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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.

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.

Background: Purpose: Anemia affects the life quality of inflammatory bowel disease (IBD) patients, but no report from Asian about anemia screening and its impact previously. We aimed to explore the prevalence and impact of anemia among the IBD patients in Taiwan. Methods: A retrospective study was conducted from January 2006 to February 2018 at National Taiwan University Hospital. Clinical characteristics and outcomes were analyzed. Results: A total of 1604 IBD patients were enrolled [494 Crohn's disease (CD) and 1110 ulcerative colitis (UC)]. Overall, 95.3% (471/494) of CD and 87.9% (976/1110) of UC patients underwent anemia screening. Anemia screening rate in IBD patients significantly increased from 62.6% (162/259) in 2006 to 77.2% (838/1086) in 2017. The mean time from IBD diagnosis to anemia screening was 122.4 days in CD patients and even longer in UC patients at 216.2 days. Persistent anemia was found in 47.3% (548/1158) of the screened patients. Risk factors of persistent anemia included low body mass index [odds ratio (OR) = 1.96, p

Background/Aims Primary sclerosing cholangitis (PSC) is associated with inflammatory bowel disease (IBD). We aimed to evaluate the prevalence, clinical manifestation, and outcomes of PSC in Taiwanese patients with IBD. Methods This retrospective study enrolled patients with IBD admitted from January 1, 1996, to December 31, 2018, to National Taiwan University Hospital. A case-matched analysis was performed comparing patients with IBD with and without PSC according to age, sex, and time of admission, with ratios of 1:4 and 1:2 in the adult and pediatric groups, respectively. Results In total, 763 patients with IBD were enrolled, 12 of whom were also diagnosed with PSC (1.57%). All these patients had ulcerative colitis (UC). A greater incidence of IBD with PSC was observed in younger patients than in older patients. Male sex was a risk factor for PSC in pediatric patients with IBD (P=0.015); 75% of these patients were diagnosed with PSC along with or after the diagnosis of UC. There was no significant difference in colitis extent and severity between the groups; however, a higher proportion of rectal sparing was observed in patients with PSC (P=0.001). There was no significant difference in cancer development between the groups (P=0.679). Conclusions A 1.57% prevalence of PSC was observed in Taiwanese patients with IBD. The majority of patients with IBD and PSC were men and were diagnosed at a younger age. Hence, routine evaluation of biliary enzymes and liver imaging is recommended in young male patients with IBD.

Abstract Background Primary signet ring cell carcinoma of the colon and rectum (PSRCCR) is rare, usually diagnosed at advanced stage with poor outcomes. We aimed to find possible diagnostic clues in order to help diagnosis. Methods A retrospective study of PSRCCR patients from 1993 to 2018 was reviewed at a single tertiary center. Colorectal adenocarcinoma patients as control group with 1:4 ratio was also enrolled. Results 18 patients with PSRCCR were identified. The prevalence rate was 0.16% (18 of 11,515). The mean age was 50.2 years-old in PSRCCR group and 63 years-old in non-SRCC colorectal cancer patients (p

Abstract Background Inflammatory bowel disease (IBD) was emerging as a worldwide epidemic disease, and the advanced therapy changed the clinical course and possibly the outcomes. Our previous study reported a higher mortality rate from (IBD) in Taiwan than in Western countries. We proposed to analyze the trend and risk factors of mortality in order to improve the care quality of IBD patients. Methods This retrospective study was conducted to analyze data for January 2001 to December 2015 from a registered database, compiled by the Taiwan’s National Health Insurance. Results Between 2001 and 2015, a total of 3806 IBD patients [Crohn’s disease (CD): 919; ulcerative colitis (UC): 2887] were registered as having catastrophic illness, and 8.2% of these patients died during follow-up. The standardized mortality ratios (SMRs) of CD and UC were 3.72 (95% CI 3.02–4.55) and 1.44 (95% CI 1.26–1.65), respectively, from 2001 to 2015, respectively. A comparison of the periods of 2011–2015 and 2001–2005 revealed a decrease in the mortality rates from both UC and CD. Multivariate Cox proportional hazards analysis identified elderly individuals; sepsis and pneumonia were the risk factors for IBD mortality. The specific risk factors of mortality were liver cancer for UC and surgeries for CD. Conclusion For further decreasing IBD-related mortality in Taiwan, we need to pay special attention toward elderly individuals, infection control, cancer screening and improvement in perioperative care.

Abstract Background Colorectal cancer (CRC) is one of the most common cancers worldwide. Screening for CRC using the fecal occult blood test (FOBT) is feasible and useful for decreasing disease‐related mortality; however, its sensitivity and compliance are unsatisfactory. Methods This study examined the efficacy of using serum placenta growth factor (PlGF) for a novel CRC screening strategy. To investigate a potential novel screening tool for CRC, we compared the sensitivity, specificity, positive predictive value, and negative predictive value of the FOBT, serum PlGF, and their combination through an examination of two independent cohorts and validation using the second cohort. All the patients and control group received the colonoscopy and FOBT, the colonoscopy was used as the gold standard for the result. Results Serum PlGF levels were significantly increased in CRC patients (16.8 ± 11.4 pg/mL) compared with controls (12.0 ± 11.2 pg/mL). The predictive model that used the serum PlGF level alone was as effective as the FOBT (AUC: 0.60 vs 0.68, P = 0.891), and it had significantly higher sensitivity than the FOBT (0.81 vs 0.39). In addition, we found serum PlGF level has a good value for predicting CRC patients in those FOBT negative populations. Finally, combining serum PlGF level and the FOBT improved the predictive power and demonstrated satisfactory sensitivity (0.71) and specificity (0.71). This result was confirmed and validated in the second independent cohort. Furthermore, no matter the stages (early/advanced) and the location (distal/proximal) of CRC, the efficacy of serum PlGF and the combined model remained quite stable. Conclusion Serum PlGF level is a potential alternative screening tool for CRC, especially for those who are reluctant to stool‐based screening methods and who were tested as negative FOBT. In addition, combining serum PlGF level and the FOBT could increase the power of CRC screening.

Background/Aims Incidences of inflammatory bowel disease (IBD), ulcerative colitis (UC), and Crohn’s disease (CD), have been increasing in Asia. In this study, we report the relevant clinical characteristics and determined the epidemiological trend of IBD in Taiwan from 2001 to 2015. Methods A retrospective study was conducted to analyze data recorded from January 2001 through December 2015 in the registered database compiled by the National Health Insurance and provided by the Ministry of Health and Welfare, Taiwan. Results A total of 3,806 patients with catastrophic IBD illness were registered from 2001 to 2015 in Taiwan (CD, 919; UC, 2,887). The crude incidence of CD increased from 0.17/100,000 in 2001 to 0.47/100,000 in 2015, whereas that of UC increased from 0.54/100,000 in 2001 to 0.95/100,000 in 2015. The prevalence of CD increased from 0.6/100,000 in 2001 to 3.9/100,000 in 2015, whereas that of UC increased from 2.1/100,000 in 2001 to 12.8/100,000 in 2015. The male-to-female ratio in the study sample was 2.19 for CD and 1.62 for UC. The median age of those registered with CD was lower than that of those registered for UC: 38.86 and 44.86 years, respectively. A significantly greater increase in CD incidence rate was identified among 20 to 39-year-old compared with other age groups. Conclusions Using Taiwan’s nationwide insurance database, we determined that the number of patients with CD increased more rapidly during the study period than the number of patients with UC, especially among age 20 to 39-year-old, resulting in a decreased UC-to-CD ratio.

Background/Aims Fecal calprotectin (fC) level is a predictive marker of mucosal healing for patients with inflammatory bowel disease (IBD). Home fC tests are now available. We evaluated the performance of the smartphone-based IBDoc home testing system in patients with IBD and obtained their feedback as an objective patient-reported outcome. Methods This prospective study enrolled consecutive patients with IBD in clinical remission. fC in the same stool sample was assessed by using both the laboratory test (Quantum Blue calprotectin test) and home test (IBDoc). The correlation between the 2 tests was analyzed using the Pearson method. In addition, the patients were asked to fill a questionnaire based on their experience. Results Fifty-one patients with IBD (68 tests and 49 questionnaires) were included. The correlation between Quantum Blue test and IBDoc was good (r=0.776, P70%) probability to use it for future monitoring if the price was acceptable. By using 250 μg/g as the cutoff, the agreement between home test and laboratory results was 80%, and by using 600 μg/g as the cutoff, the agreement increased to 92%. Conclusions The correlation between the laboratory and home tests was good. Most patients found the home test to be feasible and easy to use and preferred it over laboratory test and endoscopy for monitoring. Therefore, the home test could be used as an objective patient-reported outcome.

Background/Aims: In Taiwan, due to budget limitations, the National Health Insurance only allows for a limited period of biologics use in treating moderate to severe Crohn's disease (CD). We aimed to access the outcomes of CD patients following a limited period use of biologics, specifically focusing on the relapse rate and remission duration; also the response rate to second use when applicable.Methods: This was a multicenter, retrospective, observational study and we enrolled CD patients who had been treated with adalimumab (ADA) according to the insurance guidelines from 2009 to 2015.Results: A total of 54 CD patients, with follow-up of more than 6 months after the withdrawal of ADA, were enrolled. The average period of treatment with ADA was 16.7±9.7 months. After discontinuing ADA, 59.3% patients suffered a clinical relapse. In the univariate analysis, the reason for withdrawal was a risk factor for relapse (P=0.042). In the multivariate analysis, current smoker became an important risk factor for relapse (OR, 3.9; 95% CI, 1.2−14.8; P=0.044) and male sex was another risk factor (OR, 2.9; 95% CI, 1.1−8.6; P=0.049). For those 48 patients who received a second round of biologics, the clinical response was seen in 60.4%, and 1 anaphylaxis occurred.Conclusions: Fifty-nine percent of patients experienced a relapse after discontinuing the limited period of ADA treatment, and most of them occurred within 1 year following cessation. Male sex and current smoker were risk factors for relapse. Though 60.4% of the relapse patients responded to ADA again.

Crohn's disease (CD) is a chronic relapsing and remitting inflammatory disease of the gastrointestinal tract. CD is rare in Taiwan and other Asian countries, but its prevalence and incidence have been steadily increasing. A steering committee was established by the Taiwan Society of Inflammatory Bowel Disease to formulate statements on the diagnosis and management of CD taking into account currently available evidence and the expert opinion of the committee. Thorough clinical, endoscopic, and histological assessments are required for accurate diagnosis of CD. Computed tomography and magnetic resonance imaging are complementary to endoscopic evaluation for disease staging and detecting complications. The goals of CD management are to induce and maintain remission, reduce the risk of complications, and improve quality of life. Corticosteroids are the mainstay for inducing re-mission. Immunomodulating and biologic therapies should be used to maintain remission. Patients should be evaluated for hepatitis B virus and tuberculosis infection prior to treatment and receive regular surveillance for cancer. These consensus statements are based on current local evidence with consideration of factors, and could be serve as concise and practical guidelines for supporting clinicians in the management of patients with CD in Taiwan.

Ulcerative colitis (UC) is an inflammatory bowel disease characterized by chronic mucosal inflammation of the colon, and the prevalence and incidence of UC have been steadily increasing in Taiwan. A steering committee was established by the Taiwan Society of Inflammatory Bowel Disease to formulate statements on the diagnosis and management of UC taking into account currently available evidence and the expert opinion of the committee. Accurate diagnosis of UC requires thorough clinical, endoscopic, and histological assessment and careful exclusion of differential diagnoses, particularly infectious colitis. The goals of UC therapy are to induce and maintain remission, reduce the risk of complications, and improve quality of life. As outlined in the recommended treatment algorithm, choice of treatment is dictated by severity, extent, and course of disease. Patients should be evaluated for hepatitis B virus and tuberculosis infection prior to immunosuppressive treatment, especially with steroids and biologic agents, and should be regularly monitored for reactivation of latent infection. These consensus statements are also based on current local evidence with consideration of factors, and could be serve as concise and practical guidelines for supporting clinicians in the management of UC in Taiwan.

Background/AimsWith the recent progress in medical treatment, surgery still plays a necessary and important role in treating ulcerative colitis (UC) patients. In this study, we analyzed the surgical results and outcomes of UC in Taiwan in the recent 20 years, via a multi-center study through the collaboration of Taiwan Society of IBD.MethodsA retrospective analysis of surgery data of UC patients from January 1, 1995, through December 31, 2014, in 6 Taiwan major medical centers was conducted. The patients' demographic data, indications for surgery, and outcome details were recorded and analyzed.ResultsThe data of 87 UC patients who received surgical treatment were recorded. The median post-operative follow-up duration was 51.1 months and ranged from 0.4 to 300 months. The mean age at UC diagnosis was 45.3±16.0 years and that at operation was 48.5±15.2 years. The 3 leading indications for surgical intervention were uncontrolled bleeding (16.1%), perforation (13.8%), and intractability (12.6%). In total, 27.6% of surgeries were performed in an emergency setting. Total or subtotal colectomy with rectal preservation (41.4%) was the most common operation. There were 6 mortalities, all due to sepsis. Emergency operation and low pre-operative albumin level were significantly associated with poor survival (P=0.013 and 0.034, respectively).ConclusionsIn the past 20 years, there was no significant change in the indications for surgery in UC patients. Emergency surgeries and low pre-operative albumin level were associated with poor survival. Therefore, an optimal timing of elective surgery for people with poorly controlled UC is paramount.

Crohn's disease (CD) is a disease with chronic inflammation of unknown etiology involving any part of the gastrointestinal tract. The incidence and prevalence of CD are increasing recently in Asia. Half of the CD patients will have intestinal complications, such as strictures or fistulas, within 20 years after diagnosis. Twenty-five percentage of CD patients have had at least one small bowel stricture and 10% have had at least one colonic stricture and lead to significant complications. Most of these patients will require at least one surgery during their lifetime. Early diagnosis and evaluation with adequate managements for the patients can prevent disability and mortality of these patient. Here, we reviewed the current incidence of CD with stricture, the etiology of stricture, and how to diagnose and manage the stricture.

Since Taiwan is an endemic area for tuberculosis (TB), differential diagnosis between the intestinal TB and Crohn's disease is an important issue. The steering committee of Taiwan Society of Inflammatory Bowel Disease (TSIBD) has arranged a seminar accordingly on May 24th, 2014 and the different point of views by gastroenterologist, radiologist, pathologist and infectious disease specialist were suggested to help the proper diagnosis and management of these two diseases.

Background/AimsOnly moderate to severe Crohn's Disease (CD) patients without a satisfactory conventional therapy effect are eligible to get reimbursement from the National Health Insurance of Taiwan for using adalimumab. These are more stringent criteria than in many Western countries and Japan and Korea. We aim to explore the efficacy of using adalimumab in CD patients under such stringent criteria.MethodsA retrospective analysis was conducted in nine medical centers in Taiwan and we collected the results of CD patients receiving adalimumab from Sep 2009 to Mar 2014. The clinical characteristics, response measured by CDAI (Crohn's Disease Activity Index), adverse events and survival status were recorded and analyzed. CR-70, CR-100, and CR-150 were defined as attaining a CDAI decrease of 70, 100 or 150 points compared with baseline.ResultsA total of 103 CD patient records were used in this study. Sixty percent of these patients received combination therapy of adalimumab together with immunomodulators. CR-70 was 68.7%, 74.5% and 88.4% after week 4, 8 and 12 of treatment, respectively. The steroid-free rate, complications and survival were 47.6%, 9.7% and 99% of patients, respectively. In considering the mucosal healing, only 25% patients achieve mucosal healing after treatment for 6 to 12 months. Surgery was still needed in 16.5% of patients. Combination treatment of adalimumab with immunomodulators further decreased the level of CDAI at week 8 when compared with the monotherapy.ConclusionsEven under the stringent criteria for using adalimumab, the response rate was comparable to those without stringent criteria.

Background: No nationwide, long-term follow-up study has assessed medication-associated outcomes for Asian patients with inflammatory bowel disease (IBD). This study examined medication-associated outcomes for Taiwanese patients with IBD. Methods: In this nationwide cohort study, 3806 patients who had received catastrophic illness registration for IBD from 2001 to 2015 were enrolled. Results: A higher accumulated dosage of 5-aminosalicylic acid (5-ASA) was associated with decreased risks of hospitalization (hazard ratio (HR) = 0.6) and operation (HR = 0.5). Thiopurine was associated with increased risks of hospitalization (HR = 2.1 in the high-dosage group) and tuberculosis (TB; HR = 3.6) reactivation but not with operation risk. A higher accumulated dosage of anti-TNF-α agents was associated with increased risks of hospitalization (HR = 3.3), operation (HR = 2.9), hepatitis B (HR = 4.3), and TB (HR = 5.1) reactivation. Corticosteroids were associated with increased risks of hospitalization (HR = 3.5 in the high-dosage group), risk of operation, hepatitis B (HR = 2.8) and TB (HR = 2.8) reactivation. Conclusions: 5-ASA usage is associated with decreased risks of hospitalization and operation for patients with IBD, whereas thiopurine, corticosteroids, and anti-TNF-α agents are associated with increased risks of hospitalization and hepatitis B and TB reactivation.

The aim of this study was to gain a better understanding of the current incidence of Crohn’s disease (CD) in Taiwan and examine its clinical/genetic characteristics because there has been a trend toward increased diagnosis in the Asia-Pacific area. The genetic background seen in CD cases in Taiwan seems to be different from that in Western countries. Methods: By reviewing the database in the National Taiwan University Hospital, CD patients were identified by clinical, endoscopic, and imaging findings. The clinical characteristics were recorded and analyzed. DNA was extracted from the peripheral blood of patients after obtaining informed consent. Polymerase chain reaction was performed with specific primers followed by direct sequencing to determine the single-nucleotide polymorphisms ATG16L1, CCR6, IL12B, IL23R, LRRK2, TNFSF2, and TNFSF15 CD-associated genes. Results: Clinical data from 110 CD patients were examined from 1988 to 2008, with a mean follow-up period of 4.5 years. There was a marked increase in new CD diagnosis, especially after 2004. Among the 110 patients, 71 men and 39 women, the age at diagnosis was 30.5±17.8 years (mean±standard deviation). Stenosis occurred in 33.6% (37 of 110) and 40.9% (45 of 110) of patients who underwent surgery. The mortality rate was 2.7%, all because of sepsis. Genetic analysis of 39 patients showed that ATG16L1 and TNFSF15 were associated with susceptibility to CD in Taiwan. Conclusion: Recently, the incidence of CD diagnosis in Taiwan has markedly increased. ATG16L1 and TNFSF15 are associated with CD in Taiwan.

Peutz-Jeghers syndrome (PJS) is an autosomal dominant inherited disorder that is characterized by intestinal hamartomatous polyps and mucocutaneous pigmentation. Recently, germline mutations in the LKB1 gene have been reported to underlie PJS. The gene that encodes this serine/threonine kinase is located at chromosome 19p13.3. The aim of this study was to investigate the clinical and genetic characteristics of PJS patients in Taiwan. Methods: We searched the patient database of the National Taiwan University Hospital, a tertiary medical center in Taiwan, between January 1990 and November 2005. Patients' clinical information, demographic data, endoscopic pictures, and outcome were reviewed and analyzed. After obtaining informed consent, DNA and RNA were extracted from peripheral blood mononuclear cells and the LKB1 gene was sequenced. Results: A total of 14 unrelated patients who fulfilled the diagnostic criteria of PJS were included, and seven of them had genetic analysis performed. Mucocutaneous pigmentation was the most frequent presentation. Hamartomas occur most commonly in the small intestine (86%). Frequent abdominal complications include intussusception and gastrointestinal bleeding. Four germline mutations were found (57.1%). Three resulted in stop codons at codon 60, 162 (novel mutation), and 308. The fourth mutation was a missense mutation at codon 239 (novel mutation). Conclusion: Compared with other countries, PJS patients in Taiwan tended to have more extensive polyps in the gastrointestinal tract, with intussusception being the most common abdominal symptom. Mutations in the LKB1 gene were identified in 57% of the probands in Taiwan.

Recent three-dimensional multidetector row computed tomography (3D MDCT) can provide detailed images of a gastric tumor, including its general contour, location and depth. We therefore evaluated the efficacy of MDCT in the differential diagnosis and staging of gastric tumors in patients prepared for surgery. Methods: Seventy-nine patients with gastric tumors identified by gastric optical endoscopy were admitted for preoperative evaluation. All patients received double-contrast barium meal (DCBM) study and abdominal MDCT with 3D reconstruction before surgery. We compared the accuracy of MDCT with DCBM study in detecting and differentiating gastric tumors. In addition, the MDCT findings were correlated with surgical and pathologic results in gastric cancers for Borrmann type, T and N stages. Results: Among the 79 patients with gastric tumors, there were 24 cases of early gastric cancer, 40 cases of advanced gastric cancer, 12 cases of gastrointestinal stromal tumor, and three cases of gastric lymphoma. Both MDCT and DCBM were very accurate in picking up the lesions (100%). The diagnostic accuracies of MDCT and DCBM were similar (94% vs. 96%) in differentiating mucosal and submucosal lesions as well as classification of Borrmann type in advanced gastric cancer (70% vs. 63%). In 64 patients with gastric cancers, there was good correlation between MDCT images and pathology in 73% of T staging and 69% of N staging. Conclusion: MDCT has a similar high accuracy in the preoperative diagnosis of different gastric tumors compared with DCBM and provides additional information including tumor depth, lymph node and hepatic metastasis. Therefore, MDCT may be used as a primary tool for preoperative tumor diagnosis and staging.

Background & aimsTo date, only one gene (TNFSF15) has been identified and validated as a Crohn's disease (CD)-associated gene in non-Caucasian populations. This study was designed to identify novel CD-associated single nucleotide polymorphisms (SNPs)/genes and to validate candidate genes using a functional assay.MethodsSNPs from 16 CD patients and 16 age- and sex-matched control patients were analyzed using Illumina platform analysis. Subsequently, we expanded the study and followed 53 CD patients and 41 control patients by Sequenom MassArray analysis. Quantitative PCR and immunohistochemical staining were performed to assess mRNA and protein expression of the candidate gene on tissue isolated from CD patients. Genotype was correlated with CD phenotypes. Finally, the candidate gene was cloned and its effect on NF-κB activity assessed using a reporter luciferase assay.ResultsSLCO3A1 (rs207959) reached statistical significance in the first-stage analysis (P = 2.3E-02) and was further validated in the second-stage analysis (P = 1.0E-03). Genotype and phenotype analysis showed that the rs207959 (T) allele is a risk allele that alters SLCO3A1 mRNA expression and is associated with intestinal perforation in CD patients. Higher levels of mRNA and protein expression of SLCO3A1 were seen in CD patients compared with the control group. Overexpression of SLCO3A1 induced increased NF-κB activity and increased phosphorylation of P65, ERK, and JNK. Nicotine augmented the activation of NF-κB in the presence of SLCO3A1.ConclusionsSLCO3A1, a novel CD-associated gene, mediates inflammatory processes in intestinal epithelial cells through NF-κB transcription activation, resulting in a higher incidence of bowel perforation in CD patients.

Mutations in the SLC26A4 gene are a common cause of human hereditary hearing impairment worldwide. Previous studies have demonstrated that different SLC26A4 mutations have different pathogenetic mechanisms. By using a genotype-driven approach, we established a knock-in mouse model (i.e., Slc26a4(tm2Dontuh/tm2Dontuh) mice) homozygous for the common p.H723R mutation in the East Asian population. To verify the pathogenicity of the p.H723R allele in mice, we further generated mice with compound heterozygous mutations (i.e., Slc26a4(tm1Dontuh/tm2Dontuh) ) by intercrossing Slc26a4(+/tm2Dontuh) mice with Slc26a4(tm1Dontuh/tm1Dontuh) mice, which segregated the c.919-2A>G mutation with an abolished Slc26a4 function. Mice were then subjected to audiologic assessments, a battery of vestibular evaluations, inner ear morphological studies, and noise exposure experiments. The results were unexpected; both Slc26a4(tm2Dontuh/tm2Dontuh) and Slc26a4(tm1Dontuh/tm2Dontuh) mice showed normal audiovestibular phenotypes and inner ear morphology, and they did not show significantly higher shifts in hearing thresholds after noise exposure than the wild-type mice. The results indicated not only the p.H723R allele was non-pathogenic in mice, but also a single p.H723R allele was sufficient to maintain normal inner ear physiology in heterozygous compound mice. There might be discrepancies in the pathogenicity of specific SLC26A4 mutations in humans and mice; therefore, precautions should be taken when extrapolating the results of animal studies to humans.

Recessive mutations in the SLC26A4 gene are a common cause of hereditary hearing impairment worldwide. Previous studies have demonstrated that different SLC26A4 mutations may have different pathogenetic mechanisms. In the present study, we established a knock-in mouse model (i.e., Slc26a4(tm1Dontuh/tm1Dontuh) mice) homozygous for the c.919-2A>G mutation, which is a common mutation in East Asians. Mice were then subjected to audiologic assessment, a battery of vestibular evaluations, and inner ear morphological studies. All Slc26a4(tm1Dontuh/tm1Dontuh) mice revealed profound hearing loss, whereas 46% mice demonstrated pronounced head tilting and circling behaviors. There was a significant difference in the vestibular performance between wild-type and Slc26a4(tm1Dontuh/tm1Dontuh) mice, especially those exhibiting circling behavior. Inner ear morphological examination of Slc26a4(tm1Dontuh/tm1Dontuh) mice revealed an enlarged endolymphatic duct, vestibular aqueduct and sac, atrophy of stria vascularis, deformity of otoconia in the vestibular organs, consistent degeneration of cochlear hair cells, and variable degeneration of vestibular hair cells. Audiologic and inner ear morphological features of Slc26a4(tm1Dontuh/tm1Dontuh) mice were reminiscent of those observed in humans. These features were also similar to those previously reported in both knock-out Slc26a4(-/-) mice and Slc26a4(loop/loop) mice with the Slc26a4 p.S408F mutation, albeit the severity of vestibular hair cell degeneration appeared different among the three mouse strains.