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1.
BJOG ; 2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33586324

RESUMO

OBJECTIVE: To determine the optimal total serum bile acid (TSBA) threshold and sampling time for accurate intrahepatic cholestasis of pregnancy (ICP) diagnosis. DESIGN: Case-control, retrospective cohort studies. SETTING: Antenatal clinics, clinical research facilities. POPULATION: Women with ICP or uncomplicated pregnancies. METHODS: Serial TSBA measurements were performed pre-/post-prandially in 42 women with ICP or uncomplicated pregnancy. Third trimester non-fasting TSBA reference ranges were calculated from 561 women of black, south Asian and white ethnicity. Rates of adverse perinatal outcomes for women with ICP but peak non-fasting TSBA below the upper reference range limit were compared with healthy populations. MAIN OUTCOME MEASURES: Sensitivity and specificity of common TSBA thresholds for ICP diagnosis, using fasting and postprandial TSBA. Calculation of normal reference ranges of non-fasting TSBA. RESULTS: TSBA concentrations increased markedly postprandially in all groups, with overlap between healthy pregnancy and mild ICP (TSBA<40µmol/L). The specificity of ICP diagnosis was higher when fasting, however, corresponded to <30% sensitivity for diagnosis of mild disease. Using TSBA ≥40µmol/L to define severe ICP, fasting measurements identified 9% (1/11), while non-fasting measurements detected over 91% with severe ICP. The highest upper limit of the non-fasting TSBA reference range was 18.3µmol/L (95% confidence interval 15.0 to 35.6µmol/L). A re-evaluation of published ICP meta-analysis data demonstrated no increase in spontaneous preterm birth or stillbirth in women with TSBA <19µmol/L. CONCLUSIONS: Postprandial TSBA levels are required to identify high-risk ICP pregnancies (TSBA≥40µmol/L). The postprandial TSBA rise in normal pregnancy indicates that a non-fasting threshold of ≥19µmol/L would improve diagnostic accuracy.

2.
Clin Transplant ; : e14262, 2021 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-33619740

RESUMO

INTRODUCTION: Liver transplantation (LT) is a life-saving treatment for end-stage liver disease patients that requires significant resources. We used national data to evaluate LT outcomes and factors associated with hospital resource use. METHODS: Using the National Inpatient Sample, we identified all patients undergoing LT from 2009-2017 and defined High Resource Use (HRU) as having costs ≥90th percentile. Hierarchical regression models were used to assess factors associated with length of stay (LOS) and HRU. RESULTS: Over the study period, approximately 53,000 patients underwent LT, increasing from 5,582 in 2009 to 7,095 in 2017 (nptrend<0.001). Morbidity and mortality were 42.2% and 3.9%, respectively, with a median post-LT LOS of 10 days. Hospitalization costs increased from $106,866 to $145,868 (nptrend<0.001). Acute kidney injury (ß:4.7 days, P<0.001) and end-stage renal disease (ESRD) with dialysis (ß:4.3 days, P<0.001) were associated with greater LOS while the Northeast region (AOR:5.2, P<0.001), ESRD with dialysis (AOR:3.4, P<0.001), heart failure (AOR:2.5, P<0.001), and fulminant liver disease (AOR:1.8, P=0.01) were associated with HRU. CONCLUSION: The cost of LT has increased over time. Renal dysfunction, regional practice patterns, and patient acuity were associated with greater resource use. Transplanting patients before health deterioration may help contain costs, mitigate resource use, and improve LT outcomes.

3.
Chest ; 2021 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-33617805

RESUMO

BACKGROUND: Despite the frequency and cost of hospitalizations for acute respiratory failure, there is a paucity of literature regarding the impact of hospital safety net burden on outcomes of these hospitalizations. RESEARCH QUESTION: How does safety net burden impact outcomes of acute respiratory failure hospitalizations such as mortality, tracheostomy and resource utilization? STUDY DESIGN AND METHODS: This was a retrospective cohort study using the National Inpatient Sample 2007-2017. All patients hospitalized with a primary diagnosis of acute respiratory failure were tabulated using the International Classification of Diseases 9thand 10thRevision codes and safety net burden was calculated using previously published methodology. High and low burden hospitals were generated from proportions of Medicaid and uninsured patients. Trends were analyzed using a non-parametric rank-based test while multivariable logistic and linear regression models were utilized to establish associations of safety net burden with key clinical outcomes. RESULTS: Of an estimated 8,941,334 hospitalizations with a primary diagnosis of acute respiratory failure, 33.9% were categorized at low burden hospitals (LBH) and 31.6% at high burden hospitals (HBH). In-hospital mortality significantly decreased at HBH (22.8%-12.6%, nptrend<0.001) and LBH (22.0%-10.9%, nptrend<0.001) over the study period, as did tracheostomy placement (HBH: 5.6%-1.3%, LBH: 3.5%-0.8%, all nptrend<0.001). After adjustment for patient and hospital factors, HBH was associated with increased odds of mortality (AOR: 1.11, 95% CI: 1.10-1.12) and tracheostomy use (AOR: 1.33, 95% CI: 1.29-1.37), as well as greater hospitalization costs (ß: +$1,083, 95% CI: 882-1,294) and longer lengths of stay (ß: +3.3 days, 95% CI: 3.2-3.3). INTERPRETATION: After accounting for differences between patient cohorts, high safety net burden was independently associated with inferior clinical outcomes and increased costs following acute respiratory failure hospitalizations. These findings emphasize the need for healthcare reform in order to ameliorate disparities within these safety net centers, which treat our most vulnerable populations.

4.
Mol Aspects Med ; : 100941, 2021 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-33455843

RESUMO

Normal pregnancy is characterised by a gradual alteration in metabolism that results in elevated serum bile acids, dyslipidaemia and impaired glucose tolerance in the third trimester. Nuclear receptors play important roles in regulating metabolic pathways that influence alterations in these parameters. There is evidence for altered function of FXR and LXR in gestation; these nuclear receptors play an integral role in bile acid and lipid homeostasis. There is some evidence for influence of clock genes in late pregnancy metabolic changes, and this may be linked to alterations in placental gene expression and function, thereby influencing fetal growth. This article will review the current data from human studies and investigation of animal models to illustrate the role of nuclear receptors (namely LXR, FXR, PPARs and clock genes) in gestational alterations in metabolism and the ways this may influence susceptibility to metabolic disorders of pregnancy such as gestational diabetes mellitus and intrahepatic cholestasis of pregnancy.

5.
BMC Pregnancy Childbirth ; 21(1): 51, 2021 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-33435904

RESUMO

BACKGROUND: Severe early onset (less than 34 weeks gestation) intrahepatic cholestasis of pregnancy (ICP) affects 0.1% of pregnant women in Australia and is associated with a 3-fold increased risk of stillbirth, fetal hypoxia and compromise, spontaneous preterm birth, as well as increased frequencies of pre-eclampsia and gestational diabetes. ICP is often familial and overlaps with other cholestatic disorders. Treatment options for ICP are not well established, although there are limited data to support the use of ursodeoxycholic acid (UDCA) to relieve pruritus, the main symptom. Rifampicin, a widely used antibiotic including in pregnant women, is effective in reducing pruritus in non-pregnancy cholestasis and has been used as a supplement to UDCA in severe ICP. Many women with ICP are electively delivered preterm, although there are no randomised data to support this approach. METHODS: We have initiated an international multicentre randomised clinical trial to compare the clinical efficacy of rifampicin tablets (300 mg bd) with that of UDCA tablets (up to 2000 mg daily) in reducing pruritus in women with ICP, using visual pruritus scores as a measuring tool. DISCUSSION: Our study will be the first to examine the outcomes of treatment specifically in the severe early onset form of ICP, comparing "standard" UDCA therapy with rifampicin, and so be able to provide for the first-time high-quality evidence for use of rifampicin in severe ICP. It will also allow an assessment of feasibility of a future trial to test whether elective early delivery in severe ICP is beneficial. TRIAL IDENTIFIERS: Australian New Zealand Clinical Trials Registration Number (ANZCTR): 12618000332224p (29/08/2018). HREC No: HREC/18/WCHN/36. EudraCT number: 2018-004011-44. IRAS: 272398. NHMRC registration: APP1152418 and APP117853.

7.
Eur J Endocrinol ; 184(3): R69-R83, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33434155

RESUMO

Bile acids are lipid-solubilising molecules that also regulate metabolic processes. Farnesoid X receptor (FXR) and Takeda G-protein coupled receptor 5 (TGR5) are two bile acid receptors with key metabolic roles. FXR regulates bile acid synthesis in the liver and influences bile acid uptake in the intestine. TGR5 is mainly involved in regulation of signalling pathways in response to bile acid uptake in the gut and therefore prandial response. Both FXR and TGR5 have potential as therapeutic targets for disorders of glucose and/or lipid homeostasis. Gestation is also known to cause small increases in bile acid concentrations, but physiological hypercholanaemia of pregnancy is usually not sufficient to cause any clinically relevant effects. This review focuses on how gestation alters bile acid homeostasis, which can become pathological if the elevation of maternal serum bile acids is more marked than physiological hypercholanaemia, and on the influence of FXR and TGR5 function in pregnancy on glucose and lipid metabolism. This will be discussed with reference to two gestational disorders: intrahepatic cholestasis of pregnancy (ICP), a disease where bile acids are pathologically elevated, and gestational diabetes mellitus (GDM), characterised by hyperglycaemia during pregnancy.


Assuntos
Ácidos e Sais Biliares/metabolismo , Desenvolvimento Fetal/fisiologia , Receptores Citoplasmáticos e Nucleares/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Colestase Intra-Hepática/metabolismo , Diabetes Gestacional/metabolismo , Feminino , Humanos , Gravidez , Complicações na Gravidez/metabolismo
8.
J Hepatol ; 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-33276032

RESUMO

BACKGROUND: Intrahepatic cholestasis of pregnancy (ICP) is associated with increased stillbirth risk. This study aimed to assess the relationship between bile acid concentrations and fetal cardiac dysfunction in ICP with or without ursodeoxycholic acid (UDCA) treatment. METHODS: Bile acid profiles and NT-proBNP, a marker of ventricular dysfunction, were assayed in umbilical venous serum from 15 controls and 76 ICP cases (36 untreated, 40 UDCA-treated). Fetal ECG traces were obtained from 43 controls and 48 ICP cases (26 untreated, 22 UDCA-treated). PR interval length and heart rate variability parameters (RMSSD, SDNN) were measured in two behavioural states (quiet and active sleep). Partial correlation coefficients (r) and median [IQR] are reported. RESULTS: In untreated ICP, fetal total serum bile acids (TSBA, r=0.49, p=0.019), their hydrophobicity index (r=0.20, p=0.039), glycocholate (r=0.56, p=0.007) and taurocholate (r=0.44, p=0.039) positively correlated with fetal NT-proBNP. Maternal TSBA (r=0.40, p=0.026) and alanine aminotransferase (r=0.40, p=0.046) also positively correlated with fetal NT-proBNP. No significant correlations to NT-proBNP were observed in the UDCA-treated cohort. Fetal PR interval length positively correlated with maternal TSBA in untreated (r=0.46, p=0.027) and UDCA-treated ICP (r=0.54, p=0.026). Fetal RMSSD in active sleep (9.6 [8.8,11.3] vs. 8.7 [7.6,9.6] ms, p=0.028) and SDNN in quiet sleep (11.0 [9.5,14.9] vs. 7.9 [5.1,9.7] ms, p=0.013) and active sleep (25.4 [21.0,32.4] vs. 18.2 [14.7,25.7] ms, p=0.003) were significantly higher in untreated ICP cases than controls. Heart rate variability values in UDCA-treated cases did not differ to controls. CONCLUSIONS: Elevated fetal and maternal serum bile acid concentrations in untreated ICP are associated with an abnormal fetal cardiac phenotype characterised by increased NT-proBNP concentration, PR interval length and heart rate variability. UDCA treatment partially attenuates this phenotype.

9.
United European Gastroenterol J ; : 2050640620977034, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-33259738

RESUMO

Although pregnancy is rare in women with cirrhosis, it is increasingly prevalent in an era of modern assisted conception techniques and improved awareness, monitoring and management of underlying liver disease. After overcoming the difficulties of subfertility and becoming pregnant, women undergo a 'high-risk' pregnancy which can be complicated by variceal haemorrhage (≤50%) and hepatic decompensation (≤25%). Management of these complications are similar to non-pregnant individuals. However, there are a few caveats to consider. These pregnancies are associated with adverse maternal and foetal outcomes, such as mortality (0-8%) and prematurity (19-67%) in the newborn, and mortality (0-14%), pregnancy-induced hypertension (5-22%) and post-partum haemorrhage (5-45%) in the mother. Pre-pregnancy counselling, use of predictive scores and appropriate variceal screening during pregnancy can stratify patients and improve outcomes. This review focusses on the complications that can occur during pregnancy in women with cirrhosis.

10.
Aliment Pharmacol Ther ; 52(11-12): 1628-1639, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33070363

RESUMO

BACKGROUND: Children with intrahepatic cholestasis and genetic variants which result in the disruption of the formation and maintenance of bile (ABCB11, ABCB4 and ATP8B1) generally have a rapidly progressive clinical course. Adults with different phenotypes of cholestasis are increasingly being evaluated for variants in these genes associated with childhood diseases. AIMS: To review the literature with respect to the presence of variants in cholestasis-related genes in adults with various liver phenotypes, and provide clinical implications of the findings. METHODS: A search of the literature on variants in specific cholestasis-related genes in adults was conducted. RESULTS: The common variant p.Val444Ala in ABCB11 confers increased risk of drug-induced liver injury and intrahepatic cholestasis of pregnancy (ICP). Individuals with variants in ABCB4 are at risk of ICP and low phospholipid-associated cholelithiasis. Variants in ABCB4, and possibly ABCB11 and ATP8B1, can be identified in up to a third of patients with cryptogenic chronic cholestasis. CONCLUSIONS: Individuals with variants in ABCB11 rarely develop cholestasis until BSEP function dips below a threshold, which is also affected by other factors (e.g., drugs, hormones). However, variants in ABCB4 and consequent reduction in MDR3 protein, have a more linear dose-response curve. In individuals with an ABCB11 variant, medications known to reduce BSEP activity should be used cautiously; they should be monitored during pregnancy for ICP; and first-degree relatives should be counselled and screened. No proven management strategy exists, although ursodeoxycholic acid may be beneficial. Further work is needed to define the genotype-phenotype correlation and natural history, and to evaluate the penetrance.

11.
Int J Obes (Lond) ; 44(12): 2382-2393, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33033395

RESUMO

OBJECTIVES: We hypothesised that maternal diet-induced-obesity has adverse consequences for offspring energy expenditure and susceptibility to obesity in adulthood, and that the prebiotic polydextrose (PDX) would prevent the consequences of programming by maternal obesity. METHODS: Female mice were fed a control (Con) or obesogenic diet (Ob) for 6 weeks prior to mating and throughout pregnancy and lactation. Half the obese dams were supplemented with 5% PDX (ObPDX) in drinking water throughout pregnancy and lactation. Offspring were weaned onto standard chow. At 3 and 6 months, offspring energy intake (EI) and energy expenditure (EE by indirect calorimetry) were measured, and a glucose-tolerance test performed. Offspring of control (OffCon), obese (OffOb) and PDX supplemented (OffObP) dams were subsequently challenged for 3 weeks with Ob, and energy balanced reassessed. Potential modifiers of offspring energy balance including gut microbiota and biomarkers of mitochondrial activity were also evaluated. RESULTS: Six-month-old male OffOb demonstrated increased bodyweight (BW, P < 0.001) and white adipose tissue mass (P < 0.05), decreased brown adipose tissue mass (BAT, P < 0.01), lower night-time EE (P < 0.001) versus OffCon, which were prevented in OffObP. Both male and female OffOb showed abnormal glucose-tolerance test (peak [Glucose] P < 0.001; AUC, P < 0.05) which was prevented by PDX. The Ob challenge resulted in greater BW gain in both male and female OffOb versus OffCon (P < 0.05), also associated with increased EI (P < 0.05) and reduced EE in females (P < 0.01). OffObP were protected from accelerated BW gain on the OB diet compared with controls, associated with increased night-time EE in both male (P < 0.05) and female OffObP (P < 0.001). PDX also prevented an increase in skeletal muscle mtDNA copy number in OffOb versus OffCon (P < 0.01) and increased the percentage of Bacteroides cells in faecal samples from male OffObP relative to controls. CONCLUSIONS: Maternal obesity adversely influences adult offspring energy balance and propensity for obesity, which is ameliorated by maternal PDX treatment with associated changes in gut microbiota composition and skeletal muscle mitochondrial function.

12.
Sci Rep ; 10(1): 15284, 2020 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-32943714

RESUMO

Acute myocardial ischaemia and reperfusion (I-R) are major causes of ventricular arrhythmias in patients with a history of coronary artery disease. Ursodeoxycholic acid (UDCA) has previously been shown to be antiarrhythmic in fetal hearts. This study was performed to investigate if UDCA protects against ischaemia-induced and reperfusion-induced arrhythmias in the adult myocardium, and compares the effect of acute (perfusion only) versus prolonged (2 weeks pre-treatment plus perfusion) UDCA administration. Langendorff-perfused adult Sprague-Dawley rat hearts were subjected to acute regional ischaemia by ligation of the left anterior descending artery (10 min), followed by reperfusion (2 min), and arrhythmia incidence quantified. Prolonged UDCA administration reduced the incidence of acute ischaemia-induced arrhythmias (p = 0.028), with a reduction in number of ventricular ectopic beats during the ischaemic phase compared with acute treatment (10 ± 3 vs 58 ± 15, p = 0.036). No antiarrhythmic effect was observed in the acute UDCA administration group. Neither acute nor prolonged UDCA treatment altered the incidence of reperfusion arrhythmias. The antiarrhythmic effect of UDCA may be partially mediated by an increase in cardiac wavelength, due to the attenuation of conduction velocity slowing (p = 0.03), and the preservation of Connexin43 phosphorylation during acute ischaemia (p = 0.0027). The potential antiarrhythmic effects of prolonged UDCA administration merit further investigation.

13.
Pediatrics ; 146(3)2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32801159

RESUMO

BACKGROUND: Extracorporeal life support (ECLS) has been used for >30 years as a life-sustaining therapy in critically ill patients for a variety of indications. In the current study, we aimed to examine trends in use, mortality, length of stay (LOS), and costs for pediatric ECLS hospitalizations. METHODS: We performed a retrospective cohort study of pediatric patients (between the ages of 28 days and <21 years) on ECLS using the 2008-2015 National Inpatient Sample, the largest all-payer inpatient hospitalization database generated from hospital discharges. Nonparametric and Cochran-Armitage tests for trend were used to study in-hospital mortality, LOS, and hospitalization costs. RESULTS: Of the estimated 5847 patients identified and included for analysis, ECLS was required for respiratory failure (36.4%), postcardiotomy syndrome (25.9%), mixed cardiopulmonary failure (21.7%), cardiogenic shock (13.1%), and transplanted graft dysfunction (2.9%). The rate of ECLS hospitalizations increased 329%, from 11 to 46 cases per 100 000 pediatric hospitalizations, from 2008 to 2015 (P < .001). Overall mortality decreased from 50.3% to 34.6% (P < .001). Adjusted hospital costs increased significantly ($214 046 ± 11 822 to 324 841 ± 25 621; P = .002) during the study period despite a stable overall hospital LOS (46 ± 6 to 44 ± 4 days; P = .94). CONCLUSIONS: Use of ECLS in pediatric patients has increased with substantially improved ECLS survival rates. Hospital costs have increased significantly despite a stable LOS in this group. Dissemination of this costly yet life-saving technology warrants ongoing analysis of use trends to identify areas for quality improvement.


Assuntos
Oxigenação por Membrana Extracorpórea/mortalidade , Oxigenação por Membrana Extracorpórea/tendências , Custos Hospitalares/tendências , Mortalidade Hospitalar/tendências , Adolescente , Criança , Pré-Escolar , Estudos de Coortes , Oxigenação por Membrana Extracorpórea/economia , Feminino , Humanos , Lactente , Masculino , Estudos Retrospectivos
14.
Sci Rep ; 10(1): 11523, 2020 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-32661285

RESUMO

Women with intrahepatic cholestasis of pregnancy (ICP), a disorder characterised by raised serum bile acids, are at increased risk of developing gestational diabetes mellitus and have impaired glucose tolerance whilst cholestatic. FXR and TGR5 are modulators of glucose metabolism, and FXR activity is reduced in normal pregnancy, and further in ICP. We aimed to investigate the role of raised serum bile acids, FXR and TGR5 in gestational glucose metabolism using mouse models. Cholic acid feeding resulted in reduced pancreatic ß-cell proliferation and increased apoptosis in pregnancy, without altering insulin sensitivity, suggesting that raised bile acids affect ß-cell mass but are insufficient to impair glucose tolerance. Conversely, pregnant Fxr-/- and Tgr5-/- mice are glucose intolerant and have reduced insulin secretion in response to glucose challenge, and Fxr-/- mice are also insulin resistant. Furthermore, fecal bile acids are reduced in pregnant Fxr-/- mice. Lithocholic acid and deoxycholic acid, the principal ligands for TGR5, are decreased in particular. Therefore, we propose that raised serum bile acids and reduced FXR and TGR5 activity contribute to the altered glucose metabolism observed in ICP.

15.
Am J Physiol Gastrointest Liver Physiol ; 319(2): G197-G211, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32597707

RESUMO

Intrahepatic cholestasis of pregnancy (ICP) is characterized by elevated maternal circulating bile acid levels and associated dyslipidemia. ICP leads to accumulation of bile acids in the fetal compartment, and the elevated bile acid concentrations are associated with an increased risk of adverse fetal outcomes. The farnesoid X receptor agonist obeticholic acid (OCA) is efficient in the treatment of cholestatic conditions such as primary biliary cholangitis. We hypothesized that OCA administration during hypercholanemic pregnancy will improve maternal and fetal bile acid and lipid profiles. Female C57BL/6J mice were fed either a normal chow diet, a 0.5% cholic acid (CA)-supplemented diet, a 0.03% OCA-supplemented diet, or a 0.5% CA + 0.03% OCA-supplemented diet for 1 wk before mating and throughout pregnancy until euthanization on day 18. The effects of CA and OCA feeding on maternal and fetal morphometry, bile acid and lipid levels, and cecal microbiota were investigated. OCA administration during gestation did not alter the maternal or fetal body weight or organ morphometry. OCA treatment during hypercholanemic pregnancy reduced bile acid levels in the fetal compartment. However, fetal dyslipidemia was not reversed, and OCA did not impact maternal bile acid levels or dyslipidemia. In conclusion, OCA administration during gestation had no apparent detrimental impact on maternal or fetal morphometry and improved fetal hypercholanemia. Because high serum bile acid concentrations in ICP are associated with increased rates of adverse fetal outcomes, further investigations into the potential use of OCA during cholestatic gestation are warranted.NEW & NOTEWORTHY We used a mouse model of gestational hypercholanemia to investigate the use of obeticholic acid (OCA), a potent FXR agonist, as a treatment for the hypercholanemia of intrahepatic cholestasis of pregnancy (ICP). The results demonstrate that OCA can improve the fetal bile acid profile. This is relevant not only to women with ICP but also for women who become pregnant while receiving OCA treatment for other conditions such as primary biliary cholangitis and nonalcoholic steatohepatitis.


Assuntos
Ácidos e Sais Biliares/sangue , Ácido Quenodesoxicólico/análogos & derivados , Colestase Intra-Hepática/tratamento farmacológico , Complicações na Gravidez/tratamento farmacológico , Animais , Ácidos e Sais Biliares/metabolismo , Ceco , Ácido Quenodesoxicólico/farmacologia , Colesterol 7-alfa-Hidroxilase/genética , Colesterol 7-alfa-Hidroxilase/metabolismo , Dislipidemias/tratamento farmacológico , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Gravidez , RNA Ribossômico 16S , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo
16.
Sci Rep ; 10(1): 10361, 2020 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-32587408

RESUMO

Perturbations in the intrauterine environment can result in lifelong consequences for metabolic health during postnatal life. Intrahepatic cholestasis of pregnancy (ICP) can predispose offspring to metabolic disease in adulthood, likely due to a combination of the effects of increased bile acids, maternal dyslipidemia and deranged maternal and fetal lipid homeostasis. Whereas ursodeoxycholic acid (UDCA) is a commonly used treatment for ICP, no studies have yet addressed whether it can also prevent the metabolic effects of ICP in the offspring and fetoplacental unit. We therefore analyzed the lipid profile of fetal serum from untreated ICP, UDCA-treated ICP and uncomplicated pregnancies and found that UDCA ameliorates ICP-associated fetal dyslipidemia. We then investigated the effects of UDCA in a mouse model of hypercholanemic pregnancy and showed that it induces hepatoprotective mechanisms in the fetal liver, reduces hepatic fatty acid synthase (Fas) expression and improves glucose tolerance in the adult offspring. Finally, we showed that ICP leads to epigenetic changes in pathways of relevance to the offspring phenotype. We therefore conclude that UDCA can be used as an intervention in pregnancy to reduce features of metabolic disease in the offspring of hypercholanemic mothers.

17.
Nature ; 583(7814): 96-102, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32581362

RESUMO

Most patients with rare diseases do not receive a molecular diagnosis and the aetiological variants and causative genes for more than half such disorders remain to be discovered1. Here we used whole-genome sequencing (WGS) in a national health system to streamline diagnosis and to discover unknown aetiological variants in the coding and non-coding regions of the genome. We generated WGS data for 13,037 participants, of whom 9,802 had a rare disease, and provided a genetic diagnosis to 1,138 of the 7,065 extensively phenotyped participants. We identified 95 Mendelian associations between genes and rare diseases, of which 11 have been discovered since 2015 and at least 79 are confirmed to be aetiological. By generating WGS data of UK Biobank participants2, we found that rare alleles can explain the presence of some individuals in the tails of a quantitative trait for red blood cells. Finally, we identified four novel non-coding variants that cause disease through the disruption of transcription of ARPC1B, GATA1, LRBA and MPL. Our study demonstrates a synergy by using WGS for diagnosis and aetiological discovery in routine healthcare.


Assuntos
Internacionalidade , Programas Nacionais de Saúde , Doenças Raras/diagnóstico , Doenças Raras/genética , Sequenciamento Completo do Genoma , Complexo 2-3 de Proteínas Relacionadas à Actina/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Alelos , Bases de Dados Factuais , Eritrócitos/metabolismo , Fator de Transcrição GATA1/genética , Humanos , Fenótipo , Locos de Características Quantitativas , Receptores de Trombopoetina/genética , Medicina Estatal , Reino Unido
20.
Sci Rep ; 10(1): 3895, 2020 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-32127609

RESUMO

Ursodeoxycholic acid (UDCA) treatment can reduce itch and lower endogenous serum bile acids in intrahepatic cholestasis of pregnancy (ICP). We sought to determine how it could influence the gut environment in ICP to alter enterohepatic signalling. The gut microbiota and bile acid content were determined in faeces from 35 pregnant women (14 with uncomplicated pregnancies and 21 with ICP, 17 receiving UDCA). Faecal bile salt hydrolase activity was measured using a precipitation assay. Serum fibroblast growth factor 19 (FGF19) and 7α-hydroxy-4-cholesten-3-one (C4) concentrations were measured following a standardised diet for 21 hours. Women with a high ratio of Bacteroidetes to Firmicutes were more likely to be treated with UDCA (Fisher's exact test p = 0.0178) than those with a lower ratio. Bile salt hydrolase activity was reduced in women with low Bacteroidetes:Firmicutes. Women taking UDCA had higher faecal lithocholic acid (p < 0.0001), with more unconjugated bile acids than women with untreated ICP or uncomplicated pregnancy. UDCA-treatment increased serum FGF19, and reduced C4 (reflecting lower bile acid synthesis). During ICP, UDCA treatment can be associated with enrichment of the gut microbiota with Bacteroidetes. These demonstrate high bile salt hydrolase activity, which deconjugates bile acids enabling secondary modification to FXR agonists, enhancing enterohepatic feedback via FGF19.


Assuntos
Amidoidrolases/genética , Bacteroidetes/efeitos dos fármacos , Bacteroidetes/genética , Colestase Intra-Hepática/microbiologia , Regulação Bacteriana da Expressão Gênica , Intestinos/microbiologia , Complicações na Gravidez/microbiologia , Ácido Ursodesoxicólico/farmacologia , Animais , Estudos de Casos e Controles , Feminino , Microbioma Gastrointestinal/efeitos dos fármacos , Humanos , Camundongos , Gravidez
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