Neonatal Cholestasis Research Articles

Ultrasound shear wave elastography: does it add value to gray-scale ultrasound imaging in differentiating biliary atresia from other causes of neonatal jaundice?

Neonatal/infantile jaundice is relatively common, and most cases resolve spontaneously. However, in the setting of unresolved neonatal cholestasis, a prompt and accurate assessment for biliary atresia is vital to prevent poor outcomes. To determine whether shear wave elastography (SWE) alone or combined with gray-scale imaging improves the diagnostic performance of US in discriminating biliary atresia from other causes of neonatal jaundice over that of gray-scale imaging alone. Infants referred for cholestatic jaundice were assessed with SWE and gray-scale US. On gray-scale US, two radiology readers assessed liver heterogeneity, presence of the triangular cord sign, hepatic artery size, presence/absence of common bile duct and gallbladder, and gallbladder shape; associated interobserver correlation coefficients (ICC) were calculated. SWE speeds were performed on a Siemens S3000 using 6C2 and 9L4 transducers with both point and two-dimensional (2-D) SWE US. Both univariable and multivariable analyses were performed, as were receiver operating characteristic curves (ROC) and statistical significance tests (chi-squared, analysis of variance, t-test and Wilcoxon rank sum) when appropriate. There were 212 infants with biliary atresia and 106 without biliary atresia. The median shear wave speed (SWS) for biliary atresia cases was significantly higher (P<0.001) than for non-biliary-atresia cases for all acquisition modes. For reference, the median L9 point SWS was 2.1m/s (interquartile range [IQR] 1.7-2.4m/s) in infants with biliary atresia and 1.5m/s (IQR 1.3-1.9m/s) in infants without biliary atresia (P<0.001). All gray-scale US findings were significantly different between biliary-atresia and non-biliary-atresia cohorts (P<0.001), intraclass correlation coefficient (ICC) range 0.7-1.0. Triangular cord sign was most predictive of biliary atresia independent of other gray-scale findings or SWS - 96% specific and 88% sensitive. Multistep univariable/multivariable analysis of both gray-scale findings and SWE resulted in three groups being predictive of biliary atresia likelihood. Abnormal common bile duct/gallbladder and enlarged hepatic artery were highly predictive of biliary atresia independent of SWS (100% for girls and 95-100% for boys). Presence of both the common bile duct and the gallbladder along with a normal hepatic artery usually excluded biliary atresia independent of SWS. Other gray-scale combinations were equivocal, and including SWE improved discrimination between biliary-atresia and non-biliary-atresia cases. Shear wave elastography independent of gray-scale US significantly differentiated biliary-atresia from non-biliary-atresia cases. However, gray-scale findings were more predictive of biliary atresia than elastography. SWE was useful for differentiating biliary-atresia from non-biliary-atresia cases in the setting of equivocal gray-scale findings.

The risk factors for cholestasis in patients with duodenal atresia in a single institutional cohort.

The etiology of cholestasis in neonates is associated with several factors including gastrointestinal disease and surgery. We aimed to identify the potential risk factors for perioperative cholestasis in patients with duodenal atresia and determine specific cutoff values for the risk factors. This retrospective cohort study included 76 neonates diagnosed with duodenal atresia surgically treated during the neonatal period at our institution between January 1990 and March 2017. The neonates were categorized into two groups: those with and without cholestasis. Univariate and multivariate analyses were performed to identify the possible risk factors for cholestasis. Among the 76 neonates with duodenal atresia, 21 (27%) developed cholestasis. The duration of total parenteral nutrition was identified as a risk factor in univariate analysis; however, it was not an independent risk factor for cholestasis. Gestational age and highest C-reactive protein (CRP) values were independent risk factors, with adjusted odds ratios of 0.53 and 1.25, respectively. To predict the occurrence of cholestasis, the cutoff value for gestational age was 35.0weeks, and highest CRP value was 2.4mg/dL. The occurrence of cholestasis in patients with duodenal atresia was associated with preterm delivery and severity of the inflammatory response during the perioperative period.

Patients with cerebrotendinous xanthomatosis diagnosed with diverse multisystem involvement.

Cerebrotendinous xanthomatosis (CTX) is a lipid storage disease caused by deficiency of sterol 27-hydroxylase enzyme encoded by CYP27A1 gene. This multicenter, cross-sectional descriptive study aimed to document clinical characteristics of CTX patients of different ages, clinical presentations of early-diagnosed patients, and responses to short-term chenodeoxycholic acid (CDCA) treatment. Seven of 11 CTX patients were diagnosed in childhood. Three patients (27%) had neonatal cholestasis, seven (63%) patients had a history of frequent watery defecation started in infantile period, and eight (72.7%) patients had juvenile cataract. Four patients in the adult age group had pyramidal signs and parkinsonism symptoms. The mean Mignarri score at diagnosis was significantly lower in the pediatric patients (267.8 ± 51.4) than in the adult patients (450.0 ± 64.0, p = 0.001). No significant difference was determined between pediatric patients and adult patients regarding plasma cholestanol concentration at diagnosis (p = 0.482). The frequency of defecation decreased with treatment in six children, who had diarrhea at admission. Compared to pretreatment values, patients' body weight and standardized body mass index significantly increased at the 12th month of treatment. In conclusion, Mignarri scores are lower in the pediatric patients than in adult patients since the most determinative signs of the CTX disease are not apparent yet in the childhood. The disease is frequently overlooked in routine practice as the disease presents itself with different clinical combinations both in adults and in children. CTX is potentially a treatable disease; thereby, enhanced awareness is critically important for early diagnosis particularly in children.

The Incidence and Etiology of Neonatal Cholestasis in Newborn Infants

The Incidence and Etiology of Neonatal Cholestasis in Newborn Infants

A Japanese prospective multicenter study of urinary oxysterols in biliary atresia

Diagnosis of biliary atresia (BA) can involve uncertainties. In the present prospective multicenter study, we considered whether urinary oxysterols represent a useful marker for diagnosis of BA in Japanese children. Subjects under 6 months old at 7 pediatric centers in Japan were prospectively enrolled, including patients with cholestasis and healthy controls (HC) without liver disease. Patients with cholestasis constituted 2 groups representing BA patients and others with cholestasis from other causes (non-BA). We quantitatively analyzed 7 oxysterols including 4β-, 20(S)-, 22(S)-, 22(R)-, 24(S)-, 25-, and 27-hydroxycholesterol by liquid chromatography/electrospray ionization-tandem mass spectrometry. Enrolled subjects included 14 with BA (median age 68 days; range 26–170) and 10 non-BA cholestatic controls (59; 14–162), as well as 10 HC (57; 25–120). Total urinary oxysterols were significantly greater in BA (median, 153.0 μmol/mol creatinine; range 24.1–486.7; P < 0.001) and non-BA (36.2; 5.8–411.3; P < 0.05) than in HC (2.7; 0.8–7.6). In patients with BA, urinary 27-hydroxycholesterol (3.61; 0.42–11.09; P < 0.01) was significantly greater than in non-BA (0.71; 0–5.62). In receiver operating characteristic (ROC) curve analysis for distinguishing BA from non-BA, the area under the ROC curve for urinary 27-hydroxycholesterol was 0.83. In conclusion, this first report of urinary oxysterol analysis in patients with BA indicated that 27-hydroxycholesterol may be a useful marker for distinguishing BA from other causes of neonatal cholestasis.

Hypo-cortisolism, early onset obesity and liver disease in a child with homozygous proopiomelanocortin mutation

The peptide derivatives of proopiomelanocortin molecule are involved in energy homeostasis, regulation of food intake, skin pigmentation and augment biliary flow. Homozygous mutation in POMC gene, which is inherited in an autosomal recessive pattern, is associated with hyperphagia leading to early onset obesity, hypoglycaemia and neonatal cholestasis due to cortisol deficiency and red hair pigmentation as a result of alpha MSH deficiency. We report a child having multiple episodes of hypoglycemia with this disorder who presented like liver disease. Our case report highlights the importance of early suspicion of this rare condition and confirmation with genetic analysis.

Development and Validation of a Prediction Rule for Growth Hormone Deficiency Without Need for Pharmacological Stimulation Tests in Children With Risk Factors.

IntroductionPractice guidelines cannot recommend establishing a diagnosis of growth hormone deficiency (GHD) without performing growth hormone stimulation tests (GHST) in children with risk factors, due to the lack of sufficient evidence.ObjectiveOur goal was to generate an evidence-based prediction rule to diagnose GHD in children with growth failure and clinically identifiable risk factors.MethodsWe studied a cohort of children with growth failure to build the prediction model, and a second, independent cohort to validate the prediction rule. To this end, we assessed the existence of: pituitary dysgenesis, midline abnormalities, (supra)sellar tumor/surgery, CNS infection, traumatic brain injury, cranial radiotherapy, chemotherapy, genetic GHD, pituitary hormone deficiencies, and neonatal hypoglycemia, cholestasis, or hypogenitalism. Selection of variables for model building was performed using artificial intelligence protocols. Specificity of the prediction rule was the main outcome measure in the validation set.ResultsIn the first cohort (n=770), the resulting prediction rule stated that a patient would have GHD if (s)he had: pituitary dysgenesis, or two or more anterior pituitary deficiencies, or one anterior pituitary deficiency plus: neonatal hypoglycemia or hypogenitalism, or diabetes insipidus, or midline abnormalities, or (supra)sellar tumor/surgery, or cranial radiotherapy ≥18 Gy. In the validation cohort (n=161), the specificity of the prediction rule was 99.2% (95% CI: 95.6–100%).ConclusionsThis clinical rule predicts the existence of GHD with high specificity in children with growth disorders and clinically identifiable risk factors, thus providing compelling evidence to recommend that GHD can be safely diagnosed without recurring to GHST in neonates and children with growth failure and specific comorbidities.

Dubin-Johnson Syndrome as Differential Diagnosis for Neonatal Cholestasis.

Dubin-Johnson syndrome (DJS) is an autosomal recessive disorder in which multidrug-resistance-associated protein 2 (MRP2) deficiency causes an excretion disorder of conjugated bilirubin from hepatocytes into bile canaliculi. Its clinical presentation as neonatal cholestasis (NC) is rare but represents an important differential diagnosis. We aimed to define DJS-specific characteristics in NC, in particular in contrast to biliary atresia (BA) patients, and to highlight diagnostic tools that can help to avoid invasive diagnostic tests. We performed a review of case records from 2006 to 2020 and compared 4 DJS patients to 26 patients with proven BA consecutively diagnosed from 2014 to 2017. DJS was diagnosed by urine coproporphyrin analysis (UCA) and by genetic analysis (GA) for disease-associated ABCC2 variants. Four male patients with NC were diagnosed with DJS by UCA and GA. DJS patients presenting as NC showed significantly lower values for aspartate aminotransferase (AST) (P < 0.001), for alanine aminotransferase (ALT) (P = 0.002) and for gamma-glutamyl transferase (GGT) (P < 0.001) compared with BA patients. Other examinations, however, could not clearly discriminate them (e.g.: stool colour, serum bile acids, total serum bilirubin). DJS is not only a rare differential diagnosis in NC with a suspicious phenotype (almost normal AST, ALT) but also shows overlapping features with BA. It should, therefore, be considered in every infant with NC and an atypical liver enzyme pattern to protect patients from unnecessary, invasive examinations. For this, UCA is a fast and reliable diagnostic tool. Confirmation based on GA is recommended. DJS patients have a good long-term prognosis.

Neonatal Intrahepatic Cholestasis caused by Citrin Deficiency: In vivo and in vitro studies of the aberrant transcription arising from two novel splice-site variants in SLC25A13

Neonatal Intrahepatic Cholestasis caused by Citrin Deficiency (NICCD) is an autosomal recessive disease resulting from biallelic SLC25A13 mutations, and its diagnosis relies on genetic analysis. This study aimed to characterize the pathogenicity of 2 novel splice-site variants of SLC25A13 gene. Two patients (C0476 and C0556) suspected to have NICCD, their family members and 9 healthy volunteers were recruited as the research subjects. The SLC25A13 genotypes NG_012247.2(NM_014251.3): c.[852_855del]; [69+5G > A] in patient C0476 and c.[1453-1G > A]; [1751–5_1751-4ins (2684)] in patient C0556 were identified by means of polymerase chain reaction, long and accurate polymerase chain reaction, as well as Sanger sequencing. The 2 splice-site variants were absent in control databases and predicted to be pathogenic by computational analysis. The alternative splice variants in monocyte-derived macrophages from patient C0476 demonstrated exon 2 skipping [r.16_69del; p.(Val6_Lys23del)] in vivo, while minigene analysis revealed both exon 2-skipping and retained products from c.69+5G > A in vitro. In the patient C0556, an aberrant transcript [r.1453del; p.(Gly485Valfs*22)] resulting from c.1453-1G > A was detected on minigene splicing study. Thus, c.69+5G > A and c.1453-1G > A were both proved to be pathogenic. The 2 novel splice-site variants expanded the SLC25A13 mutation spectrum and provided reliable molecular markers for the definite diagnosis and genetic counseling of NICCD in the affected families.

Neonatal cholestasis: development of a diagnostic decision algorithm from multivariate predictive models.

Despite the recent advances involving molecular studies, the neonatal cholestasis (NC) diagnosis still relays on the expertise of medical teams. Our aim was to develop models of etiological diagnosis and unfavourable prognosis which may support a rationale diagnostic approach. We retrospectively analysed 154 patients born between January 1985 and October 2019. The cohort was divided into two main groups: (A) transient cholestasis and (B) other diagnosis (with subgroups) and also in two groups of outcomes: (I) unfavourable and (II) favourable. Multivariate logistic regression analysis identified the lower gestational age as the only variable independently associated with an increased risk of transient cholestasis and signs and/or symptoms of sepsis with infectious or metabolic diseases. Gamma-glutamyl transferase serum levels > 300 IU/L had a positive predictive value for both diagnosis of biliary atresia and for alpha-1-antitrypsin deficiency (A1ATD) and for unfavourable prognosis. A model of diagnosis for A1ATD (n = 34) showed an area under the ROC curve = 0.843 [confidence interval (CI): 0.773-0.912].Conclusion: This study identified some predictors of diagnosis and prognosis which helped to build a diagnostic decision algorithm. The unusually large subgroup of patients with A1ATD in this cohort emphasizes its predictive diagnostic model. What Is Known • The etiological diagnosis of neonatal cholestasis (NC) requires a step-by-step guided approach, and diagnostic models have been developed only for biliary atresia. • Current algorithms neither address the epidemiology changes nor the application of the new molecular diagnostic tools. What Is New • This study provides diagnostic predictive models for patients with A1ATD, metabolic/infectious diseases, and transient cholestasis, and two models of unfavourable prognosis for NC. • A diagnostic decision algorithm is proposed based on this study, authors expertise and the literature.

Knowledge and Practice of Pediatric Providers Regarding Neonatal Cholestasis in the Western Region of Saudi Arabia.

Background:Early detection of neonatal cholestasis (NC) is important for better clinical outcomes but can be challenging.Objective:The objective of this study was to evaluate the knowledge and practice styles of pediatric providers (PPs) regarding NC in the western region of Saudi Arabia.Methods:This cross-sectional, questionnaire study was conducted between November 2019 and February 2020 in three major cities of the western region of Saudi Arabia (namely, Taif, Makkah and Jeddah). PPs included pediatric residents, pediatric specialists, pediatric consultants and family physicians. The questionnaire included 15 items in five subscales (definition, causes, diagnosis and management of NC and knowledge of guidelines).Results:A total of 488 participants completed the questionnaire. Only 30.2% were aware of the correct definition of NC (P < 0.001). Two-thirds of the respondents did not consider a history of pale stool being important for evaluating NC. The importance of biliary atresia as a serious cause of NC was found to be significantly different between pediatric consultants and other pediatricians (P < 0.001). In cases of prolonged NC, 32.4% of the PPs refer to pediatric gastroenterologist. Only 18.9% of the respondents were aware of liver biopsy being the gold standard investigation of NC. The majority of the respondents (41.8%) used ursodeoxycholic acid as a supportive therapy of NC.Conclusions:This study found a significant deficit in the knowledge and practice styles of PPs in the western region of Saudi Arabia. These findings highlight the need for policymakers to develop educational materials for PPs to increase their knowledge of NC.

A Study on Seroprevalence of Hepatotropic Viruses in Neonatal Cholestasis Patients at a Tertiary Care Hospital of Central India

Introduction: Neonatal Cholestasis (NC) is defined as conjugated hyperbilirubinaemia in infancy, Diverse aetiologies and several disorders are responsible for this hepatobiliary dysfunction. Hepatotropic viral infection may have an important role in the pathogenesis of NC and related clinical outcomes. Aim: This study was aimed to estimate the seroprevalence of the hepatotropic viruses and their possible role in neonates presenting with cholestatic jaundice. Materials and Methods: This retrospective study included 51 infants who presented with cholestatic jaundice. Serum samples were collected and screened for the hepatotropic viruses. The presence of serological markers to Cytomegalovirus (CMV), Epstein-Barr Virus (EBV), Hepatitis C (HCV), Hepatitis E (HEV), Herpes Simplex Virus (HSV) and Rubella were tested using enzyme-linked immunosorbent assays. Hepatitis B Virus (HBV) serostatus was determined by using rapid card tests. Results: Of the 51 cases, 4 (7.6%) patients presented with biliary atresia. Seroprevalence of CMV (23.5%) was found to be more predominant followed by EBV (13.7%), HCV (5.8%), HEV (5.8%), HSV (1.9%) and Rubella (1.9%). Co-infections were found in 7 (13.7%) cases and CMV-EBV co-infection being the most common. Conclusion: The presence of specific serological markers to hepatotropic viruses in the NC cases strongly suggests their aetiological role in this disorder. To the best of the knowledge, this is the first report documenting the seroprevalence of hepatotropic viruses in NC patients from Central India.

Nursing of an Infant Diagnosed with Neonatal Intrahepatic Cholestasis Caused by Citrin Deficiency (NICCD) with Respiratory Syncytial Virus (RSV) Infection: A Case Report

<i>Background</i>: Citrin deficiency is an autosomal recessive genetic disorder caused by SLC25A13 genetic mutations. Understandably, Neonatal Intrahepatic Cholestasis caused by Citrin Deficiency (NICCD) was one of its clinical phenotypes, usually occurred in the neonatal period or infancy. The effective treatment of dietary intervention and symptomatic support may provide an avenue for clinicians to reduce liver damage and improve clinical prognosis. <i>Objective</i>: We report a 5-month-old infant diagnosed with Neonatal Intrahepatic Cholestasis caused by Citrin Deficiency (NICCD), coexisting Respiratory Syncytial Virus (RSV) infection. <i>Method</i>: The patient presented with rhinorrhea and cough, jaundiced skin and sclera, fat faces and hepatomegaly. Simultaneously, the child’s mother performed obvious anxious emotion. Infection control, nutrition management, and psychological guidance for the caregiver during hospitalization to discharge were achieved. Meanwhile, effective health education also plays a good role in these interventions. <i>Result</i>: After half a month, the patient’s infection was given controlled. Jaundice and hepatomegaly were improved gradually. Followeing up for 2 months, the clinical symptoms for NICCD were disappeared and the caregiver’s anxiety was alleviated effectively. The importance of follow-up and support longitudinally to improve the quality of life for patients is emphasized. <i>Conclusion</i>: Therefore, this study provided primary while valuable nursing care experience for NICCD with RSV infection patients.

Knowledge and practice of pediatric providers regarding neonatal cholestasis in the western region of Saudi Arabia

Knowledge and practice of pediatric providers regarding neonatal cholestasis in the western region of Saudi Arabia

Clinical Characteristics of Neonatal Cholestasis in a Tertiary Hospital and the Development of a Novel Prediction Model for Mortality

Clinical Characteristics of Neonatal Cholestasis in a Tertiary Hospital and the Development of a Novel Prediction Model for Mortality

Variant etiologies of neonatal cholestasis and their outcome: a Middle East single-center experience.

Aim of the studyNeonatal cholestasis (NC) constitutes a large proportion of pediatric liver disorders. Nevertheless, awareness of the variant etiologies and how to manage them appropriately are lacking. So, out of a few specialized centers, many cases pass without appropriate management. This study aimed to present our tertiary level center’s experience in NC that could increase the pediatrician’s awareness of handling this problematic and common medical morbidity efficiently.Material and methodsIt is a retrospective study in which we analyzed the NC cases admitted to the inpatient department within three years. For all recruited patients, the available data were retrieved and recorded.ResultsA total of 412 patients were reviewed with 20 different etiologies diagnosed. The most common cause was biliary atresia (n = 151, 37%), followed by progressive familial intrahepatic cholestasis (n = 51, 12%), neonatal sepsis (n = 39, 9%), and cytomegalovirus (n = 33, 8%). Of the 412 patients, 394 (81%) had follow-up ranging from 1 to 36 months. A total of 173 patients improved with supportive and/or specific therapy, while 108 patients died at a median age of 6 months. The commonest cause of death was liver failure (40.7%), followed by pneumonia (28.7%), sudden death (13%), septicemia (6.5%), and hepatorenal syndrome (5.5%).ConclusionsNC constitutes more than one-third of the inpatient admissions of all pediatric liver disorders and has a high rate of mortality. Awareness of the variety of etiologies and a rapid stepwise approach to diagnosis could have an impact on the outcome of this devastating disease.

Blind liver biopsy: a 17-year experience

Objectives: Liver biopsy is the gold standard for assessing liver inflammation, necrosis and fibrosis. The aim of the study is to evaluate clinical indications and histopathological results of percutaneus liver biopsy. Materials and methods: A total of 516 children who underwent blind liver biopsy were evaluated retrospectively. Results: Blind liver biopsy was performed for chronic active hepatitis B in 50% of the cases (n=260), neonatal cholestasis in 14% (n=68), autoimmune hepatitis in 7.7% (n=40), Wilson disease in 7.3% (n=38), isolated elevation of the liver enzymes in 5% (n=26), chronic active hepatitis C in 4.2% (n=22), metabolic disease in 3.4% (n=17), malignancies in 2.2% (n=11) and the others in 3.4% (n=17). Major complications were observed in 0.19% of the cases (n=1) and minor complications such as pain at the biopsy site in 13.5% of the cases (n=70), hypotension and tachycardia in 1.9% (n=10). Conclusions: Blind liver biopsy is a safe method in diagnosing liver diseases in childhood.

The Frequency of Genetic Alleles of Alpha-1 Antitrypsin in Infants and Children with the Cholestatic Idiopathic Hepatic Disease in Khorasan Razavi- Iran

Background: Alpha-1 antitrypsin (AAT) deficiency is a common genetic cause of childhood liver disorders. Its prevalence is highly variable around the world. Although this genetic deficiency is the main cause of neonatal jaundice, few studies have investigated AAT in Iran. Objectives: The current study aimed to investigate the association between specific alleles of AAT with idiopathic neonatal jaundice disease in patients with idiopathic jaundice. Methods: In this study, 30 neonates with a definitive diagnosis of neonatal cholestasis referred to Ghaem, and Dr. Sheikh hospitals in Mashhad (Iran) are included. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was performed on the extracted DNA from their blood samples. In the lack of commonly mutated alleles detected, the whole gene exons were DNA sequenced. Results: In the molecular test, we found no case of PiS or PiZ allele. The mutated alleles of PiS and PiZ were not appeared in patients with neonatal jaundice using the PCR-RFLP method. DNA sequencing was performed in 30 patients. Other rare missense variations were detected in the form of heterozygous (for Glu400Asp in 8 patients and Val237Ala in 2 patients), homozygous (for Glu400Asp in 1 patient), and compound heterozygous (for Glu400Asp/Val237Ala in 3 patients and Val237Ala/Asp280Val in 1 patient). Conclusions: The AAT deficiency caused by PiZ and PiS allelic variants was noted among infants with neonatal cholestasis in the Khorasan province of Iran. Other rare variants in the PiM might be caused by AAT deficiency and presenting the neonatal cholestasis. The possible functional study should be considered for the mutations identified.

Vitamin K deficiency-induced spontaneous haemopericardium and cardiac tamponade in an infant with alpha-1 antitrypsin deficiency: a case report.

Background Vitamin K deficiency bleeding is a life-threatening complication in early infancy. Exclusive breastfeeding and neonatal cholestasis syndromes, most notable α-1-antitrypsin deficiency, have been reported to be risk factors. Intracranial haemorrhage is most common. No association to haemopericardium has been reported before.Case summary We report on an 11 weeks old at term-born infant, who presented with severe anaemia and signs of cardiogenic shock. Immediately echocardiography was done and depicted cardiac tamponade. Pericardiocentesis was performed and a significant amount of haemorrhagic fluid was removed. Further workup revealed deranged coagulation parameters, cholestatic liver disease, and reduced α-1-antitrypsin levels. Despite normal brain sonography, a small cerebral haemorrhage was detected on magnetic resonance imaging. A genetic test finally proofed homozygotic mutation of the SERPINA1-gene and confirmed the diagnosis of α-1-antitrypsin deficiency as the underlaying cause. After initial replacement of coagulation factors, erythrocytes and vitamin K, the infant recovered. Eighteen weeks after discharge, the infant is still on vitamin K supplementation. She did not have any further bleedings and no neurologic or developmental impairment.Discussion Alpha-1-antitrypsin deficiency can lead to vitamin K deficiency in young infants even with adequate prophylaxis. Spontaneous haemorrhagic pericardial effusion was a new manifestation of vitamin K deficiency bleeding in our patient and should be considered and ruled out in young infants who present with acute anaemia and poor clinical condition.

Cholangiopathy and Biliary Fibrosis in Cyp2c70-Deficient Mice Are Fully Reversed by Ursodeoxycholic Acid.

Background and AimsBile acids (BAs) aid intestinal fat absorption and exert systemic actions by receptor-mediated signaling. BA receptors have been identified as drug targets for liver diseases. Yet, differences in BA metabolism between humans and mice hamper translation of pre-clinical outcomes. Cyp2c70-ablation in mice prevents synthesis of mouse/rat-specific muricholic acids (MCAs), but potential (patho)physiological consequences of their absence are unknown. We therefore assessed age- and gender-dependent effects of Cyp2c70-deficiency in mice.MethodsThe consequences of Cyp2c70-deficiency were assessed in male and female mice at different ages.ResultsCyp2c70-/- mice were devoid of MCAs and showed high abundances of chenodeoxycholic and lithocholic acids. Cyp2c70-deficiency profoundly impacted microbiome composition. Bile flow and biliary BA secretion were normal in Cyp2c70-/- mice of both sexes. Yet, the pathophysiological consequences of Cyp2c70-deficiency differed considerably between sexes. Three-week old male Cyp2c70-/- mice showed high plasma BAs and transaminases, which spontaneously decreased thereafter to near-normal levels. Only mild ductular reactions were observed in male Cyp2c70-/- mice up to 8 months of age. In female Cyp2c70-/- mice, plasma BAs and transaminases remained substantially elevated with age, gut barrier function was impaired and bridging fibrosis was observed at advanced age. Addition of 0.1% ursodeoxycholic acid to the diet fully normalized hepatic and intestinal functions in female Cyp2c70-/- mice.ConclusionCyp2c70-/- mice show transient neonatal cholestasis and develop cholangiopathic features that progress to bridging fibrosis in females only. These consequences of Cyp2c70-deficiency are restored by treatment with UDCA, indicating a role of BA hydrophobicity in disease development.