermore, the body weight, body composition, and respiratory quotient did not change. Therefore, we speculate that the increased skeletal muscle uptake of glucose may have been involved in improving glucose metabolism by BCAA. These cases suggest that BCAAs could be important for the treatment of insulin resistance associated with cirrhosis. When conventional therapy is not effective in patients with concomitant diabetes and cirrhosis, especially in patients with more advanced NASH, BCAA supplementation should be considered as an additional treatment. The authors state that they have no Conflict of Interest (COI). References 1. Ludwig J, Viggiano TR, McGill DB, Oh BJ. Nonalcohlic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease. Mayo Clin Proc 55: ,

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