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.
Centenarians have a decreased susceptibility to ageing-associated illnesses, chronic inflammation and infectious diseases
. Here we show that centenarians have a distinct gut microbiome that is ...enriched in microorganisms that are capable of generating unique secondary bile acids, including various isoforms of lithocholic acid (LCA): iso-, 3-oxo-, allo-, 3-oxoallo- and isoallolithocholic acid. Among these bile acids, the biosynthetic pathway for isoalloLCA had not been described previously. By screening 68 bacterial isolates from the faecal microbiota of a centenarian, we identified Odoribacteraceae strains as effective producers of isoalloLCA both in vitro and in vivo. Furthermore, we found that the enzymes 5α-reductase (5AR) and 3β-hydroxysteroid dehydrogenase (3β-HSDH) were responsible for the production of isoalloLCA. IsoalloLCA exerted potent antimicrobial effects against Gram-positive (but not Gram-negative) multidrug-resistant pathogens, including Clostridioides difficile and Enterococcus faecium. These findings suggest that the metabolism of specific bile acids may be involved in reducing the risk of infection with pathobionts, thereby potentially contributing to the maintenance of intestinal homeostasis.
Aim
Sarcopenia has a high prevalence and can be an adverse predictor in patients with chronic liver diseases (CLDs). We sought to assess the prevalence of sarcopenia and its prognostic significance ...in patients with CLDs at multiple centers in Japan.
Methods
In this retrospective study, we collated the data of 1624 patients with CLDs (976 men). The diagnosis of sarcopenia was determined by the sarcopenia assessment criteria of the Japan Society of Hepatology. Predictors of mortality were identified using univariate and multivariate analyses.
Results
Muscle weakness and skeletal muscle loss occurred in 33.5% and 29.3% of all subjects, respectively, while sarcopenia occurred in 13.9% of all patients. Patients with sarcopenia had a poorer prognosis among all patients, patients with hepatocellular carcinoma (HCC), and those without HCC by log‐rank test. The multivariate Cox proportional hazards model identified female gender (hazard ratio HR, 0.59; p = 0.03), alcoholic liver disease (HR, 4.25; p < 0.01), presence of HCC (HR, 6.77; p < 0.01), Child–Pugh classes A (HR, 1.42; p < 0.05), B (HR, 2.70; p < 0.01), and C (HR, 6.30; p < 0.01), and muscle weakness (HR, 2.24; p < 0.01) as significant adverse predictors. The cut‐off values of handgrip strength (HGS) for prognosis determined by maximally selected rank statistics were calculated as 27.8 kg for men and 18.8 kg for women.
Conclusion
Reduced HGS in patients with CLD was an independent adverse predictor of mortality, with cut‐off values of 27.8 kg for men and 18.8 kg for women.
The accurate and prompt diagnosis of SARS-CoV-2 infection is required for the control and treatment of the coronavirus infection disease 2019 (COVID-19). In this study, we aimed to investigate the ...time courses of the anti-severe acute corona respiratory syndrome coronavirus 2 (SARS-CoV-2) IgM and IgG titers and to evaluate the sensitivity and specificity of such tests according to the specific day after the onset of COVID-19 among a patient population in Japan. We measured the titers of SARS-CoV-2 IgM and IgG in sera from 105 subjects, including 26 symptomatic COVID-19 patients, using chemiluminescent immunoassay (CLIA) methods utilizing magnetic beads coated with SARS-CoV-2 nucleocapsid protein and spike protein. The results of a ROC analysis suggested the possibility that the cutoff values in Japan might be lower than the manufacturer's reported cutoff (10 AU/mL): 1 AU/mL for IgM and 5 AU/mL for IgG. The sensitivity of the test before Day 8 after symptom onset was less than 50%; at Days 9-10, however, we obtained a much higher sensitivity of 81.8% for both IgM and IgG. At 15 days or later after symptom onset, the SARS-CoV-2 IgG test had a sensitivity of 100%. These results suggest that if the number of days since disease onset is taken into consideration, these antibody tests could be very useful for the diagnosis of COVID-19 and similar diseases.
Eleven adults with reverse transcriptase polymerase chain reaction-confirmed SARS-CoV-2 infection were admitted to the intensive care unit (ICU) at The University of Tokyo Hospital between April 6 ...and April 21, 2020, and treated with nafamostat mesylate in combination with favipiravir. ...nafamostat mesylate therapy in combination with favipiravir may allow blockade of virus entry and replication, as well as inhibition of pathogenic host response, i.e., hyper-coagulopathy. Mechanical ventilation SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2 TMPRSS2: Transmembrane protease serine 2 VV-ECMO: Venovenous extracorporeal membrane oxygenation 1.
Difficult-to-treat infections caused by rapidly growing mycobacteria (RGM) are increasingly observed in clinical settings. However, studies on antimicrobial susceptibilities and effective treatments ...against RGM in Japan are limited.
We conducted susceptibility testing of potential antimicrobial agents, including tigecycline and tebipenem, against RGM. Clinical RGM isolates were collected from a university hospital in Japan between December 2010 and August 2013. They were identified using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and the sequencing of 16S rRNA, rpoB, and hsp65 genes. The samples were utilized for susceptibility testing using 16 antimicrobials, with frozen broth microdilution panels.
Forty-two isolates were obtained: 13, Mycobacterium abscessus complex; 12, Mycobacterium chelonae; 9, Mycobacterium fortuitum; and 8, M. fortuitum group species other than M. fortuitum. Different antimicrobial susceptibility patterns were observed between RGM species. Clarithromycin-susceptible strain rates were determined to be 0, 62, and 100% for M. fortuitum, M. abscessus complex, and M. chelonae, respectively. M. abscessus complex (100%) and >80% M. chelonae isolates were non-susceptible, while 100% M. fortuitum group isolates were susceptible to moxifloxacin. Linezolid showed good activity against 77% M. abscessus complex, 89% M. fortuitum, and 100% M. chelonae isolates. Regardless of species, all tested isolates were inhibited by tigecycline at very low minimal inhibitory concentrations (MICs) of ≤0.5 μg/mL. MICs of tebipenem, an oral carbapenem, were ≤4 μg/mL against all M. fortuitum group isolates.
Our study demonstrates the importance of correct identification and antimicrobial susceptibility testing, including the testing of potential new agents, in the management of RGM infections.
In Coronavirus disease 2019 (COVID-19) subjects, recent evidence suggests the presence of unique coagulation abnormalities. In this study, we performed clot waveform analyses to investigate whether ...specific modulations are observed in COVID-19 subjects. We analyzed the second derivative of the absorbance in routine APTT tests performed using an ACL-TOP system. We observed high frequencies of abnormal patterns in APTT second-derivative curves that could be classified into an early shoulder type, a late shoulder type, or a biphasic type, high maximum first-derivative and second-derivative peak levels, and a low minimum second-derivative peak level in COVID-19 subjects. These modulations were not observed in subjects with disseminated intravascular coagulation. These abnormal patterns are also observed in patients with lupus anticoagulant, hemophilia, or factor IX deficiency. The plasma fibrinogen levels might also be involved in the abnormal APTT waveforms, especially the high maximum first-derivative and second-derivative peak levels. The abnormal patterns in the APTT second-derivative curves appear with highest frequency at around 2 weeks after the onset of COVID-19 and were not associated with the severity of COVID-19. These results suggest the possible presence of a specific abnormal coagulopathy in COVID-19.
A number of nucleic acid amplification tests (NAATs) for SARS-CoV-2 with different reagents have been approved for clinical use in Japan. These include research kits approved under emergency use ...authorization through simplified process to stabilize the supply of the reagents. Although these research kits have been increasingly used in clinical practice, limited data is available for the diagnostic performance in clinical settings. We compared sensitivity, specificity, and cycle threshold (Ct) values obtained by NAATs using 10 kits approved in Japan including eight kits those receiving emergency use authorization using 69 frozen-stored clinical samples including 23 positive samples with various Ct values and 46 negative samples. Viral copy number of the frozen-stored samples determined with LightMix E-gene test ranged from 0.6 to 84521.1 copies/muL. While no false-positive results were obtained by any of these tests (specificity: 100% 95% CI, 88.9%-100%), sensitivity of the nine tests ranged from 68.2% 95% CI, 45.1%-86.1% to 95.5% 95% CI, 77.2%-99.9% using LightMix E-gene test as the gold standard. All tests showed positive results for all samples with greater than or equal to100 copies/muL. Significant difference of Ct values even among tests amplifying the same genetic region (N1-CDC, N2) was also observed. Difference in the diagnostic performance was observed among NAATs approved in Japan. Regarding diagnostic kits for emerging infectious diseases, a system is needed to ensure both rapidity of reagent supply and accuracy of diagnosis. Ct values, which are sometimes regarded as a marker of infectivity, are not interchangeable when obtained by different assays.
Porphyria cutanea tarda (PCT), the most common of the human porphyrias, arises from a deficiency of uroporphyrinogen decarboxylase. Studies have shown a high prevalence of hepatitis C virus (HCV) ...infection in patients with PCT. While these observations implicate HCV infection as a risk factor for PCT pathogenesis, the mechanism of interaction between the virus and porphyrin metabolism is unknown. This study aimed to assess the effect of HCV core protein on intracellular porphyrin metabolism to elucidate the link between HCV infection and PCT. The accumulation and excretion of porphyrins after treatment with 5-aminolevulinic acid, a porphyrin precursor, were compared between cells stably expressing HCV core protein and controls. Cells expressing HCV core protein had lower amounts of intracellular protoporphyrin IX and heme and had higher amounts of excreted coproporphyrin III, the oxidized form of coproporphyrinogen III, compared with controls. These observations suggest that HCV core protein affects porphyrin metabolism and facilitates the export of excess coproporphyrinogen III and/or coproporphyrin III, possibly via porphyrin transporters. Real-time PCR analysis revealed that the presence of HCV core protein increased the mRNA expression of porphyrin exporters ABCG2 and FLVCR1. Western blot analysis showed a higher expression level of FLVCR1, but not ABCG2, as well as a higher expression level of mature ALAS1, which is the rate-limiting enzyme in the heme synthesis pathway, in HCV core protein-expressing cells compared with controls. The data indicate that HCV core protein induced abnormal intracellular porphyrin metabolism, with an over-excretion of coproporphyrin III. These findings may partially account for the susceptibility of HCV-infected individuals to PCT development.
Hepatic iron overload is a risk factor for progression of hepatocellular carcinoma (HCC), although the molecular mechanisms underlying this association have remained unclear. We now show that the ...iron-sensing ubiquitin ligase FBXL5 is a previously unrecognized oncosuppressor in liver carcinogenesis in mice. Hepatocellular iron overload elicited by FBXL5 ablation gave rise to oxidative stress, tissue damage, inflammation, and compensatory proliferation of hepatocytes and to consequent promotion of liver carcinogenesis induced by exposure to a chemical carcinogen. The tumor-promoting outcome of FBXL5 deficiency in the liver was also found to be effective in a model of virus-induced HCC. FBXL5-deficient mice thus constitute the first genetically engineered mouse model of liver carcinogenesis promoted by iron overload. In addition, dysregulation of FBXL5-mediated cellular iron homeostasis was found to be associated with poor prognosis in human HCC, suggesting that FBXL5 plays a key role in defense against hepatocarcinogenesis.
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