NR1H4 disease: rapidly progressing neonatal intrahepatic cholestasis and early death.

BACKGROUND: Clinical studies on progressive familial intrahepatic cholestasis (PFIC) type 5 caused by mutations in NR1H4 are limited. METHODS: New patients with biallelic NR1H4 variants from our center and all patients from literature were retrospectively analyzed. RESULTS: Three new patients were identified to be carrying five new variants. Liver phenotypes of our patients manifests as low-γ-glutamyl transferase cholestasis, liver failure and related complications. One patient underwent liver transplantation (LT) and survived, and two other patients died without LT. Nine other patients were collected through literature review. Twelve out of 13 patients showed neonatal jaundice, with the median age of onset being 7 days after birth. Reported clinical manifestations included cholestasis (13/13, 100%), elevated AFP (11/11, 100%), coagulopathy (11/11, 100%), hypoglycemia (9/13, 69%), failure to thrive (8/13, 62%), splenomegaly (7/13, 54%), hyperammonemia (7/13, 54%), and hepatomegaly (6/13, 46%). Six of 13 patients received LT at a median age of 6.2 months, and only one patient died of acute infection at one year after LT. Other 7 patients had no LT and died with a median age of 5 months (range 1.2-8). There were 8 patients with homozygous genotype and 5 patients with compound heterozygous genotype. In total, 13 different variants were detected, and 5 out of 12 single or multiple nucleotides variants were located in exon 5. CONCLUSIONS: We identified three newly-diagnosed patients and five novel mutations. NR1H4-related PFIC typically cause progressive disease and early death. LT may be the only lifesaving therapy leading to cure.

Update on the diagnosis and management of neonatal intrahepatic cholestasis caused by citrin deficiency: Expert review on behalf of the Asian Pan-Pacific Society for Pediatric Gastroenterology, Hepatology, and Nutrition.

Citrin deficiency is an autosomal recessive metabolic liver disease caused by mutations in the SLC25A13 gene. The disease typically presents with cholestasis, elevated liver enzymes, hyperammonemia, hypercitrullinemia, and fatty liver in young infants, resulting in a phenotype known as "neonatal intrahepatic cholestasis caused by citrin deficiency" (NICCD). The diagnosis relies on clinical manifestation, biochemical evidence of hypercitrullinemia, and identifying mutations in the SLC25A13 gene. Several common mutations have been found in patients of East Asian background. The mainstay treatment is nutritional therapy in early infancy utilizing a lactose-free and medium-chain triglyceride formula. This approach leads to the majority of patients recovering liver function by 1 year of age. Some patients may remain asymptomatic or undiagnosed, but a small proportion of cases can progress to cirrhosis and liver failure, necessitating liver transplantation. Recently, advancements in newborn screening methods have improved the age of diagnosis. Early diagnosis and timely management improve patient outcomes. Further studies are needed to elucidate the long-term follow-up of NICCD patients into adolescence and adulthood.

Risk-stratified management strategies for intrahepatic cholestasis of pregnancy: A tertiary center population review over nearly 5 years.

OBJECTIVE: Intrahepatic cholestasis of pregnancy (ICP) is associated with an increased risk of adverse perinatal outcomes, resulting in a higher risk of perinatal morbidity and mortality. METHODS: The authors conducted a retrospective study of 2385 singletons with ICP who underwent risk-stratified management strategies. To explore the risks of perinatal outcomes of ICP, subgroup analyses were performed using different total bile acid (TBA) levels. RESULTS: In this study, there was only one stillbirth and one neonatal death. Among the study cohort, 2299 patients had ICP with a TBA level ≥10 µmol/L and 86 had ICP with a TBA level <10 µmol/L. The 2299 patients with ICP (TBA level ≥ 10 µmol/L) were divided into three groups: mild ICP (n = 1803), severe ICP (n = 400), and extremely severe ICP (n = 96). Increased TBA concentration was associated with an increased incidence of preterm birth, newborn asphyxia, neonatal intensive care unit hospitalization, meconium-stained amniotic fluid, and low birth weight in the three groups (P < 0.05). Furthermore, severe and extremely severe ICP with hypotonic absonant uterine contraction had a significant effect on neonatal asphyxia (odds ratio, 5.06 [95% confidence interval, 1.09-23.37]; P < 0.05) and meconium-stained amniotic fluid (odds ratio, 2.37 [95% confidence interval, 1.43-3.93]; P < 0.05). CONCLUSIONS: Hypotonic absonant uterine contractions could be high-risk stressors for severe and extremely severe ICP; hence, proper prenatal care is recommended. Risk-stratified management strategies for ICP are critical to obtaining better maternal-fetal outcomes.

Predictors of Adverse Fetal Outcomes in Intrahepatic Cholestasis of Pregnancy (ICP): a Narrative Review.

Intrahepatic cholestasis of pregnancy (ICP) is a hepatic disorder in pregnancy linked with adverse fetal outcomes, which primarily manifests in the late second and third trimesters of pregnancy. This review aims to recapitulate the existing evidence on factors that can predict detrimental perinatal outcomes in pregnant women diagnosed with intrahepatic cholestasis of pregnancy. We searched PubMed, Web of Science, Cochrane Library, Scopus, Medline, and Embase databases and selected studies related to predictors of fetal outcome in intrahepatic cholestasis of pregnancy. Studies of the articles showed that predictors of an adverse fetal outcome include in vitro fertilization (IVF) pregnancy, multifetal pregnancy, biochemical markers, gestational age of ICP onset, presence of comorbidities (preeclampsia and gestational diabetes mellitus), maternal history of ICP, and hepatobiliary disease.Intrahepatic cholestasis of pregnancy (ICP) complicates the pregnancy. Hence, early assessment of low-risk and high-risk groups will help to administer definite management protocols and strategies to prevent adverse neonatal outcomes. Further research should concentrate on the number of conditions/factors and the predictive power of different factors to determine the most reliable predictors and biomarkers that can predict adverse fetal outcomes and improve the assessment of risk in pregnancy complicated with ICP.

[Intrahepatic cholestasis of pregnancy: French College of Obstetricians and Gynecologists guidelines for clinical practice]. / La cholestase gravidique : recommandations pour la pratique clinique du Collège national des gynécologues obstétriciens français.

OBJECTIVE: To identify strategies for reducing neonatal and maternal morbidity associated with intrahepatic cholestasis pregnancy (ICP). MATERIAL AND METHODS: The quality of evidence of the literature was assessed following the GRADE methodology with questions formulated in the PICO format (Patients, Intervention, Comparison, Outcome) and outcomes defined a priori and classified according to their importance. An extensive bibliographic search was performed on PubMed, Cochrane, EMBASE and Google Scholar databases. The quality of the evidence was assessed (high, moderate, low, very low) and a (i) strong or (ii) weak recommendations or (iii) no recommendation were formulated. The recommendations were reviewed in two rounds with external reviewers (Delphi survey) to select the consensus recommendations. RESULTS: Of the 14 questions (from 12 PICO questions and one definition question outside the PICO format), there was agreement between the working group and the external reviewers on 14 (100%). The level of evidence of the literature was insufficient to provide a recommendation on two questions. ICP is defined by the occurrence of suggestive pruritus (palmoplantar, nocturnal) associated with a total bile acid level>10µmol/L or an alanine transaminase level above 2N after ruling out differential diagnoses. In the absence of suggestive symptoms of a differential diagnosis, it is recommended not to carry out additional biological or ultrasound tests. In women with CIP, ursodeoxycholic acid is recommended to reduce the intensity of maternal pruritus (Strong recommendation. Quality of the evidence moderate) and to decrease the level of total bile acids and alanine transaminases. (Strong recommendation. Quality of the evidence moderate). S-adenosyl-methionine, dexamethasone, guar gum or activated charcoal should not be used to reduce the intensity of maternal pruritus (Strong recommendation. Quality of evidence low), and there is insufficient data to recommend the use of antihistamines (No recommendation. Quality of evidence low). Rifampicin (Weak recommendation. Very low quality of evidence) or plasma exchange (Strong recommendation. Very low quality of evidence) should not be used to reduce maternal pruritus and perinatal morbidity. Serum monitoring of bile acids is recommended to reduce perinatal morbidity and mortality (stillbirth, prematurity) (Low recommendation. Quality of the evidence low). The level of evidence is insufficient to determine whether fetal heart rate or fetal ultrasound monitoring are useful to reduce perinatal morbidity (No recommendation). Birth is recommended when bile acid level is above 99µmol/L from 36 weeks gestation to reduce perinatal morbidity, in particular stillbirth. When bile acid level is above 99µmol/L is below 100µmol/L, women should be informed that induction of labor could be considered 37 and 39 weeks gestation to reduce perinatal morbidity. (Strong recommendation. Quality of evidence low). In postpartum, total bile acids and alanine transaminases level should be checked and normalized before prescribing estrogen-progestin contraception, ideally with a low estrogen dose (risk of recurrence of pruritus and cytolysis) (Low recommendation. Quality of evidence very low). CONCLUSION: Although the quality of evidence regarding ICP gestational cholestasis remains low, there is a strong consensus in France, as shown by our Delphi study, on how to manage women with ICP. The reference first-line treatment is ursodeoxycholic acid.

Iterative antibody-induced bile salt export pump deficiency after successive liver transplantations successfully treated with plasmapheresis and rituximab.

Post-transplantation evolution of progressive familial intrahepatic cholestasis type 2 patients can be complicated by antibody-induced bile salt export pump deficiency (AIBD). There is no consensus on its management. We describe a patient who presented two episodes, 9 years apart. The first episode was refractory to plasmapheresis and intravenous immunoglobulin (IVIG) started 2 months after AIBD onset, leading to graft loss. The second episode responded to plasmapheresis, IVIG and rituximab initiated less than 2 weeks after the beginning of symptoms, allowing for long-term recovery. This case suggests that intensive treatment with minimum delay after symptoms onset could sponsor a better evolution.

Intrahepatic cholestasis in sickle cell disease: A review of diagnostic criteria, treatments, and case reports.

Objective To delineate the etiology, symptomatology, and treatment of sickle cell intrahepatic cholestasis (SCIC). Sickle cell disease (SCD) is the most frequently inherited hematologic disease, and SCIC is one rare and often fatal complication and comorbid disease. The literature contains only a small number of case reports involving SCIC and hence limited guidance can be obtained. Methods We reviewed the scientific literature to evaluate the science of SCIC to determine if there were consistencies in presentation, evaluation, treatment, and clinical outcomes. Results We reviewed 6 case reports and a limited number of clinical papers on SCIC. We reported consistencies in clinical presentation and treatment outcomes among cases as well as serological and hematological finding. Conclusions While there is some consistency in the symptom presentation of individuals with SCIC, reliable evaluation and clinical procedures were not demonstrated in what we reviewed. Further research is needed to delineate the attributes of this complicated disease that occurs within SCD.

Intrahepatic cholestasis of pregnancy: an evaluation of obstetric management in German maternity units.

PURPOSE: Intrahepatic cholestasis of pregnancy (ICP) is associated with adverse fetal and neonatal outcome. Evidence for improvement by obstetric management is sparse. Common international guidelines recommend induction of labor before term, however, they differ in recommendations of monitoring the disease and time point of active management. So far, an official guideline for treatment and management of ICP in Germany does not exist. This study aims to compile common practice and policy in obstetric management of ICP in German maternity units. The objective is to gather obstetricians' opinion on management of ICP, and to estimate the need for standardization of current practice in Germany on the background of existing evidence. METHODS: A questionnaire focusing on indications for interventions was developed including fourteen multiple-choice questions comprising the areas of diagnostic criteria, laboratory testing, fetal monitoring, treatment, and delivery timing. The survey was sent to 699 maternity clinics and was distributed to participants of the annual congress hosted by the German society of perinatal medicine (DGPM). Collected data were summarized and evaluated in relation to available evidence and existing guidelines. Descriptive statistics and Fisher's exact test were used. RESULTS: 334 completed questionnaires returned corresponding to a response rate of 48.1%. Coinciding with existing international guidelines, 48.8% of the participants acknowledge bile acid concentrations above 10 µmol/L to be indicative of ICP. 85.0% of obstetricians recommend antenatal testing with cardiotocography, exceeding common standards of maternity policy guidelines; 50.3% execute active management in ICP-affected pregnancies as they generally recommend a delivery between 37 + 0 and 38 + 6 weeks of gestation. Although recent studies evinced a risk of stillbirth in ICP-affected pregnancies not until a bile acid concentration of > 100 µmol/L, 22.2% of the respondents recommend delivery before 37 + 0 weeks of gestation due to raised bile acids of 40-99 µmol/L. CONCLUSIONS: Opinions on the management of ICP in German maternity units differ widely and partly deviate by large from international standards. Reasons for this may be the lack of a national guideline and the low awareness due to the rarity of the disease on the one hand and the very slow dynamics in evidence generation and thus the uncertainty about the actual risks and optimal management on the other. The present data highlight the need for further research and clinical guidelines to standardize and optimize treatment based on the best available evidence.

A rare case of acute liver failure with intrahepatic cholestasis due to dengue hemorrhagic fever: CytoSorb® and plasma exchange aided in the recovery: case report.

BACKGROUND: Dengue haemorrhagic fever is a severe form of acute dengue infection characterized by leakage of plasma through capillaries into body spaces resulting in circulatory insufficiency leading to shock. Despite varying degrees of liver involvement occurring in acute dengue infection, intrahepatic cholestasis is very rare in the literature with only two cases reported so far. We report a challenging case of a middle-aged woman with DHF complicated by acute liver failure, coagulopathy, acute renal failure and prolonged intrahepatic cholestasis. She was successfully managed in the intensive care unit with supportive therapy, Cytosorb® and therapeutic plasma exchange. CASE PRESENTATION: A 54-year-old Sri Lankan obese woman with multiple comorbidities presented with fever, headache, vomiting and generalized malaise for 3 days and was diagnosed with dengue haemorrhagic fever. Despite the standard dengue management, she clinically deteriorated due to development of complications such as, acute liver injury, intrahepatic cholestasis and acute renal injury. Acute liver failure was evidenced by transaminitis, lactic acidosis, coagulopathy with pervaginal bleeding and severe encephalopathy necessitating elective intubation and mechanical ventilation. She was immediately transferred to intensive care facilities where she underwent supportive management for liver failure, continuous renal replacement therapy coupled with cytosorb and therapeutic plasma exchange with which she made a remarkable recovery. CONCLUSION: Acute liver failure with a prolonged phase of intrahepatic cholestasis is a very rare complication of acute dengue illness which is sparsely documented in medical literature so far. This patient was managed successfully with supportive therapy, aided by cytoSorb hemo-adsorption and therapeutic plasma exchange.

Recognizing, Diagnosing, and Managing Pregnancy Dermatoses.

Pregnancy dermatoses are inflammatory skin disorders that occur during pregnancy or immediately postpartum. This heterogenous group of disorders includes pemphigoid gestationis, polymorphic eruption of pregnancy, intrahepatic cholestasis of pregnancy, atopic eruption of pregnancy, and pustular psoriasis of pregnancy. In this article, we provide a comprehensive literature review of each condition focusing on nomenclature, epidemiology, pathogenesis, clinical presentation, diagnosis, differential diagnosis, maternal risk, fetal risk, and treatment. We aim to increase awareness and help clinicians recognize, diagnose, and manage these unique conditions.

Development of the Patient- and Observer-Reported PRUCISION Instruments to Assess Pruritus and Sleep Disturbance in Pediatric Patients with Cholestatic Liver Diseases.

INTRODUCTION: Understanding how patients experience their disease is a vital step in optimal disease management, and patient- and observer-reported outcome (PRO and ObsRO, respectively) measures can add important details to clinical information that is obtained as novel treatments are developed. Instruments that measure meaningful symptoms and impacts from the perspective of pediatric patients with cholestatic liver disease or their caregivers are needed. This study aimed to identify salient concepts in pediatric cholestatic liver disease, develop novel PRO and ObsRO instruments, and establish the instruments' content validity. METHODS: Relevant signs, symptoms, and impacts of cholestatic liver disease were identified through a literature review, interviews with expert clinicians, and concept elicitation interviews with children and caregivers of children who had progressive familial intrahepatic cholestasis (PFIC), Alagille syndrome, biliary atresia, or primary sclerosing cholangitis. Additional cognitive debriefing interviews with patients and caregivers were performed to ensure that participants could understand the instructions, questions, and response scales of the PRO and ObsRO instruments, with modifications made as necessary to improve comprehension and/or usability. RESULTS: A total of 36 interviews with patients and caregivers were conducted. Pruritus and sleep disturbance (e.g., difficulty falling or staying asleep due to itch) were identified as the most problematic symptom and significant impact, respectively, of the pediatric cholestatic liver diseases assessed. The ObsRO and PRO instruments, called PRUCISION, focus on these key disease features in the morning and evening. Several modifications were made to the draft instruments following cognitive interviews. The final PRUCISION PRO and ObsRO measures are designed as an electronic diary to be completed twice daily. The response scales include pictorial, verbal, and numeric scales. CONCLUSION: Novel PRO and ObsRO PRUCISION instruments were created that evaluate the patient experience of cholestatic pruritus in children with PFIC and other cholestatic liver diseases. The content validity of the PRUCISION instruments is established.

Bile, a greenish liquid that is made in the liver, is released into the gut to help digest food. In cholestatic liver disease (CLD), bile flow is interrupted, and bile can build up in the body. One potential effect of this buildup is pruritus, or itchiness of the skin, which can be so intense that it interferes with daily activities. In this study, interviews were done with doctors, patients, and their caregivers to develop new tools to evaluate the most impactful symptoms of CLD in children. After interviewing five doctors and 36 patients and caregivers, two questionnaires called PRUCISION were developed and refined. During this process, participants were first asked about the frequency, severity, duration, and impact of their or their child's symptoms; pruritus was identified as the most common and disruptive symptom associated with CLD, even interfering with sleep. Then, the wording of the questionnaires was modified to make them easier to understand, particularly for younger children. The researchers also had patients do a card-sorting task to ensure that they understood the picture-based responses used in the questionnaires. Finally, more details were added to the instructions for caregivers to more clearly define scratching behaviors. In summary, the questionnaires developed in this study include the perspective of the patient or their caregiver and may be useful to see if new treatments can impact the most prominent symptoms and impacts associated with CLD.

Plasma exchange treats severe intrahepatic cholestasis caused by dacomitinib: A case report.

RATIONALE: Dacomitinib-induced liver injury is often manifested by mild elevations of transaminases and bilirubin, and severe intrahepatic cholestasis caused by dacomitinib for simultaneous taking orally cytochrome P450 2D6 (CYP2D6) competitive substrates has been rarely reported. PATIENT CONCERNS: The patient was a 69-year-old woman with non-small cell lung cancer (NSCLC) who was prescribed oral dacomitinib for a month; she was given oral loratadine due to "allergic rhinitis" and metoprolol extended action tablets due to "tachycardia" separately for a few days during the course of dacomitinib treatment. The patient developed liver damage, increased fatigue, yellow urine, and pruritus, with significantly elevated serum levels of bilirubin and glutamyltranspetidase. DIAGNOSIS: Intrahepatic cholestasis, drug-induced liver injury, and NSCLC. INTERVENTIONS: After admission, the patient was prescribed adenosylmethionine, acetylcysteine, ursodeoxycholic acid capsule, methylprednisolone and fenofibrate for a month, with progressive elevation of liver biochemical parameters. Through drug enzyme gene assays in the liver tissue after percutaneous liver biopsy, we found both CYP2D6*10/*10 and ATP-binding cassette subfamily B member 1 GG variants (rs1045642) positive. After the poor response to the conventional medication, the patient underwent plasma exchange. OUTCOMES: The patient was discharged after her liver parameters improved; the parameters remained normal at several follow-up visits, and she renewed the NSCLC regimens without dacomitinib after being evaluated by oncologists. LESSONS: Dacomitinib can induce severe intrahepatic cholestasis. It is considered that patients with intermediate metabolic CYP2D6 are susceptible to drug-induced liver injury caused by dacomitinib; plasma exchange may be an effective treatment.

Intrahepatic cholestasis of pregnancy: from an obstetrician point of view.

Intrahepatic cholestasis of pregnancy (ICP) is the commonest among the specific dermatoses of pregnancy. The disease is characterised by intense pruritus and specifically by elevated bile acid levels and owing to the rarity of data published in this context, the disease carries a great challenge in both diagnosis and management. The disease is associated with significant maternal as well as perinatal adverse effects, hence, this article aims at improving the knowledge of the women's health carers with the up-to-date and evidence-based, whenever possible, recommendations while managing patients with ICP.

Navigating Uncertainty: A Case Study of Intrahepatic Cholestasis of Pregnancy.

Intrahepatic cholestasis of pregnancy (ICP), the most common liver disorder of pregnancy, is associated with complications for both a pregnant person and their fetus. The underlying cause is not well understood. The pruritus associated with ICP is uncomfortable for pregnant people; however, the primary concern is the fetal risk. Fetal risks include preterm labor and birth and intrauterine fetal demise. This is particularly significant for certain populations because of the disparities in incidence of ICP; in the United States, it disproportionately affects Latinx people, the largest and fastest-growing minority population. Diagnosis, monitoring, and treatment of ICP are vital to reduce discomfort from pruritis and avoid potential fetal demise. However, diagnosis and treatment are complicated by the lack of definitive diagnostic criteria, the frequent delay in laboratory analysis, and the cost of treatment. This case report aims to improve midwives' familiarity with ICP and discusses the epidemiology, risk factors, presentation, diagnostic criteria, and available management strategies for this disease as well as the importance of anticipatory guidance regarding increased lifetime risk of ICP in future pregnancies and hepatobiliary disease. Additionally, it discusses the challenges involved in diagnosis and access to treatment. Prompt diagnosis and initiation of treatment may reduce fetal morbidity and mortality.

[Skin and pregnancy]. / Peau et grossesse.

Pregnancy has a substantial impact on the hormonal status of the organism, consequently influencing the physiology of the skin. This results in dermatoses that only occur during pregnancy, which can also improve or exacerbate pre-existing dermatoses. In this article, we explain the management of pregnancy-specific dermatoses : atopic eruption of pregnancy, polymorphic eruption of pregnancy, pemphigoid gestationis, impetigo herpetiformis, and intrahepatic cholestasis of pregnancy. It is essential to clearly distinguish these different dermatoses as some of them, such as pemphigoid gestationis, impetigo herpetiformis and intrahepatic cholestasis of pregnancy, can have fetal consequences and as result, need to be closely monitored by the obstetricians.

La grossesse a un impact considérable sur le statut hormonal de l'organisme, influençant ainsi la physiologie cutanée. Cela se traduit par des dermatoses qui ne se manifestent que pendant la grossesse. Cette dernière peut également améliorer ou exacerber des dermatoses préexistantes. Dans cet article, nous précisons la prise en charge des dermatoses spécifiques de la grossesse : l'eczéma atopique de la grossesse, l'éruption polymorphe gravidique, la pemphigoïde gestationnelle, l'impétigo herpétiforme et la cholestase intrahépatique gravidique. Il est important de distinguer ces dermatoses, puisque la pemphigoïde gestationnelle, l'impétigo herpétiforme et la cholestase intrahépatique gravidique présentent un risque fœtal et par conséquence nécessitent un suivi obstétrical rapproché.

Pregnancy-Associated Liver Diseases.

The liver disorders unique to pregnancy include hyperemesis gravidarum, intrahepatic cholestasis of pregnancy, acute fatty liver of pregnancy, and preeclampsia-associated hepatic impairment, specifically hemolysis, elevated liver enzymes, and low platelet count syndrome (HELLP). Their importance lies in the significant maternal and fetal/neonatal morbidity and mortality. Expeditious diagnosis and clinical evaluation is critical to ensure timely, appropriate care and minimize risks to the pregnant woman and her fetus/baby. A multidisciplinary approach is essential, including midwives, maternal-fetal-medicine specialists, anesthetists, neonatologists, and hepatologists.

[Expert consensus on the diagnosis and treatment of intrahepatic cholestasis (2021 edition)].

Intrahepatic cholestasis is a clinical syndrome due to the defect of bile acid synthesis, abnormal bile excretion, and mechanical or functional disturbance of intrahepatic bile flows caused by hepatic parenchymal cell and/or intrahepatic bile duct diseases. It commonly occurs as cholestatic liver diseases, intrahepatic cholestasis of pregnancy, and genetic/metabolic-related cholestatic diseases. In recent years, new information and progress in diagnosis and treatment of intrahepatic cholestatic diseases have been achieved. In order to provide updated clinical reference and guidance for clinicians, we organized experts to compile the Expert Consensus on the Diagnosis and Treatment of Intrahepatic Cholestasis (2021), on the basis of the 2015 edition.