211 G to a variation of UDP-glucuronosyl transferase 1A1 gene and neonatal breastfeeding jaundice.

Breastfeeding jaundice is a common problem in neonates who were exclusively breastfed, but its pathogenesis is still unclear. The uridine diphosphate glucuronosyl transferase 1A1 (UGT1A1) gene polymorphism was shown to contribute to the development of neonatal hyperbilirubinemia. We hypothesize that the variation of UGT1A1 gene may contribute to neonatal breastfeeding jaundice. We prospectively enrolled 688 near-term and term infants who were exclusively breastfed (BF group) or were supplemented by infant formula partially (SF group) before onset of hyperbilirubinemia. Genotyping of the promoter and exon1 of UGT1A1 was performed in all neonates. Neonates in BF group had a significantly higher maximal body weight loss ratio, peak bilirubin level, and a greater incidence of hyperbilirubinemia than those in SF group. Neonates with nucleotide 211 GA or AA variation in UGT1A1 genotypes had higher peak serum bilirubin levels and higher incidence of hyperbilirubinemia than WTs (GG). This phenomenon was only seen in BF group but not in SF group when subset analysis was performed. This suggests that neonates who carry the nucleotide 211 GA or AA variation within coding region in UGT1A1 gene are more susceptible to develop early-onset neonatal breastfeeding jaundice.

Sn-protoporphyrin blocks the increase in serum bilirubin levels that develops postnatally in homozygous Gunn rats.

Administration of Sn-protoporphyrin to Gunn rats that are characterized by a genetically determined absence of UDP-glucuronyl transferase activity for bilirubin, 24-30 h after birth, prevented the marked increase in serum bilirubin concentration that occurs in these animals in the postnatal period. A second administration of Sn-protoporphyrin at day 6 maintained serum bilirubin levels in the neonates at the initial level for an additional 6 d. In contrast, in untreated Gunn neonates, serum bilirubin levels increased substantially as expected during the immediate 2-wk period after birth. Studies in adult Gunn rats demonstrated that Sn-protoporphyrin administration diminished biliary bilirubin output, decreased tissue heme oxygenase activity, and did not alter hepatic cytochrome P450 levels. These findings raise the possibility that Sn-protoporphyrin may prove clinically useful in maintaining low levels of serum bilirubin in congenitally jaundiced individuals, such as patients with the Crigler-Najjar syndrome.

Polymorphic variants of UGT1A1 in neonatal jaundice in southern Brazil.

Alterations in the hepatic conjugation of bilirubin due to uridyl-diphosphate-glucuronosyltransferase 1A1 (UGT1A1) polymorphisms have been proposed as risk factors to neonatal jaundice. Herein, we estimated the frequency of genotypes of the promoter region of UGT1A1 gene in newborns and evaluated its association with severe hyperbilirubinemia. Prospective study of cases and controls including all newborns admitted for phototherapy at HCPA, Brazil, during 9 months; 490 babies were enrolled and PCR was performed. Polymorphic genotypes were detected in 16% of the patients and 7 of the 10 possible genotypes were identified with higher prevalence of polymorphisms in Afro-descendants. In this sample, the variants of UGT1A1 were not associated to severe hyperbilirubinemia; other genic factors should be sought in this high miscegenation area of Brazil.

Glucose-6-phosphate dehydrogenase and red cell pyruvate kinase deficiency in neonatal jaundice cases in egypt.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency can lead to acute hemolytic anemia, chronic nonspherocytic hemolytic anemia, and neonatal jaundice. Neonatal red cell pyruvate kinase (PK) deficiency may cause clinical patterns, ranging from extremely severe hemolytic anemia to moderate jaundice. The authors aimed at studying the prevalence of G6PD and PK deficiency among Egyptian neonates with pathological indirect hyperbilirubinemia in Cairo. This case-series study included 69 newborns with unconjugated hyperbilirubinemia. All were subjected to clinical history, laboratory investigations, e.g., complete blood counts, reticulocytic counts, direct and indirect serum bilirubin levels, Coombs tests, qualitative assay of G6PD activity by methemoglobin reduction test, and measurement of erythrocytic PK levels. The study detected 10 neonates with G6PD deficiency, which means that the prevalence of G6PD deficiency among Egyptian neonates with hyperbilirubinemia is 14.4% (21.2% of males). G6PD deficiency was significantly higher in males than females (P = .01). The authors detected 2 cases with PK deficiency, making the prevalence of its deficiency 2.8%. These data demonstrate that G6PD deficiency is an important cause for neonatal jaundice in Egyptians. Neonatal screening for its deficiency is recommended. PK deficiency is not a common cause of neonatal jaundice. However, this needs further investigation on a larger scale.

Glucose-6-phosphate dehydrogenase deficiency.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common human enzyme defect, being present in more than 400 million people worldwide. The global distribution of this disorder is remarkably similar to that of malaria, lending support to the so-called malaria protection hypothesis. G6PD deficiency is an X-linked, hereditary genetic defect due to mutations in the G6PD gene, which cause functional variants with many biochemical and clinical phenotypes. About 140 mutations have been described: most are single base changes, leading to aminoacid substitutions. The most frequent clinical manifestations of G6PD deficiency are neonatal jaundice, and acute haemolytic anaemia, which is usually triggered by an exogenous agent. Some G6PD variants cause chronic haemolysis, leading to congenital non-spherocytic haemolytic anaemia. The most effective management of G6PD deficiency is to prevent haemolysis by avoiding oxidative stress. Screening programmes for the disorder are undertaken, depending on the prevalence of G6PD deficiency in a particular community.

Are glutathione S-transferase gene polymorphisms linked to neonatal jaundice?

Glutathione S-transferases (GSTs) are a major group of phase II detoxification enzymes involved in the metabolism of both endogenous and xenobiotic compounds. In addition to their catalytic function in detoxification, GSTs participate in binding to nonsubstrate ligands such as bilirubin. Ligandin, which is one of the principal hepatic-binding proteins, is also a member of the GST family. The aim of the present study was to investigate the possible relationship between neonatal jaundice and the GST gene polymorphisms. The study cohort consisted of a patient group of 116 newborns (plasma bilirubin levels > or = 15 mg/dl) and a control group of 54 newborns (plasma bilirubin levels <13 mg/dl). In the patient group, the null genotype frequencies in GSTM1 and GSTT1 were 52.6 and 19%, respectively; in the control group, these were 63 and 27.8%, respectively. The frequencies of GSTM1 and GSTT1 were similar in the patient and control groups (p > 0.05). Total bilirubin levels were found to be significantly higher in patients with the GSTM1 null genotype than in patients with the GSTM1 wild genotype (p = 0.042). There was no statistically significant difference in total bilirubin levels between patients with the null GSTT1 genotype and those with the wild GSTT1 genotype. It is conceivable that there is a relation between GSTM1 gene polymorphism and total bilirubin levels in neonatal jaundice. We suggest that GSTM1 gene polymorphisms may affect ligandin functions in hepatocytes, which are important in bilirubin transportation. Consequently, patients with the GSTM1 null genotype may have higher total levels of bilirubin.

Efficacy of clofibrate on severe neonatal jaundice associated with glucose-6-phosphate dehydrogenase deficiency (a randomized clinical trial).

Glucose-6-phosphate dehydrogenase (G6PD) deficiency may cause severe hyperbilirubinemia with bilirubin encephalopathy unless intervention is initiated. The aim of this study was to assess the efficacy of clofibrate in full term G6PD deficient neonates with jaundice. A randomized clinical trial study was performed in two groups of full-term G6PD deficient jaundiced neonates (clofibrate treated group, n = 21; control group, n = 19). Infants in the clofibrate group received a single oral dose of 100 mg/kg clofibrate, whereas control group received nothing. Both groups were treated with phototherapy. Serum total and direct bilirubin levels were measured at the onset of treatments, 16, 24 and 48 hours later. On enrollment, the mean total serum bilirubin (TSB) level in the clofibrate treated group was 18.40 +/- 2.41 and in the control group was 17.49 +/- 1.03 (p = 0.401). At 16, 24 and 48 hours of treatment, the mean TSB in the clofibrate group were 15.2 +/- 1.9, 12.6 +/- 2.4, and 10.1 +/- 2.4 and in the control group were 16.5 +/- 1.2, 13.3 +/- 2.2 and 11.4 +/- 2.4, respectively (p = 0.047). At 48 hours, 7 (33%) cases in the clofibrate group and one (5%) case in the control group were discharged with a TSB < 10 mg/dl (p = 0.031). No side effects were observed on serial examinations during hospitalization, or on the 1st and 7th days after discharge. The results show that clofibrate induces a faster decline in serum total bilirubin level, a shorter duration of phototherapy, and hospitalization with no side effects in full-term G6PD deficient neonates with jaundice.

Maternal lamotrigine treatment and elevated neonatal gamma-glutamyl transpeptidase.

Lamotrigine is an antiepileptic drug with a low adverse-effect profile. This report describes an infant born to an epileptic mother treated with lamotrigine, who had a highly elevated gamma-glutamyl transpeptidase level after birth. There was no other clinical or biochemical evidence of liver or bile duct dysfunction. Infant serum level of lamotrigine, which crosses the placenta, was within therapeutic limits. Gamma-glutamyl transpeptidase levels declined slowly during the following months. We suggest that, in the absence of additional markers of tissue damage, the infant's gamma-glutamyl transpeptidase elevation was caused by maternal intake of lamotrigine. Liver function tests should be monitored in infants of lamotrigine treated mothers, as enzyme elevation might still suggest liver damage.

Glucose-6-phosphate dehydrogenase (G6PD) variants in Malaysian Chinese.

We screened 38 G6PD-deficient male Chinese neonates for known G6PD mutations using established PCR-based techniques. We found 50.0% (19 of 38) were mutation 1376G>T, 34.2% (13 of 38) were mutation 1388G>A, 5.2% (2 of 38 ) were mutation 95A>G and 2.2% (1 of 38) was mutation 1024C>T. In 7% (3 of 38) of the cases the mutations remained uncharacterised. Sixty three percent (24 of 38) of the G6PD deficient neonates had neonatal jaundice with 28.9 % (11 of 38) developing moderate to severe hyperbilirubinemia. The group of neonates with 1388 mutation showed the highest incidence of moderate to severe hyperbilirubinemia requiring phototherapy and/or exchange transfusion respectively. Majority (70%) of the G6PD deficient neonates showed severe enzyme deficiency. However, there was no meaningful association between the level of enzyme activity and the severity of neonatal jaundice. In summary, four mutations account for more than 90% of the G6PD deficiency cases among the Chinese in Malaysia and the pattern of distribution of the molecular variants is similar to those found among the Chinese in Taiwan and southern mainland China. Our findings also suggest the possible association of nt 1388 mutation with severe neonatal jaundice.

Glucose-6-phosphate dehydrogenase (G6PD) mutations in Thailand: G6PD Viangchan (871G>A) is the most common deficiency variant in the Thai population.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common hereditary disorder in humans. Through a population study for G6PD deficiency using a cord blood quantitative G6PD assay in Bangkok, Thailand, we found that the prevalence of G6PD deficiency is 11.1% in Thai male (N=350) and 5.8% in female (N=172) cord blood samples. Among the neonates with hyperbilirubinemia, the prevalence of G6PD deficiency is 22.1% in males (N=140) and 10.1% in females (N=89). We developed a PCR-restriction enzyme-based method to identify G6PD Viangchan (871G>A), and searched for this and 9 other mutations in DNA from G6PD deficient blood samples. G6PD Viangchan (871G>A) was the most common mutation identified (54%), followed by G6PD Canton (1376G>T; 10%), G6PD Mahidol (487G>A; 8%), G6PD Kaiping (1388G>A; 5%), G6PD Union (1360C>T; 2.6%) and "Chinese-5" (1024C>T; 2.6%). Among 20 neonates with hyperbilirubinemia, G6PD Viangchan was also most frequently identified (60%), followed by G6PD Canton (10%), G6PD Mahidol, G6PD Union, and G6PD Kaiping (5% each). G6PD Viangchan appears from this study to be the most common G6PD mutation in the Thai population, bringing into question previous reports that G6PD Mahidol is most prevalent. G6PD Viangchan, together with G6PD Mahidol and G6PD Canton, are responsible for over 70% of G6PD deficiency in this study of Thais. With the data from other Southeast Asian ethnic groups such as Laotians, G6PD Viangchan (871G>A) is probably the most common variant in non-Chinese Southeast Asian population.

Heme degradation and human disease: diversity is the soul of life.

We all depend on molecular oxygen and heme for our life, as evident from the pigments in blood and daily wastes. About 80% of serum bilirubin is derived from hemoglobin of senescent erythrocytes, which have finished their mission of 120 days and have been phagocytized by macrophages in the reticuloendothelial system. Here we present an overview of the heme degradation processes and relevant disorders by focusing on heme oxygenase-1 (HO-1), a key enzyme in heme catabolism. HO-1 cleaves the porphyrin macrocycle of heme at the expense of molecular oxygen to release a linear tetrapyrrole biliverdin, carbon monoxide, and ferrous iron; biliverdin is rapidly reduced to bilirubin. Bilirubin is transported to the liver (hepatocytes), conjugated with glucuronic acid by bilirubin UDP-glucuronosyltransferase, and excreted into bile. Genetic diversity, a strategy in the host defense, is seen in the human ho-1 and UDP-glucuronosyltransferase genes. Moreover, striking interspecies variations are noted in the regulation of HO-1 expression by hypoxia, heat shock, or interferon-gamma, each of which mainly represses HO-1 expression in human cells. Implications of such a variety are discussed in relevance to the pathogenesis of severe malaria caused by Plasmodium falciparum, the most ancient foe of humans.

Phototherapy for neonatal jaundice in erythrocyte glucose-6-phosphate dehydrogenase-deficient infants.

The effectiveness of phototherapy in the management of neonatal hyperbilirubinemia in glucose-6-phosphate dehydrogenase (G6PD)-deficient infants was studied. "Prophylactic" phototherapy for six continuous days commencing from the first day of life was effective in preventing a significant rise in bilirubin levels in 12 G6PD-deficient infants in the first three days, during which period a rapid rise was observed in a control group of G6PD-deficient infants. The hemoglobin levels on the first and eighth postnatal days were comparable in both groups. "Therapeutic" phototherapy proved equally effective in reducing bilirubin levels in 24 infants with nonhemolytic hyperbilirubinemia and an equal number of infnats with hyperbilirubinemia associated with G6PD deficiency. Phototherapy was efficacious in the prevention or treatment of neonatal hyperbilirubinemia associated with G6PD deficiency; even if its use is prolonged it does not cause hemolysis in such infants.

Predischarge bilirubin screening in glucose-6-phosphate dehydrogenase-deficient neonates.

OBJECTIVE: To assess the validity of predischarge serum bilirubin values in determining or predicting hyperbilirubinemia in glucose-6-phosphate dehydrogenase (G-6-PD)-deficient neonates, and to facilitate appropriate discharge planning. METHODS: Serum total bilirubin values were determined between 44 and 72 hours of life in a cohort of term, healthy neonates at high-risk for G-6-PD deficiency but with no other risk factors for hyperbilirubinemia. Percentile-based bilirubin nomograms were constructed for G-6-PD-deficient infants and normal infants according to age at sampling. The incidence of hyperbilirubinemia (serum bilirubin value > or =256 micromol/L [15 mg/dL]) for each group was determined according to the percentiles for that group. RESULTS: In both G-6-PD-deficient neonates (n = 108) and control neonates (n = 215) with serum bilirubin values <50th percentile for age, the incidence of hyperbilirubinemia was low in the G-6-PD-deficient neonates, with no measurable incidence in the controls. The incidence of hyperbilirubinemia became clinically consequential, and significantly higher in the G-6-PD-deficient groups, when the percentiles were > or =50: for those in the 50% to 74% range the incidence was moderate (23%) for the G-6-PD-deficient and small (7%) for the control infants (relative risk, 3.29; 95% confidence interval, 1.01-10.67). Among those infants > or =75th percentile, 82% of the G-6-PD-deficient infants, compared with 25% of the control infants, were either already hyperbilirubinemic at the time of screening or subsequently developed hyperbilirubinemia (relative risk, 3.23; 95% confidence interval, 1.99-5.24). CONCLUSIONS: Timed, predischarge serum bilirubin screening can be used to identify G-6-PD-deficient neonates at low, intermediate, or high-risk of developing severe neonatal hyperbilirubinemia, and thus offer a selective approach to the discharge and follow-up surveillance of these infants.

Successful bone marrow transplantation in a child with red blood cell pyruvate kinase deficiency.

We report the first successful use of BMT for the treatment of RBC pyruvate kinase (PK) deficiency in a boy who developed neonatal jaundice and severe transfusion-dependent hemolytic anemia a few months after birth. He received a BMT at the age of 5 from an HLA-identical sister who has normal PK activity after conditioning with busulfan and cyclophosphamide. The post-transplant course was uneventful. At present, 3 years after transplant, he is 8 years old and has a normal hemoglobin level and normal RBC PK activity without evidence of hemolysis. DNA analysis has confirmed full engraftment.

Differentiation of cholestatic jaundice in infants. Utility of diethyl-IDA.

Time-activity curves of technetium-labeled diethyl-IDA were used to evaluate 31 patients in an effort to differentiate infants with cholestatic jaundice. Results can be obtained rapidly with minimal radiation exposure and no known secondary effects. The combination of diethyl-IDA time-activity curves and gamma glutamyl transferase activity was found to discriminate biliary atresia from neonatal hepatitis. The group with neonatal hepatitis was characterized by abnormal, yet lower, gamma glutamyl transferase activities and diethyl-IDA time-activity curves which peaked within 1 minute of injection, yet decayed in a manner similar to cardiac activity. The group with biliary atresia was characterized by elevated gamma glutamyl transferase activities, hepatic peaks at 8 minutes and markedly delayed decay. In that early operative intervention is associated with increased survival in biliary atresia, prompt differentiation should improve prognosis.

Enzyme deficiencies in neonates with jaundice.

Numerous findings have shown that enzyme deficiencies, especially those involved in the protection of red cells from oxidation may lead to hemolysis and hyperbilirubinemia. It is established that G6PD deficiency may be the cause of neonatal hyperbilirubinemia, as has been found in several countries and among widely different ethnic groups. We try to establish the incidence of G6PD, PK and GSSG-R deficiencies in neonates with jaundice for a better assessment of the population at risk. The present investigation was carried out in the attempt to be certain whether these enzymes could play a part in the development of neonatal jaundice. A total of 341 neonates of both sexes with jaundice were analyzed: 47 with G6PD deficiency; 9 with PK deficiency and 2 with GSSG-R deficiency.

The effect of neonatal jaundice on biotinidase activity.

BACKGROUND: Jaundice is one of the most common and one of the vexing problems that can occur in newborns. A newborn screening test for biotinidase deficiency has been added to many national screening programmes. AIM: To clarify the problem of false-positive screening tests in neonates, especially in term babies, we evaluated the biotinidase activity in the serum of fullterm, premature and small-for-dates newborn infants with jaundice. METHODS: 1296 fullterms (controls N=426), 246 prematures (controls N=86) and 156 small-for-dates babies (controls N=38) aged 2-3 days with jaundice were included in the study. In jaundiced neonates and controls, 3.0 ml of blood was drawn for the evaluation of total bilirubin (t.bil), liver enzymes and biotinidase activity in the serum using a fluorimetric method. In order to test whether or not t.bil causes an artifact in the previous method, biotinidase activity was also evaluated in a number of jaundiced newborns using an HPLC method. Additionally, a preliminary in vitro experiment was carried out to test whether t.bil is an inhibitor of the enzyme. RESULTS: Biotinidase activities in the group of controls of prematures (3.30+/-1.2 mmol/min/l) and small-for-dates babies (3.34+/-0.8 mmol/min/l) were lower than those of term babies (4.99+/-1.1 mmol/min/l, p<0.001). T.bil and liver enzymes showed a statistically significant inverse correlation with biotinidase activity (p<0.001) in all the jaundiced infants of this study. Additionally, biotinidase activity, evaluated in a number of neonates with both fluorimetric and HPLC methods showed similar results. Preincubation of the serum enzyme with t.bil (>10 mg/dl) resulted in a 50% or more inhibition. CONCLUSIONS: (a) Low biotinidase activity was found in term babies, prematures and small-for-dates with jaundice. (b) The low activity of the enzyme could be due to their impaired liver function. (c) The high t.bil levels in the studied groups may play the role of an "inhibitor" of the enzyme. (d) Gestational age as well as t.bil levels should always be written on Guthrie cards for a correct evaluation of biotinidase activity.

Transfusion requirements of patients with enzyme deficient red blood cells.

Red cell enzyme deficiency disease states are reviewed to outline the requirements for transfusion therapy in the neonatal period, during spontaneous crises, drug or infection-induced crises and chronic anemia.

Kallikrein and kininase activities excretion in newborns affected by jaundice.

In a homogeneous group of 30 newborns, aging between 10 hours--10 days, and affected by jaundice, urinary kallikrein and kininase activities were determined. The variable considered were: sex, time of life, weight and gestational age. Urinary samples were taken at the beginning and at the end of phototherapy.

Gamma-glutamyl transferase in neonatal non-hemolytic indirect hyperbilirubinemia.

Serum gamma-glutamyl transferase (GGT) activities were determined on the third day of life in healthy controls (n:15) and in infants with non-hemolytic hyperbilirubinemia (n:16). GGT activities were 39.6 +/- 28.4 units/ml and 46.6 +/- 26.7 units/ml, respectively. There was no statistical difference between both groups (p greater than 0.05).