Liver disease in neonatal lupus erythematosus

We report the cases of neonatal lupus erythematosus associated with significant hepatic involvement in three living infants and in one infant who died 3 hours after delivery. The three living infants had neonatal cholestasis as a major component of their clinical findings. Pathologic changes included giant cell transformation, ductal obstruction, and extramedullary hematopoiesis. Liver involvement has been noted incidentally in children with neonatal lupus erythematosus, but it has generally been attributed to hemodynamic compromise as a result of congenital heart block or systemic toxic reactions. We speculate that neonatal hepatitis proceeding to hepatic fibrosis may occur in neonatal lupus erythematosus, analogous to the occurrence of "idiopathic" congenital heart block. The neonatal hepatitis associated with neonatal lupus erythematosus is a form distinguishable from the "idiopathic" group. Liver involvement may be more common than was previously recognized, and prospective studies to look for maternal autoantibodies in idiopathic neonatal liver disease should be undertaken.     

Role of reovirus type 3 in persistent infantile cholestasis

The relationship between reovirus type 3 and persistent infantile cholestasis was studied by measuring antibody to the virus in the sera of affected and control babies younger than 1 year of age. One hundred sixty-seven infants were divided into four groups: those with extrahepatic biliary atresia, idiopathic neonatal hepatitis, or other cholestatic disorders, and controls. When available, maternal sera obtained simultaneously with infant sera were also studied. The results indicate that 62% of babies with extrahepatic biliary atresia and 52% of infants with idiopathic neonatal hepatitis have reovirus 3 antibodies. In contrast, less than 12% of either normal infants or babies with other cholestatic disorders have antibodies. These observations suggest that perinatal infection with reovirus type 3 may serve as an initiating event in the genesis of two closely related forms of infantile obstructive cholangiopathy: extrahepatic biliary atresia and idiopathic neonatal hepatitis.     

Neonatal cholestasis

OBJECTIVE: To warn pediatricians about the early recognition of cholestasis in newborns and infants. METHODS: A bibliographic research about cholestasis was performed using Medline, and emphasizing the most relevant publications of the last 30 years. RESULTS: The concept of cholestasis and the causes of cholestatic tendency in newborns and infants are described. Several causes of intra and extrahepatic cholestasis are reported as well. In this review, only the diseases with diagnostic, therapeutic or prognostic peculiarities are commented, including extrahepatic biliary atresia, idiopathic neonatal hepatitis, galactosemia, and Alagille s syndrome. Furthermore, several resources are discussed for the diagnosis of cholestasis. CONCLUSIONS: The establishment of the diagnosis of cholestasis through the detection of hyperbilirubinemia in newborns who present jaundice after 14 days of life is a goal that could change the prognosis of several diseases responsible for neonatal cholestasis.     

Niemann-pick disease type C in neonatal cholestasis at a North American Center

OBJECTIVE: To determine the frequency of Niemann-Pick disease type C (NPC) among children being evaluated for neonatal cholestasis during a 2-year period. METHODS: Medical records were reviewed from all infants with cholestasis and all patients with NPC evaluated at our center from January 1997 through December 1998. RESULTS: Forty neonates with cholestasis were evaluated, including three patients diagnosed with NPC (age at diagnosis, 5-21 months) who were originally labeled as having idiopathic neonatal cholestasis (INH). Two adolescents (ages 14 and 16 years) were also diagnosed with NPC during this period, one who originally had neonatal hepatitis and cirrhosis, and the other who had hepatosplenomegaly throughout childhood. Three of the patients with NPC were Hispanic. At time of NPC diagnosis, infants had mildly delayed motor development and persistent splenomegaly with or without hepatomegaly, and the adolescents had ataxia, dysarthria, hepatosplenomegaly, and paresis of vertical gaze. The diagnosis of NPC was established by demonstrating defective cellular cholesterol esterification in cultured skin fibroblasts in three patients and a specific genetic mutation in three patients. Niemann-Pick disease type C was found in 27% of infants initially diagnosed with INH and 8% of all infants evaluated for cholestasis. CONCLUSION: Niemann-Pick disease type C should be considered in all infants with cholestasis, particularly those with splenomegaly or who are of Hispanic descent. Electron microscopy and lipid analysis of liver biopsy specimens obtained during the evaluation of neonatal cholestasis may suggest this diagnosis.     

胆盐输出泵基因多态性与特发性婴儿肝炎肝内胆汁瘀积的关系

目的 探讨特发性婴儿肝炎肝内胆汁瘀积患儿胆盐输出泵(BSEP)基因的突变情况.方法 收集2008年10月- 2010年2月就诊于广西医科大学第一附属医院儿科的婴儿胆汁瘀积性肝炎患儿81例(病例组),48例无肝内胆汁瘀积、肝功能正常的婴儿为对照组.提取病例组和对照组儿童外周血DNA,采用聚合酶链反应-单链构象多态性(PCR-SSCP)和DNA测序技术检测BSEP基因上2、3、4、5、6、9、10、16、17、23、24外显子基因多态性,分析BSEP基因多态性与特发性婴儿肝炎肝内胆汁瘀积之间的关系.结果在外显子24上检测到BSEP A1028A同义突变,编码的氨基酸未改变,均为丙氨酸；其他10个外显子均未发现异常突变.A1028A基因型在病例组,CC型53例(占65.4％),TC型28例(占34.6％),C等位基因频率为82.7％；对照组中CC型32例(占66.7％),TC型16例(占33.3％),C等位基因频率为83.3％.二组基因型差异经Fisher's精确概率法检验,差异无统计学意义(P＞0.05)；等位基因频率经Fisher's精确概率法检验,差异亦无统计学意义(P＞0.05).结论 尚不能认为BSEP A1028A是特发性婴儿肝炎肝内胆汁瘀积的一个危险因素.BSEP A1028A与特发性婴儿肝炎肝内胆汁瘀积发生的易感性无关.     

Low incidence of alpha 1-antitrypsin deficiency among Filipinos with neonatal cholestatis

AIM: Alpha 1-antitrypsin (AAT) deficiency is the most common genetic cause of liver disease in children. The Pi*S carrier rate among Filipinos is <1%. Its significance in Filipino infants with neonatal cholestasis has not been investigated. The aim of the study was to determine the incidence of AAT deficiency among Filipino infants presenting with neonatal cholestasis. METHODS: Genotype determination that detects Pi*S and Pi*Z alleles was performed using Elucigene AAT reagents (Cellmark Diagnostics, UK). AAT inclusions were identified by light microscopy using periodic acid-Schiff (PAS) stain. RESULTS: Ninety-six infants (mean age: 89 days, 48 males) with a history of jaundice since 2 weeks old and a direct bilirubin level>20% of the total were recruited. Only one patient (1 month old, male) was positive for Pi*S allele and 95 were negative for Pi*S and Pi*Z alleles, with an annual incidence of 0.7%. Of the 96, 49 infants underwent diagnostic percutaneous liver biopsy. All liver biopsy specimen were subjected to PAS stain and two infants, 2 and 4 months old, both with idiopathic neonatal hepatitis, had suspicious findings of AAT globules that was confirmed on immunostain. Both infants were negative for Pi*S alleles. The only patient positive for Pi*S allele was negative for PAS globule on liver biopsy. CONCLUSION: Our results showed a low incidence of AAT deficiency caused by the Pi*S and Pi*Z alleles among Filipino infants presenting with neonatal cholestasis, similar to the low carrier rate in the population.     

Niemann-Pick variant lipidosis presenting as "neonatal hepatitis"

Neonatal hepatitis is a nonspecific term that may include a variety of disease entities. Two patients are presented who developed jaundice in the neonatal period and progressive hepatosplenomegaly. The infants were initially felt to have "neonatal hepatitis" but were subsequently found to have Niemann-Pick disease. Biochemical investigation revealed normal levels of sphingomyelinase activity in leukocytes and liver but diminished levels in cultured skin fibroblasts, compatible with Niemann-Pick type C.     

Neonatal resuscitation after severe asphyxia - a critical evaluation of 177 Swedish cases.

AIM: To evaluate neonatal resuscitation of infants born with severe asphyxia. METHOD: All case records of the 472 claims for financial compensation due to suspected medical malpractice in conjunction with childbirth in Sweden between 1990 and 2005 were scrutinized. Inclusion criteria were: gestational age > or =33 completed weeks, planned vaginal onset of delivery, a reactive CTG at onset of labour, neonatal asphyxia (defined as metabolic acidosis [pH of < 7.05 and/or a base excess of < -12]), or an Apgar score <7 at 5 min. It was assessed that 177 infants suffered from cerebral palsy or early death due to severe asphyxia presumably caused by malpractice around labour. RESULTS: Median Apgar score at 5 min was 3, indicating that all infants needed immediate and extensive resuscitation. There was insufficient adherence to guidelines concerning neonatal resuscitation, including delayed initiation of excessive resuscitation in 19 infants, lack of satisfactory ventilation in 79 infants, and untimely interruption of resuscitation in 38 infants. CONCLUSIONS: Compliance with guidelines for resuscitation of severely asphyctic newborn may be improved, especially concerning ventilation and prompt paging for skilled personnel in cases of imminent asphyxia. Documentation of neonatal resuscitation must be improved to enable reliable evaluation.     

Pre-admission consultation and late referral in infants with neonatal cholestasis

Aims:   To study factors leading to delayed referral in neonatal cholestasis at a tertiary centre in Malaysia.
Methods:   A prospective, observational study on consecutive infants with neonatal cholestasis referred to a tertiary unit paediatric liver unit in Malaysia.
Results:   Thirty-one of the 65 (43%) patients studied encountered delay or had an inappropriate action taken before referral. Factors leading to delayed referral, which adversely affected the outcome of biliary atresia (BA) and neonatal acute liver failure, were repeated reassurances by medical and paramedical staff ( n  = 17, 26%), failure of hospital services at the referring hospital ( n  = 7, 11%) and parental refusal for referral ( n  = 5, 8%). Only three (14%) of the 22 patients who developed liver failure had liver transplantation (LT). The 1-year survival rate with native liver for BA was 35%, while overall 1-year survival rate (native liver and LT) was 41%.
Conclusions:   Repeated false reassurance, failure of hospital services and parental refusal all contributed to delayed referral in neonatal cholestasis. In addition to education of medical and public health workers, and parents on the importance of early referral in neonatal cholestasis, health authorities in Malaysia should consider the feasibility of universal stool colour screening in newborn infants to improve the outcome of BA.     

Neonatal cholestasis as the presenting feature in cystic fibrosis

Between 1960 and 1994 cystic fibrosis was found in nine out of 1474 infants investigated for neonatal cholestasis. Four had delay in passing meconium. In all patients cholestatic jaundice was present during the first 48 hours and in three patients cholestasis was complete, mimicking biliary atresia. Serum cholesterol concentrations were normal in all but two children. Sweat chloride was repeatedly above 95 mmol/l in all instances. Three children had another condition enhancing the risk of cholestasis (alpha1-antitrypsin deficiency, hypopituitarism, perinatal asphyxia, and total parenteral nutrition). Liver histology displayed portal fibrosis and inflammation with bile duct proliferation; mucous plugs in bile ducts were observed in only one patient. Only one child died from cirrhosis. These results indicate that cystic fibrosis is not a major cause of neonatal cholestasis. However early signs of intestinal obstruction and low concentrations of serum cholesterol may indicate cystic fibrosis, regardless of liver histology. Neonatal cholestasis has no prognostic value concerning evolution to cirrhosis.     

Neonatal cholestasis as the presenting feature in cystic fibrosis.

Between 1960 and 1994 cystic fibrosis was found in nine out of 1474 infants investigated for neonatal cholestasis. Four had delay in passing meconium. In all patients cholestatic jaundice was present during the first 48 hours and in three patients cholestasis was complete, mimicking biliary atresia. Serum cholesterol concentrations were normal in all but two children. Sweat chloride was repeatedly above 95 mmol/l in all instances. Three children had another condition enhancing the risk of cholestasis (alpha1-antitrypsin deficiency, hypopituitarism, perinatal asphyxia, and total parenteral nutrition). Liver histology displayed portal fibrosis and inflammation with bile duct proliferation; mucous plugs in bile ducts were observed in only one patient. Only one child died from cirrhosis. These results indicate that cystic fibrosis is not a major cause of neonatal cholestasis. However early signs of intestinal obstruction and low concentrations of serum cholesterol may indicate cystic fibrosis, regardless of liver histology. Neonatal cholestasis has no prognostic value concerning evolution to cirrhosis.     

Follow-up into young adulthood after cardiopulmonary resuscitation in term and near-term newborn infants. II. Neuropsychological consequences

Aim: Brain injury after neonatal cardiopulmonary resuscitation in the term baby is often described as an all‐or‐nothing phenomenon, but little is known about possible late cognitive consequences. The aim of this study was therefore to investigate whether children who needed cardiopulmonary resuscitation because of presumed mild and moderate intra‐partum asphyxia with no evidence of neurological impairments at 18 mo of age may display neuropsychological impairments later in life. Methods: A long‐term follow‐up of young adults was carried out. A blinded comprehensive neuropsychological assessment of the main aspects of cognitive functions was made. The subjects who were resuscitated were divided into two groups according to the clinical course: 20 cases with mild asphyxia and 11 cases with moderate asphyxia, all followed prospectively and compared with 18 healthy controls. The 31 subjects were born at term or near‐term and selected randomly from 59 infants born in 1969–1978 at Sahlgren's Hospital, Göteborg. All infants with early neurological impairments were excluded. Results: No major differences could be established between the two clinical groups and normal controls in any aspects of cognitive function or intelligence. All the groups performed within the normal range in all tests. A tendency toward minor deficits in verbal ability in the mild group compared to the controls was found. Only one subject had a clear, defined memory deficit. Conclusions: Infants who underwent cardiopulmonary resuscitatation at birth without neurological deficits at 18 mo of age did not show any cognitive deficits or neuropsychological impairments in adulthood even though inferior performance on some verbal subtests was observed compared to the control group.     

Biliary lipid compositions in cholestatic diseases of infancy.

Biliary lipid compositions in infants with cholestasis were analysed. Bile acid and phospholipid values were appreciably lower in infants with idiopathic neonatal hepatitis syndrome or corrected biliary atresia than in control infants. Cholesterol values were not, however, notably lower in infants with cholestasis. When biliary lipid components were determined in terms of molar percent, bile acid values were considerably lower in infants with cholestasis than in controls, and cholesterol and phospholipids were appreciably higher, as was the lithogenic index.     

Recovery of amplitude integrated electroencephalographic background patterns within 24 hours of perinatal asphyxia

OBJECTIVE: To assess the time course of recovery of severely abnormal initial amplitude integrated electroencephalographic (aEEG) patterns (flat trace (FT), continuous low voltage (CLV), or burst suppression (BS)) in full term asphyxiated neonates, in relation to other neurophysiological and neuroimaging findings and neurodevelopmental outcome. METHODS: A total of 190 aEEGs of full term infants were reviewed. The neonates were admitted within 6 hours of birth to the neonatal intensive care unit because of perinatal asphyxia, and aEEG recording was started immediately. In all, 160 infants were included; 65 of these had an initial FT or CLV pattern and 25 an initial BS pattern. Neurodevelopmental outcome was assessed using a full neurological examination and the Griffiths' mental developmental scale. RESULTS: In the FT/CLV group, the background pattern recovered to continuous normal voltage within 24 hours in six of the 65 infants (9%). All six infants survived the neonatal period; one had a severe disability, and five were normal at follow up. In the BS group, the background pattern improved to normal voltage in 12 of the 25 infants (48%) within 24 hours. Of these infants, one died, five survived with moderate to severe disability, two with mild disability, and four were normal. The patients who did not recover within 24 hours either died in the neonatal period or survived with a severe disability. CONCLUSION: In this study there was a small group of infants who presented with a severely abnormal aEEG background pattern within six hours of birth, but who achieved recovery to a continuous normal background pattern within the first 24 hours. Sixty one percent of these infants survived without, or with a mild, disability.     

The Scottish perinatal neuropathology study: clinicopathological correlation in early neonatal deaths

BACKGROUND: A proportion of neonatal deaths from asphyxia have been shown to be associated with pre-existing brain injury. OBJECTIVES: (a) To compare the epidemiology of infants displaying signs of birth asphyxia with those not showing signs; (b) to examine the neuropathology and determine if possible the timing of brain insult comparing asphyxiated with non-asphyxiated infants; (c) to compare the clinical features of those born with birth asphyxia with and without pre-labour damage. METHODS: Over a two year period, all 22 Scottish delivery units collected clinical details on early neonatal deaths. Requests for post mortem included separate requests for detailed neuropathological examination of the brain. Infants were classified into two groups: birth asphyxia and non-birth asphyxia. Clinicopathological correlation was used to attempt to define the time of brain insult. RESULTS: Detailed clinical data were available on 137 of 174 early neonatal deaths that met the inclusion criteria. Seventy of 88 parents who had agreed to post mortem examination consented to a detailed examination of additional samples from the brain; in 53 of these cases the infant was born in an asphyxiated condition. All asphyxiated and encephalopathic infants, 38% of mature and 52% of preterm infants with features of birth asphyxia but without encephalopathy, and only one of 12 infants without any signs of birth asphyxia showed damage consistent with onset before the start of labour. CONCLUSIONS: In a large proportion of neonatal deaths, brain injury predates the onset of labour. This is more common in infants born in an asphyxiated condition.     

Transient neonatal cholestasis

Due to immaturity of mechanisms involved in bile formation, the newborn is more susceptible to develop cholestasis. The causes of neonatal cholestasis are: infection, genetic and metabolic diseases, biliary atresia, and unknown or idiopathic etiologies. Most patients in whom no etiology is found are considered to belong to the group of transient neonatal cholestasis by some authors. Transient neonatal cholestasis is characterized by: early-onset cholestasis, absence of a known cause of neonatal cholestasis, normalization of clinical and biochemical parameters during follow-up, and a history of some neonatal injurious event (asphyxia, sepsis, total parenteral nutrition, etc.).     

Hepatic steatosis and neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) in Taiwanese infants

OBJECTIVES: To explore the prevalence of hepatic steatosis and neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) in Taiwanese infants with idiopathic intrahepatic cholestasis. STUDY DESIGN: The liver specimens from 69 infants with idiopathic intrahepatic cholestasis were reviewed (1993-2004); 11 of them (14.7%) had hepatic steatosis. Six patients with hepatic steatosis participated in the genetic study for the SLC25A13 gene under parental consent. RESULTS: Infants with cholestasis and hepatic steatosis had lower aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels than those with cholestasis alone. Three of the six infants in the genetic study had homozygous 851del4 mutation; for the others, homozygous 1638ins23 mutation, compound heterozygous 851del4/IVS6+5G-->A mutation, and heterozygous IVS6+5G-->A mutation were found for each one. Eleven of the total 12 alleles (91.7%) were demonstrated to have SLC25A13 gene mutations. CONCLUSIONS: Metabolic and genetic studies for NICCD should be performed in Asian infants with idiopathic intrahepatic cholestasis and hepatic steatosis. The 851del4 mutation on the SLC25A13 gene accounts for the major genotype expression of patients with NICCD in Taiwan.     

Visual function at school age in children with neonatal encephalopathy and low Apgar scores

OBJECTIVE: To assess different aspects of visual function at school age in children who suffered from neonatal encephalopathy. METHOD: Thirty nine full term infants with neonatal encephalopathy, low Apgar scores, and early neonatal imaging were studied using a battery of tests assessing different aspects of visual function (crowding acuity, stereopsis, visual fields) at school age. The results were compared with brain magnetic resonance imaging (MRI) findings and, when possible, with the results of the assessment of visual function performed at 5 and 12 months, available in 24 of the 39 children examined at school age. RESULTS: Sixteen of the 39 children (41%) had abnormal results at school age in at least one of the visual tests used. Seven of these 16 were untestable on all tests. The remaining 23 children (59%) had normal results. CONCLUSIONS: The presence and severity of visual impairment was related to the severity of brain lesions. Moderate or severe basal ganglia lesions and severe white matter changes were always associated with abnormal visual function. Infants with normal MRI, minimal basal ganglia lesions, and minimal or moderate white matter involvement tended to have normal vision. It was also found that the assessment of visual function performed in the first year was a reliable indicator of visual function at school age. With two exceptions, the results on the 5 month visual assessment were predictive of visual outcome at school age. In the remaining two cases, a normal visual outcome at 5 years was associated with visual abnormalities at 5 months but these had already normalised by the age of 1 year.     

Cholestatic jaundice in infancy. The importance of familial and genetic factors in aetiology and prognosis.

One hundred and twenty-four infants admitted to hospitals in Norway between 1955 and 1974 during the first 3 months of life with cholestatic jaundice were studied retrospectively. Sixty-four infants had had extrahepatic atresia of the biliary tree and 60 had had intrahepatic cholestasis. This gives an incidence of about 1:9000 live births for cholestasis. In 4 of the 64 infants with extra-hepatic atresia a bile duct-to-bowel anastomosis had been performed but this was successful in only 2. Sixty of these infants had died by their 2nd birthday. Twenty-six of the infants with intrahepatic cholestasis had died by 1978 and the most common causes of death were cholestasis complicated by infection, bleeding, or hepatoma. The survivors aged between 4 and 23 years were followed up in 1978. In about two-thirds of them aetiological factors--such as alpha-1-antitrypsin deficiency, arteriohepatic dysplasia, cholestasis with lymphoedema--and other familial or genetic factors, or infections were found. Four of the 34 survivors are known to have cirrhosis. Twenty patients had biochemical abnormalities, and 12 had normal liver function tests. Two patients could not be examined. Of the 19 patients with familial or genetic aetiological factors, 4 had cirrhosis, 14 had biochemical abnormalities, and only 5 had normal liver function tests. Of 11 survivors with idiopathic disease or septicaemia, none had cirrhosis and only 4 had abnormal liver function tests.     

Theophylline for renal function in term neonates with perinatal asphyxia: a randomized, placebo-controlled trial

OBJECTIVE: To study whether prophylactic theophylline can reduce the incidence and/or severity of renal failure in term infants with perinatal asphyxia. STUDY DESIGN: Term neonates with severe perinatal asphyxia were randomized to receive a single dose of either theophylline (study group, n = 40) or placebo (control group, n = 30) during the first hour of life. Daily weight, output/input ratio, 24-hour fluid intake, and urine volumes were recorded during the first 5 days of life. Those infants with asphyxial renal failure were followed up for 1 year. RESULTS: The incidence of severe renal dysfunction was increased in the control group. Creatinine clearance was higher and excretion of beta 2 microglobulin (beta2M) was lower in the theophylline group. Conversely, the glomerular filtration rate was lower in the control group. In infants with renal failure, serum creatinine and creatinine clearance returned to normal in the neonatal period, and the increased beta2M excretion normalized by age 6 weeks. CONCLUSIONS: A single dose of theophylline within the first hour of birth in term neonates with perinatal asphyxia results in a significant decrease in serum creatinine level and urinary excretion of beta2M, along with an increase in creatinine clearance.