Background and Aims
Ursodeoxycholic acid (UDCA) is considered to be effective in the treatment of nonalcoholic steatohepatitis (NASH), particularly in combination with other pharmacological agents. ...UDCA reportedly counteracts the effects of endotoxemia. Previously, we demonstrated attenuated hepatic fibrogenesis and suppression of activated hepatic stellate cells (Ac-HSC) with an angiotensin-II (AT-II) type 1 receptor blocker (ARB). Here we evaluated the simultaneous effect of both agents on hepatic fibrogenesis in a rat model of NASH.
Methods
Fischer 344 rats were fed a choline-deficient
l
-amino-acid-defined (CDAA) diet for 8 weeks. The therapeutic effect of UDCA and ARB was evaluated along with hepatic fibrogenesis, lipopolysaccharide (LPS)-Toll-like receptor 4 (TLR4) regulatory cascade, and intestinal barrier function. The direct inhibitory effect of both UDCA and ARB on Ac-HSC was assessed in vitro.
Results
Both UDCA and ARB had a potent inhibitory effect on hepatic fibrogenesis with suppression of the HSC activation and hepatic expression of transforming growth factor (TGF)-β1 and TLR4. UDCA decreased intestinal permeability by ameliorating zonula occuludens-1 (ZO-1) disruption induced by the CDAA diet. ARB was found to directly suppress regulation of Ac-HSC.
Conclusions
UDCA and ARB have a synergistic repressive effect on hepatic fibrogenesis by counteracting endotoxemia induced by intestinal barrier dysfunction and suppressing the activation of Ac-HSC. Because both agents are currently used in clinical practice, combined UDCA and ARB may represent a promising novel therapeutic approach for NASH.
Background
Patients with primary biliary cholangitis (PBC) frequently suffer from pruritus, which can severely impair their health-related quality of life (HRQOL). Nalfurafine hydrochloride, a ...selective κ-opioid receptor agonist, was recently approved in Japan for refractory pruritus in patients with chronic liver diseases, but it still remains unclear whether this treatment improves the patient-reported outcome (PRO) in PBC patients with refractory pruritus. Herein, we conducted a multicenter, post-marketing, single-arm prospective study to investigate the efficacy of nalfurafine in terms of PRO, and the associations of the efficacy with any clinical characteristics.
Methods
After screening for pruritus in 496 patients with PBC using PBC-40 and the visual analog scale (VAS), we identified 141 patients with moderate to severe pruritus; these were invited to participate in the study. The participants received 2.5 μg nalfurafine once daily for 12 weeks, and pruritus and HRQOL were assessed in week 12 of this treatment. Generic HRQOL, short form 36, blood chemistries, and serum autotaxin levels were also measured at baseline and at week 12.
Results
Forty-four patients participated in this study. The mean PBC-40 itch domain scores and VAS declined during the study period, from 8.56 to 7.63 (
P
= 0.041) and from 42.9 to 29.3
(P
= 0.001) at baseline and at week 12, respectively, indicating a significant effect of nalfurafine. The other domains of PBC-40 and all domains of SF-36 were not significantly altered by this treatment. We failed to find any association between the change in VAS and PBC-40 itch scores and any clinical variable. Serum autotaxin levels were significantly increased during the study period.
Conclusions
This study demonstrated that nalfurafine improved pruritus in patients with PBC, independent of their clinical characteristics, but had a limited effect on the PRO.
Background
The number of people undergoing cancer screening decreased during the COVID-19 pandemic. The pandemic may have affected the willingness and motivation of undergoing cancer screening by ...those eligible for it.
Objective
This study aims to clarify the effect of the COVID-19 pandemic on the intention to undergo cancer and esophagogastroduodenoscopy (EGD) screening.
Methods
We performed a web-based survey on the intention to undergo screening among 1236 men and women aged 20-79 years. The numbers of participants by sex and 10-year age groups were equal. The survey was conducted in January 2021, during which the government declared a state of emergency because of the third wave of the COVID-19 pandemic in Japan. Emergency declarations were issued in 11 prefectures among all the 47 prefectures in Japan.
Results
In total, 66.1% (817/1236) of the participants felt anxious about undergoing screening due to COVID-19. More women than men were anxious about undergoing screening. By modality, EGD had the highest percentage of participants with anxiety due to COVID-19. Regarding the intention to change the participants’ appointment for screening, the most common strategies were to book an appointment for a time during nonpeak hours, postpone the appointment to a later date, and change the mode of transportation. In addition, 35.8% (442/1236) of the participants were willing to cancel this year’s screening appointment. Among the 1236 participants, 757 (61.2%) were scheduled for screening in 2020. Of the 757 participants in this subgroup, 68% (n=515) did not change the schedule, 6.1% (n=46) cancelled, and 26% (n=197) made some changes, including changing the appointment date, hospital, or mode of transportation. Among the 296 participants scheduled for EGD screening, 18.9% (n=56) made some changes, 5.7% (n=17) cancelled on their own, and 2.7% (n=8) cancelled on the hospital’s order. Based on the previous screening results, the percentage of participants who felt anxious about EGD due to the COVID-19 pandemic was higher in the order of those who had not undergone screening and those who were judged to be in need of further examination in screening but did not visit a hospital for it. In the logistic regression analysis, the factors associated with anxiety about EGD screening due to the COVID-19 pandemic were “viral infection prevention measures,” “waiting time,” “fees (medical expenses),” “mode of transportation,” “worry about my social position if I contracted COVID-19,” and “perceived the risk of gastric cancer.” However, “residence in declared emergency area” was not associated with EGD anxiety due to COVID-19.
Conclusions
Excessive anxiety about COVID-19 may lead to serious outcomes, such as a “decreasing intention to undergo EGD screening,” and it is necessary to thoroughly implement infection prevention measures and provide correct information to examinees.
Aims
The efficacy of the vasopressin V2 receptor antagonist tolvaptan for difficult‐to‐treat cirrhotic ascites has recently been reported. However, its effect is variable among patients. This study ...aimed to clarify the predictive factors for obtaining a good response to tolvaptan in patients with difficult‐to‐treat ascites.
Methods
Data were collected from 50 patients with liver cirrhosis having ascites (hepatitis B, n = 1; hepatitis C, n = 22; alcoholism, n = 11; and others, n = 16) after treatment with tolvaptan (3.75–7.5 mg/day) in addition to conventional diuretics. A follow‐up assessment was carried out after 7‐day tolvaptan treatment for all patients.
Results
After an uneventful 7‐day tolvaptan treatment, 18 patients (36.0%) lost more than 2 kg of their body weight (responders). Twenty‐six patients (52.0%) showed an increase in urine volume (>300 mL) on day 2. Tolvaptan was also effective for patients with pleural effusion, portal vein thrombosis, and hepatocellular carcinoma. Basal blood urea nitrogen (BUN) levels, plasma renin activity, and aldosterone levels were significantly higher in the poor responders (<2 kg weight loss), who were considered to be in the relative vascular underfilling state, than in the responders. Basal BUN was extracted as a predictive factor of responsiveness by multivariate logistic regression analysis.
Conclusions
Tolvaptan is useful and safe for the treatment of cirrhotic ascites. This report showed that BUN will predict the response of tolvaptan even when measured before tolvaptan treatment.
Objecive Patients with autoimmune hepatitis (AIH) reportedly have an impaired quality of life (QOL), mainly due to depression, even during remission. In addition, hypozincaemia has been demonstrated ...in patients with chronic liver disease, including AIH, and is known to be related to depression. Corticosteroids are known to cause mental instability. We therefore investigated the longitudinal association between zinc supplementation and changes in the mental status among AIH patients treated with corticosteroids. Materials This study enrolled 26 patients with serological remission of AIH routinely treated at our facility after excluding 15 patients who either discontinued polaprezinc (150 mg/day) within 24 months or interrupted treatment. Two questionnaires, the Chronic Liver Disease Questionnaire (CLDQ) and SF-36, were adopted to evaluate the QOL before and after zinc supplementation. Results Serum zinc levels were significantly elevated after zinc supplementation (p<0.0001). The CLDQ worry subscale significantly improved after zinc supplementation (p=0.017), but none of the SF-36 subscales was affected. Multivariate analyses demonstrated that daily prednisolone dosing was inversely related to both the CLDQ worry domain score (p=0.036) and the SF-36 mental health component (p=0.031). There was a significant negative correlation between the changes in the daily steroid dose and the CLDQ worry domain scores before and after zinc supplementation (p=0.006). No serious adverse events occurred during the observation period. Conclusion Zinc supplementation safely and efficiently improved mental impairment, possibly caused by continuous treatment with corticosteroids, in patients with AIH.
Scope
This study investigated the combined effect of the angiotensin II (AT‐II) receptor blocker losartan and branched‐chain amino acids (BCAAs) on skeletal muscle atrophy in rats with cirrhosis and ...steatohepatitis.
Method and Results
Fischer 344 rats are fed a choline‐deficient l‐amino acid‐defined (CDAA) diet for 12 weeks and treated with oral losartan (30 mg kg−1 day−1) and/or BCAAs (Aminoleban EN, 2500 mg kg−1 day−1). Treatment with losartan and BCAAs attenuated hepatic inflammation and fibrosis and improved skeletal muscle atrophy and strength in CDAA‐fed rats. Both agents reduced intramuscular myostatin and pro‐inflammatory cytokine levels, resulting in inhibition of the ubiquitin–proteasome system (UPS) through interference with the SMAD and nuclear factor‐kappa B pathways, respectively. Losartan also augmented the BCAA‐mediated increase of skeletal muscle mass by promoting insulin growth factor‐I production and mitochondrial biogenesis. Moreover, losartan decreased the intramuscular expression of transcription factor EB (TFEB), a transcriptional inducer of E3 ubiquitin ligase regulated by AT‐II. In vitro assays illustrated that losartan promoted mitochondrial biogenesis and reduced TFEB expression in AT‐II‐stimulated rat myocytes, thereby potentiating the inhibitory effects of BCAAs on the UPS and caspase‐3 cleavage.
Conclusion
These results indicate that this regimen could serve as a novel treatment for patients with sarcopenia and liver cirrhosis.
This study demonstrates that angiotensin‐II receptor blockers efficiently augment the inhibitory effects of branched‐chain amino acids on skeletal muscle atrophy in a rat liver cirrhosis model, which is based on the prevention of liver inflammation and fibrosis resulting in the myokine signaling inhibition and insulin growth factor‐1 restoration as well as promoted mitochondrial biogenesis in myotubes.
Aim
Acute‐on‐chronic liver failure (ACLF) is associated with a high risk of short‐term mortality after progression to multiple organ failure. A disintegrin‐like and metalloproteinase with ...thrombospondin type‐1 motifs 13 (ADAMTS13) is a metalloproteinase that specifically cleaves multimeric von Willebrand factor (VWF). An imbalance between ADAMTS13 enzyme and VWF substrate is associated with liver cirrhosis progression that induces ACLF. This study examined the relationship between ADAMTS13 and VWF and ACLF development to determine whether ADAMTS13 and VWF are useful predictive biomarkers for ACLF development and prognosis of patients with liver cirrhosis.
Methods
The study enrolled 67 patients with Child–Pugh class A and B liver cirrhosis. ADAMTS13 activity (ADAMTS13:AC) and VWF antigen (VWF:Ag) were measured using enzyme‐linked immunosorbent assays. The ratio of VWF:Ag to ADAMTS13:AC (VWF:Ag/ADAMTS13:AC) was used to divide patients into two groups according to the classification and regression tree based on Gray model survival analysis.
Results
Compared with patients with Child–Pugh class A liver cirrhosis, class B patients had a higher VWF:Ag/ADAMTS13:AC and a higher risk of ACLF development. Cumulative incidence of ACLF was significantly higher in patients with high (>7.9) versus low (≤7.9) VWF:Ag/ADAMTS13:AC (hazard ratio HR, 6.50; 95% CI, 2.31–18.29; p < 0.001). Cumulative survival was significantly lower in cirrhotic patients with high versus low VWF:Ag/ADAMTS13:AC (HR 5.11; 95% CI, 1.85–14.14; p = 0.002).
Conclusions
For patients with liver cirrhosis, VWF:Ag/ADAMTS13:AC is associated with functional liver reserve and predicts the development of ACLF and the prognosis.
The progression of nonalcoholic steatohepatitis (NASH) is complicated. The multiple parallel-hits theory is advocated, which includes adipocytokines, insulin resistance, endotoxins, and oxidative ...stress. Pathways involving the gut-liver axis also mediate the progression of NASH. Angiotensin-II receptor blockers (ARB) suppress hepatic fibrosis via the activation of hepatic stellate cells (HSCs). Rifaximin, a nonabsorbable antibacterial agent, is used for the treatment of hepatic encephalopathy and has been recently reported to improve intestinal permeability. We examined the inhibitory effects on and mechanism of hepatic fibrogenesis by combining ARB and rifaximin administration. Fischer 344 rats were fed a choline-deficient/l-amino acid-defined (CDAA) diet for 8 weeks to generate the NASH model. The therapeutic effect of combining an ARB and rifaximin was evaluated along with hepatic fibrogenesis, the lipopolysaccharide-Toll-like receptor 4 (TLR4) regulatory cascade, and intestinal barrier function. ARBs had a potent inhibitory effect on hepatic fibrogenesis by suppressing HSC activation and hepatic expression of transforming growth factor-β and TLR4. Rifaximin reduced intestinal permeability by rescuing zonula occludens-1 (ZO-1) disruption induced by the CDAA diet and reduced portal endotoxin. Rifaximin directly affect to ZO-1 expression on intestinal epithelial cells. The combination of an ARB and rifaximin showed a stronger inhibitory effect compared to that conferred by a single agent. ARBs improve hepatic fibrosis by inhibiting HSCs, whereas rifaximin improves hepatic fibrosis by improving intestinal permeability through improving intestinal tight junction proteins (ZO-1). Therefore, the combination of ARBs and rifaximin may be a promising therapy for NASH fibrosis.
Both autoimmune hepatitis (AIH) and eosinophilic fasciitis (EF) are known to be complicated by other autoimmune diseases. However, AIH complicated by EF has never been reported. We experienced a ...58-year-old man with AIH complicated by EF. He was admitted to our hospital with acute hepatic injury and edema of the legs in April 201X. The etiologies of these symptoms were histologically proven as AIH and EF. The administration of prednisolone (PSL) drastically improved his liver injury and edema of the legs. When we make a diagnosis of AIH, we should carefully evaluate the physical findings, including the appearance of the legs, in order to detect other coexisting autoimmune diseases.
PDF