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
. 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.
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.
Intrahepatic cholestasis of pregnancy is characterised by pruritus and elevated serum bile acids. The pruritus can be severe, and pharmacological options achieve inconsistent symptomatic improvement. ...Raised bile acids are linearly associated with adverse fetal outcomes, with existing management of limited benefit. We hypothesised that therapeutic plasma exchange removes pruritogens and lowers total bile acid concentrations, and improves symptoms and biochemical abnormalities in severe cases that have not responded to other treatments.
Four women with severe pruritus and hypercholanemia were managed with therapeutic plasma exchange. Serial blood biochemistry and visual analogue scores of itch severity were obtained. Blood and waste plasma samples were collected before and after exchange; individual bile acids and sulfated progesterone metabolites were measured with HPLC-MS, autotaxin activity and cytokine profiles with enzymatic methods. Results were analysed using segmental linear regression to describe longitudinal trends, and ratio t tests.
Total bile acids and visual analogue itch scores demonstrated trends to transiently improve following plasma exchange, with temporary symptomatic benefit reported. Individual bile acids (excluding the drug ursodeoxycholic acid), and the sulfated metabolites of progesterone reduced following exchange (P = .03 and P = .04, respectively), whilst analysis of waste plasma demonstrated removal of autotaxin and cytokines.
Therapeutic plasma exchange can lower potentially harmful bile acids and improve itch, likely secondary to the demonstrated removal of pruritogens. However, the limited current experience and potential complications, along with minimal sustained symptomatic benefit, restrict its current use to women with the most severe disease for whom other treatment options have been exhausted.
Introduction Intrahepatic cholestasis of pregnancy (ICP) is associated with adverse perinatal outcomes and maternal metabolic dysfunction. Ursodeoxycholic acid (UDCA) treatment can improve itch ...severity and reduce bile acids in cholestatic conditions. This thesis determines how UDCA affects ICP patients by assessing its impact on adverse perinatal outcomes, its role in reducing maternal pruritus, and its involvement in maternal metabolic dysfunction secondary to altered enteroendocrine signalling. Methods To understand the magnitude of adverse perinatal outcomes in women with ICP, I performed a systematic review and aggregate data meta-analysis, comparing women with ICP (5515) and uncomplicated pregnancies (165 081), using a random-effects comparison with the DerSimonian and Laird method. To determine whether these outcomes are affected by disease severity, I analysed individual patient data from 16 published studies and two unpublished cohorts and compared results for women untreated and treated with UDCA. To identify pruritogens that are modifiable by UDCA treatment, I analysed serum samples collected longitudinally from women with ICP and benign pruritus gravidarum. Results were compared with linear and logistic regression, and predictive biomarkers for ICP were identified. To determine the effect of ICP on enteroendocrine signals, I studied murine models (0.5% cholic acid-fed ± UDCA) and samples from women with ICP, uncomplicated pregnancy, and non-pregnant controls. I used 16S rRNA sequencing and whole genome shotgun metagenomic analyses to characterise the cholestatic gut microbiota, and assessed the gut metabolome using UPLC-MS. Their effects on enteroendocrine signals were determined using qPCR and enzymatic analyses on ileal tissues and serum samples obtained following a timed dietary study. Results ICP is associated with increased adverse perinatal outcomes, compared with uncomplicated pregnancies. Women with bile acids ≥100μmol/L have significantly 24 increased risks of stillbirth (hazard ratio 30.50 (8.83 to 105.30, p < 0.0001)) compared to women with lower total bile acids. UDCA treatment did not significantly affect the observed association between total bile acid concentration and stillbirth, although the observed cohort treated with UDCA had more severe disease than untreated women, and the absolute risk of stillbirth was reduced for treated women at the equivalent disease severity (determined by bile acid concentration). Sulfated progesterone metabolites and autotaxin activity are associated with disease severity (determined by pruritus intensity) for women with ICP compared to those with benign pruritis gravidarum. They are also useful predictive biomarkers prior to hypercholanaemia developing; and their levels are reduced by treatment with UDCA. UDCA treatment of women with ICP and a murine model of cholestatic pregnancy results in enrichment of the gut microbiota with Bacteroidetes compared to Firmicutes, with associated increased bile salt hydrolase activity and intestinal bile acid deconjugation. Unconjugated intestinal UDCA is thereby modified to the metabolically-active bile acid lithocholic acid, whose levels are markedly increased in the faeces of treated women. Discussion These studies have confirmed that ICP is associated with adverse perinatal outcomes, including stillbirth; UDCA treatment may lower the stillbirth risk at an equivalent bile acid concentration, but the existing evidence does not yet support this definitive conclusion. UDCA can improve the pruritus of ICP by reducing the pruritogenic sulfated progesterone metabolites, and may improve the metabolic derangements of ICP by altering the gut microbial environment to enhance bile acid-derived enterohepatic and enteroendocrine signalling.
Whilst intrahepatic cholestasis of pregnancy (ICP) is associated with adverse perinatal outcomes, the relationship between specific biochemical markers and individual pregnancy complications has not ...been established.
We performed a systematic review of the literature (PubMed, Web of Science, Embase databases from inception to August 2017, selecting studies reporting perinatal outcomes for women with ICP with serum bile acid concentrations reported. Random effects meta-analysis was performed to determine risk of adverse perinatal outcomes. Individual patient data (IPD) were collected to assess associations between biochemical markers and adverse outcomes using logistic and stepwise linear regression (PROSPERO: CRD42017069134).
22 studies were included in the meta-analysis (5515 ICP cases, 165 081 controls), with IPD from 18 studies (4163 ICP cases). Stillbirth complicated 0.83% ICP and 0.32% control pregnancies (OR 1.46 (0.73–2.89)). Stillbirth was associated with maximum total bile acid concentration (ROC AUC 0.80 (0.69–0.90)) but not alanine transaminase (ROC AUC 0.46, 95% CI 0.35–0.58). Prevalence of stillbirths was 0.20% (0.05–0.50%) with serum total bile acids <40 μmol/L, 0.29% (0.08–0.74%; hazard ratio 1.55; (0.39–6.22, p = 0.53)) with total bile acids 40–99 μmol/L and 3.08% (1.77–4.96%; hazard ratio 17.27 (27 (5.65–52.77, p < 0.0001)) with total bile acids ⩾100 μmol/L. Women with ICP had higher odds ratios of preterm birth (OR 3.54, 95%CI 2.72–4.62, related to increasing bile acid category.
The risk of stillbirth is increased in women with ICP, but not significantly greater than population rates until serum bile acids ⩾100 μmol/L. The clear bile acid threshold of 100 μmol/L beneath which stillbirth rates were not elevated is a novel and important finding in our study. As most women with ICP have bile acids below this level, they can be reassured, provided repeat bile acid testing is performed.
Gain-of-function (GOF) mutations in signal transducer and activator of transcription 1 (STAT1) cause susceptibility to a range of infections, autoimmunity, immune dysregulation, and combined ...immunodeficiency. Disease manifestations can be mild or severe and life-threatening. Hematopoietic stem cell transplantation (HSCT) has been used in some patients with more severe symptoms to treat and cure the disorder. However, the outcome of HSCT for this disorder is not well established.
We sought to aggregate the worldwide experience of HSCT in patients with GOF-STAT1 mutations and to assess outcomes, including donor engraftment, overall survival, graft-versus-host disease, and transplant-related complications.
Data were collected from an international cohort of 15 patients with GOF-STAT1 mutations who had undergone HSCT using a variety of conditioning regimens and donor sources. Retrospective data collection allowed the outcome of transplantation to be assessed. In vitro functional testing was performed to confirm that each of the identified STAT1 variants was in fact a GOF mutation.
Primary donor engraftment in this cohort of 15 patients with GOF-STAT1 mutations was 74%, and overall survival was only 40%. Secondary graft failure was common (50%), and posttransplantation event-free survival was poor (10% by 100 days). A subset of patients had hemophagocytic lymphohistiocytosis before transplant, contributing to their poor outcomes.
Our data indicate that HSCT for patients with GOF-STAT1 mutations is curative but has significant risk of secondary graft failure and death.
Abstract Background Gain of function mutations in signal transducer and activator of transcription 1 (GOF-STAT1) cause a susceptibility to a range of infections, autoimmunity, immune dysregulation, ...and combined immunodeficiency. Disease manifestations can be mild or severe and life threatening. Hematopoietic stem cell transplantation (HSCT) has been utilized in some patients with more severe symptoms to treat and cure the disorder. The outcome of HSCT for this disorder is, however, not well established. Objective To aggregate the worldwide experience of HSCT in GOF-STAT1 patients and to assess outcomes including donor engraftment, overall survival, graft versus host disease, and transplant related complications. Methods Data were collected from an international cohort of 15 GOF-STAT1 patients that had undergone HSCT using a variety of conditioning regimens and donor sources. Retrospective data collection allowed the outcome of transplantation to be assessed. In vitro functional testing was performed to confirm that each of the identified STAT1 variants was, in-fact, a gain of function mutation. Results Primary donor engraftment in this cohort of 15 GOF-STAT1 patients was 74% and overall survival was only 40%. Secondary graft failure was common (50%) and post-transplant event free survival was poor (10% by 100 days). A subset of patients developed hemophagocytic lymphohistiocytosis (HLH) prior to their transplant, contributing to their poor outcomes. Conclusion Our data indicate that HSCT for patients with GOF-STAT1 mutations is curative but has significant risk of secondary graft failure and death.
A juvenile (1 year old) female rhesus macaque (Macaca mulatta) developed a chronic active skin condition characterized by pruritus, erythema, alopecia, scaling, exfoliation, and lichenification. ...Lesions were limited to the ventrum, specifically rostral mandible and neck, axilla and inguinal regions, distal extremities, and interdigital regions. Differential diagnoses included infection, dietary deficiency, metabolic abnormality, endocrinopathy, and immunological injury. Diagnostic tests included complete hemogram, serum chemistry, skin scrapes for ectoparasite detection, hair plucks for dermatophyte culture, and a serum-based hypersensitivity panel. All results were within normal limits. Dermal biopsies revealed lesions consistent with active allergic dermatitis, and a diagnosis of atopic dermatitis was made. Oral cyclosporine (5 mg/kg daily) rapidly eliminated clinical evidence of dermatitis. Histologically, lesions resolved after 12 months of treatment. Atopic dermatitis is an inflammatory skin condition for which there are neither pathognomonic clinical or diagnostic features nor a single successful therapy. Basic criteria such as pruritus, lichenification, a chronic course, and history of allergies strongly support the diagnosis. One successful therapeutic agent is a macrolide calcineurin inhibitor, cyclosporine. It represents a safer class of immunomodulatory drugs than corticosteroids and provides targeted alteration of lymphocyte function. To our knowledge this case represents the first reported successful treatment of atopic dermatitis in a nonhuman primate utilizing cyclosporine.
A 27-year-old female rhesus macaque (Macaca mulatta) developed anisocoria. The left pupil was dilated and unresponsive to light. The macaque was euthanized because of unrelated reasons and the body ...was submitted for necropsy. On gross examination, a berry aneurysm of the right middle cerebral artery causing marked compression of the right optic tract was found. Arteriosclerotic changes were observed microscopically in the right middle cerebral and in the internal carotid arteries. The left iris was markedly degenerated, with atrophy of the constrictor muscle. Compression of the right optic tract may cause homonimus hemianopsia. A dilated and unresponsive left pupil indicated a lesion in the ipsilateral parasympathetic efferent pathway. In the absence of appreciable lesions of the left oculomotor nerve, the most likely cause of mydriasis was the iridic lesion. Intracranial aneurysms are common in humans (2 to 5%), but not in other species. Only about 10% of unruptured aneurysms are associated with neurologic deficits related to mechanical compression, such as visual deficits or anisocoria. Meticulous investigation of the ocular vascular and neural pathways led us to conclude that the anisocoria was unrelated to the aneurysm. To our knowledge, this report represents the first documented case of a naturally occurring intracranial aneurysm in nonhuman primates.
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