Severe Cholestasis Research Articles

Protective Functions of ZO-2/Tjp2 Expressed in Hepatocytes and Cholangiocytes Against Liver Injury and Cholestasis

Liver tight junctions (TJs) establish tissue barriers that isolate bile from the blood circulation. TJP2/ZO-2-inactivating mutations cause progressive cholestatic liver disease in humans. Because the underlying mechanisms remain elusive, we characterized mice with liver-specific inactivation of Tjp2. Tjp2 was deleted in hepatocytes, cholangiocytes, or both. Effects on the liver were assessed by biochemical analyses of plasma, liver, and bile and by electron microscopy, histology, and immunostaining. TJ barrier permeability was evaluated using fluorescein isothiocyanate-dextran (4 kDa). Cholic acid (CA) diet was used to assess susceptibility to liver injury. Liver-specific deletion of Tjp2 resulted in lower Cldn1 protein levels, minor changes to the TJ, dilated canaliculi, lower microvilli density, and aberrant radixin and bile salt export pump (BSEP) distribution, without an overt increase in TJ permeability. Hepatic Tjp2-defcient mice presented with mild progressive cholestasis with lower expression levels of bile acid transporter Abcb11/Bsep and detoxification enzyme Cyp2b10. A CA diet tolerated by control mice caused severe cholestasis and liver necrosis in Tjp2-deficient animals. 1,4-Bis[2-(3,5-dichloropyridyloxy)]benzene ameliorated CA-induced injury by enhancing Cyp2b10 expression, and ursodeoxycholic acid provided partial improvement. Inactivating Tjp2 separately in hepatocytes or cholangiocytes showed only mild CA-induced liver injury. Tjp2 is required for normal cortical distribution of radixin, canalicular volume regulation, and microvilli density. Its inactivation deregulated expression of Cldn1 and key bile acid transporters and detoxification enzymes. The mice provide a novel animal model for cholestatic liver disease caused by TJP2-inactivating mutations in humans.

A multi-centre, open label, randomised, parallel-group, superiority Trial to compare the efficacy of URsodeoxycholic acid with RIFampicin in the management of women with severe early onset Intrahepatic Cholestasis of pregnancy: the TURRIFIC randomised trial

BackgroundSevere early onset (less than 34 weeks gestation) intrahepatic cholestasis of pregnancy (ICP) affects 0.1% of pregnant women in Australia and is associated with a 3-fold increased risk of stillbirth, fetal hypoxia and compromise, spontaneous preterm birth, as well as increased frequencies of pre-eclampsia and gestational diabetes. ICP is often familial and overlaps with other cholestatic disorders.Treatment options for ICP are not well established, although there are limited data to support the use of ursodeoxycholic acid (UDCA) to relieve pruritus, the main symptom. Rifampicin, a widely used antibiotic including in pregnant women, is effective in reducing pruritus in non-pregnancy cholestasis and has been used as a supplement to UDCA in severe ICP. Many women with ICP are electively delivered preterm, although there are no randomised data to support this approach.MethodsWe have initiated an international multicentre randomised clinical trial to compare the clinical efficacy of rifampicin tablets (300 mg bd) with that of UDCA tablets (up to 2000 mg daily) in reducing pruritus in women with ICP, using visual pruritus scores as a measuring tool.DiscussionOur study will be the first to examine the outcomes of treatment specifically in the severe early onset form of ICP, comparing “standard” UDCA therapy with rifampicin, and so be able to provide for the first-time high-quality evidence for use of rifampicin in severe ICP. It will also allow an assessment of feasibility of a future trial to test whether elective early delivery in severe ICP is beneficial.Trial identifiersAustralian New Zealand Clinical Trials Registration Number (ANZCTR): 12618000332224p (29/08/2018). HREC No: HREC/18/WCHN/36.EudraCT number: 2018–004011-44.IRAS: 272398.NHMRC registration: APP1152418 and APP117853.

Endoscopic and percutaneous biliary interventions in patients with altered upper gastrointestinal anatomy-the Munich Multicenter Experience.

In patients with altered upper gastrointestinal anatomy, conventional endoscopic retrograde cholangiography is often not possible and different techniques, like enteroscopy-assisted or percutaneous approaches are required. Aim of this study was to analyze success and complication rates of these techniques in a large collective of patients in the daily clinical practice in a pre-endosonographic biliary drainage era. Patients with altered upper gastrointestinal anatomy with biliary interventions between March 1st, 2006, and June 30th, 2014 in four tertiary endoscopic centers in Munich, Germany were retrospectively analyzed. At least one endoscopic-assisted biliary intervention was successful in 234/411 patients (56.9%)-in 192 patients in the first, in 34 patients in the second and in 8 patients in the third attempt. Success rates for Billroth-II/Whipple-/Roux-en-Y reconstruction were 70.5%/56.7%/49.5%. Complication rates for these reconstructions were 9.3%/6.5%/6.3%, the overall complication rate was 7.1%. Success rates were highest in patients with Billroth-II reconstruction where use of a duodenoscope was possible, complication rates were also highest in this scenario. Success rates were lowest in longer-limb anatomy like Roux-en-Y reconstruction. Percutaneous biliary drainages (PTBD) were inserted 268 times with substantially higher success (90.7%) as well as complication rates (11.6%) compared to the endoscopic approach. Compared to patients treated endoscopically, patients with PTBD had a lower performance status, more severe cholestasis and a significant higher rate of malignant underlying disease. In patients with altered upper gastrointestinal anatomy, success rates of endoscopic-assisted biliary interventions are lower compared to PTBD. Still, due to the beneficial complication rates of the endoscopic approach, this technique should be preferred whenever possible and in selected patients who still need to be defined in detail, repeated endoscopic attempts are useful to help achieve the desired result.

Severe intrahepatic cholestasis as the initial manifestation of light chain amyloidosis

Severe intrahepatic cholestasis as the initial manifestation of light chain amyloidosis

Can blood eosinophil to basophil ratio, eosinophil to lymphocyte ratio and basophil to lymphocyte ratio predict the severity of intrahepatic cholestasis in pregnancy?

Purpose: The purpose of the study was to investigate the relation between inflammatory markers used for allergic diseases and intrahepatic pregnancy cholestasis (ICP). 
 Materials and Methods: In this retrospective case-control study, a total of 114 intrahepatic pregnancy cholestasis patients; 87 with mild cholestasis (group 1) and 27 with severe cholestasis (group 2) and 292 healthy pregnant women in the control group (group 3) were included in the study. The basophil, eosinophil, eosinophil-basophil ratio (EBR), eosinophil-lymphocyte ratio (ELR) and basophil-lymphocyte ratio (BLR), neutrophil-lymphocyte ratio (NLR), and platelet-lymphocyte ratio (PLR) values used in this study. 
 Results: Significant differences were detected between groups in terms of ELR, NLR and PLR values. ELR, NLR, PLR values were significantly higher in the mild cholestasis group than in the control group. To predict the pregnancy cholestasis, receiver operating characteristic curve (ROC) analysis was made, which yielded 76.3% sensitivity and 56.1% specificity when ELR’s interrupt value was 0.2243, NLR interrupt value 11.27% when sensitivity was 70% and specificity 54,000 2%, and PLR cut-off value was 194.46 when sensitivity was 60% and specificity was 58%. 
 Conclusion: Serum inflammation markers and allergy markers may be diagnostic in intrahepatic pregnancy cholestasis; however, they are not decisive in determining the severity of the disease.

S2604 Acute Severe Cholestatic Hepatitis B Infection in an Immune-Competent Patient

INTRODUCTION: Acute severe cholestatic hepatitis B is uncommon and usually reported in organ transplant recipients. We report a unique case of acute HBV infection with severe cholestasis in an immune-competent patient whose symptoms were initially felt to be secondary to complications from choledocholithiasis. CASE DESCRIPTION/METHODS: A 67-year-old female presented with right upper quadrant (RUQ) pain, vomiting, fatigue & jaundice for 2 weeks. She had a new sexual partner with unknown hepatitis status. The patient had no history of alcohol, drug use or new medications. RUQ tenderness & scleral icterus were noted on exam. Labs showed AST-629u/l (Normal[N]: 10–40 u/l), ALT-497u/l (N: 12–78 u/l), ALP-294u/l (N: 33–138 u/l), T. Bili-8.4mg/dl (N: 0.0–1.5 mg/dl), D. Bili-7.5mg/dl (N: 0.0 −1.5mg/dl), INR-1. On ultrasound of the abdomen cholelithiasis with gall bladder wall thickening with normal biliary ducts was noted. Endoscopic ultrasound revealed a 2.5 mm filling defect without shadowing in distal common bile duct (CBD) & Endoscopic retrograde pancreatic duodenoscopy showed a small filling defect in mid CBD and a distal CBD stricture about 1–2 cm in length. Biopsy of CBD stricture showed inflammation. A plastic biliary stent was deployed with good drainage. Her liver tests did not improve, and additional investigations performed were positive for Hepatitis B surface antigen (HbsAg), core antibody Total (Anti HBc Total) & core IgM, Hepatitis e antigen (HBeAg). She was negative for Hepatitis B e antibody (HBeAb) and Hepatitis B surface antibody (HBsAb). HBV PCR was 765,000,000 IU/ml. She was discharged with a follow up scheduled in liver clinic, but was readmitted 2 weeks later with worsening fatigue & liver tests. A liver biopsy showed active hepatitis without evidence of bridging fibrosis or cirrhosis & positive HBV staining. Anti-viral therapy with Tenofovir was initiated with improvement in symptoms. DISCUSSION: Although several case reports describe severe cholestasis with HBV post-liver transplantation, it has rarely been described in immunocompetent patients. Our patient's presentation was initially concerning for biliary obstruction. Despite biliary drainage patient's symptoms worsened, & further investigations revealed acute HBV infection with high replication which was confirmed by biopsy. Prompt therapy with antivirals improved the clinical course. Given these findings one should have high index of suspicion to evaluate for HBV infection in unusual presentation with cholestasis.Figure 1.: Immunohistochemical stain highlights Hepatitis B surface antigen within the cytoplasm of hepatocytes (200X magnification).Figure 2.: Hepatic parenchyma with dense mixed acute and chronic inflammation throughout the hepatic lobule and intermixed ceroid-laden macrophages removing dead hepatocytes (100x magnification).Figure 3.: Hepatic parenchyma with dense mixed acute and chronic inflammation throughout the hepatic lobule and intermixed ceroid-laden macrophages removing dead hepatocytes (200 X magnification).

S2614 Cholestatic Hepatitis From Acute Epstein-Barr Virus Infection

INTRODUCTION: Primary Epstein-Barr Virus infection (EBV) presents as a triad of fever, posterior lymphadenopathy and pharyngitis. Hepatocellular involvement is limited to transient, mild, asymptomatic elevations of aminotransferases. Clinical manifestations of hepatitis are rarely the presenting feature of the disease and severe cholestasis is exceedingly rare. We present a patient with atypical presenting features found to have cholestatic hepatitis due to acute EBV infection. CASE DESCRIPTION/METHODS: A 38-year-old male with no medical history presented with right upper quadrant (RUQ) abdominal pain for 1 week associated with malaise, dyspnea, nausea, emesis, and fever to 38.8 degrees Celsius. His social history consisted of safe sex practices, no sick contacts, and no drug or alcohol use. On examination, he was afebrile and hemodynamically stable. There was no jaundice, scleral icterus or lymphadenopathy. There was mild tonsillar erythema without edema or exudate. He had RUQ and epigastric tenderness to palpation without notable hepatosplenomegaly. His labs showed no leukocytosis with elevated aspartate aminotransferase (AST) 234 IU/L, alanine aminotransferase (ALT) 383 IU/L, alkaline phosphatase 432 IU/L, and total and direct bilirubin of 3.4 and 1.6 mg/dL, respectively. ALT and AST peaked at 743 and 582 IU/L, respectively. HIV and hepatitis panel were negative. RUQ ultrasound showed normal gallbladder (GB) wall thickness of 2.7 mm with mild distention, trace pericholecystic fluid, and no biliary dilation. Magnetic resonance cholangiopancreatography showed mild hepatosplenomegaly, a normal GB and no biliary obstruction. Further workup revealed a positive Monospot with >160 units/ml of EBV antibodies to viral capsid antigen IgM and indeterminate EBV antibody to viral capsid antigen IgG, indicating acute EBV infection. DISCUSSION: EBV cholestasis is thought to be secondary to inflammation of the bile duct and direct damage to hepatic cells by autoantibody-mediated activation of free radicals. A literature review revealed that EBV has been reported to cause a hepatocellular pattern of elevated aminotransferases however cholestatic patterns are infrequently reported and thus may cause a diagnostic dilemma. The existing literature reports this phenomenon in pediatrics, adolescents, or patients in the second decade of life. Our case highlights the importance of including EBV infection in the differential diagnosis of cholestatic hepatitis at any age, particularly when no demonstrable cholecystitis is present.Table 1.: Liver and biliary marker trend throughout hospitalizationFigure 1.: Abdominal MRI demonstrating hepatomegaly and splenomegaly, measuring 15.1 cm anterior-posteriorly, and 13.9 cm craniocaudally.Figure 2.: Abdominal MRI demonstrating hepatosplenomegaly.

Prevalence of raised Alanine Amino transaminase (ALT) in pregnant mothers: A Cross-sectional Study

bjective: To determine the prevalence of raised ALT, common causes, and associated fetomaternal morbidity in pregnant mothers presenting, at cantonment general hospital Rawalpindi
 Materials and Methods: This was a cross-sectional study conducted at cantonment general hospital Rawalpindi from July 2016 till June 2017.
 Results: Out of 1924 women, 102 were identified with raised ALT making a prevalence of 5.3%. Sixty-one (59.8%) were booked. The hypertensive group which included severe preeclampsia, chronic hypertension with superimposed preeclampsia/eclampsia were 55(53.9%), intrahepatic cholestasis of pregnancy(ICP) 32(31.7%), acute viral hepatitis 9(8.8%), Acute fatty liver of pregnancy(AFLP) 2(1.96%), and unknown cause in 4(3.92%).
 Mean ALT levels were 54.1±6.94, 71.28±23.25, 84.22±27.82, 231.5±47.37 respectively. In four cases no definitive cause could be identified with the available tests were labeled as an unknown group, having a mean ALT level of 79.25±10.07. (p=0.01).
 Term delivery occurred in 71(69.6%), while 31(30.39%) were preterm. There was one termination of pregnancy. Vaginal birth occurred in 42(42.2%), and 53(51.9%) underwent emergency cesarean. There was one peripartum hysterectomy. Meconium stain of liquor was 19(18.6%). The birth weight of most babies 73(71.5%) was between 2-3 kilograms only three were ≤ 1 kilograms.
 Eight cases of postpartum hemorrhage, three maternal deaths, and six perinatal/early neonatal deaths were observed.
 Conclusion: Raised ALT in pregnancy leads to increased fetomaternal complications. Severe preeclampsia and obstetric cholestasis were the commonest causes. Women of younger age groups were having acute viral hepatitis. Timely recognition and diagnosis are essential to institute appropriate management strategies.

Pituitary stalk interruption syndrome broadens the clinical spectrum of the TTC26 ciliopathy.

Ciliopathies are a heterogeneous group of disorders, related to abnormal ciliary function. Severe biliary ciliopathy, caused by bi-allelic mutations in TTC26, has been recently described in the context of a syndrome of polydactyly and severe neonatal cholestasis, with brain, kidney and heart involvement. Pituitary involvement has not been previously reported for patients with this condition. Pituitary stalk interruption syndrome (PSIS) is a congenital anomaly of the pituitary gland, diagnosed by characteristic MRI findings. We now describe four patients with TTC26 ciliopathy due to a homozygous c.695A>G p.Asn232Ser mutation and delineate PSIS as a novel clinical feature of this disorder, highlighting an important role of TTC26 in pituitary development.

Cholangitis lenta: An underdiagnosed lesion associated with severe cholestasis following liver transplantation.

Cholangitis lenta (CL) represents a specific histological lesion associated with severe cholestasis and related to sepsis. Despite being well known by pathologists, CL has been poorly studied in liver transplantation (LT). We performed a retrospective 12-year analysis of the incidence, risk factors, and outcome of CL in LT recipients. Biopsy samples performed within 3months after LT underwent blinded rereading to identify recipients with CL. Among 587 LT performed, 45 (7.7%) developed CL. Of these, 7 (15.6%) had no signs of clinical sepsis at the time of biopsy, but further investigations revealed positive cultures. Independent factors associated with CL were sepsis at the time of LT (OR=3.62 [95%CI=1.63-8.06]), donor age (OR=1.05 [1.03-1.08]), and operative time (OR=1.23 [95%CI=1.02-1.48]). Cholangitis lenta was associated with increased severe morbidity (71.1% vs 33.0%, P<.001), 90-day mortality (24.4% vs 5.9%, P<.001) and decreased one-year graft (62.1% vs 89.4%, P<.001) and patient survival (55.6% vs 87.9%, P<.001). Cholangitis lenta represents a possible lesion associated with cholestasis after LT, which strongly affects its outcome. In the event of an unexplained post-transplant cholestasis, the diagnosis of CL must be considered, even in the absence of clinically evident sepsis.

Histopathological findings for prediction of liver cirrhosis and survival in biliary atresia patients after Kasai procedure

BackgroundWithout early recognition and Kasai procedure, biliary atresia (BA) results in liver cirrhosis and leads to either transplantation or death at a young age. We aimed to characterize the liver histopathological findings for prediction of cirrhosis and survival in BA patients after Kasai surgery.MethodsWe retrospectively reviewed all histopathological results for BA patients who underwent liver biopsy during Kasai surgery from August 2012 to December 2018 in Dr. Sardjito Hospital, Yogyakarta, Indonesia.ResultsFifty infants with BA were ascertained in our study, of whom 27 were males and 23 were females. The median age of Kasai procedure was 102.5 days (interquartile range (IQR), 75.75–142.25 days). There were 33 (66%) and 17 (34%) BA patients with and without liver cirrhosis, respectively, while the overall survival was 52%. The patients with a severe bile duct proliferation, severe cholestasis, and severe portal inflammation have a higher risk by 27-, 22-, and 19.3-fold, respectively, to develop liver cirrhosis compared with patients with a moderate/mild bile duct proliferation, moderate/mild/without cholestasis, and moderate/mild portal inflammation, respectively (p = 3.6 × 10− 6, 5.6 × 10− 4, and 1.6 × 10− 3, respectively), while the giant cell transformation was not associate with the development of liver cirrhosis (p = 0.77). The bile duct proliferation was strongly correlated with cholestasis and portal inflammation (p = 7.3 × 10− 5 and 2 × 10− 4, respectively), and cholestasis was also significantly correlated with portal inflammation (p = 0.016). Interestingly, the age at Kasai procedure was strongly associated with the development of liver cirrhosis (p = 0.02), but not with the patients’ survival (p = 0.33), while the degree of fibrosis and cholestasis were significantly correlated with the patients’ survival, with HR of 3.9 (95% CI = 1.7–9.0; p = 0.017) and 3.1 (95% CI = 1.4–7.0; p = 0.016), respectively.ConclusionsHistopathological findings of bile duct proliferation, cholestasis, and portal inflammation can predict the liver cirrhosis development in patients with BA. Furthermore, degree of fibrosis and cholestasis affect the patients’ survival following the Kasai operation.

Cholestasis after very preterm birth was associated with adverse neonatal outcomes but no significant long-term liver disease: A population-based study.

To describe outcome linked to neonatal cholestasis in a defined cohort of very preterm infants. Population-based retrospective case-control study of preterm infants, gestational age <30weeks, surviving for 28days, in Stockholm County. Cholestasis was defined as conjugated bilirubin ≥30μmol/L exceeding 20% of total level at least twice and graded as high if exceeding 100μmol/L. Cholestatic cases were matched on gestational week with two non-cholestatic controls. The incidence rate of cholestasis was 37/250 (14.8%), with increasing rates in lower gestational weeks. Perinatal factors associated with cholestasis were pre-eclampsia and being born small for gestational age. Cholestatic infants had three times more bronchopulmonary dysplasia and eight times more retinopathy of prematurity. The mortality was 13.5% in cholestatic infants versus 2.7% in controls (P=.040). All deceased cholestatic infants had high-grade cholestasis. No surviving infants developed chronic liver disease by 10years of age. Cholestasis was common in very preterm infants and linked to disease severity and adverse outcome. Cholestasis may be an independent risk factor for bronchopulmonary dysplasia and retinopathy of prematurity and more severe cholestasis associated with increased mortality. Cholestasis was not associated with chronic liver disease later in childhood.

Outcome of patients treated with molecular adsorbent recirculating system albumin dialysis: A national multicenter study.

Background and AimThe molecular adsorbent recirculating system (MARS) is the most widely used device to treat liver failure. Nevertheless, data from widespread real‐life use are lacking.MethodsThis was a retrospective multicenter study conducted in all French adult care centers that used MARS between 2004 and 2009. The primary objective was to evaluate patient survival according to the liver disease and listing status. Factors associated with mortality were the secondary objectives.ResultsA total of 383 patients underwent 393 MARS treatments. The main indications were acute liver failure (ALF, 32.6%), and severe cholestasis (total bilirubin >340 μmol/L) (37.2%), hepatic encephalopathy (23.7%), and/or acute kidney injury–hepatorenal syndrome (22.9%) most often among patients with chronic liver disease. At the time of treatment, 34.4% of the patients were listed. Overall, the hospital survival rate was 49% (95% CI: 44–54%) and ranged from 25% to 81% depending on the diagnosis of the liver disease. In listed patients versus those not listed, the 1‐year survival rate was markedly better in the setting of nonbiliary cirrhosis (59% vs 15%), early graft nonfunction (80% vs 0%), and late graft dysfunction (72% vs 0%) (all P < 0.001). Among nonbiliary cirrhotic patients, hospital mortality was associated with the severity of liver disease (HE and severe cholestasis) and not being listed for transplant. In ALF, paracetamol etiology and ≥3 MARS sessions were associated with better transplant‐free survival.ConclusionOur study suggests that MARS should be mainly used as a bridge to liver transplantation. Survival was correlated with being listed for most etiologies and with the intensity of treatment in ALF.

The Case | Acute kidney injury after liver and kidney transplantation

A 51-year-old woman with a history of meningioma and diabetes underwent liver and kidney transplantation. She was diagnosed with liver cirrhosis due to nonalcoholic steatohepatitis. The primary kidney disease was not biopsy proven but was clinically considered to likely represent diabetic kidney disease. Two days after transplantation, she developed acute kidney injury, requiring dialysis, with liver failure. A liver biopsy showed steatosis, severe cholestasis with the ductular reaction, and bile plugging.

Preventive Effect of Bifidobacterium Supplementation on Neonatal Cholestasis in Preterm Neonates with Very Low Birth Weight.

Background Cholestasis is a common but serious clinical condition in preterm neonates. The current management for preterm neonatal cholestasis has limitations. The aim of this study was to determine effects of Bifidobacterium supplementation on the prevention and alleviation of cholestasis in preterm infants with very low birth weight. Methods Preterm neonates with very low birth weight were enrolled in the Children's Hospital of Soochow University between December 2012 and December 2017. The patients were randomly assigned into Bifidobacterium and control groups, and effects of Bifidobacterium supplementation on the outcomes were compared between the two groups. Results There was no significant difference in the baseline characteristics in the two groups. Notably, the proportion of cases with neonatal cholestasis was significantly lower, with fewer neonatal cholestasis-associated complications in the Bifidobacterium group compared with the control group (6% versus 22%, P < 0.01). Furthermore, the Bifidobacterium group exhibited less severe cholestasis and better improvement of the liver function than the control group as evidenced by the biochemical tests (P < 0.01). Furthermore, the Bifidobacterium group exhibited less severe cholestasis and better improvement of the liver function than the control group as evidenced by the biochemical tests (P < 0.01). Furthermore, the Bifidobacterium group exhibited less severe cholestasis and better improvement of the liver function than the control group as evidenced by the biochemical tests (days, P < 0.01). Furthermore, the Bifidobacterium group exhibited less severe cholestasis and better improvement of the liver function than the control group as evidenced by the biochemical tests (P < 0.01). Furthermore, the Bifidobacterium group exhibited less severe cholestasis and better improvement of the liver function than the control group as evidenced by the biochemical tests (P < 0.01). Furthermore, the Bifidobacterium group exhibited less severe cholestasis and better improvement of the liver function than the control group as evidenced by the biochemical tests (P < 0.01). Furthermore, the Bifidobacterium group exhibited less severe cholestasis and better improvement of the liver function than the control group as evidenced by the biochemical tests (P < 0.01). Furthermore, the Bifidobacterium group exhibited less severe cholestasis and better improvement of the liver function than the control group as evidenced by the biochemical tests (Conclusions Bifidobacterium supplementation has significantly preventive and other beneficial effects on the management of cholestasis in preterm infants with very low birth weight. Its long-term safety and effectiveness will need further investigation. This trial is registered with the Chinese Clinical Trial Registry (Registration No. ChiCTR1900022296).

Li-Dan-He-Ji Improves Infantile Cholestasis Hepatopathy Through Inhibiting Calcium-Sensing Receptor-Mediated Hepatocyte Apoptosis.

Infantile cholestatic hepatopathy (ICH) is a clinical syndrome characterized by the accumulation of cytotoxic bile acids in infancy, leading to serious liver cirrhosis or liver failure. The aetiology of ICH is complicated and some of them is unknown. Regardless of the aetiology, the finial pathology of ICH is hepatocyte apoptosis caused by severe and persistent cholestasis. It is already known that activation of calcium-sensing receptor (CaSR) could lead to the apoptosis of cardiomyocytes. However, the mechanism by CaSR-mediated cholestasis-related hepatocyte apoptosis is not fully understood. Li-Dan-He-Ji (LDHJ), a Traditional Chinese Medicine prescription, was developed to treat ICH. Another aim of this study was to investigate the possible mechanisms of LDHJ in cholestasis-related hepatocyte apoptosis. Using the primary hepatocytes, we first investigated the molecular mechanism of CaSR-mediated hepatocyte apoptosis in cholestasis. Then we prepared LDHJ granules and used ultra-high-performance liquid chromatography to identify the predominant drugs; confirmed the stability of the main substances; and for cell experiments screened forsythoside-A, emodin and chlorogenic acid as the three active substances of LDHJ granules. In the young rats with ANIT-induced intrahepatic cholestasis and the primary hepatocytes with TCDC-induced cholestasis-related hepatocyte apoptosis, the levels of liver injury and cholestasis-related biomarkers, calcium-sensing receptor (CaSR), hepatocyte apoptosis, Bax/Bcl-2 ratio, Cytochrome-C, caspase-3, phosphorylated-c-Jun NH2-terminal kinase (p-JNK)/JNK, and p-P38/P38 were all increased, while the levels of p-extracellular signal-regulated kinase (p-ERK)/ERK were decreased. However, LDHJ granules and its three active substances effectively reversed these changes. Furthermore, the three active substances reduced the increases in the intracellular calcium concentration ([Ca2+]i) and ROS levels and attenuated the dissipation of the mitochondria membrane potential in the TCDC-induced primary hepatocytes. The opposite results were obtained from the TCDC-induced primary hepatocytes treated with an agonist of CaSR (GdCl3) plus forsythoside-A, emodin or chlorogenic acid. Based on the results from in vivo and in vitro studies, LDHJ functions as an antagonist of CaSR to regulate hepatocyte apoptosis in cholestasis through the mitochondrial pathway and mitogen-activated protein kinase pathway.

Biallelic Mutations in Tetratricopeptide Repeat Domain 26 (Intraflagellar Transport 56) Cause Severe Biliary Ciliopathy in Humans.

The clinical consequences of defective primary cilium (ciliopathies) are characterized by marked phenotypic and genetic heterogeneity. Although fibrocystic liver disease is an established ciliopathy phenotype, severe neonatal cholestasis is rarely recognized as such. We describe seven individuals from seven families with syndromic ciliopathy clinical features, including severe neonatal cholestasis (lethal in one and necessitating liver transplant in two). Positional mapping revealed a single critical locus on chromosome 7. Whole-exome sequencing revealed three different homozygous variants in Tetratricopeptide Repeat Domain 26 (TTC26) that fully segregated with the phenotype. TTC26 (intraflagellar transport [IFT] 56/DYF13) is an atypical component of IFT-B complex, and deficiency of its highly conserved orthologs has been consistently shown to cause defective ciliary function in several model organisms. We show that cilia in TTC26-mutated patient cells display variable length and impaired function, as indicated by dysregulated sonic hedgehog signaling, abnormal staining for IFT-B components, and transcriptomic clustering with cells derived from individuals with closely related ciliopathies. We also demonstrate a strong expression of Ttc26 in the embryonic mouse liver in a pattern consistent with its proposed role in the normal development of the intrahepatic biliary system. In addition to establishing a TTC26-related ciliopathy phenotype in humans, our results highlight the importance of considering ciliopathies in the differential diagnosis of severe neonatal cholestasis even in the absence of more typical features.

Perinatal outcomes of intrahepatic cholestasis during pregnancy: An 8-year case-control study.

IntroductionPrevious studies of fetal effects have suggested that intrahepatic cholestasis of pregnancy is associated with a higher rate of adverse neonatal outcomes including preterm birth, neonatal respiratory distress syndrome, meconium-stained amniotic fluid, neonatal intensive care unit admission, and stillbirth. The objective was to compare the neonatal and maternal consequences in pregnancies affected by intrahepatic cholestasis and normal pregnancies.Material and methodsThis case-control study compares pregnancies affected by intrahepatic cholestasis (pruritus and bile acid ≥ 10 μmol/L) with low-risk pregnancies managed between December 2006 and December 2014 at a French university hospital center.ResultsThere were 83 (59.3%) cases of mild cholestasis (10≤ BA ≤39 μmol/L), 46 (32.8%) of moderate cholestasis (40≤ BA ≤99 μmol/L), and 11 (7.9%) of severe cholestasis (BA ≥100 μmol/L). No in utero fetal deaths occurred in the 140 women with cholestasis or the 560 controls analyzed. The rate of respiratory distress syndrome was higher in neonates of women with intrahepatic cholestasis (17.1% vs. 4.6%, P<0.001; crude OR 4.46 (CI95% 2.49–8.03)). This risk was also significant after adjustment for gestational age at birth and mode of delivery, adjusted OR 2.56 (CI95%1.26–5.18). The postpartum hemorrhage rate was twice as high among the case mothers (25% versus 14.1% for controls, P = 0.002).ConclusionAfter adjustment on the confounding factors we found a higher rate of respiratory distress syndrome and neonatal morbidity among neonates of the cholestasis group.

Ursodeoxycholic acid use is associated with significant risk of morbidity and mortality in infants with cholestasis

The off-label use of medications is a “right” for pediatricians, owing to lack of enough safety and effectiveness drug trials in pediatric age group. Pediatricians have to rely on their personal judicial use of medications in children.We studied off-label use of ursodeoxycholic acid (UDCA) retrospectively during 2005 to 2015 among those who attended the Pediatic Hepatology Unit, Cairo University.We analyzed data of 779 neonates and infants with cholestasis. 15% dropped out. Males comprised 374 (56.5%). Cholestasis was due to surgical causes in 129 (19.5%), neonatal hepatitis in 445 (67.2%), and paucity of intrahepatic bile ducts in 88 (13.3%). Three hundred sixty (54.4%) received UDCA (15–30 mg/kg/d), and 302 (45.6%) did not. Both groups were matched as regards causes and severity of cholestasis. Those who received UDCA had worse outcome (P < .001), and more complications (P < .001). A total of 73.1% (221) achieved cure without UDCA compared to only 45.8% (165) of those on UDCA (P < .001).UDCA is not effective and not safe in Egyptian neonates and infants with cholestasis. UDCA use compromises chance of cure, and is associated with serious morbidity, progression of disease, and death. UDCA off-label use mortality was absolutely preventable. Off- label use of UDCA in neonates and children should be utterly prohibited. Information of use of off-label medications, effectiveness, and safety, should be recorded, analyzed, and made available within context of Off-label Use Registry Studies with informed consent of parents.

Severe Variant of Sickle Cell Intrahepatic Cholestasis a Difficult Approach Diagnosis Clinical Presentation and Outcome in Adult Population in the Congo

Background: There are no consensual diagnosis criteria to make diagnosis of sickle cell intrahepatic cholestasis and identify its 2 variants. Here we delineate the frequency of the complication in its severe form and describe its clinical features. Methods: We included in the study all the patients with sickle cell disease who were presenting fever, jaundice, pain in the upper right quadrant and filling up the biological criteria of the severe sickle cell intrahepatic cholestasis (serum direct bilirubin ≥ 78.5 mg/dL). Patients with evidence of viral hepatitis or gallstones were not included in the study. Results: Sixty-two patients with an average age of 21.5 years (range 18 and 25 years) meet the inclusion criteria, minimum serum direct bilirubin: 82 versus 528 for the maximum. The liver cytolysis was major and ranged from 310 to 1550 UI/L. Forty-nine patients (83.9%) did not develop any organ failure. The symptoms and biological abnormalities resolved with supportive treatment within 7 days. The global lethality was 16.1% associated with liver failure. Conclusion: Severe sickle cell intrahepatic cholestasis is more frequent than we thought and was mainly represented by borderline clinical feature. Early intervention may reduce the progression to organ failure stage and ultimate death.