Lower Bilirubin Levels Research Articles

567. Prevention of Bilirubin Toxicity in the Gunn Rat by Long-Term Correction of Hyperbilirubinemia with Liver-Specific Plasmid-Based Gene Transfer

Background: We have previously demonstrated short-term correction of hyperbilirubinemia in the Gunn rat (GR), animal model of Crigler-Najjar Disease Type I, by hepatic venous delivery of naked plasmid (pDNA) expressing human bilirubin glucuronosyl transferase (hUGT1A1) under CMV promoter. Recently, long-term expression of coagulation factors in mouse liver was reported after tail vein injection of pDNA containing alpha-1 antitrypsin promoter along with other liver-specific elements, limited only by development of antibodies to some secreted proteins. In this study we investigated whether liver-specific regulatory sequences prolong expression of hUGT1A1 in the GR, whether immune response develops to this intracellular enzyme, and whether with this approach sufficiently low bilirubin levels can be maintained to prevent renal tubular damage, the principal manifestation of chronic bilirubin toxicity in GR.

Use of red cells preserved in extended storage media for exchange transfusion in anti‐k haemolytic disease of the newborn

Anti-k is a Kell-related antibody. There is little correlation between the maternal antibody titre and the severity of haemolytic disease of the foetus and newborn, and anaemia is usually associated with low bilirubin levels. Severe erythroblastosis has been reported with a low titre anti-k (IAT 8-16). We report a case of severe haemolytic disease of the newborn (HDN) due to anti-k. HDN was associated with a normal bilirubin level and reticulocytopenia. The foetus was monitored by ultrasound, and delivery by elective caesarean section (CS) was planned. The mother was admitted 1 week before the expected date of delivery, and the infant was delivered by urgent CS. The infant required exchange transfusion. As suitable plasma-reduced (k antigen(-)) red cell units were not readily available, k- SAGM red cell units (preserved in extended storage media: SAGM sodium chloride, adenine, glucose and mannitol) were provided. The post-transfusion Hb remained stable, and the infant did not require further transfusion support. Our findings (reticulocytopenia and normal bilirubin levels) support the hypothesis that the pathogenesis of anaemia and haemolysis in anti-k HDN may be similar to that in anti-K (suppression of erythropoesis and immune destruction of K+ erythroid progenitor cells by macrophages in the foetal liver). The ideal product for exchange transfusion is plasma-reduced RBC, less than 5-days old. We provided a 4-day-old SAGM red cell unit for exchange transfusion in a term infant, and this was uneventful. Caution should be taken, however, and renal function and electrolyte levels should be monitored closely. More information is required regarding the safety of SAGM units for exchange transfusion.

Post-radiation survival time in hepatocellular carcinoma based on predictors for CT-determined, transarterial embolization and various other parameters

In this retrospective study of unresectable hepatocellular carcinoma (HCC), we have investigated the efficacy of CT-derived parameters, laboratory measurements, clinical assessment and associated transarterial embolization (TAE) as predictors of post-radiotherapy survival time. Sixty-six patients diagnosed with unresectable HCC that had undergone radiotherapy at two medical university hospitals in Taipei were enrolled in the study. Using multivariant analysis, pre-treatment parameters including tumor number and CT confirmation of PVT and ascites were compared. Multivariant analysis was also used for comparison of the mean pretreatment values for laboratory measurements, including alpha-fetoprotein, direct/total bilirubin and GOT/GPT levels, and clinical history of chronic hepatitis across the three survival-time categories. The chi2 was used to test the significance of the relationship between survival time and TAE procedure. The P values for the above tests were deemed statistically significant where P<0.05. Portal vein thrombosis (P = 0.032) and ascites (P<0.05) were negative predictors of post-radiation survival time. Low-grade liver cirrhosis (A or B), lower tumor volume and low levels of AFT, GOT/GPT, and total bilirubin were predictors of longer post-radiation survival time (P<0.05). The CT and clinical and laboratory assessment provide a reference for, and enable estimation of, probable survival times in HCC patients after radiotherapy. Tumor volume, severity of liver cirrhosis, status with respect to portal vein thrombosis and ascites and AFT, GOT/GPT and total bilirubin values were significant predictors of survival in this study.

Modeling Phenotype Interactions in Sickle Cell Anemia.

Predicting a broad risk of selected serious vasoocclusive complications of sickle cell anemia is possible. For example, patients with higher hemoglobin concentrations are less likely to have a stroke. Yet, it has not been feasible to integrate the many clinical and laboratory abnormalities of sickle cell anemia into a predictive model that permits an understanding of the interactions among common clinical and laboratory abnormalities. From the database of the Cooperative Study of Sickle Cell Disease, we examined clinical and laboratory data from nearly 1500 individuals with sickle cell anemia, with or without coincident α thalassemia. We used these data to develop a Bayesian network that describes the interactions between clinical and laboratory data and their associations with the risk for complications of sickle cell anemia. Bayesian networks are multivariate models that represent the complex structure of interactions between many variables by a network of interrelated modules. The modules can be learned from data using statistical techniques and can be used to describe how changes in some variables affect other variables and ultimately the risk for phenotypes of interest. Our model shows that a complex network of interactions between clinical and laboratory variables underlies common complications of sickle cell anemia and ultimately death. Particularly important is the protective role that α thalassemia appears to play in common complications of sickle cell anemia. For example, α thalassemia, by decreasing erythrocyte density, reduces hemolysis and is associated with lower levels of bilirubin and an associated decreased risk for priapism. Bilirubin levels may reflect nitric oxide (NO) availability and NO may be invoved in the etiology of priapism. α thalassemia is also associated with smaller numbers of reticulocytes that are strongly associated with a decreased risk for acute chest syndrome and osteonecrosis; and it is associated with higher level of fetal hemoglobin and a reduction in leukocyte counts with a significant decreased risk for stroke and death. This model can be used to predict the occurrence of certain complications of sickle cell anemia and early death, given the presence of other disease complications and variations among common laboratory variables. For example, our model predicts a 10% risk for stroke at early age and an 11% risk for early death in patients with sickle cell anemia without α thalassemia compared with a 4% risk for stroke and 1.5% risk for early death for individuals with coincident α thalassemia. However, the predictive power of this model is limited, and we conjecture that this is a reflection of the omission of the genotypic changes that underlie the phenotypes. In related work using this same patient population, we analyzed genetic polymorphisms in candidate genes and showed than 25 SNPs and 4 clinical variables, including α thalassemia and fetal hemoglobin, were associated with increased risk of stroke and that this model predicted the occurrence of stroke in 114 individuals in a different population with 98% accuracy. The lack of the same predictive power of our current model suggests that genetic variants play a fundamental role in susceptibility to stroke and other complications of sickle cell anemia.

Kernicterus: Past, Present, and Future

The concept of a relationship between severe neonatal hyperbilirubinemia and kernicterus evolved slowly. Jaundice was recognized in ancient as well as biblical times as a manifestation of disease. However, according to Louis K. Diamond (Fig. 1), who reviewed the history of neonatal jaundice, (1) the first record concerning jaundice of the newborn appears to be by Barthomomaeus Metlinger in 1473 in his book Ein Regiment der Jungen Kinder . The occurrence of jaundice shortly after birth as well as some suggestions for homeopathic treatment were mentioned by Michael Ettmuller in his 1708 treatise “De Infantum Morbis.” (1) An early description of icterus neonatorum was published in 1742 in London by John Burton in his treatise “A Full View of All the Diseases Incident to Children.” He suggested that “jaundice generally yields to any gentle purgative.” (1) This same approach was used by Condie in 1853 in Philadelphia. (2) At that time, he wrote that icterus neonatorum seemed to be “connected with the want of a free evacuation of meconium.” He suggested the use of castor oil or a small measure of calomel or rhubarb. It is interesting that he noted that the jaundice was known at times to be accompanied by a “good deal of drowsiness.” There were several publications in France concerning neonatal jaundice in the late eighteenth and early nineteenth centuries, the most significant of which, according to Thor Hansen, (3) was the thesis submitted by Jacques Francois Hervieux and defended by him for his M.D. degree at the University of Paris in 1847. The thesis was entitled “De l’ictere des nouveau-nes” (On the jaundice of newborns). Thor Hansen, to whom we are grateful for having reviewed the original French thesis, pointed out that the introductory section of the Hervieux thesis contains a valuable review of works by …

Effect of serum albumin and bilirubin on the risk of myocardial infarction (the Framingham Offspring Study)

The goal of this study was to use data collected on participants in the Framingham Offspring Study to test the hypothesis that low levels of serum albumin (Alb) and low levels of serum bilirubin (Bil) have synergistic effects on the risk of myocardial infarction (MI). Further, we wished to evaluate whether the relation of low Alb and low Bil to MI was modified by serum cholesterol levels.

A genome scan for loci influencing anti-atherogenic serum bilirubin levels.

Epidemiological studies have shown an association of decreased serum bilirubin levels with coronary artery disease. Two segregation analyses in large pedigrees have suggested a major gene responsible for high bilirubin levels occurring in about 12% of the population. Based on a recessive model from a previous segregation analysis, we performed a genome scan using 587 markers genotyped in 862 individuals from 48 Utah pedigrees to detect loci linked to high bilirubin levels. As a complementary approach, non-parametric linkage (NPL) analysis was performed. These two methods identified four regions showing evidence for linkage. The first region is on chromosome 2q34-37 with multipoint LOD and NPL scores of 3.01 and 3.22, respectively, for marker D2S1363. This region contains a previously described gene, uridine diphosphate glycosyltransferase 1, which has been associated with high bilirubin levels. A polymorphism in the promoter of this gene was recently shown to be responsible for Gilbert syndrome which is associated with mild hyperbilirubinemia. The other regions were found on chromosomes 9q21, 10q25-26, and 18q12 with maximum NPL scores of 2.39, 1.55, and 2.79, respectively. Furthermore, we investigated in these pedigrees the association between bilirubin levels and coronary artery disease. One-hundred and sixty-one male and 41 female subjects had already suffered a coronary artery disease event. Male patients showed significantly lower bilirubin concentrations than age-matched controls. This association, however, was not observed in females. These results provide evidence that loci influencing bilirubin variation exist on chromosomes 2q34-37, 9q21, 10q25-26, and 18q12 and confirms the association of low bilirubin levels with coronary artery disease in males.

THE ASSOCIATION OF CARDIORESPIRATORY FITNESS AND SERUM BILIRUBIN

Low levels of bilirubin are a risk factor for cardiovascular disease (CVD). Moderate to high levels of cardiorespirator fitness (CRF) are protective against CVD. All the mechanisms whereby CRF protects against the development of CVD are not completely understood. Purpose: To examine the association of CRF and bilirubin. Methods: A cross-sectional study of 1546 non-smoking men (age 53.0 ± 10.7 y, BMI 26.1 ± 3.5 kg/cm2) and 334 non-smoking women (age 52.6 ± 11.0 y, BMI 23.7 ± 4.2 kg/cm2) in the Aerobics Center Longitudinal Study. Bilirubin was measured following a 12 hour fast. CRF was assessed by a maximal treadmill exercise test (Balke protocol). Based on age, gender and time on treadmill participants were categorized into fitness quintiles. Trend across fitness quintiles for bilirubin was tested using age and BMI adjusted regression models. Results: Table 1: Bilirubin (mean ± SE) across levels of fitness (See table Below). The p for trend for bilirubin was significant across fitness quintiles in both men and women. Additionally, quintile 5 had higher mean bilirubin values than quintile 1 for both men and women (p < 0.002 for both). Bilirubin has strong antioxidant properties and may be one mechanism whereby moderate and high levels of fitness provide protection against the development of CVD. Conclusion: Fitness is positively associated with bilirubin in this group of healthy non-smoking men and women. Supported in part by U.S.P.H.S research grant AG06945 from the N.J.A. and the Simmons FoundationTable: Fitness quintiles (Low to High)

Effects of light on low nocturnal bilirubin in winter depression: a preliminary report

Background: The light-absorbing pigments involved in the induction of treatment of winter depression are unknown. It has been proposed that circulating bilirubin serves as a photoreceptor, in part because of its similarity to the chromophore of phytochrome, a primary time-setting plant molecule. Methods: We measured nocturnal bilirubin levels in nine patients with winter depression, and seven age- and gender-matched normal comparison volunteers. Results: Nocturnal bilirubin levels were lower in patients than in controls (p < .02), increased in both groups during the night (p < .0001), and increased in patients after 2 weeks of morning light treatment (p = .0009), which was accompanied by clinical improvement. Conclusions: Low nocturnal bilirubin levels may be associated with winter seasonal depression.

HDAF transgenic pig livers are protected from hyperacute rejection during ex vivo perfusion with human blood.

The aim of this study was to determine if human decay-accelerating factor (hDAF) protects against hyperacute rejection in an ex vivo liver perfusion system using human blood. Pig livers were perfused ex vivo via the portal vein for an average of 5-6 h using a membrane oxygenator. Three groups were studied. Group I: Wild-type pig livers were alloperfused with fresh pig blood (n = 5). Group II: Wild-type pig livers were xenoperfused with fresh human blood (n = 5). Group III: hDAF transgenic pig livers were xenoperfused with fresh human blood (n = 5). The graft ischemic time, ratio of perfusate volume to liver weight, flow rate, and perfusate hematocrit were similar in each group. The hDAF livers perfused with human blood (Group III) had a lower ALT level, less protein and albumin losses, lower bilirubin levels in the perfusate, less weight gain, and greater bile production than the wild-type livers perfused with human blood. Histology showed classic features of hyperacute rejection in Group II, including massive hemorrhage, severe vasculitits, fibrin and C5b-9 deposition, and endothelial damage within 1 h of perfusion, whereas liver histology studies in Groups I and III were near normal. IgG and IgM deposits were seen in the xenoperfused livers. Electron microscopy (EM) and immuno-EM showed loss of endothelial cells, trapping of white blood cells and platelets, and diffuse fibrin deposits in Group II only. hDAF pig livers perfused with human blood showed superior function and histology when compared with wild-type pig livers. These data suggest that (1) hyperacute rejection may contribute to the inconsistent results using wild-type pig livers for extracorporeal liver support and (2) genetically modified pigs that express hDAF may provide a better donor source than wild-type pigs for extracorporeal liver support.

Phototherapy--traditional and nontraditional.

An observation by an English nurse in 1956 led to the discovery that visible light could lower serum bilirubin levels in newborn infants, and subsequent research showed how photons of light energy are absorbed by the bilirubin molecule converting it into isomers that are readily excreted by the liver and the kidney. Understanding the dose-response effect and other factors that influence the way light works to lower bilirubin levels has led to the effective use of phototherapy and has eliminated the need for exchange transfusion in almost all jaundiced infants.

Magnetic resonance imaging in three children with kernicterus

The incidence of kernicterus has been greatly reduced by effective monitoring and treatment for hyperbilirubinemia. Findings on magnetic resonance imaging (MRI) in patients with kernicterus are characteristic. This study presents three cases of possible kernicterus without typical symptoms but with MRI features consistent with kernicterus. These cases suggest that kernicterus can develop, especially in preterm infants, in the presence of relatively low levels of bilirubin and the absence of obvious acute symptoms. Therefore assessing the risk of kernicterus may be difficult in the neonatal period. In addition, MRI findings at the posteromedial border of the globus pallidus in patients with athetotic cerebral palsy are strong evidence of brain damage caused by kernicterus.

Relative Risk of Liver Failure in Dairy Cows with Left Abomasal Displacement

Dairy cows with left abomasal displacement (LDA) are in substantial negative energy balance and mobilize considerable amounts of non-esterified fatty acids. Thus, fatty liver is a common hepatic disorder in LDA cows. Results of a previous study showed that approximately 4-5% of LDA cows referred to our clinic for surgical correction of abomasal displacement died or were sacrified due to liver coma. We found not only cows with severe fatty liver but also cows with moderate or even mild fatty liver affected by liver failure. Characteristically, cows with liver failure showed typical clinical signs of a hepatic encephalopathy (general depression, ataxia, recumbency or coma) and a low plasma amino acid ratio (Val+Leu+Ile/Phe+Tyr), low plasma cholesterol concentrations and high plasma levels of ammonia, total bilirubin and hepatic enzymes.&#x0D; Thus, aim of the study was to calculate the risk of liver failure of dairy cows with LDA related to the hepatic triglyceride content.

Bilirubin exerts additional toxic effects in hypoxic cultured neurons from the developing rat brain by the recruitment of glutamate neurotoxicity.

Both hypoxia and bilirubin are common risk factors in newborns, which may act synergistically to produce anatomical and functional disturbances of the CNS. Using primary cultures of neurons from the fetal rat brain, it was recently reported that neuronal apoptosis accounts for the deleterious consequences of these two insults. To investigate the influence of hypoxia, bilirubin, or their combination on the outcome of neuronal cells of the immature brain, and delineate cellular mechanisms involved, 6-d-old cultured neurons were submitted to either hypoxia (6 h), unconjugated bilirubin (0.5 microM), or to combined conditions. Within 96 h, cell viability was reduced by 22.7% and 24.5% by hypoxia and bilirubin, respectively, whereas combined treatments decreased vital score by 34%. Nuclear morphology revealed 13.4% of apoptotic cells after hypoxia, 16.2% after bilirubin, and 22.6% after both treatments. Bilirubin action was specifically blocked by the glutamate receptor antagonist MK-801, which was without effect on the consequences of hypoxia. Temporal changes in [(3)H]leucine incorporation rates as well as beneficial effects of cycloheximide reflected a programmed phenomenon dependent upon synthesis of selective proteins. The presence of bilirubin reduced hypoxia-induced alterations of cell energy metabolism, as reflected by 2-D-[(3)H]deoxyglucose incorporation, raising the question of free radical scavenging. Measurements of intracellular radical generation, however, failed to confirm the antioxidant role of bilirubin. Taken together, our data suggest that low levels of bilirubin may enhance hypoxia effects in immature neurons by facilitating glutamate-mediated apoptosis through the activation of N:-methyl-D-aspartate receptors.

Association of plasma bilirubin with coronary heart disease and segregation of bilirubin as a major gene trait: the NHLBI family heart study

Decreased serum bilirubin levels have been associated with coronary heart disease (CHD). It is believed that bilirubin acts as an antioxidant, preventing formation of oxidized LDL and subsequent atherosclerosis. Serum bilirubin also segregates as a major gene, with the rarer genotype associated with elevated bilirubin levels and occurring in about 12% of the population. Using a large population-based study of random and CHD high risk families, this analysis was designed to replicate the association of lower serum bilirubin levels with early CHD (onset by age 55 for males and 65 for females) using 328 case/control samples and the major gene segregation of bilirubin levels in 555 families. There were significant differences in plasma bilirubin levels between 188 males (12.5 μmol/l) and 140 females (9.3 μmol/l, P<0.0001). Higher serum albumin and lower HDL-C significantly correlated with higher plasma bilirubin levels in females but not males. In sex-specific logistic regression models of early CHD (148 cases and 180 controls), lower plasma bilirubin was associated with increased prevalence of CHD in males with borderline significance (odds ratio=0.93 for a 1 μmol/l increase in bilirubin, P=0.056) but not in females. Bilirubin was found to segregate as a major gene using all 555 families consisting of 1292 individuals, with estimates replicating those in the previously published study. The most parsimonious model was a recessive model for high bilirubin levels that occurred in about 23% of the population. The means were separated by 1.7 standard deviations and there was a significant polygenic effect ( h 2=0.33, P=0.0009). We conclude that decreased bilirubin is mildly related to CHD in males but not in females. Because of an inverse correlation between HDL-C and bilirubin, the protective high HDL-C levels may have counteracted the CHD risk associated with lower bilirubin levels in females. The inferred major gene for bilirubin may protect against CHD, since elevated levels, rather than lower levels, were associated with this inferred gene.

Herpes Simplex Type 2 Causing Fulminant Hepatic Failure

Although exceedingly rare, fulminant hepatic failure (FHF) in immunocompetent patients can develop with primary or recurrent infection due to herpes simplex virus (HSV). The diagnosis is frequently obscured by the absence of mucocutaneous involvement. Elevated transaminase values with leukopenia and a relatively low bilirubin level may provide clues to the diagnosis. We describe an immunocompetent woman who died of FHF before a definitive diagnosis of HSV type 2 hepatitis was established. Herpes simplex virus hepatitis is one of the few causes of FHF for which potentially effective therapy is available. Thus, early diagnosis is paramount and usually requires liver biopsy. Recent studies suggest that transjugular liver biopsy is safe and effective in establishing the cause of FHF. Since the diagnosis and management of FHF are frequently influenced by the results of transjugular liver biopsy, it may become a standard diagnostic tool for managing FHF in centers where such expertise exists.

Bilirubin Induces Apoptosis via Activation of NMDA Receptors in Developing Rat Brain Neurons

Increased amounts of bilirubin, the end product of heme degradation, are known to be detrimental to the central nervous system, especially in preterm newborns. In an attempt to delineate the cellular mechanisms by which unconjugated bilirubin exerts its toxic effects on neuronal cells in the developing brain, bilirubin (0.25–5 μM) was added to the extracellular medium of 6-day-old primary cultured neurons from the embryonic rat forebrain, and cell alterations were studied over the ensuing 96 h. Bilirubin decreased cell viability dose dependently with an ED50 around 1 μM. At the dose of 0.5 μM, it triggered delayed cell death that affected 24% of the neurons. Nuclear incorporation of the fluorescent dye DAPI (4,6-diamidino-2-phenylindole) depicted the presence of apoptosis (16%). Apoptosis features were confirmed by DNA fragmentation reflected by a progressive loss of [3H]thymidine and sequential changes in macromolecular synthesis, as shown by the time course of [3H]leucine incorporation, as well as by the beneficial effects of cycloheximide and caspase inhibitors. In parallel, treatments with glutamate receptor antagonists showed that MK-801, but not NBQX, protected neurons against bilirubin neurotoxicity, suggesting a role for NMDA receptors in bilirubin effects. Coupled with previous work about glutamate toxicity in the same culture model, these data support the hypothesis that low levels of free bilirubin may promote programmed neuronal death corresponding to an apoptotic process which involves caspase activation and requires the participation of NMDA receptors, along with bilirubin-induced inhibition of protein kinase C activity.

Clinical significance of hepatitis C virus infection to alcoholics with cirrhosis in Korea

To investigate the prevalence and clinical significance of hepatitis C virus (HCV) infection and its relationship with the development of hepatocellular carcinoma (HCC), 162 consecutive alcoholic patients with cirrhosis were studied. Alcohol intake and parenteral risk factors were investigated by interview using a questionnaire. All patients had consumed at least 80 g alcohol/day for at least the past 5 years. Sera were tested for anti-HCV using a third-generation enzyme immunoassay (EIA), hepatitis B s antigen (HBsAg), anti-HBs, anti-HBc and anti-HIV. Serum HCV-RNA was detected by a one-tube reverse transcription-polymerase chain reaction (RT-PCR) method. Patients were classified into three groups accroding to the presence or absence of viral markers: (i) cases without anti-HCV or HBsAg (group A); (ii) cases with HBsAg only (group B); and (iii) cases with anti-HCV only (group C). Demographic and clinical findings were compared among the three groups. Anti-HCV was present in 17 cases (10.5%) and HBsAg was present in 47 cases (29%). No patient had both anti-HCV and HBsAg. Group C subjects were the oldest, but the duration of drinking in this group was similar to that of group A. There was no significant difference in the daily alcohol intake among the three groups. Previous surgical operations and tattooing were more frequent in group C. Only one patient in group C was an intravenous drug user. The combined rate of HCC was significantly higher in groups B and C than in groups A (34, 23.5 and 6.1%, respectively). Laboratory data showed a higher platelet count, higher albumin level, lower bilirubin level and lower aspartate aminotransferase/alanine aminotransferase ratio in group C patients than in the other two groups. Hepatitis C virus RNA was detected in 14 of 85 cases tested (16.5%), in 11 of 12 cases (91.7%) with anti-HCV and in three of 73 cases (4.1%) without anti-HCV. Hepatitis C virus infection is frequent in alcoholic patients with cirrhosis in Korea. Hepatitis C virus, as well as hepatitis B virus, infection may have a synergistic effect on the development of HCC in alcoholic patients.

Breastfeeding, Diet, and Neonatal Hyperbilirubinemia

After completing this article, readers should be able to: 1. Compare and contrast the incidence of hyperbilirubinemia between breastfed and formula-fed infants throughout the neonatal period and its relationship to early hospital discharge. 2. Describe possible reasons for the occurrence of hyperbilirubinemia in breastfed infants. 3. Compare and contrast the incidence of hyperbilirubinemia related to different infant formulas. Among the many factors related to neonatal hyperbilirubinemia is the composition of an affected infant’s diet. In 1879, Frerichs suggested that “bad nursing” could “exercise a powerful influence” on neonatal hyperbilirubinemia. Much has been learned since this suggestion was made. ### EPIDEMIOLOGY Many investigations have documented that the consumption of human milk is related to neonatal hyperbilirubinemia, including one review of 12 studies involving more than 8,000 infants in the first week of life and controlled for factors such as hemolysis to enable comparison of dietary effects alone. Moderate hyperbilirubinemia (total serum bilirubin [TSB], 205 mcmol/L [12 mg/dL]) was present in 12.9% of the breastfed infants and 4% of the formula-fed infants ( P <0.00001). Severe hyperbilirubinemia (TSB, 256 mcmol/L [15 mg/dL]) was present in 2% of the breastfed infants and 0.3% of the formula-fed infants ( P <0.00001). Breastfed infants have higher serum bilirubin levels on each of the first 5 days of life, and this hyperbilirubinemia can persist for weeks to months. The association between feedings of human milk and neonatal hyperbilirubinemia has been reported in preterm infants fed banked human milk or mixtures of human milk and formula and among various races. More recent studies of otherwise healthy newborns have used noninvasive transcutaneous devices to assess hyperbilirubinemia daily (Figs. 1⇓ and 2⇓ ). These studies agree with earlier conclusions that otherwise healthy infants exclusively fed human milk will have higher levels of hyperbilirubinemia than infants who consume formula. The difference begins to become significant …

Accidental paracetamol overdosing and fulminant hepatic failure in children.

To delineate clinical characteristics useful for identifying children with liver failure due to accidental paracetamol overdose. Retrospective review of medical records of all patients admitted from 1985 to 1998 with fulminant hepatic failure. Royal Alexandra Hospital for Children, a tertiary referral centre for paediatric liver transplantation. Contribution of paracetamol to liver failure; other risk factors for liver failure; comparison of clinical features of paracetamol group and others. 18 patients were identified. Eight were considered to have accidental paracetamol hepatotoxicity. In a further three, other risk factors were present but paracetamol was considered a major contributor to liver failure. The seven remaining patients had other risk factors for liver failure. Patients with paracetamol-induced liver failure usually had an acute prodromal illness with prolonged fasting and, at presentation, had encephalopathy, coagulopathy, very high transaminase levels, but disproportionately low total bilirubin levels. Five patients had hypoglycaemia. End-stage liver failure occurred in 4/11 of the paracetamol group compared with 7/7 of the others. Accidental paracetamol overdose is associated with fulminant hepatic failure in infants and children. Patients present with high transaminase levels and liver synthetic failure out of proportion to the level of serum bilirubin. Prompt identification of such patients is important as many recover with supportive therapy.