Hyperbilirubinemia Research Papers - Academia.edu (original) (raw)

Background Mild unconjugated hyperbilirubinemia (UH), due to reduced activity of the enzyme uridine diphosphoglucuronate-glucuronosyltransferase family, polypeptide 1 (UGT1A1), is a common clinical condition. Most cases are caused by presence in homozygous form of an A (TA) 7 TAA nucleotide sequence instead of the usual A(TA) 6 TAA sequence in promoter region of the UGT1A1 gene. In some cases, other genetic variations have been identified which differ between populations. There is need for more data on such genetic variations from India. Methods DNA from subjects with unexplained persistent or recurrent UH was tested for the presence of TA promoter insertions. In addition, all five exons and splicing site regions of UGT1A1 gene were sequenced. Several bioinformatics tools were used to determine the biological significance of the observed genetic changes. Functional analysis was done to look for effect of a splice site mutation in UGT1A1. Results Of 71 subjects with UH (68 male; median age [range], 26 [16-63] years; serum bilirubin 56 [26-219] μM/L, predominantly unconjugated) studied, 65 (91.5%) subjects were homozygous for A(TA) 7 TAA allele, five (7.0%) were heterozygous, and one (1.4%) lacked this change. Fifteen subjects with UH had missense exonic single nucleotide changes (14 heterozygous, 1 homozygous), including one subject with a novel nucleotide change (p. Thr205Asn). Bioinformatics tools predicted some of these variations (p.Arg108Cys, p.

- by and +1
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- Biology, Adolescent, Medicine, Multidisciplinary
- by Antonia Romano
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- Pediatrics, Nonparametric Statistics, Social Interaction, Autonomic Nervous System

Background: Among the red cell membrane disorders, hereditary spherocytosis (HS) is one of the most common causes of inherited hemolytic anemia. The aim of this study was to compare the flow-cytometric approach for screening of red cell membrane disorders based on osmotic fragility with the eosin-5-maleimide (E5 0 M) dye test. A group of b-thalassemia heterozygotes were also studied.

- by Prabhakar Kedar and +1
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- Adolescent, Child, Young Adult, Heme Oxygenase

Objective: To review our experience with pregnancies in women with myasthenia gravis (MG). Study design: Sixty nine pregnancies among 65 women with MG patients managed by our department over 28 years were included. The course of the disease in pregnancy, mode of delivery and postpartal period were evaluated. Results: One pregnancy miscarried. In 15% of patients the MG deteriorated in pregnancy a further 16% in the puerperium. 17% of pregnancies were delivered by cesarean section, one due to myasthenia exacerbation. All women with puerperal infections developed exacerbations. One neonatal death, not attributable to myasthenia, was recorded. Transitory neonatal myasthenia gravis (TNMG) was diagnosed in 30% infants. Its incidence was inversely associated with maternal disease duration (P < 0:05). Newborns of thymectomized mothers showed lower rate of neonatal myasthenia compared to those of non-thymectomized women (P < 0:05). Conclusions: MG patients can have normal pregnancy and delivery but the course is unpredictable. Shorter disease history and infection predispose to puerperal exacerbation. Maternal thymectomy lessens the likelihood of neonatal myasthenia. An interdisciplinary approach is required for managing the pregnant women with MG. #

- by Marina Ivanisevic
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- Treatment Outcome, Comorbidity, Birth Weight, Pregnancy

Background: Approximately 60% of term and 80% of premature infants are hospitalized for hyperbilirubinemia in the first week of life. Hyperbilirubinemia is the most common cause of infant hospitalization and readmission. Due to the high frequency of hyperbilirubinemia in infants and the high costs of treatment, it is necessary to find a way to decrease hospitalization duration.

- by Mohammad Hossein Khosravi, M.D.
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- Pharmacology, Probiotics, Phototherapy, Hyperbilirubinemia

Background: Hyperbilirubinemia, or jaundice, is a life threatening disorder in newborns. It is a multifactorial disorder with many symptoms. Generally, the physiological jaundice is the most prevalent type however in some regions pathological jaundice is also common. This review article focuses on a brief introduction to jaundice, its types and causes, measuring the bilirubin level, clinical approaches towards hyperbilirubinemia, different precautionary measures for the parents of babies suffering from hyperbilirubinemia and different remedial therapeutic measures for its treatment. Methods: The main databases including Scopus, Pubmed, MEDLINE, Google scholar and Science Direct were researched to obtain the original papers related to the newborns' hyperbilirubinemia. The main terms used to literature search were "newborns' hyperbilirubinemia‖, -newborns' jaundice‖, -Physiological Jaundice‖ and -Patholigical Jaun-dice‖. The timeframe included the obtained articles was from 1952 to 2015. Results: Neonatal jaundice due to breast milk feeding is also sometimes observed. Hemolytic jaundice occurs because of the incompatibility of blood groups with ABO and Rh factors, when the fetus and mother blood groups are not compatible and the fetus blood crosses the barrier of the umbilical cord before birth causing fetus blood hemolysis owing to severe immune response. Conclusion: Jaundice is easily diagnosable however require quick and on the spot treatment. If not treated properly, it leads to many complications. Currently the treatment options for jaundice include photo therapy, chemotherapy, and vaccinations.

- by Sana Ullah
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- Physical Therapy, Jaundice, Neonatal Hyperbilirubinemia, Newborn Jaundice

Systemic disorders in pediatric patients, such as congenital biliary atresia, acute liver failure, and biliary hypoplasia, may be the indications for a need of liver transplantation. One of the manifestations of these disorders is the elevated serum levels of bilirubin (hyperbiliru-binemia), a product of hemoglobin degradation, which is deposited in different tissues, including mineralized and soft tissues. When hyperbilirubinemia occurs during the period of dental development, these teeth can develop a green coloration, which remains permanently, because, after maturation, these tissues loose their metabolic activity. This case report describes a 9-year-old girl who required a liver transplant due to biliary atresia when she was three years old. Some of her pigmented teeth needed extraction and afterwards were submitted for histological analysis and compared with sound teeth.

- by CAROLINA GUERRA
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- Dentistry, Case Report, Child, Teeth

Kernicterus, thought to be due to severe hyperbilirubinemia, is an uncommon disorder with tragic consequences, especially when it affects healthy term and near-term infants. Early identification, prevention and treatment of severe hyperbilirubinemia should make kernicterus a preventable disease. However, national epidemiologic data are needed to monitor any preventive strategies. Recommendations are provided to obtain prospective data on the prevalence and incidence of severe hyperbilirubinemia and associate mortality and neurologic injury using standardized definitions, explore the clinical characteristics and root causes of kernicterus in children identified in the Kernicterus Pilot Registry, identify and test an indicator for population surveillance, validating systems-based approaches to the management of newborn jaundice, and explore the feasibility of using biologic or genetic markers to identify infants at risk for hyperbilirubinemia. Increased knowledge about the incidence and consequences of severe hyperbilirubinemia is essential to the planning, implementation and assessment of interventions to ensure that infants discharged as healthy from their birth hospitals have a safer transition to home, avoiding morbidity due to hyperbilirubinemia and other disorders.

- by THomas Newman
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- Public Health, United States, Follow-up studies, Incidence

Objective. To investigate the relationship of delivery type, maternal anesthesia, feeding modalities, and first feeding and meconium passage times with early bilirubin levels of healthy infants. Methods. Cord, 24 hours' and 48 hours' total bilirubin levels were measured in 388 study infants. Results. Infants born with cesarean section were fed later and more often had mixed feeding. First meconium passage was delayed with general anesthesia. Cord, 24 and 48 hours' bilirubin levels were not correlated with first feeding time, meconium passage time, mode of delivery, existence and type of anesthesia, and feeding modalities. Being in high intermediate risk zone at 72 hours of Bhutani's nomogram was only related to first feeding time and high cord bilirubin level. Late preterm infants were more frequently born with cesarean section and offered supplementary formula. Therefore, first meconium passage times and bilirubin levels were similar in the late preterm and term inf...

- by Nilgun Kultursay
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- Pregnancy, Anesthesia, Infant, Bilirubin

6 Domzdravqa"Starigrad",Beograd KRATAK SADRŽAJ Uvod Ari a sovik te rus(Ari as ic te rus)seja vqakod1-2%zdra veno vo ro đen ča diiodoj ča dinais hra nimaj či nimmlekom.Na sta jekaore zul tatne zre lo stije treiin hi bi tor nogefek tamaj či nogmle kanakli rensne konjugova nogbi liru bi na. Ciq rada Ura dujeana li zi ra napro men qi vostni voaidu ži nene konjugova nehi per bi li ru bi ne mi jekododoj ča di sAri a so vimik te ru som. Metod rada Is pi ta noje19odoj ča dimu škogi10odoj ča dižen skogpo lasAri a so vimik te ru som.Svaodoj čadsurođe nanavre me,pri rod nimpu temibezkom pli ka ci ja.Svasubi lasa monapri rod nojis hra niiop ti mal nosuna predo va la.Nikodjed nogis pi ta ni kani jedi jag no sti ko va nahe mo li zailidru goobo qe wepra će none konjugova nomhiper bi li ru bi ne mi jom. Rezultati Svade casubo lo va laodraz voj nežu ti ceupr vojne de qiporo đe wu,svred no šćune konjugova nogbi li rubi na166-260µmol/l(201,50±36,37).Naj ve ćini vone konjugova nogbi li ru bi naupost ne o na tal nompe ri o duza be le ženje upe tojne de qiporo đe wuura spo nu87-273µmol/l(166,82±45,06),aza timsespon ta noipo ste pe nosma wi vao.Sma we we ne konjugova nefrak ci jebi li ru bi nause ru muiz me đuče tvr teipe tene de qebiojesta ti stič kizna ča jan,apo sleto ga vi so kosta ti stič kizna ča jan.Ni vobi li ru bi nause ru musenormalizovaoiz me đuse damitri na estne de qa(10,41±1,68). Nikodjed nogde te tani suuoče nitok sič niefek tihi per bi li ru bi ne mi je. Zakqučak Ari a sovik te rusjebe za zlenipro la zanpo re me ćajme ta bo li zmabi li ru bi na.Ja vqasekodzdra veno vo rođen ča diiodoj ča dinais hra nimaj či nimmle kom.Žu ti cajena gla še ni jaura nomno vo ro đe nač kompe ri o du,aliposte pe noiš če za vaiz me đused meitri na e stene de qe.

- by Zoran Leković
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- Infant, Jaundice, Bilirubin, Newborn Infant

Hemolytic disease of the fetus and newborn occurs when maternal IgG antibodies cross the placenta and cause hemolysis of fetal red blood cells. Kp a is a low frequency red blood cell antigen that has rarely been implicated in hemolytic disease of the fetus and newborn. The few reported cases attributed to anti-Kp a have typically had minimal clinical consequences. We report a critically ill neonate who presented with purpura, respiratory failure, severe liver dysfunction, hyperbilirubinemia, hypoglycemia and anemia. This case report broadens the spectrum of neonatal disease associated with anti-Kp a , addresses the evaluation of hemolysis with liver failure in a neonate, and emphasizes the importance of screening for antibodies to low frequency red blood cell antigens in suspected hemolytic disease of the fetus and newborn.

- by Kari Roberts
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- Treatment Outcome, Medicine, Low Frequency, Pregnancy

There are variety serious diseases of the children liver. Biliary atresia is the most frequent surgical cause of cholestatic jaundice in neonates and should be evoked whenever this clinical sign is associated with pale stools and hepatomegaly. Early diagnosis is the greatest help for these children. Without surgical treatment these patients die during the first two years of life from the progression of the liver disease, oesophageal bleeding or infection. In this article we would like to provide a brief overview of these diseases, describe the main diagnostic criteria, and we also want to turn the attention of pediatricians and neonatologists on diagnostic difficulties during the diagnostic period. Despite of the rarity of these diseases, biliary atresia should be on the list of differential diagnoses. Thanks to early diagnosis, performance of Kasai portoenterostomy and the possibility of liver transplantation was made significant progress in the treatment of children with those diseases in the last decade.

Parenteral nutrition-associated conjugated hyperbilirubinemia (PNAC), commonly defined as direct bilirubin Ն2 mg/dL (34.2 mol/L), is primarily a pediatric disease with premature infants being the most susceptible. Severe morbidity and increased mortality are associated with bilirubin Ͼ10 mg/dL (171.0 mol/L). The lack of knowledge regarding the cause of PNAC has stymied development of prevention and treatment strategies. A systematic search of published reports was conducted to provide data on histopathology of PNAC and to review prospective, randomized, controlled trials in hospitalized infants. In experiments of young animals, parenteral nutrition (PN) with and without soy oil emulsion is directly linked to hyperbilirubinemia, and the effects are exaggerated by overfeeding. In infants, the most consistently reported risk factor for PNAC is the duration of PN. The only known effective modality is the transition to full enteral feeding and discontinuation of PN. Emerging clinical research is evaluating the role of lipid source (soy vs fish) and motility agents, such as erythromycin. Different trace element preparations are associated with varying severity of cholestasis, a finding that also deserves more study. This article reviews the prevalence, risk factors, clinical presentation, and treatment options for PNAC in neonatal intensive care units.

- by Mary Revenis
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- Treatment Outcome, Clinical research, Infant, Bilirubin

BACKGROUND: Neonatal jaundice or hyperbilirubinemia is a common occurrence in newborns. Although most cases of neonatal jaundice have a benign course, severe hyperbilirubinemia can lead to kernicterus, which is preventable if the... more

- by Amin Mohammad
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- Treatment Outcome, Clinical Chemistry, Medical Biotechnology, Clinical

Aim: Our objective was to compare the predictive ability of predischarge serum total bilirubin (STB) and clinical factors for significant hyperbilirubinemia (SHB) in newborn to see if we can improve the prediction of the hyperbilirubinemia. Methods: We conducted a prospective cohort study, recruiting healthy newborn infants of > 35 weeks gestation, in a tertiary hospital in south India. The risk factors for SHB were identified and serum bilirubin was performed between 36-48 hours of age before discharge. SHB was defined as a bilirubin level that exceeded or was within 1 mg/ dL (17µmol/L) of the hour-specific phototherapy treatment threshold recommended in the American Academy of Pediatrics (AAP) clinical practice guideline on the management of neonatal hyperbilirubinemia. SPSS 21 was used for statistical analysis. Results: Of 605 infants, 486 infants were included in final analysis, among which 72 babies (14%) developed SHB. On univariate analysis, STB, gestational age (GA) and percentage of weight loss were found to be predictive of SHB. On multiple logistic regressions, the predictive ability of predischarge STB is higher than that of percentage of weight loss and GA. The predictive accuracy of predischarge (< 48 hours) STB level was similar to that of percentage of weight loss (AUC = 0.83, 95 % CI 0.78– 0.88). However, the prediction model that combined multiple clinical risk factors (predischarge STB, GA and percentage of weight loss) had the best accuracy for predicting SHB. Conclusions: Predischarge serum total bilirubin, when combined with specific clinical factors (gestational age and percentage of weight loss), best predicts development of significant hyperbilirubinemia.

- by Elyns Group
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- Hyperbilirubinemia

Aim: The problem of kernicterus in infants with bronze baby syndrome (BBS) has been reviewed on the basis of cases reported in the literature. In addition, a new case concerning an infant with severe Rh haemolytic disease, who presented with BBS and who has developed neurological manifestations of kernicterus with magnetic resonance images showing basal ganglia abnormalities, is presented. In this patient, the total serum bilirubin (TSB) concentration ranged from 18.0 to 22.8 mg/dl (306 to 388 mmol/l) and the bilirubin/albumin (B/A) ratio was 6.0 (mg/g) (6.8 is the value at which an exchange transfusion should be considered). The case presented is important due to the fact that kernicterus appeared after an exchange transfusion was performed when the TSB level reached 22.8 mg/dl (388 mmol/l) on 6th day of life while the haematocrit was 30%. From this case and from other cases reported in the literature, we must stress that, even if the level at which hyperbilirubinemia poses a threat remains undefined, BBS may constitute an additional risk of developing kernicterus.

- by Firmino Rubaltelli and +2
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- Pediatrics, Magnetic Resonance Imaging, Risk, Phototherapy

Objective: To determine predictors of acute bilirubin encephalopathy (ABE) among term infants presenting with moderate-to-severe hyperbilirubinaemia. Methods: Babies with total serum bilirubin >15 mg/dl at the point of admission were studied in a Nigerian tertiary health facility using bivariate and multivariate analysis. Results: Out of 152 babies, 75 (49.3%) had ABE: 73 had ABE at presentation while two developed ABE after admission. Bivariate analysis showed that body weight <2.5 kg, outside delivery, low maternal education, low socioeconomic status, severe anaemia, glucose-6-phosphate dehydrogenase deficiency and metabolic acidosis were significantly associated with ABE. Multivariate analysis also showed that only outside delivery, weight <2.5 kg, presence of severe anaemia and acidosis were the predictors of ABE in this cohort of term babies. Conclusion: The identified predictors of ABE are modifiable and can be used to draw up screening tools for term babies at risk of ABE especially in the developing world.

- by Olusoga Ogunfowora
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- Nigeria, Multivariate Analysis, Prospective studies, Hospitalization

To confirm that the naproxen metabolite O-desmethylnaproxen interferes with the Jendrassik and Grof method for total bilirubin and was a possible cause of spurious hyperbilirubinemia in a case of naproxen overdose.Plasma was spiked with naproxen or O-desmethylnaproxen before total and direct bilirubin analysis.O-desmethylnaproxen concentration showed a linear relationship with measured total bilirubin.O-demethylnaproxen interferes with the total bilirubin method. Interference of glucuronide metabolites of naproxen and O-demethylnaproxen is not excluded.

- by Frances Rosenberg
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- Clinical Biochemistry, Clinical, Bilirubin, Naproxen

The goal of this study was to evaluate risk factors for readmission among late-preterm (34-36 weeks' gestation) infants in clinical practice. This was a retrospective, matched case-control study of late-preterm infants receiving care across 8 regional hospitals in 2009 in the United States. Those readmitted within 28 days of birth were matched to non-readmitted infants at a ratio of 1:3 according to birth hospital, birth month, and gestational age. Step-wise modeling with likelihood ratio tests were used to develop a multivariable logistic regression model. A subgroup analysis of hyperbilirubinemia readmissions was also performed. Of 1861 late-preterm infants delivered during the study period, 67 (3.6%) were readmitted within 28 days of birth. These were matched to 201 control infants, for a final sample of 268 infants. In multivariable regression, each additional day in length of stay was associated with a significantly reduced odds ratio (OR) for readmission (0.57, P = .004); ...

- by Neera K. Goyal
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- Length of Stay, Newborn Infant, Odds ratio, Cesarean Section

Although development of the full syndrome of kernicterus is relatively rare, neonatal jaundice continues to occur frequently. Controversy remains concerning whether or not infants with moderate elevations in bilirubin are at risk for neurodevelopmental disorders in later childhood. Sites of brain pathology associated with bilirubin neurotoxicity are identified and well established. Based on these regions of brain involvement, we apply neuroscientific principles of brain-behavior relationships to predict types of cognitive features that may accompany hyperbilirubinemia. We address a range of neurodevelopmental abnormalities that can arise as a function of elevated neonatal bilirubin levels affecting these brain regions, even in the absence of full kernicterus syndrome. Moreover, we explain the neuropathologic mechanisms that would drive these abnormalities. We thus attempt to establish a blueprint for future investigations of these conditions, to improve neurodevelopmental outcomes.

- by Leonard Koziol and +1
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- Pediatric Neurology, Brain, Neurosciences, Cognition disorders

The aim of this study was to compare predictions of hyperbilirubinaemia by eye, performed by trained physicians and nurses, with predictions obtained using two commercial bilirubinometers. Jaundice was assessed in 92 white and 48 non-white healthy full-term neonates using three non-invasive methods and by total serum bilirubin as the reference method. Clinical assessment of cephalocaudal progression of jaundice was carried out independently by a physician and by nurses. Simultaneously, the Minolta Airshields JM-102 was applied on the sternum, the BiliCheck on both the forehead and the sternum, and finally, serum bilirubin concentrations were determined. The Minolta JM-102 showed the best performance with r 2 =0.90, an intraclass correlation coefficient (ICC) of 0.93, and a 95% confidence interval (CI) of ±4 units (approx. 56 lmol/l). The BiliCheck performed slightly better on the forehead than over the sternum with r 2 =0.90, an ICC of 0.88, and a CI of ±62 lmol/l. Assessment of jaundice by eye was least accurate with r 2 =0.74, an ICC of 0.67, and a CI of ±1.5 zones (corresponding to ±75 lmol/l). Skin pigmentation and ambient light both adversely affected noninvasive bilirubin estimation. Conclusion: All three non-invasive methods are well suited for estimation of serum bilirubin but show large confidence intervals. In healthy term newborns, hyperbilirubinaemia (>250 lmol/l) can be safely ruled out by eye if jaundice does not reach the abdomen or the extremities (Kramer zones 1 and 2), with <22 units (<230 lmol/l) for the Minolta JM-102, or with a cut-off of 190 lmol/l for the Bili-Check. If these respective thresholds are exceeded, serum bilirubin concentrations should be measured.

- by Hans Bucher
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- Skin, Bilirubin, Spectrophotometry, Forehead

Hyperbilirubinaemia with or without jaundice is one of the side effects of atazanavir boosted with low-dose ritonavir (ATV/rit) related to the drug plasma levels, as a result of its metabolism by UGT1A1 – uridine diphosphate-glucuronosyl transferase. Genotyping for UGT1A1*28 before initiation of antiretroviral therapy containing atazanavir may aid in identifying individuals at risk of hyperbilirubinaemia. Our objective was to estimate the prevalence of the UGTA1A1*28 polymorphism in HIV-infected individuals in Greece and to determine its potential association with hyperbilirubinaemia in patients receiving ATV/rit. The prevalence of the UGTA1A1*28 variant was estimated in 79 HIV-infected patients prior to the administration of the first-line treatment. The UGTA1A1*28 variant was detected in 46 out of 79 individuals (58.2%). Antiretroviral therapy was administered to 64/79 patients (81%). Among them, 26/64 (40.6%) received ATV/rit. Of the ATV/rit-treated patients, 14 were found to be ...

- by Dimitrios Paraskevis
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- Medical Microbiology, Greece, Pharmacogenetics, Hiv Infection

There is no report in which three episodes of delayed hemolytic transfusion reaction (DHTR) occurred from multiple antibodies to red cells (RBCs) in the course of treatment of a patient. This paper describes episodes of anemia and hyperbilirubinemia in concert with the development of three alloantibodies in a multiple transfused patient. The patient was a 71-year-old male suering from valvular heart disease and hemophilia B with a history of transfusions. Although he received compatible RBCs from 14 donors as judged by a crossmatch test using the albumin±antiglobulin method, three episodes of DHTR occurred after surgery. The ®rst hemolytic episode on day 7 after surgery was due to anti-Di a because of clinical and laboratory evidence which included jaundice, sudden increases in total bilirubin (T-Bil) and lactate dehydrogenase (LD) levels, and a decrease (2.2 g/dl) in hemoglobin (Hb) level. The second hemolytic episode on day 16 resulted from newly producted anti-Jk b. The patient experienced fever, fatigue, nausea and anorexia, and laboratory data showed a second increase in T-Bil, a second decrease (3 g/dl) in Hb, and moderate elevations of blood urea nitrogen (BUN) and creatinine (CRE) levels. The third hemolytic episode on day 39 was due to anti-E. The patient complained of fever and fatigue and had a third unexplained drop (1.5 g/dl) in Hb despite no bleeding. This is the ®rst reported case in which three episodes of DHTR occurred from dierent red cell antibodies.

- by H. Ohto
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- Fatigue, Blood Urea Nitrogen, Recurrence, Aged

Biliary tract duplication cysts with heterotopic gastric mucosa are rare congenital anomalies, with our case representing only the fourth reported case in the literature. An 8-year-old girl with several months of abdominal pain was found to have a complex cystic mass communicating with the biliary system via the common hepatic duct. Intraoperatively, inflammation caused by the cystic mass was found to have resulted in a Mirizzi-like syndrome, with a nearly complete obstruction at the confluence of the left and right hepatic ducts. Histopathologic examination of the biliary mass revealed it to be a duplication cyst lined by heterotopic gastric mucosa with secondary ulceration and fibrosis. Biliary duplication cysts are a rare but important process that should be considered in a child with a mass in the portal triad and biliary obstruction.

- by Michael Dipietro
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- Child, Liver, Pediatric Surgery, Jejunum

. Also, statistically significant difference for total bilirubin concentration was emphasized between genotypes 6/6 and 7/7 (p<0.001) as well as 6/7 and 7/7 (p<0.001). Higher total plasma bilirubin concentrations are significantly... more

- by Lorena Honovic
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- Anthropology, Croatia, Prevalence, Collegium

D rug-induced cholestasis is estimated to be the cause of hospitalization in 2-5% of patients with jaundice. The causes and mechanisms of drug-induced cholestasis include gender, genetic factors, intrinsic drug toxicity, and the host's immunologic sensitivity. The clinical picture usually resolves quickly after drug withdrawal, but prolonged cholestasis has also been reported. 1

Purpose: To assess differences in delineated target volumes of liver metastases using contrast-enhanced CT and different MRI sequences for radiation treatment planning. Patients and Methods: 25 patients with 43 colorectal liver metastases were recruited. Tumor margins were defined by two experienced radiologists. The resulting D90 was assessed and the CT-based 3-D dose distribution merged with the according MRI dataset by employing image fusion. A theoretical D90 as a result of MRI-based treatment planning was assessed for various MRI sequences individually. Results: In venous phase contrast-enhanced CT, the mean tumor volume was 20 ml; T1-weighted (T1w) MRI, 27 ml; contrast-enhanced T1w 42 ml; T2w 65 ml. The difference between the target volumes as assessed by either CT or MRI was 181% for T1w images, 178% for contrast-enhanced T1w, and 246% for T2w sequences. All differences were statistically significant (p < 0.05). The analysis of the dose-volume histograms revealed statistically significant differences (i.e., for the D90) for the different target volumes specified by CT and MRI: mean D90 on CT, 18 Gy; plain T1w, 16 Gy; contrast-enhanced T1w, 15.5 Gy; T2w, 12 Gy. Hence, delineation of a larger target volume in T2w MRI compared to contrast-enhanced CT resulted in a smaller D90. The mean differences of tumor volumes assessed by CT and plain T1w were significantly higher in the group of patients showing local tumor recurrences as compared to patients with long-term local tumor control (p = 0.002). Conclusion: For treatment planning of liver metastases, the use of either plain T1w or T2w sequences is recommended to delineate the clinical target volume as completely as possible and not to miss potential tumor cell congregations in the surroundings as in CT.

- by Gero Wieners and +1
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- Palliative Care, Magnetic Resonance Imaging, Brachytherapy, Liver

Bilirubin, resulting largely from the turnover of hemoglobin, is found in the plasma in two main forms: unconjugated or conjugated with glucuronic acid. Unconjugated bilirubin is transported into hepatocytes. There, it is glucuronidated by UGT1A1 and secreted into the bile canaliculi. We report a genome wide association scan in 4300 Sardinian individuals for total serum bilirubin levels. In addition to the two known loci previously involved in the regulation of bilirubin levels, UGT1A1 (P 5 6.2 3 10 262 ) and G6PD (P 5 2.5 3 10 28 ), we observed a strong association on chromosome 12 within the SLCO1B3 gene (P 5 3.9 3 10 29 ). Our findings were replicated in an independent sample of 1860 Sardinians and in 832 subjects from the Old Order Amish (combined P < 5 3 10 214 ). We also show that SLC01B3 variants contribute to idiopathic mild unconjugated hyperbilirubinemia. Thus, SLC01B3 appears to be involved in the regulation of serum bilirubin levels in healthy individuals and in some bilirubin-related disorders that are only partially explained by other known gene variants.

- by Marco Masala
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- Adolescent, Italy, Biological Sciences, Human Molecular Genetics
- by Ronald Wong
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- Heme Oxygenase, Bilirubin, Clinical Sciences, Newborn Infant

Background. Hyperbilirubinemia in new-borns with glucose-6-phosphate dehydrogenase (G6PD) deficiency is a serious clinical problem because of the severity and unpredictability of its course. An innovative approach to this problem is suggested by previous experience with Sn-mesoporphyrin (SnMP), a potent inhibitor of bilirubin production, in moderating neonatal hyperbilirubinemia caused by ABO incompatibility, immaturity, and unspecified mechanisms. Objective. To compare the effectiveness of the preventive and therapeutic uses of SnMP in ameliorating the course of bilirubinemia of G6PD-deficient neonates. Methods. Neonates born at the Metera Maternity Hospital, Athens, Greece, and found to be G6PD-deficient by cord blood testing were stratified by sex and gestational age (210–265 days and >265 days) and randomized in pairs to receive SnMP (6 μmol/kg birth weight, intramuscularly) either on the first day of life (preventive use) or if and when the plasma bilirubin concentration (P...

- by Cathy Hammerman-Rozenberg
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- Pediatrics, Enzyme Inhibitors, Phototherapy, Bilirubin

The mode of presentation, clinical course, and outcome of 12 infants with cystic fibrosis and liver disease referred over an 18 year period were investigated retrospectively. Median age at presentation was 6.5 weeks (range, 5-12). Two thirds were boys. Conjugated hyperbilirubinaemia was the presenting symptom in 11 patients, and hypoalbuminaemia in one. Jaundice was cleared over a median period of 7.36 months. Eight patients had bile duct proliferation on liver biopsy and one required cholangiography to exclude biliary atresia. Classic histological features of cystic fibrosis were only present in two children biopsied at 8 and 18 months. Three patients had meconium ileus, including one infant with concomitant 1 antitrypsin deficiency, who required early liver transplantation. All other patients had no signs of significant chronic liver disease during a median follow up of 42 months (range, 10-205). Children with cystic fibrosis and infantile liver disease have a good short and medium term prognosis.

- by Giorgina Mieli-vergani
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- Pathology, Radiology, Cystic Fibrosis, Liver diseases

Crigler-Najjar syndrome type I is a rare inborn error of bilirubin metabolism due to a deficiency of the hepatic microsomal bilirubin uridine diphosphate-glucuronosyltransferase (B-UDPGT) enzyme. To reduce the risk of life threatening kernicterus, patients undergo daily session of phototherapy. The only therapeutic alternatives are liver or hepatocyte transplantation but significant risks and costs are associated with these procedures. Since all other pathways for bilirubin metabolism are functional in the patients, gene therapy may represent an alternative treatment. An excellent model of this disease exists in the Gunn rat. Previously, partial correction of hyperbilirubinemia in Gunn rats for up to 4 weeks was reported using E1-deleted adenoviral (Ad) vectors; however, the therapeutic index of E1-deleted Ad is limited due to strong host immune response to the viral proteins, acute toxicity and short duration of expression. Helper-dependent adenoviral (HD-Ad) vectors, devoid of all viral coding sequences, have a safer chronic toxicity profile compared with early generation Ad vectors and allow for long-term transgene expression. We used HD-Ad vectors and tissue-restricted expression of human B-UDPGT in Gunn rats. Complete correction of hyperbilirubinemia was achieved after a single systemic administration of 3 x 1012 viral particles/kg of HD-Ad vectors expressing human B-UDPGT under the control of the rat phosphoenolpyruvate carboxylase (PEPCK) promoter into Gunn rats. Total bilirubin levels in the plasma were stably reduced from above 7.0 mg/dL to less than 1.0 mg/dL for at least 7 months. Specific hepatic expression of human B-UDPGT was confirmed by RNA and protein analysis in liver biopsy from animals sacrificed 20 weeks post-injection. A clinically significant reduction in total bilirubin levels was observed with a dose as low as 6 x 1011 viral particles/kg. No significant increase in liver enzymes was detected at a dose as high as 1 x 1013 viral particles/kg. Transient, dose-related thrombocytopenia developed after systemic injection of the vector at higher doses and resolved in 3 weeks. We conclude that complete, long-term correction of hyperbilirubinemia may be achieved by a single HD-Ad adenoviral administration in the animal model of Crigler-Najjar syndrome type I with negligible chronic toxicity.

- by Gabriele Toietta
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- Gene Therapy, Bilirubin, Adenoviral vectors, Crigler-Najjar syndrome

Background. Immunosuppression by cyclosporin A (CsA) is associated with adverse side-effects, including nephrotoxicity, neurotoxicity and gingival overgrowth. Tacrolimus (TAC/FK506) is a new immunosuppressive agent, recently approved for use in solid-organ transplants. The mode of action of TAC is similar to that of CsA and the toxicity profile of CsA is duplicated by TAC. The effect of TAC on the gingival tissue is not yet conclusive. Sample. Gingival overgrowth was assessed in 30 liver transplant children, 20 boys and 10 girls, aged 2-19 years. Seventeen children (10 boys, seven girls) were on a CsAbased immunosuppressive regimen whereas 13 children (10 boys, three girls) were on TAC for at least 1 year (mean 4·3 ± 2·7). Results. In the CsA group, 35% of children exhibited gingival overgrowth characterized by one or more units with increased sulcus probing depth ( ≥ 4 mm), i.e. pseudopockets. In contrast to the CsA group, none of the children in the TAC group exhibited gingival overgrowth. The occurrence of enamel hypoplasia was observed in 11 children (36%) and enamel opacities were found in 23 children (76%). Six of the 12 children (50%) with hyperbilirubinaemia biliary atresia exhibited a marked greenish discoloration of the teeth. Caries experience (dmft/DMFT) among these children was 2·0 ± 2·8. Conclusion. No difference in caries experience or enamel defect was observed between the CsA and TAC group.

- by Thomas Modeer
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- Dentistry, Nonparametric Statistics, Adolescent, Paediatric Dentistry

The objective was to compare the contribution to perinatal bilirubinemia of hemolysis and UDP-glucuronosyltransferase (UGT) gene promoter polymorphism, seen in Gilbert's syndrome, between glucose-6-phosphate dehydrogenase (G-6-PD)deficient and -normal neonates. Serum total bilirubin (STB) values from 52 G-6-PD-deficient and 166 G-6-PD-normal term, male neonates, sampled within 3 h of delivery (first sample) and on d 3 (second sample), were analyzed in relation to blood carboxyhemoglobin corrected for inspired CO (COHbc), an accurate index of hemolysis, and UGT promoter genotype. COHbc values (% total Hb) were greater in G-6-PD-deficient neonates than controls: first sample 1.00 Ϯ 0.25% versus 0.84 Ϯ 0.24%, p Ͻ 0.0001; second sample 0.83 Ϯ 0.20% versus 0.76 Ϯ 0.19%, p ϭ 0.002. First sample COHbc and STB values did not correlate in either the G-6-PD-deficient or control groups, whereas second sample COHbc values correlated significantly with corresponding STB values in the control population only (r ϭ 0.28, p ϭ 0.0007). At second sampling, there was a higher allele frequency of the variant UGT promoter among those with STB values Ն75 th percentile than those Ͻ75 th among the G-6-PD-deficient ABSTRACT 532

- by E. Levy-lahad
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- Endocrinology, Genetics, Cardiology, Hematology

Arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome is a rare multisystem disorder first described in 1979 1 and recently ascribed to mutation in VPS33B, whose product acts in intracellular trafficking. 2 Arthrogryposis, spillage of various substances in the urine, and conjugated hyperbilirubinemia define an ARC core phenotype, in some patients associated with ichthyosis, central nervous system malformation, deafness, and platelet abnormalities. We describe a patient with cholestasis, aminoaciduria, ichthyosis, partial callosal agenesis, and sensorineural deafness who, although homozygous for the novel VPS33B mutation 971delA/K324fs, predicted to abolish VPS33B function, did not exhibit arthrogryposis. The phenotypes associated with VPS33B mutation may include incomplete ARC. (J Pediatr 2006;148:269-71) CASE REPORT T he first child of healthy first-cousin British parents of Pakistani origin was born at 41 weeks (birth weight, 3.37 kg). She appeared well and was discharged home. At 6 days of life (weight, 3.01 kg), she was evaluated for jaundice (serum total bilirubin [TBIL], 248 mol/L; conjugated/direct bilirubin [DBIL], 94 mol/L; alkaline phosphatase activity [ALP], 614 IU/L; alanine aminotransferase activity [ALT], 15 IU/L). Hypothyroidism was diagnosed (thyroid-stimulating hormone [TSH], 12.6 mU/L; free thyroxine [T 4 ], 17.9 pmol/L); serum cortisol was adequate (518 nmol/L). At 14 days (weight 2.93 kg), jaundice had worsened (TBIL, 396 mol/L; DBIL, 215 mol/L; ALP, 1708 IU/L; ALT, 45 IU/L) and evidence of hypothyroidism persisted (TSH, 23.9 mU/L; T 4 , 20.6 pmol/L).

- by Laura Bull
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- Genetics, Pediatrics, Kidney diseases, Membrane Proteins

Brainstem auditory evoked responses (BAER) were longitudinally recorded prospectively in 18 term infants with neonatal hyperbilirubinemia (NHB) (total serum bilirubin >15 mg/dl). Seven neonates had abnormal BAER. Wave complex IV-V was absent in eight recordings in NHB group while they were normal in the control group (p <0.001). Prolongation of latency of waves I and V and interwave conduction time (wave I-V) occurred in jaundiced infants especially when unconjugated serum bilirubin level rose above 22 mg/dl. The abnormalities in BAER reversed to normal in all seven neonates after exchange blood transfusion indicating transient nature of bilirubin toxicity to the brain. All seven neonates in the study and control group had normal hearing, development quotient and were free of neurological sequelae on follow up for one year.

- by Meharban Singh
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- India, Prospective studies, Newborn Infant, Blood Transfusion

Fetal hyperinsulinism in infants of diabetic mothers (IDMs) produces increased fetal growth leading to macrosomla, which may or may not be proportionate. Disproportionate macrosomia refers to excessive weight characterized by a high weight/length ratio. We tested the hypotheses that (1) macrosomia in IDMs would be characterized by a high ponderal index (defined as weight/length ratio) and (2) infants with macrosomla who have a high ponderal index would have increased neonatal morbldity--specifically, hyperbilirubinemla, hypoglycemia, polycythemla, and acidosis. We studied 170 IDMs and 510 non-IDMs matched 1"3 for gestational age, race, and year of delivery. Forty-five percent of iDMs had macrosomia compared with 8% of control infants (p = 0.001), and 19% of IDMs had disproportionate macrosomla compared with I% of control infants (p = 0.001). The rates of hyperbilirubinemia (p = 0.02), hypoglycemia (p = 0.01), and acidosis (p = 0.01) were greatest in infants with disproportionate macrosomia and least in nonmacrosomic infants. The Incidence of polycythemla was not significantly different between the groups. We suggest that disproportionate macrosomia in the IDM is associated with an increased likelihood of neonatal complications. (J PEDIATR 1993;122:115"9)

- by Menachem Miodovnik
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- Pediatrics, Birth Weight, Prospective studies, Pregnancy

The authors have indicated they have no financial relationships relevant to this article to disclose. What's Known on This Subject To our knowledge, no studies have evaluated the role of severity and duration of hyperbilirubinemia on language development in premature infants. What This Study Adds Although this is a negative study, the rationale of conducting this retrospective study may change the perception of a disease process, specifically how hyperbilirubinemia may affect language development. Second, we recommend future research on the subject by considering better biochemical measures such as unbound bilirubin as a predictor.

- by sanjiv amin
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- Pediatrics, Language Development, Language, Logistic Regression

Two studies were conducted to determine the relationship between variability in acoustic features of the infant cry and medical risk factors. In study 1, 3 groups of preterm infants (healthy, sick and CNS pathology) were compared with term infants at 40 weeks gestational age. The cry was analyzed by computer. The coefficient of variability of cry amplitude and the formant feature:; of the cry differed among the groups of preterm infants. In study 2, 3 groups of tern infants at low, moderate and high levels of hyperbilirubinemia were compared on the cry measures. More variability in the formant features of the cry was found in infants with higher levels of bilirubin. The correlation between the coefficient of l:mation in the cry formants and level of bilirubin was statistically significant. These two studies suggest that variability in the acoustic features of the cry relate to the medical status of the infant and may provide a measure of neurophysiological integrity.

- by gherardo rapisardi
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- Acoustics, Variability, Central Nervous System, Clinical Sciences
- by Mehdi Kalani
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- Microbiology, Medical Microbiology, Infectious Diseases, Sepsis

Glucose-6-phosphate dehydrogenase (G6PD) deficiency, a recessive X-linked trait, is the most common enzyme deficiency in the world. The most devastating clinical consequence of this deficit is severe neonatal jaundice, which results in sensorineural deficit, and severe haemolytic anemia. However, patients may be asymptomatic. The most common clinical sign is hyperbilirubinemia (h↑), that is also related to Gilbert's syndrome, a condition associated with the promoter polymorphism of the UDP-glucuronosyltransferase 1 (UGT1A1) gene. The aim of this study was to underline (as is usually done by DNA molecular analysis) to detect and to clarify the genetic deficiency that is the reason of the disorder in question. In this study, different techniques were applied to analyse a family of four individuals presenting with hyperbilirubinemia: bilirubinic dosage, electrophoresis and enzymatic activity dosage of G6PD; molecular analysis of the UGT1A promoter to detect a thymine-adenine (TA) insertion, that causes the [A(TA) 7 TAA] mutation. The results showed that in certain cases, the presence of hyperbilirubinemia is not only associated with G6PD deficiency, but may be caused by the co-presence of a mutation in the UGTA1 promoter related to Gilbert's syndrome. As being affected by these two conditions predisposes to adverse effects towards certain drug treatments, it is advisable to study the UGTA1 gene before prescribing drugs for specific antineoplastic or retroviral tratment. We emphasize that investigating both the UGT1A gene and G6PD activity is the most reliable way to make a correct differential diagnosis.

- by Manuela Leo
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- Oncology, Molecular Medicine, Cancer, Cell Cycle

Bilirubin is a potent antioxidant in vitro. To determine whether bilirubin also is an antioxidant in vivo, we studied markers of oxidative injury in the Gunn rat model exposed to hyperoxia. Homozygous jaundiced males were mated with heterozygous nonjaundiced females to obtain both jaundiced and nonjaundiced pups within a litter. Once delivered, the pups and their mother were placed in

- by Douglas Spitz
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- Free Radicals, Oxidative Stress, Free Radical, Antioxidants

Background: The aim of this study was to determine the effects of severe hyperbilirubinemia on vestibular evoked myogenic potentials (VEMP). Methods: A prospective study was designed. Seventeen term infants who suffered from severe hyperbilirubinemia in the first 5 postnatal days of age were included in the study group. The control group consisted of 17 healthy term infants. Audiological evaluation was performed, including tympanometry and transient evoked otoacoustic emissions, and VEMP tests. Results: All newborns passed audiological evaluation. Biphasic waveforms of VEMP were obtained in all of the 34 infants who had been tested. Both latencies of p13 and n23 were significantly delayed in the severe hyperbilirubinemia group (P < 0.05). Conclusion: This pilot is the first study to show that severe hyperbilirubinemia causes delay in VEMP latencies. We suggest that severe hyperbilirubinemia might affect the vestibular nuclei or the integrity of the inferior vestibular nerve and vestibulospinal tract. Further studies need to explain the relation between hyperbilirubinemia and the vestibular system.

- by Deniz Ozel
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- Pediatrics, Prospective studies, Jaundice, Newborn Infant

BACKGROUND: Activated partial thromboplastin time (aPTT) and antifactor Xa (anti-Xa) monitoring methods for unfractionated heparin (UFH) often disagree. The extent of discordance for those with elevated bilirubin remains unclear. Our objective was to evaluate concordance between activated aPTT and anti-Xa methods for hyperbilirubinemic patients on UFH.

- by Andrew R Zullo and +2
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- Pharmacy, Hemostasis and Thrombosis, Pharmacy Practice, Clinical Pharmacy

Objective. To investigate the behavioral changes induced by moderate hyperbilirubinemia in the otherwise healthy, untreated newborn infant. Methods. Fifty term neonates (23 boys) with untreated moderate hyperbilirubinemia (median: 14.3 mg/ dL; range: 13.2-20 mg/dL) and 50 matched control subjects with lower bilirubin concentrations (median: 9.1 mg/dL; range: 5.3-12 mg/dL) were administered the Brazelton Neonatal Behavioral Scale at 87 hours of life (range: 72-110 hours). A subgroup analysis was also performed at 104 hours of life (range: 96-134 hours) and at 3 weeks of age. Results. At the first examination, all behavioral clusters were significantly altered in the group with moderate hyperbilirubinemia. The visual and auditory capabilities of the hyperbilirubinemic infant were especially compromised. Although social-interactive cluster scores significantly correlated both with serum bilirubinemia and birth weight, the former accounted for 8.7% of the variance and the latter accounted for only 4.7%. The moderate hyperbilirubinemia neonates' scores also showed a negative correlation with the autonomic system and more frequent presence of tremors. After 24 hours, a decrease in serum bilirubin within the moderate hyperbilirubinemic group was associated with improved scores. At 3 weeks of age, the behavioral assessment of the 2 groups did not show significant differences. Conclusions. Untreated moderate hyperbilirubinemia is associated with a transient and apparently reversible alteration of neonatal behavior, particularly in the social-interactive area. Pediatrics 2002;110(4).

- by GIUSEPPINA MANSI
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- Pediatrics, Nonparametric Statistics, Medicine, Autonomic Nervous System

Objective-To identify genetic variation influencing serum bilirubin levels in American Indians, we performed genome-wide screening and association analyses in the Strong Heart Family Study. Bilirubin is an endogenous antioxidant that has demonstrated an inverse relationship with cardiovascular disease. Genetic variation within the promoter region of uridine diphosphate glucuronosyltransferase (UGT1A1) on chromosome 2q has been associated with elevated serum bilirubin levels in European populations. However, no study has investigated the UGT1A1 promoter in American Indians. Methods-Statistical analyses were carried out with 3,484 participants aged 14 to 93 years recruited from three geographic areas in the United States; Arizona, Oklahoma, and North and South Dakota. Results-Variance components linkage analysis detected a quantitative trait locus (QTL) for bilirubin on chromosome 2q in the combined centers (LOD = 6.61, P = 4.24 × 10 −6) and in Oklahoma (LOD = 5.65, P = 4.57 24 × 10 −5). Genetic association of the UGT1A1 promoter polymorphism was significant for all geographic locations. After adjustment using conditional linkage for UGT1A1 promoter variance, the linkage signal dropped to 1.10 in the combined sample and to 3.32 (P = 0.02) in Oklahoma, indicating this polymorphism is not completely responsible for the linkage signal in American Indians. We also detected suggestive linkage signals in the Dakotas on chromosome 10p12 (LOD = 2.18) and in the combined centers (LOD = 2.24) on chromosome 10q21. Conclusions-Replication of a serum bilirubin QTL on chromosome 2q in American Indians implicates UGT1A1 but further genotyping is warranted to identify additional causative polymorphisms. Evidence also supports a potential novel locus for bilirubin on chromosome 10.

- by Jean MacCluer
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- Evolutionary Biology, Genetics, Anthropology, Biological Anthropology

We read with great interest the article by Yang et al. 1 We would like to take this opportunity to make a few comments. The retrospective study seeks to discriminate 'early' and 'lateonset' biliary atresia (BA) using levels of "direct... more

- by Mark Davenport
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- Pediatrics, Medicine, Pregnancy, Child