Effect of add-on naldemedine treatment in patients with cancer and opioid-induced constipation insufficiently responding to magnesium oxide: a pooled, subgroup analysis of two randomized controlled trials.

OBJECTIVE: To evaluate the additive effect of naldemedine tosylate (naldemedine) on opioid-induced constipation in cancer patients insufficiently responding to magnesium oxide treatment. METHODS: We combined two randomized, double-blind, placebo-controlled, phase IIb and III trials of naldemedine and conducted a post hoc subgroup analysis. We evaluated the effect and safety of naldemedine in 116 patients who received naldemedine in addition to magnesium oxide (naldemedine group) and 117 patients who received placebo in addition to magnesium oxide (placebo group). Both groups included patients insufficiently responding to magnesium oxide for opioid-induced constipation. Effect was assessed using spontaneous bowel movement responder rate, complete spontaneous bowel movement responder rate, changes in spontaneous bowel movements and complete spontaneous bowel movements. Safety was also assessed. RESULTS: During the 2-week treatment period, the responder rates for spontaneous bowel movement and complete spontaneous bowel movement were 73.3 and 43.1% in naldemedine group, respectively, which were significantly higher (P < 0.0001) than 41.9 and 14.5% in placebo group, respectively. Median time to first spontaneous bowel movement and first complete spontaneous bowel movement was significantly shorter (P < 0.0001) in the naldemedine group (4.0 and 21.3 h, respectively) than in the placebo group (27.7 and 211.7 h, respectively). The incidence of adverse events and diarrhoea was significantly higher (P < 0.05) in the naldemedine group than in the placebo group, while the incidence of serious adverse events and severe diarrhoea was not significantly different between the naldemedine and placebo groups. CONCLUSION: The study suggested the addition of naldemedine as an effective treatment option for opioid-induced constipation in cancer patients insufficiently responding to magnesium oxide treatment.

Distribution of Fibrosis-4 index and vibration-controlled transient elastography-derived liver stiffness measurement for patients with metabolic dysfunction-associated steatotic liver disease in health check-up.

AIMS: The multisociety consensus nomenclature has introduced steatotic liver disease (SLD) with diverse subclassifications, which are metabolic dysfunction-associated steatotic liver disease (MASLD), metabolic dysfunction and alcohol-associated steatotic liver disease (MetALD), alcohol-associated liver disease (ALD), specific etiology, and cryptogenic. We investigated their prevalence, as per the new definition, in individuals undergoing health check-ups. Additionally, we analyzed the distribution of Fibrosis-4 (FIB-4) index and vibration-controlled transient elastography (VCTE)-derived liver stiffness measurement (LSM) for MASLD. METHODS: In this cross-sectional study, 6530 subjects undergoing a health check-up in Japan were included. Conventional B-mode ultrasound was carried out on all 6530 subjects, and those with MASLD underwent VCTE. RESULTS: The prevalence of SLD was 39.5%, comprising MASLD 28.7%, MetALD 8.6%, ALD 1.2%, specific etiology SLD 0.3%, and cryptogenic SLD 0.7%. Subjects with VCTE-derived LSM ≥8 kPa constituted 2.1% of MASLD. FIB-4 ≥1.3 showed that the sensitivity, specificity, positive predictive value (PPV), and negative predictive value for diagnosing VCTE-derived LSM ≥8 kPa were 60.6%, 77.0%, 5.3%, and 98.9%, respectively. The referral rate to specialists was 23.8% using FIB-4 ≥1.30. "FIB-4 ≥1.3 in subjects <65 years and FIB-4 ≥2.0 in subjects ≥65 years" showed higher PPV (6.7%) and lower referral rate (17.1%) compared with FIB-4 ≥1.3, but the sensitivity (54.5%) did not show adequate diagnostic capability as a noninvasive test for diagnosing VCTE-derived LSM ≥8 kPa. CONCLUSIONS: Acknowledging the selection bias in hepatology centers, we undertook this prospective health check-up study. Although the FIB-4 index proves to be a convenient marker, it might not perform well as a primary screening tool for liver fibrosis in the general population (UMIN Clinical Trials Registry No. UMIN000035188).

Efficacy and safety of linaclotide in treatment-resistant chronic constipation: A multicenter, open-label study.

BACKGROUND: This study aimed to evaluate the efficacy and safety of linaclotide in patients with chronic constipation (CC) or irritable bowel syndrome with constipation (IBS-C) who did not respond to treatment with magnesium oxide (MgO). METHODS: This study was designed as a multicenter, open-label, single-arm, exploratory study. Patients with CC or IBS-C who took MgO and those meeting the medication initiation criteria were administered linaclotide at a daily dosage of 500 µg for 12 weeks. The primary endpoint was a change in the Japanese version of the Patient Assessment of Constipation Quality of Life (JPAC-QOL) score from baseline, which was evaluated by using a paired t-test. KEY RESULTS: The patients' mean age (± standard deviation) was 67.6 ± 13.82 years. The full analysis set included 61 patients. The JPAC-QOL total score was 1.60 at baseline and 0.70 at 12 weeks, with a significant mean change of -0.89 ± 0.721 (p < 0.001). Several secondary endpoints also showed improvement. The frequency of spontaneous bowel movement (SBM) and complete SBM increased by 2.70 ± 7.254 (p < 0.01) and 2.81 ± 5.254 times, respectively (p < 0.001). The Bristol Stool Form Scale, abdominal bloating severity, and straining severity scores improved by 1.33 ± 1.274 (p < 0.001), -0.16 ± 0.563 (p < 0.05), and -0.46 ± 0.795 (p < 0.001) points, respectively. The safety analysis set included 65 patients, 7 of whom had diarrhea, which improved with dose reduction and drug withdrawal. CONCLUSION & INFERENCES: The study was conducted in an older adult population, similar to real clinical practice. Linaclotide may be an option for treating CC that shows an inadequate response to conventional therapy.

Naldemedine for Opioid-Induced Constipation in Patients With Cancer: A Multicenter, Double-Blind, Randomized, Placebo-Controlled Trial.

PURPOSE: Opioid-induced constipation is the most frequent and non-self-limiting adverse effect of opioid analgesia, reducing adherence and interfering with pain relief. This clinical trial aimed to clarify the preventive effect of naldemedine versus placebo for constipation in patients with cancer starting regularly dosed strong opioids therapy. METHODS: This multicenter, double-blinded, randomized, placebo-controlled, confirmatory trial was conducted between July 2021 and May 2023 at four academic hospitals in Japan (ClinicalTrials.gov identifier: jRCTs031200397). Patients with cancer starting a first-time regularly dosed strong opioid for cancer pain and age 20+ years were included. Eligible patients were randomly assigned to the naldemedine (Symproic 0.2 mg) or placebo group in a 1:1 ratio for 14 days with protocol treatment. The primary end point was the proportion of patients with a Bowel Function Index (BFI) of <28.8 on day 14. The secondary end points included frequency of spontaneous bowel movements (SBM), quality of life (QOL), and frequency of opioid-induced nausea and vomiting (OINV). RESULTS: Of the 103 patients assessed for eligibility, 99 received either naldemedine (n = 49) or placebo (n = 50). A BFI of <28.8 on day 14 was significantly more likely to occur in the naldemedine group (64.6%; 95% CI, 51.1 to 78.1) versus placebo (17.0%; 95% CI, 6.3 to 27.8), and the difference between groups was 47.6% (95% CI, 30.3 to 64.8; P < .0001). The frequency of SBM, QOL, and the severity of OINV were nominally significant in the naldemedine group than in the control group. CONCLUSION: Naldemedine prevented constipation and improved constipation-related QOL, with possible preventive effect on OINV in patients with cancer starting regularly dosed opioids therapy.

A Handheld Ultrasound Device Can Predict Constipation with Rectal Fecal Retention in a Palliative Care Setting.

Although handheld ultrasound devices (HUDs) are commonplace, their ability to diagnose fecal retention (FR) remains unclear. This prospective observational study examined HUDs' usefulness in diagnosing FR in patients with constipation in a palliative care setting. Between 10 December 2020 and 30 June 2022, we compared rectal ultrasonographic findings obtained using HUDs with clinical manifestations in 64 males and 70 females (48%, 52%, 68 ± 11 years old) with constipation who had undergone computed tomography (CT). FR was diagnosed using a HUD and compared with CT and digital rectal examination (DRE) results. In total, 42 (31%), 42 (31%), and 41 (31%) patients were diagnosed using HUDs, CT, and DRE, respectively. Thirty-nine (93%) patients in the CT group were also diagnosed with FR using HUDs. A total of 89 of 92 patients with a negative CT diagnosis also had a negative HUD diagnosis. Among the 41 patients in the DRE group, 37 were also diagnosed with FR using HUDs. Among 93 patients with a negative DRE diagnosis, 86 had a negative HUD diagnosis. The sensitivity, specificity, positive predictive value, and negative predictive value of HUDs for CT were 93%, 97%, 93%, and 97%, respectively. Those of HUDs for DRE were 88%, 94%, 86%, and 95%, respectively. The concordance rates for FR diagnosis were 128/134 for CT and HUDs and 123/134 for DRE and HUDs. HUD was useful for diagnosing FR in this setting. HUDs could provide valuable support for appropriate treatment selection. Developing a constipation treatment algorithm based on rectal ultrasonographic findings is warranted in the future.

Expert Consensus Document: An Algorithm for the Care and Treatment of Patients with Constipation Based on Ultrasonographic Findings in the Rectum.

Chronic constipation is a common gastrointestinal disorder, and its management is critical. However, it is extremely difficult to assess its subjective symptoms when patients are unable to report them due to cognitive or physical disabilities, especially in cases of patients with incurable geriatric, pediatric, palliative, psychiatric, or neurological diseases. We had previously established a protocol for observing and assessing rectal fecal retention using ultrasonography and for classifying cases into three categories based on the rectal findings: no fecal retention, fecal retention without hard stools, and fecal retention with hard stools. However, although the detection of rectal fecal retention using ultrasonography would be expected to lead to better therapeutic management, there is no standard algorithm for selecting specific treatments and defecation care options based on ultrasonographic findings. Therefore, we organized an expert consensus meeting of multidisciplinary professionals to develop such an algorithm based on rectal ultrasonography findings for patients with constipation in both residential and hospital settings.

Relationship of Metabolic Dysfunction-Associated Steatohepatitis-Related Hepatocellular Carcinoma with Oral and Intestinal Microbiota: A Cross-Sectional Pilot Study.

Background and Objectives: The incidence of metabolic dysfunction-associated steatohepatitis (MASH)-related hepatocellular carcinoma (HCC) is increasing worldwide, alongside the epidemic of obesity and metabolic syndrome. Based on preliminary reports regarding the potential association of HCC and periodontitis, this study aimed to analyze the involvement of periodontal bacteria as well as the oral and intestinal bacterial flora in MASH-related HCC (MASH-HCC). Materials and Methods: Forty-one patients with MASH and nineteen with MASH-HCC participated in the study, completing survey questionnaires, undergoing periodontal examinations, and providing samples of saliva, mouth-rinsed water, feces, and peripheral blood. The oral and fecal microbiome profiles were analyzed by 16S ribosomal RNA sequencing. Bayesian network analysis was used to analyze the causation between various factors, including MASH-HCC, examinations, and bacteria. Results: The genus Fusobacterium had a significantly higher occupancy rate (p = 0.002) in the intestinal microflora of the MASH-HCC group compared to the MASH group. However, Butyricicoccus (p = 0.022) and Roseburia (p < 0.05) had significantly lower occupancy rates. The Bayesian network analysis revealed the absence of periodontal pathogenic bacteria and enteric bacteria affecting HCC. However, HCC directly affected the periodontal bacterial species Porphyromonas gingivalis, Tannerella forsythia, Fusobacterium nucleatum, and Prevotella intermedia in the saliva, as well as the genera Lactobacillus, Roseburia, Fusobacterium, Prevotella, Clostridium, Ruminococcus, Trabulsiella, and SMB53 in the intestine. Furthermore, P. gingivalis in the oral cavity directly affected the genera Lactobacillus and Streptococcus in the intestine. Conclusions: MASH-HCC directly affects periodontal pathogenic and intestinal bacteria, and P. gingivalis may affect the intestinal bacteria associated with gastrointestinal cancer.

The safety and effectiveness of naldemedine for opioid-induced constipation in patients with advanced cancer in real-world palliative care settings: a multicenter prospective observational study.

PURPOSE: In this study, we aimed to evaluate the safety and effectiveness of naldemedine for treating opioid-induced constipation (OIC) in patients with advanced cancer, who are receiving palliative care, and particularly explored its early effects. METHODS: Palliative care teams and inpatient palliative care units across 14 institutions in Japan were included in this multicenter, prospective, observational study. Patients who were newly prescribed a daily oral dose of 0.2 mg naldemedine were enrolled. The spontaneous bowel movement (SBM) within 24 h after the first dose of naldemedine was considered the primary outcome, whereas, the secondary outcomes included weekly changes in SBM frequency and adverse events. RESULTS: A total of 204 patients were enrolled and 184 completed the 7-day study. The average age of the participants (103 males, 101 females) was 63 ± 14 years. The primary cancer was detected in the lungs (23.5%), gastrointestinal tract (13.7%), and urological organs (9.3%). A considerable proportion of patients (34.8%) had ECOG performance status of 3-4. Most patients were undergoing active cancer treatment, however, 40.7% of the patients were receiving the best supportive care. Within 24 h of the first naldemedine dose, 146 patients (71.6%, 95% CI: 65.4-77.8%) experienced SBMs. The weekly SBM counts increased in 62.7% of the participants. The major adverse events included diarrhea and abdominal pain, detected in 17.6% and 5.4% of the patients, respectively. However, no serious adverse events were observed. CONCLUSION: Conclusively, naldemedine is effective and safe for OIC treatments in real-world palliative care settings. TRIAL REGISTRATION NUMBER: UMIN000031381, registered 20/02/2018.

Associations of nutrition impact symptoms with depression in patients with advanced cancer.

PURPOSE: Advanced cancer patients have nutrition impact symptoms (NISs), while many of them have depressive moods. This study aimed to determine the associations of NISs with depression. METHODS: This study was a secondary analysis. The dietary intake and 19 NISs in patients receiving palliative care were evaluated using 10-point scales, and the patients were categorized into two groups (non-depression and depression groups) using the cutoff based on the Patient Health Questionnaire-9 (PHQ-9). To determine associations between depression and the number of NISs with a score of ≥ 4, the adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for the logistic regression model were calculated. RESULTS: A total of 225 participants were divided into the non-depression group (n = 148) and the depression group (n = 77). The prevalence of depression was 34.2%. Dietary intake was lower, and the number of NISs with a score of ≥ 4 was higher in the depression group (both p < 0.001). All NISs were more severe in the depression group. Significant differences were observed in 15 of the 19 NISs. In the logistic regression model, significantly higher adjusted ORs were observed in the groups with 4-6 NISs and 7 or more NISs with a score of ≥ 4 (10.76 [95% CI, 2.07-55.91], p = 0.016; 17.02 [95% CI, 3.08-94.22], p < 0.001) than in the group with no NISs with a score of ≥ 4. CONCLUSION: Having four or more NISs with a score ≥ 4 was associated with depression.

Recombinant human fibroblast growth factor and autogenous bone for periodontal regeneration: Alone or in combination? A randomized clinical trial.

AIM: To compare the outcomes of therapy using recombinant human fibroblast growth factor (rhFGF)-2 combined with autologous bone grafting (ABG) therapy with those of rhFGF-2 alone and ABG alone in the treatment of periodontal intraosseous defects. METHODS: Periodontal intraosseous defects were randomized to receive rhFGF-2 therapy + ABG, rhFGF-2 therapy alone, or ABG alone. Periodontal examination and periapical radiography were performed preoperatively and at 3, 6, and 12 months postoperatively. RESULTS: At the 12 months follow-up, all three groups showed significant improvement in the clinical attachment level (CAL): 5.6 ± 1.6, 5.8 ± 1.7, and 5.2 ± 1.6 mm in the rhFGF-2 + ABG, rhFGF-2 alone, and ABG alone groups, respectively, with no significant inter-group differences (p < .05). rhFGF-2 therapy (alone or in combination) resulted in greater bone defect filling (BDF) (2.3 ± 1.2 mm and 2.6 ± 1.9 mm, respectively) than ABG therapy alone (1.2 ± 1.2 mm). Gingival recession was lesser in the ABG alone (1.2 ± 1.1 mm) and rhFGF-2 + ABG groups (1.4 ± 0.8 mm) than in the rhFGF-2 alone group (2.2 ± 1.2 mm). CONCLUSION: The results of this study showed that at 12 months postoperatively, all treatments resulted in statistically significant clinical improvements compared to the baseline. From these results, it can be concluded that rhFGF-2 promotes hard tissue regeneration in intraosseous defects.

Diagnostic Ability of Ultrasonography Compared with Computed Tomography for Assessing Rectal Feces.

Objectives: Chronic constipation is a common gastrointestinal disorder, and management is crucial. Computed tomography (CT) is useful for evaluating rectal fecal mass but limited owing to radiation exposure, cost, and inaccessibility at certain facilities. Ultrasonography (US) avoids these pitfalls, but it is unknown whether it accurately assesses rectal feces. In this study, we evaluated the diagnostic performance of US compared with CT as the gold standard for assessing rectal feces. Methods: We prospectively evaluated rectal fecal mass retention using US performed within 1 h of CT to assess the degree of agreement between methodologies. Rectal stool findings were evaluated on three levels: no stool (R1), presence of stool (R2), and hard stool filling (R3). Results: The sample included 100 patients (55 men, 45 women), of whom 47 were constipated. The kappa coefficients for rectal content detection were excellent between US and CT (p <0.001). Eighty-two cases (R1: 46 cases; R2: 28 cases; R3: 8 cases) were matched with CT and US findings, and 18 were not. Cases that did not match had low urine or high gas volumes. CT and US findings showed high agreement in constipation (kappa coefficient 0.674, p <0.001) and non-constipation groups (kappa coefficient 0.677, p <0.001). All cases with R3 on CT were found in the constipation group, while more than half of the cases with R1 on CT were in the non-constipation group. Conclusions: CT and US showed high agreement in evaluating rectal fecal mass retention, indicating that US can substitute CT.

Naldemedine and Magnesium Oxide as First-Line Medications for Opioid-Induced Constipation: A Comparative Database Study in Japanese Patients With Cancer Pain.

Introduction Naldemedine and magnesium oxide are common first-line early laxative medications used in the real-world scenario in Japan, for patients with cancer pain who receive opioid prescriptions, as per a nationwide hospital claims database study. However, the real-world prescription patterns and associated outcomes are unknown. Methods In this retrospective, cohort study using the Medical Data Vision (MDV) database (January 2018 to December 2020), data were collected from eligible patients (who had a long-term prescription of strong opioids, for >30 days) in Japan with naldemedine or magnesium oxide as the first-line laxative prescription, for a long-term opioid prescription for cancer pain with ≥6 months post-opioid observation period. A laxative prescription within three days after the opioid prescription date was termed an "early" prescription. The composite incidence of dose increase or addition/change of laxatives at three months after the start of the opioid prescription was the primary endpoint after adjusting baseline characteristics between the treatment arms by propensity score matching. Results After propensity score matching, 1717 and 544 patients who were prescribed naldemedine and magnesium oxide each were included in the early prescription and non-early prescription groups, respectively. Even after matching, the incidence of death was not adjusted enough and was significantly higher in the naldemedine arm than in the magnesium oxide arm in the non-early group but comparable in the early group. The incidence of addition, change, or dose increase was significantly higher in the naldemedine arm than in the magnesium oxide arm of the early prescription group (hazard ratio (95% confidence interval), 1.08 (1.00, 1.17); p=0.0402); the incidence was comparable between the arms of the non-early group. Conclusion These findings may provide valuable insights into real-world clinical treatment patterns and preliminary evidence for the selection of first-line medications to mitigate opioid-induced constipation in Japanese patients with cancer pain.

Efficacy and safety of rifaximin in patients with chronic intestinal pseudo-obstruction: a randomized, double-blind, placebo-controlled, phase II-a exploratory trial.

Chronic intestinal pseudo-obstruction (CIPO) is a rare intractable disease with limited treatment options. Small intestinal bacterial overgrowth (SIBO) often co-occurs with several diseases, including CIPO. While rifaximin (RFX) is effective in treating SIBO, its efficacy for CIPO remains unclear. Here, we aimed to investigate the efficacy and safety of RFX in adult patients with CIPO. Twelve patients were randomly assigned to receive RFX (400 mg three times daily, n=8) or a placebo (PBO, n=4) for 4 weeks. The global symptom score for abdominal bloating (GSS-bloating) and an original whole gastrointestinal symptoms score (O-WGSS) were collected, and a glucose hydrogen breath test (GHBT) and abdominal computed tomography (CT) were performed. No significant differences were observed in the primary endpoint. GSS-bloating improved by 75% and 25% in the PBO and RFX groups, respectively, and O-WGSS improved by 25% in both groups. No significant differences were observed in secondary and other endpoints, including the SIBO eradication rate in the GHBT and small intestinal volume on CT. In a post hoc analysis of SIBO-positive patients with CIPO (4/4 and 4/8 in the PBO and RFX groups), SIBO was eradicated in 25% and 75% of the patients (PBO and RFX groups, respectively) at the end of treatment, indicating a high eradication rate in the RFX group. Furthermore, the small intestinal gas volume decreased in the RFX group, and no severe adverse events occurred. Although no significant improvements were observed in subjective indicators, RFX may be beneficial in alleviating SIBO and reducing the small intestinal gas volume in SIBO-positive patients with CIPO.

Associations of nutrition impact symptoms with dietary intake and eating-related distress in patients with advanced cancer.

BACKGROUND & AIMS: There is no definition of nutrition impact symptoms (NISs) in cancer care. Moreover, there is a lack of evidence on the associations of NISs with dietary intake and eating-related distress (ERD) in advanced cancer. Therefore, this study aimed to determine the associations of NISs with dietary intake and ERD in patients with advanced cancer. METHODS: This study entailed a secondary analysis of a multicenter self-reported questionnaire designed to develop measurements that assess ERD experienced by patients. Participants evaluated their dietary intake and 19 symptoms regarded as NISs using a 10-point scale. To determine the association between dietary intake and the number of NISs with a score ≥4, estimated adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for the logistic regression model were calculated. Furthermore, to assess the association between ERD and the number of NISs with a score ≥4, multiple regression analysis was performed. RESULTS: A total of 302 patients were included in the analysis. The higher the number of NISs with a score ≥4, the lower the dietary intake tended to be. In the logistic regression model, significantly higher adjusted ORs than in the no NISs with a score ≥4 group were observed in the 4-6 NISs group, 7-9 NISs group, and 10 or more group (0.19 [95% CI, 0.07-0.52], p = 0.001; 0.11 [95% CI, 0.03-0.42], p = 0.001; 0.07 [95% CI, 0.01-0.36], p = 0.002, respectively). In the multiple regression analysis, the number of NISs with a score ≥4 was identified as one of the factors significantly associated with ERD. CONCLUSIONS: Having 4 or more NISs with a score ≥4 was shown to be predictive of the likelihood of reduced dietary intake. Furthermore, the higher the number of NISs with a score ≥4, the more likely the eating-related quality of life was impaired in advanced cancer.

Identification of differentially methylated regions associated with both liver fibrosis and hepatocellular carcinoma.

BACKGROUND: Liver fibrosis is a major risk factor for hepatocellular carcinoma (HCC). We have previously reported that differentially methylated regions (DMRs) are correlated with the fibrosis stages of metabolic dysfunction-associated steatotic liver disease (MASLD). In this study, the methylation levels of those DMRs in liver fibrosis and subsequent HCC were examined. METHODS: The methylation levels of DMRs were investigated using alcoholic cirrhosis and HCC (GSE60753). The data of hepatitis C virus-infected cirrhosis and HCC (GSE60753), and two datasets (GSE56588 and GSE89852) were used for replication analyses. The transcriptional analyses were performed using GSE114564, GSE94660, and GSE142530. RESULTS: Hypomethylated DMR and increased transcriptional level of zinc finger and BTB domain containing 38 (ZBTB38) were observed in HCC. Hypermethylated DMRs, and increased transcriptional levels of forkhead box K1 (FOXK1) and zinc finger CCCH-type containing 3 (ZC3H3) were observed in HCC. The methylation levels of DMR of kazrin, periplakin interacting protein (KAZN) and its expression levels were gradually decreased as cirrhosis progressed to HCC. CONCLUSIONS: Changes in the methylation and transcriptional levels of ZBTB38, ZC3H3, FOXK1, and KAZN are important for the development of fibrosis and HCC; and are therefore potential therapeutic targets and diagnostic tools for cirrhosis and HCC.

Current Treatment Practices for Adult Patients with Constipation in Japan.

BACKGROUND: The prevalence of constipation in Japan is estimated to be 2-5%. Constipation is a disease found in older adults. In particular, Japan is an aging society, with 65% of men and 80.5% of women aged 65 years or older accounting for the majority of its population. Chronic constipation may be associated with survival, cardiovascular events, decreased quality of life, and death. This study summarizes the recent findings regarding constipation treatment practice in Japan. SUMMARY: Until recently, the diagnosis of constipation was mainly based on medical interviews; however, with the recent development of handheld ultrasound devices, both physicians and nurses can easily and objectively diagnose fecal retention. Magnesium oxide and stimulant laxatives have been the mainstay treatments; however, since 2012, more than five new drugs for treating constipation have become available in Japan. KEY MESSAGES: Magnesium oxide is less effective in patients who use acid-secretion inhibitors and patients who have undergone total gastrectomy and should be cared for hypermagnesemia. In addition, regular use of stimulant laxatives may lead to colonic inertia and decreased bowel movements; therefore, they should be used only occasionally. The following is an overview of the different uses of conventional and newer laxatives for treating constipation.

The Prevalence and Characteristics of Symptomatic Uncomplicated Diverticular Disease Among Asian Patients With Unexplained Abdominal Symptoms.

Background/Aims: The precise incidence of symptomatic uncomplicated diverticular disease (SUDD) and its effects on the quality of life (QOL) remain unclear, particularly in Asian patients with right-sided SUDD. We assess the prevalence of SUDD and its impact on QOL in a real-world population. Methods: Five institutional cohorts of patients who received outpatient treatment for unexplained abdominal symptoms from January 15, 2020 to March 31, 2022, were included. All patients underwent colonoscopy. SUDD was defined as the presence of recurrent abdominal symptoms, particularly pain in the lower right or left quadrant lasting > 24 hours in patients with diverticulosis at the site of pain. The 36-item short-form health survey was used to assess QOL. Results: Diverticula were identified in 108 of 361 patients. Among these 108 patients, 31% had SUDD, which was right-sided in 39% of cases. Of the 50 patients with right-sided diverticula, 36% had SUDD, as did 15 of 35 patients with left-sided diverticula (43%). Among the 33 patients with SUDD, diverticula were right-sided, left-sided, and bilateral in 39%, 45%, and 15% of patients, respectively. Diarrhea was more frequent in the SUDD group than in the non-SUDD group. Patients with SUDD had significantly lower physical, mental, and role/social component scores than those without SUDD. Conclusions: It is important to recognize that patients with SUDD account for as high as 31% of outpatients with unexplained abdominal symptoms; these patients have diarrhea and a low QOL. The presence of right-sided SUDD was characteristic of Asian patients.

Combined, elobixibat, and colestyramine reduced cholesterol toxicity in a mouse model of metabolic dysfunction-associated steatotic liver disease.

BACKGROUND: Cholesterol levels and bile acid metabolism are important drivers of metabolic dysfunction-associated steatohepatitis (MASH) progression. Using a mouse model, we investigated the mechanism by which cholesterol exacerbates MASH and the effect of colestyramine (a bile acid adsorption resin) and elobixibat (an apical sodium-dependent bile acid transporter inhibitor) concomitant administration on bile acid adsorption and MASH status. METHODS: Mice were fed a high-fat high-fructose diet with varying concentrations of cholesterol to determine changes in fatty liver according to liver status, water intake, defecation status, insulin resistance, bile acid levels, intestinal permeability, atherosclerosis (in apolipoprotein E knockout mice), and carcinogenesis (in diethylnitrosamine mice). Using small interfering ribonucleic acid (siRNA), we evaluated the effect of sterol regulatory element binding protein 1c (SREBP1c) knockdown on triglyceride synthesis and fatty liver status following the administration of elobixibat (group E), colestyramine (group C), or both (group EC). RESULTS: We found greater reductions in serum alanine aminotransferase levels, serum lipid parameters, serum primary bile acid concentrations, hepatic lipid levels, and fibrosis area in EC group than in the monotherapy groups. Increased intestinal permeability and watery diarrhea caused by elobixibat were completely ameliorated in group EC. Group EC showed reduced plaque formation rates in the entire aorta and aortic valve of the atherosclerosis model, and reduced tumor counts and tumor burden in the carcinogenesis model. CONCLUSIONS: Excessive free cholesterol in the liver can promote fatty liver disease. Herein, combination therapy with EC effectively reduced free cholesterol levels in MASH model mice. Our study provides strong evidence for combination therapy as an effective treatment for MASH.

Prevalence and associated metabolic factors of nonalcoholic fatty liver disease in the general population from 2014 to 2018 in Japan: A large-scale multicenter retrospective study.

AIM: The prevalence of nonalcoholic fatty liver disease (NAFLD) is increasing worldwide. The aim of this study was to determine the recent prevalence and clinical characteristics of NAFLD in Japan. METHODS: This study initially included 410 061 retrospectively enrolled adults from the medical health checkup registry for metabolic syndrome, chronic kidney disease, and fatty liver in Japan (MIRACLE-J; UMIN-CTR no. UMIN000049419), who were evaluated between 2014 and 2018 at 13 health centers in Japan. Individuals consuming >20 g of alcohol/day or with chronic liver disease were excluded. Fatty liver was diagnosed by ultrasonography. The probability of NAFLD with advanced fibrosis was estimated based on the fibrosis-4 index and NAFLD fibrosis score. RESULTS: A total of 71 254 participants were included in the final analysis. The overall prevalence of NAFLD was 25.8%. There was a significant, twofold difference in NAFLD prevalence between men (37.4%) and women (18.1%). Nonalcoholic fatty liver disease prevalence increased linearly with body mass index, triglycerides, and low-density lipoprotein cholesterol regardless of threshold values, even in the absence of obesity. Among patients with NAFLD, 14% had diabetes mellitus, 31% had hypertension, and 48% had dyslipidemia. The estimated prevalence of NAFLD with advanced fibrosis was 1.7% and 1.0% according to the fibrosis-4 index and NAFLD fibrosis score, respectively. CONCLUSIONS: The prevalence of NAFLD was approximately one-quarter of the general population in Japan. There was a linear relationship between NAFLD prevalence and various metabolic parameters, even in nonobese participants. The prevalence of NAFLD with advanced fibrosis was estimated to be 1%-2%.

Prior appendectomy and cerebral infarction as potential risk factors for recurrent ischemic colitis: A retrospective observational study.

Background and Aim: Ischemic colitis (IC) is a benign disease associated with acute lower gastrointestinal bleeding and frequent recurrence. While several studies have investigated risk factors for IC onset, few have assessed the risk factors for recurrent IC. This study aimed to identify risk factors for recurrent IC. Methods: Potential risk factors for recurrence were assessed by examining medical records and laboratory findings in this single-center retrospective study. We extracted the following data from the patients' medical records: patient characteristics, clinical signs and symptoms, laboratory findings, method of treatment, length of hospital stay, disease course, and the frequency of IC morbidities. Patients with IC were selected from a total of 439 312 patients over an 11-year period. Patients were divided into recurrent and nonrecurrent IC groups. Results: In total, 225 patients met the diagnostic criteria for IC during the specified study period; of these, 204 patients (90.7%) and 21 patients (9.3%) were included in the nonrecurrent and recurrent IC groups, respectively. Univariate and multivariate analyses showed a significant association between IC recurrence and both cerebral infarction (P = 0.008, odds ratio [OR] = 6.3) and history of appendectomy (P = 0.0005, OR = 6.2). The median (interquartile range [IQR]) follow-up time for all patients was 1556 (353-2768) days; this was much longer than the median (IQR) time to recurrence of 291 (64-907) days in the recurrent IC group. Conclusion: The results of this study suggest that prior cerebral infarction and appendicectomy may be risk factors for IC recurrence.