Past, current, and future trends in the prevalence of primary sclerosing cholangitis and inflammatory bowel disease across England (2015-2027): a nationwide, population-based study.

Background: Primary sclerosing cholangitis (PSC) is one of the leading indications for liver transplantation in Europe, and a major risk factor for cancer in inflammatory bowel disease (IBD). However, it is not known how the epidemiology of PSC will change as that of IBD evolves. The aim of this study is to provide nationwide statistics on the past and current prevalence of PSC and IBD across England, and forecast how this is likely to change over time. Methods: We accessed and analysed a nationwide population-based administrative healthcare registry, which houses prospectively accrued data since April 1st 2001. In so doing, the past and current prevalence of PSC-IBD and IBD alone was determined among 18-60-year-olds in England, alongside average annual percentage change rates (AAPC), between the 1st of January 2015 and 2020. Past and current prevalence data, alongside trends in incidence and event-free survival rates, were then used to forecast future prevalence between 2021 and 2027. Findings: In 2015, the prevalence of PSC with prior IBD diagnosis was 5.0 per 100,000 population, rising to 5.7 when including those with IBD diagnosed after PSC. In 2020, prevalence increased to 7.6 (8.6 accounting for IBD developing after PSC), yielding an AAPC of 8.8. In 2027, PSC-IBD prevalence is forecast to be 11.7 (95% prediction interval [PI]: 10.8-12.7), and 13.3 when accounting for IBD developing after PSC (AAPC: 6.4; 95% PI: 5.3-7.5). Comparatively, the prevalence of IBD alone rose among 18-60-year-olds from 384.3 in 2015 to 538.7 in 2020 (AAPC 7.0), and forecast to increase to 742.5 by 2027 (95% PI: 736.4-748.0; AAPC: 4.7, 95% PI: 4.6-4.8). Interpretation: The rate of growth in PSC-IBD is predicted to exceed IBD-alone. Further research is needed to understand changes in disease epidemiology, including aetiological drivers of developing (invariably progressive) liver disease in IBD, and the implications of rising case burden on health care resources. Funding: This study was supported by an unrestricted grant provided by Gilead Sciences.

Guideline No. 452: Diagnosis and Management of Intrahepatic Cholestasis of Pregnancy.

OBJECTIVE: To summarize the current evidence and to make recommendations for the diagnosis and management of intrahepatic cholestasis of pregnancy. TARGET POPULATION: Pregnant people with intrahepatic cholestasis of pregnancy. OPTIONS: Diagnosing the condition using fasting or non-fasting bile acids, classifying disease severity, determining what treatment to offer, establishing how to monitor for antenatal fetal wellbeing, identifying when to perform elective birth. BENEFITS, HARMS, AND COSTS: Individuals with intrahepatic cholestasis of pregnancy are at increased risk of adverse perinatal outcomes including preterm birth, neonatal respiratory distress and admission to a neonatal intensive care unit, with an increased risk of stillbirth when bile acid levels are ≥100 µmol/L. There is inequity in bile acid testing availability and timely access to results, along with uncertainly of how to treat, monitor. and ultimately deliver these pregnancies. Optimization of diagnostic and management protocols can improve maternal and fetal postnatal outcomes. EVIDENCE: Medline, PubMed, Embase, and the Cochrane Library were searched from inception to March 2023, using medical subject headings (MeSH) and keywords related to pregnancy, intrahepatic cholestasis of pregnancy, bile acids, pruritis, ursodeoxycholic acid, and stillbirth. This document presents an abstraction of the evidence rather than a methodological review. VALIDATION METHODS: The authors rated the quality of evidence and strength of recommendations using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. See Appendix A (Tables A1 for definitions and A2 for interpretations). INTENDED AUDIENCE: Obstetric care providers, including obstetricians, family physicians, nurses, midwives, maternal-fetal medicine specialists, and radiologists. SOCIAL MEDIA ABSTRACT: Intrahepatic cholestasis of pregnancy requires adequate diagnosis with non-fasting bile acid levels which guide optimal management and delivery timing.

Corrigendum: Genetically predicted lipids mediate the association between intrahepatic cholestasis of pregnancy and cardiovascular disease.

[This corrects the article DOI: 10.3389/fcvm.2024.1401010.].

Prognostic factors for pediatric patients with severe intestinal motility disorders: a single institution's experience.

PURPOSE: To identify the prognostic factors for pediatric severe intestinal motility disorder (IMD). METHODS: We reviewed the medical records of patients with severe IMD, who required total parenteral nutrition (TPN) for ≥ 60 days at our institution between April, 1984 and March, 2023, examining their characteristics to identify prognostic factors. RESULTS: The types of IMD in the 14 patients enrolled in this study were as follows: isolated hypoganglionosis (IHG, n = 6), extensive aganglionosis (EAG: n = 6), and chronic idiopathic intestinal pseudo-obstruction (CIIP, n = 2). There was no significant difference in mortality among the three types of severe IMD. Weaning-off TPN and the use of the colon were not significant prognostic factors, but cholestasis was a significant prognostic factor (p = 0.005). There was a high mortality rate (50%), with the major causes of death being intestinal failure-associated liver disease (IFALD) following hepatic failure, and catheter-related blood stream infection (CRBSI). One IHG patient underwent small bowel transplantation but died of acute rejection. CONCLUSION: Severe IMD is still associated with a high mortality rate and cholestasis predicts the prognosis. Thus, preventing or improving IFALD and CRBSI caused by long-term TPN is important for reducing the mortality rate.

Alagille syndrome with unusual common bile duct hypoplasia and gallbladder dysmorphism: Lesson based on a case report.

Alagille syndrome is an autosomal dominant and multisystemic disease that generally manifests itself with intrahepatic bile ducts paucity, chronic cholestasis, xanthomas and with other less frequent clinical manifestations such as congenital heart disease, skeletal abnomalies, ophthalmic, vascular, renal and growth failure. Symptoms can be subclinical or very severe. Is caused by various genetic mutations and the majority of patients have a detectable mutation in JAG1 (90%), the remainder have mutations in NOTCH2. The diagnosis is molecular and the incidence is approximately 1 in 30,000 - 50.000. Patient management can be very complex and treatment depends on the district affected and on the symptoms. In more serious cases, with terminal liver disease, liver transplantation is used. We describe a case with main bile duct hypoplasia, intrahepatic bile ducts paucity, cholestasis and gallbladder dimorphism associated with renal malrotation and butterfly vertebrae.

Portal vein hypoplasia is present in patients with biliary atresia at the time of diagnosis.

BACKGROUND: In patients with biliary atresia (BA), severe portal hypertension (HTN) develops even with successful bile flow restoration, suggesting an intrinsic factor driving portal HTN independent from bile obstruction. We hypothesize that patients with BA have abnormal portal vein (PV) development, leading to PV hypoplasia. METHODS: In this observational cohort study, we enrolled patients who were referred to a tertiary center from 2017 to 2021 to rule out BA. Newborns who underwent computed tomography (CT) angiogram as a clinical routine before intraoperative cholangiogram, and laparoscopic Kasai hepatoportoenterostomy. The diameter of the PV and hepatic artery (HA) were compared to the degree of liver fibrosis in the wedge biopsies. The jaundice clearance, native liver survival, and clinical portal hypertensive events, including ascites development and intestinal bleeding, were assessed. RESULTS: 47 newborns with cholestasis were included in the cohort; 35 were diagnosed with BA. The patients with BA had a smaller median PV diameter (4.3 vs. 5.1 mm; p < 0.001) and larger median HA diameter (1.4 vs. 1.2 mm; p < 0.05) compared to the patients with other forms of cholestasis. The median PV and HA diameter did not correlate with the degree of liver fibrosis. Among 35 patients with BA, 29 patients (82.9%) achieved jaundice clearance, and 23 patients (65.7%) were alive with their native liver at two years of age. Seven patients (20%) developed intestinal bleeding, and seven patients (20%) developed ascites, with one overlapping patient. CONCLUSION: PV hypoplasia is present in patients with BA independent of liver fibrosis at the time of diagnosis.

PPAR-Mediated Bile Acid Glucuronidation: Therapeutic Targets for the Treatment of Cholestatic Liver Diseases.

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.

Abcb4-defect cholangitis mouse model with hydrophobic bile acid composition by in vivo liver-specific gene deletion.

Progressive familial intrahepatic cholestasis (PFIC) is a liver disease that occurs during childhood and requires liver transplantation. ABCB4 is localized along the canalicular membranes of hepatocytes, transports phosphatidylcholine into bile, and its mutation causes PFIC3. Abcb4 gene-deficient mice established as animal models of PFIC3 exhibit cholestasis-induced liver injury. However, their phenotypes are often milder than those of human PFIC3, partly because of the existence of large amounts of less toxic hydrophilic bile acids synthesized by the rodent-specific enzymes Cyp2c70 and Cyp2a12. Mice with double deletions of Cyp2c70/Cyp2a12 (CYPDKO mice) have a human-like hydrophobic bile acid composition. PFIC-related gene mutations were induced in CYPDKO mice to determine whether these triple-gene-deficient mice are a better model for PFIC. To establish a PFIC3 mouse model using CYPDKO mice, we induced abcb4 gene deletion in vivo using adeno-associated viruses expressing SaCas9 under the control of a liver-specific promoter and abcb4-target gRNAs. Compared to Abcb4-deficient wild-type mice, Abcb4-deficient CYPDKO mice showed more pronounced liver injury along with an elevation of inflammatory and fibrotic markers. The proliferation of intrahepatic bile ductal cells and hematopoietic cell infiltration were also observed. CYPDKO/abcb4-deficient mice show a predominance of taurine-conjugated chenodeoxycholic acid and lithocholic acid in the liver. In addition, phospholipid levels in the gallbladder bile were barely detectable. Mice with human-like bile acids exhibit severe cholestatic liver injury when Abcb4 is knocked down using genome editing technology. This mouse model is useful for studying human cholestatic diseases and developing new treatments.

Corrigendum: LC-MS/MS untargeted lipidomics uncovers placenta lipid signatures from intrahepatic cholestasis of pregnancy.

[This corrects the article DOI: 10.3389/fphys.2024.1276722.].

Core biomarkers analysis benefit for diagnosis on human intrahepatic cholestasis of pregnancy.

BACKGROUND: The pregnant women with intrahepatic cholestasis were at high risk of fetal distress, preterm birth and unexpected stillbirth. Intrahepatic cholestasis of pregnancy (ICP) was mainly caused by disorder of bile acid metabolism, whereas the specific mechanism was obscure. METHODS: We performed proteomics analysis of 10 ICP specimens and 10 placenta specimens from patients without ICP through data-independent acquisition (DIA) technique to disclose differentially expressed proteins. We executed metabolomic analysis of 30 ICP specimens and 30 placenta specimens from patients without ICP through UPLC-MS/MS to identify differentially expressed metabolites. Enrichment and correlation analysis was used to obtain the direct molecular insights of ICP development. The ICP rat models were constructed to validate pathological features. RESULTS: The heatmap of proteomics analysis showed the top 30 up-regulated and 30 down-regulated proteins. The metabolomic analysis revealed 20 richer and 4 less abundant metabolites in ICP samples compared with placenta specimens from patients without ICP, and enrichment pathways by these metabolites included primary bile acid biosynthesis, cholesterol metabolism, bile secretion, nicotinate and nicotinamide metabolism, purine metabolism and metabolic pathways. Combined analysis of multiple omics results demonstrated that bile acids such as Glycohyocholic acid, Glycine deoxycholic acid, beta-Muricholic acid, Noncholic acid, cholic acid, Gamma-Mercholic Acid, alpha-Muricholic acid and Glycochenodeoxycholic Aicd were significantly associated with the expression of GLRX3, MYL1, MYH7, PGGT1B, ACTG1, SP3, LACTB2, C2CD5, APBB2, IPO9, MYH2, PPP3CC, PIN1, BLOC1S1, DNAJC7, RASAL2 and ATCN3 etc. The core protein ACAT2 was involved in lipid metabolic process and animal model showed that ACAT2 was up-regulated in placenta and liver of pregnant rats and fetal rats. The neonates had low birth weight and Safranin O-Fast green FCF staining of animal models showed that poor osteogenic and chondrogenic differentiation of fetal rats. CONCLUSION: Multiple metabolites-alpha-Muricholic acid, beta-Muricholic acid, Glycine deoxycholic acid and Glycochenodeoxycholic Acid etc. were perfect biomarkers to predict occurrence of ICP. Bile acids were significantly associated with varieties of protein expression and these proteins were differentially expressed in ICP samples. Our study provided several biomarkers for ICP detection and potential therapeutic targets for ICP development.

Heritable Chronic Cholestatic Liver Diseases: A Review.

Chronic cholestasis due to heritable causes is usually diagnosed in childhood. However, many cases can present and survive into adulthood. The time course varies considerably depending on the underlying etiology. Laboratory data usually reveal elevated conjugated hyperbilirubinemia, alkaline phosphatase, and gamma-glutamyl transpeptidase. Patients may be asymptomatic; however, when present, the typical symptoms are pruritus, jaundice, fatigue, and alcoholic stools. The diagnostic methods and management required depend on the underlying etiology. The development of genome-wide associated studies has allowed the identification of specific genetic mutations related to the pathophysiology of cholestatic liver diseases. The aim of this review was to highlight the genetics, clinical pathophysiology, presentation, diagnosis, and treatment of heritable etiologies of chronic cholestatic liver disease.

STING-mediated IL-6 Inhibits OATP1B1 Expression via the TCF4 Signaling Pathway in Cholestasis.

Background and Aims: Organic anion-transporting polypeptides (OATPs) play a crucial role in the transport of bile acids and bilirubin. In our previous study, interleukin 6 (IL-6) reduced OATP1B3 levels in cholestatic disease. However, it remains unclear whether IL-6 inhibits OATP1B1 expression in cholestatic diseases. This study aimed to investigate whether IL-6 can inhibit OATP1B1 expression and explore the underlying mechanisms. Methods: The effect of stimulator of interferon genes (STING) signaling on inflammatory factors was investigated in a cholestatic mouse model using RT-qPCR and enzyme-linked immunosorbent assay. To assess the impact of inflammatory factors on OATP1B1 expression in hepatocellular carcinoma, we analyzed OATP1B1 expression by RT-qPCR and Western Blot after treating PLC/PRF/5 cells with TNF-α, IL-1ß, and IL-6. To elucidate the mechanism by which IL-6 inhibits OATP1B1 expression, we examined the expression of the OATP1B1 regulator TCF4 in PLC/PRF/5 and HepG2 cells using RT-qPCR and Western Blot. The interaction mechanism between ß-catenin/TCF4 and OATP1B1 was investigated by knocking down ß-catenin/TCF4 through siRNA transfection. Results: The STING inhibitor decreased inflammatory factor levels in the cholestatic mouse model, with IL-6 exhibiting the most potent inhibitory effect on OATP1B1. IL-6 downregulated ß-catenin/TCF4, leading to decreased OATP1B1 expression. Knocking-down ß-catenin/TCF4 counteracted the ß-catenin/TCF4-mediated repression of OATP1B1. Conclusions: STING-mediated IL-6 up-regulation may inhibit OATP1B1, leading to reduced transport of bile acids and bilirubin by OATP1B1. This may contribute to altered pharmacokinetics in patients with diseases associated with increased IL-6 production.

Characteristics of Hepatobiliary Fascioliasis and the Role of Endoscopic Retrograde Cholangiopancreatography in Management: A Single Center Experience.

Background: Hepatobiliary fascioliasis has two phases, each requiring specific management approaches. Triclabendazole has been widely effective in treating the two phases of clinical fascioliasis and endoscopic retrograde cholangiopancreatography (ERCP) in the biliary phase. We aimed to characterize presentations of hepatobiliary fascioliasis and highlight the role of ERCP in management. Subjects and methods: This retrospective cohort includes patients diagnosed with clinical hepatobiliary fascioliasis between January 2013 and December 2022. Demographic data, clinical presentation, laboratory and radiological investigations, treatment, and endoscopy reports were collected from the records of 62 participants. Patients were divided into two groups: acute hepatic and chronic biliary phases. Results: Thirty-six patients were in the biliary phase, and 26 were in the hepatic phase. All patients were from rural areas, and females were predominant (76%). Hypereosinophilia was detected in 92% of acute cases and 58% of chronic biliary cases. In chronic biliary cases, the levels of liver biochemicals, including alanine transaminase (ALT), aspartate aminotransferase (AST), gamma-glutamyltransferase (GGT), and bilirubin, were higher at levels of 189 ± 76, 127 ± 47, 268 ± 77, and 2.4 ± 0.7 respectively, compared to acute hepatic cases, 35.6 ± 8.2, 32.7 ± 4.3, 69.2 ± 45.45, and 0.58 ± 0.01. The corresponding P-values were 0.003, 0.001, <0.001, and <0.001, respectively. Triclabendazole effectively cured 93.5% of patients and was used in combination with ERCP in biliary-phase cases where the fluke was extracted from the biliary system in 34 patients (94.4%). Three patients (8.8%) were diagnosed with post-ERCP pancreatitis. None of the patients experienced bleeding, perforation, or required biliary stenting. Conclusion: Clinical fascioliasis could manifest in acute hepatic or chronic biliary phases. Hypereosinophilia was more evident in the hepatic phases, while ALT, AST, GGT, and bilirubin were higher in the biliary phase. Triclabendazole is effective in the hepatic phase and when combined with ERCP in the biliary phase. ERCP is highly effective for relieving obstruction and treating biliary fascioliasis.

Effectiveness of oral methylprednisolone as adjuvant therapy for clinical improvement, biochemical markers, and inflammation in infants with cholestasis.

Aims: This study analyzed the effectiveness of methylprednisolone in improving jaundice, bilirubin levels, liver function tests, and inflammatory biomarkers in infants with cholestasis. Methods: The randomized, actively controlled, parallel-group trial (ISRCTN45080388 registry) was conducted from November 2022 to May 2023 in Dr. Soetomo General Academic Hospital, Surabaya, Indonesia, on infants with cholestasis. The ethics committee of Dr. Soetomo General Academic Hospital, Surabaya approved the study protocol. Infants 14 days to 3 months old, with cholestasis followed by acholic stool, dark urine, and hepatomegaly were included in the trial. Participants were randomly assigned to methylprednisolone 2 mg/kg/day twice daily or to placebo twice daily for two weeks. Ursodeoxycholic acid (10 mg/kg) was administered to all patients thrice daily. Clinical examination and laboratory measurements (direct and total bilirubin, Aspartate aminotransferase (AST), Alanine transaminase (ALT), Gamma-glutamyl transferase (GGT), and inflammatory biomarker) were performed at baseline and after 2-week treatment. Measurement of inflammatory biomarkers (IL-2, IL-4, IL-6, IL-10, IFN-γ, TGF-ß, and ANCA) was performed using enzyme-linked immunoassays. Data distribution was checked for normality. Analysis was carried out using SPSS ver. 21 with p significant <0.05. Results: In total, 40 participants were randomized to methylprednisolone (n = 20; mean age 8.39 ± 3.11 weeks) and placebo (n = 18; 2 drop out; mean age 8.98 ± 2.80 weeks) groups. At baseline, the methylprednisolone treatment and placebo groups significantly differed in gender (p = 0.02) but not in clinical, laboratory examination, or inflammatory biomarker levels. The methylprednisolone group had direct bilirubin 8.36 ± 4.84 mg/dL; total bilirubin 10.40 (2.70-33.25) mg/dL; AST 187.05 (42.00-911.00) U/L; ALT 170.43 ± 134.43 U/L; IL-2 171.29 (73.70-378.57) ng/L; IL-4 119.57 ± 59.69 ng/L; IL-6 71.74 ± 29.83 ng/L; IL-10 138.15 ± 70.62 ng/L; IFN-γ 42.54 ± 12.17 ng/L; TGF-ß 316.58 (163.68-606.16) ng/L; ANCA 1.70 (0.66-3.25) ng/L. After two weeks of treatment, direct bilirubin, total bilirubin, AST, IL-10, and IFN-γ levels were significantly lower in the methylprednisolone group (p < 0.05) than those in the placebo group. No serious adverse events were reported. Conclusion: Methylprednisolone was efficacious in reducing 2-week bilirubin levels. These results support the hypothesis that the immunological process is involved in cholestasis. Further studies with larger sample sizes are needed to confirm the bile duct anti-inflammatory effect of methylprednisolone in cholestasis as an opportunity for new therapies to prevent the immunopathological process of cholestasis to biliary atresia.

Large Scale Genomic Investigation of Pediatric Cholestasis Reveals a Novel Hepatorenal Ciliopathy Caused by PSKH1 Mutations.

PURPOSE: Pediatric cholestasis is the phenotypic expression of clinically and genetically heterogeneous disorders of bile acid synthesis and flow. Although a growing number of monogenic causes of pediatric cholestasis have been identified, the majority of cases remain undiagnosed molecularly. METHODS: In a cohort of 299 pediatric participants (279 families) with intrahepatic cholestasis, we performed exome sequencing as a first-tier diagnostic test. RESULTS: A likely causal variant was identified in 135 families (48.56%). These comprise 135 families that harbor variants spanning 37 genes with established or tentative links to cholestasis. In addition, we propose a novel candidate gene (PSKH1) (HGNC:9529) in 4 families. PSKH1 was particularly compelling because of strong linkage in three consanguineous families who shared a novel hepatorenal ciliopathy phenotype. Two of the four families shared a founder homozygous variant while the third had a different homozygous variant in PSKH1. PSKH1 encodes a putative protein serine kinase of unknown function. Patient fibroblasts displayed abnormal cilia that are long and show abnormal transport. A homozygous Pskh1 mutant mouse faithfully recapitulated the human phenotype and displayed abnormally long cilia. The phenotype could be rationalized by the loss of catalytic activity observed for each recombinant PSKH1 variant using in vitro kinase assays. CONCLUSION: Our results support the use of genomics in the workup of pediatric cholestasis and reveal PSKH1-related hepatorenal ciliopathy as a novel candidate monogenic form.

Odevixibat as an adjunctive treatment for refractory pruritus in rare variants of cholestatic liver disease.

Objectives: Odevixibat, a reversible ileal bile acid transport inhibitor, has been shown to reduce serum bile acids (sBA) and pruritus mostly in children with progressive familial intrahepatic cholestasis (PFIC) 1 and 2 in clinical trials and case reports. There are currently no published case reports or series describing its use in rare variants of cholestatic liver disease. Methods: We describe three children with progressive cholestatic liver disease who developed refractory pruritus, who had a genotypic diagnosis of AKR1D1, ABCB4 variant, and PKHD1 and PKHD2 variants; all being variants of unknown significance as per the American College of Medical Genetics and Genomics guidelines. Results: On Odevixibat there was a significant improvement in sBA (absolute change from baseline: -196 and -393 µmol/L) and pruritus in two children with heterozygous AKR1D1 and ABCB4 mutations. The child with ABCB4 variants was found to have features of sclerosing cholangitis along with a diagnosis of Crohn's disease, which represents the first reported usage of Odevixibat in such a case with good response. There was some reported improvement in the third child with PKHD1 and PKHD2 variants; however, we hypothesize that no sustained improvement could be due to severe and progressive nature of the disease. There were no side effects reported and it was well tolerated in all. Conclusion: We suggest that Odevixibat may be used as an adjunctive drug in refractory pruritus and could be started early in the course of disease if clinically and phenotypically indicated.

Why are rare diseases underdiagnosed? A clinical management study on detection of primary biliary cholangitis in primary care.

Background: There are about 7,000 rare diseases that affect 10% of the world population. Primary biliary cholangitis, an autoimmune chronic liver disease of the interlobular bile ducts, is one of the most common causes of chronic cholestasis. However, it is a rare, often underdiagnosed and undertreated, disease which can lead to cirrhosis and liver failure. We aimed to assess the proportion of undetected primary biliary cholangitis patients in primary care through a clinical management process. Methods: We made two extractions of the clinical data concerning liver diseases, risk factors and laboratory tests from the databases of a sample of general practitioners, with a check and correction of mistakes. The clinical data of the patients without liver disease and major risk factors, and with serum Alkaline Phosphatase above the laboratory reference values, were re-evaluated by each general practitioner with an expert gastroenterologist. The patients with elevated Alkaline Phosphatase values and without evidence of intrahepatic or extrahepatic causes of cholestasis were considered suspected for primary biliary cholangitis and assessed for antimitochondrial antibodies test and specialist' s evaluation, according to present guidelines. Results: A total of 20,480 adults attending 14 general practitioners in the province of Brescia, Northern Italy, were included in the study. Nine patients had a prior primary biliary cholangitis diagnosis, with a prevalence of 43.9/100000. After excluding 2094 (10.2%) patient with liver diseases or other causes of cholestasis, 121 subjects with Alkaline Phosphatase above the reference values were re-evaluated by the general practitioners and gastroenterologist, and 27 patients without symptoms or signs of cholestasis were considered suspected for primary biliary cholangitis: 9 of them were tested for antimitochondrial antibodies, and three new primary biliary cholangitis cases were detected (+33%). Discussion and Conclusions: This study shows that there is a not negligible burden of undetected cases of adult rare diseases that can be diagnosed in primary care, through a disease management procedure, without modifying the routine clinical practice.

Recovery from parenteral nutrition-associated cholestasis takes approximately two months in very low birth weight infants.

AIM: To investigate the clinical characteristics and course of parenteral nutrition-associated cholestasis (PNAC) in very low birth weight (VLBW) infants. METHODS: The charts of VLBW infants were retrospectively reviewed. The clinical characteristics of infants with and without PNAC were compared, trends in liver enzymes were investigated, and the characteristics of infants with PNAC were analysed based on age of onset. RESULTS: PNAC was observed in 53 (13.2%) of 403 infants who survived and completed follow-up and was associated with significantly lower gestational age, birth weight, and adverse neonatal outcomes. PNAC started at a median 32 (interquartile range 23-47) days, PN was applied for 53 (34.5-64.5) days, the maximum direct bilirubin (DB) was observed at 63 (50-76) postnatal days, and PNAC resolved at 94 (79-122) postnatal days postnatal age. PNAC lasted 61 (38-89.5) days. AST and ALT normalised at 111 (100.3-142.0) and 109.5 (97-161.3) postnatal days. Infants with early-onset PNAC had significantly longer PN duration, higher maximum DB, and higher maximum AST than those with late-onset PNAC. CONCLUSION: Elevated DB, AST, and ALT persist for a long period after discontinuing PN. We suggest a cautious approach that involves waiting and reducing the frequency of additional repetitive examinations.

Cord blood troponin I levels: biomarker evidence of fetal cardiac injury in intrahepatic cholestasis of pregnancy.

BACKGROUND: Intrahepatic cholestasis of pregnancy has been linked to sudden stillbirth. The suddenness of the stillbirths in these cases have led clinicians to suspect that the pathogenesis of stillbirth in women with intrahepatic cholestasis of pregnancy is not related to asphyxia but rather to an undefined etiology. One leading hypothesis relates certain bile acid metabolites to myocardial injury. OBJECTIVE: The purpose of this study was to determine whether cord blood troponin I levels are increased in fetuses born to mothers with a diagnosis of intrahepatic cholestasis of pregnancy. STUDY DESIGN: A prospective, case-control study was performed at a single institution between 2017 to 2019 in which 87 pregnant patients with a diagnosis of intrahepatic cholestasis of pregnancy (total bile acids ≥10 µmol/L) were enrolled as cases and 122 randomly selected pregnant patients (asymptomatic with intrapartum total bile acids <10 µmol/L) were enrolled as controls. Cord blood troponin I levels were measured at delivery in both groups using a commercially available chemiluminescent immunoassay. Values ≤0.04 ng/mL were considered negative. Values >0.04 ng/mL were considered positive. The primary outcome was the presence of elevated troponin levels in both cases and controls as a surrogate marker for cardiac status. Our secondary outcomes included neonatal intensive care unit stay, low Apgar scores, neonatal acidosis, and hypoxia indicated by cord blood pH and base excess levels at the time of birth. Chi square and t tests were performed to compare social and obstetrical variables. A P value of <.05 was considered significant. A stratification by total bile acids range of <40 µmol/L, 40 to 100 µmol/L, and >100 µmol/L was performed to assess the relationship between the different severities of intrahepatic cholestasis of pregnancy (by risk of fetal demise with those with total bile acids of >100 µmol/L considered at greatest risk) and the likelihood of a positive troponin I result. Finally, a logistic regression analysis was performed to determine if levels of ≥10 µmol/L were associated with elevated troponin levels. RESULTS: The mean gestational age at delivery was 38.96±1.47 and 37.71±1.59 weeks of gestation in the controls and cases respectively (P<.001). The mean total bile acids values were 5.2±1.28 ng/mL and 43.2±40.62 ng/mL in the controls and cases respectively (P<.001). Cord blood troponin I was positive in 15 of 122 (12.30%) controls and in 20 of 87 (22.99%) cases. (P<.001). When further stratified by total bile acids levels of <40, 40 to 100, and >100 µmol/L, we found a positive correlation between higher total bile acids levels and a positive troponin I test (P=.002). When controlling for gestational age at delivery, maternal age, and body mass index, higher total bile acids levels were associated with a positive troponin I level (adjusted odds ratio, 1.015; 95% confidence interval, 1.004-1.026). CONCLUSION: Elevated troponin I was more likely to be found in patients with intrahepatic cholestasis of pregnancy than in those without intrahepatic cholestasis of pregnancy. When stratified by total bile acids levels, a positive troponin I level was more likely to be found with higher levels of total bile acids. In addition, as total bile acids levels increased, they were more likely to be associated with a positive troponin I level. Although there were no stillbirths in our cohort, our findings suggest a potential relationship between cardiac injury and high levels of total bile acids demonstrated by the presence of elevated troponin I levels in cord blood at the time of birth.