Association of liver fibrosis with extrahepatic cancer in steatotic liver disease patients with PNPLA3 I148M GG genotype.

The impacts of patatin-like phospholipase domain-containing protein 3 (PNPLA3) I148M-rs738409, methylenetetrahydrofolate reductase (MTHFR) Ala222Val-rs1801133, and aldehyde dehydrogenase 2 (ALDH2) Glu504Lys-rs671 on the outcomes of Taiwanese patients with steatotic liver disease (SLD) have remained elusive. An 8-year prospective cohort study of patients with (n = 546) and without (n = 580) SLD (controls) was undertaken in a Taiwanese tertiary care center. The 546 SLD patients comprised 306 (56.0%) men and 240 (44.0%) women with mean ages of 53.3 and 56.4 years, respectively. Compared with the controls, SLD patients had an increased frequency of the PNPLA3 I148M-rs738409 GG genotype (25.5 vs. 5.9%, p = 0.001). Among the SLD patients, 236 (43.1%) suffered cardiovascular events, 52 (9.5%) showed extrahepatic cancers, 13 (2.38%) experienced hepatic events, including hepatocellular carcinoma (n = 3, 0.5%) and liver cirrhosis (n = 8, 1.47%), and none died. The Fibrosis-4 (FIB-4) scores were associated with extrahepatic cancer (hazard ratio [HR] 1.325; 95% confidence interval [CI], 1.038-1.691) and cirrhosis development (HR 1.532; 95% CI, 1.055-2.224), and the PNPLA3 I148M-rs738409 G allele (ß = 0.158, 95% CI, 0.054-0.325) was associated with the FIB-4 score. Stratified analyses showed that the impact of the FIB-4 score on extrahepatic cancer development was evident only in SLD patients with the PNPLA3 I148M-rs738409 GG genotype (HR 1.543; 95% CI, 1.195-1.993) and not in patients with the GC or CC genotype. Moreover, the ALDH2 Glu504Lys-rs671 G allele had a dose-dependent effect on alcoholism, and the MTHFR and ALDH2 genotypes were not significantly associated with SLD patient outcomes. In conclusion, special vigilance should be exercised for emerging extrahepatic cancer in SLD patients with the PNPLA3 I148M-rs738409 GG genotype and high FIB-4 scores.

PolyAtailor: measuring poly(A) tail length from short-read and long-read sequencing data.

The poly(A) tail is a dynamic addition to the eukaryotic mRNA and the change in its length plays an essential role in regulating gene expression through affecting nuclear export, mRNA stability and translation. Only recently high-throughput sequencing strategies began to emerge for transcriptome-wide profiling of poly(A) tail length in diverse developmental stages and organisms. However, there is currently no easy-to-use and universal tool for measuring poly(A) tails in sequencing data from different sequencing protocols. Here we established PolyAtailor, a unified and efficient framework, for identifying and analyzing poly(A) tails from PacBio-based long reads or next generation short reads. PolyAtailor provides two core functions for measuring poly(A) tails, namely Tail_map and Tail_scan, which can be used for profiling tails with or without using a reference genome. Particularly, PolyAtailor can identify all potential tails in a read, providing users with detailed information such as tail position, tail length, tail sequence and tail type. Moreover, PolyAtailor integrates rich functions for poly(A) tail and poly(A) site analyses, such as differential poly(A) length analysis, poly(A) site identification and annotation, and statistics and visualization of base composition in tails. We compared PolyAtailor with three latest methods, FLAMAnalysis, FLEPSeq and PAIsoSeqAnalysis, using data from three sequencing protocols in HeLa samples and Arabidopsis. Results show that PolyAtailor is effective in measuring poly(A) tail length and detecting significance of differential poly(A) length, which achieves much higher sensitivity and accuracy than competing methods. PolyAtailor is available at https://github.com/BMILAB/PolyAtailor.

Factors associated with treatment responses to pioglitazone in patients with steatotic liver disease: A 3-year prospective cohort study.

AIM: The response rate to pioglitazone and the predictive factors for its effects on improving liver biochemistry in patients with steatotic liver disease (SLD) remain elusive, so we aimed to investigate these issues. METHODS: A 3-year prospective cohort study of 126 Taiwanese patients with SLD treated with pioglitazone (15-30 mg/day) was conducted. Phospholipase domain-containing protein 3 I148M rs738409, methylenetetrahydrofolate reductase rs1801133, aldehyde dehydrogenase 2 (ALDH2) rs671 and lipoprotein lipase rs10099160 single nucleotide polymorphisms were assessed in the patients. RESULTS: Of 126 patients, 78 (61.9%) were men, and the mean and median ages were 54.3 and 56.5 years, respectively. Pioglitazone responders were defined as those with decreased alanine aminotransferase (ALT) levels at 6 months post-treatment, and 105 (83.3%) patients were responders. Compared with non-responders, responders were more frequently women and had higher baseline ALT levels. The proportion of patients with the ALDH2 rs671 GG genotype was lower among responders (38.6% vs. 66.6%, p = .028). Female sex [odds ratio (OR): 4.514, p = .023] and baseline ALT level (OR: 1.015, p = .046; cut-off level: ≥82 U/L) were associated with pioglitazone response. Among responders, the liver biochemistry and homeostasis model assessment of insulin resistance improved from 6 to 24 months post-treatment. The total cholesterol levels decreased within 6 months, while increases in high-density lipoprotein cholesterol levels and decreases in triglyceride levels and fibrosis-4 scores were noted only at 24 months post-treatment. The 2-year cumulative incidences of cardiovascular events, cancers and hepatic events were similar between responders and non-responders. CONCLUSIONS: Regarding liver biochemistry, over 80% of Taiwanese patients with SLD had a pioglitazone response, which was positively associated with female sex and baseline ALT levels. Insulin resistance improved as early as 6 months post-treatment, while liver fibrosis improvement was not observed until 24 months post-treatment. The link between the pioglitazone response and the ALDH2 genotype warrants further investigation.

The effect of a pay-for-performance program on health-related quality of life for patients with hepatitis in Taiwan.

PURPOSE: Chronic viral hepatitis is a major global public health problem. The guidelines suggest the long-term performance of regular ongoing liver examinations to monitor liver inflammation and screen for hepatocellular carcinoma. However, the effects of regular liver examinations on health-related quality of life (HRQoL) have not been adequately evaluated. Therefore, this study evaluated the effects of regular ongoing examinations on the quality of life of patients with hepatitis. METHODS: A cross-sectional study was conducted from October to December 2016 in four hospitals in northern Taiwan. A hepatitis pay-for-performance (P4P) program was launched in 2010 to ensure that hepatitis patients have regular ongoing liver examinations. The study group consisted of patients who joined and stayed in the program for more than one year. The study assessed HRQoL utilizing the five-level version of the EuroQol-5 Dimension (EQ-5D-5L) and the EuroQoL visual analog scale (EQ-VAS). The responses for the EQ-5D-5L in hepatitis patients were transformed into the EQ-5D index according to the Taiwanese population's value set. Sociodemographic and clinical characteristics were collected by questionnaire, and descriptive statistics were presented. A two-part model and generalized linear model with a Poisson distribution and a log link function, respectively, were used to examine the associations of the EQ-5D index and EQ-VAS score with participation in the hepatitis P4P program. We applied propensity score weighting with inverse probability weighting to control for selection bias. RESULTS: In all, 508 patients (aged 57.6 ± 11.6 years; 60.8% male) were enrolled in this study. The mean (standard deviation, SD) reported EQ-5D index and EQ-VAS scores were 0.93 (0.12) and 75.1 (13.8), and the median (interquartile range, IQR) values were 1 (0.108) and 80 (15), respectively. The study group had a moderately significantly higher EQ-VAS score (mean ratio = 1.029, P < 0.001). However, the differences in the EQ-5D index scores between the study and control groups were not significant. CONCLUSION: Patients with hepatitis partially benefited from receiving hepatitis P4P in Taiwan, which featured regular ongoing liver examinations, in that their EQ-VAS scores were enhanced but not their EQ-5D index scores.

Ropeginterferon Alfa-2b administered every two weeks for patients with genotype 2 chronic hepatitis C.

BACKGROUND: Ropeginterferon alfa-2b is a novel mono-pegylated interferon that has only one major form as opposed to the 8 to 14 isomers of other on-market pegylated interferon products, allowing every-two-week injection with high tolerability. It received European Medicines Agency marketing authorization in 2019 and Taiwan Biologics License Applications Approval in 2020 for the treatment of polycythemia vera. This study aimed to evaluate the safety and efficacy of Ropeginterferon alfa-2b plus ribavirin in genotype 2 chronic hepatitis C (CHC) patients. METHODS: Eighty-six treatment naive patients with genotype 2 CHC were randomized to weekly peginterferon alfa-2a (Peg-IFN-α2a) at 180 µg (n = 22), or every-two-week Ropeginterferon alfa-2b at 270 µg (n = 23), 360 µg (n = 21), 450 µg (n = 20), plus daily oral ribavirin 1000 mg (≤75 kg) or 1200 mg (>75 kg). Patients with rapid virologic response received 16-week regimen while those without RVR received 24-week regimen. The primary endpoint was sustained virologic response at 24 weeks post-treatment (SVR24). RESULTS: SVR24 was achieved by 95.5%, 78.3%, 85.7%, and 60% of subjects in Peg-IFN-α2a 180 µg, Ropeginterferon alfa-2b 270 µg, 360 µg, and 450 µg groups, respectively. The safety profile was similar across 4 groups. The incidence rate of adverse event during the treatment period was 0.407, 0.252, 0.395, and 0.347 per patient-week, respectively. CONCLUSION: Ropeginterferon alfa-2b, although at only half the number of injections, is as safe and effective as Peg-IFN-α2a for genotype 2 CHC. A phase 3 study to confirm safety and efficacy of Ropeginterferon alfa-2b in genotype 2 CHC is ongoing.

Triple-negative breast cancer with calcified metastases of hepatic, portal vein and inferior vena cava: Report of a case and review of the literature.

Breast cancer frequently metastasizes to the liver and this usually bears a poor prognosis. Complete calcifications of hepatic, portal vein and inferior vena cava (IVC) metastases from breast cancer after systemic chemotherapy is extremely rare and to our knowledge, has never been reported. It is important for physicians to recognize the pattern and the formation of calcified liver metastases because the radiographic features of calcifications may assist in differentiating the etiologies of underlying malignancies and provide prognostic significance. We here presented such a case of triple negative breast cancer (TNBC) with calcified liver, portal vein and IVC metastases, and reviewed the literature.

Roles of Adipokines in Digestive Diseases: Markers of Inflammation, Metabolic Alteration and Disease Progression.

Adipose tissue is a highly dynamic endocrine tissue and constitutes a central node in the interorgan crosstalk network through adipokines, which cause pleiotropic effects, including the modulation of angiogenesis, metabolism, and inflammation. Specifically, digestive cancers grow anatomically near adipose tissue. During their interaction with cancer cells, adipocytes are reprogrammed into cancer-associated adipocytes and secrete adipokines to affect tumor cells. Moreover, the liver is the central metabolic hub. Adipose tissue and the liver cooperatively regulate whole-body energy homeostasis via adipokines. Obesity, the excessive accumulation of adipose tissue due to hyperplasia and hypertrophy, is currently considered a global epidemic and is related to low-grade systemic inflammation characterized by altered adipokine regulation. Obesity-related digestive diseases, including gastroesophageal reflux disease, Barrett's esophagus, esophageal cancer, colon polyps and cancer, non-alcoholic fatty liver disease, viral hepatitis-related diseases, cholelithiasis, gallbladder cancer, cholangiocarcinoma, pancreatic cancer, and diabetes, might cause specific alterations in adipokine profiles. These patterns and associated bases potentially contribute to the identification of prognostic biomarkers and therapeutic approaches for the associated digestive diseases. This review highlights important findings about altered adipokine profiles relevant to digestive diseases, including hepatic, pancreatic, gastrointestinal, and biliary tract diseases, with a perspective on clinical implications and mechanistic explorations.

Aryl hydrocarbon receptor agonist indigo protects against obesity-related insulin resistance through modulation of intestinal and metabolic tissue immunity.

BACKGROUND/OBJECTIVES: Low-grade chronic inflammation in visceral adipose tissue and the intestines are important drivers of obesity associated insulin resistance. Bioactive compounds derived from plants are an important source of potential novel therapies for the treatment of chronic diseases. In search for new immune based treatments of obesity associated insulin resistance, we screened for tissue relevant anti-inflammatory properties in 20 plant-based extracts. METHODS: We screened 20 plant-based extracts to assess for preferential production of IL-10 compared to TNFα, specifically targetting metabolic tissues, including the visceral adipose tissue. We assessed the therapeutic potential of the strongest anti-inflammatory compound, indigo, in the C57BL/6J diet-induced obesity mouse model with supplementation for up to 16 weeks by measuring changes in body weight, glucose and insulin tolerance, and gut barrier function. We also utilized flow cytometry, quantitative PCR, enzyme-linked immunosorbent assay (ELISA), and histology to measure changes to immune cells populations and cytokine profiles in the intestine, visceral adipose tissue (VAT), and liver. 16SrRNA sequencing was performed to examine gut microbial differences induced by indigo supplementation. RESULTS: We identifed indigo, an aryl hydrocarbon receptor (AhR) ligand agonist, as a potent inducer of IL-10 and IL-22, which protects against high-fat diet (HFD)-induced insulin resistance and fatty liver disease in the diet-induced obesity model. Therapeutic actions were mechanistically linked to decreased inflammatory immune cell tone in the intestine, VAT and liver. Specifically, indigo increased Lactobacillus bacteria and elicited IL-22 production in the gut, which improved intestinal barrier permeability and reduced endotoxemia. These changes were associated with increased IL-10 production by immune cells residing in liver and VAT. CONCLUSIONS: Indigo is a naturally occurring AhR ligand with anti-inflammatory properties that effectively protects against HFD-induced glucose dysregulation. Compounds derived from indigo or those with similar properties could represent novel therapies for diseases associated with obesity-related metabolic tissue inflammation.

Traditional Chinese medicine use is associated with lower end-stage renal disease and mortality rates among patients with diabetic nephropathy: a population-based cohort study.

BACKGROUND: Diabetic nephropathy (DN) is a common complication of diabetes mellitus (DM) that imposes an enormous burden on the healthcare system. Although some studies show that traditional Chinese medicine (TCM) treatments confer a protective effect on DN, the long-term impact remains unclear. This study aims to examine end-stage renal disease (ESRD) and mortality rates among TCM users with DN. METHODS: A total of 125,490 patients with incident DN patients from 2004 to 2006 were identified from the National Health Insurance Research Database in Taiwan and followed until 2012. The landmark method was applied to avoid immortal time bias, and propensity score matching was used to select 1:1 baseline characteristics-matched cohort. The Kaplan-Meier method and competing-risk analysis were used to assess mortality and ESRD rates separately. RESULTS: Among all eligible subjects, about 60% of patients were classified as TCM users (65,812 TCM users and 41,482 nonusers). After 1:1 matching, the outcomes of 68,882 patients were analyzed. For the ESRD rate, the 8-year cumulative incidence was 14.5% for TCM users [95% confidence interval (CI): 13.9-15.0] and 16.6% for nonusers (95% CI: 16.0-17.2). For the mortality rate, the 8-year cumulative incidence was 33.8% for TCM users (95% CI: 33.1-34.6) and 49.2% for nonusers (95% CI: 48.5-49.9). After adjusting for confounding covariates, the cause-specific hazard ratio of ESRD was 0.81 (95% CI: 0.78-0.84), and the hazard ratio of mortality for TCM users was 0.48 (95% CI: 0.47-0.50). The cumulative incidence of mortality increased rapidly among TCM users with ESRD (56.8, 95% CI: 54.6-59.1) when compared with TCM users without ESRD (30.1, 95% CI: 29.4-30.9). In addition, TCM users who used TCM longer or initiated TCM treatments after being diagnosed with DN were associated with a lower risk of mortality. These results were consistent across sensitivity tests with different definitions of TCM users and inverse probability weighting of subjects. CONCLUSIONS: The lower ESRD and mortality rates among patients with incident DN correlates with the use of TCM treatments. Further studies about specific TCM modalities or medications for DN are still needed.

Incidence and Predictors of HBsAg Loss After Peginterferon Therapy in HBeAg-Negative Chronic Hepatitis B: A Multicenter, Long-term Follow-up Study.

Background: The long-term incidence and factors associated with hepatitis B surface antigen (HBsAg) loss in hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB) patients receiving peginterferon is rarely reported. Methods: From 2004 to 2016, 233 HBeAg-negative CHB patients who completed 48 weeks of peginterferon treatment from 3 medical centers in Taiwan were retrospectively enrolled. Results: During a median follow-up of 7.4 years, 27 cases achieved HBsAg loss. The cumulative incidences of HBsAg loss and HBsAg seroconversion at 3, 5, 10 years after peginterferon treatment were 4.7%, 9.4%, 14.2%, and 3.5%, 6.4%, 12.5%, respectively, in overall patients, and 15.9%, 29.1%, 37.3%, and 13.1%, 19%, 30.6%, respectively, in patients achieving sustained off-treatment virological response (SVR). By multivariate analysis, age (<35 years; hazard ratio [HR] = 3.742, P = .007), baseline HBsAg levels (<1250 IU/mL; HR = 4.849, P = .002), HBsAg decline at week 24 (≥1 log; HR = 5.660, P = .002), and achieving SVR (HR = 8.546, P = .006) were predictors of HBsAg loss. After achieving SVR, HBsAg loss rates were higher than 30% in 5 years among patients with either younger age or lower HBsAg at baseline. Conclusions: HBsAg loss rate continues to increase after peginterferon treatment in HBeAg-negative CHB patients with SVR. Age, baseline HBsAg levels, on-treatment HBsAg decline, and achieving SVR are factors associated with long-term HBsAg loss.

Safety of Perfluorobutane (Sonazoid) in Characterizing Focal Liver Lesions.

BACKGROUND: The purpose of this study was to report the safety of perfluorobutane (Sonazoid) as a vascular-phase imaging agent in characterizing focal liver lesions (FLLs). MATERIALS AND METHODS: From May 2014 to April 2015, a total of 54 individuals who received Sonazoid contrast-enhanced ultrasound (CEUS) were enrolled at 5 hospitals of 4 medical centers. All individuals were included in safety evaluation. A prospective study to evaluate the adverse effect (AE) incidences after intravenous administration of Sonazoid. RESULTS: Sonazoid was well tolerated. Treatment-emergent adverse events (TEAEs) representing AE were recorded for 13 (24.1%) patients. The most common AE was abdominal pain (9.3%), followed by heart rate irregularity (5.6%). The majority of these patients (69.2%) experienced TEAEs that were mild in intensity. Sonazoid causes no significant AEs after intravenous injection. The only noteworthy AEs are related to tolerable myalgia (3.7%), abdominal pain (1.9%), and headache (1.9%). None of the 54 patients showed serious adverse effects. CONCLUSION: Sonazoid shows good safety and tolerance of intravenous use during CEUS of the liver for evaluation of FLLs.

Corrigendum: Statins Reduce the Risk of Cirrhosis and Its Decompensation in Chronic Hepatitis B Patients: A Nationwide Cohort Study.

This corrects the article DOI: 10.1038/ajg.2017.494.

Transient portal vein thrombosis in liver cirrhosis.

In real-world clinical practice, the acceptance of anticoagulation therapy in the management of portal vein thrombosis (PVT) in patients with cirrhosis is limited by the fear of an increased bleeding risk. Additionally, accumulating evidence indicates that spontaneous recanalization of PVT may occur in the absence of antithrombotic treatment. Therefore, risk stratification based on outcomes in such patients is crucial for determining a therapeutic strategy. In this paper, we draw attention to the distinct clinical entity, "transient PVT" by introducing two cases with PVT that spontaneously recanalized in the absence of antithrombotic treatment. We reviewed the available data regarding the probability of and predictors for spontaneous recanalization of PVT. Available data suggest singling out transient thrombosis in the natural history of PVT in patients with cirrhosis because of its prognostic and management implications.

Liu Jun Zi Tang-A Potential, Multi-Herbal Complementary Therapy for Chemotherapy-Induced Neurotoxicity.

Liu Jun Zi Tang (LJZT) has been used to treat functional dyspepsia and depression, suggesting its effects on gastrointestinal and neurological functions. LJZT is currently used as a complementary therapy to attenuate cisplatin-induced side effects, such as dyspepsia. However, its effect on chemotherapy-induced neuropathic pain or neurotoxicity has rarely been studied. Thus, we explored potential mechanisms underlying LJZT protection against cisplatin-induced neurotoxicity. We observed that LJZT attenuated cisplatin-induced thermal hyperalgesia in mice and apoptosis in human neuroblastoma SH-SY5Y cells. Furthermore, it also attenuated cisplatin-induced cytosolic and mitochondrial free radical formation, reversed the cisplatin-induced decrease in mitochondrial membrane potential, and increased the release of mitochondrial pro-apoptotic factors. LJZT not only activated the peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) promoter region, but also attenuated the cisplatin-induced reduction of PGC-1α expression. Silencing of the PGC-1α gene counteracted the protection of LJZT. Taken together, LJZT mediated, through anti-oxidative effect and mitochondrial function regulation, to prevent cisplatin-induced neurotoxicity.

The effect of a hepatitis pay-for-performance program on outcomes of patients undergoing antiviral therapy.

Background: To examine the effect of a participatory pay-for-performance (P4P) program in Taiwan on health outcomes for patients with severe hepatitis B or C. Methods: This study adopted 4-year panel data from the databases of the National Health Insurance Administration (NHIA) in Taiwan. Using the caliper matching method to match patients in the P4P (experimental) group with those in the potential comparison group on a one-to-one basis for the year 2010, we tracked patients up to the year 2013 and employed Cox proportional-hazards regression models to evaluate the effect on patient outcomes. Results: The P4P group did not have a lower risk (HR = 0.44, P = 0.05) of hospital admission for severe hepatitis patients (i.e. need antiviral therapy). The risk of developing liver cirrhosis was also lower, but the reduction was not statistically significant (HR = 0.92, P = 0.77). Conclusions: This study found that participatory-type P4P has not resulted in reduced hospital admission of hepatitis B or C patients who need antiviral therapy. The means by which the participatory P4P program could strengthen patient-centered care to achieve better patient health outcomes is discussed in detail.

Long-term Nucleos(t)ides Analogues for Chronic Hepatitis B Improve Liver and Spleen Size: A Noninvasive Sonographic Study.

BACKGROUND: Histological improvement and regression of liver fibrosis after long-term use of nucleos(t)ides analogues (NUCs) have been documented. The aim of the present investigation was to evaluate the usefulness of traditional sonography to detect hepatic and splenic changes during NUC therapy in chronic hepatitis B (CHB) patients. METHODS: A total of 181 CHB patients receiving NUC treatment were enrolled in this study. The study population was divided into three groups 72 cirrhotic, 58 noncirrhotic CHB, and 51 nonreplicative hepatitis B virus carriers. All patients had blood chemistries taken and sonography at baseline and during the NUC treatment period. The changes in liver size, liver edge, spleen size, platelet count, and platelet count/spleen diameter (PC/SD) ratio were compared among the three groups of patients. RESULTS: CHB Patients with and without cirrhosis have improved clinical features during NUC therapy with lower aspartate aminotransferase, alanine aminotransferase, international normalized ratio, hepatitis B virus DNA, and spleen size and higher platelet, liver edge, liver size, and PC/SD ratio compared with the baseline data (p < 0.05). The differences in liver edge, liver size, spleen size, and PC/SD ratio are higher in the cirrhosis group than in the non-cirrhotic group (p < 0.001). A decrease in spleen size exhibited a linear relationship with treatment duration (R2 = 0.905). CONCLUSIONS: Traditional sonography is helpful to monitor changes in liver fibrosis of CHB patients under NUC therapy.Abbreviations: AFP, α-fetoprotein; ALT, alanine transaminase; AST, aspartate transaminase; CHB, chronic hepatitis B; Hb, hemoglobin; HBV, hepatitis B virus; INR, international normalized ratio; NUCs, nucleos(t)ides analogues; PC/SD, platelet count/spleen diameter; WBC, white blood cells.

Statins Reduce the Risk of Cirrhosis and Its Decompensation in Chronic Hepatitis B Patients: A Nationwide Cohort Study.

OBJECTIVES: The protective effect of statins in cirrhosis and its decompensation in chronic hepatitis B (CHB) patients remains unknown. METHODS: We conducted a population-based cohort study using data from the Taiwanese National Health Insurance Research Database from 1997 to 2009. A total of 298,761 CHB patients were identified. CHB patients using statins (n=6,543; defined as ≥28 cumulative defined daily doses (cDDD)) and a 1:1 ratio propensity score and inception point (the date of first use of statins)-matched non-statins (<28 cDDD) were followed up from the inception point until the development of cirrhosis or its decompensation or until withdrawal from insurance or December 2009. RESULTS: After adjustment for competing mortality, CHB patients using statins had a significantly lower cumulative incidence of cirrhosis (relative risk)=0.433; 95% confidence interval (CI)=0.344-0.515; modified log-rank test, P<0.001) and decompensated cirrhosis (relative risk=0.468; 95% CI=0.344-0.637; P<0.001) compared with patients not using statins. After adjustment for age, gender, comorbidity index, hypertension, diabetes, hyperlipidemia, hepatocellular carcinoma, obesity, non-alcoholic fatty liver disease, aspirin use, diabetes medication, CHB treatment, non-statin lipid-lowering drugs, and triglyceride lipid-lowering drugs using the Cox proportional hazard model, statins were still an independent protector against cirrhosis (adjusted hazard ratio (AHR)=0.512; 95% CI=0.413-0.634; P<0.001) and its decompensation (AHR=0.534; 95% CI=0.433-0.659; P<0.001). The AHRs for cirrhosis were 0.467 and 0.200, and the AHRs for decompensated cirrhosis were 0.611 and 0.231 with 91-365 and >365 cDDD of statins, respectively. CONCLUSIONS: CHB patients who receive statin therapy have a dose-dependent reduction in the risk of cirrhosis and its decompensation.

The immune-modulatory effects of a mixed herbal formula on dendritic cells and CD4+ T lymphocytes in the treatment of dust mite allergy asthma and perennial allergic rhinitis.

OBJECTIVE: Asthma and allergic rhinitis are chronic inflammatory diseases of the conducting nasal airway. Traditional Chinese medicine has long been used for supplemental therapy of allergic diseases, especially asthma and allergic rhinitis. We previously reported the effects of a mixed herbal formula in patients with allergic rhinitis. However, the immune-modulatory mechanism underlying the effects of herbal medicine for the treatment of allergic diseases remains unclear. METHODS: We investigated the physiologic changes in dendritic cell (DC) and CD4(+) T cell activity in patients with asthma and allergic rhinitis who were treated with a mixed herbal formula composed of Xin-yi-san + Xiao-qing-long-tang + Xiang-sha-liu- jun-zi-tang. Specifically, we set up in vitro autologous or heterologous co-culture experiments between DCs and CD4(+) T cells, and used flow cytometry and ELISA to analyze the expression of surface molecules on DCs and the release of cytokines by CD4(+) T cells. RESULTS: Expression of HLA-DR on DCs was suppressed following treatment with the mixed herbal formula. Surface expression of CD40, CD54 and CD86 on DCs was also attenuated after treatment. In autologous co-cultures, CD4(+) T cells increased their IL-10 production while decreasing TNF-α production. In heterologous co-cultures, IL-10 secretion by T cells was enhanced, while IL-12, IL-4, IL-5 and TNF-α secretion were reduced. CONCLUSION: Our mixed herbal formula attenuated the allergic reaction by modifying the physiologic function of the DC-CD4(+) T cell interaction. Further investigations are necessary to understand the mechanism of immune modification mediated by the mixed herbal formula.

Increased risk of cirrhosis and its decompensation in chronic hepatitis C patients with new-onset diabetes: a nationwide cohort study.

UNLABELLED: The effect of diabetes on cirrhosis, its decompensation, and their time relationship in chronic hepatitis C (CHC) patients remains unclear. We conducted a nation-wide cohort study by using the Taiwanese National Health Insurance Research Database, which is comprised of data from >99% of the entire population. Among having randomly sampled 1 million enrollees, 6,251 adult CHC patients were identified from 1997 to 2009. Diabetes was defined as new onset in CHC patients who were given the diagnosis in the years 1999-2003, but not in 1997-1998. The cohorts of CHC with new-onset diabetes (n=424) and nondiabetes (n=1,708) were followed up from inception point in diabetes and from year 1999 in the nondiabetes cohort until development of cirrhosis or its decompensation, withdrawal from insurance, or December 2009. Kaplan-Meier's survival analysis showed a significantly higher cumulative incidence of cirrhosis (relative risk [RR]=1.53; 95% confidence interval [CI]=1.11-2.11; log-rank test; P<0.001) and decompensated cirrhosis (RR=2.01; 95% CI=1.07-3.79; log-rank test; P<0.001) among patients with new-onset diabetes, as compared to those without. After adjustment for age, gender, CHC treatment, diabetes treatment, hepatocellular carcinoma, comorbidity index, hypertension, hyperlipidemia, and obesity by Cox's proportional hazard model, diabetes was still an independent predictor for cirrhosis (hazard ratio [HR]=2.505; 95% CI=1.609-3.897; P<0.001) and its decompensation (HR=3.560; 95% CI=1.526-8.307; P=0.003). CONCLUSION: CHC patients who develop diabetes are at an increased risk of liver cirrhosis and its decompensation over time.

Sustained hepatitis C virus clearance and increased hepatitis B surface antigen seroclearance in patients with dual chronic hepatitis C and B during posttreatment follow-up.

UNLABELLED: Patients dually infected with hepatitis C virus (HCV)/hepatitis B virus (HBV) have a higher risk of developing advanced liver disease or hepatocellular carcinoma compared with monoinfected patients. Yet, there is a similar rate of sustained virologic response (SVR) after peginterferon alfa-2a and ribavirin combination therapy in these patients compared with HCV-monoinfected patients and a high hepatitis B surface antigen (HBsAg) seroclearance rate. The durability of hepatitis C and B clearance in coinfected patients was investigated in a 5-year follow-up study. Patients with active HCV genotype 1, both HBV-coinfected (n = 97) and HBV-monoinfected (n = 110), underwent 48-week combination therapy with peginterferon alfa-2a plus ribavirin. In patients with active HCV genotype 2 or 3, both HBV-coinfected (n = 64) and monoinfected (n = 50) patients underwent 24-week combination therapy. A total of 295 (91.9%) patients completed treatment and 24 weeks posttreatment follow-up; 264 (89.5%) patients agreed to receive additional follow-up for up to 5 years after the end of treatment. After a median follow-up of 4.6 ± 1.0 years, six of the 232 patients achieving SVR developed HCV RNA reappearance, including five HCV genotype 1/HBV-coinfected patients and one HCV genotype 2/3-monoinfected patient. Subgenomic analysis of the HCV core gene indicated that five patients developed delayed recurrence of HCV infection. Overall, the cumulative recurrence rate of HCV infection was 2.3% (0.4%/year; 95% confidence interval [CI], 0.9%-5.5%). The cumulative HBsAg seroclearance rate was 30.0% (95% CI, 21.5%-42.0%); with 33.1% (95% CI, 21.8%-50.1%) in the 48-week combination therapy group and 24.3% (95% CI, 13.7%-42.9%) in the 24-week therapy group. CONCLUSION: Peginterferon alfa-2a and ribavirin therapy provides good HCV SVR durability and a high accumulative HBsAg seroclearance rate in patients who are coinfected with HCV and HBV. (HEPATOLOGY 2013;).