Increased Serum Bilirubin Levels Research Articles

Association between serum bilirubin and estimated glomerular filtration rate in diabetic patients with chronic kidney disease

Background and objectives: Hyperglycemia induces oxidative stress in diabetic patients by increasing reactive oxygen species production, which ultimately damage the cells and cause micro and macrovascular complications including diabetic nephropathy. Increased serum bilirubin level, within physiological range, can inhibit oxidative stress; thereby, preventing development of diabetic nephropathy. The aim of this study was to find out association between serum bilirubin and estimated glomerular filtration rate (eGFR) in diabetic patients with or without chronic kidney disease (CKD). Materials and method: Both male and female participants aged 30 to 60 years were enrolled in the study. Enrolled participants included healthy individuals (Group-1), diabetic patients without CKD (Group-2) and diabetic patients with CKD (Group-3). Clinical and biochemical parameters namely blood pressure, body mass index (BMI), fasting blood glucose (FBG), HbA1c, eGFR, serum bilirubin and spot urine ACR were measured by appropriate methods. Pearson’s correlation coefficient, ANOVA and multiple linear regression models were used to analyze the data. Result: Total 189 respondents were enrolled in 3 study groups. Each group consisted of 63 cases. Of the 63 cases in Group-3, 49 and 14 belonged to CKD stage 3 and stage 4 respectively. The mean (± SD) serum bilirubin levels of healthy individuals, diabetic patients without CKD and diabetic patients with CKD were 0.66 ± 0.31, 0.64 ± 0.21, 0.46±0.18 mg/dL respectively. Mean serum bilirubin was significantly low (p<0.001) in diabetic patients with CKD compared to healthy and diabetics without CKD. A Stepwise multiple regression analysis using eGFR as an objective variable adjusted for risk factors as explanatory variables, showed that serum bilirubin (β=0.323, p<0.001) was significantly associated with eGFR, in addition to age, BMI, HbA1c and urinary ACR. Conclusion: The study has demonstrated that low serum bilirubin level is associated with CKD in diabetic patients and it could be used as a simple marker for CKD in diabetics. IMC J Med Sci. 2024; 18(1):006. DOI: https://doi.org/10.55010/imcjms.18.006 *Correspondence: Tanzia Tahfim, Department of Biochemistry, Shaheed Monsur Ali, Medical College, Uttara, Dhaka-1230, Bangladesh. Email: tanzia.uamc@gmail.com

An Overview on Neonatal Jaundice

A significant proportion of term and preterm infants develop neonatal jaundice. Jaundice in a healthy term infant is the most common reason for readmission to hospital. Jaundice is caused by a significant increase in serum bilirubin levels, largely due to the breakdown of red blood cells. Bilirubin is transported in the blood as 'unconjugated' bilirubin, largely bound to albumin. The bilirubin is converted into a conjugated form by the liver, which is excreted in the bile. Very high levels of unconjugated bilirubin led to neurotoxicity. In most infants, severe hyperbilirubinemia is caused due to an increase in bilirubin production (e.g., due to haemolysis) and thus reducing bilirubin production is a rational approach for its management. The situation can become critical in infants with an associated impaired bilirubin elimination mechanism as a result of a genetic deficiency and polymorphism. The simplest way to reduce bilirubin levels is by phototherapy. Current management of jaundice in the UK is guided by the NICE guideline.1

The effectiveness of Lactobacillus reuteri on serum bilirubin levels in neonatal hyperbilirubinemia with phototherapy

Background Hyperbilirubinemia occurs in 60% of full term and 80% of premature infants. Phototherapy is the main treatment, but it has side effects, sometimes requires hospitalization, and causes the baby to be separated from the mother. Underdeveloped gut microflora and increased enterohepatic circulation in newborns contribute to increased serum bilirubin levels in early life.
 Objective To assess the efficacy of adding probiotic L. reuteri on phototherapy in full-term neonates with hyperbilirubinemia.
 Methods In this double-blind, randomized clinical trial, full term infants with hyperbilirubinemia at Dr. Zainoel Abidin Hospital, Banda Aceh, Aceh, Indonesia, were randomly assigned to either an intervention or control group. All subjects received phototherapy. The intervention group was also given five drops of L. reuteri once a day orally before phototherapy started, while the control group received a placebo. Bilirubin levels after 24-hour phototherapy were evaluated in both groups.
 Results A total of 42 term neonates met the inclusion criteria. The intervention group had a significantly greater decrease in total serum bilirubin (TSB) level (6,517 mg/dL) than did the control group (4,434 mg/dL) (P<0.001), as well in indirect bilirubin levels in the intervention group had decrease 6.40 mg/dL while in the control group 4.43 mg/dL after 24 hours of phototherapy (P<0.001).
 Conclusion In full-term neonates with hyperbilirubinemia who underwent 24-hour phototherapy, adding probiotic L. reuteri leads to a significantly greater reduction in total and indirect bilirubin levels compared to the control group.

Clinical profile of term neonates requiring intervention for hyperbilirubinemia

ABSTRACT Introduction: Neonatal jaundice is the imbalance between bilirubin production and conjugation, resulting in increased serum bilirubin levels. It is visible in the skin and eyes, only when the total serum bilirubin level exceeds 5–7 mg/dl. Sixty percent of the term and almost 80% of the preterm babies develop neonatal jaundice. Objectives: To identify the etiology of neonatal hyperbilirubinemia in term neonates and to determine short-term outcomes in terms of rebound hyperbilirubinemia during hospital stay and other modalities of intervention in these babies. Methods: We did a cross-sectional, descriptive, and retrospective chart-based study. The clinical profile of term neonates treated for hyperbilirubinemia was procured from the inpatient medical records and neonatal intensive care unit (NICU) discharge summaries over 5 years from January 2017 to December 2021. Short-term outcomes, such as duration of hospital stay, rebound hyperbilirubinemia, and other modalities of treatment used, were noted. Results: A total of 252 term babies who fulfilled the inclusion criteria were included in the study. Two hundred and thirty-four babies were delivered vaginally, 10 by cesarean section, and 8 extracted by instrumental delivery. Ninety-eight babies had ABO incompatibility and 19 Rh incompatibility. Twelve babies had elevated cord thyroid-stimulating hormone levels. Seventy-one babies had signs of bilirubin encephalopathy. Thirty-nine babies had sepsis. Fifty-three of them had significant weight loss suggestive of improper feeding. Thirty-three babies had cephalhematoma. Nine babies were born to mothers with gestational diabetes mellitus. All 252 babies underwent phototherapy. Thirty-two babies required a prolonged hospital stay of more than 1 week and seven had rebound hyperbilirubinemia. Nine babies required exchange transfusion. Two received intravenous immunoglobulin. Conclusions: The most common risk factor associated was ABO incompatibility, followed by inadequate breastfeeding. As only nine neonates required exchange transfusion, early and prompt initiation of phototherapy remains the best modality of treatment. Emphasis on proper feeding technique can go a long way in preventing admission to NICU, as it is the second-most common preventable cause of hyperbilirubinemia.

Association Between Serum Bilirubin, Lipid Levels, and Prevalence of Femoral and Carotid Atherosclerosis: A Population-Based Cross-Sectional Study.

Bilirubin may prevent lipid peroxidation and have important antiatherosclerotic effects. We determined associations of serum bilirubin and lipid with peripheral atherosclerosis. We included 4290 participants (35% men; median age, 60 years) from the southeast China who underwent B-mode ultrasound examination. Increased intima-media thickness or a focal structure encroaching into the arterial lumen by at least 0.5 mm or >50% of the surrounding intima-media thickness value was regarded as having atherosclerosis. Fasting serum bilirubin and lipid levels were measured. Cholesterol/(HDL [high-density lipoprotein] cholesterol+bilirubin), and LDL (low-density lipoprotein cholesterol)/(HDL+bilirubin) ratios were calculated. Unconditional and multinomial logistic regression models were used to examine associations of bilirubin or lipid with prevalence of peripheral atherosclerosis. Mediation analyses were performed to assess the effect of bilirubin on atherosclerosis risk mediated via lipid. Compared with participants with the lowest levels of bilirubin, those with the highest tertile were less likely to have carotid or femoral atherosclerosis (odds ratios were 0.55-0.74). The highest levels of bilirubin significantly reduced the odds of concurrent carotid and femoral atherosclerosis by 35% to 45%. Participants with the highest levels of cholesterol, LDL, cholesterol/(HDL+bilirubin), and LDL/(HDL+bilirubin) ratios had 2.8- to 3.7-fold increased odds of concurrent carotid and femoral atherosclerosis. LDL accounted for 25.65% of the total bilirubin-atherosclerosis association. LDL and cholesterol mediated the associations between direct bilirubin and atherosclerosis (proportion: 20.40%, 9.67%, respectively). Increased serum bilirubin levels are inversely associated with the prevalence of carotid or femoral atherosclerosis. LDL and cholesterol may mediate these associations.

Applicability of the Chronic Liver Failure-Consortium score in patients with cirrhosis and bacterial infections: a single-clinic experience

Background. The frequency and characteristics of acute-on-chronic liver failure (ACLF) are reported in numerous articles from different countries. The aim of the study was to assess the cirrhosis decompensation in patients with bacterial infections based on the Chronic Liver Failure-Consortium (CLIF-C) score in one of the city clinics in Belarus. Materials and methods. The patients underwent laboratory and instrumental studies during the hospitalization. The assessment of the syndrome of acute-on-chronic liver failure was performed using the CLIF-C score. Bacterial infections were diagnosed on the basis of standard criteria. Results. The study included 151 cirrhotic patients, 87 males and 64 females. Median age was 55 years (Q1=43; Q3=61). Cirrhosis was predominantly due to alcohol addiction— 83 patients (55%). ACLF was diagnosed in 44 of 151 patients with cirrhosis (29.1%; 95% confidence interval (CI) 22.0–37.1). Bacterial infections were detected in 67 people (44.4%; 95% CI 36.3–52.7). Most often patients had liver failure that was detected by an increase in serum bilirubin level. Among individuals with upper gastrointestinal bleedings, number needed to harm for developing ACLF was 3.3 (95% CI 2.2–4.4). The risk of developing ACLF grade 2 and 3 in cirrhotic patients with infections was 8.2, with 95% CI 1.0–69.6 (number needed to harm was 12.9; 95% CI 10.7–15.0). Bacterial infections increase the risk of acute decompensation in patients with cirrhosis (odds ratio=2.0, p=0.048). Conclusions. The CLIF-C score is quite applicable in our cohort of patients with cirrhosis.

The relationship between serum bilirubin levels and early neurological improvement in patients with acute ischemic stroke treated with intravenous tissue plasminogen activator

Background & Objective: Acute ischemic stroke is defined as the development of sudden neurological deficits resulting from a focal injury due to vascular occlusion in the central nervous system. Intravenous tissue plasminogen activator (t-PA) therapy in these patients is an internationally accepted, evidence- based effective treatment. Previous data suggest that increased serum bilirubin may reflect the intensity of oxidative stress associated with stroke severity. This study aimed to investigate the effect of bilirubin levels on early neurological improvement after intravenous t-PA treatment and whether bilirubin is a determinant in in-hospital mortality. Methods: The determinant role of admission bilirubin levels in the severity of stroke, in-hospital mortality and early neurological improvement after intravenous t-PA was investigated. An independent association of bilirubin with mortality and neurological improvement were identified by multivariate logistic regression analysis. Results: A total of 184 ischemic stroke patients who received intravenous t-PA were included in the study. Serum direct bilirubin, indirect bilirubin, and total bilirubin of patients in the group without early improvement were significantly higher than the group with improvement (p= 0.041, p= 0.030, p= 0.026, respectively). Also, in binary logistic regression analysis, total bilirubin was found to be an independent predictor for early neurological improvement (OR 6.257, 95%CI 1.482-26.413, p=0.013). Conclusions: There was a significant relationship between the severity of the stroke and in-hospital mortality and increased serum bilirubin levels in our study. Again, there was a significant relationship between the lack of early neurological improvement after intravenous t-PA and increased serum bilirubin levels, and serum direct bilirubin levels were independent predictor of neurological improvement.

Machine learning approach identifies meconium metabolites as potential biomarkers of neonatal hyperbilirubinemia

BackgroundThe gut microbiota plays an important role in the early stages of human life. Our previous study showed that the abundance of intestinal flora involved in galactose metabolism was altered and correlated with increased serum bilirubin levels in children with jaundice. We conducted the present study to systematically evaluate alterations in the meconium metabolome of neonates with jaundice and search for metabolic markers associated with neonatal jaundice. MethodsWe included 68 neonates with neonatal hyperbilirubinemia, also known as neonatal jaundice (NJ) and 68 matched healthy controls (HC), collected meconium samples from them at birth, and performed metabolomic analysis via liquid chromatography-mass spectrometry. ResultsGut metabolites enabled clearly distinguishing the neonatal jaundice (NJ) and healthy control (HC) groups. We also identified the compositions of the gut metabolites that differed significantly between the NJ and HC groups; these differentially significant metabolites were enriched in aminyl tRNA biosynthesis; pantothenic acid and coenzyme biosynthesis; and the valine, leucine and isoleucine biosynthesis pathways. Gut branched-chain amino acid (BCAA) levels were positively correlated with serum bilirubin levels, and the area under the receiver operating characteristic curve of the random forest classifier model based on BCAAs, proline, methionine, phenylalanine and total bilirubin reached 96.9%, showing good potential for diagnostic applications. Machine learning-based causal inference analysis revealed the causal effect of BCAAs on serum total bilirubin and NJ. ConclusionsAltered gut metabolites in neonates with jaundice showed that increased BCAAs and total serum bilirubin were positively correlated. BCAAs proline, methionine, phenylalanine are potential biomarkers of NJ.

P-39 The role of the prognostic nutritional index in predicting survival in advanced hepatocellular carcinoma treated with regorafenib

The link between malnutrition, immunological status and hepatocarcinoma (HCC) has been demonstrated. The Prognostic Nutritional Index (PNI) has been recognized as prognostic indicator in early-stage HCC and in patients treated with first-line therapy. Nowadays, no data have reported the role the PNI in HCC patients treated with regorafenib. We performed a multicentric analysis on a cohort of 284 patients affected by advanced HCC treated with regorafenib. The PNI was calculated as follows: 10 × serum albumin concentration (g/dL) + 0.005 × peripheral lymphocyte count (number/mm3). Univariate and multivariate analyses were performed to investigate the association between PNI and survival outcomes. A PNI cut-off value of 44.45 was calculated by performing a ROC analysis. The median overall survival (mOS) was 12.8 months and 7.8 months for patients with high (>44.45) and low (≤ 44.45) PNI, respectively (HR 0.58; 95% CI 0.43-0.77; p=0.0002). At the uni- and multivariate analyses, low PNI value and increased serum bilirubin level emerged as independent prognostic factors for OS. No differences were found between high versus low PNI in terms of progression-free survival (p=0.14). If validated, the PNI could represent an easy-to-use prognostic tool, able to guide the clinical decision-making process in HCC patients treated with regorafenib.

Role of the prognostic nutritional index in predicting survival in advanced hepatocellular carcinoma treated with regorafenib.

A link has been established between malnutrition, immunological status, and hepatocellular carcinoma (HCC). The prognostic nutritional index (PNI) has been recognized as a prognostic indicator in early-stage HCC and in patients treated with first-line therapy. However, to date, the role of the PNI in HCC patients treated with regorafenib has not been reported. We undertook a multicentric analysis on a cohort of 284 patients affected by advanced HCC treated with regorafenib. The PNI was calculated as follows: 10×serum albumin concentration (g/dl)+0.005×peripheral lymphocyte count (number/mm3 ). Univariate and multivariate analyses were used to investigate the association between PNI and survival outcomes. A PNI cut-off value of 44.45 was calculated by a receiver operating characteristic analysis. The median overall survival was 12.8 and 7.8 months for patients with high (>44.45) and low (≤44.45) PNI, respectively (hazard ratio, 0.58; 95% confidence interval, 0.43-0.77; p=0.0002). In the univariate and multivariate analyses, low PNI value and increased serum bilirubin level emerged as independent prognostic factors for overall survival. No differences were found between high and low PNI in terms of progression-free survival (p=0.14). If validated, the PNI could represent an easy-to-use prognostic tool able to guide the clinical decision-making process in HCC patients treated with regorafenib.

Plasma metals and serum bilirubin levels in workers from manganese-exposed workers healthy cohort (MEWHC)

Few studies specifically address the possible associations between multiple-metal exposures and liver damage among the occupational population. This study aimed to explore the cross-sectional relationships of plasma metals with liver function parameters. For 571 on-the-spot workers in the manganese-exposed workers healthy cohort (MEWHC), we determined liver function parameters: total bilirubin (TBILI), direct bilirubin (DBILI), indirect bilirubin (IBILI), alanine transaminase (ALT) and aspartate transaminase (AST). Total concentrations of 22 plasma metals were measured by ICP-MS. The LASSO (least absolute shrinkage and selection operator) penalized regression model was applied for selecting plasma metals independently associated with liver function parameters. Multiple linear regression analyses and restricted cubic spline (RCS) were utilized for identifying the exposure-response relationship of plasma metals with liver function parameters. After adjusting for covariates and selected metals, a 1-SD increase in log-10 transformed levels of iron was associated with increases in the levels of TBILI, DBILI and IBILI by 20.3%, 12.1% and 23.7%, respectively; similar increases in molybdenum for decreases in levels of TBILI, DBILI and IBILI by 6.1%, 2.6% and 8.3%, respectively. The effect of a 1-SD increase in plasma copper corresponded decreases of 3.2%, 3.4% and 5.0% in TBILI, AST and ALT levels, respectively. The spline analyses further clarified the non-linear relationships between plasma iron and bilirubin whilst negative linear relationships for plasma molybdenum and bilirubin. Plasma iron was positively whilst plasma molybdenum was negatively associated with increased serum bilirubin levels. Further studies are needed to validate these associations and uncover the underlying mechanisms.

Case 3: Early Severe Jaundice in a Term Infant

An appropriate-for–gestational age (AGA) African American female infant is born at term via elective, repeat cesarean section at 39 weeks’ gestation to a gravida 2, para 2 woman. The mother’s pregnancy had been complicated only by gestational hypertension, and maternal antenatal testing results were unremarkable. Maternal blood type is O positive with a negative antibody screen during pregnancy. Meconium fluid is noted at delivery; however, the infant is vigorous with a strong cry and requires only routine resuscitation with Apgar scores of 8 and 9 at 1 and 5 minutes, respectively. After resuscitation, the infant makes a transition to routine couplet care with an anticipated 48-hour stay. A cord blood sample is sent for blood type and direct antiglobulin test (DAT) per hospital protocol secondary to infant blood type finding of B-negative type with a negative DAT result. Her first 24 hours are uneventful with direct breastfeeding every 2 to 3 hours, 2 documented voids, 3 stools, and minimal weight loss. All documented vital signs and examination results are normal for a term newborn. At 24 hours after birth, a transcutaneous bilirubin test is attempted per standard newborn care plan, with the resulting value too high to detect. Serum total and direct bilirubin concentrations are found to be 21.7 mg/dL (360 μmol/L) and 0.6 mg/dL (10 μmol/L), respectively. The infant is transported directly to the NICU for continued management and preparation for possible exchange transfusion. With any case of hyperbilirubinemia, especially with early-onset or rapidly increasing levels, it is important to keep a broad differential to avoid missing benign versus more severe causes of jaundice. Categorizing by time of onset into 3 categories can be useful in establishing a differential diagnosis. These categories are based on newborn age: less than 24 hours after birth, between 24 and 72 hours after …

A study of biochemical parameters and microbial organisms in ascitic fluid of spontaneous bacterial peritonitis patients

Introduction:Spontaneous Bacterial Peritonitis (SBP) is recognized as a severe complication in patients of ascites. In recent years, it has also been diagnosed in patients without liver disease. SBP is commonly reported in patients of ascites due to cirrhosis of liver. If untreated, SBP could be a fatal complication in patients of ascites. Objective:To study the ascitic fluid biochemical parameters and causative micro-organisms in patients suffering from SBP. Materials and Methods:A prospective study was performed on 100 patients of ascites out of which 68 were males and 32 were females. After admission all patients were interviewed and detailed history and complete physical examination was performed. Results:In this study 86.7% patients had increased serum bilirubin levels, 73.4% patients had decreased serum albumin, 46.7% and 40% patients had increased blood levels of urea and creatinine respectively. 60% patients had ascitic fluid pH 250 polymorphonuclear cells/µL and 80% patients had >500 polymorphonuclear cells/ µL in ascitic fluid. 46.7% cases of SBP were culture positive and 53.3% were culture negative.Gram staining of ascitic fluid was positive in one case. Conclusion:Hypoalbuminemia, hyperbilirubinemia, low ascitic fluid pH, low ascitic fluid proteins, increased blood urea and creatinine levels are risk factors related with development of SBP in patients of ascites.The commonest micro-organism identified on culture were E-coli.

Bilirubin, a novel endocrine hormone with fat burning properties

Plasma bilirubin levels have been shown to be inversely related to obesity, diabetes, and cardiovascular events. Numerous clinical and population studies have demonstrated that increased serum bilirubin levels protect against metabolic diseases such as obesity and diabetes. Bilirubin is a potent antioxidant, and the beneficial actions of moderate increases in plasma bilirubin have been thought to be due to the antioxidant effects of the bile pigment. In the present study, we found that bilirubin has a new function as an endocrine hormone that can signal to the fat burning nuclear receptor, peroxisome proliferator‐activated receptor α (PPARα). The bilirubin‐PPARα mediated effects cause a significant decrease in lipid accumulation in adipose and liver of mice. Bilirubin is conjugated in the liver by UDP‐glucuronosyltransferase 1‐1 (UGT1A1) protein and then excreted into bile. Furthermore, we found that blockade of the UGT1A1 by either anti‐sense morpholinos or by genetic mutation caused significantly raised plasma unconjugated bilirubin levels which also heightened PPARα transcriptional activity in liver and adipose. Ultimately, increasing plasma unconjugated bilirubin decrease adiposity and lower blood glucose levels. These data indicate a new function for bilirubin as an endocrine hormone that can be regulated in the liver to control adiposity and insulin resistance in peripheral tissues. Targeting of UGT1A1 in the liver may offer future implications in the treatment of obesity and type II diabetes.Support or Funding InformationThis research was supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health under Award Number K01HL125445 (T.D.H.) and PO1HL‐51971 (D.E.S) and National Institute of General Medical Sciences P20GM‐104357 (D.E.S.).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

A Survey for Detection of the Urinary Tract Infection by Urine Culture in Younger than Eight Weeks Old Infants Suffering From Ichter in Amiralmomenin Hospital in Zabol City

Jaundice is one of the most common neonatal and infantile diseases and the most common cause of hospitalization in neonates and infants; this disorder occurs in 60% of infants and 80% of preterm infants. It is often physiologic and does not require special action, but it can be a sign of an important disease, and if not treated properly, leads to serious and dangerous complications such as Kernicterus (bilirubin deposition in the brain) that causes lifelong disability. One of the reasons for the increase in serum bilirubin levels is the transfer from fetal to infant phase and the temporary inability of the neonate liver to purify the bilirubin from the blood, because bilirubin is excreted by the pair during the fetal period; however, during the neonatal period, bilirubin is excreted by the liver cells and through the biliary and gastrointestinal tract .prolonged jaundice refers to cases where it lasts for more than two weeks in term infants and three weeks in preterm infants .

Neonatal jaundice: aetiology, diagnosis and treatment.

A significant proportion of term and preterm infants develop neonatal jaundice. Jaundice in an otherwise healthy term infant is the most common reason for readmission to hospital. Jaundice is caused by an increase in serum bilirubin levels, largely as a result of breakdown of red blood cells. Bilirubin is conveyed in the blood as 'unconjugated' bilirubin, largely bound to albumin. The liver converts bilirubin into a conjugated form which is excreted in the bile. Very high levels of unconjugated bilirubin are neurotoxic. Phototherapy is a simple and effective way to reduce the bilirubin level. Most term babies have 'physiological' jaundice which responds to a short period of phototherapy, and requires no other treatment. A few babies have rapidly rising bilirubin levels which place them at risk of kernicterus. Current management of jaundice in the UK is guided by the NICE guideline. Any infant with high serum bilirubin or a rapidly rising bilirubin level needs to be treated urgently to avoid neurotoxicity. High levels of conjugated bilirubin in a term baby can indicate biliary atresia, and babies with persisting jaundice must have their level of conjugated bilirubin measured. Preterm infants on long-term parenteral nutrition may develop conjugated jaundice which generally improves with the introduction of enteral feed and weaning of intravenous nutrition.

The role of Ntcp, Oatp2, Bsep and Mrp2 in liver injury induced by Dioscorea bulbifera L. and Diosbulbin B in mice.

Dioscorea bulbifera L. (DB) is a traditional Chinese herb used in thyroid disease and cancer. However, the clinical use of DB remains a challenge due to its hepatotoxicity, which is caused, in part, by the presence of Diosbulbin B (DIOB), a toxin commonly found in DB extracts. As abnormal expression of hepatobiliary transporters plays an important role in drug-induced liver injury, we assessed the hepatotoxicity induced by DB and DIOB, and explored their impacts on hepatobiliary transporter expression levels. Following liquid chromatography-tandem mass analysis of the DIOB content of DB extract, male ICR mice were randomly orally administered DB or DIOB for 14days. Liver injury was assessed by histopathological and biochemical analysis of liver fuction. The levels of transporter protein and mRNA were determined by western blotting and real-time PCR. Liver function and histopathological analysis indicated that both DB and DIOB could induce liver injury in mice, and that DIOB might be the primary toxic compound in DB. Moreover, down-regulation of Mrp2 blocked the excretion of bilirubin, glutathione disulfide, and bile acids, leading to the accumulation of toxic substrates in the liver and a redox imbalance. We identified down-regulated expression of Mrp2 as potential factors linked to increased serum bilirubin levels and decreased levels of glutathione in the liver and increased liver injury severity. In summary, our study indicates that down-regulation of Mrp2 represents the primary mechanism of DB- and DIOB-induced hepatotoxicity, and provides insight into novel therapies that could be used to prevent DB- and DIOB-mediated liver injury.

The molecular basis of jaundice: An old symptom revisited.

Increased serum bilirubin level is a widely used diagnostic marker for hepatic illnesses. Nevertheless, mild elevation of unconjugated serum bilirubin (such as in Gilbert syndrome) has been recently demonstrated to correlate with low risk of chronic inflammatory and/or oxidative stress-mediated diseases. In accord, a low serum bilirubin level has emerged as an important predisposing factor or a biomarker of these pathologic conditions including cardiovascular, tumour, and possibly neurodegenerative diseases. Bilirubin possesses multiple biological actions with interaction in a complex network of enzymatic and signalling pathways. The fact that the liver is the main organ controlling the bioavailability of bilirubin emphasizes the central role of this organ in human health.

Bilirubin Binding to PPARα Inhibits Lipid Accumulation.

Numerous clinical and population studies have demonstrated that increased serum bilirubin levels protect against cardiovascular and metabolic diseases such as obesity and diabetes. Bilirubin is a potent antioxidant, and the beneficial actions of moderate increases in plasma bilirubin have been thought to be due to the antioxidant effects of this bile pigment. In the present study, we found that bilirubin has a new function as a ligand for PPARα. We show that bilirubin can bind directly to PPARα and increase transcriptional activity. When we compared biliverdin, the precursor to bilirubin, on PPARα transcriptional activation to known PPARα ligands, WY 14,643 and fenofibrate, it showed that fenofibrate and biliverdin have similar activation properties. Treatment of 3T3-L1 adipocytes with biliverdin suppressed lipid accumulation and upregulated PPARα target genes. We treated wild-type and PPARα KO mice on a high fat diet with fenofibrate or bilirubin for seven days and found that both signal through PPARα dependent mechanisms. Furthermore, the effect of bilirubin on lowering glucose and reducing body fat percentage was blunted in PPARα KO mice. These data demonstrate a new function for bilirubin as an agonist of PPARα, which mediates the protection from adiposity afforded by moderate increases in bilirubin.

Identification of adverse events that have a negative impact on quality of life in a clinical trial comparing docetaxel versus S-1 with cisplatin in lung cancer

In the CATS (Cisplatin And TS-1) randomized trial comparing cisplatin plus either docetaxel (DP arm) or TS-1 (SP arm) in lung cancer, efficacy was found to be equivalent but the global quality of life (QOL) score was higher in the SP arm. The purpose of the current study was to identify which of the adverse events (AEs) contributed to the deterioration of QOL. QOL and AE data from the CATS trial were used to quantitatively analyze the relationship between deterioration of QOL score and occurrence of AEs. Subtracted values of the QOL score from post-chemotherapy to pre-chemotherapy were fully compared between patients with or without each AE (Student's t test, significance level=0.001). Multivariate linear regression analysis was also performed. Analysis of variance was performed to identify whether grade of AE(s) might be significantly correlated with the deterioration of the QOL score (significance level of 0.05). As expected, gastrointestinal (GI) toxicities were associated with worsening of a variety of QOL items in both trial arms, detected by both univariate and multivariate analysis (p<0.001 and p<0.0001, respectively). Multivariate analysis unpredictably indicated that an increase in serum bilirubin level was the only AE that was uniquely associated with worsening of physical functioning (p=0.0002), cognitive functioning (p<0.0001), and financial problems (p=0.0005) in the DP arm, although not in the SP arm. GI toxicities tended to be prolonged in the SP arm. An increase in serum bilirubin level may contribute to the worse global QOL of subjects in the DP arm in the CATS trial. The method we used here may be a unique approach to identify unpredictable AE(s) that worsen the QOL of patients treated by chemotherapy.