Cholecystocutaneous Fistula Associated with Edwardsiella tarda as a Result of Aggressive Lymphoma Development.

A cholecystocutaneous fistula is a type of external biliary fistula that occurs when there is an abnormal connection between the gallbladder and skin. We report the first case of a cholecystocutaneous fistula that occurred in association with the development of lymphoma in the gallbladder. A 76-year-old woman who was under observation for follicular lymphoma with a low tumor burden presented with fatigue and abdominal pain. Imaging studies revealed cholecystitis associated with an abdominal subcutaneous abscess, and lymphoma transformation was confirmed by a lymph node biopsy. Edwardsiella tarda was cultured from both the abdominal subcutaneous abscess and percutaneous transhepatic gallbladder drainage, demonstrating cholecystocutaneous fistula, and open cholecystectomy revealed lymphoma cell infiltration into the gallbladder. Our case showed unique complications, and its successful management was associated with aggressive lymphoma development.

Injection drug use and sexually transmitted infections among men who have sex with men: A retrospective cohort study at an HIV/AIDS referral hospital in Tokyo, 2013-2022.

Men who have sex with men (MSM) who use injection drugs (MSM-IDU) are at high risk of sexually transmitted infections (STIs), but the long-term incidence is unclear. We conducted a single-centre retrospective cohort study using the clinical records of non-haemophilia men with human immunodeficiency virus (HIV) who visited the Institute of Medical Science, the University of Tokyo (IMSUT) Hospital, located in Tokyo, Japan, from 2013 to 2022. We analysed 575 patients including 62 heterosexual males and 513 MSM patients, of whom 6.8% (35/513) were injection drug use (IDU). Compared to non-IDU MSM, MSM-IDU had a higher incidence of hepatitis C virus (HCV) (44.8 vs 3.5 /1,000 person-years (PY); incidence rate ratio (IRR) [95% confidence interval (95% CI)], 12.8 [5.5-29.3], p < 0.001) and syphilis (113.8 vs 53.3 /1,000 PY; IRR, 2.1 [1.4-3.1], p < 0.001). The incidence of other symptomatic STIs (amoebiasis, chlamydia, and gonorrhoea infections) was <4/1,000 PY. In multivariable Poisson regression analysis, HCV incidence was associated with MSM (IRR, 1.8 × 106 [9.9 × 105-3.4 × 106], p < 0.001), IDU (IRR, 10.1 [4.0-25.6], p < 0.001), and syphilis infection during the study period (IRR, 25.0 [1.2-518.3]/time/year, p < 0.001). Among men with HIV, the prevalence of IDU in MSM and the long-term incidence of STIs in MSM-IDU were high. IDU and sexual contact are important modes of transmission of HCV among HIV-infected MSM in Tokyo.

Noninvasive approach to indicate risk factors of nonalcoholic steatohepatitis overlapping autoimmune hepatitis based on peripheral lymphocyte pattern.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) clinically includes autoimmunity as indicated by antinuclear antibody (ANA) positivity and overlap of autoimmune hepatitis (AIH). Discriminating AIH-overlap NASH from NAFLD/NASH is required for proper treatment, and typically involves pathological diagnosis by invasive liver biopsy. Differential patterns of peripheral lymphocytes in NAFLD and AIH were assessed to noninvasively indicate risk factors of AIH-overlap NASH by flow cytometry (FCM). METHODS: We assessed the differential frequencies of peripheral lymphocytes in 115 patients: 70 NASH (ANA negative:positive:AIH-overlap = 36:20:14), 18 NAFL, and 27 AIH (acute:chronic = 12:15) patients diagnosed by FCM. We focused on the following populations of lymphocytes: T cells, B cells, natural killer (NK) cells, NKT cells, helper T cell (Th) subsets (Th1, Th2, and Th17), and regulatory T cells; we also examined programmed cell death (PD) 1 and cytotoxic T-lymphocyte antigen levels. RESULTS: Several significant differences in laboratory parameters and peripheral lymphocyte frequencies were found among the NAFLD and AIH subgroups. In univariate and multivariate analyses, hyaluronic acid level, liver stiffness, and the frequencies of Th17 and CD8+ PD1+ T cells were independent risk factors of NASH in NAFLD. Regarding overlap of AIH, only the frequency of CD8+ PD1+ T cells (odds ratio, 0.01; 95% CI 0.00-38.9, p = 0.004) was an independent risk factor in NASH and significantly decreased in AIH. CONCLUSIONS: The decreased frequency of peripheral CD8+ PD1+ T cells is an independent risk factor of NASH overlapping with AIH in the present cohort. Our findings will facilitate development of a new noninvasive FCM method for indicating risk factors of NASH, including autoimmunity.

Treatment and outcome of hepatorenal syndrome in Japan: a retrospective cohort study using a national inpatient database.

BACKGROUND: Hepatorenal syndrome (HRS) is a life-threatening complication of end-stage liver disease. This study aimed to clarify the status of HRS in Japan by analyzing the Japanese Diagnosis Procedure Combination database. METHODS: Patients hospitalized for cirrhosis and HRS from July 2010 to March 2019 were sampled. They were divided into two groups according to their prognosis upon discharge: the transplant-free survival group and the death or liver transplantation group. The two groups' baseline patient characteristics and treatments were compared. RESULTS: The mean age of the 1,412 participants was 67.3 years (standard deviation: 12.3 years), and 65.4% were male. The Child-Pugh grades was B and C in 18.8% and 81.2%, respectively. Hepatocellular carcinoma was present in 27.1% of the patients, and the proportion of spontaneous bacterial peritonitis was 2.3%. Albumin, noradrenaline, and dopamine were administered to 57.9%, 8.0%, and 14.9% of the patients, respectively; 7.0% of the patients underwent renal replacement therapy; and 5.0% were admitted to the intensive care unit. Intravenous antibiotics were administered to 30.8% of the patients. A total of 925 patients (65.5%) died or underwent liver transplantation. In addition to a higher proportion of patients with poor baseline liver function, the death or liver transplantation group included more males, patients with hepatocellular carcinoma, and those with spontaneous bacterial peritonitis. CONCLUSIONS: HRS in Japan has a high mortality rate. Albumin was administered to over 50% of participants. Although noradrenaline is recommended in Japanese clinical guidelines, dopamine was more frequently used as a vasoconstrictor in clinical practice.

Multi-omics of NET formation and correlations with CNDP1, PSPB, and L-cystine levels in severe and mild COVID-19 infections.

The detailed mechanisms of COVID-19 infection pathology remain poorly understood. To improve our understanding of SARS-CoV-2 pathology, we performed a multi-omics and correlative analysis of an immunologically naïve SARS-CoV-2 clinical cohort from blood plasma of uninfected controls, mild, and severe infections. Consistent with previous observations, severe patient populations showed an elevation of pulmonary surfactant levels. Intriguingly, mild patients showed a statistically significant elevation in the carnosine dipeptidase modifying enzyme (CNDP1). Mild and severe patient populations showed a strong elevation in the metabolite L-cystine (oxidized form of the amino acid cysteine) and enzymes with roles in glutathione metabolism. Neutrophil extracellular traps (NETs) were observed in both mild and severe populations, and NET formation was higher in severe vs. mild samples. Our correlative analysis suggests a potential protective role for CNDP1 in suppressing PSPB release from the pulmonary space whereas NET formation correlates with increased PSPB levels and disease severity. In our discussion we put forward a possible model where NET formation drives pulmonary occlusions and CNDP1 promotes antioxidation, pleiotropic immune responses, and vasodilation by accelerating histamine synthesis.

Comparison of two primer-probe sets of Fusobacterium nucleatum using droplet digital polymerase chain reaction for the detection of colorectal neoplasia from faecal samples.

BACKGROUND: Although faecal DNA testing of Fusobacterium nucleatum (Fn) is expected to be useful for colorectal neoplasia detection, there is no standardized quantification method of Fn. We performed this study to establish a possible standardized method. METHODS: In this study, 322 participants including 71 subjects without colorectal neoplasia (control group), 31 patients with non-advanced colorectal adenoma, 93 patients with advanced colorectal adenoma, and 127 patients with colorectal cancer were enrolled. Faecal Fn were quantified by droplet digital PCR (ddPCR) using two PCR primer-probe sets reported previously that are tentatively named Fn1 and Fn2. Fn1 has been used in ddPCR by us and Fn2 has been widely used in quantitative real-time PCR. RESULTS: The Fn copy number using Fn1 was five times higher than that using Fn2, with a linear relationship shown between them. Receiver operating characteristic curve analysis showed the area under the curve (AUC) to be almost the same between Fn1 and Fn2 in discriminating between the control group and the colorectal cancer group (AUC = 0.81 and 0.81, respectively), and between the control/non-advanced colorectal adenoma group and the advanced colorectal adenoma/colorectal cancer group (AUC = 0.74 and 0.74, respectively). CONCLUSIONS: As the diagnostic performance was quite similar between Fn1 and Fn2, ddPCR-based Fn testing using Fn1 and Fn2 could be a possible standardized method for a colorectal neoplasia screening test, considering that Fn levels quantified by Fn1 are about five times higher than those by Fn2.

Casirivimab/Imdevimab for Active COVID-19 Pneumonia Which Persisted for Nine Months in a Patient with Follicular Lymphoma during Anti-CD20 Therapy.

Immunocompromised patients are more likely to develop severe COVID-19, and exhibit high mortality. It is also hypothesized that chronic infection in these patients can be a risk factor for developing new variants. We describe a patient with prolonged active infection of COVID-19 who became infected during treatment with an anti-CD20 antibody (obinutuzumab) for follicular lymphoma. This patient had persistent RT-PCR positivity and live virus isolation for nine months despite treatment with remdesivir and other potential antiviral therapies. The computed tomography image of the chest showed that the viral pneumonia repeatedly appeared and disappeared in different lobes, as if a new infection had occurred continuously. The patient's SARS-CoV-2 antibody titer was negative throughout the illness, even after two doses of the BNT162b2 mRNA vaccine were administered in the seventh month of infection. A combination of monoclonal antibody therapy against COVID-19 (casirivimab and imdevimab) and antivirals resulted in negative RT-PCR results, and the virus was no longer isolated. The patient was clinically cured. During the 9-month active infection period, no fixed mutations in the spike (S) protein were detected, and the in vitro susceptibility to remdesivir was retained. Therapeutic administration of anti-SARS-CoV-2 monoclonal antibodies is essential in immunocompromised patients. Therefore, measures to prevent resistance against these key drugs are urgently needed.

Role of Microbiota in Viral Infections and Pathological Progression.

Viral infections are influenced by various microorganisms in the environment surrounding the target tissue, and the correlation between the type and balance of commensal microbiota is the key to establishment of the infection and pathogenicity. Some commensal microorganisms are known to resist or promote viral infection, while others are involved in pathogenicity. It is also becoming evident that the profile of the commensal microbiota under normal conditions influences the progression of viral diseases. Thus, to understand the pathogenesis underlying viral infections, it is important to elucidate the interactions among viruses, target tissues, and the surrounding environment, including the commensal microbiota, which should have different relationships with each virus. In this review, we outline the role of microorganisms in viral infections. Particularly, we focus on gaining an in-depth understanding of the correlations among viral infections, target tissues, and the surrounding environment, including the commensal microbiota and the gut virome, and discussing the impact of changes in the microbiota (dysbiosis) on the pathological progression of viral infections.

Characterization of the SARS-CoV-2 B.1.621 (Mu) variant.

The SARS-CoV-2 B.1.621 (Mu) variant emerged in January 2021 and was categorized as a variant of interest by the World Health Organization in August 2021. This designation prompted us to study the sensitivity of this variant to antibody neutralization. In a live virus neutralization assay with serum samples from individuals vaccinated with the Pfizer/BioNTech or Moderna mRNA vaccines, we measured neutralization antibody titers against B.1.621, an early isolate (spike 614D), and a variant of concern (B.1.351, Beta variant). We observed reduced neutralizing antibody titers against the B.1.621 variant (3.4- to 7-fold reduction, depending on the serum sample and time after the second vaccination) compared to the early isolate and a similar reduction when compared to B.1.351. Likewise, convalescent serum from hamsters previously infected with an early isolate neutralized B.1.621 to a lower degree. Despite this antibody titer reduction, hamsters could not be efficiently rechallenged with the B.1.621 variant, suggesting that the immune response to the first infection is adequate to provide protection against a subsequent infection with the B.1.621 variant.

HBx-induced degradation of Smc5/6 complex impairs homologous recombination-mediated repair of damaged DNA.

BACKGROUND & AIMS: HBV causes hepatocellular carcinoma (HCC). While it was recently shown that the ability of HBV X protein (HBx) to impair the Smc5/6 (structural maintenance of chromosome 5/6) complex is important for viral transcription, HBx is also a potent driver of HCC. However, the mechanism by which HBx expression induces hepatocarcinogenesis is unclear. METHODS: Degradation of the Smc5/6 complex and accumulation of DNA damage were observed in both in vivo and in vitro HBV infection models. Rescue experiments were performed using nitazoxanide (NTZ), which inhibits degradation of the Smc5/6 complex by HBx. RESULTS: HBx-triggered degradation of the Smc5/6 complex causes impaired homologous recombination (HR) repair of DNA double-strand breaks (DSBs), leading to cellular transformation. We found that DNA damage accumulated in the liver tissue of HBV-infected humanized chimeric mice, HBx-transgenic mice, and human tissues. HBx suppressed the HR repair of DSBs, including that induced by the CRISPR-Cas9 system, in an Smc5/6-dependent manner, which was rescued by restoring the Smc5/6 complex. NTZ restored HR repair in, and colony formation by, HBx-expressing cells. CONCLUSIONS: Degradation of the Smc5/6 complex by HBx increases viral transcription and promotes cellular transformation by impairing HR repair of DSBs. LAY SUMMARY: The hepatitis B virus expresses a regulatory protein called HBV X protein (or HBx). This protein degrades the Smc5/6 complex in human hepatocytes, which is essential for viral replication. We found that this process also plays a key role in the accumulation of DNA damage, which contributes to HBx-mediated tumorigenesis.

Predictors associated with a better response to the Japanese aluminum-free hepatitis A vaccine, Aimmugen® , for people living with HIV.

AIM: After the hepatitis A virus (HAV) outbreak among men who have sex with men (MSM) around 2018, the importance of HAV vaccination was emphasized, especially for MSM-living with human immunodeficiency virus (MSM-LWHIV). Aimmugen® is licensed and distributed exclusively in Japan. While administration of three doses is recommended, 85% of recipients in the general population were reported to acquire seroprotection after the second dose. In this study, we evaluated the efficacy of two or three vaccine doses along with predictors associated with the response to Aimmugen® in MSM-LWHIV. METHODS: We retrospectively examined anti-HA-IgG titers of MSM-LWHIV vaccinated with Aimmugen® in our hospital. Patients' data were collected from medical records. RESULTS: Between January 2018 and October 2019, 141 subjects whose median age was 46 years old, were examined. All the subjects were on antiretroviral therapy (ART) and the median CD4 count was 615/µL. The acquisition rate of protectable anti-HA-IgG titers after the second and third dose was 71.1% and 98.6%, respectively. In 114 subjects whose anti-HA-IgG titers were tested after the second-dose, factors significantly associated with better response were prolonged ART duration and higher CD4 count. The titers of anti-HA-IgG after the third dose were higher in those who became seropositive after the second-dose than those who did not. CONCLUSIONS: Three-dose of Aimmugen® for MSM-LWHIV was effective while two-dose was less effective compared to non-HIV-infected people. People-LWHIV with shorter duration of ART and lesser CD4 cell count achieved lower titers of anti-HA-IgG and might require an additional vaccination.

Changes in survival and causes of death among people living with HIV: Three decades of surveys from Tokyo, one of the Asian metropolitan cities.

INTRODUCTION: Survival among people living with HIV (PLWH) has dramatically improved in the antiretroviral therapy (ART) era. This is the first study in Asia to describe three decades of surveys on survival and causes of death among PLWH. METHODS: We included 1121 HIV-infected patients, categorized into three period groups according to date of first visit: 1986-1996 (Pre-ART); 1997-2007 (Early-ART); and 2008-2018 (Late-ART). RESULTS: Ten-year all-cause mortality has reduced from Pre-ART (49.6/1000 person-years) to Late-ART (6.3/1000 person-years). Mortality for AIDS-defining illnesses (ADIs) has also reduced from Pre-ART (34.4/1000 person-years) to Late-ART (2.9/1000 person-years), and mortality for non-ADIs has reduced from Pre-ART (11.7/1000 person-years) to Late-ART (2.9/1000 person-years). In the ART-era, deaths from non-AIDS-defining malignancies and unnatural events including suicide represented the majority of non-ADI-related deaths and mortality rates of non-AIDS defining malignancies and unnatural cause event were not different between each group (3.4, 1.9 and 2.5/1000 person-years). Crude cumulative survival improved over the study period, and 10-year survival ratios of HIV-infected patients to the general Japanese population approached 1.00, from Pre-ART (0.66) to Late-ART (0.99). Even in the Late-ART period, survival remained lower in patients with a history of ADIs than in those without, but the difference in 5-year mortality between these groups has shrunk in the Late-ART compared to the Pre-ART. CONCLUSIONS: Mortality for ADIs and non-ADIs in PLWH has reduced in the Early-ART and Late-ART. To improve survival for PLWH further, early HIV detection and treatment and good management of non-AIDS-defining malignancies and mental disorders are needed. (248/250).

The Oncogenic Role of Hepatitis C Virus.

Persistent infection with hepatitis C virus (HCV) is a major risk factor for hepatocellular carcinoma (HCC). Accumulating evidence suggests that not only inflammation and subsequent fibrosis but also HCV itself are associated with hepatocarcinogenesis. To date, studies using transgenic mouse and cell-culture models, in which HCV proteins are expressed, indicate the direct pathogenicity of HCV, including oncogenic activity. In particular, the core protein of HCV induces excessive oxidative stress by impairing the mitochondrial electron transfer system by disrupting the function of the molecular chaperone, prohibitin. HCV also modulates intracellular signaling pathways, including mitogen-activated protein kinase, promoting the proliferation of hepatocytes. In addition, HCV induces disorders in lipid and glucose metabolism, thereby accelerating the progression of liver fibrosis and the development of HCC. Due to the development of direct-acting antivirals, which was made possible by basic research, HCV can be eradicated from almost all infected patients. However, such patients can develop HCC long after eradication of HCV, suggesting the genetic and/or epigenetic changes induced by HCV may be persistent. These results enhance our understanding of the role of HCV in hepatocarcinogenesis and will facilitate the development of therapeutic and preventive strategies for HCV-induced HCC.

Fecal DNA Testing of TWIST1 Methylation Identifies Patients With Advanced Colorectal Adenoma Missed by Fecal Immunochemical Test for Hemoglobin.

INTRODUCTION: We have reported previously that fecal DNA testing of TWIST1 methylation in combination with the fecal immunochemical test for hemoglobin (FIT) (combination test) is useful for colorectal neoplasia screening. In this study, using larger sample sizes, we studied the clinical performance of the combination test for the detection of colorectal neoplasia and, especially, advanced colorectal adenoma. METHODS: We performed a prospective study in which FIT, fecal DNA testing of TWIST1 methylation, and colonoscopy were performed on 372 patients with colorectal neoplasia and 71 subjects without colorectal neoplasia. We assessed the individual clinical performance of each of FIT and fecal DNA testing of TWIST1 methylation and of the combination test for the detection of colorectal neoplasia including advanced adenoma based on morphologic subtypes. RESULTS: The FIT alone had a sensitivity of 7.5% (3/40) for nonadvanced adenoma, 32.3% (41/127) for advanced adenoma, and 93.7% (192/205) for colorectal cancer and a specificity of 87.3% (62/71). The combination test had a sensitivity of 35.0% (14/40) for nonadvanced adenoma, 68.5% (87/127) for advanced adenoma, and 95.6% (196/205) for colorectal cancer and a specificity of 80.3% (57/71). For morphological subtypes of advanced adenoma, the sensitivity of FIT was only 28.2% (20/71) for polypoid type and 16.1% (5/31) for nonpolypoid type, whereas the combination test increased the sensitivities to 64.8% (46/71) and 71.0% (22/31), respectively. DISCUSSION: The combination of the fecal DNA test with FIT seemed to be useful to detect colorectal neoplasia and, especially, advanced adenoma of the nonpolypoid type.

Prevalence of Hepatitis A Immunity and Decision-tree Analysis Among Men Who Have Sex With Men and Are Living With Human Immunodeficiency Virus in Tokyo.

BACKGROUND: Hepatitis A virus (HAV) can be sexually transmitted. However, the level of HAV immunity among patients living with human immunodeficiency virus (HIV) in Japan is unknown. Determining the epidemiology of HAV infections among men who have sex with men (MSM) and who are living with HIV is essential for an HAV vaccination program. This study examined HAV immunity in patients living with HIV and applied the decision-tree analysis to explore the factors of immunoglobulin G (IgG)-hepatitis A (HA) antibodies in MSM living with HIV. METHODS: We examined the presence of IgG-HA antibodies among patients living with HIV from January to December 2017 in The Hospital of The Institute of Medical Science, The University of Tokyo. We recorded each patient's age, sex, mode of HIV transmission, year of HIV diagnosis, HAV vaccine status, history of HAV infection, and history of other infectious diseases. A decision-tree algorithm was used to reveal the factors and profiles most relevant to the anti-HAV prevalence. RESULTS: Overall, 378 MSM patients living with HIV were examined for IgG-HA antibodies. After excluding 24 patients who had received a HAV vaccine, the data of 354 MSM were analyzed (median age 45 years, interquartile range 39-51 years). Of the 354 patients, 60 (16.9%) were positive for IgG-HA antibodies. The HA positivity rate increased with patients' age, and age (> 63.5 years) was extracted as the most important variable by classification of the decision-tree algorithm. CONCLUSIONS: Our study, conducted just before the HAV outbreak among MSM in Tokyo, showed that age was the most relevant factor in anti-HAV prevalences. An extensive HAV vaccination program for MSM patients living with HIV is urgently needed, particularly for younger people.

Hepatic FATP5 expression is associated with histological progression and loss of hepatic fat in NAFLD patients.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are characterized by the accumulation of excess hepatic fat. However, in the progression from NASH to cirrhosis, hepatic fat is often lost. Our aim was to elucidate the mechanism underlying hepatic fat loss during NASH progression. METHODS: Liver biopsies were performed at The University of Tokyo Hospital between November 2011 and March 2016 on 146 patients with NAFLD and 14 patients with cryptogenic cirrhosis who were not being treated with any diabetes or dyslipidemia drugs. Among them, 70 patients underwent liver biopsy after an overnight fast, and 90 patients were biopsied 5 h after an oral glucose tolerance test. Expression differences in genes encoding several fatty acid metabolism-related factors were examined and correlated with hepatic histological changes based on NAFLD activity scores. Prospective patient follow-up continued until June 2018. RESULTS: The level of fatty acid transport protein 5 (FATP5), which is associated with free fatty acid intake, was significantly and inversely correlated with features of histological progression, including ballooning and fibrosis. This was confirmed by immunohistochemical analysis. Transcript levels of genes encoding fatty acid metabolism-related proteins were comparable between NASH with severe fibrosis and cryptogenic cirrhosis. Furthermore, a prospective cohort study demonstrated that low FATP5 expression was the most significant risk factor for hepatic fat loss. CONCLUSIONS: Decreased hepatic FATP5 expression in NAFLD is linked to histological progression, and may be associated with hepatic fat loss during NASH progression to cirrhosis.

CD4/CD8 ratio predicts the cellular immune response to acute hepatitis C in HIV-coinfected adults.

Hepatitis C virus (HCV) coinfection is a strong risk factor for death of HIV-infected patients. Immune dysfunction affects the clinical course of acute hepatitis C (AHC). CD4/CD8 ratio is a biomarker of both persistent inflammation and immunosenescence in HIV-infected adults on effective antiretroviral therapy. A low CD4/CD8 ratio predicts immunosenescence and is associated with increased morbidity and mortality in both HIV-infected adults and elderly HIV-uninfected adults. Additionally, immunosenescence is associated with unresponsiveness to vaccine and could affect the immune reaction to pathogens during their primary infection. We retrospectively evaluated 12 AHC patients to assess the association between CD4/CD8 ratio and liver damage in AHC. We used the Spearman rank correlation test to assess the correlation. We found that CD4/CD8 ratio and peak alanine aminotransferase level (peak ALT) were positively correlated (r = 0.8322, p = 0.0013). The CD4 counts did not correlate with peak ALT (r = 0.5245, p = 0.0839). CD8+ T cells expansion for AHC did not affect these results, because the CD4/CD8 ratio before the onset of AHC and peak ALT positively correlate (n = 11; r = 0.7909, p = 0.0055) and there was no significant difference between CD4/CD8 ratios before and after the onset of AHC (n = 11; p = 0.9766). Immunosenescence may be negatively associated with the cellular immune response to acute HCV infection. We suggest that clinicians consider using CD4/CD8 ratio as a marker of immunosenescence in their management of patients with HIV infection and other complications.

Noninvasive diagnostic criteria for nonalcoholic steatohepatitis based on gene expression levels in peripheral blood mononuclear cells.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) consists of nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH); the latter progresses to liver cirrhosis and hepatocellular carcinoma. Discriminating NASH from NAFL typically involves liver biopsy. The mechanism of NASH progression is unclear but may involve immunological pathways. In this study, we examined expression levels of cytokine- and chemokine-encoding genes in peripheral blood mononuclear cells (PBMCs) from NAFLD patients and established immunological criteria for discriminating NASH from NAFL. METHODS: PBMCs were obtained from 54 patients diagnosed histologically with NAFLD (NAFL, 18; NASH, 36). mRNA was extracted from PBMCs, and expression levels of cytokine- and chemokine-encoding genes were determined by quantitative real-time PCR. Statistical analysis was performed by nonparametric test. RESULTS: Expression levels of interferon (IFN)γ, interleukin (IL)2, IL15, C-C-motif chemokine ligand (CCL)2, IL10, and C-X-C-motif chemokine ligand (CXCL)11 were significantly upregulated in NASH patients compared with NAFL patients. Moreover, their expression levels were positively correlated with the degree of ballooning of hepatocytes but not of steatosis or lobular inflammation. We focused on those encoding IL10, IFNγ, and CCL2, and developed a scoring system to discriminate NASH from NAFL. The discriminatory power of the criteria was validated in an independent cohort. CONCLUSIONS: Expression levels of the cytokine- and chemokine-encoding genes in PBMCs were positively correlated with ballooning, suggesting their utility for the diagnosis of NASH. The data indicate that peripheral as well as intrahepatic immunity is involved in the progression of NASH. Our findings afford new insight into immunological mechanisms of NASH and will facilitate its noninvasive diagnosis.

Helicobacter pylori infection and liver diseases: Epidemiology and insights into pathogenesis.

Both Helicobacter pylori (H. pylori) infection and liver diseases, including nonalcoholic fatty liver disease (NAFLD), viral hepatitis, and hepatocellular carcinoma (HCC), have high prevalences worldwide, and the relationship between H. pylori infection and liver disease has been discussed for many years. Although positive correlations between H. pylori and NAFLD have been identified in some clinical and experimental studies, negative correlations have also been obtained in high-quality clinical studies. Associations between H. pylori and the pathogenesis of chronic viral hepatitis, mainly disease progression with fibrosis, have also been suggested in some clinical studies. Concerning HCC, a possible role for H. pylori in hepatocarcinogenesis has been identified since H. pylori genes have frequently been detected in resected HCC specimens. However, no study has revealed the direct involvement of H. pylori in promoting the development of HCC. Although findings regarding the correlations between H. pylori and liver disease pathogenesis have been accumulating, the existing data do not completely lead to an unequivocal conclusion. Further high-quality clinical and experimental analyses are necessary to evaluate the efficacy of H. pylori eradication in ameliorating the histopathological changes observed in each liver disease.

Dysregulation of miRNA in chronic hepatitis B is associated with hepatocellular carcinoma risk after nucleos(t)ide analogue treatment.

Hepatitis B virus (HBV) infection is a major cause of hepatocellular carcinoma (HCC). Nucleos(t)ide analogue (NA) therapy effectively reduces the incidence of HCC, but it does not completely prevent the disease. Here, we show that dysregulation of microRNAs (miRNAs) is involved in post-NA HCC development. We divided chronic hepatitis B (CHB) patients who received NA therapy into two groups: 1) those who did not develop HCC during the follow-up period after NA therapy (no-HCC group) and 2) those who did (HCC group). miRNA expression profiles were significantly altered in CHB tissues as compared to normal liver, and the HCC group showed greater alteration than the no-HCC group. NA treatment restored the miRNA expression profiles to near-normal in the no-HCC group, but it was less effective in the HCC group. A number of miRNAs implicated in HCC, including miR-101, miR-140, miR-152, miR-199a-3p, and let-7g, were downregulated in CHB. Moreover, we identified CDK7 and TACC2 as novel target genes of miR-199a-3p. Our results suggest that altered miRNA expression in CHB contributes to HCC development, and that improvement of miRNA expression after NA treatment is associated with reduced HCC risk.