Serum amyloid A is a better predictive biomarker of mucosal healing than C-reactive protein in ulcerative colitis in clinical remission.

BACKGROUND: Many studies have revealed that mucosal healing improves the long-term prognosis of ulcerative colitis. Frequent colonoscopy is difficult because of its invasiveness and cost. Therefore, in diagnosing and treating ulcerative colitis, noninvasive, low-cost methods for predicting mucosal healing using useful biomarkers are required in the clinical setting. This study aimed to evaluate whether serum amyloid A is a better serum biomarker than C-reactive protein in predicting mucosal healing in ulcerative colitis patients in clinical remission. METHODS: Ulcerative colitis patients whose C-reactive protein and serum amyloid A were measured within 1 month before and after colonoscopy were included in this retrospective study, and the relationship between the C-reactive protein and serum amyloid A values and the mucosal condition was analyzed. Mucosal condition was assessed using the Mayo Endoscopic Score, with score 0 or 1 indicating mucosal healing. RESULTS: A total of 199 colonoscopic examinations were conducted in 108 ulcerative colitis patients who underwent C-reactive protein and serum amyloid A blood tests. In clinical remission patients, serum amyloid A showed a strong correlation with mucosal inflammation compared to C-reactive protein and had excellent sensitivity and specificity rates with significant statistical significance. CONCLUSIONS: Serum amyloid A is a more useful marker compared to C-reactive protein in predicting mucosal inflammation in ulcerative colitis patients in clinical remission.

CTL-associated and NK cell-associated immune responses induce different HBV DNA reduction patterns in chronic hepatitis B patients.

The activation of hepatitis B virus (HBV)-related hepatitis is associated with both natural killer (NK) cells and cytotoxic T lymphocytes (CTLs). We analyzed the association between the immune response and changes in the proportion of Pre-S deletion variants. We quantified Pre-S deleted HBV (HBV-del) and wild-type HBV (HBV-wt) DNA levels in sera obtained from HBV-infected mice and chronic hepatitis B patients. In chronic hepatitis B patients, the HBV-del proportion usually increased during or after ALT elevation but did not occur during all ALT elevations. To clarify this difference in the immunological responses, we performed in vivo analyses using HBV-infected human hepatocyte chimeric mice. Although HBV-del proportions did not change in mice with NK cell-associated hepatitis or in mice treated with entecavir, the proportions sharply increased in mice with CTL-associated hepatitis. Furthermore, the number of patients in which HBV-del proportions were greater than 5% was significantly higher in chronic hepatitis B patients than in asymptomatic carriers (P = 0.023). We identified associations between virological response in chronic hepatitis B patients and two different immune responses. The proportion of HBV-del variants could be a useful biomarker for distinguishing between chronic hepatitis and asymptomatic carriers.

Rectal Lymphoid Follicle Aphthous Lesions Frequently Progress to Ulcerative Colitis with Proximal Extension.

Objective Rectal lymphoid follicular aphthous (LFA) lesions are related to ulcerative colitis (UC) and can be initial lesions of UC. We investigated the clinical course and prognosis of rectal LFA lesions. Methods This is a retrospective analysis of the clinical records at a single center. Patients Thirteen consecutive cases with LFA lesions treated at Hiroshima University Hospital between 1998 and 2015 were evaluated. Another 49 consecutive cases with ulcerative proctitis treated in the same period were enrolled as the control group. The clinical course and prognosis of both groups were evaluated. Results The group with LFA lesions included 9 women and 4 men with a median age of 39.9 years (range, 21-70 years). A total of 11 cases progressed to typical UC at 5-51 months. Proximal extension of these typical UC lesions was observed in 7 (53.8%) cases, which was significantly higher than in the control group (10 cases, 20.8%). Three cases (5-year accumulation incidence rate, 27.3%) progressed to steroid-intractable UC, a significantly higher incidence than that of the control group (3 cases; 5-year accumulation incidence rate, 6.9%). Conclusion Rectal LFA lesions frequently progress to typical UC with proximal extension, some of which become intractable to corticosteroid treatment.

Comparison of intracellular responses between HBV genotype A and C infection in human hepatocyte chimeric mice.

BACKGROUND AND AIMS: The clinical course and responsiveness to antiviral treatments differs among hepatitis B virus (HBV) genotypes. However, the cause of these differences is unclear. In the present study, we compared mRNA expression profiles in human hepatocyte chimeric mice infected with HBV genotypes A and C. METHODS: Fifteen chimeric mice were prepared and divided into the following three groups: uninfected control mice, HBV genotype A-infected mice, and HBV genotype C-infected mice. Human hepatocytes were collected from these mouse livers and gene expression analyses were performed using next-generation RNA sequencing. RESULTS: Although similar pathways were influenced by HBV infection, including inflammation mediated by chemokine and cytokine signaling, p53, and integrin signaling pathways, expression levels of up-regulated genes by HBV genotype A or C infection were quite different. In HBV genotype A-infected hepatocytes, 172 genes, including KRT23 and C10orf54, were significantly more highly expressed than in HBV genotype C-infected cells, whereas 10 genes, including SPX and IER3, were expressed at significantly lower levels. Genes associated with the p53 pathway and the inflammation mediated by chemokine and cytokine signaling pathway were more highly expressed in cells with HBV genotype A infection, whereas genes associated with CCKR signaling map and oxidative stress response were more highly expressed in cells with HBV genotype C infection. CONCLUSION: Several differences in gene expression with respect to HBV genotype A and C infection were detected in human hepatocytes. These differences might be associated with genotypic difference in the clinical course or responsiveness to treatment.

Endoplasmic reticulum-mediated induction of interleukin-8 occurs by hepatitis B virus infection and contributes to suppression of interferon responsiveness in human hepatocytes.

The events in the immune response to hepatitis B virus (HBV) remain unclear. We analyzed the direct influence of HBV on gene expression in human hepatocytes under immunodeficient conditions using a human hepatocyte chimeric mouse model. HBV-infected or non-infected chimeric mouse livers were collected, and gene expression profiles were compared. Since IL-8 was the most significantly up-regulated gene at 8 weeks after HBV infection, we focused on IL-8 and found that HBx and the large HBs (L-HBs) protein induce transcription of IL-8 via endoplasmic reticulum stress. This stress induces IL-8 transcription via NFAT activation and contributes to suppression of interferon responsiveness in HBV-infected human hepatocytes. In the present study, we identified a novel regulatory mechanism in which the L-HBs protein activates IL-8 via endoplasmic reticulum stress, suggesting a key role for IL-8 in the immune response to HBV and a potential new target for antiviral treatments of HBV infection.

Reduction of hepatitis B surface antigen in sequential versus add-on pegylated interferon to nucleoside/nucleotide analogue therapy in HBe-antigen-negative chronic hepatitis B patients: a pilot study.

BACKGROUND: Although pegylated interferon (PEG-IFN) and nucleotide/nucleoside analogue (NA) combination therapy is considered to be optimal for accelerating serum hepatitis B surface antigen (HBsAg) reduction, the effect is limited, and the best approach to PEG-IFN treatment for chronic hepatitis B patients during long-term NA therapy has yet to be determined. METHODS: A total of 21 hepatitis B e antigen-negative chronic hepatitis B patients whose HBV DNA levels were suppressed to undetectable levels by NA therapy were administrated PEG-IFN-α2a for 48 weeks (sequential therapy: 10, add-on therapy: 11). Factors associated with HBsAg reduction by PEG-IFN therapy were analysed. RESULTS: During PEG-IFN treatment, HBsAg levels were reduced by 0.48 log IU/ml. More than 1 log IU/ml of HBsAg reduction was observed in eight patients (sequential therapy: six, add-on therapy: two), and one patient with sequential therapy achieved HBsAg loss. By univariate analysis, sequential therapy was marginally associated with more than 1 log IU/ml HBsAg reduction during PEG-IFN treatment (P=0.060). After PEG-IFN treatment, only five patients, including the patient with HBsAg loss, achieved more than 0.5 log IU/ml of HBsAg reduction by 1 year after PEG-IFN treatment. By univariate analysis, sequential therapy was significantly associated with HBsAg reduction after PEG-IFN treatment (P=0.012). In addition, alanine aminotransferase elevation during PEG-IFN therapy and lower serum interleukin-8 level at the end of PEG-IFN treatment were also significantly associated with HBsAg reduction by 1 year after PEG-IFN treatment (P=0.038, P=0.044, respectively). CONCLUSIONS: Sequential therapy may be superior to add-on therapy in reducing HBsAg levels during long-term NA therapy in chronic hepatitis B patients.