Branched‐chain amino acids (BCAAs) are a group of essential amino acids comprising valine, leucine, and isoleucine. A low ratio of plasma BCAAs to aromatic amino acids is a physiological hallmark of ...liver cirrhosis, and BCAA supplementation was originally devised with the intention of normalizing amino acid profiles and nutritional status. However, recent studies on BCAAs have revealed that, in addition to their role as protein constituents, they may have a role as pharmacological nutrients for patients with chronic liver disease. Large‐scale, multicenter, randomized, double‐blinded, controlled trials on BCAA supplementation have been performed in Italy and Japan, and results demonstrate that BCAA supplementation improves not only nutritional status, but also prognosis and quality of life in patients with liver cirrhosis. Moreover, accumulating experimental evidence suggests that the favorable effects of BCAA supplementation on prognosis may be supported by unforeseen pharmacological actions of BCAAs. This review summarizes the possible effects of BCAAs on albumin synthesis and insulin resistance from clinical and basic viewpoints. We also review the newly discovered clinical impact of BCAAs on hepatocellular carcinoma and the prognosis and quality of life of patients with liver cirrhosis. (HEPATOLOGY 2011;)
Hepatocellular carcinoma (HCC) is responsible for approximately 600 000–700 000 deaths worldwide. It is highly prevalent in the Asia–Pacific region and Africa, and is increasing in Western countries. ...The evidence‐based guideline for HCC in Japan was published in 2005 and revised in 2009. Apart from this guideline, a consensus‐based practice manual proposed by the HCC expert panel of the Japan Society of Hepatology (JSH), which reflects widely accepted daily practice in Japan, was published in 2007. At the occasion of the 45th Annual meeting of the JSH in Kobe 4–5 June 2009, a consensus meeting of HCC was held. Consensus statements were createdbased on 67% agreement of 200 expert members.This article describes the up‐to‐date consensus statements which largely reflect the real world HCC practice in Japan. We believe readers of this article will gain the newest knowledge and deep insight on the management of HCC proposed by consensus of the HCC expert members of JSH.
Insulin resistance is one of the pathological features in patients with hepatitis C virus(HCV) infection.Generally,persistence of insulin resistance leads to an increase in the risk of ...life-threatening complications such as cardiovascular diseases.However,these complications are not major causes of death in patients with HCV-associated insulin resistance.Indeed,insulin resistance plays a crucial role in the development of various complications and events associated with HCV infection.Mounting evidence indic...
Background
The prevalence of nonalcoholic fatty liver disease (NAFLD) and metabolic syndrome have been increasing worldwide. The associations between metabolic factors and the histologic severity of ...NAFLD have not yet been clarified. Therefore, we studied the relationships between relevant metabolic factors and the histological severity of NAFLD.
Methods
In a cross-sectional multicenter study conducted in Japan, we examined 1,365 biopsy-proven NAFLD patients. The frequencies of underlying lifestyle-related diseases and their relationships to the NAFLD histology were investigated.
Results
The hepatic fibrosis stages (Stage 0/1/2/3/4) were 22.6/34.1/26.7/14.5/2.1 (%) in the male patients, and 16.2/31.7/23.9/21.6/6.6 (%) in the female patients. Dyslipidemia was present in 65.7 % (hypertriglyceridemia, 45.3 %; increased low-density lipoprotein cholesterol, 37.5 %; decreased high density lipoprotein cholesterol, 19.5 %) of patients. Hypertension was present in 30.2 %, and diabetes mellitus (DM) in 47.3 %. The fibrosis stage increased with age, especially in postmenopausal females. The body mass index was positively correlated with the fibrosis stage. Deterioration of glucose control was positively correlated with the fibrosis stage, this correlation being more prominent in females. Multivariate analysis identified age and DM as significant risk factors for advanced fibrosis. No significant correlation of the fibrosis stage was observed with hypertension. There was a negative correlation between the serum triglyceride levels and the fibrosis stage.
Conclusions
DM appeared to be a significant risk factor for advanced fibrosis in patients with NAFLD, and would therefore need to be properly managed to prevent the progression of NAFLD.
Activation of the IL-6/Stat3 via IL-6 trans-signaling plays an important role in the pathogenesis of inflammatory bowel disease. Colitis-associated cancer (CAC) is a large bowel cancer and occurs ...with long-standing inflammatory bowel disease. The role of the IL-6/Stat3 in the development of CAC has not been fully understood. We investigate whether IL-6 trans-signaling contributes to the development of CAC using a mouse colitis-associated premalignant cancer (CApC) model. Chronic colitis (CC) was induced in BALB/c mice using dextran sodium sulfate. CApC was induced by dextran sodium sulfate treatment to CC-affected mice. IL-6 expression was determined by quantitative RT-PCR and immunofluorescence staining in colon. Phospho-Stat3 expression was examined by Western blotting and immunofluorescence analysis. The expression of IL-6 receptors (i.e., the IL-6R alpha-chain and gp130) and tumor necrosis factor-alpha converting enzyme in the colon was examined by laser-capture microdissection and immunofluorescence staining. Soluble IL-6R alpha (sIL-6R alpha) was examined by Western blotting of epithelial cell-depleted colonic tissues. We also investigated whether a soluble gp130-Fc fusion protein could prevent CApC. IL-6 expression was increased in the colon of CC- and CApC-affected mice and was restricted to lamina propria-macrophages. The expression of IL-6R alpha and tumor necrosis factor-alpha converting enzyme was increased in the lamina propria CD11b-macrophages of CC-affected mice. sIL-6R alpha expression was also increased in these tissues. Reduced levels of IL-6R alpha generation were observed in the colonic epithelial cells of CC- and CApC-affected mice and were associated with the increased expression of gp130 and phospho-Stat3. Treatment with soluble gp130Fc significantly reduced the CApC. IL-6 trans-signaling in epithelial cells induced by macrophage-derived IL-6/sIL-6R alpha plays a crucial role in the development of CAC.
General rules for recording endoscopic findings of esophageal varices were initially proposed in 1980 and revised in 1991. These rules have widely been used in Japan and other countries. Recently, ...portal hypertensive gastropathy has been recognized as a distinct histological and functional entity. Endoscopic ultrasonography can clearly depict vascular structures around the esophageal wall in patients with portal hypertension. Owing to progress in medicine, we have updated and slightly modified the former rules. The revised rules are simpler and more straightforward than the former rules and include newly recognized findings of portal hypertensive gastropathy and a new classification for endoscopic ultrasonographic findings.
Curcumin is a biologically active phytochemical substance present in turmeric and has pharmacologic actions that might benefit patients with ulcerative colitis (UC). The aim in this trial was to ...assess the efficacy of curcumin as maintenance therapy in patients with quiescent ulcerative colitis (UC).
Eighty-nine patients with quiescent UC were recruited for this randomized, double-blind, multicenter trial of curcumin in the prevention of relapse. Forty-five patients received curcumin, 1g after breakfast and 1g after the evening meal, plus sulfasalazine (SZ) or mesalamine, and 44 patients received placebo plus SZ or mesalamine for 6 months. Clinical activity index (CAI) and endoscopic index (EI) were determined at entry, every 2 months (CAI), at the conclusion of 6-month trial, and at the end of 6-month follow-up.
Seven patients were protocol violators. Of 43 patients who received curcumin, 2 relapsed during 6 months of therapy (4.65%), whereas 8 of 39 patients (20.51%) in the placebo group relapsed (P=.040). Recurrence rates evaluated on the basis of intention to treat showed significant difference between curcumin and placebo (P=.049). Furthermore, curcumin improved both CAI (P=.038) and EI (P=.0001), thus suppressing the morbidity associated with UC. A 6-month follow-up was done during which patients in both groups were on SZ or mesalamine. Eight additional patients in the curcumin group and 6 patients in the placebo group relapsed.
Curcumin seems to be a promising and safe medication for maintaining remission in patients with quiescent UC. Further studies on curcumin should strengthen our findings.
Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the progressive development of kidney and liver cysts. The mammalian target of rapamycin (mTOR) cascade is one of the ...important pathways regulating cyst growth in ADPKD. Branched-chain amino acids (BCAAs), including leucine, play a crucial role to activate mTOR pathway. Therefore, we administered BCAA dissolved in the drinking water to Pkd1flox/flox:Mx1-Cre (cystic) mice from four to 22 weeks of age after polyinosinic-polycytidylic acid–induced conditional Pkd1 knockout at two weeks of age. The BCAA group showed significantly greater kidney/body weight ratio and higher cystic index in both the kidney and liver compared to the placebo-treated mice. We found that the L-type amino acid transporter 1 that facilitates BCAA entry into cells is strongly expressed in cells lining the cysts. We also found increased cyst-lining cell proliferation and upregulation of mTOR and mitogen-activated protein kinase/extracellular signal–regulated kinase (MAPK/ERK) pathways in the BCAA group. In vitro, we cultured renal epithelial cell lines from Pkd1 null mice with or without leucine. Leucine was found to stimulate cell proliferation, as well as activate mTOR and MAPK/ERK pathways in these cells. Thus, BCAA accelerated disease progression by mTOR and MAPK/ERK pathways. Hence, BCAA may be harmful to patients with ADPKD.
Objectives We examined the efficacy of tolvaptan, an orally effective nonpeptide vasopressin V₂ receptor antagonist, in a Japanese clinical study in patients with intractable ascites and/or lower ...limb edema associated with decompensated liver cirrhosis. Methods Tolvaptan was orally administrated at titrated doses of 15, 30, and 60 mg once daily after breakfast for 3 days at each dose to 18 liver cirrhosis patients with persistent ascites and/or lower limb edema despite receiving oral furosemide at 40 mg/day or higher. Results Decreased body weight and abdominal circumference and improvement of ascites and edema were observed following tolvaptan administration beginning from 15 mg. Composite ascites/edema improvement rate was 88.2% at individual maximum doses and 64.7, 80.0, and 90.9%, respectively, after 3-day administration at 15, 30, and 60 mg. Changes in body weight after 3-day administration at 15, 30, and 60 mg were −1.6 ± 0.9, −2.6 ± 1.2, and −3.4 ± 2.1 kg (mean ± SD), respectively, and decreases of 1 kg or more were seen from day 2 (24 h after first dosing). Changes in abdominal circumference ranged from −2.8 to −6.0 cm. Cumulative 24-h urine volumes after 3-day administration at 15, 30, and 60 mg were, respectively, 3240.3 ± 1014.5, 3943.3 ± 1060.6, and 4537.4 ± 1621.3 mL/day (mean ± SD). Urine osmolarity was markedly decreased and remained decreased until the end of treatment. Conclusion Tolvaptan dose-dependently decreased body weight and abdominal circumference and improved ascites and edema beginning from 15 mg, demonstrating a potent aquaretic effect.
Background
Drug-induced liver injury (DILI) sometimes resembles autoimmune hepatitis (AIH) in its hepatic histology. However, there is lacking data of a comparison of the characteristics between such ...DILI and DILI without histological findings like AIH.
Methods
We enrolled 62 patients with DILI who were diagnosed using the Roussel Uclaf Causality Assessment Method, and performed a liver biopsy. These patients were classified into two groups: DILI with histology like AIH (group A,
n
= 23) and DILI without such histology (group B,
n
= 39). Sixteen patients of group A could be further classified into two groups: patients with relapse of the liver injury (group C,
n
= 8) and without relapse (group D,
n
= 8), after the recovery of the DILI. We compared the clinical and histological findings between group A and B, and group C versus D.
Results
Group A was characterized by an older age (
p
= 0.043), higher immunoglobulin G level (
p
= 0.017), positive antinuclear antibody status (
p
= 0.044), and a higher frequency of complementary alternative medicines and Chinese herbal medicines as the causative drug (
p
= 0.008). There were no significant differences between group C and D regarding the clinical data and liver histological findings.
Conclusions
The clinical characteristics of DILI, which showed histological findings similar to AIH, were revealed. In such patients, a liver biopsy is recommended in order to determine the appropriate treatment strategy. In DILI with histology like AIH patients, long-term follow-up is needed to perceive the relapse.
PDF
