Transient Cholestasis Research Articles

Acetaminophen overdose causes a breach of the blood-bile barrier in mice but not in rats.

Acetaminophen (APAP) is known to cause a breach of the blood-bile barrier in mice that, via a mechanism called futile bile acid (BA) cycling, increases BA concentrations in hepatocytes above cytotoxic thresholds. Here, we compared this mechanism in mice and rats, because both species differ massively in their susceptibility to APAP and compared the results to available human data. Dose and time-dependent APAP experiments were performed in male C57BL6/N mice and Wistar rats. The time course of BA concentrations in liver tissue and in blood was analyzed by MALDI-MSI and LC-MS/MS. APAP and its derivatives were measured in the blood by LC-MS. APAP-induced liver damage was analyzed by histopathology, immunohistochemistry, and by clinical chemistry. In mice, a transient increase of BA in blood and in peri-central hepatocytes preceded hepatocyte death. The BA increase coincided with oxidative stress in liver tissue and a compromised morphology of bile canaliculi and immunohistochemically visualized tight junction proteins. Rats showed a reduced metabolic activation of APAP compared to mice. However, even at very high doses that caused cell death of hepatocytes, no increase of BA concentrations was observed neither in liver tissue nor in the blood. Correspondingly, no oxidative stress was detectable, and the morphology of bile canaliculi and tight junction proteins remained unaltered. In conclusion, different mechanisms cause cell death in rats and mice, whereby oxidative stress and a breach of the blood-bile barrier are seen only in mice. Since transient cholestasis also occurs in human patients with APAP overdose, mice are a clinically relevant species to study APAP hepatotoxicity but not rats.

Factors associated with cholestasis after surgery for congenital duodenal atresia

Background: This study assessed the characteristics of neonates with duodenal atresia (DA) who developed transient postoperative cholestasis which resolved spontaneously, without identifiable congenital anomalies or surgical complications, and identified potential risk factors for cholestasis. Methods: Neonates with DA who underwent surgery at our institution between January 2009 and July 2022 were retrospectively reviewed. Demographic factors, intraoperative findings, placement of a trans-anastomotic tube (TAT), and postoperative outcomes were compared between patients who developed cholestasis (conjugated hyperbilirubinemia >2.0 mg/dL) after surgery (Group A) and those who did not (Group B). This report is a retrospective cohort study and complies with the STROBE statement. Results: Among 19 neonates with DA, 6 (31.6%) developed cholestasis after surgery, with the highest direct bilirubin value being 4.3 (2.4-6.5) mg/dL (median, [range]) on postoperative day 14.5 (2-23) that persisted for 67 (47-116) days until spontaneous resolution. Neonates in Group A had a significantly younger gestational age (36.6 vs. 38.0 weeks) (median) (p=0.038), a higher rate of Down syndrome (66.7 vs. 15.4%) (p=0.046), a higher rate of TAT placement (66.7 vs. 15.4%) (p=0.046), and longer administration of total parenteral nutrition (15.5 vs. 7.0 days) (p=0.027) than those in Group B. Conclusion: Transient cholestasis after surgery for DA seemed to be associated with prematurity, Down syndrome, parenteral nutrition, and TAT placement.

ГЕМОРРАГИЧЕСКИЕ ИНСУЛЬТЫ У ДЕТЕЙ РАННЕГО ВОЗРАСТА

To date, cerebrovascular diseases of childhood are poorly understood. The need to study hemorrhagic strokes in children is due to the high prevalence in early childhood, the difficulty in identifying the causes and the non-specificity of the first signs of pathology. At different stages of child development, the etiological significance of various pathogenic factors is not the same. The purpose of this study - to analyze the results of diagnosis and treatment of intracranial complications in late hemorrhagic disease of the newborn. Methods. 158 cases of treatment of patients with intracranial hemorrhages against the background of vitamin-K dependent hemorrhagic syndrome were chosen as the objects of the study. Among the sick boys prevailed and amounted to 76 percent. At the age of 40 days ± 2, the disease began in 129 (86.6%) patients. The results of treatment were monitored in 158 patients within the period from one to 3 months. Indicators reflecting the results of treatment were subjected to statistical analysis. Results. According to the type of hematoma, the patients were distributed as follows - 64 (41.1%) intracerebral hematoma, 31 (20.2%) were diagnosed with subdural hemorrhage, intraventricular hemorrhage was detected in 6 (3.8%) cases, mixed subduralintracerebral hemorrhage was detected in 15 (9.5%) patients. 43 (26.6%) patients were not operated on: with subarachnoid hemorrhages - 34 (21.4%) and 9 patients (5.7%) - with small intracerebral and suberal hemorrhages. Lethal outcome occurred in 29 children (18.4%), mortality after surgery in 8 (5.1%) cases. In 43% of cases, a follow-up study did not reveal a neurological deficit. Conclusions. Full-term infants with a combination of the following factors are susceptible to the occurrence of hemorrhagic disease of the newborn: lack of prophylactic administration of vitamin K preparations, breastfeeding, and transient cholestasis. Timely surgical treatment in most patients gives positive results, despite the operation in a very difficult general condition of the patient and unstable hemostasis. Residual neurological deficit was noted during the follow-up study mainly in patients with primary gross damage to the brain parenchyma and with late diagnosis of the disease.

Hepatocyte nuclear factors play an important role in the pathogenesis of nephropathy

Hepatocyte nuclear factors play an important role in the pathogenesis of nephropathy

Hyperinsulinemic hypoglycemia in growth restricted convalescent preterm neonates: clinical characteristics and impediments to early diagnosis.

Describe clinical characteristics, course, and risk factors for hyper-insulinemic hypoglycemia (HIH) in preterm infants and identify impediments to early diagnosis. Electronic records of infant-mother dyads were used to describe clinical characteristics, lab parameters, and course of HIH. All eight patients (gestational ages 26w0d-29w3d) had intrauterine growth restriction (IUGR) due to placental insufficiency, (4/8) were small for gestational age. All maintained normal glucose levels with glucose infusion during the first 48h six of eight patients had cholestasis despite being on parenteral nutrition for short time (average 17days). Four of eight patients were treated with diazoxide (average 22days). Four of eight patients who recovered spontaneously (average 49days after diagnosis) responded to continuous feeds and hydrocortisone for other clinical indications. In IUGR preterms, HIH is asymptomatic, may be prolonged, requiring diazoxide treatment. Transient cholestasis is seen in majority of patients. Euglycemia should be demonstrated on bolus gavage feeds, off glucocorticoids before discontinuing blood glucose monitoring.

Effect of transient obstructive cholestasis on liver histology: a cross-sectional study.

The role of transient obstructive cholestasis on liver histology remains undetermined. To investigate whether transient cholestasis impairs liver histology. Cross-sectional study at a public university hospital (UNICAMP), Brazil. 169 individuals undergoing cholecystectomy, with or without cholestasis. were enrolled. Histopathological findings were correlated with clinical and biochemical characteristics. Biliary hepatopathy was more frequent in individuals with resolved cholestasis than in those with active obstruction or no jaundice (P < 0.01), as also were fibrosis and ductular proliferation (P = 0.02). Cholestasis was commoner in individuals with resolved obstruction than in those with no history (P < 0.01) or active cholestasis (P < 0.05). Biliary hepatopathy was associated with longer duration of cholestasis (P < 0.001) and higher bilirubin levels (P = 0.02) in individuals with active obstruction; with lower body mass index (P = 0.02) and longer cholestasis (P < 0.001) in individuals with resolved obstruction; and with longer cholestasis (P < 0.001) and longer interval between endoscopic retrograde cholangiopancreatography and surgery (P = 0.03) overall. In individuals with active obstruction, duration of cholestasis (R = 0.7; P < 0.001) and bilirubin levels (R = 0.6; P = 0.004) were independently correlated with cholestasis severity. Duration of cholestasis (R = 0.7; P < 0.001) was independently correlated with ductular proliferation severity. Transient cholestasis was associated with significant histopathological changes, even after its resolution. Longer duration of obstruction correlated with greater severity of histopathological changes, especially cholestasis and ductular proliferation. This emphasizes the need for early treatment of obstructive cholestasis.

A Case Series of Four Preterm Intrauterine Growth Restricted Babies With Transient Hyper-Insulinemic Hypoglycemia and Cholestasis

Background: Premature infants with intrauterine growth restriction (IUGR) are predisposed to stress related hyper Insulinemic hypoglycemia (HIH). These babies are at risk for other prematurity related complications including direct hyperbilirubinemia. However, association of HIH with this has not been described, and transient cholestasis in HIH infants has not been reported. We present 4 such infants with perinatal stress related HIH who had cholestasis that resolved with time. Case series: In our retrospective review of these preemies with IUGR who had developed HIH, we found that 4 infants developed direct hyperbilirubinemia. Their gestational ages at birth ranged between 26 to 27 weeks, with birth weights between 527 to 642 grams. These infants had received total parenteral nutrition (TPN) for durations ranging between 12 to 19 days of life (DOL). HIH was established in them at variable ages between 55 to 75 DOL, based on an exaggerated glycemic response to glucagon. Of these, 1 baby was not started on Diazoxide due to underlying fluid overload. His HIH resolved by DOL 182. Two babies responded to therapy and while one remained on this till its resolution at 9 months age, another had the Diazoxide discontinued due to acute respiratory worsening leading to readmission. HIH in the latter resolved by 109 DOL. Fasting The last baby developed fluid overload early in therapy leading to its discontinuation without establishing response. Hypoglycemia in these infants resolved by ages between 4 to 9 months of life. Interestingly direct hyperbilirubinemia was noted by age 16 to 59 DOL. In all infants, the diagnosis of HIH was established after the onset of cholestasis. Extensive work up for hyperbilirubinemia ruled out any organic pathology. This transient cholestasis was noted to have resolved by ages 80 to 115 DOL. Conclusion: It appears from our experience in these premature infants, cholestasis may be associated with HIH. Its diagnosis preceded the establishment of HIH. We noted that HIH diagnosis was delayed by around 30 days after the onset of intermittent hypoglycemia. Both the cholestasis and HIH were transient. Whether the cholestasis may prognosticate the development of HIH or is indicative of transient HIH needs to be investigated. Any association between the two needs to be studied to address a common causality. IUGR babies with conjugated hyperbilirubinemia develop a mild and transient HI state which is self-resolving. Due to transient nature of this HIH in these IUGR babies with cholestasis, a genetic work up for HIH may be deferred.

ATP8B1, ABCB11, and ABCB4 Genes Defects: Novel Mutations Associated with Cholestasis with Different Phenotypes and Outcomes

To characterize the clinical, laboratory, histologic, molecular features, and outcome of gene-confirmed progressive familial intrahepatic cholestasis (PFIC) 1-3 among Arabs and to evaluate for "genotype-phenotype" correlations. We retrospectively reviewed charts of 65 children (ATP8B1 defect=5, ABCB11=35, ABCB4=25) who presented between 2008 and 2019 with cholestasis. The clinical phenotype of a disease was categorized based on response of cholestasis and itching to ursodeoxycholic acid and ultimate outcome, into mild (complete response), intermediate (partial response, nonprogressive), and severe (progression to end-stage liver disease). Overall, 27 different mutations were identified (ATP8B1, n=5; ABCB11, n=11; ABCB4, n=11), comprising 10 novel ones. Six patients with heterozygous missense mutations (ATP8B1, n=2; ABCB11, n=4) had transient cholestasis. Of the remaining 3 patients with PFIC1, 2 developed severe phenotype (splicing and frameshift mutations). Of the remaining 31 patients with PFIC2, 25 developed severe disease (15 due to frameshift and splicing mutations). Of 25 patients with PFIC3, 10 developed a severe phenotype (1 splicing and 3 frameshift mutations; 6 missense). Patients with PFIC2 had significantly shorter survival time and more rapid disease progression than patients with PFIC3 (P<.001). Patients with frameshift mutations in ABCB11 gene (p.Thr127Hisfs∗6) and ABCB4 gene (p.Phe210Serfs∗5) had significantly shorter survival time than missense mutations (P=.011; P=.0039, respectively). We identified genotype-phenotype correlations among mutations in ABCB11 and ABCB4 genes, which underscore the prognostic value of early genetic diagnosis. The disease course in patients with PFIC3 could be favorably modified by ursodeoxycholic acid therapy.

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.

Neonatal Cholestasis Over Time: Changes in Epidemiology and Outcome in a Cohort of 154 Patients From a Portuguese Tertiary Center

Introduction: In the last two decades there have been advances in the diagnosis and management of neonatal cholestasis, which may have changed its epidemiology, diagnostic accuracy, outcomes, and survival. Our goal was to characterize these changes over time in our setting.Methods: Retrospective cohort study in a tertiary center, enrolling patients born between January 1985 and October 2019. The cohort was divided into two periods, before (A; n = 67) and after (B; n = 87) the year 2000; and in two groups, according to patient's outcome (favorable, unfavorable). Overall survival and survival with and without orthotopic liver transplant (OLT) were evaluated in the two periods (A and B) and in different subgroups of underlying entities.Results: We found that the age of cholestasis recognition decreased significantly from period A to period B [median 43 days and 22 days, respectively, (p < 0.001)]; the changes in epidemiology were relevant, with a significant decrease in alpha-1-antitrypsin deficiency (p < 0.001) and an increase in transient cholestasis (p = 0.004). A next-generation sequencing (NGS) panel available since mid-2017 was applied to 13 patients with contributory results in 7, but, so far, only in 2 patients led to conclusive diagnosis of underlying entities. The number of cases of idiopathic cholestasis did not vary significantly. Over time there was no significant change in the outcome (p = 0.116). Overall survival and survival without OLT had no significant improvement during the period of observation (in periods A and B, 86 vs. 88%, and 85 vs. 87%, respectively). However, in period B, with OLT we achieved the goal of 100% of survival rate.Conclusions: Our data suggest that transient cholestasis became a very important subset of neonatal cholestasis, requiring specific guidance. The NGS panels can provide important inputs on disease diagnosis but, if applied without strict criteria and expertise, they can open a Pandora's box due to misinterpretation. Despite all the advances in accurate diagnosis and timely management—including early recognition of cholestasis—the improvement in patient outcomes and survival were still not significant.

Drug-induced Bile Duct Injury - A Short Review.

The liver represents the major site of drug metabolism, i.e. the key organ in the processes of detoxification and elimination of drugs from the organism. It is therefore often affected by toxic metabolites and suffers sometimes fatal consequences. The spectrum of pathologies differs by the cell type primarily damaged and the group of the cholangiopathies includes those conditions affecting the bile duct epithelium or the cholangiocytes. They can range from transient cholestasis to vanishing bile duct syndrome and sclerosing cholangitis, both leading eventually to the development of biliary fibrosis and cirrhosis. In this review article, we focus on the etiology, predisposing factors, clinical manifestations, and histopathological characteristics of bile duct injury as a consequence of drug treatment and discuss separately the different bile duct pathologies.

HNF4A-related Fanconi syndrome in a Chinese patient: a case report and review of the literature

BackgroundThe p.R63W mutation in hepatocyte nuclear factor-4 alpha (HNF4A) leads to a heterogeneous group of disorders with various clinical presentations. Recently, patients with congenital hyperinsulinism and Fanconi syndrome due to the p.R63W mutation in HNF4A have been described. Although other clinical variations such as liver dysfunction have been associated with HNF4A mutations, hearing impairment has not previously been associated. We report the case of a patient with Fanconi syndrome and hyperinsulinemic hypoglycemia caused by the mutation of HNF4A presenting with additional auditory phenotypes.Case presentationWe present a case report of a 10-year-old girl of Chinese Han ethnicity who presented with renal Fanconi syndrome, infantile hyperinsulinemic hypoglycemia, and transient cholestasis. In addition, she presented with bilateral severe hearing loss. Gene analysis showed a heterozygous p.R63W mutation in the HNF4A gene that is responsible for Fanconi syndrome and hyperinsulinemic hypoglycemia.ConclusionsThis is the first case of HNF4A mutation associated with an auditory phenotype. It expands the clinical phenotypes and supports speculation in the literature that HNF4A may be a candidate gene for deafness. In conclusion, hearing loss may be found in children with HNF4A-related Fanconi syndrome, and auditory function should be assessed.

Clinical and biochemical characteristics of infants with prolonged neonatal jaundice.

Protocols for investigating neonatal prolonged jaundice vary and the yield from screening has not been assessed. International guidelines recommend establishing cholestasis before proceeding to investigate the underlying pathology. However, in most hospitals administered by the Hospital Authority, full liver function is checked at the first neonatal jaundice clinic visit. To study the diagnostic yield of this approach, we carried out a retrospective study of all infants referred for prolonged jaundice. Attendance records from the neonatal jaundice clinic at the Tuen Mun Hospital, Hong Kong, the clinical management system, and electronic patient records were used to retrieve epidemiological, clinical, and laboratory data, and patients' clinical progress. During the 8-month study period from 8 July 2015 to 8 March 2016, 1164 infants were referred to the neonatal jaundice clinic for prolonged jaundice. Among them, 16 (1.4%) infants had conjugated hyperbilirubinaemia. Diagnoses included biliary atresia (n=1), cytomegalovirus (CMV) infection (n=3), neonatal hepatitis syndrome (n=2), and transient cholestasis (n=10). In total, 98 (8.42%) infants had elevated alanine transaminase levels. Diagnoses included biliary atresia (n=1), hepatic congestion related to congestive heart failure (n=1), CMV infection (n=5), neonatal hepatitis syndrome (n=16), and non-specific elevated alanine transaminase (n=75). In total, 59 infants had elevated alkaline phosphatase levels. A stepwise approach is recommended, in which full liver function is checked and the underlying cause of jaundice is investigated only after confirming cholestasis.

Late vitamin K deficiency bleeding despite intramuscular prophylaxis at birth - is there a need for additional supplementation?

Introduction/Objective. Vitamin K deficiency is common in newborn infants and without prophylaxis there is a risk of vitamin K deficiency bleeding (VKDB). The most frequent prophylactic approach is an intramuscular (IM) injection of vitamin K1 immediately after birth. Its efficiency to prevent late VKDB has been recently questioned by several reports. Based on our experience, we discuss the need for additional vitamin K1 supplementation after its IM administration at birth. Methods. We present a retrospective review of 12 infants, 11 with confirmed and one with probable late VKDB despite IM prophylaxis at birth, who were treated in the two largest tertiary care pediatric hospitals in Serbia during the last 15 years. Results. All the patients were exclusively breastfed. In 11 patients, daily weight gain was normal or increased, and one patient had failure to gain weight. Six infants were previously healthy, three infants received antibiotics prior to bleeding, and in two diarrhea and cholestasis, respectively, existed previously. An intracranial bleeding was documented in nine infants, four of whom died. Conclusion. Low content of phytomenadione in human milk could occasionally be attributed to late VKDB despite postnatal IM injection of vitamin K1 in otherwise healthy, exclusively breastfed infants. This might be aggravated by transient disturbance of vitamin K turnover due to antibiotic use, acute diarrhea, or transient cholestasis. We suggest that an additional vitamin K1 supplementation after postnatal IM prophylaxis could be justified in exclusively breastfed infants.

Hsp90 and hepatobiliary transformation during sea lamprey metamorphosis.

BackgroundBiliary atresia (BA) is a human infant disease with inflammatory fibrous obstructions in the bile ducts and is the most common cause for pediatric liver transplantation. In contrast, the sea lamprey undergoes developmental BA with transient cholestasis and fibrosis during metamorphosis, but emerges as a fecund adult. Therefore, sea lamprey liver metamorphosis may serve as an etiological model for human BA and provide pivotal information for hepatobiliary transformation and possible therapeutics.ResultsWe hypothesized that liver metamorphosis in sea lamprey is due to transcriptional reprogramming that dictates cellular remodeling during metamorphosis. We determined global gene expressions in liver at several metamorphic landmark stages by integrating mRNA-Seq and gene ontology analyses, and validated the results with real-time quantitative PCR, histological and immunohistochemical staining. These analyses revealed that gene expressions of protein folding chaperones, membrane transporters and extracellular matrices were altered and shifted during liver metamorphosis. HSP90, important in protein folding and invertebrate metamorphosis, was identified as a candidate key factor during liver metamorphosis in sea lamprey. Blocking HSP90 with geldanamycin facilitated liver metamorphosis and decreased the gene expressions of the rate limiting enzyme for cholesterol biosynthesis, HMGCoA reductase (hmgcr), and bile acid biosynthesis, cyp7a1. Injection of hsp90 siRNA for 4 days altered gene expressions of met, hmgcr, cyp27a1, and slc10a1. Bile acid concentrations were increased while bile duct and gall bladder degeneration was facilitated and synchronized after hsp90 siRNA injection.ConclusionsHSP90 appears to play crucial roles in hepatobiliary transformation during sea lamprey metamorphosis. Sea lamprey is a useful animal model to study postembryonic development and mechanisms for hsp90-induced hepatobiliary transformation.Electronic supplementary materialThe online version of this article (doi:10.1186/s12861-015-0097-2) contains supplementary material, which is available to authorized users.

AB089. Postnatal and prenatal diagnosis for neonatal intrahepatic cholestasis caused by citrin deficiency

Background and objective Neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) which resulted from mutation in SLC25A13 gene can present transient intrahepatic cholestasis, low birth weight, growth retardation, hypoproteinemia, prolong jaundice, chronic liver disease and so on. This study aimed to identify mutations of SLC25A13 for 649 NICCD and 46 siblings, from September 2009 to December 2014 and prenatal diagnosis for pregnancies with high risk of NICCD.

Sustained Isoprostane E2 Elevation, Inflammation and Fibrosis after Acute Ischaemia-Reperfusion Injury Are Reduced by Pregnane X Receptor Activation.

Liver grafts donated after cardiac death are increasingly used to expand the donor pool but are prone to ischaemic-type biliary lesions. The anti-inflammatory effects of the activated pregnane X receptor have previously been shown to be beneficial in a number of inflammatory liver conditions. However, its role in reducing peri-portal inflammation and fibrosis following ischaemia-reperfusion injury has not been investigated. Hepatic injury and its response to pregnane X receptor activation was examined after partial hepatic ischaemia-reperfusion injury induced by surgically clamping the left and middle lobar blood vessels in rats. Molecular and pathological changes in the liver were examined over the following 28 days. Ischaemia-reperfusion injury resulted in transient cholestasis associated with microvillar changes in biliary epithelial cell membranes and hepatocellular injury which resolved within days after reperfusion. However, in contrast to chemically-induced acute liver injuries, this was followed by sustained elevation in isoprostane E2, peri-portal inflammation and fibrosis that remained unresolved in the ischaemic reperfused lobe for at least 28 days after clamping. Administration of pregnenolone-16α-carbonitrile—a rodent-specific pregnane X receptor activator—resulted in significant reductions in cholestasis, hepatic injury, ischaemic lobe isoprostane E2 levels, peri-portal inflammation and fibrosis. Hepatic ischaemia-reperfusion injury therefore results in inflammatory and fibrotic changes that persist well beyond the initial ischaemic insult. Drug-mediated activation of the pregnane X receptor reduced these adverse changes in rats, suggesting that the pregnane X receptor is a viable drug target to reduce ischaemic-type biliary lesions in recipients of liver transplants donated after cardiac death.

Peripheral Th17 cell frequencies predict postoperative complications in patients with hepatitis B virus-related liver cirrhosis following liver transplantation

To investigate the relationship between level of Th17/CD4+T cell ratio in peripheral blood and postoperative complications in patients with hepatitis B virus (HBV)-related cirrhosis after orthotopic liver transplantation (OLT). Fifty-one patients with HBV-related cirrhosis who received OLT were enrolled in this study. Flow cytometry analysis was performed to measure the proportion of Th17 cells to CD4+T cells at the following time points:pre-OLT, and post-OLT days 7, 14 and 21. The relevant hepatic biochemistry indexes, serum concentration of FK506 and level of procalcitonin (PCT) were detected for all patients after OLT. The transplant recipients were divided into four groups according to the postoperative complication, which included acute rejection (AR, n=12), postoperative infection (POI, n=10), transient intrahepatic cholestasis (TIHC, n=12) and no complications (n=17). The Th17/CD4+T cell frequencies were notably higher in the AR patients after OLT (vs. before OLT, P less than 0.01) and this increase was positively correlated with rejection activity index (RAI; r=0.759, P=0.004). Up to post-OLT day 14, the frequencies of Th1 7/CD4+T cells in the POI group were similar to those of the AR group but they decreased to near-baseline level at post-OLT day 21.Furthermore, the percentage of Th17/CD4+T cells in the POI group was positively correlated with PCT (r=0.768, P=0.010). The frequencies of Th17/CD4+T cells in the TIHC and no complications groups showed a slowly decreasing trend after OLT and became markedly lower than the before OLT levels (P<0.01). The concentration of FK506 in the AR group was significantly lower than that in the other groups at post-OLT day 14 (P=0.000). Th17/CD4+T cell level in peripheral blood might be a useful marker for risk assessment and monitoring of OLT postoperative complications, such as acute rejection and postoperative infection, in the early stage, and might help to improve patient prognosis by allowing for timely application of anti-rejection and antibacterial agents.

The Sea Lamprey as an Etiological Model for Biliary Atresia.

Biliary atresia (BA) is a progressive, inflammatory, and fibrosclerosing cholangiopathy in infants that results in obstruction of both extrahepatic and intrahepatic bile ducts. It is the most common cause for pediatric liver transplantation. In contrast, the sea lamprey undergoes developmental BA with transient cholestasis and fibrosis during metamorphosis, but emerges as a fecund adult with steatohepatitis and fibrosis in the liver. In this paper, we present new histological evidence and compare the sea lamprey to existing animal models to highlight the advantages and possible limitations of using the sea lamprey to study the etiology and compensatory mechanisms of BA and other liver diseases. Understanding the signaling factors and genetic networks underlying lamprey BA can provide insights into BA etiology and possible targets to prevent biliary degeneration and to clear fibrosis. In addition, information from lamprey BA can be used to develop adjunct treatments for patients awaiting or receiving surgical treatments. Furthermore, the cholestatic adult lamprey has unique adaptive mechanisms that can be used to explore potential treatments for cholestasis and nonalcoholic steatohepatitis (NASH).

Cholestasis in preterm infants: when is a yellow alert?

Besides the transient bilirubin transport immaturity, preterm infants are particularly at risk for different forms and degrees of bile formation impairment because of metabolic demands that are not matched by functional maturation in the first weeks of life. Cholestasis, affecting approximately 1 of 2 500 infants, is more commonly reported in preterm infants with an incidence varying between 10 and 20%, and it is mainly due to a combination of factors including delayed enteral nutrition, low birth weight, prolonged parenteral nutrition, hypoxia, infection, liver ischemia, immaturity of bile acid metabolism, surgical procedures and multiple drug treatments [1]. This reality of the setting is defined as transient or multifactorial cholestasis [2], which is the most frequent form of cholestasis in neonatal intensive care unit, usually transient and followed by a gradual full recovery [3]. Cholestasis in preterm infants may however also be indicative of a severe liver disease such as biliary atresia (BA) or other biliary tract disorders. The development of a persistent cholestatic jaundice, even in presence of colored stools, incentives to conduct a thorough investigation [4]. Abdominal ultrasonography may support the diagnosis of BA showing: absence of gallbladder, the “triangular cord” sign or a cyst located at porta hepatis. Transient multifactorial cholestasis is a diagnosis of exclusion and a definitive diagnosis can be made only after the complete resolution of the clinical picture. Moreover, diagnosis of biliary atresia in preterm jaundiced neonates is difficult since discoloration of stools can occur several weeks after birth [4]. Besides specific cholestatic disorders for which specific medical and surgical treatment are available, there is no unequivocal evidence that any medical treatment alters the natural history of multifactorial cholestasis. Treatment with ursodeoxycholic acid may indeed be useful, although there is no evidence of effectiveness. Every effort must be made to remove all risk factors for liver injury. Consequences of cholestasis also need to be managed by administering fat -soluble vitamins, especially vitamin K and nutritional formulas containing medium-chain fatty acids. Although multifactorial transient cholestasis is the most common cause of prolonged jaundice in preterm infants, neonatologists need to be aware that premature infants can also present with signs of severe liver disease. To avoid any diagnostic delay it is mandatory to promptly identify all the conditions suitable for an early and specific treatment with a structured approach to the investigation of cholestasis tailored to the preterm infant [5].