Childhood Cholestatic Liver Diseases that Persist Into Adulthood: Lessons for the Adult Gastroenterologist.

Children with cholestatic liver diseases are increasingly living into adulthood, thanks to innovations in medical and surgical therapies. The excellent outcomes observed in pediatric liver transplantation for diseases, such as biliary atresia, have transformed the life trajectory of children born with once-fatal liver diseases. The evolution of molecular genetic testing, has helped expedite the diagnosis of other cholestatic disorders, improving the clinical management, disease prognosis, and family planning for inherited disorders, such as progressive familial intrahepatic cholestasis and bile acid synthesis disorders. The expanding list of therapeutics, including bile acids and the newer ileal bile acid transport inhibitors, has also helped slow the progression of disease and improve the quality of life for certain diseases, like Alagille syndrome. More and more children with cholestatic disorders are expected to require care from adult providers familiar with the natural history and potential complications of these childhood diseases. The aim of this review is to bridge the gap between pediatric and adult care in children with cholestatic disorders. The present review addresses the epidemiology, clinical features, diagnostic testing, treatment, prognosis, and transplant outcomes of 4 hallmark childhood cholestatic liver diseases: biliary atresia, Alagille syndrome, progressive familial intrahepatic cholestasis, and bile acid synthesis disorders.

Clinical phenotype of adult-onset liver disease in patients with variants in ABCB4, ABCB11, and ATP8B1.

Variants in ATP8B1, ABCB11, and ABCB4 underlie the most prevalent forms of progressive familial intrahepatic cholestasis. We aim to describe variants in these genes in a cohort of patients with adult-onset liver disease, and explore a genotype-phenotype correlation. Patients with onset of liver disease aged above 18 who underwent sequencing of cholestasis genes for clinical purposes over a 5-year period were identified. Bioinformatic analysis of variants was performed. Liver histology was evaluated in patients with variants. Of the 356 patients tested, at least one variant was identified in 101 (28.4%): 46 ABCB4, 35 ABCB11, and 28 ATP8B1. Patients with ABCB4 variants had chronic liver disease (71.7%) and pregnancy-associated liver dysfunction (75%), with a younger age of onset in more severe genotypes (p = 0.046). ABCB11 variants presented with pregnancy-associated liver dysfunction (82.4%) and acute/episodic cholestasis (40%), with no association between age of onset and genotype severity. ATP8B1 variants were associated with chronic liver disease (75%); however, they were commonly seen in patients with an alternate etiology of liver disease and variants were of low predicted pathogenicity. In adults with suspected genetic cholestasis, variants in cholestasis genes were frequently identified and were likely to contribute to the development of liver disease, particularly ABCB4 and ABCB11. Variants were often in heterozygous state, and they should no longer be considered recessive Mendelian traits. Sequencing cholestasis genes in selected patients with adult-onset disease should be considered, with interpretation in close collaboration with histopathologists and geneticists.

Does mild intrahepatic cholestasis of pregnancy require an aggressive management? Evidence from a prospective observational study focused on adverse perinatal outcomes and pathological placental findings.

OBJECTIVE: To ascertain the most effective approach in pregnancies complicated by mild intrahepatic cholestasis of pregnancy (mICP) by evaluating rates of adverse perinatal outcomes (APOs) and pathological placental findings. METHODS: A total of 89 pregnancies complicated by mICP (defined as total serum bile acids (TSBAs) levels <40 µmol/L) were included. One-drug (ursodeoxycholic acid [UDCA]) (n = 49, 55.1%) and combined (UDCA plus S-adenosyl methionine (SAMe)) (n = 40, 44.9%) therapies were compared. RESULTS: No differences were found in demographic, obstetric, and placental characteristics. In UDCA plus SAMe group, premature delivery was a common clinical decision (14.3 versus 25%, p-value = .201), with increased rates of instrumental vaginal delivery (VD; 28.6 versus 40%, p-value = .522), but similar cesarean section (CS) rates (26.5 versus 25%, p-value = .498). Mean placental weight was comparable (UDCA, mean 595.7 g, SD 213.1 g versus UDCA plus SAMe, mean 586.4 g, SD 102.9 g, p-value = .875). A total of 110 lesions were identified, 64 in 25 placentas of patients assigned to the UDCA and 46 in 15 placentas of patients managed by UDCA plus SAMe. Placental findings attributable to maternal malperfusion were found in 41/25 and 32/15 cases treated by UCDA and UDCA plus SAMe (165 versus 213%, p-value = .774), pathological fetal vascular supply in 17/25 and 8/15 placentas (68 versus 53%, p-value = .777), and inflammatory lesions in 6/25 and 6/15 cases (24 versus 40%, p-value = .757). CONCLUSIONS: Pregnancies complicated by mICP and managed by UDCA alone present similar APO rates and placental histopathology if compared with those treated by UDCA plus SAMe, failing to recognize advantages in the combined therapy. Further prospective studies and data sharing from ongoing RTCs could drive changes in therapeutic plan.

Intrahepatic cholestasis of pregnancy: risk factors for severe disease.

INTRODUCTION: Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-associated hepatic disorder characterized by pruritus in the setting of elevated serum bile acids (BA). Risk factors for the disease include preexisting hepatobiliary disease, personal or family history of ICP, and advanced maternal age. Recent data suggests that patients with severe ICP (BA ≥100 µmol/L) have a higher risk of adverse pregnancy outcomes including stillbirth. MATERIAL AND METHODS: This was a retrospective cohort study of patients diagnosed with ICP between 2012 and 2019 at a tertiary referral center. ICP was defined as symptomatic pruritus combined with serum BA >10 µmol/L. Maternal characteristics and outcomes were abstracted from electronic medical records. Baseline characteristics were compared between patients with mild (BA <40 µmol/L), moderate (BA 40-99 µmol/L) and severe (BA ≥100 µmol/L) ICP. Obstetrics and neonatal outcomes for patients in each category were then analyzed. Shapiro-Wilk test was used to test for normality for continuous variables, and ANOVA, Kruskal-Wallis, Chi-squared or Fisher's exact tests were used as appropriate. A p-value <.05 was considered statistically significant. RESULTS: 438 patients were included in the analysis. Individuals with pregestational diabetes (p < .01), history of ICP (p < .01), prior cholecystectomy (p < .01), and tobacco use (p < .05) were more likely to have severe disease. When compared to individuals with moderate and mild disease, individuals with severe disease were more likely to be diagnosed earlier (29w1d vs 34w1d vs 34w1d, p < .05), have gestational diabetes (50% vs 6% vs 13%, p < .01), hypertensive disorders of pregnancy (42% vs 10% vs 15%, p = .02), and abnormal aspartate aminotransferase (91% vs 65% vs 27%, p < .01) and alanine aminotransferase levels (91% vs 60% vs 26%, p < .01). There were no differences in preterm labor, meconium-stained amniotic fluid, or neonatal respiratory distress syndrome and no stillbirths in this cohort. CONCLUSIONS: In patients with ICP, those with pregestational diabetes, history of ICP, prior cholecystectomy, and tobacco use are more likely to develop severe disease. Given the adverse outcomes associated with severe disease, serial BA measurements to monitor for development of severe disease may be warranted in this population.

Epidemiology and burden of progressive familial intrahepatic cholestasis: a systematic review.

BACKGROUND: Progressive familial intrahepatic cholestasis is a rare, heterogeneous group of liver disorders of autosomal recessive inheritance, characterised by an early onset of cholestasis with pruritus and malabsorption, which rapidly progresses, eventually culminating in liver failure. For children and their parents, PFIC is an extremely distressing disease. Significant pruritus can lead to severe cutaneous mutilation and may affect many activities of daily living through loss of sleep, irritability, poor attention, and impaired school performance. METHODS: Databases including MEDLINE and Embase were searched for publications on PFIC prevalence, incidence or natural history, and the economic burden or health-related quality of life of patients with PFIC. Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. RESULTS: Three systematic reviews and twenty-two studies were eligible for inclusion for the epidemiology of PFIC including a total of 2603 patients. Study periods ranged from 3 to 33 years. Local population prevalence of PFIC was reported in three studies, ranging from 9.0 to 12.0% of children admitted with cholestasis, acute liver failure, or splenomegaly. The most detailed data come from the NAPPED study where native liver survival of >15 years is predicted in PFIC2 patients with a serum bile  acid concentration below 102 µmol/L following bile diversion surgery. Burden of disease was mainly reported through health-related quality of life (HRQL), rates of surgery and survival. Rates of biliary diversion and liver transplant varied widely depending on study period, sample size and PFIC type, with many patients have multiple surgeries and progressing to liver transplant. This renders data unsuitable for comparison. CONCLUSION: Using robust and transparent methods, this systematic review summarises our current knowledge of PFIC. The epidemiological overview is highly mixed and dependent on presentation and PFIC subtype. Only two studies reported HRQL and mortality results were variable across different subtypes. Lack of data and extensive heterogeneity severely limit understanding across this disease area, particularly variation around and within subtypes.

A nomogram based on combining systemic and hepatic inflammation markers for predicting microscopic bile duct tumour thrombus in hepatocellular carcinoma.

BACKGROUND: Bile duct invasion is a relatively rare event and is not well characterised in hepatocellular carcinoma (HCC). It remains very difficult to diagnose HCC with bile duct tumour thrombus (BDTT) before surgery. Increasing evidence has revealed that inflammation plays a critical role in tumorigenesis. This study aimed to develop nomograms based on systemic and hepatic inflammation markers to predict microscopic BDTT (micro-BDTT) before surgery in HCC. METHODS: A total of 723 HCC patients who underwent hepatectomy as initial therapy between January 2012 and June 2020 were included in the study. Logistic regression analysis was used to identify independent risk factors for micro-BDTT. The nomograms were constructed using significant predictors, including α-fetoprotein (AFP), alkaline phosphatase (ALP), direct bilirubin (DB), prognostic nutritional index (PNI), and γ-glutamyl transferase (γ-GT)/alanine aminotransferase (ALT). The prediction accuracies of the nomograms were evaluated using the area under the receiver operating characteristic (ROC) curve. RESULTS: AFP, ALP, DB, PNI, and γ-GT/ALT were independent risk factors for predicting micro-BDTT (P = 0.036, P = 0.004, P = 0.013, P = 0.012, and P = 0.006, respectively), which were assembled into the nomograms. The area under the ROC curve of the nomograms combining PNI and γ-GT/ALT for predicting micro-BDTT was 0.804 (95% confidence interval [CI]: 0.730-0.878). The sensitivity and specificity values when used in predicting micro-BDTT before surgery were 0.739 (95% CI: 0.612-0.866) and 0.781 (95% CI: 0.750-0.813), respectively. CONCLUSIONS: The nomogram based on combining systemic and hepatic inflammation markers is suitable for predicting micro-BDTT before surgery in HCC patients, leading to a rational therapeutic choice for HCC.

Perinatal complications and live-birth outcomes following assisted reproductive technology: a retrospective cohort study.

BACKGROUND: With the development of assisted reproductive technology (ART) and its increasing success rate in the mainland of China, more attention has been paid to the safety of ART. In this study, we explored the associations between conception by ART and pregnancy/perinatal complications, and neonatal outcomes compared with similar outcomes following spontaneous conception. METHODS: This retrospective cohort study of pregnancies over a 3-year period (2013-2015) was performed at Beijing Obstetrics and Gynecology Hospital, Beijing, China. Subjects were divided into two groups: conception by ART (n = 2256) or spontaneous conception (n = 6768). According to different fertilization modes, the ART group was divided into in vitro fertilization (IVF, n = 1873) and intracytoplasmic sperm injection (ICSI, n = 383) subgroups. The ART group was also divided into two different embryo transfer methods; fresh embryo transfer (ET, n = 1583) and frozen embryo transfer (FET, n = 673) subgroups. Pregnancy complications, perinatal complications, and neonatal outcomes of the enrolled subjects were investigated and analyzed by univariate analysis and multivariate logistic regression. RESULTS: After adjustment for maternal age, gravidity, parity, maternal education, smoking, alcohol consumption, and body mass index (BMI), pregnancies conceived by ART were associated with a significantly increased incidence of gestational diabetes mellitus (GDM; OR 1.88, 95% CI 1.56-2.27), gestational hypertension (OR 2.18, 95% CI 1.83-2.60), and intrahepatic cholestasis of pregnancy (ICP) (OR 2.79, 95% CI 2.15-3.64), compared with spontaneous conception. These associations were similar for the singleton group. In the twin group, only the incidence of ICP was significantly higher than in controls. We found that pregnancies conceived by ART were associated with perinatal complications, including placental abruption (OR 2.14, 95% CI 1.33-3.45), premature rupture of membranes (PROM; OR 1.24, 95% CI 1.06-1.45), postpartum hemorrhage (OR 2.89, 95% CI 2.33-3.59) and polyhydramnios (OR 2.01, 95% CI 1.29-3.16). The singleton group had a similar result with placental abruption, but not with fetal membranes ruptures before labor and polyhydramnios. There were no significant differences in the incidence of these perinatal complications in the twin group. Some neonatal outcomes, including preterm labor (OR 4.29, 95% CI 3.84-4.80) and low birth weight (OR 1.72, 95% CI 1.42-2.08), were more likely to occur with singleton births after ART. However, there were no significant differences for these outcomes from twin pregnancies. Perinatal complications and neonatal outcomes were consistent between the IVF and ICSI subgroups. The FET and ET subgroups showed a similar increase in complications, except for the incidence of placental abruption. After taking into account the effects of parity, birth plurality and maternal age, the ART group still exhibited increased maternal and neonatal complications, although some differences narrowed or disappeared. CONCLUSIONS: This retrospective cohort study demonstrated that patients who underwent ART were at increased risk of several adverse pregnancy outcomes compared with women who conceived spontaneously. These complications may be attributed in part to the relatively high multiple pregnancy rate after ART. Elective single embryo transfer should be promoted in China to reduce the obstetrical risks of ART pregnancy. Singletons of ART pregnancy exhibited increased maternal and neonatal complications as well, suggesting that underlying infertility or other maternal or parental factors may contribute to the adverse outcomes.

Systematic review of progressive familial intrahepatic cholestasis.

BACKGROUND AND AIMS: Progressive familial intrahepatic cholestasis (PFIC) is a heterogeneous group of rare genetic disorders associated with bile acid secretion or transport defects. This is the first systematic review of the epidemiology, natural history and burden of PFIC. METHODS: MEDLINE and Embase were searched for publications on PFIC prevalence, incidence or natural history, and the economic burden or health-related quality of life (HRQoL) of patients with PFIC. Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. RESULTS: Of 1269 records screened, 20 were eligible (epidemiology, 17; humanistic burden, 5; both, 2). Incidence of intrahepatic cholestasis, including but not limited to PFIC, was 1/18 000 live births in one study that did not use genetic testing. In two studies of infants and children (2-18 years) with cholestasis, 12-13% had genetically diagnosed PFIC. Of the three main PFIC subtypes, PFIC2 was the most common (21-91% of patients). Common symptoms (e.g. pruritus, jaundice, hepatomegaly, splenomegaly) generally appeared at about 3 months of age and tended to emerge earliest in patients with PFIC2. Patients reported that pruritus was often severe and led to dermal damage and reduced HRQoL. Disease progression led to complications including liver failure and hepatocellular carcinoma, with 20-83% of patients requiring liver transplantation. Mortality was 0-87% across 10 studies (treatment varied among studies), with a median age at death of ~4 years in one study. CONCLUSIONS: Patients with PFIC face debilitating symptoms and poor prognosis. Further research is needed to inform patient management and clinical trial design. Published data on the epidemiology and socioeconomic burden of PFIC is limited.

Intrahepatic cholestasis of pregnancy and associated causes of death: a cohort study with follow-up of 27-46 years.

BACKGROUND: The aim of this study was to determine whether intrahepatic cholestasis of pregnancy (ICP) is associated with causes of death during on average 35 years follow-up after the delivery. METHODS: The study population comprised 571 women with ICP in at least one pregnancy seen at Tampere University Hospital, Finland, between 1969 and 1988. ICP was verified from patient records. The previous and following subjects in the maternity ward diary were taken as controls for each ICP case. In total, there were 1333 controls. All underlying causes of death were obtained from Statistics Finland in March 2017. The deaths occurred during 1971-2015 and the causes of death were classified according to ICD-10. RESULTS: Altogether, 39 of the mothers with ICP (6.8%) and 111 of the controls (8.3%) had died by the end of 2015 (p = 0.267). There were more underlying causes of death from gastrointestinal diseases (15%) in the ICP group than in the control group (4%) (p = 0.011). The number of underlying causes of death due to diseases of the circulatory system were lower in the ICP group (13%) than in the control group (26%), although the finding was not statistically significant (p = 0.088). Moreover, neoplasms were the underlying cause of death in 46% of cases among mothers with ICP and in 41% of cases among the controls (p = 0.609). Diseases of the other organ systems were rare in both groups. CONCLUSION: Women with a history of ICP do not have an increased overall mortality. However, deaths from gastrointestinal diseases are overrepresented among women with a history of ICP.

Chronic liver diseases and the potential use of S-adenosyl-L-methionine as a hepatoprotector.

Chronic liver diseases result in overall deterioration of health status and changes in metabolism. The search for strategies to control and combat these hepatic diseases has witnessed a great boom in the last decades. Nutritional therapy for controlling and managing liver diseases may be a positive influence as it improves the function of the liver. In this review, we focus mainly on describing liver conditions such as nonalcoholic fatty liver disease, and intrahepatic cholestasis as well as using S-adenosyl-L-methionine as a dietary supplement and its potential alternative therapeutic effect to correct the hepatic dysfunction associated with these conditions.

Perinatal outcomes associated with intrahepatic cholestasis of pregnancy.

OBJECTIVE: The objective of this study is to examine perinatal outcomes associated with cholestasis of pregnancy according to bile acid level and antenatal testing practice. STUDY DESIGN: Retrospective cohort study of women with symptoms and bile acid testing from 2005 to 2014. Women were stratified by bile acid level: no cholestasis (<10 µmol/L), mild (10-39 µmol/L), moderate (40-99 µmol/L), and severe (≥100 µmol/L). The primary outcome was composite neonatal morbidity (hypoxic ischemic encephalopathy, severe intraventricular hemorrhage, bronchopulmonary dysplasia, necrotizing enterocolitis, or death). RESULTS: 785 women were included; 487 had cholestasis (347 mild, 108 moderate, 32 severe) and 298 did not. After controlling for gestational age (GA), severe cholestasis was associated with the composite neonatal outcome (aRR 5.6, 95% CI 1.3-23.5) and meconium-stained fluid (aRR 4.82, 95%CI 1.6-14.2). Bile acid levels were not correlated with the frequency of testing (p = .50). Women who underwent twice weekly testing were delivered earlier (p = .016) than women tested less frequently, but the difference in GA was ≤4 d. Abnormal testing prompting delivery was uncommon. Among women with cholestasis, there were three stillbirths. One of these women was undergoing antenatal testing, which was normal 1 d prior to the fetal demise. CONCLUSION: Severe cholestasis is associated with neonatal morbidity which antenatal testing may not predict.

Ocular findings in patients with cholestatic disorders of infancy: A single-centre experience.

BACKGROUND AND STUDY AIMS: Neonatal cholestasis can be associated with ocular findings that might aid in its diagnosis, e.g., Alagille syndrome (AGS) and Niemann Pick disease (NPD). We aimed to investigate the frequency of ocular manifestations in infants with cholestasis. PATIENTS AND METHODS: This cross-sectional study included cholestatic infants presenting to the Paediatric Hepatology Unit, Cairo University Paediatric Hospital, Cairo, Egypt. All infants underwent examination of lid, ocular motility, anterior and posterior segments and measurement of intraocular pressure, cycloplegic refraction, ocular ultrasonography and vision. RESULTS: The study included 112 infants with various cholestasis; 73 (65.2%) were males. The median age was 2months. Diagnosis was reached in 39 cases: 14 had AGS, 14 had biliary atresia (BA), 4 had NPD, 4 had post-haemolytic cholestasis, 2 had cytomegalovirus neonatal hepatitis, and one case had hepatorenal tyrosinaemia. Thirteen cases were probably having progressive familiar intrahepatic cholestasis (PFIC) type 1 or 2 considering their persistent cholestasis in the presence of normal gamma-glutamyl transpeptidase; 28 were left with a diagnosis of "idiopathic neonatal hepatitis" (INH), and 32 (28.6%) had no definite diagnosis. Ophthalmologic abnormalities were found in 39 cases (34.8%). The commonest finding was unilateral/bilateral optic nerve drusen in 12 (10.7%), followed by posterior embryotoxon in 11 (9.8%). Ocular findings were observed in 64.3% patients with AGS, 50% patients with NPD, 30.8% cases with suspected PFIC type 1or 2, 28.6% infants with INH, and 14.3% patients with BA. CONCLUSION: Ophthalmologic findings are not uncommon among cholestatic infants. Ophthalmologic examination should be routinely performed, including assessment of anterior segment, fundus examination, and ocular ultrasound.

Molecular characterization of exons 6, 8 and 9 of ABCB4 gene in children with Progressive Familial Intrahepatic Cholestasis type 3.

AIM OF WORK: To estimate the frequency of mutations involving exons 6, 8 and 9 of Adenosine triphosphate-binding cassette, subfamily B, member 4 (ABCB4) gene among children with progressive intrahepatic cholestasis with high γ-GT activity (PFIC3). SUBJECTS AND METHODS: Cross sectional study was conducted on 30 children with PFIC3. Genotyping was performed by sequencing analysis of exons 6, 8 and exon 9 of ABCB4 gene. RESULTS: Heterozygous synonymous polymorphic variant was detected in exon 6 (rs 1202283) and in exon 8 (rs 2109505). No mutations in studied exons were detected. CONCLUSION: Exons 6, 8 and 9 mutations of ABCB4 gene are not common among Egyptian children with PFIC3.

Frequency of intrahepatic cholestasis of pregnancy in Punjab Pakistan: A single centre study.

OBJECTIVE: To find out the frequency of intrahepatic cholestasis of pregnancy and its identification parameters. METHODS: The cross-sectional observational study was conducted in the Department of Medicine and the Department of Obstetrics, Combined Military Hospital, Kharian, from October 2013 to March 2014, and comprised all pregnant patients having symptoms suggestive of intrahepatic cholestasis which was confirmed after systemic inquiry, examination and biochemical analysis. Patients with cholestasis due to another reason, coagulopathies, thrombocytopenia and tumours were excluded. The patients were followed up till delivery to see the effects of cholestasis on mother and child. RESULTS: Out of 1001 obstetric patients, 31(3.1%) had intrahepatic cholestasis of pregnancy. Pruritus was the main symptom in 25 (85%) patients followed by rash in 20 (65%). In 20 (64%) patients, labour was induced. Mode of delivery was Caesarean Section in 18 (58%) patients and 9 (29%) had postpartum haemorrhage. Regarding neonatal complications, 22 (70%) required admission to neonatal intensive care and 15 (48%) had meconium aspiration. CONCLUSIONS: A high frequency of intrahepatic cholestasis of pregnancy was observed. It had significant impact on maternal and foetal health.

Byler disease: early natural history.

OBJECTIVES: Byler disease, originally described in Amish kindred, results from mutations in ATPase Class I Type 8b Member 1 (ATP8b1). Specific clinical reports of Amish Byler disease were last published 40 years ago. These investigations were directed at the present detailed clinical understanding of the early course of hepatic manifestations of Byler disease. METHODS: This study analyzed routine clinical practice and outcomes of children with Byler disease (defined by homozygous c.923G>T mutation in ATP8b1), who initially presented to Children's Hospital of Pittsburgh of UPMC between January 2007 and October 2014. Data were analyzed to the earlier of 24 months of age or partial external biliary diversion. RESULTS: Six children presented between 1 and 135 days of life: 2 presented with newborn direct hyperbilirubinemia, 2 had complications of coagulopathy, 1 had failure to thrive and rickets, and 1 sibling was identified by newborn genetic testing. Intensive fat-soluble vitamin supplementation was required to prevent insufficiencies in vitamins D, E, and K. Hyperbilirubinemia was variable both over time and between children. Serum bile acid levels were elevated, whereas γ-glutamyltranspeptidase levels were low normal. Scratching behavior (pruritus) was intractable in 4 of 6 children with onset between 6 and 12 months of age. Features of portal hypertension were not observed. Partial external biliary diversion was used during the second year of life in 4 children. CONCLUSIONS: Detailed analysis of Byler disease revealed varied disease presentation and course. Nutritional issues and pruritus dominated the clinical picture in the first 2 years of life.

Intrahepatic cholestasis of pregnancy and cancer, immune-mediated and cardiovascular diseases: A population-based cohort study.

BACKGROUND & AIMS: Intrahepatic cholestasis of pregnancy (ICP) is the most common liver disease in pregnancy. It is associated with hepatobiliary diseases that might predispose to cancer and also with gestational diabetes and preeclampsia. In this study, we examined associations between ICP and cancer, and immune-mediated and cardiovascular diseases. METHODS: By linking the Swedish Medical Birth Register and the Swedish Patient Register, we identified 11,388 women with ICP and 113,893 matched women without ICP who gave birth between 1973 and 2009. Diagnoses of cancer and immune-mediated and cardiovascular diseases both before and after delivery were obtained from the Patient Register. The main outcome measures were hazard ratios (HRs), calculated through Cox regression, for the indicated diseases after delivery. RESULTS: ICP was not associated with later overall cancer (HR 1.07, 95% confidence interval [CI] 0.94-1.21), but it was associated with later liver and biliary tree cancer (HR 3.61, 95% CI 1.68-7.77, and 2.62, 95% CI 1.26-5.46, respectively). ICP was also associated with later immune-mediated diseases (HR 1.28, 95% CI 1.19-1.38), and specifically diabetes mellitus (HR 1.47, 95% CI 1.26-1.72), thyroid disease (HR 1.30, 95% CI 1.14-1.47), psoriasis (HR 1.27, 95% CI 1.07-1.51), inflammatory polyarthropathies (HR 1.32, 95% CI 1.11-1.58) and Crohn's disease (HR 1.55, 95% CI 1.14-2.10), but not ulcerative colitis (HR 1.21, 95% CI 0.93-1.58). Women with ICP also had a small increased risk of later cardiovascular disease (HR 1.12, 95% CI 1.06-1.19). CONCLUSIONS: Women with ICP have increased risk of later hepatobiliary cancer and immune-mediated and cardiovascular diseases.

Risk factors for early and late biliary complications in pediatric liver transplantation.

BC are a common source of morbidity after pediatric LT. Knowledge about risk factors may help to reduce their incidence. Retrospective analysis of BC in 116 pediatric patients (123 LT) (single institution, 05/1990-12/2011, medium follow-up 7.9 yr). One-, five-, and 10-yr survival was 91.1%, no patient died of BC. Prevalence and risk factors for anastomotic and intrahepatic BC were examined. There were 29 BC in 123 LT (23.6%), with three main categories: 10 (8.1%) primary anastomotic strictures, eight (6.5%) anastomotic leaks, and three (2.4%) intrahepatic strictures. Significant risk factors for anastomotic leaks were total operation time (increase 1.26-fold) and early HAT (<30 days post-LT; increase 5.87-fold). Risk factor for primary anastomotic stricture was duct-to-duct choledochal anastomosis (increase 5.96-fold when compared to biliary-enteric anastomosis). Risk factors for intrahepatic strictures were donor age >48 yr (increase 1.09-fold) and MELD score >30 (increase 1.2-fold). To avoid morbidity from anastomotic BC in pediatric LT, the preferred biliary anastomosis appears to be biliary-enteric. Operation time should be kept to a minimum, and HAT must by all means be prevented. Children with a high MELD score or receiving livers from older donors are at increased risk for intrahepatic strictures.

Menopause after a history of intrahepatic cholestasis of pregnancy.

OBJECTIVE: Intrahepatic cholestasis of pregnancy is a hormone-provoked disorder that fades quickly after parturition. The aim of this study was to establish whether a history of intrahepatic cholestasis of pregnancy reduces the use of hormone therapy for menopausal symptoms and, irrespective of hormone therapy, whether intrahepatic cholestasis is associated with other health aspects after menopause. METHODS: In 2010, questionnaires were sent to a cohort of women who delivered in Tampere University Hospital, Finland, from 1969 to 1988. The study population comprised postmenopausal women with a history of intrahepatic cholestasis of pregnancy (n = 189) and their controls (n = 416). The main outcome measures were the use of hormone therapy and other means of alleviating menopausal symptoms, and the diseases the women reported. RESULTS: There were no differences in the use of hormone therapy between the two groups. Of the diseases reported, breast cancer, hepatobiliary diseases, and hypothyroidism were more frequent among women with a history of intrahepatic cholestasis of pregnancy, whereas cardiac arrhythmia was less frequent. With respect to other diseases, there were no differences. CONCLUSIONS: A history of intrahepatic cholestasis of pregnancy does not reduce the use of hormone therapy. However, when physicians prescribe hormone therapy for these women, a history of intrahepatic cholestasis of pregnancy calls for attention in view of its association with gallstones.