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Bilirubin has antioxidant and anti-inflammatory properties in vitro and in animal studies and protects against inflammatory, cardiovascular, and other diseases in observational studies; therefore, bilirubin has potential as a therapeutic agent. However, observational studies could be confounded by many factors. We used a genetic (n = 61,281) and clinical (n = 234,670) approach to define the association between bilirubin and 19 conditions with a putative protective signal in observational studies. We also tested if individuals with genetically higher bilirubin levels underwent more diagnostic tests. We used a common variant in UGT1A1 (rs6742078) associated with an 26% increase in bilirubin levels in the genetic studies. Carriers of the variant had higher bilirubin levels (P = 2.2 × 10-16 ) but there was no significant association with any of the 19 conditions. In a phenome-wide association study (pheWAS) to seek undiscovered genetic associations, the only significant finding was increased risk of "jaundice-not of newborn." Carriers of the variant allele were more likely to undergo an abdominal ultrasound (odds ratio = 1.04, [1.00-1.08], P = 0.03). In contrast, clinically measured bilirubin levels were significantly associated with 15 of the 19 conditions (P

Introduction. Mildly increased bilirubin concentration has a protective effect on oxidative stress–related diseases. However, it remains unknown whether elevated circulating bilirubin is associated with longer telomere length. The aim of this cross-sectional study was to examine the association between total bilirubin concentration and telomere length. Methods. We used the data from the National Health and Nutrition Examination Survey (NHANES) 1999-2002. The multivariable linear regression model was used to examine the association between total bilirubin concentration and telomere length. The nonlinear relationship was analyzed using a generalized additive model with the smoothing plot. Results. A total of 7818 participants with a mean age of 49.20 ± 18.82 years were included. Compared with the lowest concentration of total bilirubin (Q1), the highest quartile of total bilirubin concentration was associated with longer telomere length in male ( β = 0.04 , 95 CI%: 0.00, 0.07, P = 0.024 ) and female ( β = 0.04 , 95 CI%: 0.02, 0.04, P = 0.002 ). Furthermore, an inverted U-shaped relationship between total bilirubin and telomere length was found. On the left of turning points ( total bilirubin < 0.5 mg / dL ), total bilirubin concentration was positively associated with telomere length ( β = 0.23 , 95 CI%: 0.14, 0.32, P < 0.001 ). However, the association between total bilirubin concentration and telomere length was not significant ( β = 0.01 , 95% CI: -0.01, 0.04, P = 0.346 ) above the turning point. Conclusion. This is the first evidence based on a nationally representative survey demonstrating a positive and nonlinear association between total bilirubin concentration and telomere length. Future large-scale prospective studies are warranted to confirm our findings.

Perioperative use of probiotics serves as efficient prophylaxis against postoperative infections after liver transplantation, yet data on long-term effects of pre-transplant probiotic intake is lacking. The aim of this study was to assess the effects of pre-transplant probiotic administration on long-term results of liver transplantation. This was secondary analysis of a randomized trial. Patients were randomized to receive either 4-strain probiotic or placebo before liver transplantation. Five year graft survival was set as the primary end-point. Secondary end-points comprised serum bilirubin and C-reactive protein (CRP) concentration, international normalized ratio (INR), serum transaminases and gamma-glutamyl transferase (GGT) activity. Study group comprised 44 patients, of whom 21 received probiotics and 23 received placebo with 5-year graft survival of 81.0% and 87.0%, respectively (p = 0.591). Patients in the probiotic arm exhibited lower INR (p = 0.001) and CRP (p = 0.030) over the first 6 post-transplant months. In the absence of hepatitis B or C virus infection, pre-transplant administration of probiotics also reduced aspartate transaminase activity (p = 0.032). In the intervention arm, patients receiving probiotics for under and over 30 days had 5-year graft survival rates of 100% and 66.7%, respectively (p = 0.061). Duration of probiotic intake > 30 days was additionally associated with increased INR (p = 0.031), GGT (p = 0.032) and a tendency towards increased bilirubin (p = 0.074) over first 6 post-transplant months. Pre-transplant administration of probiotics has mild positive influence on 6-month allograft function, yet should not exceed 30 days due to potential negative effects on long-term outcomes. (ClinicalTrials.gov Identifier: NCT01735591).

Background Age has been implicated as a factor in the plateau of long-term survival after lung transplant. Methods We used data from the Scientific Registry of Transplant Recipients to identify all recipients of lung transplant aged ≥18 years of age between January 1, 2006, and February 19, 2015. A total of 14,253 patients were included in the analysis. Survival was estimated using a nonproportional hazard model and random-survival forest methodology was used to examine risk factors for death. Final selection of model variables was performed using bootstrap aggregation. Age was analyzed as both a continuous and categorical variable (age 55 years). Risk factors for death were obtained for the entire cohort and additional age-specific risk factors were identified for each age category. Results The median age at transplant was 59 years. There were 1,098 (7.7%) recipients 55 years of age. Age was the most significant risk factor for death at all time-points following transplant and its impact becomes more prominent as time from transplant increases. Risk factors for death for all patients included extremes of age, higher creatinine, single lung transplant, hospitalization before transplant, and increased bilirubin. Risk factors for death differed by age with social determinants of health disproportionately affecting survival for those in the youngest age category. Conclusions The youngest and oldest adult recipients experienced the lowest posttransplant survival through divergent pathways that may present opportunities for intervention to improve survival after lung transplant.

Hiperbilirubin adalah peningkatan kadar bilirubin di dalam jaringan ekstravaskuler sehingga konjungtiva, kulit dan mukosa akan berwarna kuning. Tujuan penelitian ini adalah mengetahui hubungan faktor-faktor yang mempengaruhi peningkatan kadar bilirubin terhadap peningkatan bilirubin bayi baru lahir di Rumah Sakit Husada. Penelitan ini dilakukan pada 54 orang responden, menggunakan desain deskriptif korelatif dengan pendekatan metode survey. Hasil penelitan ini didapatkan faktor yang mempengaruhi peningkatan kadar bilirubin pada bayi adalah faktor berat badan bayi rendah (

Background Training in advanced endoscopic techniques such as endoscopic retrograde cholangiopancreatography (ERCP) should be driven by key performance measures and standardized competence assessment in order to provide safe and high-quality interventions. We aimed to determine whether the involvement of trainees influences the outcome of the procedure and the incidence of ERCP-related adverse events. Methods This was an international, multicenter, prospective, observational study conducted at six high- and low-volume centers across Europe between October 2016 and October 2018, and included independent operators and their trainees. Standard report forms documenting indication, trainee involvement, technical outcome, and complications over a 30-day follow-up of consecutive ERCP procedures were included in the analysis. Technical success of the procedure and procedure-related adverse events were compared between procedures in the trainee group and the control group using bivariable and multivariable analysis. Results 21 trainees and 16 control endoscopists performed 1843 ERCPs during the study period. Trainee involvement in ERCP procedures did not decrease technical success (92.4 % vs. 93.7 %; P = 0.30) or increase the risk of adverse events (14.7 % vs. 14.6 %; P > 0.99). Conversely, there were significantly more moderate or severe adverse events in the control group compared with the trainee group (6.2 % vs. 3.4 %, P = 0.01). On multivariable analysis, only increased bilirubin levels, time to cannulation, and procedure difficulty level increased the risk of any procedure-related adverse event. Conclusion Trainee involvement in ERCP interventions within a proper teaching setting is safe and does not compromise the success of the procedure.

Neonatal hyperbilirubinemia is the elevation of the bilirubin level in the newborns blood, which results in yellowish staining of the skin and sclera of the newborn eyes by pigment of bile. It is due to the breakdown of RBC's (which release bilirubin into the blood) and the immaturity of newborns liver (which cannot effectively metabolize the bilirubin and prepare it for excretion into the urine). Increased bilirubin production, reduced hepatic clearance and enhanced enterohepatic circulation are the sole causes of increased prevalence of jaundice in newborn. The science of Ayurveda is supposed to add a step in order to understand the pathophysiology of neonatal jaundice that have resemblance with clinical entity of kamala (jaundice) mentioned in Kashyapa Samhita. The concept of neonatal hyperbilirubinemia in Ayurveda can be understood in the context of Pittaja stanya dushti along with the physiological variations in the newborns leading to the raised level of unconjugated bilirubin. Therefore, the patho-physiology should be known by a pediatrician in Ayurveda based on the involvement of dosha, dhatu, mala and srotas. Hence, an attempt is made in this review to discuss about the hidden concept of pathology of neonatal jaundice described in Ayurveda. These findings to understand the concept of neonatal jaundice in Ayurveda add up to the Ayurvedic science that has been developed through ages.

Multiple sclerosis (MS) is an immune-mediated, demyelinating disease of the central nervous system. In this study, an MS cohort and healthy controls were stratified into Caucasian and African American groups. Patient hematological profiles—composed of complete blood count (CBC) and complete metabolic panel (CMP) test values—were analyzed to identify differences between MS cases and controls and between patients with different MS subtypes. Additionally, random forest models were used to determine the aggregate utility of common hematological tests in determining MS disease status and subtype. The most significant and relevant results were increased bilirubin and creatinine in MS cases. The random forest models achieved some success in differentiating between MS cases and controls (AUC values: 0.725 and 0.710, respectively) but were not successful in differentiating between subtypes. However, larger samples that adjust for possible confounding variables, such as treatment status, may reveal the value of these tests in differentiating between MS subtypes.

Objective To study the effect of delayed cord clamping (DCC) on the bilirubin levels and hypoglycemia in neonates with diabetic mothers (NDMs). Methods This is a comparison between a prospective cohort and a historical control cohort. Women with gestational diabetes mellitus who performed DCC were enrolled into the prospective cohort (n = 156), and those who performed early cord clamping (ECC) were enrolled into the historical control cohort (n = 161). Results NDMs who received DCC had higher transcutaneous bilirubin than those in the ECC group whether maternal glycemic control was good or poor. DCC increased the rate of neonatal hyperbilirubinemia and phototherapy when maternal blood glucose was well controlled but not when it was poorly controlled. No differences were found in initial blood glucose levels on days 1 to 3 of life between the two groups. Conclusion Delayed cord clamping increased bilirubin levels, the risk of neonatal hyperbilirubinemia, and phototherapy in IDMs without improved initial blood glucose levels. Therefore, DCC was not recommended in NDMs.

Objective: Preterm infants are prone to increased bilirubin burden and display adverse outcomes if left unmonitored; therefore, predicting an increased bilirubin production is of paramount ...

Purpose Increased bilirubin concentrations may be related to outcome, but this has not been well studied. We evaluated the relationship between total serum bilirubin levels and outcome in critically ill patients. Materials and methods Data were analyzed from adult critically ill patients included in a 1-day international prevalence study after excluding those with an obvious underlying cause of hyperbilirubinemia. Results Serum bilirubin concentrations were >1 mg/dL in 2803 (31%) of 8973 patients, and these patients had higher mortality rates than patients with lower bilirubin concentrations (30% vs 21%, P R 2 = 0.96), with the highest hospital mortality (42%) in patients with bilirubin concentrations between 3.7 and 6.0 mg/dL. There was no further increase in the mortality rates for patients with bilirubin concentrations >6 mg/dL. A serum bilirubin concentration >1 mg/dL was an independent risk factor for mortality in multilevel analysis. Conclusions Hyperbilirubinemia without a recognized cause was common and independently associated with increased mortality. There was a linear correlation of mortality with bilirubin concentration for values between 1 and 6 mg/dL but not for higher values.

During the first week of life all newborns have increased bilirubin levels by adult standards, with approximately 60% of term babies and 85% of preterm having visible jaundice. A significant reduction in serum bilirubin analysis which is traumatic and painful, could be achieved after implementation of transcutaneous bilirubin (TCB) measurements in preterm babies. Measurements made on the forehead and sternum have the best correlation with TSB. Objectives Is to evaluate the use of non-invasive transcutaneous spectrophotometer, its efficiency and the influence of the site of measurement of transcutaneous bilirubin (forehead and sternum) on the accuracy of bilirubin levels. Subjects and methods This study was conducted on 316 clinically jaundiced neonates in NICU and post-natal clinics of Ain-Shams University Hospital, El Monira Governmental Public Hospital and El Amreky Private Hospital. Neonates of both sexes and gestational age ⩾30 weeks were included, with no hemolytic disease, no known skin disorders or receiving phototherapy or exchange transfusions. Transcutaneous bilirubin using Minolta JM-103 probe from sternum and forehead was measured and compared to serum bilirubin levels. Results There was statistically significant correlation between TSB and TCB in all the groups of studied cases, but was slightly higher in the cases with bilirubin measured in postnatal age of ⩽3 days. In preterm newborns, measurement of TCB from forehead was less accurate than from sternum. Conclusion Noninvasive TCB measurement by Minolta JM-103 has demonstrated significant accuracy compared to TSB measured by clinical laboratory methods in all cases with better accuracy in cases of IHB. TCB measurement over sternum is more accurate than forehead.

Ssstrunk (Zeit. F. Geb. u. Gyn., Bd. LXXXIX. H. I) in his studies could establish in pregnant women a 35% increased bilirubin content in the blood, while during childbirth this figure rose to 71%. The author could not notice any parallelism between this phenomenon and the increased content of bile acids in the blood usually observed during pregnancy. S. sees the reason for this phenomenon in the metabolic changes inherent in pregnancy, but not in the stagnation of bile. Among the diseases of pregnant women, the author did not find an increased content of bilirubin in the blood with the "kidney of pregnant women", and with eclampsia. on the contrary, I saw a significant increase in it.

The patient presented with recurrent epigastric pain and recent onset jaundice, with laboratory findings showing anemia (10.5 g/dL) and increased bilirubin levels (3.40 mg/dL).

Aim: Acute post liver transplant (LT) phase is characterized by hypermetabolism and increased nutrient requirements. This study aimed to provide the cardinal data on nutrition progression in the management of acute post-LT patients. Methods: This exploratory study recruited 54 adult acute post-LT recipients. The information regarding patient stay, weight status, biochemical parameters, and route of feeding was gathered. Recipients' dietary and nutrient intake was computed by 24-h dietary recall method. Results: The data exhibited a significant trend of lower hemoglobin, platelet, and albumin levels and increased bilirubin (T), alanine aminotransferase, aspartate aminotransferase, and gamma-glutamyl transferase levels (P < 0.05). In acute post-LT patients, a significant decrease in weight status (P < 0.001*) was observed. The recipients' information on daily nutrition progression showed significantly lower intake of calorie, protein, fats, calcium (P < 0.05) and lower percentage adequacy of other nutrients as compared to the recommended guidelines. The energy and protein intake from the parenteral route of feeding significantly decreased and that of through oral route significantly increased (P < 0.05) from postoperative day (POD) 2 to POD 9 and POD 12. Conclusion: There are scant data on nutrition management in acute post-LT phase. The present study provides the framework for the formulation of continuous, patient-centric, aggressive nutrition management interventions for acute post-LT recipients.

Background Neonatal asphyxia is often associated with hepatic injury. We hypothesized that this might lead to increased bilirubin concentrations. Study Design Term neonates admitted between January 2015 and April 2017 who remained hospitalized for ≥ 4 days and who had serial serum bilirubin concentrations recorded were divided into those with neonatal encephalopathy (NE) and controls. Serial serum bilirubin concentrations during the first days of life were compared between groups. Results Twenty-nine neonates with NE and 84 age-matched controls were identified. Mean total serum bilirubin concentrations of NE babies were significantly lower than those controls throughout the first days of life. At 96 hours of age, NE serum bilirubin concentrations were 4.5 (3.2, 5.8) versus controls of 10.5 (9.4, 11.5) mg/dL (p Conclusion Contrary to our hypothesis, bilirubin concentrations in NE infants are significantly lower than expected during the first 4 days postnatally. We speculate that, under conditions of severe oxidative stress, bilirubin is consumed as an antioxidant.

Background: Jaundice is frequently associated with extrahepatic systemic infections. The important causes include increased bilirubin levels due to hemolysis, hepatic dysfunction, reduced excretion and cholestasis.

Background. Diabetes mellitus characterized by hyperglycaemia presents with various complications amongst which anaemia is common particularly in those with overt nephropathy or renal impairment. The present study has examined the contribution of the hyperglycaemic environment in diabetic rats to the anaemia associated with diabetes mellitus. Method. Sixty male albino rats weighing 175–250 g were selected for this study and divided equally into control and test groups. Hyperglycaemia was induced with 170 kgbwt−1alloxan intraperitoneally in the test group while control group received sterile normal saline. Blood samples obtained from the control and test rats were assayed for packed cell volume (PCV), haemoglobin (Hb), red blood cell count (RBC), reticulocyte count, glucose, plasma haemoglobin, potassium, and bilirubin.Result. Significant reduction (P<0.01) in PCV (24.40±3.87versus40.45±3.93) and haemoglobin (7.81±1.45versus13.39±0.40) with significant increase (P<0.01) in reticulocyte count (12.4±1.87versus3.69±0.47), plasma haemoglobin (67.50±10.85versus34.20±3.83), and potassium (7.04±0.75versus4.52±0.63) was obtained in the test while plasma bilirubin showed nonsignificant increase (0.41±0.04versus0.24±0.06).Conclusion. The increased plasma haemoglobin and potassium levels indicate an intravascular haemolytic event while the nonsignificant increased bilirubin showed extravascular haemolysis. These play contributory roles in the anaemia associated with diabetes mellitus.

The interference of bilirubin in kinetic alkaline picrate creatinine assays (Jaffe) has been widely known and described in the literature (1). Many publications describe a negative interference of bilirubin in Jaffe creatinine assays (2, 3). Falsely decreased creatinine results can have far-reaching implications on the treatment of patients. Patients receiving treatment with aminoglycosides or patients subject to imaging procedures are very dependent on accurate creatinine measurements. Measurements of creatinine clearance and estimation of the glomerular filtration rate are also highly dependent on an accurate creatinine measurement. In this study, we observed a trend of falsely increased creatinine values in the presence of increased bilirubin levels, demonstrated by increasing icterus (I) indices. At our institution, we are using the Roche COBAS 6000, creatinine …

Hyperbilirubinemia is a benign transitional phenomenon that occurs in 60% to 80% of all term infants. The degree of hyperbilirubinemia and hence risk for developing bilirubin-induced neurologic dysfunction or BIND is dependent upon two major processes: (i) bilirubin production and its elimination.The aim of this review is to address the importance of hemolysis and its clinical detection in neonates with hyperbilirubinemia.In newborns, an increased bilirubin production rate due to hemolysis is often the primary cause of hyperbilirubinemia during the first week of life. If undiagnosed or untreated, it may lead to an increased risk for BIND. Therefore, the ability to identify infants with hemolytic disease is important in assessing those at risk for developing BIND. In addition, an infant's genetic profile and bilirubin binding status can also affect their overall capacity to cope with the resultant tissue bilirubin load and affect risk and guide appropriate management strategies.Therefore, the determination of a newborn's bilirubin production rate is critical to the assessment of a newborn's risk for developing unpredictable extreme hyperbilirubinemia and preventing BIND.

Introduction: Recognition of the characteristics of neonatal jaundice with different levels of severity can help the physician with appropriate treatment and prediction of complications. This study aimed to determine the characteristics of neonatal jaundice in different levels of severity. Materials and Methods: This cross-sectional study was performed on 3005 neonates referring to the Neonatal Intensive Care Unit, Clinic, and Emergency ward in Ghaem Hospital of Mashhad, Iran, from 2009 to 2018. Sampling was carried out through the convenience sampling method. The data collection tool was a researcher-made questionnaire, including laboratory evaluation, as well as assessment of maternal and neonatal characteristics. The newborns were divided into six groups based on the serum bilirubin level and then compared in terms of characteristics, causes, and prognosis according to the severity of jaundice. The data were analyzed using the Student's t-test and Chi-square test. Results: In most cases, the present of jaundice was reported between 2 and 3 days of birth, and the age of neonates' reference was between 6 and 8 days of birth. Causes of neonatal jaundice included unknown reasons (61.25%), increased production of bilirubin (22%), severe weight loss (7%), infections (5.3%), endocrine disorders (2.5%), and other causes (1.7%). In jaundice level lower than 25 mg/dl, about 15% of neonates were reported with complications; however, at the bilirubin level higher than 35 mg/dl, approximately 40% of newborns had complications. Conclusion: The known causes of the jaundice were mostly observed in the increased bilirubin production level higher than 25 mg/dl.

Rationale:Sepsis-associated liver failure is characterized by increased bilirubin levels and coagulation disorders, which has a significant impact on mortality due to the insufficient understanding of its complicated pathogenesis pathophysiology and a lack of standardized treatment.Patient c

Aim To examine if fasting affects serum bilirubin levels in clinically healthy males and females. Methods We used retrospective data from phase I clinical trials where blood was collected in either a fed or fasting state at screening and predosing time points and analysed for total bilirubin levels as per standard clinical procedures. Participants were clinically healthy males (n=105) or females (n=30) aged 18–48 inclusive who participated in a phase I clinical trial in 2012 or 2013. Results We found a statistically significant increase in total serum bilirubin levels in fasting males as compared with non-fasting males. The fasting time correlated positively with increased bilirubin levels. The age of the healthy males did not correlate with their fasting bilirubin level. We found no correlation between fasting and bilirubin levels in clinically normal females. Conclusions The recruitment and screening of volunteers for a clinical trial is a time-consuming and expensive process. This study clearly demonstrates that testing for serum bilirubin should be conducted on non-fasting male subjects. If fasting is required, then participants should not be excluded from a trial based on an elevated serum bilirubin that is deemed non-clinically significant.

We present an extremely rare case of hyperbilirubinemia with rapid progression leading to bilirubin encephalopathy in term neonate. Despite early recognition and intervention, death occurred as a total serum bilirubin reached 25 mg/dl. It was a case of Coomb’s negative microangiopathic haemolytic anaemia in a newborn period which is autosomal recessive inheritance i.e. Upshaw-Schulman Syndrome. (Congenital thrombotic thrombocytopenic purpura) characterised by numerous schistocytes on peripheral blood smear, thrombocytopenia , increased reticulocyte count, increased bilirubin and LDH level. This rare disease is often misdiagnosed especially in newborn baby. So we present this case not only for its variety but also for to create more awareness among pathologist and paediatrician as treatment protocol entirely differ.

Preterm neonates with increased bilirubin production loads are more likely to sustain adverse outcomes due to either neurotoxicity or overtreatment with phototherapy and/or exchange transfusion. Clinicians should rely on expert consensus opinions to guide timely and effective interventions until there is better evidence to refine bilirubin-induced neurologic dysfunction or benefits of bilirubin. In this article, we review the evolving evidence for bilirubin-induced brain injury in preterm infants and highlight the clinical approaches that minimize the risk of bilirubin neurotoxicity.

Blood transfusion scientists have different definitions of ‘clinical significance’. For instance, is clinical significance judged by shortened RBC survival, laboratory evidence of haemolysis (e.g. increased bilirubin, LDH, etc.), and/or clinical signs (e.g. jaundice) of a haemolytic transfusion reaction (HTR)? Are one, two, or all three of these criteria needed to make an antibody significant? For instance, is a shortened RBC survival with no obvious laboratory abnormalities and/or or clinical signs really clinically significant? The answer may be different for a haematology patient requiring regular transfusions and a surgical patient with normal erythropoiesis. It is important to answer these questions in one’s own institution as they are the basis for our choice of compatibility tests and needed for interpretation of assays predicting clinical significance. Several approaches are valuable in predicting clinical significance: (1) specificity and thermal amplitude of the antibody; (2) 1 h survival of 51Cr-labelled incompatible RBCs; (3) functional cellular assays. Only antibodies reactive at 37°C in vitro are of potential significance. The 51Cr survival and cellular assays [e.g. monocyte monolayer assay (MMA)] are usually used to help decide if incompatible RBCs can be transfused to patients with antibodies to high-incidence antigens that are sometimes significant but often are not. When the MMA = 5·1–20%, 33% of patients showed no clinical reactions, but 67%, with no clinical signs showed laboratory signs of a reaction. If the MMA is >20%, most patients show clinical (64%) or laboratory (75%) reactions. It is of interest to note that regardless of MMA or 1 h 51Cr results, most patients with antibodies to high-incidence antigens have abnormal full RBC survival studies (T50Cr), but only one-third show any clinical signs of a reaction. Thus, when interpreting results for clinicians, it is important to clearly define what you mean by ‘clinical significance’ so that they can balance decisions of transfusing incompatible blood versus time and expense of obtaining rare units lacking the cognate antigen. Cellular assays are not available for many people, so historical data on whether certain specificities have caused HTRs are the only practical approach for many.

A multicenter observational study, conducted by the Japanese Society of Hematology (JSH), evaluated the effectiveness and safety of tyrosine kinase inhibitors (TKIs) in newly diagnosed patients with chronic myeloid leukemia -chronic phase (CML-CP). The clinical data of this study were collected using the New Target system, which is an online database that can be easily accessed by physicians. A total of 506 patients were enrolled from 102 institutions between April 2010 and March 2013; data for 444 patients (median age: 56 [range 18-92] years; 65% male) were analyzed. According to the Sokal score, 201 (45.3%), 178 (40.1%), and 64 patients (14.4%) were classified into the low, intermediate, and high-risk groups. As the first-line therapy, 148 (29.8%) patients received imatinib (IM), 173 (34.8%) received nilotinib (NIL), and 146 (29.4%) received dasatinib (DAS). BCR-ABL1 % was regularly monitored every 3 months in the first year and every 6 months thereafter. TKI plasma trough concentrations were determined with LC-MS/MS at 3, 6, and 12 months. At 60 months of follow up, 5-year progression-free survival (PFS) and overall survival (OS) were 94.5% (95%CI, 91.2-96.5) and 94.8% (95%CI, 91.6-96.9), respectively. The 5-year OS curve was significantly better in patients treated with NIL or DAS than that in patients with IM (IM, 90.9% [95%CI, 83.7-95.0]; NIL, 98.0% [95%CI, 92.2-99.5]; DAS, 96.0% [95%CI, 89.4-98.5]; log-rank test: P =0.0345). An early molecular response (EMR; BCR-ABL1 Testing for BCR-ABL1mutation was performed in 101 patients. Various BCR-ABL1mutations were identified in 23 patients (IM, n=13; NIL, n=8; and DAS, n=2). T315I mutation was not identified. Exon 8/9 35bp insertion was identified in 14 patients (IM, n=8; NIL, n=5; DAS, n=1). Seven out of these 14 patients achieved DMR; and all patients with exon 8/9 35bp insertion did not progress to accelerated or blast phase . The achievement of major molecular response (MMR, BCR-ABL1 No new safety issues occurred. Among 444 analyzed patients in the safety data set, only 2 patients with NIL had peripheral arterial occlusive disease [grade 1] or acute coronary disease [grade 3]. No patients developed pulmonary arterial hypertension in this study. We measured pleural effusion (PE) in patients with DAS and liver/pancreas dysfunction in patients with NIL, which were the common adverse events. In the DAS arm, 28 patients revealed pleural effusion (grade 1, 3 patients; grade2, 22 patients; grade3, 3 patients). It occurred not only in the first year of treatment but also in the second or third year (median 10.5 [range 1-60] months). However, no statistically significant association was found between pleural effusion and trough concentration of DAS in this study (2.71 ng/mL in patients with PE vs. 2.27 ng/mL in patients without, P =0.1339). In the NIL arm, 17 patients revealed severe liver dysfunction (grade 3-4, n=6), increased bilirubin values (grade 3, n=4), or increased lipase values (grade 3-4, n=7). The adverse events occurred in 3 months in these patients with NIL, except for 4 patients. In summary, this 5-year Japanese registry using the New Target system demonstrated that TKI treatments in newly diagnosed patients with CML-CP achieved satisfying and trustworthy outcomes. Figure. Figure. Disclosures Takahashi: Bristol-Myers Squibb: Research Funding, Speakers Bureau; Pfizer: Research Funding, Speakers Bureau; Otsuka: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau. Kizaki:Nippon Shinyaku,: Research Funding, Speakers Bureau; Novartis: Speakers Bureau; Bristol-Myers Squibb: Research Funding, Speakers Bureau; Celgene: Research Funding, Speakers Bureau. Kawaguchi:Novartis Pharma K.K.: Honoraria, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Alexion: Honoraria, Speakers Bureau. Suzuki:Celgene: Honoraria; Sawai Pharmaceutical: Honoraria; Ohtsuka: Honoraria; MSD: Research Funding; Meiji Seika Pharma: Honoraria; Takeda Pharmaceuticals: Honoraria; Shionogi: Honoraria; Novartis: Honoraria; Mochida Pharmaceutical: Honoraria; Chugai Pharmaceutical: Honoraria; Kyowa-Hakko Kirin: Honoraria; Bristol-Myers Squibb: Honoraria; Sumitomo Dainippon Pharma: Honoraria; Gilead Sciences: Consultancy; MundiPharma: Consultancy; Jazz Pharmaceuticals: Consultancy. Yamamoto:Chugai: Consultancy, Honoraria, Research Funding; Meiji Seika Pharma: Consultancy; Mundipharma: Consultancy, Honoraria; Ono: Consultancy, Honoraria, Research Funding; ARIAD Pharmaceuticals: Research Funding; Bayer: Research Funding; Celgene: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Gilead Sciences: Research Funding; MSD: Research Funding; Novartis: Honoraria, Research Funding; Solasia Pharma: Research Funding; SymBio: Research Funding; Takeda: Honoraria, Research Funding; AbbVie: Research Funding; Boehringer Ingelheim: Consultancy; Zenyaku: Research Funding; Bristol-Myers Squibb: Honoraria; Kyowa Hakko Kirin: Honoraria; Otsuka: Honoraria; Pfizer: Honoraria; Sumitomo Dainippon: Honoraria; HUYA: Honoraria. Naoe:Nippon Shinyaku Co., Ltd.: Research Funding; Otsuka Pharmaceutical Co., Ltd.: Research Funding; Fujifilm Corporation: Patents & Royalties, Research Funding; Pfizer Japan Inc.: Research Funding; Astellas Pharma Inc.: Research Funding; Toyama Chemical Co., Ltd.: Research Funding. Akashi:MSD: Research Funding; Ono Pharmaceutical: Research Funding; Novartis pharma: Research Funding; Otsuka Pharmaceutical: Research Funding; Chugai Pharma: Research Funding; Astellas Pharma: Research Funding; Eisai: Research Funding; Taiho Pharmaceutical: Research Funding; sanofi: Research Funding; Asahi-kasei: Research Funding; Pfizer: Research Funding; Kyowa Hakko Kirin: Research Funding, Speakers Bureau; Eli Lilly Japan: Research Funding; Celgene: Research Funding, Speakers Bureau; Bristol-Myers Squibb: Research Funding, Speakers Bureau.

Background.Exogenous bilirubin may reduce experimental ischemia-reperfusion injury (IRI) due to its antioxidant properties. We studied if early graft exposure to high bilirubin levels in the recipient affects the early IRI and outcomes after liver transplantation (LTx).Methods.In 427 LTx patients, the AUROC curve based on bilirubin and AST at day 1 identified a cutoff of 2.04 mg/dL for the recipient pretransplant bilirubin. Recipients were grouped as having low (group L,n=152) or high (group H,n=275) bilirubin. Both groups had similar donor-related variables (age, preservation time, donor BMI > 28, and donor risk index (DRI)).Results.Alanine (ALT) and aspartate (AST) aminotransferase levels were higher in group L at day 1; ALT levels remained higher at day 2 in group L. LTx from high risk donors (DRI > 2) revealed a trend towards lower transaminases during the first two days after transplantation in group H. One month and 1-year patient survival were similar in groups L and H. High preoperative bilirubin did not affect the risk for early graft dysfunction (EGD), death, or graft loss during the first year after transplantation nor the incidence of acute rejection. LTx using donors with DRI > 2 resulted in similar rates of EGD in both groups.Conclusion.Increased bilirubin appears to reduce the early IRI after LTx yet this improvement was insufficient to improve the clinical outcome.

Jaundice in preterm, as well as full term, infants results from (a) an increased bilirubin load in the hepatocyte, (b) decreased hepatic uptake of bilirubin from the plasma, and/or (c) defective bilirubin conjugation. Hyperbilirubinaemia in preterm infants is more prevalent, more severe, and its course more protracted than in term neonates.

The pathologic phenotype of severe hyperbilirubinemia in the newborn infant is primarily due to excessive bilirubin production and/or impaired conjugation, resulting in an increased bilirubin load. This may, in turn, increase an infant's risk for the development of bilirubin-induced neurologic dysfunction (BIND). The highest-risk infants are those with increased bilirubin production rates due to hemolysis. Several immune and non-immune conditions have been found to cause severe hemolysis, and these are often exacerbated in those infants with perinatal sepsis and genetic predispositions. Therefore, identification of these infants, with novel technologies, is paramount in reducing the incidence of BIND and the long-term neurologic sequelae for these at-risk infants.

Increased hemolysis in the presence of severe neonatal hyperbilirubinemia appears to augment the risk of bilirubin neurotoxicity. The mechanism of this intensifying effect is uncertain. In direct antiglobulin titer (DAT) positive, isoimmune hemolytic disease, the bilirubin threshold at which neurotoxicity occurs appears to be lower than in DAT-negative hyperbilirubinemia. In other hemolytic conditions, the hemolysis may simply facilitate the development of extremely high serum bilirubin levels. Whether the hemolytic process per se exerts an independent effect or whether a very rapid rise in serum bilirubin might lead to greater penetration of the blood–brain barrier is unclear. In this review, we survey the synergistic role of hemolysis associated with severe hyperbilirubinemia in the potentiation of bilirubin-induced neurotoxicity and suggest methods of identifying at-risk babies with increased hemolysis to allow for their increased surveillance.

Neonatal jaundice usually occurs in the transitional period after birth, presenting as an elevation of circulating bilirubin. Bilirubin neurotoxicity can occur if the levels of bilirubin become excessive (hyperbilirubinemia). This pathologic phenotype of newborn jaundice can develop because of excessive bilirubin production or impaired conjugation, with the risk for developing bilirubin-induced neurologic dysfunction, depending on the degree of the resultant bilirubin load. The plasma bilirubin level thus can be used to assess an infant's risk for developing bilirubin neurotoxicity relative to an infant's age in hours. Because all infants have an impaired conjugation ability, infants at greatest risk are those who have increased bilirubin production rates, because of hemolysis, for example. Therefore, developing potential preventive strategies as well as noninvasive technologies to treat and to identify infants with increased bilirubin production rates, respectively, are tantamount to reducing the incidence of bilirubin-induced neurologic dysfunction.

The bilirubin content of the blood is increased in haemolytic conditions, as can be demonstrated by the indirect quantitative reaction of Van den Bergh. It seems probable, therefore, that the presence in the umbilical circulation of increased bilirubin, demonstrated by the indirect reaction, might be interpreted as early diagnostic evidence of haemolytic disease of the newborn.

We report an unusual cause for a false-positive interference in the total bilirubin method on the Beckman Coulter DxC 800 analyzer and for the hemolytic index (HI) measured on the Roche Modular D. A total bilirubin result of 53 μmol/L was obtained for a patient who had an earlier result of 7 μmol/L on the DxC 800 analyzer. The direct bilirubin concentration remained at

OBJETIVO: Avaliar a eficácia do TIPS (transjugular intrahepatic portosystemic shunt) para tratar as complicações clínicas em pacientes com hipertensão portal. MATERIAIS E MÉTODOS: Quarenta e quatro pacientes, sendo 30 do sexo masculino e 14 do feminino e com idade média de 52 anos foram analisados. A indicação para realização de TIPS foi hemorragia gastrintestinal em 28 e ascite refratária em 16. Houve 7 pacientes Child-Pugh A, 24 Child-Pugh B e 11 Child-Pugh C. RESULTADOS: O TIPS foi realizado com sucesso em todos os pacientes (100%), verificando-se queda do gradiente pressórico porto-sistêmico médio de 49,69% (de 18,98 mmHg para 9,55 mmHg). Comprovou-se melhora clínica em 35 pacientes (79,55%). A mortalidade pós-operatóriaia foi de 13,64%, sendo mais incidente nos pacientes Child-Pugh C (45,45%). Os fatores mais relevantes de mau prognóstico foram o aumento da bilirrubina e do nível de creatinina. A sobrevida média de pacientes Child-Pugh A foi de 11,5 meses, nos Child-Pugh B foi de 10,97 meses e nos Child-Pugh C foi de apenas 5,9 meses. Foram observadas complicações em nove casos (20,44%). CONCLUSÃO: O TIPS é eficiente para reduzir a pressão portal. As complicações e a morbi-mortalidade relacionadas com o procedimento podem ser consideradas aceitáveis. A mortalidade foi influenciada por alguns fatores clínicos, tais como classe Child-Pugh C e elevação dos níveis séricos de bilirrubina e creatinina. OBJECTIVE: To evaluate the efficacy of TIPS (transjugular intrahepatic portosystemic shunt) for resolving clinical complications in patients with portal hypertension. MATERIALS AND METHODS: Forty-four caucasian patients, 30 men and 14 women, with a mean age of 52 years have been evaluated. Indication for TIPS has been gastrointestinal hemorrhage in 28 patients, and refractory ascites in 16. There has been 7 Child-Pugh A patients, 24 Child-Pugh B, and 11 Child-Pugh C. RESULTS: TIPS was successfully performed in all the patients (100%), with a decrease in the mean portosystemic pressure gradient of about 49.69% (from 18.98 mmHg to 9.55 mmHg). A clinical improvement was observed in 35 patients (79.55%). The general postoperative mortality rate was 13.64%, with higher incidence in Child-Pugh C patients (45.45%). The most relevant factors associated with a poor prognosis were increase in bilirubin and creatinine seric levels. The mean survival time was 11.5 months for Child-Pugh A patients, 10.97 months for Child-Pugh B patients, and just 5.9 months for Child-Pugh C patients. Complications directly related to the procedure have been observed in nine cases (20.44%). CONCLUSION: TIPS is efficient to reduce portosystemic pressure. TIPS-related complications and morbidity-mortality may be considered as acceptable. In the present study, mortality has been directly influenced by some clinical factors such as Child-Pugh class C, and increased bilirubin and creatinin seric levels.

Abbreviations: OS: overall survival in months, LCI, UCI: lower and upper limits of the 95% confidence interval, ECOG PS: Eastern Cooperative Oncology Group Performance Score (13 patients had a score of 1 and one patient had a score of 2), BCLC: Barcelona Clinic Liver Cancer Stage, * = statistically significant difference from the corresponding reference group (ECOG PS approaching statistical significance with p =0.07), + = Liver Decompensation developed after starting sorafenib in 25 patients (2 encephalopathy, 1 variceal bleeding, 1 increased bilirubin, 21 ascites)

We read with interest the Technical Brief by Smogorzewska et al. (1) describing an artificially increased total bilirubin in a patient with a monoclonal IgM paraprotein. Monoclonal paraproteins have been shown to artifactually influence several automated assays of different methodologies, including nephelometry, turbidometry, and immunologic assays, by forming precipitates during the assay procedure (2)(3)(4)(5)(6)(7). The total bilirubin assay on the Hitachi 917 automatic chemistry analyzer (Roche Diagnostics) has been reported to yield falsely increased bilirubin values as a result of paraprotein interference (1)(8). Smogorzewska et al. (1) and Pantanowitz et al. (8) described this artifact as rare, but we have identified 6 patients at 2 hospitals with documented paraproteins who had falsely increased serum total bilirubin. Notably, patients with artifactually high total …

Bilirubin, a breakdown product of lysed red blood cells, is present in amniotic fluid in very small concentrations relative to serum (1). In an uncomplicated pregnancy, bilirubin in amniotic fluid peaks at ∼19–22 weeks of gestation at concentrations of 1.6–1.8 mg/L (1). Rh isoimmunization and its severe manifestation, erythroblastosis fetalis, are associated with intrauterine hemolysis, which leads to increases in amniotic fluid bilirubin concentrations (2) up to 9.6 mg/L (3)(4). The assessment of fetal lung maturity (FLM) in these pregnancies is sometimes necessary, but the ability to utilize current methods in the presence of increased bilirubin concentrations is unclear. The commercial TDx FLM II assay (Abbott Laboratories), which is based on fluorescence polarization technology and the dye PC-16 (5), is the most commonly used method to assess FLM (6). Although the manufacturer does not recommend testing icteric amniotic fluid samples, nothing has been published about the nature or quantification of their interference with the TDx FLM II assay. Our objective was to examine the effect of bilirubin on TDx FLM II concentrations. Frozen leftover amniotic fluid samples sent to the laboratory for physician-ordered FLM testing …

The purpose of this study was to test the hypotheses that newborn infants with moderate serum bilirubin concentrations have depressed Brazelton scores and increased brain-stem conduction time and that serum bilirubin levels correlate with Brazelton behavior scores and brain-stem auditory evoked response changes. Fifty term infants who were enrolled into either a low serum bilirubin group (less than 8 mg/dl) or a moderate serum bilirubin group (10 to 20 mg/dl) were tested with the Brazelton Neonatal Behavioral Assessment Scale and a brain-stem auditory evoked response test. Partial correlation analysis controlling for phototherapy revealed that increased bilirubin concentration correlated negatively with the Brazelton orientation and with state range clusters and individual Brazelton test items that involve auditory processing. Increased bilirubin concentration correlated with an increased latency of brain-stem auditory evoked response wave 4, 5. An increased interpeak 1-5 (brain-stem conduction time) correlated with the decreased animate visual and auditory item. We conclude that moderate hyperbilirubinemia in term infants affects both infant behavior, as measured by specific components of the Brazelton test, and brain-stem conduction time, as measured by the brain-stem auditory evoked response test.

The Incidence of Increased Bilirubin Production in Hyperbilirubinemic Neonates as Indexed by Breath Carbon Monoxide (CO)

EVIDENCE FOR INCREASED BILIRUBIN PRODUCTION IN NEWBORN INFANTS READMITTED TO HOSPITAL WITH HYPERBILIRUBINEMIA. • 960

Neonates with Down's Syndrome (DS) frequently develop hyperbilirubinemia(peak serum total bilirubin (Bili) ≥15mg/dL). The aim of the study was to determine whether jaundice in DS neonates is due to increased bilirubin production, resulting from rapid heme degradation, reflected by carboxyhemoglobin (COHb) values. Blood for COHb and Bili was sampled from DS neonates and controls on the 3rd day of life. COHb was measured by gas chromatography and expressed as% total hemoglobin (tHb). Inspired air CO concentrations were determined by electrochemistry, and measured COHb corrected for inspired CO (COHbc). Peak Bili (possibly modified by phototherapy) was recorded. Mean ± SD were calculated and compared using Student's t test. Significance is defined as p

Oral bile acid loading tests using 1 g of unconjugated chenodeoxycholic acid (CDA) were performed in subjects with Gilbert's syndrome before and after reduced caloric intake. The study was carried out to ascertain whether the hepatic handling of CDA was restricted in the same manner as recently described for ursodeoxycholic acid. In subjects with Gilbert's syndrome, the bile acid concentrations after the oral loading tests did not differ significantly from those found in reference groups. No differences were found in the serum bile acid values before and after caloric restriction, indicating that the bile acid handling was not influenced by the increased bilirubin levels obtained after fasting. Our results indicate that the hepatic handling of CDA is normal in Gilbert's syndrome.

To identify factors affecting bilirubin excretion, the effects of bile flow and bile salt excretion on bilirubin output into bile have been examined in normobilirubinemic, cholecystectomized patients with balloon-occludable, reinfusion T-tubes, 8 patients with cholesterol (CS) and 2 with pigment (PS) gallstones. Another patient with pigment gallstones, sickle cell disease (SS), and stable jaundice was studied to examine the mechanism by which an increased bilirubin load was excreted. Total bilirubin was almost entirely conjugated and excretion was related linearly to bile salt excretion in PS and CS subjects; one-third of bilirubin excretion was bile salt independent and two-thirds was bile salt associated. In the SS patient 90% of the bilirubin excretion was independent of bile salt output. In PS and CS patients, bilirubin output was linearly related to bile flow, but the SS patient showed significant bilirubin excretion at low flow rates. CS and PS patients had similar patterns of bilirubin excretion, but the increased bilirubin load in the SS patient was excreted entirely independently of bile salts. In the SS patient, unconjugated bilirubin output was hyperbolically related to bile salt output and represented a maximum of 3% of the total bilirubin output. The bile salt-independent excretion of conjugated bilirubin suggests that micelles were not required for transport into bile; whereas the hyperbolic relationship for unconjugated bilirubin and bile salt output, similar to that of the micellar lipids, cholesterol, and phospholipids, suggests interaction with micelles.

Non-artificial blood admixture in cerebrospinal fluid (CSF) can be proven by demonstrating siderophages and ‘bilirubin excess’. Bilirubin excess exists when the bilirubin concentration measured in the CSF exceeds the expected CSF bilirubin concentration. The expected CSF bilirubin concentration is calculated by multiplying the serum bilirubin concentration by the albumin quotient. Given a certain method of determination, a difference between the above-mentioned concentrations of less than 0.15 μmol/l must not be regarded as excess. Bilirubin excess was exclusively found in CSF with non-artificial blood admixture. Cytological and spectrophotometric studies are sufficient in screening for non-artificial blood admixture. When there are indications of an increased bilirubin concentration, calculations should be made in order to establish whether bilirubin excess exists. Lumbar puncture within 48 hours of the suspected haemorrhage should be avoided if possible.

4 groups of 30 primigravidas and their infants were studied prospectively. No patient with rhesus incompatibility was included in the study. The 4 groups went into labor in the following ways: 1) induced by intravenous oxytocin; 2) induced by intravenous prostagladin (PG)E2; 3) induced by extraamniotic PGE2; and 4) spontaneous labor. Mean infant bilirubin levels on day 5 were significantly higher (p.005 and p.025 respectively) for the 1st 2 groups than for the spontaneous group. Levels for the group whose labor was induced with extraamniotic PGE2 infusion were not significantly different from those in the 1st 2 groups or the spontaneous group. The mean serum-bilirubin level was significantly lower (p.025) after caesarean section than after assisted vaginal delivery. Serum-bilirubin levels were not affected by previous maternal use of oral contraceptives, maternal smoking, or methods of infant feeding. Serum bilirubin levels below 10 mg/100 ml. are considered within the normal phsyiological limits during the neonatal period. Measured by this criteria, 14, 10, 9, and 6 babies in groups 1-4 respectively had abnormally high levels. The difference between groups 1 and 4 was significant at the p.05 level. Mean Apgar scores were significantly lower for the babies whose mothers had induced delivery with extraamniotic PGE2 infusion. These results suggest that the observed hyperbilirubinemia may be due to interruption of pregnancy rather than to any direct drug effect. There is no evidence to suggest that such high bilirubin levels are harmful to the child in the long run.

Treatment of mice with phenobarbital significantly enhanced the disappearance of exogenously administered bilirubin from the plasma. Not only did this enhanced disappearance occur in the absence of biliary excretion but it was accompanied by liver bilirubin concentrations exceeding those found in controls. Both observations suggest enhanced uptake of free bilirubin by the liver as one cause of the faster rate of disappearance of bilirubin from plasma. In rats, the maximal rate of bilirubin excretion was enhanced by treatment with phenobarbital. The bile volume was also greater in phenobarbital-treated animals than in controls. The concentration of bilirubin in the bile was not significantly different, indicating that the increase in bilirubin excretion was probably due to the increase in bile volume. Indirectly, some of the data suggest that increased bilirubin conjugation may play a role in the enhanced uptake and excretion of bilirubin after phenobarbital treatment.

SummaryLigation of hepatic ducts in 4 dogs resulted in increased phosphatase but not bilirubin in the serum, increased bilirubin but not phosphatase in the urine. The dissociation in the blood is thought to be due largely to differential renal excretion and to be consistent with the “phosphatase retention” theory.

Based on clinical observation of 49 cases of jaundice in pregnancy, the authors present the following results. The presence of jaundice, regardless of origin, in pregnancy leads to a rise in acute intense contractions which shorten labor duration but increase the threat to the fetus. The course of the idiopathic jaundice in pregnancy is mild and the clinical symptoms disappear a few days after delivery. Delivery in cases of jaundice in pregnancy occurs at term and the average weight and length of the infants do not differ from those observed in normal deliveries. In idiopathic jaundice in pregnancy, complicated by pyelonephritis, premature deliveries are due to urinary tract infection rather than to the coexisting jaundice. Interrelationships between the duration of labor and the increased enzyme activity (serum transaminase, alkaline phosphatase) or increased bilirubin levels were not detected.

The amount of bilirubin produced daily was determined from analysis of the plasma disappearance curve of unconjugated [14C]bilirubin in 13 healthy volunteers and 12 patients with a reduction in the red blood cell 51Cr half-life and/or increased bilirubin production. Simultaneous measurement of the fecal urobilinogen excretion made possible a determination of the fraction of the daily bilirubin production excreted in the feces as urobilinogen. In the normal volunteers an average of 92% of the injected isotope was recovered in the feces, indicating that bilirubin and its degradation products are excreted almost exclusively in the feces. Nevertheless, only 50% of the daily bilirubin production was recovered as fecal urobilinogen. Although the bilirubin production rates (mg/kg/day) were not significantly different in males and females, females excreted a significantly smaller fraction of the bilirubin produced as fecal urobilinogen. Because of the variable relationship between bilirubin production and fecal urobilinogen excretion, 4 of the 12 subjects with increased bilirubin turnover had “normal” values for fecal urobilinogen excretion.