Topographical metal burden correlates with brain atrophy and clinical severity in Wilson's disease.

BACKGROUND: Quantitative susceptibility mapping (QSM) is a post-processing technique that creates brain susceptibility maps reflecting metal burden through tissue magnetic susceptibility. We assessed topographic differences in magnetic susceptibility between participants with and without Wilson's disease (WD), correlating these findings with clinical severity, brain volume, and biofluid copper and iron indices. METHODS: A total of 43 patients with WD and 20 unaffected controls, were recruited. QSM images were derived from a 3T MRI scanner. Clinical severity was defined using the minimal Unified Wilson's Disease Rating Scale (M-UWDRS) and Montreal Cognitive Assessment scoring. Differences in magnetic susceptibilities between groups were evaluated using general linear regression models, adjusting for age and sex. Correlations between the susceptibilities and clinical scores were analyzed using Spearman's method. RESULTS: In age- and sex-adjusted analyses, magnetic susceptibility values were increased in WD patients compared with controls, including caudate nucleus, putamen, globus pallidus, and substantia nigra (all p < 0.01). Putaminal susceptibility was greater with an initial neuropsychiatric presentation (n = 25) than with initial hepatic dysfunction (n = 18; p = 0.04). Susceptibility changes correlated negatively with regional brain volume in almost all topographic regions. Serum ferritin, but not serum copper or ceruloplasmin, correlated positively with magnetic susceptibility level in the caudate nucleus (p = 0.04), putamen (p = 0.04) and the hippocampus (p = 0.03). The dominance of magnetic susceptibility in cortical over subcortical regions correlated with M-UWDRS scores (p < 0.01). CONCLUSION: The magnetic susceptibility changes could serve as a surrogate marker for patients with WD.

Management of Crohn's disease in Taiwan: consensus guideline of the Taiwan Society of Inflammatory Bowel Disease updated in 2023.

Crohn's disease (CD) is a chronic, fluctuating inflammatory condition that primarily affects the gastrointestinal tract. Although the incidence of CD in Taiwan is lower than that in Western countries, the severity of CD presentation appears to be similar between Asia and the West. This observation indicates the urgency for devising revised guidelines tailored to the unique reimbursement system, and patient requirements in Taiwan. The core objectives of these updated guidelines include the updated treatment choices and the integration of the treat-to-target strategy into CD management, promoting the achievement of deep remission to mitigate complications and enhance the overall quality of life. Given the diversity in disease prevalence, severity, insurance policies, and access to medical treatments in Taiwan, a customized approach is imperative for formulating these guidelines. Such tailored strategies ensure that international standards are not only adapted but also optimized to local contexts. Since the inception of its initial guidelines in 2017, the Taiwan Society of Inflammatory Bowel Disease (TSIBD) has acknowledged the importance of continuous revisions for incorporating new therapeutic options and evolving disease management practices. The latest update leverages international standards and recent research findings focused on practical implementation within the Taiwanese healthcare system.

Management of ulcerative colitis in Taiwan: consensus guideline of the Taiwan Society of Inflammatory Bowel Disease updated in 2023.

Ulcerative colitis (UC) is a chronic inflammation of the gastrointestinal tract and is characterized by alternating periods of inflammation and remission. Although UC incidence is lower in Taiwan than in Western countries, its impact remains considerable, demanding updated guidelines for addressing local healthcare challenges and patient needs. The revised guidelines employ international standards and recent research, emphasizing practical implementation within the Taiwanese healthcare system. Since the inception of the guidelines in 2017, the Taiwan Society of Inflammatory Bowel Disease has acknowledged the need for ongoing revisions to incorporate emerging therapeutic options and evolving disease management practices. This updated guideline aims to align UC management with local contexts, ensuring comprehensive and context-specific recommendations, thereby raising the standard of care for UC patients in Taiwan. By adapting and optimizing international protocols for local relevance, these efforts seek to enhance health outcomes for patients with UC.

Predictors of functional cure of chronic hepatitis B virus infection - A long-term follow-up study.

BACKGROUND & AIMS: Functional cure is an essential endpoint in the management of patients with chronic hepatitis B virus (HBV) infection. We evaluated the cumulative probability and predictors of functional cure in patients with chronic HBV infection after hepatitis B e antigen (HBeAg)-seroconversion. METHODS: We retrospectively analyzed 413 (249 males and 164 females) initially HBeAg-positive chronic HBV-infected patients, who were followed up for a mean of 26.36 ± 0.53 years. All underwent HBeAg-seroconversion during follow-up. A functional cure was defined as durable HBsAg and HBV DNA loss without antiviral treatment for more than 24 weeks. RESULTS: After 10,888 person-years of follow-up, the cumulative probability of functional cure was 14.53% (n = 60). There were 24 (40%) subjects with functional cure after antiviral therapy. The annual functional cure rate was 0.55% per perperson-year, and increased to 0.96% per person-year after HBeAg-seroconversion. In subjects with functional cure, the HBsAg and HBV DNA titers after HBeAg-seroconversion were positively correlated with the time to functional cure (P < .001 and < .001, respectively). Multivariate Cox proportional hazard analysis of the cohort revealed that HBeAg-seroconversion at < 18 years of age, high genetic barrier nucleos(t)ide analogue(s) therapy before HBeAg-seroconversion, and a serum HBsAg titer < 1,000 IU/mL at 18 months after HBeAg-seroconversion were significant predictors of functional cure (P < .001, .001, and .001, respectively). CONCLUSIONS: In a cohort of chronic HBV-infected patients with long-term follow-up, HBeAg-seroconversion in childhood, high genetic barrier nucleos(t)ide analogue(s) therapy, and low HBsAg titers after HBeAg-seroconversion were significant predictors of functional cure.

Gut Bifidobacterium longum is associated with better native liver survival in patients with biliary atresia.

Background & Aims: The gut microbiome plays an important role in liver diseases, but its specific impact on biliary atresia (BA) remains to be explored. We aimed to investigate the microbial signature in the early life of patients with BA and to analyze its influence on long-term outcomes. Methods: Fecal samples (n = 42) were collected from infants with BA before and after Kasai portoenterostomy (KPE). The stool microbiota was analyzed using 16S rRNA next-generation sequencing and compared with that of age-matched healthy controls (HCs). Shotgun metagenomic sequencing analysis was employed to confirm the bacterial composition in 10 fecal samples before KPE. The correlation of the microbiome signature with liver function and long-term outcomes was assessed. Results: In the 16S rRNA next-generation sequencing analysis of fecal microbiota, the alpha and beta diversity analyses revealed significant differences between HCs and patients with BA before and after KPE. The difference in microbial composition analyzed by linear discriminant analysis and random forest classification revealed that the abundance of Bifidobacterium longum (B. longum) was significantly lower in patients before and after KPE than in HCs. The abundance of B. longum was negatively correlated with the gamma-glutamyltransferase level after KPE (p <0.05). Patients with early detectable B. longum had significantly lower total and direct bilirubin 3 months after KPE (p <0.005) and had a significantly lower liver transplantation rate (hazard ratio: 0.16, 95% CI 0.03-0.83, p = 0.029). Shotgun metagenomic sequencing also revealed that patients with BA and detectable B. longum had reduced total and direct bilirubin after KPE. Conclusion: The gut microbiome of patients with BA differed from that of HCs, with a notable abundance of B. longum in early infancy correlating with better long-term outcomes. Impact and implications: Bifidobacterium longum (B. longum) is a beneficial bacterium commonly found in the human gut. It has been studied for its potential impacts on various health conditions. In patients with biliary atresia, we found that a greater abundance of B. longum in the fecal microbiome is associated with improved clinical outcomes. This suggests that early colonization and increasing B. longum levels in the gut could be a therapeutic strategy to improve the prognosis of patients with biliary atresia.

Early predictors of intestinal complications in pediatric-onset Crohn's disease: A long-term cohort study in Taiwan.

PURPOSE: Identifying reliable prognostic factors for pediatric-onset Crohn's disease (CD) is important for guiding early treatment. This study aimed to evaluate the validity of various clinical parameters for predicting long-term intestinal complications in pediatric-onset CD patients with CD in Taiwan. METHODS: This was a single-center, retrospective study. Patients diagnosed with CD under 18 years of age at our hospital between January 1999 and December 2021 were enrolled. The baseline clinical variables and the Pediatric Crohn's Disease Activity Index (PCDAI) were obtained. Patients were categorized into low-, medium-, or high-risk groups based on the 2020 European Crohn's and Colitis Organization and European Society for Pediatric Gastroenterology Hepatology and Nutrition (ECCO-ESPGHAN) guidelines. The primary endpoint was the occurrence of new intestinal complications. RESULTS: Among 53 enrolled patients (33 males and 20 females), 8 patients (33.96%) developed intestinal complications during the follow-up period (median 6.42 years, 3.17-9.75 years). Patients in the initial ECCO-ESPGHAN medium- or high-risk group had a 4.71-fold higher risk of intestinal complications than those in the low-risk group [hazard ratio = 4.71, p = 0.023] after adjusting for PCDAI in the multivariate Cox proportional hazard analysis. The other clinical variables did not reach statistical significance in predicting intestinal complications. The positive and negative predictive values of the ECCO-ESPGHAN stratification method for intestinal complications were 48.15% and 80.77%, respectively. CONCLUSIONS: ECCO-ESPGHAN risk stratification is an effective early predictor of long-term intestinal complications in the Taiwanese population and may be used in clinical practice to guide early advanced therapy.

Clinical experience of infantile hepatic hemangioma.

PURPOSE: To describe the clinical presentation, treatment preference, and relevant complications of infantile hepatic hemangioma (IHH) in propranolol era. METHODS: The National Taiwan University Hospital integrated Medical Database (NTUH-iMD) was used to enroll twenty-one cases of IHH diagnosed from 2006 to 2020. Medical charts were retrospectively reviewed. RESULTS: In nine patients (42.9%), IHH was found incidentally, and in seven patients (33%), it was detected during postnatal self-paid ultrasonography. Focal disease was determined in 17 patients, multifocal disease in 1 patient, and diffuse disease in 3 patients. Patients with diffuse disease had a lower hemoglobulin level than patients with focal IHH (9.38 vs. 12.6 mg/dL, p = 0.045). Two patients had Kasabach-Merritt phenomenon (KMP), one had hypothyroidism, and one had both. All patients with KMP had focal hepatic hemangiomas. Among the 17 patients with focal IHH, nine were prescribed propranolol, one was treated by surgical resection of the tumor, and the others had expectant management. All patients with multifocal and diffuse IHH were administered propranolol. One infant (7.7%) treated with propranolol had bradycardia initially but it subsided after dose adjustment. CONCLUSIONS: Most IHH is found incidentally or detected during postnatal ultrasonography screening. Patients with large focal lesions should also be screened for associated complications. Propranolol is the drug of choice and a safe therapeutic option for IHH, especially for focal tumors >5 cm as well as multifocal and diffuse lesions.

Survey of hepatitis B virus infection status after 35 years of universal vaccination implementation in Taiwan.

BACKGROUND AND AIMS: Hepatitis B virus (HBV) vaccination programs in Taiwan are one of the earliest programs in the world and have largely reduced the prevalence of HBV infection. We aimed to demonstrate the vaccination efficacy after 35 years and identify gaps toward HBV elimination. METHODS: A total of 4717 individuals aged 1-60 years were recruited from four administrative regions based on the proportion of population distribution. Serum levels of hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (anti-HBs), and hepatitis B core antibody (anti-HBc) levels were assessed. HBV viral load, genotypes and HBsAg 'ɑ' determinant variants were evaluated if indicated. RESULTS: After 35 years of vaccination, the overall seropositivity rates for HBsAg and anti-HBc in Taiwan were 4.05% and 21.3%, respectively. The vaccinated birth cohorts exhibited significantly lower seropositivity rates for both markers compared to the unvaccinated birth cohorts (HBsAg: 0.64% vs. 9.78%; anti-HBc: 2.1% vs. 53.55%, respectively; p < 0.0001). Maternal transmission was identified as the main route of HBV infection in breakthrough cases. Additionally, increased prevalences of genotype C and HBsAg escape mutants were observed. CONCLUSION: The 35-year universal HBV vaccination program effectively reduced the burden of HBV infection, but complete eradication of HBV infection has not yet been achieved. In addition to immunization, comprehensive screening and antiviral therapy for infected individuals, especially for pregnant women, are crucial strategies to eliminate HBV.

The incidence of Clostridium difficile infection in children with and without inflammatory bowel diseases: A single-center study in Taiwan from 2006 to 2019.

BACKGROUND: The incidence of Clostridium difficile infection (CDI) is increasing around the world, and patients with inflammatory bowel disease (IBD) have a higher risk of obtaining CDI. The data on the incidence rate of CDI in the Asian pediatric IBD population was lacking. METHODS: We retrospectively collected data from a tertiary medical center in Taipei, Taiwan. All patients aged 1-18 years old who visited the outpatient department or were admitted to our hospital between 2006 and 2019 were included. CDI was defined as positive stool C. difficile toxin or C. difficile culture results with appropriate antibiotic use within the range of 7 days prior or 14 days after the result. RESULTS: We compared the average annual incidence of CDI before and after 2013. The average incidence of community-acquired CDI (CA-CDI) increased from 0.063 to 0.564 cases per 1,000 visits, with a rate ratio (RR) of 8.82 (95% CI 5.74-14.38). In patients with IBD, the rate increased from 26.738 to 278.873 cases per 1,000 visits (RR=10.12, 95% CI: 4.57-29.02). The average incidence rate increased from 0.685 to 1.874 cases per 1,000 admissions in pediatric general patients (RR = 2.72, 95% CI 1.82-4.20) and from 14.706 to 62.500 cases per 1,000 admissions in pediatric IBD patients (RR = 3.77, 95% CI 0.71-93.53). CONCLUSIONS: Both CA-CDI and healthcare facility-onset CDI (HO-CDI) were increasing substantially in the pediatric population over the past decade in Taiwan. Compared to the general pediatric population, pediatric IBD patients had a much higher incidence of CDI.

CTLA-4 haplotype predicts HBsAg and HBcrAg levels and HBeAg seroconversion age in children with chronic HBV infection.

Background & Aim: Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) attenuates cytotoxic T lymphocyte (CTL) activation. This study was performed to examine the relationships between CTLA-4 genotypes/haplotypes, hepatitis B surface antigen (HBsAg), and hepatitis B core-related antigen (HBcrAg) levels, and their potential impact on the clinical course of chronic HBV infection. Methods: We recruited 145 treatment-naïve patients with genotype B or C chronic HBV infection who were initially hepatitis B e-antigen (HBeAg)-positive and had been followed from a mean age of 7.08 years for a total of 4,787 person-years in the study cohort. We also recruited another 69 treatment-naïve adults with genotype B or C chronic HBV infection as a validation cohort. We assessed the CTLA-4 gene single nucleotide polymorphisms rs4553808 (-A1661G)/rs5742909 (-C318T) in both cohorts, and the serum HBsAg and HBcrAg levels in the study cohort. Results: CTLA-4 promoter haplotypes were associated with HBsAg and HBcrAg levels at 10 and 15 years of age in the study cohort. Patients with the CTLA-4 AA/CC haplotype showed earlier spontaneous HBeAg seroconversion (hazard ratio = 1.58; p = 0.02), and a more rapid annual decline in the serum HBsAg level than other patients (0.09 vs. 0.03 log10 IU/ml/year, p = 0.02). The CTLA-4 AA/CC haplotype was also predictive of HBeAg seroconversion in the validation cohort (p = 0.01). Conclusions: Chronic HBV-infected patients with a CTLA-4 AA/CC haplotype had lower serum HBsAg and HBcrAg levels in childhood and earlier spontaneous HBeAg seroconversion. Impact and implications: The role of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) in chronic HBV-infected children has not been studied previously. In a very long-term cohort followed from childhood to adulthood, we showed that CTLA-4 haplotypes are associated with HBV biomarker levels in childhood and are correlated with the clinical course of chronic HBV infection. CTLA-4 pathway may serve as a future target for the development of therapeutic agents against HBV infection.

Tenofovir alafenamide or tenofovir disoproxil fumarate in pregnancy to prevent HBV transmission: Maternal ALT trajectory and infant outcomes.

BACKGROUND: The use of antiviral agents, specifically tenofovir disoproxil fumarate (TDF), in pregnant women to prevent mother-to-child HBV transmission is a key step towards hepatitis elimination. However, data on using tenofovir alafenamide (TAF) is insufficient. The frequent occurrence of postpartum ALT flares may impact the clinical implementation. METHODS: The maternal and infant outcomes were compared in multi-centre trials of high viral load HBsAg/HBeAg+ pregnant women receiving TAF or TDF from the third trimester until 2 weeks postpartum with intensive follow-ups. To explore the dynamic pre- and postpartum changes in ALT levels, we used a group-based trajectory model for analysing data of 332 women from three prospective studies. RESULTS: After treatment, the maternal HBV DNA levels significantly decreased from baseline to delivery: 7.87 ± 0.59 to 3.99 ± 1.07 Log10 IU/mL TAF (n = 78) and 8.30 ± 0.36 to 4.47 ± 0.86 Log10 IU/mL (TDF, n = 53), with viral load reductions of 3.87 versus 3.83 Log10 IU/mL. The HBsAg-positive rates among 12-month-old infants were 1.28% (1/78) versus 1.82% (1/55) respectively (p = 1.00). Of the TAF or TDF-treated mothers, 25.64% versus 16.98% experienced ALT > 2X ULN, and 11.54% versus 1.89% received extended antiviral treatment. Our model revealed four distinct ALT patterns: stable ALT (87.2%), moderate (8.0%) or marked (2.4%) postpartum flares, or prepartum elevations (2.4%). CONCLUSIONS: TAF effectively reduces mother-to-child HBV transmission, but prophylaxis failure still occurred in few cases. Postpartum ALT flares are common in women receiving TAF or TDF during pregnancy. Approximately 12.8% of mothers may require extended postpartum antiviral treatment. CLINICAL TRIAL NUMBER: NCT03695029 (ClinicalTrials.gov).

The magnetic resonance imaging and age-adjusted matrix metalloproteinase-7 assist the diagnosis of biliary atresia.

BACKGROUND: We investigated the utilities of the liver-to-psoas apparent diffusion coefficient ratios (LTPAR) yielded by diffusion-weighted magnetic resonance imaging (DWMRI) and the age-adjusted serum matrix metalloproteinase-7 (MMP-7) for the diagnosis of biliary atresia (BA) in cholestatic infants. METHODS: In total, 170 cholestatic infants were recruited, of whom 50 (29.41%) were diagnosed with BA after cholestatic workups. The LTPAR and MMP7 levels were assessed. RESULTS: The LTPAR was significantly lower in BA infants, and the age-adjusted MMP7 ratio was significantly higher, compared to other cholestatic infants (both p < 0.001). Receiver operating characteristic curve analysis yielded a cutoff > 0.1 ng/mL.day for the age-adjusted MMP-7 ratio, and an LTPAR < 1.01 for the optimal prediction of BA (both p < 0.001). Univariate logistic regression analysis revealed that both an age-adjusted MMP-7 ratio > 0.1 ng/mL.day and an LTPAR < 1.01 were significant predictors of BA among cholestatic infants (odds ratio = 30.98 and 13.28; p < 0.001 and < 0.001, respectively). The significance of the age-adjusted MMP-7 ratio and the LTPAR persisted on multivariate logistic regression analysis after adjusting for sex and the serum gamma-glutamyl transferase level (p < 0.001 and < 0.001, respectively). The negative predictive values (NPVs) for BA were 91.49% and 94.17%, respectively, for the LTPAR and age-adjusted MMP-7 ratio. CONCLUSION: The age-adjusted MMP-7 ratio and the LTPAR are both significant non-invasive predictors of BA. The consideration of both serum and imaging parameters may enhance BA diagnostic performance in cholestatic infants.

Antagonism Between Gut Ruminococcus gnavus and Akkermansia muciniphila Modulates the Progression of Chronic Hepatitis B.

BACKGROUND & AIMS: A long immune-tolerant (IT) phase lasting for decades and delayed HBeAg seroconversion (HBe-SC) in patients with chronic hepatitis B (CHB) increase the risk of liver diseases. Early entry into the immune-active (IA) phase and HBe-SC confers a favorable clinical outcome with an unknown mechanism. We aimed to identify factor(s) triggering IA entry and HBe-SC in the natural history of CHB. METHODS: To study the relevance of gut microbiota evolution in the risk of CHB activity, fecal samples were collected from CHB patients (n = 102) in different disease phases. A hepatitis B virus (HBV)-hydrodynamic injection (HDI) mouse model was therefore established in several mouse strains and germ-free mice, and multiplatform metabolomic and bacteriologic assays were performed. RESULTS: Ruminococcus gnavus was the most abundant species in CHB patients in the IT phase, whereas Akkermansia muciniphila was predominantly enriched in IA patients and associated with alanine aminotransferase flares, HBeAg loss, and early HBe-SC. HBV-HDI mouse models recapitulated this human finding. Increased cholesterol-to-bile acids (BAs) metabolism was found in IT patients because R gnavus encodes bile salt hydrolase to deconjugate primary BAs and augment BAs total pool for facilitating HBV persistence and prolonging the IT course. A muciniphila counteracted this activity through the direct removal of cholesterol. The secretome metabolites of A muciniphila, which contained small molecules structurally similar to apigenin, lovastatin, ribavirin, etc., inhibited the growth and the function of R gnavus to allow HBV elimination. CONCLUSIONS: R gnavus and A muciniphila play opposite roles in HBV infection. A muciniphila metabolites, which benefit the elimination of HBV, may contribute to future anti-HBV strategies.

Twnbiome: a public database of the healthy Taiwanese gut microbiome.

With new advances in next generation sequencing (NGS) technology at reduced costs, research on bacterial genomes in the environment has become affordable. Compared to traditional methods, NGS provides high-throughput sequencing reads and the ability to identify many species in the microbiome that were previously unknown. Numerous bioinformatics tools and algorithms have been developed to conduct such analyses. However, in order to obtain biologically meaningful results, the researcher must select the proper tools and combine them to construct an efficient pipeline. This complex procedure may include tens of tools, each of which require correct parameter settings. Furthermore, an NGS data analysis involves multiple series of command-line tools and requires extensive computational resources, which imposes a high barrier for biologists and clinicians to conduct NGS analysis and even interpret their own data. Therefore, we established a public gut microbiome database, which we call Twnbiome, created using healthy subjects from Taiwan, with the goal of enabling microbiota research for the Taiwanese population. Twnbiome provides users with a baseline gut microbiome panel from a healthy Taiwanese cohort, which can be utilized as a reference for conducting case-control studies for a variety of diseases. It is an interactive, informative, and user-friendly database. Twnbiome additionally offers an analysis pipeline, where users can upload their data and download analyzed results. Twnbiome offers an online database which non-bioinformatics users such as clinicians and doctors can not only utilize to access a control set of data, but also analyze raw data with a few easy clicks. All results are customizable with ready-made plots and easily downloadable tables. Database URL: http://twnbiome.cgm.ntu.edu.tw/ .

Combining Panel-Based Next-Generation Sequencing and Exome Sequencing for Genetic Liver Diseases.

OBJECTIVES: To determine how advanced genetic analysis methods may help in clinical diagnosis. STUDY DESIGN: We report a combined genetic diagnosis approach for patients with clinical suspicion of genetic liver diseases in a tertiary referral center, using tools either tier 1: Sanger sequencing on SLC2SA13, ATP8B1, ABCB11, ABCB4, and JAG1 genes, tier 2: panel-based next generation sequencing (NGS), or tier 3: whole-exome sequencing (WES) analysis. RESULTS: In a total of 374 patients undergoing genetic analysis, 175 patients received tier 1 Sanger sequencing based on phenotypic suspicion, and pathogenic variants were identified in 38 patients (21.7%). Tier 2 included 216 patients (39 of tier 1-negative patients) who received panel-based NGS, and pathogenic variants were identified in 60 (27.8%). In tier 3, 41 patients received WES analysis, and 20 (48.8%) obtained genetic diagnosis. Pathogenic variants were detected in 6 of 19 (31.6%) who tested negative in tier 2, and a greater detection rate in 14 of 22 (63.6%) patients with deteriorating/multiorgan disease receiving one-step WES (P = .041). The overall disease spectrum is comprised of 35 genetic defects; 90% of genes belong to the functional categories of small molecule metabolism, ciliopathy, bile duct development, and membrane transport. Only 13 (37%) genetic diseases were detected in more than 2 families. A hypothetical approach using a small panel-based NGS can serve as the first tier with diagnostic yield of 27.8% (98/352). CONCLUSIONS: NGS based genetic test using a combined panel-WES approach is efficient for the diagnosis of the highly diverse genetic liver diseases.

Clinical Characteristics, Genetic Features, and Long-Term Outcome of Wilson's Disease in a Taiwanese Population: An 11-Year Follow-Up Study.

OBJECTIVE: aaWilson's disease (WD) is a rare genetic disorder of copper metabolism, and longitudinal follow-up studies are limited. We performed a retrospective analysis to determine the clinical characteristics and long-term outcomes in a large WD cohort. METHODS: aaMedical records of WD patients diagnosed from 2006-2021 at National Taiwan University Hospital were retrospectively evaluated for clinical presentations, neuroimages, genetic information, and follow-up outcomes. RESULTS: aaThe present study enrolled 123 WD patients (mean follow-up: 11.12 ± 7.41 years), including 74 patients (60.2%) with hepatic features and 49 patients (39.8%) with predominantly neuropsychiatric symptoms. Compared to the hepatic group, the neuropsychiatric group exhibited more Kayser-Fleischer rings (77.6% vs. 41.9%, p < 0.01), lower serum ceruloplasmin levels (4.9 ± 3.9 vs. 6.3 ± 3.9 mg/dL, p < 0.01), smaller total brain and subcortical gray matter volumes (p < 0.0001), and worse functional outcomes during follow-up (p = 0.0003). Among patients with available DNA samples (n = 59), the most common mutations were p.R778L (allelic frequency of 22.03%) followed by p.P992L (11.86%) and p.T935M (9.32%). Patients with at least one allele of p.R778L had a younger onset age (p = 0.04), lower ceruloplasmin levels (p < 0.01), lower serum copper levels (p = 0.03), higher percentage of the hepatic form (p = 0.03), and a better functional outcome during follow-up (p = 0.0012) compared to patients with other genetic variations. CONCLUSION: aaThe distinct clinical characteristics and long-term outcomes of patients in our cohort support the ethnic differences regarding the mutational spectrum and clinical presentations in WD.

A Pilot Study of Biliary Atresia Newborn Screening Using Dried Blood Spot Matrix Metalloproteinase-7.

OBJECTIVES: Timely diagnosis is a critical challenge and is associated with improved survival of biliary atresia (BA) patients. We aimed to measure matrix metalloproteinase-7 (MMP-7) levels in BA patients within 3 days of birth using the dried blood spot (DBS) method and evaluate its potential as a screening tool. METHODS: The study enrolled 132 patients, including 25 patients diagnosed with BA and 107 non-BA patients with other congenital or perinatal conditions from the National Taiwan University Children Hospital. The stored DBS samples collected from 48 to 72 hours of life were retrieved from newborn screening centers. MMP-7 on the DBS was quantified using a sensitive sandwich enzyme-linked immunosorbent assay (ELISA). RESULTS: The MMP-7 levels of BA patients on the DBS were significantly higher than those of non-BA patients (19.2 ± 10.4 vs 5.6 ± 2.7 ng/mL, P value < 0.0001). MMP-7 levels in non-BA patients, including 5 patients with hepatobiliary structural anomaly, 9 patients with intrahepatic cholestasis, and 93 patients with other perinatal diseases, were 11.6 ± 4.2 ng/mL, 6.9 ± 3.0 ng/mL, and 5.2 ± 2.1 ng/mL, respectively. The DBS MMP-7 level showed good accuracy for identifying BA, with an area under the curve of 93.7% [95% confidence interval (CI): 87.7%-99.7%]. The MMP-7 cutoff at 8.0 ng/mL showed a sensitivity of 92.0% (95% CI: 75.0%-98.6%) and specificity of 92.5% (95% CI: 85.9%-96.1%) for detecting BA from other congenital or perinatal diseases. CONCLUSIONS: MMP-7 DBS analysis can be used to distinguish BA from other conditions as early as 3 days of age.

Real-World Evidence of Effectiveness and Safety of Vedolizumab for Inflammatory Bowel Disease in Taiwan: A Prospective Nationwide Registry (VIOLET) Study.

BACKGROUND: This nationwide prospective registry study investigated the real-world effectiveness, safety, and persistence of vedolizumab (VDZ) in inflammatory bowel disease (IBD) patients in Taiwan. Disease relapse rates after VDZ discontinuation due to reimbursement restriction were assessed. METHODS: Data were collected prospectively (January 2018 to May 2020) from the Taiwan Society of IBD registry. RESULTS: Overall, 274 patients (147 ulcerative colitis [UC] patients, 127 Crohn's disease [CD] patients) were included. Among them, 70.7% with UC and 50.4% with CD were biologic-naïve. At 1 year, 76.0%, 58.0%, 35.0%, and 62.2% of UC patients and 57.1%, 71.4%, 33.3%, and 30.0% of CD patients achieved clinical response, clinical remission, steroid-free remission, and mucosal healing, respectively. All patients underwent hepatitis B and tuberculosis screening before initiating biologics, and prophylaxis was recommended when necessary. One hepatitis B carrier, without antiviral prophylaxis due to economic barriers, had hepatitis B reactivation during steroid tapering and increasing azathioprine dosage, which was controlled with an antiviral agent. No tuberculosis reactivation was noted. At 12 months, non-reimbursement-related treatment persistence rates were 94.0% and 82.5% in UC and CD patients, respectively. Moreover, 75.3% of IBD patients discontinued VDZ due to mandatory drug holiday. Relapse rates after VDZ discontinuation at 6 and 12 months were 36.7% and 64.3% in CD patients and 42.9% and 52.4% in UC patients, respectively. CONCLUSIONS: The findings demonstrated VDZ effectiveness in IBD patients in Taiwan, with high treatment persistence rates and favorable safety profiles. A substantial IBD relapse rate was observed in patients who had mandatory drug holiday.

PIM1-Induced Cytoplasmic Expression of RBMY Mediates Hepatocellular Carcinoma Metastasis.

BACKGROUND & AIMS: Metastasis indicates a grave prognosis in patients with hepatocellular carcinoma (HCC). Our previous studies showed that RNA binding motif protein Y-linked (RBMY) is potentially a biomarker for poor survival in HCC patients, but its role in metastasis is largely unclear. METHODS: A total of 308 male patients with primary HCC were enrolled. RBMY expression was traced longitudinally by immunostaining from the manifestation of a primary HCC tumor to the formation of a distant metastasis, and its upstream regulators were screened with a protein microarray. A series of metastasis assays in mouse models and HCC cell lines were performed to explore new functional insights into RBMY. RESULTS: Cytoplasmic expression of RBMY was associated with rapid distant metastasis (approximately 1 year after resection) and had a predictive power of 82.4% for HCC metastasis. RBMY conferred high migratory and invasive potential upon phosphorylation by the provirus integration in Moloney 1 (PIM1) kinase. Binding of PIM1 to RBMY caused mutual stabilization and massive translocation of RBMY from nuclei to mitochondria, thereby preventing mitochondrial apoptosis and augmenting mitochondrial generation of adenosine triphosphate/reactive oxygen species to enhance cell motility. Depletion of RBMY suppressed Snail1/zinc finger E-box binding homeobox transcription factor 1-mediated epithelial-mesenchymal transition and dynamin-related protein 1-dependent mitochondrial fission. Inactivation and knockout of PIM1 down-regulated the expression of RBMY. In nude mice, cytoplasmic RBMY promoted liver-to-lung metastasis by increasing epithelial-mesenchymal transition, mitochondrial proliferation, and mitochondrial fission, whereas nuclear-restricted RBMY impeded the mitochondrial switch and failed to induce lung metastasis. CONCLUSIONS: This study showed the regulation of HCC metastasis by PIM1-driven cytoplasmic expression of RBMY and suggested a novel therapeutic target for attenuating metastasis.