RESUMEN

This is the case of a 25-year-old patient, with the notion of unprotected sexual relations with multiple partners consulted for cholestatic icterus with pruritus evolving for 2 months. The general examination found an intense mucocutaneous icterus. The examination of the lymph nodes revealed multiple lymph nodes. A thoracic-abdominal-pelvic scanner showed peri-portal edema and adenopathies above and below the diaphragm without suspicious lesions. Biologically, there was acute cytolysis with ASAT at 1612IU/L, ALAT at 1506IU/L, and icteric cholestasis, the acute viral serologies and other autoantibodies were all negative. Given the presence of adenopathy and sexual risk factors, a syphilis serology was requested and was positive: a TPHA at 2560UI/L, and a VDRL at 1/32 UI/L. A liver biopsy was performed, which showed the presence, on immunohistochemistry, of anti-treponemal-pallidum antibodies. After eliminating all etiologies of cytolytic hepatitis, we retained the diagnosis of syphilitic hepatitis. Therapeutically, we started a treatment based on ceftriaxone 2g/dl with spectacular biological improvement at H48 of the beginning of treatment.

Asunto(s)

Antibacterianos , Hepatitis , Sífilis , Humanos , Adulto , Sífilis/diagnóstico , Sífilis/complicaciones , Masculino , Hepatitis/etiología , Hepatitis/diagnóstico , Hepatitis/microbiología , Antibacterianos/administración & dosificación , Enfermedad Aguda , Ceftriaxona/administración & dosificación , Biopsia , Colestasis/etiología , Colestasis/diagnóstico

RESUMEN

OBJECTIVE: Aim: Experimental justification for creation of bile offtake into the duodenum with minimally invasive methods in cases of obstruction of the distal part of common bile duct and failure of transpapillary interventions and studying the first results of such intervention application. PATIENTS AND METHODS: Materials and Methods: The anatomical relationships between the duodenum and the common bile duct in its distal parts starting from its retroduodenal part to the sphincter of Oddi were studied. The possibility of transillumination of the walls of the common bile duct and the duodenum by a light source introduced into the lumen of the common bile duct is determined. RESULTS: Results: The length of a conventional straight line between the lumens is from 7.1±0.2 mm at a distance of 50 mm from the sphincter of Oddi to 4.7±0.1 mm at a distance of 30 mm from the sphincter of Oddi. In the distance up to 40 mm from the sphincter of Oddi, the common bile duct and the duodenum are in close proximity to each other without free spaces, that predispose for the connection formation between the lumens of the duodenum and the common bile duct. The technology of endoscopic light-guided choledochoduodenostomy is substantiated, developed and implemented. CONCLUSION: Conclusions: Created method of endoscopic light-guided choledochoduodenostomy allows to perform a conjunction between the lumens of the duodenum and the common bile duct. This intervention can be used when endoscopic transpapillary drainage of the common bile duct is impossible and has advantages over open draining bile duct operations in patients with tumor distal common bile duct obstruction.

Asunto(s)

Coledocostomía , Humanos , Coledocostomía/métodos , Conducto Colédoco/cirugía , Masculino , Femenino , Persona de Mediana Edad , Colestasis/cirugía , Duodeno/cirugía , Anciano

RESUMEN

Cholestatic liver injury results from the accumulation of toxic bile acids in the liver, presenting a therapeutic challenge with no effective treatment available to date. Andrographolide (AP) has exhibited potential as a treatment for cholestatic liver disease. However, its limited oral bioavailability poses a significant obstacle to harnessing its potent therapeutic properties and restricts its clinical utility. This limitation is potentially attributed to the involvement of gut microbiota in AP metabolism. In our study, employing pseudo-germ-free, germ-free and strain colonization animal models, along with 16S rRNA and shotgun metagenomic sequencing analysis, we elucidate the pivotal role played by gut microbiota in the C-sulfonate metabolism of AP, a process profoundly affecting its bioavailability and anti-cholestatic efficacy. Subsequent investigations pinpoint a specific enzyme, adenosine-5'-phosphosulfate (APS) reductase, predominantly produced by Desulfovibrio piger, which catalyzes the reduction of SO42- to HSO3-. HSO3- subsequently interacts with AP, targeting its C=C unsaturated double bond, resulting in the formation of the C-sulfonate metabolite, 14-deoxy-12(R)-sulfo andrographolide (APM). Inhibition of APS reductase leads to a notable enhancement in AP bioavailability and anti-cholestatic efficacy. Furthermore, employing RNA sequencing analysis and farnesoid X receptor (FXR) knockout mice, our findings suggest that AP may exert its anti-cholestatic effects by activating the FXR pathway to promote bile acid efflux. In summary, our study unveils the significant involvement of gut microbiota in the C-sulfonate metabolism of AP and highlights the potential benefits of inhibiting APS reductase to enhance its therapeutic effects. These discoveries provide valuable insights into enhancing the clinical applicability of AP as a promising treatment for cholestatic liver injury.

Asunto(s)

Disponibilidad Biológica , Diterpenos , Microbioma Gastrointestinal , Animales , Microbioma Gastrointestinal/efectos de los fármacos , Diterpenos/metabolismo , Diterpenos/farmacología , Ratones , Colestasis/metabolismo , Colestasis/tratamiento farmacológico , Colestasis/microbiología , Masculino , ARN Ribosómico 16S/genética , Ácidos y Sales Biliares/metabolismo , Bacterias/metabolismo , Bacterias/clasificación , Bacterias/genética , Bacterias/efectos de los fármacos , Bacterias/aislamiento & purificación , Humanos , Ratones Endogámicos C57BL , Hígado/metabolismo , Hígado/efectos de los fármacos , Receptores Citoplasmáticos y Nucleares/metabolismo , Receptores Citoplasmáticos y Nucleares/genética , Modelos Animales de Enfermedad

RESUMEN

Gut microbiota dysbiosis is involved in cholestatic liver diseases. However, the mechanisms remain to be elucidated. The purpose of this study was to examine the effects and mechanisms of Lactobacillus acidophilus (L. acidophilus) on cholestatic liver injury in both animals and humans. Bile duct ligation (BDL) was performed to mimic cholestatic liver injury in mice and serum liver function was tested. Gut microbiota were analyzed by 16S rRNA sequencing. Fecal bacteria transplantation (FMT) was used to evaluate the role of gut microbiota in cholestasis. Bile acids (BAs) profiles were analyzed by targeted metabolomics. Effects of L. acidophilus in cholestatic patients were evaluated by a randomized controlled clinical trial (NO: ChiCTR2200063330). BDL induced different severity of liver injury, which was associated with gut microbiota. 16S rRNA sequencing of feces confirmed the gut flora differences between groups, of which L. acidophilus was the most distinguished genus. Administration of L. acidophilus after BDL significantly attenuated hepatic injury in mice, decreased liver total BAs and increased fecal total BAs. Furthermore, after L. acidophilus treatment, inhibition of hepatic Cholesterol 7α-hydroxylase (CYP7α1), restored ileum Fibroblast growth factor 15 (FGF15) and Small heterodimer partner (SHP) accounted for BAs synthesis decrease, whereas enhanced BAs excretion was attributed to the increase of unconjugated BAs by enriched bile salt hydrolase (BSH) enzymes in feces. Similarly, in cholestasis patients, supplementation of L. acidophilus promoted the recovery of liver function and negatively correlated with liver function indicators, possibly in relationship with the changes in BAs profiles and gut microbiota composition. L. acidophilus treatment ameliorates cholestatic liver injury through inhibited hepatic BAs synthesis and enhances fecal BAs excretion.

Asunto(s)

Ácidos y Sales Biliares , Colestasis , Microbioma Gastrointestinal , Lactobacillus acidophilus , Hígado , Ratones Endogámicos C57BL , Probióticos , Ácidos y Sales Biliares/metabolismo , Animales , Colestasis/metabolismo , Colestasis/microbiología , Ratones , Humanos , Masculino , Probióticos/farmacología , Probióticos/administración & dosificación , Hígado/metabolismo , Heces/microbiología , Colesterol 7-alfa-Hidroxilasa/metabolismo , Colesterol 7-alfa-Hidroxilasa/genética , Femenino , Factores de Crecimiento de Fibroblastos/metabolismo , Factores de Crecimiento de Fibroblastos/genética , Trasplante de Microbiota Fecal , Disbiosis/microbiología , Disbiosis/terapia , ARN Ribosómico 16S/genética , Persona de Mediana Edad , Adulto , Modelos Animales de Enfermedad , Íleon/microbiología , Íleon/metabolismo

RESUMEN

INTRODUCTION: Cholestasis is bile flow disruption that leads to bile accumulation, which could lead to liver fibrosis. Ursodeoxycholic acid (UDCA) has a hepatoprotective effect. Glutathione (GSH) is an endogenous antioxidant that plays a role in maintaining the function and structure of liver cells. This study aimed to examine the effect of UDCA-GSH combination therapy in multiple doses on liver function in the Sprague-Dawley rats' liver fibrosis model. MATERIALS AND METHODS: This was a randomised post-testonly study. A total of 28 rats were assigned into four groups: Group 1 is control group (C), samples had bile duct ligation and UDCA monotherapy 20 mg; Group 2, bile duct ligation + UDCA 10 mg + glutathione 10 mg (P1); Group 3, bile duct ligation + UDCA 20 mg + glutathione 15 mg (P2); Group 4, bile duct ligation + UDCA 30 mg + glutathione 20 mg (P3). Serum AST, ALT, ALP activity, total, direct and indirect bilirubin were collected. Shapiro-Wilk test was used for the normality test. All groups' data were compared using Kruskall-Wallis and Mann-Whitney tests. RESULTS: There was a significant difference in the ALP level in all rats and between the C and P2 groups. ALP level of all groups decreased significantly compared to the control group. Combination therapy group showed lower bilirubin levels. ALT levels significantly differed between the C-P1, P1-P2, and P1-P3 groups. CONCLUSION: UDCA-GSH therapy improves liver function in BDL rats' models compared to UDCA monotherapy.

Asunto(s)

Colestasis , Quimioterapia Combinada , Glutatión , Ratas Sprague-Dawley , Ácido Ursodesoxicólico , Animales , Ácido Ursodesoxicólico/administración & dosificación , Ácido Ursodesoxicólico/farmacología , Ácido Ursodesoxicólico/uso terapéutico , Colestasis/tratamiento farmacológico , Colestasis/etiología , Glutatión/metabolismo , Ratas , Masculino , Hígado/efectos de los fármacos , Distribución Aleatoria , Modelos Animales de Enfermedad , Colagogos y Coleréticos/administración & dosificación , Pruebas de Función Hepática

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Cholestatic liver diseases (CLD) are liver disorders resulting from abnormal bile formation, secretion, and excretion from various causes. Due to the lack of suitable and safe medications, liver transplantation is the ultimate treatment for CLD patients. Isoastragaloside I (IAS I) is one of the main saponin found in Astragalus membranaceus (Fisch.) Bge. var. mongholicus (Bge.) Hsiao or Astragalus membranaceus (Fisch.) Bge, which has been demonstrated to obviously alleviate CLD. Nevertheless, the IAS I's specific anti-CLD mechanism remains undecipherable. AIM OF THE STUDY: This study's purpose was to elucidate the protective consequence of IAS I on 0.1% 3, 5-diethoxycarbonyl-1,4-dihydroxychollidine (DDC) diet-induced CLD mice, and to reveal its potential mechanism. MATERIALS AND METHODS: In this study, mice with CLD that had been fed a 0.1% DDC diet were distributed two doses of IAS I (20 mg/kg, 50 mg/kg). The effects of IAS I on CLD models were investigated by assessing blood biochemistry, liver histology, and Hyp concentrations. We investigated markers of liver fibrosis and ductular reaction using immunohistochemistry, Western blot, and qRT-PCR. Liver inflammation indicators, arachidonic acid (ARA), and ω-3 fatty acid (FA) metabolites were also analyzed. Quantitative determination of 39 bile acids (BAs) in different organs employing UHPLC-Q-Exactive Orbitrap HRMS technology. Additionally, the H&E and Western blot analysis were used to evaluate differences in intestinal barrier function in DDC-induced mice before and after administering IAS I. RESULTS: After treatment with IAS I, serum biochemical indicators and liver hydroxyproline (Hyp) increased in a dose-dependent manner in CLD mice. The IAS I group showed significant improvement in indicators of liver fibrosis and ductular response, including as α-smooth muscle actin (α-SMA) and cytokeratin 19 (CK19), and transforming growth factor-ß (TGF-ß)/Smads signaling pathway. And inflammatory factors: F4/80, tumor necrosis factor-α (TNF-α), Interleukin-1ß (IL-1ß), ARA and ω-3 FA metabolites showed significant improvement following IAS I treatment. Moreover, IAS I significantly ameliorated liver tau-BAs levels, particularly TCA, THCA, THDCA, TCDCA, and TDCA contents, which were associated with enhanced expression of hepatic farnesoid X receptor (FXR), small heterodimer partner (SHP), cholesterol 7α-hydroxylase (Cyp7a1), and bile-salt export pump (BSEP). Furthermore, IAS I significantly improved pathological changes and protein expression related to intestinal barrier function, including zonula occludens protein 1 (ZO-1), Muc2, and Occludin. CONCLUSIONS: IAS I alleviated cholestatic liver injury, relieved inflammation, improved the altered tau-BAs metabolism and restored intestinal barrier function to protect against DDC-induced cholestatic liver diseases.

Asunto(s)

Ácidos y Sales Biliares , Colestasis , Saponinas , Animales , Ácidos y Sales Biliares/metabolismo , Masculino , Ratones , Colestasis/tratamiento farmacológico , Colestasis/metabolismo , Colestasis/patología , Saponinas/farmacología , Saponinas/uso terapéutico , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Ratones Endogámicos C57BL , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Hepatopatías/tratamiento farmacológico , Hepatopatías/metabolismo , Hepatopatías/patología , Hepatopatías/prevención & control , Modelos Animales de Enfermedad , Medicamentos Herbarios Chinos

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Yin-Chen-Si-Ni Decoction is a classical traditional Chinese medicine (TCM) prescription that is used clinically for treating cholestatic liver injury (CLI) and other hepatic diseases. However, the material basis and underlying mechanisms of YCSND are not clear. AIM OF THE STUDY: To investigate effective components and mechanisms of YCSND in the treatment of CLI using serum pharmacochemistry, metabolomics, and network pharmacology. MATERIALS AND METHODS: Biochemical indicators, liver index, and histopathology analysis were adopted to evaluate the protective effect of YCSND on ANIT-induced CLI rats. Then, a UPLC-Q-Exactive Orbitrap MS/MS analysis of the migrant components in serum and liver including prototype and metabolic components was performed in YCSND. In addition, a study of the endogenous metabolites using serum and liver metabolomics was performed to discover potential biomarkers, metabolic pathways, and associated mechanisms. Further, the network pharmacology oriented by in vivo migrant components was also used to pinpoint the active ingredients, core targets, and signaling pathways of YCSND. Finally, molecular docking and molecular dynamics simulation (MDS) were used to predict the binding ability between components and core targets, and a real-time qPCR (RT-qPCR) experiment was used to measure the mRNA expression of the core target genes. RESULTS: Pharmacodynamic studies suggest that YCSND could exert obvious hepatoprotective effects on CLI rats. Furthermore, 68 compounds, comprising 32 prototype components and 36 metabolic components from YCSND, were found by serum pharmacochemistry analysis. Network pharmacology combining molecular docking and MDS showed that apigenin, naringenin, 18ß-glycyrrhetinic acid, and isoformononetin have better binding ability to 6 core targets (EGFR, AKT1, IL6, MMP9, CASP3, PPARG). Additionally, PI3K, TNF-α, MAPK3, and six core target genes in liver tissues were validated with RT-qPCR. Metabolomics revealed the anti-CLI effects of YCSND by regulating four metabolic pathways of primary bile acid and biosynthesis, phenylalanine, tyrosine and tryptophan biosynthesis, taurine and hypotaurine metabolism, and arachidonic acid metabolism. Integrating metabolomics and network pharmacology identified four pathways related to CLI, including the PI3K-Akt, HIF-1, MAPK, and TNF signaling pathway, which revealed multiple mechanisms of YCSND against CLI that might involve anti-inflammatory and apoptosis. CONCLUSION: The research based on serum pharmacochemistry, network pharmacology, and metabolomics demonstrates the beneficial hepatoprotective effects of YCSND on CLI rats by regulating multiple components, multiple targets, and multiple pathways, and provides a potent means of illuminating the material basis and mechanisms of TCM prescriptions.

Asunto(s)

1-Naftilisotiocianato , Medicamentos Herbarios Chinos , Hígado , Metabolómica , Farmacología en Red , Animales , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/química , Masculino , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , 1-Naftilisotiocianato/toxicidad , Ratas , Ratas Sprague-Dawley , Colestasis/tratamiento farmacológico , Colestasis/inducido químicamente , Colestasis/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Biomarcadores/sangre

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Yajieshaba (YJSB), approved by the Yunnan Provincial Food and Drug Administration in 2008, are known for their anti-inflammatory, antiviral, and pro-apoptotic properties, effectively treating Hepatic fibrosis (HF). However, its mechanism of action remains unclear. AIM OF THE STUDY: The objective of this investigation is to explore how YJSB influences the TGF-ß1/Smad signaling pathway as a strategy for reducing HF. METHODS: The establishment of a HF model in mice involved ligation of the common bile duct, followed by administration of YJSB. Body and liver weights were measured, and the liver index calculated. Serum levels of ALT, AST, ALP, TBA, and TBIL were assessed using colorimetric methods. Additionally, liver homogenates were analyzed for PIIINP, Col-IV, LN, HA, and Hyp, as well as TGF-ß1 activity, using ELISA. Histological analyses of liver sections, stained with H&E, Ag, and Masson's trichrome, were performed to examine inflammation and the accumulation of collagen and reticular fibers. These studies aimed to elucidate the pharmacodynamic effects of YJSB on HF in mice with bile duct obstruction. The target pathways of YJSB were preliminarily identified through immunofluorescence detection of TGF-ß1, P-Smad2L, P-Smad2C, P-Smad3L, P-Smad3C, and Smad4 proteins. In vitro experiments included the induction of hepatic stellate cell (HSC-T6) activation by H2O2. A cell injury model was established for HSC-T6, and the CCK-8 assay was used to determine the optimal YJSB concentration and treatment duration. After pirfenidone (PFD) administration, which inhibits the TGF-ß1/Smad pathway, the effects of YJSB on HSC-T6 cell proliferation were observed. ELISA assays quantified Col-III, α-SMA, and Col-I in cell lysates to assess YJSB's impact on collagen synthesis in HSC-T6 cells. Western blot analysis was performed to assess the protein levels within the TGF-ß1/Smad signaling cascade. RESULTS: In the HF mouse model, administration of YJSB notably augmented the body weight and reduced the liver index. Concurrently, there was an elevation in serum concentrations of ALP, AST, ALT, TBA, and TBIL. Similarly, in the liver homogenates of HF mice, increases were observed in the levels of HA, PIIINP, Col-IV, LN, Hyp, and TGF-ß1. Histological assessments using H&E, Ag, and Masson stains indicated a substantial diminution in liver tissue damage. Through immunofluorescence analysis, it was discerned that YJSB modulated the expression of TGF-ß1, P-Smad2L, P-Smad2C, and P-Smad3L downwards, while elevating P-Smad3C and Smad4 protein expressions. Additional investigations revealed a significant reduction in α-SMA, Col-I, and Col-III levels in cell culture fluids, suggesting a decrease in collagen synthesis and a protective role against cellular damage. Western blot analyses demonstrated that the TGF-ß1/Smad pathway inhibitor, PFD, acted in synergy with YJSB, enhancing its regulatory effects on this pathway, decreasing levels of TGF-ß1, P-Smad2L, P-Smad2C, P-Smad3L, and promoting the expression of P-Smad3C. CONCLUSIONS: YJSB demonstrates a pharmacodynamic effect against HF, enhancing liver functionality and effectively mitigating the damage associated with bile duct obstruction. The proposed action mechanism of YJSB involves modulation of the TGF-ß1/Smad signaling pathway. Research indicates that YJSB might play a role in suppressing the movement, programmed cell death, and activation of HSC-T6, potentially decelerating the advancement of hepatic fibrosis.

Asunto(s)

Colestasis , Células Estrelladas Hepáticas , Peróxido de Hidrógeno , Cirrosis Hepática , Transducción de Señal , Factor de Crecimiento Transformador beta1 , Animales , Cirrosis Hepática/tratamiento farmacológico , Cirrosis Hepática/metabolismo , Cirrosis Hepática/patología , Factor de Crecimiento Transformador beta1/metabolismo , Ratones , Masculino , Peróxido de Hidrógeno/metabolismo , Colestasis/metabolismo , Colestasis/patología , Colestasis/tratamiento farmacológico , Células Estrelladas Hepáticas/efectos de los fármacos , Células Estrelladas Hepáticas/metabolismo , Transducción de Señal/efectos de los fármacos , Medicamentos Herbarios Chinos/farmacología , Línea Celular , Modelos Animales de Enfermedad , Hígado/efectos de los fármacos , Hígado/patología , Hígado/metabolismo , Proteínas Smad/metabolismo , Ratones Endogámicos C57BL , Proteína Smad2/metabolismo

Asunto(s)

Colangiopancreatografia Retrógrada Endoscópica , Colestasis , Drenaje , Humanos , Drenaje/métodos , Colangiopancreatografia Retrógrada Endoscópica/métodos , Colestasis/etiología , Colestasis/cirugía , Colestasis/diagnóstico por imagen , Colestasis/terapia , Endoscopía del Sistema Digestivo/métodos , Masculino , Neoplasias de los Conductos Biliares/complicaciones , Neoplasias de los Conductos Biliares/diagnóstico por imagen , Anciano , Femenino

Asunto(s)

Anastomosis Quirúrgica , Endosonografía , Humanos , Endosonografía/métodos , Constricción Patológica/cirugía , Constricción Patológica/etiología , Anastomosis Quirúrgica/efectos adversos , Anastomosis Quirúrgica/métodos , Ultrasonografía Intervencional , Masculino , Yeyunostomía/métodos , Yeyuno/cirugía , Femenino , Colestasis/cirugía , Colestasis/etiología , Colestasis/diagnóstico por imagen , Persona de Mediana Edad , Anciano

RESUMEN

BACKGROUND: Mass-forming intrahepatic cholangiocarcinoma (mICC) is the most frequent type of ICC. In contrast-enhanced computed tomography, mICC is visualized as a hypodense lesion with distal dilatation of intrahepatic bile ducts. The presented case illustrates the unusual manifestation of mICC in a 71-year-old male patient, where despite the extensive tumor mass and the hilar infiltration, the dilatation of intrahepatic bile ducts and cholestasis were not noted. METHODS: A literature review on PubMed was performed. Primarily, 547 records were identified, and the titles and abstracts were systematically searched. Regarding the inclusion and exclusion criteria, 31 papers describing the non-cancerous liver lesions mimicking ICC were included in the further analysis. RESULTS: In 41.9% of the analyzed non-cancerous lesions, the obstruction of the bile ducts was not noted, similar to our patient. A significant cholestasis has been found in 30.03% of analyzed patients. The invasion of the liver hilum was noted in one-third of the patients. CONCLUSIONS: Atypical radiological features in lesions suspected of ICC, such as the absence of intrahepatic bile-duct dilation, are common in benign lesions. In the case of radiologically atypical lesions suspected of ICC, the diagnostic imaging needs to be correlated with clinical data, and the diagnosis should be confirmed with a pathological examination.

Asunto(s)

Neoplasias de los Conductos Biliares , Colangiocarcinoma , Anciano , Humanos , Masculino , Neoplasias de los Conductos Biliares/complicaciones , Neoplasias de los Conductos Biliares/diagnóstico , Neoplasias de los Conductos Biliares/patología , Conductos Biliares Intrahepáticos/diagnóstico por imagen , Conductos Biliares Intrahepáticos/patología , Colangiocarcinoma/complicaciones , Colangiocarcinoma/diagnóstico , Colestasis/diagnóstico , Colestasis/etiología , Diagnóstico Diferencial , Tomografía Computarizada por Rayos X/métodos

RESUMEN

Cholestatic liver diseases, including primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), result from an impairment of bile flow that leads to the hepatic retention of bile acids, causing liver injury. Until recently, the only approved treatments for PBC were ursodeoxycholic acid (UDCA) and obeticholic acid (OCA). While these therapies slow the progression of PBC in the early stage of the disease, approximately 40% of patients respond incompletely to UDCA, and advanced cases do not respond. UDCA does not improve survival in patients with PSC, and patients often have dose-limiting pruritus reactions to OCA. Left untreated, these diseases can progress to fibrosis and cirrhosis, resulting in liver failure and the need for transplantation. These shortcomings emphasize the urgent need for alternative treatment strategies. Recently, nuclear hormone receptors have been explored as pharmacological targets for adjunct therapy because they regulate enzymes involved in bile acid metabolism and detoxification. In particular, the peroxisome proliferator-activated receptor (PPAR) has emerged as a therapeutic target for patients with PBC or PSC who experience an incomplete response to UDCA. PPARα is predominantly expressed in the liver, and it plays an essential role in the regulation of cytochrome P450 (CYP) and uridine 5'-diphospho-glucuronosyltransferase (UGT) enzymes, both of which are critical enzyme families involved in the regulation of bile acid metabolism and glucuronidation, respectively. Importantly, PPARα agonists, e.g., fenofibrate, have shown therapeutic benefits in reducing elevated markers of cholestasis in patients with PBC and PSC, and elafibranor, the first PPAR (dual α, ß/δ) agonist, has been FDA-approved for the second-line treatment of PBC. Additionally, newer PPAR agonists that target various PPAR isoforms (ß/δ, γ) are under development as an adjunct therapy for PBC or PSC, although their impact on glucuronidation pathways are less characterized. This review will focus on PPAR-mediated bile acid glucuronidation as a therapeutic pathway to improve outcomes for patients with PBC and PSC.

Asunto(s)

Ácidos y Sales Biliares , Humanos , Ácidos y Sales Biliares/metabolismo , Receptores Activados del Proliferador del Peroxisoma/metabolismo , Receptores Activados del Proliferador del Peroxisoma/agonistas , Colestasis/metabolismo , Colestasis/tratamiento farmacológico , Animales , Cirrosis Hepática Biliar/metabolismo , Cirrosis Hepática Biliar/tratamiento farmacológico , Colangitis Esclerosante/tratamiento farmacológico , Colangitis Esclerosante/metabolismo

RESUMEN

 Benign biliary strictures (BBS) ensue from inflammatory conditions (e.g., chronic pancreatitis) or post surgery (e.g., cholecystectomy and liver transplant). High-quality cross-sectional imaging studies such as computed tomography or magnetic resonance cholangiopancre atography are essential in the diagnosis and planning of therapeutic interventions and in ruling out malignancy. Endoscopic retrograde cholangiopancreatography with dilation and stenting is the mainstay treatment for BBS, while surgery is reserved for failed endoscopy or refractory cases.

Asunto(s)

Colangiopancreatografia Retrógrada Endoscópica , Colestasis , Stents , Humanos , Constricción Patológica/etiología , Colestasis/etiología , Colestasis/terapia

RESUMEN

End-ischemic normothermic mechanical perfusion (NMP) could provide a curative treatment to reduce cholestatic liver injury from donation after circulatory death (DCD) in donors. However, the underlying mechanism remains elusive. Our previous study demonstrated that air-ventilated NMP could improve functional recovery of DCD in a preclinical NMP rat model. Here, metabolomics analysis revealed that air-ventilated NMP alleviated DCD- and cold preservation-induced cholestatic liver injury, as shown by the elevated release of alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin, and γ-glutamyl transferase (GGT) in the perfusate (p < .05) and the reduction in the levels of bile acid metabolites, including ω-muricholic acid, glycohyodeoxycholic acid, glycocholic acid, and glycochenodeoxycholate (GCDC) in the perfused livers (p < .05). In addition, the expression of the key bile acid metabolism enzyme UDP-glucuronosyltransferase 1A1 (UGT1A1), which is predominantly expressed in hepatocytes, was substantially elevated in the DCD rat liver, followed by air-ventilated NMP (p < .05), and in vitro, this increase was induced by decreased GCDC and hypoxia-reoxygenation in the hepatic cells HepG2 and L02 (p < .05). Knockdown of UGT1A1 in hepatic cells by siRNA aggravated hepatic injury caused by GCDC and hypoxia-reoxygenation, as indicated by the ALT and AST levels in the supernatant. Mechanistically, UGT1A1 is transcriptionally regulated by peroxisome proliferator-activator receptor-γ (PPAR-γ) under hypoxia-physoxia. Taken together, our data revealed that air-ventilated NMP could alleviate DCD- and cold preservation-induced cholestatic liver injury through PPAR-γ/UGT1A1 axis. Based on the results from this study, air-ventilated NMP confers a promising approach for predicting and alleviating cholestatic liver injury through PPAR-γ/UGT1A1 axis.

Asunto(s)

PPAR gamma , Animales , Ratas , PPAR gamma/metabolismo , PPAR gamma/genética , Masculino , Humanos , Glucuronosiltransferasa/metabolismo , Glucuronosiltransferasa/genética , Hígado/metabolismo , Hígado/patología , Colestasis/metabolismo , Perfusión , Ratas Sprague-Dawley , Preservación de Órganos/métodos , Trasplante de Hígado

RESUMEN

BACKGROUND: Whether endobiliary radiofrequency ablation (EB-RFA) changes the standard role of stent placement in treating unresectable malignant biliary obstruction (MBO) remains unclear. The aim of this study is to compare percutaneous EB-RFA and metal stent placement (RFA-Stent) with metal stent placement alone (Stent) in treating unresectable MBO using a propensity score matching (PSM) analysis. METHODS: From June 2013 to June 2018, clinical data from 163 patients with malignant biliary obstruction who underwent percutaneous RFA-Stent or stenting alone were retrospectively analyzed using a nearest-neighbor algorithm to one-to-one PSM analysis to compare primary and secondary stent patency (PSP, SSP), overall survival (OS) and complications between the two groups. RESULTS: Before matching, for whole patients, RFA-Stent resulted in longer median PSP (8.0 vs. 5.1 months, P = 0.003), SSP (9.8 vs. 5.1 months, P < 0.001) and OS (7.0 vs. 4.5 months, P = 0.034) than the Stent group. After matching (54 pairs), RFA-Stent also resulted in better median PSP (8.5 vs. 5.1 months, P < 0.001), SSP (11.0 vs. 6.0 months, P < 0.001), and OS (8.0 vs. 4.0 months, P = 0.007) than Stent. RFA-Stent was comparable with Stent for complication rates. In Cox analysis, RFA-Stent modality and serum total bilirubin level were independent prognostic factors for PSP. RFA-Stent modality, performance status score and combination therapy after stent were independent prognostic factors for OS. CONCLUSION: Percutaneous RFA-Stent was superior to Stent in terms of PSP, SSP, and OS in selected patients with unresectable MBO.

Asunto(s)

Colestasis , Puntaje de Propensión , Ablación por Radiofrecuencia , Stents , Humanos , Estudios Retrospectivos , Masculino , Femenino , Anciano , Colestasis/etiología , Colestasis/cirugía , Ablación por Radiofrecuencia/métodos , Persona de Mediana Edad , Neoplasias de los Conductos Biliares/complicaciones , Neoplasias de los Conductos Biliares/cirugía , Resultado del Tratamiento , Anciano de 80 o más Años

RESUMEN

BACKGROUND: Alagille syndrome (ALGS) is a multisystem genetic disorder frequently characterized by hepatic manifestations. This study analyzed the clinical, pathological, and molecular genetic features of ALGS to improve the efficiency of clinical diagnosis. METHODS: We retrospectively analyzed the clinical manifestations, pathological examination findings, and genetic testing results of 17 children diagnosed with ALGS based on the revised criteria and hospitalized at our center from January 2012 to January 2022. RESULTS: The clinical manifestations are as follows: Cholestasis (16/17, 94%), characteristic facies (15/17, 88%), heart disease (12/16, 75%), butterfly vertebrae (12/17, 71%) and posterior embryotoxon (7/12, 58%). Among the 15 patients who underwent liver pathology examination, 13 (87%) were found to have varying degrees of bile duct paucity. Genetic testing was performed on 15 children, and pathogenic variants of the jagged canonical Notch ligand 1 (JAG1) gene were identified in 13 individuals, including 4 novel variants. No pathogenic variant in the notch homolog 2 (NOTCH2) gene were identified, and 2 children exhibited none of the aforementioned gene pathogenic variants. The median follow-up duration was 7 years. Of the remaining 15 patients (excluding 2 lost to follow-up), 11 remained stable, 4 deteriorated, and no patient died during the follow-up period. CONCLUSIONS: Among children diagnosed with ALGS, cholestasis stands as the most common feature. To minimize the risk of misdiagnosis, genetic testing should be performed on children exhibiting cholestasis, followed by the application of the revised diagnostic criteria for ALGS. While pharmacological therapy has shown effectiveness for ALGS patients, liver transplantation may be considered in instances of severe pruritus.

Asunto(s)

Síndrome de Alagille , Pruebas Genéticas , Proteína Jagged-1 , Humanos , Síndrome de Alagille/genética , Síndrome de Alagille/diagnóstico , Masculino , Femenino , Estudios Retrospectivos , Preescolar , Lactante , Proteína Jagged-1/genética , Niño , Colestasis/genética

RESUMEN

Cholestatic liver diseases, such as primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), lead to inflammation and severe hepatic damage with limited therapeutic options. This study assessed the efficacy of the inverse RORγt agonist, GSK805, both in vitro using the hepatic stellate cell-line LX-2 and in vivo using male bile duct-ligated BALB/c mice. In vitro, 0.3 µM GSK805 reduced alpha-smooth muscle actin expression in LX-2 cells. In vivo, GSK805 significantly decreased IL-23R, TNF-α, and IFN-γ expression in cholestatic liver. Despite high concentrations of GSK805 in the liver, no significant reduction in fibrosis was noticed. GSK805 significantly increased aspartate aminotransferase and alanine aminotransferase activity in the blood, while levels of glutamate dehydrogenase, alkaline phosphatase, and bilirubin were not substantially increased. Importantly, GSK805 did neither increase an animal distress score nor substantially reduce body weight, burrowing activity, or nesting behavior. These results suggest that a high liver concentration of GSK805 is achieved by daily oral administration and that this drug modulates inflammation in cholestatic mice without impairing animal well-being.

Asunto(s)

Ratones Endogámicos BALB C , Animales , Ratones , Masculino , Humanos , Actinas/metabolismo , Hígado/metabolismo , Hígado/efectos de los fármacos , Células Estrelladas Hepáticas/metabolismo , Células Estrelladas Hepáticas/efectos de los fármacos , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/metabolismo , Línea Celular , Inflamación/metabolismo , Inflamación/tratamiento farmacológico , Colestasis/metabolismo , Colestasis/tratamiento farmacológico

RESUMEN

The role of endoscopy in pathologies of the bile duct and gallbladder has seen notable advancements over the past two decades. With advancements in stent technology, such as the development of lumen-apposing metal stents, and adoption of endoscopic ultrasound and electrosurgical principles in therapeutic endoscopy, what was once considered endoscopic failure has transformed into failure of an approach that could be salvaged by a second- or third-line endoscopic strategy. Incorporation of these advancements in routine patient care will require formal training and multidisciplinary acceptance of established techniques and collaboration for advancement of experimental techniques to generate robust evidence that can be utilized to serve patients to the best of our ability.

Asunto(s)

Drenaje , Endosonografía , Stents , Humanos , Drenaje/instrumentación , Drenaje/métodos , Endosonografía/métodos , Endosonografía/instrumentación , Insuficiencia del Tratamiento , Metales , Conductos Biliares/diagnóstico por imagen , Conductos Biliares/cirugía , Colestasis/cirugía , Colestasis/diagnóstico por imagen , Colestasis/terapia , Colestasis/etiología , Colangiopancreatografia Retrógrada Endoscópica/instrumentación , Colangiopancreatografia Retrógrada Endoscópica/métodos

RESUMEN

INTRODUCTION: Palliation of malign biliary obstruction is important which is commonly carried out by percutaneous biliary stenting. Our primary aim with this study was assessment of performance of wall stents, and nitinol stents for the palliation of malign biliary obstruction. METHODS: The medical records of 157 patients who underwent biliary stenting in our department between January 1, 1995, and December 31, 2005, were retrospectively analyzed. Technical success, treatment success, mortality in the first 30 days, minor, and major complications were evaluated and compared among the wall stent, and the nitinol stent groups in all patients which constituted the primary study endpoints. Additionally, stent patency, and mean patient survival times after stent implantation were evaluated in patients for whom follow-up information could be obtained. RESULTS: A total of 213 metallic stents were placed in 157 patients. Wall stent was placed in 83 of the patients with mean age, and SD of 60.4 and 13.5. Nitinol stent was placed in 74 of the patients with mean age of 57.8, and SD of 15.5. Gender ratio was equal in both groups. Biliary stent dysfunction was observed in 13 patients in each of nitinol, and wall stent groups throughout the study period. There was no statistical difference among re-occlusion rates (p = 0.91). For the nitinol stent group median primary patency time was 119 days (90-185 days CI 95%), and for the wall stent group median primary patency time was 81 days (60-150 days CI 95%). CONCLUSION: Nitinol stents, and wall stents are safe options that can be safely used in the percutaneous treatment of malignant biliary obstruction with similar treatment and therapeutic success, low complication rates, and patency times that can extend beyond expected survival times.

Asunto(s)

Aleaciones , Colestasis , Stents , Humanos , Masculino , Femenino , Persona de Mediana Edad , Colestasis/etiología , Colestasis/terapia , Colestasis/cirugía , Estudios Retrospectivos , Stents/efectos adversos , Anciano , Cuidados Paliativos/métodos , Resultado del Tratamiento , Neoplasias de los Conductos Biliares/complicaciones

RESUMEN

In this study, we evaluated the hepatoprotective effects of astaxanthin, a natural carotenoid, against the cholestatic liver fibrosis induced by bile duct ligation (BDL). Toward this end, male rats were subjected to BDL and treated with astaxanthin for 35 days. Afterwards, their serum and liver biochemical factors were assessed. Also, histopathological and immunohistochemical analyses were performed to determine the fibrosis and the expression levels of alpha-smooth muscle actin (α-SMA) and transforming growth factor beta (TGF-ß1) in the liver tissue. Based on the results, BDL caused a significant increase in liver enzyme levels, blood lipids, and bilirubin, while decreasing the activity of superoxide dismutase(SOD), catalase (CAT), and glutathione (GSH) enzymes. Also, in the BDL rats, hepatocyte necrosis, infiltration of inflammatory lymphocytes, and hyperplasia of bile ducts were detected, along with a significant increase in α-SMA and TGF-ß1 expression. Astaxanthin, however, significantly prevented the BDL's detrimental effects. In all, 10 mg/kg of this drug maintained the bilirubin and cholesterol serum levels of BDL rats at normal levels. It also reduced the liver enzymes' activity and serum lipids, while increasing the SOD, CAT, and GSH activity in BDL rats. The expression of α-SMA and TGF-ß1 in the BDL rats treated with 10 mg/kg of astaxanthin was moderate (in 34%-66% of cells) and no considerable cholestatic fibrosis was observed in this group. However, administrating the 20 mg/kg of astaxanthin was not effective in this regard. These findings showed that astaxanthin could considerably protect the liver from cholestatic damage by improving the biochemical features and regulating the expression of related proteins.

Asunto(s)

Conductos Biliares , Colestasis , Cirrosis Hepática , Ratas Wistar , Xantófilas , Animales , Xantófilas/farmacología , Xantófilas/uso terapéutico , Masculino , Ratas , Colestasis/patología , Colestasis/metabolismo , Colestasis/tratamiento farmacológico , Cirrosis Hepática/metabolismo , Cirrosis Hepática/patología , Cirrosis Hepática/tratamiento farmacológico , Cirrosis Hepática/prevención & control , Ligadura , Conductos Biliares/cirugía , Hígado/efectos de los fármacos , Hígado/patología , Hígado/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo