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Background & Aims: Although primary biliary cholangitis (PBC) is considered a rare disorder, accurate determination of its incidence and prevalence remains challenging due to limited comprehensive population-based registries. We aimed to assess the incidence and prevalence of PBC in the Netherlands over time through the nationwide Dutch PBC Cohort Study (DPCS). Methods: DPCS retrospectively included every identifiable patient with PBC in the Netherlands from 1990 onwards in all 71 Dutch hospitals. Incidence and prevalence were assessed between 2008-2018 by Poisson regression between sex and age groups over time. Results: On the 1st of January 2008, there were 1,458 patients with PBC in the Netherlands. Between 2008-2018, 2,187 individuals were newly diagnosed, 46 were transplanted and 468 died. The yearly incidence of PBC in 2008 was 1.38, increasing to 1.74 per 100,000 persons in 2018. When compared to those aged <45 years, females aged 45-64 years (adjusted incidence rate ratio 4.21, 95% CI 3.76-4.71, p <0.001) and males ≥65 years (adjusted incidence rate ratio 14.41, 95% CI 9.62-21.60, p <0.001) were at the highest risk of being diagnosed with PBC. The male-to-female ratio of patients newly diagnosed with PBC during the study period was 1:14 in those <45 years, 1:10 in patients aged 45-64 years, and 1:4 in those ≥65 years. Point prevalence increased from 11.9 in 2008 to 21.5 per 100,000 persons in 2018. Average annual percent change in this time period was 5.94% (95% CI 5.77-6.15, p <0.05), and was the highest among the population aged ≥65 years (5.69%, 95% CI 5.32-6.36, p <0.001). Conclusions: In this nationwide cohort study, we observed an increase in both the incidence and prevalence of PBC in the Netherlands over the past decade, with marked age and sex differences. Impact and implications: This nationwide Dutch primary biliary cholangitis (PBC) Cohort Study, including all hospitals in the Netherlands, showed that the incidence and prevalence of PBC have increased over the last decade. The age-dependent PBC incidence rate differed for males (highest risk ≥65 years) and females (highest risk between 45 and 65 years), which may be related to a difference in the timing of exposure to environmental triggers of PBC. The largest increase in PBC prevalence over time was observed in the population aged ≥65 years, which may have implications for the use of second-line therapies. These results therefore indicate that further studies are needed to elaborate on the advantages and disadvantages of add-on therapies in the elderly population.
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Hyperammonemia can lead to encephalopathy and may be accompanied by a diagnostic dilemma. Imaging as well as biochemical analyses are the cornerstone for identifying possible underlying causes such as severe liver disease or urea cycle defect. We report a case of a patient that presented with neurological deficits based on hyperammonemia in the presence of a large pancreatic neuroendocrine tumor (PNET) and portosystemic shunts in the liver. Prior cases are rather scarce, and the exact mechanism is not fully understood. The case illustrates the added value of a multimodality imaging approach in patients presenting with hyperammonemia-induced encephalopathy.
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BACKGROUND: Management of focal nodular hyperplasia (FNH) and hepatocellular adenoma (HCA), is multidisciplinary and subject to practice variation. We aimed to evaluate variation in clinical management of FNH and HCA in Europe. METHODS: We distributed an online survey (November 2021-March 2022) among 294 European experts. The survey included questions on local practice and included eight clinical vignettes. The clinical vignettes focused on FNH or HCA management in the setting of sex, lifestyle modification, and pregnancy. RESULTS: The response rate was 32% and respondents included surgeons (38%), gastroenterologists/hepatologists (25%), radiologists (32%), and pathologists (1.6%) from ten European countries. We observed practice variation with regard to lifestyle modification and imaging follow-up in patients with FNH, and with regard to the management of HCA >5 cm before and during pregnancy. Finally, the management of HCA >5 cm after lifestyle modification deviated from EASL guideline recommendations. CONCLUSION: Our survey illustrates variability in FNH and HCA management in Europe. Several areas were identified for future research and guideline recommendations, including FNH follow-up and the management of HCA >5 cm. We propose the organization of Delphi consensus meetings to prioritize areas of research and update current guidelines to optimize management for all patients with benign liver tumors.
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Adenoma de Células Hepáticas , Hiperplasia Nodular Focal , Neoplasias Hepáticas , Humanos , Neoplasias Hepáticas/patología , Adenoma de Células Hepáticas/patología , Hiperplasia Nodular Focal/diagnóstico , Hiperplasia Nodular Focal/patología , Europa (Continente) , Hígado/patología , Diagnóstico Diferencial , Imagen por Resonancia Magnética/métodos , Medios de ContrasteRESUMEN
Prehabilitation improves surgical outcomes in patients undergoing surgery. However, patients preparing for orthotopic liver transplantation (OLT) are physically "frail" and suffer from comorbidities that generally hamper physical activity. This systematic review aims to evaluate the physical effects, safety and feasibility of prehabilitation in OLT candidates. Relevant articles were searched, in Embase, Web of Science, Cochrane, Medline and Google Scholar, to December 2021. Studies reporting on specified preoperative exercise programs, including adult OLT candidates with end-stage liver disease, with a model for end-stage liver disease (MELD) score ≥12 or Child-Pugh classification B/C, were included. This resulted in 563 potentially eligible studies, out of which eight were selected for inclusion, consisting of 1,094 patients (male sex 68%; mean age 51-61 years; mean MELD score 12-21). Six of the included studies were classified as low-quality by the GRADE system, and three studies had high risk for ineffectiveness of the training program according to the i-CONTENT tool. Significant improvement was observed in VO2 peak, 6-minute walking distance, hand grip strength, liver frailty index and quality of life. Feasibility ranged from an adherence of 38%-90% in unsupervised-to >94% in supervised programs. No serious adverse events were reported. In conclusion, prehabilitation in patients awaiting OLT appears to improve aerobic capacity, and seems feasible and safe. However, larger clinical trials are required to accurately examine the preoperative and postoperative effects of prehabilitation in this specific patient population.
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Enfermedad Hepática en Estado Terminal , Trasplante de Hígado , Adulto , Enfermedad Hepática en Estado Terminal/cirugía , Estudios de Factibilidad , Fuerza de la Mano , Humanos , Masculino , Persona de Mediana Edad , Complicaciones Posoperatorias/prevención & control , Cuidados Preoperatorios/métodos , Ejercicio Preoperatorio , Calidad de Vida , Índice de Severidad de la EnfermedadRESUMEN
Organ transplantation is a life-saving treatment for patients with end-stage disease, but survival rates after transplantation vary considerably. There is now increasing evidence that the gut microbiome is linked to the survival of patients undergoing hematopoietic cell transplant, yet little is known about the role of the gut microbiome in solid organ transplantation. We analyzed 1370 fecal samples from 415 liver and 672 renal transplant recipients using shotgun metagenomic sequencing to assess microbial taxonomy, metabolic pathways, antibiotic resistance genes, and virulence factors. To quantify taxonomic and metabolic dysbiosis, we also analyzed 1183 age-, sex-, and body mass index-matched controls from the same population. In addition, a subset of 78 renal transplant recipients was followed longitudinally from pretransplantation to 24 months after transplantation. Our data showed that both liver and kidney transplant recipients suffered from gut dysbiosis, including lower microbial diversity, increased abundance of unhealthy microbial species, decreased abundance of important metabolic pathways, and increased prevalence and diversity of antibiotic resistance genes and virulence factors. These changes were found to persist up to 20 years after transplantation. Last, we demonstrated that the use of immunosuppressive drugs was associated with the observed dysbiosis and that the extent of dysbiosis was associated with increased mortality after transplantation. This study represents a step toward potential microbiome-targeted interventions that might influence the outcomes of recipients of solid organ transplantation.
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Microbioma Gastrointestinal , Trasplante de Células Madre Hematopoyéticas , Trasplante de Órganos , Disbiosis , Microbioma Gastrointestinal/genética , Humanos , Factores de VirulenciaRESUMEN
INTRODUCTION: Benign liver tumours and cysts (BLTCs) comprise a heterogeneous group of cystic and solid lesions, including hepatic haemangioma, focal nodular hyperplasia and hepatocellular adenoma. Some BLTCs, for example, (large) hepatocellular adenoma, are at risk of complications. Incidence of malignant degeneration or haemorrhage is low in most other BLTCs. Nevertheless, the diagnosis BLTC may carry a substantial burden and patients may be symptomatic, necessitating treatment. The indications for interventions remain matter of debate. The primary study aim is to investigate patient-reported outcomes (PROs) of patients with BLTCs, with special regards to the influence of invasive treatment as compared with the natural course of the disease. METHODS AND ANALYSIS: A nationwide observational cohort study of patients with BLTC will be performed between October 2021 and October 2026, the minimal follow-up will be 2 years. During surveillance, a questionnaire regarding symptoms and their impact will be sent to participants on a biannual basis and more often in case of invasive intervention. The questionnaire was previously developed based on PROs considered relevant to patients with BLTCs and their caregivers. Most questionnaires will be administered by computerised adaptive testing through the Patient-Reported Outcomes Measurement Information System. Data, such as treatment outcomes, will be extracted from electronic patient files. Multivariable analysis will be performed to identify patient and tumour characteristics associated with significant improvement in PROs or a complicated postoperative course. ETHICS AND DISSEMINATION: The study was assessed by the Medical Ethics Committee of the University Medical Center Groningen and the Amsterdam UMC. Local consultants will provide information and informed consent will be asked of all patients. Results will be published in a peer-reviewed journal. STUDY REGISTRATION: NL8231-10 December 2019; Netherlands Trial Register.
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Adenoma de Células Hepáticas , Quistes , Neoplasias Hepáticas , Humanos , Adenoma de Células Hepáticas/cirugía , Estudios Prospectivos , Países Bajos/epidemiología , Neoplasias Hepáticas/cirugía , Estudios de Cohortes , Estudios Observacionales como Asunto , Estudios Multicéntricos como AsuntoRESUMEN
OBJECTIVE: Benign liver tumours (BLT) are increasingly diagnosed as incidentalomas. Clinical implications and management vary across and within the different types of BLT. High-quality clinical practice guidelines are needed, because of the many nuances in tumour types, diagnostic modalities, and conservative and invasive management strategies. Yet, available observational evidence is subject to interpretation which may lead to practice variation. Therefore, we aimed to systematically search for available clinical practice guidelines on BLT, to critically appraise them, and to compare management recommendations. DESIGN: A scoping review was performed within MEDLINE, EMBASE, and Web of Science. All BLT guidelines published in peer-reviewed, and English language journals were eligible for inclusion. Clinical practice guidelines on BLT were analysed, compared, and critically appraised using the Appraisal of Guidelines, Research and Evaluation (AGREE II) checklist regarding hepatic haemangioma, focal nodular hyperplasia (FNH), and hepatocellular adenoma (HCA). Preferred Reporting Items for Systematic Reviews and Meta-Analyses recommendations (PRISMA) for scoping reviews were adhered to. RESULTS: The literature search yielded unique 367 papers, 348 were excluded after screening of title/abstract, and 16 after full-text screening. Three guidelines were included: the American College of Gastroenterology (ACG; 2014), Brazilian Society of Hepatology (SBH; 2015), and European Association for the Study of the Liver (EASL; 2016). There was no uniformity in the assessment methods for grading and gravity of recommendations between guidelines. Among observed differences were: (1) indications for biopsy in all three tumours; (2) advices on contraceptive pills and follow-up in FNH and HCA; (3) use of an individualised approach to HCA; (4) absence of recommendations for treatment of HCA in men; and (5) approaches to HCA subtype identification on magnetic resonance imaging. CONCLUSION: Recognising differences in recommendations can assist in harmonisation of practice standards and identify unmet needs in research. This may ultimately contribute to improved global patient care.
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Adenoma de Células Hepáticas , Hiperplasia Nodular Focal , Neoplasias Hepáticas , Adenoma de Células Hepáticas/diagnóstico , Humanos , Neoplasias Hepáticas/diagnóstico , Imagen por Resonancia Magnética , MasculinoRESUMEN
BACKGROUND: Hepatocellular adenomas (HCA) are benign liver tumors at risk of hemorrhage. The influence of pregnancy on HCA growth and potential bleeding remains unclear. This study investigates HCA-associated behavior and bleeding complications during or shortly after pregnancy. METHODS: (I) Single center retrospective cohort study of HCA during and after pregnancy (II) Systematic literature review. RESULTS: The retrospective study included 11 patients, of which 4 with HCA ≥5 cm. In only two patients HCA showed growth during pregnancy. In this local cohort, no HCA-related hemorrhages occurred during median follow-up of 34 months (interquartile range 19-58 months). The systematic review yielded 33 studies, totaling 90 patients with 99 pregnancies. Of 73 pregnancies without prior HCA-related intervention, 39 HCA remained stable (53.4%), 11 regressed (15.1%), and 23 (31.5%) progressed. Fifteen HCA-related hemorrhages occurred in HCA measuring 6.5-17.0 cm. Eight patients experienced bleeding during pregnancy, two during labor and five postpartum. CONCLUSION: Although hemorrhage of HCA during or shortly after pregnancy is rare and only reported in HCA ≥6.5 cm, it can be fatal. Pregnancy in women with HCA, regardless of size, warrant a close surveillance strategy. Observational studies on behavior and management of HCA ≥5 cm during and immediately after pregnancy are needed.
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Adenoma de Células Hepáticas , Carcinoma Hepatocelular , Neoplasias Hepáticas , Adenoma de Células Hepáticas/diagnóstico por imagen , Femenino , Humanos , Periodo Posparto , Embarazo , Estudios RetrospectivosRESUMEN
Portal biliopathy refers to biliary tree abnormalities in patients with peribiliary collateral vessels and non-neoplastic extrahepatic portal vein occlusion. These biliary abnormalities are caused by vascular compression and ischemic damage of the biliary tree, which can result in bile duct compression, stenosis, fibrotic strictures, bile duct dilation, and thickening of the bile duct wall. Portal biliopathy is difficult to distinguish from cholangiocarcinoma, IgG4-related disease, and sclerosing cholangitis. Although most patients are asymptomatic, portal biliopathy can lead to serious complications, such as recurrent cholangitis. This case illustrates the importance of including portal biliopathy in the differential diagnosis at an early stage, especially in patients with portal hypertension. With early recognition, the need for additional invasive diagnostic procedures such as biopsies is minimized. Pathogenesis, clinical presentation, diagnostics, and treatment options of portal biliopathy are described in the article.
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BACKGROUND & AIMS: Hepatocellular adenomas (HCA) are rare, hormone-driven, benign liver tumours. HCA >50 mm are associated with haemorrhage and malignant transformation. Guidelines recommend cessation of oral contraceptive pills (OCP) for size reduction; however, it is currently unknown how HCA respond to cessation of OCP. We sought to investigate the effect of OCP cessation on HCA size. METHODS: A retrospective cohort study was performed including HCA patients who stopped OCP intake within 6 months of imaging between 2005 and 2018. Biometrics and hormonal medication use were evaluated with self-designed questionnaires. Response of the largest HCA was evaluated according to Response Evaluation Criteria in Solid Tumours (RECISTv1.1). Cox regression was performed for analysis of factors influencing HCA regression. RESULTS: Seventy-eight HCA patients were included, diagnosed at a median (interquartile range) age of 32 (26-41) years. Follow-up was 1.6 (0.4-2.9) years. HCA size at diagnosis ranged 10-167 mm. After a median time of 1.3 (0.6-2.6) years after OCP cessation, 37.2% of HCA showed ≥30% regression, 5.1% complete regression, 56.4% stability and 1.3% progression. No HCA-induced complications were observed during follow-up. Cox regression analysis demonstrated a significant association of HCA size with rate of regression; 50 ≤ HCA < 100 mm (HR 2.4, 95% CI 1.1-5.3; P < 0.05), HCA ≥ 100 mm (HR 8.3, 95% CI 3.3-21.6; P < 0.001). CONCLUSIONS: Ninety-eight per cent of HCA remained stable or regressed after OCP cessation. A longer wait-and-see period was associated with a larger proportion of regressing HCA, without HCA-related complications during follow-up.
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Adenoma de Células Hepáticas/patología , Anticonceptivos Orales/efectos adversos , Estrógenos/efectos adversos , Neoplasias Hepáticas/patología , Adenoma de Células Hepáticas/diagnóstico por imagen , Adulto , Anticonceptivos Orales/administración & dosificación , Estrógenos/administración & dosificación , Femenino , Humanos , Neoplasias Hepáticas/diagnóstico por imagen , Imagen por Resonancia Magnética , Países Bajos , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Tomografía Computarizada por Rayos XRESUMEN
PURPOSE OF REVIEW: Primary biliary cirrhosis (PBC) can lead to end-stage liver disease and death. Ursodeoxycholic acid (UDCA) treatment can normalize serum liver enzymes in PBC, and such UDCA-responsive patients have a similar life expectancy as age and sex-matched controls. Nearly up to 50% of the patients with PBC, depending on sex and age at diagnosis, show an incomplete biochemical response to UDCA and require additional/alternative treatment. The purpose of this review is to critically evaluate the molecular mechanisms and clinical benefit of fibrate treatment in these patients. RECENT FINDINGS: Fibrates have anticholestatic, anti-inflammatory, and antifibrotic effects in animal and in-vitro studies. The mechanisms that underlie these effects are complementary, and largely mediated through activation of peroxisome proliferator activated receptors. Fibrate treatment ameliorated liver biochemical tests in UDCA unresponsive patients, either as mono-therapy or in combination with UDCA. These results, however, were obtained in case series and small pilot studies. The results of phase III studies, such as the Bezafibrate in Combination With Ursodeoxycholic Acid in Primary Biliary Cirrhosis (BEZURSO) trial, are currently awaited. SUMMARY: A considerable body of observational evidence supports the safety and efficacy of fibrate treatment in PBC patients with an incomplete response to UDCA. These results encourage the evaluation of its effects on liver-related morbidity and mortality in larger clinical trials.
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Ácidos Fíbricos/uso terapéutico , Cirrosis Hepática Biliar/tratamiento farmacológico , Antiinflamatorios no Esteroideos/uso terapéutico , Quimioterapia Combinada , Humanos , Hipolipemiantes/uso terapéutico , Insuficiencia del Tratamiento , Resultado del Tratamiento , Ácido Ursodesoxicólico/uso terapéuticoRESUMEN
Cholestasis, a hallmark feature of hepatobiliary disease, is characterized by the retention of biliary constituents. Some of these constituents, such as bile acids, inflict damage to hepatocytes and bile duct cells. This damage may lead to inflammation, fibrosis, cirrhosis, and eventually carcinogenesis, sequelae that aggravate the underlying disease and deteriorate clinical outcome. Canalicular ATP-binding cassette (ABC) transporters, which mediate the excretion of individual bile constituents, play a key role in bile formation and cholestasis. The study of these transporters and their regulatory nuclear receptors has revolutionized our understanding of cholestatic disease. This knowledge has served as a template to develop novel treatment strategies, some of which are currently already undergoing phase III clinical trials. In this review we aim to provide an overview of the structure, function, and regulation of canalicular ABC transporters. In addition, we will focus on the role of these transporters in the pathogenesis and treatment of cholestatic bile duct and liver diseases.
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Transportadoras de Casetes de Unión a ATP/metabolismo , Canalículos Biliares/metabolismo , Colestasis/etiología , Colestasis/metabolismo , Transportadoras de Casetes de Unión a ATP/química , Animales , Bilis/metabolismo , Humanos , Modelos Biológicos , Preparaciones Farmacéuticas/metabolismo , Receptores Citoplasmáticos y Nucleares/metabolismoRESUMEN
BACKGROUND & AIMS: Severe unconjugated hyperbilirubinemia, as occurs in Crigler-Najjar disease and neonatal jaundice, carries the risk of neurotoxicity. This neurotoxicity is related to the increased passage of free bilirubin (UCB(free)), the fraction of bilirubin that is not bound to plasma proteins, into the brain. We hypothesized that albumin treatment would lower the UCB(free) fraction, and thus decrease bilirubin accumulation in the brain. METHODS: We treated chronic (e.g., as a model for Crigler-Najjar disease) and acute hemolytic (e.g., as a model for neonatal jaundice) moderate hyperbilirubinemic Gunn rats with phototherapy, human serum albumin (HSA) or phototherapy+HSA. RESULTS: In the chronic model, adjunct HSA increased the efficacy of phototherapy; it decreased plasma UCB(free) and brain bilirubin by 88% and 67%, respectively (p<0.001). In the acute model, adjunct HSA also increased the efficacy of phototherapy; it decreased plasma UCB(free) by 76% (p<0.001) and completely prevented the hemolysis-induced deposition of bilirubin in the brain. Phototherapy alone failed to prevent the deposition of bilirubin in the brain during acute hemolytic jaundice. CONCLUSIONS: We showed that adjunct HSA treatment decreases brain bilirubin levels in phototherapy-treated Gunn rats. We hypothesize that HSA decreases these levels by lowering UCB(free) in the plasma. Our results support the feasibility of adjunct albumin treatment in patients with Crigler-Najjar disease or neonatal jaundice.
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Albúminas/farmacología , Bilirrubina/metabolismo , Encéfalo/metabolismo , Síndrome de Crigler-Najjar/metabolismo , Síndrome de Crigler-Najjar/terapia , Fototerapia/métodos , Enfermedad Aguda , Animales , Bilirrubina/sangre , Enfermedad Crónica , Modelos Animales de Enfermedad , Hiperbilirrubinemia/metabolismo , Hiperbilirrubinemia/terapia , Ictericia/metabolismo , Ictericia/terapia , Masculino , Distribución Aleatoria , Ratas , Ratas GunnRESUMEN
OBJECTIVES: Polyethylene glycol (PEG) is a frequently used laxative agent. It is unknown, however, whether PEG affects the absorptive capacity of the intestine. Reduced lipid (dietary fat and cholesterol) absorption induced by long-term PEG treatment could negatively affect growth in children. We tested whether PEG accelerates gastrointestinal transit and alters lipid absorption and plasma lipid levels. METHODS: Wistar rats were administered drinking water with or without PEG (7%) for 2 weeks. We studied whole gut transit time by recording the first appearance of red feces after intragastric carmine red administration. We measured plasma concentrations of cholesterol and triglycerides, dietary fat absorption by 48-hour fat balance and by plasma appearance of intragastrically administered stable-isotope labeled fats, and cholesterol absorption with a dual stable isotope technique. RESULTS: PEG decreased whole gut transit time by 20% (P=0.028) without causing diarrhea. PEG treatment did neither affects overall dietary fat balance nor fat uptake kinetics, cholesterol absorption, or plasma lipid concentrations. CONCLUSIONS: PEG does not affect lipid absorption nor steady-state plasma lipid levels in rats, although it accelerates the gastrointestinal transit.
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Colesterol en la Dieta/metabolismo , Grasas de la Dieta/metabolismo , Tránsito Gastrointestinal/efectos de los fármacos , Laxativos/uso terapéutico , Metabolismo de los Lípidos/efectos de los fármacos , Lípidos/sangre , Polietilenglicoles/uso terapéutico , Animales , Absorción Intestinal/efectos de los fármacos , Laxativos/efectos adversos , Laxativos/farmacología , Masculino , Polietilenglicoles/efectos adversos , Polietilenglicoles/farmacología , Ratas , Ratas WistarRESUMEN
We recently demonstrated that acceleration of the gastrointestinal transit by polyethylene glycol (PEG) treats unconjugated hyperbilirubinemia in jaundiced Gunn rats. It is unclear whether acceleration of gastrointestinal transit also (partly) underlies the therapeutic effects of established hypobilirubinemic treatments or whether PEG cotreatment might enhance these effects. We treated Gunn rats with phototherapy (17 µW/cm2/nm), orlistat (200 mg/kg chow), ursodeoxycholate (5 g/kg chow), or calcium phosphate (CaP) (20 g/kg chow) either as single treatment or in combination with PEG. Three weeks of phototherapy, orlistat, ursodeoxycholic acid, or CaP treatment decreased plasma unconjugated bilirubin (UCB) levels by 47, 27, 28, and 45%, respectively (each p < 0.001), without a significant impact on gastrointestinal transit time. PEG cotreatment accelerated the gastrointestinal transit in all treatment groups, which resulted in an additive hypobilirubinemic effect of -20% and -26% (final plasma UCB -67 and -53%, respectively) in phototherapy- and orlistat-treated animals. PEG cotreatment did not enhance the hypobilirubinemic effect of ursodeoxycholic acid or CaP. We conclude that phototherapy, orlistat, ursodoxycholic acid, and CaP do not exert their hypobilirubinemic effect via acceleration of the gastrointestinal transit. PEG cotreatment enhanced the hypobilirubinemic effects of phototherapy and of orlistat treatment. Current results support a clinical trial to evaluate PEG cotreatment during phototherapy.
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Tránsito Gastrointestinal/efectos de los fármacos , Hiperbilirrubinemia/tratamiento farmacológico , Hiperbilirrubinemia/terapia , Fototerapia/métodos , Polietilenglicoles/farmacología , Animales , Bilirrubina/sangre , Fosfatos de Calcio/farmacología , Fosfatos de Calcio/uso terapéutico , Terapia Combinada , Lactonas/farmacología , Lactonas/uso terapéutico , Masculino , Orlistat , Polietilenglicoles/uso terapéutico , Ratas , Ratas Gunn , Ácido Ursodesoxicólico/farmacología , Ácido Ursodesoxicólico/uso terapéuticoRESUMEN
BACKGROUND AND AIMS: Several conditions that delay gastrointestinal transit are associated with unconjugated hyperbilirubinaemia. We hypothesised that the gastrointestinal transit time is directly related to plasma unconjugated bilirubin (UCB) concentrations, and that this relationship can be used to develop a new therapeutic strategy for severe unconjugated hyperbilirubinaemia in the Gunn rat model. METHODS: Gunn rats received, for various time periods, oral polyethylene glycol (PEG) with or without conventional phototherapy treatment to accelerate, or oral loperamide to delay gastrointestinal transit. Gastrointestinal transit time and UCB concentrations in plasma, faeces, intestinal content and bile were determined. Results Within 36 h, PEG administration accelerated gastrointestinal transit by 45% and simultaneously decreased plasma UCB concentrations by 23% (each p<0.001). The decrease in plasma UCB coincided with an increased small intestinal UCB content (+340%, p<0.05) and an increased faecal UCB excretion (+153%, p<0.05). After 2 weeks, PEG decreased plasma UCB by 41% as single treatment, and by 62% if combined with phototherapy (each p<0.001). Loperamide delayed gastrointestinal transit by 57% and increased plasma UCB by 30% (each p<0.001). Dose-response experiments showed a strong, linear relation between the gastrointestinal transit time and plasma UCB concentrations (r=0.87, p<0.001). CONCLUSION: Gastrointestinal transit time and plasma UCB concentrations are linearly related in Gunn rats. This relationship can be exploited by pharmacologically accelerating the gastrointestinal transit, which increases transmucosal UCB diffusion and thereby effectively treats unconjugated hyperbilirubinaemia. Present results support the feasibility of PEG treatment, either solitary or combined with phototherapy, in patients with severe unconjugated hyperbilirubinaemia.
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Tránsito Gastrointestinal/efectos de los fármacos , Hiperbilirrubinemia/tratamiento farmacológico , Polietilenglicoles/farmacología , Animales , Antidiarreicos , Bilis/metabolismo , Bilirrubina/sangre , Bilirrubina/metabolismo , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos/métodos , Heces/química , Tránsito Gastrointestinal/fisiología , Hiperbilirrubinemia/metabolismo , Hiperbilirrubinemia/fisiopatología , Intestino Delgado/metabolismo , Loperamida , Masculino , Fototerapia/métodos , Polietilenglicoles/uso terapéutico , Ratas , Ratas GunnRESUMEN
BACKGROUND & AIMS: We tested the hypothesis that oral administration of bile salts, which are known to increase the biliary excretion of unconjugated bilirubin (UCB), decreases unconjugated hyperbilirubinemia in the Gunn rat model. METHODS: Adult Gunn rats were fed a standard diet or the same diet supplemented with 0.5 weight % ursodeoxycholic acid (UDCA) or cholic acid (CA) for 1 or 6 weeks. UCB and urobilinoids, a family of intestinal UCB breakdown products, were determined in plasma, feces, or both. After 6 weeks of treatment, tracer 3H-UCB was administered intravenously to determine steady-state UCB kinetics over the next 60 hours. RESULTS: One-week treatment with UDCA or CA decreased plasma UCB concentrations by 21% and 30%, respectively (each P < .01). During the first 4 days of treatment, both UDCA and CA increased the combined fecal excretion of UCB and urobilinoids (+52% and +32%, respectively; each P < .01). Prolongation of treatment to 6 weeks caused a persistent decrease in plasma UCB concentrations to approximately 40% below baseline (each bile salt P < .001). (3)H-UCB kinetic studies showed that UDCA and CA administration decreased UCB pool size (-33% and -32%, respectively; each P < .05) and increased UCB fractional turnover (+33% and +25%, respectively; each P < .05). CONCLUSIONS: Dietary bile salt administration induces a large, persistent decrease in plasma UCB concentrations in Gunn rats. Both UDCA and CA enhance UCB turnover by increasing its fecal disposal. These results support the application of oral bile salt treatment in patients with unconjugated hyperbilirubinemia.