Mac-2 binding protein glycosylation isomer, the FIB-4 index, and a combination of the two as predictors of non-alcoholic steatohepatitis.

Approximately 10% non-alcoholic fatty liver disease (NAFLD) cases progress to non-alcoholic steatohepatitis (NASH). Liver biopsy, the gold standard for diagnosing NASH and associated liver fibrosis, is invasive with a risk of life-threatening complications. Therefore, reliable non-invasive biomarkers for predicting NASH are required to prevent unnecessary liver biopsies. We evaluated the performance of two non-invasive fibrosis markers, Mac-2 binding protein glycosylation isomer (M2BPGi) and the FIB-4 index for predicting the fibrosis staging, NAFLD activity scoring (NAS) index, and NASH. We also analyzed the correlation between the two markers. The sensitivities, specificities, positive predictive values (PPV), and negative predictive values of the FIB-4 index, M2BPGi, and a combination of both markers for NASH diagnosis were evaluated. The M2BPGi and FIB-4 index showed a good performance in diagnosing NASH, the fibrosis stage, and the NAS index in NAFLD patients. While both markers were well-correlated with each other in most cases, no correlation was found in some patients. Compared with the FIB-4 index or the M2BPGi alone, a combination of the two showed a higher specificity, PPV, and accuracy for NASH diagnosis. The M2BPGi and the FIB-4 index are easily accessible and reliable liver fibrosis markers. Diseases other than liver disease may cause dissociation between the two markers, causing failure to predict NASH. However, the combination of both markers can compensate for their disadvantages. Because the PPV of the combination was relatively high, patients who test positive for both markers should undergo liver biopsy for NASH diagnosis.

Trends of hepatitis B virus genotype distribution in chronic hepatitis B patients in Japan.

BACKGROUND: Hepatitis B virus (HBV) is one of the most prevalent chronic viral infections that causes chronic hepatitis B (CHB). In Japan, genotypes B and C account for most of acute and chronic cases of hepatitis. However, previous studies showed that the prevalence of genotype A in CHB gradually increased every 5 years. Therefore, we have conducted a nationwide survey to comprehensively investigate the trends of HBV genotype distribution in CHB patients in Japan. METHODS: 4421 CHB patients were recruited between 2015 and 2016. Clinical characteristics and distribution of CHB patients among different age groups and genotypes in 2015-2016 was compared with those in 2000-2001, 2005-2006, and 2010-2011. RESULTS: The percentages of genotype A, B, C, and D were 4.0, 16.2, 79.1, and 0.7%, respectively. While the overall percentage of CHB patients with genotype A did not change in the past 5 years, CHB with genotype A increased in young adults. On the other hand, the peak distribution of CHB with genotypes B and C, two genotypes with the largest patient population, has shifted to an older age group. CONCLUSIONS: In Japan, the peak distribution for CHB with genotypes B and C advanced to an older age group while CHB with genotype A expanded in a younger age group. Given the universal HBV vaccination launch in Japan in 2016, these pre-vaccination survey data provide important baseline information for comparative studies of the impact of universal vaccination on HBV genotypes.

Experience with Photodynamic Therapy Using Indocyanine Green Liposomes for Refractory Cancer.

We reported the development of an effective cancer treatment using a multidisciplinary treatment, including photodynamic therapy (PDT) with indocyanine green (ICG) liposomes and a combination of Lentinula edodes mycelia (LEM) and hydrogen gas inhalation therapy. ICG liposomes were prepared by adding 5 mg of ICG to 50 mL liposomes. Later, 25 mL of ICG liposomes were diluted with 250 mL of 5% glucose solution and administered intravenously to the patient. We selected the multi-laser delivery system (MLDS), a laser irradiator for performing PDT. Further, the patients received a combination of LEM and hydrogen gas inhalation therapy throughout the treatment. We reported two cases of PDT therapy, one with middle intrathoracic esophagus carcinoma and the other with hypopharyngeal cancer. In the first case, the MLDS laser was directly attached to the endoscope and directed to the cancer area with wavelengths of 810 nm. After the treatment, a biopsy demonstrated no tumor recurrence. In the second case, the patient was treated with endovascular PDT using ICG liposomes and MLDS fiber optics. Later, tumor shrinkage was demonstrated after the first round and disappeared after six months. In conclusion, the present findings suggest that the effect of PDT using ICG liposomes with LEM and hydrogen gas may eradicate cancer without burdening patients by enhancing tumor immunity.

Nutrition and Cancer Risk from the Viewpoint of the Intestinal Microbiome.

There are various important factors in reducing the risk of cancer development and progression; these factors may correct an unbalanced intake of nutrients to maintain the living body's homeostasis, detoxify toxic materials, acting as an external factor, and maintain and strengthen the body's immune function. In a normal cell environment, nutrients, such as carbohydrates, lipids, proteins, vitamins, and minerals, are properly digested and absorbed into the body, and, as a result, an environment in which cancer can develop and progress is prevented. It is necessary to prevent toxic materials from entering the body and to detoxify poisons in the body. If these processes occur correctly, cells work normally, and genes cannot be damaged. The most important factor in the fight against cancer and prevention of the development and progression of cancer is the immune system. This requires a nutritional state in which the immune system works well, allowing the intestinal microbiome to carry out all of its roles. In order to grow intestinal microbiota, the consumption of prebiotics, such as organic vegetables, fruits, and dietary fiber, and probiotics of effective intestinal microbiota, such as fermented foods and supplements, is required. Symbiosis, in which these organisms work together, is an effective means of reducing the risk of cancer. In addition, fecal microbiota transplantation (FMT) using ultrafine bubble water, produced specially by the Association for Clinical Research of Fecal Microbiota Transplantation Japan, is also useful for improving the nutritional condition and reducing the risk of cancer.

Personalized Nutritional Therapy Based on Blood Data Analysis for Malaise Patients.

As medical doctors, we routinely check patient blood chemistry and CBC data to diagnose disease. However, these data and methods of analysis are very rarely used to find pre-disease conditions or treat undiagnosed malaise. Masatoshi Kaneko Ph.D. found that many pre-disease conditions and types of malaise could be detected using his unique method of blood data analysis, and could also be treated using personalized nutritional therapy as an alternative to using drugs. The authors of this article introduce personalized nutritional therapy based on blood data analysis (Kaneko's method), and present and discuss some clinical cases. In total, 253 pre-disease or undiagnosed patients were treated using this nutritional therapy approach, and most of them recovered from their chronic symptoms and pre-disease conditions. This novel nutritional therapy has the potential to help many presymptomatic and undiagnosed patients suffering from malaise.

The Onset of Dental Erosion Caused by Food and Drinks and the Preventive Effect of Alkaline Ionized Water.

In recent years, the incidence of dental erosion caused by the ingestion of acidic foods and drinks, including sports drinks, has been increasing in Japan and elsewhere. Therefore, the problems associated with this injury can no longer be ignored in dental clinical practice. The ingestion of these foods and drinks is important from the viewpoint of overall health and disease prevention. For example, fermented foods, such as Japanese pickles, enhance the nutritional value of foodstuffs and promote the absorption of nutrients into the body, and sports drinks are useful for preventing heat stroke and dehydration. Therefore, eliminating these intakes is not a viable solution. In this paper, we outline the mechanism of dental erosion caused by acidic beverages and also describe the effectiveness of alkaline ionized water (AIW) at preventing acid erosion. Given the fact that the complete elimination of acidic beverage consumption is highly unlikely, remedies such as the use of alkaline ionized water (AIW) may be helpful.

Green Tea Catechin Association with Ultraviolet Radiation-Induced Erythema: A Systematic Review and Meta-Analysis.

Catechins are a part of the chemical family of flavonoids, a naturally occurring antioxidant, and a secondary metabolite in certain plants. Green tea catechins are well recognized for their essential anti-inflammatory, photo-protective, antioxidant, and chemo-preventive functions. Ultraviolet radiation is a principal cause of damage to the skin. Studies observed that regular intake of green tea catechins increased the minimal dose of radiation required to induce erythema. The objectives of this systematic review and meta-analysis are to determine the effectiveness of green tea catechins in cutaneous erythema and elucidate whether green tea catechin consumption protects against erythema (sunburn) inflammation. A comprehensive literature search was conducted to identify the relevant studies. Two researchers carried out independent screening, data extraction, and quality assessment according to the guidelines of Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA). The pooled effect of green tea catechins on protection against erythema was assessed using approaches fixed-effects or random-effects model to quantify the effectiveness of green tea catechins in the erythema dose-response. Studies not be included in meta-analyses were summarized narratively. Six randomized controlled studies of enrolled studies regularly administrated green tea catechins orally for 6 to 12 weeks involving healthy volunteers comprising a total of 100 participants were included in the analysis. The results revealed green tea catechins have favorable protection against erythema inflammation even at increased minimal erythema dose (MED) of ultraviolet radiation. Meta-analysis results confirm oral supplementation of green tea catechins is highly effective at low-intensity ultraviolet radiation-induced erythema response (MED range; 1.25-1.30) compared to placebo, showing a significant pooling difference (p = 0.002) in erythema index (SMD: -0.35; 95% CI, -0.57 to -0.13; I2 = 4%, p = 0.40) in the random-effects model. The pro-inflammatory signaling pathways through oral supplementation with green tea catechins are an attractive strategy for photo-protection in healthy human subjects and could represent a complementary approach to topical sunscreens. Therefore, studies that involved green tea catechin in topical applications to human subjects were also evaluated separately, and their meta-analysis is presented as a reference. The evidence indicates that regular green tea catechin supplementation is associated with protection against UV-induced damage due to erythema inflammation.

Development of Kampo（traditional Japanese medicine）e-learning program: evaluation of the flipped classroom for medical students.

In May 2019, the World Health Assembly, in an unprecedented move, endorsed the inclusion of traditional medicine in the International Classification of Diseases, 11th Revision. In Japan, traditional medicine (known as Kampo) is regulated by the government and prescribed by over 90% of physicians along with modern medicine under the national health insurance system. Although Kampo education must be included in Japan's core medical curricula, there are significant challenges to implementation. In the educational context, the flipped classroom teaching method has received considerable attention in recent years. This study developed a Kampo e-learning program and verified the effectiveness of a flipped classroom using Kampo e-learning. The Kampo e-learning Committee determined three courses and assigned an administrator for each. The administrators appointed lecturers who developed Kampo e-learning lessons. Physicians, pharmacists, medical students, and pharmacy students were asked to participate in the e-learning program, and their comments and suggestions were collected after program completion. The flipped classroom was evaluated by implementing Kampo e-learning in the Kampo session with fourth-year students at Keio University School of Medicine in Japan. Seven courses were created, including four based on volunteer suggestions. The 'Systematic Kampo Curricula' featured 88 lessons developed by 54 Kampo specialists. Out of 118 fourth-year medical students who participated in the flipped classroom, 113 registered for the Kampo e-learning program, 100 attended the session, and 88 answered the post-session questionnaire. Among the students who answered the questionnaire, 86.4% were satisfied with the flipped classroom, 79.5% replied that the program made them understand Kampo and 80.7% stated that it should be adopted. The flipped classroom using Kampo e-learning program was shown to be attractive in one medical school. Further expanded study is necessary in the near future to reveal the usefulness of the flipped classroom of Kampo learning.

Influence of nicotine on choline-deficient, L-amino acid-defined diet-induced non-alcoholic steatohepatitis in rats.

Nicotine, a major compound in cigarette smoke, decreases food intake and body weight gain in mammals; however, the influence of nicotine on the progression of non-alcoholic steatohepatitis (NASH) remains controversial. This study aimed to investigate the effect of nicotine on NASH in rat models. Male Wistar rats were fed choline-deficient, l-amino acid-defined (CDAA) diet and treated with nicotine or saline. Food intake, body weight gain, presence of hepatic steatosis, inflammation, and fibrosis were assessed 6 weeks after the rats were fed CDAA diet. Hepatic branch vagotomy was performed to elucidate the mechanism through which nicotine affected steatohepatitis. CDAA diet induced hepatic steatosis, inflammation, and fibrosis, as well as increased the expression of inflammation-related genes. Conversely, nicotine significantly attenuated food intake, body weight gain, and inhibited the CDAA-diet-induced hepatic steatosis, inflammation, and fibrosis, together with increased expression of inflammation-related genes. Hepatic branch vagotomy by itself decreased food intake, body weight gain, and attenuated the CDAA-diet-induced hepatic steatosis, but not inflammation. However, nicotine did not change the food intake, body weight gain, and CDAA diet-induced hepatic steatosis and inflammation in vagotomized rats. These results suggest that nicotine attenuates the CDAA-diet-induced hepatic steatosis and inflammation through the hepatic branch of the vagus nerve in rats.

Conophylline inhibits non-alcoholic steatohepatitis in mice.

Conophylline (CnP), a vinca alkaloid extracted from the leaves of the tropical plant Ervatamia microphylla, attenuates hepatic fibrosis in mice. However, little is known about whether CnP inhibits steatosis, inflammation, and fibrosis in non-alcoholic steatohepatitis (NASH) in mice. A methionine-choline-deficient (MCD) diet was administered to male db/db mice as a NASH model, and CnP (1 µg/kg/d) was co-administered. Eight weeks after the commencement of the MCD diet, hepatic steatosis, inflammation, and fibrosis, and hepatic fat metabolism-, inflammation-, and fibrosis-related markers were examined. Feeding on an MCD for 8 weeks induced hepatic steatosis, inflammation, and fibrosis. CnP significantly attenuated the MCD-induced increases in hepatic steatosis, as well as hepatic inflammation and fibrosis. The MCD diet increased hepatic transforming growth factor-ß (TGF-ß) mRNA levels, which are correlated with hepatic steatosis, inflammation, and fibrosis. The diet also attenuated acyl-coenzyme A oxidase 1 (ACOX1) and carnitine palmitoyltransferase 1 (CPT1) mRNA levels, which are involved in ß-oxidation. The putative mechanism of the CnP effect involves reduced hepatic TGF-ß mRNA levels, and increased mRNA levels of hepatic peroxisome proliferator-activated receptor (PPAR) α and its target genes ACOX1 and CPT1. The results of this study indicate that CnP inhibits steatohepatitis, possibly through the inhibition of hepatic TGF-ß mRNA levels, and induces an increase in PPARα mRNA levels, resulting in the attenuation of hepatic steatosis, inflammation, and fibrosis in mice. CnP might accordingly be a suitable therapeutic option for NASH.

Ezetimibe for the treatment of non-alcoholic fatty liver disease: A meta-analysis.

AIM: Several studies on the efficacy of ezetimibe, a potent inhibitor of cholesterol absorption, in treating non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) have been published; however, the results are inconsistent. We undertook a meta-analysis to evaluate the efficacy of ezetimibe in treating NAFLD and NASH. METHODS: PubMed, Medline, and Cochrane Library Full Text Database were searched until June 2016. The main inclusion criteria included original studies investigating the use of ezetimibe for the treatment of NAFLD and NASH. Identification of published work and data extraction were carried out by two reviewers based on the inclusion and exclusion criteria. All analyses were carried out using Comprehensive Meta-Analysis version 3 software. RESULTS: An initial search identified 103 peer-reviewed articles and abstracts. Six studies (two randomized controlled and four single-arm trials) involving 273 participants with NAFLD and NASH were identified. Ezetimibe significantly reduced serum aspartate aminotransferase, alanine aminotransferase, and γ-glutamyl transpeptidase levels, and hepatic steatosis and hepatocyte ballooning. However, hepatic inflammation and fibrosis did not improve by ezetimibe treatment in patients with NAFLD and NASH. In randomized controlled trials, only hepatocyte ballooning improved with ezetimibe treatment. CONCLUSIONS: Although ezetimibe attenuated serum liver enzymes and hepatic steatosis and ballooning in six studies, it improved only hepatocyte ballooning in randomized controlled trials. Larger studies and more randomized placebo-controlled trials are necessary to determine the effects of ezetimibe on NAFLD and NASH.

Physiological effects of epigallocatechin-3-gallate (EGCG) on energy expenditure for prospective fat oxidation in humans: A systematic review and meta-analysis.

Green tea catechins (GTCs) are known to improve fat oxidation (FOX) during fasted, rested and exercise conditions wherein epigallocatechin-3-gallate (EGCG) is thought to be the most pharmacologically active and has been studied extensively. From the available data of randomized controlled trials (RCTs) on EGCG, we carried out a systematic review and meta-analysis to elucidate whether EGCG consumption indeed increase energy expenditure (EE) and promote FOX. A systematic review of the literature was conducted using electronic databases (PubMed, Embase, Cochrane Library, CINAHL, JICST, JSTPLUS, and JMEDPLUS and others) and eight RCTs were included. RCTs were reviewed using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and methodological quality was assessed. After data extraction, results were aggregated using fixed- and random-effect approaches and expressed to quantify the relationship between the dose of EGCG for respiratory quotient (RQ), EE and rate of FOX to compare the EGCG and placebo treatments. The meta-analysis results of verities of studies in terms of dose and length of duration revealed that EGCG supplementation provided significant mean difference (MD) when compared with placebo for RQ [MD: -0.02; 95% confidence intervals (95% CI), -0.04 to 0.00; I2=67%; P=.01] and EE [MD: 158.05 kJ/day; 95% CI, 4.72 to 311.38; I2=0%; P=.04] in fixed-effect approach. Changes in FOX did not reach the level of statistical significance. Meta-analyses of EGCG influence on the body mass index, waist circumference and total body fat mass (TBFM) were also examined and their impact on the promotion of FOX is reported. Effect of EGCG doses was also systematically reviewed. Finding showed that EGCG intake moderately accelerates EE and reduces RQ. The analyses revealed that the EGCG resulted in difference in RQ and EE but the effect on the other measures of energy metabolism was relatively mild. Possibly, EGCG alone has the potential to increase metabolic rate at 300 mg dose. Collectively, the outcome supports the findings that EGCG has an effect on metabolic parameters. However, the large prospective trials are needed to confirm the findings.

Glucagon-like peptide-1 analogue prevents nonalcoholic steatohepatitis in non-obese mice.

AIM: To investigate whether a glucagon-like peptide-1 (GLP-1) analogue inhibits nonalcoholic steatohepatitis (NASH), which is being increasingly recognized in Asia, in non-obese mice. METHODS: A methionine-choline-deficient diet (MCD) along with exendin-4 (20 µg/kg per day, ip), a GLP-1 analogue, or saline was administered to male db/db mice (non-obese NASH model). Four or eight weeks after commencement of the diet, the mice were sacrificed and their livers were excised. The excised livers were examined by histochemistry for evidence of hepatic steatosis and inflammation. Hepatic triglyceride (TG) and free fatty acid (FFA) content was measured, and the expression of hepatic fat metabolism- and inflammation-related genes was evaluated. Oxidative stress-related parameters and macrophage recruitment were also examined using immunohistochemistry. RESULTS: Four weeks of MCD feeding induced hepatic steatosis and inflammation and increased the hepatic TG and FFA content. The expression of fatty acid transport protein 4 (FATP4), a hepatic FFA influx-related gene; macrophage recruitment; and the level of malondialdehyde (MDA), an oxidative stress marker, were significantly augmented by a 4-wk MCD. The levels of hepatic sterol regulatory element-binding protein-1c (SREBP-1c) mRNA (lipogenesis-related gene) and acyl-coenzyme A oxidase 1 (ACOX1) mRNA (ß-oxidation-related gene) had decreased at 4 wk and further decreased at 8 wk. However, the level of microsomal triglyceride transfer protein mRNA (a lipid excretion-related gene) remained unchanged. The administration of exendin-4 significantly attenuated the MCD-induced increase in hepatic steatosis, hepatic TG and FFA content, and FATP4 expression as well as the MCD-induced augmentation of hepatic inflammation, macrophage recruitment, and MDA levels. Additionally, it further decreased the hepatic SREBP-1c level and alleviated the MCD-mediated inhibition of the ACOX1 mRNA level. CONCLUSION: These results suggest that GLP-1 inhibits hepatic steatosis and inflammation through the inhibition of hepatic FFA influx and oxidative stress in a non-obese NASH model.

Vitamin E has a beneficial effect on nonalcoholic fatty liver disease: a meta-analysis of randomized controlled trials.

OBJECTIVES: Vitamin E is often used in the treatment of nonalcoholic fatty liver disease (NAFLD), including nonalcoholic steatohepatitis (NASH); however, the magnitude of treatment response associated with vitamin E in improving liver function and histology in NAFLD/NASH has not, to our knowledge, been quantified systematically. Thus, we conducted a meta-analysis of randomized controlled trials (RCTs) using vitamin E in the treatment of NAFLD/NASH. METHODS: PubMed, Medline, and Cochrane Library Full Text Database, and Japan Medical-Literature Database (Igaku Chuo Zasshi) were searched until March 2014, and five RCTs were identified for meta-analysis. RESULTS: According to a random effect model analysis of the five studies, vitamin E significantly reduced aspartate transaminase (AST) by -19.43 U/L, alanine aminotransferase (ALT) by -28.91 U/L, alkaline phosphatase (ALP) by -10.39 U/L, steatosis by -0.54 U/L, inflammation by -0.20 U/L, and hepatocellular ballooning by -0.34 U/L compared with the control group. Vitamin E treatment with NASH adult patients showed obvious reductions in not only AST of -13.91 U/L, ALT by -22.44 U/L, steatosis of -0.67 U/L, inflammation of -0.20 U/L, but also fibrosis of -0.30 U/L compared to the control treatment. CONCLUSIONS: Vitamin E significantly improved liver function and histologic changes in patients with NAFLD/NASH.

A rare congenital extrahepatic portosystemic shunt affecting the inferior mesenteric vein, inferior vena cava, and left ovarian vein.

PURPOSE: To observe a case of congenital extrahepatic portosystemic shunt and discuss it from the embryological and clinical viewpoints. METHODS: An 85-year-old female cadaver was employed for a dissection course at Aichi Medical University in 2009. RESULTS: There was no evidence of liver cirrhosis macroscopically or microscopically. A portosystemic shunt was observed that involved communication between the inferior mesenteric vein, inferior vena cava (IVC), and left ovarian vein by a single Y-shaped shunt vessel. CONCLUSIONS: To the best of our knowledge, this is the first reported case of the above-mentioned three veins being connected by a single Y-shaped shunt vessel. Considering the other venous diameters, the shunt appeared to flow into the splenic vein and IVC. It cannot be denied that this shunt may have led to hepatic encephalopathy, although the shunt effect may have been minimal. Embryological development of IVC appears to occur close to the plexus of anastomosing vitelline veins, forming the portal vein.