Paediatric fatty liver disease (PeFLD): All is not NAFLD - Pathophysiological insights and approach to management.

The recognition of a pattern of steatotic liver injury where histology mimicked alcoholic liver disease, but alcohol consumption was denied, led to the identification of non-alcoholic fatty liver disease (NAFLD). Non-alcoholic fatty liver disease has since become the most common chronic liver disease in adults owing to the global epidemic of obesity. However, in paediatrics, the term NAFLD seems incongruous: alcohol consumption is largely not a factor and inherited metabolic disorders can mimic or co-exist with a diagnosis of NAFLD. The term paediatric fatty liver disease may be more appropriate. In this article, we summarise the known causes of steatosis in children according to their typical, clinical presentation: i) acute liver failure; ii) neonatal or infantile jaundice; iii) hepatomegaly, splenomegaly or hepatosplenomegaly; iv) developmental delay/psychomotor retardation and perhaps most commonly; v) the asymptomatic child with incidental discovery of abnormal liver enzymes. We offer this model as a means to provide pathophysiological insights and an approach to management of the ever more complex subject of fatty liver.

Effect of Early Skin-to-Skin Contact to Breast Milk Volume and Breastfeeding Jaundice at 48 Hours after Delivery.

Objective: To evaluate effect of maternal-infant skin-to-skin contact in the first hour postbirth to breast milk volume and breastfeeding jaundice at 48 hours after delivery. Material and Method: This was a prospective cohort study. The subjects were 133 postpartum women, who delivered without complications between October 2013 and July 2014 at MSMC and was allocated into early skin-to-skin contact (SSC) and control groups. In the SSC group, the newborns were placed prone on mothers' bare chest after finishing routine newborn care for at least 30 minutes. The breast milk volume were collected at 16-24 hours, 40-48 hours postpartum and before discharge. The infants' microbilirubins were measured at 48 hours postbirth. Demographic data including age, parity, GA at delivery, birth weight and gender of the newborns were collected. Data were analyzed using descriptive statistics, Chi-square test and t-test. Results: The mean breast milk volume in the SSC group were 5.68+5.46, 16.98+11.09, and 31.44+20.06 milliliters at 16-24 hours, 40-48 hours postpartum and before discharge, respectively, while the mean breast milk volume in the control group were 6.19+5.77, 13.99+13.07 and 25.81+20.26 milliliters, respectively in the same period of time, and no statistically difference of the breast milk volume was found between the two groups. The percentage of mothers who had the onset of lactation within 24 hours postpartum in the SSC group (95.51%, 85/89) was significantly higher than the control group (77.27%, 34/44, p<0.01). The percentages of breastfeeding jaundice cases were 16.85 in the SSC group and 27.27 in the control group, and had no significant difference. Conclusion: Early skin-to-skin contact had no direct effect to breast milk volume and incidence of breastfeeding jaundice at 48 hours after delivery but related to the onset of lactation within 24 hours postpartum.

Bodyweight loss in predicting neonatal hyperbilirubinemia 72 hours after birth in term newborn infants.

BACKGROUND: Severe dehydration is generally believed to be a cause of significant hyperbilirubinemia in newborn babies. This study aimed to analyze the weight loss of healthy term newborn infants at 24, 48 and 72 hours after birth to predict significant hyperbilirubinemia at 72 hours. METHODS: From January 2007 to December 2008, we conducted this retrospective chart review by measuring total bilirubin (transcutaneous and serum) in 343 healthy, term newborns with a birth body weight of more than 2500 g. We then analyzed the association between body weight loss (BWL) and significant hyperbilirubinemia (total bilirubin more than 15 mg/dL) 72 hours after birth. Receiver operating characteristic curves were used to evaluate the appropriate cutoff BWL percentages on the first three days after birth for the prediction of neonatal hyperbilirubinemia 72 hours after birth. RESULTS: A total of 115 (33.5%) neonates presented with significant hyperbilirubinemia 72 hours after birth, and the percentages of BWL on the first three days were all higher than those in the non-significant hyperbilirubinemia group (all p < 0.05). Breastfeeding was not statistically correlated with significant hyperbilirubinemia (p=0.86). To predict significant hyperbilirubinemia 72 hours after birth, receiver operating characteristic curve analysis showed that the optimum cutoff BWL percentages were 4.48% on the first day of life (sensitivity: 43%, specificity: 70%, positive likelihood ratio [LR+]: 1.43, and negative likelihood ratio [LR-]: 0.82), 7.60% on day 2 (sensitivity: 47%, specificity: 74%, LR+: 1.81, LR-: 0.72), and 8.15% on day 3 (sensitivity: 57%, specificity: 70%, LR+: 1.92, LR-: 0.61) (all p < 0.05). CONCLUSIONS: BWL on the first three days after birth may be a predisposing factor for neonatal hyperbilirubinemia, and may also serve as a helpful clinical factor to prevent significant hyperbilirubinemia 72 hours after birth. The optimal BWL cutoff percentages on the first three days after birth presented in this study may predict hyperbilirubinemia and indicate the need for supplementary feeding.

Clinical update: understanding jaundice in the breastfed infant.

Breastfed infants are more likely to be jaundiced than infants who are formula fed. Community practitioners need to understand the physiology of jaundice and the issues associated with breastfeeding so that they can support parents. Visible jaundice is a result of hyperbilirubinaemia and, in most cases, is harmless and caused by normal physiological processes. It does, however, require detection monitoring and sometimes treatment to prevent rare but serious health complications. Although some debate remains over the association between breastfeeding and jaundice, the literature suggests that in the breastfed infant, early onset jaundice may be a result of insufficient intake of breast milk and prolonged jaundice may be related to a constituent of breast milk itself (breast milk jaundice). Early breastfeeding support to promote good positioning, attachment and baby-led feeding may help prevent early onset jaundice. Management of jaundice in the breastfed infant involves referral to local services to determine bilirubin levels and exclude pathologies.

Prevention of neurodevelopmental sequelae of jaundice in the newborn.

Although its cause, jaundice in the newborn, is extremely common, the disabling neurological disorder kernicterus is very rare. Kernicterus may be prevented by selecting those infants who are at risk of extreme jaundice or who may be particularly vulnerable to bilirubin neurotoxicity. Because the tools for achieving that goal are inadequate, a secondary strategy is needed. This involves a plan for emergency treatment of severely jaundiced infants, in particular those who present with neurological symptoms. In this paper I review the strategies for preventing extreme jaundice, and for reversing neurotoxicity in those infants for whom the principal strategies fail. Briefly, the tools for prevention include measurement of bilirubin while the infant is staying in the maternity unit, plotting the value on an hour-specific chart, assessing other risk factors for jaundice, and educating the parents. Emergency treatment should include immediate, high-irradiance phototherapy, consideration of intravenous immune globulin, and preparation for an exchange transfusion.

The role of inflammation in cholestasis: clinical and basic aspects.

Hepatobiliary transport systems are essential for the uptake and excretion of a variety of compounds including bile acids. Disruption and dysregulation of this excretory pathway result in cholestasis, leading to the intrahepatic accumulation of bile acids and other toxic compounds with progression of liver pathology. Cholestasis induced by inflammation is a common complication in patients with extrahepatic infections or inflammatory processes, generally referred to as sepsis-associated cholestasis. Microbial products, including endotoxin, induce signaling pathways within hepatocytes either directly, or through activation of proinflammatory cytokines, leading to rapid and profound reductions in bile flow. The expression and function of key hepatobiliary transporters are suppressed in response to inflammatory signaling. These proinflammatory signaling cascades lead to repressed expression and activity of a large number of nuclear transcriptional regulators, many of which are essential for maintenance of hepatobiliary transporter gene expression. Interestingly, recently discovered molecular crosstalk between bile acid activated nuclear receptors and proinflammatory nuclear mediators may provide new means of understanding adaptive processes within liver. Inflammation-induced cholestasis and the effects of retained molecules in cholestasis on inflammatory signals are interwoven in the liver, providing potential opportunities for research and therapeutics.

The spectrum of liver diseases related to ABCB4 gene mutations: pathophysiology and clinical aspects.

Class III multidrug resistance P-glycoproteins, Mdr2 in mice and MDR3 in human, are canalicular phospholipid translocators involved in biliary phospholipid (phosphatidylcholine) excretion. The role of an ABCB4 gene defect in liver disease has been initially proven in a subtype of progressive familial intrahepatic cholestasis called PFIC3, a severe pediatric liver disease that may require liver transplantation. Several ABCB4 mutations have been identified in children with PFIC3 and are associated with low level of phospholipids in bile leading to a high biliary cholesterol saturation index. ABCB4 mutations are associated with loss of canalicular MDR3 protein and /or loss of protein function. There is evidence that a biallelic or monoallelic ABCB4 defect causes or predisposes to several human liver diseases (PFIC3, low phospholipid associated cholelithiasis syndrome, intrahepatic cholestasis of pregnancy, drug-induced liver injury, transient neonatal cholestasis, adult biliary fibrosis, or cirrhosis). Most patients with MDR3 deficiency have a favorable outcome with ursodeoxycholic acid (UDCA) therapy, but some PFIC3 patients who do not respond to UDCA treatment still require liver transplantation. The latter should be good candidates for a targeted pharmacologic approach and/or to cell therapy in the future.

The influence of skin temperature and skin perfusion on the cephalocaudal progression of jaundice in newborns.

AIM: Despite being widely recognized, the cephalocaudal progression of jaundice in newborns (Kramer's Rule) has never been satisfactorily explained. The aim of this study was to test the hypothesis that the cephalocaudal progression of jaundice in newborns is related to regional differences in skin temperature and skin perfusion. METHODS: A convenience sample of 50 infants was included in the study. On each infant, a transcutaneous bilirubin, skin temperature and capillary refill time measurement was made at five sites; the forehead, sternum, lower abdomen, mid thigh and sole. The relationship between the three variables was studied by analysis of variance. RESULTS: The transcutaneous bilirubin measurements upheld Kramer's observation, being significantly higher at the head and chest than at the thigh and sole (P < 0.001). A similar pattern was found for both skin temperature and capillary refill, both significantly different at the head compared to the sole (P < 0.001). CONCLUSION: The results of the study support the hypothesis that the cephalocaudal progression of jaundice in newborns is a consequence of diminished capillary blood flow in distal parts of the body. It is hypothesized that newborn infants preferentially perfuse their head and proximal parts of their body in the first few days of life, leading to higher temperatures and increased bilirubin deposition at these sites.

Association of a Delayed Cord-Clamping Protocol With Hyperbilirubinemia in Term Neonates.

OBJECTIVE: To evaluate the implementation of a delayed cord-clamping protocol at an academic medical center, and its short-term associations on term neonates. METHODS: This was a retrospective cohort study of women aged 18 years or older delivering a term neonate at an academic medical center before and 5-7 months after implementation of a universal delayed cord-clamping protocol (October-December 2015 and October-December 2016, respectively). The primary outcome measure was the mean peak neonatal transcutaneous bilirubin level, with secondary outcome measures including mean initial transcutaneous bilirubin levels, mean serum bilirubin levels, number of serum bilirubin levels drawn, incidence of clinical jaundice, and phototherapy. RESULTS: Protocol adherence was 87.8%. Data are presented on 424 neonates. The mean peak neonatal transcutaneous bilirubin levels were significantly higher among neonates in the postprotocol group (10.0±3.4 mg/dL vs 8.4±2.7 mg/dL, P<.01). More neonates in the postprotocol group were diagnosed with jaundice (27.2% vs 16.6%; odds ratio [OR] 1.88; 95% CI 1.17-3.01) and required serum blood draws (43.7% vs 29.4%; OR 1.86; 95% CI 1.25-2.78). However, there were no differences in mean peak serum bilirubin levels between groups (9.7±3.0 mg/dL vs 9.1±3.1 mg/dL, P=.17) or need for phototherapy (5.2% vs 6.6%, OR 1.28; 95% CI 0.57-2.89). CONCLUSION: Implementation of a delayed cord-clamping protocol for term neonates was associated with significantly higher mean transcutaneous bilirubin levels, an increased number of serum blood draws, and more clinical diagnoses of jaundice, although there was no increase in the incidence of phototherapy.

Effect of metoclopramide administration to mothers on neonatal bilirubin and maternal prolactin: a randomized, controlled, clinical trial.

BACKGROUND: Jaundice is a common neonatal problem. This study was conducted to determine the effect of metoclopramide on neonatal bilirubin and maternal prolactin (primary outcomes) and milk volume (secondary outcome). METHODS: This triple-blind, randomized, controlled, clinical trial was conducted on 112 mothers. The participants were assigned to the intervention (metoclopramide) and control groups (placebo) using block randomization. Ten-mg metoclopramide and placebo tablets were taken by the participants three times a day. The intervention began in the first 2-10 hours after childbirth and continued until the fifth day. The mothers' prolactin level was measured on the first morning after the intervention and on the sixth day (1 day after the intervention was over). Neonatal total bilirubin was also measured before the intervention and on the sixth day. RESULTS: After the intervention, the two groups did not differ significantly in terms of the mean neonatal indirect bilirubin (P = 0.565) and milk volume (P = 0.261), but the mean serum prolactin was significantly higher in the metoclopramide group compared to the placebo group (adjusted mean difference 37; 95% confidence interval 58.1-16.5; P = 0.001). CONCLUSIONS: Metoclopramide increased maternal serum prolactin but had no effects on neonatal jaundice. The insufficient numbers of studies on this subject mandate further research.

Tau and S100B proteins as biochemical markers of bilirubin-induced neurotoxicity in term neonates.

We investigated the relationship between total serum bilirubin and serum Tau and S100B protein levels, and predicted a cutoff level of bilirubin-induced neurotoxicity in term newborns. Total serum bilirubin, serum Tau, and S100B levels were measured in 92 jaundiced term newborns. A neurologic examination, electroencephalogram, brainstem auditory-evoked response, and otoacoustic emission were performed in the infants on admission and at age 3 months. Serum Tau (r = 0.921, P < 0.001) and S100B (r = 0.927, P < 0.001) levels were correlated with total serum bilirubin levels in all infants. Serum Tau and S100B protein levels remained at a steady level up to a total serum bilirubin level of 19.1 mg/dL, and then demonstrated a significant increase. Mean total serum bilirubin, serum Tau, and S100B levels of infants who manifested auditory neuropathy, neurologic abnormalities, or electroencephalogram abnormalities were significantly higher than in infants without these abnormalities (P < 0.05). Clinical and laboratory findings of bilirubin-induced neurotoxicity developed after a total serum bilirubin level of 22 mg/dL was reached. Serum levels of Tau and S100B proteins in jaundiced term newborns were strongly correlated with early-phase bilirubin encephalopathy.

Toward understanding the connections between infant jaundice and infant feeding.

Parents face a paradox when they are told: Breast is best; bottle-feeding is hazardous to health. But breast-fed babies are more likely to become severely jaundiced than bottle-fed babies, and severe jaundice can lead to brain damage. This article will explore the natural physiology of jaundice with a focus on breast-feeding-associated jaundice, primary prevention of hyperbilirubinemia, and current evidence-based recommendations about feeding jaundice breast-fed infants.

An experimental model of postnatal jaundice in the suckling rat. Suppression of induced hyperbilirubinemia by Sn-protoporphyrin.

A model of experimental postnatal hyperbilirubinemia in the rat has been developed utilizing the heme precursor delta-aminolevulinic acid (ALA) to produce jaundice during a selective time period after birth. This time period is defined as that between 7 d postnatally, when the initial postpartum alterations of serum bilirubin and heme metabolism in the neonate have subsided, and 21 d, when the hepatic conjugation mechanism for the bile pigment appears fully developed. Administration of ALA in this time period led to a rapid, consistent, and significant dose-dependent increase in serum bilirubin levels in the newborn animals. Heme administration produced a qualitatively similar but enhanced effect. Both compounds, in addition, induced a dose-dependent increase in hepatic heme oxygenase activity concomitant with the increase in serum bilirubin levels. Neither compound increased serum bilirubin levels significantly when administered at or after 21 d postnatally. Administration of the synthetic metalloporphyrin, Sn-protoporphyrin, to ALA-treated neonates resulted in a dose-dependent decrease in serum bilirubin levels and hepatic heme oxygenase activity. Mn- and Zn-protoporphyrin in comparable doses did not significantly inhibit ALA-induced hyperbilirubinemia. Sn-protoporphyrin also inhibited the hyperbilirubinemia produced by heme in the suckling animals. ALA administration to newborn rats during the specific postnatal period described provides a simple and convenient model of experimental jaundice in the developing neonate which permits an examination of the potential ability of synthetic metalloporphyrins or other compounds to suppress induced hyperbilirubinemia in the newborn animal. The ability to induce a consistent and significant degree of jaundice in the postnatal rat by the method described may also be useful for other types of studies concerned with the biological disposition and effects of endogenously formed bilirubin in the neonate. The results of this study confirm in another model system the potent ability of Sn-protoporphyrin to suppress jaundice in the neonate, and suggest that suppression of heme oxidation by synthetic heme analogues may represent a useful therapeutic approach to the problem of severe hyperbilirubinemia in human premature newborn.

Randomized, controlled trial of early intravenous nutrition for prevention of neonatal jaundice in term and near-term neonates.

BACKGROUND: This study was undertaken to investigate the effects of early parenteral nutrition on prevention of neonatal jaundice in term and near-term neonates who could not be enterally fed. PATIENTS AND METHODS: Seventy-two infants were randomized into 2 groups: the early parenteral nutrition group (group 1) received 1.0 g/kg/d amino acids beginning within the first day and 1.0 g/kg/d lipid added the next day. The conventional nutrition group (group 2) started on a solution containing 10% glucose and electrolytes in the first 72 hours of life, followed by 0.5 g/kg/d amino acids and lipid. Amino acids and lipid were each increased by 0.5 g/kg/d to a maximum of 3.0 g/kg/d in both groups. Main outcome measures were energy intake; serum bilirubin levels at 24, 48, and 72 hours; need for phototherapy; and duration of phototherapy. RESULTS: Higher energy intake was achieved after the first day in group 1. Daily serum bilirubin levels did not significantly differ between groups. Nine patients in each group required phototherapy. The initiation times of phototherapy were 92.9 hours +/- 25.5 in group 1 and 83.1 hours +/- 28.5 in group 2. Durations of phototherapy were 37.3 hours +/- 11.1 in group 1 and 52.0 hours +/- 20.7 in group 2. There were no significant differences in the requirement, initiation time, and duration of phototherapy. CONCLUSIONS: Early parenteral nutrition has no proven benefit in terms of therapy requirement or severity and duration of neonatal jaundice compared with conventional parenteral nutrition in term and near-term infants who could not be enterally fed.

An emergency medicine approach to neonatal hyperbilirubinemia.

Jaundice (also known as hyperbilirubinemia) is a yellowish-greenish pigmentation of the sclera and skin caused by an increase in bilirubin production or a defect in bilirubin elimination. Management of hyperbilirubinemia is one of the most common reasons for readmission of a newborn. Prolonged unconjugated hyperbilirubinemia can result in acute bilirubin encephalopathy and eventually develop into chronic bilirubin encephalopathy (kernicterus). Kernicterus, the feared complication of hyperbilirubinemia, was considered almost extinct but has recently re-emerged despite virtual elimination of Rh disease. This review provides a systematic approach to the presentation, evaluation, and management of the jaundiced newborn.

Maternal and neonatal factors affecting physiological jaundice in western U.P.

Several maternal and fetal factors are responsible for neonatal jaundice, which is a common observation in large number of newborns. However, role of these factors in causation of this condition is not well established. Fifty pregnant mothers and their fifty two newborns were studied in the present study. Mothers with complicated pregnancy or septicemia at the time of delivery were excluded. In addition newborns with congenital or chromosomal abnormalities were excluded. Serum concentrations of bilirubin of all neonates were measured on days 1, 3 and 5. It was found to be lower on day 1, with a peak at day 3. The area under serum bilirubin level-time curve (AUC) for each neonate was also calculated. Fetal sex and birth weight were not found to significantly affect the neonatal hyperbilirubinemia. Newborn of bipara mothers were found to have significantly lower (P < 0.05) serum bilirubin level on day 1 as compared to primipara mothers only but higher (P < 0.05) on day 3 as compared to either primi or multipara mothers. Yet, AUC of serum bilirubin curve was significantly higher (P < 0.05) in newborns of bipara mothers than others. Significantly (P < 0.05) higher serum bilirubin on day 1 was also observed in preterm neonates than full term ones. However, maternal haemoglobin and mode of delivery were not shown to affect the neonatal bilirubin levels in these newborns.

Management options for cholestatic liver disease in children.

INTRODUCTION: Due to a peculiar age-dependent increased susceptibility, neonatal cholestasis affects the liver of approximately 1 in every 2500 term infants. A high index of suspicion is the key to an early diagnosis, and to implement timely, often life-saving treatments. Even when specific treatment is not available or curative, prompt medical management and optimization of nutrition are of paramount importance to survival and avoidance of complications. Areas covered: The present article will prominently focus on a series of newer diagnostic and therapeutic options of cholestasis in neonates and infants blended with consolidated established paradigms. The overview of strategies for the management reported here is based on a systematic literature search published in English using accessible databases (PubMed, MEDLINE) with the keywords biliary atresia, choleretics and neonatal cholestasis. References lists from retrieved articles were also reviewed. Expert commentary: A large number of uncommon and rare hepatobiliary disorders may present with cholestasis during the neonatal and infantile period. Potentially life-saving disease-specific pharmacological and surgical therapeutic approaches are currently available. Advances in hepatobiliary transport mechanisms have started clarifying fundamental aspects of inherited and acquired cholestasis, laying the foundation for the development of possibly more effective specific therapies.

Neonatal liver disease.

Establishing a rapid and accurate diagnosis of the cause of neonatal liver disease is an urgent matter. The initial detection of this condition relies on the sensitivity of the primary care provider or pediatrician to the signs and symptoms of jaundice and abnormal stool and urine color. It is critical to evaluate jaundice in any infant older than 2 weeks with measurement of fractionated bilirubin, and further assessment is necessary if the direct value is above 1.0 mg/dL in the setting of a total bilirubin of less than 5.0 mg/dL or a direct bilirubin of more than 20% of total if the total is more than 5.0 mg/dL. A diagnostic algorithm for the evaluation of infants who meet these criteria can guide physicians in selecting appropriate and timely diagnostic testing and referral to pediatric gastroenterology for these patients, whose outcome will rely on rapid diagnosis.