Serum Direct Bilirubin Levels Research Articles

Intrahepatic Cholestasis of Pregnancy: Spontaneous vs in vitro Fertilization.

Aim:Intrahepatic cholestasis of pregnancy (ICP) is the most common liver disease in pregnancy. Although it was shown that multiple pregnancy and hormone therapies increase the risk of ICP, there is limited information that compared spontaneous fertilization and in vitro fertilization (IVF) from the aspect of developing ICP. In our study, we investigated the potential relationship between ICP and IVF/ spontaneous pregnancy.Materials and methods:We reviewed the records (between June 2007 and December 2014) of pregnancies with ICP who were referred to gastroenterology clinics in three different hospitals. Fifty-nine pregnancies (43 spontaneous fertilization, 16 IVF) with ICP were analyzed from the aspect of age, fertilization type, multiple/singleton pregnancy, delivery week, and biochemical results.Results:We found that serum bile acid levels were higher in the IVF group than the spontaneous fertilization group (32.8 ± 20 vs 19.6 ± 19 μmol/L; p < 0.05). There was a significant inverse correlation between serum bile acid levels and gestational age (r = -0.42, p < 0.01) in the whole group. There was no difference between IVF and spontaneous fertilization groups in term of age, onset time of symptoms, serum alanine aminotransferase (ALT), alkaline phosphatase (ALP), total and direct bilirubin levels, prothrombin time (PT), international normalized ratio (INR), and platelet count.Conclusion:Our results suggest that the serum bile acid levels are higher in IVF than in spontaneous pregnancies with ICP, but its clinical implications are not clear. Further prospective studies with large number of ICP cases are needed to clarify the effect of IVF on ICP.How to cite this article: Bolukbas FF, Bolukbas C, Balaban HY, Aygun C, Ignak S, Ergul E, Yazicioglu M, Ersahin SS. Intrahepatic Cholestasis of Pregnancy: Spontaneous vs in vitro Fertilization. Euroasian J Hepato-Gastroenterol 2017;7(2):126-129.

Percutaneous US-guided Cholecystocholangiography with Microbubbles for Assessment of Infants with US Findings Equivocal for Biliary Atresia and Gallbladder Longer than 1.5 cm: A Pilot Study.

Purpose To evaluate the feasibility of ultrasonographically (US) guided percutaneous cholecystocholangiography (PCC) for early exclusion of biliary atresia (BA) in infants suspected of having BA with equivocal US findings or indeterminate type of BA and a gallbladder longer than 1.5 cm at US. Materials and Methods This study was approved by the ethics committee; written informed parental consent was obtained. From February 2016 to December 2016, nine infants (four boys, five girls; mean age, 60.2 days; median age, 57 days; age range, 23-117 days) with conjugated hyperbilirubinemia and gallbladder longer than 1.5 cm at US were referred for US-guided PCC after US findings were equivocal for BA (n = 7) or the type of BA was unclear (n = 2). PCC was performed with a US machine with incorporated contrast pulse sequencing, contrast-specific software, and a linear transducer by injecting diluted contrast material via an 18-gauge needle. Images from US and US-guided PCC were evaluated in consensus by two radiologists. US criteria for BA were fibrotic cord sign (>2 mm) and gallbladder length-to-width ratio greater than 5.2. BA was excluded at PCC when contrast material was visualized in the gallbladder, common hepatic ducts, and common bile duct and during passage to the duodenum. Patients in whom BA was diagnosed after PCC underwent surgery or liver biopsy as the reference standard. Nonparametric and Fisher exact tests were used. Results US-guided PCC was successful in all patients. There were no procedural-related complications. BA was excluded in five of the nine patients. The median serum direct bilirubin level in these patients slightly decreased 1 week after PCC, from 91.1 μmol/L (interquartile range [IQR], 81.6-113.8 μmol/L) to 65.3 μmol/L (IQR, 57.8-74.7 μmol/L); however, this difference was not statistically significant (P = .062). BA was diagnosed in four patients, with the diagnosis confirmed at surgery (n = 2) or liver biopsy (n = 2). BA in two patients with unclear type of BA was defined as type III without patency of the common bile duct in one patient and as type III with patency of the common bile duct in the other. Conclusion In this highly selected group of infants with indeterminate type of BA or inconclusive US findings, US-guided PCC enabled the diagnosis of BA in four infants and the exclusion of BA in five. US-guided PCC may be a safe and effective tool to exclude BA early in infants with equivocal US findings. © RSNA, 2017.

Association of serum bilirubin with oxidant damage of human atherosclerotic plaques and the severity of atherosclerosis.

Bilirubin has protective effects against atherosclerotic cardiovascular diseases hypothetically due to its antioxidant-antilipoperoxidative properties. Thus, we investigated whether serum bilirubin is associated with oxidant damage, namely lipid peroxidation, of human atherosclerotic plaques and the severity of atherosclerosis. In this regard, we correlated the levels of serum total bilirubin (STB), direct (conjugated) bilirubin (SDB) and indirect (unconjugated) bilirubin (SIB) with those of fluorescent damage products of lipid peroxidation (FDPL) and lipid hydroperoxides (LOOH) of 32 endarterectomy-derived carotid atherosclerotic plaques. Moreover, we compared the levels of serum bilirubin and plaque lipoperoxides between two groups of patients of the study population with different severity of atherosclerosis as judged by the carotid stenosis degree, i.e., <90% (group A, n=23) and ≥90% (group B, n=9). Remarkably, the levels of STB were strongly inversely correlated with those of plaque FDPL (rS=-0.70, P<0.0001) and LOOH (rS=-0.66, P<0.0001), as were those of SIB (FDPL: rS=-0.68, P<0.0001; LOOH: rS=-0.63, P<0.0001). SDB had a weaker association with plaque FDPL (rS=-0.41, P<0.05) and LOOH (rS=-0.35, P<0.05). Moreover, the levels of STB, SDB and SIB were lower and those of plaque lipoperoxides higher in group B than in group A, pointing to the association of serum bilirubin and plaque oxidant burden with the severity of atherosclerosis. In conclusion, lowered serum bilirubin is associated with oxidant damage of human atherosclerotic plaques and the severity of atherosclerosis.

DEVELOPMENT OF CARBON TETRACHLORIDE-INDUCED CHRONIC HEPATOTOXICITY MODEL IN RATS AND ITS APPLICATION IN EVALUATION OF HEPATOPROTECTIVE ACTIVITY OF SILYMARIN

Objective: The objective of the present work is to develop carbon tetrachloride (CCl4)-induced chronic hepatotoxicity model in rats and its applicationin evaluation of hepatoprotective activity of silymarin.Methods: Animals were divided into four groups. Three groups were the disease induction group and 4th was the treatment group. In disease inductiongroups, chronic liver injury was induced by administration of CCl4 through intraperitoneal route (1 ml/kg) for 7-8 weeks. For treatment Group, 1 mlsilymarin suspension (orally) and CCl4 was given for 7-8 weeks. During disease induction and treatment period (7-8 weeks), blood samples werecollected and serum was separated which in turn used to analyze liver function tests such as serum glutamate oxaloacetate transaminase (SGOT),serum glutamate pyruvate transaminase (SGPT), alkaline phosphate (ALP), direct bilirubin, total protein (TP), and albumin (Alb) levels. Along withliver functional tests, tests to check cholesterol, glucose, and malondialdehyde (MDA) were also performed. Liver fibrosis and cirrhosis was quantifiedby histopathological studies of small portion of the excised liver. Model was validated by repetition of the experiment. Intermediate dissection wascarried out to measure an extent of liver damage.Result: Serum SGOT, SGPT, ALP, and direct bilirubin were found to be significantly higher in CCl4 intoxicated rats. TP and Alb were decreased, andMDA was found to be significantly higher in CCl4 intoxicated rats, which is the main end product of lipid peroxidation. Whereas in the treatment groupsilymarin improved the liver functions in CCl4 toxicated drug.Conclusion: We conclude that protein oxidation may play a role in the pathogenesis of CCl4 induced liver injury. The accumulation of oxidized proteinsmay be an early indication of CCl4 induced liver damage and silymarin found to be effective in liver injury by inhibiting protein oxidation.

Relationship between Serum Bilirubin Levels and Metabolic Syndrome in Patients with Schizophrenia Spectrum Disorders

ObjectiveWe investigated the relationship between serum bilirubin levels and metabolic syndrome (MetS), and the longitudinal effects of baseline serum bilirubin concentrations on MetS in patients with schizophrenia spectrum disorders undergoing atypical antipsychotics.MethodsThe sample of this study consisted of 131 patients with schizophrenia spectrum disorders. Waist circumference, blood pressure, and levels of triglycerides, high-density lipoprotein cholesterol, fasting glucose, and insulin were evaluated at baseline and at month six. Serum bilirubin levels were measured at baseline. Serum bilirubin levels of the patients with and without MetS criteria were compared. We also compared patients with high and low bilirubin levels (upper and lower 50th percentiles of serum bilirubin levels) in terms of MetS criteria, MetS frequency, and course of MetS.ResultsSerum direct bilirubin levels were more consistently related to MetS and MetS-related variables. The waist circumference and triglyceride criteria for MetS were significantly related to low serum direct bilirubin at baseline; waist circumference and fasting glucose criteria, and insulin resistance were associated with low serum direct bilirubin at follow-up. MetS diagnosis and the presence of the waist circumference criterion were more frequent at the baseline and the follow-up in low bilirubin group. At the end of the follow-up period, the rate of reverse MetS was significantly higher in the high bilirubin group.ConclusionOur results have suggested that serum direct bilirubin levels showed a more reliable and stable relationship with abdominal obesity for MetS components.in patients with schizophrenia spectrum disorders using antipsychotics. Further studies are required.

Protective Effect of Morin against Flutamide-Induced Hepatotoxicity in Mal Wister Rats

Aim of the work: The aim of this work was to investigate the protective role of morin against the hepatotoxic effect of flutamide (FLU) that is widely used drug for treatment of metastatic prostate adenocarcinoma. Administration of FLU to male rats in a dose of 100 mg/ kg b.w. daily for 4 weeks resulted in serious hepatic injury. Materials and Methods: Male Wistar rats were equally divided into six experimental groups (n = 10): Group I (control group) received appropriate vehicle (carboxy methyl cellulose, CMC) for 8 weeks, Group II (CM group) received CMC for 4 weeks then morin for another 4 weeks, Group III ( M group) were treated with morin for 8 weeks, Group IV (CF group) received CMC for 4 weeks then FLU for another 4 weeks, Group V (CMF group) received CMC for 4 weeks then morin for another 4 weeks then received morin associated with FLU for additional4 weeks and Group VI (MMF group) was pretreated with morin for 4 weeks then treated with morin simultaneously with FLU for additional 4 weeks. Results: In FLU treated rats, highly significant increases in each of serum ALT, AST, direct and total bilirubin as well as hepatic MDA were observed relative to the control group. Moreover, highly significant decrease in hepatic SOD, GSH and GST activities were observed. On the other hand, administration of morin with FLU resulted in mild and marked reduction in the elevated serum ALT, AST, direct and total bilirubin and hepatic MDA levels induced by FLU intoxication, respectively (regardingco-treatment and pretreatment with FLU). Conclusion:These data showed protective effect of morin against FLU-induced hepatic damage, especially when administered prior to and concomitantly with FLU.

Protective effects of petroleum ether extracts of Herpetospermum caudigerum against α-naphthylisothiocyanate-induced acute cholestasis of rats

Ethnopharmacological relevanceThe ripe seeds of Herpetospermum caudigerum have been used in Tibetan folk medicine for treatment of bile or liver diseases including jaundice, hepatitis, intumescences or inflammation. Previously reports suggested that the seed oil and some lignans from H. caudigerum exhibited protective effects against carbon tetrachloride (CCl4)-induced hepatic damage in rats, which may be related to their free radical scavenging effect. However, the protective effect of H. caudigerum against cholestasis is still not revealed. The aim of the present study was to investigate the pharmacological effect and the chemical constituents of the petroleum ether extract (PEE) derived from H. caudigerum against α-naphthylisothiocyanate (ANIT)-induced acute cholestasis in rats. Materials and methodsMale cholestatic Sprague-Dawley (SD) rats induced by ANIT (60mg/kg) were orally administered with PEE (350, 700 and 1400mg/kg). Levels of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), γ-Glutamyl transpeptidase (γ-GTP), total bilirubin (TBIL), direct bilirubin (DBIL) and total bile acid (TBA), as well as bile flow, and histopathological assay were evaluated. Hepatic malondialdehyde (MDA), myeloperoxidase (MPO), superoxide dismutase (SOD), glutathione S-transferase (GST), and nitric monoxide (NO) in liver were measured to explore the possible protective mechanisms. Phytochemical analysis of PEE was performed by gas chromatography-mass spectrometer (GC-MS). ResultsPEE have exhibited significant and dose-dependent protective effect on ANIT-induced liver injury by reduce the increases in serum levels of ALT, AST, ALP, γ-GTP, TBIL, DBIL and TBA, restore the bile flow in cholestatic rats, and reduce the severity of the pathological tissue damage induced by ANIT. Hepatic MDA, MPO and NO contents in liver tissue were reduced, while SOD and GST activities were elevated in liver tissue. 49 compounds were detected and 39 of them were identified by GC-MS analysis, in which long-chain fatty acids were the main constituents. ConclusionsPEE exhibited a dose-dependently protective effect on ANIT-induced liver injury in cholestatic rats with the potential mechanism of attenuated oxidative stress in the liver tissue, and the possible active compounds were long-chain fatty acids.

Effect of Bilineaster Drop on Neonatal Hyperbilirubinemia

Background: Hyperbilirubinemia is considered one of the most prevalent problems in newborns. Phototherapy, exchange transfusion, and herbal medicine are common therapeutic approaches for preventing any neurologic damage in infants with neonatal jaundice. However, herbal medicine is less commonly used. Aim: This study aimed to investigate the effect of bilineaster drop on neonatal hyperbilirubinemia. Method: This study was a randomized clinical trial conducted on 98 term neonates (aged 2-14 days) with neonatal jaundice admitted to Ghaem Hospital of Mashhad, Iran, during 2015. These newborns were randomly assigned into intervention (phototherapy and bilineaster drop) and control (only phototherapy) groups. Total and direct serum bilirubin levels were measured at the time of admission and then 12, 24, 36, and 48 h after treatment. Data were analyzed using independent t-test and repeated measures ANOVA through Stata software (Version 12). Results: The mean ages of the newborns at the time of admission were 6.2 ±2.5 and 6.04 ±2.4 days in the intervention and control groups, respectively. The intervention group showed higher reduction in mean duration of hospital stay, readmission rate, and bilirubin levels 12 and 24 h after the intervention, compared to the control group (P>0.001). However, the two groups demonstrated no statistically significant difference 36 h and 48 h after the intervention (P=0.06, P=0.22, respectively). Repeated measures ANOVA indicated that the intervention had no significant effect on the reduction trend of bilirubin levels (P=0.10 [total], P=0.06 [indirect]) in both groups. Nonetheless, bilirubin levels significantly diminished in both groups over time (P<0.001). Implications for Practice: The results of this study demonstrated that the use of bilineaster drop along with phototherapy could cause a significant decrease in the levels of total and direct bilirubin; however, the intervention had no effect on the downward trend of bilirubin.

An Investigation of Hepatoprotective Activity of Methanolic Extract of Ipomoea reniformis on Experimentally Induced Ethanol Hepatotoxicity in Rats

Objective: The present study evaluated the hepatoprotective activity of Methanolic Extract of Ipomoea reniformis (MEIR) in experimentally-induced hepatotoxic rats. Methods: Hepatoprotective activity of MEIR was studied against ethanol (4 g/kg p.o.)-induced hepatotoxicity rats. Silymarin (100 mg/kg p.o.) was used as a standard reference. The following parameters were evaluated; serum biomarkers such as Serum Glutamate Oxaloacetic Transaminase (SGOT), Serum Glutamate Pyruvate Transaminase (SGPT), total and direct bilirubin, Total Protein (TP) and tissue antioxidant levels such as Glutathione (GSH) and Lipid Peroxidation (LPO). Results and conclusion: The control group did not exhibit increase in serum parameters, but ethanol toxicant group showed significant increase in serum parameters such as SGOT, SGPT, bilirubin (total and direct), and LPO, whereas GSH and TP levels were markedly reduced. Silymarin, MEIR low dose (200 mg/kg p.o.) and high dose (400 mg/kg p.o.) treated groups showed significant decrease in SGOT, SGPT, total and direct bilirubin, TB, LPO and increase in GSH and TP levels. Based on the study findings in serum marker enzyme levels and antioxidant parameters, it is concluded that MEIR possesses hepatoprotective activity.

Association Between Early Idiopathic Neonatal Jaundice and Urinary Tract Infections.

Background and purpose:Etiologic role, incidence, demographic, and response-to-treatment characteristics of urinary tract infection (UTI) among neonates, its relationship with significant neonatal hyperbilirubinemia, and abnormalities of the urinary system were studied in a prospective investigation in early (≤10 days) idiopathic neonatal jaundice in which all other etiologic factors of neonatal hyperbilirubinemia were ruled out.Patients and methods:Urine samples for microscopic and bacteriologic examination were obtained with bladder catheterization from 155 newborns with early neonatal jaundice. Newborns with a negative urine culture and with a positive urine culture were defined as group I and group II, respectively, and the 2 groups were compared with each other.Results:The incidence of UTI in whole of the study group was 16.7%. Serum total and direct bilirubin levels were statistically significantly higher in group II when compared with group I (P = .005 and P = .001, respectively). Decrease in serum total bilirubin level at the 24th hour of phototherapy was statistically significantly higher in group I compared with group II (P = .022).Conclusions:Urinary tract infection should be investigated in the etiologic evaluation of newborns with significant hyperbilirubinemia. The possibility of UTI should be considered in jaundiced newborns who do not respond to phototherapy well or have a prolonged duration of phototherapy treatment.

Inverse Association between Serum Bilirubin Levels and Retinopathy in Patients with Type 2 Diabetes Mellitus.

Oxidative stress plays a central role in the pathogenesis of Diabetic Retinopathy (DR) and serum bilirubin has been shown to have antioxidant properties. To investigate the association between serum bilirubin concentration and DR in patients with Type 2 Diabetes Mellitus (DM). This was a hospital based, cross- sectional study where in 86 patients with Type 2 DM and 30 controls were recruited. The study was conducted at a tertiary care centre in Southern India between January 2014 and December 2014. The presence and the severity of DR were determined by fundus examination and grading of colour fundus photographs using the international clinical disease severity scale for DR. Serum total, direct and indirect bilirubin levels were determined in all subjects and the association between bilirubin levels and severity of DR was studied. Among the 86 diabetics, 24 had no retinopathy and 62 had DR of varying grades. The mean total bilirubin level among diabetic subjects (0.52±0.17) and controls (0.51±0.19) were found to be similar. The mean total as well as direct bilirubin levels were found to be lower in patients with retinopathy as compared to no retinopathy group (p<0.001). The severity of DR was inversely proportional to the serum bilirubin levels (p=0.010). Serum total bilirubin was found to have a negative association with glycosylated haemoglobin and served as an independent determinant of DR even after adjusting for risk factors known to be associated with DR (p=0.001). Low serum bilirubin levels are significantly associated with increased risk of DR independent of classic risk factors. Serum bilirubin can serve as a useful biomarker in identifying patients at risk for developing proliferative DR.

Potential Ameliorative Effects of Alpha Lipoic Acid and Silymarin on Thioacetamide-Induced Hepatic Damage in Rats

The present study was designed to study the protective effects of alpha lipoic acid (ALA) and silymarin (SIL) against thioacetamide (TAA)-induced hepatic damage. Sixty male albino rats were divided into 6 groups (10 rats each); control group, TAA-treated group: injected intraperitoneally with TAA 250 mg/kg bwt/day three times a week, ALA-treated group: received ALA 100 mg/kg bwt/day) orally three times a week, SIL-treated group: received SIL 100 mg/kg bwt/day orally three times a week, TAA+ALA-treated group, and TAA+SIL-treated group at the same previous doses and routes for ten weeks. Results showed that TAA induced a significant increase in serum liver enzymes, total and direct bilirubin, total cholesterol and triglycerides levels after four and ten weeks of the treatments. While the serum levels of total proteins, albumin and high density lipoprotein-cholesterol revealed a significant decrease. TAA injection resulted in an increase in the hepatic lipid peroxidation and decreased antioxidant biomarker levels. Histopathologically, TAA revealed marked degenerative, necrotic and fibrotic alterations in the liver, particularly during ten weeks post-treatment. ALA and SIL- treatment ameliorated TAA-induced oxidative damage, alterations in the liver function tests and liver histopathology. However, ALA demonstrated better hepatic protection against TAA-induced liver damage as compared to SIL. The study clearly concluded that ALA has more powerful antioxidant properties than SIL.

Antioxidant and Hepatoprotective Potential of Phenol-Rich Fraction of Juniperus communis Linn. Leaves.

Background:Juniperus communis Linn. is an important plant in India traditional system of medicine which is widely used by different tribes in many countries.Objective:In the present study, the antioxidant, cytotoxic and hepatoprotective activities of Juniperus communis leaves were investigated against various models.Materials and Methods:ethanolic extract (70% v/v) of J. communis leaves was successively extracted using hexane and ethyl acetate to prepare various fractions. Total phenol content was resolute by the Folin-Ciocalteau's process. The antioxidant properties of the different fractions/extract of leaves of J. communis were examined by 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity and Fe2+ chelating ability. Cytotoxic activity was examined by cell viability assay on HepG2 cells. Hepatoprotective activity of ethyl acetate fraction (EAF) evaluated against PCM-Paracetamol-induced hepatic damage in Wistar albino rats.Results:Total phenol content was found maximum 315.33 mg/GAE/g in EAF. Significant scavenging activity were found for EAF (IC50 = 177 μg/ml) as compared to standard BHT (IC50 = 138 μg/ml), while EAF showed good Fe2+ chelating ability having an IC50 value of 261 mg/ML compared to standard ethylenediaminetetraacetic acid (7.7 mg/mL). It was found that EAF treated group shows remarkable decrease in serum Aspartate aminotransferase, serum Alanine aminotransferase, total bilirubin, direct bilirubin, and alkaline phosphatase level in treatment group as compared to the hepatotoxic group.Conclusion:EAF of J. communis leaves is found to be potent antioxidant and hepatoprotective without any cytotoxicity and it can also be included in nutraceuticals with notable benefits for mankind or animal health.SUMMARY Phenol-rich fraction (PRF) and other fractions/extract of Juniperus communis leaves were screened for antioxidant, cytotoxic, and hepatoprotective activity.Significant antioxidant and hepatoprotective activity without any cytotoxicity were found while treating with ethyl acetate fraction (EAF). Abbreviations used: HepG2: Liver hepatocellular carcinoma, BHT: Butylated hydroxytoluene, PCM: Paracetamol, IC50: Half maximal inhibitory concentration, RSA: Radical Scavenging Activity, WST: Water-soluble tetrazolium.

Guideline for the Evaluation of Cholestatic Jaundice in Infants: Joint Recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition.

Cholestatic jaundice in infancy affects approximately 1 in every 2500 term infants and is infrequently recognized by primary providers in the setting of physiologic jaundice. Cholestatic jaundice is always pathologic and indicates hepatobiliary dysfunction. Early detection by the primary care physician and timely referrals to the pediatric gastroenterologist/hepatologist are important contributors to optimal treatment and prognosis. The most common causes of cholestatic jaundice in the first months of life are biliary atresia (25%-40%) followed by an expanding list of monogenic disorders (25%), along with many unknown or multifactorial (eg, parenteral nutrition-related) causes, each of which may have time-sensitive and distinct treatment plans. Thus, these guidelines can have an essential role for the evaluation of neonatal cholestasis to optimize care. The recommendations from this clinical practice guideline are based upon review and analysis of published literature and the combined experience of the authors. The committee recommends that any infant noted to be jaundiced after 2 weeks of age be evaluated for cholestasis with measurement of total and direct serum bilirubin, and that an elevated serum direct bilirubin level (direct bilirubin levels >1.0 mg/dL or >17 μmol/L) warrants timely consideration for evaluation and referral to a pediatric gastroenterologist or hepatologist. Of note, current differential diagnostic plans now incorporate consideration of modern broad-based next-generation DNA sequencing technologies in the proper clinical context. These recommendations are a general guideline and are not intended as a substitute for clinical judgment or as a protocol for the care of all infants with cholestasis. Broad implementation of these recommendations is expected to reduce the time to the diagnosis of pediatric liver diseases, including biliary atresia, leading to improved outcomes.

Direct bilirubin: A new risk factor of adverse outcome in idiopathic pulmonary arterial hypertension

BackgroundPrevious studies have shown that elevated total bilirubin was associated with advanced heart failure, yet no study has ascertained the predictive value of direct serum bilirubin (DBIL) in idiopathic pulmonary arterial hypertension (IPAH). This study aimed to investigate the predictive value of both baseline and follow-up DBIL in patients with IPAH. MethodsSerum DBIL was measured in 404 IPAH patients at enrollment. Almost 92% patients received specific drugs after diagnosis confirmed. Serum DBIL was repeated in 237 patients after a mean of 8.3months treatment. Survival rate among normal DBIL group and abnormal DBIL group was compared using the Kaplan–Meier method. The prognostic value of baseline variables was tested by Cox regression models. ResultsDuring median follow-up period of 40months, 153 patients died. Baseline DBIL levels were significantly higher in non-survivors compared with survivors (p<0.001). DBIL levels in survivors decreased significantly during PAH therapy, whereas there was almost no decrease in non-survivors. Patients with abnormal DBIL at baseline or during therapy had a significantly lower survival rates than those with normal DBIL group, according to Kaplan–Meier survival analysis (p=0.002 and p<0.0001, respectively). According to multivariate analyses, baseline DBIL was an independent risk factor of mortality in IPAH. ConclusionsSerum DBIL could predict severity and outcomes of IPAH: in particular, no obvious decrease in DBIL during PAH-specific drug therapy is strongly associated with worse prognosis in IPAH.

Higher direct bilirubin levels during mid-pregnancy are associated with lower risk of gestational diabetes mellitus.

Bilirubin concentrations have been recently reported to be negatively associated with type 2 diabetes mellitus. We examined the association between bilirubin concentrations and gestational diabetes mellitus. In a prospective cohort study, 2969 pregnant women were recruited prior to 16 weeks of gestation and were followed up until delivery. The value of bilirubin was tested and oral glucose tolerance test was conducted to screen gestational diabetes mellitus. The relationship between serum bilirubin concentration and gestational weeks was studied by two-piecewise linear regression. A subsample of 1135 participants with serum bilirubin test during 16-18 weeks gestation was conducted to research the association between serum bilirubin levels and risk of gestational diabetes mellitus by logistic regression. Gestational diabetes mellitus developed in 8.5 % of the participants (223 of 2969). Two-piecewise linear regression analyses demonstrated that the levels of bilirubin decreased with gestational week up to the turning point 23 and after that point, levels of bilirubin were increased slightly. In multiple logistic regression analysis, the relative risk of developing gestational diabetes mellitus was lower in the highest tertile of direct bilirubin than that in the lowest tertile (RR 0.60; 95 % CI, 0.35-0.89). The results suggested that women with higher serum direct bilirubin levels during the second trimester of pregnancy have lower risk for development of gestational diabetes mellitus.

Nomograms incorporated serum direct bilirubin level for predicting prognosis in stages II and III colorectal cancer after radical resection.

An elevated serum bilirubin has been reported to be associated with a reduced risk of some cancer; however, the prognostic significance of serum bilirubin in colorectal cancer wasn’t fully understood. The purpose of this study was to evaluate whether serum bilirubin could predict the prognosis of patients in stages II and III colorectal cancer. A retrospective cohort of 986 patients with colorectal cancer who received surgical resection between January 2005 and December 2010 was included in the study. Levels for serum bilirubin were obtained from medical records. Survival analysis was used to evaluate the predictive value of bilirubin. Serum direct bilirubin (DBIL) was validated as a significant prognostic factor by univariate cox regression test for both overall survival (OS) and disease free survival (DFS) (P < 0.05). X-tile program identified 3.6 as optimal cutoff values for DBIL in terms of OS and DFS. Patients were then divided into DBIL high (DBIL ≥ 3.60 μmol/l) and low group (DBIL < 3.60 μmol/l) according to the optimal cutoff. High DBIL had higher percentage of lymph node metastasis and lymphovascular invasion as compared with low DBIL levels (P < 0.05). Multivariate cox regression analyses confirmed that high DBIL level was an independently prognostic factor for both OS (HR: 1.337, 95% CI: 1.022–1.748, P = 0.034) and DFS (HR: 1.312, 95% CI: 1.049–1.643, P = 0.018). In addition, nomograms on OS and DFS were established according to all significant factors, and c-indexes were 0.715 (95% CI: 0.683–0.748) and 0.704 (95% CI: 0.678–0.730), respectively. Nomograms based on OS and DFS can be recommended as practical models to evaluate prognosis for CRC patients.

Percutaneous intraductal radiofrequency ablation in the management of unresectable Bismuth types III and IV hilar cholangiocarcinoma

PurposeTo assess the feasibility and safety of percutaneous intraductal radiofrequency ablation (RFA) for unresectable Bismuth types III and IV hilar cholangiocarcinoma.ResultsPercutaneous intraductal RFA combined with metal stent placement was successful in all patients without any technical problems; the technical success rate was 100%. Chemotherapy was administered to two patients. After treatment, serum direct bilirubin levels were notably decreased. Six patients died during the follow-up period. Median stent patency from the time of the first RFA and survival from the time of diagnosis were 100 days (95% confidence interval (CI), 85–115 days) and 5.3 months (95% CI, 2.5–8.1 months), respectively. No acute pancreatitis, bile duct bleeding and perforation, bile leakage, or other severe complications occurred. Four cases of procedure-related cholangitis, three cases of postoperative abdominal pain, and five cases of asymptomatic transient increase in serum amylase were observed. One patient who presented with stent blockage 252 days' post-procedure underwent repeat ablation.Materials and MethodsBetween September 2013 and May 2015, nine patients with unresectable Bismuth types III and IV hilar cholangiocarcinoma who were treated with percutaneous intraductal RFA combined with metal stent placement after the percutaneous transhepatic cholangial drainage were included in the retrospective analysis. Procedure-related complications, stent patency, and survival after treatment were investigated.ConclusionPercutaneous intraductal RFA combined with metal stent placement is a technically safe and feasible therapeutic option for the palliative treatment of unresectable Bismuth types III and IV hilar cholangiocarcinoma. Its long-term efficacy and safety is promising, but needs further study via randomized and prospective trials that include a greater number of patients.

Acute Fatty Liver of Pregnancy: A Retrospective Analysis of 56 Cases.

Background:Acute fatty liver of pregnancy (AFLP) is a rare but life-threatening complication occurring in the third trimester. It is often fatal to both mother and fetus. The complicated clinical manifestations as well as an insufficient understanding of the disease make the precise diagnosis and effective treatment of AFLP challenging. A full understanding of the risk factors, clinical features, and test findings of AFLP is critical for its timely diagnosis and treatment.Methods:We performed a retrospective study of 56 patients with AFLP between June 2008 and July 2013. We analyzed the clinical features, laboratory results, perioperative management, and patient outcomes.Results:The initial symptoms varied considerably, with nausea and vomiting (13/56, 23%) being the most common. Liver-function indexes were remarkable, including elevated levels of serum alanine aminotransferase (262.16 ± 281.71 U/L), aspartate aminotransferase (260.98 ± 237.91 U/L), lactic dehydrogenase (1011.76 ± 530.34 U/L), and direct bilirubin (85.59 ± 90.02 μmol/L). Coagulation disorders were indicated by abnormal levels of fibrinogen (245.95 ± 186.11 mg/dL), D-dimer (2.46 ± 4.01 mg/L), and fibrin degradation products (43.62 ± 48.71 mg/L). The main maternal complications were hypoproteinemia (75%), coagulopathy (54%), and acute renal failure (39%). Multivariate logistic regression analysis identified prothrombin time (PT; odds ratio [OR] = 1.558, 95% confidence interval [CI] =1.248–1.946, P = 0.016) and international normalized ratio (INR; OR = 40.034, 95% CI = 2.517–636.693, P = 0.009) as risk factors. The perinatal infant death rate was related to gestational age at delivery (OR = 1.298, 95% CI = 1.040–1.618, P = 0.021), direct bilirubin (OR = 1.05, 95% CI = 1.008–1.094, P = 0.020), and fibrin degradation products (OR = 0.973, 95% CI = 0.950–0.996, P = 0.021).Conclusions:Nausea and vomiting may be the most common symptoms of AFLP. Indexes of liver dysfunction and coagulation disorders should also be considered. PT and INR are risk factors for fatal complications in patients with AFLP, and perinatal mortality is linked to the level of fibrin degradation products. Timely delivery is crucial to controlling the development of AFLP.

Inhibition of hepatic cytochrome P450 enzymes and sodium/bile acid cotransporter exacerbates leflunomide-induced hepatotoxicity

Leflunomide is an immunosuppressive agent marketed as a disease-modifying antirheumatic drug. But it causes severe side effects, including fatal hepatitis and liver failure. In this study we investigated the contributions of hepatic metabolism and transport of leflunomide and its major metabolite teriflunomide to leflunomide induced hepatotoxicity in vitro and in vivo. The metabolism and toxicity of leflunomide and teriflunomide were evaluated in primary rat hepatocytes in vitro. Hepatic cytochrome P450 reductase null (HRN) mice were used to examine the PK profiling and hepatotoxicity of leflunomide in vivo. The expression and function of sodium/bile acid cotransporter (NTCP) were assessed in rat and human hepatocytes and NTCP-transfected HEK293 cells. After Male Sprague-Dawley (SD) rats were administered teriflunomide (1,6, 12 mg · kg(-1) · d(-1), ig) for 4 weeks, their blood samples were analyzed. A nonspecific CYPs inhibitor aminobenzotriazole (ABT, 1 mmol/L) decreased the IC50 value of leflunomide in rat hepatocytes from 409 to 216 μmol/L, whereas another nonspecific CYPs inhibitor proadifen (SKF, 30 μmol/L) increased the cellular accumulation of leflunomide to 3.68-fold at 4 h. After oral dosing (15 mg/kg), the plasma exposure (AUC0-t) of leflunomide increased to 3-fold in HRN mice compared with wild type mice. Administration of leflunomide (25 mg·kg(-1) · d(-1)) for 7 d significantly increased serum ALT and AST levels in HRN mice; when the dose was increased to 50 mg·kg(-1) · d(-1), all HRN mice died on d 6. Teriflunomide significantly decreased the expression of NTCP in human hepatocytes, as well as the function of NTCP in rat hepatocytes and NTCP-transfected HEK293 cells. Four-week administration of teriflunomide significantly increased serum total bilirubin and direct bilirubin levels in female rats, but not in male rats. Hepatic CYPs play a critical role in detoxification process of leflunomide, whereas the major metabolite teriflunomide suppresses the expression and function of NTCP, leading to potential cholestasis.