Analysis on mechanisms of Jindan Tablets, Xiaoyan Lidan Tablets and ursodeoxycholic acid in the treatment of gallstones and cholecystitis based on network pharmacology / 国际中医中药杂志

Objective:To analyze the mechanism of Jindan Tablets, Xiaoyan Lidan Tablets and ursodeoxycholic acid in the treatment of gallstone and cholecystitis based on network pharmacology; To conduct a comparative analysis.Methods:The chemical components of Jindan Tablets, Xiaoyan Lidan Tablets and ursodeoxycholic acid and their drug targets were collected from Traditional Chinese Medicine Database and Analysis Platform (TCMSP). DAVID 6.8 database was used to search for the associated diseases of the drug targets. The disease targets of gallstone and cholecystitis were collected from GeneCards and other databases. The protein-protein interactions network was established based on the intersecting targets of three drugs and two diseases. KEGG enrichment analysis was performed based on the DAVID 6.8 database. Cytoscape 3.7.1 software was used to construct a complex network and topology analysis of component- target- disease between three drugs and diseases.Results:222 chemical components and 3 133 drug targets were collected for Jindan Tablets. 104 chemical components and 1 425 action targets were collected for Xiaoyan Lidan Tablets. 1 chemical component and 119 action targets were collected for ursodeoxycholic acid. The three drugs were associated with 31 diseases. 1 382 disease targets for gallstones and cholecystitis were collected. There were 237, 163 and 33 targets for gallstones and cholecystitis in the three drugs, of which 17 were shared by the three drugs and 20 were shared by Jindan Tablets and Xiaoyan Lidan Tablets. Based on the DAVID database, 113, 74 and 10 significant KEGG enrichment pathways were obtained for the three drugs respectively.Conclusions:The three drugs shared many targets and pathways in the treatment of gallstones and cholecystitis, which all had the function of regulating metabolism and inhibiting inflammatory response, while participating in apoptosis, oxidative stress and cancer pathology process. However, they had their own special effects, with Jindan Tablets favoring involving in the cancer process and inhibition of inflammation, and promoting angiogenesis. Xiaoyan Lidan Tablets and ursodeoxycholic acid focused on regulating cholesterol metabolism, and Xiaoyan Lidan Tablets also regulated steroid metabolism and inhibit inflammation, while ursodeoxycholic acid regulated bile acid metabolism.

A meta-analysis of cholelithiasis after metabolic and bariatric surgery / 国际外科学杂志

Objective:To analyze the incidence of gallstone formation after Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) by meta-analysis.Methods:English terms for this meta-analysis included "bariatric surgery, gastric bypass, Roux-n-Y gastric bypass, RYGB, sleeve gastrectomy, SG, cholelithiasis, cholecystectomy, gallstone". Researched articles in Pubmed, Medline and Embase databases were searched up to February 2023 and retrieved for further analysis. The quality of each article was evaluated with Newcastle-Ottawa Scale (NOS). Generated data were analyzed with Revman 5.4.Results:Nine relevant cohort studies were retrieved for this meta-analysis, including a total of 24 255 RYGB patients and 4 500 SG patients. All articles met the requirements after the quality evaluation of NOS. The meta-analysis results showed that the incidence of postoperative gallstones in RYGB group was higher than that in SG group ( P<0.001). In subgroup analysis, by administering ursodeoxycholic acid (UDCA) for gallstone prevention, the incidence had no difference between the two groups ( P=0.090), while in the study without UDCA, the incidence of gallstones after RYGB was higher than SG ( P=0.005). In the studies with follow-up time no more than 24 months, the incidence of postoperative gallstones in RYGB group was higher than that in SG group ( P=0.050), but there was no statistical difference when following-up beyond 24 months ( P=0.240). Conclusions:Within 2 years after surgery, RYGB patients have more chances to develop gallstones than SG patients. However, beyond 2-year follow-up, there is no difference between the two procedures. Prophylactical utilization of UDCA after RYGB can effectively reduce the incidence of gallstone formation.

Epidemiological characteristics of SARS-CoV-2 pneumonia in kidney transplant recipients : a single-center retrospective study / 器官移植

Objective To investigate the epidemiological characteristics of SARS-CoV-2 pneumonia in kidney transplant recipients and analyze the risk and protective factors of severe/critical infection with SARS-CoV-2. Methods Clinical data of 468 kidney transplant recipients infected with SARS-CoV-2 were retrospectively analyzed. According to the severity of infection, they were divided into mild SARS-CoV-2 infection recipients (n=439) and SARS-CoV-2 pneumonia group (n=29). Among the 439 mild SARS-CoV-2 infection recipients, 87 recipients who were randomly matched with their counterparts in the SARS-CoV-2 pneumonia group according to sex, age and transplantation time at a ratio of 3∶1 were allocated into the mild SARS-CoV-2 infection group. Twenty-nine recipients in the SARS-CoV-2 pneumonia group were divided into the moderate SARS-CoV-2 pneumonia group (n=21) and severe/critical SARS-CoV-2 pneumonia group (n=8). Baseline data of all recipients were collected. The risk and protective factors of SARS-CoV-2 infection in kidney transplant recipients were identified. Results The proportion of recipients complicated with 2-3 types of complications in the SARS-CoV-2 pneumonia group was higher than that in the mild SARS-CoV-2 infection group, and the proportion of recipients treated with tacrolimus(Tac)+mizoribine+glucocorticoid immunosuppression regimen in the SARS-CoV-2 pneumonia group was lower than that in the mild SARS-CoV-2 infection group, and significant differences were observed (both P<0.05). In 29 kidney transplant recipients with SARS-CoV-2 pneumonia in the SARS-CoV-2 pneumonia group, white blood cells, the absolute values of lymphocytes, eosinophils, total T cells, CD4+T cells and CD8+T cells, and serum uric acid levels were significantly lower, whereas ferritin levels were significantly higher than the values prior to SARS-CoV-2 pneumonia, and significant differences were observed (all P<0.05). Compared with the moderate SARS-CoV-2 pneumonia group, the proportion of recipients with hypoxemia was higher, the proportion of recipients treated with Tac/ciclosporin (CsA)+mycophenolate mofetil+glucocorticoid immunosuppression regimen was higher, and the proportion of recipients administered with 2-3 doses of SARS-CoV-2 vaccine was lower in the severe/critical SARS-CoV-2 pneumonia group, and significant differences were observed (all P<0.05). Conclusions More complications and immunosuppression regimen containing mycophenolate mofetil are the risk factor for SARS-CoV-2 infection in kidney transplant recipients. Vaccination with SARS-CoV-2 vaccine and immunosuppression regimen containing mizoribine are probably the protective factors for lowering the risk of SARS-CoV-2 infection. The levels of inflammatory cytokines are associated with the severity of SARS-CoV-2 pneumonia.

Therapeutic effect of ursodeoxycholic acid-berberine supramolecular nanoparticles on ulcerative colitis based on supramolecular system induced by weak bond / 中国中药杂志

Ulcerative colitis(UC) is a recurrent, intractable inflammatory bowel disease. Coptidis Rhizoma and Bovis Calculus, serving as heat-clearing and toxin-removing drugs, have long been used in the treatment of UC. Berberine(BBR) and ursodeoxycholic acid(UDCA), the main active components of Coptidis Rhizoma and Bovis Calculus, respectively, were employed to obtain UDCA-BBR supramolecular nanoparticles by stimulated co-decocting process for enhancing the therapeutic effect on UC. As revealed by the characterization of supramolecular nanoparticles by field emission scanning electron microscopy(FE-SEM) and dynamic light scattering(DLS), the supramolecular nanoparticles were tetrahedral nanoparticles with an average particle size of 180 nm. The molecular structure was described by ultraviolet spectroscopy, fluorescence spectroscopy, infrared spectroscopy, high-resolution mass spectrometry, and hydrogen-nuclear magnetic resonance(H-NMR) spectroscopy. The results showed that the formation of the supramolecular nano-particle was attributed to the mutual electrostatic attraction and hydrophobic interaction between BBR and UDCA. Additionally, supramolecular nanoparticles were also characterized by sustained release and pH sensitivity. The acute UC model was induced by dextran sulfate sodium(DSS) in mice. It was found that supramolecular nanoparticles could effectively improve body mass reduction and colon shortening in mice with UC(P<0.001) and decrease disease activity index(DAI)(P<0.01). There were statistically significant differences between the supramolecular nanoparticles group and the mechanical mixture group(P<0.001, P<0.05). Enzyme-linked immunosorbent assay(ELISA) was used to detect the serum levels of tumor necrosis factor-α(TNF-α) and interleukin-6(IL-6), and the results showed that supramolecular nanoparticles could reduce serum TNF-α and IL-6 levels(P<0.001) and exhibited an obvious difference with the mechanical mixture group(P<0.01, P<0.05). Flow cytometry indicated that supramolecular nanoparticles could reduce the recruitment of neutrophils in the lamina propria of the colon(P<0.05), which was significantly different from the mechanical mixture group(P<0.05). These findings suggested that as compared with the mechanical mixture, the supramolecular nanoparticles could effectively improve the symptoms of acute UC in mice. The study provides a new research idea for the poor absorption of small molecules and the unsatisfactory therapeutic effect of traditional Chinese medicine and lays a foundation for the research on the nano-drug delivery system of traditional Chinese medicine.

Papel del ácido ursodesoxicólico en 40 años de tratamiento para la colangitis biliar primaria / Role of ursodeoxycholic acid in 40 years of treatment for primary biliary cholangitis

La colangitis biliar primaria es una enfermedad hepática autoinmune que conduce a la destrucción progresiva de los conductos biliares intrahepáticos, lo que aumenta el riesgo de desarrollar cirrosis e hipertensión portal. Actualmente, el ácido ursodesoxicólico es el medicamento de primera línea para el tratamiento de esta entidad. Este medicamento desplaza los ácidos biliares hidrofóbicos y aumenta las concentraciones de ácidos biliares hidrofílicos en la bilis, lo cual favorece la integridad de los conductos biliares, adicionalmente, tiene efectos antiinflamatorios y propiedades inmunomo-duladoras y antiapoptóticas. En los últimos 40 años, numerosos ensayos clínicos han respaldado la eficacia clínica del ácido ursodesoxicólico y su seguridad cuando se utiliza en pacientes con colan-gitis biliar primaria. Se realiza una revisión del ácido ursodesoxicólico en el contexto de colangitis biliar primaria, se describe su historia, mecanismos de acción, efectos secundarios y dosificación. Finalmente, se menciona su uso en situaciones especiales como son el embarazo y la lactancia

Primary biliary cholangitis is an autoimmune liver disease that leads to progressive destruction of intrahepatic bile ducts, increasing the risk of developing cirrhosis and portal hypertension. Currently, ursodeoxycholic acid is the first-line drug for the treatment of this condition. This drug displaces hy-drophobic bile acids and increases concentrations of hydrophilic bile acids in the bile, which favors the integrity of the bile ducts, additionally, it has anti-inflammatory effects and immunoprotective and antiapoptotic properties. Over the past 40 years numerous clinical trials have supported the clinical efficacy of ursodeoxycholic acid and its safety when used in patients with primary biliary cholangitis. A review of ursodeoxycholic acid in the context of primary biliary cholangitis is carried out, and its history, mechanisms of action, side effects and dosage are described. Finally, its use in special situations such as pregnancy and lactation are discussed.

Ursodeoxycholic acid induces sarcopenia associated with decreased protein synthesis and autophagic flux

Background Skeletal muscle generates force and movements and maintains posture. Under pathological conditions, muscle fibers suffer an imbalance in protein synthesis/degradation. This event causes muscle mass loss and decreased strength and muscle function, a syndrome known as sarcopenia. Recently, our laboratory described secondary sarcopenia in a chronic cholestatic liver disease (CCLD) mouse model. Interestingly, the administration of ursodeoxycholic acid (UDCA), a hydrophilic bile acid, is an effective therapy for cholestatic hepatic alterations. However, the effect of UDCA on skeletal muscle mass and functionality has never been evaluated, nor the possible involved mechanisms. Methods We assessed the ability of UDCA to generate sarcopenia in C57BL6 mice and develop a sarcopenic-like phenotype in C2C12 myotubes and isolated muscle fibers. In mice, we measured muscle strength by a grip strength test, muscle mass by bioimpedance and mass for specific muscles, and physical function by a treadmill test. We also detected the fiber's diameter and content of sarcomeric proteins. In C2C12 myotubes and/or isolated muscle fibers, we determined the diameter and troponin I level to validate the cellular effect. Moreover, to evaluate possible mechanisms, we detected puromycin incorporation, p70S6K, and 4EBP1 to evaluate protein synthesis and ULK1, LC3 I, and II protein levels to determine autophagic flux. The mitophagosome-like structures were detected by transmission electron microscopy. Results UDCA induced sarcopenia in healthy mice, evidenced by decreased strength, muscle mass, and physical function, with a decline in the fiber's diameter and the troponin I protein levels. In the C2C12 myotubes, we observed that UDCA caused a reduction in the diameter and content of MHC, troponin I, puromycin incorporation, and phosphorylated forms of p70S6K and 4EBP1. Further, we detected increased levels of phosphorylated ULK1, the LC3II/LC3I ratio, and the number of mitophagosome-like structures. These data suggest that UDCA induces a sarcopenic-like phenotype with decreased protein synthesis and autophagic flux. Conclusions Our results indicate that UDCA induces sarcopenia in mice and sarcopenic-like features in C2C12 myotubes and/or isolated muscle fibers concomitantly with decreased protein synthesis and alterations in autophagic flux.

Respuesta terapéutica al ácido ursodesoxicólico en pacientes cubanos con colangitis biliar primaria

Introducción: La colangitis biliar primaria es una enfermedad hepática, crónica y progresiva. El tratamiento con ácido ursodesoxicólico ha ampliado la esperanza de vida de estos pacientes. Objetivo: Describir la respuesta terapéutica al ácido ursodesoxicólico en pacientes con colangitis biliar primaria. Métodos: Estudio descriptivo, longitudinal y ambispectivo en pacientes atendidos en el Instituto de Gastroenterología entre septiembre de 2003 y enero de 2020. Se evaluaron variables clínicas, de laboratorio, histológicas y terapéuticas. El análisis de los resultados se realizó con el paquete SPSS. Resultados: Se incluyeron 45 pacientes. Hubo un predominio del sexo femenino (95,6 %) y una mediana de edad de 54 años. Los niveles bajos de aspartato amino transferasa (p=0,009 HR=0,98) y fosfatasa alcalina (p=0,005, HR=0,99), así como la presencia del síndrome de superposición (p=0,046 HR=3,08) se relacionaron con una buena respuesta al ácido ursodesoxicólico. La mayoría de los que no respondieron al tratamiento tenían cirrosis hepática (68 %). No se observaron diferencias en la supervivencia de los pacientes de acuerdo con su respuesta al tratamiento (p =0,585). Conclusiones: La respuesta terapéutica fue efectiva en menos de la mitad de los tratados con ácido ursodesoxicólico. La cirrosis hepática, el síndrome de superposición y los niveles elevados de aspartato amino transferasa y fosfatasa alcalina se asociaron a la mala respuesta terapéutica.

Introduction: Primary biliary cholangitis is a chronic and progressive liver disease. Treatment with ursodeoxycholic acid has extended the life expectancy of these patients. Objective: To describe the therapeutic response to ursodeoxycholic acid in patients with primary biliary cholangitis. Methods: Descriptive, longitudinal and ambispective study in patients treated at the Institute of Gastroenterology between September 2003 and January 2020. Clinical, laboratory, histological and therapeutic variables were evaluated. The analysis of the results was performed with the SPSS package. Results: Forty-five patients were included, with a predominance of female gender (95.6%) and a average age of 54 years. Low levels of aspartate amino transferase (p=0.009 HR=0.98) and alkaline phosphatase (p=0.005, HR=0.99), as well as the presence of overlap syndrome (p=0.046 HR=3.08) were associated with a better response to ursodeoxycholic acid. Less than half of the patients responded to conventional treatment with UDCA (47.7 %), most of the non-responders suffer from liver cirrhosis (68 %). No differences were observed in patient survival according to their response to treatment (p =0.585). Conclusions: Therapeutic response was effective in less than half of those treated with ursodeoxycholic acid. Liver cirrhosis, overlap syndrome, and elevated aspartate amino transferase and alkaline phosphatase levels were associated with poor therapeutic response.

Comparison of the efficacy of 3 kinds of drugs such as Danning tablet on preventing the recurrence of choledo-cholithiasis after endoscopic retrograde cholangiopancreatography / 中国药房

OBJECTIVE To compare the efficacy of Danning tablet， taurosodeoxycholic acid and ursodeoxycholic acid in preventing the recurrence of choledocholithiasis after endoscopic retrograde cholangiopancreatography （ERCP）. METHODS The clinical data of 153 patients who underwent ERCP choledocholithotomy from January 2017 to January 2020 in Nantong First People’s Hospital were retrospectively analyzed. According to the different drug treatment received after surgery， patients were divided into three groups， namely， Danning tablet group （group A， 49 cases）， tauroursodeoxycholic acid group （group B， 44 cases） and ursodeoxycholic acid group （group C， 60 cases）. The above groups of drugs are all single-use， starting from 2 weeks after surgery for a course of 180 days. The effects of bile component indicators [total bilirubin （Tbil）， direct bilirubin （Dbil）， alkaline phosphatase （ALP）， glutamyltransferase （GGT）]， lipid metabolism indicators [total cholesterol （TC）， triglyceride （TG）， low-density lipoprotein （LDL）， high-density lipoprotein （HDL）]， the occurrence of clinical symptoms （abdominal pain， bloating， nausea， and poor appetite） at 6 months after ERCP， and the recurrence of choledocholithiasis at 6， 12， 18 and 24 months after surgery were compared among 3 groups. RESULTS Compared with before surgery， the serum levels of Tbil， Dbil， ALP， GGT， TC， TG and LDL were significantly reduced （P＜0.05）， while serum HDL levels were significantly increased （P＜0.05） in the three groups at 6 months after surgery. The proportion of patients who experienced abdominal pain， bloating， nausea， and poor appetite at 6 months after surgery was significantly reduced （P＜0.05）. The Tbil levels of groups A and B were significantly lower than those of group C （P＜0.05）， while the Dbil and ALP levels of group A were significantly lower than those of groups B and C （P＜0.05）； however， there was no statistically significant difference in GGT levels among the 3 groups （P＞0.05）. Compared with groups A and C， the levels of four lipid metabolism indicators in group B were significantly improved （P＜0.05）； the proportion of patients with abdominal pain， bloating， and poor appetite in group A was significantly lower than groups B and C （P＜0.05）， but there was no statistically significant difference in the proportion of patients with nausea among the 3 groups （P＞0.05）. At 6，12 and 18 months after surgery， there was no statistically significant difference in the rate of choledocholithiasis recurrence among the 3 groups （P＞0.05）； at 24 months after surgery， the rate of choledocholithiasis recurrence in group A （2.04%） was significantly lower than group B （15.91%） and group C （15.00%） （P＜0.05）. CONCLUSIONS Compared with tauroursodeoxycholic acid and ursodeoxycholic acid， the application of Danning tablet after ERCP is more beneficial to reduce the secretion of bile acid， prevent the recurrence of gallstones， and improve clinical symptoms， but tauroursodeoxycholic acid can significantly accelerate the lipid metabolism of patients compared with the other two drugs.

A Comparative Study of Phototherapy Versus Phototherapy Plus Ursodeoxycholic Acid in the Treatment of Indirect Hyperbilirubinemia in Neonate

Background: Hyperbilirubinemia is a common neonatal problem. Phototherapy and exchange transfusion is the conventional treatment for indirect hyperbilirubinemia. In the treatment of cholestatic liver disorders, Ursodeoxycholic acid (UDCA) is a bile acid widely used. Few studies have been conducted using UDCA in indirect hyperbilirubinemia. Aim of the study: This study was planned to assess the additive effect of UDCA on reducing indirect hyperbilirubinemia in neonates receiving phototherapy. Material & Methods:This prospective randomized controlled trial was conducted among neonates with indirect hyperbilirubinemia in the neonatal wards of Bangladesh Shishu Hospital and Institute, Dhaka, Bangladesh from June 2018 to July 2020. Finally, 140 neonates were included in the study. Eligible cases were randomized into two groups by the lottery method. Group A (n=70) received phototherapy and Group B (n=70) received UDCA at a dose of 10 mg/kg/day orally twice daily in addition to phototherapy. Total serum bilirubin levels were measured every 12 hours until serumbilirubinlevel falls below 10 mg/dl and then phototherapy was stopped. Demographic data, clinical features, laboratory parameters, outcome variables, and complications were recorded in a pre-format sheet. CBC with PBF, Total and indirect bilirubin, Blood grouping and Rh and typing, CRP, Reticulocyte count, and Coombs test were obtained at enrolment. Comparison of parameters among themselves was done by unpaired t-test and chi-square test. Analyzed outcomes were: time for resolution of jaundice, total duration of phototherapy, length of hospital stays, and adverse effects of the drug. The two groups did not differ statistically in age, sex or weight. The mean total serum bilirubin level measured at 12, 24, 36, 48, and 60 hours of treatment in group A was 16.10±1.43, 14.76±1.45, 13.34±1.68, 11.84±1.35, and, 10.57±0.74 respectively, and in the group, B was,15.18±1.63, 13.18±2.25, 11.39±1.56, 9.84±0.81 and, 9.44±0.46 respectively (p<0.001). The mean duration of phototherapy (64.11±10.8 vs. 47.18±7.51 hours, p<0.001) and length of hospital stay (2.80 ±0.40 vs. 2.19±0.39 days, p=<0.001).Conclusion:The inclusion of UDCA as an adjuvant to phototherapy is more effective in reducing indirect hyperbilirubinemia in neonates.

Colangitis biliar primaria: experiencia de cinco años en el Hospital Clínico de la Universidad de Chile / Primary biliary cholangitis. Experience in 179 patients

BACKGROUND: Primary biliary cholangitis (PBC) is a chronic autoimmune cholestatic disease, which can progress to cirrhosis. It mainly affects middle-aged women. Its most frequent form of presentation is asymptomatic with biochemical cholestasis and the presence of antimitochondrial antibodies (AMA). AIM: To describe the epidemiological characteristics, clinical presentation and treatment for patients with PBC at a clinical hospital. MATERIAL AND METHODS: Descriptive, observational, retrospective study, carried out between January 2015 and December 2020. Results: 179 patients (158 women) were cared in the study period. At the time of diagnosis, the median age was 54 years (range 24-76), 55% of them were asymptomatic, 45% had fatigue and 28% had pruritus. Positive AMA were present in 65% of patients, antinuclear antibodies (ANA) in 51%, and anti-smooth muscle antibodies (ASMA) in 9%. Immunoglobulin M (IgM) was elevated in 30% of the patients and 50% of patients were biopsied. Splenomegaly and esophageal varices were present in 24 and 22% of patients, respectively. PBC was associated with Sjogren's syndrome in 15%, hypothyroidism in 14%, osteoporosis in 13%, and scleroderma in 8%. CONCLUSIONS: The epidemiological characteristics of our patients agree with those published abroad. Laboratory cholestasis associated with the presence of AMA, currently allows diagnosis without the need for histological study. Ursodeoxycholic acid (UDCA) is the first-line treatment for patients with PBC. The use of biochemical response criteria is essential to identify patients who require other UDCA alternatives for isolated or combined treatment.

Hepatotoxicidad por talidomida: caso clínico y revisión de la literatura / Hepatotoxicity by thalidomide: case report and literature review

La talidomida fue desarrollada e introducida al mercado por los laboratorios Grünenthal en 1953, siendo usada principalmente como sedante y también para el tratamiento de las náuseas durante el embarazo. Los informes dan cuenta de aproximadamente 10.000 niños que nacieron con focomelia, dando lugar a la denominada "tragedia de la talidomida", que obligó a su retiro del mercado en 1962. Luego de casi 60 años, es nuevamente utilizada en otros campos de la medicina, entre ellos, para el tratamiento de la lepra y del mieloma múltiple, debido a sus propiedades antinflamatorias, inmunomoduladoras y antiangiogénicas, con expresas advertencias sobre su utilización durante el embarazo; no obstante, con su nuevo uso han sido reportados múltiples efectos adversos, entre los que se encuentra la hepatitis aguda o crónica inducida por este fármaco. Se presenta el caso de una paciente de 34 años con lepra, que estaba en tratamiento con talidomida desde hacía 4 años para combatir las lesiones de piel asociadas a esta enfermedad. Presentó malestar general, vómito, pérdida de peso, artralgias, ictericia, edemas de miembros inferiores, ascitis, coluria y acolia. Se sospechó toxicidad por talidomida, por lo que se suspendió su uso, y se trató con ácido ursodesoxicólico y N-acetilcisteína con mejoría sintomática y de laboratorio, desde la primera semana hasta los 41 días de seguimiento. Las entidades clínicas para las cuales se aprobó talidomida en 1998, pueden traer nuevos problemas y desafíos clínicos. Este caso muestra hepatotoxicidad crónica por talidomida, situación que hasta el momento no se había reportado en la literatura.

Thalidomide was developed and introduced to the market by Grünenthal laboratories in 1953, being used mainly as a sedative and also for the treatment of nausea during pregnancy. Reports give account of approximately 10,000 children who were born with phocomelia, giving rise to the so-called "thalidomide tragedy", which forced its withdrawal from the market in 1962. After almost 60 years, it is usedagain in other fields of medicine, including the treatment of leprosy and multiple myeloma, due to its anti-inflammatory, immunomodulatory and anti-angiogenic properties, with clear warnings about its use during pregnancy; however, multiple adverse effects have been reported in patients with leprosy and multiple myeloma, including acute or chronic hepatitis. We present the case of a 34-year-old patient with leprosy, who had been on thalidomide therapy for 4 years to treat skin lesions associated with this disease. She presented general malaise, vomiting, weight loss, arthralgia, jaundice, lower limb edema, ascites, choluria and acholia. Thalidomide toxicity was suspected, so its use was suspended, and treatment with ursodeoxycholic acid and N-acetylcysteine was initiated, with symptomatic and laboratory improvement from the first week up until 41 days of follow-up. The new range of medical conditions for which thalidomide was approved for in 1998 may bring clinical challenges. This case shows chronic hepatotoxicity due to thalidomide, a situation that had not been reported previously in the literature.

Research advances in obeticholic acid and fibrates in treatment of primary biliary cholangitis with poor response or intolerance to ursodeoxycholic acid / 临床肝胆病杂志

Poor response or intolerance to ursodeoxycholic acid may occur in the treatment of primary biliary cholangitis (PBC), and after switch to obeticholic acid or fibrates alone or in combination, poor response or intolerance is also observed in some treatment regimens. Clinical studies on obeticholic acid and fibrates will gradually solve these issues, and obeticholic acid/fibrates combined with ursodeoxycholic acid is safe and effective in PBC patients without advanced liver cirrhosis.

Efficacy and influencing factors of ursodeoxycholic acid in the treatment of cholesterol gallstone / 中华消化杂志

Objective:To study the efficacy and influencing factors of ursodeoxycholic acid (UDCA) in the treatment of cholesterol gallstone, so as to provide reference for the treatment of cholesterol gallstone by internal medicine.Methods:From March 1, 2017 to March 31, 2018, at outpatient department of gastroenterology of 9 Beijing medical centers including Peking University People′s Hospital, the Sixth Medical Center of PLA General Hospital, Beijing Huaxin Hospital, PLA Rocket Force Characteristic Medical Center, Peking University Aerospace Center Hospital, Beijing Youan Hospital of Capital Medical University and Beijing Tiantan Hospital of Capital Medical University, Beijing Tongren Hospital of Capital Medical University, and Beijing Shijitan Hospital of Capital Medical University, the data of patients with cholesterol gallstone treated by UDCA were collected. The inclusion criteria were that the largest diameter of stone was ≤10 mm and the stone was not detected under X-ray. The treatment plan was taking UDCA orally for 6 months at a dose of 10 mg·kg -1·d -1. The basic information of patients, the ultrasound examination results before treatment and 6 months after treatment, and scores of biliary abdominal pain and dyspepsia symptom were collected. Univariate and multivariate logistic regression were used to analyze the influencing factors of the efficacy in gallstrone dissolution by UDCA, and Wilcoxon signed rank test was used for statistical analysis. Results:A total of 215 patients were enrolled. The complete dissolution rate of gallstone was 19.5% (42/215) and partial dissolution rate was 50.7% (109/215), and the total effective rate was 70.2% (151/215). The complete dissolution rate of sandy stone was significantly higher than that of lumped stones (37.0%(17/46) vs. 14.8%(25/169); OR=3.377, 95% confidence interval (95% CI) 1.621 to 7.035, P=0.001). In lumped stones, the complete dissolution rate of the stones with diameter ≤5 mm was significantly higher than that of the stones with diameter >5 mm (37.5%(9/24) vs. 11.0%(16/145); OR=4.837, 95% CI 1.823 to 12.839, P=0.002). The complete dissolution rate of patients with higher body mass index ( OR=0.872, 95% CI 0.764 to 0.995, P=0.043) and longer disease course ( OR=0.942, 95% CI 0.912 to 0.973, P<0.001) was low. The results of multivariate logistic analysis indicated that long disease course of gallstone ( OR=0.940, 95% CI 0.908 to 0.974, P=0.001), rough gallbladder wall ( OR=0.438, 95% CI 0.200 to 0.962, P=0.040) and lumped stone ( OR=0.236, 95% CI 0.101 to 0.550, P=0.001) were independent risk factors of influencing the efficacy of stone dissolution by UDCA. As for lumped stones, the independent risk factors included long disease course of gallstone ( OR=0.926, 95% CI 0.877 to 0.978, P=0.006) and stone diameter >5 mm ( OR=0.142, 95% CI 0.043 to 0.470, P=0.001). After 6 months of UDCA treatment, score of biliary abdominal pain decreased from 0 (0 to 6) to 0 (0 to 0) and the score of dyspepsia symptom decreased from 1 (0 to 2) to 0 (0 to 0), and the differences between before treatment and after treatment were statistically significant ( Z=-8.50, and -9.13, both P<0.001). Conclusions:UDCA has a certain efficacy in cholesterol gallstone dissolution and can ease biliary abdominal pain and dyspepsia symptom. Long disease course of gallstone, rough gallbladder wall and stone diameter >5 mm are independent risk factors of poor efficacy in gallstone dissolution by UDCA.

The effect of Farnesoid X receptor agonist tropifexor on liver damage in rats with experimental obstructive jaundice

ABSTRACT Purpose: To investigate experimentally the effects of Tropifexor, a farnesoid X receptor agonist, on liver injury in rats with obstructive jaundice. Methods: Forty healthy Wistar albino female rats were divided randomly in selected groups. These groups were the sham group, control group, vehicle solution group, Ursodeoxycholic acid group and Tropifexor group. Experimental obstructive jaundice was created in all groups, except the sham one. In the blood samples obtained, aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT), total bilirubin and direct bilirubin levels were established and recorded. Additionally, liver malondialdehyde, myeloperoxidase and catalase enzyme activity in the tissue samples were studied. Histopathological analysis was also performed. Results: No statistical difference was found between the control group and the Tropifexor group when AST, ALT and ALP values were compared. However, it was found that the Tropifexor group had statistically significant decreases in the values of GGT, total bilirubin and direct bilirubin (p < 0.05). Additionally, Tropifexor decreased the median values of malondialdehyde and myeloperoxidase, but this difference was not statistically significant compared to the control group. Finally, the Tropifexor group was statistically significant in recurring histopathological liver damage indicators (p < 0.05). Conclusions: Tropifexor reduced liver damage due to obstructive jaundice.

Colangitis esclerosante primaria / Primary sclerosing cholangitis

La colangitis esclerosante primaria (CEP) se define por la inflamación, fibrosis y estenosis de los conductos biliares intra o extrahepáticos que no pueden ser explicadas por otras causas. La prevalencia de CEP está estimada entre 0 a 16,2 por 100.000 habitantes, mientras que la incidencia está entre 0 y 1,3 casos por cada 100.000 personas por año. Las causas siguen siendo difíciles de dilucidar y en muchos casos se establece como de origen idiopático. Sin embargo, se han propuesto factores genéticos, ambientales e isquémicos asociados, además de un componente autoinmune. Existe además una fuerte asociación entre la enfermedad inflamatoria intestinal y la CEP. Los síntomas suelen ser inespecíficos, 50% de los pacientes son asintomáticos, presentando únicamente alteración en el perfil hepático de patrón colestásico, con predominio de elevación de la fosfatasa alcalina. La ictericia es un signo de mal pronóstico que con frecuencia se asocia a colangiocarcinoma. La confirmación diagnóstica se hace por colangiopancreatografía retrógrada endoscópica (CPRE) e imágenes por resonancia magnética. Aún no existe un tratamiento establecido, y en la mayoría de los casos coexiste con otras patologías. El tratamiento es multimodal con fármacos, terapia endoscópica y trasplante hepático.

Primary sclerosing cholangitis (PSC) is defined by inflammation, fibrosis, and stenosis of the intra or extrahepatic bile ducts that cannot be explained by other causes. The prevalence of PSC is estimated between 0 to 16.2 per 100,000 inhabitants, while the incidence is between 0 and 1.3 cases per 100,000 persons-year. The causes remain elusive and, in many cases, it is established as idiopathic in origin. However, genetic, environmental and ischemic factors have been proposed in addition to an autoimmune component. There is also a strong association between inflammatory bowel disease and PSC. Symptoms are usually nonspecific, 50% of the patients are asymptomatic, presenting only an alteration in the liver profile with a cholestatic pattern, and predominance of elevated alkaline phosphatase. Jaundice is a poor prognostic sign and is frequently associated with cholangiocarcinoma. Diagnostic confirmation is made by endoscopic retrograde cholangiopancreatography and magnetic resonance imaging. There is still no established treatment, and in most cases, the disease coexists with other pathologies. Treatment is multimodal with drugs, endoscopic therapy and liver transplantation.

Desenlaces perinatales, en un centro de tercer nivel de México de pacientes con colestasis intrahepática del embarazo / Perinatal outcomes of patients with intrahepatic cholestasis of pregnancy in a third level center in Mexico

Resumen OBJETIVO: Describir la atención, tratamiento, desenlaces perinatales y complicaciones asociadas con la colestasis intrahepática del embarazo. MATERIALES Y MÉTODOS: Estudio de serie de casos, retrospectivo y observacional de pacientes embarazadas, con diagnóstico de colestasis intrahepática atendidas en el Instituto Nacional de Perinatología entre los meses de enero de 2016 a diciembre de 2020. Se evaluaron las características obstétricas, los datos demográficos, clínicos, bioquímicos y de tratamiento, la finalización del embarazo y los desenlaces perinatales. RESULTADOS: Se analizaron 67 casos de colestasis intrahepática que arrojaron una incidencia de 0.57%. La edad promedio de las pacientes fue 29.0 ± 6.8 años, 30 de 67 eran primigestas, 12 tuvieron el antecedente de colestasis intrahepática en el embarazo previo y 7 de óbito. El inicio de la enfermedad fue en el tercer trimestre en 41 de 67 pacientes. En los estudios de bioquímica 32 de 67 tuvieron valores de ácidos biliares entre 10 y 39 μM/L; 12 de las 67: 40-99 μM/L y 23 más de 100 (μM/L). Se administró tratamiento con ácido ursodesoxicólico a 63 de 67 y ante la falta de respuesta se agregó rifampicina. El promedio de semanas de gestación fue 35.6 ± 2.0 semanas con peso promedio de 2397 ± 572 g. Se encontró líquido amniótico con meconio en 10 neonatos y restricción del crecimiento en 20 de 67; se registraron 2 óbitos. CONCLUSIONES: Este es el primer estudio efectuado en México que describe la incidencia de la enfermedad y se utiliza la determinación de los ácidos biliares para establecer el diagnóstico. Los desenlaces perinatales coinciden con lo reportado en la bibliografía.

Abstract OBJECTIVE: To describe the care, treatment, perinatal outcomes and complications associated with intrahepatic cholestasis of pregnancy. MATERIALS AND METHODS: A retrospective and observational case series study of pregnant patients with a diagnosis of intrahepatic cholestasis seen at the National Institute of Perinatology between January 2016 and December 2020. Obstetric characteristics, demographic, clinical, biochemical and treatment data, pregnancy termination and perinatal outcomes were evaluated. RESULTS: Sixty-seven cases of intrahepatic cholestasis were analyzed, yielding an incidence of 0.57%. The mean age of the patients was 29.0 ± 6.8 years, 30 of 67 were primigravidases, 12 had a history of intrahepatic cholestasis in the previous pregnancy and 7 had an abortion. The onset of the disease was in the third trimester in 41 of 67 patients. In biochemistry studies 32 of 67 had bile acid values between 10 and 39 μM/L; 12 of 67: 40-99 μM/L and 23 more than 100 (μM/L). Treatment with ursodeoxycholic acid was administered to 63 of 67 and rifampicin to 4 patients. The mean number of weeks of gestation was 35.6 ± 2.0 weeks with a mean weight of 2397 ± 572 g. Amniotic fluid with meconium was found in 10 neonates and growth restriction in 20 of 67; there were 2 recorded abortions. CONCLUSIONS: This is the first study carried out in Mexico in which the incidence of the disease is described, and the determination of bile acids is used to establish the diagnosis. Perinatal outcomes coincide with those reported in the literature.

Early response of hepatobiliary biochemical indexes after short-term ursodeoxycholic acid treatment in patients with primary biliary cholangitis / 中华风湿病学杂志

Objective:To explore the early response of hepatobiliary biochemical indexes after short-term ursodeoxycholic acid treatment in patients with primary biliary cholangitis (PBC).Methods:According to the Child-Pugh (C-P) score, the patients with newly diagnosed PBC were divided into groups A, B and C. The early biochemical response was defined as the improvement of hepatobiliary biochemical indexes while daily dose of 13-15 mg/kg ursodeoxycholic acid(UDCA) was administrated for 3-4 weeks. Rank sum test was used to compare the alkaline phosphatase (ALP), γ-glutamyl transpeptidase (GGT), aspartate aminotransferase (AST), total bile acid (TBA) and total bilirubin (TBil) before and after treatment between groups. Chi-square test was used to analyze the differences in numerical data between groups. ROC curve was also used for data an-alysis.Results:The levels of AST, ALP, GGT and TBil of groups A and B after treatment were lower than those of before treatment ( P<0.05). And there was no significant difference in group C ( P>0.05). On the contrast, TBA levels after treatment in group A, B and C were significantly higher than those of before ( P<0.05). ROC curve analysis of the baseline ALP, GGT and AST indexes that declineed less than 20% showed that their cut-off value of indexes were 211.00, 285.85 and 86.68 U/L respectively in group A. And then the cut-off value of above parameters in group B was 505.00, 353.10 and 179.15 U/L respectively. But no statistical significant difference was found in ROC curve analysis of above indexes of group C. The baseline TBil level declined synchronously with the decline of ALP, AST and GGT less than 20% were analyzed by ROC curve, but no statistical significant difference was found in group A, B and C. ROC curve analysis of the treatment showed that increased of TBA level was synchronously to the decline of ALP, AST and GGT less than 20% showed that cut-off value were 38.75 and 35.95 μmol/L respectively in group A and B. There was no statistically significant difference in ROC curve analysis of TBA in group C. As for baseline ALP, GGT and AST their level were decreased with treatment, and less than 40%, ROC curve analysis did not find statistical significant difference in above indexes. Conclusion:After 3-4 weeks of UDCA treatment, the cut off values of ALP, GGT and AST in Grade A or B of C-P are met, and the biochemical response could be reduced by 20% or more, among which the accuracy of ALP is higher. The TBA level of C-P in grade A or B PBC patients after UDCA treatment increases, and when the Cut-off value is met, it suggests that ALP, GGT and AST indexes may decrease by 20% or more. Total bilirubin does not show response to treatment.

Pregnancy outcome in patients with intrahepatic cholestasis of pregnancy: an observational case control study

Background: Intrahepatic cholestasis of pregnancy (IHCP) is the most common cholestatic liver disease, which may impact the foeto-maternal health. The present study is conducted to determine various factors including maternal and neonatal outcome in IHCP comparing with the controls.Methods: In this prospective case control study, pregnancy with IHCP is compared with asymptomatic non-IHCP controls. Classical pruritus, icterus, elevated liver enzymes were considered in diagnostic criteria of IHCP. Dermatological lesion, acute or chronic liver disease, and other causes of pruritus were excluded from study.Results: Out of 100 patients, 50 cases and 50 controls were included in this study. Incidence of IHCP was seen 3.914% of which 66% were primi presented maximum at 31-33 weeks. 86% of IHCP responded to medication. Mean value of ALT, AST and ALP was found significantly raised (p value-<0.001) in IHCP patients. 66% in IHCP and 64% in non-IHCP group had normal delivery and remaining 34% and 36 % had caesarean delivery respectively. There was no significant increase in foetal distress or low Apgar (<7 at 5 min) at birth or adverse neonatal or maternal outcome in IHCP group. However, there was a statistically high meconium stained liquor (MSL), neonatal jaundice, IUGR and NICU admission were noted in the IHCP group in comparison to non-IHCP group.Conclusions: There is a significant incidence of IHCP in the obstetrical population. The biochemical changes, meconium stained liquor, neonatal jaundice, IUGR and NICU admission were significantly high in IHCP in pregnancy.

Effectiveness of ursodeoxycholic acid therapy in intrahepatic cholestatsis of pregnancy

Background: Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy specific disorder and commonly presents with maternal pruritus, abnormal liver function tests and adverse maternal -foetal outcomes. ICP lacks protocol-based therapy as etiology is multifactorial and is based on symptomatic treatment. The overall incidence of ICP is variable from 0.1 to 15.6% worldwide. The aim of this study is to assess the effectiveness of UDCA in ICP with regards to reduction in pruritus, normalizing LFTs and maternal-foetal outcomes.Methods: This multicentric prospective study was performed from June 2017 to December 2019 in pregnant women with ICP attending the Antenatal clinic at INHS Patanjali, MH Dehradun, INHS Asvini, INHS Sandhani. In this study, 50 women with ICP. who satisfied the inclusion and exclusion criteria were started on UDCA therapy. The effectiveness of therapy was evaluated on the basis of normalization of LFT levels, reduction in pruritus, safe confinement, maternal-foetal outcomes and adverse effects if anyResults: The pregnant women with ICP on UDCA therapy showed marked improvement in pruritus, near normal LFT levels. After the UDCA therapy the frequency and intensity of pruritus was reduced in 50 (100%) of women. Safe confinement was achieved, with normal delivery in 45 (90%) women with no any major adverse effects and adverse maternal-foetal outcomes.Conclusions: This study shows the effectiveness of URCA therapy in reducing the ICP associated pruritus, normalizing LFTs and safe confinement without any major adverse effects. UDCA therapy is an effective and safe option in ICP.

Protective effect of Echinochrome against intrahepatic cholestasis induced by alpha-naphthylisothiocyanate in rats / Efeito protetor de Echinochrome contra colestase intra-hepática induzida por isotiocianato de alfa-naftilo em ratos

Abstract The present study was designed to evaluate the protective effects of echinochrome (Ech) on intrahepatic cholestasis in rats induced by a single (i.p.) injection of alpha-naphthylisothiocyanate (ANIT) (75 mg/kg body weight). The rats were pre-treated orally for 48hr (one dose / 24hr) with Ech (1, 5 and 10 mg/kg body weight) or ursodeoxycholic acid (UDCA) 80 mg/kg body weight drug then, injected with ANIT. ANIT markedly increased serum activities of alanine amino transaminase (ALT), aspartate amino transaminase (AST) and alkaline phosphatase (ALP), which was accompanied by a massive inflammation of epithelial cells on bile duct at 24h after ANIT injection. ANIT also increased the levels of total protein (TP), total bilirubin (TB), direct bilirubin (DB), indirect bilirubin (IB), however decrease albumin content (ALB). In addition ANIT increased hepatic MDA and NO level and decreased GSH level and GST activity. The Ech exerted hepatoprotective and anticholestatic effects as assessed by a significant decrease in the activities of serum AST, ALT and ALP, and the levels of TP, TB, DB and IB as well as liver MDA level and NO level. In conclusion, Ech was found to possess hepatoprotective effect against intrahepatic cholestasis induced by hepatotoxin such as ANIT.

Resumo O presente estudo destinou-se a avaliar os efeitos protetores do Ech na colestase intra-hepática em ratos induzidos por uma única injeção (i.p.) de alfa-naftilisotiocianato (ANIT) (75 mg / kg de peso corporal). Os ratos foram pré-tratados oralmente durante 48 horas (uma dose / 24 horas) com cada (1, 5 e 10 mg / kg de peso corporal) e ácido ursodeoxicólico (UDCA) 80 mg / kg de peso corporal, em seguida, injetado com ANIT. ANIT atividades de soro marcadamente aumentadas de alanina amino transaminasa (ALT), aspartato de amino transaminases (AST) e fosfatase alcalina (ALP), que foi acompanhada por uma inflamação maciça de células epiteliais no ducto biliar às 24h após a injeção de ANIT. A ANIT também aumentou os níveis de proteína total (TP), bilirrubina total (TB), bilirrubina direta (DB), bilirrubina indireta (IB), no entanto, diminuem o teor de albumina (ALB). Além disso, a ANIT aumentou o nível de MDA hepático e NO e diminuiu o nível de GSH e a atividade de GST. O Ech exerceu efeitos hepatoprotectores e anticolestáticos como avaliado por uma diminuição significativa nas atividades de AST sérica, ALT e ALP e os níveis de TP, TB, DB e IB, bem como o nível de MDA no fígado e o nível de NO. Ech foi encontrado para possuir efeito protetor no fígado contra a colestase intra-hepática induzida por hepatotoxina, como a ANIT.